Professional Documents
Culture Documents
Endocrinology Lecture 2012
Endocrinology Lecture 2012
Author:
IONELA M. PASCANU
MD, PhD
Consultant in Endocrinology, Associate Professor
Department of Endocrinology
University of Medicine and Pharmacy Tg Mures
Co-authors:
Florina Gliga, MD, PhD student
Consultant in Endocrinology
University Assistant
Department of Physiopathology
University of Medicine and Pharmacy
Tg Mures
Consultant in Endocrinology
University Assistant
Department of Endocrinology
University of Medicine and Pharmacy
Tg Mures
Consultant in Endocrinology
Consultant in Endocrinology,
University Assistant
Department of Endocrinology
University of Medicine and Pharmacy
Tg Mures
2012
1
CONTENTS
CHAPTER I - INTRODUCTION IN ENDOCRINOLGY ........................................................................5
Mechanism of action and hormonal regulation systems .............................................................. 5
The chemical structure of hormones...........................................................................................7
The hormonal synthesis and transport ........................................................................................7
Hormone-receptor interaction .....................................................................................................8
Hormone receptors regulation ....................................................................................................9
Endocrine diseases ....................................................................................................................9
CHAPTER II - HIPOTHALAMUS AND PITUITARY GLAND.............................................................. 11
Hypophysiotropic Hormones..................................................................................................... 12
Other hypothalamic functions ................................................................................................... 14
Craniopharyngioma (CF) .......................................................................................................... 15
Congenital hypothalamic dysfunctions ...................................................................................... 16
Functional GnRH deficit............................................................................................................ 18
Neurohypophyseal hormones....................................................................................................... 19
Diabetes Insipidus (DI) ............................................................................................................. 20
The Syndrome of Inappropriate Secretion of ADH (SIADH)....................................................... 25
Adenophypophyseal hormones ................................................................................................ 26
Pituitary tumors ........................................................................................................................ 32
Prolactinomas .......................................................................................................................... 35
Acromegaly and gigantism ....................................................................................................... 38
Cushings disease .................................................................................................................... 41
TSH secreting pituitary adenoma.............................................................................................. 43
Gonadotropin-Secreting Pituitary Adenomas ............................................................................ 43
Alpha Subunit-Secreting Pituitary Adenomas............................................................................ 44
Nonfunctional Pituitary Adenomas............................................................................................ 44
Pituitary failure (PF) - Hypopituitarism....................................................................................... 44
Empty sella syndrome .............................................................................................................. 50
CHAPTER III - THE THYROID......................................................................................................... 51
Anatomy, histology and embryology ............................................................................................. 51
Thyroid hormone synthesis and secretion................................................................................. 52
Thyroid hormone metabolism ................................................................................................... 53
The thyroid hormone transport.................................................................................................. 53
Control of the thyroid hormone production ................................................................................ 54
Thyroid autoregulation.............................................................................................................. 55
The Thyroid Hormone Receptors and Mechanisms of Action .................................................... 55
Physiologic effects of the thyroid hormones .............................................................................. 56
Thyroid morphologic and functional evaluation ......................................................................... 57
Functional in vivo exploration.................................................................................................... 58
Hyperthyroidism and thyrotoxicosis .......................................................................................... 60
Hypothyroidism and thyroidites................................................................................................. 72
Chronic thyroiditis (Hashimoto thyroiditis, lymphocytic thyroiditis, CTH) .................................... 79
Subacute thyroiditis ( SAT) ....................................................................................................... 82
Other forms of thyroiditis .......................................................................................................... 83
Endemic goiter and other iodine deficit disorders ...................................................................... 83
Endemic cretinism (EC) and other forms of IDD........................................................................ 88
Thyroid neoplasia..................................................................................................................... 90
Euthyroid sick syndrome .......................................................................................................... 98
Thyroid hormone and TSH resistance syndromes..................................................................... 98
Thyroid disorders in pregnancy................................................................................................. 99
CHAPTER IV - THE PARATHYROID GLANDS AND CALCIUM-PHOSPHATE METABOLISM....... 102
Anatomy, histology and embryology of the parathyroid glands .................................................... 102
Biosynthesis and secretion of PTH ............................................................................................. 102
Metabolism and assay of PTH.................................................................................................... 103
2
the protein hormones have a half-life of a few minute and the thyroid and steroid
hormones have a half-life of hours
Hormone-receptor interaction
There are 2 types of endocrine receptors:
Transmembrane receptors (for the water soluble hormones which cannot
cross the lipid membranes barrier) consist of several classes:
1. Receptor tyrosine kinase for example the insulin and IGF-1 receptors.
2. Receptor serine/treonine kinase for example the activin and inhibin
receptors.
3. Receptor guanylate cyclase for the natriuretic atrial factor.
4. Ligand-gated ion channels acetylcholine receptors.
5. G protein coupled receptors receptors for epinephrine, glycoprotein
hormones, PTH, glucagon.
6. Cytokine receptors GH, PRL and leptin receptors.
In the first four categories fall bifunctional molecules that can act as enzymes
or ion channels, but can bind hormones as well. The last 2 categories of membrane
receptors need some intermediary molecules (G protein, other kinases Janus
tyrosine kinase - JAK) in order to transmit the information to second messengers.
The membrane receptors use, as second messengers, the following: AMPc,
diacylglycerol, phosphatidylinositol. They start a cascade reaction which ends with
the recruitment of nuclear proteins and regulation of transcription.
Nuclear receptors are used by the liposoluble hormones, small molecules
which can pass rapidly through the membrane either passively or with a transporting
protein. The ligands for these receptors arent coded. They belong to one of the
following categories:
Classic hormones:
Thyroid hormones,
Progesterone,
Testosterone,
Estradiol,
Cortisol,
Aldosterone.
Vitamins vitamin D, transretinoic or 9-cis retinoic acid,
Intermediary metabolism products fatty acids, bile acids,
Endobiotics (e.g., medicinals and toxins found in plants) and xenobiotics
(compounds that are not naturally occurring).
The steroid hormone receptors have a similar structure, which denotes the
existence of an ancient protein from which theyre derived. Some of them bind with
their ligand in the cytoplasm (glucocorticoid, progesterone, testosterone and
mineralocorticoid receptors) after which they undergo a homodimerization and enter
the nucleus and act as transcription factors. Other receptors (thyroid hormones,
estradiol, retinoic acid receptors) bind with their ligand directly in the nucleus and act
after heterodimerization.
The receptor has a highly conserved domain by which the dimers bind with
specific DNA sequences called HRE (hormone response elements). Some of the
steroid hormones and the thyroid hormones act also rapidly on target cells probably
through ion channels or membrane receptors.
8
10
differences in the size and frequency of GnRH release as well as feedback from
estrogens and androgens; low-frequency pulses favor FSH release while highfrequency pulses result in LH release.The embryological origin of GnRH secreting
neurons is the epithelial tissue of the nasal placode, which explains the Kallmann
syndrome (there is also anosmia). In the hypothalamus, these neurons can be found
in the preoptic area. For women the negative feed-back control can be found both in
the hypothalamus and the pituitary. In the hypothalamus, the estrogens regulate the
frequency and amplitude of the GnRH secretion; in the hypophysis the estrogens
modulate the pituitary hormones response to GnRH. In men, the testosterone has a
negative effect on the pulsatile secretion of GnRH.
Synthetic GnRH can be administered in a pulsatile manner in hypogonadotropic
hypogonadism caused by GnRH deficit. The depot GnRH agonist causes initially a
stimulation of the LH and FSH release and then a down-regulation of their own
receptors, causing the decrease of the pituitary hormones secretion. These agonists
can be used in some cancers (breast, prostate) or in the treatment of precocious
puberty. GnRH antagonists are used in the prevention of premature ovulation in
assisted reproduction, benign gynecological diseases (fibromatous uterus,
endometriosis).
GHRH (Growth HormoneReleasing Hormone) has 44 aminoacides and
stimulates in a dose-dependent manner the GH secretion and causes sometimes a
light increase in the PRL level. Both IGF-1 and GH have a negative feed-back effect
on the GH secretion through lowering the GHRH and the rise of somatostatin. The
GHRH secreting neurons are located in the arcuate and ventromedial nuclei.
Serotonin activates the GHRH secretion and GH and GABA inhibit it. Non-sense
mutations in the GHRH receptor (GHRH-R) cause a rare familial form of GH deficit.
A different system of GH stimulation involves a peptide called Ghrelin which interacts
with a different receptor GH secretagogue receptor (GHS-R). The predominant
source of circulating ghrelin is the gastrointestinal tract, primarily from the stomach,
but also in smaller amounts from the intestine. ARNm molecules and GHS-R can be
found both in the hypothalamus and the pituitary. Ghrelin can increase the PRL,
ACTH, cortisol and aldosterone levels, but its main role appears to be in the
regulation of appetite and food intake.
Somatostatin (somatotropin releaseinhibiting factor) has 2 active forms:
one with 14 aminoacides (predominant in the CNS) and one with 28 aminoacides.
The first one inhibits the TSH and GH secretion, its origin being in the neurons of the
periventricular nucleus, above the optic chiasm and the arcuate and ventromedial
nuclei. The 28 aa form can be found in the D pancreatic cells, intestinal mucosa or
the thyroid C cells. Through paracrine and endocrine effects, the somatostatin
inhibits the secretion of:
Insulin
Glucagon
Cholecystokinin
Gastrin
Secretin
VIP (vasoactive intestinal polypeptide).
13
Neurohoromone or function
ADH, Oxytocin
magnocelullar neurons: ADH, Oxytocin
parvocellular neurons: TRH, CRH, VIP
Circadian rhythm and pineal function
VIP, ADH
GnRH, GHRH, Dopamine, Somatostatin
appetite regulation
Somatostatin
GHRH, Somatostatin
satiety center
hunger center
GnRH
14
Anterior hypothalamus
Posterior hypothalamus
Craniopharyngioma (CF)
Etiology and pathogenesis
The craniopharyngioma is the most frequent neoplasm of nonglial origin and it
is the tumor most often associated with hypothalamic-pituitary dysfunction. Its origin
is supposed to be from epithelial remains of the Rathkes pouch. The most frequent
localization is supraselar, but it can be found in the sella turcica, or, rarely, in the
nasopharynx or the third ventricle. CF has a first peak in incidence in childhood (6-14
years of age) and a second one in the fifth decade.
The tumor varies in size from small, solid, well defined masses to great
tumors, with multiple cysts which invade the sella turcica and the nearby regions.
Cystic degeneration (the liquid contains cholesterol crystals) is frequent. From the
pathologists view the epithelium is mucous, squamous or adamantoid, calcified in
70% of the cases. Malignant degeneration is rare, but possible, after multiple
recurrences and radiotherapy.
Signs and symptoms
The most frequent signs and symptoms of the CF are pituitary failure, visual
field defects, severe headache which can be associated with other signs of
intracranial hypertension (vomiting, papillary edema or optical atrophy).
In children:
o Growth retardation is constant and is associated with other signs of
pituitary growth failure
o Delayed puberty
o Central hypothyroidism and secondary adrenal failure
In adults:
o The most frequent symptom is sexual dysfunction amenorrhea
respectively erectile dysfunction
o Clinical signs of hypothyroidism and adrenal failure are associated
o Sometimes there are non-specific signs like depression without other signs
of endocrine dysfunction. This can be the result of frontal lobe and limbic
system extension of the tumor.
Both in childhood and adulthood neurohypohyseal dysfunctions can appear,
manifested both as diabetes insipidus or inadequate secretion of ADH.
Paraclinical and laboratory findings
Considering the pituitary failure dynamic tests are mandatory. PRL level can
be increased, decreased or normal depending on the location and the size of the
tumor. For positive diagnostic theres the need of imaging confirmation, either by CT
or MRI. In over 80% of the cases the tumor has cystic degeneration or calcifications
(these can be observed on the cranial radiograph scan).
It is mandatory to perform an ophthalmological exam, with visual field
determination before surgery.
Differential diagnosis
15
Treatment
The treatment consists primary of surgical excision of the tumor. The small
tumors can be excised by transphenoidal approach, but the big ones need
craniotomy. Surgical treatment must be individualized extended resection can lead
to increased mortality. Conventional radiotherapy is indicated after surgery for
diminishing the risk of recurrence.
In case o recurrence, mostly due to cyst reaccumulation, there are the
following options:
drainage through stereotactic punction
the use of sclerosing substances with chemotherapeutic effect
intralesional radiotherapy.
Evolution, complications, prognostic.
The great majority of patients will have plurihormonal pituitary failure after
surgery which requires the correct substitution of all deficient hormonal axes.
Almost half of the patients develop morbid obesity due to the damage of the
ventromedial nucleus (with consequent increased parasympathetic activity and
hyperinsulinemia) and/or the paraventricular nuclei. Inhibiting the insulin secretion
can be beneficial.
There are sleep disturbances that can appear, caused by the dysregulation of
the circadian rhythm, going up to narcolepsy. These disturbances can sometimes be
treated with melatonin. An important complication can be the lesion of the thirst
center and liquid intake. In case theres a diabetes insipidus association, this can put
the life of the patient in danger.
Congenital hypothalamic dysfunctions
Kallmann syndrome and the congenital GnRH deficit (isolated hypogonadal
hypogonadism)
Kallmann syndrome is defined by the association of hypogonadotropic
hypogonadism with hypo- or anosmia due to the agenesis or hypoplasia of the
olfactory bulb. The congenital GnRH deficit refers to the absence of the GnRH
secretion in the hypothalamus or a defect in its action by receptor mutation in the
hypophysis. It is more frequent in males. Its characterized by the absence of
secondary sexual characteristics (underdeveloped musculature and the absence of
axillary and body hair). Boys have microphalus, cryptorchidism, small testicles and
the girls have primary amenorrhea.
There are other clinical findings:
median line defects cleft lip and palate;
deafness, optical atrophy;
renal anomalies;
16
18
Neurohypophyseal hormones
The posterior pituitary is not a gland but only the distal axon terminals of the
magnocellular neurons located in supraoptic and paraventricular nuclei of the
hypothalamus.
Vasopressin and oxytocin are nonapeptides that are synthesized as part of a
larger precursor peptide, are packaged in neurosecretory granules and then travel
down the long axons through the stalk to the posterior pituitary. During transport,
peptide enzymes (peptidases) cleave the prohormone into vasopressin, oxytocin,
neurophysin, and a glycopeptide (for vasopressin only).
Antidiuretic hormone (ADH) and vasopressin (arginine vasopressin AVP)
represent the same hormone, both names reflecting its double function: regulation of
plasma osmolality and pressure.
The stimulation of AVP secretion is determined by elevation of plasma
osmolality (an increase as little as 1% is enough), reduction of plasma volume, but
also by acetylcholine, angiotensin II or rise of ambient temperature. The elevation of
both blood pressure and volume, reduction of plasma osmolality, noradrenalin, betaendorphins and decreasing external temperature inhibit AVP secretion.
In physiological point of view separate stimuli exist for osmolality and pressure
regulation in the secretion of AVP and also separate receptors in target organs:
- V1 receptors in blood vessels mediate vasoconstriction responsible for blood
pressure rise;
- V2 receptors in renal collecting tubules are involved in water retention, by
increasing free water flux from tubular lumen to interstitium. This flux
produces a rise of the urinary concentration and a decrease of the urinary
volume.
- V3 receptors in anterior pituitary: through them ADH is implicated in central
regulation of ACTH, enhancing the action of CRH to release ACTH.
The main antidiuretic action is realized via aquaporins, which act as water
channels and are intracellular organelles mediating rapid water transport across cell
membranes of collecting tubs according to osmotic gradient. Vasopressin regulates
directly the movement of intracytoplasmic aquaporin 2 to apical membrane of
collecting tubs, allowing water entrance into the cells.
Oxytocin secretion is stimulated by suckling, uterus dilatation, cervical
distension, acetylcholine, dopamine. In contrary, serotonin, alcohol and anxiety,
fever, pain act as inhibitors. Oxytocin has the role to stimulate pregnant uterus
contraction, especially at the end of pregnancy when uterine sensibility to oxytocin
may increase as much as 200-fold comparatively to a non pregnant uterus.
Estrogens increase, and progesterone reduces the sensitivity of the uterus for
oxytocin. The second physiological role of oxytocin is to stimulate milk ejection, and
data exist regarding its role as a behavioral modulator.
The synthetic preparation of oxytocin may be administered to induce
parturition in uterine atony or used in milk stasis in breast.
19
Clinical manifestations
The characteristic symptomatology is persistent polyuria associated with
polydipsia. In humans a 3-4 liter/day polyuria is well tolerated. The patient is
requested to record a liquid balance in order to determine the amount of polyuria,
which may achieve 20 liters/day. Nocturia is regulary present and may cause
chronice fatigue syndrome.
The elevation of plasma osmolality due to hypotonic polyuria stimulates the
thirst center causing dipsic behaviour changes and ingestion of large amount of
liquids (especially cold) to avoid dehydration. If the morphofunctional integrity of the
thirst center is compromised or liquid ingestion is not possible for some reasons
(unconsciousness, coma, anesthesia), then hypertonic dehydration will develope,
manifested by fever, circulatory insufficiency, coma and death.
The clinical picture is completed by the manifestations of basic disease: visual
defects, headache, weight loss etc. Symptomatology may develop suddenly or
gradually.
Laboratory and paraclinical findings
If diuresis exceeds 50 ml/kg/day, and urine density is under 1010, a thirst test
or a dehydration test must be performed. Biochemical evaluation at baseline
generally does not show any important modifications, because most of patients
consume enough liquids to avoid dehydration.
Dehydration test (liquid deprivation test, thirst probe) requires a serious followup of urine (OsmU) and plasma (OsmP) osmolality but also of general state of the
patient in condition of liquid restriction requiring hospitalization in an endocrinologic
service. A normal liquid intake is allowed for 12 hours before the test is started, but
avoiding excessive coffee, tea, salt, protein ingestion and smoking is recommended.
The steps of this test are the following:
1. Body weight measurement at the beginning of the test and serum
sodium and plasma osmolality (OsmP) determination
2. Liquid intake is not allowed and urine volume (Vu), density (Du) and
osmolality (OsmU) is registered for every urine probe.
3. If two successive values of OsmU differs with less than 10% and the
patient has lost 2% of body weight, Na+, OsmP and plasma
vasopressin are measured.
4. Synthetic desmopressin (ddAVP), a synthetic ADH-analogue is
administered in dose of 10-20 mcg intranasal or 1-2 mcg sc.
5. Vu, Du and OsmU is followed-up continuously for other 2-4 hours and
at the end of the test OsmP is determined once again.
6. The test may last 18 hours, but if the patient loses weight more than
3%, the test is interrupted.
21
Differential diagnosis
The syndrome of polyuria and polydipsia may appear as a consequence of
osmotic diuresis determined by glucosuria in diabetes mellitus or by excessive
urea excretion in hyperproteic diets.
Central DI must be differentiated from:
1. Nephrogenic DI, characterized by a reduced urine concentration capacity
as a consequence of a resistance to ADH, destruction of medullary interstitium or
reduction of NaCl reabsorption in Henles loop.
The hereditary form is caused by mutations of V2 receptors gene (Xlinked heterosomal recessive inheritance) or of the aquaporine 2 gene
(autosomal recessive inheritance). Contrary to the hereditary form of
central DI, these diseases manifest at birth with polyuria, fever,
constipation, vomiting, hypernatremia.
The aquired forms appear in:
Kidney diseases involving renal parenchyma: pyelonephritis,
polycystic renal disease, drepanocytosis, renal infarctions,
sarcoidosis.
Reduced synthesis and/or function of aquaporine 2 as a
consequence of the inadequate binding of ADH to V2 receptors.
It can be described after administration of lithium carbonate,
demeclocycline, but also in hypercalcaemia and potassium
deficiency.
2. Primary polydipsia is characterized by a primary increase in water intake
and may develop:
in some psychiatric diseases such as schizophrenia, mania, obsessivecompulsive disorders it is named psychogenic polydipsia;
as a consequence of altered control of thirst osmoregulation dypsogenic DI mostly is idiopathic, but it may develop secondary to
multiple sclerosis, tubercular meningitis, trauma or tumors.
25
Clinical manifestations can be discrete or absent in mild forms (Na above 120
mEq/L). Nausea, vomiting, confusion, irritability, anorexia may appear. In severe
forms (Na below 110 mEq/L) the neurological involvement is constantly present:
areflexia, lethargy, epileptiform convulsions, but cardiac arrhythmias or coma by
water intoxication are also described.
In chronic forms the treatment requires liquid restriction and graduated
correction of hyponatremia (hypertonic saline solutions in association with loop
diuretics, such as Furosemid 20 mg are used), and administration of
Demeclocycline, a tetracycline derivate, in doses of 600-1200 mg/day or a V1 and V2
receptor antagonists, Conivaptan, (intravenous infusion, in hospitalized persons).
Tolvaptan is a selective V2 receptor antagonist that can be administered orally and is
approved to treat severe hyponatremia (serum Na < 125 mEq/L).
Hyponatremia must be corrected slowly (with approximately 10 mEq/L during
24 hours), because it carries a risk of osmotic demyelination. Brain shrinkage is
thought to be the cause of a syndrome of myelinolysis which was first described in
the ponshence the term central pontine myelinolysis. The syndrome consists of
neurologic deterioration over several days. Eventually, these patients may develop
pseudobulbar palsy with difficulty in swallowing and dysarthria, even leading to
quadriparesis. Recovery from this syndrome is variable.
Adenophypophyseal hormones
Anterior pituitary consists of a series of endocrine cells, classified in the past
in acidophils, basophils, and chromophobe cells. Immunohistochemical techniques
now permit classification of pituitary cells by their specific secretory product:
- somatotrophs approximately 50%, synthesize and secrete GH;
- lactotrophs, 10-25%, secrete PRL;
- corticotrophs, 15-25%, synthesize pro-opio-melanocortin (POMC);
- gonadotrophs, 10-25%, synthesize LH and FSH;
- thyrotrophs, 3-5%, secrete TSH,
- folliculostellate cells being considered nonsecreting cells.
The morphogenesis of anterior pituitary and the development of different type
of cells involve sequential expression of genes codifying various transcriptional
factors. Their role in pituitary development was elucidated by the description of
inactivating mutations determining hereditary syndromes of isolate or multiple
pituitary insufficiency (the lack of synthesis and/or secretion of one or more pituitary
tropins). For example, Pit1 transcriptional factor binds to a specific DNA segment
and determine the development and normal function of somatotroph, lactotroph and
thyreotroph cells. If mutation of the gene for this transcriptional factor occurs, loss of
these cells and consecutive hormonal deficiency of GH, PRL and TSH are
described.
In biochemical point of view adenopituitary hormones may be:
- peptides: ACTH and relative peptides, GH and PRL;
- glycoproteins: TSH, LH, FSH.
26
GH secretion
Physiologic
Sleep
Exersise
Postprandial hyperglycaemia
Relative hypoglycaemia
Pharmacologic
Insulin-induced hypoglycaemia
Hormons: ACTH, AVP, GHRH, estrogens,
Ghrelin
Neurotransmitters:
alpha- adrenergic agonists (Clonidine),
dopamine agonists,
Beta-adrenergic antagonists (propranolol)
GABA agonists,
serotonin precursors
Potassium infusion, pyrogens (endotoxins)
Pathologic
Protein depletion
Obesity
Anorexia nervosa
PRL secretion
Physiologic
Pregnancy, nursing,
nipple stimulation
Coitus
Sleep
Exercise
Physical and psychologic stress
Pharmacologic
Hormons: TRH, estrogens, VIP
Dopamine antagonists(phenothiazines, haloperidol, risperidone
metoclopramide, reserpine, methyldopa, amoxapine, opioids)
Monoamine oxidase inhibitors
Cimetidine (intravenous)
Verapamil
Pathologic
Hormons:dopamine
Dopamine agonists
(levodopa, apomorphine,
bromocriptine, pergolid),
Pseudohypoparathyroidism
Lymphocytic hypophysitis
Pituitary destruction or
removal
GABA
subunit is responsable for the specificity of TSH action. The two subunits are
separately synthesized being codified by different genes, then they are assambled
and the heterodimer is than glycolised. Recombinant TSH is approved for use in
monitoring patients who have been treated for well-differentiated thyroid cancers.
The half-life of TSH is 50-60 minutes. It has a pulsatile secretion with a
reduced amplitude which does not create difficulties when hormonally assayed. It
has a circadian rhythm with a secretion peak registered at night. TSH circulates
without binding to any protein, and its receptors are found on thyrocytes. After
coupling adenilate cyclase is activated and enzymes implicated in thyroid hormone
synthesis are phosphorylated. TSH stimulates the iodine uptake by the thyroid cells
and also induces the thyroid hypertrophy and an increase in the vascularisation of
this gland.
The regulation of TSH secretion is realised partly in hypothalamus by
stimulation through TRH and inhibition by somatostatin and dopamine, and on the
other hand by the negative feed-back of peripheral thyroid hormones which act on
pituitary (short feed-back) and on hypothalamus (long feed-back).
The plasmatic measurement of TSH is realised with IRMA assay and its
normal range is 0.5-4.5 mU/L. TSH level is elevated immediately after birth, then it
remains constant during lifetime.
LH and FSH (pituitary gonadotroph hormones, luteinizing hormone and
follicle-stimulating hormone)
Similarly to TSH, both pituitary gonadotrophins are glycopeptides (synthesized
in one and the same cell), with two subunits and , the last assuring the specificity
of the action. Glycosilation is mandatory to maintain biological activity. Human
chorionic gonadotrophin (hCG) is structurally very similar with LH.
The half-life of LH is shorter (50 minutes) than that of FSH (220 minutes), and
consequently the secretional dinamics of LH is more rapid even if it is secreted by
the same cell.
LH and FSH bind to their own receptors on the ovary and testicle,
respectively, regulate gonadal function by stimulating the secretion of gonadal
steroids and gametogenesis.
In men LH binds to Leydig cells and stimulates testosterone synthesis.
Spermatozoa production requires both LH and FSH, respectively, the last being
coupled to its own receptors on Sertoli cells and seminiferous tubules cells.
In women the development of ovarian follicle is under FSH control (with
receptors on granulosa cells) but the synthesis of estrogens on this level has dual
control: FSH and LH. A sudden elevation of LH at the middle of menstrual cycle
(MC) induces ovulation and subsequently a continuous secretion of LH after
ovulation maintains an adequate secretion of progesterone in the lutheal phase.
Ovarian LH receptors are localised mainly on thecal cells of ovarian folllicles.
LH and FSH secretion is controlled by GnRH, which initiates puberty,
maintains basal secretion of LH and FSH, generates phasic release of
gonadotrophines necessary for ovulation. The secretion of LH and FSH is pulsatile
and ultradian (at about 90 minutes) under the influence of hypothalamic GnRH
pulsations. There are other factors involved in the regulation of hypothalamopituitary-gonadal axis (e.g. gonadal proteins with similar structure to TGF- and AMH
or MIF - anti mullerian hormone/mllerian-inhibiting factor):
31
visual field defect but other modifications of this type are also described,
related to tumor invasion and extension;
- visual impairment, scotomas, quadranopsies, uni- or bilateral sight loss,
stasis, papillar edema or retinal hemorrhages
- ptosis, diplopia, ophthalmoplegia, facial numbness caused by compression of
oculomotor nerve, palsy of IV, V and VI cranial nerves- in parasellar extension
of pituitary adenomas;
- temporal lobe epilepsy (uncinate seizures),
- anosmia, personality disturbances in case of frontal lobe involvement
- hypothalamic compression determines disturbances in temperature, sleep,
apetite (with obesity or cashexia) or thirst regulation, dysfunctions of
autonomous nervous system;
- rhinorea with cerebrospinal fluid in adenomas with inferior extension;
- hydrocephaly rare, in case of large, extensive tumors.
A pituitary tumor mass may also present as an accidental discovery, during a
cranial imagistic exploration for other reasons, and in this case the pituitary tumoral
mass is called incidentaloma.
Paraclinical investigations and laboratory
I. In case of clinically manifested endocrine syndrome (it is evaluated at every tumor
type) laboratory consists of plasma pituitary hormone levels determinations.
Hormonal hypersecretion is caused only by pituitary adenomas. Consequently, the
demonstration of hormonal hypersecretion identifies the sellar mass as a pituitary
adenoma and also identifies the type of adenoma. In the absence of clinical
manifestations the following screening tests became necesarry:
o A serum prolactin concentration >200 ng/mL generally identifies a
lactotroph adenoma; values that are between 20 and 200 ng/mL could
be due to a lactotroph adenoma or to any other sellar mass.
o IGF-1 level and GH during OGTT (oral glucose tolerance test) see
acromegaly
o Urinary free cortisol or plasma cortisol after inhibition with 1 mg
Dexamethasone see Cushings disease.
II. Imagistic investigations are mandatory for the positive diagnosis they
incude:
- Magnetic resonance imaging (MRI) is the single best imaging procedure for
most sellar masses, and there is usually no need to perform any other
imaging study. MRI shoud be focused on hypophyseo-hypothalamic system
(high resolution sections) and should be performed before and after
administration of contrast media agent with Gadolinium (Gadoliniumenhanced image).
- Computed tomography (CT) allows better visualisation of bone structures
sellar flour , clinoidal processes and if present, intratumoral calcifications.
- One can use positron emission tomography (PET), scintigraphy with
radioactive octreotid (octreoscan) or SPECT (single photon-emission
computed tomography).
- Sella turcica X-ray lateral incidence can evidentiate the enlargement of the
sella, wall erosion (lost continuity), double contour, dorsal wall verticalisation,
clinoidal hypertrophy. There are four grades in the development of a pituitary
tumor on Xray:
34
35
Clinical findings
In women the main signs and symptoms are: oligomenorrhea, bradimenorrhea, hypomenorrhea, primary or secondary amenorrhea, galactorrhea and
infertility. Especially at the debut we can also find metrorrhagia dysfunctional
uterine bleeding due to luteal insufficiency. Other signs are the decreased libido,
hot flashes, atrophic vaginitis. If left untreated, the hypogonadism (due to the
inhibition of the pulsatile GnRH secretion) can lead to osteopenia and osteoporosis.
In men, sexual dysfunction manifests itself by the decrease or disappearance
of the libido, erectile dysfunction (impotence, premature ejaculation, loss of the
erections). Its cause is unclear, because testosterone replacement may not reverse
it if hyperprolactinemia is not corrected. Male infertility accompanied by reduction in
sperm count is a less common initial complaint.
Both in men and women the pituitary tumor syndrome can be associated or it
can precede the endocrine symptoms (for reference see also the pituitary tumors).
Laboratory and paraclinical evaluation
The serum PRL levels are positively correlated with the size of the tumor and
the clinical findings. Values over 100 ng/ml suggest a microadenoma, while those
over 200 ng/ml are suggestive for a macroadenoma. The PRL evaluation can be
carried out independently to the moment of the day. Sleep, intense physical activity
or a hyperproteic food intake can all determine a slight elevation of the PRL level.
Levels between 20 and 40 ng/ml are usually considered functional hyperprolactinemias; those between 40-100ng/ml appear in case of hypothalamic-pituitary
dysfunction. An elevated level needs to be confirmed by a second evaluation in order
to sustain the diagnostic of hyperprolactinemia. False positive or negative results are
possible (for example elevated values due to big PRL glycosylated fractions,
biologically inactive).
The evaluation of the other pituitary hormones is recommended: IGF-1, for
the exclusion of a combined secreting adenoma, but also TSH and fT4, plasmatic
cortisol for the exclusion of a pituitary failure.The pituitary gonadotropes are usually
within normal ranges because the hypogonadism is caused by the modification of
the GnRH regulation, but the plasmatic estradiol and testosterone are decreased.
The imaging evaluation and the neurologic and ophthalmologic consults are
necessary for the final diagnosis and the evaluation of the complications.
Differential diagnosis
The PRL secreting adenoma must be first of all differentiated from pituitary
hyperplasia and non-tumoral syndromes as well as from the para- and suprasellar
tumors for reference see also the pituitary tumors.
Hyperprolactinemia can also be caused by:
1. Physiologic factors, systemic and metabolic diseases (table 1.2.),
endocrine causes (hypothyroidism, hyperestrogenemia, Addisons disease
or polycystic ovary syndrome).
2. Pharmacological factors the list of medications causing hyperprolactinemia includes anesthetics, neuroleptics (prometazine, haloperidol, etc),
antidepressants (amitriptyline), antiepileptic (phenitoine), histamine
H2 antagonist (cymetidine), antihypertensive, dopamine receptor blockers
(metoclopramide), dopamine synthesis inhibitors, estrogens, opioids, TRH.
36
The radiation therapy is only indicated after surgery for recurrence preventions, due to its lack of supplemental benefice over the medication.
In case of pregnancy the cessation of the treatment is recommended along
with a periodic check-up of the visual field. Macroprolactinomas have a 20% risk of
growing in this period, in which case it is recommended to restart medical treatment.
Acromegaly and gigantism
Etiology and pathogenesis
These diseases are caused by the exaggerate secretion of GH and have a
prevalence of 40-70/1 million people, with even sex distribution and a maximal
incidence in the 4th decade
The disease can be caused by:
1. GH excess
GH secreting pituitary adenoma isolated, combined GH and PRL
secreting, or plurihormonal
Genetic syndromes McCune Albright, MEN 1, familial
acromegaly, Carney syndrome
Extrapituitary GH secretion lymphomas or pancreatic endocrine
tumors.
2. GHRH excess always accompanied by a hyperplasia of the somatotroph
pituitary cells
Hamartomas or other hypothalamic tumors
Peripheral tumors (ectopic secretion) small cell lung carcinoma,
carcinoid bronchial tumors, pheochromocytoma, etc.
The GH secreting adenoma is the most frequent cause of acromegaly, the
great majority of them being macroadenomas at the time of diagnosis.
Clinical findings
The clinical findings are different depending of the age of onset. Before
puberty, the growth plates are opened and a linear growth can be observed with
consequent gigantism. Once the growth plates close, the acromegaly develops with
extremity and visceral hypertrophy. The symptoms usually develop slowly, with a 5
to 10 years delay of the diagnosis. At diagnosis, most patients have classic
manifestations, and acral and soft tissue changes are always present.
The main signs and symptoms are the following:
I.
Signs determined by the GH excess:
1. Hypertrophy of the hand, feet, tongue and vocal chords. The hands and
feet are large, thickened, and bulky. Theres a frequent change in shoe
size, gloves, rings; the voice changes its tonality.
2. Thickness of the skin, with increased oiliness and sweating, acne,
acanthosis nigricans, cutis verticis gyrata.
3. A gradually change of the physiognomy through the appearance of frontal
bossing (frontal hyperostosis), prominence of the supraorbital ridges,
zygomatic hypertrophy, a massive nasal pyramid, downward and forward
growth of the mandible, which leads to prognathism and widely spaced
teeth (dental diastema), lip and ear lobe hypertrophy.
4. Musculo-skeletal signs paresthesia of the limbs, arthralgia, osteoarthritis,
carpal tunnel syndrome, proximal myopathy, jaw arthritis.
38
II.
III.
39
Differential diagnosis
The pituitary tumor must be differentiated from other intra- and parasellar
masses. The elevated basal GH level can be found in physiologic states like puberty,
pregnancy, intense physical activity, but also in some pathological states: liver or
renal failure, malnutrition.
The limb hypertrophy (especially of the hands) can be found in people doing
manual labor, obesity, primary amiloidosis, myxedema, hypertrophic pulmonary
osteoarthropathy (Pierre Marie Bamberger syndrome which appears most often in
case of lung tumors), pachydermoperiostosis (the hereditary form of the previous
finger clubbing) or in acromegaloidism, in which the physical features suggesting GH
excess appear with familial inheritance, but theres no tumor.
Evolution, complications, prognosis
Theres a slow evolution of the disease, but the complications are frequent:
neurologic, cardiovascular, metabolic and pulmonary. The risk for neoplasia is high,
especially in the colon. The mortality rate is increased; after age 45, the death rate
in acromegaly from cardiovascular and cerebrovascular atherosclerosis, respiratory
diseases, and colon cancer is two to four times that of the normal population.
Treatment
The main objectives of the therapy should be: reduction or total excision of the
tumor, lowering the GH and IGF-1 secretion, prevention or correction of the
complication with preservation of the anterior and posterior pituitary function.
The first line of treatment is considered surgical resection of the tumor, with a
transsphenoidal approach if possible. The rate of recurrence is low for the patients
who have IGF-1 levels and dynamic test results similar with normal subjects.
If after surgery there are signs of GH excess, the medical treatment should be
started. It includes:
Somatostatin analogues with prolonged time of action (depot
preparations). They have the advantage of lowering the GH secretion and
sometimes reducing the size of the tumor (in 20-30% of the cases).
Frequent side effects include gastro-intestinal symptoms and the
development of gallstones. They can be administered in association with
pegvisomant.
o Sandostatin-LAR (octreotide) is a molecule containing the first 8
aminoacides of the natural somatostatin, built in microspheres with
prolonged release; it is administered i.m. 20-40 mg each 4 weeks.
o Lanreotide is a cyclic analogue of the octapeptide, administered
every 7-14 days, i.m. 30mg. There is also a subcutaneous
administration formula (Somatuline Gel), administered every 4
weeks in dose of 60-120 mg.
GH receptor antagonists synthetic analogs of GH which prevent it from
binding with its receptors. They have a lowering effect on the IGF-1 level,
but do not influence the GH level and can determine a slight increase in
tumor size. Side effects elevation of the liver enzymes and lipodystrophy
and pain at the injection site.
o Pegvisomant is administered in daily s.c. injections, in dose of 1030 mg/day.
Dopamine agonists
40
o Bromocriptine (20 mg) and cabergoline (0.5 mg/day) can reduce the
GH secretion in adenoma with combined secretion, but the doses
are higher than those used in prolactinomas.
Radiation therapy is used as an adjuvant method in case the other options failed.
Conventional radiotherapy 40-50 Gy administered in 5 weeks has the
disadvantage of hypopituitarism.
Proton beam therapy.
Gamma knife surgery.
Cushings disease
Etiology and pathogenesis
Cushings disease is defined as ACTH excess due to a pituitary adenoma
which will determine bilateral adrenal hyperplasia and non-suppressible cortisol
secretion. Most frequently its a basophile or cromophobe microadenoma. Electronic
microscopy shows secretory granules of 200-700nm in the tumoral cells. The
adrenal glands are big 12-24g (normal range 8-10g).
Cushings disease is more frequent in women with a sex ratio of 8:1 in favor of
them. In contrast, the ectopic ACTH syndrome occurs more commonly in men
(male:female ratio of 3:1). The usual age range is 20 to 40 years, but Cushing
disease has been reported in infants and in patients over 70.
The term Cushing syndrome is reserved for other causes of hypercorticism.
Cushings syndrome etiology:
I.
ACTH dependent
ACTH secreting pituitary adenoma
ACTH secreting tumors ectopic secretion causes 15-20% of the Cushing
syndromes
Hypothalamic CRH excess Itenko Cushing disease
Ectopic paraneoplastic CRH secretion, especially in carcinoid tumors.
II.
ACTH independent
Benign adrenal tumors (adenomas) causing 10% of the Cushing syndromes
Adrenal carcinomas rare
Micronodular adrenal hyperplasia
Macronodular adrenal hyperplasia
Ectopic cortisol secretion in ovarian or testicular tumors extremely rare.
III.
Weight increase, with central obesity, with special distribution on the trunk
and face (moon-like facies), abdominal, interscapular (buffalos neck)
Thin skin, with capillary fragility, purple striae (thighs, abdomen, axillae),
bruises, skin ulcerations, acne, facial hyperemia, fungal skin infections,
slow healing of skin lesions
Inferior limb edema
Hypotrophy and hypotonia of the proximal muscular groups
Arterial hypertension
Impaired glucose tolerance or diabetes mellitus
Osteopenia or osteoporosis with vertebral or fragility fractures, avascular
necrosis of the femoral head
Hyperpigmentation and hypokalemia are seldomly seen (<10% of patients)
or never in Cushings disease. They are characteristic for the ectopic
ACTH secretion.
Bipolar psychosis
Secondary amenorrhea, hirsutism, erectile dysfunctions
Leucocytosis, lymphopenia, eosinopenia, a fall of the immunity, frequent
infections
Growth arrest in children.
Differential diagnosis
First of all it must be differentiated from the reactive hypercorticism seen in
obesity, pregnancy or professional athletes. Cushing syndrome must be also
differentiated from the primary glucocorticoid resistance.
Evolution, complications, prognosis
Without treatment the evolution is with aggravation and death. The most
frequent complications are cardiovascular due to arterial hypertension, embolic
strokes, infections, fractures especially in the vertebrae and wide bones, steroid
diabetes complications.
If bilateral adrenalectomy is performed Nelson syndrome can occur growth
of the pituitary tumor with neurologic and ophthalmologic syndrome caused by the
supra- and parasellar extension; clinical findings include intense hyperpigmentation,
adrenal failure; laboratory findings include extremely high ACTH levels (due to lack
of negative feedback from glucocorticoids). This syndrome can be prevented with
pituitary radiation and adequate glucocorticoid substitution. Its a rare complication
nowadays considering the diagnostic and therapeutic means available.
Treatment
Surgery through transsphenoidal approach is the treatment of choice for
Cushings disease. The recurrence rate is higher in case of macroadenomas. If
surgery is not successful in removing the ACTH source, reintervention, conventional
radiotherapy and stereotactic radiation are the next options. The last two can cause
pituitary failure in time.
Medical treatment is indicated just as adjuvant therapy or in case of
inoperable tumors. It acts through inhibition of various steps of steroidogenesis.
Their use has replaced the bilateral adrenalectomy employed before in case the
surgery didnt achieve a satisfying lowering of cortisol secretion.
The medication available:
42
It represents one of the most rare pituitary masses (under 1%), being
responsible for less than 1% of the total causes of hyperthyroidism. Nevertheless,
the TSH secreting adenoma must be considered in the differential diagnosis of
hyperthyroidism with diffuse goiter, in absence of extrathyroid signs of Graves
disease. Almost 25% of TSH secreting tumors have a combined secretion
(especially GH and PRL, rarely gonadotropes).
Besides the thyreotoxicosis (fore reference see also Graves disease), the
pituitary tumor syndrome is often seen, with visual field defects. Menstrual
disturbances and galactorrhea can occur due to the secretion of PRL or to the
pituitary stalk syndrome.
The characteristic biochemical finding is the association of elevated thyroid
hormone levels (both the free fraction and total level) with improper high levels of
TSH (it can reach 500 mUI/ml). In 85% of patients the subunit of the glycoproteic
hormones is also elevated. The imaging evaluation (CT or preferably pituitary MRI) is
mandatory and usually shows a macroadenoma.
The differential diagnosis implies primarily the pituitary form of the thyroid
hormone resistance syndrome in which case the TSH is elevated and there are
clinical signs of hyperthyroidism, but also with the other forms of thyreotoxicosis.
The first line of treatment is surgery associated in case of inadequate
response with medical treatment: dopamine agonists or octreotide in doses similar
with those used in acromegaly. Radio-iodine therapy or thyrostatic drugs is not
recommended because the thyroid hormone inhibition can lead to increased
secretion of TSH and tumor size.
Gonadotropin-Secreting Pituitary Adenomas
Although many pituitary adenomas synthesise gonadotropins (especially
FSH) and their subunits, only a minority of these patients have elevated serum levels
of FSH or LH. The majority of these tumors produce FSH and the alpha subunit.
Gonadotropin-secreting pituitary adenomas are usually large chromophobe
adenomas presenting with visual impairment. Most patients have hypogonadism and
many have panhypopituitarism. Hormonal evaluation reveals elevated FSH in some
patients accompanied by normal LH values. Basal levels of the alpha subunit may
also be elevated.
The presence of elevation of both FSH and LH should suggest primary
hypogonadism. TRH stimulation leads to an increase in FSH secretion or in LH- in
some patients.
43
Genetic
defect
Mutation type
Phenotype
IA
Recessive
GH-1
Micro- deletions,
substitutions, nonsense mutations
IB
Recessive
GH-1/
GHRH-R
Substitutions, splicing
defects
-H-4DS,
-no response to treatment,
development of GH antibody
-Dysmorphic features: frontal
bossing, midfacial hypoplasia,
2nd dentition delay
-GH detectable at stimulation
tests
-No GH antibody development
II
Dominant
GH-1
Splicing defects,
missense mutations
III
Recessive X
linked
NB!! T4 should not be administered until adrenal function, including ACTH reserve,
has been evaluated and either found to be normal or treated. In a patient with
coexisting hypothyroidism and hypoadrenalism, treatment of the hypothyroidism
alone may increase the clearance of the little cortisol that is produced, thereby
increasing the severity of the cortisol deficiency. Glucocorticoid substitution can
reveal a DI through rising the arterial pressure and renal flow.
Empty sella syndrome
Empty sella syndrome occurs when the subarachnoid space extends into the
sella turcica, partially filling it with cerebrospinal fluid. This process causes
remodeling and enlargement of the sella turcica and flattening of the pituitary gland.
Primary empty sella syndrome results from congenital incompetence of the
diaphragma sellae. It is the most frequent cause of enlarged sella turcica.
The secondary form appears after surgery, radiation therapy, pituitary
infarction or hemorrhage.
From the clinical point of view, the symptoms can be absent, or it can
associate signs of PF, high PRL, headache, visual disturbances or CSF rhinorrhea.
Its more frequent in middle-aged obese women, with hypertension and pseudotumor
cerebri. For the confirmation of the diagnosis imaging exploration is mandatory (CT
or MRI) which can exclude a tumor.
Usually it requires only symptomatic treatment. Substitution therapy in case of
PF or dopamine agonists in case of high PRL can be necessary. Surgery is only
indicated in case of bilateral temporal hemianopia.
.
50
iodide from MIT and DIT will be recycled (through the iodotyrosine dehalogenase)
and is retrieved for hormone synthesis.
The release of T4 is inhibited primarily by iodide. This mechanism is responsible
for the rapid improvement of thyroid function in case of hyperthyroidism after iodide
administration. Lithium has a similar effect, but the mechanism is unknown so far.
T3 is 10 times more active than T4. Approximately 20% of the T3 comes from
thyroid secretion; the rest of 80% is formed by the extrathyroid deiodination of T4, a
reaction mediated by the 5-deiodinase. This enzyme has two forms:
Type I predominant in the liver, kidney, thyroid, skeletal and heart
muscle, and other tissues. It is sensitive to PTU.
Type II it is found in brain and pituitary where it maintains a constant
level of intracellular T3 in the central nervous system. It is not inhibited by
PTU.
The corticosteroids and beta-blockers have an inhibitory effect on type I 5deiodinase. The enzyme contains selenocysteine, therefore, lack of selenium causes
functional disturbances. The reverse T3 (rT3) is biologically inactive and comes from
the peripheral conversion of T4 mediated by the 5-deiodinase, an enzyme which is
ubiquitary but predominates in brain, placenta and fetal tissues.
Thyroid hormone metabolism
The T4 production rate is 80-100 g/day; the whole quantity is produced in the
thyroid. The rate of T4 degradation is 10% per day. Approximately 80% is
deiodinated with T3 and rT3 formation in proportional quantities, the rest of 20%
being glucurono- or sulphoconjugated, deaminated or decarboxylated with formation
of the tetraiodothyroacetic acid (TETRAC).
The T3 production rate is 30-40 g/day. The degradation of T3 is mainly by
deiodination in a more rapid pace then T4 approximately 75%/day.
The thyroid hormone transport
Both T4 and T3 circulate bonded with different proteins, for example, thyroxinbinding-globulin (TBG), transthyretin (TTR), albumin or lipoproteins. This large
circulating thyroid hormone pool with a stable 7-day plasma half-life ensures the
homogeneous distribution of thyroid hormones in target tissues.
The free fraction of T4 represents only 0.04 % of total T4 (TT4), meaning 2
ng/dl (20 pmol/l); the free T3 fraction represents 0.4 % of total T3 (TT3), meaning 0.4
ng/dl (6 pmol/l). The laboratory assays for total T4 and T3 measure both the free and
bonded fractions of the hormones. Therefore, factors affecting the concentrations of
the binding proteins can influence the TT4 and TT3 values, although the free
fractions are not modified and the patient is euthyroid.
Causes of TBG elevation:
Hereditary form, with a dominant X-linked inheritance.
A raise in the estrogen level in pregnant women, those using oral
contraceptives, estrogen secreting tumors, etc.
Hepatitis.
Drugs or medications: 5-fluorouracil, clofibrate, heroin, methadone.
Acute intermittent porphyria.
53
INHIBITORY
Dopamine and dopamine agonists
Somatostatin and its analogs (octreotide)
Dobutamine
Glucocorticoids in high doses
1 Interleukin, interleukin 6
Tumor necrosis factor- (TNF)
Phenytoin
The extrathyroid T3 production is regulated by all the factors that influence the
iodothyronine deiodinases (table 6): the types I and II (5 deiodinases which mediate
the formation of T3 from T4) and type III (5 deiodinase responsible for the T4
inactivation via rT3 formation).
54
Type I
Type II
?
Brain,
pituitary
Type III
Thyroid autoregulation
It refers to thyroids capacity to modify its function in order to adapt to changes
in the diet iodine availability, independently from TSH. The main adjustment to the
reduced iodine concentration in the diet is the preferential T3 over T4 synthesis in
the thyroid.
On the other hand, an excessive quantity of iodine administered to a euthyroid
person leads to an initial reduction in the synthesis and secretion of thyroid
hormones, but also of the iodide transport, cAMP generation or hydrogen peroxide
formation. This inhibitory effect is called Wolff Chaikoff effect. After 2-4 weeks theres
an escape phenomenon described, the normal thyroid resumes the hormone
production. The Wolff-Chaikoff effect is used in medical practice for rapid reduction
of thyroid function with therapeutic doses of iodide. Iodide administration 10-14 days
before surgery has also an important reduction effect on thyroid vascularization.
A great susceptibility to the Wolff-Chaikoff effect appears in case of:
Autoimmune disorders Hashimotos thyroiditis,
During fetal life due to inadequate iodide organification,
Radioactive iodine administration in Basedows disease or external thyroid
irradiation.
In these situations a goiter and severe hypothyroidism may develop after
excessive iodine administration for a long period because the thyroid may be
incapable of escaping from iodide-induced inhibition of its function.
Useful to note that iodine excess may also have the effect of exacerbating
hyperthyroidism especially in patients with multinodular toxic goiter, latent Basedows
disease or even in people without any apparent thyroid malfunction.
The Thyroid Hormone Receptors and Mechanisms of Action
Thyroid hormones (TH), that are unbound in plasma, are transported
intracellularly, by either specific carriers including monocarboxylate transporter 8
(MCT8), MCT10, and organic anion transporting polypeptide (OATP1C1).
TH act via 2 mechanisms:
1. Genomic action T3 binding to specific nuclear receptors and
regulation of other genes activity.
2. Non-genomic action T3, T4 interaction with certain enzymes
(Calcium dependent ATP-ase, adenylate cyclase), mitochondrial
proteins or enabling glucose and some aminoacids transport.
55
reflexes, tremor, hyperactivity, anxiety. Slow reflexes, depression, somnolence are often signs of myxedema.
6. Glucose and lipid metabolism TH determine an increase in glycogenolysis and liver neoglucogenesis, favoring also glucose absorption
from the bowel. Diabetic patients with hyperthyroidism can have a
worsening of their glycemic control. Cholesterol synthesis and metabolism
are positively influenced by TH, especially by increasing the number of
LDL receptors in the liver and its clearance. A rise in the LDL fraction and
of total cholesterol as well can be found in case of hypothyroidism.
7. Endocrine system TH affect hormone production, receptor sensitivity and
the metabolic clearance of some hormones. In case of hypothyroidism
during childhood the growth is profoundly affected as a consequence of a
decrease in GH release. Both delayed and precocious puberty are
described in case of myxedema. The former appears because of GnRH
and gonadotroph affected release; the latter is caused by the increased
effect of TSH on the LH and FSH receptors. In adulthood myxedema can
cause hyperprolactinemia and consecutively dysfunctional uterine
bleeding, amenorrhea, anovulation and infertility. The responsiveness of
the hypothalamic-pituitary-adrenal axis to stress is blunted in hypothyroid
patients. Hyperthyroidism can be associated with gynecomastia, as a
consequence of increased androgen aromatization and SHBG levels. All
the endocrine malfunctions are reversible through adequate treatment and
reestablishing the euthyroid state.
Thyroid morphologic and functional evaluation
In vitro evaluation
Basal determinations
1. TSH measurement is the most frequently used test for evaluating thyroid
function. Immunometric (IMA) or radioimmunometric (RIA) assays can be used.
The great majority of laboratories now use methods with a range limit below 0.02
mUI/l (UI/ml). Normal TSH values: 0.5 - 4.5 mUI/l.
2. TH can be measured as total quantity, including that bonded with proteins (TT4
and TT3) and also as free form (fT4 and fT3), the latter with a broader utilization.
Normal fT4 values: 9-30 pmol/l (0.7-2.5 ng/dl) and fT3: 3-8 pmol/l (0.2-0.5ng/dl).
There is an inverse logarithmic relationship between TSH and peripheral thyroid
hormone values. An elevated () TSH associated with a decreased () fT4 and
fT3 means primary hypothyroidism, while a TSH below 0.1 mUI/l associated with
elevated fT4 and fT3 is found in case of hyperthyroidism. There are situations in
which the TSH value is not correlated with the thyroid hormone values, among
which the following:
Central hypothyroidism (pituitary or hypothalamic) with normal or slightly
decreased TSH and low fT4 and fT3.
Subclinical hypothyroidism with TSH and normal fT4 and fT3.
Subclinical hyperthyroidism with TSH and normal fT4 and fT3.
Elevated TSH with elevated fT4 and fT3 TSH secreting pituitary
adenoma or thyroid hormone resistance.
During systemic illness normal or fT4 with TSH in the acute phase
and in the recovery phase.
57
Clinical findings
The main symptoms of Graves disease are: hyperactivity, irritability,
dysphoria, hyperhidrosis, termophobia, palpitations, weakness, and fatigue, weight
loss with preserved appetite and polyphagia, dyspnea, increased bowel movements.
In young people clinical findings are dominated by nervousness, hyperkinetic
cardiac syndrome, fatigue, hyperkinesia, weight loss and diarrhea. In children the
linear growth and bone maturation are accelerated, while in people over 60 years of
age the cardio-vascular and muscular (frequent myopathy) signs are frequently
described (the clinical findings in elderly are mostly atypical).
The physical examination can highlight different changes in almost all
systems:
1. Skin, hair, nails:
Warm, sweat, soft, moist skin, with friable hair,
Onycholysis, thin and smooth nails,
Vitiligo,
Diffuse or localized alopecia,
Dermopathy marked thickening of the skin is noted, usually over the
pretibial area (pretibial myxedema) with a livid color and orange peel
aspect,
Hyperpigmentation especially of the eyelids (Jellinek sign) caused by
cortisols accelerated metabolism and secondary rise of ACTH.
2. Cardio-vascular system:
Increased heart rate, sinus tachycardia (at rest, during sleep, and
exaggerated during exercise),
Increased cardiac output and wide pulse pressure, these will determine
systolic hypertension,
Celer et altus pulse, with augmented cardiac sounds,
Decreased peripheral resistance due to the vasodilation,
Cardiac failure with normal or increased cardiac output in case of severe
hyperthyroidism,
Atrial fibrillation or flutter and extrasystolic arrhythmia,
Exertional dyspnea, which is due more to respiratory and skeletal muscle
weakness than cardiac dysfunction.
3. Respiratory system:
Dyspnea through elevation of O2 consumption and hypercapnia,
Respiratory muscle weakness,
Exacerbation of a preexisting asthma.
4. Digestive system:
Weight loss due to increased metabolic rate (hypermetabolism),
Malabsorption, increased bowel motility, hyperdefecation, sometimes,
steatorrhea,
Hyperphagia, in the elderly anorexia,
Celiac disease is more frequent in patients with Graves disease,
Abnormalities in liver function tests, particularly high serum alkaline
phosphatase concentrations, and rarely cholestasis.
5. Urinary and reproductive system:
Polyuria, nycturia, nocturnal enuresis in children,
In women olygomenorrhea, anovulation and infertility,
62
6.
7.
8.
9.
o Female gender;
o Smoking;
o The type of treatment used for BGD: radioactive iodine therapy may
increase the risk and the severity of GO;
o The titer of TRAb.
The clinical manifestations may be absent or they can be represented by the
sensation of grittiness, eye discomfort, excessive tearing, pain, double vision or even
sight loss.
Physical examination reveals conjunctival modifications such as erythema or
chemosis, and periorbital edema. In severe cases, proptosis may cause corneal
exposure and damage, especially if the lids fail to close during sleep. The
impossibility to obtain and maintain convergence (convergence asynergism) is a sign
of extrinsic ocular muscle involvement which typically is due to fibrosis and failure of
muscle relaxation, limiting the function of the antagonist muscle. The inferior rectus
is the most commonly involved muscle in the infiltrative process. By failing to relax
normally, upward gaze limitation is the most common physical finding in patients with
eye muscle involvement. The next most commonly involved muscle is the medial
rectus, impairing lateral gaze.
Exophthalmos or ocular protrusion is measured objectively with the Hertel
exophthalmometer. The normal upper limit is 19-20 mm in white and 22 mm in black
population.
NOSPECS classification, an acronym with the following meaning, was
introduced to evaluate objectively GO:
o Class 0 No symptoms or signs the lack of clinical signs and
symptoms;
o Class I Only signs, no symptoms eyelid retraction or other signs of
sympathycotonia;
o Class II Soft tissue involvement: periorbital edema, congestion or
redness of the conjunctiva, and edema of the conjunctiva (chemosis);
o Class III Proptosis: exophthalmos, as measured with the Hertel
exophthalmometer;
o Class IV Extraocular muscle involvement the involvement of
extrinsic ocular muscles (the inferior rectus and the medial rectus are
the muscles most commonly involved in the infiltrative process);
o Class V Corneal involvement corneal lesions or ulcerations due to
lagophthalmos;
o Class VI Sight loss as a consequence of optic nerve injury.
Laboratory tests and paraclinical investigations
Hormonal assessment: TSH is usually below 0.05 mIU/L, fT4 and fT3 are
increased. In the initial phase of the disease TSH is decreased, fT4 may be normal,
but fT3 is increased. The TRAb titer is elevated in the majority of patients, 70-80% of
persons with BGD present an increase of the anti TPO antibodies as well, and 2040% also have high levels of anti TG antibodies.
Other biochemical examinations can show: high glucose level, increased
alkaline phosphatase, normochromic normocytic anemia, prothrombotic state, low
total and HDL-cholesterol levels.
Scintigraphy and radioactive iodine uptake (RAIU) show increased thyroid
volume, with a diffuse aspect, elevated RAIU values at 6 and 24 hours. Thyroid
64
65
Advantages
Thionamides
(administered
for 1-2 years)
-Chance of
permanent remission
-Avoiding permanent
hypothyroidism
- Low cost
Radioactive
iodine
Surgery
Disadvantages
67
months after discontinuation of the drug. Amiodarone inhibits deiodinase activity, and
its metabolites function as weak antagonists of thyroid hormone action.
Amiodarone may induce hypothyroidism (the most frequent complication in
iodine-sufficient areas). Amiodarone treatment causes thyrotoxicosis in 10% of
patients living in areas of low iodine intake and in 2% of patients in regions of high
iodine intake. There are two types of amiodarone-induced thyrotoxicosis (AIT),
although some patients have features of both.
Type 1 AIT is associated with an underlying thyroid abnormality (preclinical
Graves' disease or nodular goiter). Thyroid hormone synthesis becomes
excessive as a result of increased iodine exposure (Jod-Basedow
phenomenon).
Type 2 AIT occurs in individuals with no intrinsic thyroid abnormalities and
is the result of drug-induced destructive thyroiditis.
The distinction between the two types can be sometimes made by Color-Flow
Doppler ultrasound: in type I the vascularization is increased and thyroid volume is
enlarged and in type II vascularization is absent or reduced and the thyroid volume is
normal or reduced. Thyroid scintiscans are difficult to interpret in this setting because
the high endogenous iodine levels diminish tracer uptake. However, the presence of
normal or rarely increased uptake favors type 1 AIT.
The treatment consists of the following recommendations:
The drug should be stopped, if possible, although this is often
impractical because of the underlying cardiac disorder.
In type I AIT: 20-60 mg/day methimazole until thyroid function is
normalized, which may be associated with potassium perchlorate
2x500 mg/day for 1-2 weeks.
In type II AIT: 20-40mg/day prednisone for 4-6 weeks.
In some situations the distinction between type I and II is not possible
by clinical manifestations and paraclinical findings, so in these cases
combined therapy with ATS and glucocorticoids is preferred.
In patients who are nonresponsive to pharmacologic therapy total
thyroidectomy may be needed.
Transient (accompanying) thyrotoxicosis
In these forms thyroid parenchyma is destroyed and there is a release of Tg
and thyroid hormones, leading to a transient thyrotoxicosis, followed by the recovery
of thyroid function or the development of transient or permanent hypothyroidism.
RAIU is always reduced. The principal forms are:
1. autoimmune (Hashimotos) thyroiditis has received the name of
Hashitoxicosis in the phase of thyrotoxicosis;
2. silent (painless) thyroiditis is considered also a form of autoimmune
thyroiditis;
3. postpartum thyroiditis;
4. subacute (postviral or de Quervains) thyroiditis appears at 2-3 weeks
after a viral infection, it is associated with local pain in the thyroid bed
and increased erythrocyte sedimentation rate (ESR). The course of
thyroid function in subacute thyroiditis: after the initial phase of
thyrotoxicosis appeared due to the release of thyroglobulin in the
bloodstream, a short phase of euthyroid state develops, followed by a
transient TSH-elevation and then complete recovery of thyroid function.
70
5.
6.
Thyroid storm
Thyroid storm is the most severe acute complication of hyperthyroidism. It
may occur in patients with neglected chronic hyperthyroidism but is most frequently
triggered by an acute event like:
Thyroid or non-thyroid surgery;
Traumas;
Infections;
Administration of high dose iodine or RIT;
Sudden suspension of ATS;
Other severe diseases: myocardial infarction, uncontrolled diabetes
mellitus.
The clinical manifestations are an exaggeration of the typical thyrotoxicosis
picture: tachycardia with heart rate over 140/min or atrial fibrillation; occasionally
heart failure occurs. Fever ranges from 38C to 41C and is associated with flushing
and sweating. Significant agitation, anxiety, delirium or even coma may develop.
Gastrointestinal symptoms include nausea, vomiting, diarrhea, and jaundice. A fatal
outcome is associated with heart failure and shock.
The treatment of thyroid storm besides the prompt intervention on the trigger
cause consists of:
ATS like methimazole; MTU is the antithyroid drug of choice in thyroid
storm: PTU 250 mg every 6 hours p.o. The drugs can be given by rectal
suppository or enema if the patient is unable to take medication by mouth.
Iodide can be administered one hour after the first dose of ATS, as Lugols
solution 4-6 x10 drops/day or iopanoic acid 0.5-1 g/day.
Hydrocortisone hemisuccinate 100 mg i.v., every 6 hour, Dexamethasone
8 mg/day p.o., in a unique dose or 2 mg i.v., every 6 hour. The beneficial
effects of glucocorticoids are attributed to reduce thyroid hormone
secretion and inhibition of peripheral conversion of T4 into T3. These
agents have antithermic action as well.
Intravenous administration of propranolol in dose of 1-2 mg at 10 minutes
maximal dose 10 mg;
In the presence of severe heart failure or asthma and arrhythmia, where
beta blockers may be contraindicated cautious intravenous
administration of verapamil in a dose of 5 to 10 mg is recommended;
Lithium carbonate 600 mg/day;
Proper fluid, electrolyte, and nutritional support are important (parenteral
administration of normal saline solution or 5% glucose solution);
Vigorous treatment of hyperpyrexia, antibiotherapy in case of infections;
Sedatives: phenobarbital (may be useful because it accelerates the
peripheral metabolism and inactivation of T4 and T3) or diazepam;
Oxygen, digoxin or dobutamine (2.5-10 g/kg/min) in heart failure;
The prophylaxis of thrombotic events with heparin and fraxiparine in atrial
fibrillation;
71
Etiopathogenesis
Hypothyroidism is a clinical syndrome resulting from a deficiency of thyroid
hormones, which in turn results in a generalized slowing down of metabolic
processes. This can be primary (in 99% of cases), appeared due to loss or
permanent distruction of thyroid tissue, or central (secondary and tertiary) due to
insufficent stimulation of thyroid gland as a consequence of pituitary, hypothalamic
diseases or TSH defect.
Classification of hypothyroidism:
1. Primary hypothyroidism:
Aquired:
Hashimotos autoimmune thyroiditis (HAT).
Iodine deficiency (endemic goiter), use of goitrogenic
substances.
Drugs: iodine excess (including iodine-containing contrast media
and amiodarone), lithium, antithyroid drugs, thyrozin-kinase
inhibitors (sunitinib) or cytokines (interferon , interleukin 2)
Thyroid infiltration (amyloidosis, hemochromatosis, sarcoidosis,
scleroderma, Riedels thyroiditis).
Iatrogenic: 131I treatment, subtotal or total thyroidectomy,
external irradiation of neck for lymphoma or cancer
Consumptive: rapid degradation of thyroid hormones in large
hemangiomas caused by high expression of 5-deiodinase (DIII)
Transient (in adulthood):
o Subacute thyroiditis,
o Silent thyroiditis,
o Postpartum thyroiditis.
Congenital:
i. Thyroid agenesis, dysplasia or ectopy (85% of congenital
forms).
ii. Disturbances in thyroid hormone synthesis and secretion:
Iodide transport or utilization defect (mutations in
NIS),
Organification disorder (TPO deficiency or dysfunction), a variant: Pendreds syndrome characterised by deafness, goiter and congenital
myxedema,
Defect in TG synthesis or processing.
iii. Transient
Severe deficiency or excess of iodine,
Transfer of blocking antibodies from the mother,
ATS administration to the mother.
72
2. Central:
Aquired:
i. Secondary ( pituitary origin),
ii. Tertiary (hypothalamic),
iii. Dopamine administration,
iv. Bexarotene (retinoid X receptor agonist)
v.
Severe illness.
Congenital:
i. TSH deficiency or structural abnormality,
ii. Plurihormonal pituitary insufficiency,
iii. TSH receptor defect.
3. Resistance to thyroid hormones:
Generalised,
Peripheral.
Thyroid hormone deficiency is manifested in every tissue by accumulation of
glycosaminoglycans, especially hyaluronic acid due to their decreased metabolism.
This accumulation of hydrophilic substances in interstitial tissues increases capillar
permeability to albumine and account for the interstitial nonpitting edema (especially
in skin, myocardium and striated muscle).
Clinical manifestations
These manifestations are largely independent of the underlying disorder but
are a function of the degree of hormone deficiency, time of onset (acute or chronic,
slowly progressive) and the age of clinical onset. The term myxedema (sometimes
still used as a synonym for hypothyroidism) refers to the appearance of the skin and
subcutaneous tissues in the patient who is in a severely hypothyroid state.
Clinical manifestations in children
The term of endemic cretinism have been introduced for children born in
iodine deficiency areas with severe mental retardation, dwarfism and neurological
anomalies. In iodine-sufficent areas the major causes of congenital myxedema are
thyroid agenesia or ectopy, defects in hormonogenesis, excessive iodine or ATS
administration to the mother.
The incidence of congenital hypothyroidism varies between 1:1000 to 1:4000
in newborns, the transient forms being more frequent.
NB: More than 90% of newborns with congenital hypothyroidism do not
present at birth clinical signs or have just minor signs; thats why the introduction of
neonatal screening for precocious detection is justified.. Newborn baby with
congenital hypothyroidism frequently has a gestational age over 42 weeks. During
the first few months of life, symptoms and signs of hypothyroidism include:
respiratory difficulty;
feeding problems, failure to thrive, constipation,
hoarse cry,
somnolence,
jaundice.
In succeeding months, especially in severe cases, protuberance of the
abdomen, umbilical hernia, dry skin, delayed eruption of the deciduous teeth become
evident. The characteristic appearance includes a broad, flat nose; periorbital
puffiness; large protruding tongue. Important delay of bone maturation (at birth,
73
absence of the proximal tibial epiphysis and distal femoral epiphysis) and large
fontanelles are described. Palpable goiter appeares after a few months in case of
dyshormonogenesis;
Thyroid hormone deficiency in fetal life or at birth affects neurologic
development including hypoplasia of cortical neurons, retarded myelinisation and
reduced vascularity. The uncorrected hypothyroidism immediately postnatal (first 4
months) determines irreversible CNS lesions, clinically manifested by retardation in
neuromotor development. The parameters of normal development are severely
delayed: the child can not hold his head at 3 months of age, can not sit around 6months and can not walk at 1-year of age.
In children and adolescents the main clinical sign of hypothyroidism is linear
growth impairment and dwarfism, as a consequence of reduced protein synthesis,
especially due to decreased GH and IGF-1 secretion. Disproportionated dwarfism
(short neck and limbs, epiphyseal dysgenesis delay in appearance of ossification
nuclei) and dental defects appear constantly in untreated children. Reduced school
performance, cognitive disturbances are frequently described. Deafness and mutism
or balbism may be present. The typical signs and symptoms of hypothyroidism seen
in adults may be present.
Delayed sexual maturation or premature puberty may develop.
Clinical presentation in adults
In adulthood hypothyroidism is well tolerated, mainly if it develops gradually.
The major signs and symptoms are described in table 8.
Table 8. Signs and symptoms of hypothyroidism
Symptoms
Tiredness, weakness
Dry skin
Sensation of cold
Hair loss
Difficulty concentrating and impaired memory
Constipation
Weight gain with poor appetite
Dyspnea
Hoarse voice
Menorrhagia (later oligomenorrhea or amenorrhea)
Paresthesia
Impaired hearing
Signs
Dry, coarse skin; cold extremities
Puffy face, hands, and feet (myxedema)
Diffuse alopecia
Loss of eyebrows
Carotenemia
Bradycardia
Peripheral edema
Delayed tendon reflex relaxation
Carpal tunnel syndrome
Serous cavity effusions
Skin. The skin is cool and pale in patients with hypothyroidism because of
decreased blood flow. Sweating is decreased because of decreases in calorigenesis
and acinar gland secretion. Nonpitting edema (myxedema) occurs in severe
hypothyroidism and may be generalized. Reduced conversion of carotene to vitamin
A and increased blood levels of carotene may give the skin a yellow tint. In central
hypothyroidism skin infiltration is less expressed.
Cardiovascular signs. Hypothyroidism is manifested by impaired ventricular
contraction, bradycardia, and increased peripheral resistance, resulting in diminished
cardiac output. Increased peripheral resistance may be accompanied by
hypertension, particularly diastolic.
Cardiac enlargement may occur, due to:
74
interstitial edema,
left ventricular dilation,
nonhemodynamically significant pericardial effusion.
The electrocardiogram (ECG) may reveal low voltage of QRS complexes and
P and T waves. Coronary artery disease is more common in patients with
hypothyroidism, likely related to increased levels of total cholesterol, LDL cholesterol,
and possibly other nontraditional atherogenic factors such as lipoprotein A and
homocysteine. In patients with angina pectoris, hypothyroidism may protect the heart
from ischemic stress, and replacement therapy may aggravate the angina by
increasing myocardial oxygen consumption.
Respiratory system Fatigue, shortness of breath on exertion, rhinitis,
bronchial infections and decreased exercise capacity may result. Sleep apnea
occurs in some patients with hypothyroidism, mostly as a result of macroglossia.
Gastrointestinal disorders Decreased gut motility results in constipation
(may determine even marked ileus). Other gastrointestinal problems that can occur
in hypothyroidism are:
Decreased taste sensation;
Galbladder hypotonia;
Gastric atrophy due to the presence of antiparietal cell antibodies;
A modest weight gain due to decreased metabolic rate and accumulation of fluid (nonpitting edema) is a frequent finding. However,
marked obesity is not characteristic of hypothyroidism!!
AnemiaThere are at least four mechanisms that may contribute to anemia
in patients with hypothyroidism:
(1) impaired hemoglobin synthesis as a result of thyroxine deficiency;
(2) iron deficiency from increased iron loss with menorrhagia;
(3) folate deficiency from impaired intestinal absorption of folic acid;
(4)pernicious anemia, with vitamin B12-deficient megaloblastic anemia.
Pernicious anemia is often part of a cluster of autoimmune diseases, including
hypothyroidism due to Hashimoto or autoimmune thyroiditis associated with thyroid
autoantibodies, pernicious anemia associated with parietal cell autoantibodies,
diabetes mellitus associated with islet cell autoantibodies, and adrenal insufficiency
associated with adrenal autoantibodies (Schmidt syndrome; the polyglandular failure
syndrome)
Renal function is impaired; renal blood flow, glomerular filtration rate, tubular
reabsortion and secretion are all reduced; there is also an impaired ability to excrete
a water load. This predisposes the hypothyroid patient to hyponatremia from water
intoxication, if excessive free water is administered.
Reproductive abnormalities Women with hypothyroidism may have either
oligo- or amenorrhea or hypermenorrhea-menorrhagia. These menstrual changes
result in decreased fertility. If pregnancy does occur, there is an increased likelihood
for early abortion. Hyperprolactinemia with amenorrhea or galactorrhea may occur.
Decreased libido, erectile dysfunction, and delayed ejaculation are found in
some of the hypothyroid men, but are reversible under treatment with thyroid
hormones.
Central and peripheral nervous system are equally affected in hipothyroidism.
All intellectual functions are slowed, with loss of initiative, lethargy, somnolence.
Decreased intellectual performances and even dementia may appear. Other
75
Differential diagnosis
In children, differential diagnosis of congenital hypothyroidism has to be made
with other dwarfisms associated with mental retardation: Down syndrome,
mucopolysaccharidoses (Hurler, Hunter syndrome), but also with pituitary dwarfism,
Turner syndrome, pseudohypoparathyroidism.
76
Dose (g/kg/day)
10-15
6-8
5-6
4-5
1-3
1-2
Although dessicated animal thyroid preparations are available, they are not
recommended because the ratio of T3 to T4 is nonphysiologic. The use of
levothyroxine combined with liothyronine (triiodothyronine, T3) has been investigated, but benefit has not been confirmed. There is no place for liothyronine alone as
long-term replacement, because the short half-life necessitates (three or four daily
doses) and is associated with fluctuating T3 levels.
77
In children and in the majority of adult patients the treatment is started with
the total estimated dose; the final dose is adjusted based on serum TSH level after
4-6 weeks. The goal is to normalize the serum TSH. In older patients or patients with
underlying heart disease, it is best to start with a low dose of T4 (eg, 0.025 mg daily)
and increase the dose at 4- to 6-week intervals based on serum TSH
measurements.
The contraindications of the medication are: acute myocardial infarction,
untreated cardiovascular conditions, hyperthyroidism.
In children treatment monitoring is performed at 2-4 weeks at the beginning,
then at 3-6 months. At 2-years of age the medication could be withdrawn for 6 weeks
and determination made for fT4 and TSH in order to evaluate thyroid function and
diagnosis (transient forms with normalised hormone levels do not need further
treatment).
In adults once full replacement is achieved and TSH levels are stable, followup measurement of TSH is recommended at 6 months and than at annual intervals.
The restabilization of euthyroid state may increase T4 clearance and consequently
dose adjustement is needed. In some situations thyroxin requirement is increased:
Pregnancy;
Gastrointestinal disorders associated with malabsorption;
Treatment with different drugs or substances which decrease T4
absorption:
o Cholestyramine,
o Sucralfate,
o Aluminium hydroxide,
o Calcium supplements,
o Iron compounds
Treatment with substances which increase T4 metabolism :
o Carbamazepine,
o Estrogens,
o Phenytoin.
Inhibition of deiodinase synthesis in:
o Selenium deficiency,
o Cirrhosis;
Administration of soy products.
LT4 requirement decreases with age or androgen administration in women.
In subclinical form (TSH above 4.5 mU/L and normal fT4 and fT3) some
controversy exist regarding the opportunity of substitutive treatment, although it is
indicated in one of the following situations:
The presence of some symptoms of reduced or moderate intensity
(depression, constipation etc.);
Pregancy or infertility;
Dyslipidemia (usually hypercholesterolemia);
Very high titer of anti TPO antibodies and goiter.
Myxedema coma
The most redutabil complication of hypothyroidism is myxedema coma with a
high mortality rate ( 50%). Predisposing factors for coma are:
Cold exposure;
Infections, pneumonia;
78
Traumas;
Myocardiac infarction, gastrointestinal hemorrhage;
Some drug, such as sedativs and opioids, anesthetics.
Hypoventilation, leading to hypoxia and hypercapnia, plays a major role in
pathogenesis; hypoglycemia and dilutional hyponatremia also contribute to the
development of myxedema coma.
Clinically it appears with the signs of myxedema with insidious course to
extreme asthenia, lethargia and coma. Bradycardia, and marked hypothermia with
body temperature as low as 24C (75F) are unmissing clinical sings.
Laboratory:
Very elevated TSH in primary form and usualy very high titer of anti TPO ab;
Lactescent serum with very high serum cholesterol;
Increased cerebrospinal fluid protein
Hypoglycemia, hypo- or hypercalcemia, hyponatremia, LDH, CPK.
The state of counsciousness is significantly affected, with obnubilation or
rarely agitation. Epileptic seizures or only EEG modifications appear.
The treatment of myxedema coma is an emergency and must be treated in an
intensive care unit; the patient needs periodical monitoring of blood gases and
mechanic ventilation.
In myxedema coma thyroid hormone must be administered intravenously (the
digestive absorption is profound alterated), T4 in high initial doses of 300-400 g,
then 100 g/day. If this treatment is not followed by evident clinical improvement, 5
g intravenous T3 is administered, every 6 hours.
External warming is indicated only if the temperature is <30C, as it can result
in cardiovascular collapse.
Any precipitating factors should be treated, including the early use of broadspectrum antibiotics, pending the exclusion of infection.
Maximal precaution at liquid administration must be taken due to risk of
hyponatremia. Primary or pituitary adrenal insufficiency may be associated, so
hydrocortisone hemisuccinate in 100 mg doses i.v. is administered, followed by 50
mg intravenously every 6 hours.
Chronic thyroiditis (Hashimoto thyroiditis, lymphocytic thyroiditis, CTH)
It is the most frequent cause of hypothyroidism in iodine-sufficient areas, it
affects about 3% of adult population, predominantly the female gender, but it
manifests also in children and adolescents.
Idiopatic myxedema is considered the final stage of CTH, when atrophic
thyroiditis develops by complete destruction of follicular parenchyma.
Etiopathogenesis of CTH
CTH is considered a multifactorial disease, appeared as a consequence of
interactions between genetic factors responsible for the susceptibility to this disease
and environmental factors. The frequent association with BGD inside families and
even transition of BGD in CTH and viceversa in some patients suggests a close
physiopathological interrelation. Anyway, it may be considered that the spectrum of
thyroid autoimmune diseases has two extremes represented by idiopathic
myxedema and BGD and multiple intermediate variants.
79
80
Clinical forms
The following entities are considered variants of CTH:
Silent (painless) thyroiditis is more frequent in women. The major clinical
manifestation is thyrotoxicosis, that last from two to eight weeks before subsiding.
This phase may be followed by recovery or by hypothyroidism (usually clinically
mild or even asymptomatic) for two to eight weeks. The thyroid is diffusely
enlarged. The erytrocyte sedimentation rate (ESR) is sometimes moderately
elevated. RAIU shows low uptake and TSG could not be performed. Eventually,
however, up to 50 percent of patients develop chronic autoimmune thyroiditis with
permanent hypothyroidism, goiter, or both.
Postpartum thyroiditis is similar clinically and pathogenetically to painless
thyroiditis except that, by definition, it occurs in women within one year after
parturition (or after spontaneous or induced abortion). The onset of thyrotoxicosis
is usually in 3-4 months postpartum. It needs to be differentiated from Graves'
hyperthyroidism, which can also begin during the postpartum period, either as
recurrent or new-onset hyperthyroidism. The risk of recurrence of postpartum
thyroiditis at the following pregancies is higher. Selenium administration (200
mcg/day) to pregnant women with positive anti TPO ab can reduce the risk of
postpartum thyroiditis.
Riedels thyroiditis is a very rare form of CTH with extensive sclerosing fibrosis
which invades not only the thyroid but also the surrounding tissue. Riedels
thyroiditis clinically appears as a goiter of stony hard consistency, fixed, and often
not clearly separable from the adjacent tissues. It is probably a primary fibrosing
disorder, and has been reported in patients who also had mediastinal and
retroperitoneal fibrosis. Most patients are euthyroid, but a few are hypothyroid.
Glucocorticoids have been used for treatment, with sporadic improvement. The
use of tamoxifen has also been successful in some patients. Surgery may be
indicated to relieve tracheal or esophageal compression and occasionally to
exclude carcinoma.
Differential diagnosis
It has to be made with non-differentiated or differentiated forms of thyroid
carcinoma, subacute, or acute thyroiditis and non-toxic goiter.
Treatment
The indications of treatment are goiter and hypothyroidism. Subclinical forms
require 25-50 g/day LT4 and overt hypothyroidism 100-150 g/day LT4. If only a
high antithyroid antibody titer does exist treatment is not necessary.
The administration of iodine containing preparation must be avoided.
In thyrotoxic phases of postpartum or silent thyroidites beta-adrenergic
blocker administration is enough (Propranolol 40-80 mg/day or Atenolol 25-50
mg/day).
Chronic thyroiditis may be a component of a multisystemic autoimmune
disease, therefore patient must be monitoring for other conditions such as pernicious
anemia, adrenal insufficiency, type I diabetes mellitus or lymphocytic hypophysitis
(especially in postpartum form) and their adequate treatment are required.
81
Endemic goiter
A geographic area is arbitrarily defined as an endemic goiter area if more than
5% of the children aged 6 to 12 years have a goiter. The disease may be seen
throughout the Andes of central South America, in the Himalayas, in the European
Alps where iodide prophylaxis has not yet reached the entire population, in the
Middle Eastern countries, Indonesia, in many foci in the People's Republic of China.
With the widespread use of iodized salt and the introduction of iodides into
fertilizers, animal feeds and food preservatives, iodide deficiency in developed
countries has become relatively rare. However, there are large areas where iodine
intake is still markedly deficient.
It is estimated that 50 percent of the world population still live in countries with
significant iodine deficiency and may risk its consequences.
Iodine nutrition at the community level is best assessed by:
measurements of urinary iodine,
thyroid size,
serum TSH and thyroglobulin.
The urinary iodine concentration indicates current iodine nutrition, while
thyroid size and the serum thyroglobulin concentration reflect iodine nutrition over a
period of months or years.
A system for classifying iodine deficiency and sufficiency has been developed
based upon the median urinary iodine concentration in a population (table 10)
Table 10. Urinary iodine concentration
Median urinary
iodine concentration (mcg/L)
<20
20-49
50-99
100-199
200-299
299
Iodine nutrition
Severe deficiency
Moderate deficiency
Mild deficiency
Optimal
More than adequate
Possible excess
flattened epithelium (coloid goiter). Markedly distended follicles may fuse to form
colloid cysts, which are characteristic of nontoxic goiters.
A later stage is the formation of small nodules of different size and
consistency throughout the entire thyroid gland. The formation of nodules in nontoxic
goiters (adenomatous goiter) can only be explained by a constitutive heterogeneity
of the growth responses of individual thyroid follicular cells. There is an increase in
the total mass of follicular cells with autonomous iodine metabolism during goiter
growth. In large, old goiter areas of hemorrhagic necrosis, fibrosis, and even
calcification can be found. Repeated episodes of hyperplasia are followed by
involution and atrophy, the result being a gland containing a mixed bag of nodules,
zones of hyperplasia and involuting, degenerative, and repair elements.
Clinical manifestations
Anamnesis has to mention the place where the patient was born and raised,
eventually a goitrogens /drugs intake, the moment when goiter started to develop
and its growth pattern.
In most cases, a small goiter in a young person doesnt cause any symptoms
but only an esthetic discomfort. The changes in breathing, swallowing or speaking,
or even minor discomfort are present only in larger goiters.
The clinical general exam (inspection, palpation) has to focus on the position
and size of the goiter, the presence of nodules, their consistency and thyroid
consistency as a whole, mobility, sensibility, presence/absence of laterocervical
lymph nodes and compresive phenomena.
By palpation, a thyroid is considered goitrous when each lateral lobe has a
volume greater than the terminal phalanx of the thumbs of the subject being
examined.
The following simplified classification of goiter by palpation has been
proposed by WHO:
Grade 0: No palpable or visible goiter.
Grade 1: A goiter that is palpable but not visible when the neck is in the normal
position (i.e., the thyroid is not visibly enlarged). Nodules in a thyroid that is
otherwise not enlarged
fall into this category.
Grade 2: A swelling in the neck that is clearly visible when the neck is in a normal
position and is consistent with an enlarged thyroid when the neck is palpated.
The consistency of a goiter or of the nodules can be: soft, elastic or firm.
Hypertrophy can affect the entire thyroid or it can involve a lobe (lobar goiter). From
the point of view of its localization, it can be situated cervically (most frequently), at
the base of the tongue, intrathoracic (the inferior pole cannot be identified by
palpation), in the mediastin (retrosternally, usually without any conection with the
cervical thyroid). The mobility of the goiter with swallowing is usually maintained, and
the locoregional lymph nodes (laterocervical, submandibular, sub and
supraclavicular) are absent.
Laboratory and imagistic work-up
In most of the cases the patient has a normal thyroid function, with normal
fT3, fT4, TSH or TSH is slighly elevated and fT4 decreased; antibodies: anti TPO,
anti-TG and anti TSHR are negative. Urinary iodine excretion is diminished.
RAIU (radioiodine uptake) has high values (the thyroid is hungry for iodine)
and the scintigraphy of the thyroid reveals the marked heterogeneity of the goiters
86
and often cold or hot nodules. Thyroid ultrasound represents the most sensitive
method to evaluate thyroid volume, to identify and keep under surveillance possibly
existent nodules. Sometimes it is necessary to use other imagistic techniques:
thoracic X ray, MRI (for the mediastinal region, for example).
Differential diagnosis
The differential diagnosis with sporadic goiters (these appear in regions where
iodine is sufficient and have autoimmune mechanisms, or they are due to goitrogens,
drugs or even iodine excess) is established mainly by epidemiologic criteria.
Differential diagnosis of the endemic goiter is also made with benign tumors
(especially toxic adenoma) or malignant tumors, but also with other tumors from the
cervical region (thyrogloso-ductal cysts, parathyroid adenoma, lipoma, dermoid cysts
etc). If the pain is present, acute or subacute thyroiditis has to be also considered.
The thyroid in chronic thyroiditis has a firmer consistency and the antibodies are
positives.
Evolution and complications
Large goiters, which may displace or compress the trachea, esophagus, and
the neck vessels, can be associated with symptoms and signs including inspiratory
stridor, dysphagia, and a choking sensation. Compression of the recurrent laryngeal
nerve, resulting in hoarseness, suggests carcinoma rather than nontoxic goiter, but
vocal cord paralysis can occasionally result from benign nodular goiters.
The extension of the goiter towards the anterior mediastin can determine the
partial occlusion of the thoracic aperture, with consecutive obstruction of the venous
circulation. When the patient is asked to raise his arms above his head, this
maneuver narrows even more the thoracic inlet and it will be followed in a few
minutes by the external jugular venous obstruction and the appearance of the facial
congestion (Pemberton sign).
Another complication that can appear during this stage is the thyroid
inflammation called strumitis.
The nodules in an endemic goiter can be transformed as follows:
Toxic (autonomous) transformation of one of the nodules- appears
mostly because of a high iodine intake (drugs that contain a large
amount of iodine, contrast substances or excessive supplimentation of
iodine in food and water)
Cystic transformation can usually happen, and it leads to:
o Colloid cysts, formed by the coalescence of the macrofollicules,
o Hemorrhagic cysts (thyroid hematocell). One of the nodules
increases dramatically in volume, it is accompanied by acute pain.
Malignant transformation (rarely, especially a follicular carcinoma).
Treatment
Nontoxic goiters, endemic or sporadic, usually grow slowly over decades, and
can never cause any problems. The current management for many cases consists
simply of observation, without any specific therapy.
The main indications for treatment of patients with nontoxic goiter are:
compression effects,
progressive growth of the entire goiter or of individual nodules,
87
89
Thyroid neoplasia
Thyroid nodules are extremely common - the prevalence of palpable thyroid
nodules has been estimated to be about 4% of the adult population. Because of the
massive use of high-performance ultrasonography in clinical practice, it is estimated
that about 60% of healthy individuals can be diagnosed with thyroid nodules, the
vast majority of them being palpatory undetectable. These nonpalpable nodules,
called incidentalomas, have the same risk of malignancy as palpable nodules.
Table 11. Etiology of Benign Thyroid Nodules
Benign tumors
Multinodular goiter
Focal Hashimoto thyroiditis
Cyst: colloid, simple, hemorrhagic
Follicular adenoma: macro/microfollicular (cellular)
Hrthle cell adenoma (oxyfile): macro/microfollicular
The majority of thyroid nodules are benign (table 11), only about 5% to 10% of
nodules coming to medical attention are carcinomas. Thyroid cancer is considered a
rare disease, it represents 1% of the malign tumors, with an estimated annual
incidence of approximately 8.7 per 100,000 population. It appears 2-3 times more
frequently in women. Thyroid neoplasms can arise in each of the cell types that
populate the gland, including thyroid follicular cells, calcitonin-producing C cells,
lymphocytes, and stromal and vascular elements, as well as metastases from other
sites( tabel 12).
Table 12. The most frequent types of malignant thyroid nodules and their
origin
Malignant
Approximate Prevalence, %
Follicular epithelial cell
Well-differentiated carcinomas
Papillary carcinomas
Pure papillary
Follicular variant
Diffuse sclerosing variant
Tall cell, columnar cell variants
Follicular carcinomas
Minimally invasive
Widely invasive
Hrthle cell carcinoma (oncocytic)
Insular carcinoma
Undifferentiated (anaplastic) carcinomas
80-85
510
C cell (calcitonin-producing)
Medullary thyroid cancer
Other malignancies
12
Lymphomas
Sarcomas
Metastases
Others
90
Folicular
adenoma
Papillary
carcinoma
Follicular
carcinoma
Anaplastic
carcinoma
Medullary
carcinoma
Frequently
involved genes
TSH receptor
Chromosomal
involvement
14q31
Gs-alpha subunit
20q13.2
Point mutation
H-RAS
K-RAS
N-RAS
RET/PTC
11p15.5
12p12.1
1p13.2
10q11.2
Point mutations
TRK (NTRK1)
1q 23
Rearrangements
BRAF
PAX8-PPAR 1
2q13, 3p25
H-RAS
K-RAS
N-RAS
11p15.5
12p12.1
1p13.2
p53
17p13
BRAF
Activating mutations
RET
10q11.2
Point mutations
91
92
Figure 4. Decision matrix for work-up of a thyroid noduleadapted after Gardner DG, Shobank, Greenspans Basic and Clinical
Endocrinolog, 9-th edition
93
is negative, the patient is likely free of disease. On the other hand, if the serum
thyroglobulin concentration rises above 2 ng/mL and/or if the radioiodine scan is
positive, the patient is likely to have either persistent thyroid remnant tissue or
residual thyroid cancer. Neck sonography, CT, or MRI should be considered in this
circumstance to look for evidence of residual thyroid cancer. If disease is localized
anatomically and proven to be thyroid cancer, additional surgery may be warranted.
If the stimulated thyroglobulin is greater than 20 ng/mL and other anatomic imaging
studies are negative, some experts recommend empiric radioiodine therapy because
of the high suspicion of residual disease that might then be visualized on the
posttreatment scan. The risk of leukemia and of solid cancers rises significantly with
a cumulative activity greater than 500 mCi of 131I.
Follow-up at intervals of 6 to 12 months should include careful examination of
the neck, sometimes including neck ultrasound, looking for recurrent masses. If an
abnormal lymph node is discovered, FNAB is indicated to confirm or rule out cancer.
The patient's serum TSH should be checked to be certain it is adequately
suppressed. The serum thyroglobulin should be periodically assessed to be certain it
is undetectable. A rise in serum thyroglobulin to detectable levels while TSH is
suppressed suggests tumor recurrence, and imaging studies such as neck
ultrasound, CT, and MRI are necessary. PET scanning may also be useful to localize
residual disease, especially in patients with very high serum thyroglobulin levels (>50
ng/mL) when conventional imaging studies have been unrevealing.
Thyroglobulin autoantibodies present in 20% of patients interfere with
accurate measurement of thyroglobulin in radioimmunometric assays causing falsely
low values. Patients with thyroglobulin autoantibodies must be followed with periodic
imaging studies, such as thyroid ultrasound or CT scan.
For patients with noniodine-avid metastatic disease that is progressive, recent
studies have shown that several kinaseinhibiting drugs, including
sorafenib and sunitinib, can be effective in halting further tumor growth for 1 to 2
years. The kinases involved include the vascular endothelial growth factor receptor
family (VEGF), RET, and BRAF. For patients with bone or brain metastases,
combined external radiation and 131I therapy may be effective.
Patients with MC needs only early and adequate initial thyroidectomy
associated with cervical node dissection followed by thyroid hormone substitution
therapy. They should be followed postoperatively with periodic measurement of
serum markers (eg, calcitonin and CEA) that indicate residual disease.
Chemotherapy with tyrosine kinase inhibitors, especially the experimental RET
inhibitor vandetanib (ZD 6474), has recently been shown to be highly effective in
preventing disease progression in many patients with medullary cancer.
Treatment for anaplastic carcinoma consists of surgery in order to debulk the
tumor and prevent tracheal compression. Standard treatment incorporates combined
radiotherapy and chemotherapy with doxorubicin, which is sometimes combined with
other agents
The prognostic of the thyroid carcinoma depends on its histology type, the
subjects age, sex (better outcomes for females), and the quality of the treatment.
The best 10 years survival is for PC (80-95%), followed by FC (50-70% if there is a
minimal or franc invasion of the tumoral capsula) and medullar carcinoma with lymph
node invasion (40-50%). The most unfavorable outcome is for the anaplastic
carcinoma, with a 10 years survival of only 3%.
97
generalized form, the increased levels of T3 and T4 compensate in part for the
receptor defect, and treatment is not necessary. In some children, administration of
thyroid hormones may be necessary to correct defects in growth or mental
development.
Selective pituitary RTH is less common and usually presents with symptoms
of mild hyperthyroidism, goiter, elevated serum T4 and T3, and normal or elevated
serum TSH. It is currently thought that this form is not a distinct syndrome, but
rather the result of the poor sensitivity and specificity of the signs and symptoms of
hyperthyroidism, and the fact that thyroid hormone resistance is not necessarily
complete and may vary from tissue to tissue. In fact, identical mutations in the TR
receptor have been found in patients with diferent clinical variants of thyroid hormone
resistance.
Inactivating mutations in the TSH-receptor gene produce resistance to TSH
with uncompensated or compensated hypothyroidism. Affected individuals have
normal or hypoplastic thyroid glands, high serum TSH concentrations, and normal or
low serum T4 and T3 concentrations. Some patients may have normal growth and
development but persistently elevated serum TSH. Others may be severely
hypothyroid (cretinoid), with low fT4 levels, elevated TSH.
Individuals with partially compensated or uncompensated forms should be
treated with LT4, like any other hypothyroid patient. Because these individuals have
normal responsiveness to thyroid hormone, the goal is to normalize their serum TSH
concentration.
Thyroid disorders in pregnancy
The most important physiological changes that affect the thyroid during
pregnancy are:
A doubling in blood TBG levels (thyroxine binding-globuline) because of
the stimulation produced by estrogens, but also as a result of a reduced
metabolism. The TBG rise will lead to TT4 and TT3 rises, but their free
fractions remain the same
A rise in seric hCG, which mildly stimulate the thyroid (TSH-like). hCG
reaches a maximum at 10-12 weeks of pregnancy. fT4 and fT3 can
slightly increase during this period, without exceeding the limits, and TSH
decreases correspondenly.
The fetus has developed its own thyroid by 10-12 weeks gestation, which can
concentrate iodine and synthesize iodothyronines, but the thyroid hormones
synthesis begins only by 18-20 weeks of pregnancy, after which the secretion of the
thyroid rises constantly.
Immediately after birth, the new-born TSH level rises to 50-80mUI/L and then
decreases to 10-15 mUI/L during the first 48 hours, and T3 and T4 rise to levels that
are superior to adults levels.
Iodine suplimentation during pregnancy has to be carefully done, so that the
intake doesnt exceed 300 mcg/day. An increased iodine intake during pregnancy
can manifest as goiter and hypothyroidism in the child, while iodine deficit is
responsible of endemic cretinism or mental retardation.
99
101
adenosine-3',5'-monophosphate (cAMP) generation. The negative feedback relationship of PTH with serum [Ca2+] is steeply sigmoidal, with the steep portion of the
curve corresponding exactly to the normal range of serum calcium (Figure 5). The
setpoint is the calcium concentration at which there is half-maximal inhibition of
PTH secretion.
Besides calcium, there are several regulators of PTH secretion. Prolonged
depletion of magnesium will paralyze PTH secretion. Catecholamines, acting through
beta-adrenergic receptors, stimulate the secretion of PTH. This effect does not
appear to be clinically significant. Transcription of the PTH gene is also regulated by
vitamin D: high levels of 1, 25(OH)2 D inhibit PTH gene transcription. Vitamin D
analogs are used to treat secondary hyperparathyroidism in dialysis patients with
renal osteodystrophy.
Setpoint
Figure 5. The relationship between the serum-ionized calcium level and the
simultaneous serum concentration of intact PTH in normal humans.
The serum calcium concentration was altered by the infusion of calcium (closed
circles) or citrate (closed triangles). Parathyroid sensitivity to changes in serum
calcium is maximal within the normal range (the shaded area). Low concentrations of
PTH persist in the face of hypercalcemia.
bones, abdominal groans and psychic moans. A number of symptoms and signs
accompany hypercalcemia. They include:
Central nervous system effects such as:
memory loss, lethargy, depression,
psychosis, ataxia,
confusion, stupor, and coma.
Neuromuscular and skeletal effects such as:
weakness,
proximal myopathy;
arthritis.
Cardiovascular effects such as:
hypertension,
bradycardia (and eventually asystole),
deposition of calcium in heart valves, coronary arteries, and myocardial
fibers,
a shortened QT interval.
Renal effects such as:
renal stones, nephrocalcinosis,
polyuria, polydipsia, decreased glomerular filtration,
nephrogenic diabetes insipidus
hyperchloremic acidosis;
renal insufficiency.
Gastrointestinal effects such as:
nausea, vomiting,
constipation,
anorexia,
pancreatitis, peptic ulcer,
epulis - benign lesion situated on the gingiva.
Others:
eye findings such as band keratopathy;
systemic metastatic calcification.
The clinical manifestations that are directly related to PHPT include:
Bone disease, reflects a generalized increase in osteoclastic bone
resorption, is characterized clinically by:
o bone pain,
o generalized demineralization of bone, decreased bone mineral density
(BMD), in particular at more cortical sites (forearm and hip) as
compared with trabecular bone (spine),
o the classic manifestation, osteitis fibrosa cystica with:
subperiosteal bone resorption often most evident in the phalanges of the
hands,
bone cysts, usually multiple,
brown tumors, consist of collections of osteoclasts intermixed with fibrous
tissue,
pathologic fractures.
Nephrolithiasis, because of increased production of calcitriol,
Hypophosphatemia and hypomagnesemia,
Proximal renal tubular acidosis,
106
109
hypercalcemia that is known or suspected to be driven mainly by osteoclastic bone resorption: Pamidronate, 60-90 mg IV over 2-4 hours or
Zolendronate, 4 mg IV over 15-30 min,
calcitonin, can be useful as a temporary measure early in therapy: 4-8 IU/kg
SC,
intravenous glucocorticoids, 100-200 mg hydrocortisone IV at 4-6 hours,
should be considered in patients with suspected vitamin Ddependent
hypercalcemia (lymphoma or granulomatous disease),
dialysis, may be indicated in some patients,
urgent parathyroidectomy, after initial medical stabilization.
Hypoparathyroidism (hPT)
Hypoparathyroidism can be hereditary or acquired.
Hereditary hPT is often manifest within the first decade but may appear later.
There are different forms:
- Isolated hereditary hypoparathyroidism - the inheritance may be autosomal
dominant, autosomal recessive, and X-linked. Examples: gain-of-function
mutations in CaSR gene in autosomal dominant hypocalcemic hypercalciuria
(ADHH) or mutations in PTH gene.
- Hypoparathyroidism associated with mitochondrial dysfunction and
myopathy because of mutations or deletions in mitochondrial genes.
- DiGeorge syndrome, or the velo-cardio-facial syndrome (defective development of both the thymus and the parathyroid glands) dimorphic facies,
cardiac defects, immune deficiency, and hypoparathyroidism.
- Polyglandular autoimmune type 1 deficiency a complex hereditary autoimmune syndrome involving failure of the parathyroid glands, the adrenals,
the ovaries and the immune system, in association with recurrent mucocutaneous candidiasis, alopecia.
Acquired hypoparathyroidism is usually the result of:
- inadvertent surgical removal of all the parathyroid glands; in some instances
when not all the tissue is removed a transient form exist: normal parathyroid
function may return due to hyperplasia or recovery of remaining tissue,
- radiation-induced damage of parathyroid glands subsequent to radioiodine
therapy,
- glandular damage in patients with hemochromatosis or hemosiderosis,
Copper or Aluminium deposition,
- severe infections,
- autoimmune hypoparathyroidism (with autoantibodies to the CaSR)
sometimes still termed idiopathic hypoparathyroidism.
Severe magnesium depletion temporarily paralyzes the parathyroid glands,
preventing secretion of PTH (functional hypoparathyroidism). Magnesium depletion
also blunts the actions of PTH on target organs (kidney and bone) to counteract the
hypocalcemia. This is seen with magnesium losses due to gastrointestinal and renal
disorders and alcoholism.
Clinical features
Most of the symptoms and signs of hypocalcemia occur because of increased
neuromuscular excitability (tetany, paresthesias, seizures, organic brain syndrome)
111
114
Osteoporosis
Osteoporosis is defined as a reduction in the strength of bone that leads to an
increased risk of fractures. Loss of bone tissue is associated with deterioration in
skeletal microarchitecture that results in fractures with minimal trauma. Osteoporotic
fractures are a major public health problem for older women and men in Western
society. More than 50% of fractures among postmenopausal women, including hip
fractures, occur in this group with low bone density.
Etiopathogenesis
Osteoporosis results from bone loss due to age-related changes in bone
remodeling as well as extrinsic and intrinsic factors that exaggerate this process.
During growth, the skeleton increases in size by linear growth and by
apposition of new bone tissue on the outer surfaces of the cortex. The latter process
is called modeling, a process that also allows the long bones to adapt in shape to the
stresses placed on them. Increased sex hormone production at puberty is required
for skeletal maturation, which reaches maximum mass and density in early
adulthood. Nutrition and lifestyle also play an important role in growth, but genetic
factors primarily determine peak skeletal mass and density.
In adults, bone remodeling, not modeling, is the principal metabolic skeletal
process. Bone remodeling has two primary functions:
(1) to repair microdamage within the skeleton to maintain skeletal strength,
(2) to supply calcium from the skeleton to maintain serum calcium.
Remodeling may be activated by microdamage to bone as a result of
excessive or accumulated stress. Acute demands for calcium involve osteoclastmediated resorption as well as calcium transport by osteocytes. Chronic demands
for calcium result in secondary hyperparathyroidism, increased bone remodeling,
and overall loss of bone tissue.
Bone remodeling is also regulated by several circulating hormones, including
estrogens, androgens, vitamin D, and parathyroid hormone (PTH), as well as locally
produced growth factors such as IGF-I, transforming growth factor (TGF-),
parathyroid hormonerelated peptide (PTHrP), interleukins (ILs), prostaglandins, and
members of the tumor necrosis factor (TNF) superfamily.
These factors primarily
modulate the rate at which new remodeling sites are activated, a process that results
initially in bone resorption by osteoclasts, followed by a period of repair during which
new bone tissue is synthesized by osteoblasts. The osteoblast, the principal boneforming cell, arises from a pool of mesenchymal stem cells in the bone marrow,
which as they differentiate, acquire a set of characteristics, including expression of
PTH and vitamin D receptors. Osteoblasts that remain within cortical bone during the
remodeling process become osteocytes. The osteoclast is a multinucleated giant
cell that is specialized for resorption of bone. Osteoclasts are terminally differentiated
116
cells that arise from hematopoietic precursors in the monocyte lineage and do not
divide. Osteoblasts stimulate both osteoclast formation and activation.
The cytokine responsible for communication between the osteoblasts, other
marrow cells, and osteoclasts has been identified as RANK ligand (RANKL)
[receptor activator of nuclear factor-kappa-B (NFB); RANKL]. RANKL, a member of
the TNF family, is secreted by osteoblasts and certain cells of the immune system.
The osteoclast receptor for this protein is referred to as RANK. Activation of RANK
by RANKL is a final common path in osteoclast development and activation.
Osteoblasts can also secrete osteoprotegerin (OPG) which binds and neutralizes
RANKL, leading to a block in osteoclastogenesis and decreased survival of
preexisting osteoclasts
Modulation of osteoclast recruitment and activity appears to be related to the
interplay among these three factors: OPG, RANK, RANKL. Additional influences
include nutrition (particularly calcium intake) and physical activity level.
The term primary osteoporosis denotes reduced bone mass and fractures in
postmenopausal women (postmenopausal osteoporosis) or in older men and women
due to age-related factors. The term secondary osteoporosis refers to bone loss
resulting from specific clinical disorders. There is overlap in these designations; for
example, many postmenopausal women with low bone mass have vitamin D
insufficiency or deficiency which could be considered a secondary cause of
osteoporosis.
Bone loss can occur because bone resorption is increased or bone formation
is decreased. Primary osteoporosis appears because of the following factors:
1. The central role of estrogen deficiency in the pathogenesis of osteoporosis
in postmenopausal women has been recognized for many years. Estrogen
inhibits bone resorption and, after the menopause, estrogen deficiency
results in increased bone resorption and rapid bone loss.
2. Progressive deficits in renal and intestinal function that impair the whole
body calcium economy during normal human aging.
3. The failure to reach peak bone mass as a young adult. The amount of bone
mineral present at any time in adult life represents that which has been
gained at skeletal maturity (peak bone mass) minus that which has been
subsequently lost. Bone acquisition is completed in the late teenage years
and early twenties in girls and by the second decade in boys. Heredity
accounts for most of the variance in bone acquisition. Other factors
contributing to the acquisition of peak bone mass include circulating gonadal
steroids, physical activity, and nutrient intake. The consequence of an
inadequate adolescent bone acquisition will be a lower peak bone mass and
less reserve to accommodate to future losses.
Causes of secondary osteoporosis:
I. Endocrinopathies:
Thyrotoxicosis or excess thyroid hormone replacement,
Hyperprolactinemia,
Primary hyperparathyroidism,
Acromegaly,
Hypogonadism,
Glucocorticoid excess,
Diabetes mellitus.
117
II. Gastrointestinal/nutritional:
Vitamin D deficiency,
Chronic liver disease,
Celiac sprue because of impaired calcium and vitamin D absorption, but a
chronic inflammatory component also contributes to the bone disorder,
Malabsorption,
Gastrectomy,
Parenteral nutrition.
III. Hematological disorders:
Hemochromatosis,
Leukemia and lymphoma,
Mastocytosis,
Multiple myeloma may cause rapid bone loss because the malignant cells
produce stimulators of resorption and inhibitors of formation,
Sickle cell anemia,
Thalassemia.
IV. Medications:
Glucocorticoids,
Immunosuppressants (cyclosporine),
Antiseizure medications (particularly phenobarbital and phenytoin) by
impairment of vitamin D metabolism,
GnRH agonists and antagonists,
Heparin - stimulates bone resorption and inhibits bone formation,
Proton pump inhibitors.
V. Genetic disorders:
Hypophosphatasia,
Osteogenesis imperfecta,
Homocystinuria due to cystathionine deficiency.
VI. Other:
Alcoholism,
Rheumatoid arthritis,
Chronic obstructive pulmonary disease.
Osteoporosis induced by endocrine disorders
Hypogonadism, which can occur in men or women, has multiple causes.
Patients with primary hypogonadism related to ovarian or testicular failure or
secondary hypogonadism related to hypothalamic or pituitary disease lose bone
rapidly and often have fragility fractures. The hypogonadotropic group includes
patients with anorexia nervosa, athletic amenorrhea, prolactinoma, or lesions of the
pituitary gland or hypothalamus, including tumors.
The frequency of drug-induced hypogonadism is increasing. Long-acting
progestins used for contraception in young women cause bone loss that is usually
reversible. Gonadotropin-releasing hormone (GnRH) analogues and aromatase
inhibitors, which are used to block sex hormone production in women with breast
cancer or endometriosis and men with prostate cancer, can cause rapid bone loss.
Thyroid hormone excess may increase the risk of fractures in postmenopausal women. In young women with hyperthyroidism who are treated early, only
118
small changes in bone mass may occur because increases in formation rates match
those of resorption.
Patients with insulin-dependent diabetes mellitus often have low bone mass
and diminished bone formation, perhaps because they lack an anabolic effect of
insulin.
Disorders of calcium-regulating hormones cause bone loss in hyperparathyroidism and rickets or osteomalacia in vitamin D deficiency. Milder degrees of
parathyroid hormone (PTH) excess or vitamin D deficiency can contribute to the
pathologic changes of osteoporosis. Decreased calcium and vitamin D intake and
reduced sun exposure can lead to secondary hyperparathyroidism, which
undoubtedly plays a role in age-related bone loss. Hyperparathyroid bone disease is
associated with greater loss of cortical than trabecular bone and more preservation
of trabecular connections, as compared with osteoporosis.
Calcitonin inhibits bone resorption, and it has been thought that calcitonin
deficiency could contribute to osteoporosis. However, while bone turnover is
decreased in patients given exogenous calcitonin, endogenous calcitonin is not an
important determinant of osteoporosis.
Glucocorticoid-Induced Osteoporosis
Initiation of glucocorticoid therapy leads to rapid bone loss, resulting in
significant BMD deficits within even a few months with a greater impact on trabecular
than cortical bone. The magnitude of bone loss can be large, typically approaching
40% reduction of the initial BMD.
Approximately half of long-term glucocorticoid-treated patients suffer a
fracture. Skeletal fragility is not the only risk factor for fracture in steroid-treated
patients, because glucocorticoids (and the illnesses for which they are prescribed)
are also associated with muscle weakness, which itself creates instability and
increases the risk of falling.
Glucocorticoid-induced bone loss generally follows sustained administration of
systemic doses greater than 5 mg/d of prednisone or its equivalent. Patients
receiving maintenance hydrocortisone dosages (eg, 20 mg/d) for adrenocortical
insufficiency do not generally have an increased skeletal risk. Glucocorticoids affect
mineral balance through alterations in renal, intestinal, and skeletal function:
Renal calcium losses within a few days after initiating therapy, direct
inhibition of renal tubular calcium reabsorption leads to hypercalciuria.
Intestinal calcium losses - glucocorticoids, given in high doses for several
weeks, inhibit intestinal calcium absorption, lowering plasma ionized [Ca2+].
This is thought to stimulate compensatory hypersecretion of PTH, which
restores ionized [Ca2+] by activating bone turnover to increase delivery of
calcium to the circulation from bone.
Direct stimulation of bone resorption via increased RANK-L expression and
decreased OPG production. Glucocorticoids also inhibit osteoblastic
maturation and activity. Glucocorticoids also promote apoptosis in osteoblasts and osteocytes. In patients chronically treated with glucocorticoids,
bone formation is suppressed.
High-dose glucocorticoid administration also suppresses gonadotropin
secretion and creates a hypogonadal state in both men and women.
119
Clinical manifestation
Osteoporosis has no clinical manifestations until there is a fracture. This is an
important fact, since many patients with achy hips or feet assume that their
complaints are due to osteoporosis. This is unlikely to be true in the absence of
fracture. In comparison, pain is common in osteomalacia in the absence of fractures
or other bone deformities.
Osteoporotic fractures (fragility fractures, low-trauma fractures) are those
occurring from a fall from a standing height or less, without major trauma such as a
motor vehicle accident.
Vertebral fracture is the most common clinical manifestation of osteoporosis.
Most of these fractures (about two-thirds) are asymptomatic; they are diagnosed as
an incidental finding on chest or abdominal x-ray. In some patients, the presence of
vertebral fractures may become apparent because of height loss or kyphosis.
Other fractures: hip fractures are relatively common in osteoporosis and in
addition, distal radius fractures (Colles fractures) may occur. Colles fractures are
more common in women shortly after menopause, whereas the risk of hip fracture
rises exponentially with age.
There are a number of risk factors for fracture.
Nonmodifiable risk factors:
Personal history of fracture as an adult,
History of fracture in first-degree relative,
Female sex,
Advanced age,
White race,
Dementia.
Potentially modifiable risk factors:
Low calcium intake,
Estrogen deficiency (prolonged premenstrual amenorrhea early
menopause or bilateral ovariectomy),
Alcoholism,
Inadequate physical activity,
Current cigarette smoking,
Low body weight [BMI <18 kg/m2].
Laboratory and paraclinical investigations
Patients with a suspected acute compression fracture should be evaluated with a
plain x-ray of the dorsolumbar spine, to confirm the diagnosis. Osteoporosis may
lead to several types of vertebral abnormalities including wedge fractures, biconcave
or "codfish" deformities, and compression fractures.
Several noninvasive techniques are available for estimating skeletal mass or
density; bone mineral density - BMD. They include dual-energy x-ray absorptiometry
(DXA), single-energy x-ray absorptiometry (SXA), quantitative CT, and ultrasound
(US).
Dual-energy x-ray absorptiometry (DXA) DXA measures bone mineral content
(BMC, in grams) and bone area (BA, in square centimeters), then calculates "areal"
BMD (aBMD) in g/cm2 by dividing BMC by BA. An x-ray tube generates photon
beams of two different energy levels, thus the term "dual-energy." The difference in
attenuation (reduction in intensity) of the two photon beams as they pass through
120
body tissue of variable composition distinguishes bone from soft tissue and allows
quantification of BMD. DXA has become the standard for measuring bone density
because it gives very precise and accurate measurements at clinically relevant
skeletal sites (ie, those with major clinical consequences when a fracture occurs: hip,
lumbar spine and distal radius) and can be used for diagnostic classification. Tscore, the value used for diagnosis of osteoporosis, is calculated by subtracting the
mean BMD of a young-adult reference population from the patient's BMD and
dividing by the standard deviation (SD) of young-adult population. Bone mineral
density T-score criteria (WHO) for osteopenia and osteoporosis are:
Normal -1.0 SD,
Low bone mass (osteopenia): between -1.0 and -2.5 SD,
Osteoporosis -2.5 SD,
Severe (established) osteoporosis -2.5 SD and fragility fracture.
Z-score, used to compare the patient's BMD to a population of peers, is
calculated by subtracting the mean BMD of an age-, ethnicity-, and sex-matched
reference population from the patient's BMD and dividing by the SD of the reference
population it is used in children.
Quantitative computed tomography (QCT) measures volumetric BMD
(vBMD) in mg/cm3, most often at the spine. At the present time, QCT
is primarily a research tool because it is more expensive, less
reproducible, and requires a higher radiation dose than DXA.
Quantitative ultrasonography (QUS) QUS does not measure BMD,
but instead measures the reflectance of the ultrasound waves from
the bone surface. Potential advantages of QUS include low cost,
portability, and lack of radiation exposure. Measurements are most
commonly made at the calcaneus (heel). QUS cannot be used for
diagnostic classification or to monitor response to therapy.
Routine laboratory evaluation includes
complete blood count,
serum and 24-h urine calcium,
renal and hepatic function, serum albumin, cholesterol,
measurement of serum 25(OH)D level. Vitamin D levels should be
optimized in all individuals being treated for osteoporosis.
There is no established algorithm for the evaluation of women who present
with osteoporosis but in order to exclude secondary forms it can be useful:
- PTH, if hypo- or hyperparathyroidism is suspected,
- TSH, for evaluation of hyperthyroidism,
- urinary free cortisol levels or a fasting serum cortisol should be
measured after overnight dexamethasone if Cushing syndrome is a
suspicion,
- testosterone or E2, LH, FSH for hypogonadism,
- testing for antigliadin, antiendomysial, or transglutaminase antibodies
for celiac disease,
- serum and urine electrophoresis and evaluation for light chains in urine
in the case of suspicion for myeloma.
Several biochemical tests are available that provide an index of the overall
rate of bone remodeling. Biochemical markers usually are characterized as those
related primarily to bone formation or bone resorption. These tests measure the
121
overall state of bone remodeling at a single point in time. Bone formation markers
are:
Serum bone-specific alkaline phosphatase,
Serum osteocalcin,
Serum propeptide of type I procollagen.
Bone resorption markers are:
Urine and serum cross-linked N-telopeptide,
Urine and serum cross-linked C-telopeptide,
Urine total free deoxypyridinoline.
The markers of bone resorption may help:
in the prediction of fracture risk, independently of bone density, particularly in
older individuals,
for monitoring the response to treatment (the primary use of biochemical
markers),
ensure long-term adherence to treatment.
Differential diagnosis
Although most postmenopausal women and older men do not have a
definable secondary cause, those who do can be treated more effectively. This
possibility should be considered for every patient. Other disorders that should be
consider for differential diagnosis:
rickets and osteomalacia disorders of the mineralization of newly synthesized
organic matrix determined by vitamin D deficiency,
primary bone tumor or bone metastasis,
osteomyelitis,
Paget disease of bone (osteitis deformans) - a focal disorder of bone
remodeling that leads to greatly accelerated rates of bone turnover, disruption
of the normal architecture of bone, and sometimes to gross deformities of bone.
The clinical features of Paget disease are pain, fractures and bone deformity.
fibrous dysplasia of bone, a component of the McCune-Albright syndrome.
Treatment and prophylaxis of osteoporosis
Assessment of fracture risk can be estimated by using FRAX calculators that
are available online (http://www.shef.ac.uk/FRAX/tool). Patients should be educated
to reduce the impact of modifiable risk factors associated with bone loss and falling:
Women with osteoporosis (or seeking to prevent it) should exercise (prudently)
for at least 30 minutes three times per week, as exercise has been associated
with improvements in or maintenance of bone density and a reduced risk of hip
fracture in older women.
Smoking cessation because smoking cigarettes accelerates bone loss.
An optimal diet for treatment (or prevention) of osteoporosis includes an
adequate intake of calories (to avoid malnutrition), calcium, and vitamin D.
Postmenopausal women (and older men) should take adequate supplemental
elemental calcium such that their total calcium intake, including food calcium,
approximates 1200 mg/day. Women should also ingest a total of 800 IU of
vitamin D daily. Higher doses are required if they have malabsorption or rapid
metabolism of vitamin D due to concomitant anticonvulsant drug therapy.
Hip protectors may reduce fractures in high-risk populations.
122
Bisphosphonates
For the treatment of osteoporosis in postmenopausal women, bisphosphonates are first-line therapy. Bisphosphonates are synthetic analogues of native
pyrophosphate that inhibit osteoclastic bone resorption. Mechanism of action:
- they attach to hydroxyapatite binding sites on bony surfaces, particularly surfaces
of active remodeling,
- bisphosphonates reduce osteoclast activity by decreasing osteoclast progenitor
development and recruitment and by promoting osteoclast apoptosis.
Bone formation is often reduced by bisphosphonates, which is probably an
indirect effect of inhibition of bone resorption.
Despite their structural similarities, there are important differences among the
bisphosphonates in potency and toxicity. The nitrogen-containing bisphosphonates,
like zoledronic acid, risedronate, ibandronate or alendronate, are approved for
prevention and treatment of osteoporosis. Some bisphosphonates have very long
retention in the skeleton and may exert long-term effects.
All the approved bisphosphonates have been shown to reduce vertebral
fractures by approximately 50% to 60%. Alendronate, risedronate, and zoledronic
acid have also been shown to reduce the risk of nonvertebral fractures. Alendronate
(70 mg) and risedronate (35 mg) are approved for weekly dosing, and risedronate
and ibandronate (150 mg) are approved for monthly dosing. Intravenous therapy can
be given conveniently for zoledronic acid (5 mg annually) and ibandronate (3 mg
quarterly).
Oral bisphosphonate absorption is very low, less than 1% of the administered
dose. Consequently, patients must take these medications on first arising in the
morning, on an empty stomach, with at least 250 ml of water, remain upright to
ensure passage of the pill into the stomach, and ingest nothing else for 30 minutes
for alendronate and risedronate, and 60 minutes for ibandronate.
123
124
BMD but also reduce the risk of fractures. The decisive element apparently that
determines the effects of PTH to be destructive or therapeutic is whether PTH
concentrations in blood are elevated constantly or only intermittently. In severe
hyperparathyroidism, PTH concentrations remain high, varying little throughout the
day. Administration of PTH as daily pulse injections has been shown to produce a
substantial increase in trabecular bone mass with little loss or even a gain in cortical
bone in the femur.
Treatment with PTH is likely to be the most effective approach in patients who
lose bone or continue to have fractures on antiresorptive therapy.
Teriparatide or rhPTH(1-34) was approved for use in both men and
postmenopausal women with osteoporosis who are at high risk for fractures as well
as in glucocorticoid-induced osteoporosis or in patients who cannot use other
osteoporosis treatments. It is given in daily subcutaneous doses for a maximum of 2
years. The limitation is indicated because a long-term carcinogenicity study showed
that rats treated with rhPTH(1-34) showed a dose-related incidence of
osteosarcoma.
Recombinant PTH 1-84 is also effective for the treatment of osteoporosis.
Strontium Ranelate
Strontium ranelate has been proposed as an anabolic agent that also may be
antiresorptive. The dose used is 2 g/day. There is evidence that strontium ranelate is
effective for reducing the risk of vertebral fractures, and to a lesser extent, nonvertebral fractures. Although side effects are minimal (e.g. diarrhea), there are
reports of rare but severe allergic reactions.
Emerging therapies
There are several novel therapies under investigation for the treatment of
osteoporosis. They are in various stages of development. As examples:
- Sclerostin inhibitors, stimulates bone formation.
- Integrin antagonists inhibits the adhesion of osteoclasts to the bone surface, an
important initial step for bone resorption.
- Cathepsin-K inhibitors inhibit bone matrix dissolution and decrease bone
resorption.
The patients under treatment for osteoporosis should be monitored periodically. Markers of bone turnover are an option for patients who have conditions that
might interfere with drug absorption or efficacy, such as small bowel resections or
other types of malabsorption, or in patients who are reluctant to take antiosteoporosis medications regularly. In such patients, urinary N-telopeptide (NTX) or
serum carboxy-terminal collagen crosslinks (CTX) before and three to six months
after starting bisphosphonate or other antiresorptive therapy may be determined.
For patients starting on therapy it is also recommended to repeat DXA of the
lumbar spine and total hip every one to two years until stability is achieved, and
every two years or at less frequent intervals thereafter.
126
127
Gene
Chromosomal region
CYP11A1
15q23-q24
HSD3B2
1p13.1
17-Hydroxylase/17,20 lyase
CYP17
10q24.3
21-Hydroxylase
CYP21A2
6p21.3
11-Hydroxylase
CYP11B1
8q24.3
Aldosterone synthase
CYP11B2
8q24.3
day, with some secretory episodes with lower amplitudes associated with
meals and exercise. Interindividual variations do exist and biorhythm
could be lost in condition of physical stress (traumas, starvation etc.),
psychological stress (anxiety, depression), CNS and pituitary lesions, liver
and kidney failure, Cushings syndrome, alcoholism.
2. The ACTH and cortisol response to stress appear in different conditions
such as traumas, hypoglycemia and is mediated also through CRH and
CNS. This response may be reduced by high dose glucocorticoids
administered before stress.
3. Negative feedback control refers to the inhibitory effect of cortisol or
synthetic glucocorticoids (GC) on both CRH and ACTH. Continuous
administration of GC determines a lack of response of AC-pituitaryhypothalamus to stress or common stimuli, due to ACTH and CRH
suppression and the atrophy of the fasciculata and reticulata zones.
Adrenal androgens production in adults is also under the control of ACTH, both
DHEA and androstenedione having a circadian periodicity superposed on that of
ACTH and are suppressed after GC administration. On the contrary, DHEA-S does
not present diurnal fluctuations because of a much more reduced rate of metabolism.
The control of aldosterone secretion, the most important hormone with
mineralocorticoid effect is realized mostly by angiotensin II and hyperkalemia, both
having direct effect on zona glomerulosa, stimulating pregnenolone synthesis from
cholesterol and conversion of corticosterone into aldosterone. Atrial natriuretic
peptide (ANP), dopamine and heparin inhibit aldosterone secretion.
In normal individuals both renin and aldosterone release vary inversely with salt
intake hyponatremia has a stimulatory effect and hypernatremia an inhibitory
action on aldosterone release.
ACTH exerts a rapid but short stimulatory effect on aldosterone, the effect being
limited firstly by the increased secretion of DOC dependent on ACTH, hydric
retention and consecutive reduction of both aldosterone and renin.
If aldosterone is administered to a healthy person with adequate salt intake,
water and NaCl retention with K+ wasting appear initially, which determines an
elevation of blood pressure and body weight. After an approximately 3 kg weight
gain an escape phenomenon with spontaneous urine output appears and plasma
volume returns to normal, determined by atrial natriuretic peptide and hemodynamic
kidney mechanism.
Molecular mechanisms of glucocorticoids and mineralocorticoids
In contrast to the thyroid hormone receptors which are located in the nucleus,
the glucocorticoid (GC) receptors are situated intracytoplasmatic and are coupled
with hsp (heat shock protein). In target cells these proteins are dislocated when GC
bind to their own receptor after cell membrane diffusion.
Receptor-hormone complexes suffer a subsequent phosphorylation which favors
their transport into the nucleus, where they form homo- and heterodimers with other
complexes. Specific sequences of DNA-binding domains situated on the dimerized
receptors interact with hormone-responsive elements for GC (GRE), with highly
conserved structures, containing 15 nucleotides. Together with other transcription
factors, GRE stimulate or inhibit the expression of specific gene and the transcription
of specific mRNA.
131
Certain actions of GC, similar with the nongenomic actions of thyroid hormones,
appear more rapidly and cannot be justified by the effect on gene expression. A part
of them may be realized through some membrane or cytoplasm proteins which use
intracytoplasmic signal pathways such as Ca channels or cyclic-AMP/protein kinase.
This mechanism may explain the rapid effect of GC on immune function, apoptosis
and inhibition of ACTH secretion.
Mineralocorticoid type activity reflects both the free plasma hormone availability
and their affinity for receptors. Aldosterone and DOC have similar affinity for
mineralocorticoid receptors but aldosterone exerts a more important effect because it
exists as a free form in a higher proportion. The mineralocorticoid action of plasma
cortisol is comparable with those two, having similar affinity for receptors, but its
action is limited in certain target tissues (kidneys, colon etc.) as a consequence of
local degradation into cortisone by 11 beta hydroxysteroid dehydrogenase. Cortisone
cannot bind to mineralocorticoid receptors.
Mineralocorticoid effects are mediated by aldosterone binding to mineralocorticoid receptor in epithelial cells, mainly renal ones, followed by the transport of
these complexes into the nucleus and their coupling to specific binding domains of
some genes whose expression is thus increased. One of the most important
intermediate elements is a kinase controlled by aldosterone with a modulating effect
on apical sodium channel.
Biological effects of adrenal steroids
Steroid hormones exert their effects by binding to specific receptors, that are
present virtually in all tissues. Synthetic GC obtained by the modification of the
natural GC structure, have a lower metabolic rate and a more increased affinity for
cytosolic receptor; in addition, many of these synthetic glucocorticoids have
negligible mineralocorticoid effects.
GC effects on intermediary metabolisms consist in maintaining plasma glucose
in starvation conditions antihypoglycemic action and elevation of blood glucose in
stress period hyperglycemic action. These effects are a consequence of the
following:
Increased liver gluconeogenesis and liver glycogen synthesis;
Inhibition of peripheral glucose uptake by the reduction of protein synthesis
and increased release of amino-acids;
Lipolysis stimulation with glycerol and free fatty acids release (amino-acids
will be used as substrate for gluconeogenesis).
GCs generally inhibit DNA synthesis, in most tissues they inhibit RNA and
protein synthesis and accelerate protein catabolism. The single exception is the liver
were both the protein and RNA synthesis are stimulated by GC.
GC effects on other tissues or functions:
1. Connective tissue. GC inhibit the proliferation of keratinocytes and fibroblasts
with formation of striae, skin thinning, poor wound healing etc.
2. Bone tissue and phosphate-calcium metabolism. GC reduce intestinal
absorption of calcium, they cause secondary hyperparathyroidism, but also
increase urinary calcium excretion, with hypercalciuria, phosphaturia. The GC
excess results in negative calcium balance, although serum calcium level is
maintained within normal range but at the expense of net bone resorption.
Osteolysis is associated with an increase in biochemical markers of bone
turnover. Glucocorticoids directly inhibit bone formation by decreasing cell
132
3. The insulin tolerance test Hypoglycemia causes the central CRH release
and consequently, the ACTH and cortisol secretion. Insulin 0.05-0.15 UI/kg
is being administered and cortisol and serum glucose are measured at -30,
0, 30, 60 and 90 minutes. The normal response implies a rise in serum
cortisol to over 18 g/dl. The test is conclusive only if the serum glucose
reaches 2.2 mmol/l (40mg/dl). The ACTH response to hypoglycemia is more
than 100 pg/ml.
4. CRH stimulation test In case of primary hypoadrenalism, after the
intravenous CRH injection, theres an exaggerated ACTH response after 45
minutes. In case of pituitary failure, theres no response. This test is also
used for diagnosing Cushings disease and can be carried out after the
DXM test. An ACTH rise of 40-50% and cortisol 15-20% pleads for
Cushings disease.
The adrenal androgen measurements are used for diagnosing congenital adrenal
hyperplasia (caused by enzymatic deficits), adrenal tumors and the evaluation of
hirsutism. In adults the serum DHEA level is 0.2-1.3 g/dl (7-31 nmol/l), while the
DHEA sulphate can reach 470 g/dl (12 mol/l). Both these hormones are elevated
in case of an androgen secreting adrenal adenoma or carcinoma, but also in the
following enzymatic deficits (associated with congenital adrenal hyperplasia):
21 hydroxylase,
11 hydroxylase,
3 hydroxysteroid dehydrogenase.
On the other hand, SCC and 17 hydroxylase/17,20 lyase deficits are associated
with low or even non-detectable androgen levels. In the case of aldosterone
synthase deficiency, the androgen levels are normal.
In male patients, testosterone measurement is not significant for estimating
adrenal function, because the main percentage of this hormone is secreted by the
testis. In female patients, on the other hand, approximately 2/3 of circulating
testosterone derives from adrenal secreted precursors.
Total plasma testosterone has the following normal values:
In prepubertal patients 5-20 ng/dl (0.17-0.7 nmol/l),
In male patients 300-1000 ng/dl (10-35 nmol/l),
In female patients 20-70 ng/dl (0.7-2.6 nmol/l).
The plasma testosterone is elevated in testosterone secreting adrenal adenomas
or carcinomas, 21 hydroxylase deficiency and 11 hydroxylase deficiency; it has
normal values in CYP11B2 mutations, while in case of 3 hydroxysteroid
dehydrogenase and 17 hydroxylase deficiencies the level is very low or nondetectable including the male patients.
Although rarely used nowadays, 17 ketosteroid urinary excretion can estimate the
adrenal androgen secretion. Normal ranges are 8-10 mg/24 hours in female and 1215 mg/24 hours in male. Elevated values are caused by the same disorders as the
DHEA and DHEA-S high values. Their measurement is influenced by the use of
many drugs spironolactone, nalidixic acid, penicillin, etc. but it can be used in
monitoring the glucocorticoid substitution in congenital adrenal hyperplasia alongside
the 17 hydroxy- progesterone level.
The most frequent cause of CAH, the 21 hydroxylase deficit is confirmed by the
measurement of 17 hydroxyprogesterone. The normal values for this hormone are
under 82 ng/dl (2.5 nmol/l) in children and under 200 ng/dl (5 nmol/l) in females.
136
Clinical features
The possible presence of Cushing's syndrome is suggested by certain symptoms
and signs. Unfortunately, none of these are pathognomonic, and many are
nonspecific:
Obesityis the most common manifestation and weight gain is usually the
initial symptom. It is classically central, affecting mainly the face ("moon"
face), neck, trunk, and abdomen, with relative sparing of the extremities. A
"buffalo hump" or dorso-cervical fat pad is common; the bulging
supraclavicular fat pads make the neck appear thick and shortened.
Growth decelerationIn children, nearly all (> 95%) show decreasing linear
growth. Weight gain accompanying decreasing linear growth in a child should
prompt an evaluation for CS.
Skin changes: atrophy of the epidermis and its underlying connective tissue
leads to thinning (a transparent appearance of the skin) and facial plethora.
There is easy bruising following minimal trauma and striae (in 50-70 %, red to
purple, depressed and wider than the pinkish-white striae that may occur with
pregnancy or rapid weight gain over 1 cm). These striae are most commonly
abdominal but may also occur over the breasts, hips, buttocks, thighs, and
axillae. Acne presenting as pustular or papular lesions may result from
glucocorticoid excess or hyperandrogenism. Minor wounds may heal slowly
and mucocutaneous fungal infections are frequent.
Hyperpigmentation of the skin is rare in Cushing's disease or adrenal tumors
but is common in ectopic ACTH syndrome.
Hypertension is a classic feature of spontaneous CS; it is present in about
75% of cases, often the diastolic blood pressure is greater than 100 mm Hg.
Muscle weakness is more often proximal and is usually most prominent in the
lower extremities (because of low fat-free muscle mass and hypopotassemia)
and it can lead to muscle wasting.
Osteoporosis patients may present with multiple fragility fracturestypically
of the feet, ribs, or vertebrae (compression fractures). Avascular necrosis of
bone has been associated with exogenous glucocorticoid administration.
Emotional lability, increased irritability, anxiety, depression, euphoria, poor
concentration, insomnia and poor memory may also be present. Severe
depression, psychosis with delusions or hallucinations and paranoia occur in
a few patients. Some patients have committed suicide.
Gonadal dysfunction in females, as a result of elevated androgens:
amenorrhea, accompanied by infertility, hirsutism (increased hair growth
occurs over the face, abdomen, breasts, chest, and upper thighs). Acne and
seborrhea usually accompany hirsutism. Virilization with temporal balding,
deepening of the voice, clitoral hypertrophy, usually occur only in girls or
women with extremely high serum concentrations of androgens due to an
adrenal carcinoma.
Decreased libido is frequent in males and some have decreased body hair
and soft testes.
Renal calculi are induced by hypercalciuria.
Thirst and polyuriaare rarely due to overt hyperglycemia but theyre usually
caused by glucocorticoid inhibition of vasopressin (antidiuretic hormone).
139
143
146
In case of more severe trauma, the patient can administer 4 mg DXM IM until
medical assistance is available. Every patient should wear a medical alert bracelet
and should have several ready to inject syringes, for IM administration.
Medical ambulatory interventions, carried out with local anesthesia, do not
necessitate the increment of usual substitution doses. For surgical procedures with
mild stress, hemisuccinate hydrocortisone 50 mg 2-3 times a day is administered IV
the first dose with the pre-anesthetic drugs. In case of major surgery, with general
anesthesia, 100 mg HHS is given every 8 hours with dose decrement once the
clinical state allows it.
Female patients with hypoadrenalism can become pregnant, the dose increment
being usually necessary only in the third trimester and during labor, when parenteral
preparations should be administered as well.
Treatment monitoring is based mainly on clinical grounds disappearance of
mineralo- and glucocorticoid deficiency signs. Good appetite and sense of wellbeing, are the guides to the adequacy of replacement and signs of Cushing
syndrome indicate overtreatment. In primary hypoadrenalism, some authors
recommend measurement of basal ACTH level. A low ACTH level indicates
overdosage of the substitution therapy. Free urinary cortisol is not used for
monitoring the therapy.
For mineralocorticoid replacement monitoring one can use blood pressure
measurement both in recumbent and supine position, electrolyte balance and
plasma renin activity.
Acute adrenal insufficiency
It represents a medical emergency. In children and neonates, the salt-loss
syndrome can also appear in case of genetic steroid genesis disturbances, which
generate congenital adrenal hyperplasia. In adults, acute adrenal insufficiency may
occur in the following situations:
in a previously undiagnosed patient with decreased adrenal resources who
associates severe infection, trauma or other major stress;
in patients with abrupt cessation of long standing corticoid therapy and
decompensating secondary hypoadrenalism;
after pituitary infarction/apoplexy;
in a patient with known primary adrenal insufficiency who does not take more
glucocorticoid during an infection or other major illness, or has persistent
vomiting caused by viral gastroenteritis or other gastrointestinal disorders;
after bilateral adrenal hemorrhage or infarction
Clinical signs of adrenal crisis:
Marked hypotension, dehydration and hypovolemic shock; signs unjustified by
current illness severity.
Abdominal pain which can mimic acute abdomen.
Fever caused by concomitant infection or by the hormonal deficit per se.
Confusion, apathy.
Coma and death without adequate treatment.
The biochemical panel shows hyponatremia, severe hyperkalemia,
hypoglycemia, acidosis, lymphocytosis and eosinophilia.
In acute forms the treatment must be initiated as soon as the diagnosis is
suspected. The major goals are dehydration treatment, correction of hypovolemia
149
151
Table 15. Main phenotype and hormonal features of different types of CAH
StAR
3-HSD
17Hydroxylase
21Hydroxylase
11Hydroxylase
Aldosterone
synthase
Present in ,
Present in ,
Discrete in
Present in
Present in
Present in
No
++
Rare
Salt-wasting
Glucocorticoids
Normal
Mineralocorticoids
Androgens
in, in .
Normal
Increased
intermediate
metabolites
DHEA,
17-OH
pregnenolone.
DOC,
corticosterone
17-OH
progesterone
DOC,
11deoxycortisol
Corticosterone
18-hydroxycorticosterone
Blood pressure
Electrolyte balance
Na+ ; K +
Na+ ; K +
Na+; K +
Na+ ; K +
Na+ ; K +
Na+ ; K +
Deficient enzyme
Traits
External genitalia
ambiguity
Adrenal crisis
152
and in
men
in
cases of
Primary aldosteronism
In the past, clinicians would not consider the diagnosis of primary
aldosteronism unless the patient presented with spontaneous hypokalemia.
Nowadays it is estimated that approximately 5-13% of all patients with hypertension
have low plasma renin activity (PRA) because of an increased production of
aldosterone and many of them have normal electrolytes. It appears mostly in women
who are in the third to sixth decade.
Etiopathogenesis
Hypertension, suppressed plasma renin activity and increased aldosterone
excretion characterize the syndrome of primary aldosteronism which can be
determined by:
Aldosterone-producing adenoma (APA)- Conns disease, 30% of the cases (in
the past it was considered that it was responsible for 60-70% of all primary
aldosteronism cases), more frequent in the left adrenal. The tumor is more
frequently small (under 3 cm), composed of glomerular cells, partially
autonomous, meaning that the circadian aldosterone production rhythm is
maintained, but with no response to angiotensin II.
Bilateral idiopathic hyperplasia (IHA) 60% of cases; incompletely elucidated
mechanism, possibly an increase of the glomerular region sensibility to
angiotensin II.
Primary (unilateral) adrenal hyperplasia (PAH) 2% of cases.
Aldosterone-producing adrenocortical carcinoma -<1% of cases, voluminous
tumor (larger than 6 cm), with distant metastases.
Familial Hyperaldosteronism (FH):
o Type I glucocorticoid-remediable hyperaldosteronism, <1%, with an
autosomal dominant inheritance, appears because of a chimeric gene
duplication that results from unequal crossing-over between the
promoter sequence of CYP11B1 gene (encoding 11 -hydroxylase)
and the coding sequence of CYP11B1 gene (encoding aldosteronesynthase). The result is an ectopic expression of aldosterone synthase
activity in the cortisol-producing zona fasciculata, which is controlled by
ACTH.
o Type II, <2%, aldosterone-producing adenoma or bilateral idiopathic
hyperplasia which appear in a familial context;
Ectopic aldosterone-producing adenoma or carcinoma (in the ovaries or the
kidney), extremely rare, <0,1% of cases.
The rise of aldosterone production, with no regard to its origin, leads to an
increased sodium reabsorption, an increase in circulating and intracellular sodium,
an increase in water reabsorption, a potassium depletion that leads to an increased
renal secretion of hydrogen ions, a rise of plasma bicarbonates and alkalosis. The
large magnesium depletion and the alkalosis are responsible for the tetany.
Consecutively, there is a suppression of the renin-angiotensin system.
156
Clinical presentation
The patients are in their third to sixth decade, have high systolic-diastolic
blood pressure (a constant sign), with an average of 160-180/110-120 mmHg,
usually considered resistant to drugs (there is no significant BP decrease when the
standard doses of 3 hypotensive drugs are administered, including a diuretic).
In patients with hypokalemia the following clinical signs can also appear:
Asthenia, muscular weakness, sometimes myasthenia-like,
Acute tetany with facial paresthesia and muscular cramps,
Headaches,
Palpitations (premature ventricular contractions),
Polyuria, polydipsia, nocturia resistance to ADH and, in time, kaliopenic
nephropathy (with degenerative lesions in small arterial vessels and
proximal tubes),
Periodic paralysis is rare, except in the Asian population.
Edema is not present in these patients, even though water and sodium
retention exists, because of the mineralocorticoid escape. Left heart hypertrophy is
an usual finding. When matched for age, blood pressure, and duration of
hypertension, patients with primary aldosteronism have greater left ventricular mass
by echocardiographic measurements than patients with other types of hypertension
(eg, pheochromocytoma, Cushing syndrome, or essential hypertension).
Laboratory and paraclinical exams:
In classical forms we find:
Hypokalemia the blood must be collected during a diet with a normal
amount of sodium, without a tourniquet and with spironolactone
discontinued at least 6 weeks before testing.
Hyperkaliuria more than 30 mEq/24 h, with a low urinary Na/K ratio.
Hypernatremia can be absent, Na can be normal or just slightly high.
Hypomagnesemia.
Hyperchloremia.
What needs to be underlined is the fact that hypokalemia is inconstant in
patients with primary aldosteronism. In 2008, Endocrine Society elaborated
diagnosis guides and set the categories of hypertensive patients in which a primary
aldosteronism should be ruled out:
Hypertension in young persons, or in persons with a family history of
hypertension at a young age,
Hypertension with adrenal incidentaloma,
Hypertension and spontaneous hypokalemia, or hypokalemia after small
doses of diuretics,
Severe hypertension (systolic >160 mm Hg or diastolic >100 mmHg) or
hypertension resistant to treatment,
Hypertension and family history of primary aldosteronism (first degree
relatives).
Laboratory investigations should be done in more steps: first identifying the
patients by concomitantly dosing plasma aldosterone concentration and plasma
renin activity, usually followed by confirmation tests and establishment the
etiopathological subtype.
157
Hormonal tests:
1. Plasma aldosterone concentration, collected under strict conditions:
normal salt intake, 1g salt/day supplemented 4 days before collecting the
blood, spironolactone discontinued 6 weeks before. The rest of medication
needs a 2 to 4 weeks discontinuation. Only drugs that do not interfere with
renin-angiotensin/aldosterone feedback loops can be used (prazosin,
guanetidine). The blood kalium levels should be normal because
hypokalemia decreases the aldosterone production. The normal values in
the morning are between 7 and 15 ng/dl, higher values confirming the
hyperaldosteronism, but not differentiating between primary and
secondary forms.
2. PRA is low and does not rise after diuretics. Normal values 1,5-2,5
ng/ml/h, and 6-8 ng/ml/h after stimulation.
3. The best screening test for hyperaldosteronism is the dosing of both PAC
and PRA and calculating the ratio between the two. The blood samples
are taken in the morning, between 8 and 10 AM. ACE inhibitors can falsely
elevate PRA. Therefore, in a patient treated with an ACE inhibitor, the
finding of a detectable PRA level or a low PAC/PRA ratio does not exclude
the diagnosis of primary aldosteronism. Each laboratory has a detection
limit for PRA (usually under 0,1 ng/mL/h). The medium values of PAC/PRA
in patients with essential hypertension are between 4 and 10, in
comparison with 30-50 in those with primary aldosteronism. Because PRA
is low in a significant number of patients with essential hypertension, PAC
>15 ng/dL (416 pmol/L) represents an additional diagnosis criteria for
primary aldosteronism.
4. Other tests: 18-hydroxicorticosterone, urinary aldosterone or its
metabolites, especially aldosterone 18-glucuronide.
The confirmatory tests are necessary and they highlight the inadequate
secretion of aldosterone; the PAC/PRA ratio is not considered a diagnostic test, but
only a screening test. The suppression tests are:
Oral sodium loading test: Only after controlling hypertension and
hypokalemia, patients should receive a high-sodium diet for 3 days, with a goal
sodium intake of 5000 mg Na (12.8 g NaCl). In the third day a 24h urine specimen is
collected. Urinary sodium has to be >200 mEq and urinary aldosterone more than 12
mg/24 hours in order to prove an autonomous secretion of aldosterone).
Intravenous saline infusion test. In this test 2 liters of 0.9% sodium chloride
solution are infused intravenously with an infusion pump over 4 hours with the
patient in a recumbent position. Blood pressure and heart rate are monitored during
the infusion. At the completion of the infusion, blood is drawn for measurement of
PAC. PAC levels in normal subjects decrease to less than 5 ng/dl; most patients with
primary aldosteronism do not suppress to less than 10 ng/dl. Post-saline infusion
PAC values between 5 and 10ng/dl are indeterminate and can be seen in patients
with IHA.
Fludrocortisone suppression test is no longer used by most centers.
Captopril test: 2 hours after the administration of 25 mg Captopril, PAC
decreases in adrenal hyperplasia and in normal persons, while in Conns syndrome
the values remain the same.
The last step in diagnosing primary aldosteronism is establishment of its
etiology. First, abdominal CT scan, emphasizing the adrenals, has a higher
158
sensibility in comparison with MRI. The aldosterone-producing adenoma is a welldefined hypodense tumor, more than 1cm in diameter.
Other imagistic investigations are abdominal ultrasound and I131-cholesterol
scintigraphy. Sometimes differentiating a unique adenoma from an idiopathic
bilateral hyperplasia can be challenging, especially because surgery should only be
performed in the former. What needs to be done is adrenal venous sampling with
bilateral dosing of PAC and cortisol, with calculation of the ratio or correction of
aldosterone/cortisol and a comparison between the values obtained from the two
veins. A ratio greater than 4:1 suggests a unilateral secretion.
Differential diagnosis
Primary aldosteronism hypertension has to be differentiated first from the
essential hypertension. Attention should be paid to secondary hyperaldosteronism
with high PRA, with a different physiopathological mechanism and a clinical picture
that sustains the diagnosis. Secondary hyperaldosteronism appears in:
Congestive heart disease;
Renovascular hypertension (PAC/PRA ratio<10);
Malignant hypertension;
Prolonged treatments with diuretics associated with low-sodium diet;
Pheochromocytoma;
Pregnancy associated hypertension or contraceptive-induced
hypertension;
Coarctation of the aorta.
If both PRA and PAC values are small, a weak mineralocorticoid excess is
suspicioned (generally aldosterone precursors), or a cortisol excess which ends up
in stimulating mineralocorticoid receptors. Usually these forms are rare:
Congenital adrenal hyperplasia: 11-Hydroxylase deficiency (with
virilization)
and
17-Hydroxylase
deficiency
(with
associated
hypogonadism);
Exogenous mineralocorticoid administration;
DOC-secreting tumors;
Primary resistance to glucocorticoids;
Liddle syndrome appears as a consequence of the activation of Na+
amiloride sensible channels form the collecting tubes. Clinically the
presentation is similar to hyperaldosteronism. Hypokalemia does not
respond to spironolactone, but only to triamterene or amiloride (it
specifically inhibits the Na+ channels);
Apparent
mineralocorticoid
excess:
11-beta-hydroxysteroid
dehydrogenase type 2 (11HSD-2) deficit, hereditary or acquired (licorice
or carbenexolone ingestion). 11HSD-2 inactivates cortisol in the kidney,
transforming it into cortisone. A rise of the cortisol/cortisone ratio is
responsible for binding the cortisol to mineralocorticoid receptors. In the
secondary form the enzyme is inhibited by the ingestion of carbenexolone
or an increased ingestion of glycyrrhizic acid, the active principle of licorice
root (Glycyrrhiza glabra), used as a sweetener in candies, chewing gum
and some sodas.
Cushings syndrome:
o Exogenous excess of glucocorticoids,
159
162
Beta1
Beta2
Beta3
Dopamine1
Dopamine2
Preganglionic nerves
Adipose cells
Brain
Myocardium
Adipose cells
Most tissues
Vascular smooth
muscle
Bronchiolar smooth
muscle
Liver
Intestinal smooth
muscle
Pancreatic islet cells
Adipose cells
Vascular smooth
muscle
Sympathetic nerves
Pituitary lactotrophes
Gastrointestinal tract
and bladder regions but can be found in the chest arising in the anterior or posterior
mediastinum or the heart. Pelvic paragangliomas may involve the bladder wall and
obstruct the ureters. Non-chromaffin parasympathetic paragangliomas are typically
found in the head and neck. Unlike chromaffin sympathetic paragangliomas, usually
these tumors do not secrete catecholamines.
Catecholamine-secreting tumors are rare neoplasms, probably occurring in
less than 0.2 percent of patients with hypertension. It is estimated that the annual
incidence of pheochromocytoma is approximately 2 to 8 per million people, but this is
likely an underestimation. Although pheochromocytomas may occur at any age, they
are most common in the fourth to fifth decade and are equally common in men and
women.
Most pheochromocytomas occur sporadically. The "rule of tens" for
pheochromocytomas states that about 10% are bilateral, 10% are extra-adrenal, and
10% are malignant.
Based on family history, it was formerly thought that only about 10% of
patients with these tumors developed it as part of a genetic syndrome. With genetic
testing, it is now clear that about 25% of patients with pheochromocytomas or
paragangliomas carry a germline mutation associated with a familial syndrome.
There are several familial disorders associated with pheochromocytoma, all of
which have autosomal dominant inheritance:
von Hippel-Lindau (VHL) syndrome. The VHL phenotype includes
pheochromocytoma (frequently bilateral), paraganglioma (rarely),
retinal
angiomas,
cerebellar
hemangioblastoma,
epididymal
cystadenoma, renal and pancreatic cysts, pancreatic neuroendocrine
tumors, and renal cell carcinoma.
MEN 2 - activating mutations throughout the RET proto-oncogene
Neurofibromatosis type 1 characterized by neurofibromas, cafe au lait
spots, axillary and inguinal freckling, and iris hamartomas (Lisch
nodules).
Familial paraganglioma is an autosomal dominant disorder characterized by
paragangliomas that are located most often in the head and neck but also in the
thorax, abdomen, pelvis, and urinary bladder. Most cases of familial paraganglioma
are caused by mutations in the succinate dehydrogenase (SDH) subunit genes
(SDHB, SDHC, SDHD, SDHAF2, SDHA), which compose portions of mitochondrial
complex II.
Pheochromocytomas are typically encapsulated and firm in texture. The
average diameter is 3-5 cm. Larger tumors frequently contain large areas of
hemorrhagic necrosis that have undergone cystic degeneration. Malignant
pheochromocytomas are histologically and biochemically the same as benign ones.
The only reliable clue to the presence of a malignant pheochromocytoma is local
invasion or distant metastases, which may occur as late as 20 years after resection
Clinical manifestations
The symptoms of pheochromocytomas are the consequence of the
hemodynamic and metabolic effects of tumoral hypersecretion of epinephrine,
norepinephrine and dopamine. The classic triad of symptoms in patients with a
pheochromocytoma consists of episodic headache, sweating, and tachycardia.
Blood pressure patterns vary among patients with pheochromocytomas:
164
165
Differential diagnosis
Among patients suspected to have a pheochromocytoma, the diagnosis is
rarely confirmed. The differential diagnosis must be made especially with:
Pseudopheochromocytoma or hyperadrenergic spells, with paroxysmal
hypertension an abrupt elevation of blood pressure associated with
palpitations, flushing, anxiety and increase in plasma catecholamines
documented during attacks. Differentiation can be done by clonidine test.
Antihypertensive and psychopharmacologic agents or psychological
intervention can control pseudopheochromocytoma.
Severe anxiety and panic disorders.
Primary hypogonadism (menopausal syndrome).
Carcinoid syndrome - patients present with flushing and diarrhea rather
than pallor with associated pheochromocytoma-like symptoms.
Pharmacologic causes
o Withdrawal of adrenergic-inhibitor, like clonidine because of the
rebound effect,
o Sympathomimetic drug ingestion (amphetamine),
o Illegal drug ingestion (cocaine, phencyclidine, lysergic acid
diethylamide LSD ). Cocaine inhibitis the norepinephrine reuptake
by blocking the presynaptic reuptake pumps (transporters) and may
also enhance the release of catecholamines from central and
peripheral stores.
o Combination of a monoamine oxidase inhibitor and foods contain
relatively high concentrations of tyramine.
168
Treatment
The treatment of choice for pheochromocytoma is complete surgical
resection which requires an experienced team consisting of an endocrinologist,
anesthesiologist and endocrine surgeon. Careful preoperative pharmacologic
preparation is very important.
Preoperative management it takes 7 to 10 days (a longer duration is
indicated for patients with catecholamine cardiomyopathy). It should be started with
-adrenergic blockade. The beta-adrenergic blocker should never be started first
because blockade of vasodilatory peripheral beta-adrenergic receptors with
unopposed alpha-adrenergic receptor stimulation can lead to a further elevation in
blood pressure. On the second or third day of -adrenergic blockade, patients are
encouraged to start a diet high in sodium content (5 g/day) because of the
catecholamine-induced volume contraction and the orthostasis associated with adrenergic blockade. This degree of volume expansion may be contraindicated in
patients with congestive heart failure or renal insufficiency. After adequate adrenergic blockade has been achieved, -adrenergic blockade is initiated, typically
2 to 3 days preoperatively.
Alpha-adrenergic blockade - Phenoxybenzamine is the preferred drug for
preoperative preparation. It is an irreversible, long-acting, nonspecific -adrenergic
blocking agent. The initial dosage is 10 mg once or twice daily (with maximum final
dosage of 100 mg daily). The patient should be warned about the orthostasis and
marked fatigue that occur in almost all patients. With their more favorable side effect
profiles, selective 1-adrenergic blocking agents (e.g., prazosin, terazosin,
doxazosin) are preferable to phenoxybenzamine when long-term pharmacologic
treatment is indicated. However, treatment with these agents is not routinely used
preoperatively because of incomplete -adrenergic blockade.
Beta-adrenergic blockade is indicated to control the tachycardia and
should be administered only after -adrenergic blockade is effective. It should be
used cautiously and at a low dose (e.g.10 mg of propranolol every 6 hours)
Combined - and -adrenergic blocking agent Labetalol, with the
inconvenience of a stronger beta-blocker effect than the alpha-blocker one.
Catecholamine synthesis inhibitor Metyrosine inhibits catecholamine
synthesis by blocking the enzyme tyrosine hydroxylase. It should be used with
caution and only in patients who cannot be treated with the typical combined - and
-adrenergic blockade protocol. Metyrosine may be added to - and -adrenergic
blockade if the resection will be difficult or if destructive therapy is planned. The main
side effect with short-course therapy is hypersomnolence.
Calcium channel blockers - block norepinephrine-mediated calcium transport
into vascular smooth muscle. Nicardipine is the most commonly used calcium
channel blocker in this setting (2x30 mg/day). It is used to supplement the combined
- and -adrenergic blockade protocol.
Acute hypertensive crises may occur before or during an operation,
and they should be treated with intravenously administered drugs:
Phentolamine is a short-acting, nonselective -adrenergic blocker. An initial
test dose of 1 mg is administered and is followed, if necessary, by repeat 5-mg
boluses or continuous infusion. The response to phentolamine is maximal 2 to 3
minutes after a bolus injection and lasts 10 to 15 minutes.
169
172
174
175
Ovotesticular DSD
This is an extremely rare syndrome, with only about 500 cases being reported
so far. Ovotesticular DSD (formerly called true hermaphroditism) occurs when both
an ovary and a testis, either in the same gonad (ovotestis) or different gonads are
found in one individual. Phenotype is highly variable, most commonly EG are
ambiguous with hypospadias, or at least one testis is palpable in the inguinal canal.
At puberty, menses usually occur (rudimentary uterus or hemiuterus are present in
the ipsilateral ovary or ovotestis part) and breast development occurs also, with
possible virilization or feminization depending on the predominance of one of the two
tissues. Karyotype may be 46, XX/46, XY in 20% of cases, 46, XX in 75% of cases
and 46, XY in the rest. Management of these cases depends of the ambiguity of EG.
If female gender is chosen, testicular tissue must be removed. If the phallus size and
masculinization of EG is adequate, ovarian tissue requires removal at puberty.
Defects in testosterone synthesis and action
17-hydroxysteroid dehydrogenase type 3 deficiency - the enzyme responsible
for conversion of androstendione to testosterone has several isoforms, one of which
is expressed in the testes and its deficiency is responsible for the absence of the
virilization of EG. In most cases, the phenotype is female with rudiment of the vagina
and the testes are present in the inguinal canals. Typically, gynecomastia and
pronounced virilization occur in puberty due to increased peripheral conversion of
androstendione to testosterone.
Steroid 5-reductase type 2 deficiency is similar to the previous, testes are
normally differentiated, but the enzyme that converts testosterone into DHT
(considered the active hormone, about 50 times stronger than testosterone) is
missing. The optimal masculinization of EG cannot take place. These patients can
present with microphallus, small scrotum, hypospadias, urogenital sinus and blindending vagina. IG are male. Increased virilization appears again at puberty but
without acne and gynecomastia. The explanation lies in the presence of two
isoenzymes. The type I enzyme is expressed in the skin and type II isoenzyme in the
EG and prostate. The T/DHT ratio is abnormally high and confirms the diagnosis.
Leydig cell hypoplasia occurs due to mutations in the LH/hCG receptor with
variable phenotype. EG are frequently female, but hypospadias, microphallus and
cryptorchidism (with small testes) can occur. Mllerian duct derivatives disappear
due to normal Sertoli cell function. Pubertal masculinization is missing.
Androgen insensitivity syndromes.
Mutations in the androgen receptor (AR) cause resistance to androgen
(testosterone, DHT) action or the androgen insensitivity syndrome (AIS). The
disorder is inherited as a X-linked recessive trait.
46, XY individuals with complete AIS (CAIS, formerly called testicular
feminization syndrome) have:
o unambiguously female external genitalia with normal or slightly
underdeveloped labia and clitoris; short and blind-ending vagina,
o testes, that may be located in the abdomen, the inguinal canals, or the
labia,
o absent or hypoplastic Wolffian ducts derivates.
At puberty LH synthesis is augmented with subsequent increases in plasma
testosterone (normal male range) which will be aromatized to estradiol in peripheral
tissues thus normal breast development occurs, but axillary and pubic hair is
176
180
Normal puberty
Cognitive, psychosocial and biologic maturation of the individual takes place
at the age of adolescence. The most remarkable biologic transformations in this
period are growth spurt and the appearance of secondary sexual characteristics. In
the same time, changes in body composition, the gain of reproductive function,
changes in bone mineralization and structure, and in cardiovascular system also
occur.
During embryo-fetal development, the hypothalamic-pituitary-gonadal axis is
activated, but shortly after birth there is a decrease in pituitary gonadotropins and
they remain inhibited until puberty. This suppression is realized at the level of CNS
by the tonic inhibition of the pulsatile GnRH generator situated in the arcuate nucleus
of the hypothalamus. The pituitary maintains its sensibility to GnRH during this
period. The intrinsic inhibitory mechanism of the CNS responsible for prepubertal
blockade of the GnRH pulse generator is realized mainly by gamma-amino-butyric
acid (GABA) but also by dopaminergic, serotoninergic or opioid mechanisms.
Puberty matches with the disinhibition of the pulsatile GnRH secretion translated in
nocturnal LH secretion in boys and cyclic LH and FSH secretion in girls.
In addition, other neural structures are involved in the onset of puberty and
leptin (produced and secreted by adipocytes) is an essential component of pubertal
development, although it doesnt seem to play a major role in the onset of puberty.
Stages of pubertal development are described for both sexes, in a succession
of physiologic changes with large chronologic limits. The whole period lasts for 4-5
years and starts at ages 9-10 years old in girls and 10-11 years in boys.
In girls breast development (telarche), pubic hair development (pubarche) and
the onset of menses (menarche) are observed according to Tanner and Marshall
pubertal stages. Breast development stages (B1-B5) are presented in Figure 10:
o stage B1: prepubertal,
o stage B2: breast bud stage, elevation of breast
and papilla as a small mound; enlargement of
areolar diameter,
o stage B3: further enlargement of breast and
areola with no separation of their contour,
o stage B4: projection of areola and papilla to
form a second mound above the level of the
breast,
o stage B5: mature stage, projection of papilla
only, resulting from recession of the areola to
the general contour of the breast.
181
Figure 11. Stages of female (left) and male (right) pubic hair development, P2-P5,
(according to Marshall, WA, Tanner, JM, Arch Dis Child 1970)
First sign of puberty in girls is telarche, followed by pubarche along with vulvar
development (vaginal opening becomes horizontal, there is thickening and
pigmentation of the labia, the clitoris becomes erectile). The uterus, vagina and
ovaries enlarge in relationship with secondary sexual characteristics and menarche
occurs after an average of 2.6 years after the onset of telarche
The onset of puberty in girls is influenced by genetic and environmental factors
(including endocrine disruptors). In the last years the onset of puberty and also the
age of menarche have decreased due to improvement of socioeconomic status and
health.
Clinical manifestations
Clinically, in GDPP, first signs are those of sexual maturation with the
appearance of secondary sexual characteristics earlier, but in the same order as in
normal puberty (in girls telarche precedes pubarche, and in boys testis enlargement
is followed by pubic hair development). Gametogenesis occurs in both sexes.
Individuals with a peripheral source of gonadal hormones (GIPP) are more likely to
display deviations from the normal sequence of puberty.
Central and peripheral precocious puberty is accompanied by increased
height velocity, somatic development and rate of skeletal maturation. If treatment is
delayed this accelerated epiphyseal activity can lead to rapid growth in the first
phase followed by the closing of epiphyseal cartilages and compromising of the final
stature. This is the paradox of a tall child compared to those of his/her generation
who will end as an adult with short stature. In addition, emotional distress due to
intellectual immaturity is constant.
Paraclinical explorations and laboratory findings
Serum estradiol, testosterone, basal FSH and LH are often measured in
children with precocious puberty. Levels of LH and sex steroids should be measured
using assays with detection limits adapted to the pediatric age group (LH detection
limits near 0.1 mIU/mL). In most laboratories, prepubertal levels of LH are below 0.1
mIU/mL.
184
Children with GDPP can be distinguished from those with GIPP (and from
normal prepubertal children) on the basis of measurements of serum LH
concentrations, at baseline and after administration of exogenous gonadotropinreleasing hormone (GnRH).
In GDPP, basal levels of LH and FSH are often at pubertal levels and will
increase with GnRH stimulation. Peak LH levels above 5 to 8 mIU/mL suggest
GDPP. In GIPP, LH and FSH levels are low at baseline (prepubertal range) and will
not increase with GnRH stimulation.
Imaging for bone age radio-carpal X-rays show a progress of bone age by
at least one year compared to the chronologic age in precocious sexual
development. If the patient has a normal bone age, he or she is unlikely to have
GDPP.
For differential diagnosis additional tests including thyroid function studies,
cortisol, DHEA, DHEAS, 17-hydroxyprogesterone and hCG in boys are used
In girls, pelvic (uterus, ovaries) ultrasound is mandatory: it can identify the
presence of an ovarian cyst or tumor. Uterus volume > 1.8 ml, or a length of the
uterus above 34 mm suggest progressive puberty. Ultrasound examination of the
testes is indicated in boys with GIPP to evaluate for the possibility of Leydig-cell
tumor.
Radiologic exploration by CT or MRI of the CNS, hypothalamic-pituitary
region, pineal gland, is required considering the possible tumoral etiology (more
frequent in boys). A diagnosis of idiopathic GDPP is a diagnosis of exclusion.
Differential diagnosis
True, central precocious puberty must be differentiated from other forms of
sexual precocity:
1. In both sexes peripheral precocious puberty can occur in severe,
untreated hypothyroidism (probably by the TSH directly acting on FSH
receptors and activating them), in McCune-Albright syndrome (initially
peripheral sexual precocity, it can be transformed into true, central
precocious puberty) or after administration of medication, cosmetics or
even food containing sex steroids (iatrogenic effect),
2. Isosexual precocious puberty in girls, GIPP can be determined by:
functioning ovarian cysts,
estrogen secreting ovarian or adrenal tumors,
Peutz-Jeghers syndrome (it is associated with perioral
hyperpigmentation and intestinal polyposis with malignant potential)
3. Isosexual precocious puberty in boys appears in :
hCG secreting tumors that can occur in the gonads, brain
(chorionepitheliomas,
germinomas),
liver,
retroperitoneum,
mediastinum,
congenital adrenal hyperplasia (21-alpha-hydroxilase or 11hydroxilase deficiency),
virilizing adrenal tumors,
Leydig cell tumors or adenoma,
familial testotoxicosis: autosomal dominant syndrome, manifested
only in boys, caused by activating mutations of the LH receptor
gene, which results in premature Leydig cell maturation and
185
188
191
Sperm volume
Normal
1,5-5 mL
Abnormal
Aspermia no sperm
Hypospermia < 1,5 ml
Hyperspermia > 5 ml
Sperm color
white
Hemospermia
Pyospermia
Sperm
concentration
Motility
> 15 million/mL
Morphology
4% normal forms
(by strict criteria
excluding sperm with
mild abnormalities)
Liquefaction time
Sperm fertilizing
potential
Biochemical
Notice
Retrograde
ejaculation
Prostate disorders
Inflammations
Tumors,
tuberculosis,
prostate stones
Acute and chronic
inflammations
infertility
infertility
3-25 minutes
Migration, survival
and vitality tests,
acrosome reaction
study
carnitine, fructose,
citric acid, zinc, acid
phosphatase
infertility
Functions of
epididymis,
prostate, seminal
vesicles
6. Testicular biopsy is primarily indicated in hypogonadal men with normalsized testes and azoospermia in order to distinguish between spermatogenic failure
and ductal obstruction. Testicular sperm extraction for possible intracytoplasmic
sperm injection (ICSI) into ova may be performed at the same time.
7. hCG stimulation test (LH-like action). Plasma T is determined before and
after 4 days of daily hCG (2000-5000 IU) administration. Normal response: T is
doubled after the last administration of hCG. It is used for differential diagnosis
between bilateral cryptorchidism and bilateral anorchia.
Male Hypogonadism
Hypogonadism in a man refers to a decrease in one or both of the two major
functions of the testes: sperm production and testosterone production. These
abnormalities usually result from disease of the testes (primary hypogonadism) or
disease of the pituitary or hypothalamus (central, secondary or tertiary
hypogonadism). Sometimes disorders can affect all levels (combined hypogonadism:
in the elderly, in alcoholism, hemochromatosis).
192
cholesterol, pain at the injection site, skin reactions at the application site. Androgen
therapy may cause premature fusion of the epiphyses in an adolescent.
Cryptorchidism
Defined as unilateral or bilateral absence of the testicle in the scrotum, due to
their retention on the normal path of descent. The incidence varies in preterm infants
(20-25%) compared with full term infants (2-4%). In many cases of cryptorchidism
noted at birth, spontaneous testicular descent occurs during the first year of life,
reducing the incidence to 1% by 1 year of age. Unilateral cryptorchidism is 5 to 10
times more common than bilateral.
Localization of the cryptorchid testes:
50% are located at the external inguinal ring or in a high scrotal
position;
19% lie within the inguinal canal, between the internal and external
inguinal rings;
9% are intra-abdominal.
Ectopic testes are located outside the defined normal path of testicular
descent, in most cases being found superficially above the external inguinal ring, in
Scarpa's triangle or perineum.
Etiopathogenesis
Testicle and epididymis descent into the scrotum takes place between 7-9
months of intrauterine life, therefore at birth the testes should be present in the
scrotum or get there no later than 1 year of age. The pathogenesis of cryptorchidism
is not fully understood. Some of the possible causes are the following:
GnRH hyposecretion or decreased pituitary sensitivity to GnRH - in case of
hypothalamic-pituitary diseases;
primary testicular damage: in Klinefelter's syndrome, 46, XY DSD;
environmental endocrine disruptors with estrogen or antiandrogen activity,
such as phthalates or bisphenol A, have been proposed as a cause of the
increased incidence of cryptorchidism seen in recent years.
idiopathic - probably multifactorial etiology, candidate genes: Insulin-like factor
3 (INSL3)
The whole fetal hypothalamic-pituitary-gonadal axis participates in the normal
descend process as well as inhibin (required for differentiation of gubernaculum
testis) and anti-Mllerian hormone. Low intra-abdominal pressure and mechanical
obstacles (tight inguinal canal in 3% of cases) may deviate testes from their normal
trajectory, leading to ectopic testes.
Clinical features
A careful physical examination should be performed to assess the location of
testes within the scrotum or inguinal canal. Clinical signs of hypogonadism or
ambiguity of EG (hypospadias, micropenis, etc.) may be present. The examination
should be performed with warm hands, in a calm atmosphere, sometimes after
scrotal warming or a hot bath to facilitate testicular descent. For detection of a
retractile testes, applying continuous pressure over the lower abdomen in the
direction of the inguinal canal may be helpful. The volume of the undescended testis
is usually lower. Other malformations, especially renal should always be sought.
196
1.
2.
3.
4.
Differential diagnosis
Retractile testes (pseudo-cryptorchidism) is due to hyperactive cremasteric
reflex. Testes can be lowered into the scrotum, but they return to the inguinal
canal after release. Low temperatures, fear, inadequate palpation can activate
this reflex (more pronounced between 5 and 6 years).
Ectopic testes: are outside the normal path of descent.
Bilateral anorchia: is associated with increased gonadotropins, decreased T
and lack of response to hCG stimulation test.
Congenital adrenal hyperplasia - virilization forms. Female infants with severe
forms at birth may have an apparent male phenotype with bilateral
cryptorchidism. Electrolyte and karyotype is recommended because of the
possible disastrous consequences (acute adrenal insufficiency).
198
Etiopathogenesis
Table 18 lists various pathological conditions and drugs that may be associated with erectile dysfunction.
Vascular
Leriche
syndrome
Pelvic vascular
insufficiency
Sickle cell
disease
Venous leaks
Aging
Aorto-illiac or
aorto-femoral
reconstruction
Neurologic
Urogenital
Anterior
temporal lobe
lesions
Spinal cord
lesions
Autonomic
neuropathy
Lumbar
sympathectomy
199
Systemic
Illness
Trauma
Cardiac
Castration
failure
Priapism
Cirrhosis
Peyronie
Uremia
disease
Respiratory
Perineal
failure
prostatectomy
Lead
poisoning
Clinical manifestations
Patients may complain of constant or episodic inability to initiate or
maintain an erection, decreased penile turgidity, decreased libido, or a
combination of these difficulties. The differentiation between psychogenic and
organic erectile dysfunction can usually be made on the basis of the patients
history.
Physical examination should include the following: a search for visual
field defects, patient's secondary sexual characteristics, presence of
gynecomastia. A careful assessment of femoral and peripheral pulses is also
important, as well as the search for evidence of peripheral or autonomic
neuropathy, a search for penile plaques indicative of Peyronie's disease,
examination of the testicles, evaluation of the cremasteric reflex (this is elicited
by stroking the inner thighs and observing ipsilateral contraction of the scrotum).
Clinically, men with androgen deficiency most commonly present reduced
sexual desire and erectile dysfunction. ED with normal libido advocates for
vascular or neurogenic causes. If libido and erection are maintained, but
premature ejaculation occurs the psychogenic form is very likely.
Paraclinical and laboratory explorations
1. Routine laboratory exams: blood count, lipid profile, parameters of liver
and kidney function, PSA (prostate specific antigen), fasting and 2-hour
postprandial blood glucose measurements
2. Hormonal determinations: T, FSH, LH, PRL, TSH, FT4, cortisol, etc.
3. Specialized tests at selected patients on the basis of established
criteria:
psychiatric and psychological evaluation,
nocturnal penile tumescence testing,
vascular investigations: Doppler ultrasonography with
spectral analysis following intracorporeal injection of a
vasoactive drug, penile arteriography, cavernosometry
pelvic and pituitary CT or MRI .
Treatment
The treatment of underlying risk factors (eg weight loss, exercise, stress
reduction, smoking cessation) and comorbidities (effective therapy of an
underlying systemic or endocrine disorder) may improve erectile function.
Available treatment options for male sexual dysfunction:
1. Oral agents. PDE5 inhibitors (Sildenafil Viagra 25-100 mg, tadalafil
Cialis or vardenafil Levitra) are taken orally about 1 hour before
anticipated intercourse.
the relaxant effect of NO on smooth muscle is prolonged,
improving erection quality and duration but does not stimulate the
libido,
these agents are absolutely contraindicated in men receiving oral
or
transdermal
nitrates
for
vascular
disease.
Other
contraindications: association with alpha adrenergic antagonists
(can cause long-term hypotension, simultaneous therapy is strictly
prohibited), after heart attack or stroke,
side effects include headache, facial flushing, visual disturbances.
200
204
CHAPTER IX - OVARY
Ovary is a paired intrapelvic organ that has the size of 2.5 2 1 cm and
weight of 4-8 g (variable during the ovarian cycle), located on the posterior surface of
the broad ligament. Adult ovary is covered by a coating germinal epithelium and by a
thin conjunctival capsule, and consists of two parts: outer cortex and central medulla.
The cortical area contains a conjunctival stroma that includes ovarian
follicles in different stages of maturation and albicans corpora.
The medullary area contains vessels and medullary nerves. Near the hilum
(the place where blood and lymphatic vessels, as well nerves enter into the
ovary), the medullary area contains cells with similar morphology to
testosteron-producing Leydig cells.
Ovarian follicle, the morpho-functional unit of mature ovary coordinates the
two gonadal functions:
the release of a mature oocyte (egg) every 28-30 days,
the production of specific steroid hormones: estrogens, progesterone
(necessary for endometrial nidation) and small amounts of androgens.
The hypothalamus plays a fundamental role in regulating hormones during
female reproductive period. Ovarian functionality is ensured by hypothalamic
pulsatile secretion of GnRH with a stimulatory effect on pituitary production of
gonadotropins (LH and FSH). In adult women the pulse frequency of GnRH varies
during menstrual cycle (a pulse at every 60-90 minutes in the follicular phase, and at
every 1 to 3-5 hours in the luteal phase). GnRH stimulation in combination with
feedback regulation of ovarian hormones (estrogens exert a negative feedback
mechanism by GABA during the follicular phase, and a positive one in the
preovulatory stage) generates a phasic secretion of LH and FSH (monthly or
circatrigintan biorhythm) in pituitary gonadotrophic cells.
Ovarian cycle with a duration of 28-30 days, includes a follicular phase
dominated by the secretion of estrogens and a luteal phase dominated by the
production of estrogens and progesterone. Ovulation takes place between these two
phases. Luteal phase length is relatively constant between 12 and 14 days in normal
cycles; thus, the major variability in cycle length is due to variations in the follicular
phase. Estrogens, produced primarily in follicular phase of the ovarian cycle,
modulate GnRH secretion and pituitary sensitivity to GnRH. This increased pituitary
responsiveness to GnRH is responsible for the preovulatory surge of LH.
Progesterone is primarily secreted by the corpus luteum; its high serum level
reduces the pulse frequency of GnRH secretion by increasing hypothalamic
concentrations of opioid peptides (beta-endorphins) with inhibitory effects. Its level
starts to increase preovulatory being responsible at least in part for the increase of
FSH and its coordination with the LH preovulator peak.
Follicular phase is initiated by the increase of FSH in the first 5 days of the
cycle which "selects" a dominant follicle (privileged); this will undergo full
maturation, from a stock of follicles "recruited" by virtue of a genetic program of
development incompletely elucidated. After selection, FSH decreases, and the rest
of the follicular maturation process goes on through paracrine coordination.
Through the cooperation between theca and granulosa cells - the ovarian follicle
produces and releases large amounts of estrogens, the plasma concentration of
which increases exponentially and produces simultaneously a new and mild FSH
rise.
205
Barr test - highlights the sexual chromatin in buccal mucosa cells. Normally, Barr
corpuscle is present in 20-80% of female cells and in 0.4% of male cells;
Karyotype counts the number and analyses the morphology of chromosomes is useful in the diagnosis of gonadal dysgenesis.
Ovulation tests:
Basal body temperature monitoring - basal temperature (oral or rectal measuring
at the same time of the day) increases postovulatory (after plasma progesterone
increases) by about 0.4 degrees and it maintains itself during the luteal phase,
cervical mucus smear,
cytovaginal exam aims histological and tinctorial changes of vaginal epithelium
cells, depending on the phases of the menstrual cycle,
ovarian ultrasound - monitors the development and maturation of ovarian follicles,
demonstrate the presence of ovarian tumors,
Measurement of LH surge by ovulation strips (colorimetric determination of LH
amount in urine in the midcycle period),
progesterone measurement in day 21 of the menstrual cycle (if
serum
progesterone level >5 ng/mL ovulation is likely).
Hormonal measurements are presented in table 19.
Table 19. Hormonal measurements in female
Investigated hormone
Estradiol (E2)
prepubertal
follicular phase
ovulatory peak
luteal phase
menopause
Progesterone
follicular phase
luteal phase
Testosterone
Normal values
Utility, interpretation
< 50 pg/ml
50 100 pg/ml
200 400 pg/ml
50 150 pg/ml
< 50 pg/ml
0,5 5 ng/ml
10-27 ng/ml
20-70 ng/dl
(0.7- 2.6 nmol/l)
To investigate infertility
FSH
follicular phase
ovulatory peak
luteal phase
menopause
1,5 15 U/l
60 80 U/l
1,5 15 U/l
> 80U/l
LH
follicular phase
ovulatory peak
luteal phase
5 - 25 U/l
60 100 U/l
5 25 U/l
PRL
< 20 ng/ml
< 480 microUI/ml
207
Female hypogonadism
The classification of female hypogonadism is based on etiopathogenesis and
clinical appearance which vary considerably according to the time of onset
(prepubertal or postpubertal):
Hypergonadotropic hypogonadism (primary or gonadal
dysfunction),
Hypogonadotropic hypogonadism (tertiary/hypothalamic or
secondary/ pituitary cause).
Hypergonadotropic hypogonadism (premature ovarian failure - POF)
The physiopatological mechanisms of POF are the accelerated follicular
atresia and inadequate stimulation of the ovarian follicle. Premature ovarian failure
(POF) is a heterogeneous syndrome defined as the occurrence of ovarian
insufficiency before the age of 40 years. In this category we find the following clinical
entities:
Turner syndrome, with all its cytogenetic variants.
Ovarian agenesis - lack of development of the ovaries, of unknown cause.
46,XX gonadal dysgenesis the ovaries are dysgenetic, beign replaced with
fibrous streaks. Turner stigmata and short stature are absent.
46,XY gonadal dysgenesis (Swyer syndrome) and mixed gonadal dysgenesis
(45,X/46,XY) - in both cases the testicle becomes inactive before internal and
external genitalia develops, so the phenotype is female. Gonads harbour a 10208
30% risk for malignancy due to the presence of Y chromosome and their
removal is indicated.
Certain forms of CAH: deficiency of StAR (with severe adrenal insufficiency),
17-hydroxylase (association of hypertension, hypokalemia and sexual
infantilism), aromatase deficiency (with concomitant maternal virilization during
pregnancy).
Translocations, submicroscopic deletions or polysomies (like 47,XXX or other
variants) of chromosome X.
FMR1 gene premutation carriers (the gene is responsible for the appearance of
the fragile X syndrome). It is estimated that in 3-16% of women with POF the
number of CGG repeats in the promoter of this gene is between 55 and 200
(premutation).
Iatrogenic or exposure to toxins (alkylating agents, smoking), radiation, viral
infections (cytomegalovirus, mumps virus), bilateral oophorectomy.
Autoimmune POF - occurs especially in the context of autoimmune
pluriglandular syndromes type I and II, when it may be associated with
autoimmune thyroid disease or adrenal insufficiency. Immunosuppressive
therapy can restore ovarian function in rare cases.
Galactosemia - it is thought to be caused by the toxic effects of galactose
metabolites.
Resistant ovary syndrome - controversial entity, where the ovarian
gonadotropin receptors may be affected (FSH or LH receptor mutations have
been described in some cases). Ovarian biopsy may reveal numerous
primordial follicles, without further development.
Clinical signs
Physical examination and morphogram appreciate waist, chest perimeter, the
relationship between certain distances (pubis-ground, pubis-vertex) and diameters
(bitrochanteric, biacromial) enrolling them in a graph and then correlating them to a
standard morphograme. An assessment of breast development (eg, by Tanner
staging B1-B5) and of pubertal hair development (eg, by Tanner staging P1-P5)
should be performed. Evaluation for the classic physical features of Turner syndrome
should be noted but also examination of the skin for hirsutism, acne, striae,
hyperpigmentation and vitiligo.
If the onset is prepubertal, the most common features are:
primary amenorrhea,
amastia or hypomastia,
rare/absent pilosity or thinned axillary or pubic hair,
infant, rudimentary external genitalia (vulva, vagina, clitoris)
congenital malformations or Turner stigmata.
Postpubertal estrogen deficiency is characterized by normal female
morphotype conservation, but:
involution of primary (genitalia) and secondary sexual characteristics, in
variable degree,
decreased libido and sexual dysfunction,
energy deficit,
menstrual cycle disturbances (hypo-, oligomenorrhea or secondary
amenorrhea) with chronic anovulation and infertility,
209
diagnosis between primary hypogonadism (low E2, increased FSH and LH ) and
central one (low E2, low or inadequately normal FSH, LH). The differential diagnosis
should include all cases of primary and secondary amenorrhea.
Treatment
Primary hypogonadisms benefit from combined estrogen-progestin therapy. In
prepubertal forms, the scope is the development of secondary sexual characteristics;
hormone replacement therapy requires a progressive administration, starting with
low doses of estrogen (2, then 5, 10 and 20 mcg/day ethinyl estradiol, each dose for
6-12 months) and introduction of a progestine when withdrawal bleeding is present.
Then standard preparations as oral contraceptive or hormone replacement therapy
(HRT) used in menopause are indicated.
In HRT several types of estrogen may be continuously administered; the
equivalent doses are :
1 mg/day micronized 17-estradiol, per os =
0.625 mg/day conjugated estrogens, per os =
10 g/day ethinyl estradiol, per os =
50 g/day 17-estradiol valerate transdermal administered.
Most women have an intact uterus, so progestin preparations are
administered cyclically, for 10-14 days per month (synthetic progestin preparations:
5-10 mg/day medroxyprogesterone acetate, 10-20 mg/day dydrogesterone or natural
micronized progesterone). Some newer progestin preparations are in use:
drospirenone, with antimineralocorticoid and antiandrogenic action, at doses of 0.5 to
2 mg/day. Treatment is usually indicated until about age of 50 years, the average
age of normal menopause, in order to prevent cardiovascular and skeletal
complications resulting from the absence of estrogens. Breast cancer risk is not
higher than in women with normal ovarian function.
Amenorrhea
Amenorrhea can be primary (PA), if a girl has not had at least one
menstruation by age of 16 years, or secondary (SA), if menstrual period is absent for
at least 6 months in a woman who had previously menses.
Primary amenorrhea may be due to:
1. Hypothalamic and pituitary etiology (represent 25% of all PA) - both were
discussed at hypogonadotropic hypogonadism. Constitutional delayed
puberty is included in this group.
2. Ovarian causes are responsible for 50% of PA; see hypergonadotropic
hypogonadism
(especially ovarian dysgenesis), and polycystic ovary
syndrome (PCOS).
3. Uterine or vaginal etiology (causes 20% of PA) - in case of congenital
anomalies, agenesis of the uterus, cervix or in:
Mayer-Rokitansky-Kuster-Hauser Syndrome agenesis of the uterus and
the upper portion of the vagina, with normal sexualisation.
Imperforate hymen is associated with cyclic pelvic pain and hematocolpos.
Transverse vaginal septum.
4. Other causes, due to receptor or enzyme defects: complete androgen
insensitivity syndrome, 17 alpha-hydroxylase deficiency, 5-alpha reductase
deficiency etc
211
Differential diagnosis
The most important aspect is to differentiate benign lesions from breast
cancer. The last one has several clinical features: single lesion, rapid increase,
invasive, infiltrating, becoming adherent to adjacent tissues. The orange peel skin
appearance or nipple retraction may become visible. Locoregional, especially
axillary, sub- and supraclavicular lymphadenopathy is present. Bloody nipple
discharge is another suggestive sign for both the intraductal lesions or ductal ectasy.
Other breast tumors should also be excluded, usually benign lesions: breast
lipoma, fat necrosis (posttraumatic or postsurgical, can mimic the clinical appearance
of a breast carcinoma), galactocele (a milk-filled cyst occuring frequently in lactating
or pregnant women), idiopathic granulomatous mastitis or other infiltrative lesions
(sarcoidosis).
Treatment
Cyclic breast pain can be treated with NSAIDs. In non-responder cases other
drugs are used:
Tamoxifen 10-20 mg/day, with the benefit of reducing the risk of breast
carcinoma. But long-term treatment increases the risk of uterine carcinoma,
thromboembolism or development of cataract. Side effects: hot flashes, joint
aches.
Raloxifene 60 mg/day.
Danazol 100-400 mg/day is the drug of choice for severe symptoms; due to
androgenic effect it can cause clinical signs of virilization, acne, seborrhea,
liver disorders, weight gain, amenorrhea.
Bromocriptine (2.5 to 7.5 mg/day) - only in the case of hyperprolactinemia.
GnRH agonists.
Topic ointments with progesterone or NSAIDs.
Some observational studies have shown some improvement of breast pain by
changing lifestyle (low fat diet, reducing coffee consumption), using vitamin E or
evening primrose oil, but so far data are not considered conclusive.
216
Clinical manifestations
Oligomenorrhea/secondary amenorrhea, or dysfunctional uterine
bleeding;
Premenstrual syndrome occurs in one third of women with PCOS;
Chronic anovulation with secondary infertility;
Signs of hyperandrogenism: hypertrichosis - increased hair growth
density, but without exceeding the normal distribution areas, hirsutism 217
CAH.
Ovarian or adrenal androgen secreting tumors (like Cushings
syndrome).
Iatrogeny drugs that induce hirsutism (some progestins, phenytoin,
diazoxide, metirapon etc).
Idiopathic hirsutism.
observations suggest the onset of menopause at around the same age in mother
and daughter, large studies could not demonstrate this.
Perimenopause refers to the time period preceding menopause, when fertility
wanes and menstrual cycle irregularity increases, until the first year after cessation of
menses. The onset of perimenopause precedes the final menses by 2 to 8 years, with
a mean duration of four years.
Early menopause is a premature ovarian failure, the term is no longer in
use.
The main pathogenic mechanism of menopause is a decreasing ovarian
follicular reserve (by apoptosis - genetically programmed cell death), reaching a
critical threshold, when accelerated follicular depletion is present.
Three stages of menopause are considered:
perimenopause - a relative excess of estrogen through the lack
of progesterone,
menopausal estrogen deprivation,
postmenopause.
In perimenopause the responsiveness of ovarian follicles to gonadotropins
decreases, resulting in a decline in progesterone production in the luteal phase and
inhibin B, with a consequent rise in FSH firstly and than in LH. As follicular atresia
progresses, estradiol levels show a great fluctuation presenting very high or very
low values.
Follicular maturation being impaired there is no more ovulation; anovulatory
cycles with a short follicular phase induces progesterone deficiency, and relative
hyperestrogenism with frequent bleedings. The tendency for anovulatory cycles
that produce this hyperestrogenic, hypoprogestagenic environment may be
responsible for the increased incidence of dysfunctional uterine bleeding,
endometrial hyperplasia or carcinoma and leiomyoma among women of
perimenopausal age. Benign mastopathies can exacerbate. Later on, irregular
menses turn into secondary amenorrhea due to the significant reduction of
estradiol synthesis.
Menopause is not a complete lack of estrogens. Androstenedione secreted
by adrenal gland and by ovarian stroma under the influence of elevated LH levels,
is converted to estrone by aromatization in adipose tissue. Estrone through
peripheral conversion forms small amounts of estradiol. This explains why estrogen
deficiency is less severe in obese women, so they are more prone to endometrial
cancer.
The cause of hot flashes is unknown. They are thought to be due to thermoregulatory dysfunction, initiated in the hypothalamus by estrogen withdrawal. The
close proximity of the medial preoptic area (the major thermoregulatory area in
mammals) and a high density of GnRH containing neurons suggest the possibility
of simultaneous activation of a burst of GnRH release and thermoregulatory
changes.
A speculative mechanism for the initiation of hot flashes is endogenous
opioid peptide withdrawal. Estrogen increases central opioid peptide activity, and
estrogen deficiency may be associated with decreased or absent endogenous
central opioid activity.
221
Clinical manifestations
1. Precocious clinical features:
Bleeding patterns anovulatory bleeding and endometrial hyperplasia
cause oligomenorrhea (irregular cycles) and episodes of heavy
dysfunctional bleeding. It should be noted that menorrhagia requires an
evaluation to rule out uterine disorders.
Vasomotor symptoms the most common acute change during
menopause is the hot flash, which occurs in up to 75 percent of women.
They are self-limited, usually resolving without treatment within one to
five years, although some women will continue to have hot flashes until
after age 70. Hot flashes typically begin as the sudden sensation of heat
centered on the upper chest and face that rapidly becomes generalized.
The sensation of heat lasts from two to four minutes, is often associated
with profuse perspiration and occasionally palpitations, and is often
followed by chills and sometimes a feeling of anxiety. Hot flashes usually
occur several times per day, although the range may be from only one or
two each day to as many as one per hour during the day and night. Hot
flashes are particularly common at night.
Genitourinary symptoms: The epithelial lining of the vagina and urethra
are very sensitive to estrogen, and estrogen deficiency leads to thinning
of the vaginal epithelium. This results in vaginal atrophy (atrophic
vaginitis), causing symptoms of vaginal dryness, itching and often,
dyspareunia. Recurrent urinary tract infections are also a problem for
many postmenopausal women.
Skin changes The collagen content of the skin and bones is reduced by
estrogen deficiency. Decreased cutaneous collagen may lead to
increased aging and wrinkling of the skin. Hirsutism can occur.
Psycho affective disorders anxiety, irritability, insomnia, depression,
decreased ability to concentrate and generally a decrease in selfconfidence can be present but with great variability.
2. Long-term issues. Gradual weight gain and fat redistribution that becomes
predominant at a visceral level, associated to dyslipidemia with atherogenic effect,
result in an increased risk of ischemic heart disease and stroke. Accelerated bone
loss, especially in women with other risk factors, causes osteoporosis.
Paraclinical and laboratory investigations
Initially in perimenopause, during anovulatory cycles: low levels of
progesterone and inhibin;
In menopause gonadotropins are increased, especially FSH>50
U/l; repeated measurements are necessary because the secretion
of gonadotropins has ultradian rhythm;
Estradiol is low, its main source remains the peripheral conversion
of estrone. Serum estradiol is 10-20 pg/ml;
Estrone/estradiol ratio increases;
DHEA decreases with age, testosterone and androstenedione
remain relatively constant until late postmenopause. Androgens
are aromatized in estrone in tissues (especially in the fat one).
Finally all circulating androgens will decrease but less dramatically
comparing to estrogens.
Androgen/estrogen ratio increases in comparison with
222
224
CHAPTER X - OBESITY
Etiopathogeny of Obesity
Obesity is a state of excess adipose tissue mass. Although often viewed as
equivalent to increased body weight, this need not be the caselean but very
muscular individuals may be overweight by numerical standards without having
increased adiposity. Obesity more effectively defined by assessing its linkage to
morbidity or mortality.
Many surveys performed especially in the United States have found a
significant increase in the prevalence of overweight and obesity over the past 30
years. The percentage of the American adult population with obesity (BMI >30) has
increased from 14.5% (between 1976 and 1980) to 33.9% (between 2007 and
2008). Obesity is more common among women and in the poor, and among blacks
and Hispanics; the prevalence in children is also rising at a worrisome rate.
Although not a direct measure of adiposity, the most widely used method to
diagnose obesity is the body mass index (BMI), which is equal to weight/height2 (in
kg/m2). Other approaches to quantifying obesity include anthropometry (skinfold
thickness), densitometry (underwater weighing), CT or MRI, and electrical
impedance.
Table 20. Weight Classification by Body Mass Index (BMI)
BMI (kg/m2)
underweight
Normal
Overweight
Obesity class 1
Obesity class 2
Obesity class 3
<18,5
18,5-24,9
25,0-29,9
30,0-34,9
35,0-39,9
40
calorie diets (VLCDs) are prescribed as a form of aggressive dietary therapy but they
need close metabolic monitoring.
Physical Activity Therapy . Exercise can improve glycemic control and insulin
sensitivity, has beneficial effects on serum lipoprotein concentrations, body
composition, and aerobic capacity and also reduces feelings of depression and
anxiety. The recommendations for heart disease prevention are at least 150
min/week. A high amount of physical activity (more than 300 min of moderateintensity activity a week) is often needed to lose weight and sustain weight loss.
Behavioral Therapy. Cognitive behavioral therapy is used to help change and
reinforce new dietary and physical activity behaviors.
Drug therapy. It can be considered for those with a BMI greater than 30
kg/m2, or a BMI of 27 to 30 kg/m2 if they have comorbid conditions. Weight loss
medications are often associated with many undesirable side effects. Currently there
are four main categories of weight loss medications: adrenergic agents, serotonergic
agents, combination of both adrenergic/serotonergic agents, and lipase inhibitors.
The classic sympathomimetic adrenergic agents (like phentermine) function
by stimulating norepinephrine release or by blocking its reuptake. In contrast,
sibutramine functions as a serotonin and norepinephrine reuptake inhibitor. It can
cause dry mouth, insomnia, tachycardia, high BP.
Fluoxetine, a selective serotonin reuptake inhibitor, approved for the treatment
of depression, may facilitate weight loss in the short run.
Orlistat is currently the only available drug that alters fat digestion. It does so
by inhibiting pancreatic lipases. As a result, ingested fat is not completely hydrolyzed
to its constituent fatty acids and glycerol, and fecal fat excretion is increased. The
recommended dose is 120 mg three times daily. A lower dose (60 mg), over-thecounter version is approved and available in some countries. Side effects: diarrhea,
flatulence, fecal urgency and incontinence, abdominal pain, dyspepsia.
Other medications:
o Metformin is a biguanide that is approved for the treatment of diabetes
mellitus, produces modestly weight loss.
o Leptin - leptin resistance can be overcome with high doses of leptin,
but whether the effect can be sustained is not known. Leptin therapy is
effective in some patients with lipodystrophy.
o Bupropion is a drug approved for the treatment of depression and for
the use in prevention of weight gain when trying to stop smoking.
o Rimonabant, an endocannabinoid receptor antagonist, was successful
in producing modest weight loss and improving metabolic
complications. However, adverse central nervous system side effects
of rimonabant including depression and anxiety precluded introduction
of this drug into clinical practice.
o short- or long-acting GLP1 agonists (exenatide, liraglutide), used for
diabetes are associated with a decrease in body weight.
Bariatric surgery .There are three main types of bariatric surgeries:
1. restrictive - includes horizontal gastroplasty, vertical banded
gastroplasty, adjustable gastric banding.
2. malabsorptive - include the oldest of all bariatric procedures, the
jejunoileal bypass, biliopancreatic diversion etc.
3. those that have both a restrictive and a malabsorptive component - is
the most commonly used bariatric surgery worldwide. The Roux-en-Y
231
232