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Hiperandrogenismo Artigo
Hiperandrogenismo Artigo
https://doi.org/10.1210/clinem/dgac673
Advance access publication 21 November 2022
Approach to the Patient
Abstract
Postmenopausal hyperandrogenism is a condition caused by relative or absolute androgen excess originating from the ovaries and/or the adrenal
glands. Hirsutism, in other words, increased terminal hair growth in androgen-dependent areas of the body, is considered the most effective
measure of hyperandrogenism in women. Other symptoms can be acne and androgenic alopecia or the development of virilization, including
clitoromegaly. Postmenopausal hyperandrogenism may also be associated with metabolic disorders such as abdominal obesity, insulin
resistance, and type 2 diabetes. Mild hyperandrogenic symptoms can be due to relative androgen excess associated with menopausal
transition or polycystic ovary syndrome, which is likely the most common cause of postmenopausal hyperandrogenism. Virilizing symptoms,
on the other hand, can be caused by ovarian hyperthecosis or an androgen-producing ovarian or adrenal tumor that could be malignant.
Determination of serum testosterone, preferably by tandem mass spectrometry, is the first step in the endocrine evaluation, providing
important information on the degree of androgen excess. Testosterone >5 nmol/L is associated with virilization and requires prompt
investigation to rule out an androgen-producing tumor in the first instance. To localize the source of androgen excess, imaging techniques are
used, such as transvaginal ultrasound or magnetic resonance imaging (MRI) for the ovaries and computed tomography and MRI for the
adrenals. Bilateral oophorectomy or surgical removal of an adrenal tumor is the main curative treatment and will ultimately lead to a
histopathological diagnosis. Mild to moderate symptoms of androgen excess are treated with antiandrogen therapy or specific endocrine
therapy depending on diagnosis. This review summarizes the most relevant causes of hyperandrogenism in postmenopausal women and
suggests principles for clinical investigation and treatment.
Key Words: hyperandrogenism, hirsutism, virilization, postmenopausal women, ovarian hyperthecosis, androgen-producing tumor
Abbreviations: 17-OHP, 17-hydroxyprogesterone; A4, androstendione; ACTH, adrenocorticotropic hormone; AMH, antimüllerian hormone; BMI, body mass
index; CAH, congenital adrenal hyperplasia; CT, computed tomography; DHEAS, dehydroepiandrosterone sulfate; DHT, dihydrotestosterone; FSH,
follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LC–MS/MS, liquid chromatography-tandem mass spectrometry; LH, luteinizing
hormone; MRI, magnetic resonance imaging; NC, nonclassic; PCOS, polycystic ovary syndrome; SHGB, sex hormone–binding globulin; SV, simple virilizing;
SW, salt wasting.
Received: 1 August 2022. Editorial Decision: 16 November 2022. Corrected and Typeset: 12 December 2022
© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which
permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
1244 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 5
Abbreviations: DHEAS, dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; LH, luteinizing hormone; SHBG, sex hormone–binding globulin.
Table 2. Mild to moderate and virilizing symptoms of hyperandrogenism diagnose PCOS after menopause. The Endocrine Society
in postmenopausal women Clinical Practice Guideline has therefore suggested that a diag
nosis of PCOS in a postmenopausal woman can be based upon
Symptoms of hyperandrogenism a history of oligo/amenorrhea and hyperandrogenism during
Mild to moderate symptoms Hirsutism the reproductive years (20).
Acne and oily skin The reproductive phenotype of PCOS usually improves by
Virilizing symptoms Severe hirsutism and acne age due to loss of ovarian follicles, leading to more regular
Androgenic alopecia cycles and decreased ovarian volume (21). However, the de
Deepening of the voice crease in ovarian volume and serum AMH during menopausal
Breast atrophy transition may be relatively less in women with PCOS than in
Increased muscle mass other women (22, 23). Consequently, the average age of
Enlargement of clitoris menopause is approximately 2 years later in PCOS than in
healthy controls (24). As androgen levels gradually decrease
by age, symptoms of hyperandrogenism like hirsutism may
improve in women with PCOS (25). Still, the prevalence of
PCOS Prevalence: 8% to 13% in the whole <2 nmol/L Persistent or increased hirsutism but no virilizing
female population of fertile age symptoms
History of oligo/amenorrhea and hyperandrogenism
during reproductive years
Later menopause
Overweight, abdominal obesity
Ovarian hyperthecosis Prevalence: 9.3% in postmenopausal >5 nmol/L Gradual development of virilizing symptoms in a peri-
women with hyperandrogenism (2) or postmenopausal woman
Isolated increase in testosterone
Severe insulin resistance, acanthosis nigricans,
metabolic syndrome, and/or type 2 diabetes
Bilaterally enlarged ovaries
Androgen-secreting ovarian Prevalence: 2.7% in postmenopausal >5 nmol/L Rapid onset of virilizing symptoms
tumor women with hyperandrogenism (2) Serum testosterone often in the male range,
accompanying increase in A4 and 17-OHP, but
usually not DHEAS
Unilateral ovarian tumor
Androgen-secreting adrenal Incidence: 1 to 2 cases/million >5 nmol/L Rapid onset of virilizing symptoms
tumor population/year (14) Serum testosterone in the male range, DHEAS, and
cortisol usually elevated
Unilateral adrenal tumor
Nonclassic congenital Prevalence: 1% to 10% in women with <5 nmol/L Gradual increase in hirsutism since puberty
adrenal hyperplasia hirsutism (15) Similar symptoms as in PCOS
Serum testosterone moderately increased, 17-OHP
elevated
Cushing’s syndrome Incidence: 1.8 to 3.2 cases/million <2 nmol/L New-onset hirsutism but seldom virilizing symptoms
population/year (16) Typical signs of Cushing syndrome such as moon face,
abdominal obesity, striae, buffalo hump
ACTH-secreting pituitary adenoma or a
cortisol-producing tumor
Abbreviations: 17-OHP, 17-hydroxyprogesterone; A4, androstenedione; ACTH, adrenocorticotropic hormone; DHEAS, dehydroepiandrosterone sulfate;
PCOS, polycystic ovary syndrome.
1246 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 5
Ovarian Hyperthecosis
Ovarian hyperthecosis is a relatively rare disorder presenting
with slow progress of severe symptoms of hyperandrogenism
in a perimenopausal or postmenopausal woman (Table 3)
(38). It is likely the second most frequent cause of hyperandro
genism in postmenopausal women. The prevalence of ovarian
hyperthecosis was reported to be 9.3% in postmenopausal
women undergoing investigation for symptoms of androgen
excess (2).
The condition is often described as an extreme form of Figure 2. Clinical signs of severe hyperandrogenism and virilizing
symptoms of hyperandrogenism in a perimenopausal and
PCOS; however, there is no clear evidence of a link between postmenopausal women including (A) androgenic alopecia, (B) breast
ovarian hyperthecosis and PCOS, and most women with atrophy and hirsutism, and (C) clitoromegaly.
PCOS will never develop ovarian hyperthecosis. In contrast
to PCOS, ovarian hyperthecosis will progress into virilizing
symptoms, including severe hirsutism, androgenic alopecia, metabolic symptoms are often more severe than in women
deepening of the voice, breast atrophy, and clitoromegaly with PCOS. Due to peripheral conversion of androgens to es
(Table 2, Fig. 2). In addition, the ovaries are bilaterally clearly trogens via aromatase, women with ovarian hyperthecosis
enlarged with a volume up to 10 cm3, compared with a vol also have an increased risk of endometrial pathology, includ
ume between 1 and 5 cm3 of a normal postmenopausal ovary ing polyps, hyperplasia, and cancer (44, 45), as well as breast
in women with or without PCOS (39-41). Ovarian hyperthe cancer (46).
cosis is strongly associated with metabolic symptoms, includ Ovarian hyperthecosis is caused by nests of luteinized theca
ing abdominal obesity, hypertension, hyperlipidemia, insulin cells in the ovarian stroma producing high amounts of testos
resistance, and acanthosis nigricans, in other words, the terone in the absence of other elevated androgens (47). Serum
metabolic syndrome and type 2 diabetes (39, 42, 43). The testosterone is usually increased above 5 nmol/L (38, 41),
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 5 1247
which distinguishes this condition from PCOS (Table 3). The resonance imaging (MRI). Asymmetry of the ovaries may sug
etiology of ovarian hyperthecosis is not known, although a gest a tumor.
genetic disposition and association with PCOS have been sug
gested (48). Several mechanisms behind the increased testos Androgen-Secreting Adrenal Tumors
terone production have been proposed. One is related to the
Androgen-secreting adrenal tumors are less common than
“2-cell hypothesis” where ovarian testosterone production
the corresponding ovarian tumors. Benign adrenal adenomas
by theca cells is uncovered in a postmenopausal woman by
include nonsecretory (incidentalomas) and secretory aden
the loss of granulosa cell–mediated aromatization of testoster
omas, of which the latter can cause hyperandrogenism.
one to estradiol (49). Another mechanism involves increased
Adrenocortical carcinomas, on the other hand, are usually
gonadotrophin stimulation by elevated levels of LH after
highly malignant tumors, and approximately 25% of cases
menopause (50). Thirdly, there is support that insulin resist
are associated with severe symptoms of hyperandrogenism
ance and hyperinsulinemia may induce stromal luteinization
leading to virilization (Table 3) (2, 58-60). The incidence is
causing androgen overproduction (51).
1 to 2 cases/million population per year. There is a bimodal
The most important differential diagnosis for ovarian hy
age distribution, with peaks before the age of 5 and in the
perthecosis is an androgen-producing tumor, which can be
of testosterone and adrenal androgen precursors (A4, DHEA, and rapid development of virilizing symptoms suggest a
and DHEAS) are also increased. The diagnosis is confirmed hormone-producing tumor, whereas slow development of vir
by genetic testing and detection of a mutation causing enzyme ilizing symptoms in a perimenopausal or postmenopausal
deficiency and impaired corticosteroid synthesis. woman is typical of ovarian hyperthecosis. In contrast, early
symptom onset and slow progression of mild to moderate hy
Cushing Syndrome perandrogenic symptoms are more consistent with PCOS or
another endocrine disorder (Fig. 3).
Cushing syndrome is a rare disorder, which can be either
Clinical signs of mild to virilizing symptoms of hyperan
ACTH-dependent and caused by pituitary hypersecretion of
drogenism are shown in Table 2. Hirsutism has been consid
ACTH (Cushing disease, about 70%) or ACTH independent
ered the most effective measure of androgen excess in
due to adrenocortical adenoma or carcinoma (about 20%)
women (74). It is defined as excessive facial and body ter
(65). ACTH-dependent Cushing is associated with elevated
minal hair in androgen-dependent body areas. Evaluation
ACTH levels causing bilateral adrenocortical hyperplasia and
of hirsutism can be assessed by the modified Ferriman–
hypersecretion of cortisol. In contrast, ACTH-independent
Gallwey score, 0 (no terminal hair) to 4 (marked hirsutism),
Cushing disease is related to suppressed ACTH secretion due
in 9 body areas: upper lip, chin and cheeks, upper chest,
Iatrogenic
Iatrogenic causes of hyperandrogenism due to overuse or Endocrine Evaluation
abuse of androgenic drugs should be considered. Systemic tes Symptoms of hyperandrogenism and particularly virilizing
tosterone and DHEA treatment of hypoactive sexual desire symptoms (including, eg, clitoromegaly, deepening of the
disorder or other androgen deficiency–related symptoms in voice, and breast atrophy besides severe hirsutism and pos
postmenopausal women may lead to overtreatment if not sibly androgenic alopecia) in a postmenopausal woman
carefully monitored by measurement of serum testosterone should be evaluated by endocrine screening, preferably se
(69). Furthermore, treatment with the antiepileptic drug val rum FSH, LH, testosterone, SHBG, A4, DHEAS, estradiol,
proic acid has been shown to increase the risk of a 17-OHP, and inhibin B (Table 4). For steroid hormone
PCOS-like phenotype in epidemiological studies (70). The determination, it is highly recommended to use LC–MS/MS
mechanism is attributed to direct stimulation of ovarian an instead of immunological methods as mentioned above.
drogen production by valproic acid (71). The anabolic steroid Using receiver operating characteristic analysis, the diagnostic
danazol, previously used for treatment of endometriosis and threshold for serum testosterone as measured by LC–MS/MS
still used as therapy for hereditary angioedema, has been re to identify an androgen-producing tumor was defined as
ported to induce hirsutism (72). It is well known that anabolic testosterone ≥5.1 nmol/L (sensitivity, 90%; specificity,
steroids can cause virilization in women when abused (73). 81%) (33). Serum testosterone >5 nmol/L is clearly associ
ated with virilizing symptoms (Table 2) (38, 81). It is there
fore suggested to use this value of testosterone as the
Evaluation
cut-off in the first step of investigation to rule out a hormone-
Clinical Symptoms producing tumor or a nontumor cause of severe hyperandro
The patient’s history of onset and development of symptoms genism such as ovarian hyperthecosis in a postmenopausal
should always be a guide for further investigation. Late onset woman (Fig. 3).
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 5 1249
Postmenopausal hyperandrogenism
• Clinical history
• Physical examination
• Endocrine evaluation
Figure 3. Algorithm for principles of investigation and treatment of different causes of hyperandrogenism in postmenopausal women. The cut-off of
5 nmol/L for serum testosterone is based on LC–MS/MS measurement. ACTH, adrenocorticotropic hormone; CT, computed tomography; GnRH,
gonadotropin-releasing hormone; 17-OHP, 17-hydroxyprogesterone; MRI, magnetic resonance imaging; NC CAH, nonclassical congenital adrenal
hyperplasia; PCOS, polycystic ovary syndrome.
Women with virilizing symptoms between tumorous and nontumorous causes of virilizing
Testosterone levels tend to be higher (in the lower male range) symptoms.
and gonadotropin levels lower in association with a virilizing Ovarian hyperthecosis is typically associated with an iso
ovarian tumor than in ovarian hyperthecosis; however, no lated increase in testosterone, while other androgens usually
cut-off value of testosterone has been proposed for discrimin are within the reference values (2), see the patient case above.
ating between a hormone-producing tumor and ovarian hy Furthermore, insulin resistance is characteristic for ovarian
perthecosis (29, 41, 82). The next step is therefore to hyperthecosis (39, 42, 43), and therefore fasting insulin and
proceed with diagnostic imaging (Fig. 3), see below. Further glucose for calculating the Homeostatic Model Assessment
endocrine evaluation may still be helpful for distinguishing or HbA1c should be considered. In the case of hormone-
producing ovarian tumors, hormones other than testosterone
may also be elevated, including inhibin B, AMH, A4,
Table 4. Investigation of hyperandrogenism in postmenopausal women 17-OHP, and estradiol, whereas DHEAS and cortisol are nor
mal (52, 82). In contrast, androgen-producing adrenal tumors
Assessment are associated with increased DHEAS levels, often higher than
twice the upper normal limit (>19 µmol/L), together with in
Clinical Hirsutism: modified Ferriman–Gallwey score
creases in testosterone, A4, and cortisol (2).
symptoms Acne
Androgenic alopecia: Ludwig score The gonadotropin-releasing hormone (GnRH) agonist test
Clitoromegaly: >1.5 × 2.5 cm can be used for distinguishing androgen-producing ovarian
Endocrine Serum analyses of FSH, LH, testosterone, SHBG, and adrenal tumors and successfully confirm an ovarian
evaluation A4, DHEAS, estradiol, 17-OHP, and inhibin B source from an adrenal source by suppression of testosterone
HOMA index or HbA1C as marker for insulin (41). However, the test cannot differentiate between ovarian
resistance can be considered hyperthecosis and an ovarian tumor, as both disorders are go
ACTH stimulation test to rule out NC CAH nadotropin dependent and will respond to GnRH with testos
24-hour urinary free cortisol and dexamethasone terone inhibition (83).
test to rule out Cushing’s syndrome
Selective ovarian and adrenal venous catheterization can lo
Imaging Transvaginal ultrasound calize an androgen-producing tumor by demonstrating differ
MRI, CT
ential gradients in androgen levels between ovarian, adrenal,
Abbreviations: 17-OHP, 17-hydroxyprogesterone; A4, androstenedione; and peripheral veins. However, success rates are poor, and
ACTH, adrenocorticotropic hormone; CT, computed tomography; DHEAS, this invasive method carries potential risks. A recent systemat
dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; ic review and meta-analysis concluded that there is limited evi
HOMA, Homeostatic Model Assessment; LH, luteinizing hormone; MRI,
magnetic resonance imaging; NC CAH, nonclassical congenital adrenal dence for the use of selective venous sampling in identifying
hyperplasia; SHBG, sex hormone–binding globulin. androgen-producing tumors in postmenopausal women (84).
1250 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 5
Women with mild to moderate symptoms of of an ovarian source of androgen excess (ovarian tumor, ovar
hyperandrogenism ian hyperthecosis) is primarily treated with surgery, in other
In postmenopausal women with mild to moderate symptoms words, laparoscopic bilateral oophorectomy, with or without
of hyperandrogenism and testosterone <5 nmol/L, PCOS is hysterectomy (38, 41, 87). As in the patient case presented, tes
the most likely diagnosis, as supported by a premenopausal tosterone levels will normalize rapidly within a couple of weeks
history of menstrual irregularities, hyperandrogenism, and/ after surgery while symptoms of androgen excess, including
or polycystic ovaries (Fig. 3). In these women, androgen levels hirsutism and oily skin and acne, will gradually resolve.
are slightly higher than in controls, but serum testosterone is Although swelling of the clitoris may regress, clitoral hyper
in most cases below 2 nmol/L (30-33). Transvaginal ultra trophy usually persists. The same applies to androgenic alope
sound is recommended (see below) but further endocrine cia; severe hair loss usually remains even after normalized
evaluation is not needed if screening samples are normal and testosterone levels. Deepening of the voice caused by androgen
the diagnosis is supported by medical history. excess is also a symptom that does not regress after treatment. It
In the case of an increased morning value of 17-OHP is therefore important to diagnose at an early stage for prompt
(>9 nmol/L), the ACTH stimulation test should be performed management of potentially severe causes of hyperandrogenism,
although androgen-producing ovarian tumors are seldom ma
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