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Predictors for Response to Letrozole as an Ovulation Induction in Anovulatory

Infertile Polycystic Ovarian Syndrome Women

Article · December 2019

DOI: 10.28969/IJEIR.v9.i1.r6

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 IRAQI JOURNAL OF EMBRYOS AND INFERTILITY RESEARCHES (IJEIR)
Alizzi, et al, Vol. 9 , Issue 1 , Pp. 89-110, (2019) Original Research
DOI: http://doi.org/10.28969/IJEIR.v9.i1.r6 E-ISSN: 2616-6984 P-ISSN: 2218-0265

Predictors for Response to Letrozole as an

Ovulation Induction in Anovulatory
Infertile Polycystic Ovarian Syndrome
Received: 26-May-2019 Accepted: 23-Oct-2019 Published: 24-Nov-2019

Women
Fadia J Alizzi a*, Hind Abdul Khaliq Showman a, Hayder A Fawzi b
a
Department of Obstetrics, Gynecology and Infertility, College of Medicine, Al Mustansiriyah
University, Baghdad, Iraq. * [email protected]
b
Department of Pharmacy, Al-Esraa university college, Baghdad, Iraq.

Abstract
To assess the predictive value of different clinical, laboratory, and ultrasound
parameters in Letrozole when used as an ovulation induction in anovulatory
infertile PCOS women. The current study was done in the secondary-referral
infertility clinic in AL-Yarmouk teaching hospital, and Al-Mustansiriyah
medical college. Sixty-seven anovulatory infertile women with the polycystic
ovarian syndrome. Letrozole was given orally on day 2 or 3 of the menstrual
cycle for five days and repeated for three consecutive cycles. The primary
outcome measures were to evaluate the response rate in the form of successful
ovulation and clinical pregnancy. The ovulation rate was (64.2%), with
clomiphene naïve vs. previous clomiphene use; it was 87.5%, 51.2%
respectively, while pregnancy rate was (32.8%), 41.6% with clomiphene naïve
vs. 27.9% with previous clomiphene use. Clinical (age, BMI, Waist
circumference, cycle length and days between cycle, infertility period and type,
previous reproductive outcome, androgen symptom and m-FG score),
laboratory (E2, FSH, LH, testosterone, FAI, FBS, fasting insulin, HOMA – IR,
and AMH) and ultrasound (mean ovarian volume, mean AFC and antral
follicular diameter) parameters were founded to affect ovulation and pregnancy
in different extent. After putting all variables in a scoring system, it was found
that if the patients had > 26 points for the score, it's more likely that the woman
becomes pregnant. A predictive pregnancy score was developed from basic
clinical, laboratory, and ultrasound parameters. It may help the clinician to
individualized ovulation induction protocol in PCOS women; however, external
validation of this system is recommended in a more extensive prospective study.

Keywords: Letrozole, Polycystic ovarian syndrome (PCOS), infertility.

Alizzi, et al. http://doi.org/10.28969/IJEIR.v9.i1.r6 89

 [5] [6] [7]
1. Introduction al , Kamath, et al , Quintero, et al ),
Polycystic ovarian syndrome (PCOS) is a and because of its short history in this
very common heterogeneous ovarian respect, concepts like letrozole resistance
endocrinopathy affecting 6–8% of women, and failure were not addressed. As the first
leading to several health complications, line of treatment, letrozole can be used
including menstrual dysfunction, because it is ovulation, pregnancy, and live
hirsutism, acne, obesity, and metabolic birth rate are higher as well as lower
syndrome, and it is the most frequent cause multiple pregnancy rates, although the
of anovulatory infertility accounting for reluctance to adopt such new therapy is
>80% of all cases (Ding, et al [1], Norman, frequent in clinical practice (McCartney,
[8] [9] [10]
et al [2], The Thessaloniki ESHRE/ASRM- et al , Legro, et al , Casper, RF ,
[11]
Sponsored PCOS Consensus Workshop Alizzi, FJ ). Taken in considerations
Group [3]). Induction of ovulation safely is that the presence/ absence of all PCOS
essential for women with WHO group II- features whether clinical or biochemical
PCOS who wish to conceive. there are will help the clinicians to manage these
many medical options which can be used patients correctly and that the recognition
to treat ovulation disorders and infertility, of predictors of treatment response to OI is
including estrogen receptor modulators essential for the success of a therapy
(such as clomiphene and tamoxifen), because their identification could lead
aromatase inhibitors (such as letrozole), clinicians to the best-individualized
insulin-sensitizing drugs (such as treatment to improve the efficacy of the
metformin), and direct hormonal therapy, while optimizing its safety profile
[12]
stimulation of the ovaries (gonadotropins) (Rausch, et al ). Several types of
(Wang, et al [4]
). The majority of the research had studied predictors of patient
studies done on letrozole were on patients responses to ovulation induction with
with clomiphene resistance (Mitwally, et clomiphene citrate in anovulatory infertile

Alizzi, et al. http://doi.org/10.28969/IJEIR.v9.i1.r6 90

 [13]
women due to PCOS (Ellakwa, et al , fit infertile PCOS women aged 18-35
[14] [15]
Mahran, et al , Imani, et al ). In years and their Body mass index (BMI) of
comparison, few researchers studied 19-35 kg/m² were enrolled in the study.
letrozole predictors to response Diagnosis of PCOS depending on
[16]
(Palihawadana, et al ). The aim of modified Rotterdam criteria, which
current study is to investigate whether include two out of three criteria, abnormal
clinical, biochemical, endocrine, and ovulatory function (amenorrhea or
Sonographic characteristics during initial oligomenorrhea), clinical and or
assessment of anovulatory infertile women biochemical hyperandrogenism, and
due to PCOS may predict the ovarian ultrasound features of polycystic ovaries
response to letrozole treatment whether it (Rotterdam ESHRE/ASRM-Sponsored
[17]
is used as a first-line or as a second line PCOS Consensus Workshop Group ).
after clomiphene resistant or failure and to All participants had hysterosal-
develop a possible applicable scoring pingography that proved patent fallopian
system to help clinician for OI tubes, and their partners had normal semen
individualization. analysis parameters according to the
2. Materials and Methods modified criteria of the World Health
i. Materials Organization. Clinical, laboratory
A prospective cohort study conducted in (biochemical &endocrine), and
the infertility unit at Al-Yarmouk teaching Sonographic screening was carried out
hospital. The institutional review board of before initiation of letrozole treatment.
the hospital approved the protocol; all
a. Clinical Screening
participants were given written informed
Full history and examination questioner
consent and enrollment began from May
formula fulfilled and include: age,
2017 and was completed in July 2018.
menstrual cycle history (regular,
Eligible participants who were medically

Alizzi, et al. http://doi.org/10.28969/IJEIR.v9.i1.r6 91

oligomenorrhea, and amenorrhoea) and hormone-binding globulin (SHBG) (nmol/
days between cycles, period and type of L)) and HOMA – IR was measured using
infertility (primary or secondary with the formula= Fasting Glucose (mg/dl) x
previous reproductive outcome), previous Fasting Insulin (μU/ml) / 405). Less than
medication use (as hormonal 1.0 means insulin-sensitive which is
contraceptives, insulin-sensitizing agents optimal, above 1.9 indicates early insulin
and other OI- pre clomiphene citrate use resistance and above 2.9 indicates
for the last three months) and surgery. The significant insulin resistance. All patients
BMI was calculated, androgen symptoms had normal serum prolactin, thyroid-
were assessed, and hirsutism was scored stimulating hormone (TSH) and 17-OH
according to the modified Ferriman- progesterone. a participant with elevated
Gallwey score (m-FG score) (Hatch, et al prolactin level, congenital adrenal
[18]
). hyperplasia, thyroid problem, Cushing’s
syndrome, and androgen-secreting tumors
b. Laboratory (biochemical &
endocrine) screening were excluded. Although there is no
accepted national or international clinical
Baseline laboratory testing was performed
standard for determining the accuracy of a
after an overnight fasting on 2nd –3rd day
testosterone assay, hyperandrogenemia
of menstrual cycle using Immulite 2000
was diagnosed either clinically
XPi immunoassay system /Siemens to test
(acne/hirsutism) or biochemically
hormones: FSH, LH, plasma levels of
(testosterone ≥2.5 nmol/l or free androgen
estradiol (E2), S. Testosterone, sex-
index [FAI] ≥5) (Rosner, et al [19]).
hormone-binding globulin (SHBG), S.
fasting insulin, FBS, S. Prolactin, TSH and
AMH. Free androgen index (FAI)
measured using the formula: FAI= total
testosterone (nmol/ L)) x 100 /sex

Alizzi, et al. http://doi.org/10.28969/IJEIR.v9.i1.r6 92

 c. Transvaginal Ultrasound ii. Methods
Screening letrozole (Femara, Novartis
nd
All the participants are seen on their 2 or Pharmaceuticals) 5mg were given orally
rd
3 spontaneous menstrual cycle day or from the 2nd-3rd-day cycle and for five
after progesterone-induced withdrawal continuous days followed by TVU
bleeding where baseline transvaginal tracking of follicular growth and
ultrasound TVU were done using 7.5 MHz endometrial thickness from 9 days of the
vaginal probes (R7-Samsung-Korea). menstrual cycle and repeated every
Polycystic ovaries are present when one or alternate day till dominance was
both ovaries demonstrate 12 or more confirmed or excluded 2 weeks after the
follicles measuring 2–9 mm in diameter or end of treatment. when one follicle size
the ovarian volume exceeds 10 cm3. Only ≥17 mm, Recombinant human chorionic
one ovary meeting either of these criteria gonadotropin (hCG) alpha (ovidrel, 250
is sufficient to establish the presence of mcg, Merck Serono Pharmaceutical) was
[20]
polycystic ovaries (Balen, et al ). given subcutaneously but should be
Ovarian volume; Antral Follicular Count prevented if patients have >3 follicles (15–
(AFC), Antral Follicular Size (AFS) and 18) mm. Patients were advised to have
endometrial thickness assessed and intercourse 24 to 36 hours after the hCG
measured. Ovarian volume measured injection. Midluteal serum progesterone
according to the formula: 0.5 × lengths × was assayed one week after hCG injection,
width × thickness of the ovary (Orsini, et levels 7.9 ng/ml (˃25 nmol/L) indicate
[21]
al ). AFS categorized estrogen two ovulation. The level of serum hCG was
groups: group one (2-5 mm antral follicles measured 14 days after the hCG
size) and group two (6-9 mm antral administration in the absence of
follicles size). menstruation for the detection of
biochemical pregnancy and clinical

Alizzi, et al. http://doi.org/10.28969/IJEIR.v9.i1.r6 93

pregnancy then after confirmed by TVU. follow it we use Anderson darling test, for
If ovulation occurred, the regime repeated analyzing the differences in means
unaltered for three consecutive cycles between two groups we use two samples t-
unless pregnancy occurred. Once test, for calculating the odd ratio (OR) and
pregnancy occurred, letrozole respond is their 95% confidence intervals we use
achieved, failure to achieve pregnancy Binary logistic regression analysis.
termed letrozole failure and failure to Receiver operator curve used to see the
achieve ovulation termed letrozole validity of different parameters in
resistant. Primary outcome measures were separating active cases from control
to evaluate the response rate in the form of (negative cases) and area under the curve
successful ovulation and clinical i.e. AUC and its p-value prescribe this
pregnancy and secondary outcome validity (if AUC ≥ 0.9 mean excellent test,
measures were to assess clinical, 0.8 – 0.89 means good test, 0.7 – 0.79 fair
biochemical, endocrine and ultrasound test otherwise unacceptable).
parameters as a predictor to response to
3. Results
letrozole.
At the end of the study period, a total of
iii. Statistical Analysis 67 infertile PCOS women were enrolled.
SPSS 22.0.0 (Chicago, IL), MedCalc Table (1) shows the demographic and
Statistical Software version 14.8.1 clinical characteristics of the eligible
(MedCalc Software bvba, Ostend, women that were included in the study.
Belgium; 2014), a software package used The mean age of them was (27.9 ± 5.5
to make the statistical analysis, if the p- years), mean BMI was (27.6 ± 3.5 Kg/m2)
value less than 0.05 considered being with mean WC (86.2 ± 16.4 cm), around
significant. For assessment of the normal two-thirds of the participants had primary
distribution and if continuous variables infertility, hirsutism was seen in 83.4% of

Alizzi, et al. http://doi.org/10.28969/IJEIR.v9.i1.r6 94

the women and the m-FG score was 8-15. Table (1): Demographic and clinical characteristics
Forty-three women (64.2%) had the Variables Value
Number 67
previous history of clomiphene citrate use Age (years), mean ± SD 27.9 ± 5.5
BMI (kg/m2), mean ± SD 27.6 ± 3.5
for three cycles before the enrollment in
Waist circumference
86.2 ± 16.4
this study and ended with either failure or (cm) , mean ± SD
Cycle length: N (%)
resistant. Table 2 shows the related Regular 10 (14.9%)
Oligomenorrhea 52 (77.6%)
laboratory and ultrasonic characteristics of Amenorrhea 5 (7.5%)
Days between cycles: N (%)
the study group. Regarding ultrasound, the 23-34 8 (11.9%)
35 – 45 23 (34.3%)
mean ovarian volume and mean AFC for 46 – 55 22 (32.8%)
56 – 65 10 (14.9%)
both ovaries was 10.8 ± 0.5 cm³ and 14.4 >65 4 (6.0%)
± 2.4 cm3 respectively. The antral follicles Infertility period
22.1 ± 9.0
(months), mean ± SD
size was 2-5 mm in around 30% of Type of infertility: N (%)
Primary 44 (65.7%)
participants, while 70% had a size of 6-9 Secondary 23 (34.3%)
Previous reproductive outcome:
mm. Table 3 and figure 1 display the Parity: N (%)
Null 44 (65.7%)
primary outcome measures of the study Single 18 (26.9%)
Multiple 5 (7.5%)
(ovulation and pregnancy rate) where the Abortion: N (%)
ovulation rate in the whole participants Null 51 (76.1%)
Single 14 (20.9%)
was 64.2% and the pregnancy rate was Twice 2 (3.0%)
Androgen symptoms: N (%)
32.8%. The ovulation rate was higher in Hirsutism 56 (83.6%)
Acne 9 (13.4%)
the clomiphene naïve group than those Seborrhea 9 (13.4%)
m-MF score, n (%); N (%)
who used clomiphene (87.5% vs. 51.2%); <8 11(16.4%)
8-15 56 (83.6%)
also there was a difference in the rate of Previous use of clomiphene citrate: N (%)
pregnancy between the two groups (41.6% Clomiphene naïve 24 (35.8%)
Used with Failure 18 (26.9%)
vs 27.9%). In Table (4) we can see that Used with Resistance 25 (37.3%)

most of the clinical, ultrasound and different between the women who
hormonal variables are significantly achieved success ovulation vs. those who

Alizzi, et al. http://doi.org/10.28969/IJEIR.v9.i1.r6 95

failed ovulation, except the age, insulin testosterone, free androgen index, insulin,
level, and HOMA-IR where statistically HOMA-IR, AMH, dominant follicle size,
there was no significant difference. The and mean AFC, while the increases in the
significant difference in most of the following variables predict increase in the
variables where existed also between the odds for having successful ovulation: E2,
women who achieved pregnancy vs. the SHBG, endometrial thickness and antral
failure, as it is showed in Table (5). The follicular diameter, as illustrated in table 7.
univariate analysis (logistic regression Patients with secondary infertility
test) showed that the increases in the (compared to primary) had a 2.8-fold
following variables predict decrease in the increase odd of achieving ovulation and it
odds for having successful ovulation: days was significant, and a 2.5-fold increase the
between cycle, infertility period, BMI, odds of achieving pregnancy but it was not
waist circumference, mean ovarian statistically significant. Previous use of
volume, modified FG score, androgen clomiphene with failure in pregnancy had
symptoms, LH, testosterone, free 4.2 folds increased odd of achieving
androgen index, FBS, AMH, and mean successful pregnancy compared to those
AFC, while the increases in the following used clomiphene and had with resistance
variables predict increase in the odds for outcome (it was statistically significant),
having successful ovulation: E2, SHBG, also those that did not use previously
endometrial thickness and antral follicular clomiphene had 3.75 folds increased odd
diameter as illustrated in table 7. The of achieving successful pregnancy (but it
increases in the following variables predict was not statistically significant). Patients
decrease in the odds for having successful with previous pregnancy had 3.75 folds
pregnancy: days between cycle, infertility increase odd of achieving ovulation and 8
period, BMI, waist circumference, mean folds increased odd of achieving
ovarian volume, modified FG score, LH, pregnancy (compared to those who

Alizzi, et al. http://doi.org/10.28969/IJEIR.v9.i1.r6 96

 Table 2: Ultrasound and laboratory characteristics of Table 4: The difference in characteristic variables
the study group between the ovulation successes vs. failure
Variables Value No p-
Variables Ovulation
Ultrasound predictors ovulation value
Mean ovarian volume(cm3) ± SD 10.8 ± 0.5 Number 24 43 -
Mean AFC ± SD 14.4 ± 2.4 Age 29.1 ± 5.7 27.3 ± 5.3 0.186
Antral follicular diameter N (%) BMI 30.8 ± 3.9 25.9 ± 1.6 <0.001
2 – 5 mm 20 (29.9%) WC 100.1 ± 18.3 78.4 ± 8.1 <0.001
6 – 9 mm 47 (70.1%)
Infertility
Laboratory predictors 30.3 ± 9.1 17.6 ± 4.8 <0.001
Period
E2 (pmol/l), mean ± SD 124.8 ± 27.0
Mean
FSH (IU/L), mean ± SD 5.1 ± 0.9
Ovarian 11.4 ± 0.4 10.4 ± 0.2 <0.001
LH(IU/L), mean ± SD 9.7 ± 3.6
Volume
SHBG(nmol/l), mean ± SD 39.9 ± 7.7
Testosterone(nmol/l), mean ± SD 1.7 ± 0.2 Mean AFC 17.3 ± 0.8 12.7 ± 0.9 <0.001
Free androgen index, mean ± SD 4.4 ± 1.3 ET 7.1 ± 0.1 8.5 ± 0.6 <0.001
FBS(mg/dl), mean ± SD 93.0 ± 7.9 m-FG score 10.1 ± 1.6 6.3 ± 3.5 <0.001
Insulin(miu/ml), mean ± SD 5.04 ± 1.8 E2 96.0 ± 11.7 140.9 ± 18.2 <0.001
HOMA – IR, mean ± SD 1.16 ± 0.43 FSH 5.4 ± 1.1 5.0 ± 0.8 0.115
AMH(ng/ml), mean ± SD 6.6 ± 0.8 LH 13.7 ± 2.4 7.5 ± 1.6 <0.001
Table 3: Response to letrozole in the study group SHBG 35.0 ± 6.3 42.6 ± 7.2 <0.001
Variables Value Testosterone 1.9 ± 0.2 1.6 ± 0.1 <0.001
Cycle number: N (%) Free
2 16 (23.9%) Androgenic 5.5 ± 1.3 3.8 ± 0.8 <0.001
3 51 (76.1%) Index
Total cycles number 185 FBS 99.3 ± 4.2 89.5 ± 7.4 <0.001
Mean diameter of the Insulin 4.8 ± 1.6 5.2 ± 2.0 0.340
dominant follicle. (mm) ± 20.1 ± 1.4 HOMA-IR 1.2 ± 0.4 1.2 ± 0.4 0.859
SD AMH 7.3 ± 0.6 6.2 ± 0.5 <0.001
The number of dominant follicles: N (%)
1 41 (95.3%)
2 2 (4.7%)
Endothelial 22 Responding
8.0 ± 0.8
thickness(mm)±SD 21 Failure
Progesterone(nmol/l) 27 ± 2.3
Ovulation, n (%) 43 (64.2%) 24 Resistance
Pregnancy, n (%) 22 (32.8%) 35.82 32.84
Ovulation in clomiphene Figure 1: Overall
21/24 (87.5%)
naive, n/total (%) response rate
Pregnancy in clomiphene
10/24 (41.6%) (Responding=pregnanc 31.34
naïve, n/total (%)
y, failure=ovulation
Ovulation in previous use of without pregnancy,
22/43 (51.2%)
clomiphene, n/total (%) resistant=failure of
Pregnancy in previous use ovulation).
12/43(27.9%)
of clomiphene, n/total (%)

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 Table (5): The difference in characteristic Table (6): ROC (receiver operator characteristic)
variables between pregnancy success vs. failure analysis of various predictors for Ovulation

No p- Cut
Variables Pregnancy Variables AUC SN SP
pregnancy value point
Number 45 22 - Clinical predictors
Age 28.8 ± 6.0 26.2 ± 3.7 0.031 Days between ≤ 35 –
0.905 70% 96%
Infertility cycles 45
25.2 ± 9.1 15.9 ± 4.5 <0.001
Period Infertility
BMI 28.4 ± 3.9 26.0 ± 1.8 0.001 period 0.875 ≤30 100% 58%
90.9 ± (months)
WC 76.5 ± 8.9 <0.001 BMI 0.837 ≤28.9 100% 75%
17.2
Mean Waist
0.826 ≤92 100% 75%
Ovarian 10.9 ± 0.5 10.4 ± 0.1 <0.001 circumference
Volume Modified FG
0.904 ≤8 84% 83%
Dominant score
20.9 ± 1.6 19.4 ± 0.9 0.001
Follicle Size Ultrasound predictors
ET 7.5 ± 0.6 8.9 ± 0.3 <0.001 Mean ovarian
0.997 ≤10.7 93% 100%
m-FG score 8.3 ± 3.3 6.3 ± 3.5 0.026 volume
109.4 ± Mean AFC 1.0 ≤15 99% 99%
E2 156.5 ± 6.6 <0.001
18.2 Endometrial
0.995 >7.2 98% 100%
FSH 5.2 ± 1.0 5.0 ± 0.8 0.603 thickness
LH 10.9 ± 3.7 7.3 ± 1.8 <0.001 Laboratory predictors
SHBG 36.9 ± 6.0 45.9 ± 7.5 <0.001 E2 0.976 >110 98% 92%
Testosterone 1.8 ± 0.2 1.6 ± 0.1 <0.001 LH 0.970 ≤13.85 100% 83%
Free SHBG 0.810 >35 79% 67%
Androgenic 4.9 ± 1.2 3.5 ± 0.8 <0.001 Testosterone 0.912 ≤1.7 93% 83%
Index Free
FBS 93.8 ± 8.5 91.4 ± 6.6 0.254 androgen 0.869 ≤4.57 81% 83%
Insulin 5.4 ± 2.0 4.2 ± 1.0 0.002 index
HOMA-IR 1.3 ± 0.5 1.0 ± 0.3 0.002 FBS 0.887 ≤92 72% 100%
AMH 6.7 ± 0.8 6.2 ± 0.5 0.001 AMH 0.948 ≤6.8 91% 92%
Mean AFC 15.1 ± 2.5 12.8 ± 0.8 <0.001 ROC: receiver operator characteristic, AUC: area
under the curve. SN: sensitivity, SP: specificity

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 Table (7): Regression analysis (logistic regression) of possible predictors of ovulation and pregnancy

Ovulation Pregnancy
Variables
OR (95% CI) p-value OR (95% CI) p-value
Clinical predictors
Age 0.939 (0.856 – 1.030) 0.185 0.907 (0.817 – 1.008) 0.070
Days between cycles 0.067 (0.016 – 0.276) <0.001 0.377 (0.195 – 0.727) 0.004
Infertility period 0.775 (0.683 – 0.879) <0.001 0.788 (0.686 – 0.905) 0.001
BMI 0.567 (0.432 – 0.744) <0.001 0.786 (0.647 – 0.954) 0.015
Waist circumference 0.892 (0.845 – 0.942) <0.001 0.924 (0.878 – 0.972) 0.002
Androgen symptoms 0.192 (0.059 – 0.623) 0.006 0.547 (0.155 – 1.930) 0.348
Modified FG score 0.108 (0.033 – 0.355) <0.001 0.850 (0.732 – 0.987) 0.033
Infertility (secondary) 2.812 (1.002 – 7.895) 0.049 2.449 (0.839 – 7.150) 0.101
Previous CC use
Not used 3.750 (0.980 – 14.355) 0.054
Failure Can’t be estimated 4.200 (1.018 – 17.322) 0.047
Resistance Reference
Previous reproductive outcome
Previous pregnancy 3.750 (1.019 – 13.795) 0.047 8.0 (2.237 – 28.605) 0.001
Abortion 2.062 (0.579 – 7.347) 0.264 0.229 (0.026 – 2.047) 0.187
No past pregnancy Reference Reference
Ultrasound predictors
1.9 x 10-14 (4.2 x 10-15 –
Mean AFC 0.001 0.549 (0.382 – 0.788) 0.001
4.3 x 10-8)
Antral follicular 1.7 x 1010 (8.1 x 109 – 1.4 x 109 (8.1 x 108 – 2.5
10 0.001 0.001
diameter 7.8 x 10 ) x 109)
Mean ovarian volume <0.001 <0.001 0.013 (0.001 – 0.177) 0.001
Laboratory predictors
E2 1.204 (1.088 – 1.331) <0.001 38.037 (11.291 – 48.231) 0.001
FSH 0.647 (0.374 – 1.119) 0.119 0.858 (0.486 – 1.514) 0.597
LH 0.425 (0.294 – 0.616) <0.001 0.637 (0.477 – 0.850) 0.002
SHBG 1.220 (1.087 – 1.369) 0.001 1.212 (1.096 – 1.341) <0.001
5 x 10-8 (1 x 10-11 – 2 x 2.2 x 10-4 (1.6 x 10-7 – 5.9
Testosterone <0.001 0.001
10-4) x 10-3)
Free androgen index 0.160 (0.062 – 0.413) <0.001 0.198 (0.085 – 0.464) <0.001
FBS 0.761 (0.666 – 0.870) <0.001 0.963 (0.902 – 1.027) 0.251
Insulin 1.158 (0.858 – 1.563) 0.338 0.528 (0.295 – 0.946) 0.032
HOMA – IR 0.899 (0.282 – 2.861) 0.857 0.062 (0.006 – 0.669) 0.022
AMH 0.014 (0.001 – 0.132) <0.001 0.333 (0.151 – 0.735) 0.006
OR: odds ratio, CI: confidence interval
Patients with no ovulation had no active follicle (so odd ratio for dominant follicle size can’t be calculated)

Alizzi, et al. http://doi.org/10.28969/IJEIR.v9.i1.r6 99

did not have previous pregnancy (it was LH, SHBG, free androgen index, and
significant), those with previous abortion dominant follicle size. Also, the following
had no statistical difference compared to markers had a fair ability to predict
those without previous pregnancy, pregnancy: days between cycles, waist
Patients with Antral follicular diameter 6- circumference, modified FG score,
9 mm significantly correlated with testosterone, insulin, HOMA-IR, AMH,
successful ovulation and pregnancy and mean AFC. As illustrated in table 8.
compared to those with 2-5 mm, as After putting all variables in a scoring
illustrated in table 7. The internal system we can see that the individual
validation of different variables was done points of the summary score were
using ROC-AUC, which revealed that the calculated based on their odd ratio
following markers had an excellent ability (different weighing according to the
to predict ovulation: days between cycles, magnitude of the OR), and for each subject
mean ovarian volume, modified FG score, we calculate their score based on the cut
E2, LH, testosterone, AMH, mean AFC, point calculated in the ROC analysis (of
and endometrial thickness. Also, the the above the threshold than we give the
following variables had a good ability: respective point; and add for each domain
infertility periods, BMI, waist to calculate the score), this summary score
circumference, SHBG, FBS, and free than analyzed using ROC to find the
androgen index, as clarified in Table 6. optimal cut point to predict pregnancy.
Regarding the predictors of pregnancy, the Summary score
following markers had excellent ability to
1. If days between cycles is ≤ 35 – 45
predict pregnancy: endometrial thickness
days, then give three points
and E2 levels, while the following markers
2. If infertility period ≤18 months than
had a good ability to predict pregnancy:
giving one point
infertility period, mean ovarian volume,

Alizzi, et al. http://doi.org/10.28969/IJEIR.v9.i1.r6 100

 3. If BMI ≤ 28.9 kg/m2 than give one 16. If it has a previous pregnancy
point without abortion than give four
points otherwise zero.
4. If waist circumference ≤92 cm than
give one point 17. If the previous use of clomiphene
leads to ovulation without pregnancy give
5. If m-FG score ≤ 8.0 than give one
four points, if the patients did not use
point
clomiphene previously gives two points,
6. If mean antral follicular count ≤13.0
else zero.
give two points
18. If the patient with antral follicular
7. If mean ovarian volume ≤ 10 give
diameter 6 – 9 mm give 5 points, else zero
five points
Finally, If the patients had > 26 points for
8. If E2 > 142 give four points
the score that is highly likely to become
9. If LH ≤ 7.0 gives one point pregnant (score range from 0 – 50), as
illustrated in Table 9 and Figure 2.
10. If SHBG >44 give one point

11. If total testosterone ≤ 1.6 give five 4. Discussion

points The primary outcome measure for
letrozole as an OI in the study shows that
12. If free androgenic index ≤ 4.21 give
the overall clinical response in the form of
four points
ovulation and pregnancy was 64.2% and
13. If fasting insulin ≤ 4.17 give two 32.8%, respectively, and these results were
points lower than those seen in other studies

14. If HOMA-IR < 0.99 give four (Alizzi FJ [11], Amer, et al [22], Palomba, et

points al [23]). The lower ovulation and pregnancy

rate seen could be due to the
15. If AMH ≤ 6.8 gives three points

Alizzi, et al. http://doi.org/10.28969/IJEIR.v9.i1.r6 101

 Table (8): ROC (receiver operator characteristic) Table (9): Assessment of the score as a predictor
analysis of the predictors for pregnancy of pregnancy

Cut Cut
Markers AUC SN SP AUC SN SP PPV NPV
point point
Clinical predictors 0.967 >26 100% 82% 73% 100%
Days between ≤ 35 AUC: area under the curve. SN: sensitivity, SP:
0.730 68% 64%
cycles – 45 specificity, PPV: positive predictive value.,
Infertility NPV: negative predictive value
0.837 ≤18 86% 69%
period
BMI 0.684 ≤28.9 100% 40%
Waist
0.747 ≤92 100% 40%
circumference
Modified FG
0.712 ≤8 82% 51%
score
Ultrasound predictors
Mean ovarian
0.802 ≤10.5 100% 69%
volume
Mean AFC 0.744 ≤13 91% 64%
Dominate
0.801 <19.9 64% 76%
follicle size
Endometrial
0.985 >8.3 100% 91%
thickness
Laboratory predictors
E2 1.0 ≥142 99% 99%
LH 0.809 ≤7 82% 80%
SHBG 0.831 >44 64% 91%
Testosterone 0.796 ≤1.6 73% 73%
Free Figure (2): ROC (receiver operator
androgen 0.844 ≤4.21 82% 76% characteristic) curve of the score to predict
index pregnancy
Insulin 0.724 ≤4.17 95% 49%
HOMA – IR 0.749 ≤0.99 95% 67%
AMH 0.732 <6.8 100% 58%
ROC: receiver operator characteristic, AUC:
area under the curve. SN: sensitivity, SP:
specificity

Alizzi, et al. http://doi.org/10.28969/IJEIR.v9.i1.r6 102

inclusion of 64.2% of the study population period, BMI, waist circumference,
who used clomiphene previously and modified FG score and androgen
encountered clomiphene failure (26.9%) symptoms, predict decrease having
and clomiphene resistant (37.3). (Morad successful ovulation and pregnancy.
[24]
and Farag ) showed that the pregnancy Ultrasonographic predictors to response in
rate was 20% in letrozole use after our study show that an increase in mean
clomiphene failure while ovulation and ovarian volume and AFC and a decrease in
pregnancy rate after clomiphene resistant antral follicular diameter (group one 2-5
was 44.24% and 23.89% respectively in mm) decrease in the odds of having
[25]
(Rahmani, et al ) study vs. 51.2% and successful ovulation and pregnancy.
27.9% respectively in our study; on the Laboratory predictors to response in the
[26]
other hand, (Mitwally and Casper ) study show that increase in LH,
study showed ovulation rate of 75% and testosterone, free androgen index, AMH
the pregnancy rate of 25%. In clinical predicts the decrease in the odds for having
practice searching for predictors to successful ovulation and pregnancy while
response to OI treatment in women with an increase in insulin and HOMA-IR
PCOS may help the clinicians to manage reduction in the odds for having successful
these patients appropriately. In the current pregnancy while an increase in both E2 and
study, we took different clinical, SHBG enhance both ovulation and
laboratory and ultrasonographic pregnancy. Our study goes with Mary E.
parameters to show its effect on clinical Rausch et al. Study who established
response in the form of improving samples to predict successful ovulation,
ovulation and increasing pregnancy rate. conception, pregnancy, and live birth in a
Regarding clinical predictors to response participant with PCOS have induction of
to letrozole, we found that increases in the ovulation, and they find that the factors
variables: days between cycle, infertility that were persistently significant in all

Alizzi, et al. http://doi.org/10.28969/IJEIR.v9.i1.r6 103

models were baseline BMI, FAI, that assess the response to different
proinsulin level, and duration of infertility ovulation protocols, there were many trials
(Rausch, et al [12]). On the contrary, the age to have a scoring system or module to put
in our study was not a predictor for the different clinical, laboratory, and
response, and this may be due to the ultrasound features to predict the response.
exclusion of women above 35 years of age. Statistical analysis with logistic regression
Also, in our research, the existence of test, followed by internal validation using
hirsutism was found to have an adverse ROC-AUC analysis to clarify the cutoff
prognosis for both ovulation and point of different variables, this
[12]
pregnancy, while in (Rausch, et al ) assessment has brought a scoring system
Study the presence of hirsutism was noted from 0-50 points, and those who above 26
to have an adverse prognosis on have a high probability of success of
conception, pregnancy, and live birth, but ovulation and pregnancy. It is agreed that
no ovulation. Obesity also shows negative such scoring systems or postulated
impacts on stimulation in ovulation modules need further validation by
induction cycles in both studies. Some external validation through a prospective
studies found that resistance to clomiphene study that should include a large sample
is more common in women with insulin with similar inclusion criteria (Fauser, et al
[28]
resistant, obese, and hyperandrogenism ). Limitations of the current study may
[27]
(Imani, et al ) whether these agents possibly be due to a small sample size and
predispose to letrozole resistance, too, is using pregnancy as the primary outcome
still not well known. Our study showed measure rather than LB, although it is of
insulin resistant, obesity, and significant value in clinical practice and
hyperandrogenism does negatively affect used as a primary outcome measure in
pregnancy rate in women using letrozole many studies. Another possible limitation
as an OI. As it is seen in most of the studies of the study is the exclusion of women

Alizzi, et al. http://doi.org/10.28969/IJEIR.v9.i1.r6 104

above 35 years of age since, after this age, Author Contribution
the chance of pregnancy diminished; also, All authors certify that they have
women with BMI above 35 were excluded participated sufficiently in work to take
public responsibility for the content,
to encourage the women to decrease
including participation in the concept,
weight before starting OI as recommended design, analysis, writing, or revision of the
by WHO. manuscript.
Conflict of Interest
5. Conclusions
The authors report no conflict of interest.
A predictive pregnancy score was
Ethical Clearance
developed from basic clinical, laboratory,
The study was approved by the
and ultrasound parameters. It may help the
Ethical Approval Committee.
clinician to individualized ovulation
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 Resistant Patients with Polycystic Biography
Ovary Syndrome: A Prospective
Prof. Dr. Fadia J Alizzi
Interventional Study. Obstetrics and
Gynecology International. Hindawi ORCID
Limited; 2012;2012:1–4. Doi: She is currently working as a
http://dx.doi.org/10.1155/2012/75850 senior lecturer at Al-
8 [Hindawi] Mustansiryaha Medical
[26] Mitwally MF, Casper RF. Use of College, Department of
aromatase inhibitor for ovulation Obstetrics, Gynecology &
Infertility and as a Consultant
induction in patients with an
OBG at Al-Yarmouk Teaching Hospital, Baghdad,
inadequate response to clomiphene Iraq. She is a member in the scientific Committee of
citrate. Fertility and Sterility. Elsevier Arab Board OBG in Iraq and member in the scientific
BV; 2001,75(2):305–309. Doi: committee of Iraqi board in Reproductive Medicine
https://doi.org/10.1016/s0015- and Infertility. She is participating in the clinical
0282(00)01705-2 [PubMed] [Elsevier] training of postgraduate fellows who are allocated to
Al-Yarmouk hospital as a part of fulfillment for the
[27] Imani B, Eijkemans MJ., te Velde degree of Arab Board& Iraqi Board and supervising
ER, Habbema JDF, Fauser BCJ. A their thesis as well supervising many master and PhD
nomogram to predict the probability of student in the field of Obstetrics, Gynaecology and
live birth after clomiphene citrate Infertility and she has many research published in
induction of ovulation in these fields.
normogonadotropic oligoamenorrheic Dr. Hind Abdul Khaliq
infertility. Fertility and Sterility. Showman
Elsevier BV; 2002;77(1):91–7. Doi:
She is a graduate from the
https://doi.org/10.1016/S0015- University of Baghdad College of
0282(01)02929-6 [PubMed] [Elsevier] Medicine, in 1996. She occupied
[28] Fauser BCJM, Diedrich K, Devroey the position of senior house
P. Predictors of ovarian response: officer during her permanency in
progress towards individualized obstetrics and gynecology from
1998 until the start of her residency program in 2001,
treatment in ovulation induction and
when she remained a resident until she graduated as a
ovarian stimulation. Human specialist in obstetrics and gynecology in 2006. From
Reproduction Update. Oxford 2006 onwards, she became a senior lecturer at the Al-
University Press (OUP); Mustansiryah University, College of Medicine,
2007;14(1):1–14. Doi: Department of obstetrics and gynecology. She is also
https://doi.org/10.1093/humupd/dmm a practicing consultant obstetrician and gynecologist
at Al-Yarmouk hospital since 2006.
034 [PubMed] [OxFord]

Alizzi, et al. http://doi.org/10.28969/IJEIR.v9.i1.r6 109

 Dr. Hayder A Fawzi
Graduated from college of
pharmacy, University of Baghdad
in 2011, after that start working in
2012 at Baghdad Teaching
Hospital – Medical City Campus
as pharmacist, in 2013 start
working as clinical pharmacist in
Baghdad Teaching Hospital, in
2015 start residency as residence clinical pharmacist,
in 2019 completed his residency and attain his degree
of “Iraqi Board for Medical Specializations”.
Currently work as Lecturer in AL-Esraa University
college – department of pharmacy.

How to cite:
Alizzi FJ, Showman HAK, Fawzi HA. Predictors
for Response to Letrozole as an Ovulation Induction
in Anovulatory Infertile Polycystic Ovarian
Syndrome Women; Iraqi Journal of Embryos and
Infertility Researches (IJEIR), (2019); 9(1): 89-110.
Doi: http://doi.org/10.28969/IJEIR.v9.i1.r6

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