Polycystic ovarian disease is a disorder of chronic hyperandrogenic anovulation that affects 5–8% of women of reproductive age. Insulin resistance is the hallmark of polycystic ovarian disease and plays an important role in its pathogenesis by contributing to both androgen overproduction and metabolic disturbances 1. This disorder manifests as obesity, hirsutism, acne, menstrual disturbances, male pattern baldness, recurrent abortions, infertility, anovulation, and psychological and psychosexual morbidity 2. However, little is known about polycystic ovary syndrome (PCOS) in lean women.
The current European Society of Human Reproduction and Endocrinology (ESHRE)/American Society of Reproductive Medicine (ASRM) recommendation for ultrasonographic (US) evaluation of polycystic ovaries states that the transvaginal US scans should be performed during the early follicular phase (days 3–5) or 3–5 days following abnormally induced bleed in women with chronic anovulation. This recommended time of US corresponds to a time during the natural menstrual cycle in which the follicle population is markedly increasing 3. Doppler analysis of the uterine and intraovarian arteries may provide additional information about the etiopathogenesis of PCOS and partly explain the clinical implications of the condition 4. The aim of the present study was to investigate the status of PCOS in lean women and the degree of their response to ovulation induction.
Participants and methods
The present study was carried out on 150 women attending the Outpatient Gynecology Clinic at Kasr El Aini Hospital from January 2012 to May 2013. The study was approved by the Department of Obstetrics and Gynecology Ethical Committee, and all participants gave consent to the study after counseling.
Women were included if proved to have polycystic ovarian disease according to the Rotterdam criteria as having two of three characteristics: oligo-ovulation/anovulation (menstrual cycles <21 or >35 days), clinical and/or biochemical evidence of hyperandrogenism (modified Ferriman–Gallwey score>6), and/or polycystic ovaries on US (≥12 follicles measuring 2–9 mm in diameter or an ovarian volume>10 cm3). We excluded those with history of ovarian drilling or those with other factor of infertility such as uterine anomalies, tubal factor, or male factor of infertility. We also excluded those with other endocrine disorders – for example, Cushing disease, hyperprolactinemia, hyperthyroidism, and congenital adrenal hyperplasia.
Patients were divided into two groups: lean patients with polycystic disease with BMI less than 25 kg/m2 (100 patients) and the control group (individuals not diagnosed as PCOS; 50 patients). For all women, complete history taking and examination were performed including BMI. BMI was calculated as: weight (kg)/height (m2). We considered lean women if BMI was 19.0–24.9 kg/m2. Serum samples were collected from each patient and examined for total testosterone, free testosterone, and sex hormone binding globulin.
Two-dimensional US examination was carried out as a part of the overall clinical assessment of the patients using Accuvix VQ (Medison, Seoul, South Korea) US machine with transvaginal probe (5–7.5 MHz). Transvaginal US was performed to all patients assessing the following: number of follicles per ovary, largest follicle diameter, ovarian volume, and endometrial thickness.
Participants were then subjected to ovulation induction with clomiphene citrate 100 mg/day starting from day 2 of the cycle (spontaneous or hormonally induced bleeding) for 5 days. Thereafter, the US assessment (number of dominant follicles, largest follicle diameter, and endometrial thickness) was repeated after ovulation induction from day 11 to 14 and the response was monitored.
The previous data were analyzed by different statistical methods comparing different characteristics between both groups. All parameters were given as mean±SD. The Newman–Keuls multiple comparison, Student’s t-test, and χ2-test were used when appropriate. A P value less than 0.05 was considered statistically significant. Data analysis was performed using the SPSS (version 9.0; SPSS Inc., Chicago, Illinois, USA).
More than half of lean PCOS patients (59%) had oligomenorrhea and 15% had amenorrhea, whereas 66% of them had hirsutism. Total testosterone was found to be 57.3 ng/dl, free testosterone 33.2 pmol/l, and sex hormone binding globulin (SHBG) 32.8 nmol/l. US on day 2 showed mean antral follicle count (AFC) 24 follicles, endometrial thickness 5.4 mm, and ovarian volume 9.7 ml. After stimulation, US on day 11–14 showed mean number of dominant follicles 3.4, largest follicles 19.3 mm, and endometrial thickness 10.1 mm. Doppler studies demonstrated resistance index (RI) of ovarian artery 0.59 and RI of uterine artery 0.91, whereas pulsatility index (PI) of ovarian artery was 2.51 and PI of uterine artery was 3.83.
In contrast, lean non-PCOS women had only one case with hirsutism, two cases had oligomenorrhea, and none had amenorrhea. Total testosterone was found to be 30.1 ng/dl, free testosterone 17.5 pmol/l, and SHBG 45.6 nmol/l. US on day 2 showed mean AFC 12 follicles, endometrial thickness 4.7 mm, and ovarian volume 9.1 ml. The mean number of dominant follicles was 1.2 on US day 11–14, largest follicles 17.1 mm, and endometrial thickness 10.2 mm, and Doppler studies demonstrated RI of ovarian artery 0.71 and RI of uterine artery 0.79, whereas PI of ovarian artery was 3.42 and PI of uterine artery was 2.52 (Tables 1 and 2).
Very few studies have been published evaluating the response of lean PCOS women to ovulation induction. The 1990 National Institutes of Health (NIH) conference proposed the diagnostic criteria of oligo-ovulation/anovulation and biochemical and/or clinical hyperandrogenism. In 2003, Rotterdam conference organized by the ESHRE/ASRM broadened the definition of PCOS by adding PCO morphology. The second criterion essential to diagnose PCOS according to the American endocrinology society is either anovulation or polycystic ovarian morphology. The principle features of PCOS are insulin resistance and hyperandrogenism 5. The role of obesity as a contributing factor in the development of PCOS is widely accepted 6, and particularly the abdominal phenotype (central obesity) may be responsible for IR and associated hyperinsulinemia in women with PCOS 7,8.
In the present study, we tried to evaluate the impact of BMI on response to ovulation induction in PCOS women. Obesity is usually a sign of PCOS and investigators used to advise weight loss for these women. The lean women with PCOS appear to have a form of insulin resistance that is intrinsic and perhaps unique to the syndrome and is poorly understood 9. They showed no difference in mean arterial blood pressure between lean PCOS patients and the control group, as mean arterial blood pressure in lean PCOS was 96.2, whereas in non-PCOS patients as in lean controls it was 94.9. Of the health risk manifestations, hypertension occurred in both groups (PCOS and non-PCOS) with a similar frequency (41 vs. 35.5%) 9.
In the present study, PCOS was closely linked to hyperandrogenism, as total testosterone in lean controls and lean PCOS was 30.1±3.2 and 57.3±5.4 ng/dl (P<0.01), respectively, and free testosterone in lean controls and lean PCOS was 17.5±2.9 and 33.2±3.5 pmol/l (P<0.01), respectively, whereas SHBG in lean controls and lean PCOS was 45.6±4.2 and 32.8±3.7 nmol/l (P<0.01), respectively.
US findings in the present study were interesting, as before starting induction with clomiphene citrate, the AFC in lean controls and lean PCOS, respectively, was 15.2±1.3 and 24±2.4 (P<0.05), whereas the largest follicle diameter in lean controls and lean PCOS was 7.4±3.5 and 6.1±1.2 mm (P>0.05), respectively; the endometrial thickness in lean controls and lean PCOS was 6.3±2.3 and 5.4±1.1 mm (P>0.05) and ovarian volume in lean controls and lean PCOS was 5.9±2.2 and 9.7±2.1 cm3 (P<0.05), respectively. This is in contrast to other investigators who found that the mean and median ovarian volumes were 12.5±8.1 and 10.1 cm in PCOS cases. The mean and median follicle number in the PCOS group was 9.8±2.8 and 10, respectively. In the control group, the mean and median ovarian volumes were 5.4±1.8 and 5.5 cm. The Mean and median follicle number of controls was 5±1.5 and 5, respectively 10.
On carrying out the Doppler US on ovarian and uterine artery, we revealed the following data in lean controls and lean PCOS patients, respectively: RI of ovarian artery was 0.71±0.3 and 0.59±0.1 (P<0.05), PI of ovarian artery was 3.42±0.8 and 2.51±1.1 (P<0.05), RI of uterine artery was 0.79±0.1 and 0.91±0.2 (P<0.05), and PI of uterine artery was 2.52±1.1 and 3.83±1.5 (P<0.05). This agrees with the study carried out by Dereli et al.11 on 43 lean controls and 43 lean PCOS, respectively: RI of ovarian artery was 0.92±0.08 and 0.76±0.38 (P<0.05), PI of ovarian artery was 3.24±1.53 and 1.73±0.87 (P<0.05), RI of uterine artery was 0.88±0.1 and 0.9±0.8 (P>0.05), and PI of uterine artery was 2.34±1.42 and 2.91±1.04 (P<0.05).
However, this disagrees with the results of the study carried out by Tugrul et al.12 who concluded that it is not beneficial to use color Doppler transvaginal US in the clinical diagnosis of patients with PCOS. They found out that the mean PI of ovarian artery in the PCOS group was 0.84±0.23, and the mean PI of ovarian artery in the control group was 0.88±0.14, whereas the mean PI of uterine artery in the PCOS group was 3.25±0.98, and the mean PI of uterine artery in the control group was 3.17±0.93 12. Although it was more common for the PCOS patients to be resistant to induction with Clomid, once ovulating they had a higher risk for multiple follicles growing.
In conclusion, nonobese PCOS seems to respond easily to ovulation induction with higher number of follicles than normo-ovulatory. Special considerations should be paid to decrease the dose of clomiphene citrate in these women to avoid the possibility of multiple pregnancy.
Conflicts of interest
There are no conflicts of interest.
1. Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al.. Androgen Excess Society. Positions statement: criteria for defining polycystic ovary syndrome
as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91:4237–4245.
2. Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al.. Task Force on the Phenotype of the Polycystic Ovary Syndrome
of The Androgen Excess and PCOS Society. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome
: the complete task force report. Fertil Steril 2009; 91:456–488.
3. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO.The prevalence and features of the polycystic ovary syndrome
in an unselected population. J Clin Endocrinol Metab 2004; 89:2745–2749.
4. Ehrmann DA.Polycystic ovary syndrome
. N Engl J Med 2005; 352:1223–1236.
5. Dasgupta S, Reddy BM.Present status of understanding on the genetic etiology of polycystic ovary syndrome
. J Postgrad Med 2008; 54:115–125.
6. Diamanti-Kandarakis E.Role of obesity and adiposity in polycystic ovary syndrome
. Int J Obes (Lond) 2007; 31Suppl 2S8–S13.
7. Chen X, Ni R, Mo Y, Li L, Yang D.Appropriate BMI levels for PCOS patients in Southern China. Hum Reprod 2010; 25:1295–1302.
8. Dudeja V, Misra A, Pandey RM, Devina G, Kumar G, Vikram NK.BMI does not accurately predict overweight in Asian Indians in northern India. Br J Nutr 2001; 86:105–112.
9. Majumdar A, Singh TA.Comparison of clinical features and health manifestations in lean vs. obese Indian women with polycystic ovarian syndrome. J Hum Reprod Sci 2009; 2:12–17.
10. Köşüş N, Köşüş A, Turhan NÖ, Kamalak Z.Do threshold values of ovarian volume and follicle number for diagnosing polycystic ovarian syndrome in Turkish women differ from western countries? Eur J Obstet Gynecol Reprod Biol 2011; 154:177–181.
11. Dereli D, Ozgen G, Buyukkececi F, Guney E, Yilmaz C.Platelet dysfunction in lean women with polycystic ovary syndrome
and association with insulin sensitivity. J Clin Endocrinol Metab 2003; 88:2263–2268.
12. Tugrul S, Oral O, Güçlü M, Kutlu T, Uslu H, Pekin O.Significance of Doppler
ultrasonography in the diagnosis of polycystic ovary syndrome
. Clin Exp Obstet Gynecol 2006; 33:154–158.
Keywords:© 2014 Lippincott Williams & Wilkins, Inc.
induction of ovulation; polycystic ovary syndrome; Doppler