Polycystic ovary syndrome (PCOS) is a disorder
that requires comprehensive long term evaluation
and management which affects several body systems.
It is observed in 5-7% of women in reproductive
age and causes endocrinopathy in women (
It is a syndrome of hyperandrogenic chronic anovulation.
Etiology of this syndrome is unknown
and long term effects is poorly documented. Many
symptoms characterize it and there is no certain
clinical treatment, yet (
First, Poly cystic ovaries: when there are 12 or more follicles in each ovary, with diameter of 2-9 mm and/or ovarian volume >10 ml. Neither distribution of the follicles nor stromal density is included in this category. One polycystic ovary is sufficient for diagnosis. Second, oligo-/anovulation: it is clinically diagnosed as oligo-/amenorrhea which is menstrual cycles less than 10 times each year or longer duration than 35 days.
Third, Hyperandrogenism: in clinical or biochemical terms (
Approximately, %50 of women with PCOS are overweight or obese. Different studies have reported endocrine and metabolic differences between lean and obese PCOS women (
We investigated the effect of Flutamid and Clomiphen citrate in PCOS patients; Futamid is an oral nonsteroidal anti androgen drug along with clomiphen citrate stimulate the release of hormones needed for ovulation.
In this prospective study, ninety six PCOS patients under age of 37 referred to Royan Research Center with history of infertility, irregular menstruation or hirsutism between 2005 to 2006. The subjects were studied by sampling method in treatment and control groups using Flutamide and Clomiphene Citrate or Placebo and Clomiphene Citrate, respectively. The study was approved by Institutional Review Board of Royan Institute Research Center and Royan Ethics Committee. The patients signed consent forms before enrolling in the research and treating with Clomiphene Citrate. Discontent of attending, being allergic to the drugs (Flutamide or Clomiphene Citrate), hyperprolactinemia, thyroid dysfunction, age over 37, and body mass index (BMI) > 30 were the causes to exclude of the study. Estradiol, testosterone, prolactin, thyroid tests, hepatic tests, and luteinizing hormone (LH)-follicle stimulating hormone (FSH) were taken from all patients on day three of their menstruations followed by signing the consent forms. Placebo samples (Daroupakhsh Pharmaceutical Company, Iran) were prepared and confidentially coded by an individual from out of the research team. Then, the patients were randomly divided into two groups, A (53 subjects) and B (43 subjects). Triple-blind method was applied for the treatment group. Group A daily received Flutamide tab 250 mg (Pharmascience, Canada), started on day 3 till end of their menstrual cycles. Group B received placebo, started on day 3 till end of their menstrual cycles. This continued for their next 2 cycles. Also, Clomiphene Citrate 50 mg (Parsminoo- Iran) was given to both groups, started on day 3 to day 7 of their menstrual cycles and it was carried on for two consecutive cycles. The dosage of Clomiphene Citrate was gradually increased, the patients daily received Clomiphene Citrate 100 mg from day 3 to day 7 in the first cycle; while, the daily dose from day 3 to day 7 changed to 150 mg for the second cycle. However, group A and B used fixed dose of Flutamide and Placebo.All the patients were monitored by a sonography.
When follicle size reached ≥18 mm, human chorionic gonadotrophine (hCG) was injected up to 10/000 units followed by measuring progesterone on days 19 and 21 of their menstruations to determine ovulation. These two therapeutic cycles were continued with patient agreement. Ovulation in two groups was studied at the end of the second cycles. Furthermore, considerable effects of Flutamide on ovulation were measured through different statistical tests between both groups. Hirsutism was also assessed in both group using Ferriman-Gallway score (
Ninety and six PCOS patients, age of 18 - 37, were participated in this research. Mean age was 26.96 years old. The mean of age, BMI, duration of infertility, LH, basic estradiol, thyroid stimulating hormone (TSH), T4, T3, prolactin, testosterone, progesterone on days 19 and 21 of their menstruations, size of follicles and volume of ovaries are separately shown in the
According to the data shown on tables
Characteristics of patients
|Variable||Group A Mean ± SE||Group B Mean ± SE||P value|
|27.19± 0.53||26.65± 0.65||NS|
|27.51± 4.29||27.27± 4.26||NS|
|6.5 ± 0.5||5.78± 0.43||NS|
|Regular||17 (32.1%)||15 (34.9%)||NS|
|Irregular||36 (67.9%)||28 (65.1%)||NS|
|7.78± 0.78||7.88± 0.9||NS|
|77.9± 10.2||102.87 ± 24.1||NS|
|19.75± 5.9||18.53± 6.98||NS|
|20.35± 4.99||22.85± 5.44||NS|
|1.97± 0.19||1.79± 0.22||NS|
|196.9± 34.1||189.1± 57.97||NS|
|2.79± 2.1||2.95± 2.1||NS|
|1.9 ± 0.61||2.85± 0.86||NS|
|2.69± 0.86||3.55± 1.17||NS|
|9 ± 0.53||8.4 ± 0.47||NS|
|8.1 ± 0.54||7.66± 0.52||NS|
NS; Non significant.
Outcome cycle 1, 2
|Group A Mean ± standard error (SE)||Group B Mean ± standard error (SE)||P value|
|15.45± 0.54||14.83 ± 0.36||NS|
|14.6 ± 0.62||14.44 ± 0.49||NS|
|18.96± 0.63||19.33 ± 0.57||NS|
|19.41± 0.7||18.37 ± 0.57||NS|
NS; Non significant.
Outcome with regard to physical characteristics cycle 1
|Group A Ovulation||Group B Ovulation||P value|
|33(63.5%)||19(36.5%)||26 (60.5%)||17 (39.5%)|
|12(80.0%)||3 (20.0%)||10 (55.6%)||8 (44.4%)||NS|
|21(56.8%)||16(43.2%)||16 (64.0%)||9 (36.0%)||NS|
|19||(73.1%)||7 (26.9%)||13 (59.1%)||9 (40.9%)||NS|
NS; Non significant.
Outcome with regard to physical characteristics cycle 2
|Variables||Group A Ovulation||Group B Ovulation||P value|
|10(55.6%)||8 (44.4%)||12 (70.6%)||5 (29.4%)||NS|
|9 (42.9%)||12(57.1%)||7 (53.8%)||6 (46.2%)||NS|
|19(48.7%)||20(51.3%)||19 (63.3%)||11 (36.7%)||NS|
|12(57.1%)||9 (42.9%)||8 (66.7%)||4 (39.3%)||NS|
|6 (35.3%)||11 (64.7%)||11 (61.1%)||7 (38.9%)|
NS; Non significant.
In obese and normal weight patients with PCOS, Flutamide has been studied as an anti-androgenic drug to improve ovulation. The results of some studies have shown that low dose of Flutamide/ Metformin/ Oral Contraceptive Pill (OCP) in young PCOS patients with normal weight improves the resistance to insulin and dyslipidemia which are long-term side effects of PCOS administration. Therefore, this compound is an appropriate treatment for young and thin PCOS women (
Effective role of Clomiphene Citrate has been long known. Thus, our intentional is to study the effect of Flutamide along with clomiphene on ovulation induction.
Despite other studies indicate Flutamide (
In this study, Flutamide is not effective in regulating cycles and improvement of ovulation in two therapeutic cycles in A and B groups. However, Flutamide is effective element in other studies (
Our study showed that Flutamide has no effect on improving ovulation in patients with the history of PCOS undergoing induction.