Effect of finasteride on ovulation induction in nonresponder (hyperandrogenic) polycystic ovary syndrome (PCOS) women Massimo Tartagni, M.D.,a Ettore Cicinelli, M.D.,b Giovanni De Pergola, M.D.,c Cristina Lavopa, M.D.,a Edoardo Di Naro, M.D.,a Maria Antonietta De Salvia, Ph.D.,d and Giuseppe Loverro, M.D.a a Clinica Ostetrica e Ginecologica III; b Clinica Ostetrica e Ginecologica IV; c Sezione di Medicina Interna, Endocrinologia e Malattie Metaboliche, Dipartimento dell’Emergenza e Trapianti d’Organo; and d Sezione di Farmacologia, Dipartimento di Farmacologia e Fisiologia Umana, University of Bari, Bari, Italy Objective: To evaluate whether the addition of finasteride (a 5h-reductase inhibitor) to conventional protocol of ovarian stimulation with gonadotropin can improve ovarian follicular growth in polycystic ovary syndrome (PCOS) women who did not respond to previous stimulation with gonadotropin alone. Design: Double-blind randomized study. Setting: Outpatient in an academic research environment. Patient(s): Thirty-six PCOS patients in whom the previous multifollicular stimulation protocols with gonadotropin failed. Intervention(s): The patients were randomly assigned to two treatment groups: group 1 underwent ovarian stimulation with recombinant FSH (rFSH) plus finasteride, and group 2 received rFSH alone. When the dominant follicle reached a mean diameter of 18 mm, hCG was administered and finasteride withdrawn. Main Outcome Measure(s): Ovulation rate in women with PCOS. Result(s): Follicular growth and ovulation occurred in eight patients in group 1, whereas no cases were detected in group 2. Conclusion(s): This study confirms that hyperandrogenism interferes with follicular growth and suggests that administration of finasteride during ovarian stimulation with rFSH improves ovulation rate in selected hyperandrogenic anovulatory women. (Fertil SterilÒ 2010;94:247–9. Ó2010 by American Society for Reproductive Medicine.) Key Words: Finasteride, gonadotropin stimulation, hyperandrogenism, ovulation induction, PCOS Ovulation induction in women affected by polycystic ovary syndrome (PCOS) is a challenging issue owing to the high incidence of extreme results: hyperstimulation syndrome on the one hand and poor response to conventional stimulation protocol on the other (1). PCOS is the major cause of hyperandrogenism and anovulatory infertility in young women (2). The hormonal profile of PCOS is characterized by increased plasma levels of LH or LH/FSH ratio, high androgen concentration [testosterone (T) and/or androstendione (A)], and lower concentrations of SHBG with consequent higher levels of free T (3). A high activity of 5h-reductase (5hR), the enzyme that converts T into its active form of dihydrotestosterone (DHT), is also demonstrated in PCOS women (4). Androgens interfere with the follicular growth process; they are considered to play a key role in inhibiting follicular maturation and determining atresia, a hormonally controlled apoptotic process. Interestingly, in PCOS the majority of ovarian follicles undergo atresia (5). Received April 21, 2008; revised January 13, 2009; accepted January 28, 2009; published online April 1, 2009. M.T. has nothing to disclose. E.C. has nothing to disclose. G.D.P. has nothing to disclose. C.L. has nothing to disclose. E.D.N. has nothing to disclose. M.A.D.S. has nothing to disclose. G.L. has nothing to disclose. Reprint requests: Massimo Tartagni, M.D., Clinica Ostetrica e Ginecolog di Bari, Policlinico, Piazza Giulio Cesare, 70124 Bari, ica III, Universita Italy (E-mail: m.tartagni@gynecology3.uniba.it). 0015-0282/$36.00 doi:10.1016/j.fertnstert.2009.01.150 Finasteride, 17-b-N-tert-butylcarbamoyl-4-aza-5-a-androstan-1-en-3-one, a synthetic 4-azasteroid, is a new antiandrogen drug that competitively inhibits 5hR type 2 (the enzyme responsible for metabolizing T into biologically active DHT). Our intention in the present study was to evaluate the hypothesis that the hyperandrogenic milieu of PCOS women could contribute to explaining the results in ovulation induction compared with non-PCOS women. We thus added finasteride to the conventional protocol of ovarian stimulation to evaluate whether the use of a 5hR inhibitor could counteract the atresic process and improve ovarian follicular growth in PCOS women who were shown to be resistant to conventional stimulation with gonadotropin. MATERIALS AND METHODS Sixty PCOS volunteers, age range 21–37 years, who failed to ovulate with gonadotropin in two previous attempts, were enrolled in the study. The study was approved by the Institutional Review Board of the hospital. All patients gave their informed consent after being briefed on drug characteristics and the potential risks of treatment on male fetus; all women were, therefore, invited to use nonhormonal types of contraception. All patients had high serum levels of T, A, DHT, serum LH/FSH ratio R2, enlarged polycystic ovaries at ultrasounds and a hirsutism score (HS) R20 according to Fertility and Sterilityâ Vol. 94, No. 1, June 2010 Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc. 247 TABLE 1 Clinical characteristics of the two groups of patients. Age (y) BMI (kg/m2) Hirsutism score Group 1 Group 2 28.5  4.06 25.05  4.84 23.6  1.90 29.3  3.69 25.5  1.52 23.0  2.08 Note: Values are mean  SD. BMI ¼ body mass index. Tartagni. Effect of finasteride on PCOS. Fertil Steril 2010. modified Ferriman-Gallwey scoring system (6); all had menstrual irregularities (oligomenorrhea) and chronic anovulation. Body mass index (BMI) (weight/height2, expressed as kg/m2) was recorded at the beginning of the study. The patients had normal glucose tolerance and normal markers of thyroid, liver, and kidney function. None of them had been on oral contraceptives or undergone other hormonal treatment in the 6 months before starting the study, nor were any on them on a particular diet. Patients were randomly assigned to two treatment groups on the basis of a computergenerated randomization sequence. Thirty-four patients (group 1) underwent ovarian stimulation with recombinant FSH (rFSH) (follitropin â; Puregon; NV Organon, Oss, The Netherlands) starting at a daily dose of 100 IU on the third day of a spontaneous or progesterone-induced cycle. In addition they received finasteride 5 mg (Finastid; Neopharmed, Rome, Italy) from day 1 of the cycle. Twenty-six patients (group 2) received ovarian stimulation with gonadotropin alone, at the same starting dosage as in group 1. Transvaginal ultrasounds were performed before starting ovarian stimulation and every other day from day 5 of treatment until the dominant follicle reached a mean diameter of 14 mm. Ultrasound evaluation was then performed daily. If no growing follicle was detected on day 5, the daily dosage of FSH was increased to 150 IU. Human chorionic gonadotropin (10,000 IU; Gonasi; Amsa, Rome, Italy) was administered when the follicle reached a mean diameter of at least 18 mm; at that moment finasteride administration was stopped. In the event of no follicular growth after 3 weeks of stimulation, all medication was withdrawn. Serum levels of the hormones LH, FSH, T, A, DHT, and E2 were measured on day 1 of the menstrual cycle by using recombinant immunoassay. Blood samples for T, DHT, A, and E2 were repeated on the day of hCG administration. Commercial kits were used for these analyses (Diagnostic System Laboratories, Webster. TX), the intra-assay and interassay coefficients of variation were <10%. Ovulation occurrence was assessed by ultrasound on day 7 after hCG administration and with P4 level evaluation (ovulation value >7 ng/mL). Statistical Analysis Values are expressed as mean  SD. Student unpaired test and j2 test were used for comparison between treatment groups. P values of < .05 were considered to be statistically significant. RESULTS The two groups of women were homogeneous regarding mean age, BMI, and HS (Table 1). Table 2 shows, hormone levels on day 1 and on the day of hCG administration. Mean serum levels of FSH, LH, T, DHT, A, and E2 on cycle day 1 were similar in the two groups. At the second hormone evaluation, DHT serum levels were significantly lower (P<.001) in the group treated with finasteride; notably, in group 1 E2 serum levels were higher (P<.001) compared with group 2. Ovulation occurred in 13 patients (38.2%) in group 1, whereas no ovulation was detected in group 2 (P<.001). DISCUSSION Finasteride has Food and Drug Administration approval for the treatment of benign prostatic hypertrophy and male hair loss. In recent years, several studies have demonstrated the TABLE 2 Serum hormonal profiles at cycle day 1 and at hCG administration day in the two groups of patients. Group 1 FSH, mIU/mL LH, mIU/mL T, ng/dL DHT ng/dL A, ng/mL E2, pg/mL Normal range follicular phase 3.2–12.2 1.4–15.3 14.0–76.0 11.6–42 0.6–3.0 11–165 Group 2 Cycle day 1 hCG administration day Cycle day 1 hCG administration day 6.3  1.60 14.26  3.93 77.0  3.06 41.9  3.00 3.65  0.56 55.8  5.80 / / 77.4  2.6 38,9  2.6a 3.79  0.75 155.08  6.01b 6.69  1.40 14.90  3.6 77.7  1.46 41.9  2.35 3.80  0.23 55.9  7.15 / / 77.9  1.98 42.0  2.54a 3.85  0.16 58.46  8.60b P value < .001a < .001b Note: Values are mean  SD. DHT ¼ dihydroxytestosterone. a DHT at the end of ovarian stimulation: P< .001 (Student t test) vs. group 2. b E2 at the end of ovarian stimulation: P< .001 (Student t test) vs. group 2. Tartagni. Effect of finasteride on PCOS. Fertil Steril 2010. 248 Tartagni et al. Effect of finasteride on PCOS Vol. 94, No. 1, June 2010 efficacy of finasteride in the treatment of female hyperandrogenism (5, 7–10). Until now, only one study has investigated the effects of finasteride on the ovulatory function in normal women, demonstrating no change of gonadotropin secretion or follicular development (11). To the best of our knowledge, the present study is the first to evaluate the effects of finasteride combined with gonadotropin to induce ovulation in hyperandrogenic women resistant to conventional ovulation induction protocols. The results clearly show that in these women the combination of finasteride with gonadotropin improved results of ovarian stimulation. Indeed, ovulation was obtained in 40% of the women who received combined treatment. An increase in in the T/DHT ratio was also observed in all of the women from group 1. The results of this study make it possible for us to speculate that finasteride may have a positive influence on hormonal environment of follicles so that they can escape atretic destiny. Follicular growth is affected by competition between aromatase and 5h-reductase (5hR) activities and in particular by the competition between their products, E2 and DHT, respectively (5, 12). Follicular growth is the result of a complex interplay between endocrine, autocrine and paracrine factors (5). Gonadotropins, local ovarian growth factors (insulin-like growth factor 1, epidermal growth factor 1, transforming growth factor h, basic fibroblastic growth factor), cytokine (interleukin-1â), and estrogens activate intracellular pathways involved in follicle development (5). In contrast, high intrafollicular DHT levels block these intracellular pathways (5). The results make it worth pointing out that androgen receptor blockers and testosterone antibodies can inhibit the occurrence of follicle atresia (13, 14). Appropriate exposure of antral follicles to FSH is the most critical stimulus for the follicles to escape atresia and reach the preovulatory follicle stage (8, 15). Binding of FSH to their membrane receptors in granulosa cells results in the activation of adenylate cyclase and subsequently in the activation of a protein kinase A signaling pathway (16). This mechanism seems to be hampered in hyperandrogenic women. Consistent with the hypothesis that androgens may play a detrimental role in follicle development, it has been reported that two out of three women affected by homozygous 5hR type II deficiency delivered nonidentical twins (17). This favors the hypothesis that high E2/DHT ratios in these women might promote supernormal follicular growth. The use of finasteride in ovulation induction protocols may raise some concerns due to the known teratogenety of this compound. In the present study, finasteride was administered for an average of 14 days in each cycle. Its terminal elimination half-life has been reported to be 4.7–7.1 hours, but a single dose suppresses serum DHT levels for up 4 days (18). 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