Finasteride* in the treatment of hirsutism: new therapeutic perspectives

Size: px

Start display at page:

Download "Finasteride* in the treatment of hirsutism: new therapeutic perspectives"

Derick Hunt
5 years ago
Views:

1 FERTILITY AND STERILI'fY Copyright 1996 American Society for Reproductive Medicine Printed on acid-free paper in U. S. A. Finasteride* in the treatment of hirsutism: new therapeutic perspectives Achille Tolino, Ph.D., M.D.t:J: Alfredo Petrone, M.D.t Francesca Sarnacchiaro, M.D. Domenico Cirillo, M.D. t Salvatore Ronsini, M.D. t Gaetano Lombardi, Ph.D., M.D. Carmine Nappi, Ph.D., M.D.t Department of Obstetrics and Gynecology and Department of Molecular and Clinical Endocrinology and Oncology, School of Medicine "Federico II" University, Naples, Italy Objective: To determine of the clinical and hormonal effects of finasteride (Proscar; Merck, Sharp, and Dohme, Rahway, NJ) in the treatment of idiopathic hirsutism and hirsutism in patients with polycystic ovary syndrome (PCOS). Design: Controlled clinical study. Setting: Istitute of Obstetrics and Gynecology, University of Naples "Federico II." Patients: Ten women affected by idiopathic hirsutism and 15 women with PCOS. Interventions: Finasteride was administered orally at a daily dose of 5 mg for a period of 6 months. Main Outcome Measures: Rating of hirsutism with the Ferriman-Gallwey method; serum androgen assays. Results: Finasteride produced a reduction in the average hirsutism scores (>50% in all patients), whereas no change was observed in serum T, androstenedione, and DHEAS levels. A significant reduction was measured in serum dihydrotestosterone and 3a,17.B-androstenediol glucuronide levels. Conclusions: This study demonstrates that symptomatic hirsutism has to be considered as a skin disease associated with the increased activity of the 5a-reductase. It also indicates that the selective 5a-reductase inhibitor, finasteride, is very effective and well tolerated in the treatment of both idiopathic hirsutism and of hirsutism in patients with PCOS. Fertil Steril 1996;66:61-5 Key Words: Idiopathic hirsutism, polycystic ovary syndrome, 5a-reductase, hyperandrogenism, finasteride Hirsutism is considered as resulting from increased androgen production by the ovaries or by the adrenal glands. Nevertheless, idiopathic hirsutism, one of the most common types, may be defined as hirsutism in women with normal ovulatory cycles and without any other evident endocrine disorder (1). Several authors maintain that the term "idio- Received April 3, 1995; revised and accepted February 8, * Proscar; Merck, Sharp, and Dohme, Rahway, New Jersey. t Department of Obstetrics and Gynecology, University ofnapies "Federico II." * Reprint requests: Achille Tolino, Ph.D., M.D., Via Monteleone 12,80134 Naples, Italy (FAX: ). Department of Molecular and Clinical Endocrinology and Oncology, University of Naples "Federico II." pathic" is indeed a misnomer and that hirsutism in this condition primarily is due to the increased 5areductase activity in peripheral tissues (especially in the skin) (2, 3). This pathogenetic hypothesis is suggested also for the polycystic ovary syndrome (peos) (4, 5). No ideal therapy exists for hirsutism and several pharmacologic approaches (6) have been evaluated so far, such as: oral cyproterone acetate (7), oral contraceptive agents, spironolactone (8), cimetidine (9), flutamide (10). Presently, however, none of these drugs is sufficiently effective and without side effects. Finasteride, a member of a new class of drugs called azasteroids, inhibits 5a-reductase activity and blocks the conversion oft into dihydrotestosterone (DHT) in peripheral tissues (11). In this study we have evaluated the effects of this drug in Tolino et al. Hirsutism and its treatment with finasteride 61

2 the treatment of hirsutism both with and without hyperandrogenism. Subjects MATERIALS AND METHODS Thirty-nine women with hirsutism gave their written informed consent before participating in this study. Ten women between 19 and 26 years of age, affected by idiopathic hirsutism had regular menses; normal body weight; normal serum LH, FSH, and androgen levels; and no abnormality of the adrenal and ovarian hormonal levels. Fifteen hirsute women between 20 and 30 years of age were affected by PCOS and had a positive anamnesis of menstrual irregularities (oligomenorrhea), chronic anovulation, enlargement of ovaries on pelvic examination, obesity, and elevated serum androgen levels, with clinical symptoms of hyperandrogenism. The serum LH:FSH ratio was >3. The 25 described patients were administered finasteride (Proscar; Merck, Sharp, and Dohme, Rahway, NJ) at daily dose of 5 mg for a period of 6 months. Another group of 14 hirsute women (7 with idiopathic hirsutism and 7 with PCOS) between 20 and 26 years of age were administered placebo and formed the control group. We randomly assigned the hirsute women to the placebo or finasteride group but only patients were blinded; placebo administration was continued for only 3 months because of the patients' spontaneous dropping out of the study, as they were disappointed with their clinical results. The difference in the clinical and laboratory findings between the group treated with finasteride and the one treated with placebo was already statistically significant after 3 months of therapy. Our patients were administered no other drug during the study. The study was approved by the local Ethical Committee. Clinical Evaluation In all patients, the body hairs score was evaluated according to the method of Ferriman and Gallwey and rated on a scale from 0 to 4 over nine body regions (12). Pretreatment scores were determined twice, with a 3-month interval between the two determinations. Both examinations were performed by the same one physician so as to avoid any significant variability due to different examiners. Subsequent evaluations were performed by the same physician after 3 and 6 months of treatment. Furthermore, self-evaluation of the clinical outcome of the treatment was obtained from all patients. Biochemical Tests and Assays All patients underwent a hormonal assessment before the treatment with finasteride or placebo and 62 Totino et al. Hirsutism and its treatment with finasteride 30 :i!ai en z ~20 ::I - ~ 15 o & ::I en ~ 5' II: :E BASELINE 3 MONTHS 6 MONTHS Figure 1 Average Ferriman-Gallwey scores in patients with idiopathic hirsutism and PC OS treated with finasteride. Evaluations were performed before starting the treatment (baseline) and subsequently after 3 and 6 months of treatment. I11III, idiopathic hirsutism; Iff.!, PCOS. *P < 0.05 versus basal. 3 and 6 months later. Mter suitable blood sampling, hydrolysis, and chromatosalpingographical separation, as described previously (13-20), the serum levels of T, DHT, androstenedione (A), DHEAS, and 3a,17,B-androstenediol glucuronide (3a-dioIG) were measured by means of specific RIAs sold in commercial kits (Diagnostic Systems Laboratories, Webster, TX for 3a-dioIG; Radim, Pomezia, Italy for T, A, DHT, and DHEAS). Statistical Analysis The results were analyzed by means of Student's t-test for paired and nonpaired data. P < 0.05 was considered significant. Clinical and hormonal data were expressed as mean ± SEM and mean ± SD. Clinical Effects RESULTS In women with idiopathic hirsutism, the average hirsutism score, measured according to the Ferriman-Gallwey method, was high before the treatment with finasteride (21.4 ± 1.9 [mean ± SEM]). It showed an already statistically significant reduction after 3 months oftreatment with finasteride (13.2 ± 2.1) (P < 0.05) and had decreased further after 6 months of treatment (8.5 ± 1.9) (P < 0.05). Similarly, in women with PCOS, the average hirsutism score, which was high before the treatment with finasteride (24.6 ± 1.8), had decreased after 3 months (12.3 ± 1.4) and even more after 6 months of treatment (8.9 ± 2.4) (P < 0.05). There was no change in the placebo group (29.5 ± 3.1 versus 25.7 ± 2.8) (Fig. 1); not only the total mean hair score of the placebo Fertility and Sterility

Table 1 Serum Hormonal Profiles in 10 Women With Idiopathic Hirsutism Before and During Treatment With Finasteride* Basal 3 Months 6 Months Normal range T (ng/ml) 0.47 ± 0.1 0.5 ± 0.08 0.45 ± 0.07 <0.

3 Table 1 Serum Hormonal Profiles in 10 Women With Idiopathic Hirsutism Before and During Treatment With Finasteride* Basal 3 Months 6 Months Normal range T (ng/ml) 0.47 ± ± ± 0.07 <0.6 A (ll-gll) 1.5 ± ± ± to 1.8 DHEAS (ng/ml) 3570 ± ± ± to 4,300 DHT (ng/ml) ± ± 0.03t ± 0.06t to a-diolG (ng/ml) 5.94 ± ± 0.55t 1.1 ± O.4t 0.3 to 2.1 * Values are means ± SD. Conversion factors to SI units are as follows: T, 3.467; A, 3.492; DHEAS, ; DHT, 3.448; and 3a-dioIG, t p < group but also the mean hair score of the single group (idiopathic hirsutism and peos) were compared individually with treatment group with statistically significant results (P < 0.05). Patients' ratings of their own clinical outcome at the end of the study was as follows: very good: 2 patients, good: 7 patients, medium: 1 patient, poor: o patients, in the group of women with idiopathic hirsutism who had been administered finasteride; very good: 4 patients, good: 8 patients, medium: 2 patients, poor: 1 patient, in the group of women with peos who had been administered finasteride; and very good: 0 patients, good: 0 patients, medium: 0 patients; poor: 14 patients, in the control group which had been administered placebo. Hormonal Effects In the group with idiopathic hirsutism, the circulating androgen levels were in the normal range before and after the treatment with finasteride, except for the serum levels ofdht and 3a-diolG which were high before the treatment and showed a reduction after 3 months (0.498 ± 0.06 versus ± 0.03 ng/ml for DHT [conversion factor to SI unit, 3.448] and 5.94 ± 1.2 versus 1.50 ± 0.55 nglml for 3adiolG [conversion factor to SI unit, 2.136], P < 0.05) and after 6 months (0.118 ± 0.06 ng/ml for DHT and 1.1 ± 0.4 nglml for 3a-dioIG; P < 0.05) oftreatment with finasteride (Table 1). In the group with peos, the circulating androgen levels were high but not markedly so. After the treatment with finasteride, no significant change was observed in serum T, A, or DHEAS levels, whereas serum DHT and 3adiolG levels were significantly lower after 3 months of treatment (0.536 ± versus ± nglml for DHT and 5.5 ± 0.98 versus 1.9 ± 0.1 ngl ml for 3a-dioIG; P < 0.05). This unchanged result persisted after 6 months of treatment with finasteride (0.09 ± 0.04 nglml for DHT and 1.45 ± 0.2 ngl ml for 3a-dioIG; P < 0.05) (Table 2). There was no significant hormonal change in the average DHT and 3a-diolG levels in the control group before and after 3 months of placebo administration (0.623 ± 0.06 versus ± ng/ml for DHT and 6.2 ± 1.0 versus 5.97 ± 0.89 ng/ml for 3a-dioIG). Furthermore, comparing DHT and 3a-diolG levels at the end of the third month, the effect of the finasteride treatment was significantly different from that of placebo (P < 0.05). Side Effects Finasteride was well tolerated by all patients. They complained of no side effects during the 6 months oftreatment and no patient discontinued the therapy. DISCUSSION Hirsutism may be an endocrinopathy resulting from increased androgen production, but often can be developed also in the presence of normal androgen production and may be absent in some cases of hyper androgen ism (1). Several authors suggested that hirsutism in general is a disorder due to increased 5a-reductase activity in peripheral tissues, particularly in the pilosebaceous apparatus (21). In idiopathic hirsutism, Kutten et al. (3) first demonstrated that 5a-reductase is increased primitively in those hirsute patients in whom ovarian and adrenal androgen levels are normal. In this condition, DHT and its metabolite, 3a-dioIG, are the only serum and urinary markers for increased 5a-reductase activity (13, 19,20) in peripheral tissues. Moreover, in other studies, it has been demonstrated that also in patients with peos there is elevated 5a-reductase activity in the skin, independently of the circulating levels of ovarian and adrenal androgens (3). On the basis of this finding, we believe that hirsutism in a large number of cases has to be regarded as a skin disease. Ovarian and adrenal implications could be important but not the only cause for hirsutism in the peos (4). On the basis of this pathogenetic hypothesis for hirsutism both in idiopathic hirsutism and in peos, the treatment with drugs inhibiting 5a-reductase activity appears appropriate (11, 22, 23). Recently, two isoenzymes of 5a-reductase have Tolino et ai. Hirsutism and its treatment with finasteride 63

Table 2 Serum Hormonal Profiles in 15 Women with PCOS Before and During Treatment With Finasteride* Basal 3 Months 6 Months Normal range T (ng/ml) A (j.

4 Table 2 Serum Hormonal Profiles in 15 Women with PCOS Before and During Treatment With Finasteride* Basal 3 Months 6 Months Normal range T (ng/ml) A (j.lgll) DHEAS (ng/ml) DHT (ng/ml) 3a-diolG (ng/ml) 0.7 ::±: ::±: ::±: ::±: ::±: ::±: ::±: ::±: ::±: 0.029t 1.9 ::±: O.lt 0.72 ::±: ::±: ::±: ::±: 0.04t 1.45 ::±: 0.2t < to to 4, to to 2.1 * Values are means::±: SD. Conversion factors to SI units are as follows: T, 3.467; A, 3.492; DHEAS, ; DHT, 3.448; and 3a-dioIG, t p < been identified in human tissues: type 1 was identified in scalp skin and type 2 in the prostate (24, 25). In our study, the administration of finasteride, a 4- azasteroid potent inhibitor of human 5a-reductase activity of type 2, to 25 women (10 with idiopathic hirsutism and 15 with PCaS) proved very effective. The treatment, which was administered for 6 months, produced an improvement of hirsutism in all patients, as shown by their Ferriman-Gallwey scores. As a consequence of the action of finasteride, the hormonal tests in all patients showed a modification only in DHT and a 3a-diolG, whereas all other hormones (T, A, DHEAS) did not show any modification in both the group with idiopathic hirsutism and the one with pcas. The results of this study confirm the hypothesis reported in the literature on the pathogenesis ofhirsutism. They also indicate a new and more rational therapeutic approach to hirsutism, as they proved that treatment with finasteride (5 mg/d) significantly decreased hirsutism scores and serum DHT and 3a-diolG levels, which did not happen with the administration of placebo (P < 0.05). Considering that the drugs today used for the treatment ofhirsutism (cyproterone acetate, oral contraceptive agents, spironolactone, cimetidine) are still far from being ideal (7-10), because of their limited therapeutic effectiveness and of their side effects during long-term treatments, finasteride appears to be so much more useful. So, according to our experience with hirsute patients, this effective and well-tolerated drug can be used alone for the treatment of idiopathic hirsutism and either alone or in association with other, before-mentioned, conventional drugs for the treatment of pcas. Therefore, further studies will be useful to evaluate the effectiveness and tolerability of finasteride in long-term treatments of hyperandrogenic states. REFERENCES 1. Sciarra F, Toscano V. Sindromi iperandrogeniche. In: Benagiano G, Negri M, editors. Endocrinologia della riproduzione umana. Torino: Unione-Tipografico-Editrice-Torinese 1993: Tolino et al. Hirsutism and its treatment with finasteride 2. Serafini P, Lobo RA. Increased 5a-reductase activity in idiopathic hirsutism. Fertil Steril 1985;43: Kutten F, Mowszowicz I, Schaison G, Mauvais-Jarvis P. Androgen production and skin metabolism in hirsutism. J Endocrinol 1977; 75: Stewart PM, Shackleton CHL, Beastall GH, Edwards CRW. 5a-reductase activity in polycystic ovary syndrome. Lancet 1990;335: Lobo RA, Goebelsmann U, Horton R. Evidence for the importance of peripheral tissue events in the development ofhirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab 1983;57: Boisselle A, Tremblay RR. New therapeutic approach to the hirsute patient. Fertil Steril 1979;32: Underhill R, Dewhurst CJ. Further clinical experience in the treatment of hirsutism with cyproterone acetate. Br J Obstet Gynaecol 1979;86: Chapman MG, Dowsett M, Dewhurst CJ, Jeffcoate SL. Spironolactone in combination with an oral contraceptive: an alternative treatment for hirsutism. Br J Obstet Gynaecol 1985; 92: Vigersky RA, Mehlman I, Glass AR, Smith CEo Treatment of hirsute women with cimetidine. N Engl J Med 1980;303: Marugo M, Bernasconi D, Meozzi M, Cuva A, Fazzuoli L. Efficacy of flutamide in the treatment of hirsute women. J Endocrinol Invest 1991; 14: Dallob AL, Sadick NS, Unger W, Lipert S, Geissler LA, Gregoire SL, et al. The effect offinasteride, a 5a-reductase inhibitor, on scalp skin testosterone and dihydrotestosterone concentrations in patients with male pattern baldness. J Clin Endocrinol Metab 1994; 79: Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961;21: Morimoto I, Edmiston A, Hawks D, Horton R. Studies on the origin of androstanediol and androstanediol glucuronide in young and elderly men. J Clin Endocrinol Metab 1981;52: Horton R, Endres D, Galmarini M. Ideal conditions for hydrolysis of androstanedioi3a,17,6-diol glucuronide in plasma. J Clin Endocrinol Metab 1984;59: Thorneycroft IH, Ribeiro WO, Stone S, Tillson SA. Radioimmunoassay of androstenedione. Steroids 1973;21: Ito T, Horton R. DHT in human peripheral plasma. J Clin Endocrinol Metab 1970;31: Barberia J, Pages L, Horton R. Measurement of androstanediol in plasma in a radioimmunoassay using celite column chromatography. Fertil Steril 1976;27: Kinouchi T, Pages L, Horton R. A specific RIA for testosterone in peripheral plasma. J Lab Clin Med 1973;82: Paulson RJ, Serafini PC, Catalino JA, Lobo RA. Measurements of 3a,17,6-glucuronide in serum and urine and the cor- Fertility and Sterility

5 relation with skin 5a-reductase activity. Fertil Steril 1986; 46: Kirschner MA, Samojlik E, Szmal E. Clinical usefulness of plasma androstanediol glucuronide measurements in women with idiopathic hirsutism. J Clin Endocrinol Metab 1987; 65: Toscano V. Hirsutism: pilosebaceous unit dysregulation role of peripheral and glandular factors. J Endocrinol Invest 1991; 14: Stoner E. The clinical development of a 5a-reductase inhibitor, finasteride. J Steroid Biochem Mol BioI 1990;37: Gormley GJ, Stoner E, Rittmaster RS, Gregg H, Thompson DL, Lasseter KC, et al. Effects offinasteride (MK-906), a 50' reductase inhibitor, on circulating androgens in male volunteers. J Clin Endocrinol Metab 1990; 70: Thigpen AE, Silver RI, Guileyardo JM, Casey ML, McConnell JD, Russel DW. Tissue distribution and ontogeny of steroid 5a-reductase isoenzyme expression. J Clin Invest 1993;92: Jenkins EP, Andersson S, Imperato-McGinley J, Wilson JD, Russell DW. Genetic and pharmacological evidence for more than one human steroid 5a-reductase. J Clin Invest 1992;89: Tolino et al. Hirsutism and its treatment with finasteride 65

* Supported by grants from the Consiglio Nazionale delle Ricerche (INY ) and the Italian Ministry of Higher Education and Scientific Research.

* Supported by grants from the Consiglio Nazionale delle Ricerche (INY ) and the Italian Ministry of Higher Education and Scientific Research. r FERTILITY AND STERILITY Copyright,( 1996 American Society for Reproductive Medicine Printed on acid-free paper in U. S. A. Outcome of long-term treatment with the Sa-reductase inhibitor finasteride in