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1 Gynecology-endocrinology FERTILITY AND STERILITY Copyright c 1994 The American Fertility Society Vol. 61, No.5, May 1994 Printed on acid-free paper in U. S. A. Treatment of moderate and severe hirsutism by gonadotropinreleasing hormone agonists in women with polycystic ovary syndrome and idiopathic hirsutism Leopoldo Falsetti, M.D.* Edda Pasinetti, M.D. Department of Gynecologic Endocrinology, University of Brescia, Brescia, Italy Objective: To compare the therapeutic effects of a GnRH-agonist (GnRH-a), leuprolide acetate (LA) depot, versus LA plus an oral contraceptive (OC) containing cyproterone acetate in the treatment of hirsutism. Design: Randomized study. Setting: Women addressed to the Department of Gynecological Endocrinology, University of Brescia, Brescia, Italy. Patients: Thirty-two patients suffering from moderate and severe hirsutism secondary to polycystic ovary syndrome (PCOS) or idiopathic causes were selected. Intervention: Leuprolide acetate was injected 1M every 28 days in all patients; 16 women, randomly allocated, received LA plus ~C. At the beginning and at the end of treatment hirsutism score and hair diameters were evaluated. Results: Both treatment arms resulted in a decrease of hirsutism score and hair diameter, both in idiopathic hirsutism (16% to 31 % versus 24% to 32%) and in hirsutism secondary to PCOS (23% to 33% versus 24% to 36%). Conclusions: Gonadotropin-releasing hormone agonist can improve moderate and severe hirsutism effectively. It is necessary to add an ~C. Fertil Steril 1994;61: Key Words: GnRH-a, hyperandrogenism, idiopathic hirsutism, polycystic ovary syndrome Hirsutism, a sensitive marker for increased production or action of androgens, is an important clinical and psychosocial problem. In most cases it depends on a glandular overproduction of androgens or on a hypersensitivity of the pilosebaceous unit towards normal levels of free androgens (idiopathic hirsutism) (1-5). The pathogenesis ofhirsutism is seldom organic or congenital; in these cases it requires a specific therapy (6-8). According to Barbieri (2), female hirsutism is caused by polycystic Received June 10, 1993; revised and accepted December 27, 1993, * Reprint requests: Leopoldo Falsetti, M.D., via M. Tirandi, 13-Scala F, Brescia, Italy (FAX: ), ovarian syndrome (PCOS) or by ovarian hyperthecosis in 78% of cases and by idiopathic hirsutism in 15% of cases. Medical treatment available for hirsutism can vary between drugs suppressing the glandular production of androgens (oral contraceptives [OCs] [9, 10], glucocorticoids [ll]) and drugs acting at a peripherallevel (cyproterone acetate [CPA] [12, 13], spirono-lactone [14], flutamide [15]). So far, however, therapeutic results, especially in severe hirsutism, have been rather poor. Gonadotropin-releasing hormone agonists (GnRH-a), because of their specific, selective inhibition of ovarian steroidogenesis, might represent a good alternative therapy in treating hirsutism (16, 17). Our study aimed to evaluate the efficacy of a long- Vol. 61, No.5, May 1994 Falsetti and Pasinetti GnRH-a in moderate and severe hirsutism 817

2 releasing GnRH-a (leuprolide acetate [LA]) and of LA plus an OC containing CPA on moderate and severe hirsutism. MATERIALS AND METHODS For 6 consecutive months, 32 women with moderate and severe hirsutism (Ferriman and Gallwey score between 11 and 25) (18) suffering from either PC OS (16 patients, 50%) or idiopathic hirsutism (16 patients, 50%) were administered an 1M injection of LA (Enantone Depot; Takeda, Catania, Italy) every 28 days, starting from the 1st day ofthe spontaneous or induced cycle. Two randomized treatment arms were created: LA versus LA plus an OC containing mg ethinyl-e 2 (EE) and 2 mg of CPA (Diane; Schering, Berlin, Germany), which was administered for six consecutive cycles according to OC standard regimen. Each treatment arm included 16 patients: 8 suffering from PCOS and 8 with idiopathic hirsutism. The study was approved by the Ethical Committee of our university and informed consent was obtained from every patient. The patients' mean parameters were age, 25 ± 4 years (mean ± SD); fasting glycemia, 82 ± 4 mg/dl (conversion factor to SI unit, ); body mass index (BMI) 23 ± 2; Ferriman and Gallwey score 16 ± 4. Before and after the treatment all patients underwent pelvic ultrasound, hirsutism evaluation, bone densitometry, and hormonal assay, including LH, FSH, PRL, E 2, T, DHEAS, androstenedione (A), free T, 17a-hydroxyprogesterone (17-0HP), and insulin (I), assessed for 3 consecutive days between 8 and 9 A.M. Sex hormone-binding globulins (SHBG) were also tested, as well as the free androgen index calculated with the formula T X 100/ SHBG. Luteinizing hormone, FSH, and SHBG were tested by immunoradiometric assay method (kits by Ares-Serono, Rome, Italy for LH and FSH; kit by Farmos, Milan, Italy for SHBG); the remaining hormones were tested by RIA method by the following commercial kits: Diagnostic Products Corporation, Genova, Italy (E 2, free T); Diagnostic System Laboratories, Webster, TX (A); Mallinckrodt, Milan, Italy (T); Radim, Rome, Italy (DHEAS); Eurogenetics, Tourin, Italy (17-0HP); Sclavo, Siena, Italy (I); and Biodata Serono, Rome, Italy (PRL). Hirsutism was assessed by a global scoring system (Ferriman and Gallwey) (18), in which a single observer (E.P.) assessed hair growth in 11 body Table 1 Basal Hormonal Parameters in Patients With PCOS and Idiopathic Hirsutism and in Normal Women* LH (mui/ml) FSH (mui/ml) A (ng/mllt T (ng/ml):j: Free T (pg/ml):j: 17-0HP (ng/ml) DHEAS (!lg/ml)ii I (!lui/ml) SHBG (nmol/l) Free androgen index PCOS 8.5 ± ± ± ± ± ± ± ± ± ± Idiopathic hirsutism 3.1 ± ± ± ± ± ± ± ± ± ± 0.2 Normal women 3.6 ± ± ± ± ± ± ± ± ± ± 0.4 t Conversion factor to SI unit, :j: Conversion factor to SI unit, Conversion factor to SI unit, II Conversion factor to SI unit, P < 0.01 PCOS versus idiopathic hirsutism and versus normal women. areas on a 0 to 4 scale. Hairs were shaved from four different surfaces (preauricular area of the face, abdominal wall immediately below the umbilicus, anterior midthigh, and forearm) for assessment of hair diameter. Ten terminal hairs were taken from each area. Shaved hairs were mounted on glass microscope slides and measurements were made with a micrometer by a single observer (E.P.). Hair diameter for each area is expressed as the mean value of the 10 hairs shaved from each area ± SD. Ovarian morphology was evaluated by ultrasound; ovarian volume was assessed by the simplified formula for ellipsoids ( X length X width X depth) (19). Ovarian volume in normal fertile women is 4 to 6 cm 3 Every 2 months, during a talk with the physician, patients related any side effects and any possible complications. Bone density measurements were performed by dual-energy roentgenogram absorptiometry in the lumbar spine (L 2 to L 4 ) with a Norland Scientific Instruments XR- 26 Mark II (Fort Atkinson, WI) both at the beginning and at the end of treatment. The control group was formed by 16 women, mean age 23 ± 2 years, mean BMI 21 ± 3, who had regular ovulatory cycles and did not suffer from hirsutism. In these women hormonal assays were taken in follicular phase (6th to 8th day of the cycle). Progesterone was evaluated in the luteal phase (22nd to 24th day of the cycle). Statistical evaluation of results was carried out through Student's t-test for paired data and through Wilcoxon's test for unpaired data. All 818 Falsetti and Pasinetti GnRH-a in moderate and severe hirsutism Fertility and Sterility

3 reported data are expressed as mean ± SD. A P < 0.05 was regarded as significant. RESULTS Hormonal and clinical data allowed diagnosis for PCOS in 16 patients and for idiopathic hirsutism in the remaining 16 patients. The two groups did not differ significantly in age, BMI, and glucose plasmatic levels. Patients with normal levels of androgens and with regular cycles were diagnosed with idiopathic hirsutism. In patients suffering from PCOS (Table 1), LH, A, T, free T, 17-0HP, and I serum levels were significantly higher (P < 0.01) than in controls and in women affected with idiopathic hirsutism, as was free androgen index, whereas SHBG levels were significantly lower (P < 0.01). Dehydroepiandrostenedione-sulphate and PRL levels were normal in all groups. Table 2 records basal clinical parameters in the two groups of hirsute women. Cycle alterations (oligoamenorrhea) affected all PC OS patients (100%). Twelve (75%) women with idiopathic hirsutism had regular ovulatory cycles, whereas four (25%) of them presented with oligoamenorrhea, which had first appeared within the last 6 months. Basal ovarian volume was significantly larger in PCOS (14 ± 4 versus 6.4 ± 0.9 cm 3 ). All PCOS (100%) and three (19%) idiopathic hirsutism patients presented a multicystic ovarian morphology with hyperplasia of the cortical stroma. Basal Ferriman and Gallwey scores did not differ in the two groups (17.5 ± 4 versus 15.3 ± 4) nor did the various hair diameters. Hormonal Results Table 3 records hormonal results after 6 months of therapy. In PCOS and idiopathic hirsutism, re- Table 2 Basal Clinical Parameters in Patients With PCOS and Idiopathic Hirsutism* Regular cycles Oligoamenorrhea Ovarian volume (cm 3 ) Ferriman and Gallwey score Hair diameter (/lm) Face Abdomen Thigh Forearm PCOS 16.0 (100) 14.0 ± ± ± ± ± ± 7.7 t Values in parentheses are percentages. + P < Idiopathic hirsutism 12.0 (75)t 4.0 (25) 6.4 ± ± ± ± ± ± 8.9 spectively, LA therapy caused a significant reduction (P < 0.01) in LH (92% to 71%), FSH (48% to 45%), A (61 % to 43%), T (50% to 33%), free T (69% to 50%), and 17-0HP (54% to 43%). Dehydroepiandrostenedione-sulphate, I, and SHBG levels didnot alter. Free androgen index decreased by 73% in PCOS and by 38% in idiopathic hirsutism (P < 0.01). Leuprolide acetate plus EE and CPA treatment resulted in an overlapping reduction in hormonal parameters. The only differences were a significant decrease (P < 0.01) in DHEAS (PCOS, 38%; idiopathic hirsutism, 31 %) and in free androgen index (PCOS, 94%; idiopathic hirsutism, 85%) and an increase (P < 0.01) in SHBG (PCOS, 697%; idiopathic hirsutism, 237%). In PCOS and idiopathic hirsutism, the percentage reduction was, respectively, LH, 93% to 81 %; FSH, 58% to 55%; A, 64% to 48%; T, 57% to 50%; free T, 76% to 60%; and 17-0HP, 73% to 57%. The comparison between the hormonal results obtained with the two therapeutic regimens showed that LA plus EE and CPA treatment caused a significant increase in SHBG and a reduction in DHEAS and free androgen index, both in PCOS and in idiopathic hirsutism patients. Free T presented a reduction only in absolute values, decreasing by 76% (versus 69%) in PCOS and by 60% (versus 50%) in idiopathic hirsutism. Clinical Results Leuprolide acetate treatment (Table 4) caused a Ferriman and Gallwey score reduction by 20% both in PCOS and in idiopathic hirsutism. Hair diameter significantly decreased by 23% to 33% in PCOS (P < 0.01) and by 16% to 31 % in idiopathic hirsutism (P < 0.01). Abdominal hair proved to be the most responsive to therapy and was reduced by 33% in PC OS and by 31 % in idiopathic hirsutism. Forearm hair, on the contrary, proved to be the least responsive one (23% to 16% decrease). Ovarian volume shrank (P < 0.01) both in patients suffering from PCOS (from 14.0 ± 1.4 to 11.1 ± 1.4 cm 3, 21 %) and in patients affected with idiopathic hirsutism (from 6.4 ± 0.9 to 5.3 ± 0.5 cm 3, 17%). All microcysts disappeared. Fourteen patients (87%) reported hot flushes, more frequent at the third and fourth cycles. In 10 cases (62%), this symptom was associated with sweating. Five patients (32%) related headache whereas two women (12%) complained of vaginal dryness, especially Vol. 61, No.5, May 1994 Falsetti and Pasinetti GnRH-a in moderate and severe hirsutism 819

Table 3 Hormonal Asset After 6 Months of LA and LA Plus De Treatment of Patients With peds and Idiopathic Hirsutism* LA LA plus De peds Idiopathic hirsutism peds Idiopathic hirsutism LH (mui/ml) 0.

4 Table 3 Hormonal Asset After 6 Months of LA and LA Plus De Treatment of Patients With peds and Idiopathic Hirsutism* LA LA plus De peds Idiopathic hirsutism peds Idiopathic hirsutism LH (mui/ml) 0.7 ± 0.2t 0.9 ± 0.5t FSH (mui/ml) 2.7 ± 0.9t 3.2 ± LOt A (ng/ml) 1.3 ± 0.3t 1.2 ± 0.2t T (ng/ml) 0.7 ± 0.2t 004 ± 0.2t Free T (pg/ml) 1.6 ± 0.8t 1.0 ± 0.2t 17-DHP (ng/ml) 0.5 ± 0.2t 004 ± 0.2t DHEAS (l'g/ml) 1.7 ± ± 0.1 I (I'UI/mL) 10.3 ± ± 0.9 SHBG (nmol/l) 20.0 ± ± 7.0 Free androgen index 204 ± 0.8t 0.8 ± 0.3* t p < 0.01 versus baseline levels. 0.6 ± 0.2t 0.6 ± 0.2t 2.2 ± LOt 2.6± 0.7t 1.2± O.lt 1.1± 0.2t 0.6 ± 0.3t 0.3 ± O.lt 1.2 ± 0.5t 0.8± 0.2t 0.3 ± 0.2t 0.3 ± O.lt 1.3 ± 0.3t:j: 1.1± 0.2t:j: loa ± ± ± 37.0t* ± 25.0t* 0.5 ± 0.2t* 0.2 ± 0.1t:j: * P < 0.01 versus LA treatment. during the last two cycles. After 6 months of LA treatment, the patients' bone density significantly decreased (P < 0.01); it shrank from ± g/cm 2 to ± g/cm 2 (mean reduction 4.2%). In patients suffering from idiopathic hirsutism, bone density reduction was higher (4.4%) than in PCOS (4.0%). Leuprolide acetate plus EE and CPA treatment (Table 4) caused a Ferriman and Gallwey score reduction by 26% in PCOS (P < 0.01) and by 23% in idiopathic hirsutism. Hair diameter significantly decreased by 24% to 36% in PCOS (P < 0.01) and by 24% to 32% in idiopathic hirsutism (P < 0.01). With this therapy, too, the higher response was reached in abdominal hair diameter (PCOS, 36%; idiopathic hirsutism, 32%) whereas the lower response was reached in forearm hair diameter (PCOS and idiopathic hirsutism, 24%). With this therapy, ovarian volume significantly shrank (from 14.0 ± 1.4 to 10.1 ± 1.6 cm 3, 28%, in PCOS and from 6.4 ± 0.9 to 5.0 ± 0.6 cm 3, 22%, in idiopathic hirsutism). Microcysts completely disappeared. This therapeutic regimen did not cause side effects or bone density modifications (1.122 ± versus ± g/cm 2 ). The comparison between the clinical results obtained with the two therapeutic regimens did not show any differences, except for the significant decrease in facehair diameter in women with idiopathic hirsutism treated with LA plus EE and CPA. DISCUSSION The therapeutic approach in hirsutism secondary to PCOS and idiopathic hirsutism aims toward the suppression of the gland responsible for hyperandrogenism and/or of the pilosebaceous unit, as the latter is the cause of hyperandrogenic symptoms (3, 20). In our study, LA therapy proved efficacious in significantly reducing gonadotropins and ovarian androgens' whereas it did not alter DHEAS, I, and SHBG. In the anovulatory women (PCOS) LA sup- Table 4 Ferriman and Gallwey Score and Hair Diameter After 6 Months of LA and LA Plus De Treatment in Patients With peds and Idiopathic Hirsutism* LA LA plus De peds Idiopathic hirsutism peds Idiopathic hirsutism Ferriman and Gallwey score Hair diameter (I'm) Face Abdomen Thigh Forearm 14.0 ± ± 4.2* 55.7 ± 4.2* 60.0 ± 2.7* 39.3 ± 5.6* 12.2 ± ± 4.5* 54.2 ± 4.5* 58.1 ± 5.3* 40.0 ± 4.6* 13.0 ± 2.6* 37.8 ± 3.6* 52.8 ± 5.8* 59.7 ± 3.2* 39.7 ± 4.2* t P < 0.01 versus basal levels. * P < 0.01 versus LA treatment ± ± 4.1*t 5404 ± 5.2* 58.1 ± 5.2* 35.7 ± 7.2* 820 Falsetti and Pasinetti GnRH-a in moderate and severe hirsutism Fertility and Sterility

pressed serum A, T, and free T by 61%, 50%, and 69%, respectively, compared with 43% (A), 33% (T), and 50% (free T) in the ovulatory women (women with idiopathic hirsutism).

5 pressed serum A, T, and free T by 61%, 50%, and 69%, respectively, compared with 43% (A), 33% (T), and 50% (free T) in the ovulatory women (women with idiopathic hirsutism). Leuprolide acetate plus EE and CPA obtained overlapping hormonal results, except for a significant increase in SHBG and a significant reduction in DHEAS in all patients. Furthermore, this regimen caused a higher reduction of free T in women suffering from PC OS and idiopathic hirsutism, probably related to the SHBG increase. The reduction of DHEAS, adrenal androgen, is caused by the use of OCs (10). Free androgen index significantly reduced with both therapies, although the decrease was higher in patients treated with LA plus EE and CPA (P < 0.01). Our clinical results prove that GnRH-a can effectively improve hirsutism, both in PC OS and in idiopathic hirsutism patients. Ferriman and Gallwey scores (subjective evaluation) decreased by 20% both in PCOS and in idiopathic hirsutism with LA, whereas they decreased by 26% (P < 0.01) in PC OS and by 23% in idiopathic hirsutism with LA plus EE and CPA. Hair diameters (objective evaluation) decreased by 23% to 33% and by 16% to 31 %, respectively, in PC OS and idiopathic hirsutism with LA and by 24% to 36% and by 24% to 32%, respectively, with LA plus EE and CPA therapy. With both regimens, in all patients, abdominal, thigh, and facial hairs were, decreasingly, the most responsive ones. The comparison between the therapeutic results obtained with the two regimens both on the Ferriman and Gallwey score and on hair diameter does not show any significant difference, except for facial hair diameter in women with idiopathic hirsutism treated with LA plus EE and CPA. The latter treatment, however, in accordance with hormonal data, causes a higher reduction in the absolute values of the Ferriman and Gallwey score and hair diameter in both groups of patients. Leuprolide acetate plus EE and CPA treatment did not cause any side effects or a reduction in bone density (21, 22). On the contrary, LA treatment caused side effects in 87% of cases and mean bone density reduced by 4.2%. Patients with normal levels of estrogens and androgens (idiopathic hirsutism) seemed to have a higher bone loss after LA (23). In conclusion, GnRH -a proved efficacious in treating moderate and severe hirsutism in women suffering from PCOS and from idiopathic hirsutism. Gonadotropin-releasing hormone agonist efficacy in idiopathic hirsutism seems to prove that the significant reduction in androgens, although basally normal, can influence 5-a reductase activity on the pilosebaceous unit (24). Based on our clinical results of bone density and side effects, it is always necessary to add an OC, especially in case of prolonged GnRH-a treatment. REFERENCES 1. Breckwoldt M, Zahradnik HP, Wieaker P. Hirsutism, its pathogenesis. Hum Reprod 1989;4: Barbieri RL. Hyperandrogenic disorders. Clin Obstet Gynecol 1990;33: Toscano V. Hirsutism: pilosebaceous unit disregulationrole of peripheral and glandular factors. J Endocrinol Invest 1991;14: Serafini P, Lobo RA. Increased 5-a reductase activity in idiopathic hirsutism. Fertil Steril1985;43: Mauvais-Jarvis P. Androgen metabolism in human skin: mechanism of control. In: Martini L, Motta M, editors. Androgens and antiandrogens. New York: Raven Press, 1977: Barnes RB. Adrenal dysfunction and hirsutism. Clin Obstet Gynecol 1991;34: Aiman J. Virilizing ovarian tumors. Clin Obstet Gynecol 1991;34: Schriock EA, Schriock ED. Treatment of hirsutism. Clin Obstet Gynecol 1991;34: Givens JR, Andersen RN, Wiser WI, Fish SA. Dynamics of suppression and recovery of plasma LH, FSH, androstenedione and testosterone in polycystic ovarian disease using an oral contraceptive. J Clin Endocrinol Metab 1974;38: Wiebe RH, Morris CV. Effect of an oral contraceptive on adrenal and ovarian androgenic steroids. Obstet Gynecol 1984;63: Aydinlik S, Kaufmann J, Lachnit-Fixon U, Lehnert J. Long-term therapy of signs of androgenization with a lowdosed anti-androgen-oestrogen combination. Clin Trials J 1990;27: Falsetti L, Dordoni D, Gastaldi C, Gastaldi A. A new association of ethinyl estradiol (0.035 mg) and cyproterone acetate (2 mg) in the therapy of polycystic ovary syndrome. Acta Eur FertiI1986;17: Cumming DC, Yang JC, Rebar RW, Yen SS. Treatment of hirsutism with spironolactone. JAMA 1982;247: Cusan L, Dupont A, Tremblay R, Labrie F. Treatment of hirsutism with the pure antiandrogen fiutamide. Recent Res Gynecol Endocrinol1988;1: Rittmaster RS, Loriaux DL, Cutler GB Jr. Sensitivity of cortisol and adrenal androgens to dexamethasone suppression in hirsute women. J Clin Endocrinol Metab 1985;61: Adashi EY. Potential utility of gonadotropin-releasing hormone agonists in the management of ovarian hyperandrogenism. Fertil Steril1990;53: Andreiko JL, Monroe SE, Jaffe RB. Treatment of hirsutism with a gonadotropin-releasing hormone agonist (nafarelin). J Clin Endocrinol Metab 1986;63: Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961;21: Vol. 61, No.5, May 1994 Falsetti and Pasinetti GnRH-a in moderate and severe hirsutism 821

6 19. Orsini LF, Rizzo N, Calderoni P, Pilu G, Bovicelli L. Ultrasound monitoring of ovarian follicular development: a comparison of real time and static scanning techniques. J Clin Ultrasound 1983;11: Lobo RA. Hirsutism in polycystic ovary syndrome: current concepts. Clin Obstet Gynecol 1991;34: Judd HL. Gonadotropin-releasing hormone agonists: strategies for managing the hypoestrogenic effects of therapy. Am J Obstet Gynecol 1992;166: Leather AT, Studd JWW, Watson NR, Holland EFN. The prevention of bone loss in young women treated with GnRH-analogues with "add-back" estrogen therapy. Obstet Gynecol 1993;81: Buchanan JR, Hospodar P, Myers C, Leuenberger P, Demers LM. Effect of excess endogenous androgens on bone density in young women. J Clin Endocrinol Metab 1988;67: Andreiko JL, Marshall LA, Dumesic DA, Jaffe RB. Therapeutic uses of gonadotropin-releasing hormone analogs. Obstet Gynecol Surv 1987;42: Falsetti and Pasinetti GnRH-a in moderate and severe hirsutism Fertility and Sterility

Treatment of hirsutism with a gonadotropin-releasing hormone agonist and estrogen replacement therapy*

Gynecology-endocrinology FERTILITY AND STERILITY Copyright 1994 The American Fertility Society Printed on acid-free paper in U S. A. Treatment of hirsutism with a gonadotropin-releasing hormone agonist