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

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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 and estrogen replacement therapy* Roy N, Morcos, M.

1 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 and estrogen replacement therapy* Roy N, Morcos, M.D.t Michael E, Abdul-Malak, M,D, Evan Shikora, D,O, Department of Obstetrics and Gynecology, St. Elizabeth Hospital Medical Center, Youngstown, and Northeastern Ohio Universities College of Medicine, Rootstown, Ohio Objective: To determine the efficacy of treatment of significant hirsutism with a GnRH agonist (GnRH-a) and estrogen and progestin replacement therapy. Design: Clinical series. Setting: Ambulatory gynecology clinic in a community hospital. Patients: Ten women with significant hirsutism caused by polycystic ovarian disease. Interventions: The patients were treated with leuprolide acetate 20 JIg/kg per day in combination with E2 (2 mg) and medroxyprogesterone acetate (5 mg) for 6 months. Main Outcome Measure: Hirsutism scores and hair growth rates determined before and upon completion of treatment protocol. Results: Hirsutism scores and hair growth rates significantly decreased by 23% and 26%, respectively. The duration of hirsutism was the only significant covariate for hirsutism scores and hair growth rates. Only two patients had minimal, irregular bleeding that was corrected by increasing the estrogen dose, Conclusion: The combination of a GnRH -a and estrogen replacement therapy was an effective and well-tolerated treatment in a small group of women with significant hirsutism caused by PCOD. Fertil Steril 1994;61: Key Words: Hirsutism, GnRH -a, estrogen replacement therapy Hirsutism is a common and significant problem in young women. The causes are polycystic ovarian disease (PCOD), Cushing's Syndrome, congenital adrenal hyperplasia (CAH), androgen-secreting ovarian or adrenal tumors, and drug-induced and idiopathic hirsutism. The two most common causes, PCOD and idiopathic hirsutism, are characterized by onset at or shortly after puberty with Received July 19, 1993; revised and accepted October 26, * Supported in part by TAP Pharmaceuticals, Deerfield, Illinois. t Reprint requests: Roy N. Morcos, M.D., Department of Obstetrics and Gynecology, St. Elizabeth Hospital Medical Center, 1044 Belmont Avenue, Youngstown, Ohio persistence and often gradual worsening of the hair growth. When hirsutism is associated with chronic anovulation, as in PCOD, the patient's risks of infertility and adenocarcinoma of the endometrium are increased. Hirsutism is generally caused by an increased production and secretion of androgens, except in patients with idiopathic hirsutism who have increased sensitivity of the pilosebaceous unit to normal levels of circulating androgens. The treatment goal is a reduction in the production, bioavailability, or binding of the androgens to their target organ. In PCOD, the androgens are primarily of ovarian origin with a relatively minor contribution by the adrenals in some patients. The traditional treatment of PCOD-related hirsutism has been with Morcos et al. Hirsutism therapy with GnRH-a and ERT 427

combination oral contraceptives (OCs) but the results have often been disappointing because of the incomplete suppression of ovarian function and also because the progestin component of most OC pills

2 combination oral contraceptives (OCs) but the results have often been disappointing because of the incomplete suppression of ovarian function and also because the progestin component of most OC pills is derived from T and therefore has some androgenic activity. Another drug used in the treatment of hirsutism with adequate results but with a significant incidence of dysfunctional uterine bleeding is spironolactone (1, 2). Cyproterone acetate has also been shown to be effective (3), and there is widespread experience with this drug in Europe. Unfortunately, it is not available in the United States. The GnRH agonists (GnRH-a) such as leuprolide acetate (LA, Lupron; TAP Pharmaceuticals, Deerfield, IL) are known to produce a state of complete, yet reversible, suppression of pituitary gonadotropin secretion. This results in suppression of both ovarian functions, namely, ovulation and steroidogenesis. In cases of hirsutism caused by excess ovarian androgen production, a GnRH-a would, therefore, be of great benefit. Leuprolide acetate has been shown to be effective in suppressing ovarian androgen levels in several studies (4-6) resulting in significant improvement in hirsutism. Leuprolide acetate therapy however results in a reversible medical menopause with a number of predictable side effects and complications, such as vasomotor symptoms, genital atrophy, increased risk of osteoporosis, and probably an increased risk of heart disease. All of these complications can be prevented by the addition of physiological doses of estrogen replacement therapy (ERT). The purpose of this study is to evaluate the use of LA in combination with an ERT regimen in the treatment of hirsutism secondary to PCOD. MATERIALS AND METHODS Eleven women with the diagnosis of PCOD who presented themselves consecutively to the Ambulatory Care Center at St. Elizabeth Hospital Medical Center were asked to participate in the study. They had significant hirsutism that had failed to respond to conventional therapies, such as combination OCs. All but one woman agreed to participate, and we were careful to obtain consent in accordance with the requirements of the Institutional Review Board. The patient who declined participation was discouraged by the need for daily SC injections for the duration of the study protocol. The diagnosis of PCOD was a clinical one, based on the history, ex- amination, and relevant laboratory investigations. It also was based on the exclusion of other PCODlike syndromes, such as adrenal dysfunction, Cushing's Syndrome, congenital adrenal hyperplasia, androgen-producing tumors, and thyroid dysfunction. A detailed history, including the chronology of symptoms and the time course of development of androgenic signs was essential. Vaginal sonographic evaluation of the ovaries was performed, and the presence of multiple small follicles bilaterally without dominance was of value in confirming the diagnosis. Furthermore, all cases had total (bound and free) serum levels oft in the high-normal or moderately elevated ranges. None had a T level> 200 ngjdl (7 nmoljl), which could indicate the presence of an androgen-secreting tumor. None of the patients were planning a pregnancy for the duration of therapy and barrier contraception was recommended, when appropriate. After the initial clinical and biochemical evaluation, including measurement of baseline serum T and DHEAS levels, the patients were started on LA 20 JLgjkg per day SC (7). Micronized E 2, 2 mg by mouth daily from days 1 through 25 each month and medroxyprogesterone acetate (MDPA) 5 mg by mouth daily from days 14 through 25 each month, were added. The patients were treated for a period of 6 months. Hirsutism scores were determined before and upon completion of the treatment protocol, using a modified Ferriman-Gallwey method (8). Only eight midline skin areas were evaluated by giving each a score of zero to four, depending upon the nature and extent of hair. Before starting the treatment, initial hair growth rates were evaluated by weighing hair obtained by shaving a well-defined infraumbilical area (10 X 4 cm) and reshaving the same area 3 weeks later. The hair growth rates were calculated again upon completion of the study. Each patient therefore could act as her own control. The statistical analysis of the hirsutism scores and of the hair growth was performed by the Wilcoxon signed rank test, because the differences (before and after treatment) did not follow a normal distribution. To determine if significant factors were associated with treatment effect, regression analysis was performed on age, weight, and duration of disease. RESULTS The patient's ages ranged from 18 to 31 years and weights from 48 to 107 kg, with a mean of 80.3 kg. 428 Morcos et al. Hirsutism therapy with GnRH-a and ERT Fertility and Sterility

3 Table 1 Study Population Table 3 Changes in Hair Growth Rate Patient Age Weight Duration Menses y kg y Oligomenorrhea Oligomenorrhea Amenorrhea Oligomenorrhea Oligomenorrhea Oligomenorrhea Oligomenorrhea Oligomenorrhea Amenorrhea Amenorrhea Mean They all had long-standing hirsutism of 2 to 18 years duration with a mean of 7.7 years (Table 1). The treatment was well tolerated. None of the patients reported hot flushes, vaginal dryness, or weight changes. All women had regular, moderate menstrual flow. Only two had occasional, minimal, dysfunctional bleeding that occurred at the end of each treatment cycle. This was attributed to a relative estrogen deficiency that was managed by increasing the dose of E2 from 2 to 3 gm/d. The modified Ferriman -Gallwey scores decreased by 23% after 6 months of therapy. The mean difference in the modified Ferriman-Gallwey scores, before and after treatment, was 4.2 ± The decrease in the scores, after treatment, was significant with a P value of (Table 2). Similarly, Before After Patient treatment treatment Difference mg/wk mg/wk mg/wk Mean * * p = 0.002; the difference in the mean growth rate before and after treatment was 26%. the hair growth rates decreased by 26%. The mean difference in hair growth rates was ± mg/wk. The decrease in hair growth rates was significant with a P value of (Table 3). The initial DHEAS levels were all < 700 tlg/dl (19 tlmoljl). The T levels decreased significantly from an initial mean of 108 ng/dl (3.8 nmoljl) to 33.8 ng/dl (1.2 nmol/l) after treatment. The mean difference was 75.0 with a P value of (Table 4). To determine significant factors associated with Table 4 Androgen Levels DHEAS Testosteronet Table 2 Changes in Modified Ferriman-Gallwey scores Before After Patient treatment treatment Difference Mean t 8 midline areas each score 0 to 4: upper lip, chin, neck, cheek, chest, abdomen, upper thigh, upper back, and lower back. t p = 0.008; the difference in mean scores before and after treatment was 23%. Before Before After Patient treatment treatment treatment p.g/dl ng/dl ng/dl Mean 108:j: 33.8 Difference Normal: 82 to 338 Ilg/dL (2.2 to 9.2 Ilmol/L). t Normal: 6 to 86 ngjdl (0.2 to 3 nmol/l). :j:n = 7. p = 0.016; the difference in the mean T level before and after treatment was 66% Morcos et al. Hirsutism therapy with GnRH-a and ERT 429

treatment effect, the differences between modified Ferriman -Gallwey before and after treatment, hair growth rate, and T levels were each regressed on age, weight, and duration of disease.

4 treatment effect, the differences between modified Ferriman -Gallwey before and after treatment, hair growth rate, and T levels were each regressed on age, weight, and duration of disease. The duration of hirsutism was the only significant covariate for hair growth rates and modified Ferriman-Gallwey scores but not for T levels. Both modified Ferriman-Gallwey scores and hair growth rates were negatively correlated with duration of disease. DISCUSSION Some women with PCOD disease have minimal hirsutism that can be adequately managed by combination oral contraceptives, often in conjunction with local measures, such as bleaching, shaving, or electrolysis. Others, however, have severe hirsutism that does not respond to the same therapies, mostly because the OCs fail to completely suppress ovarian androgen production. The GnRH -a cause a virtual cessation of pituitary gonadotropin secretion resulting in castrate levels of ovarian steroid production. This is a predictable and completely reversible effect that has been well documented. Several studies have been reported showing the efficacy of GnRH -a therapy of hirsutism. Andreyko et al. (5) reported a decrease in ovarian androgens and hirsutism scores in six women (4 with PCOD and 2 with idiopathic hirsutism) treated with a GnRH-a for 6 months. Rittmaster (7) treated 10 moderately to severely hirsute women (5 with idiopathic hirsutism and 5 with PCOD) with gradually increasing doses of LA until maximum suppression of E2 and T occurred. Leuprolide acetate was then continued for a total of 6 months. Maximal T suppression required 15 to 20 Jig/kg per day in 7 of the 10 women. Symptomatic improvement in hirsutism occurred in 9 women. Hirsutism scores decreased from 27.3 to 23.7 (P = 0.07), and hair growth rates decreased by a mean of 27%. All 5 women with PCOD had decreased hair growth rates and were subjectively improved, while hair growth rates decreased in only 3 of the 5 women with idiopathic hirsutism. All women developed hot flushes, and vaginal dryness occurred in 2. Monroe and Andreyko (9) used a GnRH-a in 6 women with hirsutism (4 with PCOD and 2 with idiopathic hirsutism). The mean T level and hirsutism scores decreased significantly but most patients reported hot flushes. Rittmaster and Thompson (10) had similar results using'la 10 Jig/kg per day to treat 19 women with hirsutism (10 with PCOD and 9 with idio- pathic hirsutism). Hair growth rates decreased by 37% in PCOD and by 14% in idiopathic hirsutism. All women developed hot flushes and 5 noted intermittent, vaginal dryness. After completing the study, 1 woman was maintained on LA with the addition of cyclic estrogen and progestin replacement. She had continued improvement in hirsutism and the side effects were alleviated. These side effects of GnRH -a therapy are predictable due to the suppression of ovarian estrogen production and would preclude long-term treatment because ofthe increased risk of osteoporosis and cardiovascular disease. To avoid these potential complications associated with hypoestrogenism, Falsetti et al. (11) reported on the use of a GnRH-a in conjunction with a combination OC pill containing mg of ethinyl E 2 They randomized 10 women with idiopathic hirsutism and 10 women with PCOD to receive either a GnRH -a alone or in combination with an OC pill containing mg ethinyl E2 and 2 mg cyproterone acetate. In the PCOD cases, the hirsutism scores and hair diameters were similarly decreased in both treatment groups. Only those women in the GnRH-a alone group reported significant hot flushes. The authors concluded that the addition of a OC pill did not affect the clinical results but was necessary to prevent side effects of hypoestrogenism. In our study, we have used a GnRH -a with a physiological replacement of E2 and a progestin. Such replacement effectively prevented side effects of estrogen deficiency without the potential risks of high doses of synthetic compounds found in OCs. Although the sample size was small, our treatment protocol was effective in reducing hair growth rates over a period of 6 months, and we believe that continuing the treatment for longer periods of time could result in further improvement of hirsutism. The 10 patients in our study protocol were not preselected or referred to us for treatment. They were the first to present to our Ambulatory Care Center after the protocol was approved. The treatment was very well tolerated and a Lupron depot formulation that can be administered 1M once a month will provide obvious advantages over daily injections. The high cost of this medication is the main obstacle that would prevent its widespread use in the treatment of significant hirsutism caused by PCOD. The response to therapy was negatively correlated with the duration of disease. This finding underscores the importance of early diagnosis and treatment of hirsutism. Long- 430 Morcos et al. Hirsutism therapy with GnRH-a and ERT Fertility and Sterility

5 term randomized controlled studies are needed to compare this new therapy with conventional treatments of hirsutism. Acknowledgments. The authors thank Gloria Caldito, Ph.D., for the statistical analysis of the data and Mrs. Bonnie Willis for typing the manuscript. REFERENCES 1. Loriaux DL. Spironolactone and endocrine dysfunction. Ann Int Med 1976;85: Helfer EL, Miller JL, Rose L. Side-effects of spironolactone therapy in the hirsute women. J Clin Endocrinol Metab 1988;66: Belisle S, Love EJ. Clinical efficacy and safety of cyproterone acetate in severe hirsutism: results of a multi centered Canadian study. Fertil Steril 1986;46: Chang RJ, Lanfer LR. Steroid secretion in polycystic ovarian disease after ovarian suppression by a long-acting gonadotropin releasing hormone agonist. J Clin Endocrinol Metab 1983;56: Andreyko JL, Monroe SE, Jaffe RB. Treatment of hirsutism with a gonadotropin-releasing hormone agonist (Nafarelin). J Clin Endocrinol Metab 1986;63: Steingold K, DeZiegler D. Clinical and hormonal effects of chronic gonadotropin-releasing hormone agonist treatment in polycystic ovarian disease. J Clin Endocrinol Metab 1987;65: Rittmaster RS. Differential suppression of testosterone and estradiol in hirsute women with the superactive gonadotropin-releasing hormone agonist Leuprolide. J Clin Endocrinol Metab 1988;67: Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961;21: Monroe SE, Andreyko J. Treatment of uterine leiomyomas and hirsutism with Nafarelin. J Reprod Med 1989;34: Rittmaster RS, Thompson DL. Effect of Leuprolide and Dexamethasone on hair growth and hormone levels in hirsute women: the relative importance of the ovary and the adrenal in the pathogenesis of hirsutism. J Clin Endocrinol Metab 1990;70: Falsetti I, Pasinetti E, Chiode C, Grigolato PG. Treatment of moderate and severe hirsutism with a gonadotropin-releasing hormone agonist (letter). Hum Reprod 1992;6:894. Morcos et al. Hirsutism therapy with GnRH-a and ERT 431

Polycystic Ovary Syndrome

Polycystic Ovary Syndrome Definition: the diagnostic criteria Evidence of hyperandrogenism, biochemical &/or clinical (hirsutism, acne & male pattern baldness). Ovulatory dysfunction; amenorrhoea; oligomenorrhoea