Efficacy of the combination ethinyl oestradiol and cyproterone acetate on endocrine, clinical and ultrasonographic profile in polycystic ovarian syndrome

Leopoldo Falsetti 0 Alessandro Gambera 0 Giancarlo Tisi 0 0 Department of Gynaecological Endocrinology, University of Brescia , Brescia 25128 , Italy 1To whom correspondence should be addressed at: Via XXV Aprile 10, 24058 Romano di L. (BG), Italy. This study shows the effect of a long-term treatment (60 cycles) with the ethinyl oestradiol/cyproterone acetate pill, and the follow-up after 6 months from cessation, in polycystic ovarian syndrome. The 140 studied women had polycystic ovaries and moderate or severe acne, 108 also presented hirsutism. The endocrine profile significantly modified after six cycles (P < 0.001), with a further significant decrease of gonadotrophins, oestrogens and androgens after 12 cycles, and a greater increase of sex hormone-binding globulins and insulin-like growth factor-binding globulins. Between the 12th and 60th cycle there was only a significant reduction of dehydroepiandrosterone sulphate (P < 0.05). Acne disappeared in all patients within 12-24 cycles, but hirsutism was still present in 30.6% after 60 cycles. Mild-moderate hirsutism disappeared in 36-60 cycles, whereas severe hirsutism substantially decreased, but persisted. Ovarian volume, microcyst numbers and stroma percentage significantly decreased (P < 0.01). After 6 months from the end of the therapy, endocrine parameters were identical to the starting ones, acne and hirsutism reappeared, whereas ovarian morphology was between the initial and final condition. Ovaries were polycystic in 42 (30%) patients and multifolliculars in 98 (70%). Our results show the effectiveness of this combination on androgenic symptoms, especially on acne, and suggest that acne and hirsutism are induced by different peripheral mechanisms. - Polycystic ovarian syndrome (PCOS) is an heterogeneous disorder characterized by abnormal gonadotrophin secretion, chronic anovulation, hyperandrogenism and a variety of metabolic effects such as obesity (3060%) and insulin resistance present in 3046% of lean and in 5778% of obese women (Falsetti and Eleftheriou, 1996; Prevelic, 1997; Acien et al., 1999). The alteration of the system insulin/insulin-like growth factor-I (IGF-I)/insulin-like growth factor-binding proteins (IGFBPs), in synergy with LH, promotes the mitotic activity and hyperplasia of the ovary theca/stromal compartment in PCOS and increases androgen production (Duleba et al., 1998). In PCOS, hyperandrogenism is clinically silent in ~30% of European women and 8090% of Oriental women (Aono et al., 1977), or induces hirsutism in 6083% of the cases and acne in 1143% of the cases (Goldzieher and Green, 1962; Conway et al., 1989; Lobo, 1991). Clinical expression depends on the events which occur in the pilosebaceous unit, where individual sensitivity to androgens is different (McKenna, 1993). Dehydroepiandrosterone (DHEA), androstenedione and testosterone, penetrating the cells of the peripheral sensitive tissues, are converted to the more potent dihydrotestosterone (DHT) by 5-reductase (5-R). Testosterone and DHT can bind to androgen receptors, but the receptor affinity for DHT is ~10-times that of testosterone (McKenna, 1993). DHT is metabolized into 3- and 3-androstanediol and their glucuronide conjugates (3-, 3-diolG). Hirsute women with or without hyperandrogenism exhibit a consistently increased 3-diolG indicating a 5-R hyperactivity and preferential use of the DHT/3-diolG route in the hair follicle (Matteri et al., 1989; Speroff and Glass, 1994). In fact, numerous studies have documented that in hirsute women the 5-R activity in the skin was steadily elevated (Paulson et al., 1986). In hyperandrogenic patients with acne alone, 3-diolG is not as high as in hirsutism (Toscano et al., 1993). Two isoforms of 5-R have been identified, called type 1 and 2 (5-R1 and 5-R2). Studies using specific inhibitors of 5-R1 and 5-R2 have shown that 5-R2 enzymatic activity is predominant in the urogenital sinus, in genital skin, in the adult scalp and in the hair follicles, whereas 5-R1 is predominant in the central nervous system, in sebaceous glands, in pubic skin and in the non-sex skin of normal women and hirsute patients (Harris et al., 1992; Mestayer et al., 1996; Paus and Cotsarelis, 1999). However, the distribution and role of the two isoforms are not clear. Hair follicles and sebaceous glands may use different androgens and metabolic paths or different types of 5-R (type 1 or 2) resulting in higher DHT production in hair follicles compared with sebaceous glands (Carmina et al., 1991; McKenna, 1993; Toscano et al., 1993). The bioactive androgens in sebaceous glands would be testosterone or androstenedione and its metabolites which appear to be more effective than testosterone in stimulating sebaceous cell mitosis and sebum production (Ebling et al., 1973). Oral contraceptives have been used to treat androgenic symptoms because of their ability to suppress the secretion of gonadotrophins, ovarian or adrenal androgens, and to stimulate the hepatic synthesis of sex hormone-binding globulins (SHBG) resulting in decreased free testosterone fraction. By increasing the insulin-like growth factor binding protein-1 (IGFBP-l), oral contraceptives decrease the active proportion of IGF-I and thus the stimulus to 5-R and hair growth (Suikkari et al., 1991). Cyproterone acetate (CPA) is a synthetic progestogen derived from 17-hydroxyprogesterone with antigonadotrophic and antiandrogenic peripheral activity. It inhibits testosterone and DHT action by binding competitively to intracellular receptors and decreases ovarian androgen secretions by inhibiting LH release. Furthermore, this drug decreases 5-R activity (Mowszowitcz et al., 1986) and increases metabolic testosterone clearance (Marcondes et al., 1990). The aim of this study was to investigate the endocrine, clinical and ultrasonographic modifications induced by a longterm use of the monophasic combination EE/CPA and to quantify the restoration of the starting profiles after 6 months from the end of the treatment, in women with PCOS. Materials and methods A total of 140 premenopausal women with PCOS and acne, with or without hirsutism, who had been referred to the Department of Gynaecological Endocrinology of the University of Brescia, was selected for the study, after written informed consent had been given. The women, with an average age of 24.1 4.9 years and mean body mass index (BMI) of 23.9 3.1 kg/m2, were treated for 60 consecutive cycles with a monophasic combination containing 0.035 mg of ethinyl oestradiol and 2 mg of cyproterone acetate (EE/CPA, Diane 35; Schering, Milan, Italy). None of the patients wished to become pregnant or had contraindications with the use of oral contraceptives. All patients completed the study. PCOS was diagnosed by clinical, endocrine and ultrasonographic findings. Obese patients (BMI 30 kg/m2) were excluded from the study because of possible weight gain with the use of the EE/CPA pill. Oligomenorrhoea was present in 10 (...truncated)