Clinical and hormonal effects of the combination gonadotrophin-releasing hormone agonist plus oral contraceptive pills containing ethinyl-oestradiol (EE) and cyproterone acetate (CPA) versus the EE-CPA pill alone on polycystic ovarian disease-related hyperandrogenisms.

Human Reproduction Clinical and hormonal effects of the combination gonadotrophin-releasing hormone agonist plus oral contraceptive pills containing ethinyl-oestradiol (EE) and cyproterone acetate (CPA) versus the EE-CPA pill alone on polycystic ovarian disease-related hyperandrogenisms P.Acien 2 3 M.Mauri 0 2 M.Gutierrez 1 2 0 Hormone Laboratory, General University Hospital of Alicante, University of Alicante , Alicante , Spain 1 Biochemistry Laboratory, San Juan University Hospital and School of Medicine 2 de Ginecolog a, Facultad de Medicina, Campus de San Juan , Apartado de Correos 374, 03080 Alicante , Spain 3 Department of Gynecology European Society for Human Reproduction and Embryology - The aim of this study was to compare the clinical and hormonal effects of the combination of a long-acting gonadotrophin-releasing hormone analogue (GnRH-a) plus an oral contraceptive (OC) pill containing ethinyl-oestradiol (EE) and cyproterone acetate (CPA) versus the EECPA pill alone in patients with polycystic ovarian disease (PCOD) and related hyperandrogenisms, in order to evaluate whether the addition of GnRH-a has any advantage. A total of 12 PCOD patients were treated with the EECPA pill alone for 10 consecutive cycles according to an OC standard regimen. A further 12 patients were treated with GnRH-a, one i.m. injection every 28 days for a total of eight injections, combined with the EECPA pill for 10 consecutive cycles. The latter was thus prolonged for two cycles more than GnRH-a. Clinical evaluations (symptoms, weight, FerrimanGallwey score) and hormonal and biochemical analyses were assessed before, during (at 3 or 6 months) and after treatment, either when spontaneous cycles had resumed or after 3 months of amenorrhoea. There was a significant improvement in hirsutism, and a strong reduction in gonadotrophin, oestradiol, testosterone, androstenedione and 17-OH-progesterone concentrations in both treatment groups but with no significant differences between them, except in the gonadotrophin concentrations. Cortisol and triglyceride concentrations increased during treatment in both groups. The FerrimanGallwey score remained significantly decreased in both groups after treatment, as did androstenedione in the GnRH-a plus EECPA pill group, but there were no significant differences between the two groups. No changes were observed in prolactin, dehydroepiandrosterone sulphate (DHEA-S), insulin, glycaemia and cholesterol concentrations. However, when only the obese and more hirsute patients were considered, significant differences between the two groups were found during treatment in the FerrimanGallwey score and the gonadotrophin and DHEA-S concentrations (which increased during treatment in obese patients with the pill alone), and after treatment in the FerrimanGallwey score and the concentration of 17-OH-progesterone in the more hirsute patients, with the GnRH-a plus pill group having better results. In conclusion, a cyclic prolonged treatment with OC EECPA pills is not improved in most PCOD patients by the addition of GnRH-a, and is complicated and expensive. However, the addition of a long-acting GnRH-a may be recommended in obese and severely hirsute patients. Key words: cyproterone acetate/GnRH analogues/hyperandrogenism/oral contraceptive pill/polycystic ovarian disease Several therapeutic approaches have been applied to polycystic ovarian disease (PCOD) patients, including diet (Guzick et al., 1994) and pharmacological agents. As the treatment goal, especially for related hirsutism, is a reduction in the production, bioavailability or binding of the androgens to their target organs, the traditional treatment has been the combination of oral contraceptives (OC) and anti-androgens, such as cyproterone acetate (CPA). The results of OC treatments have often been disappointing, not only because of the incomplete suppression of ovarian function, but also because the progestin component of most OC pills is derived from 19-nor-testosterone and therefore has some androgenic activity (Morcos et al., 1994). CPA has also been reported to be effective alone, associated with OC pills or in combination with oestrogens as an OC pill (Belisle and Love, 1986; Falsetti and Galbignani, 1990; Neumann, 1994). This combination [CPA 1 oestrogens (EE)] can simultaneously decrease androgen production and block androgen action, and it appears to be especially suited to the treatment of hirsutism, acne or both (Barbieri, 1992; Neumann, 1994). Spirolactone has also been used in the treatment of hirsutism with adequate results but with a significant incidence of dysfunctional uterine bleeding (Helfer et al., 1988). Subsequently, flutamide was shown to be even more effective (Marcondes et al., 1992; Cusan et al., 1994; Moghetti et al., 1995; Pucci et al., 1995), but because of its potential hepatotoxicity, it requires constant surveillance of liver function (Wysowski and Fourcroy, 1994; Moghetti et al., 1995). Finally, it has been reported that finasteride is useful in idiopathic hirsutism (Ciotta et al., 1995), and ketoconazole in PCOD patients (Gokmen et al., 1996). In recent years, gonadotrophin-releasing hormone agonistic analogues (GnRH-a) have been introduced for the evaluation and treatment of PCOD patients. These produce a state of complete, yet reversible, suppression of pituitary gonadotrophin secretion. This results in the suppression of both ovarian functions, namely ovulation and steroidogenesis. Hence, in cases of ovarian hyperandrogenism, GnRH-a has been reported to be of great benefit (Chang et al., 1983; Andreyko et al., 1986; Steingold et al., 1987; Falsetti and Pasinetti, 1994; Goni et al., 1994; Morcos et al., 1994). Long-acting GnRH-a can be used alone (Goni et al., 1994), although this causes hypooestrogenic-related symptoms and decreases bone mineral content, or in combination with an oestrogen and progestin replacement therapy (Morcos et al., 1994), with either standard OC pills (Carr et al., 1995; Elkind-Hirsch et al., 1995) or OC pills containing ethinyl-oestradiol (EE) and CPA (Falsetti and Pasinetti, 1994; Ciotta et al., 1996). The aim of this study was to compare the clinical and hormonal effects of the combination of a long-acting GnRH-a plus OC pills containing EE and CPA, versus OC pills alone in PCOD patients so as to evaluate whether the addition of a GnRH-a is advantageous and, if so, in which situations. Materials and methods Subjects A total of 24 patients with an average age of 23.2 years (range 14 32), diagnosed as having PCOD with hirsutism (96%), amenorrhoea or oligomenorrhoea (92%), obesity (61%), seborrhoea (37%) or acne (17%), were included in this study. A further five patients were included initially, but later excluded because of the absence of information in the third and sixth months of treatment. The diagnosis of PCOD was established from the patients clinical history, examination, relevant laboratory investigations [including eleva (...truncated)