Vol. 55, No.5, May 1991

FERTILITY AND STERILITY

Printed on acid-free paper in U.S.A.

Copyright @ 1991 The American Fertility Society

Long-term treatment of hirsutism: desogestrel compared with cyproterone acetate in oral contraceptives*

Arnaldo Porcile, M.D.H Enrique Gallardo, M.D.§ School of Medicine of the University of Chile, Hospital del Salvador, Santiago, Chile

Objective: Effectiveness of 2-year treatment of hirsutism with low estrogen oral contraceptives (OCs) containing nonandrogenic or antiandrogenic progestogen. Evaluation of changes in plasma lipids. Design: Ten patients treated with desogestre1150 fJ,g + 30 fJ,g ethinyl estradiol, 6 with desogestrel 150 fJ,g + 50 fJ,g ethinyl estradiol, 10 with cyproterone acetate 2 mg + 35 fJ,g ethinyl estradiol. Random allocation. Paired comparisons. Control group: 19 normal women, not treated. Setting: Academic tertiary care. Patients: Women with hirsutism (idiopathic and/or polycystic ovary), 24 of 26 completed treatment. Intervention: Two-year treatment. Main Outcome Measures: Hirsutism score, plasma testosterone, and lipids. Results: Initial hirsutism scores (11.8 ± 0.6 SE) declined with treatment (-7.2 ± 0.4, P < 0.01) to 4.7 ± 0.6, almost reaching control (3.6 ± 0.3). Initial plasma cholesterol (4.33 mmol/L ± 0.30 SE), similar to control (4.78 ± 0.24), increased slowly over 2 years (+2.04 ± 0.34, P < 0.01). Highdensity lipoproteins cholesterol (1.05 mmol/L ± 0.04 SE), similar to control (1.12 ± 0.07), did not change the 1st year and increased at 2 years (+0.57 ± 0.11, P < 0.01). No differences appeared among treatment groups. Conclusions: Treatment is very effective, 2 years for best results. The OCs tested are equally efficacious. Changes in plasma lipids are of some concern but of difficult interpretation. Fertil Steril 55:877,1991

Hirsutism can be successfully treated with combinations of estrogens (Es) and progestogens in oral contraceptives (OCS).l,2 Progestogens, having weak androgen receptor binding capacity (e.g., levonorgestrel), were commonly employed in OCs till a few years ago. 3 However, OCs containing progestogens with a very low androgenic activity (e.g., desogestrel) are available, and they could be more suitable for Received June 27, 1990; revised and accepted January 22, 1991. * Supported in part by Hormoquimica de Chile, Ltd., Santiago, Chile and Instituto de Estudios Medicos Avanzados, Santiago, Chile. t Reprint requests: Arnaldo Porcile, M.D., 2251 Los Conquistadores, Apt. 2, Santiago (Providencia), Chile. :j: Department of Obstetrics and Gynecology, Hospital del Salvador. § Department of Endocrinology and Metabolism, Hospital del Salvador. Vol. 55, No.5, May 1991

hirsutism treatment. 3 ,4 There are, in addition, OCs containing progestogens with antiandrogenic activity (e.g., cyproterone acetate) that may offer a further additional therapeutic advantage. 5 The majority of the OCs preparations proven to be useful in the management of hirsutism contain fairly high doses of E. 1 ,2,6,7 The most recent OCs, containing low doses (30 or 35 J.Lg) of ethinyl estradiol, have not yet been demonstrated equally efficacious. 8 - 10 We therefore decided to test OCs with low E contents in women suffering from hirsutism, planning a comparison of preparations containing either a progestogen without androgenic effect (desogestrel) or a progestogen with antiandrogenic properties (cyproterone acetate). A contraceptive containing 50 J.Lg of ethinyl estradiol was also included in the trial to assess the effect of increased E dosage.

PorcHe and Gallardo

Hirsutism: desogestrel or cyproterone

877

An important aspect to be considered in studies of this type is the alteration in plasma lipids. In nonhirsute women using OCs, some of the changes in lipids have been attributed to the androgenic properties ofprogestogens and to the relatively high dose of E. l l ,12 We decided to use this opportunity to measure the changes in plasma lipids in the hirsute women being treated with OCs of the type indicated in the above paragraph. Because these changes may take a long time in making themselves apparent and because hirsutism requires months or years of treatment,6 a duly prolonged design was imperative, in this case lasting 2 years. MATERIALS AND METHODS

Twenty-six women with hirsutism, idiopathic or in polycystic ovary disease and without previous treatment, were enrolled in the study after being informed and giving their consent. A careful clinical and laboratory evaluation was made to exclude patients with tumors of the ovaries or of the adrenal glands, Cushing's disease, 21-hydroxylase deficiency, drug induced hirsutism, or hyperprolactinemia. The patients were randomly assigned, to fill up the following treatment groups: desogestrel 150 Ilg and ethinyl estradiol 30 Ilg (10 patients); desogestrel 150 Ilg and ethinyl estradiol 50 Ilg (6 patiepts); cyproterone acetate 2 mg and ethinyl estradiol 35 Ilg (10 patients). The OCs were supplied as 21-pill packages by Hormoquimica de Chile, Ltd., Santiago, Chile. Treatment was given during 21 days followed by a 7 -day rest; these cycles were repeated without interruption for 2 years. Two patients dropped out, and they are excluded from calculations; therefore, 24 ended the trial, and their distribution in the treatment groups is shown on Table 1. We were also able to obtain the cooperation of 19 healthy nonhirsute, normally cycling women, who did not receive treatment; they became the control group. Hirsutism was quantified using Lorenzo score,13 adding up only the points for the upper lip, chin and Table 1

neck, anterior chest, infraumbilical region, and thighs, with a maximum score of 20. The body mass index (BMI) , body weight in kg divided by the square of the height in meters, was recorded at the beginning of the study and at the end of each semester of follow-up. Blood samples were drawn from control women and from hirsute patients before beginning treatment, between the 5th and the 8th day of the menstrual cycle (if cycling regularly) or at a convenient day in those on amenorrhea. Blood sampling was repeated in patients with hirsutism at 12 and 24 months of therapy, on the same days of the cycle. The following plasma concentrations were measured: 17a- hydroxyprogesterone (17-0HP), dehydroepiandrosterone sulphate (DHEAS), total testosterone (T), free T, prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH), total cholesterol, cholesterol in high-density lipoproteins (HDL), and plasma triglycerides. The hormone determinations were performed through immunoassays at the Institute for Advanced Medical Studies, Santiago, Chile. Commercial kits from Diagnostic Products Corporation (Los Angeles, CA) were used for steroid determinations. The reagents and standard preparation (LER-907) for LH and FSH were obtained from the National Institute of Arthritis, Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland. The plasma lipid determinations were done with combined enzymatic and colorimetric reactions, and the HDL fraction was precipitated with heparinheavy metal reagent. These assays were under external quality control from the Institute of Public Health of the Republic of Chile, Santiago, Chile. Statistical analysis was performed through ANOVA (for matched and nonmatched data) and multiple comparison tests (Scheffe's and Fisher PLSD), using software Statview (Abacus Concepts, Inc., Berkeley, CA). In case of unequal variances or of discrete variables we used nonparametric tests

Initial Characteristics of Hirsute Women, Divided According to Assigned Treatment and Compared With Control Groupa Treatment groups

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Figure 1 Evolution of hirsutism in relation to time of treatment. Markers correspond to the mean and brackets show ±SE for each treatment group: squares are desogestrel150 mg + ethinyl estradiol 30 fJ.g, circles are desogestrel150 mg + ethinyl estradiol 50 fJ.g, and crosses are cyproterone acetate 2 mg + ethinyl estradiol 35 fJ.g. The shaded area shows the mean ± 1 SE for the control group. Vol. 55, No.5, May 1991

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At the beginning of the treatment, 11 of the 24 patients ending the trial were regularly cycling, oligomenorrhea was present in 5 of them, polymenorrhea in 1, and 7 were in secondary amenorrhea. Hirsutism scores at the beginning (mean 11.8 ± 2.85 SD) were remarkably high (in comparison with control group), but they were similar in the three treatment groups (Table 1). During treatment, there was a steady decline in the hirsutism score, of similar magnitude in the three experimental groups (Fig. 1). The reduction in this score (-7.15 ± 1.93 SD) was significant (P < 0.005), and it should be noticed that hirsute patients reached, at 24 months oftreatment, a level (mean 4.7 ± 2.8 SD) that is not statistically different from the control group. Initially, the BMI averages did not differ among the experimental groups (Table 1); the initial mean (±SD) for the hirsute patients was 23.4 ± 2.9 kgjm 2 , which is not significantly different from the control group. A small and not significant weight gain was seen with 2 years of treatment, on average +0.99 ± 3.84 kg (mean ± SD). The initial values of T and free T (Fig. 2) were very similar for the three treatment groups (mean ± SD: T 2.86 ± 1.48 nmoljL; free T 16.3 ± 4.84 pmoljL), but they were significantly higher than the controls (T 1.34 ± 0.40 nmoljL; free T 6.24 ± 1.88 pmoljL; P < 0.001). With treatment, there was a remarkable lowering in T and free T values already

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at 1 year (P < 0.01) when they leveled with controls, remaining equally low at 24 months. The initial DHEAS plasma levels were also higher than the controls (P = 0.04). A significant decline with treatment (P < 0.01) was seen in the DHEAS plasma levels, being more gradual than the reduction in T and free T, but at 24 months there was no significant difference in DHEAS between treatment and control groups. The PRL values (all within normal range) were not modified by treatment. Plasma 17 -OHP levels, originally not different from controls, also were not modified by therapy. The FSH and LH plasma levels were measured only in the hirsute patients. Their mean values (±SD) were initially FSH: 73.9 ± 26.9 ng LER-907 jmL and LH: 38.2 ± 30.9 ng LER907 jmL. They did not change significantly with time of treatment, and there appeared no differences among treatment groups (at 12 months FSH: 58.6 ± 40.1 and LH: 36.6 ± 31.4 ng LER-907jmL; at 24

PorcHe and Gallardo

Hirsutism: desogestrel or cyproterone

879

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months FSH: 82.9 ± 63.4 and LH: 30.85 ± 20.4 ng LER-907/mL). Initially, circulating plasma lipid levels (mean ± SD: total cholesterol 4.33 ± 1.4 mmoljL, HDL cholesterol 1.05 ± 0.2 mmoljL, triglycerides 0.92 ± 0.30 mmol/L) did not differ among treatment groups nor with the control group (mean ± SD: total cholesterol 4.78 ± 1.1 mmoljL; HDL cholesterol 1.12 ± 0.32 mmoljL; triglycerides 1.04 ± 0.32 mmoljL) (Fig. 3). With treatment, total cholesterol levels increased (+2.0 ± 1.6 mmoljL, P < 0.001), gradually but progressively in time (multiple comparison test, P < 0.05). Also HDL cholesterol augmented with treatment (+0.57 ± 0.5 mmoljL, P < 0.001), but this increment emerged later than total cholesterol, becoming significantly different at 24 months in comparison with the previously found values (Fig. 3). The total cholesteroljHDL cholesterol ratio was significantly increased (P = 0.0011) at 12 months but at 24 months returned to levels similar to those of the control group (Fig. 3). With respect to triglycerides, they show a moderate and persistent increment with time of treatment, as seen in Fig. 3 (paired increment ± SD: 0.33 ± 0.52 mmoljL, P = 0.0009). With these data, it is possible to calculate values for plasma low-density lipoprotein (LDL) cholesterol with the formula: LDL cholesterol = [total cholesterol] - [triglycerides/2.2] - [HDL cholesterol] mmoljL. The LDL cholesterol mean (±SD) was 3.18 ± 0.93 mmol/L for the control group, and the initial value for all the hirsute patients was 2.86 ± 1.30 mmol/L, not statistically different. It increased equally for the three treatment groups, becoming 3.88 ± 1.75 mmolfL at 12 months (P = 0.0011 compared with initial values) and 4.18 ± 1.19 mmoljL at 24 months (not statistically different from the values at 12 months). DISCUSSION

Desogestrel or cyproterone acetate, in low E OCs (ethinyl estradiol 30 to 35 Ilg) are very effective for the treatment of hirsutism, although it may be necessary to give them for 2 years. The OCs with antiandrogenic progestogen (in a dose that is lower than the one used as a plain antiandrogen)5 does not show any advantage over the one with nonandrogenic progestogen. No difference is seen among the effects ofthe various OCs tested, although ethinyl estradiol contents range from 30 to 50 Ilg. Apparently, 30 Ilg of ethinyl estradiol would be enough for hirsutism treatment; but the results of the alternative, due exclusively to 880

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progestogen action, cannot be disproved with our experimental design. Indeed, ethinyl estradiol and progestogen may act synergistically. The improvement in hirsutism is very slow, but very significant benefits may be obtained with time; our results show that at 24 months of therapy there is no statistical difference between the treated hirsutepatients and the control group. The rate of decline in hirsutism reported in this paper is very similar to that obtained by other investigators, who used OCs containing equal or higher doses of E.5,6,9,lO,14 Hirsutism scores correlate significantly before treatment with levels of T and free T (r = 0.64 and r = 0.86, respectively, with P < 0.01). The main reduction in T and free T occurs at 12 months of treatment (Fig. 1), before a major decline in body hair and suggesting a causal relationship. However, the reduction in hirsutism scores with 2 years of treatment is not correlated with the reduction in T or free T, possibly because plasma T and free Tare important but not unique determinants of hirsutism and also OCs may reduce hair through additional mechanisms. The reduction of T and free T is not associated to a fall in LH or FSH; we found that the gonadotropins do not apparently change with treatment. However, further research is needed because gonadotropins were measured only on a single day, at the beginning of the cycle. The reduction of DHEAS is also dissociated from the evolution of T and free T, is less marked, and takes longer time; this observation is compatible with different control mechanisms for both steroids. 15 In the hirsute women, initial values of total cholesterol, HDL cholesterol, and triglycerides are not

Hirsutism: desogestrel or cyproterone

Fertility and Sterility

different from the ones of the control group. We do not find changes suggesting androgenization of the plasma lipoprotein pattern,!l as seen by others. 16,17 The changes induced by treatment in total cholesterol and triglycerides are of equal magnitude in the three groups, without any relation to E dose. They occur in the same direction as the ones reported for nonhirsute women treated with OCS. 11 ,12 The rise in both these lipids persists during the 2 years of treatment, in contrast to a transient effect described by other investigators in nonhirsute women using OCS. 12 ,18 With prolongation of the treatment for 2 years, a late increase in HDL cholesterol can be detected. The ratio total cholesteroljHDL cholesterol, elevated at the end of the 1st year, becomes normal at the end of the 2nd year. This rise of HDL cholesterol in our sample of hirsute women occurs later than a similar change reported in nonhirsute women using low E OCsy,12,19 The LDL cholesterol, calculated indirectly, increases with time oftreatment at about the same rate in the three groups. This change in LDL cholesterol may be cautiously interpreted as an increased risk of cardiovascular disease, whereas the elevation of the ratio total cholesteroljHDL cholesterol may be interpreted as a reduced risk. The findings are not impressive, and they appear after prolonged observation of plasma lipids; they should not deter from useful application ofthis kind of OCs. Summarizing, the changes occurring in plasma lipids are of difficult interpretation,11,12,20 and it is necessary to emphasize the importance of longtime studies. In conclusion, hirsutism can be efficaciously treated with nonandrogenic as well as with antiandrogenic progestogens in low E OCs. Treatment should be prolonged to be effective. Acknowledgments. We thank Miss Patricia Duarte and Mrs. Olivia Munoz for careful keeping of patient records, and Mrs. Cecilia Keitel and Mrs. Trinidad Lira (Instituto de Estudios Medicos Avanzados) for their dedication to hormonal and biochemical determinations. We gratefully acknowledge the gift of radioimmunoassay reagents and standard preparation (LER-907) for the determination ofLH and FSH from the National Institute of Arthritis, Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, under the National Pituitary Hormones Program.

REFERENCES 1. Casey JH: Chronic treatment regimens for hirsutism in women. Effects on blood production rates of testosterone and hair growth. Clin Endocrinol (OxO 4:313, 1975

Vol. 55, No.5, May 1991

2. Ettinger B, Goldfield EB, Burrill KC, Von Werder K, Forsham PH: Plasma testosterone stimulation-suppression dynamics in hirsute women. Correlation with long-term therapy. Am J Med 54:195, 1973 3. Bergink EW, Klosterboer HS, Vander Vies J: Binding of progestogens to receptor proteins in MCF-7 cells. J Steroid Biochem 20:1057, 1984 4. Runnebaum T, Rabe T: New progestogens in oral contraceptives. Am J Obstet Gynecol 157:1059, 1987 5. Neumann F: Pharmacology and potential use of cyproterone acetate. Horm Metab Res 9:1, 1977 6. Porcile A, Martinez E: Tratamiento del hirsutismo en el sindrome de ovarios micropoliquisticos con estrogenos y progestageno secuencial. Rev Chil Obstet GinecoI47:8, 1982 7. Andersson RN, Givens JR, Weiser WL, Umstot ES: Response of the binding capacity of plasma testosterom!-estradiolbinding globulin to norethindrone, 2 mg, and mestranol, 0.1 mg, in polycystic ovarian disease. Am JObst Gynecol 125: 166, 1976 8. Shailaja GR, Madhwa HGR, Talbert LM, Sloan C, Hicks B: Normalization of testosterone levels using a low estrogen containing oral contraceptive in women with polycystic ovary syndrome. Obstet Gynecol 60:15, 1982 9. Cullberg G, Hamberger L, Mattsson L-A, Mobacken H, Samsioe G: Effects of a low-dose desogestrel-ethinylestradiol combination on hirsutism, androgens and sex hormone binding globulin in women with a polycystic ovary syndrome. Acta Obstet Gynecol Scand 64:195,1985 10. Dewis P, Petsos P, Newman M, Anderson DC: The treatment of hirsutism with a combination of desogestrel and ethinyl oestradiol. Clin Endocrinol (OxO 22:29, 1985 11. Gaspard U: Metabolic effects of oral contraceptives. Am J Obstet Gynecol 157:1029, 1989 12. Upton GV: Lipids, cardiovascular disease, and oral contraceptives: a practical perspective. Fertil Steril 53:1, 1990 13. Lorenzo EM: Familial study of hirsutism. J Clin Endocrinol Metab 31:556, 1970 14. Kutten F, Rigaud C, Wright F, Mauvais-Jarvis P: Treatment of hirsutism by oral cyproterone acetate and percutaneous estradiol. J Clin Endocrinol Metab 51:1107, 1980 15. Steinberger E, Smith KD, Rodriguez-Rigau LJ: Testosterone, dehydroepiandrosterone and dehydroepiandrosterone sulfate in hyperandrogenic women. J Clin Endocrinol Metab 59:471, 1984 16. Mattsson L-A, Cullberg G, Hamberger L, Samsioe G, Silfverstolpe G: Lipid metabolism in women with polycystic ovary syndrome: possible implications for an increased risk of coronary heart disease. Fertil Steril 42:579, 1984 17. Wortsman J, Soler NG: Abnormalities of fuel metabolism in the polycystic ovary syndrome. Obstet Gynecol 60:342, 1982 18. Samsioe G: Some metabolic effects of progestins. In Progestogens in Therapy, Edited by G Benagiano, P Zulli, E Diczfalusy. New York, Raven Press Inc., 1983, p 169 19. Gevers Leuven JA, de Pagter HAT, Dersjant-Roorda MA, Helmerhorst FA, Roelofsen J: Effect of two monophasic oral contraceptives containing gestodene or desogestrel on serum lipoprotein lipid levels. Int J Fertil 34(Suppl.):55, 1989 20. Goldzieher JW: Hormonal contraception: benefits versus risks. Am J Obstet GynecoI157:1023, 1987

PorcHe and Gallardo

Hirsutism: desogestrel or cyproterone

881

Long-term treatment of hirsutism: desogestrel compared with cyproterone acetate in oral contraceptives.

Effectiveness of 2-year treatment of hirsutism with low estrogen oral contraceptives (OCs) containing nonandrogenic or antiandrogenic progestogen. Eva...
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