- Email: [email protected]
Comparison of Diane 35 and Diane 35 plus spironolactone in the treatment of hirsutism
FERTILITY
AND STERILITY”
VOL. 69, NO. I, JANUARY 1998 Copyright 01998 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A.
Comparison of Diane 35 and Diane 35 plus spironolactone in the treatment of hirsutism Fahrettin Kelegtimur, M.D.* and Yilmaz $ahin, M.D.t Erciyes University, Faculty of Medicine,
Kayseri, Turkey
Objective: To compare the clinical efficacy and safety of Diane 35 (cyproterone acetate [2] mg and ethinyl estradiol [35 Fg]) plus spironolactone [lo0 mg] combination and Diane 35 alone in the treatment of hirsutism. Design: Prospective clinical study. Setting: Outpatients in Erciyes University Medical School. Patient(s): Fifty women with hirsutism. Intervention(s): Group I patients (n = 22) were treated with Diane 35 alone and group II patients (n = 28) with Diane 35 plus spironolactone [lo0 mg]. Main Outcome Measure(s): The basal hormone levels total and free T, androstenedione, DHEAS, sex hormone-binding globulin (SHBG), and prolactin (PRL) were measured by RIA before the study. Free T, SHBG, and DHEAS were also measured at 6-month intervals for 12 months. Hirsutism was graded at 6-month intervals. Result(s): The basal hormone levels were similar between the groups. Hirsutism score significantly decreased at the end of the therapy in both groups. The reduction in hirsutism score in group II at 12 months was greater than in group I. But the scores before the treatment, at 6 and 12 months were similar between the groups. Conclusion(s): Although the actual hirsutism score and free T concentration are not significantly different between the two groups at 12 months, percentage change in the hirsutism score at 12 months was higher in the Diane 35 plus spironolactone group. Therefore, the addition of spironolactone to Diane 35 may have a synergistic effect on hirsutism score. (Fertil Steril@ 1998;69:66-9. 01998 by American Society for Reproductive Medicine.) Key Words: Diane 35, spironolactone, hirsutism Received April 24, 1997; revised and accepted August 12, 1997. *Department of Endocrinology. tDepartment of Obstetrics and Gynecology. Reprint requests: Fahrettin Keleqtimur, M.D., Department of Endocrinology, Erciyes University, Faculty of Medicine, 38039 Kayseri, Turkey (FAX: 00-90-352 -437 57 02). 00150282/98/$19.00 PII s0015-0282(97)00427-5
66
Hirsutism, the presence of male type hair in a male distribution in a woman, is the result of either androgen excess of increased sensitivity of hair follicles to normal levels of androgens (1). Unfortunately, treatment of hirsutism is far from satisfactory. Most treatments are only partially effective. Cosmetic measures including plucking, bleaching, depilatory creams, electrolysis, waxing, and shaving are of great value but also have disadvantages. Hormonal treatment options include adrenal suppression (2), ovarian suppression (3), the use of antiandrogens (4), and the use of 5-cz-reductase inhibitors (5).
Therapy for hirsutism includes glucocorticoids, estrogens, and nonestrogenic antiandrogens. Glucocorticoidsused in the treatment of hirsutism secondary to all forms of congenital and late-onset adrenal hyperplasia have some well-known side effects. Estrogens may be contraindicated in those with obesity, hypertension, and migraine. Spironolactone has been widely used for hirsutism. Spironolactone, a potassiumsparing diuretic, decreases hair growth primarily by acting peripherally and interferes with the interaction of dihidrotestosterone and its intracellular receptor. Testosterone production also is
inhibited by this drug (6). The clinical effectiveness of spironola&me varies among patients. Cyproterone acetate is a powerful progestogen that also acts as an antiandrogen at target sites and it seems to be effective in a large number of patients (7). Various drug combinations have been used for the treatment of hirsutism with some success. Our preliminary data showed that Diane plus spironolactone is a more effective therapeutic option in decreasing Ferriman-Gallwey score when comparing Diane 35 alone (8). We wished to compare the clinical efficacy of these two treatments and to see whether the addition of spironolactone to Diane 35 has an synergistic effect.
MATERIALS AND METHODS Fifty Turkish women were recruited into the study from our outpatient hirsutism clinic. This study was approved by the ethics committee of Erciyes University Medical School. Each woman gave informed consent. Patients with Cushing’s syndrome, androgen-secreting tumors, prolactinoma, or any other disease were excluded. The diagnosis of congenital adrenal hyperplasia was excluded by 17-hydroxyprogesterone response to ACTH (data not demonstrated). ACTH stimulation test was performed in the patients by administration of a single IV bolus of 0.25 mg synthetic ACTH-( l-24) (Synacthen, Ciba, Basel, Switzerland) at 0800 hours in the midfollicular phase. ACTH stimulated 17-OH P levels >30 nmol/L were considered as the criterion of late onset 21-hydroxylase deficiency (9). For at least 6 months before the study, patients had not taken medications known to affect the pituitary-gonadal function. No patient had clitoromegaly or other evidence of true virilism. Hirsutism score was graded according to modified Ferriman-Gallwey scoring system (10) by the same observer (Y.S.) at 6-month intervals. The hirsute patients (modified Ferriman-Gallwey score >8) were randomly divided into two treatment groups. Patients were randomized by the treating physician in altemating sequence. Twenty-two patients (group I) were treated with Diane 35 (2 mg cyproterone acetate plus 35 pg ethinil estradiol) and 28 patients (group II) with Diane 35 plus 100 mg spironolactone. The observer was not aware of the drugs given the patients. The treating physician and the observer who scored the hirsutism were different. The treating physician was aware of the treatment assignment, but the remainder of the study was double blinded. Study groups were equal in number at the beginning of the study, but six patients in group I left the study before the first evaluation. We gave spironolactone continuously. A treatment period of 12 months was chosen to reduce any error introduced by seasonal variation in hair growth and to allow the full therapeutic effect to develop (11). Forty-one percent and 50% of women were oligo/ FERTILITY & STERILITY@
amenorrheic in group I and group II, respectively. Of the 22 women in group I, 6 left the study after 6 months of treatment and 16 completed the study. Six patients in group II left the study before the third evaluation and 22 patients completed the study. These 12 patients dropped out because of unknown reasons. Serum hormone levels were measured before the study. Free T, sex hormone-binding globulin (SHBG), and DHEAS were also measured at 6-month intervals for 12 months. Blood samples were drawn from the women after an overnight fasting before beginning treatment in the midfollicular phase of the menstrual cycle (if cycling regularly) or at a convenient day in those with amenorrhea. Blood sampling was repeated in the patients at 6 and 12 months of therapy, on the same day of the cycle. Sera were stored at -20°C until assayed. Serum total T and free T, androstenedione (A), SHBG, DHEAS, and prolactin (PRL) levels were determined by RIA, using commercial kits (total T and free T, Diagnostic Products Corp., Los Angeles, CA; A, DSL Inc, Webster, TX; SHBG, Orion D, Espoo, Finland; DHEAS, ICN Biomedicals, Inc., Costa Mesa, CA). The intraassay and interassay precision coefficients of variation were 4.3% and 5.5% for free T; 10% and 10.4% for total T; 4.3% and 6% for A; 5.3-5.5% and 3.3-6.9% for SHBG; 14.8% and 16.6% for DHEAS, respectively. The body mass index (BMI), body weight in kilograms divided by the square of the height in meters, was recorded at the beginning of the study. For statistical analysis Student’s unpaired t-test was used for comparisons between the groups. A P value of CO.05 was regarded as statistically significant. The paired t-test using Bonferroni’s correction was performed to compare the changes in basal hirsutism score and hormone levels within each treatment group. Values are expressed as means t SD.
RESULTS The mean age + SD of the patients in group I (22.4 + 5.6; range, 17-38 years) was similar to the mean age 2 SD of the patients in group II (23.1 2 6.8; range, 15-35 years). The mean BMI It SD for group I (23.7 +- 5.6 kg/m*) and group II (22.7 + 8.3 kg/m*) was also similar (P >O.OS). Basal mean serum total T (70.95 + 31.44 and 77.88 +- 28.84 ng/dL), A (4.46 ? 2.65 and 4.92 + 1.81 ng/mL), and PRL levels (18.31 f- 11.06 and 15.84 ? 6.56 ng/mL) were also similar between group I and group II, respectively. Hirsutism scores, free T, DHEAS, and SHBG levels during treatments are shown in Table 1. The scores before the treatment, at 6 and 12 months were similar between the groups. Hirsutism score significantly reduced at the end of the therapy in both groups (P <0.0005). The reductions in hirsutism scores (mean% f SD) at 6 (40.2 -+ 21.0 and 41.6 2 16.5, P >0.05) and 12 months (54.3 + 22.1 and 67
Hirsutism scores and hormonal parameters before and after Diane 35 and Diane 35 plus spironolactone treatments. Parameters Hirsutism score Diane 35 Diane plus spironolactone Free T (pg/mL) Diane 35 Diane plus spironolactone DHEAS (pg/dL) Diane 35 Diane plus spironolactone SHBG (nmol/L) Diane 35 Diane plus spironolactone
Month 6
Month 12
15.9 ? 5.3*t
10.1 k 6.2*
7.5 k 5.1*
17.9 ? 5.3t
10.8 2 4.8
6.3 2 3.4
3.78 ? 1.94*t
1.51 i 1.05*
1.34 ? 1.35*
4.56 2 1.72t
1.49 ? 1.09
1.24 -c 0.76
289 ? 108*
249 2 107*
230 2 lOO*
3 11 2 134
261 2 123
261 2 122
Baseline
36.3 ? 17.4*1_
199.2 2 167.7*
225.2 t 178.9%
38.8 2 23.6t
150.4 2 66.7
165.1 F 53.9
Note. Values are means 2 SD. * P >0.05, compared with Diane 35 plus spironolactone t P <0.0005, compared with 6- and 12-month values.
68.82 19.6, P <0.025) in illustrated
groups
group.
I and II, respectively,
are
in Figure 1.
Free T levels were similar between the groups at 6 and 12 months. The reductions (mean% + SD) in free T levels were similar at 6 (47.06 ? 41.61 and 65.61 + 26.70, P BO.05) and 12 months (56.05 2 43.20 and 73.80 + 18.62, P >0.05) in groups I and II, respectively. SHBG levels before the treatment and during the therapy were similar between the groups (P>0.05). SHBG levels increased significantly at the end of the therapy in both groups when compared with basal levels (P<0.0005). The increases (mean% 2 SD) in SHBG levels were similar at 6 (580.8 ? 398.0 and 410.1 ? 272.4) and 12 months (765.5 2 671.8 and 433.0 -+ 261.4) in groups I and II, respectively (P BO.05). The levels in DHEAS between the groups were similar (P >0.05) at 6 and 12 months, and DHEAS levels did not change during both treatments. There were no side effects requiring cessation of therapy in the patients of the groups.
sites (12). Spironolactone binds to the androgen receptor with about 67% of the aftinity of dihydrotestosterone (13). Despite the widespread use of CPA and spironolactone in the treatment of hirsutism, their combination has not been used. We believe that the combination of these two drugs may occupy more receptors than the one drug alone occupies. Free T levels and hirsutism scores decreased significantly in both groups during treatment. The addition of spironolactone to Diane 35 resulted in a greater decrease in hirsutism score but not in free T levels. Carmina and Lobo (14) also found that with spironolactone therapy, the reduction in hirsutism scores did not correlate with the changes in androgen levels. In that study, nine women received spironolactone 100 mg/day for 1 year and did not have significant changes in serum free T but had a significant reduction in the hirsutism score. Serum free T was found to be unaltered by spironolactone and it was suggested that the antiandrogenic effect of spironolactone are primarily related to its peripheral effect (15). In contrast, spironolactone was also reported as a highly effective and safe agent for the treatment of hirsutism through its inhibitory action on both ovarian androgen secretion including free T and peripheral androgen action (16, 17). In our study, the most significant reduction in hirsutism score appeared at 12 months in the patients receiving Diane 35 plus spironolactone when the reduction in free T levels were similar between the groups. It seems that
Changes in the hirsutism score during 12 months of therapy with Diane 35 or Diane 35 plus spironolactone. Values for hirsutism score are expressed as a percentage of baseline (time 0) mean hirsutism score. *P ~0.025 (vs. Diane 35 group).
-
Diane
-
Diane plus spironolactone
DISCUSSION Hirsutism is a common clinical condition in women characterized by excessive growth of terminal hair in the androgensensitive skin regions. Some drugs have been used in the treatment of hirsutism with various success. Among these drugs, CPA is a powerful progestogen that also acts as an antiandrogen at target sites. It seems to be effective in a large number of patients (7). Spironolactone has been widely used for hirsutism, particularly in those women in whom estrogens are contraindicated. It is a steroid and reduces androgen synthesis and competes with dihydrotestosterone for target organ-binding
68
Kele$imur
and Sahin
Diane
and Diane
plus
spironolactone
O-l
I 0
6
12
Months of treatment
in hirsutism
Vol. 69, No. 1, January
1998
spironolactone decreases hirsutism score through its inhibitory effect on peripheral androgen action rather than androgen secretion. The SHBG levels increased significantly at the end of the therapy in both groups. We found that spironolactone did not affect SHBG levels, as the increase in SHBG levels in group II was not greater than in group 1. It was found that after treatment with spironolactone (200 mg/d), for 3 months, SI-IBG was not significantly altered (15). Ethinyl estradiol included in Diane 35 was responsible for the increase in SHBG levels in both groups. The most important effects of estrogen are reduced androgen synthesis, direct antiandrogenie activity at the target site, and altered androgen metabolism by induction of synthesis of SHBG (12). Both kinds of therapy did not significantly reduce DHEAS levels at the end of the l-year therapy. Spironolactone (100 mg/d), has been shown previously to decrease the hirsutism score but did not affect androgen levels, both of glandular and peripheral origin including DHEAS (14). Therefore, spironolactone does not change serum concentration of DHEAS (6). By giving the combination of Diane 35 plus spironolactone, we have treated the patients with CPA, estrogen, and spironolactone. Thus, by this therapy it has been possible to decrease androgen levels, both of glandular and peripheral origin, and interfere with the interaction of dihydrotestosterone and its intracellular receptor. In conclusion, the present data demonstrate that Diane 35 alone and Diane 35 plus spironolactone 100 mg combination are effective and safe in the treatment of hirsutism. Although, the actual hirsutism score and free T concentration are not significantly different between the two groups at 12 months, percentage change in the Ferriman-Gallwey score at 12 months from baseline level was higher in the patients treated with Diane 35 plus spironolactone than in the patients treated with Diane 35
FERTILITY
& STERILITY@
alone. Therefore, the addition of spironolactone to Diane 35 may have a synergistic effect on hirsutism score. References 1. McCenna TJ. The use of anti-androgens in the treatment of hirsutism. Clin Endocrinol 1991;35:1-3. 2. Rittmaster RS, Thompson DL. Effect of leuprolide and dexamethasone on hair growth and hormone levels in hirsute women: The relative importan:e of the ovary and the adrenal in the pathogenesis of hirsutism. J Clin Endocrinol Metab 1990:70:1096-102. 3. Givens JR. Role of oral contraceptives in the treatment of hyperandrogenism of hirsute women. In: Mahesh VB, Greenblatt RB, editors. Hirsutism and virilism: Pathogenesis, diagnosis and treatment. Boston: John Wright, PSG Inc., 1983:351-67. Miller JA. Jacobs HS. Treatment of hirsutism and acne with cvuroterone acetate. Clin Endocrinol Metab 1986;15:373-89. ._ Brooks JR. Treatment of hirsutism with 5 cu-reductase inhibitors. Clin Endocrinol Metab 1986;15:391-405. Schriock EA, Schriock ED. Treatment of hirsutism. Clin Obstet Gynecol 1991;34:852-63. Hammerstein J, Meckies J, Leo-Rossberg I. Use of cyproterone acetate (CPA) in the treatment of acne, hirsutism and virllism. J Steroid Biochem Mol Biol 1975;6:827-36. 8. Kelestimur F, Sahin Y, Turan R, Avata D. A comparison of Diane 35 plus spironolactone and diane 35 [ii the treatment of hirsutism (Abstract). J Endocrinol 1993;139(Suppl):91. 9. New MI. Lorenzen F. Lemer AJ. Kohn B. Obertield SE. Pollack MS. et al. Genotyping steroid 21-hydroxylase deficiency: hormonal refer: ence data. J Clin Endocrinol Metab 1983:57:320-6. 10. Hatch R. Rosenfield RL, Kim MH, Tredway D. Hirsutism: Implications, etiology, and management. Am J Obstet Gynecol 1981;140:81530. 11. Casey JH, Moxham A, Nabarro JDN. Idiopathic hirsutism: Seasonal variation of hair growth and response to estrogen administration. Lancet 1964;i:587-8. 12. Jeffcoate W. The treatment of women with hirsutism. Clin Endocrinol 1993;39:143-50. 13. Eil C, Edelson SK. The use of human skin fibroblasts to obtain potency estimates of drug binding to androgen receptors. J Clin Endocrinol Metab 1984;59:51-5. 14. Carmina E, Lobo RA. Peripheral androgen blockade versus glandular androgen suppression in the treatment of hirsutism. Obstet Gynecol 1991;78:845-9. 15. Lobo RA, Shoupe D, Serafini P, Brinton D, Horton R. The effects of two doses of spironolactone on serum androgens and anagen hair in hirsute women. Fertil Steril 1985;43:200-5. 16. Cumming DC, Yang JC, Rebar RW, Yen SC. Treatment of hirsutism with suironolactone. J Am Med Assoc 1982:247:1295-8. 17. YlSstrdo P, Heikkinen J, Kauppila A, Pakarinen A, Jarvinen PA. Low dose spironolactone in the treatment of female hirsutism. Int J Fertil 1987;32:41-5
69
AND STERILITY”
VOL. 69, NO. I, JANUARY 1998 Copyright 01998 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A.
Comparison of Diane 35 and Diane 35 plus spironolactone in the treatment of hirsutism Fahrettin Kelegtimur, M.D.* and Yilmaz $ahin, M.D.t Erciyes University, Faculty of Medicine,
Kayseri, Turkey
Objective: To compare the clinical efficacy and safety of Diane 35 (cyproterone acetate [2] mg and ethinyl estradiol [35 Fg]) plus spironolactone [lo0 mg] combination and Diane 35 alone in the treatment of hirsutism. Design: Prospective clinical study. Setting: Outpatients in Erciyes University Medical School. Patient(s): Fifty women with hirsutism. Intervention(s): Group I patients (n = 22) were treated with Diane 35 alone and group II patients (n = 28) with Diane 35 plus spironolactone [lo0 mg]. Main Outcome Measure(s): The basal hormone levels total and free T, androstenedione, DHEAS, sex hormone-binding globulin (SHBG), and prolactin (PRL) were measured by RIA before the study. Free T, SHBG, and DHEAS were also measured at 6-month intervals for 12 months. Hirsutism was graded at 6-month intervals. Result(s): The basal hormone levels were similar between the groups. Hirsutism score significantly decreased at the end of the therapy in both groups. The reduction in hirsutism score in group II at 12 months was greater than in group I. But the scores before the treatment, at 6 and 12 months were similar between the groups. Conclusion(s): Although the actual hirsutism score and free T concentration are not significantly different between the two groups at 12 months, percentage change in the hirsutism score at 12 months was higher in the Diane 35 plus spironolactone group. Therefore, the addition of spironolactone to Diane 35 may have a synergistic effect on hirsutism score. (Fertil Steril@ 1998;69:66-9. 01998 by American Society for Reproductive Medicine.) Key Words: Diane 35, spironolactone, hirsutism Received April 24, 1997; revised and accepted August 12, 1997. *Department of Endocrinology. tDepartment of Obstetrics and Gynecology. Reprint requests: Fahrettin Keleqtimur, M.D., Department of Endocrinology, Erciyes University, Faculty of Medicine, 38039 Kayseri, Turkey (FAX: 00-90-352 -437 57 02). 00150282/98/$19.00 PII s0015-0282(97)00427-5
66
Hirsutism, the presence of male type hair in a male distribution in a woman, is the result of either androgen excess of increased sensitivity of hair follicles to normal levels of androgens (1). Unfortunately, treatment of hirsutism is far from satisfactory. Most treatments are only partially effective. Cosmetic measures including plucking, bleaching, depilatory creams, electrolysis, waxing, and shaving are of great value but also have disadvantages. Hormonal treatment options include adrenal suppression (2), ovarian suppression (3), the use of antiandrogens (4), and the use of 5-cz-reductase inhibitors (5).
Therapy for hirsutism includes glucocorticoids, estrogens, and nonestrogenic antiandrogens. Glucocorticoidsused in the treatment of hirsutism secondary to all forms of congenital and late-onset adrenal hyperplasia have some well-known side effects. Estrogens may be contraindicated in those with obesity, hypertension, and migraine. Spironolactone has been widely used for hirsutism. Spironolactone, a potassiumsparing diuretic, decreases hair growth primarily by acting peripherally and interferes with the interaction of dihidrotestosterone and its intracellular receptor. Testosterone production also is
inhibited by this drug (6). The clinical effectiveness of spironola&me varies among patients. Cyproterone acetate is a powerful progestogen that also acts as an antiandrogen at target sites and it seems to be effective in a large number of patients (7). Various drug combinations have been used for the treatment of hirsutism with some success. Our preliminary data showed that Diane plus spironolactone is a more effective therapeutic option in decreasing Ferriman-Gallwey score when comparing Diane 35 alone (8). We wished to compare the clinical efficacy of these two treatments and to see whether the addition of spironolactone to Diane 35 has an synergistic effect.
MATERIALS AND METHODS Fifty Turkish women were recruited into the study from our outpatient hirsutism clinic. This study was approved by the ethics committee of Erciyes University Medical School. Each woman gave informed consent. Patients with Cushing’s syndrome, androgen-secreting tumors, prolactinoma, or any other disease were excluded. The diagnosis of congenital adrenal hyperplasia was excluded by 17-hydroxyprogesterone response to ACTH (data not demonstrated). ACTH stimulation test was performed in the patients by administration of a single IV bolus of 0.25 mg synthetic ACTH-( l-24) (Synacthen, Ciba, Basel, Switzerland) at 0800 hours in the midfollicular phase. ACTH stimulated 17-OH P levels >30 nmol/L were considered as the criterion of late onset 21-hydroxylase deficiency (9). For at least 6 months before the study, patients had not taken medications known to affect the pituitary-gonadal function. No patient had clitoromegaly or other evidence of true virilism. Hirsutism score was graded according to modified Ferriman-Gallwey scoring system (10) by the same observer (Y.S.) at 6-month intervals. The hirsute patients (modified Ferriman-Gallwey score >8) were randomly divided into two treatment groups. Patients were randomized by the treating physician in altemating sequence. Twenty-two patients (group I) were treated with Diane 35 (2 mg cyproterone acetate plus 35 pg ethinil estradiol) and 28 patients (group II) with Diane 35 plus 100 mg spironolactone. The observer was not aware of the drugs given the patients. The treating physician and the observer who scored the hirsutism were different. The treating physician was aware of the treatment assignment, but the remainder of the study was double blinded. Study groups were equal in number at the beginning of the study, but six patients in group I left the study before the first evaluation. We gave spironolactone continuously. A treatment period of 12 months was chosen to reduce any error introduced by seasonal variation in hair growth and to allow the full therapeutic effect to develop (11). Forty-one percent and 50% of women were oligo/ FERTILITY & STERILITY@
amenorrheic in group I and group II, respectively. Of the 22 women in group I, 6 left the study after 6 months of treatment and 16 completed the study. Six patients in group II left the study before the third evaluation and 22 patients completed the study. These 12 patients dropped out because of unknown reasons. Serum hormone levels were measured before the study. Free T, sex hormone-binding globulin (SHBG), and DHEAS were also measured at 6-month intervals for 12 months. Blood samples were drawn from the women after an overnight fasting before beginning treatment in the midfollicular phase of the menstrual cycle (if cycling regularly) or at a convenient day in those with amenorrhea. Blood sampling was repeated in the patients at 6 and 12 months of therapy, on the same day of the cycle. Sera were stored at -20°C until assayed. Serum total T and free T, androstenedione (A), SHBG, DHEAS, and prolactin (PRL) levels were determined by RIA, using commercial kits (total T and free T, Diagnostic Products Corp., Los Angeles, CA; A, DSL Inc, Webster, TX; SHBG, Orion D, Espoo, Finland; DHEAS, ICN Biomedicals, Inc., Costa Mesa, CA). The intraassay and interassay precision coefficients of variation were 4.3% and 5.5% for free T; 10% and 10.4% for total T; 4.3% and 6% for A; 5.3-5.5% and 3.3-6.9% for SHBG; 14.8% and 16.6% for DHEAS, respectively. The body mass index (BMI), body weight in kilograms divided by the square of the height in meters, was recorded at the beginning of the study. For statistical analysis Student’s unpaired t-test was used for comparisons between the groups. A P value of CO.05 was regarded as statistically significant. The paired t-test using Bonferroni’s correction was performed to compare the changes in basal hirsutism score and hormone levels within each treatment group. Values are expressed as means t SD.
RESULTS The mean age + SD of the patients in group I (22.4 + 5.6; range, 17-38 years) was similar to the mean age 2 SD of the patients in group II (23.1 2 6.8; range, 15-35 years). The mean BMI It SD for group I (23.7 +- 5.6 kg/m*) and group II (22.7 + 8.3 kg/m*) was also similar (P >O.OS). Basal mean serum total T (70.95 + 31.44 and 77.88 +- 28.84 ng/dL), A (4.46 ? 2.65 and 4.92 + 1.81 ng/mL), and PRL levels (18.31 f- 11.06 and 15.84 ? 6.56 ng/mL) were also similar between group I and group II, respectively. Hirsutism scores, free T, DHEAS, and SHBG levels during treatments are shown in Table 1. The scores before the treatment, at 6 and 12 months were similar between the groups. Hirsutism score significantly reduced at the end of the therapy in both groups (P <0.0005). The reductions in hirsutism scores (mean% f SD) at 6 (40.2 -+ 21.0 and 41.6 2 16.5, P >0.05) and 12 months (54.3 + 22.1 and 67
Hirsutism scores and hormonal parameters before and after Diane 35 and Diane 35 plus spironolactone treatments. Parameters Hirsutism score Diane 35 Diane plus spironolactone Free T (pg/mL) Diane 35 Diane plus spironolactone DHEAS (pg/dL) Diane 35 Diane plus spironolactone SHBG (nmol/L) Diane 35 Diane plus spironolactone
Month 6
Month 12
15.9 ? 5.3*t
10.1 k 6.2*
7.5 k 5.1*
17.9 ? 5.3t
10.8 2 4.8
6.3 2 3.4
3.78 ? 1.94*t
1.51 i 1.05*
1.34 ? 1.35*
4.56 2 1.72t
1.49 ? 1.09
1.24 -c 0.76
289 ? 108*
249 2 107*
230 2 lOO*
3 11 2 134
261 2 123
261 2 122
Baseline
36.3 ? 17.4*1_
199.2 2 167.7*
225.2 t 178.9%
38.8 2 23.6t
150.4 2 66.7
165.1 F 53.9
Note. Values are means 2 SD. * P >0.05, compared with Diane 35 plus spironolactone t P <0.0005, compared with 6- and 12-month values.
68.82 19.6, P <0.025) in illustrated
groups
group.
I and II, respectively,
are
in Figure 1.
Free T levels were similar between the groups at 6 and 12 months. The reductions (mean% + SD) in free T levels were similar at 6 (47.06 ? 41.61 and 65.61 + 26.70, P BO.05) and 12 months (56.05 2 43.20 and 73.80 + 18.62, P >0.05) in groups I and II, respectively. SHBG levels before the treatment and during the therapy were similar between the groups (P>0.05). SHBG levels increased significantly at the end of the therapy in both groups when compared with basal levels (P<0.0005). The increases (mean% 2 SD) in SHBG levels were similar at 6 (580.8 ? 398.0 and 410.1 ? 272.4) and 12 months (765.5 2 671.8 and 433.0 -+ 261.4) in groups I and II, respectively (P BO.05). The levels in DHEAS between the groups were similar (P >0.05) at 6 and 12 months, and DHEAS levels did not change during both treatments. There were no side effects requiring cessation of therapy in the patients of the groups.
sites (12). Spironolactone binds to the androgen receptor with about 67% of the aftinity of dihydrotestosterone (13). Despite the widespread use of CPA and spironolactone in the treatment of hirsutism, their combination has not been used. We believe that the combination of these two drugs may occupy more receptors than the one drug alone occupies. Free T levels and hirsutism scores decreased significantly in both groups during treatment. The addition of spironolactone to Diane 35 resulted in a greater decrease in hirsutism score but not in free T levels. Carmina and Lobo (14) also found that with spironolactone therapy, the reduction in hirsutism scores did not correlate with the changes in androgen levels. In that study, nine women received spironolactone 100 mg/day for 1 year and did not have significant changes in serum free T but had a significant reduction in the hirsutism score. Serum free T was found to be unaltered by spironolactone and it was suggested that the antiandrogenic effect of spironolactone are primarily related to its peripheral effect (15). In contrast, spironolactone was also reported as a highly effective and safe agent for the treatment of hirsutism through its inhibitory action on both ovarian androgen secretion including free T and peripheral androgen action (16, 17). In our study, the most significant reduction in hirsutism score appeared at 12 months in the patients receiving Diane 35 plus spironolactone when the reduction in free T levels were similar between the groups. It seems that
Changes in the hirsutism score during 12 months of therapy with Diane 35 or Diane 35 plus spironolactone. Values for hirsutism score are expressed as a percentage of baseline (time 0) mean hirsutism score. *P ~0.025 (vs. Diane 35 group).
-
Diane
-
Diane plus spironolactone
DISCUSSION Hirsutism is a common clinical condition in women characterized by excessive growth of terminal hair in the androgensensitive skin regions. Some drugs have been used in the treatment of hirsutism with various success. Among these drugs, CPA is a powerful progestogen that also acts as an antiandrogen at target sites. It seems to be effective in a large number of patients (7). Spironolactone has been widely used for hirsutism, particularly in those women in whom estrogens are contraindicated. It is a steroid and reduces androgen synthesis and competes with dihydrotestosterone for target organ-binding
68
Kele$imur
and Sahin
Diane
and Diane
plus
spironolactone
O-l
I 0
6
12
Months of treatment
in hirsutism
Vol. 69, No. 1, January
1998
spironolactone decreases hirsutism score through its inhibitory effect on peripheral androgen action rather than androgen secretion. The SHBG levels increased significantly at the end of the therapy in both groups. We found that spironolactone did not affect SHBG levels, as the increase in SHBG levels in group II was not greater than in group 1. It was found that after treatment with spironolactone (200 mg/d), for 3 months, SI-IBG was not significantly altered (15). Ethinyl estradiol included in Diane 35 was responsible for the increase in SHBG levels in both groups. The most important effects of estrogen are reduced androgen synthesis, direct antiandrogenie activity at the target site, and altered androgen metabolism by induction of synthesis of SHBG (12). Both kinds of therapy did not significantly reduce DHEAS levels at the end of the l-year therapy. Spironolactone (100 mg/d), has been shown previously to decrease the hirsutism score but did not affect androgen levels, both of glandular and peripheral origin including DHEAS (14). Therefore, spironolactone does not change serum concentration of DHEAS (6). By giving the combination of Diane 35 plus spironolactone, we have treated the patients with CPA, estrogen, and spironolactone. Thus, by this therapy it has been possible to decrease androgen levels, both of glandular and peripheral origin, and interfere with the interaction of dihydrotestosterone and its intracellular receptor. In conclusion, the present data demonstrate that Diane 35 alone and Diane 35 plus spironolactone 100 mg combination are effective and safe in the treatment of hirsutism. Although, the actual hirsutism score and free T concentration are not significantly different between the two groups at 12 months, percentage change in the Ferriman-Gallwey score at 12 months from baseline level was higher in the patients treated with Diane 35 plus spironolactone than in the patients treated with Diane 35
FERTILITY
& STERILITY@
alone. Therefore, the addition of spironolactone to Diane 35 may have a synergistic effect on hirsutism score. References 1. McCenna TJ. The use of anti-androgens in the treatment of hirsutism. Clin Endocrinol 1991;35:1-3. 2. Rittmaster RS, Thompson DL. Effect of leuprolide and dexamethasone on hair growth and hormone levels in hirsute women: The relative importan:e of the ovary and the adrenal in the pathogenesis of hirsutism. J Clin Endocrinol Metab 1990:70:1096-102. 3. Givens JR. Role of oral contraceptives in the treatment of hyperandrogenism of hirsute women. In: Mahesh VB, Greenblatt RB, editors. Hirsutism and virilism: Pathogenesis, diagnosis and treatment. Boston: John Wright, PSG Inc., 1983:351-67. Miller JA. Jacobs HS. Treatment of hirsutism and acne with cvuroterone acetate. Clin Endocrinol Metab 1986;15:373-89. ._ Brooks JR. Treatment of hirsutism with 5 cu-reductase inhibitors. Clin Endocrinol Metab 1986;15:391-405. Schriock EA, Schriock ED. Treatment of hirsutism. Clin Obstet Gynecol 1991;34:852-63. Hammerstein J, Meckies J, Leo-Rossberg I. Use of cyproterone acetate (CPA) in the treatment of acne, hirsutism and virllism. J Steroid Biochem Mol Biol 1975;6:827-36. 8. Kelestimur F, Sahin Y, Turan R, Avata D. A comparison of Diane 35 plus spironolactone and diane 35 [ii the treatment of hirsutism (Abstract). J Endocrinol 1993;139(Suppl):91. 9. New MI. Lorenzen F. Lemer AJ. Kohn B. Obertield SE. Pollack MS. et al. Genotyping steroid 21-hydroxylase deficiency: hormonal refer: ence data. J Clin Endocrinol Metab 1983:57:320-6. 10. Hatch R. Rosenfield RL, Kim MH, Tredway D. Hirsutism: Implications, etiology, and management. Am J Obstet Gynecol 1981;140:81530. 11. Casey JH, Moxham A, Nabarro JDN. Idiopathic hirsutism: Seasonal variation of hair growth and response to estrogen administration. Lancet 1964;i:587-8. 12. Jeffcoate W. The treatment of women with hirsutism. Clin Endocrinol 1993;39:143-50. 13. Eil C, Edelson SK. The use of human skin fibroblasts to obtain potency estimates of drug binding to androgen receptors. J Clin Endocrinol Metab 1984;59:51-5. 14. Carmina E, Lobo RA. Peripheral androgen blockade versus glandular androgen suppression in the treatment of hirsutism. Obstet Gynecol 1991;78:845-9. 15. Lobo RA, Shoupe D, Serafini P, Brinton D, Horton R. The effects of two doses of spironolactone on serum androgens and anagen hair in hirsute women. Fertil Steril 1985;43:200-5. 16. Cumming DC, Yang JC, Rebar RW, Yen SC. Treatment of hirsutism with suironolactone. J Am Med Assoc 1982:247:1295-8. 17. YlSstrdo P, Heikkinen J, Kauppila A, Pakarinen A, Jarvinen PA. Low dose spironolactone in the treatment of female hirsutism. Int J Fertil 1987;32:41-5
69