Pharmacologic Treatment of Polycystic Ovary Syndrome

David A. Ehrmann; Daniel Rychlik

doi:10.1055/s-2003-43305

Seminars in Reproductive Medicine, Table of Contents

Semin Reprod Med 2003; 21(3): 277-284
DOI: 10.1055/s-2003-43305

Pharmacologic Treatment of Polycystic Ovary Syndrome

David A. Ehrmann¹ , Daniel Rychlik²

¹Department of Medicine, Section of Endocrinology, The University of Chicago, Chicago, Illinois
²Department of Obstetrics and Gynecology, Section of Reproductive Endocrinology, The University of Chicago, Chicago, Illinois

Abstract

ABSTRACT

Women with polycystic ovary syndrome (PCOS) most often seek treatment for reduction of hair growth and/or acne, restoration of menstrual cyclicity, and infertility. In addition, these patients are increasingly seeking advise and treatment for the metabolic abnormalities related to PCOS (e.g., insulin resistance and type 2 diabetes). In this review, we outline the pathophysiologic events underlying the cutaneous manifestations of androgen excess and provide a rationale for use of the various pharmacologic agents available for treatment. Options for the treatment of the reproductive abnormalities (menstrual dysfunction and interfility) are presented. Finally, the metabolic manifestations of PCOS are reviewed and their treatment is discussed.

KEYWORDS

Polycystic ovary syndrome - hirsutism - oligomenorrhea - insulin resistance - type 2 diabetes mellitus

Full Text

References

REFERENCES

1 Kuhl H. Comparative pharmacology of newer progestogens. Drugs . 1996; 51 188-215
2 Krattenmacher R. Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contraception . 2000; 62 29-38
3 Mowszowicz I, Wright F, Vincens M. Androgen metabolism in hirsute patients treated with cyproterone acetate. J Steroid Biochem . 1984; 20 757-761
4 Miller J, Jacobs H. Treatment of hirsutism and acne with cyproterone acetate. Clin Endocrinol Metab . 1986; 15 373-389
5 Miller J, Wojnarowska F, Dowd P. Antiandrogen treatment in women with acne: a controlled trial. Br J Dermatol . 1986; 114 705-716
6 Barth J, Cherry C, Wojnarowska F, Dawber R. Spironolactone is an effective and well tolerated systemic antiandrogen therapy for hirsute women. J Clin Endocrinol Metab . 1989; 68 966-970
7 O'Brien R, Cooper M, Murray R. Comparison of sequential cyproterone acetate versus spironolactone/oral contraceptive in the treatment of hirsutism. J Clin Endocrinol Metab . 1991; 72 1008-1013
8 Crosby P, Rittmaster R. Predictors of clinical response in hirsute women treated with spironolactone. Fertil Steril . 1991; 55 1076-1081
9 Givens J. Treatment of hirsutism with spironolactone. Fertil Steril . 1985; 43 841-843
10 Neri R, Monahan M. Effects of a novel nonsteroidal antiandrogen on canine prostatic hyperplasia. Invest Urol . 1972; 10 123-130
11 Cusan L, Dupont A, Belanger A, Tremblay R, Manhes G, Labrie F. Treatment of hirsutism with the pure antiandrogen flutamide. J Am Acad Dermatol . 1990; 23 462-469
12 Pazos F, Escobar-Morreale H F, Balsa J, Sancho J M, Varela C. Prospective randomized study comparing the long-acting gonadotropin-releasing hormone agonist triptorelin, flutamide, and cyproterone acetate, used in combination with an oral contraceptive, in the treatment of hirsutism. Fertil Steril . 1999; 71 122-128
13 Rittmaster R. Differential suppression of testosterone and estradiol in hirsute women with the superactive gonadotropin-releasing hormone agonist leuprolide. J Clin Endocrinol Metab . 1988; 67 651-655
14 Sidenius-Johansen J, Juel-Riis B, Hassager C, Moen M, Jacobson J, Christiansen C. The effect of a gonadotropin-releasing hormone agonist analog (nafarelin) on bone metabolism. J Clin Endocrinol Metab . 1988; 67 701-706
15 Matta W, Shaw R, Hesp R, Evans R. Reversible trabecular bone density loss following induced hypooestrogenism with the GnRH analogue buserelin in premenopausal women. Clin Endocrinol (Oxf) . 1988; 29 45-51
16 Adashi E. Potential utility of gonadotropin-releasing hormone agonists in the management of ovarian hyperandrogenism. Fertil Steril . 1990; 53 765-779
17 Rittmaster R, Loriaux D, Cutler G. Sensitivity of cortisol and adrenal androgens to dexamethasone suppression in hirsute women. J Clin Endocrinol Metab . 1985; 61 462-466
18 Steinberger E, Rodriguez-Rigau L, Weidman E, Smith K, Ayala C. Glucocorticoid therapy in hyperandrogenism. Baillieres Clin Obstet Gynaecol . 1990; 4 457-471
19 Azziz R, Rafi A, Smith B R, Bradley Jr L E, Zacur H A. On the origin of the elevated 17-hydroxyprogesterone levels after adrenal stimulation in hyperandrogenism. J Clin Endocrinol Metab . 1990; 70 431-436
20 Liang T, Rasmusson G, Brooks J. Biochemical and biological studies with 4-aza-steroidal 5α-reductase inhibitors. J Steroid Biochem . 1983; 19 385-390
21 Rittmaster R S. 5alpha-Reductase inhibitors. J Androl . 1997; 18 582-587
22 Jafari K, Tavaheri C, Ruiz G. Endometrial adenocarcinoma and the Stein-Leventhal syndrome. Obstet Gynecol . 1978; 51 97-100
23 Coulam C, Annegers J, Kranz J. Chronic anovulation syndrome and associated neoplasia. Obstet Gynecol . 1983; 61 403-407
24 Farhi D, Nosanchuk J, Silverberg S. Endometrial adenocarcinoma in women under 25 years of age. Obstet Gynecol . 1986; 68 741-745
25 Bayer S, DeCherney A. Clinical manifestations and treatment of dysfunctional uterine bleeding. JAMA . 1993; 269 1823-1828
26 Group P TW. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA . 1995; 273 199-208
27 Woodruff J, Pickar J. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. Am J Obstet Gynecol . 1994; 170 1213-1223
28 Messinis I, Milingos S. Current and future status of ovulation induction in polycystic ovary syndrome. Hum Reprod Update . 1997; 3 235-253
29 Barnes R. Diagnosis and therapy of hyperandrogenism. Baillieres Clin Obstet Gynaecol . 1997; 11 369-396
30 Hammond M, Halme J, Talbert L. Factors affecting the pregnancy rate in clomiphene citrate induction of ovulation. Obstet Gynecol . 1983; 62 196-202
31 Gysler M, March C, Mishell D, Bailey E. A decade's experience with an individualized clomiphene treatment regimen including its effects on the post-coital test. Fertil Steril . 1982; 37 161-167
32 Glueck C J, Phillips H, Cameron D, Sieve-Smith L, Wang P. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril . 2001; 75 46-52
33 Sagle A, Hamilton-Fairley D, Kiddy D, Franks S. A comparative, randomized study of low-dose human menopausal gonadotropin and follicle-stimulating hormone in women with polycystic ovarian syndrome. Fertil Steril . 1991; 55 56-60
34 Buvat J, Buvat-Herbaut M, Marcolin G. Purified follicle-stimulating hormone in polycystic ovary syndrome: slow administration is safer and more effective. Fertil Steril . 1989; 52 553-559
35 Shoham Z, Patel A, Jacobs H. Polycystic ovarian syndrome: safety and effectiveness of stepwise and low-dose administration of purified follicle-stimulating hormone. Fertil Steril . 1991; 55 1051-1056
36 Mizunuma H, Takagi T, Yamada K. Ovulation induction by step-down administration of purified urinary follicle-stimulating hormone in patients with polycystic ovarian syndrome. Fertil Steril . 1991; 55 1195-1196
37 Homburg R, Levy T, Ben-Rafael Z. A comparative prospective study of conventional regimen with chronic low-dose administration of follicle-stimulating hormone for anovulation associated with polycystic ovary syndrome. Fertil Steril . 1995; 63 729-733
38 Brzyski R, Grow D, Sims J, Seltman H. Increase in androgen:estrogen ratio specifically during low-dose follicle-stimulating hormone therapy for polycystic ovary syndrome. Fertil Steril . 1995; 64 693-697
39 Hugues J, Cedrin-Durnerin I, Avril C. Sequential step-up and step-down regimen: an alternative method for ovulation induction with follicle-stimulating hormone in polycystic ovarian syndrome. Hum Reprod . 1996; 11 2581-2584
40 van Santbrink E, Fauser B. Urinary follicle-stimulating hormone for normogonadotropic clomiphene-resistant anovulatory infertility: prospective, randomized comparison between low dose step-up and step-down dose regimens. J Clin Endocrinol Metab . 1997; 82 3597-3602
41 White D, Polson D, Kiddy D. Induction of ovulation with low-dose gonadotropins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225 women. J Clin Endocrinol Metab . 1996; 81 3821-3824
42 Homburg R, Levy T, Berkovitz D. Gonadotropin-releasing hormone agonist reduces the miscarriage rate for pregnancies achieved in women with polycystic ovarian syndrome. Fertil Steril . 1993; 59 527-531
43 Balen A, Tan S, MacDougall J, Jacobs H. Miscarriage rates following in-vitro fertilization are increased in women with polycystic ovaries and reduced by pituitary desensitization with buserelin. Hum Reprod . 1993; 8 959-964
44 Campo S. Ovulatory cycles, pregnancy outcome and complications after surgical treatment of polycystic ovary syndrome. Obstet Gynecol Surv . 1998; 53 297-308
45 Amar N, Lachelin G. Laparoscopic ovarian diathermy: an effective treatment for anti-oestrogen resistant anovulatory infertility in women with the polycystic ovary syndrome. Br J Obstet Gynaecol . 1993; 100 161-164
46 Donesky B, Adashi E. Surgically induced ovulation in the polycystic ovary syndrome: wedge resection revisited in the age of laparoscopy. Fertil Steril . 1995; 63 439-463
47 Kiddy D S, Hamilton-Fairley D, Bush A. et al . Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) . 1992; 36 105-111
48 Velazquez E M, Mendoza S G, Wang P, Glueck C J. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism . 1997; 46 454-457
49 Hasegawa I, Murakawa H, Suzuki M. Effect of troglitazone on endocrine and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome. Fertil Steril . 1999; 71 323-327
50 Azziz R, Ehrmann D, Legro R S. et al . Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab . 2001; 86 1626-1632
51 Nestler J, Jakubowicz D, Evans W, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med . 1998; 338 1876-1880
52 Inzucchi S E, Maggs D G, Spollett G R. et al . Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med . 1998; 338 867-872
53 Ehrmann D, Cavaghan M, Imperial J, Sturis J, Rosenfield R, Polonsky K. Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome. J Clin Endocrinol Metab . 1997; 82 524-530
54 Nestler J E, Jakubowicz D J. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med . 1996; 335 617-623
55 Nestler J E, Stovall D, Akhter N, Iuorno M J, Jakubowicz D J. Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome. Fertil Steril . 2002; 77 209-215
56 Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab . 1996; 81 3299-3306
57 Ehrmann D, Schneider D, Sobel B. et al . Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab . 1997; 82 2108-2116