Use of ethinylestradiol/drospirenone combination in patients with the polycystic ovary syndrome

REVIEW Use of ethinylestradiol/drospirenone combination in patients with the polycystic ovary syndrome Ruchi Mathur 1 Olga Levin 1 Ricardo Azziz 1 1 Cedars-Sinai Medical Center, Los Angeles, CA, US Abstract: Polycystic ovary syndrome (PCOS) is one of the most common endocrine/metabolic disorders found in women, affecting approximately 105 million women worldwide. It is characterized by ovulatory dysfunction, often presenting as oligomenorrhea or amenorrhea and either clinical or biochemical hyperandrogenism. Combined oral contraceptive (COC) therapy has long been a cornerstone of care for women with PCOS. COC therapy often provides clinical improvement in the areas of excessive hair growth, unpredictable menses, acne, and weight gain. One of the main issues in COC therapy is choosing the most appropriate progestin component to provide the greatest anti androgenic effects. Drospirenone, a relatively new progestin, has shown benefit in the PCOS population when used in conjunction with ethinyl estradiol. We now review the role of COCs in PCOS, focusing specifically on drospirenone. Controversy over metabolic effects of COCs in PCOS is also discussed. Keywords: polycystic ovary syndrome, PCOS, oral contraceptives, drospirenone, treatment Introduction Correspondence: Ricardo Azziz 8635 W 3rd Street, Ste #160W, Los Angeles, CA 90048, USA Tel +1 310 423 7433 Fax +1 310 423 3470 Email Polycystic ovary syndrome (PCOS) is one of the most common endocrine/metabolic disorders found in women. While the definition remains a point of controversy for some, PCOS is characterized by ovulatory dysfunction, usually presenting as oligomenorrhea or amenorrhea, and either clinical or biochemical hyperandrogenism (Azziz et al 2006). The hyperandrogenism can result in hirsutism, oligo-amenorrhea, acne, and alopecia. The prevalence of PCOS (based on the NIH 1990 criteria) in women of reproductive age is approximately 6.5%–8.0% (Michelmore et al 1999). This encompasses approximately 5 million women in the United States and 105 million women worldwide. Clinically, PCOS is a heterogeneous disorder of functional androgen excess and the features of PCOS can run through a spectrum of severity. The clinical features may differ according to ethnicity, environmental factors, and medical co-morbidities (Table 1). Most features can be elicited by performing a precise history and physical examination. The primary aspects of PCOS that require treatment are oligo-amenorrhea, hyperandrogenism, and metabolic concerns such as insulin resistance (Lobo 2006). While the majority of these patients show functional hyperandrogenism clinically, studies have found conflicting results (Pugeat et al 1993; Knochenhauer et al 1998; Legro et al 1998; Laven et al 2002; Azziz et al 2006) regarding absolute androgen levels. The ovaries are the primary site of implication in excessive production of androgens in PCOS. Theca cells (under the influence of lutenizing hormone [LH]) are overactive in steroidogenesis, subsequently providing excess androgens to function as a substrate for estradiol production through the process of aromatization (Azziz et al 2006). LH hypersecretion by the pituitary gland may be present or concentrations of LH may be elevated due to increased amplitude and frequency of LH pulse. Therapeutics and Clinical Risk Management 2008:4(2) 487–492 © 2008 Dove Medical Press Limited. All rights reserved 487 Mathur et al Table 1 Clinical manifestations of polycystic ovary syndrome Oral contraceptives in PCOS Menstrual abnormalities (including oligo-amenorrhea, polymenorrhea, and dysfunctional uterine bleeding) Excess facial and body terminal hair growth, and hirsutism Seborrhea and acne Alopecia Obesity and central (visceral) fat distribution Acanthosis nigricans and acrochordons Polycystic ovaries Combined oral contraceptives (COC) are a common treatment for PCOS and have a long history of use in this group of patients. Adolescents and women with PCOS have a number of different clinical symptoms that play a role in their daily quality of life. Excessive hair growth, irregular and unpredictable menses, acne and weight gain are all part of the clinical constellation seen in this population. COC has long been considered a first line of therapy for women experiencing these symptoms and who do not wish to get pregnant. Publications from the 1960s (Mauvais-Jarvis et al 1965) reported the inhibition of androgens with the use of “ovulation inhibitors”. Since then multiple reports have confirmed this finding particularly with the use of antiandrogenic progestin components. The key mechanism of COC action is folliculogenesis inhibition through either suppression of pituitary gonadtorophin secretion or direct influence on ovarian function when the COC agent has weaker anti-gonadotrapin activity. COC can also lead to a decrease in circulating albumin levels, leading to a decrease in dehydroepiandrosterone sulphate (DHEAS), which is strongly bound to albumin (Carlstrom et al 2002) and androgen production (Vrbikova and Cibula 2005) and a decrease in peripheral androgen production through an inhibition of 5α reductase in the skin and a subsequent decrease in dihydrotestosterone levels (Cassidenti et al 1991). The combined effect is an overall decrease in gonadotropins and resulting androgens, which is a major goal of PCOS treatment. In addition, the estrogen component of COC increases sex hormone binding globulin (SHBG) production by the liver (Wiegratz et al 2003), which in turn reduces the circulating levels of free testosterone and its bioavailability. One of the main issues in choosing COC for the treatment of PCOS is finding the most appropriate progestin component to provide the greatest anti androgenic effects. The criteria for oral contraceptive selection has not been thoroughly evaluated. It should be based on currently available clinical data, as well as on patient tolerance and response. Selection of a COC is based on 3 main variables: the type of estrogenic compound used, the type of progestin compound used, and the dosage of each when combined. In general, while the use of a monophasic compound may be preferred by the patient for its ease of use, the choice of a monophasic, biphasic or triphasic compound does not have any significant effect on androgen production (Vrbikova and Cibula 2005). Today, the vast majority of COCs contain ethinyl estradiol (EE) as their estrogen, and thus only the type of progestin and the dosages of the steroids contained remain to be assessed. Modified with permission from Azziz R, Nestler JE, et al eds. 2006. Androgen excess disorders in women, polycystic ovary syndrome and other disorders. 2nd ed.Totowa, New Jersey: Humana Press. This is most often accompanied by a decrease in circulating follicle stimulating hormone (FSH). Both the LH and the FSH profiles are thought secondary to a fundamental increase in GnRH from the hypothalamus which ultimately favors the gene expression of LH (...truncated)