Treatment for Polycystic Ovary Syndrome: A Critical Appraisal of Treatment Options

Shahla Nader

Disclosures

Expert Rev Endocrinol Metab. 2008;3(3):349-359. 

In This Article

Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, affecting approximately 6% of this population.[1] The clinical issues in PCOS relate to menstrual irregularities, symptoms of excess androgen and cystic ovaries.[2] While not universal, and not part of the definition, insulin resistance and obesity are also extremely common accompaniments of this syndrome.[2,3] This phenotypic nonuniformity and the variability of presentation have made it difficult to define the syndrome. The 1990 NIH-sponsored conference definition required oligo-ovulation, clinical or biochemical hyperandrogenism and the exclusion of other known disorders, such as late-onset congenital adrenal hyperplasia and Cushing's syndrome. The more recent 2003 Rotterdam consensus workshop was in response to an increasing awareness that the clinical expression of PCOS may be broader.[4] It defined PCOS as a syndrome encompassing two out of three criteria, namely oligo-ovulation, clinical and/or biochemical signs of hyperandrogenism and polycystic ovaries, after the exclusion of other entities. While this has been a practical working definition, others believe that hyperandrogenism should be an integral part of the definition.[5] This brief overview outlines the management options for women with PCOS. Given the limited clinical goals, it should be straightforward but, clearly, it is not. The phenotypic diversity, differences in underlying pathogenesis and the secondary effects of medications administerd to ameliorate symptoms, such as those of hyperandrogenism, and outcomes, such as anovulatory infertility, make treatment decisions for the practicing physician quite difficult. The complexity of these effects and decisions forms the basis of this review.

The over-riding androgenic symptoms that the individual presents will vary from patient to patient: for some, it is mainly hirsutism but for others it is acne and/or alopecia. Many have both hirsutism and acne and a few complain of significant acne, hirsutism and alopecia. Those with acne have often used topical treatment and oral medications, such as antibiotics and isotretinoin, and have relapsed.

Overall, 70-80% of women with excess androgen demonstrate hirsutism,[6] usually defined as a Ferriman-Gallway score of at least 8, although this prevalence is less in certain ethnic groups, such as East Asians, who may have fewer hair follicles endowed per unit area of skin. Androgens increase the growth rate of hair and transform vellus hair to terminal hair. Reduction of androgens reduces new hair growth and slows the growth of terminal hair already present.[7,8] Hair grows in nonsynchronous cycles. The growth or anagen phase varies according to body area and is approximately 4 months for facial hair. Given this long hair growth cycle, the effects of hormonal therapy require more than 6 months to be maximal.

Oral Contraceptive Pills. Oral contraceptive pills (OCPs) contain varying doses of ethinylestradiol and varying doses and formulations of progestins. The androgen-lowering effect of OCPs relate to the progestin-induced reduction of luteinizing hormone (LH), which stimulates ovarian androgen secretion, and the estrogen-mediated increase in sex hormone-binding globulin (SHBG). Increased SHBG binds testosterone. This dual effect (decreased secretion and increased binding of androgens) lowers free, biologically active androgens, hence the beneficial effects of OCPs on hirsutism.[9,10,11] The higher the estrogen content the greater the effect on SHBG. Available low-dose OCPs (defined as <50 µg) contain ethinylestradiol in doses ranging from 15 to 35 µg in Europe and 20 to 35 µg in the USA. Some biphasic and triphasic formulations contain up to a 40-µg dose for a few days of the cycle.[11] In addition, an important consideration for the progestin component is the degree of androgenicity of the progestin.[11] Newer OCPs contain less androgenic progestins (such as desogestrel and norgestimate) and two progestins: cyproterone acetate (CPA), used in low doses in OCPs, and drospirenone, function as androgen receptor antagonists, CPA being more potent in its effect. CPA may also inhibit 5-α-reductase activity, decreasing the availability of the more potent androgen, dihydrotestosterone.[12] Unfortunately, CPA-containing OCPs are not available in the USA. A third anti-androgenic progestin, dienogest, has recently become available in Europe and combined with estradiol as an OCP.

Anti-androgens. Spironolactone, which is an aldosterone antagonist, is a dose-dependent competitive inhibitor of the androgen receptor and can also inhibit 5-α-reductase activity.[13] It has demonstrable effects on hirsutism over and above those induced by OCPs.[14] While generally well tolerated, it occasionally causes fatigue, postural hypotension and dizziness and, administered alone in high doses, may cause menstrual irregularity. The risk of feminizing a male fetus, if pregnancy occurs, precludes its use as monotherapy in sexually active women with PCOS. Thus, it is often used with OCPs.

Cyproterone acetate is a progestogenic compound with anti-androgenic activity. Used in high doses (50-100 mg) and in reverse sequential regimen (for the first 10 days of cycle), in combination with ethinylestradiol 20-50 µg (to ensure regular menses), it was shown to be more effective than finasteride, a 5-α-reductase inhibitor.[15] CPA is generally well tolerated, although it may cause headaches, nausea, weight gain, breast tenderness, loss of libido and, rarely, hepatotoxicity effects. As with spironolactone, there is a risk of feminizing a male fetus. CPA by itself is also not available in the USA.

Flutamide is a nonsteroidal, selective, anti-androgen without progestogenic effect. In a dose of 500 mg daily, it was found to be similarly effective as spironolactone 100 mg[16] in women with idiopathic hirsutism and, in a recent study, the minimal effective dose was found to be 125 mg daily.[17] Its major concern is serious hepatotoxicity, although doses up to 375 mg have been used without any significant hepatotoxicity.[17,18]

Finasteride inhibits type 2 5-α-reductase.[19] However, enhanced 5-α-reductase activity in hirsutism probably involves both type 1 and 2 enzymes. Hirsutism scores were lowered in studies of finasteride.[20,21] Comparison of finasteride with spironolactone has shown equal[21] or lesser efficacy of finasteride.[22] Finasteride has also been used in combination with a CPA-containing OCP, and the addition of finasteride 5 mg to the OCP was shown to be better than the OCP alone.[23] When finasteride was compared directly with an OCP containing low-dose CPA, the effect was equivalent.[24] While finasteride has a low side-effect profile, its feminizing effects on a male fetus preclude its use in most patients.

Glucocorticoids. Glucocorticoids suppress adrenal androgen secretion and have been used in patients with adrenal hyperandrogenism. Their use is most legitimate in patients with classic congenital adrenal hyperplasia, where they can help prevent and manage hirsutism and allow ovulatory cycles. In nonclassic congenital adrenal hyperplasia, and in functional adrenal androgen excess (a minority of PCOS patients), their role is more limited.[25] Suppression of adrenal androgens results in a minor improvement of hirsutism, although prolonged remission after therapy withdrawal can be obtained.[26] A trial of CPA versus hydrocortisone in patients with late-onset congenital adrenal hyperplasia showed a greater decrease in hirsutism scores with 1 year of CPA compared with hydrocortisone (54 vs 26%). These results occurred despite a greater reduction of androgens with glucocorticoids, highlighting the importance of peripheral receptivity to androgens.[27] Overdosing can occur, leading to adrenal atrophy, weight gain and decreased bone mineral density.

Gonadotropin-releasing Hormone Agonists. Since lowering of LH reduces ovarian androgen secretion, benefits would be expected from gonadotropin-releasing hormone (GnRH) agonist use. However GnRH agonists cannot be used long-term alone because the hypoestrogenic state induced is detrimental to bone health. Administered with estrogen-progestin add-back, they were shown to be more effective for hirsutism than an OCP in two trials.[28,29] Their expense, parenteral administration and side effects essentially preclude their use, except for patients who are severely hirsute, such as those with hyperthecosis.

Insulin-lowering Agents. Both metformin and thiazolidinediones may lower ovarian androgen secretion, mainly through their insulin-lowering effects.[30] In a Cochrane Databse Systematic Review article, limited data in a small numbers of patients have shown no evidence of a difference in effect between metformin and OCPs on hirsutism and acne.[31] Some effects of rosiglitazone on hirsutism was shown by Yilmaz et al.,[30] and troglitazone (no longer available) improved hirsutism in women with PCOS.[32]

Direct Hair Removal. Electrolysis has been is use for many years to remove unwanted hair. A fine needle is inserted into the hair follicle and an electrical current is applied. Erythema and postinflammatory pigment changes may occur and scarring is possible.[33] Photoepilation uses laser and nonlaser light sources to damage hair follicles but vellus hair remains and can be converted to terminal hair. While laser treatment is more expensive, it is less painful and much faster.[34] There is potential for depigmentation and scarring with laser use, especially in darker-skinned women.

Topical Treatment. Eflornithine is an inhibitor of ornithine decarboxylase, an enzyme necessary for hair growth. A topical preparation of this inhibitor is available for unwanted facial hair, taking 6-8 weeks for its effect to be apparent.[35] It can be combined with laser treatment.

Combination Therapy. In the Endocrine Society Practice Guidelines discussing the evaluation and treatment of hirsutism in premenopausal women, it was recommended that oral contraceptives or direct hair removal be used initially. Then, if at least 6 months of OCP therapy has not significantly decreased the rate of hair growth, anti-androgens may be added.[36]

Both OCPs and anti-androgens have been used successfully in the treatment of acne.[37] Within 3-6 months of OCP treatment, inflammatory acne counts are reduced by 30-60%, with improvement in 50-90% of patients.[38] OCPs are especially useful in patients with deep-seated nodules and helpful in patients relapsing on isotretinoin.

There are no extensive trials for alopecia but OCPs and androgen blockers are usually administered and, in limited studies, CPA has had some effect, as has finasteride.[39]

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