eMedicine Specialties > Obstetrics and Gynecology > Reproductive Endocrinology and Infertility

Androgen Excess: Treatment & Medication

Author: Luca Sabatini, MD, MRCOG, Consultant in Obstetrics and Gynecology, Specialist in Reproductive Medicine and Surgery, St Bartholomew's Hospital and London NHS Trust, UK
Contributor Information and Disclosures

Updated: Aug 18, 2009

Treatment

Medical Care

Medical treatment needs to be maintained for a long time because satisfactory clinical effects of drugs take several months to appear.

Pharmacologic measures aim to correct symptoms by lowering the levels of free androgen in serum and blocking the peripheral androgen action.

• Suppression of ovarian androgens by administration of estrogens and/or progestins (ie, contraceptive pill) or GnRH agonist and add-back estrogen therapy
• Suppression of adrenal androgens by administration of glucocorticoids (dexamethasone, prednisolone)
• Use of antiandrogens (spironolactone, flutamide, cyproterone acetate)
• Use of the 5 α -reductase inhibitor (finasteride)
• Use of bromocriptine in hyperprolactinemia
• Use of insulin-sensitizing drugs (metformin, thiazolidinediones)

The rationales for drug selection are as follows:

• Oral contraceptives (OCs) combined with antiandrogens is the first-line approach to nonadrenal hyperandrogenism. OCs alone have limited efficacy in treating androgen excess; however, they provide reliable contraception, help in the treatment of acne, and counteract the risk of endometrial cancer associated with anovulation and unopposed estrogen stimulation. Antiandrogens are best added to OC therapy to maximize the results in hirsutism treatment.
• Progestins in adequate doses suppress the ovarian function and, therefore, reduce hirsutism. Progestins do not offer additional advantages and are used only in patients in whom combined OCs are not indicated.
• Adrenal hyperandrogenism (CAH, Cushing syndrome) responds to glucocorticoid treatment with prednisolone or dexamethasone in a low dose. The long-term effect of low-dose glucocorticoid therapy on bone metabolism and dysmetabolic syndrome is not entirely clear; therefore, the steroid dose should be lowered or discontinued after 3 months.
• Suppression of androgen secretion has limited efficacy for reducing hair growth; the best results are obtained by using antiandrogens. Antiandrogen drug availability varies among different countries; for example, the US Food and Drug Administration (FDA) does not approve the use of the antiandrogen cyproterone acetate in hyperandrogenism.
• Antiandrogens alone or in combination with OC pills are effective for treatment of hyperandrogenism. Spironolactone, finasteride, flutamide, and cyproterone acetate have all been demonstrated to be equally effective. Antiandrogens are class D or X in pregnancy, and can cause ambiguous genitalia and feminization of a male fetus; therefore, women of childbearing age require an effective form of contraception when using these drugs.
• GnRH agonists are effective in severe hirsutism and virilism secondary to ovarian hyperandrogenism. GnRH agonists suppress ovarian androgen production by inhibiting gonadotrophin secretion. Hormone therapy (HT) add-back can be used to relieve the symptoms of hypoestrogenism. HT also increases SHBG and decreases free testosterone. Any HT regimen, either sequential or continuous combined, can be used. For the first few months, the addition of 100-200 mg/d of spironolactone may help. After improvement of both the serum testosterone values and hirsutism, these patients can stop the GnRH agonist and switch to an OC with or without spironolactone.
• Insulin-sensitizing drugs have a role in hyperandrogenism associated with PCOS because they decrease hyperinsulinemia and insulin resistance.

Hirsutism treatment

• A combination of mechanical and medical methods best treats hirsutism. Medical therapy does not work on terminal hairs; these should be removed by cosmetic measures, including mechanical and chemical methods.
• An OC combined with an antiandrogen is the first-line approach to hirsutism. medroxyprogesterone (Depo-Provera) or estradiol and medroxyprogesterone (Lunelle) are also good choices.
• The progestin component of the OC lowers both the ovarian androgen production and the adrenal DHEAS production. The estrogenic component increases levels of SHBG production, thus lowering the free androgen level.
• An OC containing ethinylestradiol and the antiandrogen cyproterone acetate (Diane) is on the market in many countries but not in United States.
• The antiandrogenic efficacy of Yasmin, a new OC that contains the progestin drospirenone (a 17 α -spironolactone derivative), has yet to be demonstrated.
• A GnRH agonist is the best choice for managing severe hirsutism and virilism secondary to hyperthecosis.
• Hirsutism secondary to adrenal hyperandrogenism responds to glucocorticoid treatment with prednisolone or dexamethasone in a low dose.
• Monotherapy with spironolactone, finasteride, flutamide, or cyproterone acetate is equally effective. An effective form of contraception is required when using these drugs.
• Spironolactone is the least expensive and most extensively used antiandrogen. A potential side effect is abnormal uterine bleeding; therefore, the use of an OC is advocated. This also protects against the risk of pregnancy and feminization of male fetuses.
• Cyproterone acetate is a steroid with progestin, antiandrogen, and glucocorticoid activity. It is an effective treatment for hirsutism but not licensed in the United States.
• The efficacy of insulin-sensitizing drugs on hirsutism appears limited and more studies are needed.
• Topical eflornithine (Vaniqa) is available for the treatment of facial hirsutism. Eflornithine blocks ornithine carboxylase in the hair follicle, thus reducing hair growth. Its efficacy has been shown in randomized controlled trials, but the effect rapidly reverses after stopping the treatment.

Acne treatment

• Therapy for acne is directed toward reducing sebum production, normalizing keratin production, clearing comedones, and eliminating the Propionibacterium acnes colonization that causes inflammation and infection. Topical and systemic treatments exist. The drugs that decrease hirsutism also decrease acne.
• In randomized placebo-controlled trials, mild-to-moderate acne has been shown to improve with OCs. A review of the literature indicates that all OCs studied are efficacious. The comparative effectiveness of different OCs is unrelated to the particular progestin components they contain.
• Topical retinoids help to normalize keratinocyte differentiation and reduce cell proliferation and inflammation. They are the first choice in patients with comedonal acne, but they can cause skin irritation and increase skin photosensitivity and therefore should be applied at bedtime.
• Oral isotretinoin (Accutane) is useful in severe inflammatory acne and in cases that are unresponsive to other treatments. It is category X and teratogenic; therefore, 2 effective forms of contraception are required. In the United States, isotretinoin is approved for marketing only under an FDA-approved restricted distribution program, called iPLEDGE.
• Antibacterial drugs can be used alone or in association with topical retinoid. Azelaic acid (Azelex) topical has been shown to possess antimicrobial activity against Propionibacterium acnes and Staphylococcus epidermidis.
• Topical or oral tetracycline, erythromycin, and clindamycin can all be used effectively. Oral antibiotics should be given in a short course if absolutely necessary. Tetracycline is the preferred oral antibiotic due to its low cost and high efficacy.

Ovulatory dysfunction and infertility treatment⁴

• Androgen excess can cause anovulation and infertility.
• Ovulation induction with clomiphene citrate 50-200 mg/d for 5 days, commencing on day 2 or 3 of the menstrual cycle is first-line treatment. Of anovulatory women, 25% do not respond to clomiphene and can be treated with gonadotrophins. A clinician who is expert in assisted reproduction techniques must supervise the treatment because hyperstimulation syndrome and multiple pregnancy rates of up to 25% are recognized complications.
• A short course of dexamethasone can be added to clomiphene to restore ovulation.
• Metformin has been shown to increase both spontaneous and clomiphene-induced ovulation rates.

Surgical Care

Ovarian and adrenal tumors need to be removed surgically.

• In severe cases of hyperthecosis and severe hirsutism, oophorectomy may be considered in women older than 35 years who have completed their family. Estrogen replacement therapy following oophorectomy prevents osteoporosis and vasomotor symptoms and improves hyperandrogenic conditions.
• Ovarian drilling by either laser or fulguration is effective in restoring ovulation in patients with PCOS wishing to conceive who are resistant to clomiphene. An ovulation rate of 70% has been reported. Ovarian drilling is not indicated for hirsutism, and a lowering effect on circulating androgens has yet to be fully demonstrated.
• Cosmetic measures include bleaching the hair in white people to make it less noticeable, shaving, waxing, electrolysis, laser removal, and use of depilatory creams to remove hair chemically.

Consultations

• Consultation with the appropriate practitioner for any surgical procedure described above is indicated.
• In complicated cases, consultation with an internal medicine endocrinologist or a reproductive endocrinologist would be appropriate for further workup and treatment and for interpretation of unusual results.

Diet

Decreasing central body fat decreases hyperinsulinemia and increases SHBG, thereby decreasing ovarian androgen production and serum free androgens. Although difficult to achieve, weight loss should be encouraged in all patients, particularly those with PCOS who are obese because they are at risk of metabolic complications.⁵

Weight loss improves menstrual irregularity in as many as 80% of patients and can restore ovulation and fertility.

Activity

The Androgen Excess and Polycystic Ovary Syndrome Society recommends lifestyle management as the primary therapy for metabolic complications in overweight and obese women with PCOS.⁵ Emerging evidence suggests that exercise offers additional benefits to reduced-calorie diet for treating the reproductive features of PCOS.⁵   

Medication

Medical treatment of androgen excess is aimed at lowering ovarian or adrenal androgen production, reducing the free androgen level, and blocking the peripheral androgen action. However, patients with androgen excess typically seek medical attention for the treatment of primary symptoms, such as hirsutism, acne, and menstrual disorders.

Hirsutism is best treated by a combination of mechanical and chemical methods. The mechanical methods remove hair immediately, and the chemical methods prevent further differentiation of vellus to terminal hairs.

PCOS associated with insulin resistance can be treated with metformin and/or an OC with or without an added antiandrogen (spironolactone). PCOS not associated with insulin resistance is best treated with an OC with or without added spironolactone.

Acne treatment is aimed at decreasing skin sloughing and proliferation of P acnes through the use of topical and systemic agents. Suppression of androgen production decreases production of sebum and reduces acne.

Oral contraceptives

Oral contraceptives (OCs) decrease ovarian androgen production and increase SHBG, therefore reducing free testosterone by approximately 50%. OCs also decrease adrenal androgen production, particularly DHEAS. The reduction in ovarian androgens is in relation to the OCs capacity to inhibit ovulation. Low-strength preparations (20 µg ethinyl estradiol) are less efficient than standard or high-strength preparations in inhibiting ovulation. The presence of less androgenic progestin (desogestrel, norgestimate) in third-generation OCs is not associated with better outcome compared with older OCs. By promoting regular bleeding, OCs reduce the incidence of endometrial hyperplasia and cancer.

OCs alone or in combination with antiandrogens are the first choice for the treatment of hirsutism in women needing contraception. All strengths of OC pills have been shown to improve acne. The choice of an OC should be based solely on personal preference of the health care provider and patient. The new OC containing the antiandrogens drospirenone and ethinyl estradiol (Yasmin) has not shown advantages over other preparations.

Oral contraceptives

Any combination OC can be prescribed. No preparation has any advantage over the others.

Drospirenone and ethinyl estradiol (Yasmin)

Drospirenone 3 mg and ethinyl estradiol 30 µg

Antiandrogens

Spironolactone (Aldactone), cyproterone acetate (Androcur), flutamide (Eulexin), and drospirenone are agents that bind to the androgen receptor and block its action. Finasteride (Proscar) is a 5 a -reductase inhibitor that blocks the intracellular conversion of testosterone to DHT prevalently in the skin and in the sebaceous gland. Finasteride is comparable to spironolactone as an effective drug in hirsutism. Only spironolactone, flutamide, and finasteride are available in the United States. Drospirenone (3 mg) is available in combination with 30 µg of ethinyl estradiol as an oral contraceptive (Yasmin). Cyproterone acetate (not available in the US) is available in combination with 35 µg or 50 µg of ethinyl estradiol (Diane-35, Diane-50) and is marketed for acne and other hyperandrogenic conditions. Flutamide is used in prostate cancer and has been used successfully to treat hirsutism. Spironolactone, a potassium-sparing diuretic, has been available for many years and is a safe and effective antiandrogen. Drospirenone and spironolactone are similar in structure. Theoretically, ingestion of any of these agents during pregnancy could result in the feminizing of a male fetus; therefore, effective contraception should be used in conjunction with these agents.

Spironolactone (Aldactone)

Used most effectively in combination with an OC. First choice because of few adverse effects, cost, and clinical experience.

Flutamide (Eulexin)

Nonsteroidal antiandrogen that inhibits androgen uptake or binding of androgen to target tissues.

Cyproterone acetate (Androcur, Diane-35, Diane-50)

Available in combination with ethinyl estradiol:

Diane-35, 2 mg cyproterone acetate and 35 µg ethinyl estradiol, reverse sequential.
Diane-50, 2 mg cyproterone acetate and 50 µg ethinyl estradiol, reverse sequential.
Powerful antiandrogen usually administered with estrogens to maintain regular menstruation and to prevent conception. Not available in United States.

Finasteride (Proscar, Propecia)

Predominantly a type 2, 5 a -reductase inhibitor. Inhibits the production of DHT. Efficacy in hirsutism is similar to that of spironolactone.

GnRH agonists/antagonists

These agents, which suppress pituitary LH and FSH secretion, suppress ovarian hormone secretion to a greater degree than OCs. Examples of GnRH agonists in the United States include Lupron, Synarel, and Zoladex. The endometriosis doses are the ones used for hirsutism. Significant osteoporosis may occur if treatment lasts longer than 6 months; in these cases, estrogen add back with HRT or OC pills should be given.

Leuprolide acetate (Lupron, Lupron Depot)

Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels.

Nafarelin acetate (Synarel)

Suppresses secretion of LH and FSH, which in turn reduces ovarian and testicular steroid production. Available as nasal solution (2 mg/mL).

Goserelin (Zoladex)

Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels.

Corticosteroids

Adrenal hyperandrogenism responds well to low-dose glucocorticoid therapy with dexamethasone or prednisolone. These agents are used with variable success in women with adrenal hirsutism, CAH, and idiopathic adrenal hyperandrogenism. Glucocorticoids have anti-inflammatory properties and cause profound and varied metabolic effects. Changes suggesting Cushing disease may develop in patients receiving long-term therapy.

Dexamethasone (Decadron, AK-Dex, Alba-Dex, Baldex, Dexone, Dexasone)

May reduce steroid hormone production. Decreases immune reactions.

Prednisone (Deltasone, Sterapred, Orasone)

May reduce steroid hormone production. Decreases immune reactions.

Insulin-sensitizing drugs

Insulin resistance is a metabolic disturbance in hyperandrogenism. Insulin-sensitizing drugs, by reducing the insulin levels, ameliorate hyperandrogenism associated with PCOS. Metformin in many, but not all, studies successfully treated hirsutism in patients with PCOS associated with insulin resistance. Not effective if patient does not have insulin resistance. Troglitazone was found to cause hepatic damage and was removed from the market. A proof-of-concept study found that the addition of low-dose pioglitazone (7.5 mg/d) to flutamide, metformin, and an OC in women with androgen excess led to improvements in the endocrine-metabolic condition, low-grade inflammation, total and visceral adiposity, and  markers of cardiovascular health.⁶

Metformin (Glucophage)

Reduces hepatic glucose output, decreases intestinal absorption of glucose, and increases glucose uptake in the peripheral tissues (muscle and adipocytes). Major drug used in patients who are obese and have type 2 diabetes. Effective in inducing ovulation in PCOS anovulatory women.

Topical skin products

May be used to reduce hair growth on the face and adjacent areas under the chin.

Eflornithine 13.9% cream (Vaniqa)

Prescription topical cream that acts as a growth inhibitor of hair. Takes up to 2 mo to work in approximately 30% of patients.

Dopamine agonists

Women with hyperandrogenism who also have hyperprolactinemia may benefit from therapy with a dopamine receptor agonist (bromocriptine, cabergoline). These agents improve menstrual cycle, ovulation, and hirsutism in women with PCOS and hyperprolactinemia.

Bromocriptine (Parlodel)

Semisynthetic ergot alkaloid derivative; strong dopamine D2-receptor agonist; partial dopamine D1-receptor agonist. Inhibits prolactin secretion with no effect on other pituitary hormones. May be given with food to minimize possibility of GI irritation.

Cabergoline (Dostinex)

Semisynthetic ergot alkaloid derivative; strong dopamine D2-receptor agonist with low affinity for D1 receptors.

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