Background
Androgen excess is the most common endocrine disorder in women of reproductive age. Characterized by an excessive androgen production by the adrenal glands and/or the ovary, androgen excess may result from increased local tissue sensitivity to circulating androgens. Androgen excess affects different tissues and organ systems, causing clinical conditions ranging from acne to hirsutism to frank virilization.
To understand how androgen excess develops and affects organs and systems, the physiology of androgen production and secretion should be briefly reviewed.
Sources of androgens in women
Androgen sources in women are the endocrine glands (adrenal glands and ovaries) and peripheral tissues such as fat and skin. Liver and gut play a minor role in androgen production, particularly in the peripheral conversion of testosterone to the most active form dihydrotestosterone (DHT).
The endocrine glands secrete 5 androgens through a similar pathway : dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione, testosterone, and androstenediol (has both androgenic and estrogenic activity). Testosterone is the only androgen with direct androgenic activity, while DHEAS, DHEA, and androstenedione are all precursors of testosterone.
The ovaries, under the control of luteinizing hormone (LH), produce 50% of the total testosterone that rises to 75% at midcycle. The ovaries also secrete 50% of the total androstenedione and small amounts (20%) of DHEA. Testosterone is used as a marker of ovarian androgen secretion; however, the adrenals, via peripheral conversion of androstenedione to testosterone, also contribute to total testosterone.
The adrenal glands produce all the DHEAS and 80% of the DHEA. The adrenals also secrete 50% of androstenedione and 25% of the circulating levels of testosterone. DHEAS and 11-androstenedione are not secreted by the ovaries and, therefore, are used as markers of adrenal androgen secretion. Their secretion depends on adrenocorticotropic hormone (ACTH); prolactin and estrogen can effect adrenal androgen production.
Skin, fat, liver, and urogenital systems are important peripheral sites of androgen production. Androstenedione, and to some degree DHEA, are converted to testosterone in the skin.
DHT is an intracrine hormone that is produced, acts, and is metabolized within the target tissues. DHT is produced by the action of the 5a-reductase enzymes on testosterone, androstenedione, and DHEA. Two different 5a-reductase enzymes exist: type 1 is found primarily in the skin and liver, and type 2 is found mainly in the urogenital system.In the pilosebaceous unit and peripheral tissues, DHT is metabolized further to 3a-androstanediol. 3a-androstanediol glucuronide, the final metabolite, can be measured in the plasma and indicates the level of activity of target tissue conversion of testosterone and androstenedione to DHT. The relative activity of the 5a-reductase enzymes can be determined by measuring 3a-androstanediol glucuronide in either urine or blood.
Androgen circulation
Androgen circulates in the blood in a protein-bound and an unbound fashion. Albumin has a low affinity but high capacity for binding steroids. DHEAS, DHEA, and androstenedione are almost entirely bound to albumin. Sex hormone-binding globulin (SHBG) binds steroids with high affinity but low capacity. Testosterone and DHT are bound primarily to SHBG and to a lesser degree, albumin.
In healthy women, 80% of testosterone is bound to SHBG, 19% is bound to albumin, and 1% circulates freely in the blood stream. In women who are hirsute, 79% of testosterone is bound to SHBG, 19% is bound to albumin, and 2% circulates freely. In men, 78% is bound to SHBG, 19% is bound to albumin, and 3% circulates freely.
Androgenicity depends mainly on the unbound fraction and in part on the fraction associated with albumin (bioavailable androgens). The binding capacity is decreased by androgen.
The levels of SHBG increase and decrease based on conditions and medications.
- SHGB levels increase because of the following:
- Estrogens
- Thyroid hormone
- Pregnancy
- Estrogen-containing preparations
- SHGB levels decrease because of the following:
- Androgens
- Synthetic progestins (norethindrone, norgestrel, desogestrel, norgestimate)
- Glucocorticoids
- Growth hormone
- Insulin
- Obesity
- Acromegaly
- Hypothyroidism
- Hyperinsulinemia
Mechanism of androgen action
In the target tissues, androgens enter the cell cytoplasm by simple diffusion across the cell membrane. Once inside the cell, the androgens bind and activate the androgen receptor. The androgen-receptor complex attaches to a specific DNA site and stimulates the production of messenger RNA, which, in turn, stimulates the production of the enzymes and proteins necessary to affect androgen action.
Androgen effects
Androgens induce maleness and are responsible for forming the male external genitalia in the fetus; their absence or the absence of testosterone receptors results in a female phenotype despite the presence of a 46 XY karyotype. Androgens are responsible for the development of the secondary sexual organs and ducts, the seminal vesicles, and the prostate. Postnatal females are not as sensitive as the fetus to androgens, which induce the growth of sexual hair, temporal balding, acne, clitoral growth, sebum production, and a deepening of the voice. Oral androgens decrease high-density lipoprotein (HDL) cholesterol and increase low-density lipoprotein (LDL) cholesterol. With androgen excess, the extent of these changes is dependent on the level of androgens in the blood.
Pathophysiology
Androgen excess affects mainly the pilosebaceous unit (PSU) and the reproductive systems.
The pilosebaceous unit secretes sebum and is the unit from which hair grows. Two types of hair (ie, lanugo or vellus, and terminal hairs) exist. The fine hairs of the fetus are lanugo and the peach fuzz hair of adults is vellus hair. These hairs are fine, short, and nonpigmented. Thick and pigmented hair is referred to as terminal hair. Those hairs of the pubic, axillary, sternal, and facial areas are responsive to androgens and those in other parts of the body are androgen-independent. Their prevalence depends largely on genetics. As androgen levels rise, more vellus hairs in the androgen-sensitive areas are converted into terminal hairs. This results in hirsutism. Androgens prolong the growth phase of hair and promote their conversion from vellus type to terminal. Hirsutism affects 70-80% of women with androgen excess. Sebum production from the pilosebaceous unit is also increased by androgens.
Lesions of the pilosebaceous unit are called acne. Acne can be aggravated or initiated by increased androgen levels as the excess sebum production and the shedding of hyperkeratinized epithelium may occlude the hair follicle. Propionibacterium acne proliferates and triglycerides of sebum are then hydrolyzed by the bacterial lipases to form glycerol and free fatty acids, which are inflammatory. An inflammatory lesion develops. The progressive stages of acne lesions are the following:
- Noninflammatory lesions
- Closed comedone (whitehead)
- Open comedone (blackhead)
- Inflammatory lesions
- Papule
- Pustule
- Nodule
In polycystic ovarian syndrome (PCOS), the most common cause of androgen excess and hirsutism, the ovarian theca cells increase their ovarian androgen production under the stimulatory activity of the raised LH levels. Hyperinsulinemia due to peripheral insulin resistance is often present in those women and it promotes hyperandrogenemia through the binding of insulin to the IGF-1 receptor. Insulin mimics the action of IGF-1, which augments androgen production by the theca cell in response to LH. Since insulin decreases levels of SHBG, the circulating levels of free testosterone are also increased. Most of those patients are infertile due to anovulation as the increased LH activity causes a defective granulosa cells' aromatization of androgens to estrogens and results in reduced estrogen levels. Spontaneous miscarriages also increase.
Obesity and hyperinsulinemia often present in patients with PCOS can cause abnormal lipid metabolism that can lead to atherosclerosis and a predisposition to coronary artery disease.
The increase of 5a-reductase activity in the peripheral tissues or an increased sensitivity of the androgen receptors could be at the origin of idiopathic hirsutism, the second most common cause of hirsutism. In this condition, the clinical signs do not correspond to an increased level of serum androgens.
An enzyme defect in the adrenal or ovarian steroidogenic pathways can also cause androgen excess. Congenital adrenal hyperplasia (CAH) due to an autosomal-recessive disorder is the most common cause of an enzyme defect. In 90% of cases, the enzyme 21-hydroxylase is missing or defective, whereas in a minority of cases, the 11a-hydroxylase enzyme or the 3a-hydroxy-steroid dehydrogenase enzyme is missing or defective. When these enzymes are missing or functioning at low levels, the body cannot make adequate amounts of the adrenal steroid hormones cortisol and aldosterone.
High levels of ACTH that stimulate adrenal hyperplasia and hypersecretion of androgen precursors for cortisol and aldosterone synthesis ensue. CAH can appear in utero or develop postnatally. Pseudohermaphroditism may be present at birth. The administration of corticosteroids corrects the hyperandrogenism, but failure to take steroids can increase androgen levels in adults and can result in further androgenization and/or virilization.
The 21-hydroxylase deficiency is the most common autosomal-recessive disorder (more common than cystic fibrosis) and manifests itself with elevated levels of 17-hydroxyprogesterone. The 11a-hydroxylase deficiency is characterized by elevated levels of 11-deoxy-cortisol (compound S) and results in elevated levels of deoxycorticosterone (DOC), a mineralocorticoid. Hypertension and hypokalemia can be a prominent feature of 11a-hydroxylase deficiency.
Another form of CAH, 3a-hydroxy-steroid dehydrogenase deficiency, results in elevated levels of pregnenolone, 17-hydroxy-pregnenolone, and DHEA. This condition is lethal if not detected because no corticosteroids are synthesized.
A partial defect in the above enzymes that manifests after puberty results in elevated levels of adrenal steroids via the same mechanism. The elevations are not as marked as they are with the congenital condition and this condition is referred to as nonclassical (maturity-onset or late-onset) CAH.
Ovarian or adrenal tumors are rare causes of hyperandrogenism. These tumors secrete high levels of androgens, causing an abrupt onset of signs of androgen excess and a rapid progression of the symptoms.
Ovarian androgen-secreting tumors
- Sertoli-Leydig cell tumors
- Leydig cell tumors
- Lipoid or lipid cell tumors
- Granulosa-theca cell tumors
- Hilus cell tumors
- Gynandroblastoma
- Steroid cell tumors
- Teratoma
- Gonadoblastoma
Adrenal androgen-secreting tumors
- Carcinoma
- Adenoma
Ingestion of androgens or agents with androgenlike activity can result in hirsutism, acne, and virilization. Oral contraceptive progestins are listed as potentially causing hirsutism because of their derivation from testosterone; however, oral contraceptive progestins are not androgenic in women in clinical doses. Androgenic effects are observed only in high doses in rodents.
Frequency
United States
The incidence rate of androgen excess is 8%.
International
The international incidence rate is dependent on the particular culture, but, essentially, it is similar to that of the
Mortality/Morbidity
No mortality or morbidity exists per se, but androgen excess is associated with insulin resistance, dyslipidemia, hypertension, and vascular diseases; therefore, it is a forerunner for cardiovascular disease (CVD).
- Impaired glucose tolerance and type II diabetes affect about 40% of women with PCOS.
- The presence of PCOS is an independent cardiovascular risk factor and women who have anovulatory PCOS have the greatest cardiovascular risk compared with women who have ovulatory PCOS and idiopathic hyperandrogenism.
- Androgen-secreting tumors are rare and about 30% of them are malignant.
Race
Androgen excess occurs equally in all races. CAH prevalence due to 21-hydroxylase deficiency is greater among those of Ashkenazi Jewish descent.
Sex
CAH occurs equally in both sexes; however, this article focuses on females.
Age
The most common causes of hyperandrogenism begin in early adolescence or in childbearing age. Androgen-producing tumors may rarely affect postmenopausal women.
Treatment
Medical Care
Medical treatment needs to be maintained for a long time because satisfactory clinical effects of drugs appear after several months.
Pharmacologic measures aim to correct symptoms by lowering the serum-free androgen levels 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 5α-reductase inhibitor (finasteride)
- Use of bromocriptine in hyperprolactinemia
- Use of insulin-sensitizing drugs (metformin, thiazolidinediones)
- Oral contraceptive (OC) 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), respond to glucocorticoid treatment with prednisolone or dexamethasone in a low dose. The long-term effect of low-dose glucocorticoid therapy on the 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 on hair growth and the best results are obtained by using antiandrogens. Antiandrogen drug availability in different countries is inconsistent; 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 treatments of hyperandrogenism. Spironolactone, finasteride, flutamide, and cyproterone acetate have all been demonstrated to be equally effective. Antiandrogens are class D or X in pregnancy; therefore, an effective form of contraception is required when using these drugs. They can cause ambiguous genitalia and feminization of a male fetus.
- GnRH agonists are effective in severe hirsutism and virilism secondary to ovarian hyperandrogenism. The GnRH agonist suppresses the ovarian androgen production by inhibiting the gonadotrophin secretion. Hormone replacement therapy (HRT) add back can be used to relieve the symptoms of hypoestrogenism. HRT also increases SHBG and decreases free testosterone. The HRT add back can be any HRT, either sequential or continuous combined. For the initial 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 both 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.
- OC combined with an antiandrogen is the first-line approach to hirsutism. Depo-Provera or Lunelle are also good choices.
- The progestin component of the contraceptive pill lowers both the ovarian androgen production and the adrenal DHEAS production. The estrogenic component increases levels of SHBG production, thus lowering the free androgens.
- A contraceptive pill containing ethinylestradiol and the antiandrogen cyproterone acetate (Diane) is on the market in many countries but not in United States.
- The efficacy of the new OC Yasmin, which contains the new progestin drospirenone (a 17a-spironolactone derivative), has yet to be demonstrated.
- A GnRH agonist best manages 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, and 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 the 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 to reduce the sebum production, normalize the keratin production, clear comedones, and eliminate the propionibacterium acne colonization that causes inflammation and infection. Topical and systemic treatment exists. 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 the OC pill shows no differences in the different progestin components it contains.
- Topical retinoids help to normalize keratinocyte differentiation and reduce cell proliferation and inflammation. They are the first choices 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 teratogenetic, therefore 2 effective forms of contraception are required.
- 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 treatment
- 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. Clinician experts 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.
Weight loss improves menstrual irregularity in as many as 80% of patients and can restore ovulation and fertility.
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, the treatment of primary symptoms such as hirsutism, acne, and menstrual disorders usually brings the patient with androgen excess to the doctor’s attention.
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 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 using topical and systemic agents. Suppression of androgen production decreases production of sebum and reduces acne.
Drug Category: 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 the third generation pills is not associated with better outcome compared with other OCs. By promoting regular bleeding, OCs reduce the incidence of endometrial hyperplasia and cancer.
OCs alone or in combination with antiandrogens are 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 oral contraceptive should be based solely on personal preference of the health care provider and patient. The new OC pill containing the antiandrogens drospirenone and ethinyl estradiol (Yasmin) has not shown advantages over other preparations.
| Drug Name | Oral contraceptives |
|---|---|
| Description | Any combination OC can be prescribed. No preparation has any advantage over the others. |
| Adult Dose | 1 tab PO qd |
| Pediatric Dose | Postmenarche: Administer as in adults |
| Contraindications | Documented hypersensitivity; pregnancy; breastfeeding; liver diseases; endometrial and breast cancer; thromboembolic disorders; systemic lupus erythematosus; porphyria; undiagnosed vaginal bleeding; smokers older than 35 y; cardiovascular disease |
| Interactions | The effect is reduced by drugs that induce hepatic enzyme activity (eg, phenobarbital, phenytoin, paramethadione, carbamazepine, troglitazone, rifampicin, and griseofulvin); broad spectrum antibiotics (eg, ampicillin, doxycycline) reduce OC effect; OCs may reduce hypoprothrombinemic effects of anticoagulants |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Caution in patients who smoke and those with hepatic impairment, obesity, hypertension, migraines, seizure disorders, cerebrovascular disorders, or family history of thromboembolic disease |
| Drug Name | Drospirenone and ethinyl estradiol (Yasmin) |
|---|---|
| Description | Drospirenone 3 mg and ethinyl estradiol 30 µg |
| Adult Dose | 1 tab PO qd |
| Pediatric Dose | Postmenarche: Administer as in adults |
| Contraindications | Yasmin increases serum potassium level and should not be used in hepatic dysfunction, renal insufficiency or adrenal insufficiency; past and present thromboembolic disorders; cardiovascular and cerebrovascular diseases; documented hypersensitivity; pregnancy; breastfeeding; liver diseases; endometrial and breast cancer; systemic lupus erythematosus; porphyria; undiagnosed vaginal bleeding; smokers older than 35 y |
| Interactions | The effect is reduced by drugs that induce hepatic enzyme activity (eg, phenobarbital, phenytoin, paramethadione, carbamazepine, troglitazone, rifampicin, and griseofulvin); broad spectrum antibiotics (eg, ampicillin, doxycycline) reduce OC effect; OCs may reduce hypoprothrombinemic effects of anticoagulants |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | The combined use with other potassium- increasing drugs (NSAID, potassium- sparing diuretics, ACE inhibitors, angiotensin-II receptors antagonists, heparin) must be avoided; obesity, hypertension, smoking, migraines, seizure disorders, cerebrovascular disorders, or family history of thromboembolic disease |
Drug Category: 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 5a-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
| Drug Name | Spironolactone (Aldactone) |
|---|---|
| Description | Used most effectively in combination with an OC. First choice because of few adverse effects, cost, and clinical experience. |
| Adult Dose | 50 to 200 mg/d PO |
| Pediatric Dose | Postmenarche: 1.5-3.5 mg/kg/d PO in divided doses q6-24h |
| Contraindications | Documented hypersensitivity; anuria; renal failure; hyperkalemia |
| Interactions | May decrease effect of anticoagulants; potassium and potassium-sparing diuretics may increase toxicity of spironolactone |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | Caution in renal and hepatic impairment; contraception must be used |
| Drug Name | Flutamide (Eulexin) |
|---|---|
| Description | Nonsteroidal antiandrogen that inhibits androgen uptake or binding of androgen to target tissues. |
| Adult Dose | 250 mg PO qd/tid |
| Pediatric Dose | Administer as in adults; only administered postmenarche |
| Contraindications | Documented hypersensitivity |
| Interactions | None reported |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Use with contraception; strict monitoring of liver function tests indicated; adverse effects include hepatotoxicity, nausea, gastralgia, dry skin, fatigue, and breast tenderness; flutamide should be used with OCs |
| Drug Name | Cyproterone acetate (Androcur, Diane-35, Diane-50) |
|---|---|
| Description | 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. |
| Adult Dose | 50-100 mg/d PO on days 1-10 with oral contraceptive |
| Pediatric Dose | Administer as in adults; only administered postmenarche |
| Contraindications | Documented hypersensitivity; children; breastfeeding; same contraindications as other OC agents |
| Interactions | None reported |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Monitor liver function; adverse effects include weight gain, fatigue, loss of libido, mastodynia, nausea, headaches, depression; risk of venous thromboembolism associated with antiandrogen OC use is at least as high as with third-generation oral contraceptive use |
| Drug Name | Finasteride (Proscar, Propecia) |
|---|---|
| Description | Predominantly a type 2, 5a-reductase inhibitor. Inhibits the production of DHT. Efficacy in hirsutism is similar to that of spironolactone. |
| Adult Dose | 5 mg/d PO |
| Pediatric Dose | Administer as in adults; only administered postmenarche |
| Contraindications | Documented hypersensitivity; breastfeeding; children |
| Interactions | None reported |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Must be used with contraception as it may cause ambiguous genitalia development in male fetus; monitor liver function; monitor patients with severely diminished urinary flow for obstructive uropathy (if possible avoid in these patients) |
Drug Category: 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
| Drug Name | Leuprolide acetate (Lupron, Lupron Depot) |
|---|---|
| Description | Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels. |
| Adult Dose | 3.5-7.5 mg/mo IM; not to exceed 6 mo without adding low-dose estrogen and progestin therapy |
| Pediatric Dose | Administer as in adults; only administered postmenarche |
| Contraindications | Documented hypersensitivity; undiagnosed vaginal bleeding; spinal cord compression |
| Interactions | None reported |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Urinary tract obstruction, tumor flare, and bone pain may occur; monitor patients for weakness and paresthesias; consider estrogen add back if therapy is longer than 6 mo |
| Drug Name | Nafarelin acetate (Synarel) |
|---|---|
| Description | Suppresses secretion of LH and FSH, which in turn reduces ovarian and testicular steroid production. Available as nasal solution (2 mg/mL). |
| Adult Dose | 1 spray (200 µg) into 1 nostril am and 1 spray into other nostril pm; start treatment between d 2 and 4 of menstrual cycle; may require up to 800 µg if amenorrhea is not achieved or in cases of ovarian hyperthecosis |
| Pediatric Dose | Administer as in adults; only administered postmenarche |
| Contraindications | Documented hypersensitivity to GnRH or related products; undiagnosed abnormal vaginal bleeding; pregnancy or women who may become pregnant while receiving drug; pernicious anemia |
| Interactions | None reported |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Ovarian cysts may occur in first 2 mo of therapy, especially in patients with PCOS; cystic enlargements may occur but may resolve spontaneously (generally by 4-6 wk of therapy); caution in patients with risk factors for decreased bone mineral content; consider estrogen add back if therapy continues for more than 6 mo |
| Drug Name | Goserelin (Zoladex) |
|---|---|
| Description | Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels. |
| Adult Dose | 3.6 mg SC q28d or 10.8 mg SC q12wk for 6 mo |
| Pediatric Dose | Administer as in adults; only administer postmenarche |
| Contraindications | Documented hypersensitivity; undiagnosed vaginal bleeding; spinal cord compression |
| Interactions | None reported |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Urinary tract obstruction, tumor flare, and bone pain may occur; monitor patients for weakness and paresthesias |
Drug Category: 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.
| Drug Name | Dexamethasone (Decadron, AK-Dex, Alba-Dex, Baldex, Dexone, Dexasone) |
|---|---|
| Description | May reduce steroid hormone production. Decreases immune reactions. |
| Adult Dose | 0.25-0.5 mg PO qd or qod |
| Pediatric Dose | Not recommended (until growth finished) |
| Contraindications | Documented hypersensitivity; active bacterial or fungal infection |
| Interactions | Effects decrease with coadministration of barbiturates, phenytoin, and rifampin; dexamethasone decreases effect of salicylates and vaccines used for immunization |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Administer for 3 mo, then dose should be halved or discontinued; monitor for adrenal insufficiency when tapering because abrupt discontinuation of glucocorticoids may cause adrenal crisis; complications of glucocorticoid use include severe infections, hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections |
| Drug Name | Prednisone (Deltasone, Sterapred, Orasone) |
|---|---|
| Description | May reduce steroid hormone production. Decreases immune reactions. |
| Adult Dose | 5-7.5 mg PO qd |
| Pediatric Dose | Not recommended (until growth finished) |
| Contraindications | Documented hypersensitivity; active bacterial or fungal infection |
| Interactions | Coadministration with estrogens may decrease prednisone clearance; when used with digoxin, digitalis toxicity secondary to hypokalemia may increase; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Administer for 3 mo, then dose should be halved or discontinued; monitor for adrenal insufficiency when tapering because abrupt discontinuation of glucocorticoids may cause adrenal crisis; complications of glucocorticoid use include severe infections, hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections |
Drug Category: 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 has been found to cause hepatic damage and has been removed from the marked.
| Drug Name | Metformin (Glucophage) |
|---|---|
| Description | 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. |
| Adult Dose | 1.5-2.5 g/d; 500 mg PO qd for week 1, initial dose; increase to 500 mg tab PO bid for week 2; increase to 500 mg PO tid for week 3 |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; acute myocardial infarction; septicemia; renal disease |
| Interactions | Diuretics, thyroid products, OCs, phenytoin, calcium channel blocking drugs, and phenothiazines may decrease effects of metformin; cimetidine may increase metformin levels |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Caution in renal insufficiency and in impaired liver function; Adverse GI effects (eg, diarrhea, nausea, vomiting) |
Drug Category: Topical skin products
May use to reduce hair growth in face and adjacent areas under the chin.
| Drug Name | Eflornithine 13.9% cream (Vaniqa) |
|---|---|
| Description | Prescription topical cream that acts as a growth inhibitor of hair. Takes up to 2 mo to work in approximately 30% of patients. |
| Adult Dose | Apply to skin bid at least 8 h apart, and area of application should not be washed for at least 4 h |
| Pediatric Dose | <12 years: Not recommended >12 years: Administer as in adults |
| Contraindications | Documented hypersensitivity |
| Interactions | None reported |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | External use only; decrease to qd if skin irritation develops |
Drug Category: 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.
| Drug Name | Bromocriptine (Parlodel) |
|---|---|
| Description | 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. |
| Adult Dose | 1.25-2.5 mg PO initially; increase gradually every few days to approximately 5-10 mg daily in divided doses. |
| Pediatric Dose | Not recommended |
| Contraindications | Documented hypersensitivity; ischemic heart disease, uncontrolled hypertension, peripheral vascular disorders; breastfeeding |
| Interactions | Toxicity may increase with ergot alkaloids; amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, and reserpine may decrease effects |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Caution in renal or hepatic disease; generally stopped during pregnancy but can be restarted if symptoms recur; perform regular visual-field testing during pregnancy to monitor for tumor growth; can cause postural hypotension and nausea |
| Drug Name | Cabergoline (Dostinex) |
|---|---|
| Description | Semisynthetic ergot alkaloid derivative; strong dopamine D2-receptor agonist with low affinity for D1 receptors. |
| Adult Dose | 0.25-1 mg PO twice/wk; start with a low dose and increase q4wk based on prolactin levels |
| Pediatric Dose | Not recommended |
| Contraindications | Documented hypersensitivity; ischemic heart disease, uncontrolled hypertension, peripheral vascular disorders; breastfeeding |
| Interactions | Toxicity may increase with ergot alkaloids; amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, and reserpine may decrease effects |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Caution in renal or hepatic disease; generally stopped during pregnancy but can be restarted if symptoms recur; perform regular visual-field testing during pregnancy to monitor for tumor growth; can cause postural hypotension and nausea |
