eMedicine Specialties > Obstetrics and Gynecology > Reproductive Endocrinology and Infertility
Androgen Excess
Updated: May 29, 2007
Introduction
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 (see Media file 1): 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 5 a -reductase enzymes on testosterone, androstenedione, and DHEA. Two different 5 a -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 3 a -androstanediol. 3 a -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 5 a -reductase enzymes can be determined by measuring 3 a -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 5 a -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 11 a -hydroxylase enzyme or the 3 a -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 11 a -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 11 a -hydroxylase deficiency.
Another form of CAH, 3 a -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 United States.
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.
Clinical
History
A thorough history and focused physical examinations are essential for the androgen excess evaluation. Laboratory tests should serve to confirm the diagnosis.
- Family history and cultural background
- A patient is not hirsute if she does not notice a difference compared with her relatives.
- CAH is inherited so a family history is important.
- A family history of type II diabetes may indicate insulin resistance.
- Patient age at thelarche, adrenarche, and menarche
- CAH is a genetic condition that causes androgen excess in early childhood.
- Androgen excess in childhood, if untreated, results in rapid growth and early puberty with short stature in adulthood.
- Detailed history of menstrual pattern: Oligomenorrhea, anovulation, and dysfunctional uterine bleeding are often associated with androgen excess.
- Reproductive history, including miscarriages
- History of galactorrhea or symptoms of thyroid dysfunction
- Detailed history of age at onset and progressions of features of androgen excess
- Hirsutism, acne, alopecia, excessive sebum, and seborrhea could all be signs of androgen excess.
- Rapid onset of hirsutism is characteristic of androgen-secreting tumors, whereas slow onset is more likely to be an endocrine disorder of adrenal, ovary, or pilosebaceous unit.
- Signs of virilization include deepening of voice, temporal balding, clitoromegaly, and changes in bra size.
- Use of androgenic drugs should be excluded.
Physical
- Height, weight, body mass index (BMI) and waist-to-hip ratio (WHR) should be determined. Increased BMI and WHR are associated with increased coronary artery disease and mortality.
- Hirsutism is excessive recognizable hair growth characterized by an increase in the number and length of terminal hairs in androgen-sensitive areas. Racial, familial, genetic, and ethnic differences all affect the occurrence of hirsutism. Hirsutism is difficult to quantitate. The entire body needs to be inspected and the findings must be documented carefully. Particular attention should be directed to the chin, lip, sideburns, breasts, and sternum, the midline between the umbilicus and the pubis and the thigh.
- Ferriman and Gallwey published a rating scale that is illustrated in the table below.1 This scale allows the physician to measure a response to therapy objectively. This system is the most widely used and evaluates body areas for absent-to-severe hirsutism with scores of 0-4, respectively. Scores of 8 and higher are consistent with a diagnosis of hirsutism. This scale does not measure the thickness of the hair, which is another way of objectively assessing excess hair.
- Scoring systems are a useful aid in quantifying hirsutism and in evaluating treatment response; however, they remain somewhat subjective. The absolute score does not define hirsutism. Even with scores greater than 8, the patient provides the definition. From a clinical standpoint, the patient can determine if he or she notices a difference. Photographs are helpful for documentation and for following the progress of therapy.
- Ferriman-Gallwey Scoring System
Open table in new window
[ CLOSE WINDOW ]Table
Body Area Evaluated Score
(Graded from 0-4*)Upper lip Chin Upper abdomen Lower abdomen Upper arm Thighs Upper back Lower back/buttocks *0 = No hirsutism, 4 = Severe hirsutismBody Area Evaluated Score
(Graded from 0-4*)Upper lip Chin Upper abdomen Lower abdomen Upper arm Thighs Upper back Lower back/buttocks
- Virilization is relatively uncommon; it occurs with extreme hyperandrogenism.
- Virilization is characterized by temporal balding, breast atrophy, androgenic muscle development, clitoral hypertrophy, amenorrhea, deepening of the voice, and extreme hirsutism.
- Clitoromegaly is defined when the product of the sagittal and transverse diameters of the glans of the clitoris are greater than 35 mm.
- Acne as an isolated symptom might not be considered a sign of hyperandrogenism.
- The severity of the acne lesions needs to be assessed, including the number, type, and distribution of the lesions.
- Several areas of the body need to be examined, including the face, chest, and back. Photographic documentation is helpful.
- Acanthosis nigricans is a skin hyperpigmentation usually present on the back of the neck, under the arms, and in the groin region. The skin is velvety and the color can range from light brown to black. Acanthosis nigricans in the presence of hirsutism raises the suspicion of insulin resistance and hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN) syndrome (see Acanthosis Nigricans).
- The breasts should be examined for presence of galactorrhea and the thyroid gland should be palpated.
Causes
Excessive androgen production by the ovaries, and/or the adrenal glands are the most common causes of androgen excess. An abnormal steroid metabolism, androgen receptor dysfunction, and the use of androgenlike drugs may also be causes.
- Polycystic ovarian syndrome (PCOS) is the most common hyperandrogenic disorder, affecting 5-10% of all women. PCOS involves irregular ovulation in combination with excess androgens and possibly polycystic ovaries. An extreme form, hyperthecosis, can have testosterone levels in the tumor range.
- Tumors of the ovary secrete high levels of testosterone. The testosterone levels exceed 2.0 ng/mL (200 ng/dL, 8.92 nmol/L) or 2.5 times the upper limit of the reference range. Sertoli-Leydig cell tumors, hilus cell tumors, and lipoid cell (adrenal rest) tumors are the most common. Sertoli-Leydig cell tumors reach palpable size at the time of clinical diagnosis, whereas hilar cell and lipoid cell tumors are difficult to detect by any means because of their small size.
- Tumors of the adrenal glands (adenomas, carcinomas), which secrete elevated levels of androgens, are known but rare. They are suspected when DHEAS exceeds 7 μg/mL (18 μmol/L).
- Classical and nonclassical (late-onset) CAH
- Cushing syndrome: Patients with Cushing syndrome secrete elevated androgens, but diagnosing this disease by hyperandrogenic manifestations without the other signs and symptoms of Cushing syndrome would be unusual.
- Hyperandrogenic, insulin resistance, and acanthosis nigricans (HAIR-AN) syndrome
- Mild androgenic disorders: These are common androgenic disorders that do not cause an ovulatory dysfunction.
- Ovulatory PCOS - Ovulatory hyperandrogenic patients with polycystic ovary at ultrasonography
- Idiopathic hyperandrogenism - Ovulatory hyperandrogenic patient but with normal ovaries at ultrasonography
- Idiopathic hirsutism - Androgenic phenotype with normal androgens
- Factitious: Ingestion of androgens can result in hirsutism, acne, and virilization. Agents such as oral contraceptive progestins are listed as potentially causing hirsutism; however, these agents are not androgenic in women in the doses used clinically. Drugs that can induce hirsutism by their inherent androgenic effects include DHEAS, testosterone, danazol, and anabolic steroids.
- Pregnancy: Testosterone rises throughout the normal pregnancy, reaching values around 600-800 ng/dL by term. The increase in SHBG and the placenta aromatization of androgens to estrogens protect the mother and fetus. Placental aromatase enzyme deficiency can cause hyperandrogenemia in both mother and fetus and causes virilization.
More on Androgen Excess |
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| Follow-up: Androgen Excess |
| Multimedia: Androgen Excess |
| References |
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Further Reading
Keywords
androgen excess, excessive androgen production, adrenal glands, ovary, endocrine glands, testosterone, dihydrotestosterone, DHT, dehydroepiandrosterone sulfate, DHEAS, dehydroepiandrosterone (DHEA), androstenedione, androstenediol luteinizing hormone, LH, adrenocorticotropic hormone, ACTH, 11-androstenedione, adrenal androgen secretion, albumin, sex hormone-binding globulin, SHBG, congenital adrenal hyperplasia, CAH, enzyme defect, adrenal steroid hormone, cortisol, aldosterone, hyperandrogenism, deoxycorticosterone, DOC, hypertension, hypokalemia, hydroxylase deficiency, 3α-hydroxy-steroid dehydrogenase deficiency, pregnenolone, 17-hydroxy-pregnenolone, cardiovascular disease, CVD, acanthosis nigricans, hirsutism, polycystic ovarian syndrome, PCOS, hyperthecosis, Sertoli-Leydig cell tumor, hilus cell tumor, lipoid cell tumor
