Virilization (Masculinization) in Women

Male sex hormones known as androgens are present in both males and females. In men, the testes produces most of the androgens with small amounts contributed by the adrenal glands. In women, both the adrenal glands and ovaries produce androgens but the more significant quantity is the adrenal androgens. Disorders that give rise to large quantities of adrenal androgens causes virilization (maculinization) in women. Another rare cause of virilization is a tumor of the hilus cells in the ovary.

What is virilization?

Virilization is the development of secondary male characteristics in women due to an excess of androgens (male hormones). Most cases are due to overproduction of androgens by the adrenal glands in women. Virilization cannot change one’s gender but rather contributes to those physical features that are characteristic of males. This includes features such as a gruff voice, facial and body hair and larger muscle bulk.

Testosterone in Women

The adrenal glands are two small glands that sit on top of each kidney in both the male and female body. These glands secrete several important hormones that contribute to a wide range of functions like cortisol (glucocorticoids) and aldosterone (mineralocorticoids). One group of hormones that are secreted by the outer cortex of the adrenal glands are the male hormones (androgens) – dehydroepiandrosterone (DHEA) and androstenedione (andro). Both these hormones are converted into testosterone. Adrenocorticotropin hormone (ACTH), the hormone that controls cortisol secretion, also regulates androgen formation in the adrenal glands.

The precursor for DHEA and andro is the 17-hydroxypregnelone and 17-hydroxyprogesterone respectively. These precursors are derived by converting cholesterol into pregnelone. Only small amounts of 17-hydroxypregnelone and 17-hydroxyprogesterone are converted into androgens. The remainder are converted into cortisol by the enzyme 21-hydroxylase. This enzyme is also responsible for those amounts of pregnelone which are converted into progesterone and then into aldosterone. A deficiency of this hormone, 21-hydroxylase, may mean that more pregnelone is eventually converted into DHEA and andro.

Causes of Virilization

Excess androgen secretion by the adrenal gland may occur on its own or along with other adrenocortical hormones like cortisol or aldosterone (mixed syndromes).

• In Cushing syndrome, excess androgens along with high cortisol levels accounts for the typical presentation of Cushing syndrome which is more prominent in females.
• Adrenal tumors both benign (adenoma) and malignant (carcinoma) may account for excess androgen secretion. This is often seen with excess cortisol (hypercortisolism).
• Androgen-secreting tumors may occur in sites outside of the adrenal gland.
• Congenital adrenal hyperplasia (CAH) is an enlargement of the adrenal gland with excess androgen secretion. Aldosterone and cortisol secretion is usually lower than normal which is a major component of the disease process. In CAH there is a deficiency or total lack of the enzyme 21-hydroxylase prevents pregnelone conversion into aldosterone and cortisol. Instead the pregnelone is used for androgen production. Since the cortisol levels are low, the anterior pituitary secretes more ACTH. This further compounds the problem by stimulating more androgen production and secretion.
• Anabolic steroids taken by athletes cause an excess of androgens in the system. In this case, discontinuing the drug will cause the androgen levels to restore to normal levels in most cases and virilization subsides.
• Ovarian cysts in conditions like polycystic ovarian syndrome (PCOS) may also increase the androgen production by the enlarged ovary. Virilization is possible but uncommon as the ovary cannot usually produce androgens to the high levels needed for virilization even when diseased.

Signs and Symptoms of Virilization

Symptoms associated with CAH will be seen in the perinatal period or even late childhood. Rarely it starts in adulthood. With other causes, symptoms may be seen at any age but tend to be seen in adulthood.

• Excess and abnormal hair growth on the face, chest and back more prominent in women (hirsutism).
• Deep gruff voice
• Hair loss – baldness (androgenic alopecia) or thinning hair
• Increase in muscle mass
• Increased sex drive
• Acne

In women, other signs and symptoms will also be apparent. This includes :

• Initially scanty or irregular menses (oligomenorrhea) and eventually cessation of periods (amenorrhea)
• Breasts become smaller
• Clitoris enlarges and uterus shrinks

If there are other symptoms like excessive fat deposition on the upper trunk, particularly on the back with purple striae on the skin, then it is likely that Cushing’s dynrome (hypercortisolism ~ high cortisol levels).

Salt wasting sydrome may be seen with CAH as the adrenal glands cannot convert pregnelone into aldosterone (mineralocorticoid). This causes low sodium levels (hyponatremia) and high potassium levels (hyperkalemia). Acidosis and hypotension (low blood pressure) then arise. This can reach a level where there is cardiovascular collapse and even death.

Diagnosis of Virilization

The clinical presentation is an obvious indication of virilization. A blood test to assess the level of testosterone can be conducted. It is important to assess the effect of ACTH in contributing to the excess androgen levels and this can be ascertained with a dexamethasone suppression test. If high levels of androgens are due to ACTH secretion as is seen with ACTH-dependent Cushing syndrome and congenital adrenogenital hyperplasia then the androgen levels will drop as dexamethasone decreases ACTH secretion. This should be followed up by a CT scan and/or MRI of the adrenal glands.

Treatment of Virilization

• Adrenal hyperplasia – low dose corticosteroids may decrease ACTH secretion which then lowers androgen levels.
• Adenoma and carcinoma – surgical removal of the adrenal gland (unilateral or bilateral adrenalectomy)
• Ovarian cysts – oral contraceptives and/or other measures discussed under polycystic ovarian syndrome treatment.