Androgen excess in women

Physiology of androgens in women

Androgen production in women is best understood by the concept of production from glandular tissues, namely the ovaries and adrenals, and from nonglandular (peripheral) tissues. This third compartment of production and modification of androgens includes many peripheral tissues and, for our discussion of hyperandrogenism, principally means the PSU itself, which not only responds to androgen but can modify it by enzymatic modifications. From a quantitative perspective, the major androgen produced by the ovaries is testosterone and that of the adrenal glands is dehydroepiandrosterone sulfate (DHEAS) . Measurement of the amount of these two steroids in the circulation provides clinically relevant information regarding the presence and source of increased androgen production. In addition to glandular production of androgens, conversion of androstenedione and dehydroepiandrosterone (DHEA) to testosterone occurs in peripheral tissues.

The ovaries secrete only approximately 0.1 mg of testosterone/day, mainly from the thecal and stroma cells. Other androgens secreted by the ovary are androstenedione (1 to 2 mg/day) and DHEA (<1 mg/day). The adrenal glands, in addition to secreting large quantities of DHEAS (6 to 24 mg/day), secrete approximately the same daily amount of androstenedione (1 mg/day) as the ovaries and less than 1 mg of DHEA/day. The normal adrenal gland secretes little testosterone, although some adrenal tumors have the ability to produce testosterone directly.

Androstenedione and DHEA do not have strong androgenic activity but are peripherally converted at a slow rate to the biologically active androgen, testosterone. Because the ovaries and adrenal gland secrete approximately equal amounts of androstenedione and DHEA, approximately two-thirds (0.22 mg) of the daily testosterone produced in a woman originates from the ovaries. Thus increased circulating levels of testosterone usually indicate abnormal ovarian androgen production. Clinical measurements of testosterone have not been sufficiently sensitive to differentiate normal from slightly elevated values; however, more laboratories are now moving toward using mass spectrometry and related methods, which are far more sensitive.

For practical purposes, circulatory levels of DHEAS reflect an adrenal source of production , and in women more than 95% is adrenal derived. Occasionally, in women who have increased production of ovarian DHEA, such as some with polycystic ovary syndrome (PCOS), the elevated levels of DHEAS might have an ovarian component because DHEA may be converted to DHEAS in the circulation. Another specific marker of adrenal androgen production, used for research purposes, is 11 β -hydroxyandrostenedione, because the adrenal primarily has the ability to 11-hydroxylate androstenedione, whereas the ovary has a limited ability to do so.

Just in the last few years it has been realized using mass spectroscopy techniques that 11-oxygenated androgens produced by the adrenal circulate in blood in large quantities. It has been suggested that these androgens are the predominant circulating androgens in women with PCOS ( ) Fig. 38.3 . Some of these steroids such as 11-keto dihydrotestosterone are extremely potent and likely enhance androgen action. In the future it is likely that some of these androgens will be measured more routinely to have a better understanding of abnormal secretion and how they may be affected by treatment.

Although DHEAS serves as a good marker of adrenal hyperandrogenism, several guidelines for the evaluation of androgen excess in women omit this measurement, because DHEAS itself is a “weak” androgen and may not contribute much to the overall androgenicity. Nevertheless it is our perspective that the measurement of DHEAS gives a more complete picture of androgen production.

Most testosterone in the circulation (≈85%) is tightly bound to sex hormone–binding globulin (SHBG) and is believed to be biologically inactive. An additional 10% to 15% is loosely bound to albumin, with only approximately 1% to 2% not bound to any protein ( free testosterone ). Both the free and albumin-bound fractions (often called unbound biologically active) are . Serum testosterone can be measured as the total amount, the amount that is believed to be biologically active (unbound, or non-SHBG bound), and as the free form. As discussed later, because commercial laboratory measurements of “free” testosterone are not accurate, it may be useful to measure the ratio of testosterone and SHBG.

To exert a biologic effect, testosterone is metabolized peripherally in target tissues to the more potent androgen 5 α -dihydrotestosterone (DHT) by the enzyme 5 α -reductase . 5 α -reductase activity is important for testosterone action peripherally (as in the PSU) as well as in the genitalia ( ). It is not necessary for testosterone action in other areas such as in muscle or bone. After further 3-keto reduction, DHT is converted to another metabolite, 5 α -androstane-3 α ,17 β -diol (3 α -diol). 3 α -Diol is conjugated to the sulfate or glucuronide. The glucuronide, 5 α -androstane-3 α ,17 β -diol glucuronide (3 α -diol-G) , is a stable, irreversible product of intracellular 5 α -reductase activity and reflects this activity in blood ( Fig. 38.4 ).

Even with normal circulatory levels of androgen, increased 5 α -reductase activity in the PSU results in increased androgenic activity, producing hirsutism ( ; ) ( Fig. 38.5 ). Measurements of 5 α -reductase activity in skin biopsies have found that the level of activity correlated well with the degree of hirsutism present ( ). The activity level is elevated in “idiopathic” hirsutism, where circulating levels of androgens are thought to be normal ( Fig. 38.6 ). The degree of 5 α -reductase activity can be measured in skin biopsy specimens by a variety of methods. This technique is only used for investigational purposes; if necessary for diagnostic reasons, 3 α -diol-G levels can be directly measured in serum. We have found that the measurement of this metabolite is the most accurate indicator of the degree of peripheral androgen metabolism in women, as long as the level of glandular production (testosterone) is appreciated. Although serum levels of total testosterone are similar in normal and hirsute women, there are significant differences in 3 α -diol-G ( ) ( Fig. 38.7 ). In general, whereas non–SHBG-bound testosterone has been found to be elevated in approximately 60% to 70% of hirsute women, levels of 3 α -diol-G have been found to be elevated in more than 80% of women in this setting.

In summary, there are three markers of androgen production in serum, one for each compartment in which androgens are produced ( Table 38.2 ). These measurements best reflect the area of interest, although it is clear that each compartment also produces other hormones. Interpretation of levels of 3 α -diol-G is controversial because these levels are highly dependent on circulating levels of precursor androgens, such as testosterone and also androstenedione. A reasonable argument may be that if testosterone and DHEAS are normal but there is significant hirsutism, then measuring 3 α -diol-G may not be necessary and one may merely assume a peripheral source of androgen excess. As suggested earlier, it is envisioned that in the future the measurement of 11-oxygenated androgens will be part of our armamentarium.

Causes of androgen excess

Although most causes will result in hirsutism, each of the diagnostic categories can lead to any of the manifestations of androgen excess: acne, hirsutism, or alopecia. One common causative factor of signs of androgen excess is the administration of androgenic medication. In addition to testosterone itself, various anabolic steroids, 19-norprogestogens, and danazol have androgenic effects. Thus a careful history of medication intake is important for all women with hirsutism.

Hirsutism or virilization can also be associated with some forms of abnormal gonadal development. With this cause, individuals have signs of external sexual ambiguity or primary amenorrhea, in addition to findings of androgen excess, and a Y chromosome is often present.

Signs of androgen excess during pregnancy can be caused by increased ovarian testosterone production. This is usually caused by a luteoma of pregnancy or hyperreactio luteinalis . The former is a unilateral or bilateral solid ovarian enlargement; the latter is bilateral cystic ovarian enlargement. After pregnancy is completed, the excessive ovarian androgenic production resolves spontaneously and the androgenic signs regress.

A diagnosis of these three causes of androgen excess can usually easily be made by means of a careful history and physical examination. The remaining causes of androgen excess, together with the origin of hyperandrogenism, are listed in Table 38.3 . Details of each of these causes will be described. “Idiopathic” hirsutism and PCOS are the most common disorders, together making up more than 90% of cases. PCOS is the most common disorder, and because of its overall prevalence and importance among reproductive women, it is covered in detail in a separate chapter.

Stromal hyperthecosis

Stromal hyperthecosis is an uncommon benign ovarian disorder in which the ovaries are typically bilaterally enlarged to approximately 5 to 7 cm in diameter. Histologically, there are nests of luteinized theca cells within the stroma ( Fig. 38.8 ). The capsules of these ovaries are thick, similar to those found in PCOS, but, unlike in PCOS, subcapsular cysts are uncommon. The theca cells produce large amounts of testosterone, as determined by retrograde ovarian vein catheterization. The ultrasound picture of stromal hyperthecosis may be variable ( ). Like PCOS, this disorder has a gradual onset and is initially associated with anovulation or amenorrhea and hirsutism; however , unlike PCOS, with increasing age the ovaries secrete steadily increasing amounts of testosterone. Thus when women with this disorder reach the fourth decade of life, the severity of the hirsutism increases and signs of virilization , such as temporal balding, clitoral enlargement, deepening of the voice, and decreased breast size, appear and gradually increase in severity. By this time, serum testosterone levels are often in the range of 2 ng/mL, similar to levels found in ovarian and adrenal testosterone-producing tumors; however, with tumors, the symptoms of virilization appear and progress much more rapidly. Stromal hyperthecosis has also been found to be a cause of androgen excess in postmenopausal women. Here the ovaries are enlarged but not as large as in premenopausal women with the disorder; and testosterone levels are not as high.