Too much androgen activity can have significant health consequences

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Features of Androgen Excess
Androgens are a vital group of human hormones. They are hydrophobic compounds and steroids and are primarily protein-bound in the plasma.

Proper androgen production and metabolism is essential to various important biological activities, the development and distribution of hair in the human body being one of the major ones.

Androgens trigger the conversion of vellus hair to terminal hair in the human body. This is a normal biological process that begins at puberty with increased androgen production, continues through adult life and slows down with reproductive capacity in both sexes.

However, excess androgen production of both adrenal and gonadal source results in unwanted hair development and the ailment is defined as hirsutism. Hirsutism in turn can be the result of various other associated ailments, though most prevalent among them are those associated to androgen excess disorders. The key features of androgen excess are:

Excess hair production

Its primary manifestation is excess, unwanted hair and adult male like terminal hair growth in females. This primarily occurs in the androgen-receptive and sexual body areas like chin and upper lip (like beard and moustache in men), ears, nose, sternum, back, abdomen, upper pubic triangle etc.

Sensitivity of hair follicles to androgen excess

The development of sexual hair is totally regulated by androgens. Hirsutism occurs due to the sensitivity of hair follicles to the changes in the level of androgens.

Biologically, the variations in androgen receptor and 5a-reductase factor of the skin of a particular body part, determines its androgen-triggered hair growth pattern. For instance, the skin of the eyelash, eyebrow and lateral and occipital aspects of the scalp (mainly non-sexual skin) are comparatively less sensitive to androgens.

On the other hand ambosexual skin (includes the lower pubic triangle and the axillary parts) are more receptive to androgens, where vellus hair is converted to the terminal kind with the lightest androgen trigger. The process of conversion to terminal hair in these body regions start in early puberty, with only a minimal rise in adrenal androgen levels.

Then there are the skins of sexual areas (chest, lower abdomen, the lower back, the upper thighs, the upper arms, the chin, the face, and the upper pelvic triangle) that are sensitive to only high levels of androgens.

Hence, when formations of terminal hairs in these parts are male-like and when they occur in women due to excess androgens it can be apparently diagnosed as hirsutism.

Sebaceous gland disorder

Along with the overproduction of hair, excess androgen also causes an enlargement of the oil producing sebaceous glands. Women have vellus hair before puberty. Also the sebaceous glands in androgen-receptive follicles are small before puberty. However, with the onset of puberty there is an increase in androgen levels for the conversion of the vellus hair to the terminal sexual hair at androgen-receptive body areas. If the androgen is produced in excess in women, it results in hirsutism. This also results in excess oil production, as the excess increased androgen also dramatically increase the size of the sebaceous glands. In many body parts however, though there is excess oil production the hair does not convert from the vellus to the terminal kind. However, the pathogenesis of this condition is still unclear.

Acne vulgaris

This skin condition can occur due to androgen excess but with or without hirsutism. It generally occurs on the face, neck, chest, upper arm, fore head and upper back because of increased sebaceous gland activity. This causes acne lesions, coupled with increased oil production. This is a common problem that occurs with puberty as the androgen levels increase.

Excess sebum accumulation and bacterium (propionibacterium acnes) interaction results in the formation papules, pustules and nodules of acne.

Acne is a sign of hyperandrogenism, which may be coupled with regular menses and hirsutism without noticeable endocrine cause. Clinical tests include those for increased androgen levels and serum progesterone in luteal phase. This apart, checking for a previous use of 13-cis retinoic acid for acne cure is a helpful indicator of hyperandrogenism.

Menstrual irregularity, obesity and infertility

Irregularity in the ovulation process (menses) is also often a marked feature of androgen excess. It is generally associated with the underlying cause of Polycystic Ovary Syndrome (PCOS) which is caused by over activity of androgen. This results in menstrual irregularity, mainly oligomenorrhea (menses of 6 weeks to 6 months), amenorrhea, or dysfunctional uterine bleeding. Most PCOS cases are chronically amenorrheic, since they record an absence of the progesterone-regulated follicular stage of ovulation. These cases are however not estrogen deficient.

The ovulation problems can occur as early as the pre-pubertal years and aggravate with age-related weight increase. Obesity marked by increased waist-hip proportion or the “apple body” shape often occurs herein. Acanthosis mgricans is also common in obese PCOS cases.

Stein and Leventhal also suggested infertility in their original definition of PCOS. However, more recent findings suggest that women with PCOS have irregular ovulation at best, and infertility may be too farfetched a conclusion and very rare. But infertility may be the manifestation of anovulation.

Other symptoms such as male like (temporal) alopecia and acne may be a result of hyperandrogenism, though in PCOS they are generally mild to moderate. A rapid onset of hyoerandrogenic symptoms or virilization (including thicker muscle mass, voice deepening, masculine body formation, clitoromegaly and speedy hirsutism etc) is rare in PCOS. They could rather indicate secondary causes of hyperandrogenism.

Obesity is also a feature of another androgen excess disorder called the hyperandrogenic insulin-resistant acanthosis nigricans syndrome (HAIR-AN). Its other symptoms include brown velvety hyper-pigmented skin (acanthosis nigricans), hypertension, hyperlipidemia, established family history of diabetes. Although acanthosis nigricans is a manifestation of insulin resistance and hyperandrogenism (HAIR-AN syndrome), it is prevalent in around 5% of such cases. Many other ailments with acanthosis nigricans, hyperandrogenism, insulin-resistant diabetes, and distinctive phenotypic characteristics have also been traced. They include lipoatrophic diabetes, leprechaunism (intrauterine development disorder, gonadal swelling, elfin facies etc), Rabson-Mendenhall syndrome (peculiar facies, pineal hypertrophy, dental precocity, thickened nails, and ovarian swelling) and type A syndrome (adolescent onset, virilization, and diabetes mellitus).

Again hypothyroidism associated with androgen disorder also has obesity as a symptoms, along with weakness, record of thyroid ablation, amenorrhea etc.

Hyperprolactinemia a very rare cause rare cause of hirsutism also features amenorrhea, galactorrhea and infertility. On the other hand rounded facies, a buffalo hump, truncal obesity, hypertension, purple striae and proximal muscle infirmity could suggest Cushing’s syndrome.

Virilization and masculinization

Virilization is generally associated with the androgen excess disorder of 21-hydroxylase non-classic I adrenal hyperplasia (late-onset CAH) is a syndrome which is marked by acute hirsutism as well. An established family history of CAH, stunted height and signs of masculinity are its other symptoms. 21-hydroxylase-deficient congenital adrenal hyperplasia shows symptoms more or less similar to late-onset CAH, with congenital virilization.

Androgen-secreting tumors are also marked by virilization, masculinization (clitoral enlargement) and excess hair growth (hirsutism). Herein they develop speedily in a span of 3–6 months, whereas in PCOS triggered hirsutism it occurs over several years. But one must note that many younger patients with signs of virilization may have another ailment called the hyperandrogenic insulin-resistant acanthosis nigricans syndrome, which also causes hirsutism. Androgenic tumors are also marked by Cushingoid features. Androgen-secreting tumors are more commonly ovarian in origin and rarely sourced to the adrenal cortex.

Postmenopausal virilization can indicate ovarian hyperthecosis. Clinical imaging can help detect hyperthecosis that causes hirustism. An enlarged ovary without follicular formations is the main indicator. A testosterone examination is also necessary to confirm it. For if circulating testosterone test result is 2.5 or more times the upper limits of normal or 200 or more ng/dL, it could be androgen-secreting tumors. However, only 20 to 30 percent of women recording such levels will have androgenic tumors, since most will have either a hyperthecosis or hilar cell hyperplasia. One can also use a gonadotropin-releasing hormone agonist in the evaluation of postmenopausal virilization due to ovarian hyperthecosis.

Familial features

Hirsutism caused by androgen excess is often marked by a strong familial factor. In Lorenzo’s study of hirsutism (refer to Lorenzo EM. Familial study of hirsutism) the familial trait has been elaborately evaluated. This study was conducted on 300 random untreated cases (irrespective of racial differences) from a public health survey group in Michigan. Its score pattern was based on only five body regions namely chin, upper lip, chest, abdomen, and thighs and the count was the conventional 0 to 4. This survey recorded a hirsutism tally over 5 among many of the cases studied.

This familial survey based their results on 90 hirsute ‘probands’ and their families. The first step to this study was to get hold of a family history of all the patients. Thereafter, volunteering mothers and sisters underwent a partial medical test, but only of the facial area. This group also underwent a full evaluation of hirsutism and other androgenic examinations.

Results of the investigation:

  • Increased prevalence of hirsutism among the female relatives
  • Acne and/or frontal balding among the male family members of the hirsute patients under survey

The strong genetic variations of hirsutism can be best adjudged in patients with sparse terminal body hair combined with androgen receptor insensitivity and 5a-reductase inadequacy. This is similarly noted in the much lesser intensity of hirsutism seen in Asian cases with polycystic ovary syndrome despite similar circulating androgen levels.