Biology of Disease

Disorders of Sex Hormones

Disorders associated with male sex hormones include hypogonadism and

gynecomastia. In the former, there is deficient sperm production and decreased

testosterone secretion. Hypogonadism can occur because of testicular disease,

referred to as primary or hypergonadotrophic hypogonadism, or to a defect

in the hypothalamus or pituitary gland leading to secondary or hypogonado-

trophic hypogonadism. In the latter, there may be a deficiency of both gonado-

trophins or only of LH. The causes of primary hypogonadism are varied.

They include congenital defects, such as Klinefelter syndrome (Chapter 15), a

deficiency of 5A-reductase activity, testicular agenesis (failure of the testes to

develop), acquired defects due to testicular infections, for example mumps or

cytotoxic drugs, trauma or irradiation. The causes of secondary hypogonad-

ism include pituitary tumors and hypothalamic disorders such as Kallmann’s

syndrome. The treatment of hypogonadism is usually directed at the underly-

ing cause. Testosterone is given in cases of testosterone deficiency. However, if

fertility is required then gonadotrophins may have to be administered.

Gynecomastia, or breast development in males, is usually related to a

disturbance in the balance of estrogens to androgens. In puberty, it occurs in

approximately 50% of normal boys due to a temporary increase in the secretion

of estrogens. Other than at puberty, the condition is pathological. It may

arise because of decreased androgen activity in hypogonadism or because of

increased estrogen production from various endocrine tumors. Such tumors

may secrete large quantities of estrogens or may secrete hCG that stimulates

estrogen production. Some drugs possess estrogen or antiandrogen activity

and their use can lead to gynecomastia.

Disorders associated with female sex hormones include amenorrhea,

oligomenorrhea, infrequent menstruation, and virilism, with the development

of hirsutism, muscle mass, deepening of the voice and male psychological

characteristics. Amenorrhea can be primary where menstruation fails to

occur by the age of 16 years, or secondary, where menstruation stops for three

months or more after normal menstruation has been established and before

menopause. The other clinical features of amenorrhea include hirsutism,

acne, menstrual cycle disturbances and obesity, although these features vary

in their severity and prevalence. A common reason for secondary amenorrhea

in females is pregnancy. This condition must be excluded before other possible

causes, for example stress, severe weight loss, polycystic ovary syndrome

(PCOS, see below), gonad dysgenesis, such as in Turner syndrome (Chapter

15 ), the decrease in gonadotrophin secretion associated with some tumors,

hyperprolactinemia and congenital adrenal hyperplasia, are investigated. The

causes of amenorrhea are investigated by measuring the concentrations of

FSH, LH and prolactin in plasma as outlined in Figure 7.41. A high value for

FSH indicates ovarian failure. One for prolactin suggests hyperprolactinemia

and requires further investigations to confirm this diagnosis. If, however,

the values for FSH, LH and prolactin are normal, further tests to investigate

pituitary or hypothalamic diseases are necessary. The management of

amenorrhea is aimed at treating its underlying cause.

Patients with virilism present with enlargement of the clitoris, deepening

of the voice, atrophy of the breasts and hirsutism. Hair growth is not only

excessive but shows a male-like distribution. The cause of virilism is increased

androgen secretion although abnormally low levels of SHBG can also increase

the free testosterone fraction. In some cases virilism occurs because of an

increased sensitivity to androgens by target cells. Its causes include PCOS,

androgen secreting tumors, congenital adrenal hyperplasia, Cushing’s

syndrome and may be iatrogenic following treatment with androgens and

progesterone. Its commonest cause is PCOS, characterized by multiple cysts

in the ovaries that arise from follicles that have failed to ovulate. The ovaries

secrete large amounts of androgens although why this is so is unclear. Many

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