A. Pituitary Insufficiency
Pituitary insufficiency may result from tumors, infarcts, surgery, radiation, or infiltrative and granulomatous processes. In sickle cell anemia, pituitary and testicular microinfarcts from sickling of red blood cells are suspected of causing infertility. Men with sickle cell anemia have decreased testosterone and variable LH and FSH levels. β-Thalassemia patients have mutations in the β-globin gene that lead to an imbalance in α and β globin composition of hemoglobin; these patients are mainly of Mediterranean or African origin. Infertility is also believed to result from the deposition of iron in the pituitary gland and testes. Similarly, hemochromatosis results in iron deposition within the liver, testis, and pituitary and is associated with testicular dysfunction in 80% of cases.

B. Hyperprolactinemia
Another form of hypogonadotropic hypogonadism is due to elevated circulating prolactin. If hyperprolactinemia occurs, secondary causes such as stress during the blood draw, systemic diseases, and medications should be ruled out. With these causes excluded, the most common and important cause of hyperprolactinemia is a prolactin-secreting pituitary adenoma. High-resolution CT scanning or MRI of the sella turcica has classically been used to distinguish between microadenoma (< 10 mm) and macroadenoma (> 10 mm) forms of tumor. Stratification of disease based on radiologic diagnosis alone is misleading, as surgery for hyperprolactinemia almost always reveals a pituitary tumor. Elevated prolactin usually results in decreased FSH, LH, and testosterone levels and causes infertility. Associated symptoms include loss of libido, impotence, galactorrhea, and gynecomastia. Signs and symptoms of other pituitary hormone derangements (adrenocorticotropic hormone, thyroid-stimulating hormone) should also be investigated.

C. Exogenous or Endogenous Hormones
1. Estrogens - An excess of sex steroids, either estrogens or androgens, can cause male infertility due to an imbalance in the testosterone-estrogen ratio. Hepatic cirrhosis increases endogenous estrogens because of augmented aromatase activity within the diseased liver. Likewise, excessive obesity may be associated with testosterone-estrogen imbalance owing to increased peripheral aromatase activity. Less commonly, adrenocortical tumors, Sertoli cell tumors, and interstitial testis tumors may produce estrogens. Excess estrogens mediate infertility by decreasing pituitary gonadotropin secretion and inducing secondary testis failure. Exposure to exogenous estrogens has been implicated as a reason for the controversial finding of decreased sperm concentrations in men over the last 50 years. Supporters of this claim suggest that men are overexposed to estrogenic compounds during fetal life, which results in compromised semen quality later (Carlsen et al, 1992). Postulated sources of exposure include anabolic estrogens in livestock, consumed plant estrogens, and environmental estrogenic chemicals like pesticides. This xenoestrogen exposure theory, however, remains unproved as a cause of impaired sperm quality.

2. Androgens - An excess of androgens can suppress pituitary gonadotropin secretion and lead to secondary testis failure. The use of exogenous androgenic steroids (anabolic steroids) by as many as 15% of high school athletes, 30% of college athletes, and 70% of professional athletes may result in temporary sterility due to this effect. Initial treatment is to discontinue the steroids and reevaluate semen quality every 3-6 months until spermatogenesis returns. The most common reason for excess endogenous androgens is congenital adrenal hyperplasia, in which the enzyme 21-hydroxylase is most commonly deficient. As a result, there is defective cortisol synthesis and excessive adrenocorticotropic hormone production, leading to abnormally high production of androgenic steroids by the adrenal cortex. High androgen levels in prepubertal boys results in precocious puberty, with premature development of secondary sex characteristics and abnormal enlargement of the phallus. The testes are characteristically small because of central gonadotropin inhibition by androgens. In young girls, virilization and clitoral enlargement may be obvious. In cases of the classic 21-hydroxylase-deficient congenital adrenal hyperplasia that presents in childhood, normal sperm counts and fertility have been reported, even without glucocorticoid treatment. This disorder is one of the few intersex conditions associated with fertility. Other sources of endogenous androgens include hormonally active adrenocortical tumors or Leydig cell tumors of the testis.

3. Glucocorticoids - Exposure to excess glucocorticoids either endogenously or exogenously can result in decreased spermatogenesis. Elevated plasma cortisone levels depress LH secretion and induce secondary testis failure. Sources of exogenous glucocorticoids include chronic therapy for ulcerative colitis, asthma, or rheumatoid arthritis. Cushing syndrome is a common reason for excess endogenous glucocorticoids. Correction of the problem usually improves spermatogenesis.

4. Hyper- and hypothyroidism - Abnormally high or low levels of serum thyroid hormone affect spermatogenesis at the level of both the pituitary and testis. Thyroid balance is important for normal hypothalamic hormone secretion and for normal sex hormone-binding protein levels that govern the testosterone-estrogen ratio. Thyroid abnormalities are a rare cause (0.5%) of male infertility.

5. Growth hormone - There is emerging evidence that growth hormone may play a role in male infertility. Some infertile men have deficient responses to growth hormone challenge tests and may respond to growth hormone treatment with improvements in semen quality. Growth hormone is an anterior pituitary hormone that has receptors in the testis. It induces insulin-like growth factor-1, a growth factor important for spermatogenesis. The routine measurement of serum growth hormone is presently not indicated in the infertility evaluation.