Hormonal Considerations

An appropriate hormonal milieu must exist for the reproductive organs to produce, mature and transport the highly specialized male gamete to the ejaculatory duct.

The entire system of hormone balance is initiated by the pulsatile hypothalamic release of GnRH ( gonadotropin-releasing hormone). Pituitary LH ( luteinizing hormone) secretion is determined by GnRH pulses from the hypothalamus, that occur approximately every two hours and are carried via a venous portal network to the pituitary. This hypothalamohypophyseal portal connection allows an exact synchrony of GnRH and LH pulse secretion. FSH ( follicle-stimulating hormone) secretion is also stimulated by GnRH, but FSH and LH are differentially regulated by hormonal and other factors that are poorly understood. The factors influencing FSH secretion are produced by Sertoli cells and other components of the testis that probably includes peptides of the inhibin and activin families. Within the testis, LH stimulates Leydig cell synthesis of testosterone. Testosterone production by the Leydig cell provides locally high intratesticular concentrations of this hormone that stimulates spermatogenesis. Testosterone concentrations in peripheral blood of men change dramatically during the life cycle. Testosterone reaches a maximum concentration during the second or third decade of life, then reaches a plateau, and declines thereafter. Additionally, annual and daily rhythms in testosterone concentration occur, typically with a testosterone peak in the early morning. Other, irregular fluctuations in testosterone concentration may also be detectable in peripheral blood. Testosterone is normally aromatized in peripheral tissue to estrogens. Excessive testosterone levels, associated with gonadotropin, clomiphene citrate or flutamide treatment, may paradoxically result in increased feminization from conversion of androgens to estrogens by aromatase. Similarly, increased aromatase activity is associated with alcoholism and chronic liver disease, as well as testis tumors.

Accurate clinical assessment of the pituitary gonadotropins LH and FSH must take into account their pulsatile release. During clinical research studies, three serum samples are obtained, one every 30 minutes, and the sera pooled for accurate determination of mean gonadotropin levels. This process is usually not necessary in clinical practice, but the clinician should be aware of the potential for LH and FSH peaks to be measured in a single gonadotropin determination, and perform repeat evaluation if LH and FSH hormone levels are both elevated. Testosterone levels may be decreased in the late afternoon or evening. Interpretation of serum testosterone levels should take the diurnal secretion of this hormone into account. Prolactin, another pituitary hormone, may affect fertility by decreasing LH production, resulting in a decrease in testosterone and subsequently, decreased libido. The release of prolactin is mediated by dopamine, and the dopamine antagonist bromocriptine will ameliorate the antifertility effects of hyperprolactinemia.

Testosterone is converted intracellularly within most androgen-sensitive organs to dihydrotestosterone. Function of the prostate, seminal vesicles, vas deferens, and other sex accessory organs are all androgen-dependent. The degree to which partial androgen deprivation in the hypogonadal man affects the function of these organs is unknown. Furthermore, the effects of "low-normal" serum testosterone levels on these organs and a man's fertility potential are unknown. Abnormally elevated serum testosterone levels are peripherally converted by the aromatase enzyme to estrogens. In addition, chromosomal abnormalities such as Klinefelter's syndrome(xxy), and some testicular tumors have elevated aromatase levels. Some obese patients may also have increased aromatase activity, since aromatase levels are high in adipose tissue, as well as fat. Therefore, hormonal evaluation of the infertile man should include determination of serum LH, FSH, testosterone and prolactin. For men with clinical gynecomastia, serum estradiol should be measured.