Male gonadal differentiation begins at 7 weeks of gestation, with organization of the gonadal blastema into interstitium and germ cell–containing testicular cords. Primitive Sertoli’s cells and spermatogonia become visible within the cords, while the epithelium differentiates to form the tunica albuginea (9). Leydig’s cells derived from the undifferentiated interstitium are visible by the end of the eighth week of gestation and are capable of androgen synthesis at this time. By 14 weeks of gestation these cells make up as much as 50% of the cell mass, but as the tubules develop they account for a smaller percentage of the tissue. The fetal testes grow from approximately 20 mg at 14 weeks of gestation to 800 mg at birth; at 5 to 6 months they descend into the inguinal canal in association with the epididymis and the ductus deferens (9). Testicular secretion of testosterone (T) in the fetus reaches a peak late in the first trimester and then declines until parturition (10). The fetal testis also produces anti-müllerian hormone,
which causes dedifferentiation of the müllerian duct system in the male fetus (11). In the first year of life, there is a transient increase in T, after which the testis remains relatively quiescent until the onset of puberty. The pulsatile secretion of gonadotropin-releasing hormone (GnRH) causes pulsatile secretion of gonadotropins (Gns). Plasma levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the fetus increase after the establishment of the hypothalamic–pituitary portal system until midgestation and then decrease toward term as inhibitory control begins to function; mean levels of fetal plasma FSH are higher in females than in males (12). During the first 2 years after birth, plasma levels of LH and FSH increase intermittently to adult values and occasionally higher, and then they remain low until puberty.

In the adult male, GnRH and Gns are secreted in discrete pulses. The secretory pulses of LH occur at a frequency of 8 to 14 pulses per 24 hours and vary in magnitude (13). Pulsatile secretion of FSH is temporally coupled to that of LH but is lower in amplitude (14). The secretion of LH is controlled by the negative feedback action of gonadal steroids on the hypothalamus and the pituitary. Both T and estradiol (E₂) can effect this inhibition. T can be converted to E₂ in the brain and the pituitary, but on the basis of the results of many studies the two hormones are thought to act independently (15,16). LH stimulates Leydig’s cells to secrete T and, to a minor extend, E₂ (17). Also, LH appears to govern testicular aromatization in Leydig’s cells. In the normal adult male, T, dihydrotestosterone (DHT), and to some extend E₂ circulate in the plasma bound in part to sex hormone–binding globulin (SHBG), which is synthesized in the liver (18). Thyroxine (T₄) increases serum SHBG levels (18,19). Sex hormones bound to SHBG are inactive and appear not to be readily metabolized (18). The unbound sex hormones or those bound to albumin are biologically active. The T concentration in the testes is maintained at a high concentration relative to serum by androgen-binding protein secreted by Sertoli’s cells under the influence of FSH. The high intratesticular concentration of T may be necessary for normal Sertoli’s cell function or may play a role in spermatogenesis or sperm transport (20). In certain tissues, especially the prostate, circulating T enters the cell and is metabolized to more active products, especially DHT, through the action of the enzyme 5α-reductase II. In other tissues, 5α-reductase I is the major isoenzyme (21). Although DHT is the active androgen in some areas, T itself is an active androgen in some tissues that lack the enzyme, such as muscle. There is a decline in testicular function due to age (22), although the interplay of lifestyle and disease processes probably plays a role (23).

Although the testicular secretion of E₂ is important, the major source of circulating hormone derives from aromatization of T in peripheral tissues, including adipose tissue, muscle, and skin; however, little aromatization appears to occur in the liver (24). These estrogens are further metabolized, primarily in the liver, to estriol and the catechol estrogens (25). The hypothalamus and pituitary can aromatize androgens, so it is uncertain whether T itself or the estrogens formed locally from T are the main negative feedback mechanisms for LH release (26). However, there is good evidence that one of the major factors controlling LH release is T itself. Inhibin is a major factor in the control of FSH secretion (27).

Therefore, masculinization in men depends on the actions of both T and DHT. The exact role of E₂ is uncertain, but it appears in some processes, like bone formation, to play an important role.

The effects of thyroid hormone alterations on the reproductive system have been studied extensively in animals and have generally shown that changes from normal thyroid function resulted in decreased sexual activity and fertility (28,29). The underlying mechanisms, however, are not constant throughout all species, and results from different studies disagree.

In intact rats, the administration of T₄ resulted in decreased serum gonadotropin levels (30). In immature male mice aged less than 4 weeks, the administration of slightly supraphysiologic T₄ doses resulted in a tendency toward early maturation and shortening of the mice development period. Conversely, larger thyroid hormone doses resulted in decreased testes weights and seminal vesicles, both in mice and rabbits (28). Direct effects of T₄ resulted in minimal oxygen consumption changes in the testes when T₄ was present in testicular slice incubations (31). Administration of excess T₄ to mature male rats also resulted in a decrease in total lipids, cholesterol, and phospholipids in the testes and rats rendered thyrotoxic by excess T₄ administration were shown to synthesize increased amounts of T (30,32). Finally, the effects of T₄ on spermatogenesis are conflicting, but it would appear that T₄ does not exert a direct effect on spermatogenesis in mature rats or rams (33).

In rat, triiodothyronine (T₃) affects testis maturation, and thyroid receptors (TR)α and TRβ are known to be expressed in rats’ testes (34). TRα1 is the specific TR isoform that has been proposed to be involved in testis function and development. Maximal Sertoli cell proliferation coincides with maximal T₃ binding capacity in the testis, suggesting that the main target of T₃ action is the Sertoli cell. However, T₃ also plays a significant role in differentiation of the seminiferous epithelium, and studies in rodents have shown that T₃ is an important factor in the maturation of Leydig cells. The presence of T₃ is necessary to initiate differentiation of mesenchymal cells into Leydig progenitor cells and T₃ works in concert with other hormones [LH, insulin growth factor (IGF)-1] to promote Leydig cell development (1,35).

Data from other animal species (such as deer, sheep, cattle, birds, mink) also suggest that T₃ is a component of the neuroendocrine system that regulates seasonal cycles of reproductive activity (1). Although the underlying mechanisms remain unknown, it has been postulated that T₃ triggers cessation of reproduction at the end of the reproduction season, since circulating T₃ levels in deer rise at the time of seasonal transition to the non-breeding state and thyroidectomy results in absence of seasonal regression of the testis. T₃ may also interact with – and modulate – the action of other hormonal systems such as growth hormone and steroids.