(PRL) is known to enhance the effect of LH on spermatogenesis. The physiological importance of PRL in the regulation of Leydig cell function was first determined using three animal models [41, 42]: the golden hamster, where testicular regression can be induced by short photoperiod; hypophysectomized mice; and the hereditary dwarf mouse with congenital PRL deficiency and infertility. In all three models there is a deficiency in plasma concentrations of PRL and testosterone and testicular atrophy is evident. PRL therapy, on the other hand, stimulates spermatogenesis in the dwarf mouse and restores testicular function in the golden hamster; in hypophysectomized animals, PRL, in the presence of LH, induces spermatogenesis and restores plasma testosterone. In men, PRL has an important role in the control of testosterone and reproductive function [49]. At very high concentrations (hyperprolactinemia), PRL has an antigonadal effect in men, inhibiting testicular function, and is associated with hypogonadism [50].
Other Regulatory Factors
The effects of other regulatory factors, such as growth hormone (GH), on testicular steroidogenesis have not been fully clarified. However, in view of the structural similarities between PRL and GH, it is thought that both hormones may have comparable effects on Leydig cell function [42]. The effect of GH may be more significant during puberty (see Chapter 6). However, administration of gonadal steroids to intact animals is known to cause reduced androgen production, an effect that has been attributed to inhibition of gonadotropin secretion with secondary effects on testicular endocrine function. Estrogen receptors have also been detected in interstitial tissue of the testis and since decreased testosterone levels are not correlated with a corresponding change in plasma LH, some authors suggest that estrogen may exert a direct inhibitory action on Leydig cell function [51, 52]. The effects of corticosteroids on Leydig cell function have been noted. Boars treated with adrenocorticotropin (ACTH) experienced increased testicular testosterone simultaneously with increased secretion of adrenal corticosteroids [53]. A transient increase in peripheral circulation of both corticosteroids and testosterone was first observed in boars following acute treatment with ACTH, while a decrease in testosterone occurred following chronic treatment [54]. These authors concluded that prolonged stressful conditions may lead to chronic elevation in ACTH levels, thus suppressing testosterone production and inducing poor breeding activity.
In reviewing the literature, Tilbrook et al. [55] have determined that stress‐related influences on reproduction are complicated and not fully understood, but the process may involve a number of endocrine, paracrine, and neural systems. The significance of stress‐induced secretion of cortisol varies with species. In some instances, there appears to be little impact of short‐term increases in cortisol concentrations, and protracted increases in plasma concentration seem to be required before any deleterious effect on reproduction are apparent. In a comprehensive review, Moberg [56] describes the influence of the adrenal axis on gonadal function in mammals. Subsequently, the same author published a detailed review [57] of the impact of behavior on domestic animal reproductive performance and placed particular emphasis on how intensive livestock management practices can contribute to stress‐induced disruption of normal reproductive function. However, the emphasis has primarily been on studies investigating the effects of stress‐induced ACTH release in females.
Elevated plasma ACTH results in increased adrenal corticosteroid synthesis and under chronic conditions may inhibit gonadotropin‐releasing hormone and gonadotropin hormone production, thereby reducing gonadotropin (LH) release from the pituitary gland and thus impacting normal ovarian function in females. Nevertheless, studies have shown that stress‐induced elevation in ACTH affects males in a physiologically similar manner by impacting gonadotropin regulation of testicular function. Liptrap and Raeside [58] observed the effects of cortisol on gonadotropin‐releasing hormone in boars, while Matteri et al. [59] observed that stress or acute ACTH treatment suppresses gonadotropin‐releasing hormone‐induced LH release in the ram. In Holstein bulls treated with a bolus of ACTH (0.45 IU/kg), plasma LH or FSH concentrations did not appear to be negatively affected, but it did appear to reduce plasma testosterone concentrations [60]. Pharmacological concentrations of ACTH (200 IU every eight hours) over a six‐day period resulted in reduced plasma testosterone in yearling and mature bulls within eight hours and four days of initial treatment, respectively, and this decrease persisted in both age groups for an additional 24 hours after the last ACTH injection [61]. While semen viability, concentration, and sperm output were unaffected by the prolonged ACTH treatment concomitant with a subsequent marked increase in glucocorticoids and decrease in testosterone, a small increase in semen content of immature sperm or sperm with abnormal heads was observed [61]. Thus, it appears that under prolonged stressful conditions, gonadotropin secretion is more likely to be suppressed, thus inhibiting reproductive performance. In addition, studies have demonstrated that glucocorticoids can inhibit gonadotropin secretion in some circumstances. Tilbrook et al. [55] conclude that suppression of reproduction is more likely to occur under conditions of chronic stress and may involve actions at the level of the hypothalamus or pituitary. In addition, they indicate that there are likely to be species differences in the effect of glucocorticoids on gonadotropin secretion, and the presence of sex steroids and the sex of an individual are also likely to be factors.
Cytokines are members of the family of growth factors, and the interleukins in particular may act at the level of the hypothalamus where they may control the release of gonadotropin‐releasing hormone, thus influencing the release of pituitary gonadotropins and ultimately gonadal steroid synthesis and release. Svechniko et al. [62] have reported that testicular interleukin (IL)‐1 may play a role in the paracrine regulation of Leydig cell steroidogenesis in rats. Others have reported that testicular interleukins may play an important functional role in both normal testicular function and under pathological conditions [63]. There is some evidence in the bovine that cytokines such as tumor necrosis factor (TNF)‐α and interferon (IFN)‐γ may play a role in nitric oxide regulation in luteal endothelial cells by increasing inducible nitric oxide synthase (iNOS) activity, thereby accelerating luteolysis, while progesterone is thought to suppress iNOS expression in bovine luteal cells [64]. Whether these or other cytokines have similar effects on testicular cells of the bull has yet to be reported.
Steroid Synthesis by Leydig Cells
Since the beginning of the twentieth century, Leydig cells have been considered the probable source of testicular androgens [65]. Berthold [66] was the first to observe from experimentation with the rooster that the testes produced a substance that influenced secondary sex organ development and maintenance [26]. The first isolation of an androgen, androsterone, from human urine [67] and the crystallization of testosterone from bull testes [11] established the major site of testosterone production as the testis. Extensive literature has emerged over the past 50 years on the function of the Leydig cell. These studies, employing a variety of techniques, have identified and confirmed the Leydig cells as the primary source of testicular androgens and elucidated the important pathways in androgen biosynthesis [5, 26, 52, 68]. LH has also been confirmed as the major pituitary hormonal stimulus on the Leydig cells [46]. Ewing et al. [68] have suggested that because Leydig cells are concentrated in clusters in the interstitial tissue of the testis, they must influence seminiferous tubular and peripheral androgen‐dependent functions (accessory sex glands) by hormonal signals rather than by cell‐to‐cell interaction.
The primary steroids produced and secreted by the bull testis are shown in Table 2.1. The conversion of the precursor cholesterol to androgens and estrogen is facilitated by a series of enzymatic reactions involving hydroxylation, dehydrogenation, isomerization, C–C side‐chain cleavage (lyase), and aromatase activity. Testosterone is now recognized as the principal steroid responsible for the endocrine functions of the testis since it is synthesized in copious amounts by mammalian Leydig cells. The Leydig cell has also been identified as a major source of other androgens and estrogens [5, 69]. In addition, the Leydig cells of the boar testis produce large amounts of the musk‐smelling steroids, Δ16‐androstenes [70]. It has become apparent that the primary
