Testosterone and Reproductive Dysfunction in Eunduance Trained Men part 1 and 2

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Anthony C Hackney, Exercise Physiology and Nutrition
University of North Carolina, Chapel Hill, North Carolina 27599 USA

Basic Endocrinology and Physiology
Methodological Concerns
Exercise and Testosterone
Physiological Impact of Lower Testosterone
Conclusions
Further Reading

Endurance training can result in dysfunction in the reproductive system of humans. Research within the sports medicine community has primarily focused upon reproductive dysfunction associated with athletic women. Not until recently have studies seriously addressed the question of how exercise training affects the male reproductive system. Research findings in this area have led some investigators to suggest that the effect of exercise training on the male reproductive system may be comparable to some degree to that found in women. For example, endurance-trained athletes of both sexes have abnormally low levels of the major sex hormones: testosterone in men, and estrogen in women.

The objective of this paper is to present an overview of how endurance exercise training affects testosterone and other aspects of the male reproductive system. The material is divided into four major sections. The first section deals with the basic endocrinology and physiology of testosterone in the male. The second section deals with physiological and methodological issues surrounding the interpretation of research on hormones. The third section covers the changes in testosterone in response to exercise training and acute or prolonged exercise bouts. Finally, in the fourth section the physiological impact of the changes observed in testosterone levels associated with endurance training are discussed.

Basic Endocrinology and Physiology

Regulation of Testosterone Production

Testosterone is a steroid hormone. Other steroids in the body include cholesterol, bile acids, vitamin D, and hormones of the adrenal glands and ovary. The majority of circulating testosterone in men comes from production in the interstitial cells of Leydig at the testicles. The adrenal gland also produces small amounts. Regulation of testicular production occurs via a negative feedback loop system involving the anterior pituitary, hypothalamus, and testicles; referred to as the hypothalamic-pituitary-testicular axis.

Periodically the hypothalamus releases pulses of gonadotrophin-releasing hormone (GnRH) into the hypophyseal circulation, which supplies the hypothalamus and anterior pituitary. The GnRH stimulates the anterior pituitary to produce and release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The pulsatile release of GnRH results in LH and FSH also being released into the systemic circulation in a similar pulsatile manner. For normal, healthy males approximately 2 to 4 LH and FSH pulses are observed over a 6- to 8-hour period, however the amplitudes of the LH pulses are much greater than those observed for FSH. At the testicles, LH and FSH interact with their primary target tissue receptors (LH, Leydig cells; FSH, Sertoli cells) located on the respective cell membranes. Once a hormone-receptor complex is formed, there is an adenyl cyclase-mediated increase of cyclic AMP, which produces a phosphorylation of intracellular proteins by activation of a protein kinase mechanism. In the Leydig cells this protein kinase activation leads to a mobilization of steroid precursors, in particular the activation of pregnenolone synthesis from cholesterol. Pregnenolone serves as the parent compound from which testosterone is derived. Several other hormones participate in these regulatory events. One worth noting is the anterior pituitary hormone prolactin, which in low concentrations acts as a potentiator of LH at the Leydig cells. This hormone will be discussed later in this article.

Synthesized testosterone diffuses from the Leydig cells into the testicular vascular system and/or into adjacent testicle compartments containing the Sertoli cells. In the Sertoli cells, testosterone plays an essential role in the facilitation of the spermatogenesis process. (The FSH receptor-hormone formation at the Sertoli cell results in the initiation of the spermatogenesis process.) The pulsatile release of LH results in some fluctuations of testosterone levels in the circulation and additionally there are circadian cycles in which large nocturnal elevations in testosterone can be observed

The majority of the circulating testosterone is transported bound to various carrier proteins (sometimes referred to as binding proteins). The principal carrier protein is sex steroid-binding globulin (SSBG), however other plasma proteins can also bind and carry testosterone to a lesser degree (e.g., albumin, cortisol-binding globulin). The remaining non-bound circulating testosterone is referred to as free testosterone. This free testosterone is considered the biologically active form of the hormone, as this portion of the hormone can interact at the target tissue receptors. Circulating bound and free testosterone are collectively referred to as total testosterone; sometimes in the literature the term testosterone is used synonymously for total testosterone.


Metabolic Roles of Testosterone

Testosterone has several physiological roles within the male. These roles can be divided into two major categories: androgenic effects, related to reproductive function and the development of a male's secondary sex characteristics, and anabolic effects, pertaining more generally to stimulation of tissue growth.

Androgenic Effects. A major reproductive role of testosterone involves the development of the sperm cell. At the Sertoli cells of the testicles, testosterone induces a nuclear activation process which stimulates and catalyses the maturation and development of sperm during the process of spermatogenesis. Maintenance of testosterone levels within the Sertoli cells is essential for the development of adequate numbers of mature, viable sperm that are necessary for a male to be fertile.

Testosterone also assists in the development and functioning of the male accessory sex glands (prostate, seminal vesicles, and epididymides), which aid in the sperm development and function, as well as in the act of copulation. Also attributed to the influence of testosterone are the secondary sex characteristics of males, such as the typical deeper male voice, increased levels of body hair, penile growth, sex drive (libido), and more aggressive behavior patterns.

Testosterone also helps red-blood cell development and can produce increased sodium reabsorption in the kidneys. Animal based research has also suggested testosterone plays a role in the increase of tissue glycogen synthesis and storage.

Effectors of Testosterone Levels: Physiological Concerns

The level of testosterone in the circulation is a function of the amount of hormone entering (testicular production and secretion) and the amount leaving (metabolic clearance) the blood pool. The rates for these processes are affected by any changes in the physiological state that alter metabolic turnover of the hormone.

Production and Secretion. Testicular testosterone production in the normal, average male is approximately 7 mg per day. This rate is affected by circulating production stimulators (LH), testicle LH receptor numbers, and synthesis substrate availability.

LH and testosterone levels are directly related. However, it is believed that only a small percentage of the total testicular LH receptors need to be occupied to achieve maximum stimulation of the Leydig cells. Reductions in the numbers of testicular LH receptors can result in reduced levels of testosterone production even in the presence of elevated LH. Receptor numbers can be reduced by certain pathological conditions (e.g. hypergonadotrophic hypogonadism) or a down-receptor phenomena" related state. Persistent elevations in circulating LH can produce a down-regulation of receptor numbers and thereby reduce testicular sensitivity to further changes in blood LH levels. The conditions of hyperprolactinaemic and hypercortisolemic can also produce lowered testosterone levels. The exact mechanism for this lower testosterone effect is uncertain, but may be due to interference with Leydig cell receptors and/or direct inhibition of the steroidogenic synthesis pathway. Finally, any reduction in availability of steroid hormone precursors (cholesterol, and pregnenolone) can produce a lower rate of testosterone synthesis.

Secretion is affected mainly by testicular blood flow through the testicular area, since testosterone is lipid soluble and thus freely diffusible. Furthermore, the testicles apparently have little or no storage capacity for testosterone. Testicular blood flow moreover is a function of the levels of vascular vasoconstriction or vasodilatation. Therefore, anything that influences vascular tone can affect the rate of testosterone secretion.

Metabolic Clearance. Testosterone is cleared from the blood by uptake in target tissues and by degradation in the liver. The degradation process involves the conversion of testosterone into 17-ketosteroids and glucuronide, which are excreted into the urine. The hepatic removal process is primarily a function of hepatic blood flow. Thus any changes in the hepatic blood flow can result in concomitant changes in the removal rate of testosterone. Moreover, a small portion of the testosterone is removed from the circulation by select body tissues and then converted to estradiols.

 

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Part 2

It is also important to realize changes observed in blood levels of testosterone may not necessarily reflect alterations in production, secretion, or metabolic clearance rates. A prime example, relative to exercise studies, involves the effect of shifts in plasma. Owing to the binding of testosterone to carrier proteins, increases or decreases in plasma volume lead to a dilution or concentration that is not indicative of changes in the normal hormonal turnover rate. Whether these changes in concentration have a physiological impact is a point of debate.

Methodological Concerns

When discussing factors affecting blood levels of testosterone, consideration must be given to non-physiological factors that could be sources of variation between studies. Examples include blood sampling method, diurnal variations in hormone concentrations, hormone detection methodology, and research protocol.

The timing and method of blood sampling are considerations that must be carefully addressed when comparing or evaluating testosterone results of different studies. The pulsatile release of LH produces fluctuations in the circulating levels of testosterone. Furthermore, as noted earlier there is a daily circadian pattern in blood testosterone levels. A single blood sample will therefore provide an imprecise estimate of the average hormonal level. Use of multiple or serial blood sampling will provide a more accurate assessment. Ideally, the use of a serial method of blood sampling would be preferred and considered more informative of the true status of circulating testosterone.

The hormonal biochemical assay methodology must also be considered a source of variability in results. Currently, radioimmunoassays (RIA) are the most common means of assessing testosterone concentrations in blood samples. Since the development of the technique, over 30 years ago, tremendous refinements in procedural and technical aspects have occurred and are still constantly happening. Hence, comparison of hormonal values between studies becomes complicated if a number of years separates the experiments. A comparison problem may also develop if the RIA for the hormone is via a commercial kit versus a laboratory developed technique. In such comparisons, absolute numbers are difficult to contrast directly to one another and the reader must look at relative changes for the most part. The RIA technique is a relatively easy bioassay to use, as well as inexpensive, and has a high degree of reliability, but there is a limitation: the results represent the immunological activity of the hormone and not necessarily the biological activity. The biological activity depends not only on hormonal levels but also on receptor availability and sensitivity within the individual subject.

Finally, examination of the research protocols of studies that compare the hormonal status of exercising and non-exercising subjects reveals several problems. For example, to examine the effects of endurance training most studies have compared aerobically trained men with untrained sedentary-control men, in a retrospective fashion. The problem with this approach is the trained men have subjected themselves to the rigors of the training program, typically for years and the investigator is observing the end result. Because of the wide variations in response to training, as well as variations in the exact type of training, considerable divergence can be observed in the testosterone responses of these subjects. Another problem develops from the large discrepancy in what individual authors define as exercise training and exercise-trained states. For example, some researchers may consider an individual as chronically trained if they have performed regular exercise for one year, while other research may indicate that a five-year period is necessary. Additionally, one of the principal assumptions made within these retrospective studies is that the observed effects on testosterone levels are the results of the exercise training performed by the subject. Obviously, this assumption is not valid unless such things as psychological stresses, sleep loss, diet, weight loss, and hereditary factors, all of which affect testosterone level, are controlled.

Exercise and Testosterone

Changes at Rest

The results of the retrospective comparative studies examining isolated, single blood samples suggest lower testosterone levels in chronically endurance-trained males. The subjects in these studies have typically been distance runners who had been involved with the physical training aspects of their sport for 1 to 15 years. In these studies, testosterone levels of the endurance-trained men were found to be 60-85% of the levels of matched, untrained men.

Prospective studies have also been conducted in which blood samples have been collected over days or weeks while exposing subjects to endurance training regimens. Findings thus far have been inconsistent, as some reports reveal significant reductions in resting testosterone following 1 to 6 months of intensive training, while others found no significant resting testosterone changes after 2 to 3 months of training. Differences in the initial training status of the subjects or the training administered may explain these discrepancies.

Endurance-trained males with lower testosterone also display other reproductive hormonal abnormalities. The most frequently reported changes involve decreased resting levels of prolactin and more importantly, no significant elevations in resting LH, even though there is decreased testosterone. These findings of altered prolactin and LH levels at rest in endurance trained men with low testosterone have been labeled by some researchers as a dysfunction of the hypothalamic-pituitary-testicular (HPT) regulatory axis. These findings with prolactin and LH have been reported in retrospective and prospective studies.

Several investigators have also conducted retrospective investigations where resting blood samples were collected every 20 or 30 min for 4- to 8-hour periods from chronically endurance-trained men and untrained controls. Results are similar to those of the isolated-sampling studies: resting testosterone concentration of the trained subjects were typically 70-80% of those found in the controls. As with isolated blood sampling studies, resting LH levels have not been significantly elevated. Again, these findings have been cited as a dysfunction in the HPT axis. These studies have been performed mainly with endurance runners, but it is likely that the effects apply to endurance athletes generally.

Mechanisms of HPT Axis Dysfunction. Several studies have attempted to elucidate the mechanism of the proposed HPT axis dysfunction found in endurance-trained men. These studies have focused on examining whether the dysfunction is central (hypothalamic or pituitary) or peripheral (testicular).

Centrally, the research work has focused upon alterations in LH release and/or prolactin release. Alterations in LH and prolactin release have been an area of extensive research relative to the study of exercising women who develop reproductive dysfunction. An exaggerated prolactin release to an exogenous stimulus of drugs or synthetic hormones has been found in endurance-trained males with low testosterone. Conversely, an attenuated release of LH due to doses of GnRH has been detected in endurance-trained males. Prolactin presents an interesting paradox in reproductive physiological function. Small amounts of prolactin seem necessary to work synergistically at the testicle with LH, while excessive levels disrupt both central and peripheral aspects of the HPT axis. Several investigators have found this altered prolactin and LH release. Figures 1 illustrates the findings of Hackney and associates for this unusual prolactin and LH hormonal response in trained males. Interestingly, although overall LH response is decreased, results are contradictory as to whether LH pulsatile characteristics (i.e., pulse frequency and amplitude) are affected by endurance training.

 

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