HPG Axis

Intratesticular testosterone levels are vital to the growth and maturation of sperm. High testicular concentrations of testosterone are required to maintain spermatogenesis, and intratesticular testosterone levels are approximately 40 to 100 times higher than serum levels. Thus, small variations in serum testosterone levels may represent massive fluctuations in the intratesticular environment. Testosterone is produced primarily by Leydig cells in the interstitium of the testis. Luteinizing hormone (LH) produced from the pituitary gland is chiefly responsible for steroidogenesis by Leydig cells. LH binds to its receptor, which initiates a cyclic adenosine monophosphate (cAMP)-mediated pathway leading to testosterone production and release via mitochondrial and smooth endoplasmic reticulum membranes. These androgens then diffuse out of the Leydig cell structure into capillaries and adjacent tissue within the interstitium and surrounding germinal epithelium.

Once in the capillaries, testosterone is quickly bound by proteins in circulation, mainly sex-hormone binding globulin (SHBG) and to a lesser extent albumin. Some testosterone is further metabolized by aromatase and 5α-reductase to estrogen and dihydrotestosterone, respectively. Serum testosterone is the primary source of hypothalamic feedback inhibition, whereas estrogens modulate gonatotropin secretion in response to gonadotropin-releasing hormone (GnRH) in the pituitary.

The hypothalamus produces GnRH in a pulsatile manner in response to input from other parts of the brain, various neurotransmitters and neuropeptides, and serum testosterone levels ( Fig. 1 ). This pulsatile GnRH then acts on the pituitary gonadotropes to produce LH and follicle-stimulating hormone (FSH). In addition to the influence of testosterone and estrogen on LH production, FSH is further regulated by 2 proteins secreted by Sertoli cells in the seminiferous tubules. Inhibin, or more accurately inhibin B, selectively suppresses FSH production by the gonadotropes, whereas activins stimulate production of FSH. Follistatin, which is produced by Sertoli cells and, to a lesser extent, germ cells, plays a role in local inhibition of activin secretion within the testis and regulates germ cell growth and division. FSH stimulates Sertoli cells to chaperone germ cells throughout spermatogenesis. FSH is not strictly required for spermatogenesis in humans, but it does augment Sertoli cell function and, through feedback with Sertoli cells, is a core component of optimal testicular function (see Fig. 1 ).

HPG axis and effects.

Nongonadotrope Hormones

Regulation of androgens is more complex than previously believed. The role of prolactin and growth hormone (GH), and several other hormones that have been implicated in spermatogenic function, is discussed in this section.

In men, prolactin is a peptide hormone produced by pituitary lactotropes and in the prostate. The physiologic role of prolactin in the male remains unclear. There is evidence to suggest that prolactin may play a role in the physiologic regulation of testosterone. Receptors found on the choroid plexus and hypothalamus also suggest there may be a more central role in the maintenance of male fertility. There is evidence to support prolactin regulation by factors within the testis and pituitary gland. Prolactin may also play a role in sexual behavior and activity. However, more commonly it does not have an obvious target organ.

GH is produced by somatotropes in the pituitary gland. It is primarily regulated positively and negatively by hypothalamic secretion of growth hormone–releasing hormone (or somatocrinin) and growth hormone–inhibiting hormone (or somatostatin), respectively. GH production is also stimulated by the neuropeptide ghrelin and by testosterone. Unlike in females, estrogens may not regulate GH release in males. Among other effects, GH has anabolic properties, such as increases in muscle mass, protein synthesis, organ growth, and gluconeogenesis, as well as catabolic effects such as lipolysis. GH activates production of insulinlike growth factor 1 (IGF-1) through instigation of the JAK-STAT signaling pathway at target organs. IGF-1 is a member of the insulin/IGF/relaxin subfamily of proteins, which may play a role in the regulation of spermatogenesis, and is discussed later.

Although most hormonal stimuli on the testis are likely from gonadotropes in the pituitary, there are probably direct and indirect effects on the testis from a different class of hormones altogether. The insulin/IGF/relaxin family of proteins is stimulated by GH from somatotropes in the pituitary, as well as indirectly from various other organ systems. Feedback control of growth hormone production in the pituitary is a complex process, and it is unclear how seemingly non–sex steroid feedback plays a role in regulating spermatogenesis. However, ghrelin from the stomach and leptin from adipocytes activate GH secretion, and IGF-I and IGF-II from the liver inhibit GH production. Further complicating elucidation of the role of GH is paracrine activity of GH within the pituitary itself. LH may induce GH release from somatotrophs, which could theoretically undergo amplification of GH release through autoregulation. Thus, a direct GH effect on neighboring gonadotropes could lead to LH release inhibition.

Members of the insulin/IGF/relaxin family of proteins seem to play important adjuvant roles in sperm production or function ( Table 1 ). Other than IGF-1, only relaxin has been studied in the arena of male infertility. Relaxin is produced primarily in the prostate and/or seminal vesicles. Relaxin may also affect the fertilizing ability of sperm, possibly via immune desensitization of the female reproductive tract.

Homologs of relaxin include insulinlike peptides (INSL). Specific INSL proteins may play roles in stimulating and regulating spermatogenesis. INSL3 is produced in large quantities by Leydig cells. It readily crosses into seminiferous tubules, and does not seem to vary by fluctuations in the HPG axis. INSL5 and ISNL6 knockout mice show impaired spermatogenesis and INSL6 gene transcripts are expressed in large amounts by meiotic and postmeiotic germ cells in both rodents and humans. Despite this work, the role of INSL in human spermatogenesis remains unclear.

Paracrine factors within the microenvironment of the seminiferous tubule are equally, if not more complex, regulators of spermatogenesis. So-called stem cell factors represent various signaling factors believed to induce the progression from gonocyte to spermatogonium. Germ cell-Sertoli cell gap junctions may also have a direct influence on the developing spermatocyte. Thus, although this discussion is limited to global hormonal influences, complex interactions with paracrine hormone regulators at the cellular level are influential in the growth and maturation of sperm.

Endogenous Dysfunction

Dysfunction within the HPG axis can occur for many reasons. To some degree, this is a natural consequence of aging, as testosterone levels decline with advancing age. However, as stated previously, assayed total testosterone level alone is not an accurate marker of androgen activity in serum, or by extension in the testis, as circulating testosterone exists in a dynamic state of being free and bound to circulating proteins such as albumin and SHBG. As SHBG increases with age, evaluation of total testosterone in isolation is prone to error ( Fig. 2 ). Bioavailable testosterone, or the testosterone that is either freely bound or able to disassociate with bound SHBG or albumin, becomes a more accurate assessment of true testosterone status. Ideally, free testosterone would be an accurate assessment, and indeed the percentage or total amount of free testosterone that is measured from serum is an accurate indicator of testosterone status. However, most commercial assays assess free testosterone by an indirect enzyme-linked immunosorbent assay test, which is notoriously inaccurate, rather than performing an equilibrium dialysate that can accurately determine testosterone status. According to a consensus of laboratory researchers, calculated bioavailable testosterone is the most reliable method of assessing testosterone status. Bioavailable calculators are freely available on the Internet, as a smartphone application, or at www.issam.ch/freetesto.htm .

Age-dependent levels of SHBG and testosterone.

Thus, bioavailable testosterone provides a more accurate assessment of a man’s androgenic function and may offer insight into other disease states. For example, SHBG levels increase not only with age but also in disease states such as liver disease, collagen vascular disease, and chronic illness. SHBG binds and subsequently decreases the amount of testosterone that is available to support proper spermatogenesis.

Male androgenic potential decreases with age, and age-associated hypergonadotropic hypogonadism is the most common associated finding with the decrease in sperm counts. It seems that inherent deficiencies within the sperm itself can also contribute to decreased fertility as men age. Traditionally, it is accepted that testosterone levels start to decrease by 110 ng/dL/decade after the fifth decade of life. However, in certain individuals, this decline starts at an earlier age. The number of potential gene activity triggers for this early decline is rapidly growing, although no commercially available assay is currently available to screen those at risk.

Hypogonadotropic hypogonadism is a less common reason for testicular dysfunction and hypospermatogenesis. Hypogonadotropic hypogonadism can be caused by Kallman syndrome, or congenital hypogonadotropic hypogonadism, or idiopathic hypogonadotropic hypogonadism (IHH). Kallman syndrome may be inherited as an X-linked, autosomal dominant, or autosomal recessive disorder. Kallman syndrome may be diagnosed with delayed puberty, whereas in IHH, puberty may have occurred as a result of sufficient stimulation of testicular maturation. Patients with IHH may still have attenuated differentiation of gonocytes within the testes, causing oligospermia and even azoospermia. The endocrine definition of hypogonadotropic hypogonadism varies, but generally is accepted as FSH and LH values less than 2.5 mIU/mL with concomitant hypogonadism. Congenital adrenal hyperplasia (CAH) can lead to an increase in endogenous androgen, thus causing a hypogonadotropic state through negative feedback. Although not hypogonadal, these patients still exhibit oligospermia or azoospermia secondary to the hypogonadotropic state.

Although hypergonadotropic hypogonadism is most commonly found in late-onset hypogonadism, when found earlier in life, the possibility of chromosomal disorders must be explored. Klinefelter syndrome, or the presence of an extra X chromosome in an XY male, leads to seminiferous tubule sclerosis and consequently increased FSH and LH levels. FSH levels are often markedly increased in these men. Despite increases in LH, plasma levels of testosterone are decreased in 50% to 60% of patients. A less common cause of hypergonadotropic hypogonadism is XX male syndrome, where patients presumably have a sex-determining portion of the Y chromosome on their X compliment. Genetic studies do not always corroborate that assumption. However, endocrine findings are similar to the patient Klinefelter syndrome. Although it is possible that these patients may have enough AZF region loci to produce sperm, as yet there have been no reports of sperm being isolated from an XX male. Although congenital unilateral absence of a testis (either secondary to malformation or in utero torsion) does not seem to affect fertility potential, there is some evidence to suggest that torsion later in life may adversely affect semen and testosterone parameters.

Isolated deficiencies of FSH and LH have also been reported. Isolated LH deficiency is a rare condition that leads to eunuchoid body habitus, large testes, and small volume ejaculates that contain few spermatozoa. Plasma testosterone is low as expected, although FSH levels are normal. Isolated FSH deficiency is also a rare disorder that leads to normal virilization and testosterone levels with low levels of FSH and oligospermia or azoospermia. Potential causes can be an inherent FSH β-subunit deficiency, an idiopathic genetic defect, or excess inhibin B that is idiopathic or a result of a granulosa cell tumor. Some genetic causes of endocrine dysfunction are presented in Table 2 .

Iatrogenic Dysfunction

Testicular dysfunction can occur because of inborn errors of growth and metabolism as outlined earlier, or from iatrogenic injury. The most common form of testicular hypofunction is testosterone replacement therapy. Although there are many commercially available forms of testosterone replacement, the increase in serum testosterone levels from any given therapy leads to direct inhibition of the HPG axis as well as indirect inhibition through peripheral aromatization of estradiol as outlined earlier. Thus, the microenvironment of the testis is suboptimal for the growth and maturation of sperm.

What is surprising is that testosterone replacement does not always lead to severe oligospermia or azoospermia, and therefore testosterone monotherapy is not completely effective as male birth control. This may be due to sufficient endogenous testosterone production allowing for spermatogenesis in a few individuals. Some medications also have steroidomimetic effects. Spironolactone may affect semen parameters through its antiandrogenic effects. Opioids cause direct inhibition of the HPG axis and therefore can suppress testosterone levels. Dose and duration effects of spermatogenesis remain unclear. Phytoestrogens in foods such as soy likely do not play a significant role in oligospermia or azoospermia, although dietary testosterone replacement can.

Testicular causes of androgen deficiency are rarely a direct consequence of nonhormonal medical treatment. Chemotherapy regimens are usually unlikely to cause permanent dysfunction in the interstitium of the testis, as this represents the most resistant moiety of the testicular apparatus. However, damage to the germinal epithelium can have more lasting effects. Previous testicular sperm extraction (TESE) or microTESE can lead to hypogonadism as a result of direct injury to the interstitium. This leads to further attenuation of the endocrine microenvironment within the testis, which can further decrease sperm counts.

Obesity contributes to endocrine dysfunction in a variety of ways. Estrogen excess from peripheral aromatization in adipose tissue can lead to a direct inhibitory effect on pituitary function and therefore spermatogenesis. Abnormalities in the metabolism of IGF-1 may lead to direct impairment in spermatogenesis. Other relaxin family peptides may also be attenuated in obesity, thus adding to direct inhibition of spermatogenesis. Glucocorticoid excess, which can occur with certain forms of obesity, can lead to pituitary dysfunction among gonadotropes. This is usually seen in the setting of Cushing syndrome, in which glucocorticoid excess can not only suppress LH function but may also have a direct contributing role in hypospermatogenesis or maturation arrest. Obesity can also cause an increase of testicular temperature and, although not an endocrine source of dysfunction, this can lead to hypospermatogenesis nonetheless.

The complete list of medical conditions that can affect fertility is long. Any effect on vascular function can adversely affect testosterone levels and thus reflect the decreasing quality of the intratesticular environment, leading to a decrease in semen parameters. It is unclear how some of these medications mediate endocrine dysfunction.

Growth Hormone

Although there has been an increase in the body of literature to suggest that GH may play a more significant role than previously imagined with endocrine dysfunction in fertility, clinical data are lacking. Part of the difficulty in assessing GH has been the difficulty in identifying a reliable method of measuring secretion patterns as they may relate to fertility. However, measurement of IGF-1 levels as a surrogate for GH activity does provide some insight. One study investigated initial GH treatment followed by a washout period, and subsequent treatment with pegvisomant (an IGF-1 inhibitor). Results showed an initial increase in IGF-1 and estradiol with GH, and decrease with pegvisomant, which suggests that GH/IGF-1 may increase aromatase activity, and thus excess GH may actually inhibit spermatogenesis. Acromegaly may inhibit spermatogenesis. However, larger studies are needed to elucidate the causal relationship, as relaxin family peptides have been shown to positively affect spermatogenesis as detailed earlier in the article.

Conservative Therapy

Endocrine manipulation in male infertility starts with eliminating possible endocrine disruptors. On a population scale, there has been a large focus of research on micropollutants in the environment (common water supplies, food sources, and so forth) that may be contributing to an overall decline in population male fertility. These studies have largely focused on the elimination of steroid mimetics from common food and water supplies. It is unclear how big a role environmental endocrine disruptors play on a population scale, as there are conflicting data within certain populations about the decline of male fertility.

On a population-based scale, elimination of the disruptors mentioned in the previous section may help endocrine dysfunction and overall fertility. However, on an individual scale, 1 of the more recent offenders has been the increase in phytoestrogen use. Because many so-called testosterone boosters have been more commercially available than in years past, the infertile patient must be queried about the use of these nutriceuticals. Many commercially available dietary supplements contain significant levels of plant phytoestrogens that are homologs of testosterone and estrogen. Although no large study has been conducted to determine the overall effects of steroidomimetic dietary boosters on male infertility, animal models have shown a dose-dependent relationship between dietary phytoestrogens and spermatogenesis.

The most common endocrine disruptor studied in male fertility has been obesity. As detailed in the previous section, obesity causes multiple effects on the endocrine system not limited to a simple increase in estrogen. Weight loss theoretically can aid the many effects of obesity not limited to endocrine dysfunction, and can improve overall semen parameters. However, clinical data are lacking, as only small case series have demonstrated a reversible effect. With larger scale studies underway, more insight into the true benefit on overall fertility may be demonstrated.

Thus, lifestyle modifications and elimination of exogenous steroids or steroidomimetics account for a significant part of an overall treatment program. It is important to do a thorough history to account for dietary supplements as well as known androgen use, as many patients are simply unaware of the effects of these supplements and therefore may not voluntarily admit to their use. Regardless, testosterone supplementation seems to be reversible. In 1 study, sperm counts returned to normal in 98% of men on testosterone undeconoate at 12 months, and the rest in a 3-month follow-up window. However, these studies are largely based on testosterone as a possible contraceptive, and usually only on a 2- to 3-year window of medication (30 months in Gu and colleagues’ study ). This situation may not be representative of a population that was initially hypogonad before treatment and therefore possibly subfertile. Thus, the authors recommend concomitant use of endocrine treatment as outlined in the next section and not simply cessation of the exogenous testosterone.

Pituitary Stimulation

As detailed earlier, the main treatment paradigm with regard to male fertility centers around the HPG axis. We use a morning endocrine profile using testosterone, SHBG, albumin (the latter 2 to calculate bioavailable testosterone) as well as FSH, LH, and estradiol for reasons summarized in previous sections. Prolactin is sometimes assessed when history and physical examination dictate as detailed earlier. Likewise, if there is evidence of thyroid dysfunction by history and/or physical examination, then a thyroid panel is performed.

Pituitary stimulation of the testis remains a mainstay of endocrine treatment. A simplified version of treatment is summarized in Table 3 . Specific medication choice depends on the hormone profile in the individual patient. Clomiphene and tamoxifen are selective estrogen receptor modifiers (SERMs) that are commonly used to treat endocrine dysfunction in male infertility. By allowing for selective inhibition of estrogen at the level of the pituitary, both FSH and LH levels increase. This subsequent increase in gonadotropic hormones leads to an increase in intratesticular testosterone and therefore a more favorable microenvironment within the testis for sperm growth and maturation. Thus, in patients with primary or secondary hypogonadism and oligospermia, clomiphene has been used as monotherapy in the hypogonadal male to achieve normal semen parameters and subsequent pregnancy. We suggest a starting dose of 25 mg daily that can be titrated up to 100 mg daily pending morning endocrine measurements of testosterone. As clomiphene is normally distributed in 50-mg tablets, a starting dose of 50 mg every other day is acceptable. Using criteria delineated in the previous section, a calculated bioavailable serum level of testosterone of 210 ng/dL is used as a soft target for sufficient testosterone production in the testis but we only treat men who have a bioavailable testosterone level less than 155 ng/dL.

Table 3

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