Endocrinology of Male Reproduction

Reproduction and fertility are regulated by coordinated syn­chrony of the endocrine orchestra involving the hypothala­mus, pituitary, and gonads called the hypothalamic- pituitary-gonadal (HPG) axis controlling the stimulation and inhibition of sex steroid secretion and gonadal functions.

19.2.1 Hypothalamic-Pituitary-Gonadal

(HPG) Axis

HPG axis comprises three main components, namely hypo­thalamus, pituitary, and gonads. The gonadotropin-releasing hormone (GnRH) of the hypothalamus is the key regulator of the HPG axis in vertebrates. GnRH secreting neuronal cell bodies are clustered around the medial preoptic area (POA), arcuate nucleus, and their projections terminate at median eminence. GnRH is carried to the anterior pituitary via the portal circulation. Under the influence of GnRH, the gonadotrophs of anterior pituitary secret luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which facilitates gametogenesis and steroidogenesis in the gonads. The gonads produce both sex steroids and gametes under the control of LH and FSH. The sex steroids, namely oestrogen, progesterone, and androgen, exert negative feedback on GnRH release to control gametogenesis and reproductive cyclicity (Fig. 19.16).

19.2.1.1 Hypothalamic GnRH Secretion

The secretion of GnRH from the hypothalamus occurred in two modes, pulsatile and surge modes. In pulsatile mode, GnRH releases in an episodic manner during childhood, whereas surge mode causes transient and copious GnRH release around puberty. Both these pulsatile and surge modes of GnRH secretion are under neuroendocrine control. Pulsatile GnRH is regulated by a GnRH pulse generator at the mediobasal hypothalamic area (MBH). Sex steroids exert negative feedback over this pulse generator via opioid neurons.

In contrast, the GnRH surge generator at the preoptic area (POA) is influenced by GABA and arginine vasopressin (AVP) neurons. The functionality of GnRH pulse and surge generator depends on complex interactions between glutamatergic cells, GnRH, and other neurons together with certain neuropeptides. Among these neuropeptides, kisspeptin and RFamide-related peptide-3 (RFRP-3) have emerged as stimulatory and inhibitory neuroendocrine integrators, respectively, to control the HPG axis. The Kiss1 gene encodes kisspeptin is a potent stimulatory neuro­peptide of GnRH secretion. The inhibitory neuropeptide of GnRH secretion is RFRP-3, encoded by the Rfrp gene. The avian orthologue of RFRP-3 is called gonadotropin­inhibiting hormone (GnIH).

19.2.1.2 Pituitary Gonadotropin Secretion

Two glycoprotein hormones, namely LH and FSH, secreted from the gonadotrophs of the anterior pituitary (adenohy­pophysis) control spermatogenesis (LH/FSH) and testoster­one production (LH). Secretion of FSH or LH from gonadotropes depends upon the character of GnRH pulse. Low amplitude and irregular pulse of GnRH facilitate FSH secretion. In contrast, the release of LH is stimulated by a high-frequency GnRH pulse. After the synthesis, LH and FSH are stored in different secretory granules to release upon GnRH stimulation. Measurable quantities of LH and FSH in the peripheral blood are seen around the 12th week of gestation in humans. FSH is predominant over LH during foetal life, and the female foetus has a higher FSH/LH ratio, which gradually changes during development.

Fig. 19.16 Hypothalamus-Pituitary-Gonadal (HPG) (HPT or hypothalamic-hypophysis-Testis HHT) axis. [Up-regulations (marked as a bold arrow on the left side) are controlled by the GnRH gonadotropin-releasing hormone, secreted from the hypothalamus; FSH follicle-stimulating hormone and LH luteinising hormone, secreted from anterior pituitary (AP) act over Sertoli cells and Leydig cells, respectively; PRL prolactin, release from AP and act over Leydig cell for testosterone synthesis; Act activin, released from Sertoli cells and acts over the AP for FSH synthesis; Kiss kisspeptin, released from the preoptic areas of hypothalamus and promote GnRH release.

19.2.1.3 Gonadal Steroidogenesis

Pituitary LH acts over the Leydig cells to stimulate testoster­one synthesis. LH acts through LH/chorionic gonadotropin receptors (LHCGR). The receptor-ligand binding activates adenylyl cyclase and increases cAMP production. cAMP stimulates the transcription of steroidogenic acute regulatory protein (StAR), which helps in the cholesterol transportation to the inner mitochondrial membrane to initiate steroidogen­esis to produce testosterone. Testosterone is transported in the plasma in conjugation with sex hormone-binding globu­lin (SHBG) of hepatocytes or androgen binding protein (ABP) of testes. A considerable amount of testosterone returns to the seminiferous tubule through the testicular coun­tercurrent exchange mechanism to ensure a steady supply of testosterone in the tubule to support spermatogenesis. A high testosterone level inhibits LH secretion and thus exerts negative feedback on the HPG axis.

In addition to testosterone, Sertoli cells also produce two protein hormones, activin and inhibin, to regulate the HPG axis. Activin stimulates GnRH secretion, and inhibin inhibits FSH secretion.

19.2.2 Development of Hypothalamic- Pituitary-Gonadal (HPG) Axis

Among the domestic animal species, the ontogeny of HPG axis development is mainly studied in ovine species. In sheep, the first GnRH neurons appeared in the medial portion of the nasal placode around the 26th day of embryonic life. These neurons are migrated along with the nasal septum towards cribriform plate during 26-35th days of embryonic life and ultimately lodged into their final site in the preoptic area during 35-45th days of gestation. The axonal projections of GnRH neurons reach the median eminence during 45-60th embryonic days. The GnRH neurons become functional from embryonic days 80-120 as indicated by the expression of the β chain of LH receptors, and pulsatile release of LH starts. LH pulses facilitate the release of testos­terone in male foetuses. The LH secretion ceases from 120th day to gestation up to postnatal day 60, which reappears around 70-140, but the frequency is low. From 140 to 210 postnatal days, the LH pulses increase in frequency but at a lower amplitude.

19.2.3 Endocrinology of Male Sex Determination

The initial gonadal differentiation is genetically controlled by male and female determining factors around 6 weeks of gestation (discussed in earlier Chap. 18). The post gonadal sex determination is under endocrine control. Anti-mullerian hormone (AMH), testosterone, and insulin-like factor three produced from foetal testes are the key regulator of male sex determination. LH controls the foetal testicular steroidogene­sis, and FSH stimulates Sertoli cells to produce AMH. The initial gonadal steroidogenesis is gonadotropin independent; then placental hCG controls the steroidogenesis up to 10-20 weeks, then gradually declines in humans.

2 (SRD5A2) stimulates the development of the prostate, penis, and scrotum. Androstenedione is the predominant foetal androgen as 17β-hydroxysteroid dehydrogenase type

3 (HSD17B3) is not expressed in FLC. The foetal androgens promote the development of Wolffian duct derivatives to form external male genitalia. The AMH causes regression of Mullerian ducts around 8-10 weeks of gestation in humans. Insulin-like 3 (INSL3) mediates testicular descent.

19.2.4 Pre-pubertal Suppression of HPG Axis

GnRH pulsatility is more during the infantile period but diminishes during the juvenile period. This juvenile period of sexual quiescent known as neurobiological brake occurred by two different mechanisms.

19.2.4.1 Steroid-Dependent Mechanism (Gonadostat Hypothesis)

According to the gonadostat hypothesis, gonadal steroids negatively affect GnRH neuronal activity. The GnRH secret­ing neurons show higher sensitivity to the gonadal steroids, and a small amount of androgens can suppress GnRH secre­tion. The steroid sensitivity of GnRH neurons gradually decreases during the pre-pubertal periods, which leads to increased secretion of GnRH and HPG activation. This pre-pubertal HPG axis suppression mechanism is validated in sheep, hamsters, ferrets, and cattle.

19.2.4.2 Steroid-Independent Mechanism

The ‘gonadostat’ is failed to explain the pre-pubertal HPG axis suppression in rats and monkeys as neonatal castration leads to lower gonadotropins levels during the infantile period, which increases progressively during the juvenile phase. Further, the GnRH neurons lack oestrogen receptor α (ERα) in these species. Therefore, a steroid-independent mechanism involving neuronal pathways was proposed to explain pre-pubertal sexual quiescent in these species.

19.2.5 Mini Puberty

The neonatal activation of the HPG axis is called mini puberty, occurred in some mammals with an increased level of testosterone around mid-gestation and early postnatal life. In cattle and sheep, this testosterone peak is seen during the last third of gestation and diminished at birth, but in rodents, the event occurs during the early postnatal period. Mini puberty helps to develop the genital organs.

19.2.6 Endocrine Regulation of Puberty

Puberty is triggered when the neurobiological brake is removed and the GnRH pulse generator is reactivated. Kisspeptin plays a significant role in controlling the onset of puberty through activating the GnRH pulse generator for intermittent release of GnRH. The suppressive action of oestrogen and GABA on kisspeptin synthesis is diminished around puberty, and kisspeptin reactivates GnRH pulse generation. The kisspeptin induced GnRH pulse generation is mediated through the kisspeptin/neurokinin B/dynorphin A (KNDy) neuronal pathway. KNDy neuronal cluster is situated at the arcuate nucleus of the hypothalamus compris­ing kisspeptin, neurokinin B, and dynorphin A. KNDy neurons secrete neurokinin B, which binds with tachykinin NK3 receptor (NK3R) and triggers Ca²+ influx into KNDy neurons in an autocrine/paracrine manner. Increased intracel­lular calcium stimulates KNDy neurons for pulsatile kisspeptin secretion, which in turn controls pulsatile GnRH secretion from the median eminence of hypothalamus through a G protein-coupled receptor named (GPR54/ KISS1R).

The exact cues that initiate the timing of puberty are yet to be elucidated. But, several sensory inputs from the internal and external environment like growth, body fat/composition, photoperiod, and olfactory signals are thought to be involved in the timing of puberty. Out of these factors, energy metab­olism and photoperiod emerge as important determinants of the HPG axis activation around puberty.

19.2.6.1 Energy Metabolism and HPG Axis Activation

The timing of puberty coincides with the optimum body reserve, and leptin, an adipocytokine (cytokine synthesized from adipose tissue), is thought to be involved in this inte­gration. Serum leptin levels are positively correlated with the fat mass, and leptin concentration is decreased upon starva­tion. Therefore, leptin signals the hypothalamus for the opti­mal energy level of an individual. In the arcuate nucleus of hypothalamus, KNDy neuronal clusters coexist with the lep­tin receptor (leptin Receptor Long Isoform, LepRb). The leptin signalling is mediated through the activation of KNDy pathways. But the optimum leptin level is required to stimulate the HPG axis. Too low leptin during starvation and high leptin in obesity can suppress the HPG axis. The malnutrition suppresses the HPG axis through neuropeptide Y (discussed later). Overnutrition leads to central leptin resis­tance and decreases the expression of Kiss1 or NKB and its receptor to induce reproductive dysfunctions.

19.2.6.2 Photoperiod and HPG Axis Activation

In seasonal breeders, the day length (photoperiod) regulates the activation of the HPG axis around puberty to ensure successful birth during the favourable time of the year. The effect of photoperiod on the HPG axis is controlled by the photo-neuroendocrine circuit, where melatonin secreted from the pineal gland is the central player (Fig. 19.17). The dark and light information is perceived through photoreceptors at the retina. The photoreceptors transmit the dark light signal to the suprachiasmatic nuclei (SCN) of the hypothalamus through the retinohypothalamic tract (RHT). SCN controls the melatonin synthesis from the pineal gland via the polysynaptic pathway. The synthesis and release of melato­nin are restricted during the night-time. So, the short melato­nin peaks are seen during long days (LD) in summer and short days (SD) during winter which are associated with longer melatonin peaks. Melatonin affects the GnRH secret­ing neurons through the stimulatory signal of Kisspeptin (Kiss) and the inhibitory signal of RFRP. But melatonin peaks and associated neuroendocrine effects (kisspeptin and RFRP signalling) are reversed in short-day and long-day breeders. In long-day breeders (Syrian hamsters), the short melatonin peaks during summer stimulate the release of kisspeptin and inhibit RFRP, which initiates puberty during summer. In contrast, the longer melatonin peaks during short days in winter facilitate puberty in short-day breeders (sheep) by stimulating kisspeptin and inhibiting RFRP.

19.2.7 Endocrine Regulation of Sertoli Cell Functions

The activity of Sertoli cells after puberty is controlled primar­ily by FSH through the inhibin-activin-follistatin axis. Vari­ous growth factors also regulate Sertoli cell function in an autocrine and paracrine manner.

19.2.7.1 Role of Inhibin, Activin, and Follistatin

Activin and inhibin are secreted from Sertoli cells. Activin exerts stimulatory and inhibin inhibitory effects on FSH secretion. Activin is a cytokine, a member of the TGF-β protein superfamily. It enhances FSH biosynthesis and secre­tion from the anterior pituitary. But, excess activin-A produc­tion reduces the release of FSH. The concentration of the spermatozoa in the tubule controls the secretion of activin and inhibin. At low sperm concentration, the inhibin secre­tion is decreased, and activin triggers FSH release from the pituitary to stimulate spermatogenesis. Follistatin is secreted from the anterior pituitary and negatively stimulates FSH secretion. The inhibin feedback on the pituitary FSH is set up during early postnatal life, but the maximum sensitivity is seen at the age of puberty. The FSH stimulates the metabolic activity of Sertoli cells and spermatogenesis after the attain­ment of puberty. But, when Sertoli cells are exhaustive and sperm counts are too high in tubules, a glycoprotein hormone inhibin (inhibin B) suppresses the synthesis and release of FSH from the anterior pituitary via a negative feedback mechanism. It also reduces the secretion of extracellular matrix components from Sertoli cells. Follistatin is an auto­crine glycoprotein secreted from the anterior pituitary when the FSH level is more. Follistatin is an activin-binding protein (or FSH-suppressing protein, FSP) that binds and neutralizes activin, and hence FSH is decreased at the peripheral circula­tion or the pituitary level.

Fig. 19.17 Effect of photoperiod on HPG axis [The action of melato­nin to control the reproductive function in males is summarized; mela­tonin biosynthesis is explained stepwise in the inset. The light stimulates photoreceptors in the retina of the eye and sends impulses to the SCN of hypothalamus. SCN (suprachiasmatic nucleus) stimulates the pineal gland for melatonin biosynthesis. During short-day photoperiod (in winter), at long dark phase (night), the SNAT (serotonin-N- acetyltransferase) and HIMOT (hydroxy indole-O-methyltransferase) enzymes are activated, and melatonin synthesis increases. The reverse mechanism is occurred in long-day breeders (during summer). Increased

19.2.7.2 Role of Other Proteins

Several growth factors like insulin-like growth factor (IGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and transforming growth factor α (TGFα) are involved in the Sertoli cell functions, but IGF is primarily involved in regulating Sertoli cell number and testicular size. The secretion of IGF is FSH dependent. Two crucial enzymes involved in Sertoli cell activity are 5^,-adenosine monophosphate-activated protein kinase (AMPK) and silent mating type information regulation two homolog 1 (Sirtuin 1 or SIRT1). The major gene responsible for Sertoli cell proliferation is c-Myc (cellular Myelocytomatosis). The c-Mycis an oncogene expressed under the influence of tes­tosterone. Certain cyclin-dependent kinase inhibitors inhibit the Sertoli cell proliferation, viz. p21Cip1, p27Kip, p19INK4, and the gap junction protein connexin 43 (Cx43). Some xenobiotic agents like ethane di-methanesulphonate have a cytotoxic effect on Sertoli cells.

19.2.8 Endocrine Regulation of Leydig Cell Functions

The differentiation of ALC and steroidogenesis is controlled by pituitary LH and some locally produced factors. The LH melatonin suppresses GnIH (gonadotropin-inhibitory hormone). It activates GnRH (gonadotropin-releasing hormone) pulse generator in hypothalamus resulting in the secretion of FSH (follicle-stimulating hormone) and LH (luteinising hormone) from anterior pituitary gland to promote spermatogenesis and sexual behaviour. The entire pathway is explained with the bold line with a positive (+) sign. Decreased melato­nin level increases GnIH and suppresses GnRH pulse generator to reduce the secretion of FSH and LH, resulting in inhibition of testoster­one secretion, marked by a dotted line with a negative sign (-)]

receptors (LHR) in the foetal Leydig cells (FLCs) start expressing from embryonic day 16 in mice, and LH binds with its receptor (LHR) on Leydig cells and initiates intracel­lular signalling mechanisms for steroidogenesis (details in Sect. 19.2.1.3). Androgens secreted from FLCs cause foetal masculinization, the development of male external genitalia, the accessory sex organs, and the male-specific neuronal network in the brain. Desert hedgehog (DHH) protein and platelet-derived growth factor (PDGF, PDGF-A, and PDGF- B), produced from the Sertoli cells, induce FLC differentia­tion. Its number increases throughout the foetal period. The differentiation of Sertoli cells is also influenced by transcrip­tion factors GATA-4 and IGF-I. The FLCs decline after birth, and the number of ALCs rapidly increases to occupy the interstitial space of the adult testis during the pubertal period. Androgens, along with other proteins such as nuclear recep­tor subfamily 5 group A member 1 (NR5A1), Wilms tumor protein (WT1) and DHH protein, promote the differentiation of FLCs to form ALCs. The steroidogenesis is regulated within a precise range as excess or overproduction is detrimental.

Along with LH, several growth factors and cytokines act in an autocrine/paracrine manner to regulate steroidogenesis. Insulin growth factor I (IGF-I) and fibroblast growth factor 9 (FGF9) promote steroidogenesis, whereas transforming growth factor-beta (TGFβ), AMH, tumour necrosis factor­alpha (TNFα), IL-6 and IL-1 have inhibitory effects on ste­roidogenesis. Epidermal growth factor receptor (EGFR) also inhibits LH-induced steroidogenesis. 5’ AMP-activated pro­tein kinase (AMPK) is an enzyme involving cellular energy homeostasis that negatively regulates steroidogenesis. The activity of ALCs and testosterone production gradually diminished with age due to the reduced activity of steroido­genic enzymes, like Cyp11a1, Hsd3b, Cyp17a1, 17-ketoreductase, and Hsd11b2. The decreased activity of antioxidants enzymes, like copper and zinc superoxide dismutase (Sod1), manganese superoxide dismutase (Sod2), and glutathione peroxidase (Gpx), also affect the Leydig cell function in old age. Due to the failure of antioxidant activity, ROS production is increased. It interferes with cholesterol transport to the mitochondria and its conversion to pregneno­lone in the steroidogenic pathway. Ghrelin and leptin reduce the activity of key steroidogenic enzymes, hence reducing testosterone release. INSL3 is the major secreted product of the ALC and is used as a biomarker of LC function and the onset of puberty. Prolactin increases the affinity of LH receptors to its ligand on Leydig cells to increase testosterone production. Thus, excess testosterone production in hyperprolactinemia causes downregulation of the H-P-G axis, leading to hypogonadism. Oestradiol suppresses the enzyme 17β-hydroxysteroid dehydrogenase and decreases testosterone synthesis. In boar and stallion, the production of oestradiol from testosterone by aromatase can reach the interstitial space and binds with its receptor at LC to affect steroidogenesis.

The Relationship Between LH and Testosterone Release Generally, every LH pulse is followed by a GnRH pulse (Fig. 19.18). But, every LH pulse does not yield testos­terone release (Fig. 19.19). Normally the testosterone pulses are followed by a few narrowly spaced LH pulses. In mice, the LH pulse and testosterone pulse ratio is about 2:1. The testosterone release occurs within 10 min after the LH pulse appearance, which peaked within 20-30 min and gradually declined to reach baseline within 60-80 min (Table 19.3).

19.2.8 Stress-Induced HPG Axis Suppression

19.2.9.1 Role of Hypothalamic-Hypophyseal- Adrenal (HPA) Axis

Stress is a well-known suppressor of gonadal functions in males and females by inhibiting the GnRH pulse generator. During stress, the hypothalamic-hypophyseal-adrenal (HPA) axis is activated to release the secretion of corticotropin-releasing hormone (CRH) from the hypothala­mus, adrenocorticotropin-releasing hormone (ACTH) from the pituitary, and glucocorticoids (corticosterone) from the

Fig. 19.18 Relative blood concentration and associations among GnRH, FSH, and LH in adult male mammals. [GnRH gonadotropin­releasing hormone (solid line); FSH follicle-stimulating hormone (dot­ted line with a circle); LH luteinizing hormone (dotted line). Secretion of FSH occurs immediately after the GnRH pulse, and LH secretion starts at the end of the GnRH pulse. The LH pulses are sharp and decline within10-20 min due to less half-life, whereas FSH pulses are flat, indicating more persistency than LH (five times more) than LH secre­tion. The concentration of FSH is comparatively less than LH due to the continuous release of inhibin]

Fig. 19.19 Relationship between luteinizing hormone and testosterone in male mouse. [Luteinizing hormone presented (dotted line) and testos­terone (solid line)]

adrenal gland. CRH suppresses the synthesis and secretion of GnRH by changes in the expression of GnRH and its receptor (GnRHR) genes in the hypothalamic-hypophyseal unit. But, evidence has suggested that stress hormones (corticotrophin- releasing hormone and corticosterone) cannot suppress the HPG axis alone. Good numbers of other endocrine and neural signalling are implicated in stress-induced downregulation of the HPG axis. Some authors postulated that stress-induced suppression of the HPG axis is mediated through prostaglandins (PGs) as the stressors induce the activity of brain cyclooxygenase-2 (COX-2), an enzyme required for PG-synthesis. Recently the role of RFRP-3 GnRH and LH inhibition during stress has been documented.

19.2.9.2 Role of Anorexigenic Peptides

Orexigenic and anorexigenic peptides are released to convey information about the nutritional status of an animal. The

Fig. 19.20 Stress-induced suppression of the H-P-G axis. [The downregulation of the H-P-G axis under negative energy balance (NEB) through orexigenic factors like MCH (melanin-concentrating hormone), orexin (from lateral hypothalamus), and NPY (neuropeptide Y, from the arcuate nucleus, ARH). These orexigenic peptides directly suppress the neurokinin B(NKBB)-stimulated firing of kisspeptin (Kiss 1) neurons in the anteroventral periventricular nucleus (AVPV), the PMV (ventral pre-mammillary nucleus). The decreased secretion of anorexigenic peptides like Ins (insulin), Leptin (Lep), and αMSH (melanocyte-stimulating hormone) during negative energy bal­ance also suppresses the HPG axis. The optimum nutrition favours the release of Leptin (Lep) which stimulates GnRH release through the kisspeptin/neurokinin B/dynorphin A (KNDy) pathway. In obesity, SOCS-3 (suppressor of cytokine signalling) is inhibited, causing leptin resistance followed by downregulation of GnRH. Secretion of glucocorticoids (stress or Cushing’s syndrome) suppresses the H-P-G axis through gonadotropin-inhibiting hormone (GnIH) or RFRP (RFamide-Related Peptide) secretion. Glucocorticoids also affect the activity of Cox-2 (cyclooxygenase inhibitor-2), which decreases PG (prostaglandin) synthesis resulting in inhibition of LH secretion; glucocorticoids suppress the testosterone synthesis in the Leydig cell (LC) of the testis by inducing LC apoptosis and inhibiting the activity of LH receptor, P450SCC, StAR, CYP17, and 11β-HSD enzymes cause the suppression of spermatogenesis; testosterone action in the epididy­mis, vas deferens, the prostate is also affected by glucocorticoids. The function of LC is followed by testosterone production. The thyroid dysfunctions (hyperthyroidism and hypothyroidism) also affect sper­matogenesis. EDCs (endocrine disruptors) and ROS (reactive oxygen species)] also affect the testicular functions]

orexigenic peptides like neuropeptide Y (NPY) originate during calorie restriction or hypoglycaemia and secrete anorexigenic peptides (leptin, insulin, and αMSH) during optimum body growth as well as obesity to control the appetite and feeding behaviour. These anorexigenic and orexigenic peptides modulate the HPG axis (Fig. 19.20). The stimulatory action of anorexigenic peptides, particularly leptin, has been discussed in ‘energy metabolism and HPG axis activation’ (Sect. 19.2.6.1). The orexigenic peptides like NPY and αMSH directly suppress the neurokinin B-stimulated firing of kisspeptin neurons and hence the HPG axis during malnutrition.

19.2.9.3 Role of Endocrine Disruptors Chemicals (EDCs) on the H-P-G Axis

Various phytoestrogen, persistent organic pollutants (POPs), and organochlorine insecticides negatively affect the HPG axis. They are collectively called Endocrine disruptors (EDCs). They exert their actions by modulating synthesis, release, transport, metabolism, and eliminating other neuro­endocrine factors involved in the HPG axis. The potential EDCs are agricultural waste, like triazoles, Imidazoles, and triazines; industrial products, like nonyl-phenols, octyl­phenols, bisphenol A, phthalates, organotins, perfluorooctane sulphonate, parabens, cadmium, etc.; metals, like cadmium. The EDCs damage the germ cells, Sertoli cells, and Leydig cells, alter various enzymatic activity, disrupt the antioxidant system, and lower the level of FSH and LH, which ultimately results in reduced testosterone synthesis, decreased sperm concentration, increased production of abnormal spermatozoa with hypomotility.

The role of different neuroendocrine factors in the H-P-G axis regulation is summarized in Table 19.5.

Table 19.5 Various neuroendocrine factors involved in the H-H-G axis

19.3