Reproductive endocrine physiology

Introduction

The male reproductive physiology involves external structures (scrotum and penis) and internal structures (testis, epididymis, vas deferens, and prostate). These are well vascularized and supported by several other glands. The primary male androgen hormone is testosterone produced by Leydig cells in the testis, but other hormones like inhibin and Mullerian-inhibiting substance produced by Sertoli cells also contribute to the male reproductive physiology. Follicular-stimulating hormone (FSH) and luteinizing hormone (LH), produced from the anterior pituitary, under control of the hypothalamic hormone, gonadotropin- releasing hormone (GnRH) are involved in the regulation of the male reproductive physiology and together these hormones form the hypothalamic–pituitary–gonadal axis.

Functions of male reproductive organs

The male reproductive system, through the hypothalamic–pituitary–gonadal axis, is responsible for male sexual development/maturity, including the formation of secondary sex characteristics for males. In addition, it is necessary for sperm production (spermatogenesis) and lifelong maintenance of male sexuality. The male reproductive system also assists in the transport of generated sperms into the female reproductive system for fertilization. Sperm production and transport occur in the testis, alongside the production of the male androgen, testosterone. Thus, the testes have exocrine and endocrine functions simultaneously.

Spermatogenesis

This is the process of sperm production, beginning at puberty and continues throughout a man’s life, occurring in cycles of about 64 days (ranges from 42 to 76 days), with cycles beginning about every 16 days. There is no synchrony between different sections of the seminiferous tubules, though.

Spermatogenesis occurs through three phases ( Fig. 2.2 ):

• 1.

  Proliferation phase: This involves the division of spermatogonia for either self-renewal or differentiation into daughter cells that will become mature gametes. It comprises a single cell division resulting in two identical diploid daughter cells (type B spermatogonia to primary spermatocyte). Type B spermatogonia are derived by the division of pale type A spermatogonia in the basal, stem cell niche of seminiferous tubules. One of type B spermatogonia remains a spermatogonium to undergo further mitosis, the other proceeds to meiotic phase. Cytoplasm between the spermatogonial cells forms connections between cells, which persist throughout spermatogenesis and are thought to be crucial for cellular development and gene expression.

• 2.

  Meiotic phase: This is the phase of division, with the reduction of germ cells to haploid spermatids with half the DNA. Unlike mitosis where two diploid genetically identical daughter cells are formed, in meiosis, four haploid genetically diverse daughter cells are formed. This involves two steps: primary spermatocyte to secondary spermatocyte and secondary spermatocyte to Sa spermatid.

• 3.

  Spermiogenesis phase: Sa spermatids change to mature spermatozoa through nucleus and cytoplasmic modifications including cytoplasmic loss, organelle migration, acrosome formation, flagellum formation from a centriole, nuclear compression leading to asymmetrical shape and mitochondrial restructuring. These changes are assisted by various cellular elements. When spermatid elongation is complete, Sertoli cell cytoplasm is pulled back, thus removing excess cytoplasm and pushing the developed sperm into the tubular lumen. Almost 300 sperms per gram of testis per second are produced.

Structure of formed sperm

The volume of the sperm is 85,000 times less than an ovum, and daily about 100–300 million sperms are produced. A mature sperm consists of the head, containing minimal cytoplasm, a compact nucleus and the acrosome “cap” with lysosomal enzymes that aid the penetration of the ovum; mid-piece containing mitochondria for ATP production that is necessary for flagella movement; tail, which mainly contains the flagella ( Fig. 2.3 ).

Physiology of male sexual response

There are four stages of male sexual response: excitement, plateau, orgasm, and resolution. The initial event is erection, followed by orgasm and then ejaculation as detailed as follows:

Penile erection: This results from various neurovascular, molecular, psychological, and endocrinological factors. It is initiated by visual, olfactory, or imaginative stimuli in the medial preoptic area and paraventricular nucleus in the hypothalamus and involves dopamine, norepinephrine, oxytocin, nitric oxide (NO), α-melanocyte-stimulating hormone, and opioid peptides. Tactile genital stimulation mediates penile tumescence through parasympathetic sacral reflex arc, whereas psychogenic tumescence mainly involves central suppression of sympathetic stimulation. Neuronal and endothelial NO synthases increase NO levels during initiation and maintenance of erection, respectively, causing vasodilatation and smooth muscle relaxation, thus increasing blood flow to the penis with reduced venous return.

Orgasm: This is the period preceding ejaculation after penile erection, which involves hyperventilation, tachycardia, high blood pressure, pelvic muscle and rectal sphincter contractions, and facial grimacing.

Ejaculation: It involves the emission of semen into the urethra and expulsion out of the urethra. Emission is mediated by sympathetic nerves in the pelvic plexus, eliciting contraction of smooth muscles in vas deferens, seminal vesicles, and prostate and has a central cerebral control, whereas expulsion is mediated by efferent pathways in pudendal nerves through the contractions of striated muscles (bulbospongiosus and ischiocavernosus).

Male sex hormones and functions

Male sex hormones, termed “androgens,” include testosterone, the primary male sex hormone, dihydrotestosterone (DHT), and androstenedione.

Testosterone

Testosterone is secreted from the interstitial cells of Leydig, which are in large concentration in the testis in newborns and adult males after puberty. About 97% of testosterone gets bound to plasma albumin or sex-hormone-binding globulin and circulates to the tissues, where most of the testosterone is converted to DHT, particularly in male fetus (for development of external genitalia) and adult prostate. Unused testosterone is converted in the liver to androsterone and dehydroepiandrosterone (DHEA) and conjugated as glucuronides or sulfates, which are excreted by the gut or kidney. The biosynthesis of testosterone is summarized in Fig. 2.4 A .

Mechanism of action: Testosterone is converted to DHT by cytoplasmic 5α-reductase. DHT combined with a receptor protein, enters the nucleus, and binds to nuclear proteins, where it induces DNA–RNA transcription, increasing cellular protein production and increased cell numbers.

Functions of testosterone: These have been detailed in Table 2.1 . In general, testosterone is mainly responsible for specific male masculine characteristics. During early fetal life (first trimester), chorionic gonadotropin stimulates testosterone production, to adult levels. This is to enable masculine genital tract differentiation. In infant boys, serum testosterone (T) concentrations that are gonadal in origin increase to pubertal concentrations between 1 and 3 months of age and fall to prepubertal values around 6 months of age, and this is of undetermined significance. After this surge, testosterone production stops through infantile age, due to tonically suppressed GnRH production; this is then followed by another surge at ages 10–13 years, when anterior pituitary gonadotropic hormones stimulate its production at puberty onset, in response to the intermittent GnRH production. This production continues till age 50 years where production reduces gradually.

Table 2.1

Functions of testosterone in males.

Function	Description
Fetal male development	Testosterone secreted by genital ridge and fetal testis stimulates the formation of penis, scrotum, prostate, seminal vesicles, and male genital ducts. It suppresses female genital organ formation
Descent of testis	Testis descend in scrotum in last 2–3 months of gestation under the influence of testosterone
Development of adult primary sexual characteristics	After puberty, testosterone causes penile, scrotal, and testicular enlargement
Development of adult secondary sexual characteristics: these include:
- Distribution of body hair	Testosterone causes male-pattern hair distribution over the pubis, along linea alba, face, chest, and back
- Male-pattern baldness	Testosterone decreases hair growth on top of the head
- Male voice	Testosterone stimulates laryngeal enlargement and hypertrophy of laryngeal mucosa, leading to male voice
- Increased skin thickness	Testosterone contributes to ruggedness in male skin and increases secretion from sebaceous glands
- Protein formation and muscle development	Testosterone stimulates protein synthesis and deposition alongside increasing muscle mass
- Increased bone matrix and calcium retention	Due to protein anabolic effect, testosterone increases overall bone matrix and thus calcium salt retention. Testosterone also increases epiphyseal union. Effects on pelvis include lengthening, narrowing, giving it funnel-like shape, and strengthening for load bearing
- Increased basal metabolic rate	Increased testosterone levels during early adulthood contribute to 5%–10% increased metabolic rate, possibly due to protein anabolic effect by increased enzyme formation
- Increased red blood cells	Males have 700,000 more red blood cells vs women, possibly due to increased metabolic rate
- Effect on water and electrolyte balance	Testosterone has a small effect on increasing sodium reabsorption at distal renal tubules. During puberty, this could contribute to increased weight due to blood and extracellular fluid volume expansion by 5%–10%

Interplay of endocrine and reproductive systems

The male reproductive system is controlled by GnRH from the arcuate nucleus of hypothalamus, which is released in a pulsatile manner every 1–3 h, and transported through the hypophysio-pituitary portal system to the anterior pituitary where it stimulates gonadotrope cells to release gonadotropins: FSH and LH. LH production is more pulsatile than FSH and both gonadotropins work by stimulating cAMP second messenger systems ( Fig. 2.4 B).

FSH stimulates spermatogenesis by its action on Sertoli cells in seminiferous tubules, whereas LH stimulates testicular Leydig cells to produce testosterone. Both FSH and testosterone are needed for spermatogenesis.

Testosterone production provides a negative feedback to the hypothalamus to reduce GnRH production and to the pituitary to reduce LH production. Thus, both FSH and LH productions are regulated by circulating testosterone levels.

Inhibin, a glycoprotein produced by Sertoli cells when spermatogenesis proceeds increasingly, plays a role in inhibiting FSH release, thus regulating spermatogenesis.