Reproductive Physiology 1

Reproductive Physiology 1 December 1, 2014

GnRH released into the portal system between the hypothalamus and anterior pituitary triggers the release of LH and FSH from the anterior pituitary. • These gonadotropins regulate sexual function. GnRH, LH and FSH

Loss of GnRH release from the hypothalamus results in a loss of FSH and LH secretion. • GnRH release into the portal system is pulsatile (i.e., the GnRH-producing hypothalamic neurons fire periodically, but at regular intervals). GnRH, LH and FSH • Secretion of LH faithfully follows the pulses of GnRH. However, the secretion of FSH, although pulsatile, is not as tightly linked to oscillations in GnRH release.

Continuous release of GnRH causes an inhibition of LH and FSH secretion. • Thus, administration of drugs with a similar structure as GnRH to maintain continuously-high levels of the peptide suppresses sexual function. GnRH, LH and FSH • For example, implants that release GnRH analogs (such as Supprelin-LA) are used to delay sexual maturity in children with precocious puberty (a condition where sexual development begins at too early of an age).

Sexual maturity is triggered when hypothalamic neurons that release GnRH begin to fire together at regular intervals. • GnRH secretion and release of LH and FSH from the anterior pituitary begin in utero, as sex steroids play an important role in sexual differentiation, particularly in males (testosterone is critical for the development of male sexual organs). GnRH, LH and FSH • Fetal plasma levels of testosterone are approximately the same as in adult males, and there is another peak just after birth. However, release of GnRH and gonadotropins cease within the first year, and the levels remain negligible until the start of puberty. • GnRH release suppression is mediated through neurons that inhibit the GnRH-releasing hypothalamic neurons.

Leydig and Sertoli Cells • Two cell types are present in the testis: Leydig Cellsand Sertoli Cells • Leydig Cells have LH receptors and produce the male sexual hormone, testosterone. • Sertoli cells form the walls of the seminiferous tubules, where sperm production occurs.

Testosterone Synthesis

LH Stimulates Testosterone Production • Binding of LH to receptors on the membrane of Leydig cells activates a G-protein coupled mechanism that increases the production of enzymes needed for testosterone synthesis. • Hence, LH regulates the production of testosterone in the testis.

FSH Stimulates Sertoli Cells • Binding of FSH to receptors on the membrane of Sertoli cells activates a G-protein coupled mechanism that increases the production of a variety of proteins: growth factors that stimulate Leydig cells, aromatase (which converts testosterone to estradiol), androgen binding protein (which sequesters testosterone in the seminiferous tubule), and inhibins.

Crosstalk Between Leydig and Sertoli Cells • Binding of FSH to receptors on Sertoli cells generates factors and estradiol that stimulates testosterone production. • In other words, both FSH and LH participate in testosterone secretion (LH has a direct role, FSH has an indirect role). • Conversely, testosterone produced by Leydig cells is critical for spermiogenisis(which is facilitated by Sertoli cells). • Thus, Leydig and Sertoli cells facilitate the functions of the other.

Testosterone binds to receptors in the hypothalamus, and decreases firing of GnRH neurons. • Testosterone also binds to receptors in the anterior pituitary, mainly in LH-producing cells, to inhibit LH secretion (mechanism discussed later) • Inhibin is a protein and cannot cross the blood-brain barrier. It binds to receptors on the surface of FSH-releasing pituitary cells to inhibit their function. • Thus, testosterone mainly has feedback inhibition on LH release whereas inhibin mainly has feedback inhibition on FSH release. Feedback Regulation of FSH and LH Secretion

Estradiol has the same effect as testosterone in the anterior pituitary. This is because LH-secreting cells contain aromatase, which converts testosterone to estradiol. Binding of estradiol to estradiol receptors in the pituitary inhibits LH release. • Artificially providing estradiol to men can thus inhibit testosterone release. • Progesterone at high levels can bind to androgen receptors, thereby having the same effects as testosterone. • Thus, giving female hormones to an uncastrated male can result in infertility (since testosterone secretion will drop). Feedback Regulation of FSH and LH Secretion

Male sexual development Enlargement of male genitalia and growth of body hair Support of spermiogenesis Baldness Deepening of the voice Changes in skin characteristics Muscle development Changes in bone structure Increases in metabolic rate Increases in hematocrit Increases in sodium retention Psychological effects Functions of Testosterone

In some tissues (e.g., skeletal muscle and testis), testosterone enters cells and binds directly to androgen receptors. • In other tissues, testosterone must be converted to dihydrotestosterone by 5-a reductase in order to bind to the androgen receptor. Such tissues include the skin and prostate gland. Thus, 5-a reductase inhibitors (e.g., Propecia) prevent the actions of testosterone in those tissues, but not tissues where testosterone binds directly to androgen receptors. • Yet other tissues (e.g., bone and anterior pituitary) contain aromatase, which converts testosterone to estradiol. In those tissues, there are no androgen receptors, but estradiol receptors. Thus, estradiol and testosterone have equivalent effects in those tissues. Mechanisms of Testosterone Action

The 5-a reductase inhibitor finasteride is marketed under two trade names by Merck: Proscar® and Propecia®. Why are there two trade names for the same drug? So there are two separate patents, and two patent expiration dates.

Testosterone Levels Drop in an Adult Male • Secondary sexual characteristics are retained • Infertility occurs • Muscle mass development becomes more difficult • Behavioral effects of testosterone diminish • An Adult Male Takes Anabolic Steroids • Easier to increase muscle mass • Aggressive tendencies (“roid rage”) • Infertility (although blood levels of T are high, testicular levels are low) • Testosterone is present in a child • During development, leads to development of male sexual organs • If present in early childhood, can result in premature puberty What Happens if Testosterone Levels Are Wrong?

An amalgam of Sertoli cells forms the seminiferous tubules where sperm mature. • Sertoli cells are joined by tight junctions that form the blood-testis barrier. • Immature germ cells migrate into the testis during embryogenesis, and are located near the basal lamina of the seminiferous tubule. Spermiogenesis • During and after puberty (under the influences of testosterone and the products of Sertoli cells), the immature sperm cells (spermatogonia) begin to divide mitotically.

} Spermiogenesis 16-18 Days 23 Days 1 Day 23 Days (most outside seminiferous tubule) Total: ~70 Days

The rate of spermiogenesis is constant and cannot be accelerated by hormones such as gonadotropins or androgens. • If the environment in the testis becomes unfavorable during spermiogenesis (e.g., testosterone levels fall), all of the developing sperm cells degenerate and are eliminated. • In 20-year-old men, the production rate is ~6.5 million sperm per gram of testicular parenchyma per day. • The rate falls progressively with age and averages ~3.8 million sperm per gram of testicular parenchyma per day in men 50 to 90 years old. • This decrease is probably related to the high rate of degeneration of germ cells during meiotic prophase. • Among fertile men, those aged 51 to 90 years exhibit a significant decrease in the percentage of morphologically normal and motile spermatozoa. Facts about Spermiogenesis

Sperm cells are nestled in cytoplasmic processes of Sertoli cells as the develop. • Gap junctions between Sertoli cells and spermatozoa allow material exchange between the two. • A high concentration of testosterone is needed in the seminiferous tubule to facilitate spermiogenesis. Sertoli Cells Support Spermiogenesis

Each spermatozoon is composed of a head and a tail. • On the outside of the anterior two thirds of the head is a thick cap called the acrosome that is formed mainly from the Golgi apparatus. This contains a number of enzymes similar to those found in lysosomes of the typical cell, which play important roles in allowing the sperm to enter the ovum and fertilize it. • Back-and-forth movement of the tail (flagellar movement) provides motility for the sperm. Sperm Cells • The normal motile, fertile sperm are capable of flagellated movement through the fluid medium at velocities of 1 to 4 mm/min. The activity of sperm is greatly enhanced in a neutral and slightly alkaline medium, as exists in the ejaculated semen.

Sperm are produced in seminiferous tubules and transported via the rete testis and efferent ductules to the epididymis. • Further maturation of sperm occurs in the epididymis. Maturation of Sperm

The epididymis empties into the vas deferens. • The vas deferens contains muscle layers whose contractions facilitate sperm movement. • The vas deferens passes to the posterior and inferior aspect of the urinary bladder, where it is joined by the duct arising from the seminal vesicle. • Together, they form the ejaculatory duct, which joins the urethrain the prostate. • Sperm are stored in the epididymis as well as in the proximal end of the vas deferens prior to ejaculation. Maturation of Sperm

Only 10% of the volume of semen is sperm cells. The remainder is seminal plasma. • The seminal plasma originates primarily from the seminal vesicles (70%), while the prostate gland and the bulbourethral glands contribute the rest. • Due to the secretions, semen is isotonic or slightly alkaline (pH 7.3-7.7). • The secretion contains a plethora of sugars and ions. • The typical ejaculate volume in a 20 year-old male is 2-6 ml and contains between 150 and 600 million spermatozoa. • Prior to ejaculation, Cowper’s gland secretes a viscous pre-ejaculatory fluid. This fluid lubricates the urethra, and neutralizes acidic urine. Seminal Plasma

Seminiferous epithelium is sensitive to elevated temperature, and will be adversely affected by temperatures as high as normal body temperature. • Consequently, the testes are located outside the body in a sack of skin called the scrotum. • The optimal temperature is maintained at 2 °C below body temperature. • Hence, men with failure of the testis to descend into the scrotum, or men who consistently maintain elevated scrotal temperatures (e.g., professional cyclists), will have reduced or absent sperm count. Temperature and Spermiogenesis

Parasympathetic activity initiates the male sexual response by causing vasodilation in the penis, resulting in engorgement of the corpus cavernosum with blood. (mediated by nitric oxide) • Parasympathetic activity also triggers secretory activity of the epithelia of the male accessory glands. • Emission begins with contraction of the smooth muscle in the vas deferens and the epididymis under the control of the sympathetic nervous system • The internal urinary sphincter also contacts to prevent backflow of semen into the bladder. • Then, contractions of the muscular coat of the prostate gland followed by contraction of the seminal vesicles expel prostatic and seminal fluid also into the urethra, forcing the sperm forward. • Subsequent rhythmic contractions of the striated muscles of the perineal area (under somatic control) result in ejaculation. Male Sexual Response

For an unknown reason, hyperplasia of the prostate is a common problem in aging men. • The hyperplasia is usually benign, although prostate cancer is the second leading cancer killer in men. • Prostate hyperplasia can cause difficulty in urination and ejaculation. The Prostate • Prostate hyperplasia is testosterone dependent, and can be treated with 5α-reductase inhibitors (since testosterone is converted to dihydrotestosterone in the prostate via this enzyme). • Prostate-specific antigen (PSA) increases during hyperplasia of the prostate. The PSA test has been used to monitor for prostate cancer, but the test is now controversial.

Lack of germ cells in the testis • Diabetes and hypertension, which can damage nerves or vessels in the genitalia • Surgeries that damage nerves innervating the genitalia • Variocele, a venous drainage problem that results in elevated temperature in the testes. • Many types of drugs • a-adrenergic antagonists • Muscarinic antagonist • Antidepressants • H2 receptor antagonists • Damage or twisting of ducts that transport sperm Male Sexual Dysfunction Causes

Reproductive Physiology 1