- In a normal adult man, the GnRH-secreting neuroendocrine cells in the hypothalamus fire a brief burst of action potentials approximately every 90 min, secreting GnRH at these times.
- The GnRH reaching the anterior pituitary gland via the hypothalamo–hypophyseal portal vessels during each periodic pulse triggers the release of both LH and FSH from the same cell type, although not necessarily in equal amounts.
- Therefore, plasma concentrations of FSH and LH also show pulsatility—rapid increases followed by slow decreases over the next 90 min or so as the hormones are slowly removed from the plasma.
Actions of FSH and LH within the testes
- There is a separation of the actions of FSH and LH within the testes (see Figure 17.14).
- FSH acts primarily on the Sertoli cells to stimulate the secretion of paracrine agents required for spermatogenesis.
- LH, by contrast, acts primarily on the Leydig cells to stimulate testosterone secretion.
Testosterone effect in testes
- In addition to its many important systemic effects, the testosterone secreted by the Leydig cells also acts locally, in a paracrine manner, by diffusing from the interstitial spaces into the seminiferous tubules.
- Testosterone enters Sertoli cells, where it facilitates spermatogenesis.
- Despite the absence of a direct effect on cells in the seminiferous tubules, LH exerts an essential indirect effect because the testosterone secretion stimulated by LH is required for spermatogenesis
LH negative feedback
- The last components of the hypothalamo–hypophyseal control of male reproduction that remain to be discussed are the negative feedback effects exerted by testicular hormones.
- Even though FSH and LH are produced by the same cell type, their secretion rates can be altered to different degrees by negative feedback inputs.
- Testosterone inhibits LH secretion in two ways (see Figure 17.14):
- (1) It acts on the hypothalamus to decrease the amplitude of GnRH bursts, which results in a decrease in the secretion of gonadotropins; and
- (2) it acts directly on the anterior pituitary gland to decrease the LH response to any given amount of GnRH.
How do the testes reduce FSH secretion?
- The major inhibitory signal, exerted directly on the anterior pituitary gland, is the protein hormone inhibin secreted by the Sertoli cells (see Figure 17.14).
- This is a logical completion of a negative feedback loop such that FSH stimulates Sertoli cells to increase both spermatogenesis and inhibin production, and inhibin decreases FSH release.
Testosterone secretion pattern
- Despite all these complexities, the total amounts of GnRH, LH, FSH, testosterone, and inhibin secreted and of sperm produced do not change dramatically from day to day in the adult male.
- However, testosterone secretion does follow a circadian pattern with a peak in the morning (look back at Section 1.8 in Chapter 1).
- This is different from the cyclical variations of reproductive function characteristic of the adult woman.
- In addition to its essential paracrine action within the testes on spermatogenesis and its negative feedback effects on the hypothalamus and anterior pituitary gland, testosterone exerts many other effects, as summarized in Table 17.3.
- In Chapter 11, we mentioned that some hormones undergo transformation in their target cells in order to be more effective.
- This is true of testosterone in some of its target cells.
- In some cells, like in the adult prostate, after its entry into the cytoplasm, testosterone is converted to dihydrotestosterone (DHT), which is more potent than testosterone (see Figure 17.6).
- This conversion is catalyzed by the enzyme 5-α-reductase, which is expressed in several androgen target tissues.
- In certain other target cells (e.g., the brain), testosterone is transformed to estradiol, which is the active hormone in these cells.
- The enzyme aromatase catalyzes this conversion. In the latter case, the “male” sex hormone is converted to the “female” sex hormone to be active in the male.
Pathophysiological implications of testosterone conversion
- The fact that, depending on the target cells, testosterone may act as testosterone or be converted to dihydrotestosterone or estradiol has important pathophysiological implications because some genetic (46,XY) males lack 5-α-reductase or aromatase in some tissues.
- Therefore, they will exhibit certain signs of testosterone deficiency but not others.
- For example, a 46,XY fetus with 5-α-reductase deficiency will have normal differentiation of male reproductive duct structures (an effect of testosterone) but will not have normal development of external male genitalia, which requires DHT.
- Therapy for prostate cancer makes use of these facts: Prostate cancer cells are stimulated by dihydrotestosterone, so the cancer can be treated with inhibitors of 5-α-reductase.
- Furthermore, male pattern baldness may also be treated with 5-α-reductase inhibitors because the hair follicles express 5-α-reductase and the resultant locally produced DHT tends to promote hair loss from the scalp.
Accessory Reproductive Organs
- The fetal differentiation and later growth and function of the entire male duct system, glands, and penis all depend upon testosterone (see Figures 17.2 and 17.3).
- If there is a decrease in testicular function and testosterone synthesis for any reason, the accessory reproductive organs decrease in size, the glands significantly reduce their secretion rates, and the smooth muscle activity of the ducts is diminished.
- Sex drive (libido), erection, and ejaculation are usually impaired.
- These defects lessen with the administration of testosterone.
- This would also occur with castration (removal of the gonads), or with drugs that suppress testosterone secretion or action.
Summary of hormonal control of male reproductive function
- Summary of hormonal control of male reproductive function.
- Note that FSH acts only on the Sertoli cells, whereas LH acts primarily on the Leydig cells.
- The secretion of FSH is inhibited mainly by inhibin, a protein hormone secreted by the Sertoli cells, and the secretion of LH is inhibited mainly by testosterone, the steroid hormone secreted by the Leydig cells.
- Testosterone, acting locally on Sertoli cells, stimulates spermatogenesis, whereas FSH stimulates inhibin release from Sertoli cells.
Puberty is the period during which the reproductive organs mature and reproduction becomes possible.
Puberty in males
- In males, this usually occurs between 12 and 16 years of age.
- Some of the first signs of puberty are due not to gonadal steroids but to increased secretion of adrenal androgens, probably under the stimulation of adrenocorticotropic hormone (ACTH).
- These androgens cause the very early development of pubic and axillary (armpit) hair, as well as the early stages of the pubertal growth spurt in concert with growth hormone and insulin-like growth factor I (see Chapter 11).
- The other developments in puberty, however, reflect increased activity of the hypothalamo–pituitary–gonadal axis.
Male puberty and GnRH secretion
- The other developments in puberty, however, reflect increased activity of the hypothalamo–pituitary–gonadal axis.
- The amplitude and pulse frequency of GnRH secretion increase at puberty, probably stimulated by input from kisspeptin neurons in the hypothalamus.
- This causes increased secretion of pituitary gonadotropins, which stimulate the seminiferous tubules and testosterone secretion.
- Testosterone, in addition to its critical role in spermatogenesis, induces the pubertal changes that occur in the accessory reproductive organs, secondary sex characteristics, and sex drive.
- There appear to be peripheral inputs to the kisspeptin neurons that signal the brain to increase GnRH pulses at the onset of puberty.
- One important event is that the brain becomes less sensitive to the negative feedback effects of gonadal hormones at the time of puberty.
Secondary Sex Characteristics and Growth
- Virtually all the male secondary sex characteristics are dependent on testosterone and its metabolite, DHT.
- For example, a male lacking normal testicular secretion of testosterone before puberty has minimal facial, axillary, or pubic hair.
- Other androgen-dependent secondary sexual characteristics are deepening of the voice resulting from the growth of the larynx, thick secretion of the skin oil glands (that can cause acne), and the masculine pattern of fat distribution.
- Androgens also stimulate bone growth, mostly through the stimulation of growth hormone secretion.
- Ultimately, however, androgens terminate bone growth by causing closure of the bones’ epiphyseal plates.
- Androgens are “anabolic steroids” in that they exert a direct stimulatory effect on protein synthesis in muscle.
- Finally, androgens stimulate the secretion of the hormone erythropoietin by the kidneys; this is a major reason why men have a higher hematocrit [the ratio of the volume of red blood cells to the total volume of blood] than women.
- Androgens are essential in males for the development of sex drive at puberty, and they are important in maintaining sex drive (libido) in the adult male.
- Whether endogenous androgens influence other human behaviors in addition to sexual behavior is not certain.
- However, androgen-dependent behavioral differences based on gender do exist in other mammals. For example, aggression is greater in males and is androgen-dependent.
Anabolic Steroid Use
- The abuse of synthetic androgens (anabolic steroids) is a major public health problem, particularly in younger athletes.
- Although there are positive effects on muscle mass and athletic performance, the negative effects—such as overstimulation of prostate tissue and increase in aggressiveness—are of significant concern.
- Ironically, the increase in muscle mass and other masculine characteristics in men belies the fact that negative feedback has decreased GnRH, LH, and FSH secretion.
- This results in a decrease in both endogenous testosterone and spermatogenesis in Sertoli cells.
- This actually induces a decrease in testicular size and low sperm count (infertility) as described in the next section.
- In fact, administration of low doses of anabolic steroids is being tested as a potential male birth control pill.
- A decrease in testosterone release from the testes— hypogonadism—can be caused by a wide variety of disorders.
- They can be classified into testicular failure (primary hypogonadism) or a failure to supply the testes with appropriate gonadotrophic stimulus (secondary hypogonadism).
- The loss of normal testicular androgen production before puberty can lead to a failure to develop secondary sex characteristics such as deepening of the voice, pubic and axillary hair, and increased libido, as well as a failure to develop normal sperm production.
- A relatively common genetic cause of primary hypogonadism is Klinefelter’s syndrome, another disorder of sexual development.
- The most common form, occurring in 1 in 500 male births, is an extra X chromosome (47,XXY) caused by meiotic nondisjunction.
- Non-disjunction is the failure of a pair of chromosomes to separate during meiosis, such that two chromosome pairs go to one daughter cell and the other daughter cell fails to receive either chromosome.
- The extra X chromosome can come from either the egg or the sperm.
- Because of the presence of the SRY gene and expression of SRY protein in the developing offspring, testes develop (47,XXY male).
- Boys who are 47,XXY male appear normal before puberty. However, after puberty, the testes remain small and poorly developed, with insufficient Leydig and Sertoli cell function.
- The abnormal Leydig cell function results in decreased concentrations of plasma and testicular testosterone; this, in turn, leads to abnormal development of the seminiferous tubules and therefore decreased sperm production.
- Normal secondary sex characteristics do not appear, and breast size increases (gynecomastia).
- Men with this set of characteristics have relatively high gonadotropin concentrations (LH and FSH) due to loss of androgen and inhibin negative feedback.
- Men with Klinefelter’s syndrome can be treated with androgen-replacement therapy to increase libido and decrease breast size.
secondary hypogonadism and hyperprolactinemia
- Hypogonadism in men can also be caused by a decrease in LH and FSH secretion (secondary hypogonadism).
- Although there are many causes of the loss of function of pituitary gland cells that secrete LH and FSH, hyperprolactinemia (increased prolactin in the blood) is one of the most common.
- Although prolactin probably has only minor physiological effects in men under normal conditions, the pituitary gland still has cells (lactotrophs) that secrete prolactin.
- Pituitary gland tumors arising from prolactin-secreting cells can develop and secrete too much prolactin.
- One of the effects of increased prolactin concentrations in the blood is to inhibit LH and FSH secretion from the anterior pituitary gland. (This occurs in men and women.)
Secondary hypogonadism: hypopituitarism
- Another cause of secondary hypogonadism is a significant decrease in anterior pituitary gland function, called hypopituitarism or panhypopituitarism.
- There are many causes of hypopituitarism, including head trauma, infection, and inflammation of the pituitary gland.
- When all anterior pituitary gland function is decreased or absent, male patients need to be treated with testosterone.
- In addition, male and female patients are treated with cortisol because of low ACTH, and with thyroid hormone because of low TSH.
- Children and some adults are also treated with growth hormone injections.
- In most circumstances, posterior pituitary gland function remains intact so that vasopressin analogs do not need to be administered to avoid diabetes insipidus.