Feedback regulation of the hypothalamic-pituitary-testicular axis in males. Stimulatory effects are shown by ® and negative feedbacks inhibitory effects are shown by ©. GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone.
anterior pituitary gland. In the absence of GnRH secretion from the hypothalamus, the gonadotropes in the pituitary gland secrete almost no LH or FSH.
LH and FSH are glycoproteins. They exert their effects on their target tissues in the testes mainly by activating the cyclic adenosine monophosphate second messenger system, which in turn activates specific enzyme systems in the respective target cells.
Testosterone—Regulation of Its Production by LH. Testosterone is secreted by the interstitial cells of Leydig in the testes, but only when they are stimulated by LH
from the anterior pituitary gland. Furthermore, the quantity of testosterone secreted increases approximately in direct proportion to the amount of LH available.
Mature Leydig cells are normally found in a child's testes for a few weeks after birth but then disappear until after the age of about 10 years. However, either injection of purified LH into a child at any age or secretion of LH at puberty causes testicular interstitial cells that look like fibroblasts to evolve into functioning Leydig cells.
Inhibition of Anterior Pituitary Secretion of LH and FSH by Testosterone—Negative Feedback Control of Testosterone Secretion. The testosterone secreted by the testes in response to LH has the reciprocal effect of inhibiting anterior pituitary secretion of LH (see Figure 80-10). Most of this inhibition probably results from a direct effect of testosterone on the hypothalamus to decrease the secretion of GnRH. This in turn causes a corresponding decrease in secretion of both LH and FSH by the anterior pituitary, and the decrease in LH reduces the secretion of testosterone by the testes. Thus, whenever secretion of testosterone becomes too great, this automatic negative feedback effect, operating through the hypothalamus and anterior pituitary gland, reduces the testosterone secretion back toward the desired operating level. Conversely, too little testosterone allows the hypothalamus to secrete large amounts of GnRH, with a corresponding increase in anterior pituitary LH and FSH secretion and consequent increase in testicular testosterone secretion.
Regulation of Spermatogenesis by FSH and Testosterone
FSH binds with specific FSH receptors attached to the Sertoli cells in the seminiferous tubules. This causes these cells to grow and secrete various spermatogenic substances. Simultaneously, testosterone (and dihy-drotestosterone) diffusing into the seminiferous tubules from the Leydig cells in the interstitial spaces also has a strong tropic effect on spermatogenesis. Thus, to initiate spermatogenesis, both FSH and testosterone are necessary.
Negative Feedback Control of Seminiferous Tubule Activity— Role of the Hormone Inhibin. When the seminiferous tubules fail to produce sperm, secretion of FSH by the anterior pituitary gland increases markedly. Conversely, when spermatogenesis proceeds too rapidly, pituitary secretion of FSH diminishes.The cause of this negative feedback effect on the anterior pituitary is believed to be secretion by the Sertoli cells of still another hormone called inhibin (see Figure 80-10). This hormone has a strong direct effect on the anterior pituitary gland to inhibit the secretion of FSH and possibly a slight effect on the hypothalamus to inhibit secretion of GnRH.
Inhibin is a glycoprotein, like both LH and FSH, having a molecular weight between 10,000 and 30,000. It has been isolated from cultured Sertoli cells. Its potent inhibitory feedback effect on the anterior pitu itary gland provides an important negative feedback mechanism for control of spermatogenesis, operating simultaneously with and in parallel to the negative feedback mechanism for control of testosterone secretion.
Psychic Factors That Affect Gonadotropin Secretion and Sexual Activity
Many psychic factors, feeding especially from the limbic system of the brain into the hypothalamus, can affect the rate of secretion of GnRH by the hypothalamus and therefore can also affect most other aspects of sexual and reproductive functions in both the male and the female. For instance, transporting a prize bull in a rough truck is said to inhibit the bull's fertility— and the human male is hardly different.
Human Chorionic Gonadotropin Secreted by the Placenta During Pregnancy Stimulates Testosterone Secretion by the Fetal Testes
During pregnancy, the hormone human chorionic gonadotropin (hCG) is secreted by the placenta, and it circulates both in the mother and in the fetus. This hormone has almost the same effects on the sexual organs as LH.
During pregnancy, if the fetus is a male, hCG from the placenta causes the testes of the fetus to secrete testosterone. This testosterone is critical for promoting formation of the male sexual organs, as pointed out earlier. We discuss hCG and its functions during pregnancy in greater detail in Chapter 82.
Initiation of the onset of puberty has long been a mystery. But it has now been determined that during childhood the hypothalamus simply does not secrete significant amounts of GnRH. One of the reasons for this is that, during childhood, the slightest secretion of any sex steroid hormones exerts a strong inhibitory effect on hypothalamic secretion of GnRH. Yet, for reasons still not understood, at the time of puberty, the secretion of hypothalamic GnRH breaks through the childhood inhibition, and adult sexual life begins.
Male Adult Sexual Life and Male Climacteric. After puberty, gonadotropic hormones are produced by the male pituitary gland for the remainder of life, and at least some spermatogenesis usually continues until death. Most men, however, begin to exhibit slowly decreasing sexual functions in their late 40s or 50s, and one study showed that the average age for terminating intersexual relations was 68, although the variation was great. This decline in sexual function is related to decrease in testosterone secretion, as shown in Figure 80-9. The decrease in male sexual function is called the male climacteric. Occasionally the male climacteric is associated with symptoms of hot flashes, suffocation, and psychic disorders similar to the menopausal symptoms of the female. These symptoms can be abrogated by administration of testosterone, synthetic androgens, or even estrogens that are used for treatment of menopausal symptoms in the female.
Abnormalities of Male Sexual Function
The prostate gland remains relatively small throughout childhood and begins to grow at puberty under the stimulus of testosterone. This gland reaches an almost stationary size by the age of 20 years and remains at this size up to the age of about 50 years. At that time, in some men it begins to involute, along with decreased production of testosterone by the testes.
A benign prostatic fibroadenoma frequently develops in the prostate in many older men and can cause urinary obstruction. This hypertrophy is caused not by testosterone but instead by abnormal overgrowth of prostate tissue itself.
Cancer of the prostate gland is a different problem and is a common cause of death, accounting for about 2 to 3 per cent of all male deaths. Once cancer of the prostate gland does occur, the cancerous cells are usually stimulated to more rapid growth by testosterone and are inhibited by removal of both testes so that testosterone cannot be formed. Prostatic cancer usually can be inhibited by administration of estrogens. Even some patients who have prostatic cancer that has already metastasized to almost all the bones of the body can be successfully treated for a few months to years by removal of the testes, by estrogen therapy, or by both; after this therapy the metastases usually diminish in size and the bones partially heal. This treatment does not stop the cancer but does slow it and sometimes greatly diminishes the severe bone pain.
When the testes of a male fetus are nonfunctional during fetal life, none of the male sexual characteristics develop in the fetus. Instead, female organs are formed. The reason for this is that the basic genetic characteristic of the fetus, whether male or female, is to form female sexual organs if there are no sex hormones. But in the presence of testosterone, formation of female sexual organs is suppressed, and instead, male organs are induced.
When a boy loses his testes before puberty, a state of eunuchism ensues in which he continues to have infantile sex organs and other infantile sexual characteristics throughout life. The height of an adult eunuch is slightly greater than that of a normal man because the bone epiphyses are slow to unite, although the bones are quite thin and the muscles are considerably weaker than those of a normal man. The voice is childlike, there is no loss of hair on the head, and the normal adult masculine hair distribution on the face and elsewhere does not occur.
When a man is castrated after puberty, some of his male secondary sexual characteristics revert to those of a child and others remain of adult masculine character. The sexual organs regress slightly in size but not to a childlike state, and the voice regresses from the bass quality only slightly. Conversely, there is loss of masculine hair production, loss of the thick masculine bones, and loss of the musculature of the virile male.
Also in a castrated adult male, sexual desires are decreased but not lost, provided sexual activities have
Adiposogenital syndrome in an adolescent male. Note the obesity and childlike sexual organs. (Courtesy Dr. Leonard Posey.)
been practiced previously. Erection can still occur as before, although with less ease, but it is rare that ejaculation can take place, primarily because the semen-forming organs degenerate and there has been a loss of the testosterone-driven psychic desire.
Some instances of hypogonadism are caused by a genetic inability of the hypothalamus to secrete normal amounts of GnRH. This often is associated with a simultaneous abnormality of the feeding center of the hypothalamus, causing the person to greatly overeat. Consequently, obesity occurs along with eunuchism. A patient with this condition is shown in Figure 80-11; the condition is called adiposogenital syndrome, Frohlich's syndrome, or hypothalamic eunuchism.
Interstitial Leydig cell tumors develop in rare instances in the testes, but when they do develop, they sometimes produce as much as 100 times the normal quantities of testosterone. When such tumors develop in young children, they cause rapid growth of the musculature and bones but also cause early uniting of the epiphyses, so that the eventual adult height actually is considerably less than that which would have been achieved otherwise. Such interstitial cell tumors also cause excessive development of the male sexual organs, all skeletal muscles, and other male sexual characteristics. In the adult male, small interstitial cell tumors are difficult to diagnose because masculine features are already present.
Much more common than the interstitial Leydig cell tumors are tumors of the germinal epithelium. Because germinal cells are capable of differentiating into almost any type of cell, many of these tumors contain multiple tissues, such as placental tissue, hair, teeth, bone, skin, and so forth, all found together in the same tumorous mass called a teratoma. These tumors often secrete few hormones, but if a significant quantity of placental tissue develops in the tumor, it may secrete large quantities of hCG with functions similar to those of LH. Also, estrogenic hormones are sometimes secreted by these tumors and cause the condition called gynecomastia (overgrowth of the breasts).
Pineal Gland—Its Function in Controlling Seasonal Fertility in Some Animals
For as long as the pineal gland has been known to exist, myriad functions have been ascribed to it, including its (1) being the seat of the soul, (2) enhancing sex, (3) staving off infection, (4) promoting sleep, (5) enhancing mood, and (6) increasing longevity (as much as 10 to 25 per cent). It is known from comparative anatomy that the pineal gland is a vestigial remnant of what was a third eye located high in the back of the head in some lower animals. Many physiologists have been content with the idea that this gland is a nonfunctional remnant, but others have claimed for many years that it plays important roles in the control of sexual activities and reproduction, functions that still others said were nothing more than the fanciful imaginings of physiologists preoccupied with sexual delusions.
But now, after years of dispute, it looks as though the sex advocates have won and that the pineal gland does indeed play a regulatory role in sexual and reproductive function. In lower animals that bear their young at certain seasons of the year and in which the pineal gland has been removed or the nervous circuits to the pineal gland have been sectioned, the normal periods of seasonal fertility are lost. To these animals, such seasonal fertility is important because it allows birth of the offspring at the time of year, usually springtime or early summer, when survival is most likely. The mechanism of this effect is not entirely clear, but it seems to be the following.
First, the pineal gland is controlled by the amount of light or "time pattern" of light seen by the eyes each day. For instance, in the hamster, greater than 13 hours of darkness each day activates the pineal gland, whereas less than that amount of darkness fails to activate it, with a critical balance between activation and nonacti-vation. The nervous pathway involves the passage of light signals from the eyes to the suprachiasmal nucleus of the hypothalamus and then to the pineal gland, activating pineal secretion.
Second, the pineal gland secretes melatonin and several other, similar substances. Either melatonin or one of the other substances is believed to pass either by way of the blood or through the fluid of the third ventricle to the anterior pituitary gland to decrease gonadotropic hormone secretion.
Thus, in the presence of pineal gland secretion, gonadotropic hormone secretion is suppressed in some species of animals, and the gonads become inhibited and even partly involuted. This is what presumably occurs during the early winter months when there is increasing darkness. But after about 4 months of dysfunction, gonadotropic hormone secretion breaks through the inhibitory effect of the pineal gland and the gonads become functional once more, ready for a full springtime of activity.
But does the pineal gland have a similar function for control of reproduction in humans? The answer to this question is unknown. However, tumors often occur in the region of the pineal gland. Some of these secrete excessive quantities of pineal hormones, whereas others are tumors of surrounding tissue and press on the pineal gland to destroy it. Both types of tumors are often associated with hypogonadal or hypergonadal function. So perhaps the pineal gland does play at least some role in controlling sexual drive and reproduction in humans.
Anderson RA, Baird DT: Male contraception. Endocr Rev 23:735, 2002.
Barry MJ, Roehrborn CG: Benign prostatic hyperplasia. BMJ 323:1042, 2001.
Brennan J, Capel B: One tissue, two fates: molecular genetic events that underlie testis versus ovary development. Nat Rev Genet 5:509, 2004.
Cajochen C, Krauchi K, Wirz-Justice A: Role of melatonin in the regulation of human circadian rhythms and sleep. J Neuroendocrinol 15:432, 2003.
Cheng CY, Mruk DD: Cell junction dynamics in the testis: Sertoli-germ cell interactions and male contraceptive development. Physiol Rev 82:825, 2002.
Cooke HJ, Saunders PT: Mouse models of male infertility. Nat Rev Genet 3:790, 2002.
de Kretser DM: Is spermatogenic damage associated with Leydig cell dysfunction? J Clin Endocrinol Metab 89:3158, 2004.
DeMarzo AM, Nelson WG, Isaacs WB, Epstein JI: Pathological and molecular aspects of prostate cancer. Lancet 361:955, 2003.
Foresta C, Moro E, Ferlin A: Y chromosome microdeletions and alterations of spermatogenesis. Endocr Rev 22:226, 2001.
Heinlein CA, Chang C: Androgen receptor (AR) coregula-tors: an overview. Endocr Rev 23:175, 2002.
Jobling MA, Tyler-Smith C: The human Y chromosome: an evolutionary marker comes of age. Nat Rev Genet 4:598, 2003.
Kandeel FR, Koussa VK, Swerdloff RS: Male sexual function and its disorders: physiology, pathophysiology, clinical investigation, and treatment. Endocr Rev 22:342, 2001.
Lahn BT, Pearson NM, Jegalian K: The human Y chromosome, in the light of evolution. Nat Rev Genet 2:207,2001.
Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E: Klinefelter's syndrome. Lancet 364:273, 2004.
Liu PY, Death AK, Handelsman DJ: Androgens and cardiovascular disease. Endocr Rev 24:313, 2003.
Nelson WG, De Marzo AM, Isaacs WB: Prostate cancer. N Engl J Med 349:366, 2003.
Nelson PS, Montgomery B: Unconventional therapy for prostate cancer: good, bad or questionable? Nat Rev Cancer 3:845, 2003.
O'Donnell L, Robertson KM, Jones ME, Simpson ER: Estrogen and spermatogenesis. Endocr Rev 22:289, 2001.
Plant TM, Marshall GR: The functional significance of FSH in spermatogenesis and the control of its secretion in male primates. Endocr Rev 22:764, 2001.
Reckelhoff JF: Gender differences in the regulation of blood pressure. Hypertension 37:1199, 2001.
Rhoden EL, Morgentaler A: Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 350:482, 2004.
Riggs BL, Khosla S, Melton LJ 3rd: Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 23:279, 2002.
Shabsigh R, Anastasiadis AG: Erectile dysfunction. Annu Rev Med 54:153, 2003.
Simonneaux V, Ribelayga C: Generation of the melatonin endocrine message in mammals: a review of the complex regulation of melatonin synthesis by norepinephrine, peptides, and other pineal transmitters. Pharmacol Rev 55:325, 2003.
Was this article helpful?
Who Else Wants To Sleep From Lights Out 'Til Sunrise Without Staring At The Ceiling For Hours Leaving You Feeling Fresh And Ready To Face A New Day You know you should be asleep. You've dedicated the last three hours in the dark to trying to get some sleep. But you're wide awake.