Endocrine Regulation of Reproduction

The functions of the testes and ovaries are regulated by gonadotropic hormones secreted by the anterior pituitary. The gonadotropic hormones stimulate the gonads to secrete their sex steroid hormones, and these steroid hormones, in turn, have an inhibitory effect on the secretion of the gonadotropic hormones. This interaction between the anterior pituitary and the gonads forms a negative feedback loop.

The embryonic testes during the first trimester of pregnancy are active endocrine glands, secreting the high amounts of testosterone needed to masculinize the male embryo's external genitalia and accessory sex organs. Ovaries, by contrast, do not mature until the third trimester of pregnancy. Testosterone secretion in the male fetus declines during the second trimester of pregnancy, however, so that the gonads of both sexes are relatively inactive at the time of birth.

Before puberty, there are equally low blood concentrations of sex steroids—androgens and estrogens—in both males and females. Apparently, this is not due to deficiencies in the ability of the gonads to produce these hormones, but rather to lack of sufficient stimulation. During puberty, the gonads secrete increased amounts of sex steroid hormones as a result of increased stimulation by gonadotropic hormones from the anterior pituitary.

Interactions Between the Hypothalamus, Pituitary Gland, and Gonads

The anterior pituitary produces and secretes two gonadotropic hormones—FSH (follicle-stimulating hormone) and LH (luteinizing hormone). Although these two hormones are named according to their actions in the female, the same hormones are secreted by the male's pituitary gland. The go-nadotropic hormones of both sexes have three primary effects on the gonads: (1) stimulation of spermatogenesis or oogenesis (formation of sperm or ova); (2) stimulation of gonadal hormone secretion; and (3) maintenance of the structure of the gonads (the gonads atrophy if the pituitary gland is removed).

The secretion of both LH and FSH from the anterior pituitary is stimulated by a hormone produced by the hypothalamus and secreted into the hypothalamo-hypophyseal portal vessels (chapter 11). This releasing hormone is sometimes called LHRH (luteinizing hormone-releasing hormone). Since attempts to find a separate FSH-releasing hormone have thus far failed, and since LHRH stimulates FSH as well as LH secretion, LHRH is often referred to as gonadotropin-releasing hormone (GnRH).

If a male or female animal is castrated (has its gonads surgically removed), the secretion of FSH and LH increases to much higher levels than in the intact animal. This demonstrates

Test Yourself Before You Continue

1. Define the terms diploid and haploid, and explain how the chromosomal sex of an individual is determined.

2. Explain how the chromosomal sex determines whether testes or ovaries will be formed.

3. List the male and female accessory sex organs and explain how the development of one or the other set of organs is determined.

4. Describe the abnormalities characteristic of testicular feminization syndrome and of 5a-reductase deficiency and explain how these abnormalities are produced.

Clinical Investigation Clue

Remember that Gloria has normal secondary sexual characteristics and used to have regular periods. ■ Do you think it likely that Gloria may suffer from any of the problems in sexual development discussed in this section?

■ Figure 20.8 A simplified biosynthetic pathway for the steroid hormones. The sources of the sex hormones secreted in the blood are also indicated.

that the gonads secrete products that exert a negative feedback effect on gonadotropin secretion. This negative feedback is exerted in large part by sex steroids: estrogen and progesterone in the female, and testosterone in the male. A biosynthetic pathway for these steroids is shown in figure 20.8.

The negative feedback effects of steroid hormones occurs by means of two mechanisms: (1) inhibition of GnRH secretion from the hypothalamus and (2) inhibition of the pituitary's response to a given amount of GnRH. In addition to steroid hormones, the testes and ovaries secrete a polypeptide hormone called inhibin. Inhibin is secreted by the Sertoli cells of the seminiferous tubules in males and by the granulosa cells of the ovarian follicles in females. This hormone specifically inhibits the anterior pituitary's secretion of FSH without affecting the secretion of LH.

Figure 20.9 illustrates the process of gonadal regulation. Although hypothalamus-pituitary-gonad interactions are similar in males and females, there are important differences. Secretion of go-nadotropins and sex steroids is more or less constant in adult males. Secretion of gonadotropins and sex steroids in adult females, by contrast, shows cyclic variations (during the menstrual cycle). Also, during one phase of the female cycle—shortly before ovulation— estrogen exerts a positive feedback effect on LH secretion.

Studies have shown that secretion of GnRH from the hypothalamus is pulsatile rather than continuous, and thus the secretion of FSH and LH follows this pulsatile pattern. This pulsatile secretion is needed to prevent desensitization and downregulation of the target glands (discussed in chapter 11). It appears that the frequency of the pulses of secretion, as well as their amplitude (how much hormone is secreted per pulse), affects the target gland's response to the hormone. For example, it has been proposed that a slow frequency of GnRH pulses in women preferentially stimulates FSH secretion, while faster pulses of GnRH favor LH secretion.

Hypothalamus

GnRH

Anterior pituitary

Gonadotropins

Inhibin

Sex steroids

Gonads

Gametes (sperm or ova)

■ Figure 20.9 Interactions between the hypothalamus, anterior pituitary, and gonads. Sex steroids secreted by the gonads have a negative feedback effect on the secretion of GnRH (gonadotropin-releasing hormone) and on the secretion of gonadotropins. The gonads may also secrete a polypeptide hormone called inhibin that functions in the negative feedback control of FSH secretion.

If a powerful synthetic analogue of GnRH (such as na-farelin) is administered, the anterior pituitary first increases and then decreases its secretion of FSH and LH. This decrease, which is contrary to the normal stimulatory action of GnRH, is due to a desensitization of the anterior pituitary evoked by continuous exposure to GnRH. The decrease in LH causes a fall in testosterone secretion from the testes, or of estradiol secretion from the ovaries. The decreased testosterone secretion is useful in the treatment of men with benign prostatic hyperplasia. In this condition, common in men over the age of 60, testosterone supports abnormal growth of the prostate. The fall in estradiol secretion in women given synthetic GnRH analogues can be useful in the treatment of endometrio-sis. In this condition, ectopic endometrial tissue from the uterus (dependent on estradiol for growth) is found growing outside the uterus—for example, on the ovaries or on the peritoneum. These treatments illustrate the reasons why GnRH and the go-nadotropins are normally secreted in a pulsatile fashion, and are particularly beneficial clinically because they are reversible.

The Onset of Puberty

Secretion of FSH and LH is high in the newborn, but falls to very low levels a few weeks after birth. Gonadotropin secretion remains low until the beginning of puberty, which is marked by rising levels of FSH followed by LH secretion. Experimental

642 Chapter Twenty

Table 20.2 Development of Secondary Sex Characteristics and Other Changes That Occur During Puberty in Girls

Characteristic

Age of First Appearance

Hormonal Stimulation

Appearance of breast buds

8-13

Estrogen, progesterone, growth hormone, thyroxine, insulin, cortisol

Pubic hair

8-14

Adrenal androgens

Menarche (first menstrual flow) Axillary (underarm) hair Eccrine sweat glands and sebaceous glands; acne (from blocked sebaceous glands)

10-16

About 2 years after the appearance of pubic hair About the same time as axillary hair growth

Estrogen and progesterone Adrenal androgens Adrenal androgens

Table 20.3 Development of Secondary Sex Characteristics and Other Changes That Occur During Puberty in Boys

Table 20.3 Development of Secondary Sex Characteristics and Other Changes That Occur During Puberty in Boys

Age of First Appearance

Characteristic

Hormonal Stimulation

Growth of testes Pubic hair Body growth Growth of penis Growth of larynx (voice lowers) Facial and axillary (underarm) hair Eccrine sweat glands and sebaceous glands; acne (from blocked sebaceous glands)

10-14

10-15

11-16 11-15

Same time as growth of penis About 2 years after the appearance of pubic hair About the same time as facial and axillary hair growth

Testosterone, FSH, growth hormone Testosterone

Testosterone, growth hormone

Testosterone

Testosterone

Testosterone

Testosterone evidence suggests that this rise in gonadotropin secretion is a result of two processes: (1) maturational changes in the brain that result in increased GnRH secretion by the hypothalamus and (2) decreased sensitivity of gonadotropin secretion to the negative feedback effects of sex steroid hormones.

The maturation of the brain that leads to increased GnRH secretion at the time of puberty appears to be programmed— children without gonads show increased FSH secretion at the normal time. Also during this period of time, a given amount of sex steroids has less of a suppressive effect on gonadotropin secretion than the same dose would have if administered prior to puberty. This suggests that the sensitivity of the hypothalamus and the pituitary to negative feedback effects decreases at puberty, which would also help to account for rising gonadotropin secretion at this time.

During late puberty there is a pulsatile secretion of gonadotropins—FSH and LH secretion increase during periods of sleep and decrease during periods of wakefulness. These pulses of increased gonadotropin secretion during puberty stimulate a rise in sex steroid secretion from the gonads. Increased secretion of testosterone from the testes and of estradiol-170 (estradiol is the major estrogen, or female sex steroid) from the ovaries during puberty, in turn, produces changes in body characteristic of the two sexes. Such secondary sex characteristics (tables 20.2 and 20.3) are the physical manifestations of the hormonal changes occurring during puberty. These changes are accompanied by a growth spurt, which begins at an earlier age in girls than in boys (fig. 20.10).

The age at which puberty begins is related to the amount of body fat and level of physical activity of the child. The aver-

10 12 14

Age (years)

■ Figure 20.10 Growth as a function of sex and age. Notice that the growth spurt during puberty occurs at an earlier age in females than in males.

age age of menarche—the first menstrual flow—is later (age 15) in girls who are very active physically than in the general population (age 12.6). This appears to be due to a requirement for a minimum percentage of body fat for menstruation to begin; this may represent a mechanism favored by natural selection to ensure that a woman can successfully complete a pregnancy and nurse the baby. Recent evidence suggests that the secretion of leptin from adipocytes (chapter 19) is required for puberty. Later in life, women who are very lean and physically active may

Reproduction have irregular cycles and amenorrhea (cessation of menstruation). This may also be related to the percentage of body fat. However, there is also evidence that physical exercise may act to inhibit GnRH and gonadotropin secretion.

Clinical Investigation Clue

Remember that Gloria has normal secondary sexual development and used to have regular periods. ■ Could her low body weight and strenuous exercise be responsible for her symptoms? How?

Pineal Gland

The role of the pineal gland in human physiology is poorly understood. It is known that the pineal, a gland located deep within the brain, secretes the hormone melatonin as a derivative of the amino acid tryptophan (fig. 20.11) and that production of this hormone is influenced by light-dark cycles.

The pineal glands of some vertebrates have photoreceptors that are directly sensitive to environmental light. Although no such photoreceptors are present in the pineal glands of mammals, the secretion of melatonin has been shown to increase at night and decrease during daylight. The inhibitory effect of light on melatonin secretion in mammals is indirect. Pineal secretion is stimulated by postganglionic sympathetic neurons that originate in the superior cervical ganglion; activity of these neurons, in turn, is inhibited by nerve tracts that are activated by light striking the retina. The physiology of the pineal gland was discussed in chapter 11 (see fig. 11.32).

There is abundant experimental evidence that melatonin can inhibit gonadotropin secretion and thus have an "antigo-nad" effect in many vertebrates. However, the role of mela-tonin in the regulation of human reproduction has not yet been clearly established.

The Human Sexual Response

The sexual response, similar in both sexes, is often divided into four phases: excitation, plateau, orgasm, and resolution. The excitation phase, also known as arousal, is characterized by myo-tonia (increased muscle tone) and vasocongestion (the engorgement of a sexual organ with blood). This results in erection of the nipples in both sexes, although the effect is more intense and evident in females than in males. The clitoris swells (analogous to erection of the penis), and the labia minora swell to more than twice their previous size. Vasocongestion of the vagina leads to secretion of fluid, producing vaginal lubrication. Vasocongestion also causes considerable enlargement of the uterus, and in women who have not breast-fed a baby the breasts may enlarge as well.

During the plateau phase, the clitoris becomes partially hidden behind the labia minora because of the continued engorgement of the labia with blood. Similarly, the erected nipples become partially hidden by continued swelling of the areolae

■ Figure 20.11 A simplified biosynthetic pathway for melatonin.

Secretion of melatonin by the pineal gland follows a circadian (daily) rhythm tied to daily and seasonal changes in light.

(pigmented areas surrounding the nipples). Pronounced engorgement of the outer third of the vagina produces what Masters and Johnson, two scientists who performed pioneering studies of the human sexual response, called the "orgasmic platform."

In orgasm, which lasts only a few seconds, the uterus and orgasmic platform of the vagina contract several times. This is analogous to the contractions that accompany ejaculation in a male. Orgasm is followed by the resolution phase, in which the body returns to preexcitation conditions. Men, but not women, immediately enter a refractory period following orgasm, during which time they may produce an erection but are not able to ejaculate. Women, by contrast, lack a refractory period and are thus capable of multiple orgasms.

Test Yourself Before You Continue

1. Using a flow diagram, show the negative feedback control that the gonads exert on GnRH and gonadotropin secretion. Explain the effects of castration on FSH and LH secretion and the effects of removal of the pituitary on the structure of the gonads and accessory sex organs.

2. Explain the significance of the pulsatile secretion of GnRH and the gonadotropic hormones.

3. Describe the two mechanisms that have been proposed to explain the rise in sex steroid secretion that occurs at puberty. Explain the possible effects of body fat and intense exercise on the timing of puberty.

4. Describe the effect of light on the pineal secretion of melatonin and discuss the possible role of melatonin in reproduction.

5. Compare the phases of the sexual response in males and females.

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