sexology

HORMONES: THE ENDOCRINE SYSTEM

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Fetal Sexual Development
Hormonal Control of Sexual Maturation
Gonadal Steroids and Sexual Maturation
Male Reproductive Function
Female Reproductive Function

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From the moment of conception to maturity, sexual development depends on a complex interaction of genetic and dynamic hormonal interrelationships that regulate hypothalamic, pituitary, and gonadal function. The development of neuroendocrine function in relation to growth and sexual maturation of both the female and the male throughout the life cycle is covered here. This discussion focuses on the normal patterns; the various changes, abnormalities, problems, and treatment modalities involving the neuroendocrine system are covered under such topics as castration, compulsion, gender, infertility, impotence, menopause, menstruation, pheromones, physical disabilities, pregnancy, and transsexualism.

Fetal Sexual Development

The sequence of embryonic and physiologic changes that control the sexual differentiation of the fetus begins with fertilization. The sex of the embryo is genetically determined at the instant of fertilization, with the XX karyotype conferring female sex and the XY karyotype conferring male sex.

The embryo has indifferent gonads that can become either testes or ovaries. In the absence of a Y chromosome, the indifferent gonads differentiate into ovaries nine to ten weeks after conception. At about 18 to 20 weeks, the internal and external female genitalia develop, establishing female genital sex. The presence of the Y chromosome causes the indifferent gonads to differentiate into testes at six to eight weeks. Shortly afterwards, testicular Leydig cells begin to secrete testosterone, which stimulates the development of internal and external male genitalia, establishing male genital sex.

In the human fetus of either sex, the fetal gonad is affected by three gonadotropins: placental chorionic gonadotropin (hCG) early in gestation, and later by follicle stimulating hormone (FSH) and luteinizing hormone (LH), both secreted by the fetal pituitary. Fetal serum hCG peaks around the tenth week of gestation and stimulates testosterone secretion by the testes of the male fetus. Unlike the testis, the fetal ovary is only minimally affected by the early appearance of hCG. Growth and function of the fetal ovary is more dependent on the later appearance of the pituitary gonadotropins.

Hormonal Control of Sexual Maturation

The hormonal relationship of the hypothalamic-pituitary-gonadal axis becomes established by two years of age in either sex, functioning quietly until the onset of puberty. In childhood, the negative-feedback response of this axis is extremely sensitive to the small amounts of circulating gonadal steroids, contributing to the low levels of gonadotropins secreted from the pituitary.

Adolescence generally refers to the time between the onset of puberty and the completion of physical maturation. During adolescence, maturation of the gonads is accompanied by accelerated growth, development of secondary sex characteristics, and attainment of reproductive capability manifested by spermatogenesis in the male and ovulation in the female. In anticipation of the onset of puberty, serum concentrations of pituitary FSH rise between the ages of 6 and 8, and at approximately 10 years of age there follows an increase in the secretion of LH by the anterior pituitary. The secretions of LH and FSH are believed to be controlled via the hypothalamus by a single gonadotropin releasing hormone (GnRH). The elevated serum levels of LH and FSH stimulate the growth of the gonads to their adult size, stimulate gametogenesis, and greatly increase the secretion of gonadal steroids. The gonadal-steroid secretion initiates the first physical signs of sexual maturation with development of secondary sexual characteristics. In the female, this includes breast development (thelarche), pubic hair growth (pubarche), axillary hair growth (which usually follows pubarche), somatic growth acceleration, and finally the menarche, or initiation of menses. In the male, a deepening voice; pubic, axillary, and facial hair growth, testicular and phallic enlargement; and somatic growth acceleration indicate sexual maturation. This process generally begins between the ages of 8 and 13 in females, and occurs about two years later in males, with full development over a three-year period. The order of appearance of pubertal features varies greatly among individuals.

In women, release of the gonadotropins occurs on a cyclical basis, creating the reproductive or menstrual cycle. In men, the release is relatively steady, although there are a number of pulses of gonadotropin release in a 24-hour period.

Gonadal Steroids and Sexual Maturation

In females, there are two major reproductive steroids, estradiol (an estrogen) and progesterone (a progestin). The most frequent first sign of female sexual maturation is breast budding, which occurs in response to the increased pubertal levels of estrogen. Both the mammary glands and the adipose tissue of the breast are stimulated to increase in size by estrogen. Increases in body fat and its characteristic deposition, a broader pelvis, and a shorter period of growth of long bones are also effects of estrogen. Progesterone is primarily involved in the menstrual cycle, which is discussed later on.

The major steroid secreted in males is testosterone, although the testes also secrete small amounts of estrogen. Testosterone is responsible for the development of male secondary sexual characteristics. Testosterone helps to initiate the growth spurt of male adolescence and also ultimately ends that growth spurt by stimulating closure of the epiphyses of the long bones. It causes enlargement of the larynx, which deepens the male voice, generally coinciding with the growth spurt. Testicular enlargement occurs, followed by phallic enlargement 12 to 18 months later. Testosterone stimulates growth of muscles and is probably responsible for the higher hematocrit level of men. Gynecomastia, or development of breast tissue, is a normal male response during early puberty, probably due to the higher ratio of estrogen to testosterone secreted by the testes during early and mid-puberty. Testosterone stimulates the growth of facial, body, and pubic hair, and it is a contributing factor in male pattern baldness. It is also required for spermatogenesis and plays an important role in the establishment of sexual interest, or libido.

The adrenal cortex of both sexes also produces small amounts of androgen as a by-product of synthesis of aldosterone and cortisol. The major androgen produced is dehydroepiandrosterone (DHEA). Although a weaker androgen than testosterone, DHEA plays an important role in female sexual development. This adrenal androgen is primarily responsible for the growth of pubic and axillary hair in women and also contributes to the female adolescent growth spurt. DHEA, along with a small amount of androgen secreted by the ovaries, also appears to be responsible for female libido, rather than the "female" sex hormones estrogen and progesterone.

Male Reproductive Function

In the male, the hypothalamus secretes gonadotropin releasing hormone in pulsatile bursts throughout the day. One effect of GnRH is to stimulate the pituitary to increase secretion of the gonadotropins FSH and LH. Pituitary FSH controls spermatogenesis, which occurs in the Sertoli cells. Inhibin is then selected by the Sertoli cells, exerting a negative-feedback control and diminishing the amount of FSH released by the pituitary.

Biosynthesis and secretion of testosterone, the primary male androgen, are carried out by the Leydig (interstitial) cells. Pituitary LH is primarily responsible for stimulating the Leydig cells' secretion of testosterone. Testosterone then acts as an inhibitor of both GnRH secretion from the hypothalamus and LH secretion from the pituitary, another example of a hormonal negative-feedback loop.

Levels of testosterone rise throughout puberty and reach their maximum value by about the age of 20. These relatively high testosterone levels are maintained until the fourth decade, when they begin a gradual decline. The degree of decrease in testosterone levels varies widely from one individual to the next. This decreasing level of testosterone is often compared to the menopausal period of female development.

As testosterone levels decrease, so too does their negative-feedback inhibition on both the hypothalamus and pituitary. This creates a coincidental rise in gonadotropin levels in an effort to stimulate the aging testes to produce more testosterone. In response to diminishing levels of testosterone, target tissues up-regulate their testosterone receptors, cushioning the effects of the lowered levels of androgen. This promotes maintenance of functioning of accessory structures and also helps maintain a level of sexual interest. Spermatogenesis, which is mostly independent of testicular function and levels of testosterone, continues throughout the male life span following puberty.

Female Reproductive Function

The ovaries of the sexually mature female undergo regular cycles, beginning with maturation and ovulation of a follicle. A period of time follows during which hormones secreted by the remnant of the ovulated follicle create a uterine environment receptive to implantation of an embryo. The maturing follicle also functions as an endocrine organ, secreting estradiol, the main source of estrogen in women who are not pregnant. During ovulation, the mature follicle bursts, releasing an ovum into the body cavity, from which it is swept by the fimbriae into a Fallopian tube, where it may be fertilized.

As a follicle matures, it becomes an active endocrine tissue. Just as in the male reproductive system, the hypothalamus secretes GnRH, stimulating the anterior pituitary to secrete both LH and FSH. Both LH and FSH are needed for ovarian cycles. LH stimulates the thecal cells of the mature follicle to supply the granulosa cells of the follicle with androgen, which is converted by the granulosa cells to estradiol and secreted into the blood. Granulosa cells also secrete inhibin, which acts in a negative-feedback relationship as an inhibitor of anterior pituitary release of FSH. LH secretion is not affected by inhibin. Estradiol is responsible for the regulation of LH levels by a negative-feedback loop involving both the hypothalamus and the anterior pituitary. LH secretion does not always behave as if it were regulated by negative feedback, however; the surge of LH that causes ovulation occurs even though estradiol levels are rising. This surge can be explained by the fact that the anterior pituitary responds differently to rising levels of estradiol than it does to moderate, nonfluctuating levels. At moderate, steady levels of estradiol, the anterior pituitary predominantly shuts off its LH secretion by means of negative feedback. When estradiol levels rise rapidly to high levels, as they do during the follicular phase, the pituitary is actually stimulated to secrete a surge of LH.

In the final stage of follicular maturation, the follicle is called a graafian follicle and visibly bulges from the surface of the ovary. Occasionally, more than one graafian follicle is matured and ovulated. If both are fertilized, this multiple ovulation may lead to fraternal twins. Fraternal twins are genetically different and may be of different sexes.

The surge of LH that follows the rise in estrogen level at this time is coupled with a smaller increase in FSH. The rise in FSH level is considerably smaller due to the continued effects of inhibin on the anterior pituitary. The ovum is released from the graafian follicle about 12 to 24 hours after LH has reached its peak concentration. This is called the ovulation phase of the menstrual cycle and occurs 14 days prior to the onset of menstruation.

The ovum is then swept up by fimbriae and carried toward the uterus by the ciliary activity and smooth-muscle contractions of the Fallopian tube. An ovum can be fertilized for only 10 to 12 hours after ovulation. Spermatozoa can survive for up to three days in the female reproductive tract, allowing for a relatively brief span of time in which fertilization can occur during each menstrual cycle.

The female endocrine system relating to pregnancy is a complex interaction of hormones secreted by the corpus luteum, placenta, uterus, and pituitary. The hormones of pregnancy, labor, and lactation include estrogen, progesterone, placental somatomammotropin, oxytocin, relaxin, and prolactin. (Hormones of pregnancy, labor, and lactation are not covered in this entry.)

Following ovulation, the remnant of the follicle becomes a secretory organ called the corpus luteum, which maintains the receptivity of the uterus to a pregnancy by secreting estrogen and progesterone. If pregnancy does not occur, the corpus luteum degenerates approximately 14 days later, and the resultant decrease in levels of estrogen and progesterone causes the uterine endometrium to be shed, initiating menstruation.

The average menstrual cycle lasts 28 days, with a normal range from 21 to 35 days. The first menstrual day is numbered as day 1 and marks the beginning of the follicular phase of the ovarian cycle. Ovulation, which occurs approximately on day 14 of the 28-day cycle, marks the transition from the follicular phase to the luteal phase of the ovarian cycle. During the luteal phase of the cycle, the presence of progesterone secreted by the corpus luteum modifies the responsiveness of the pituitary to the high levels of circulating estrogen, preventing recurrent surges of LH. During the luteal phase, the negative-feedback system again predominates, and LH and FSH remain at relatively low levels. The estrogen and progesterone secreted by the corpus luteum also interact to convert the uterine endometrium into a structure specialized to receive an embryo. The endometrium thickens and becomes a secretory organ, secreting uterine milk, a carbohydrate-rich fluid capable of nourishing the embryo until implantation in the uterine wall occurs.

It is not uncommon for ovulating women to complain of a complex of symptoms during the last week of the menstrual cycle. This symptom complex, known as premenstrual syndrome (PMS), does not occur in children, pregnant women, or anovulatory women. The symptoms may include breast tenderness, bloating, edema of the extremities, and mood swings. Symptoms abate with the onset of menstruation. No specific etiology for PMS has been found, although progesterone secreted by the corpus luteum is strongly suspected to play a significant role.

The cycles of estrogen and progesterone secretion by the ovaries continue throughout the woman's sexually mature years until the menopausal transition, which usually takes place between 45 and 55 years of age. Menopausal transition is characterized by longer cycles and irregular bleeding. These irregular cycles can persist for months or years before complete amenorrhea occurs. During this time, the ovaries undergo an obliterative endarteritis that leads to a reduction in ovarian size and the replacement of the secretory parenchyma with connective tissue. As the ovaries become less able to secrete steroids in response to gonadotropins, the negative-feedback loop disintegrates and gonadotropin levels rise. Thus, as with the testes, the effect of aging is seen at the ovaries rather than the pituitary or hypothalamus. As gonadotropin levels rise and estrogen levels decline, the woman may experience a variety of signs and symptoms of menopause, including sweating, hot flashes, and a reduction in the feminization that occurred at puberty, such as diminishing fat deposits and atrophy of the breast, vulva, and vagina. Prolonged estrogen deficiency is a risk factor for a decrease in bone calcification, leading to the development of osteoporosis. It is increasingly common for women of menopausal years to take estrogen and progesterone supplements to reduce the effects of the failing ovaries.