sex hormones Reproduction in both sexes is ultimately controlled by a hierarchy of hormonal secretions form three sites: the hypothalamus (in the brain), the pituitary gland, and the gonads (the testes or ovaries). The gonads require hormones from ‘higher’ sites to initiate and maintain their activity, and these are known as gonadotrophins. (Trophin, from the Greek, means something that nourishes — not strictly appropriate, except in the broad sense of maintaining the healthy function of the gonads.)

The sequence is this: neurons in the hypothalamus secrete gonadotrophin-releasing hormone (GnRH), which is transported through local blood capillaries to the nearby anterior lobe of the pituitary gland. Here GnRH stimulates the cells which synthesize and release the pituitary gonadotrophins — luteinizing hormone (LH) and follicle stimulating hormone (FSH). LH and FSH are secreted into the circulating blood and transported to the ovaries or testes, where they stimulate the production of the steroid hormones specific to each sex — oestrogen and progesterone, or testosterone. The gonadotrophic hormones and the gonads' own steroid hormones act together to maintain the prime function of the gonads: the production of mature eggs (ova) or sperm. The whole cascade of hormone secretions, from the hypothalamus to the anterior pituitary gland to the gonads, is tightly controlled by feedback effects of the gonadal steroids, which in turn act on both the hypothalamus and the pituitary gland to regulate the secretion of GnRH and of gonadotrophins. In the male these feedback effects are always negative. This means that when secretion of the male hormone, testosterone, increases, the release of GnRH and LH will decrease — inhibited by the rising level of testosterone in the blood. Conversely, when testosterone secretion declines, the hypothalamic and pituitary secretions increase (Fig. 1). Similar negative feedback effects are seen with the female hormones, oestrogen and progesterone. However, in females a unique event in the control of hormone secretions occurs just before ovulation. In the ovary, oestrogen production by the cells surrounding the maturing eggs reaches a peak, and the rise of oestrogen level in the blood exerts a positive feedback effect: there is an increase in both the release of GnRH and the responsiveness of the pituitary gland to GnRH. The result is a huge surge of LH secretion, and a smaller surge of FSH secretion from the pituitary gland; a few hours later the egg bursts from a mature ovarian follicle — the phenomenon of ovulation.

GnRH and the pituitary gonadotrophins are the same in both males and females. (The names used for the gonadotrophins (LH and FSH) refer to the female: ‘luteinizing’ and ‘follicle stimulating’ are their actions in the ovary. Identical hormones were found to exist also in the male, but the names have persisted.) It is the different steroid hormones secreted by the gonads themselves which are important not only in controlling their own function but also for the development and maintenance of sexual characteristics in the rest of the body.

The major hormone secretions of the ovaries and testes are steroid hormones, which are all synthesized from the same precursor — cholesterol. Cholesterol is derived from animal fats in the diet, and reaches the gonads in the circulating blood, where it is bound to low density lipoproteins (LDLs). The LDL-cholesterol complexes are taken up by the gonads and broken down there to release free cholesterol. Alternatively, cholesterol can be synthesized within the gonads themselves from its percursor molecule, acetate; this is the preferred pathway for generating cholesterol in the testis, but not in the ovary. The synthesis of steroid hormones involves many chemical steps from cholesterol to finished product. In both sexes, molecules related to progesterone (progestogens) are formed first; androgens — male-type steroids — follow, and these give rise to testosterone and also to the oestrogens. The production of the appropriate end products depends on the presence of different enzymes in the respective gonads (Fig. 2). So there is a common chemical pathway through which both male hormones (androgens) and female hormones (progestogens and oestrogens) are synthesized, but the relative proportions of these different ‘male’ and ‘female’ hormones produced within the gonads depend on whether the process is occuring in a testis or an ovary. Testosterone is the major steroid synthesized in the testis, with much smaller amounts of oestrogens, while oestrogen and progesterone predominate in the ovary with lesser amounts of androgens.

In the testes

Testosterone is synthesized by the interstitial, or Leydig, cells, which lie between the seminiferous tubules, under the stimulating influence of LH. In adults testosterone diffuses into the tubules and, together with FSH, helps to maintain spermatogenesis; also, via the circulating blood, it exerts negative feedback effects on the hypothalamus and pituitary gland, inhibiting gonadotrophin release — signalling that stimulation of more testosterone production is unecessary. In the fetal testis, testosterone production is responsible for the virilization of the male reproductive tract. At puberty an increase in testosterone secretion stimulates the changes associated with sexual maturation, including growth, pubic hair development, genital enlargement, and the breaking voice. For these generalized effects to take place, it is necessary for the ‘target’ cells, to which the circulating hormone attaches, to possess a particular enzyme which converts testosterone itself into a closely related, but crucially different steroid molecule — DHT (5α-dihydrotestosterone). When this enzyme is missing, a rare condition known as testicular feminization occurs: a male has the external appearance of a female.

In the ovaries

Steroid synthesis here is more complicated. Whereas the testis requires only LH stimulation the ovary requires the actions of both LH and FSH for the production of progesterone and oestrogen. The two gonadotrophins act on two different cell types (the thecal and the granulosa cells of the developing ovum-containing follicles). Once follicles becomes sensitive to the gonadotrophins, the outer thecal cells respond to LH and synthesize progesterone and androgens. The androgens then diffuse into the inner granulosa cell layer and here, under the influence of FSH, they are converted to oestrogens. Then, at mid-cycle, the single dominant follicle that is destined to release a mature egg develops receptors for LH in the granulosa cell layer, and the action of LH (in its ‘surge’ of secretion described above) precipitates ovulation. After ovulation the empty follicle is ‘luteinized’ — turns yellowish — it becomes a corpus luteum, secreting predominantly progesterone and some oestrogen under the influence of the gonadotrophins, until the next menstrual cycle begins.

Like testosterone secreted by the testes, the oestrogen and progesterone which the ovaries secrete not only act within the ovaries themselves to stimulate their function, but also enter the circulation to exert feedback effects on the hypothalamus and pituitary gland and to act on other target organs including the uterus, vagina, and breasts. However, unlike testosterone, which plays such a crucial role in the fetal development of the male reproductive system, the ovarian hormones have little if any effect on the fetal differentiation of the female reproductive system: this simply occurs in the absence of the male hormone. The female sex hormones do, however, become important later during puberty for growth of the breasts, changes in body shape and composition, and other characteristic physical changes. After the menopause the ovaries no longer produce sex hormones, although the cortex of the adrenal gland does produce small amounts of androgens. These can be converted to oestrogens, and are thus an important source of oestrogens in post-menopausal women, but they are not produced in sufficient amounts to replace the loss of oestrogen secretions from the ovary.

It is becoming clear that oestrogens, and to a lesser extent progestogens, have important effects on a variety of body functions apparently unrelated to reproduction. Thus, changes in the secretion of oestrogens and progestogens (occurring during the menstrual cycle, during pregnancy, and after the menopause) can, for example, influence mood, metabolism, bone structure, and cardiovascular and immune function, and can cause water retention and breast tenderness.

Aside from the steroid hormones, the gonads also produce a wide range of protein and peptide hormones, which may simply act as local regulatory hormones, such as growth factors, within the gonads themselves or may circulate in the blood and influence pituitary gonadotrophin secretion; one such is ‘inhibin’, from the testis, which can depress FSH secretion.

Synthetic sex hormones are widely used for contraception and hormone replacement therapy. Oestrogens may also be prescribed to suppress lactation and as a palliative measure in cancer of the breast or prostate, and progestogens for menstrual problems and for habitual abortion.

Saffron Whitehead

Sex hormones

Sex hormones are steroids (fat soluble compounds) that control sexual maturity and reproduction. These hormones are produced mainly by the endocrine glands. The endocrine glands in females are ovaries and those in males are testes. While both males and females have all types of hormones present in their bodies, females produce the majority of two types of hormones, estrogens and progesterone, while males produce mainly androgens such as testosterone. Most androgens produced by females are converted to estrogens and some androgens in males are also converted to estrogens. Sex hormones are synthesized from cholesterol (a fatty acid) and other compounds and secreted throughout a person's lifetime at different levels. Their production increases at puberty and normally decreases in old age.

Hormone Production

The production of hormones is a complex process. At puberty, the brain's hypothalamus gland produces increased amounts of gonadotropin-releasing hormone. This hormone stimulates the nearby pituitary gland to release two other hormones: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Finally, these two hormones signal the sex glands (gonads) to produce the sex hormones.

Female Reproductive Cycle

Females produce three estrogens: estradiol, estriol, and estrone. These estrogens stimulate growth of the ovaries and begin preparing the uterus for pregnancy. Estrogens also control the body's secondary sex characteristics, including breast and pelvic development and the distribution of fat and muscle. Progesterone maintains uterine conditions during pregnancy. It also acts on the central nervous system in a way that isn't yet understood.

During the monthly reproductive cycle, FSH stimulates growth of an ovarian body called the graafian follicle. The follicle encloses the egg. LH aids in the rupture of the follicle, sending the egg to the fallopian tubes. LH also promotes growth of the corpus luteum (a yellow, progesterone-secreting mass of cells that forms from an ovarian follicle after the release of a mature egg) as the ovary prepares to release the egg into the uterus.

If no pregnancy occurs within 10-12 days, the corpus luteum withers and the uterus sheds the blood supply that was formed to nourish a fetus. This shedding of the uterine lining and blood supply is called menstruation (the period). The production of estrogens and progesterone drops dramatically, and the cycle begins again.

Male Reproduction

In males, LH stimulates the development of the testes. The testes produce the androgens testosterone and androsterone. When FSH activates the testes' sperm-forming cells, testosterone maintains the process of forming sperm. This is the ten-week process results in sperm constantly ready for release by ejaculation from the penis. The androgens also promote the secondary sex characteristics of muscle growth, lowered voice range, the Adam's apple, and increased body hair.

History

Sex hormones were studied intensively during the 1920s. Discovery of their steroid structure and relationship to other steroids was the key to their isolation and synthesis. The first breakthroughs came in 1929 with the female hormones. American biochemist Edward Doisy (1893-1986) isolated a crystalline form of estrone. Five years later, German biochemist Adolf Butenandt (1903-) and his colleagues isolated progesterone.

In 1931, American biochemists H. L. Fevold, F. L. Hisaw, and S. L. Leonard discovered luteinizing hormone (LH) and follicle-stimulating hormone (FSH). That same year, Butenandt and Kurt Tscherning isolated the male hormones. In further male hormone developments, Swiss biochemist Leopold Ruzicka (1887-1976) soon determined the structure of testosterone. In 1934, Ruzicka partly synthesized androsterone from cholesterol, after proposing its structure. This was the first synthesis of a sex hormone and the first proof of the relationship between cholesterol and sex hormones.

Butenandt's group also showed that the sex hormones were related to cholesterol and bile acids, and in 1939 converted cholesterol into progesterone. For their work in demonstrating the structure of steroids, including the sex hormones, Ruzicka and Butenandt shared the 1939 Nobel Prize in chemistry.

Commercial Synthesis

Commercial synthesis came next. In the 1930s, Austrian chemists were synthesizing male and female hormones from soybean sterols (cholesterol-like substances). This process was expensive because it was hard to separate the sterols from each other. American chemist Percy Julian (1899-1975) discovered a much easier way to separate sterols, which permitted inexpensive synthesis of both progesterone and testosterone. American chemist Carl Djerassi (1923-) is also noted for synthesizing estrone and estradiol (estrogens) from plant materials.

Medical Uses of Hormones

In 1941 American surgeon Charles Huggins (1901-) was the first researcher to use chemotherapy (the chemical treatment of disease). Huggins treated prostate cancer with female sex hormones. For his work, he received the 1966 Nobel Prize in medicine. Today both male and female hormones are used to treat many kinds of cancer. Estrogen is also administered to treat menopause-related conditions and osteoporosis (the loss of bone calcium).

In addition to its use in the treatment of cancer, testosterone is administered by injection to treat men's sexual dysfunctions, such as impotence (inability to have an erection) and low sperm counts.

A synthetic progesterone called progestin was used in the first female oral contraceptive (birth control pill). The pill was developed by Americans Gregory Pincus (1903-1967), Min-Chueh Chang (1908-), and John Rock (1890-1984). Today a variety of pills containing varying amounts of progesterone and estrogen are available by prescription.

[See also Birth control ; Hormone ; Pincus, Gregory ; Steroids ]

sex hormones Chemical ‘messengers’ secreted by the gonads (testes and ovaries). They regulate sexual development and reproductive activity and influence sexual behaviour. In males, they include testosterone, made by the testes; in females, the sex hormones oestrogen and progesterone are produced by the ovaries.

hormones, sex Male hormones, or androgens, include testosterone, dihydrotestosterone and androsterone; female hormones include progesterone and the oestrogens (oestradiol and oestrone). Chemically, all are steroids, derived from cholesterol.

sex hormones Steroid hormones that control sexual development. The most important are the androgens and oestrogens.