sex hormones

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

See also steroids.