Biosynthesis of Gonadal Steroids

As shown in Figure 34-1, pregnenolone is the precursor to progesterone. It is also the precursor to dehydroepiandrosterone and androstenedione (two androgens secreted by the adrenal gland and discussed in Chapter 33) and to testosterone (the major androgen in males). The adrenal and gonadal androgens are converted to estrogens by aromatase, an enzyme that forms the aromatic A-ring necessary for the selective high-affinity binding of estradiol, estrone, and estriol to estrogen receptors.

In females, ovarian thecal cells secrete small quantities of testosterone. In males, about 95% of testosterone is produced by Leydig cells in the testes, and the remainder is derived from the adrenal cortex. Testosterone is synthesized in the testes by the same pathways as in the ovaries. Testosterone is subsequently converted to dihydrotestosterone (DHT) by 5α-reductase in the prostate, hair follicles, and skin. In the plasma, testosterone is primarily bound to sex steroid–binding globulin. In the liver, it is converted to androstenedione and other metabolites, including sulfate and glucuronide conjugates. About 90% of these metabolites are excreted in the urine.

Although both testosterone and DHT activate androgen receptors, DHT has greater receptor affinity and forms a more stable receptor-ligand complex than testosterone. If DHT formation is inhibited, this significantly reduces androgenic stimulation of the prostate gland and hair follicles. The androgen receptor located in target cells interacts with response elements in target genes and thereby stimulates protein synthesis in the same manner as other gonadal steroids.

Physiologic Actions of Estrogens and Progesterone

In females, estrogens and progesterone have multiple actions and interactions that are necessary for reproductive activity. Estrogens are formed in the granulosa cells of the ovary, whereas progesterone is primarily produced by the corpus luteum in response to LH secretion. Estrogens promote the development and growth of the fallopian tubes, uterus, and vagina, as well as secondary sex characteristics such as breast development, skeletal growth, and axillary and pubic hair patterns.

The pattern of hormonal changes occurring during the menstrual cycle is depicted in Figure 34-2. During the follicular phase of the cycle, ovarian follicles are recruited and a dominant estrogen-secreting follicle develops. Estrogen levels gradually increase, whereas progesterone levels remain very low. A surge of LH is released at mid-cycle in response to positive estrogen feedback to the pituitary gland, and this LH surge triggers ovulation. During the luteal phase of the cycle, the follicle becomes the corpus luteum (“yellow body”) that secretes both estrogen and progesterone in response to LH. Together, these hormones prepare the uterus for implantation of a fertilized egg as the endometrium becomes more vascular and secretory. If pregnancy does not occur, the corpus luteum ceases to produce estrogen and progesterone, resulting in menstruation. If pregnancy occurs, the placenta produces human chorionic gonadotropin, which maintains the production of progesterone by the corpus luteum. After about 3 months, the placenta becomes the predominant source of progesterone. This hormone serves to maintain pregnancy and prevents endometrial sloughing and miscarriage.

Estrogens have a number of other actions that are important in reproduction and other bodily functions. They sensitize the myometrium to oxytocin at parturition, and this facilitates labor. They stimulate protein synthesis in the brain and may thereby affect mood and emotions. Estrogens influence the distribution of body fat and thereby contribute to the development of feminine body contours. They enhance blood coagulation by increasing the synthesis of clotting factors, and they prevent osteoporosis by inhibiting bone resorption. In males and females, estrogens are responsible for epiphyseal closure, which halts linear bone growth.

Estrogens and progestins have different effects on serum lipoprotein levels. Estrogens decrease the levels of low-density lipoprotein (LDL) cholesterol and lipoprotein (a) while increasing the levels of high-density lipoprotein (HDL) cholesterol. In contrast, progestins produce a dose-related increase in LDL levels and a decrease in HDL levels.

Progesterone and other progestins increase basal body temperature by 0.5° C to 0.8° C (1.0° F to 1.5° F) at ovulation and throughout the luteal phase. They also affect the emotional state and have mild mineralocorticoid (salt-retaining) properties. Some of the synthetic progestins have other effects that are attributed to their androgenic activity (see later).

Physiologic Actions of Testosterone

LH stimulates testosterone synthesis in Leydig cells, whereas FSH promotes spermatogenesis by Sertoli cells in the seminiferous tubules. These cells provide an environment rich in testosterone, which is necessary for germ cell development. Sertoli cells also produce a protein called inhibin, which acts in concert with DHT as a feedback regulator of FSH secretion by the pituitary.

Testosterone is responsible for the development of secondary sex characteristics in males during puberty. These include growth of the larynx, thickening of the vocal cords, and growth of facial, axillary, and pubic hair. In addition to stimulating growth of the penis, scrotum, seminal vesicles, and prostate gland, testosterone stimulates and maintains sexual function in males. Testosterone and other androgens also do the following: increase lean body mass; stimulate skeletal growth; accelerate epiphyseal closure; increase sebaceous gland activity and sebum production, thereby contributing to the development of acne in both sexes; increase the production of erythropoietin in the kidneys; and decrease the levels of HDL cholesterol.

Synthetic Progestins

Synthetic progestins are primarily used as oral contraceptives (see later), but they are also used to treat dysmenorrhea, endometriosis, and uterine bleeding in the same manner as the progesterone esters.

Most of the synthetic progestins are derivatives of nortestosterone (testosterone without a methyl group on carbon-19) and have varying degrees of estrogenic, antiestrogenic, and androgenic activity. Norgestrel has more androgenic activity than other progestins, whereas desogestrel and norgestimate have less androgenic and more progestational activity. Drospirenone is a spironolactone derivative with antiandrogenic effects. The synthetic progestins also contain molecular entities that increase their oral bioavailability and duration of action. Their half-lives range from 7 to 24 hours, whereas the half-life of progesterone is only about 5 minutes.

Hormone Replacement Therapy

Menopause refers to the cessation of menstruation that occurs in most women between the ages of 45 and 55. Before menopause, the supply of eggs in a woman’s ovaries declines and ovulation becomes irregular. The ovarian follicles fail to develop and secrete normal amounts of estrogen. When estrogen levels are no longer sufficient to suppress FSH secretion by the pituitary gland, FSH levels rise. When FSH levels are above 40 IU/L, a woman is said to be in menopause.

Although estrogens can be used alone for HRT in women who have had a hysterectomy, estrogen should be used in combination with a progestin for women with a uterus. This is because giving estrogen alone increases the risk of endometrial cancer in these women.