Female Reproduction Ovarian Steroids
Miss RB, a 24-year-old woman, presented to her GP complain- ing of increasing hair growth over her chin and face with greasy skin and acne. The hair growth had been present for 5 or 6 years but over the last 2 years had become much worse, such that she was shaving her chin three times a week and using a number of depilatory creams purchased at the chemists. On questioning she revealed that she had also noticed increased hair growth around her nipples, over her lower abdomen and on the lower part of her back. Her periods started when she was 12 years old but she had never had a regular cycle; her periods only occurred every 6–10 weeks and on one occasion she had missed her period for 4 months. She had always been ‘overweight’ but had gained 2 stones in weight over the last 2 years. Her mother had had irregular menses and had been treated for subfertility prior to conceiving RB. Her maternal grandmother had Type 2 diabetes mellitus. On examination RB was found to be obese with a body mass index of 32 kg/m ndrogendependent hirsutism and a Ferriman and Galwey score was found to be 16. The diagnosis of polycystic ovary syndrome was confirmed when subsequent biochemical investigations showed her to have a raised testosterone concentration of 3.2 nmol/L, LH 14.5 U/L, FSH 3.3 U/L and an ultrasound scan of the ovaries showed bilaterally enlarged ovaries with numerous peripherally sited follicles. After discussion she was treated with diet, exercise and the drug metformin, all of which lower insulin resistance and reduce ovarian androgen secretion. This combination resulted in improvement in the hirsutism and establishment of a more regular menstrual cycle.
Polycystic ovary syndrome is the commonest cause of hirsutism and irregular menstrual cycles. Patients have a long history, usually dating back to the menarche. It is important in the assessment of women with hirsutism to exclude those with a short history and features of virilization that might suggest androgen-secreting tumours of the ovary or adrenal glands.
Physiological actions of estrogens
The effects of the estrogens can be classified in chronological order of the major reproductive events of the female (Fig. 26a). Overall, their main influence is on the maintenance of fertility. Sexual differentiation. During fetal development, estrogens are not required for the normal differentiation and development of the female genitalia and accessory sex organs, but they are needed for sexual differentiation of the brain.
Puberty. During puberty (see Chapter 24), estrogens stimulate development of the breast stroma, endometrium, myometrium and vagina. Estrogens cause epiphyseal closure and characteristic fat deposition in peripheral tissues.
Adult. In the adult female, estrogens maintain the menstrual cycle and female secondary sexual characteristics. Estrogens facilitate the actions of progesterone by stimulating the synthesis of progesterone receptors, notably in the brain and uterus.
Pregnancy. During pregnancy, estrogens increase the blood flow to and through the uterus, they cause hypertrophy of the uterine myometrium and stimulate breast ductal proliferation. They enhance fluid retention and stimulate uterine progesterone receptor synthesis. Shortly before parturition (birth), estrogens stimulate the synthesis of oxytocin receptors in the uterus myo- metrium. Oxytocin is involved in parturition through its contractile action on the uterus (see Chapter 34).
Metabolic effects. Estrogen inhibits bone resorption, an action which becomes apparent after the menopause, when estrogen wanes. Estrogens decrease bowel motility. They affect liver function by stimulating protein synthesis, including that of sex hormone-binding globulin (SHBG) and thyroxine-binding globulin (see 13). Estrogens affect blood coagulability by stimulating the production of factors II, VII, IX, and X but decreasing platelet aggregation. They have important effects on plasma lipids, decreasing total cholesterol, increasing high-density lipoprotein (HDL) and decreasing low-density lipoprotein (LDL) concentrations.
Menopause marks the cessation of natural female reproductive life. The ovaries no longer produce ova, and the secretion of estrogens declines and eventually ceases. The symptoms asso- ciated with the menopause vary from individual to individual and between cultural groups. Vasomotor instability causing hot flushes and sweating, vaginal dryness and an increased rate of bone resorption, potentially leading to osteopaenia and osteoporosis, are the only established features of estrogen deficiency and are relieved by estrogen replacement therapy.
Mechanism of action of estrogens Estrogens travel in the bloodstream, largely bound to plasma proteins, and diffuse into the cell and the nucleus where they bind to specific receptor proteins (Chapter 4).
Two main forms of the estrogen receptor have been discovered, namely ER-α and ER-β. ER-α is the form that dictates much of sexual function and behaviour, and may be the form of the receptor responsible for breast and other estrogen-mediated cancers. There is evidence that the ratio of ER-α: ER-β is an important determinant of health and disease, especially with regard to carcinogenicity of estrogen. The estrogen receptor proteins have been characterized and have different multifunctional domains (Fig. 26b). The receptor has at least two transcriptional activation functional sites (TAF-1 and 2; see also Chapter 4), a DNA-binding domain, which is similar for many of the DNA- binding receptors, and a hormone-specific binding domain.
The ovary is also an important source of androgen production in the female, accounting for about 50% (the rest being adrenal in origin). Androstenedione and testosterone are synthesized in the theca cell layer of the maturing follicle under the influence of LH. They diffuse into granulosa cells where they are aromatized to form estrogens (Fig. 26c). Androgens and the other steroid and peptide hormones produced in the developing follicle are important local regulators of ovarian function and folliculogenesis. In mature females, many of the common disorders of reproductive function are associated with excessive androgen production, disordered folliculogenesis and ovulation and subsequent subfertility associated with the peripheral effects of excess androgen production (Figs 26d and e).