Physiological principles of endocrine replacement: estrogen.

The major biologically active circulating estrogen in both males and females is estradiol (E(2)). Circulating E(2) is a product of the ovarian granulosa cell and the testicular Leydig cell. Its gonadal formation is dependent on A-ring aromatization of its immediate precursor, testosterone, by a particular isoform of the enzyme aromatase, which also catalyses the conversion of the much weaker androgen, androstenedione, to the weak estrogen, estrone. E(2) is also formed in non-gonadal tissues, such as adipose tissue, liver, muscle and brain. Only adipose tissue makes significant extra-gonadal contributions to circulating estrogen. Loss of ovarian function during reproductive life, as a result of loss of gonadotropin secretion (secondary hypogonadism) or as a result of premature ovarian failure (generally defined as cessation of ovarian function prior to age 40), results in loss of the majority of circulating E(2) and of luteal progesterone. Loss of ovarian function at the menopause likewise results in a 90% loss of circulating E(2). The consequences of loss of ovarian function during reproductive life may be severe. Symptoms include hot flushes, night sweats, vaginal dryness and dyspareunia, loss of libido, loss of bone mass with subsequent osteoporosis and abnormalities of cardiovascular function, including a substantial increase in the risk of ischemic heart disease. Various regimens of estrogen replacement have been employed, aiming to eliminate symptoms, restore well-being and avert the consequences of estrogen depletion. The commonly adopted form of replacement is with the low-dose oral contraceptive pill for reasons of convenience, cost, efficacy, general freedom from side effects and the psychological advantage that many of the patient's peer group are also "taking the pill". An often neglected aspect of hormone therapy in the reproductive age group is the therapeutic use of testosterone. The application of such principles to the postmenopausal period is more problematic, as there is a common perception that the menopause is a normal physiological occurrence and that it is therefore not physiological to offer hormone therapy at that time. The pragmatic approach is to recommend standard therapy with estrogen and progestogen for the management of menopausal symptoms and to recommend longer term hormone replacement in the light of the individual's needs and current data with regard to efficacy for protection from osteoporosis and cardiovascular disease.