Sources of Estrogens in Women

The estrogen compounds to which target tissues in women, including the vascular system, may be exposed are multiple and they arise from endogenous and exogenous sources. The naturally occuring estrogens 17 ^-estradiol (E2), estrose (E1), and estriol (E2) are C18 steroids and are derived from cholesterol in steroidogenic cells. In the premenopausal women, the primary source of estrogens are the ovaries. E1 and E3 are primarily formed in the liver from E2 (10). After menarche, when circulating E2 levels increase and begin to cycle, levels range from 10 to 80 pg/mL during the follicular phase to 600 pg/mL at midcycle. Following ovulation, progesterone is secreted from the luteinized cells during the luteal phase of the cycle. Progesterone has two main functions in the body, namely, transformation of the endometrium after estrogen priming (luteomimetic effect) and opposition to estrogen (anti-estrogenic effect), limiting proliferation of the endometrium.

After menopause, estrogen concentrations fall to levels that are equivalent to those in males (5-30 pg/mL), and most of the estrogen is formed by extragonadal conversion of testosterone through aromatization, mainly in adipose tissue. E1 is the predominant estrogen in these women. The level of estrogen synthesis in extragonadal tissues increases as a function of age and body weight (10).

In the circulation, estrogen binds to sex hormone binding globulin (SHBG) produced in the liver and, with less affinity, to albumin (11). Only about 2%-3% of estrogen is free. Changes in SHBG levels may influence the tissue availability of free estrogen and also free androgen because the latter also binds to SHBG. Estrogens themselves increase, whereas androgens and high insulin levels decrease SHBG levels. During the menopause, the drop of estradiol reduces SHBG levels, which in turn, results in decreased binding and an increased concentration of free androgens. Consequently, estrogens decrease to a greater extent than do androgens resulting in an increase of the androgen/ estrogen ratio and a relative androgen excess in postmenopausal women. Some of the signs and symptoms observed after menopause and, in particular, changes in body composition are caused by this altered balance between estrogens and androgens (12).

In addition to endogenously derived estrogens, there are other important exogenous sources in humans. Oral contraceptives usually contain a combination of ethinyl-estra-diol and a synthetic progestogen. Estrogen replacement therapy (ERT) in postmenopausal women is usually in the form of conjugated equine estrogens (CEE) or other oral or transdermal forms of synthetic estrogens. To avoid the risk of endometrial hyperplasia and carcinoma associated with the use of unopposed estrogens, it is advised that women with an intact uterus use progestogen either cyclically or in a continuous combined regimen (HRT) (13). Progestogens are derived from either progesterone itself (C21 progestogens) or testosterone (C19 progestogens) (13).

A new synthetic steroid tibolone with a combination of weak estrogenic, progestoge-nic, and androgenic activity is also available for HRT (14). Additionally, selective estrogen receptor modulators (SERMS), such as raloxifene are used for the treatment of osteoporosis and it is likely that vascular-specific SERMS will also soon be available (15). Furthermore, phytoestrogens, a diverse group of compounds found in various plant-derived foods and beverages, can have both estrogenic and antiestrogenic effects (16).

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