The biologic rationale for estrogen therapy

Morris Notelovitz
Adult Women’s Health & Medicine, Boca Raton, Florida and Washington DC, USA

Introduction

Premenopausal estrogen steroidogenesis and function are the foundation on which the health and wellbeing of postmenopausal women depend. The contribution of postmenopausal estrogen synthesis – although much reduced – plays a pivotal role in maintaining health and reducing the morbidity of diseases prevalent in postmenopausal women, such as osteoporosis.

Appreciation of the differences in pre- and postmenopausal estrogen biosynthesis and function and the physiology/pathology of bone, coronary arteries, breast and the brain allows for the selective choice of appropriate estrogen therapy for a given individual, at a given point in time – based on sound biologic and pharmacologic principles.

Estrogen biosynthesis and function: generic and individualized

Androgens are pro-hormones to estrogen biosynthesis. Postmenopausally, the androgen substrates are derived primarily from the adrenal gland and the ovarian stroma, with peripheral tissues such as the muscle and fat being the primary site for the aromatization of androgen to estrogen. The synthesis of estrogen also occurs in tissues such as breast and bone; the net result is much higher (and not measurable) levels of estrogen in these tissues than in blood. The liver is the major site for the metabolism of endogenous estrogen and the production of metabolites of varying estrogenic potency, which may, for example, have a carcinogenic or anti-carcinogenic influence on breast epithelial cells. The biologic potency of the synthesized estrogen will also be governed by the liver’s production of factors such as sex hormone binding globulin. All of the above is pre-determined by genes that influence enzymes involved in local estrogen synthesis – sulfatase, aromatase and 17ß-hydroxydehydrogenase activity – and estrogen metabolism. The polymorphism of an individual’s genetic make-up determines the need for – and safety of – hormone therapy. Central to this point is the fact that estradiol and estrone are the only bioavailable estrogens synthesized in non-pregnant women. Premenopausally, estradiol is the predominant estrogen produced; postmenopausally the ratio of estradiol to estrone favors the latter.

Estrogen initiates its function via genomic or cell membrane binding of ‘free’ estradiol to estrogen receptors. Two estrogen receptors, ERa and ERß, are present in most tissues in the body, in varying dimeric patterns: ERa/ERa; ERß/ERß or ERa/ERß. The binding to the estrogen response element is further modulated by co-activators and co-repressors. Estrogen receptors are found in the brain, coronary artery smooth muscle, breast and bone. The presence of estrogen receptors in osteoblasts, osteoclasts and osteocytes serves as an excellent example of how estrogen (together with other factors) ensures bone protection by optimizing bone mass premenopausally, and modulating bone loss postmenopausally.

In summary, estrogen biosynthesis and function are generic to all women, but specific to individuals. Postmenopausal women are estrogen-deficient (relative to the premenopause) but not estrogen-depleted. Estrogen receptors are present in all tissues but vary in type and distribution; hepatic function determines the bioavailability of estrogen.

Estrogen replacement vs. estrogen therapy

Based on the pharmacokinetics and the pharmacodynamics of estrogen therapy, it is possible to adjust the type of therapy to the physiologic needs of menopausal women. Thus, for women who experience a premature menopause (natural or surgical), it is possible to replicate (replace) the premenopausal estrogen milieu with transdermal or percutaneous estradiol therapy; the normal estrone : estradiol ratio of estrogen in postmenopausal women can be maintained but increased (replenished) via oral estradiol therapy. This ‘physiologic’ approach can only be achieved by adjusting the dose prescribed to pretreatment estradiol levels, by use of ‘simple’ estrogen compounds such as estradiol. A similar ‘pharmacological’ response can be achieved with complex estrogens (such as conjugated equine estrogen) which have estrogen activity, but are not native to women.

Dosage is critical. As noted, estrogen therapy is additive to endogenous estrogen synthesis, and needs to be tailored to the total needs of the individual – and not only to the most obvious clinical indication.

Recommendation for estrogen therapy

Choose the route and type of estrogen therapy according to the chronologic and menopausal age of the individual and her clinical preferences and needs. This will necessitate testing of surrogate biomarkers such as fasting lipid profile, glucose, C-reactive protein (in older women), bone density (bone markers), mammography (breast density), vaginal pH, and, selectively, serum estradiol (total and free) and FSH/SHBG levels.

Three biologic approaches may be considered:

(1) Estrogen replacement therapy: to meet the physiologic hormonal requirement of younger menopausal women (< 50 years)
(2) Estrogen replenishment therapy: the pharmacologic addition of estrogen to ensure quality of life and maintenance of tissue integrity and health (50–65 years)
(3) Estrogen maintenance therapy: continuation of previously prescribed and well-tolerated estrogen therapy (65 years and above)

All of the above are subject to the following clinical caveats: prescribe the lowest effective dose of estrogen; adjust the dose over time to meet the dual objectives of efficacy and safety; monitor annually.

Note: Conditions such as dyslipidemia, diabetes, hypertension require disease-specific therapy.

Conclusion

Estrogen therapy has a well-defined biologic rationale and role in the primary prevention and secondary intervention of conditions such as osteoporosis, cardiovascular disease and the maintenance of cognition. Estrogen therapy enhances the quality of life of menopausal women.