Clinical Opinion: The Biologic and Pharmacologic Principles for Age-Adjusted Long-term Estrogen Therapy

Morris Notelovitz, MD, PhD, MB BCh, FACOG, FRCOG

In This Article


Estrogen therapy (ET) is pharmacologic but can be adjusted to replicate the physiologic endocrine milieu of women in order to achieve and maintain the physiologic homeostasis of various organ functions. Recognition of the age-related pathogenesis of ET-responsive conditions and diseases is essential (Figure 1). For example, hot flashes frequently precede the menopause but decrease in prevalence and intensity over time. Symptoms associated with urogenital atrophy (UGA) postdate the onset of menopause but increase in frequency and severity with aging. Each of these symptom complexes has the same etiology -- estrogen deficiency -- but they differ in terms of timing, type, and duration of ET that would be appropriate. Osteoporosis, cardiovascular disease (CVD), and breast cancer have multifactorial etiologies, with endogenous estrogen being a contributing protective or aggravating factor.

Age-adjusted hormone therapy and the pathogenesis of estrogen-related conditions.

Timing of exogenous ET and matching the dose, route, and possibly the duration of therapy to meet the needs of a given individual require adjustment to ensure appropriate and safe therapy. In this context, there are 3 pharmacologic approaches one might consider, each of which is governed by the pharmacokinetics of the ET and the age and health of the individual (Figure 1). The first is estrogen replacement therapy (ERT), which sets out to replicate the estrogen milieu of premenopausal women (both in terms of the blood levels of estrogen and ratio of estradiol to estrone [E2/E1]). The second is estrogen additive therapy (EAT), which entails complementing endogenous postmenopausal estrogen with exogenous estrogen, tailored to meet the indication for ET. And finally, estrogen maintenance therapy (EMT) is an extension of previously prescribed ET, but at gradually reduced dosages, with the objective of maintaining the individual's state of well-being.

The initiation and type of ET required to meet these goals vary: ERT is relevant to women experiencing a premature or early menopause (ie, < 50 years of age) or premature ovarian failure; EAT is the most common form of ET prescribed, primarily for management of the symptomatic menopause, and when indicated, for the prevention of osteoporosis (50 to 60 years of age); EMT is less commonly practiced (or recommended) and has to be balanced with the potential for estrogen-associated breast cancer (> 60 years of age).

Irrespective of age, appropriate lifestyle, exercise, and nutritional measures should be advised and prescribed. Disease-specific drugs are required for overt conditions, eg, diabetes, dyslipidemia, and hypertension, but these diseases do not necessarily contraindicate the concomitant use of ET.


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