"Menopause-related hot flashes are usually treated with a standardized dose of estrogen. This general approach to the most prevalent menopausal symptom is predicated on the belief that all menopausal women will respond to a uniform dose of estrogen, irrespective of the type or route of administration."
Morris Notelovitz, MD, Ph.D., MB BCh, FRCOG  

                However, many perimenopausa1 menstruating women (with adequate endogenous estrogen levels) have estrogen responsive hot flashes during their luteal and menstrual phases, and 20% of naturally and 10% of surgically menopausal women (all of whom are estrogen deficient) never experience hot flashes. "Furthermore, the subjectivity of the sensation of heat and accompanying symptoms such as sweating, palpitations, anxiety and irritability is extremely variable, as is the duration of this often debilitating symptom. Hot flashes can persist for up to 15 years after menopause in about 20% of women. Given the heterogeneity in clinical presentation and response to various doses of estrogen therapy, it is clinically prudent to regard hot flashes as a symptom of a multifactorial syndrome that involves estrogen deficiency as one of many other relevant vasoactive and endocrine factors. The role of androgens is central to this concept and the need for individualizing therapy."

                 Hot flashes often correlate more closely with fluctuating estrogen concentrations than with absolute hormone values. Persistent hot flashes in women receiving "adequate" estrogen therapy are often indicative of reduced bioavailability of estrogen due to excess binding with sex hormone binding globulin (SHBG). This can be confirmed with measured plasma FSH levels in a "menopausal", range (>50miU/L) and estradiol values in an appropriate premenopausal "therapeutic" range (>40-50 pg/mL).

                In most symptomatic women, hot flashes cease within 5 years of onset. A recent study showed that high androgen levels are a significant predictor of early amelioration and cessation of hot flashes. These women have relatively low FSH: and luteinizing hormone levels and relatively high estradiol levels. This outcome is attributed to the peripheral aromatization of androgens to estrogen.

                Androgen therapy can be used to relieve vasomotor symptoms in women whose hot flashes are refractory to adequate estrogen replacement. Estrogen and androgen receptors are present in the areas of the central nervous system relevant to hot flashes. Androgens are a chemical precursor to the synthesis of estrogen and to the bioavailability of free estrogen in peripheral tissues. In addition, androgens have direct central nervous system effects that modulate other endocrine factors associated with hot flashes.

Mayo Clin Proc. 2004 Apr;79(4 Suppl):S8-13

It is essential that all forms of hormone replacement therapy are administered using the most appropriate route, dose, and dosage form to optimize benefits and minimize the risk of side effects.