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To the Editor.

To the Editor: The recent comments of Stanczyk after the publication of Portman et al entitled ‘‘Lack of effect of intravaginal dehydroepiandrosterone (DHEA, prasterone) on the endometrium in postmenopausal women’’ have no direct relevance to intravaginal DHEA or to Portman et al’s publication. To protect the endometrium in the absence of progesterone after the arrest of estradiol secretion by the ovary at menopause, millions of years of evolution have introduced high serum levels of DHEA as a unique source of tissue-specific intracellular sex steroids. In fact, after menopause, women still need active sex steroids in most of their tissues to support their normal functioning, especially the vasomotor system, vagina, sexual function, bone, muscles, metabolism, and possibly the brain. To avoid stimulation of the endometrium after menopause, serum estradiol should remain at biologically inactive concentrations, namely below the 95% centile of normal postmenopausal values, or 9.2 pg/mL, as measured by validated mass spectrometry-based assays. The remarkable achievement of 500 million years of evolution is that the estrogens and androgens made in peripheral tissues according to the mechanisms of intracrinology are inactivated in the same cells where biosynthesis takes place, thus minimizing the amount of active sex steroids required and avoiding any influence on the other tissues. The endometrium, in the absence of aromatase, does not transform DHEA into estradiol, thus providing the protection required after menopause. The problem with DHEA, however, is that its secretion starts decreasing after about 30 years of age, and has already decreased by an average of 60% at the time of menopause and continues to decrease thereafter. That decrease in serum DHEA seriously limits the availability of sex steroids and is responsible for the sex steroid-related menopausal symptoms. The fact that endometrial atrophy is observed in all normal postmenopausal women in the presence of significant concentrations of DHEA and its metabolites in the blood is a clear demonstration that DHEA or any of its derivatives, including androstenediol, has no stimulatory effect on the postmenopausal endometrium. Accordingly, after its intravaginal administration to women with vulvovaginal atrophy, DHEA, the precursor of all sex steroids, administered in a small amount, permits a strictly local action in the vagina without any biologically significant change in serum DHEA and any of its metabolites, thus avoiding any issue of systemic exposure. Androstenediol is not relevant more than any other steroid because the serum levels of DHEA and its metabolites all remain within the normal postmenopausal range after intravaginal DHEA administration, and all normal postmenopausal women with normal circulating DHEA have an atrophic endometrium. As expected from the physiology of DHEA and its abovementioned protective role on the endometrium, Portman et al have shown endometrial atrophy or an inactive endometrium in all the 668 endometrial biopsy samples collected at baseline and after at least 12 weeks of treatment, including 422 women treated for 52 weeks. It is also of practical interest to mention that although endometrial atrophy is well recognized in all normal postmenopausal women who show average serum DHEA concentrations of 1.95 1.18 (SD) ng/mL with an upper 95th centile at 3.99 ng/mL, it seems that the upper limit of serum DHEA having no effect on the endometrium is much higher, thus providing a relatively large window of DHEA concentrations which maintain atrophy of the endometrium. In fact, endometrial biopsies were performed after 12 months of daily percutaneous administration of 4 to 6 g of 10% DHEA cream to 15 postmenopausal women showing serum DHEA concentrations increased to 10.8 1.04 ng/mL or 5.5-fold above the normal postmenopausal concentrations or even 2.4-fold above the normal premenopausal values. At these relatively high serum DHEA concentrations, no change in the atrophy of the endometrium was observed. Accordingly, in addition to the common knowledge that normal serum DHEA is always accompanied by an atrophic endometrium in all postmenopausal women, it seems that the window of no effect of serum DHEA on the endometrium after menopause can be extended to 2.4and 5.5-fold above normal preand postmenopausal values, respectively, thus providing additional protection to the endometrium. Because the daily intravaginal administration of 6.5 mg DHEA maintains all serum steroid levels within normal postmenopausal values, there is therefore no reason for any concern for any potential effect of any DHEA-derived steroid, including androstenediol, on the endometrium. The phase I studies mentioned with a steroid sulfatase and an aromatase inhibitor performed in 14 and 19 participants, respectively, do not apply to the postmenopausal situation. Contrary to what seems to be suggested, Bonney et al concluded that the similar concentrations of adrenal ‘‘androgens’’ in the normal and cancerous endometrium did not support a role for adrenal androgens, including androstenediol, in endometrial cancer. It should also be mentioned that Bonney et al have found no transformation of DHEA into