Review
DHEA – a precursor of ERβ ligands

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Highlights

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    DHEA as a precursor of ERβ ligands.

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    Pharmacological uses of DHEA.

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    DHEA as a route of detoxification of cholesterol.

Abstract

What is DHEA and why is there so much public interest in this steroid which has been touted as the fountain of youth and is supposed to have all kinds of health benefits? Endocrinologists have been fascinated with DHEA for a long time because of its high production in the fetal adrenals and its continued high levels until the 7th decade of life. Yet there is still little agreement about its physiological functions. In its simplest terms endocrinology is the communication between at least three organs: one sends a message, one releases a hormone into the blood in response to the message and one responds to the hormone. DHEA is produced by a specific zone of the adrenal cortex, the zona reticularis, whose sole function is to produce this steroid. Glucocorticoids and mineralocorticoids which are C21 steroids are produced in two other zones of the adrenal cortex called the zona fasicularis and the zona glomerulosa, respectively. Being C21 steroids, they cannot be synthesized from DHEA which is a C19 steroid. To date there is no known hormone which specifically stimulates the zona reticularis and there is no known specific receptor for DHEA. Thus DHEA does not qualify as a hormone. DHEA could have autocrine or paracrine effects but, so far, there is no known effect of DHEA on either the cells of the zona glomerulosa or the zona fasicularis. Of course DHEA could have functions as a local precursor of androgens or estrogens and many studies have reported on the beneficial effects of transdermal or transvaginal administration of DHEA in postmenopausal women. This review will consider two of the potential functions of DHEA as a precursor of estrogen receptor beta (ERβ) ligands.

Section snippets

Levels of DHEA

Circulating levels of DHEA are higher than those of any other steroid hormone (Table 1). DHEA circulates at concentrations in the 30 nM range while its sulfate conjugate DHEAS, circulates at several hundred times that level, in the 10 μM range [1], [2], [3].

DHEA and ERβ ligands

There is no doubt that estradiol (E2) is the endogenous ligand for estrogen receptor alpha (ERα) and both testosterone (T) and 5α-dihydrotestosterone (DHT) are ligands for the androgen receptor (AR). It is still not clear how many endogenous ligands there are for ERβ and what determines cell specific activation of this receptor [4]. One of the remaining mysteries to endocrinologists is why the body makes DH`T when T is a perfectly good AR agonist. One possible answer to this question is that

Pharmacological uses of DHEA

Oral consumption of low doses of DHEA is unlikely to have health benefits in humans because of the efficient conversion to DHEAS in the liver. In large doses, oral DHEA can increase plasma levels of DHEA but the health benefits of these large doses are not clear. On the other hand trans dermal and trans vaginal DHEA have been found to improve collagen content of the skin [27], [28] and health of the mucosal membranes of postmenopausal women [29]. Whether or not DHEA is converted to an estrogen

DHEA an unlikely route of detoxification of cholesterol

Via the entero-hepatic system, the body handles grams of cholesterol each day. Cholesterol absorbed from the diet and that lost in the feces in the form of bile acids is tightly balanced by the synthesis of cholesterol in hepatocytes which amounts to about 1 g per day [33], while circulating cholesterol levels in LDL and HDL are in the 5 mM range. Excretion of DHEA in the urine is in the range of 1 mg per day and DHEA synthesis in the adrenal cortex is 25 mg per day. Both LDL receptor and SRB1 are

Conclusion

DHEA remains a fascinating molecule. Although we can find pharmacological uses for it, we do not understand why a whole zone of the adrenal gland is devoted to the synthesis of this steroid and, even more mysterious, why the very large fetal zone of the embryonic adrenal gland produces so much DHEA.

Acknowledgements

This paper was supported by grants from The Emerging Technology Fund of Texas, CPRIT, The Welch Foundation(E-0004) and The Swedish Cancer Society.

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