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Menopause Live - IMS Updates
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Date of release: 13 October, 2014

Cell- and tissue-specific sex steroid formation and inactivation in menopausal women: intracrinology

Labrie [1] recently published a review describing that, while DHEA (dehydroepiandrosterone, prasterone) is present in the blood during the whole life of women, the sex steroid precursor DHEA becomes the only source of sex steroids after menopause [2,3], a time when the ovaries have stopped secreting estrogens [3,4], most likely to protect the endometrium [5].
 
It took 500 million years of evolution to insert the sequences of the proper peripheral steroidogenic enzymes in the human genome [6], a condition joined 20 million years ago in the primates by a high secretion rate of DHEA by the adrenals [4]. The conditions were then finally favorable for the introduction of menopause characterized mainly by the arrest of ovarian estrogen secretion in the blood, thus leading to biologically inactive serum levels of estradiol [3,4]. However, while the uterus is protected by the arrest of ovarian estradiol secretion, sex steroids remain very important in women after menopause for proper functioning of most other tissues. This requirement for a permanent supply of sex steroids after menopause is met by the continuing availability of DHEA (Table), mostly (~80%) secreted by the adrenals and about 20% by the ovary [2]. 
 
Table Origin of sex steroids in pre- and postmenopausal women. After menopause, all estrogens are made in peripheral target tissues from DHEA [2,4]. The androgens made in the ovary during premenopause are mostly used to make estrogens and are not secreted as such in the blood in significant amounts. Some DHEA, however, is secreted in the blood, where it adds to the DHEA of adrenal origin. DHEA then reaches the peripheral tissues where it can make androgens and/or estrogens depending upon the level of expression of the steroidogenic enzymes present. In fact, androgens are all made in peripheral tissues from DHEA during the whole life of women [2]
 
Sex steroidsPremenopausePostmenopause
EstrogensOvaryNo
+ DHEADHEA only
AndrogensDHEA only DHEA only
 
DHEA is then transformed specifically in each cell of each peripheral tissue into the proper amounts of estrogens and/or androgens, depending upon the level of expression of the appropriate steroid-metabolizing enzymes in each cell type [7]. Most importantly, the sex steroids synthesized and acting intracellularly in each cell according to the mechanisms of intracrinology [3,8] are also inactivated locally [9], thus maintaining the serum levels of estradiol and testosterone at biologically inactive concentrations [3,4]. Accordingly, systemic exposure to sex steroids is avoided during menopause [4].

Comment

Our research group has been fortunate, somewhat early, to be able to measure accurately the very low blood concentrations of estradiol and testosterone as well as a series of related sex steroids in postmenopausal women, using reliable, accurate and sensitive mass spectrometry-based assays [10]. Without such precise and specific steroid assays, it would have been impossible to progress in the understanding of the physiology of sex steroids in women and consequently propose a change in the paradigm of treatment of menopause. It should be mentioned that the very low levels of circulating estradiol observed in postmenopausal women result exclusively from the small leakage of the estrogens made intracellularly in peripheral tissues [8,11]. Accordingly, this recent understanding of intracrinology should be followed closely when designing novel treatments of menopause and simultaneously avoiding safety issues.
 
Intracrinology is perfect to protect the uterus and probably other tissues but there is one obvious problem with DHEA; however, this problem pertains to its serum levels which decrease markedly with age [2]. Moreover, the blood levels of DHEA vary markedly between different women [2]. Consequently, while an estimated 20% of women have a sufficient supply of sex steroids coming from DHEA transformation to show no obvious clinical sign or symptom of menopause, about 80% of women suffer from one or more symptoms and/or signs of menopause [12,13] due to hormonal deficiency. The problem for such a majority of women is that evolution did not have sufficient time to put in place a control system able to increase DHEA secretion in women with low DHEA activity. In fact, DHEA secretion by the adrenals is stimulated by ACTH (adrenocorticotropin), secreted by the anterior pituitary gland at a rate essentially controlled by the serum levels of cortisol, while DHEA, by itself, has no feedback control independent from that of cortisol.
 
Although a series of appropriately powered clinical trials need to be performed for each medical indication related to the sex steroid deficiency of menopause [4], the detailed knowledge already obtained about the structure and expression of the human steroidogenic enzymes in peripheral tissues [7] and the precise information obtained about the serum levels [10,11] of the most important sex steroids in both women and men (especially in prostate cancer) have paved the way to a potential but needed 'revolution' in the treatment of menopause and sex steroid-related diseases [12-14]. It should be mentioned that DHEA is considered as a new chemical entity (NCE) which needs to be developed in accordance with the guidelines of the FDA and other regulatory agencies for NCE compounds.
 
Evolution has created intracrinology, a highly sophisticated mechanism, which permits each cell in each peripheral target tissue, using its specific set of intracellular steroidogenic and steroid-inactivating enzymes, to maintain or attempt to maintain, despite low serum levels of DHEA, the right amount of estrogens and/or androgens needed for its normal functioning without any risk of stimulation of the endometrium.
 
The present scientific information summarized in reference 1 has the potential to open the way to a prodrug replacement therapy, already well illustrated by the beneficial effects of intravaginal DHEA observed on the symptoms and signs of vulvovaginal atrophy [12] and sexual dysfunction [13]. The prodrug prasterone (DHEA) is well recognized to be without a safety issue for the reasons mentioned above and is very strongly supported by the fact that about 20% of postmenopausal women have sufficient DHEA activity to avoid the clinical symptoms and signs of menopause while showing no negative effect of their normal serum DHEA levels. The administration to sex steroid-deficient women of an appropriate amount of DHEA able to correct, as indicated in reference 1, the symptoms of vulvovaginal atrophy (mostly estrogen-sensitive) and sexual dysfunction (androgen-sensitive), and potentially, in the future, other problems of menopause, does simply permit the sex steroid-deficient women to reach a normal/sufficient level of sex steroids in specific tissues using the enzymes [7] developed over 500 million years [6] to permit a better quality of life during the menopausal years.

Fernand Labrie
EndoCeutics Inc., Quebec City, Canada

    References

  1. Labrie F. All sex steroids are made intracellularly in peripheral tissues by the mechanism of intracrinology after menopause. J Steroid Biochem Mol Biol 2014 Jun 9. Epub ahead of print
    http://www.ncbi.nlm.nih.gov/pubmed/24923731

  2. Labrie F, Martel C, Balser J. Wide distribution of the serum dehydroepiandrosterone and sex steroid levels in postmenopausal women: role of the ovary? Menopause 2011;18:30-43
    http://www.ncbi.nlm.nih.gov/pubmed/20683211

  3. Labrie F. DHEA after menopause Sole source of sex steroids and potential sex steroid deficiency treatment. Menopause Management 2010;19:14-24
    http://www.menopausemgmt.com/dhea-after-menopause/

  4. Labrie F, Labrie C. DHEA and intracrinology at menopause, a positive choice for evolution of the human species. Climacteric 2013;16:205-13.
    http://www.ncbi.nlm.nih.gov/pubmed/23126249

  5. Hammond CB, Jelovsek FR, Lee KL, Creasman WT, Parker RT. Effects of long-term estrogen replacement therapy. II. Neoplasia. Am J Obstet Gynecol 1979;133:537-47
    http://www.ncbi.nlm.nih.gov/pubmed/220875

  6. Baker ME. Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors. Mol Cell Endocrinol 2004;215:55-62
    http://www.ncbi.nlm.nih.gov/pubmed/15026175

  7. Luu-The V, Zhang Y, Poirier D, Labrie F. Characteristics of human types 1, 2 and 3 17β-hydroxysteroid dehydrogenase activities: oxidation-reduction and inhibition. J Steroid Biochem Mol Biol 1995;55:581-7
    http://www.ncbi.nlm.nih.gov/pubmed/8547185

  8. Labrie F. Intracrinology. Mol Cell Endocrinol 1991;78:C113-18
    http://www.ncbi.nlm.nih.gov/pubmed/1838082

  9. Bélanger B, Bélanger A, Labrie F, et al. Comparison of residual C-19 steroids in plasma and prostatic tissue of human, rat and guinea pig after castration: unique importance of extratesticular androgens in men. J Steroid Biochem 1989;32:695-8
    http://www.ncbi.nlm.nih.gov/pubmed/2525654

  10. Labrie F, Bélanger A, Bélanger P, et al. Androgen glucuronides, instead of testosterone, as the new markers of androgenic activity in women. J Steroid Biochem Mol Biol 2006;99:182-8
    http://www.ncbi.nlm.nih.gov/pubmed/16621522

  11. Labrie F, Martel C, Berube R, et al. Intravaginal prasterone (DHEA) provides local action without clinically significant changes in serum concentrations of estrogens or androgens. J Steroid Biochem Mol Biol 2013;138:359-67
    http://www.ncbi.nlm.nih.gov/pubmed/23954500

  12. Labrie F, Archer D, Bouchard C, et al. Intravaginal dehydroepiandrosterone (Prasterone), a physiological and highly efficient treatment of vaginal atrophy. Menopause 2009;16:907-22
    http://www.ncbi.nlm.nih.gov/pubmed/19436225

  13. Labrie F, Archer D, Bouchard C, et al. Effect on intravaginal dehydroepiandrosterone (Prasterone) on libido and sexual dysfunction in postmenopausal women. Menopause 2009;16:923-31
    http://www.ncbi.nlm.nih.gov/pubmed/19424093

  14. Labrie F. Drug Insight: breast cancer prevention and tissue-targeted hormone replacement therapy. Nature Clin Pract Endocrinol Metab 2007;3:584-93
    http://www.ncbi.nlm.nih.gov/pubmed/17643129