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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.

Comentario

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


El siguiente comentario es una traduccin de una contribucin original en Ingls enviada a los miembros el Agosto 19, 2013. La traduccin ha sido gentilmente efectuada por el

Dr Faustino Perez Lopez

Edad de la menopausia, la historia reproductiva y el riesgo de TEV

Recientemente, Canonico y sus colegas publicaron un análisis del ensayo clínico de terapia hormonal (TH) de la Iniciativa de la Salud de la Mujer (WHI) (tanto de estrógeno y estrógeno + progestina) sobre riesgo de tromboembolismo venoso (TEV) y marcadores de la vida reproductiva relacionados a la exposición de por vida a estrógeno endógeno [1]. Estos marcadores incluyeron: edad de la menarquia y la menopausia, el número de embarazos a término (paridad), la ooforectomía bilateral, o el tiempo transcurrido desde la menopausia. Se evaluaron las interacciones de la TH con estas características y el riesgo de TEV. En la línea de base se incluyeron para el análisis mujeres postmenopáusicas sin antecedentes de TEV (n = 27,035); el tiempo promedio de seguimiento fue de 6.2 años. Al análisis no hubo interacción entre los marcadores individuales y el tratamiento asignado sobre el riesgo de un primer evento TEV. Tampoco se encontraron asociaciones significativas al efectuar un análisis agrupado de primer evento TEV por marcadores individuales. Sin embargo, el análisis agrupado restringido a primer episodio de TEV no relacionado con el procedimiento encontró una interacción significativa (p < 0.01) para la edad de la menopausia (una relación en forma de U). En relación a las mujeres que tuvieron su menopausia a sus cuarenta años, aquellas con una menopausia temprana (edad < 40 años) o menopausia tardía (edad > 55 años) mostraron un riesgo significativamente mayor de TEV. El análisis para trombosis venosa profunda pero no para embolia pulmonar y edad de la menopausia arrojó resultados similares.

Comentario

En el estudio HERS (Heart and Estrogen/Progestin Replacement Study), 2,763 mujeres postmenopáusicas con enfermedad de arteria coronaria, pero sin antecedentes de TEV fueron asignadas al azar a estrógenos conjugados 0.625 mg acetato de medroxiprogesterona 2.5 mg o placebo. Las mujeres tenían 44–79 años de edad (promedio 67 años) y fueron seguidas durante el estudio por un promedio de 4.1 años. El análisis multivariado determinó que la edad de presentación de la última menstruación superior a 52 años fue un factor predictivo e independiente de TEV (p < 0.001) [2]. El ESTHER (Estrogen and venous THromboEmbolism Risk) fue un estudio caso-control basado en hospital de 191 mujeres postmenopáusicas con un primer episodio de TEV idiopático y 417 controles apareados por edad, comparado con mujeres con menopausia ocurrida entre los 46 y 54 años. En este estudio se determinó que las mujeres con menopausia a la edad ≥ 55 años tuvieron un aumento significativo del riesgo de TEV y al análisis ajustado las mujeres con una menopausia ≤ 45 mostraron un riesgo disminuido [3]. La paridad también estuvo relacionada con el riesgo de TEV: las mujeres con más de dos hijos presentaban un riesgo significativamente mayor de TEV que las que tenían dos o menos hijos. The Longitudinal Investigation of Thromboembolism Etiology study pooled two population-based cohort studies (the Atherosclerosis Risk in Communities study and the El estudio Iowa de la Salud de las Mujeres (Iowa Health’s Study) compuesto de una cohorte de 40,377 mujeres seguidas por casi 20 años, encontró una "modesta" disminución del riesgo de TEV incidental a mayor edad de presentación de la menopausia, en comparación con aquellas con una menopausia < 45 años. La paridad no estuvo relacionada con el riesgo de TEV [4]. El estudio “Investigación Longitudinal sobre la Etiología del Tromboembolismo” agrupó dos estudios de cohorte de base poblacional (el Atherosclerosis Risk in Communities Study y el Cardiovascular Health Study) e incluyó 8,236 mujeres postmenopáusicas en los análisis. No se encontró asociación significativa entre la incidencia de TEV y la edad de la menopausia o la paridad [5]. La TH oral y, en menor medida, la transdérmica se ha asociado a un aumento del riesgo de TEV. Aunque el riesgo absoluto de TEV en las mujeres postmenopáusicas es bajo, este aumenta con la edad. Se ha evaluado en una serie de estudios la exposición a los estrógenos endógenos a lo largo de la vida y el riesgo de TEV, arrojando resultados variables. Aunque algunos estudios han sugerido que a mayor paridad se asocia a un mayor riesgo de TEV, la mayoría no han confirmado esto. Algunos estudios (aunque no todos) si sugieren que a mayor edad de presentación de la menopausia se relaciona con el aumento en el riesgo de TEV. Sin embargo, el estudio realizado por Canonico y sus colegas puede ser el primero en sugerir que la menopausia que ocurre antes de los 40 años se asocia con un aumento del riesgo de TEV en comparación con aquellas con una menopausia que ocurre entre las edades de 40 y 49. Este resultado debe considerarse con cautela, ya que no ha sido confirmado por otros estudios que evalúen el riesgo de TEV y la edad de la menopausia y es un análisis post hoc del WHI en que muchos análisis se realizaron, haciendo probable que algunos resultados ocurran por casualidad.

James H. Pickar

Obstetrics and Gynecology, Columbia University Medical Center, New York, NY, USA

References

  1. Canonico M, Plu-Bureau G, OSullivan MJ, et al. Age at menopause, reproductive history, and venous thromboembolism risk among postmenopausal women: the Womens Health Initiative hormone therapy clinical trials. Menopause 2013;21. Epub ahead of print
    http://www.ncbi.nlm.nih.gov/pubmed/23760439

  2. Grady D, Wenger NK, Herrington D, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. Ann Intern Med 2000;132:689-96.
    http://www.ncbi.nlm.nih.gov/pubmed/10787361

  3. Simon T, De Jonage-Canonico MBY, Oger E, et al. Indicators of lifetime endogenous estrogen exposure and risk of venous thromboembolism. J Thromb Haemostasis 2006;4:71-6.
    http://www.ncbi.nlm.nih.gov/pubmed/16409454

  4. Lutsey PL, Virnig BA, Durham SB, et al. Correlates and consequences of venous thromboembolism: the Iowa Womens Health Study. Am J Public Health 2010;100:1506-13.
    http://www.ncbi.nlm.nih.gov/pubmed/19910349

  5. Ohira T, Folsom, AR, Cushman M, et al. Reproductive history, hormone replacement, and incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology. Br J Haematol 2010;149:606-12.
    http://www.ncbi.nlm.nih.gov/pubmed/20230397

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