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All sex steroids are made intracellularly in peripheral tissues by the mechanisms of intracrinology after menopause
Abstract
Following the arrest of estradiol secretion by the ovaries at menopause, all estrogens and all androgens in postmenopausal women are made locally in peripheral target tissues according to the physiological mechanisms of intracrinology. The locally made sex steroids exert their action and are inactivated intracellularly without biologically significant release of the active sex steroids in the circulation. The level of expression of the steroid-forming and steroid-inactivating enzymes is specific to each cell type in each tissue, thus permitting to each cell/tissue to synthesize a small amount of androgens and/or estrogens in order to meet the local physiological needs without affecting the other tissues of the organism. Achieved after 500 million years of evolution, combination of the arrest of ovarian estrogen secretion, the availability of high circulating levels of DHEA and the expression of the peripheral sex steroid-forming enzymes have permitted the appearance of menopause with a continuing access to intratissular sex steroids for the individual cells/tissues without systemic exposure to circulating estradiol. In fact, one essential condition of menopause is to maintain serum estradiol at biologically inactive (substhreshold) concentrations, thus avoiding stimulation of the endometrium and risk of endometrial cancer. Measurement of the low levels of serum estrogens and androgens in postmenopausal women absolutely requires the use of MS/MS-based technology in order to obtain reliable accurate, specific and precise assays. While the activity of the series of steroidogenic enzymes can vary, the serum levels of DHEA show large individual variations going from barely detectable to practically normal "premenopausal" values, thus explaining the absence of menopausal symptoms in about 25% of women. It should be added that the intracrine system has no feedback elements to adjust the serum levels of DHEA, thus meaning that women with low DHEA activity will not be improved without external supplementation. Exogenous DHEA, however, follows the same intracrine rules as described for endogenous DHEA, thus maintaining serum estrogen levels at substhreshold or biologically inactive concentrations. Such blood concentrations are not different from those observed in normal postmenopausal women having high serum DHEA concentrations. Androgens, on the other hand, are practically all made intracellularly from DHEA by the mechanisms of intracrinology and are always maintained at very low levels in the blood in both pre- and postmenopausal women. Proof of the importance of intracrinology is also provided, among others, by the well-recognized benefits of aromatase inhibitors and antiestrogens used successfully for the treatment of breast cancer in postmenopausal women where all estrogens are made locally. Each medical indication for the use of DHEA, however, requires clinical trials performed according to the FDA guidelines and the best rules of clinical medicine.
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“Indeed, peripheral tissues produce estrogens71, and estrogens play a vital role in wound healing27,28.”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [71]
In the citing paper
“It should be noted that this peripheral estrogen production often functions in a paracrine and intracrine manner and as such circulating concentrations are not reflective of the concentrations achieved locally [304,305].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [305]
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“…and the effects of MHT. Postmortem analyses of the brain tissues of postmenopausal women revealed the accumulation of progesterone in the amygdala, cerebellum, and hypothalamus (Bixo et al., 1997), suggesting local synthesis of progestagens in the brain even postmenopausally (Labrie, 2015).”
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“However, in females, the peripheral aromatization of T to E2 also amplifies estrogen signaling [79], an effect that is particularly evident after the menopausal transition or in other situations where ovarian estrogen synthesis declines [80].”
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“This article is published with open access at Springerlink.com and journal.hep.com.cn hormone synthesis and the conversion involves enzymes belonging to 3β-HSD, 17β-HSD, 5α-reductase and aromatase families (Labrie, 2015).”
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“ways involved, the female menopause is probably best characterised—in particular, the complete cessation of oestrogen production by the ovaries [57].”
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“The subsequent increase in the resorption rate is associated with the increase in the amount of the latent TGFβ (LTGFβ), leading to the stimulation of PC proliferation (Langdahl et al., 1997).”
BackgroundLin, L.-T., Wang, P.-H., Wen, Z.-H., Li, C.-J., Chen, S.-N., Tsai, E.-M., Cheng, J.-T., & Tsui, K.-H. (2017) · International Journal of Medical Sciences · doi:10.7150/ijms.18706 · Cited by 32
“DHEA, an endogenous steroid produced by the zona reticularis of the adrenal glands and by ovarian theca cells, is a precursor to estradiol and testosterone [9].”
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Li, T., Stephen, P., Zhu, D., Shi, R., & Lin, S. (2019) · FEBS Journal · doi:10.1111/febs.14784 · Cited by 30
Estrone Is a Strong Predictor of Circulating Estradiol in Women Age 70 Years and Older
Davis, S. R., Martínez, A., Robinson, P. J., Handelsman, D. J., Desai, R., Wolfe, R. S., Bell, R. J., & ASPREE Investigator Group (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa429 · Cited by 31
Neurosteroids: A novel promise for the treatment of stroke and post‐stroke complications
Xu, J., Zhou, Y., Yan, C., Wang, X., Lou, J., Luo, Y., Gao, S., Wang, J., Wu, L., Gao, X., et al. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15503 · Cited by 32
“…that neurosteroids can be synthesized both by neurons and glial cells at different sites in the nervous system (Baulieu, 1997; Baulieu et al., 2001; Labrie, 2015), and the most important place for steroidogenesis is the mitochondria where vital steroidogenic enzymes are located (Papadopoulos &…”
BackgroundHormone Replacement Therapy and Cardiovascular Health in Postmenopausal Women
Xia, W., & Khalil, R. A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26115078 · Cited by 35
Local synthesis of sex hormones: are there consequences for the ocular surface and dry eye?
Gibson, E., Stapleton, F. J., Wolffsohn, J. S., & Golebiowski, B. (2017) · British Journal of Ophthalmology · doi:10.1136/bjophthalmol-2017-310610 · Cited by 30
Steroid sulfatase inhibitors: the current landscape
Anbar, H. S., Isa, Z., Elounais, J. J., Jameel, M. A., Zib, J. H., Samer, A. M., Jawad, A. F., & El–Gamal, M. I. (2021) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2021.1910237 · Cited by 31
“Generally, in postmenopausal women steroids synthesis mainly depend on enzymatic conversions in peripheral tissues as ovarian activity stimulation has been diminished at menopause[32].”
BackgroundKe, Y., Labrie, F., Gonthier, R., Simard, J.-N., Bergeron, D., Martel, C., Vaillancourt, M., Montesino, M., Lavoie, L., Archer, D. F., et al. (2015) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2015.08.016 · Cited by 29
“In fact, since these women are deficient in sex steroids derived from circulating DHEA [40,41], the increase from an average of 1800 93.”
BackgroundSelf-citationIto, K., Miki, Y., Suzuki, T., McNamara, K. M., & Sasano, H. (2016) · Endocrine-Related Cancer · doi:10.1530/erc-15-0470 · Cited by 29
“2011, Labrie 2015), and several studies reported that the serum levels of androgens between ovarian and peripheral veins were significantly different between early and late menopausal women, suggesting that the production of androgens by the ovaries could persist even 10 years after the onset of…”
Sauer, U., Talaulikar, V. S., & Davies, M. C. (2018) · Maturitas · doi:10.1016/j.maturitas.2018.07.016 · Cited by 30
Impact of Estrogens on the Regulation of White, Beige, and Brown Adipose Tissue Depots
Bernasochi, G. B., Bell, J. R., Simpson, E. R., Delbridge, L. M. D., & Boon, W. C. (2019) · Comprehensive physiology · doi:10.1002/cphy.c180009 · Cited by 34
Intracrine Testosterone Activation in Human Pancreatic β-Cells Stimulates Insulin Secretion
Xu, W., Schiffer, L., Qadir, M. M. F., Zhang, Y., Hawley, J. M., de Sa, P. M., Keevil, B. G., Wu, H., Arlt, W., & Mauvais‐Jarvis, F. (2020) · Diabetes · doi:10.2337/db20-0228 · Cited by 27
“Alternatively, following an intracrine principle, E2 locally produced in the b-cell could directly and efficiently interact with ERs in the same b-cells followed by inactivation in the same cells (24).”
BackgroundRungseevijitprapa, W., Yingngam, B., & Chaiyasut, C. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13071068 · Cited by 27
Steroids, steroid associated substances and gestational diabetes mellitus
Hill, M., Pařı́zek, A., Šimják, P., Koucký, M., Anderlová, K., Krejčí, H., Vejražková, D., Ondřejíková, L., Černý, A., & Kancheva, R. L. (2021) · Physiological Research · doi:10.33549/physiolres.934794 · Cited by 27
Steroid Hormones: Synthesis, Secretion, and Transport
Acconcia, F., & Marino, M. (2018) · Endocrinology · doi:10.1007/978-3-319-44675-2_4 · Cited by 29
Sinclair, M. J., Gow, P. J., Angus, P., Hoermann, R., Handelsman, D. J., Wittert, G., Martin, S., & Grossmann, M. (2016) · Liver International · doi:10.1111/liv.13122 · Cited by 28
Adipose Tissue Sex Steroids in Postmenopausal Women With and Without Menopausal Hormone Therapy
Hetemäki, N., Robciuc, A., Vihma, V., Haanpää, M., Hämäläinen, E. K., Tikkanen, M. J., Mikkola, T. S., & Savolainen-Peltonen, H. M. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae458 · Cited by 26
Androgen receptor signalling in non-prostatic malignancies: challenges and opportunities
Dotto, G. P., Buckinx, A., Özdemir, B. C., & Simon, C. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-024-00772-w · Cited by 26
Cornel, K. M. C., Krakstad, C., Delvoux, B., Xanthoulea, S., Jori, B., Bongers, M. Y., Konings, G. F. J., Kooreman, L. F. S., Kruitwagen, R. F., Salvesen, H. B., et al. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.11.030 · Cited by 26
Konings, G. F., Cornel, K. M., Xanthoulea, S., Delvoux, B., Skowron, M. A., Kooreman, L., Koskimies, P., Krakstad, C., Salvesen, H. B., van Kuijk, K., et al. (2018) · The Journal of Pathology · doi:10.1002/path.5004 · Cited by 26
“In addition, local estrogen synthesis through 17β-hydroxysteroid dehydrogenases (17β-HSDs) also contributes significantly to estrogen exposure in endometrial cells [3,4].”
BackgroundCarletto, B., Koga, A. Y., Novatski, A., Mainardes, R. M., Lipinski, L. C., & Farago, P. V. (2021) · Colloids and Surfaces B Biointerfaces · doi:10.1016/j.colsurfb.2021.111720 · Cited by 28
Englert-Golon, M., Andrusiewicz, M., Żbikowska, A., Chmielewska, M., Sajdak, S., & Kotwicka, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126216 · Cited by 24
Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens
Schiffer, L., Bossey, A., Kempegowda, P., TAYLOR, A. E. R., Akerman, İ., Scheel‐Toellner, D., Storbeck, K., & Arlt, W. (2021) · European Journal of Endocrinology · doi:10.1530/eje-20-1077 · Cited by 22
“Intracrine androgen activation from adrenal androgen precursors contributes a large proportion of androgen receptor activation in peripheral target cells and tissues of androgen action (17, 26).”
BackgroundEffects of Age and Estradiol on Gene Expression in the Rhesus Macaque Hypothalamus
Eghlidi, D. H., & Urbanski, H. F. (2015) · Neuroendocrinology · doi:10.1159/000381063 · Cited by 22
Assi, N., Rinaldi, S., Viallon, V., Dashti, S. G., Dossus, L., Fournier, A., Cervenka, I., Kvaskoff, M., Fortner, R. T., Bergmann, M. M., et al. (2019) · International Journal of Cancer · doi:10.1002/ijc.32324 · Cited by 22
“Hormones and SHBG are involved in complex biological pathways that regulate a host of metabolic functions.(20,40) It had previously been suggested that sex-hormones could be involved in the underlying mechanism of the alcohol and BC association.”
BackgroundIs Estradiol a Biomarker of Type 2 Diabetes Risk in Postmenopausal Women?
Mauvais‐Jarvis, F. (2017) · Diabetes · doi:10.2337/dbi16-0063 · Cited by 22
“tissue, muscle, and bone from circulating sources of adrenal androgens, mainly dehydroepiandrosterone, which is converted to androstenedione, which in turn undergoes aromatization to estrone (E1) (15).”
BackgroundKASE, N. G., Friedman, E. G., Brodman, M. L., Kang, C., Gallagher, E. J., & LeRoith, D. (2020) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2020.05.051 · Cited by 24
Endo, S., Morikawa, Y., Kudo, Y., Suenami, K., Matsunaga, T., Ikari, A., & Hara, A. (2020) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2020.105586 · Cited by 21
Impact of aromatase absence on murine intraocular pressure and retinal ganglion cells
Chen, X., Liu, Y., Zhang, Y., Kam, W. R., Pasquale, L. R., & Sullivan, D. A. (2018) · Scientific Reports · doi:10.1038/s41598-018-21475-x · Cited by 20
17β-Hydroxysteroid dehydrogenases and neurosteroid metabolism in the central nervous system
He, X., Dobkin, C., & Yang, S. (2018) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2018.10.002 · Cited by 20
Paatela, H., Wang, F., Vihma, V., Savolainen-Peltonen, H., Mikkola, T. S., Turpeinen, U., Hämäläinen, E., Jauhiainen, M., & Tikkanen, M. J. (2016) · European Journal of Endocrinology · doi:10.1530/eje-15-0831 · Cited by 19
Prasterone: A Review in Vulvovaginal Atrophy
Heo, Y. (2019) · Drugs & Aging · doi:10.1007/s40266-019-00693-6 · Cited by 19
Dehydroepiandrosterone as a potential agent to slow down ovarian aging
Lin, L., Cheng, J., Wang, P., Li, C., & Tsui, K. (2017) · Journal of obstetrics and gynaecology research · doi:10.1111/jog.13456 · Cited by 19
“Dehydroepiandrosterone (DHEA), a precursor of estradiol and testosterone, originates in the adrenal zona reticularis and in ovarian theca cells.(10,11) The concentration ofDHEA in the serumdecreases gradually as age increases and reaches a nadir in 50–60-year-olds,(12,13)”
BackgroundFrycz, B. A., Murawa, D., Borejsza‐Wysocki, M., Wichtowski, M., Spychała, A., Marciniak, R., Murawa, P., Drews, M., & Jagodziński, P. P. (2017) · Oncology Letters · doi:10.3892/ol.2017.5881 · Cited by 18
“In the aromatase signaling pathway, adione and testosterone are converted into E1 and E2, respectively, by mRNA expression of steroidogenic enzymes, steroid hormone receptors and their coregulators in gastric cancer aromatase (CYP19A1) (14).”
Labrie, F., & Martel, C. (2017) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2016-0042 · Cited by 17
“Concerning DHEA, the exclusive source of sex steroids after menopause [1, 13], it should be remembered that the normal endometrium does not possess the enzymes required to transform DHEA into estrogens or androgens [85, 86], thus explaining the atrophy seen in the endometrium after menopause in all normal women [87],…”
BackgroundSelf-citationImtiaz, S., Sohail, S., Din, F. U., Ali, Z., Batool, S., Malik, M., Nawaz, A., Alamri, A. H., Lahiq, A. A., Alsharif, S. T., et al. (2024) · Pharmaceutical Development and Technology · doi:10.1080/10837450.2024.2382437 · Cited by 16
“%) of the physiologically active oestrogen produced after menopause is created locally in BC (Labrie 2015).”
Metadata
- Authors
- Labrie, F.
- Corresponding author
- Labrie, Fernand
- Venue
- The Journal of Steroid Biochemistry and Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 145
- Pages
- 133-138
- ISSN
- 0960-0760 (ISSN-L)
- OpenAlex
- W1969438694
- Cited by
- 227
- References
- 50
- Citations by year
- 2026: 15 · 2025: 8 · 2024: 14 · 2023: 14 · 2022: 17 · 2021: 18 · 2020: 14 · 2019: 17 · 2018: 24 · 2017: 34 · 2016: 29 · 2015: 19
- FWCI
- 3.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Steroid Biochemistry and Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- intracrinology, menopause, postmenopausal women, androgen production, dehydroepiandrosterone, steroidogenic enzymes, serum estradiol, endometrial cancer risk, DHEA supplementation, menopausal symptoms, androgen insensitivity syndrome
- MeSH terms
- Breast Neoplasms, Dehydroepiandrosterone, Estrogens, Female, Humans, Hydrocortisone, Menopause, Ovary, Progesterone, Steroids, Estrogen Receptor Modulators, Aromatase Inhibitors
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