Cited by 227Estrogen and related hormone effectsMenopause: Health Impacts and TreatmentsHormonal and reproductive studies

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All sex steroids are made intracellularly in peripheral tissues by the mechanisms of intracrinology after menopause

Labrie, Fernand·2015·The Journal of Steroid Biochemistry and Molecular Biology

DOI 10.1016/j.jsbmb.2014.06.001

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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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Labrie, 2010, DHEA after menopause–sole source of sex steroids and potential sex steroid deficiency treatment, Menopause Management, 19, 14
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BackgroundInfluential
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“According to the physiological mechanism of intracrinology, sex steroids are made in target tissues and exert their action locally without release in the circulation [30].”
Background
Effects of Ziyin Jianghuo Ningxin decoction plus dehydroepiandrosterone and femoston in treatment of patients with menopausal symptoms
Jing, L., Zhu, J., Fubo, T., Chen, L., Zhang, Y., Wang, Y., Mingyan, W., Gober, H.-J., Li, D., & Wang, L. (2018) · 中医杂志：英文版 · doi:10.1016/s0254-6272(18)30920-8 · Cited by 6
Effects of 17β-HSD2 inhibition in bones on osteoporosis based on an animal rat model
Müller, S. T., Pählig, S., Merabet, A., Abdelsamie, A. S., van Koppen, C. J., Marchais‐Oberwinkler, S., Hartmann, R. W., Zierau, O., & Vollmer, G. (2019) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2019.105405 · Cited by 6
Timing of first childbirth and age-related cataract
Park, S., & Choi, N. (2017) · Menopause The Journal of The North American Menopause Society · doi:10.1097/gme.0000000000000887 · Cited by 5
Influence of breast cancer risk factors and intramammary biotransformation on estrogen homeostasis in the human breast
Pemp, D., Geppert, L. N., Wigmann, C., Kleider, C., Hauptstein, R., Schmalbach, K., Ickstadt, K., Esch, H. L., & Lehmann, L. (2020) · Archives of Toxicology · doi:10.1007/s00204-020-02807-1 · Cited by 5
“The general consensus is that blood levels of estrogens contribute to breast tissue levels, yet whether levels of circulating estrogens serve as surrogate for levels of estrogens in breast tissues, or more precisely, in GLT or ADT, is a matter of debate (Lønning et al. 2011; Bulun et al. 2012; Colditz and Bohlke 2014;…”
BackgroundInfluential
Serum estrone concentration, estrone sulfate/estrone ratio and BMI are associated with human epidermal growth factor receptor 2 and progesterone receptor status in postmenopausal primary breast cancer patients suffering invasive ductal carcinoma
Vincze, B., Kapuvári, B., Udvarhelyi, N., Horváth, Z., Mátrai, Z., Czeyda‐Pommersheim, F., Köhalmy, K., Kovács, J., Boldizsár, M., Láng, I., et al. (2015) · SpringerPlus · doi:10.1186/s40064-015-1171-8 · Cited by 6
“The associations between E1 and E1S and between E2 and E1S and between DHEAS and E1 indicate the importance of circulating E1S and DHEAS as peripheral estrogen pools in serum (Labrie 2015).”
Background
Qualitative and quantitative differences in estrogen biotransformation in human breast glandular and adipose tissues: implications for studies using mammary biospecimens
Pemp, D., Kleider, C., Schmalbach, K., Hauptstein, R., Geppert, L. N., Köllmann, C., Ickstadt, K., Eckert, P., Neshkova, I., Jakubietz, R. G., et al. (2019) · Archives of Toxicology · doi:10.1007/s00204-019-02564-w · Cited by 5
“2012; Labrie 2015; Stanczyk et al.”
Tumor board presentation of a woman with metastatic, hormone receptor‐positive, mismatch repair‐deficient endometrial cancer
Bennett, J. A., Fleming, G. F., Kurnit, K. C., Mills, K. A., & van Weelden, W. J. (2022) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21715 · Cited by 5
“Intracrinology describes the process of intracellular production of biologically active estrogens from circulating forms of inactive types of estrogens in a multistep process.(42,43) In the setting of endocrine therapy, intratumoral secretion of estrogens could be an escape mechanism that maintains estrogenic exposure…”
Background
Is testosterone important in LUT function in men and women? ICI‐RS 2015
Badawi, J. K., Bosch, J. L. H. R., Djurhuus, J. C., & Hanna‐Mitchell, A. T. (2017) · Neurourology and Urodynamics · doi:10.1002/nau.23041 · Cited by 5
“In addition, the adrenal prohormones didehydroepiandrosterone (DHEA) and didehydroepiandrosterone sulphate (DHEA-S) are upstream precursors of T,(1) and an important source of both T and E2 in postmenopausal women.(3) Thus, androgens play important roles in biological functions both directly through androgen signaling…”
Background
Sex-specific association of serum dehydroepiandrosterone and its sulfate levels with osteoporosis in type 2 diabetes
Li, S., Li, W., Chang, L., Wan, J., Chen, S., Zhang, X., He, Q., & Liu, M. R. (2024) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-024-01511-9 · Cited by 4
“Because of DHEA and DHEAS, as precursors of estrogen and testosterone, could exert their effects in a tissue-specific manner [43].”
Unveiling estrogen’s role: a comprehensive review of its impact on skin health and disease
Yi, L., Deng, N., Luo, X., Tan, Y., Huang, Z., Liu, Y., Xing, J., Zeng, Y., & Yi, J. (2026) · APOPTOSIS · doi:10.1007/s10495-025-02244-4 · Cited by 4
“Furthermore, the decline in 17β-estradiol levels is considered the primary cause of skin aging after menopause [58], which is linked to cellular aging and oxidative stress [59].”
A highly sensitive LC-MS/MS method for the simultaneous quantitation of serum androstane-3α, 17β-diol and androstane-3β, 17β-diol in post-menopausal women
Ke, Y., Dury, A. Y., & Labrie, F. (2019) · Journal of Chromatography B · doi:10.1016/j.jchromb.2019.03.007 · Cited by 4
Self-citation
Quantitative analysis of specific androgens in serum and urine samples from male, pre, and postmenopausal subjects using LC-MRM-MS
Masood, M. A., Khatoon, R., & Veenstra, T. D. (2022) · Steroids · doi:10.1016/j.steroids.2022.109060 · Cited by 4
Increased risk of ovarian and breast malignancies in women with polycystic ovary syndrome: a review article
Chen, H., Jiang, Q., & Yin, Y. (2023) · Cellular and Molecular Biology · doi:10.14715/cmb/2023.69.14.3 · Cited by 4
Intracrinology: The New Science of Sex Steroid Physiology in Women
Labrie, F. (2018) · ISGE series · doi:10.1007/978-3-319-63540-8_1 · Cited by 4
Self-citation
Cryochemical Synthesis of Polymorphous Nanostructures of a Steroid Neurohormone
Морозов, Ю. Н., Chistyakov, D. V., Chernyshev, V. V., & Сергеев, Г. Б. (2017) · Molecules · doi:10.3390/molecules22081378 · Cited by 4
“The choice of DHEA as the study object is associated with its tendency to form polymorphous structures [15,16].”
Background
Roles of Type 10 17β-Hydroxysteroid Dehydrogenase in Health and Disease
He, X., Frackowiak, J., & Yang, S. (2025) · Journal of Personalized Medicine · doi:10.3390/jpm15080346 · Cited by 3
Female Adipose Tissue Sex Steroid Biosynthesis
Hetemäki, N., Mikkola, T. S., & Savolainen-Peltonen, H. M. (2025) · Seminars in Reproductive Medicine · doi:10.1055/s-0045-1811952 · Cited by 5
“While the role of local estrogen production in adipose tissue is well established in postmenopausal women, 3,4,7,177 the extent and importance of adipose tissue production of estrogens is lessintuitive inwomenbefore menopause.”
Dehydroepiandrosterone sulfate (DHEAS) in excreta is a good indicator of serum DHEAS in Japanese macaques (Macaca fuscata)
Mouri, K., & Shimizu, K. (2023) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2023.114277 · Cited by 3
Potential therapeutic efficacy of photodynamic therapy on female hormonal-dependent cancers in a hormonal simulated microenvironment
Chu, E. S. M., Wu, R. W. K., & Huang, Z. W. (2024) · Photodiagnosis and Photodynamic Therapy · doi:10.1016/j.pdpdt.2024.103998 · Cited by 3
Overviews of Stem Cells for Gonadal and Adrenal Steroidogenic Cells
Yazawa, T. (2015) · American Journal of Life Sciences · doi:10.11648/j.ajls.s.2015030302.21 · Cited by 3
“Therefore, ovarian androgen and estrogen production ceases in post-menopausal women [21, 22].”
Background
Investigating the mechanism of PAD in the treatment of acne based on network pharmacology and molecular docking: A review
Yan, Q., Zhang, F., Qiao, Z., Jin, Y., Zheng, R., & Wu, J. (2024) · Medicine · doi:10.1097/md.0000000000038785 · Cited by 3
“[31] Estrogen can be synthesized locally in the skin, promote keratinocyte and fibroblast function, induce stromal deposition and promote anti-inflammatory (M2) cytokines, and conversely inhibit pro-inflammatory (M1) cytokines, thereby inhibiting inflammation and reducing wound protease levels.”
Background
Plasma Steroids are Not Associated with Resting and Exercise Blood Pressure
He, Z., Rankinen, T., Leon, A. S., Skinner, J. S., Tchernof, A., & Bouchard, C. (2018) · International Journal of Sports Medicine · doi:10.1055/a-0660-0121 · Cited by 3
Menopause: The Concepts and the Biological Background
Cano, A. (2017) · Springer eBooks · doi:10.1007/978-3-319-59318-0_2 · Cited by 3
Estrone Sulfatase Inhibitors as New Anticancer Agents
Morozkina, S. N., & Shavva, A. G. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.85850 · Cited by 3
“In postmenopausal women estrogens are produced in peripheral tissues such as adipose tissues, skin, and mammary glands [10, 11].”
Background
To the Editor
Portman, D. J., Archer, D. F., Martel, C., & Labrie, F. (2016) · Menopause The Journal of The North American Menopause Society · doi:10.1097/gme.0000000000000638 · Cited by 3
Self-citation
What can we learn from the history of steroid metabolites and the ongoing identification of novel biologically active steroid metabolites?
Odermatt, A., & Morris, D. J. (2026) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2026.106954 · Cited by 2
Hormones
Löfqvist, H. (2022) · Springer eBooks · doi:10.1007/978-3-030-92735-6_2 · Cited by 2
Quality of life in heterosexual menopausal women: The indirect effect of sexual and marital satisfaction, menopause representations, and psychological morbidity
Pereira, M. G., Bernardo, A. C., Fernandes, I., & Almeida, A. C. (2023) · Health Care For Women International · doi:10.1080/07399332.2023.2245374 · Cited by 1
“Approximately 70% of women in Europe and North America report symptomatology (Shaheen et al., 2015), in a decline of 10–15% in labor productivity, a 23% increase in sickness leave, and 40% increase in health care costs (Labrie, 2015).”
Intravaginal DHEA for the Treatment of Vulvovaginal Atrophy, Intracrinology at Work
Labrie, F. (2018) · ISGE series · doi:10.1007/978-3-319-63540-8_24 · Cited by 1
Self-citation
Effect of menopausal hormone therapy on the skin as a component of healthy aging
Yureneva, S. V., & Ilina, L. M. (2018) · Meditsinskiy sovet = Medical Council · doi:10.21518/2079-701x-2018-6-156-160 · Cited by 1
“Благодаря так называемой «интракринологии» [16] эстрогены могут локально синтезироваться в коже, поскольку ее клетки содержат все необходимые ферменты, участвующие в их метаболизме и продуцируемые клетками кожи и волосяными фолликулами [3, 14].”
МЕНОПАУЗАЛЬНИЙ МЕТАБОЛІЧНИЙ СИНДРОМ: ПОГЛЯД ЕНДОКРИНОЛОГА
Чернявська, І., & Mykytyuk, M. (2021) · PROBLEMS OF ENDOCRINE PATHOLOGY · doi:10.21856/j-pep.2021.2.16 · Cited by 1
Hormonal Regulation of Vaginal Mucosa
Kallak, T. K. (2015) · Cited by 1
Incorporation of Testicular Ultrasonography and Hair Steroid Concentrations in Bull Breeding Soundness Evaluation
Cotticelli, A., Navas, L., Calabria, A., Bifulco, G., Campanile, G., Peric, T., Prandi, A., D’Occhio, M. J., & Russo, M. (2023) · Veterinary Sciences · doi:10.3390/vetsci10060373 · Cited by 1
“This relationship may have been partly due to the prohormonal role of DHEA-S and its conversion to androgens and/or estrogens in peripheral target tissues [34].”
Background
New Insights for Hormone Therapy in Perimenopausal Women Neuroprotection
Russu, M. C., & Antonescu, A. C. (2018) · InTech eBooks · doi:10.5772/intechopen.74332 · Cited by 1
“A special analysis is to be made on DHEA(S)—the “youth” hormone—for which human body does not have receptors, but it is a source of intracrinology, with different enzymes for steroidforming and/or for steroid-inactivating, permitting each cell/tissue to synthesize a small amount of androgens and/or estrogens in order…”
Background
Therapeutic Strategies to Spinal Cord Injury
Jendelová, P. (2018) · MDPI eBooks · doi:10.3390/books978-3-03897-407-9 · Cited by 1
Gender Bias in Medicine: “How Women Continue to Get the Shaft When It Comes to Testosterone Therapies”
DeRosa, A. (2021) · Androgens Clinical Research and Therapeutics · doi:10.1089/andro.2021.0005 · Cited by 1
New Insights on the Environment of Sex Steroids in Adipose Tissue of Postmenopausal Women at Hormone Therapy
Spritzer, P. M., & dos Santos, B. R. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae758 · Cited by 1
Onkologie und Versorgung in Fach- und Publikumsmedien
Gaisser, A. (2013) · Der Onkologe · doi:10.1007/s00761-013-2580-3
Postnatal Hypothalamic-Pituitary-Gonadal Axis Activation (i.e., Minipuberty) in Full-term and Preterm Infants
Kuiri‐Hänninen, T. (2015)
Response to the comments by Per E. Lønning
Vihma, V., Tikkanen, M. J., & Hämäläinen, E. K. (2016) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2016.02.025
“It is generally accepted that after the menopause estrogens are synthesized in adipose and other peripheral tissues and the circulating levels merely reflect the local estrogen metabolism in tissues [6,7].”
Background
Onkologie und Versorgung in Fach- und Publikationsmedien
(KID), K., & Gaisser, A. (2016) · Der Onkologe · doi:10.1007/s00761-016-0039-z
“So stieg in einer Studiemit postmenopausalenFrauen derÖstrogenspiegel unterDHEA-Therapie an [22], was auf extragonadale Bildung unter Mitwirkung von Aromatase zurückgeht [21].”
Background
Plasma Steroids and Cardiorespiratory Fitness Response to Regular Exercise
He, Z., Rankinen, T., Leon, A. S., Skinner, J. S., Tchernof, A., & Bouchard, C. (2017) · Research and perspectives in endocrine interactions · doi:10.1007/978-3-319-72790-5_3
“Steroid hormones are mainly synthesized from cholesterol in the gonads and adrenal glands but some are also produced in other tissues such as skeletal muscle (Sato and Lemitsu 2015), adipose tissue, liver and others (Luu-The and Labrie 2010; Labrie 2015).”
Background
Genitourinary Syndrome of Menopause (GSM): the Role of Intravaginal DHEA (Prasterone)
Phillips, N. A., & Bachmann, G. A. (2018) · Current Sexual Health Reports · doi:10.1007/s11930-018-0149-2
“There is no boxed warning stating that intravaginal DHEA is contraindicated in women who have had breast cancer, although it is referenced that DHEA has not been studied in this population [16]. Curr Sex Health Rep (2018) 10:109–113 111”
Background
Induced ablation of skeletal muscle-specific estrogen receptor-alpha in adult female mice increased the susceptibility to develop skeletal muscle inflammation and glucose intolerance under chronic lipid overload
InÌƒigo, M. M. R. (2018) · The Scholarship East Carolina University's Institutional Repository (East Carolina University)
The Passing of Dr. Fernand Labrie (1937–2019): The legacy of excellence in science
Tchernof, A., Lin, S. X., Luu-The, V., & Simard, J. (2019) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2019.02.005
Der rätselhafte Fall
Segerer, S. E. (2020) · Journal für Gynäkologische Endokrinologie/Schweiz · doi:10.1007/s41975-020-00128-1
The role of DHEA in the aetiology of modern chronic disease
Powrie, Y. S. L. (2020) · SUNScholar (Stellenbosch University)
Die Behandlung mit Hormonen in den Wechseljahren
Löfqvist, H. (2021) · Springer eBooks · doi:10.1007/978-3-662-62710-5_3

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)
DOI: 10.1016/j.jsbmb.2014.06.001
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
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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All sex steroids are made intracellularly in peripheral tissues by the mechanisms of intracrinology after menopause

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