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Cited by 545Estrogen and related hormone effectsHormonal and reproductive studiesAdrenal Hormones and Disorders

Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone

Labrie, Fernand, Luu-The, Van, Labrie, Claude, Bélanger, Alain, Simard, Jacques, Lin, Sheng-Xiang, Pelletier, Georges·2003·Endocrine Reviews
DOI 10.1210/er.2001-0031
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Abstract

Serum androgens as well as their precursors and metabolites decrease from the age of 30 -40 yr in women, thus suggesting that a more physiological hormone replacement therapy at menopause should contain an androgenic compound.It is important to consider, however, that most of the androgens in women, especially after menopause, are synthesized in peripheral intracrine tissues from the inactive precursors dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) of adrenal origin.Much progress in this new area of endocrine physiology called intracrinology has followed the cloning and characterization of most of the enzymes responsible for the transformation of DHEA and DHEA-S into androgens and estrogens in peripheral target tissues, where the locally produced sex steroids are exerting their action in the same cells in which their synthesis takes place without significant diffusion into the circulation, thus seriously limiting the interpretation of serum levels of active sex steroids.The sex steroids made in peripheral tissues are then inactivated locally into more water-soluble compounds that diffuse into the general circulation where they can be measured.In a series of animal models, androgens and DHEA have been found to inhibit breast cancer development and growth and to stimulate bone formation.In clinical studies, DHEA has been found to increase bone mineral density and to stimulate vaginal maturation without affecting the endometrium, while improving well-being and libido with no significant side effects.The advantage of DHEA over other androgenic compounds is that DHEA, at physiological doses, is converted into androgens and/or estrogens only in the specific intracrine target tissues that possess the appropriate physiological enzymatic machinery, thus limiting the action of the sex steroids to those tissues possessing the tissue-specific profile of expression of the genes responsible for their formation, while leaving the other tissues unaffected and thus minimizing the potential side effects observed with androgens or estrogens administered systemically.(Endocrine Reviews 24: 152-182, 2003) I. Androgens and Their Role in Women A. Introduction B. Decrease of serum DHEA, androgens, and their metabolites with age C. Androgens and bone physiology D. Other roles of androgens in women II.DHEA Is Predominantly Converted into Androgens in Women A. Intracrinology B. Structure of the human steroidogenic enzymes C. Women produce about two thirds of the androgens synthesized in men III.Androgens Inhibit Breast Cancer A. Clinical data B. Preclinical data IV.DHEA Inhibits Breast Cancer A. Preclinical studies B. Epidemiological studies C. DHEA and other cancers V. Rationale for the Use of DHEA as a Source of Androgens in Postmenopausal Women A. Tissue-specific androgenic and/or estrogenic activity of DHEA B. Benefits of DHEA in postmenopausal women

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that women produce substantial androgens, largely via peripheral intracrine conversion of adrenal DHEA/DHEA-S, and that these androgens decline with age. It synthesizes preclinical and clinical evidence that androgens and DHEA inhibit breast cancer and that physiological DHEA replacement may benefit postmenopausal women without stimulating the endometrium.

Key findings

  • Serum DHEA falls by 70% in 50–60-year-old women versus 20–30-year-old peak values, and mean serum testosterone decreases from approximately 1.3 to 0.61 nM between ages 21 and 40.
  • Based on serum ADT-G, 3α-diol-G, and 3β-diol-G, women produce about 71% (“two thirds”) of the total androgens synthesized in men, mostly from peripheral intracrine conversion of DHEA/DHEA-S.
  • Androgens/DHEA inhibit breast cancer in models: DHT blocked E2-stimulated ZR-75-1 growth; DHEA reduced DMBA tumor incidence to 22%, 11%, and 3.8% at serum DHEA levels of 7.09, 17.5, and 27.2 nM versus 68% in controls; DHEA inhibited ZR-75-1 xenograft growth by 50.4%, 76.8%, and 80.0% at 0.3, 1.0, and 3.0 mg/day.
  • In a 12-month study of 60–70-year-old women (n=15), percutaneous 10% DHEA increased bone mineral density by 2.3% at the hip, 3.75% at Ward’s triangle, and 2.2% at the lumbar spine, with no endometrial stimulation; fasting glucose and insulin decreased by 12% and 17%, respectively.

Methods

  • Narrative review integrating the author’s and others’ endocrine, preclinical, and clinical studies; no systematic search or meta-analysis is described.
  • Evidence includes serum steroid/metabolite measurements across ages, DHEA administration studies, human breast cancer cell lines (ZR-75-1, MCF-7), DMBA-induced rat mammary carcinoma, nude mouse xenografts, and clinical DHEA replacement studies.
  • Main analysis is descriptive synthesis comparing intracrine enzyme expression, serum androgen metabolites, tumor outcomes, and bone/clinical endpoints.

Limitations

  • The paper states that serum testosterone and E2 poorly reflect intracellular/intracrine androgen and estrogen activity, and that animal models such as rats, mice, and guinea pigs do not secrete significant adrenal DHEA/DHEA-S, limiting translation.
  • The paper notes contradictory epidemiological data on androgens and breast cancer risk, attributed to small cancer numbers, methodology, and low predictive value of serum sex steroid measurements; it also notes possible differences in metabolic clearance rates affecting androgen-pool estimates.
  • Evident from the text: this is a narrative review, not a systematic review, and many key preclinical and clinical findings come from the author’s group; the described 12-month DHEA clinical study had n=15 and the text does not report a control group.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1210/er.2001-0031

Cites

338 of 338 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 297 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Women produce approximately 71% or two thirds of the total androgens synthesized in men.

    “As assessed by measurement of the circulating levels of these conjugated metabolites of DHT, it can be estimated that women produce approximately 71% or two thirds of the total androgens synthesized in men (Table 1);”
    • Also stated in: § C. Women produce about two thirds of the androgens synthesized in men · plain
      “C. Women produce about two thirds of the androgens synthesized in men”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Table 1

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    • cites [23] Labrie, 1997, Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging., J Clin Endocrinol Metab source

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  • Findingown data

    Treatment with DHEA caused an increase in serum ADT-G, 3␣-diol-G, and 3␤-diol-G of approximately 125%, 140%, and 120%, respectively.

    “treatment with DHEA caused an increase in serum ADT-G, 3␣-diol-G, and 3␤diol-G of approximately 125% (Fig. 13A), 140% (Fig. 13B), and 120% (Fig. 13C), respectively.”
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    • cites Fig. 13A

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    • cites Fig. 13B

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    • cites Fig. 13C

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  • Findingown data

    After daily percutaneous DHEA, serum 4-dione and testosterone increased by about 100% and 50% over control, respectively.

    “whereas serum 4-dione and testosterone increased by about 100% and 50% over control, respectively (Fig. 12).”
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    • cites Fig. 12

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  • Findingcitation

    Between ages 21 and 40 yr, mean serum testosterone in normal women decreases from approximately 1.3 to 0.61 nM.

    “between the ages of 21 and 40 yr, mean serum testosterone in normal women decreases from approximately 1.3 to 0.61 nm (Ref.26; Fig. 2).”
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    • cites Ref.26

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  • Findingown data

    In the 50-to 60-yr-old group, serum DHEA has already decreased by 70% from its 20-to 30-yr-old peak values in women.

    “in the 50-to 60-yr-old group, serum DHEA has already decreased by 70% from its 20-to 30-yr-old peak values in women (Fig. 1).”
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    • cites Fig. 1

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  • The quote only partly states this claim. 3
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    Findingcitation

    After percutaneous administration of DHEA in 60-to 70-yr-old men and women, changes in serum DHEA within the physiological range led only to small or nonsignificant changes in serum testosterone, DHT, or E2, whereas the concentration of conjugated metabolites of DHT were markedly increased.

    “We then observed that changes in serum DHEA within the physiological range of young adult men and women led only to small or nonsignificant changes in serum testosterone, DHT, or E 2 , whereas, on the other hand, the concentration of the conjugated metabolites of DHT were markedly increased (27).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Labrie, 1997, Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: intracrinology., J Clin Endocrinol Metab source

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    Findingown data

    After daily percutaneous administration of DHEA (10 ml 20% solution for 2 wk) in postmenopausal women, serum DHEA, DHEA-S, and DHEA fatty acid esters increased approximately 175%, 130%, and 250% above control, respectively.

    “After daily administration of a single dose of DHEA percutaneously, serum DHEA, DHEA-S, and DHEA fatty acid esters increased approximately 175%, 130%, and 250% above control, respectively (Fig. 11),”
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    • cites Fig. 11

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    Findingown data

    Elevations in serum DHEA within the physiological range found in young adult women led to only small or even no significant changes in serum testosterone, DHT, or E2, whereas concentrations of conjugated metabolites of DHT are markedly elevated.

    “The present data show that elevations in serum DHEA within the physiological range found in young adult women led to only small or even no significant changes in serum testosterone, DHT, or E 2 , whereas, by contrast, the concentrations of the conjugated metabolites of DHT are markedly elevated,”
    Quote in the paperSubstantial claim

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    Findingcitation

    4-Dione also led to significant growth inhibition in ZR-75-1 cells, although the active concentrations (IC50, 15 nM) are in the upper range of the plasma concentrations (1-10 nM) found in women.

    “4-Dione also led to significant growth inhibition in ZR-75-1 cells, although the active concentrations (IC 50 , 15 nm) are in the upper range of the plasma concentrations (1-10 nm) found in women (215-218).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [215] Rochefort, 1983, The estrogenic and antiestrogenic activities of androgens in female target tissues., Pharmacol Ther source

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    • cites [216] Abraham, 1974, Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle., J Clin Endocrinol Metab source

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    • cites [217] Vermeulen, 1979, Factors affecting sex hormone levels in postmenopausal women., J Steroid Biochem source

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    • cites [218] Mistry, 1986, Endogenous C19-steroids and estradiol levels in human primary breast tumor tissues and their correlation with androgen and estrogen receptors., J Steroid Biochem source

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    Findingcitation

    The pure steroidal antiestrogen EM-139 not only completely reversed the effect of E2 but further inhibited cell number by 30% below control values (P<0.01).

    “the pure steroidal antiestrogen EM-139 (228), on the other hand, not only completely reversed the effect of E 2 but further inhibited cell number by 30% below control values (P Ͻ 0.01; Fig. 18B).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [228] Lévesque, 1991, Synthesis and biological activity of new halo-steroidal antiestrogens., J Med Chem source

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    Findingcitation

    In ZR-75-1 cells, DHT not only completely blocked the stimulatory effect of E2 on cell proliferation but also reduced cell growth in the absence of estrogens.

    “DHT not only completely blocked the stimulatory effect of E 2 on cell proliferation but also reduced cell growth in the absence of estrogens.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [208] Poulin, 1988, Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line., Breast Cancer Res Treat source

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    Findingcitation

    In ZR-75-1 cells, concentrations of DHT in the incubation medium similar to the plasma levels found in normal women and breast cancer patients (0.3-0.7 nM) are potent inhibitors of the mitogenic effect of E2 and even inhibit growth in the absence of estrogens.

    “In ZR-75-1 cells, concentrations of DHT in the incubation medium similar to the plasma levels found in normal women (215-217) and breast cancer patients (Ref.218; 0.3-0.7 nm) are potent inhibitors of the mitogenic effect of E 2 and even inhibit growth in the absence of estrogens (208).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [208] Poulin, 1988, Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line., Breast Cancer Res Treat source

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    • cites [215] Rochefort, 1983, The estrogenic and antiestrogenic activities of androgens in female target tissues., Pharmacol Ther source

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    • cites [216] Abraham, 1974, Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle., J Clin Endocrinol Metab source

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    • cites [217] Vermeulen, 1979, Factors affecting sex hormone levels in postmenopausal women., J Steroid Biochem source

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    • cites [218] Mistry, 1986, Endogenous C19-steroids and estradiol levels in human primary breast tumor tissues and their correlation with androgen and estrogen receptors., J Steroid Biochem source

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    Findingcitation

    The growth-inhibitory effect of DHT is clearly additive to that induced by maximally effective concentrations of the antiestrogen LY156758, indicating an action mediated by a mechanism different from interaction with the ER.

    “it was found that the growth-inhibitory effect of DHT is clearly additive to that induced by maximally effective concentra- tions of the antiestrogen LY156758, thus indicating an action mediated by a mechanism different from interaction with the estrogen receptor (ER; 229).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [229] de Launoit, 1991, Characteristics of the biphasic action of androgens and of the potent antiproliferative effects of the new pure antiestrogen EM-139 on cell cycle kinetic parameters in LNCaP human prostatic cancer cells., Cancer Res

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    Findingown data

    Treatment with DHT not only completely reversed the stimulatory effect of E2 on tumor growth but also decreased total tumor area to 48 ± 10% of its original size.

    “Treatment with DHT, on the other hand, not only completely reversed the stimulatory effect of E 2 on tumor growth but also decreased total tumor area to 48 Ϯ 10% of its original size.”
    Quote in the paperSubstantial claim

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    Findingown data

    The androgenic effect was observed at subnanomolar concentrations of the nonaromatizable androgen DHT, regardless of the presence of estrogens, and was competitively reversed by the antiandrogen hydroxyflutamide.

    “The androgenic effect was observed at subnanomolar concentrations of the nonaromatizable androgen DHT, regardless of the presence of estrogens, and was competitively reversed by the antiandrogen hydroxyflutamide.”
    Quote in the paperSubstantial claim

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    Findingcitation

    The antiproliferative activity of androgens in estrogen-deprived ZR-75-1 cells is more pronounced and is additive to that exerted by antiestrogens.

    “Moreover, the antiproliferative activity of androgens in estrogen-deprived ZR-75-1 cells is more pronounced and is additive to that exerted by antiestrogens (208,241).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [208] Poulin, 1988, Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line., Breast Cancer Res Treat source

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    • cites [241] Poulin, 1989, Antiestrogenic properties of keoxifene trans-4-hydroxytamoxifen, and ICI 164384, a new steroidal antiestrogen, in ZR-75-1 human breast cancer cells., Breast Cancer Res Treat source

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    Findingcitation

    The inhibition constant (Ki) value for the reversal of DHT action by hydroxyflutamide was estimated at 39 nM, in agreement with the affinity of the antagonist for the AR.

    “The inhibition constant (K i ) value for the reversal of DHT action by hydroxyflutamide was estimated at 39 nm (233), in agreement with the affinity of the antagonist for the AR (227).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [233] Cheng, 1973, Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (I50) on an enzymatic reaction., Biochem Pharmacol source

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    • cites [227] Simard, 1986, Characteristics of interaction of the antiandrogen flutamide with the androgen receptor in various target tissues., Mol Cell Endocrinol source

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    Findingcitation

    Size of ZR-75-1 tumors increased by 9.4-fold over 291 d in ovariectomized nude mice supplemented with E1; in control ovariectomized mice receiving vehicle alone, tumor size decreased to 36.9% of initial value.

    “the size of the ZR-75-1 tumors increased by 9.4-fold over a 291-d period (9.5 months) in ovariectomized nude mice supplemented with E 1 ; in contrast, in control ovariectomized mice that received the vehicle alone, tumor size decreased to 36.9% of the initial value during the course of the study (265).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [265] Couillard, 1998, Effect of dehydroepiandrosterone and the antiestrogen EM-800 on the growth of human ZR-75-1 breast cancer xenografts., J Natl Cancer Inst source

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    Findingown data

    An increase of 135% over control in plasma osteocalcin was observed, suggesting increased bone formation.

    “An increase of 135% over control (P Ͻ 0.05) in plasma osteocalcin was concomitantly observed, thus suggesting increased bone formation in agreement with our preclinical data (296).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [296] Martel

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    Findingcitation

    Anthropometric measurements showed no change in body weight but a 9.8% decrease in sc skin fold thickness at 12 months in 60- to 70-yr-old women treated with DHEA.

    “Anthropometric measurements showed no change in body weight but a 9.8% decrease in sc skin fold thickness at 12 months (P Ͻ 0.05; Ref. 297).”
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    • cites [297] Diamond, 1996, Metabolic effects of 12-month percutaneous DHEA replacement therapy in postmenopausal women., J Endocrinol

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    Findingcitation

    DHEA administration stimulated vaginal epithelium maturation in 8 of 10 women who had a maturation value of zero at onset, and in three women with intermediate vaginal maturation before therapy.

    “DHEA administration stimulated vaginal epithelium maturation in 8 of 10 women who had a maturation value of zero at the onset of therapy, whereas a stimulatory effect was also seen in the three women who had an intermediate vaginal maturation before therapy.”
    Quote in the paperNot a substantial claim

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    Findingnone given

    The index of sebum secretion was 79% increased after 12 months of DHEA therapy, with a return to pretreatment values 3 months after cessation of treatment.

    “The index of sebum secretion was 79% increased after 12 months of DHEA therapy, with a return to pretreatment values 3 months after cessation of treatment.”
    Quote in the paperNot a substantial claim

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    Findingcitation

    The estrogenic stimulatory effect observed in the vagina was not found in the endometrium, which remained completely atrophic in all women after 12 months of DHEA treatment.

    “the estrogenic stimulatory effect observed in the vagina was not found in the endometrium, which remained completely atrophic in all women after 12 months of DHEA treatment (280).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [280] Labrie, 1997, Effect of 12-month DHEA replacement therapy on bone, vaginum, and endometrium in postmenopausal women., J Clin Endocrinol Metab source

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    Findingcitation

    Changes in body fat and muscular surface areas were associated with a 12% decrease of fasting plasma glucose and a 17% decrease in fasting plasma insulin levels.

    “These changes in body fat and muscular surface areas were associated with a 12% decrease (P Ͻ 0.05) of fasting plasma glucose and a 17% decrease (P Ͻ 0.05) in fasting plasma insulin levels.”
    Quote in the paperSubstantial claim

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    Premisenone given

    In animal models, androgens and DHEA inhibit breast cancer development and growth and stimulate bone formation.

    “In a series of animal models, androgens and DHEA have been found to inhibit breast cancer development and growth and to stimulate bone formation.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Serum DHEA and DHEA-S decrease by 50% between the ages of 21 and 40 yr, and a similar decrease is observed for serum testosterone.

    “serum DHEA and DHEA-S decrease by 50% between the ages of 21 and 40 yr but also that a similar decrease is observed for serum testosterone (26).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Zumoff, 1995, Twenty-four-hour mean plasma testosterone concentration declines with age in normal premenopausal women., J Clin Endocrinol Metab

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  • May combine two claims.

    Interpretationreasoning

    Local biosynthesis and action of androgens in target tissues eliminates the exposure of other tissues to androgens and minimizes the risks of undesirable masculinizing or other androgen-related side effects.

    “Such local biosynthesis and action of androgens in target tissues eliminates the exposure of other tissues to androgens and thus minimizes the risks of undesirable masculinizing or other androgen-related side effects.”
    Quote in the paperSubstantial claim

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    Interpretationcitation

    The best estimate of the intracrine formation of estrogens in peripheral tissues in women is in the order of 75% before menopause and close to 100% after menopause.

    “Our best estimate of the intracrine formation of estrogens in peripheral tissues in women is in the order of 75% before menopause and close to 100% after menopause (25).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Labrie, 1991, Intracrinology., Mol Cell Endocrinol source

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    Premisecitation

    At 70 yr of age, serum DHEA-S levels are decreased to approximately 20% of their peak values, whereas they can decrease by 95% by the age of 85-90 yr.

    “at 70 yr of age, serum DHEA-S levels are decreased to approximately 20% of their peak values, whereas they can decrease by 95% by the age of 85-90 yr (22).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Migeon, 1957, Dehydroepiandrosterone and androsterone levels in human plasma. Effect of age and sex: day-to-day and diurnal variations., J Clin Endocrinol Metab source

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  • May combine two claims.

    Interpretationreasoning

    These steroids are then metabolized in the same cells into inactive glucuronidated and sulfated metabolites, which diffuse into the extracellular compartment and can be measured in the circulation.

    “These steroids are then metabolized in the same cells into inactive glucuronidated and sulfated metabolites, which finally diffuse in the extracellular compartment and can be measured in the circulation.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Western women having a low excretion of adrenal androgenic metabolites respond more poorly to endocrine therapy and have a shorter survival time.

    “it has been found that Western women having a low excretion of adrenal androgenic metabolites respond more poorly to endocrine therapy and have a shorter survival time (188 -190).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [188] Bulbrook, 1973, Effect of steroidal contraceptives on levels of plasma androgen sulphates and cortisol., Lancet source

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    • cites [189] Juret, 1968, New biological evidence on the hormone dependence of breast cancer (preliminary note)., Rev Fr Etud Clin Biol

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    • cites [190] Masnyk, 1978, Prediction of response to adrenalectomy in the treatment of advanced breast cancer., J Natl Cancer Inst source

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  • May combine two claims.

    Premisecitation

    The postmenopausal ovary secretes testosterone, and most authors agree that it also secretes some 4-dione.

    “In fact, the postmenopausal ovary is well known to secrete testosterone, and most authors agree that it also secretes some 4-dione (147, 148).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [147] Judd, 1974, Endocrine function of the postmenopausal ovary: concentration of androgens and estrogens in ovarian and peripheral vein blood., J Clin Endocrinol Metab source

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    • cites [148] Longcope, 1980, Steroid secretion by the postmenopausal ovary., Am J Obstet Gynecol source

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  • May combine two claims.

    Premisecitation

    Peripheral serum testosterone decreases by 50% after ovariectomy in postmenopausal women, indicating that the approximately equal contribution of the ovaries and adrenals to serum testosterone remains after menopause.

    “Peripheral serum testosterone decreases by 50% after ovariectomy in postmenopausal women, thus indicating that the approximately equal contribution of the ovaries and adrenals to serum testosterone remains after menopause.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [158] Judd, 1974, Effect of oophorectomy on circulating testosterone and androstenedione levels in patients with endometrial cancer., Am J Obstet Gynecol source

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    • cites [159] Maroulis, 1976, Ovarian and adrenal contributions to peripheral steroid levels in postmenopausal women., Obstet Gynecol

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  • May combine two claims.

    Interpretationreasoning

    The evidence obtained leaves little doubt that the antiproliferative effect of androgens does not result from competition for binding to the ER, but rather is caused by an AR-mediated mechanism that is additive to blockade of the ER by an antiestrogen.

    “the evidence obtained leaves little doubt that the antiproliferative effect of androgens does not result from competition for binding to the ER, but rather is caused by an AR-mediated mechanism that is additive to blockade of the ER by an antiestrogen.”
    Quote in the paperSubstantial claim

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    Premisecitation

    MPA is a compound having progestational, glucocorticoid, and androgenic activities.

    “As previously described, MPA is a compound having a complex series of activities, namely progestational, glucocorticoid, and androgenic (231).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [231] Poulin, 1990, Multiple actions of synthetic “progestins” on the growth of ZR-75-1 human breast cancer cells: an in vitro model for the simultaneous assay of androgen, progestin, estrogen and glucocorticoid agonistic and antagonistic activities of compounds., Breast Cancer Res Treat source

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  • May combine two claims.

    Interpretationreasoning

    Such data on ER expression provide an explanation for at least part of the antiestrogenic effects of androgens on breast cancer cell growth and provide an explanation for the observations showing that the specific inhibitory effects of androgen therapy are additive to the standard treatment limited to blockade of estrogens by antiestrogens.

    “Such data on ER expression provide an explanation for at least part of the antiestrogenic effects of androgens on breast cancer cell growth and provide an explanation for the observations showing that the specific inhibitory effects of androgen therapy are additive to the standard treatment limited to blockade of estrogens by antiestrogens (229).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [229] de Launoit, 1991, Characteristics of the biphasic action of androgens and of the potent antiproliferative effects of the new pure antiestrogen EM-139 on cell cycle kinetic parameters in LNCaP human prostatic cancer cells., Cancer Res

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The inhibitory effect of androgens on intracellular ER concentrations may leave the relative effectiveness of competitive blockade of estrogen action by antiestrogens unaffected, while decreasing the efficiency of residual estrogenic stimulation of cell growth.

    “This inhibitory effect of androgens on intracellular ER concentrations may be expected to leave the relative effectiveness of the competitive blockade of estrogen action by antiestrogens unaffected, while decreasing the efficiency of any residual estrogenic stimulation of cell growth.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Human adrenals secrete large amounts of precursor steroids DHEA and DHEA-S, both converted into androgens in target intracrine tissues.

    “the human adrenals secrete large amounts of the precursor steroids DHEA and DHEA-S, both of which are converted into androgens in target intracrine tissues (25,35,78,92,249,254,255).”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [25] Labrie, 1991, Intracrinology., Mol Cell Endocrinol source

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    • cites [35] Labrie

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    • cites [78] Labrie, 1988, Androgenic activity of dehydroepiandrosterone and androstenedione in the rat ventral prostate., Endocrinology source

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    • cites [92] Labrie, 1997, The key role of 17β-HSDs in sex steroid biology., Steroids source

      Not checked in the free run.

    • cites [249] Labrie, 1989, Stimulation of androgen-dependent gene expression by the adrenal precursors dehydroepiandrosterone and androstenedione in the rat ventral prostate., Endocrinology source

      Not checked in the free run.

    • cites [254] Labrie, 1996, High bioavailability of DHEA administered percutaneously in the rat., J Endocrinol

      Not checked in the free run.

    • cites [255] Labrie, 1995, DHEA and peripheral androgen and estrogen formation: intracrinology., Ann NY Acad Sci source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Testosterone propionate was the first androgen successfully used in treatment of advanced breast cancer.

    “the first androgen successfully used in the treatment of advanced breast cancer was testosterone propionate (250).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [250] Nathanson, 1947, Endocrine aspects of human cancer., Recent Prog Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DHEA possesses relatively potent androgenic activity and stimulates androgen-dependent gene expression in the rat ventral prostate.

    “Labrie and colleagues (78, 249) first demonstrated that DHEA possesses relatively potent androgenic activity and stimulates androgen-dependent gene expression in the rat ventral prostate.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [78] Labrie, 1988, Androgenic activity of dehydroepiandrosterone and androstenedione in the rat ventral prostate., Endocrinology source

      Not checked in the free run.

    • cites [249] Labrie, 1989, Stimulation of androgen-dependent gene expression by the adrenal precursors dehydroepiandrosterone and androstenedione in the rat ventral prostate., Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DHEA can be converted in vivo and in vitro into weak estrogen 5-diol, which interacts with ER and can exert weak estrogen-like effects independent from aromatase.

    “DHEA can be converted in vivo and in vitro into the weak estrogen 5-diol, which interacts with the ER and can exert weak estrogen-like effects independent from aromatase (253,(267)(268)(269).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 253,(267)(268)(269)

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human ZR-75-1 breast cancer cells do not express 3β-HSD and are unable to synthesize androgens.

    “human ZR-75-1 breast cancer cells do not express 3␤-HSD and are thus unable to synthesize androgens, thus explaining the stimulatory effect of DHEA on the growth of these cells under in vitro conditions (253)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [253] Poulin, 1986, Stimulation of cell proliferation and estrogenic response by adrenal C19-Δ5 -steroids in the ZR-75-1 human breast cancer cell line., Cancer

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An absence of estrogens does not exist in women; comparable levels of E2 are found in breast cancer tissue in pre- and postmenopausal women.

    “an absence of estrogens does not exist in women where comparable levels of E 2 are found in breast cancer tissue in pre-and postmenopausal women (272).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [272] Poortman, 1983, Subcellular distribution of androgens and oestrogens in target tissue., J Steroid Biochem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recent data suggest progestins exert a negative impact on breast cancer, with recent reports indicating an increased risk of the disease in women.

    “recent data suggest that progestins exert a negative impact on breast cancer (2-5), with recent reports indicating an increased risk of the disease in women (6,7).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [2] Horwitz, 1992, The molecular biology of RU486. Is there a role for antiprogestins in the treatment of breast cancer?, Endocr Rev

      Not checked in the free run.

    • cites [3] Musgrove, 1991, Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor α, epidermal growth factor receptor, c-fos, and c-myc genes., Mol Cell Biol source

      Not checked in the free run.

    • cites [4] Clarke, 1990, Progestin regulation of cellular proliferation., Endocr Rev source

      Not checked in the free run.

    • cites [5] Colditz, 1995, The use of estrogens and progestins and the risk of breast cancer in postmenopausal women., N Engl J Med source

      Not checked in the free run.

    • cites [6] Ross, 2000, Effect of hormone replacement therapy on breast cancer risk: estrogen vs. estrogen plus progestin., J Natl Cancer Inst source

      Not checked in the free run.

    • cites [7] Magnusson, 1999, Breast-cancer risk following long-term oestrogen- and oestrogen-progestin-replacement therapy., Int J Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DHEA is converted into androgens, and treatment with DHEA induces androgen-sensitive gene expression in the rat ventral prostate.

    “DHEA is well known to be converted into androgens, and treatment with DHEA is known to induce androgen-sensitive gene expression in the rat ventral prostate (78, 249).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [78] Labrie, 1988, Androgenic activity of dehydroepiandrosterone and androstenedione in the rat ventral prostate., Endocrinology source

      Not checked in the free run.

    • cites [249] Labrie, 1989, Stimulation of androgen-dependent gene expression by the adrenal precursors dehydroepiandrosterone and androstenedione in the rat ventral prostate., Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    By itself, DHEA does not possess significant androgenic or estrogenic activity; its activity depends on transformation into androgens and/or estrogens in peripheral target intracrine tissues.

    “by itself, DHEA does not possess any significant androgenic or estrogenic activity, its activity being dependent upon its transformation into androgens and/or estrogens in peripheral target intracrine tissues (25).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Labrie, 1991, Intracrinology., Mol Cell Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    DHEA, secondary to its predominant transformation into androgens in mammary gland tissue, exerts an inhibitory effect on mammary carcinoma development and growth, an effect that counteracts and can even completely neutralize the stimulatory effect of estrogens.

    “DHEA, secondary to its predominant transformation into androgens in mammary gland tissue, exerts an inhibitory effect on mammary carcinoma development and growth, an effect that counteracts and can even completely neutralize the stimulatory effect of estrogens.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    It is likely that endogenous androgens and DHEA play an important physiological role in control of normal breast tissue growth and function and that antagonism between androgens and estrogens is also operative in breast cancer.

    “it is likely that endogenous androgens and DHEA play an important physiological role in the control of normal breast tissue growth and function and that this antagonism between androgens and estrogens is also operative in breast cancer.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    DHEA is inhibitory on breast cancer growth in the presence of estrogens, whereas it can be stimulatory on experimental models in which estrogens are absent.

    “A group of researchers have reported that DHEA is inhibitory on breast cancer growth in the presence of estrogens, whereas it can be stimulatory on experimental models in which estrogens are absent (197,270).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [197] Secreto, 1991, Serum and urinary androgens and risk of breast cancer in postmenopausal women., Cancer Res

      Not checked in the free run.

    • cites [270] Boccuzzi, 1992, Opposite effects of dehydroepiandrosterone on the growth of 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinomas., Anticancer Res

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    All benefits of DHEA, including improved libido, have been obtained without significant side effect.

    “all these benefits, including improved libido, have been obtained without significant side effect (73, 74).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [73] Baulieu, 2000, Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a sociobiomedical issue., Proc Natl Acad Sci USA source

      Not checked in the free run.

    • cites [74] Stomati, 2000, Six-months oral dehydroepiandrosterone supplementation in early and late postmenopause., Gynecol Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The 70-95% reduction in formation of DHEA and DHEA-S by the adrenals during aging results in a dramatic reduction in formation of androgens and estrogens in peripheral target tissues, which could be involved in pathogenesis of age-related diseases such as insulin resistance and obesity.

    “The 70 -95% reduction in the formation of DHEA and DHEA-S by the adrenals during aging results in a dramatic reduction in the formation of androgens and estrogens in peripheral target tissues, which could well be involved in the pathogenesis of age-related diseases such as insulin resistance (307, 308) and obesity (309 -311).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [307] Schriock, 1988, Divergent correlations of circulating dehydroepiandrosterone sulfate and testosterone with insulin levels and insulin receptor binding., J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [308] Coleman, 1982, Therapeutic effects of dehydroepiandrosterone (DHEA) in diabetic mice., Diabetes source

      Not checked in the free run.

    • cites [309] Nestler, 1988, Dehydroepiandrosterone reduces serum low density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men., J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [310] MacEwen, 1991, Obesity in the dog: role of the adrenal steroid dehydroepiandrosterone (DHEA)., J Nutr source

      Not checked in the free run.

    • cites [311] Tchernof, 1995, Reduced testosterone and adrenal C19 steroid levels in obese men., Metabolism source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DHEA has immunomodulatory effects in vitro and in vivo in fungal and viral diseases, including HIV, and a stimulatory effect on the immune system in postmenopausal women.

    “DHEA has been shown to have immunomodulatory effects in vitro (313) and in vivo in fungal and viral diseases (314), including HIV (315), and a stimulatory effect of DHEA on the immune system has been described in postmenopausal women (316).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [313] Suzuki, 1991, Dehydroepiandrosterone enhances IL2 production and cytotoxic effector function of human T cells., Clin Immunol Immunopathol source

      Not checked in the free run.

    • cites [314] Rasmussen, 1992, Effectiveness of dehydroepiandrosterone in reduction of cryptosporidial activity in immunosuppressed rats., Antimicrob Agents Chemother source

      Not checked in the free run.

    • cites [315] Henderson, 1992, Dehydroepiandrosterone (DHEA) and synthetic DHEA analogs are modest inhibitors of HIV-1 IIIB replication., AIDS Res Hum Retroviruses source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DHEA replacement in Addison's disease is associated with improvement in psychological well-being, mood, and fatigue.

    “DHEA replacement in Addison's disease is associated with an improvement in psychological well-being, mood, and fatigue (70).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] Hunt, 2000, Improvement in mood and fatigue after dehydroepiandrosterone replacement in Addison’s disease in a randomized, double blind trial., J Clin Endocrinol Metab

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Testosterone administration to elderly men increases the fractional synthetic rate of muscle protein as well as muscle strength.

    “Testosterone administration to elderly men increases the fractional synthetic rate of muscle protein as well as muscle strength (320).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [320] Urban, 1995, Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis., Am J Physiol

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Women at menopause are not only deprived from estrogens because of rapid loss of ovarian activity but also have been deprived from androgens for a longer period because of progressive decrease of serum DHEA levels starting years before menopause.

    “women, at menopause, are not only deprived from estrogens because of a rapid loss of ovarian activity but also have been deprived from androgens for a longer period because of a progressive decrease of serum DHEA levels starting quite a few years before menopause.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [23] Labrie, 1997, Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging., J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [25] Labrie, 1991, Intracrinology., Mol Cell Endocrinol source

      Not checked in the free run.

    • cites [27] Labrie, 1997, Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: intracrinology., J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [33] Labrie, 2000, Intracrinology: role of the family of 17β-hydroxysteroid dehydrogenases in human physiology and disease., J Mol Endocrinol source

      Not checked in the free run.

    • cites [84] Labrie, 1992, Structure, function and tissue-specific gene expression of 3β-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase enzymes in classical and peripheral intracrine steroidogenic tissues., J Steroid Biochem Mol Biol source

      Not checked in the free run.

    • cites [86] Labrie, 1995, The human type II 17β-hydroxysteroid dehydrogenase gene encodes two alternatively-spliced messenger RNA species., DNA Cell Biol source

      Not checked in the free run.

    • cites [90] Labrie, 1994, Structure, regulation and role of 3β-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase and aromatase enzymes in formation of sex steroids in classical and peripheral intracrine tissues., Baillière’s Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [92] Labrie, 1997, The key role of 17β-HSDs in sex steroid biology., Steroids source

      Not checked in the free run.

    • cites [261] Labrie, 1992, Structure and tissue-specific expression of 3β-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase genes in human and rat classical and peripheral steroidogenic tissues., J Steroid Biochem Mol Biol source

      Not checked in the free run.

    • cites [280] Labrie, 1997, Effect of 12-month DHEA replacement therapy on bone, vaginum, and endometrium in postmenopausal women., J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Use of ERT requires addition of progestins to counteract endometrial proliferation induced by estrogens, whereas both estrogens and progestins could increase risk of breast cancer.

    “The use of ERT requires the addition of progestins to counteract the endometrial proliferation induced by estrogens, whereas both estrogens and progestins could increase the risk of breast cancer (5,318).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Colditz, 1995, The use of estrogens and progestins and the risk of breast cancer in postmenopausal women., N Engl J Med source

      Not checked in the free run.

    • cites [318] Bardon, 1985, RU486, a progestin and glucocorticoid antagonist, inhibits the growth of breast cancer cells via the progesterone receptor., J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The observed stimulatory effect of DHEA on bone mineral density and increase in serum osteocalcin indicate a unique activity of DHEA on bone physiology, namely stimulation of bone formation, whereas ERT and HRT can only reduce the rate of bone loss.

    “The observed stimulatory effect of DHEA on bone mineral density and the increase in serum osteocalcin, a marker of bone formation, are of particular interest for the prevention and treatment of osteoporosis and indicate a unique activity of DHEA on bone physiology, namely a stimulation of bone formation, whereas ERT and HRT can only reduce the rate of bone loss.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    At physiological replacement doses, DHEA does not stimulate the endometrium, thus removing the need to use a progestin to counteract stimulation of the endometrium by estrogen.

    “at physiological replacement doses, DHEA does not stimulate the endometrium, thus removing the need to use a progestin to counteract the stimulation of the endometrium by estrogen.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Although bone formation, inhibition of mammary gland proliferation, stimulation of sebaceous glands, muscle mass increase, and improved libido are attributed to formation of androgens in corresponding target tissues, decreased insulin resistance and vaginal maturation are best explained by local formation of estrogens.

    “Although bone formation, inhibition of mammary gland proliferation, stimulation of sebaceous glands, muscle mass increase, and improved libido are attributed to the formation of androgens in the corresponding target tissues, the decreased insulin resistance and vaginal maturation are best explained by the local formation of estrogens.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Absence of stimulation of the endometrium by DHEA eliminates the need for progestin replacement therapy, thus avoiding the fear of progestin-induced breast cancer added to the well-known stimulatory effect of estrogens.

    “The absence of stimulation of the endometrium by DHEA eliminates the need for progestin replacement therapy, thus avoiding the fear of progestininduced breast cancer added to the well known stimulatory effect of estrogens.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Significant improvement in mood and well-being was observed in patients with major depression and midlife asthenia, whereas no effect was detected in perimenopausal women.

    “A significant improvement in mood and well-being was observed in patients with major depression (331) and midlife asthenia (332), whereas no effect was detected in perimenopausal women (333).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [331] Wolkowitz, 1999, Double-blind treatment of major depression with dehydroepiandrosterone., Am J Psychiatry source

      Not checked in the free run.

    • cites [332] Bloch, 1999, Dehydroepiandrosterone treatment of midlife dysthymia., Biol Psychiatry source

      Not checked in the free run.

    • cites [333] Barnhart, 1999, The effect of dehydroepiandrosterone supplementation to symptomatic perimenopausal women on serum endocrine profiles, lipid parameters, and health-related quality of life., J Clin Endocrinol Metab

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    At physiological replacement doses, DHEA has been found in clinical studies to induce a series of beneficial effects closely associated with protection of women's health, whereas no negative effects have been observed.

    “In summary, at physiological replacement doses, DHEA has been found in clinical studies to induce a series of beneficial effects closely associated with the protection of women's health, whereas no negative effects have been observed.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from the animal models and cell lines used in the paper are predictive of DHEA's effects on breast cancer and other outcomes in women.

  • May combine two claims.

    Premisecitation

    Scores of activity of daily living were improved by DHEA in patients with myotonic dystrophy, whereas no change was observed in healthy elderly men.

    “scores of activity of daily living were improved by DHEA in patients with myotonic dystrophy (329), whereas no change was observed in healthy elderly men (330).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [329] Sugino, 1998, A pilot study of dehydroepiandrosterone sulfate in myotonic dystrophy., Neurology source

      Not checked in the free run.

    • cites [330] Flynn, 1999, Dehydroepiandrosterone replacement in aging humans., J Clin Endocrinol Metab

      Not checked in the free run.

58 of 58

  • The paper relies on this without support.

    The sum of serum concentrations of ADT-G, 3α-diol-G, and 3β-diol-G reflects relative total androgen production in men and women despite possible differences in metabolic clearance rates.

    “Although the metabolic clearance rates of the three main androgen metabolites are likely to show differences between men and women, an estimate of the relative amount of total androgens in women and men calculated on the basis of the sum of the serum concentrations of these three metabolites suggests that total androgen production in women is more than two thirds, or 71%, of that observed in men (”

  • The paper relies on this without support.

    Findings from the animal models and cell lines used in the paper are predictive of DHEA's effects on breast cancer and other outcomes in women.

    “Such data also suggest a potential use of DHEA as a physiological approach for the prevention of breast cancer in women.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Type 2 17␤-HSD is described as both oxidative and reductive

    Minor

    The paper classifies type 2 17␤-HSD as catalyzing an oxidative reaction, but later attributes a reductive action to the same enzyme.

  • DHEA is called the only sex-steroid source despite E 1 supplementation

    Minor

    The statement that exogenous DHEA is the only source of sex steroids in the ovariectomized mice conflicts with the description of the DHEA-treated mice as supplemented with E 1.

2 of 2

Cites

1 retracted

Flagged first, then by citations

50 of the 388 references couldn’t be matched to a known paper.

Research works printed but not linked: 7

  1. Barrett-Connor, 1999, A two-year, double-blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women., J Reprod Med, 44, 1012
  2. Davis, 1996, Androgens and postmenopausal women., J Clin Endocrinol Metab, 81, 2759
  3. Ulrich, 1939, Testosterone (hormone mâle) et son role possible dans le traitement de certains cancers du sein., Acta Unio Internationalis Contra Cancrum, 4, 377
  4. Cusan, 1993, Flutamide in the treatment of female androgenic alopecia., Can J Dermatol, 5, 421
  5. Labrie, 1996, High bioavailability of DHEA administered percutaneously in the rat., J Endocrinol, 150, S107
  6. Jordan, 1978, Use of the DMBA-induced rat mammary carcinoma system for the evaluation of tamoxifen as a potential adjuvant therapy., Rev Endocr Relat Cancer, (Suppl), 49
  7. Diamond, 1996, Metabolic effects of 12-month percutaneous DHEA replacement therapy in postmenopausal women., J Endocrinol, 150, S43

Cited by

Sorted by citations

Related

Authors
Labrie, F., Luu-The, V., Labrie, C., Bélanger, A., Simard, J., Lin, S.-X., & Pelletier, G.
Affiliations
  • Centre hospitalier de l'Université Laval (CA)
  • Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (Centre Hospitalier de l’Université Laval) and Laval University, Québec City, Québec G1V 4G2, Canada
Corresponding author
Labrie, Fernand
ORCID
Venue
Endocrine Reviews
Publisher
The Endocrine Society
Published
2003-04-01
Volume
24
Issue
2
Pages
152-182
ISSN
  • 0163-769X (ISSN-L)
  • 1945-7189
DOI
10.1210/er.2001-0031
OpenAlex
W2145801998
Semantic Scholar
5f3da77db259eaf579a8b039f88e7736457e19f2
Cited by
544
References
388
Citations by year
2026: 9 · 2025: 6 · 2024: 8 · 2023: 11 · 2022: 32 · 2021: 17 · 2020: 11 · 2019: 14 · 2018: 20 · 2017: 16 · 2016: 24 · 2015: 18 · 2014: 26 · 2013: 19 · 2012: 22
FWCI
3.85
Type
journal article
Language
en
Open access
closed
Locations
  • Endocrine Reviews (publishedVersion)
  • PubMed (publishedVersion)
Funders
Université Laval
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
dehydroepiandrosterone, DHEA sulfate, intracrinology, menopause, hormone replacement therapy, breast cancer prevention, bone mineral density, bone formation, androgen receptor, aromatase, 17β-hydroxysteroid dehydrogenase
MeSH terms
Adult, Aged, Aged, 80 and over, Androgens, Animals, Breast Neoplasms, Dehydroepiandrosterone, Female, Humans, Menopause, Middle Aged, 17-Hydroxysteroid Dehydrogenases, Bone Density

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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