Endocrine and Intracrine Sources of Androgens in Women: Inhibition of Breast Cancer and Other Roles of Androgens and Their Precursor Dehydroepiandrosterone

In the paper

“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”

What the sources say

• Not checked yetcites Table 1
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites Fig. 13A
• Not checked yetcites Fig. 13B
• Not checked yetcites Fig. 13C

In the paper

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

What the sources say

• Not checked yetcites Fig. 12

In the paper

“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).”

What the sources say

• Not checked yetcites Ref.26

In the paper

“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).”

What the sources say

• Not checked yetcites Fig. 1

In the paper

“only a small proportion, estimated at 10 -15% of the intracellular content of these androgens, diffuses out of the intracellular compartment without prior metabolism and can be measured as active androgen in the circulation.”

In the paper

“The serum concentration of the aboveindicated conjugated androgen metabolites decreases by 47.5-72.7% between the 20-to 30-and 70-to 80-yr age groups in women,”

What the sources say

• Not checked yetcites [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

In the paper

“No significant effect was observed on serum E 1 , E 2 , or DHT.”

In the paper

“in the absence of E 2 , EM-139 and DHT alone caused 21% (P Ͻ 0.01) and 43% (P Ͻ 0.01) inhibitions of basal cell growth, respectively.”

In the paper

“the first demonstration of a potent and direct inhibitory effect of androgens on human breast cancer growth was obtained in the estrogensensitive human breast cancer cell line ZR-75-1 (208).”

What the sources say

• Not checked yetcites [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

In the paper

“At low cell density (Fig. 17B), it can be seen that DHT completely prevented breast cancer cell growth.”

What the sources say

• Not checked yetcites Fig. 17B

In the paper

“The specific uptake of [ 3 H]E 2 in intact ZR-75-1 cell monolayers was decreased by as much as 88% after a 10-d preincubation with increasing concentrations of DHT (Fig. 20).”

What the sources say

• Not checked yetcites Fig. 20

In the paper

“The addition of 1 nm DHT, on the other hand, caused a 78% blockade (P Ͻ 0.01) of E 2 -induced ZR-75-1 cell growth,”

In the paper

“A half-maximal effect of DHT on [ 3 H]E 2 uptake was observed at 70 pm (209).”

What the sources say

• Not checked yetcites [209] Poulin, 1989, Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells., Breast Cancer Res Treat source

In the paper

“After a 12-d incubation of ZR-75-1 cells in the presence of 0.1 nm E 2 in phenol red-free medium, cell number was increased 2.8-fold above control (P Ͻ 0.01; Fig. 18A).”

What the sources say

• Not checked yetcites Fig. 18A

In the paper

“E 2 caused a progressive increase in total tumor area from 100% (which corresponds to an average of 0.23 Ϯ 0.08 cm 2 ) at the start of the experiment to 226 Ϯ 31% after 100 d of treatment.”

In the paper

“It can also be seen in Fig. 18B that the inhibitory effect of DHT is completely prevented by the addition of the pure antiandrogen OH-flutamide.”

What the sources say

• Not checked yetcites Fig. 18B

In the paper

“the antiandrogen OH-flutamide competitively reversed the effect of DHT and 4-dione with an apparent dissociation constant (K i , ϳ110 nm) consistent with its known affinity for the AR (226,227).”

What the sources say

• Not checked yetcites [226] Neri, 1979, Anti-androgenicity of flutamide and its metabolite Sch 16423., Biochem Soc Trans source
• Not checked yetcites [227] Simard, 1986, Characteristics of interaction of the antiandrogen flutamide with the androgen receptor in various target tissues., Mol Cell Endocrinol source

In the paper

“the potency of DHT and testosterone to induce antiproliferative effects (IC 50 , ϳ0.10 and 0.50 nm, respectively) is in agreement with their relative binding affinity for androgen specific binding sites in intact ZR-75-1 cells as well as in other human breast cancer cells (219,220).”

What the sources say

• Not checked yetcites [219] Horwitz, 1978, Steroid receptor analyses of nonhuman breast cancer cell lines., Cancer Res
• Not checked yetcites [220] MacIndoe, 1981, The specific binding of androgens and the subsequent distribution of androgen receptor complexes within MCF-7 human breast cancer cells., Steroids source

In the paper

“our previous studies have clearly demonstrated that androgens exert a direct inhibitory effect on the proliferation of human breast cancer cells (208 -213).”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [209] Poulin, 1989, Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells., Breast Cancer Res Treat source
• Not checked yetcites [210] Poulin, 1989, Down-regulation of estrogen receptors by androgens in the ZR-75-1 human breast cancer cell line., Endocrinology source
• Not checked yetcites [211] Simard, 1989, Inhibitory effects of estrogens on GCDFP-15 mRNA levels and secretion in ZR-75-1 human breast cancer cells., Mol Endocrinol source
• Not checked yetcites [212] Dumont, 1989, Antagonism between estrogens and androgens on GCDFP-15 gene expression in ZR-75-1 cells and correlation between GCDFP-15 and estrogen as well as progesterone receptor expression in human breast cancer., J Steroid Biochem source
• Not checked yetcites [213] Simard, 1990, Regulation of progesterone-binding breast cyst protein GCDFP-24 secretion by estrogens and androgens in human breast cancer cells: a new marker of steroid action in breast cancer., Endocrinology source

In the paper

“Furthermore, testosterone, at concentrations observed in adult women (1)(2)(3), is also a potent inhibitor of cell growth.”

What the sources say

• Not checked yetcites [1] Christiansen, 1982, Pathophysiological mechanisms of estrogen effect on bone metabolism. Dose-response relationships in early postmenopausal women., J Clin Endocrinol Metab source
• Not checked yetcites [2] Horwitz, 1992, The molecular biology of RU486. Is there a role for antiprogestins in the treatment of breast cancer?, Endocr Rev
• Not checked yetcites [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

In the paper

“Similar inhibitory effects were observed on the levels of ER mRNA measured by ribonuclease protection assay (209).”

What the sources say

• Not checked yetcites [209] Poulin, 1989, Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells., Breast Cancer Res Treat source

In the paper

“The addition of hydroxyflutamide, a nonsteroidal antiandrogen devoid of agonistic activity and with no significant affinity for receptors other than the AR (226, 227) competitively reversed inhibition of [ 3 H]E 2 specific uptake by DHT.”

What the sources say

• Not checked yetcites [226] Neri, 1979, Anti-androgenicity of flutamide and its metabolite Sch 16423., Biochem Soc Trans source
• Not checked yetcites [227] Simard, 1986, Characteristics of interaction of the antiandrogen flutamide with the androgen receptor in various target tissues., Mol Cell Endocrinol source

In the paper

“Moreover, the inhibitory effect of DHT on ER content was competitively reversed by the antiandrogen hydroxyflutamide (226,227).”

What the sources say

• Not checked yetcites [226] Neri, 1979, Anti-androgenicity of flutamide and its metabolite Sch 16423., Biochem Soc Trans source
• Not checked yetcites [227] Simard, 1986, Characteristics of interaction of the antiandrogen flutamide with the androgen receptor in various target tissues., Mol Cell Endocrinol source

In the paper

“This study showed for the first time that androgens strongly suppress ER content in the human breast cancer cell line ZR-75-1, as measured by radioligand binding and anti-ER monoclonal antibodies.”

In the paper

“The concentration of DHT needed to exert a half-maximal suppression of ER binding activity (0.07-0.1 nm) is lower than the concentration known to induce binding and nuclear retention of the ER (215, 234).”

What the sources say

• Not checked yetcites [215] Rochefort, 1983, The estrogenic and antiestrogenic activities of androgens in female target tissues., Pharmacol Ther source
• Not checked yetcites [234] Lippman, 1976, The effect of androgens and antiandrogens on hormone-responsive human breast cancer in long-term tissue culture., Cancer Res

In the paper

“Inhibitions of 50.4%, 76.8%, and 80.0% were achieved at 9.5 months of treatment with the daily doses of DHEA of 0.3, 1.0, or 3.0 mg per animal, respectively (Fig. 23).”

In the paper

“tumor size in the group of animals treated with the highest dose (6 ϫ 3.0-cm long implants) of DHEA was similar to that found in ovariectomized animals (Fig. 22)”

In the paper

“At the highest dose of DHEA used, which corresponds to serum DHEA values of 27.2 Ϯ 2.2 nm, the incidence of tumors was reduced to only 3.8%.”

In the paper

“serum levels of DHEA of 7.09 Ϯ 0.64 nm and 17.5 Ϯ 1.1 nm led to a dramatic inhibition of tumor development to 22% and 11% of animals bearing mammary carcinoma compared with 68% in control intact animals.”

In the paper

“Treatment with increasing doses of DHEA delivered constantly by SILASTIC-brand implants of increasing length and number caused a progressive inhibition of tumor development (258).”

What the sources say

• Not checked yetcites [258] Li, 1993, Prevention by dehydroepiandrosterone of the development of mammary carcinoma induced by 7,12-dimethylbenz(a)anthracene (DMBA) in the rat., Breast Cancer Res Treat source

In the paper

“treatment with increasing doses of percutaneous DHEA caused a progressive inhibition of E 1 -stimulated ZR-75-1 tumor growth.”

In the paper

“In fact, the only two tumors that developed in the group of animals treated with both compounds disappeared before the end of the experiment (279).”

What the sources say

• Not checked yetcites [279] Luo, 1997, Effect of dehydroepiandrosterone on bone mass, serum lipids, and dimethylbenz(a)anthracene-induced mammary carcinoma in the rat., Endocrinology source

In the paper

“DHEA exerts an inhibitory effect on the growth of the same cancer cells under in vivo conditions in nude mice, the androgens originating from neighboring or distant cells that possess the required mechanisms to transform DHEA into androgens in sufficient amounts to affect other cells after diffusion from their site of synthesis (271).”

What the sources say

• Not checked yetcites [271] Luo, 1996, Relative potencies of flutamide and casodex: preclinical studies., Endocrine-Related Cancer source

In the paper

“treatment with DHEA led to a marked decrease in the average weight of the tumors remaining at the end of the experiment.”

In the paper

“Interestingly, combination of the two compounds led to a significantly greater inhibitory effect than that achieved by each compound administered alone (P Ͻ 0.01 vs. DHEA or EM-800 alone).”

In the paper

“95% of control animals developed palpable mammary tumors by 279 d after DMBA administration.”

In the paper

“Bone mass density was increased by 2.3% at the hip, 3.75% at the hip Ward's triangle, and 2.2% at the lumbar spine level (all P Ͻ 0.05; Ref. 280).”

What the sources say

• Not checked yetcites [280] Labrie, 1997, Effect of 12-month DHEA replacement therapy on bone, vaginum, and endometrium in postmenopausal women., J Clin Endocrinol Metab source

In the paper

“Measurements of midthigh fat and muscle areas by computed tomography have shown a 3.8% decrease (P Ͻ 0.05) of femoral fat and a 3.5% increase (P Ͻ 0.05) in femoral muscular area at 12 months of treatment with DHEA (297).”

What the sources say

• Not checked yetcites [297] Diamond, 1996, Metabolic effects of 12-month percutaneous DHEA replacement therapy in postmenopausal women., J Endocrinol

In the paper

“These changes in bone mineral density were accompanied by significant decreases at 12 months of 38% and 22% in urinary hydroxyproline and in plasma bone alkaline phosphatase, respectively (all P Ͻ 0.05).”

In the paper

“There was no significant change in abdominal fat measurements.”

In the paper

“| Total | 76.2 | 54.1 (71%) |”

In the paper

“TABLE 2 . Distribution of intracrine steroidogenic enzymes in the monkey”

• Also stated in: § B. Benefits of DHEA in postmenopausal women · plain

  “| Tissue | Steroid sulfatase | 3␤-HSD | 17␤-HSD androgen | 17␤-HSD estrogen | Aromatase | 5␣-Reductase |”

In the paper

“Insulin resistance decreased a,b”

In the paper

“Endometrium a”

In the paper

“Mammary gland inhibition a”

In the paper

“| 3␤-Diol-G | 30.2 | 17.3 (57%) |”

In the paper

“Improved libido a,b,c”

In the paper

“We have also determined that the serum levels of DHEA using a 10% cream (280) were comparable to the ones obtained after daily oral administration of 100 mg of DHEA (our unpublished data).”

What the sources say

• Not checked yetcites [280] Labrie, 1997, Effect of 12-month DHEA replacement therapy on bone, vaginum, and endometrium in postmenopausal women., J Clin Endocrinol Metab source

In the paper

“TABLE 1 . Comparison of serum androgen metabolites (20 -80 yr of age; nM) a”

• Also stated in: § B. Benefits of DHEA in postmenopausal women · plain

  “| ADT-G | 37.5 | 32.5 (87%) |”

In the paper

“Sebaceous gland stimulation a”

In the paper

“Muscle mass increase a”

In the paper

“Bone formation a”

• Also stated in: § B. Benefits of DHEA in postmenopausal women · boosted

  “a Demonstrated in postmenopausal women.”

In the paper

“Vaginal mucosa maturation a”

In the paper

“Plasma triglycerides were not affected.”

In the paper

“there was an overall trend for a 3-10% decrease in total cholesterol.”

In the paper

“Treatment with DHEA had no undesirable effect on the lipid or lipoprotein profile.”

In the paper

“| 3␣-Diol-G | 8.5 | 4.3 (51%) |”

In the paper

“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”

• Also stated in: § A. Intracrinology · plain

  “synthesis of active steroids in peripheral target tissues in which the action is exerted in the same cells where synthesis takes place without release of the active steroids in the extracellular space and general circulation (25).”

What the sources say

• Not checked yetcites [25] Labrie, 1991, Intracrinology., Mol Cell Endocrinol source

In the paper

“The recent data of the Women's Health Initiative Study show that the combination of Premarin and Provera (Prempro) causes a 26% increase in the risk of breast cancer at 5.2 yr of follow-up”

What the sources say

• Not checked yetcites [8] 2002, Risks and benefits of estrogen plus progestin in healthy postmenopausal women., JAMA source

In the paper

“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.”

What the sources say

• Not checked yetcites [25] Labrie, 1991, Intracrinology., Mol Cell Endocrinol source
• Not checked yetcites [35] Labrie

In the paper

“thus seriously limiting the interpretation of serum levels of active sex steroids.”

• Also stated in: § B. Decrease of serum DHEA, androgens, and their metabolites with age · boosted

  “Such data clearly indicate the poor value of measurements of serum androgens and estrogens as parameters of total androgenic and estrogenic activities in men and women.”

In the paper

“Serum androgens as well as their precursors and metabolites decrease from the age of 30 -40 yr in women”

• Also stated in: § I. Androgens and Their Role in Women · boosted

  “progressive and dramatic fall in circulating dehydroepiandrosterone (DHEA), which starts early at the age of 30 -40 yr (18 -23).”

What the sources say

• Not checked yetcites [18] Vermeulen, 1982, Adrenocortical function in old age: response to acute adrenocorticotropin stimulation., J Clin Endocrinol Metab source
• Not checked yetcites [19] Vermeulen, 1976, Radioimmunoassays of 17β-hydroxy-5α-androstan-3-one, 4-androstene-3,17-dione, dehydroepiandrosterone, 17β-hydroxyprogesterone and progesterone and its application to human male plasma., J Steroid Biochem source
• Not checked yetcites [20] Orentreich, 1984, Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood., J Clin Endocrinol Metab source
• Not checked yetcites [21] Bélanger, 1994, Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men., J Clin Endocrinol Metab
• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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 (23,27).”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [25] Labrie, 1991, Intracrinology., Mol Cell Endocrinol source
• Not checked yetcites [77] Labrie, 1985
• Not checked yetcites [78] Labrie, 1988, Androgenic activity of dehydroepiandrosterone and androstenedione in the rat ventral prostate., Endocrinology source

In the paper

“in the 50-to 60-yr-old age group, serum DHEA has already decreased by 70%, compared with the 20-to 30-yr-old peak values (Ref.23; Fig. 1).”

What the sources say

• Not checked yetcites [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

In the paper

“The availability of a compound such as DHEA, an inactive precursor that is transformed into active androgens only in specific target tissues, would be an important advantage over androgens exerting systemic effects in all tissues possessing AR.”

In the paper

“in women, most of these androgens originate from the transformation of DHEA and DHEA-S into testosterone and DHT in peripheral intracrine tissues.”

What the sources say

• Not checked yetcites [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

In the paper

“Because the postmenopausal ovary does not secrete estrogens, intratumoral E 2 is necessarily made from adrenal precursor steroids (25).”

What the sources say

• Not checked yetcites [25] Labrie, 1991, Intracrinology., Mol Cell Endocrinol source

In the paper

“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.”

In the paper

“Such data suggest that both estrogens and androgens are required to acquire normal bone mineral density.”

What the sources say

• Not checked yetcites [44] Munnuz-Torres, 1995, Bone mass in androgen-insensitivity syndrome: response to hormonal replacement therapy., Calcif Tissue Int source
• Not checked yetcites [45] Soule, 1995, Osteopenia as a feature of the androgen insensitivity syndrome., Clin Endocrinol (Oxf) source

In the paper

“The 44.5% fall that occurs in serum DHEA from 20 -30 yr of age to the age of 40 -50 yr in women could well explain the bone loss that precedes menopause (27)(28)(29)(30).”

What the sources say

• Not checked yetcites (27)(28)(29)(30)

In the paper

“the absence of significant difference in the intracellular levels of E 2 in breast cancer tissue between premenopausal and postmenopausal women (79).”

What the sources say

• Not checked yetcites [79] Thijssen, 1986, Uptake and concentration of steroid hormones in mammary tissues., Ann NY Acad Sci source

In the paper

“Man is unique, with some other primates, in having adrenals that secrete large amounts of the precursor steroids DHEA and DHEA-S, which are converted into 4-dione and then into potent androgens and/or estrogens in peripheral tissues (Refs.25, 77, and 78; Fig. 3).”

What the sources say

• Not checked yetcites [25] Labrie, 1991, Intracrinology., Mol Cell Endocrinol source
• Not checked yetcites [77] Labrie, 1985
• Not checked yetcites [78] Labrie, 1988, Androgenic activity of dehydroepiandrosterone and androstenedione in the rat ventral prostate., Endocrinology source

In the paper

“The serum concentrations of the conjugated metabolites of DHT, namely ADT-G, 3␣-diol-G, and 3␤-diol-G, are the most reliable parameters of the total androgen pool in women,”

In the paper

“Transformation of the adrenal precursor steroids DHEA-S and DHEA into androgens and/or estrogens in peripheral target tissues depends upon the level of expression of the various steroidogenic and metabolizing enzymes in each of these tissues.”

In the paper

“administration of the antiestrogen raloxifene for only 3 yr in postmenopausal women led to a 76% decrease in the incidence of breast cancer (82)”

What the sources say

• Not checked yetcites [82] Cummings, 1999, The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation., JAMA source

In the paper

“Such data obtained in normal postmenopausal women offer unique proof that the serum levels of androgens and estrogens are poor indicators of total androgenic and estrogenic activities in women.”

In the paper

“thus suggesting a parallel decrease in the total androgen pool with age (23).”

What the sources say

• Not checked yetcites [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

In the paper

“The amount of stromal hyperplasia in postmenopausal ovaries is correlated with the ovarian vein levels of 4-dione and testosterone (124).”

What the sources say

• Not checked yetcites [124] Sluijmer, 1998, Relationship between ovarian production of estrone, estradiol, testosterone, and androstenedione and the ovarian degree of stromal hyperplasia in postmenopausal women., Menopause source

In the paper

“Studies have convincingly shown that androgen plus estrogen was more efficient than estrogen in improving bone mineral density in postmenopausal women (42,43,50,(52)(53)(54)(55).”

What the sources say

• Not checked yetcites (42,43,50,(52)(53)(54)(55)

In the paper

“Such data showing the presence of relatively high levels of androgens in normal women strongly suggest that the androgens play a major physiological role in women.”

In the paper

“the changes in precursor androgen secretion by the adrenals precede by 10 -20 yr the detectable decrease in ovarian steroidogenesis that occurs abruptly at menopause (23).”

What the sources say

• Not checked yetcites [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

In the paper

“whereas serum testosterone is mostly a measure of direct secretion of testosterone by the ovaries and/or adrenals.”

In the paper

“A parallel decrease is observed for serum DHEA and DHEA-S, thus suggesting the role of DHEA in the progressive decline in serum testosterone between the ages of 21 and 40 yr in normal women.”

In the paper

“approximately 50% of total androgens in the prostate of adult men derive from these adrenal precursor steroids (77, 87, 88).”

What the sources say

• Not checked yetcites [77] Labrie, 1985
• Not checked yetcites [87] Bélanger, 1986, Levels of plasma steroid glucuronides in intact and castrated men with prostatic cancer., J Clin Endocrinol Metab source
• Not checked yetcites [88] Labrie, 1993, Science behind total androgen blockade: from gene to combination therapy., Clin Invest Med

In the paper

“supplementation with physiological amounts of exogenous DHEA permits the biosynthesis of androgens (essentially testosterone and DHT) and estrogens only in the target tissues that contain the specific steroidogenic enzymes (25,33).”

What the sources say

• Not checked yetcites [25] Labrie, 1991, Intracrinology., Mol Cell Endocrinol source
• Not checked yetcites [33] Labrie, 2000, Intracrinology: role of the family of 17β-hydroxysteroid dehydrogenases in human physiology and disease., J Mol Endocrinol source

In the paper

“treatment of ovariectomized monkeys with testosterone decreased by about 40% the stimulation of mammary epithelial proliferation induced by E 2 (200).”

What the sources say

• Not checked yetcites [200] Zhou, 2000, Testosterone inhibits estrogen-induced mammary epithelial proliferation and suppresses estrogen receptor expression., FASEB J source

In the paper

“Such calculations are in agreement with other data showing that serum ADT-G levels reflect essentially adrenal androgen secretion (161).”

What the sources say

• Not checked yetcites [161] Giagulli, 1993, Origin and significance of plasma androsterone glucuronide levels: a parameter of adrenal androgen secretion and hepatic 5 α-reductase activity., J Clin Endocrinol Metab

In the paper

“the contribution of the ovaries decreases to about 20% after menopause (158, 159),”

What the sources say

• Not checked yetcites [158] Judd, 1974, Effect of oophorectomy on circulating testosterone and androstenedione levels in patients with endometrial cancer., Am J Obstet Gynecol source
• Not checked yetcites [159] Maroulis, 1976, Ovarian and adrenal contributions to peripheral steroid levels in postmenopausal women., Obstet Gynecol

In the paper

“It is well recognized that the postmenopausal ovary is a steroid-secreting gland (145, 146).”

What the sources say

• Not checked yetcites [145] Adashi, 1994, The climacteric ovary as a functional gonadotropin-driven androgen-producing gland., Fertil Steril source
• Not checked yetcites [146] Longcope, 1998, The relationship of ovarian production of hormones and degree of ovarian stromal hyperplasia in postmenopausal women., Menopause

In the paper

“These clinical observations indicate that the benefits obtained with androgen therapy in breast cancer cannot be due solely to a suppression of pituitary gonadotropin secretion but must result, at least in part, from a direct effect on tumor growth in women.”

In the paper

“The role of androgens as direct inhibitors of breast cancer growth is well supported by the presence of AR in a large proportion of human breast cancers (178 -181).”

What the sources say

• Not checked yetcites [178] Trams, 1977, Specific binding of estradiol and dihydrotestosterone in human mammary cancers., Cancer Res
• Not checked yetcites [179] Allegra, 1979, Distribution, frequency and quantitative analysis of estrogen, progesterone, androgen and glucocorticoid receptors in human breast cancer., Cancer Res
• Not checked yetcites [180] Miller, 1985, Androgen receptor activity in human breast cancer and its relationship with estrogen and progesterone receptor activity., Eur J Cancer Clin Oncol source
• Not checked yetcites [181] Bryan, 1984, Androgen receptors in breast cancer., Cancer source

In the paper

“There is also genetic evidence in agreement with a protective role of androgens against breast cancer (186, 187).”

What the sources say

• Not checked yetcites [186] Wooster, 1992, A germline mutation in the androgen receptor in two brothers with breast cancer and Reifenstein syndrome., Nat Genet source
• Not checked yetcites [187] Lobaccaro, 1993, Androgen receptor gene mutation in male breast cancer., Hum Mol Genet source

In the paper

“well recognized observations have shown that androgens such as testosterone propionate (162, 167-169), fluoxymesterone (170, 171), and calusterone (172) used in the adjuvant therapy of breast cancer have an efficacy comparable to that achieved with other types of endocrine manipulations (165,169,173,174).”

What the sources say

• Not checked yetcites [162] Ulrich, 1939, Testosterone (hormone mâle) et son role possible dans le traitement de certains cancers du sein., Acta Unio Internationalis Contra Cancrum
• Not checked yetcites [170] Kennedy, 1958, Fluxymesterone therapy in treatment of advanced breast cancer., N Engl J Med source
• Not checked yetcites [172] Gordan, 1973, Calusterone (7β,17α-dimethyltestosterone) as primary and secondary therapy of advanced breast cancer., Oncology source

In the paper

“although the ovaries and adrenals contribute about equally to the serum levels of 4-dione in premenopausal women (158, 159),”

What the sources say

• Not checked yetcites [158] Judd, 1974, Effect of oophorectomy on circulating testosterone and androstenedione levels in patients with endometrial cancer., Am J Obstet Gynecol source
• Not checked yetcites [159] Maroulis, 1976, Ovarian and adrenal contributions to peripheral steroid levels in postmenopausal women., Obstet Gynecol

In the paper

“only about 10% of intracellular testosterone synthesized from DHEA leaks into the general circulation.”

In the paper

“In fact, in primary breast cancer, AR has been found in 54% of premenopausal and 48% of postmenopausal patients (180,182).”

What the sources say

• Not checked yetcites [180] Miller, 1985, Androgen receptor activity in human breast cancer and its relationship with estrogen and progesterone receptor activity., Eur J Cancer Clin Oncol source
• Not checked yetcites [182] Würz, 1982

In the paper

“Measurement of the conjugated metabolites of androgens is the only approach that permits an accurate estimate of the total androgen pool in women.”

In the paper

“Moreover, mutations in AR have been linked with breast cancer in men (199).”

What the sources say

• Not checked yetcites [199] Rebbeck, 1999, Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat., Am J Hum Genet source

In the paper

“Most importantly, a higher response rate and a longer time to disease progression have been observed when androgens were combined with an antiestrogen, compared with an antiestrogen alone (171, 175).”

What the sources say

• Not checked yetcites [171] Tormey, 1983, Evaluation of tamoxifen doses with and without fluoxymesterone in advanced breast cancer., Ann Intern Med source
• Not checked yetcites [175] Ingle, 1991, Combination hormonal therapy with tamoxifen plus fluoxymesterone vs. tamoxifen alone in postmenopausal women with metastatic breast cancer. A phase II study., Cancer source

In the paper

“Giagulli et al. (161) have concluded that DHEA-S accounts for 70 -80% of serum ADT-G levels.”

What the sources say

• Not checked yetcites [161] Giagulli, 1993, Origin and significance of plasma androsterone glucuronide levels: a parameter of adrenal androgen secretion and hepatic 5 α-reductase activity., J Clin Endocrinol Metab

In the paper

“It is of interest that suppression of androgens in men is associated with breast growth (198).”

What the sources say

• Not checked yetcites [198] Staiman, 1997, Tamoxifen for flutamide/finasteride-induced gynecomastia., Urology source

In the paper

“One can thus estimate, as illustrated schematically in Fig. 16, that after menopause the contribution of the ovaries to the intracellular concentration of testosterone is only about 10%.”

What the sources say

• Not checked yetcites Fig. 16

In the paper

“In another study, human chorionic gonadotrophin stimulation and dexamethasone suppression tests in postmenopausal women have suggested that the ovary contributes about 50% of testosterone and 30% of 4-dione in the peripheral circulation (160).”

What the sources say

• Not checked yetcites [160] Vermeulen, 1976, The hormonal activity of the postmenopausal ovary., J Clin Endocrinol Metab source

In the paper

“The benefits of combined treatment with fluoxymesterone and tamoxifen vs. tamoxifen alone were observed in postmenopausal women with metastatic breast cancer (175), both in terms of response rate and time to progression of disease.”

What the sources say

• Not checked yetcites [175] Ingle, 1991, Combination hormonal therapy with tamoxifen plus fluoxymesterone vs. tamoxifen alone in postmenopausal women with metastatic breast cancer. A phase II study., Cancer source

In the paper

“The overwhelming clinical evidence for tumor regression observed in 20 -50% of pre-and postmenopausal breast cancer patients treated with various androgens (173) favors the view that naturally occurring androgens might constitute an as yet overlooked, direct inhibitory control of mammary cancer cell growth.”

What the sources say

• Not checked yetcites [173] Gordan, 1976

In the paper

“The present data clearly demonstrate that DHEA and DHEA-S are converted in a series of intracrine tissues into the active androgens and/or estrogens that exert their biological effects at their site of synthesis.”

In the paper

“DHT has been shown to be formed from testosterone and 4-dione in human breast cancer tissue both in vitro in tissue pieces and in vivo (214).”

What the sources say

• Not checked yetcites [214] Thériault, 1990, Hormonal regulation of estradiol 17β-hydroxysteroid dehydrogenase activity in the ZR-75-1 human breast cancer cell line., Ann NY Acad Sci source

In the paper

“female athletes and transsexuals taking androgens show atrophy of mammary gland epithelial tissue (202, 203).”

What the sources say

• Not checked yetcites [202] Korkia, 1997, Indications of prevalence, practice and effects of anabolic steroid use in Great Britain., Int J Sports Med source
• Not checked yetcites [203] Burgess, 1993, An immunohistochemical study of the long-term effects of androgen administration on female-to-male transsexual breast: a comparison with normal female breast and male breast showing gynaecomastia., J Pathol source

In the paper

“Because ovariectomized animals supplemented by exogenous estrogen were used in these studies, such data provide further support for a direct inhibitory action of androgens at the tumor cell level under in vivo conditions,”

In the paper

“In DMBA-induced tumors, high doses of DHT (0.5-4.0 mg/d) for several weeks caused the regression of 60% of established tumors (163).”

What the sources say

• Not checked yetcites [163] Huggins, 1959, Rapid induction of mammary carcinoma in the rat and the influence of hormone on the tumors., J Exp Med source

In the paper

“The androgen DHT is thus a potent inhibitor of the stimulatory effect of E 2 on ZR-75-1 human breast carcinoma growth in in vivo athymic mice.”

In the paper

“The ability of 4-dione to induce an antiproliferative effect (IC 50 , ϳ15 nm) most likely results from its metabolic transformation into testosterone and DHT (223-225) than from its direct interaction with the AR (K D , ϳ200 nm).”

What the sources say

• Not checked yetcites [223] Perel, 1985, The relationship between growth and androstenedione metabolism in four cell lines of human breast carcinoma cells in culture., Mol Cell Endocrinol source
• Not checked yetcites [224] Griffiths, 1972
• Not checked yetcites [225] Perel, 1983, The metabolism of androstenedione and testosterone of C10-metabolites in breast carcinoma, and benign prostatic hypertrophy tissue., J Steroid Biochem source

In the paper

“Several lines of evidence show that the potent growthinhibitory effect of androgens observed in ZR-71-1 cells is mediated through their specific interaction with the AR.”

In the paper

“Dauvois et al. (242) have shown that constant release of the androgen DHT in ovariectomized rats bearing DMBA-induced mammary carcinoma caused a marked inhibition of tumor growth induced by E 2 (Fig. 21).”

What the sources say

• Not checked yetcites [242] Dauvois, 1989, Inhibitory effect of androgens on DMBA-induced mammary carcinoma in the rat., Breast Cancer Res Treat source

In the paper

“in vivo studies have demonstrated that controlled release of low-dose MPA, a compound having androgenic activity, also exerts a potent inhibitory effect on the development and growth of DMBA-induced mammary carcinoma in the rat (243, 244).”

What the sources say

• Not checked yetcites [243] Li, 1992, Growth inhibition of 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors by controlled-release low-dose medroxyprogesterone acetate., Breast Cancer Res Treat source
• Not checked yetcites [244] Labrie, 1993, Controlled release low dose medroxyprogesterone acetate (MPA) inhibits the development of mammary tumors induced by dimethylbenz(a)anthracene in the rat., Breast Cancer Res Treat source

In the paper

“Down-regulation of ER expression by androgens might be of crucial importance in their physiological mode of action, i.e., when estrogens are simultaneously present in normal as well as cancerous mammary gland tissue.”

In the paper

“Thus, the primary site of action of DHT on [ 3 H]E 2 -specific binding was clearly consistent with a specific interaction with the AR, rather than a direct activation and processing of the ER by DHT (234 -239).”

What the sources say

• Not checked yetcites [234] Lippman, 1976, The effect of androgens and antiandrogens on hormone-responsive human breast cancer in long-term tissue culture., Cancer Res
• Not checked yetcites [235] Zava, 1977, Estrogen receptors in androgen-induced breast tumor regression., Cancer Res
• Not checked yetcites [236] Garcia, 1978, Androgen effects mediated by estrogen receptor in 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors., Cancer Res
• Not checked yetcites [237] Zava, 1978, Human breast cancer: androgen action mediated by estrogen receptor., Science source
• Not checked yetcites [238] Kasid, 1984, A novel nuclear form of estradiol receptor in MCF-7 human breast cancer cells., Science source
• Not checked yetcites [239] Engel, 1978, Establishment and characterization of three new continuous cell lines derived from human breast carcinomas., Cancer Res

In the paper

“Thus, in normal breast tissue, endogenous as well as locally produced androgens are likely to contribute to the regulation of the level of ER, thus modulating the sensitivity to estrogens.”

In the paper

“thus suggesting the role of AR in the beneficial effects of MPA in breast cancer in women (246, 247).”

What the sources say

• Not checked yetcites [246] Birrell, 1998, Role of the androgen receptor in human breast cancer., J Mammary Gland Biol Neoplasia source
• Not checked yetcites [247] Birrell, 1995, Medroxyprogesterone acetate therapy in advanced breast cancer: the predictive value of androgen receptor expression., J Clin Oncol source

In the paper

“Such data demonstrated, for the first time, that androgens are potent inhibitors of DMBA-induced mammary carcinoma growth by an action independent from inhibition of gonadotropin secretion and suggested an action exerted directly at the tumor level, thus further supporting in vitro data obtained with the human ZR-75-1 breast cancer cell line (208,209).”

What the sources say

• Not checked yetcites [242] Dauvois, 1989, Inhibitory effect of androgens on DMBA-induced mammary carcinoma in the rat., Breast Cancer Res Treat source
• Not checked yetcites [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
• Not checked yetcites [209] Poulin, 1989, Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells., Breast Cancer Res Treat source

In the paper

“In the specific case of human breast cancer, endogenous androgens may reduce the tumor cell sensitivity to estrogens by decreasing ER levels.”

In the paper

“The effect of androgens on ZR-75-1 cell proliferation, however, cannot be solely explained by the suppression of ER expression, because androgens still exert very potent inhibitory effects on growth in the absence of estrogens, even after prolonged periods of estrogen deprivation before exposure to androgens (208,211).”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [211] Simard, 1989, Inhibitory effects of estrogens on GCDFP-15 mRNA levels and secretion in ZR-75-1 human breast cancer cells., Mol Endocrinol source

In the paper

“That DHT acts through interaction with the AR in DMBA-induced mammary carcinoma is well supported by the finding that simultaneous treatment with the antiandrogen flutamide completely prevented DHT action.”

What the sources say

• Not checked yetcites [242] Dauvois, 1989, Inhibitory effect of androgens on DMBA-induced mammary carcinoma in the rat., Breast Cancer Res Treat source

In the paper

“suggested an action exerted directly at the tumor level, thus further supporting in vitro data obtained with the human ZR-75-1 breast cancer cell line (208,209).”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [209] Poulin, 1989, Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells., Breast Cancer Res Treat source

In the paper

“MPA has in fact been clearly shown to exert androgenic inhibitory effects on the growth of human breast cancer cells in vitro (209, 231, 245), thus suggesting the role of AR in the beneficial effects of MPA in breast cancer in women (246, 247).”

What the sources say

• Not checked yetcites [209] Poulin, 1989, Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells., Breast Cancer Res Treat source
• Not checked yetcites [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
• Not checked yetcites [245] Bentel, 1999, Androgen receptor agonist activity of the synthetic progestin, medroxyprogesterone acetate, in human breast cancer cells., Mol Cell Endocrinol source

In the paper

“Such data clearly show that AR mediates the down-regulation of the ER by DHT observed in ZR-75-1 cells.”

In the paper

“The data summarized above clearly support the hypothesis that at least part of the antagonism observed between the action of androgens and estrogens in breast cancer cells (208,211,215,240) may be explained by the heterologous downregulation of the ER by an AR-mediated mechanism.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [211] Simard, 1989, Inhibitory effects of estrogens on GCDFP-15 mRNA levels and secretion in ZR-75-1 human breast cancer cells., Mol Endocrinol source
• Not checked yetcites [215] Rochefort, 1983, The estrogenic and antiestrogenic activities of androgens in female target tissues., Pharmacol Ther source

In the paper

“Such data clearly demonstrate that circulating levels of the precursor adrenal steroid DHEA comparable to those observed in normal adult premenopausal women (259) exert a potent inhibitory effect on the development of mammary carcinoma induced by DMBA in the rat.”

What the sources say

• Not checked yetcites [259] Liu, 1990, Marked attenuation of ultradian and circadian rhythms of dehydroepiandrosterone in postmenopausal women: evidence for a reduced 17,20-desmolase enzymatic activity., J Clin Endocrinol Metab source

In the paper

“The additive inhibitory effects of an androgen and an antiestrogen on the growth of human breast carcinoma cell line ZR-75-1 have also been observed in vivo in nude mice (230).”

What the sources say

• Not checked yetcites [230] Dauvois, 1991, Additive inhibitory effects of an androgen and the antiestrogen EM-170 on estradiol-stimulated growth of human ZR-75-1 breast tumors in athymic mice., Cancer Res

In the paper

“Although the rat adrenals do not secrete significant amounts of DHEA (80)”

What the sources say

• Not checked yetcites [80] Bélanger, 1989, Comparison of residual C-19 steroids in plasma and prostatic tissue of human, rat and guinea pig after castration: unique importance of extratesticular androgens in men., J Steroid Biochem source

In the paper

“in vitro studies have provided the first demonstration of the direct antiproliferative activity of androgens on the growth of human mammary carcinoma cells using the cell line ZR-75-1 as model (208, 253).”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“it is reasonable to suggest that the present data showing a potent inhibitory effect of DHEA on the development of DMBA-induced mammary carcinoma can be at least partially explained by the androgenic action of the steroids synthesized by the enzymes present in the peripheral target tissues, an action exerted through intracrinology.”

In the paper

“the recent results of the Women's Health Initiative Study (8) clearly indicate that this compound is not recommended for longterm use in normal women where the stimulatory progestational component could well be predominant.”

What the sources say

• Not checked yetcites [8] 2002, Risks and benefits of estrogen plus progestin in healthy postmenopausal women., JAMA source

In the paper

“Poulin et al. (208) have found that the inhibitory effect of androgens on the growth of ZR-75-1 human breast carcinoma cells is additive to that of an antiestrogen.”

What the sources say

• Not checked yetcites [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

In the paper

“Many studies subsequently confirmed the beneficial effects of androgens on breast cancer (165, 167-174, 251, 252).”

What the sources say

• Not checked yetcites [165] McGuire, 1975
• Not checked yetcites [167] Fels, 1944, Treatment of breast cancer with testosterone propionate. A preliminary report., J Clin Endocrinol source
• Not checked yetcites [168] Segaloff, 1951, Hormonal therapy in cancer of the breast. 1. The effect of testosterone propionate therapy on clinical course and hormonal excretion., Cancer source
• Not checked yetcites [169] 1964, Testosterone propionate therapy of breast cancer., JAMA source
• Not checked yetcites [170] Kennedy, 1958, Fluxymesterone therapy in treatment of advanced breast cancer., N Engl J Med source
• Not checked yetcites [171] Tormey, 1983, Evaluation of tamoxifen doses with and without fluoxymesterone in advanced breast cancer., Ann Intern Med source
• Not checked yetcites [172] Gordan, 1973, Calusterone (7β,17α-dimethyltestosterone) as primary and secondary therapy of advanced breast cancer., Oncology source
• Not checked yetcites [173] Gordan, 1976
• Not checked yetcites [174] Segaloff, 1977, The use of androgens in the treatment of neoplastic disease., Pharm Ther
• Not checked yetcites [251] Adair, 1946, The use of testosterone propionate in the treatment of advanced carcinoma of the breast., Ann Surg source

In the paper

“The DMBA-induced mammary carcinoma in the rat has been widely used as a model of hormone-sensitive breast cancer in women (242,256,257).”

What the sources say

• Not checked yetcites [242] Dauvois, 1989, Inhibitory effect of androgens on DMBA-induced mammary carcinoma in the rat., Breast Cancer Res Treat source
• Not checked yetcites [256] Asselin, 1978, Effects of estradiol and prolactin on steroid receptor levels in 7,12-dimethylbenz(a)anthracene-induced mammary tumors and uterus in the rat., J Steroid Biochem source
• Not checked yetcites [257] Asselin, 1977, Control of hormone receptor levels and growth of 7,12-dimethylbenz(a)anthracene-induced mammary tumors by estrogens, progesterone and prolactin., Endocrinology source

In the paper

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

In the paper

“the enzymes required for the formation of androgens and estrogens are expressed in rat peripheral tissues (260,261).”

What the sources say

• Not checked yetcites [260] Martel, 1992, Distribution of 17β-hydroxysteroid dehydrogenase gene expression and activity in rat and human tissues., J Steroid Biochem Mol Biol source
• Not checked yetcites [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

In the paper

“the serum DHEA levels in normal 20-to 30-yr-old women ranges between 8.3 and 17.3 nm (259).”

What the sources say

• Not checked yetcites [259] Liu, 1990, Marked attenuation of ultradian and circadian rhythms of dehydroepiandrosterone in postmenopausal women: evidence for a reduced 17,20-desmolase enzymatic activity., J Clin Endocrinol Metab source

In the paper

“A recent study in rats has shown that the addition of methyltestosterone inhibits the marked proliferation of the mammary gland epithelium induced by a low-dose oral contraceptive (248).”

What the sources say

• Not checked yetcites [248] Jayo, 2000, Effects of an oral contraceptive combination with or without androgen on mammary tissues: a study in rats., J Soc Gynecol Investig source

In the paper

“thus showing a complete blockade of estrogen action by DHEA.”

In the paper

“Taken together, these data strongly suggest that DHEA exerts its inhibition of breast cancer development and growth through its conversion to androgens and activation of the AR.”

In the paper

“and that the combination of an androgenic compound with a pure antiestrogen has improved efficacy compared with each compound used alone in the prevention and treatment of breast cancer in women.”

In the paper

“That the inhibitory effect of DHEA on breast cancer MCF-7 cell growth is due to interaction with AR is supported by the finding that the antiandrogen flutamide reversed the inhibitory effect of DHEA on MCF-7 human breast cancer cell proliferation, whereas the antiestrogen tamoxifen had no effect (274).”

What the sources say

• Not checked yetcites [274] Boccuzzi, 1993, Dehydroepiandrosterone antiestrogenic action through androgen receptor in MCF-7 human breast cancer cell line., Anticancer Res

In the paper

“the androgens originating from neighboring or distant cells that possess the required mechanisms to transform DHEA into androgens in sufficient amounts to affect other cells after diffusion from their site of synthesis (271).”

What the sources say

• Not checked yetcites [271] Luo, 1996, Relative potencies of flutamide and casodex: preclinical studies., Endocrine-Related Cancer source

In the paper

“we have recently shown that DHEA exerts an almost exclusively androgenic effect in the rat mammary gland (177).”

What the sources say

• Not checked yetcites [177] Sourla, 1998, Almost exclusive androgenic action of dehydroepiandrosterone in the rat mammary gland., Endocrinology source

In the paper

“The lack of inhibitory action of DHT in some MCF-7 cell lines is most likely due to the presence of a high level of 3␣-HSD activity in these cells, thus preventing DHT from exerting its inhibitory effect before its transformation into 3␤-diol, a compound having intrinsic estrogenic activity (our unpublished data; and Ref. 273).”

What the sources say

• Not checked yetcites [273] Najid, 1991, Comparative studies of steroidogenesis inhibitors (econazole, ketoconazole) on human breast cancer MCF-7 cell proliferation by growth experiments, thymidine incorporation and flow cytometric DNA analysis., Tumori source

In the paper

“In the ovariectomized mouse, exogenous DHEA represents the only source of sex steroids in peripheral tissues, including the mammary gland.”

In the paper

“the inhibition of tumor growth seen after DHEA treatment in ovariectomized animals results from its intracrine in situ conversion into androgens in the mammary gland (25,35,78,92,255).”

What the sources say

• Not checked yetcites [25] Labrie, 1991, Intracrinology., Mol Cell Endocrinol source
• Not checked yetcites [35] Labrie
• Not checked yetcites [78] Labrie, 1988, Androgenic activity of dehydroepiandrosterone and androstenedione in the rat ventral prostate., Endocrinology source
• Not checked yetcites [92] Labrie, 1997, The key role of 17β-HSDs in sex steroid biology., Steroids source
• Not checked yetcites [255] Labrie, 1995, DHEA and peripheral androgen and estrogen formation: intracrinology., Ann NY Acad Sci source

In the paper

“women with breast cancer were found to have low urinary levels of androsterone and etiocholanolone, two metabolites of DHEA (283, 284).”

What the sources say

• Not checked yetcites [283] Bulbrook, 1962, Abnormal excretion of urinary steroids by women with early breast cancer., Lancet source
• Not checked yetcites [284] Cameron, 1970, Benign and malignant breast disease in south Wales: a study of urinary steroids., Br Med J source

In the paper

“DHT exerts a potent inhibitory effect on breast cancer cell proliferation in ZR-75-1 human breast cancer cells (208, 210)”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [210] Poulin, 1989, Down-regulation of estrogen receptors by androgens in the ZR-75-1 human breast cancer cell line., Endocrinology source

In the paper

“treatment with DHEA markedly delayed the appearance of breast tumors in C3H mice that were genetically bred to develop breast cancer (285).”

What the sources say

• Not checked yetcites [285] Schwartz, 1979, Inhibition of spontaneous breast cancer formation in female C3H (Avy/a) mice by long-term treatment with dehydroepiandrosterone., Cancer Res

In the paper

“such a hypothetical situation of an absence of estrogens does not exist in normal women, even after menopause.”

In the paper

“women with primary operable breast cancer had urinary levels of 11-deoxy-17-ketosteroids (derived mainly from DHEA-S and DHEA) lower than normal, thus suggesting that a low secretion rate of DHEA and DHEA-S could precede the development of breast cancer.”

In the paper

“the absence of a stimulatory effect of DHEA on the human endometrium (73, 280) eliminates the need to administer a progestin to neutralize the stimulatory effect of estrogens in this tissue.”

What the sources say

• Not checked yetcites [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 yetcites [280] Labrie, 1997, Effect of 12-month DHEA replacement therapy on bone, vaginum, and endometrium in postmenopausal women., J Clin Endocrinol Metab source

In the paper

“low serum DHEA levels have been associated with breast cancer in women (281)”

What the sources say

• Not checked yetcites [281] Zumoff, 1981, Abnormal 24-hr mean plasma concentrations of dehydroepiandrosterone and dehydroisoandrosterone sulfate in women with primary operable breast cancer., Cancer Res

In the paper

“To our knowledge, these data provide the first demonstration of the inhibitory effect of DHEA on the growth of human breast cancer xenografts in nude mice.”

In the paper

“Such data obtained in vivo support our previous findings that the inhibitory effects of androgens and antiestrogens on mammary carcinoma are exerted at least in part by different mechanisms”

In the paper

“That this hypothesis of competition with 5-diol is most unlikely to apply is supported by the observation that increasing doses of diethylstilbestrol, a highly potent estrogen, do not interfere with the inhibitory effect of DHEA on human breast cancer MCF-7 cell proliferation (270).”

What the sources say

• Not checked yetcites [270] Boccuzzi, 1992, Opposite effects of dehydroepiandrosterone on the growth of 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinomas., Anticancer Res