The-Clitoris.com - Androgens and Female Sexuality: Medical Article Summaries, Part 2

Source: Gynecol Endocrinol. 2000 Oct;14(5):342-63.

Title: Six-month oral dehydroepiandrosterone [DHEA] supplementation in early and late postmenopause.

Authors: Stomati M, Monteleone P, Casarosa E, Quirici B, Puccetti S, Bernardi F, Genazzani AD, Rovati L, Luisi M, Genazzani AR.

The adrenal production of the delta 5-androgens, dehydroepiandrosterone (DHEA) and its sulfate ester dehydroepiandrosterone sulfate (DHEAS), declines linearly with aging. The evidence that DHEA or DHEAS administration may alleviate some of the problems related to aging has opened new perspectives for clinical research. The present study aims to investigate the effects of a 6-month DHEA supplementation in early and late postmenopausal women, with normal or overweight body mass index (BMI), on the level of circulating steroids, sex hormone binding globulin (SHBG), beta-endorphin and gonadotropins, and on the adrenal gland response to dexamethasone suppression and adrenocorticotropic hormone (ACTH) stimulation. Early postmenopausal women (50-55 years) both normal weight (BMI 20-24, n = 9) and overweight (BMI 26-30, n = 9) and late postmenopausal women (60-65 years) both of normal weight and overweight, were treated with oral DHEA (50 mg/day). Circulating DHEA, DHEAS, 17-OH pregnenolone, progesterone, 17-OH progesterone, allopregnenolone, androstenedione, testosterone, dihydrotestosterone, estrone, estradiol, SHBG, cortisol, luteinizing hormone, follicle stimulating hormone and beta-endorphin levels were evaluated monthly and a Kupperman score was performed. The product/precursor ratios of adrenal steroid levels were used to assess the relative activities of the adrenal cortex enzymes. Before and after 3 and 6 months of therapy, each women underwent an ACTH stimulating test (10 micrograms i.v. in bolus) after dexamethasone administration (0.5 mg p.o.) to evaluate the response of cortisol, DHEA, DHEAS, androstenedione, 17-OH pregnenolone, allopregnanolone, progesterone and 17-OH progesterone. The between-group differences observed before treatment disappeared during DHEA administration. Levels of 17-OH pregnenolone remained constant during the 6 months.

Levels of DHEA, DHEAS, androstenedione, testosterone and dihydrotestosterone increased progressively from the first month of treatment. Levels of estradiol and estrone significantly increased after the first/second month of treatment. Levels of SHBG significantly decreased from the second month of treatment only in overweight late postmenopausal women, while the other groups showed constant levels. Progesterone levels remained constant in all groups, while 17-OH progesterone levels showed a slight but significant increase in all groups. Allopregnanolone and plasma beta-endorphin levels increased progressively and significantly in the four groups, reaching values three times higher than baseline. Levels of cortisol and gonadotropins progressively decreased in all groups. The product/precursor ratios of adrenal steroid levels at the sixth month were used to assess the relative activities of the adrenal cortex enzymes and were compared to those found before therapy. The 17,20-desmolase, sulfatase and/or sulfotransferase, 17,20-lyase and 5 alpha-reductase activities significantly increased, while the 3 beta-hydroxysteroid-oxidoreductase activity did not vary. On the contrary, the 11-hydroxylase and/or 21-hydroxylase activities showed a significant decrease after 6 months of treatment. In basal conditions, dexamethasone significantly suppressed all the adrenal steroids and this suppression was greater after 3 and 6 months of treatment for DHEA, DHEAS and allopregnanolone, while it remained unchanged for other steroids. Before treatment, ACTH stimulus induced a significant response in all parameters; after the treatment, it prompted a greater response in delta 5- and delta 4-androgens, progesterone and 17-OH progesterone, while cortisol responded less in both younger and older normal-weight women. The endometrial thickness did not show significant modifications in any of the groups of postmenopausal women during the 6 months of treatment. Treatment with DHEA was associated with a progressive improvement of the Kupperman score in all groups, with major effects on the vasomotor symptoms in

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Source: Menopause. 2006 Jan-Feb;13(1):46-56.

Title: Hypoactive sexual desire disorder in postmenopausal women:

Authors: Leiblum SR, Koochaki PE, Rodenberg CA, Barton IP, Rosen RC.

OBJECTIVE: To determine the prevalence of hypoactive sexual desire disorder (HSDD) among US women by reproductive status and age and to explore the correlates of sexually related distress.

DESIGN: The Women's International Study on Health and Sexuality questionnaire was mailed to a national sample of US women in 2000. The survey included validated questionnaires: the Short Form-36, which measures overall health status; the Profile of Female Sexual Function, which assesses sexual desire; and the Personal Distress Scale, which measures distress caused by low desire. Four groups of women were studied: surgically postmenopausal, aged 20 to 49 years and 50 to 70 years; premenopausal, aged 20 to 49 years; and naturally postmenopausal, aged 50 to 70 years. Clinically derived cutoff Profile of Female Sexual Function and Personal Distress Scale scores were used to classify women with HSDD and determine its prevalence. The relations between sexual desire and frequency of sexual activity or relationship satisfaction were assessed. Overall health status of HSDD women and women with normal desire were compared.

RESULTS: The prevalence of HSDD ranged from 9% in naturally postmenopausal women to 26% in younger surgically postmenopausal women. The prevalence of HSDD was significantly greater among surgically postmenopausal women, aged 20 to 49 years, than premenopausal women of similar age, whereas there were no significant differences in the prevalence between surgically postmenopausal women, aged 50 to 70 years, and naturally postmenopausal women. For many women, HSDD was associated with emotional and psychological distress as well as significantly lower sexual and partner satisfaction. HSDD was also associated with significant decrements in general health status, including aspects of mental and physical health.

CONCLUSIONS: HSDD is prevalent among women at all reproductive stages, with younger surgically postmenopausal women at greater risk, and is associated with a less active sex life and decreased sexual and relationship satisfaction.

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Source: Menopause. 2005 Sep-Oct;12(5):496-511; quiz 649. Epub 2005 Sep 1.

Title: The role of testosterone therapy in postmenopausal women: position statement of The North American Menopause Society.

Authors: North American Menopause Society.

OBJECTIVE: To create an evidence-based position statement regarding the role of exogenous testosterone in postmenopausal women.

DESIGN: The North American Menopause Society (NAMS) enlisted a panel of clinicians and researchers acknowledged to be experts in the field of testosterone therapy to review the evidence obtained from the medical literature, compile supporting statements and conclusions, and reach consensus on recommendations. The document was reviewed and approved by the NAMS Board of Trustees.

RESULTS: Endogenous testosterone levels have not been clearly linked to sexual function in postmenopausal women. Published evidence from randomized controlled trials, although limited, indicates that exogenous testosterone, both oral and nonoral formulations, has a positive effect on sexual function, primarily desire, arousal, and orgasmic response, in women after spontaneous or surgically induced menopause. Data are inadequate to support recommending testosterone use for any other indication, including preserving or increasing bone mineral density, reducing hot flashes, increasing lean body mass, or improving well-being. Hirsutism and acne have been associated with testosterone therapy, but the actual risks are not well defined. It is not known whether testosterone therapy increases the risk of breast cancer, cardiovascular disease, or thromboembolic events. There are few data regarding the safety and efficacy of testosterone therapy in women not using concomitant estrogen therapy or for the use of testosterone therapy for longer than 6 months. Clinically available laboratory assays do not accurately detect testosterone concentrations at the values typically found in women, and no testosterone level has been clearly linked to a clinical syndrome of hypoandrogenism or testosterone insufficiency.

CONCLUSIONS: Postmenopausal women with decreased sexual desire associated with personal distress and with no other identifiable cause may be candidates for testosterone therapy. Testosterone treatment without concomitant estrogen therapy cannot be recommended because of a lack of evidence. When evaluating a woman for testosterone therapy, recommendations are to rule out causes not related to testosterone levels (eg, physical and psychosocial factors, medications) and to ensure that there is a physiologic cause for reduced testosterone levels (eg, bilateral oophorectomy). Laboratory testing of testosterone levels should be used only to monitor for supraphysiologic levels before and during therapy, not to diagnose testosterone insufficiency. Monitoring should also include subjective assessments of sexual response, desire, and satisfaction as well as evaluation for potential adverse effects. Transdermal patches and topical gels or creams are preferred over oral products because of first-pass hepatic effects documented with oral formulations. Custom-compounded products should be used with caution because the dosing may be more inconsistent than it is with government-approved products. Testosterone products formulated specifically for men have a risk of excessive dosing, although some clinicians use lower doses of these products in women.

Testosterone therapy is contraindicated in women with breast or uterine cancer or in those with cardiovascular or liver disease. It should be administered at the lowest dose for the shortest time that meets treatment goals. Counseling regarding the potential risks and benefits should be provided before initiating therapy.

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Source: Ann Clin Biochem. 2006 May;43(Pt 3):189-95.

Title: Investigation into possible causes of interference in serum testosterone measurement in women.

Authors: Heald AH, Butterworth A, Kane JW, Borzomato J, Taylor NF, Layton T, Kilpatrick ES, Rudenski A.

BACKGROUND: Direct (non-extracted) testosterone immunoassays may give spuriously high results in women. The presumed interferents may be removed if testosterone is extracted into an organic phase before being measured. We aimed to clarify possible causes and effects of interference in testosterone measurement in women.

METHODS: Women who had a blood sample referred to Hope Hospital Clinical Biochemistry laboratory for measurement of serum testosterone concentration over a six-month period were studied. Clinical and treatment data were recorded. A difference (direct-minus-extracted testosterone) of less than 1.0 nmol/L was used to define a group with low interference. A difference of 2.5 nmol/L or more was used to define a group with significant interference.

RESULTS: The distribution of interference in 1271 serum samples from female patients was unimodal. There were no group differences in clinical presentation or treatment. The median degree of interference was 1.4 nmol/L. In 42 female patients with varying degrees of interference, identified on routine assay, regression analysis showed strong association between dehydroepiandrosterone sulphate (DHEA-S) and interference (direct-minus-extracted testosterone) (r = 0.77, P < 0.001).

CONCLUSIONS: Given that DHEA-S is present in very variable amounts in blood, it is possible that even with a low cross reactivity, DHEA-S or one of its metabolites significantly interferes in the testosterone assay when at higher concentrations.

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Source: Cancer Epidemiol Biomarkers Prev. 2006 May;15(5):972-8.

Title: Reproducibility of plasma steroid hormones, prolactin, and insulin-like growth factor levels among premenopausal women over a 2- to 3-year period.

Authors: Missmer SA, Spiegelman D, Bertone-Johnson ER, Barbieri RL, Pollak MN, Hankinson SE.

Few studies have evaluated whether a single blood hormone measurement, as is available in most epidemiologic studies, sufficiently characterizes a premenopausal woman's long-term hormone levels; there is particular concern whether sex steroid hormones, which fluctuate during the menstrual cycle, are reliable. We conducted a prospective study within the Nurses' Health Study II to examine the reproducibility of plasma estrogens, androgens, progesterone, prolactin, sex hormone binding globulin, insulin-like growth factor-I (IGF-I), and IGF binding protein-3 (IGFBP-3). One blood sample per year over 3 years was collected from 113 premenopausal women during both the follicular and luteal phases of the menstrual cycle. We calculated intraclass correlation coefficients (ICC) across the three samples for all women. Among estrogens, ICCs ranged from 0.38 (estradiol) to 0.60 (estrone sulfate) in the follicular phase and from 0.44 (estrone) to 0.69 (estrone sulfate) in the luteal phase. Among androgens, ICCs ranged from 0.58 (androstenedione) to 0.94 [dehydroepiandrostenedione sulfate (DHEAS)] in the follicular phase and from 0.56 (testosterone) to 0.81 (DHEAS) in the luteal phase. When values were averaged across the follicular and luteal phases, the ICC for prolactin was 0.64 whereas ICCs for IGF-I and IGFBP-3 were 0.86 and 0.82, respectively. The ICC for progesterone in the luteal phase was only 0.29. These data suggest that for androgens, estrone sulfate, prolactin, IGF-I, and IGFBP-3, a single measurement can reliably categorize average levels over at least a 3-year period in premenopausal women. For estrone and estradiol, where ICCs were relatively low, it is important to use reproducibility data such as those to correct for measurement error in epidemiologic studies.

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Source: J Clin Endocrinol Metab. 2006 May;91(5):1683-90. Epub 2006 Feb 14.

Title: Effects of testosterone replacement in androgen-deficient women with hypopituitarism: a randomized, double-blind, placebo-controlled study.

Authors: Miller KK, Biller BM, Beauregard C, Lipman JG, Jones J, Schoenfeld D, Sherman JC, Swearingen B, Loeffler J, Klibanski A.

CONTEXT: Hypopituitarism in women is characterized by profound androgen deficiency due to a loss of adrenal and/or ovarian function. The effects of testosterone replacement in this population have not been reported.

OBJECTIVE: The objective of the study was to determine whether physiologic testosterone replacement improves bone density, body composition, and/or neurobehavioral function in women with severe androgen deficiency secondary to hypopituitarism.

DESIGN: This was a 12-month randomized, placebo-controlled study.

SETTING: The study was conducted at a general clinical research center.

STUDY PARTICIPANTS: Fifty-one women of reproductive age with androgen deficiency due to hypopituitarism participated.

INTERVENTION: Physiologic testosterone administration using a patch that delivers 300 microg daily or placebo was administered.

MAIN OUTCOME MEASURES: Bone density, fat-free mass, and fat mass were measured by dual x-ray absorptiometry. Thigh muscle and abdominal cross-sectional area were measured by computed tomography scan. Mood, sexual function, quality of life, and cognitive function were assessed using self-administered questionnaires.

RESULTS: Mean free testosterone increased into the normal range during testosterone administration. Mean hip (P = 0.023) and radius (P = 0.007), but not posteroanterior spine, bone mineral density increased in the group receiving testosterone, compared with placebo, as did mean fat-free mass (P = 0.040) and thigh muscle area (P = 0.038), but there was no change in fat mass. Mood (P = 0.029) and sexual function (P = 0.044) improved, as did some aspects of quality of life, but not cognitive function. Testosterone at physiologic replacement levels was well tolerated, with few side effects. CONCLUSIONS: This is the first randomized, double-blind, placebo-controlled study to show a positive effect of testosterone on bone density, body composition, and neurobehavioral function in women with severe androgen deficiency due to hypopituitarism.

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Source: Menopause. 2006 May-Jun;13(3):387-96.

Title: Efficacy and safety of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial.

Authors: Davis SR, van der Mooren MJ, van Lunsen RH, Lopes P, Ribot J, Rees M, Moufarege A, Rodenberg C, Buch A, Purdie DW.

OBJECTIVE: Evaluation of the use of testosterone therapy for hypoactive sexual desire disorder (HSDD) after oophorectomy has mostly involved women treated with oral estrogen preparations. We investigated the efficacy and safety of a testosterone patch in surgically menopausal women receiving concurrent transdermal estrogen.

DESIGN: Women with HSDD after oophorectomy, for whom this was a concern, who were using transdermal estrogen, were recruited to a 24-week, randomized, double-blind, placebo-controlled trial in Europe and Australia. Patients were randomly allocated to placebo (n = 40) or testosterone 300 microg/day (n = 37) treatment. Primary endpoints were changes in sexual desire measured by the sexual desire domain of the Profile of Female Sexual Function and the frequency of satisfying sexual activity at 24 weeks.

RESULTS: Sixty-one women (79%) completed the trial. All subjects who received at least one application of study medication were included in analysis. The testosterone-treated group experienced a significantly greater change from baseline in the domain sexual desire score compared with placebo (change from baseline, 16.43 versus 5.98; P = 0.02). The domain scores for arousal, orgasm, decreased sexual concerns, responsiveness, and self-image as well as decreased distress were also significantly greater with testosterone therapy than placebo. The frequency of satisfactory sexual events increased but was not statistically different between treatment groups (P = 0.06) Adverse events occurred with similar frequency in both groups, and no serious risks of therapy were observed.

CONCLUSIONS: In this study, transdermal testosterone therapy via a skin patch improved sexual desire and other sexual function domains. It was well tolerated in these oophorectomized women with HSDD receiving concomitant transdermal estrogen.

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Source: Semin Reprod Med. 2006 Apr;24(2):106-14.

Title: Testosterone therapy in premenopausal women.

Authors: Kalantaridou SN, Calis KA.

Testosterone therapy for postmenopausal women and women with surgical menopause, albeit controversial, is becoming more widespread. However, only limited data are available to support its use in premenopausal women. Androgens have important biological roles in young women, influencing bone and muscle mass, mood and well-being, and libido. Pathophysiological states affecting ovarian and adrenal function or both may result in androgen deficiency in premenopausal women. Young women with hypothalamic amenorrhea, premature ovarian failure, oophorectomy, premenstrual syndrome, acquired immunodeficiency wasting syndrome, adrenal insufficiency, and hypopituitarism may have testosterone deficiency. Young women with loss of libido may also have testosterone deficiency. Medications that may lead to testosterone insufficiency include oral estrogen, oral contraceptives, and corticosteroids. Testosterone deficiency in young women may be underdiagnosed because the symptoms generally are nonspecific and the measurement of total and free testosterone is inaccurate with commonly used techniques. Only a few studies investigating the effects of testosterone therapy have been performed thus far in premenopausal women. Long-term trials evaluating safety and effectiveness of testosterone therapy in premenopausal women are lacking. Common adverse effects include hirsutism and acne, which reverse with discontinuation of treatment. The availability of testosterone regimens specifically designed for women is expected to help maintain testosterone levels within the normal range and clarify whether the apparent beneficial effects of testosterone therapy are physiological or pharmacological.

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Source: Semin Reprod Med. 2006 Apr;24(2):97-105.

Title: Dehydroepiandrosterone [DHEA] therapy as female androgen replacement.

Authors: Saltzman E, Guay A.

Dehydroepiandrosterone (DHEA) is an abundant circulating androgen precursor preferentially produced by the adrenal glands. DHEA has been shown to exert its effects via downstream conversion to sex steroid hormones, neuromodulation, improvement in endothelial cell function, and possibly by acting on a cell membrane-bound receptor. Low levels of circulating DHEA have been demonstrated in women with diminished libido and other symptoms of sexual dysfunction. DHEA deficiency has also been associated with various drugs, and endocrine, nonhormonal, and age-related disorders. DHEA supplementation has been shown to produce beneficial effects in women with adrenal insufficiency. However, DHEA supplementation in healthy euadrenal subjects (including premenopausal and postmenopausal women with androgen insufficiency) is controversial; studies have yielded conflicting results regarding its beneficial effects on sexual function, metabolism, and overall well-being. Further research is needed to better elucidate the efficacy and safety of DHEA supplementation for the treatment of androgen insufficiency in women.

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Source: Int J Cancer. 2006 Nov 15;119(10):2402-7.

Title: Serum concentrations of estrogens, sex hormone-binding globulin, and androgens and risk of breast cancer in postmenopausal women.

Authors: Adly L, Hill D, Sherman ME, Sturgeon SR, Fears T, Mies C, Ziegler RG, Hoover RN, Schairer C.

We assessed the relationship between serum concentrations of estrogens, androgens, and sex hormone-binding globulin and risk of breast cancer among postmenopausal women. Study participants provided serum prior to breast biopsy or mastectomy in 3 hospitals in Grand Rapids, Michigan between 1977 and 1987. A total of 179 subjects with localized breast cancer were compared to 152 subjects with nonproliferative breast changes that have not been associated with elevated breast cancer risk. Increasing serum concentrations of estrone and estrone sulfate were associated with increases in breast cancer risk; the odds ratios (ORs) in the fourth quartiles compared to the first were 2.3 (95% confidence interval (CI) 1.1-4.6) for both (p-trend = 0.02 and 0.03, respectively). Estradiol and bioavailable estradiol concentrations were associated with nonstatistically significant increases in risk. Androstenediol levels were associated with risk (p-trend = 0.01); the OR in the fourth compared to the first quartile was 2.2 (95% CI 1.0-4.6). Testosterone, dehydroepiandrosterone and androstenedione levels were not associated with increased risk. Sex hormone-binding globulin was associated with a nonsignificant decrease in risk. Associations with estrone and estrone sulfate persisted after adjustment for androstenediol (ORs for fourth compared to first quartiles were 2.0 (95% CI 0.9-4.5) and 2.2 (95% CI 1.0-4.6), respectively (p-trend = 0.16 for both). The association with androstenediol was attenuated after adjustment for estrone (OR for fourth compared to first quartile was 1.6 (95% CI 0.7-3.6); p-trend = 0.13). Higher serum concentrations of estrogens were associated with increased breast cancer risk in postmenopausal women. Androgen levels were not independently associated with substantially increased risk.

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Source: Endocr Relat Cancer. 2006 Jun;13(2):335-55.

Title: Future perspectives of selective estrogen receptor modulators used alone and in combination with DHEA.

Authors: Labrie F.

Breast cancer is the most frequently diagnosed and the second cause of cancer death in women, thus making breast cancer a most feared disease. Since breast cancer metastasizes early and it is unlikely that improvements in the treatment of metastatic disease could permit a cure in most cases in the foreseeable future, it is clear that prevention is essential in order practically to eliminate deaths from breast cancer. Tamoxifen is the only selective estrogen receptor modulator (SERM) currently registered for use in breast cancer prevention; the tamoxifen versus raloxifene study should indicate the efficacy of this compound compared with raloxifene. The recent benefits of aromatase inhibitors over tamoxifen indicate the advantages of a blockade of estrogens more complete than the one achieved with tamoxifen, a SERM having some estrogenic activity in the mammary gland and an even higher estrogenic action in the uterus. However, it is unlikely that the general estrogen ablation achieved with aromatase inhibitors will be acceptable for the long-term use required for prevention. It is thus important to develop SERMs with highly potent and pure antagonistic activity in the mammary gland and uterus while possessing estrogen-like activity in tissues of particular importance for women's health, namely the bones and the cardiovascular system. However, it is expected that a SERM alone will not meet all the requirements of women's health at the postmenopause when ovarian estrogen secretion has ceased and peripheral formation of androgens and estrogens from DHEA by intracrine mechanisms is decreased by 60% or more. One possibility is to combine a SERM with DHEA, a precursor of sex steroids that permits, somewhat like SERMs, tissue-specific formation of androgens and/or estrogens according to the level of expression of the steroidogenic and steroid-inactivating enzymes. DHEA could thus compensate for the important loss of androgens that accompanies aging and could also permit sex steroid formation and action in the brain while breast cancer prevention would be achieved by the SERM.

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Source: Cancer Epidemiol Biomarkers Prev. 2006 May;15(5):967-71.

Title: The association of plasma DHEA and DHEA sulfate with breast cancer risk in predominantly premenopausal women.

Authors: Tworoger SS, Missmer SA, Eliassen AH, Spiegelman D, Folkerd E, Dowsett M, Barbieri RL, Hankinson SE.

Concentrations of adrenal androgens are positively associated with postmenopausal breast cancer risk; however, results in premenopausal women are conflicting. Therefore, we conducted a prospective nested case-control study within the Nurses' Health Study II cohort to examine the relationship of DHEA and DHEA sulfate (DHEAS) with breast cancer risk in predominantly premenopausal women. Blood samples were collected from 1996 to 1999. The analysis included 317 cases of breast cancer diagnosed after blood collection and before June 1, 2003; for each case, two controls were matched on age, fasting status, time of day and month of blood collection, race/ethnicity, and timing of blood draw within the menstrual cycle. No associations were observed between DHEA or DHEAS levels and breast cancer risk overall [in situ and invasive; DHEA relative risk (RR), top versus bottom quartile, 1.2; 95% confidence interval (95% CI), 0.8-1.8, P(trend) = 0.53; DHEAS RR, 1.3; 95% CI, 0.9-2.0; P(trend) = 0.07]. However, both DHEA and DHEAS were positively associated with estrogen receptor-positive/progesterone receptor-positive breast cancer (DHEA RR, 1.6; 95% CI, 0.9-2.8, P(trend) = 0.09; DHEAS RR, 1.9; 95% CI, 1.1-3.3, P(trend) = 0.02). We observed a significant interaction by age, with an RR for DHEAS of 0.8 (95% CI, 0.4-1.5, P(trend) = 0.62) for women <45 years old and 2.0 (95% CI, 1.2-3.5, P(trend) = 0.003) for women >/=45 years old; results were similar for DHEA. Our results suggest that adrenal androgens are positively associated with breast cancer among predominately premenopausal women, especially for estrogen receptor-positive/progesterone receptor-positive tumors and among women over age 45 years.

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Source: Arch Intern Med. 2006 Jul 24;166(14):1483-9

Title: Combined estrogen and testosterone use and risk of breast cancer in postmenopausal women.

Authors: Tamimi RM, Hankinson SE, Chen WY, Rosner B, Colditz GA.

BACKGROUND: The role of androgens in breast cancer etiology has been unclear. Epidemiologic studies suggest that endogenous testosterone levels are positively associated with breast cancer risk in postmenopausal women. Given the increasing trend in the use of hormone therapies containing androgens, we evaluated the relation between the use of estrogen and testosterone therapies and breast cancer.

METHODS: We conducted a prospective cohort study in the Nurses' Health Study from 1978 to 2002 to assess the risk of breast cancer associated with different types of postmenopausal hormone (PMH) formulations containing testosterone. During 24 years of follow-up (1 359 323 person-years), 4610 incident cases of invasive breast cancer were identified among postmenopausal women. Information on menopausal status, PMH use, and breast cancer diagnosis was updated every 2 years through questionnaires.

RESULTS: Among women with a natural menopause, the risk of breast cancer was nearly 2.5-fold greater among current users of estrogen plus testosterone therapies (multivariate relative risk, 2.48; 95% confidence interval, 1.53-4.04) than among never users of PMHs. This analysis showed that risk of breast cancer associated with current use of estrogen and testosterone therapy was significantly greater compared with estrogen-only therapy (P for heterogeneity, .007) and marginally greater than estrogen and progesterone therapy (P for heterogeneity, .11). Women receiving PMHs with testosterone had a 17.2% (95% confidence interval, 6.7%-28.7%) increased risk of breast cancer per year of use.

CONCLUSION: Consistent with the elevation in risk for endogenous testosterone levels, women using estrogen and testosterone therapies have a significantly increased risk of invasive breast cancer.

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Source: J Clin Oncol. 2006 Apr 20;24(12):1823-30. Epub 2006 Mar 27.

Title: Endogenous steroid hormone concentrations and risk of breast cancer: does the association vary by a woman's predicted breast cancer risk?

Authors: Eliassen AH, Missmer SA, Tworoger SS, Hankinson SE.

PURPOSE: To examine whether the associations of endogenous estrogens and testosterone with breast cancer risk differ between high- and low-risk women, as determined by the Gail model and the Rosner and Colditz model, and by family history of breast cancer.

METHODS: We conducted a prospective nested case-control study within the Nurses' Health Study. From 1989 or 1990 until June 2000, blood samples were collected, 418 breast cancer patient cases were identified, and two controls (total n = 817) were matched to each case. We classified women as high or low risk based on their family history of breast cancer, their 5-year Gail risk score, and their 5-year Rosner and Colditz risk score. Multivariate relative risks (RR) and 95% CI were calculated by unconditional logistic regression, adjusting for matching and breast cancer risk factors.
RESULTS: Estrone sulfate was statistically significantly associated with breast cancer risk among women with low (< 1.66%) and high (> or = 2.52%; 75th percentile) Gail predicted risk (fourth v first quartile RR = 3.6; 95% CI, 1.9 to 7.0; RR = 2.5; 95% CI, 1.2 to 5.1, respectively). Testosterone results were similar across strata of predicted risk, with two times the risk in the fourth (v first) quartile. Estradiol appeared more strongly associated with breast cancer in women with higher predicted risk (RR = 4.5; 95% CI, 2.1 to 9.5) compared with women with lower risk (RR = 2.1; 95% CI, 1.2 to 3.6), but differences were not statistically significant. Results were similar across predicted Rosner and Colditz risk scores.

CONCLUSION: These data suggest that higher levels of endogenous estrogens and testosterone are associated with increased breast cancer risk, regardless of predicted risk or family history of breast cancer.