Abdulmaged M. Traish1✸ , Katharina Fetten1, Martin Miner2,3, Michael L. Hansen4,5 and Andre Guay6

1 Departments of Biochemistry and Urology, Boston University School of Medicine Boston, MA, USA 2 Men’s Health Center, Miriam Hospital, Providence, RI, USA 3 Swansea Family Practice Group, Swansea, MA, USA 4 Department of OB/GYN, Stavanger University Hospital, Stavanger, Norway 5 Copenhagen Cardiovascular Clinic, Copenhagen, Denmark 6 Center for Sexual Function/Endocrinology Lahey Clinic Northshore, Peabody, MA, USA.

Keywords: androgen excess; androgen therapy; aromatase inhibitors; breast cancer; estradiol; hormone replacement therapy; menopause; polycystic ovary disease; sex hormone binding globulin; testosterone.

✸Corresponding author: Abdulmaged M. Traish, MBA, PhD, Professor of Biochemistry and Urology, Director, Laboratories for Sexual Medicine, Institute for Sexual Medicine, Boston University School of Medicine, Center for Advanced Biomedical Research, 700 Albany Street, W607, Boston, MA 02118, USA Phone: +1-617-638-4578, Fax: +1-617-638-5412; E-mail: atraish@bu.edu.


The objective of this review was to examine data from preclinical, clinical and epidemiological studies to evaluate if testosterone (T) poses increased risk of breast cancer in women. Appraisal of the existing literature produced several lines of evidence arguing against increased breast cancer risk with T. These include: (i) Data from breast tumor cell lines treated with androgens did not corroborate the notion that T increases breast cancer risk. On the contrary, androgens appear to be protective, as they inhibit tumor cell growth. (ii) Many of the epidemiological studies claiming an association between T and breast cancer did not adjust for estrogen levels. Studies adjusted for estrogen levels reported no association between T and breast cancer. (iii) Data from clinical studies with exogenous androgen treatment of women with endocrine and sexual disorders did not show any increase in incidence of breast cancer. (iv) Women afflicted with polycystic ovary disease, who exhibit high levels of androgens do not show increased risk of breast cancer compared to the general population. (v) Female to male transsexuals, who receive supraphysiological doses of T for long time periods prior to surgical procedures, do not report increased risk of breast cancer. (vi) Finally, women with hormone responsive primary breast cancer are treated with aromatase inhibitors, which block conversion of androgens to estrogens, thus elevating androgen levels. These women do not experience increased incidence of contralateral breast cancer nor do they experience increased tumor growth. In conclusion, the evidence available strongly suggests that T does not increase breast cancer risk in women.


Testosterone (T) therapy in women has been utilized since 1938 to treat various gynecological and sexual disorders (1). However, T therapy in women remains controversial, even with the plethora of information that exists in the literature. A glance at the randomized clinical studies reported to date on T therapy in women (Table 1) provides evidence for improved overall general and sexual health in women with surgical or natural menopause and with minimal side effects. T safety in women treated for sexual dysfunction has been reviewed recently and deemed use of T to be safe based on clinical data over a 3-year period (2-5). However, some argued that T therapy in women is associated with increased risk of breast cancer based on epidemiological studies (6). It should be noted that many epidemiological studies did not adjust for estrogen levels and therefore result in serious drawbacks of T measurements in women (7). To date, there are no studies which unequivocally demonstrated that T directly or indirectly causes initiation, promotion or growth of breast tumors in women. Therefore, claims that T is associated with increased breast cancer risk are unsubstantiated.

Table 1. Clinical trials of testosterone treatment in women.


Estrogens are critical for normal development, differentiation and growth of the mammary gland and normal breast tissue expresses estrogen receptors (ERs), which regulate estrogen action in the breast (8). Approximately 65% of human breast tumors retain expression of ERa, which allows tumor cells to grow in response to circulating estrogens (9). Indeed, tumors that are ER positive and progesterone receptor (PR) positive (ER+/PR + ) are considered hormone sensitive. This concept is utilized clinically to treat patients with hormone responsive breast cancer with anti-estrogens, such as tamoxifen, to inhibit tumor growth and as a prognostic factor for management of women with breast cancer (10, 11).

Androgens serve as precursors of estrogen biosynthesis and estrogens can promote tumor growth (8). Aromatase inhibitors were introduced to treat patients with ER + tumors because it deprives the tumor of circulating estrogens (12-17). Although this treatment increases intracellular T levels, it does not increase tumor growth in response to androgens. In this review, we discuss data from preclinical, clinical and epidemiological studies, which provided evidence suggesting that T does not directly increase breast cancer risk in women.

Anti-proliferative effects of androgens in human breast cancer cells in vitro and in vivo

Several preclinical studies using human breast tumor cell lines have investigated the effects of androgens on breast cancer cell growth and proliferation (Table 2). In the majority of studies (13 out of 16) androgens inhibited cellular growth and proliferation and only few studies showed mixed results. The inhibitory effect of 5α-dihydrotestosterone (5α-DHT), T and Δ4-androstenedione (Δ4-Adione) was demonstrated on the growth of the estrogen-sensitive human breast cancer cell line ZR-75-1 (18). The antiproliferative effect of androgens was competitively reversed by the antiandrogen, hydroxyflutamide, indicating an androgen receptor (AR)-mediated mechanism. Similarly, the effects of T and 5α-DHT on cell growth were examined in four different breast cancer cell lines (MCF-7, T47D, MDA MB 435S and BT-20) and demonstrated that T and 5α-DHT inhibited cell growth of all tumor cell lines investigated (19). These observations were corroborated by other studies, demonstrating that androgens inhibit the proliferation of MCF-7 breast cancer cells (20). In human ZR-75-1 breast cancer cells, 5α-DHT alone inhibited basal cell proliferation without a significant influence on cell cycle distribution. Moreover, pretreatment with 5α-DHT for 8 days, while decreasing ZR-75-1 cell number, did not result in loss of estrogen sensitivity. These observations suggest that 5α-DHT which is non-aromati-zable to estrogen, is a potent inhibitor of the stimulatory effect on estrogens on breast cancer cell proliferation (21).

Table 2. Preclinical studies on breast cancer cell growth in the presence of androgens.


Human breast cancer MCF7 cells, which were stably impregnated with functional ARs, retained their capacity to proliferate when estrogens were added, but did not proliferate when androgens were added to growth medium (Figure 1) (22). MCF-7 cells transfected with AR proliferated maximally in the presence of E2; however, natural and synthetic androgens inhibited cellular proliferation. The inhibition of cell proliferation occurred at physiological androgen concentrations (1 nM) and the effect was reversed by AR antagonist, Casodex. These observations strongly suggest androgen-induced inhibition of cell proliferation via AR-mediated mechanisms (22).


Figure 1. Androgen-induced inhibition of proliferation in human breast cancer MCF 7 cells transfected with androgen receptors. Panel (A) represents a dose-response curve to estradiol (open circles) or to the synthetic high affinity non-aromatizable androgen methyltrieneolone (R1881) (solid circles). Cells were grown for 5 days in 10% charcoal-dextran treated human serum (CDHuS). Panel (B) represents a dose-response curve to R1881. Cells were grown for 5 days in 10% CDHuS supplemented with 0.1 nM (open circles) or 1 nM (solid circles) estradiol. The y-axis shows cell number per well (mean + SD; the x-axis represents the concentration of R1881 added in pM [Adopted with permission from Ref. (22)].

A similar study suggested that 5α-DHT produced in tumor tissue by 5α-reductase 1 possesses an antiproliferative effect primarily in tumors expressing the AR and that aromatase inhibitors are more effective in patients with tumors expressing AR and 5α-reductase type 1 (23, 24). This was attributed to increasing local synthesis of 5α-DHT from T as a result of increased activity of 5α-reductase with concomitant reduction in the available T levels as a substrate for the aromatase thus reducing the aromatase activity and estradiol synthesis (23, 24). Both 5α-DHT and the synthetic androgen mibolerone inhibited E2-induced proliferation of T-47D breast cancer cells. The effects of androgens were reversed by an AR antagonist, suggesting that androgen action was mediated, at least in part, by the AR (25). Androgens have been hypothesized to stimulate breast cancer simply as substrates for the aromatase acting as estrogen precursors (26).

Additional evidence for the antiproliferative effects of androgens on breast cancer cell growth were derived from studies, in which both aromatizable (Δ4-Adione) and non-aromatizable (5α-DHT) androgens inhibited MCF-7 cell proliferation (27). This effect was mostly noted when estrogen concentrations were low or absent. This is also noted in breast cancer cells with low expression of aromatase activity. Interestingly, blockade of AR function with the antiandrogen, Casodex, or with the small interfering RNA (siRNA) to block AR protein expression, inhibited the antiproliferative effect of 5α-DHT. In addition it has been suggested that T-mediated growth effects in breast cancer cells were com-pletely inhibited by the aromatase inhibitors letrozole and 4-hydroxy-androstenedione (28). Studies of expression of estrogen-regulated proteins confirmed that T was aromatized to estrogen in the MCF-7 cells. Thus, the results indicate that epithelial breast cancer cells possess the ability to aromatize circulating androgens to estrogens (28). These findings, together with data from other studies, suggest that aromatase inhibitors can exert their beneficial effects on breast cancer by increasing the local concentrations of androgens, thus inducing cell apoptosis through membrane androgen receptor activation (29). It should be noted that aromatase inhibitors are currently the treatment of choice for hormone responsive breast cancer, limiting estrogen production with concomitant increase in intracellular androgen levels (30).

Reduced mammary epithelial ERα and increased ERβ expression in response to T was reported, resulting in a marked reversal of the ERα/β ratio and reduced proliferation in the estrogen-treated monkey (31). Moreover, T treatment is associated with a significant reduction in mammary epithelial myc gene expression, suggesting that anti-estrogenic effects of T in the mammary gland involve changes in ERα signaling to myc. These changes in signaling could be responsible for reduced cellular proliferation in the presence of androgens. The antiproliferative actions of androgens are mediated via activation of the intracellular androgenic signaling (27). In a study of 88 women, addition of T counteracts breast cell proliferation as induced by estrogen and progestin therapy in postmenopausal women (32). Recently, a novel mechanism for specific and direct inhibition of ERα activity by AR in breast cancer cells was identified, adding additional evidence that androgens could be protective in breast cancer (33). This novel mechanism involves binding of AR to consensus estrogen response elements in vitro, and to a subset of endogenous ERα regulatory sites in vivo (33). More importantly, ERα activity was inhibited by wild type AR and AR variants, with minimal intrinsic transcriptional capacity (33). These observations suggest that the effect of androgens on breast cancer cells could be mediated via inhibition of ERα signaling but not necessarily via activation of AR target gene expression. This novel hypothesis is partially supported by data demonstrating that the constitutive or truncated AR inhibited E2-induced human breast cancer cell pro-liferation and reduced expression of E2-regulated targets such as the PR. These data provide compelling arguments to binding of AR to ERa-regulated genes in vivo and permits proposing of a novel mechanism by which AR regulates ERα activity in breast cancer cells (33).

Alternative views on the role of androgens and ARs in modulating breast cancer cell growth were proposed by several investigators (8, 34, 35). Androgens were hypothesized to exert protective effects on breast tissue, ameliorating proliferative effects of estrogen alone or combined estrogen-progestin therapy.

Clinical and epidemiological studies in premenopausal women

Table 3 lists epidemiological studies, which investigated the potential association of breast cancer risk with T levels in premenopausal women. None of these studies, however, provided unequivocal data to support such contention. The European Perspective on Investigation of Cancer (EPIC) cohort with 370 breast cancer cases suggested that increased androgen levels are associated with increased breast cancer risk (36). Similarly, 65 breast cancer cases were examined and an association between f (T) and breast cancer was noted (37). Data from 197 cases were analyzed and a non-statistically significant increase in overall breast cancer risk based on T, f (T) and Δ4-Adione was found (38). Significant correlations, however, were found in invasive as well as ER+/ PR+ breast cancers. Noted limitations of the studies described above include absence of matching sex steroid hormones to menstrual cycle phase and lack of an association between estrogen levels and breast cancer risk. This raises serious doubts on the validity of the data and the conclusions made, given that estrogens promote tumor growth in hormone responsive cancer.

Table 3. Association of testosterone with breast cancer risk in premenopausal women.


Associations between androgen levels and risk of breast cancer in premenopausal women have been deemed nonsignificant (39). However, in postmenopausal women, serum T levels were shown to have a significant positive association with the odds of having breast cancer. Interestingly, the values of T in postmenopausal women were far greater than in premenopausal women and approached > 155 ng/dL (5.38 nmol/L), a value that is inconsistent with physiological levels of androgens in untreated women, as reported by others (40, 41). Furthermore, the only significant association was noted at values > 155 ng/dL (5.38 nmol/L), which raises suspicion on the conclusions of this study. On the contrary, others have reported no significant association between androgen levels and breast cancer risk (42, 43). Thus, studies in premenopausal women do not provide unequivocal conclusions linking T to increased breast cancer risk.

Clinical and epidemiological studies in postmenopausal women

Table 4 lists epidemiological studies attempting to establish an association between androgens, estrogens and breast cancer risk in postmenopausal women. However, most of these studies have serious methodological limitations (44-50). Data on androgen levels in most of these studies were not adjusted for estrogen levels. Furthermore, these studies relied mainly on use of inaccurate and insensitive radioimmunoassays to measure total T or f (T) in blood samples in women. Total T was often utilized as a measure of androgen activity, without accounting for the effect of SHBG on the fraction of the active f (T) in women. Because sex steroid hormone levels in women diminish during menopause it is relevant that not only total T is measured but also f (T) and SHBG to account for androgenic activity (30).

Table 4. Potential positive association of testosterone with breast cancer risk in postmenopausal women.


Meta-analyses of nine studies were performed finding associations between each circulating sex steroid and breast cancer (51). However, the authors acknowledged that limitation of the androgen assays could confound the findings and stated that: ‘‘Given this variability it is clear that the reported hormone concentrations are not directly comparable between studies and that any pooled estimate of breast cancer risk in relation to such measures would have to take this into account.” Association between T, E2 and breast cancer was found via meta-analyses of five studies, but serious flaws of the process were acknowledged (52). The authors stated that ‘‘However possible differences between E2 and T assay precision, stability within women over time, and intracellular conversion of androgens to estrogens complicate the interpretation of these epidemiological analyses. ' '

Contrary to the conclusions drawn from the studies cited above, several recent studies reached a different conclusion (Table 5) (53-56). Mostly, correlations between sex hormones and increased breast cancer risk were only found for E1 and/or E2, whereas T showed no significant association. It should be noted that the estrogen levels were adjusted for in the latter studies. A study which evaluated postoperative breast cancer cases came to the following conclusion ‘‘There was no association of T with breast cancer risk'' (55). Associations between Δ4-Adione and breast cancer were observed, however. Sex steroid levels in patients with benign or malignant breast tumor tissue were assessed, and decreased T levels in all primary breast cancer cases were observed (57). Δ4-Adione was initially deemed to associate with increased breast cancer risk; however, after adjustment for E1 this risk was attenuated (56). Cross-analysis of two previously completed studies measured mammary cell proliferation via fine needle aspiration (58). Assessing cellular proliferation activity utilizing fine needle aspiration breast biopsy, in response to serum sex steroid levels, demonstrated a correlation with estrogens, but no associations with androgens were found. Comparisons between healthy women and breast cancer patients confirmed antiproliferative effects of androgens on aspirated breast cells and suggest that antiproliferative properties in breast cancer patients could be mediated via downregulation of PR.

Table 5. Potential negative association of testosterone with breast cancer risk in postmenopausal women.


Breast hyperplasia was assessed in response to sex steroids in serum samples provided before biopsy, showing only estrogens to be associated with a significant increase in risk (59). The authors noted: ‘‘We found that higher serum estrogen levels -but not androgen or SHBG -were strongly associated with moderate or florid hyperplasia with or without atypia, breast cancer risk factors, and possible precursors, associated with at least 2-fold increase in breast cancer risk.'' The assessment based on tissue proliferation marker (ki-67) demonstrated a correlation with estrogens; however, no associations with androgens were found. One might argue that directly measuring tissue activity is a better prognostic tool than depending on serum sex steroid levels, specifically as serum levels are not always representative of activity lev-els of androgens within the tissue.

A study utilizing the data fromNSABP (National Surgical Adjuvant Breast and Bowel Project) found no associations between any sex steroids and increased breast cancer risk (10). This cohort was considered to be a high-risk population for breast cancer, yet no sex steroids were deemed to be associated with its risk. This and other studies highlight the drawbacks of utilizing endogenous sex steroid hormones to identify high-risk breast cancer patients.

In a recent large study of 646 postmenopausal women the association of plasma androgen levels with breast, ovarian and endometrial cancer risk factors among postmenopausal women was assessed (60). The authors concluded that ‘‘Overall breast cancer risk was not associated with any of the androgens.'' Furthermore, a study on the effect of addition of T on combined estrogen and progesterone therapy on breast cancer cell proliferation and mammographic breast density in clinical study concluded that ‘‘testosterone and other androgens may have a protective influence on the breast” (61). In addition, T therapy over a 52-week period had no significant effect on digitally quantified absolute or percent dense mammographic area in postmenopausal women (62). These findings strongly argue against an association between T and increased breast cancer risk.

Clinical studies with estrogen and testosterone therapy

‘‘There is no materially increased risk of breast cancer in users of estrogen alone or esterified estrogen with methyl-testosterone compared with non-users. There is an increased risk among those using conjugated estrogen plus progestin”(63). In contrast, the effect of adding T to estrogen replacement therapy was assessed utilizing the Nurse's Health Study (64)in which 4610 breast cancer cases were identified during the 24 years of follow-up, with updates on diagnoses occurring every 2 years. Adding T to estrogen therapy showed a 2.5-fold greater risk of breast cancer. The risk was deemed significantly larger than estrogen alone and marginally greater than E + P. However, the study provided no evidence that T alone modulated tumor growth responses in ER+/PR + tumors. Thus, increased breast cancer risk could be explained by the increased E2 levels rather than increased T levels.

What is perplexing in analysis of these data is that T users had an increased risk when the preparation was used for less than 5 years only. When treated for duration longer than 5 years, no significant associations were observed. This finding casts serious doubts on the outcome of this study and does not support the conclusions made by the authors that an association exits between increased breast cancer risk and T. These findings are also contrary to the conclusion made by several authors (32, 63-69). Thus, it is possible that these data are a result of confounding recruitment bias similar to that noted in the UK Million Women Study.

Non-significant associations were found between estrogen plus testosterone treatment and invasive breast cancer utilizing the WHI cohort (65). However, an increased risk for Estratest, a preparation of esterified estrogens and methyltestosterone was noted. Yet, significance was only reached in cases that had been taking the preparation for less than 1 year, with non-significant results for long-term users. This is difficult to reconcile based on the mechanism of action of sex steroid hormones.

The beneficial effects of T treatment in women's health have been proposed to warrant closely monitored and cautious use, particularly as there is only insufficient valid evidence to link T to breast cancer risk (57, 66). Addition of T to hormone replacement therapy (HRT) has been observed to decrease estrogen/progestogen (E/P) induced breast cell proliferation over a period of 6 months (32). The authors concluded: “Addition of T may counteract breast cell proliferation as induced by estrogen/progestogen therapy in postmenopausal women.''

Breast cancer incidence in 508 postmenopausal women was assessed upon addition of T to HRT (69). Lowest incidence was found when only T treatment was used (238 per 100,000 women years), whereas E/P/T treatment led to an incidence of 293 per 100,000 women years. The very low incidence of breast cancer rates in response to T treatment lead to the hypothesis that T could lower the risk of conventional HRT.

Breast cancer recurrence and testosterone

Endogenous T levels have been proposed to serve as prog-nostic factor for breast cancer, whereas elevated levels are suggested to predict recurrent disease (70, 71). The above mentioned studies did not address the methodological limitation of reduced androgen and estrogen levels in women following menopause, and the shortcoming of T and f (T) assays. The concept of utilizing T as a prognostic factor also contradicted use of aromatase inhibitors as first line therapy in postmenopausal breast cancer. Inhibiting the conversion of androgens to estrogens increases intracellular androgen levels and limits the amount of estrogens available for biological activity. The authors made no effort to address how T increases risk of recurrence without conversion to estrogen while failing to adjust T levels for the estrogen effect (Table 6). However, multiple studies contradicted this conclusion with the following statement: “These data do not support the use of endogenous sex hormone levels to identify women who are at particular risk of breast cancer...” (10, 72). Lamenting further “Contrary to expectations we did not observe a relationship between serum T concentrations and risk for recurrence'' (10).

Table 6. Testosterone association with breast cancer recurrence.


Testosterone and mammographic density and breast cancer

Circulating levels of E2 and T were found to be associated with breast cancer before and after adjusting for mammo-graphic density, suggesting sex steroid levels to be associated with breast cancer independent of mammographic density (73). However, the authors failed to adjust T levels for estrogens and did not address the occurrence of higher estrogen and androgen levels in premenopausal women. In line with the authors' argument, higher sex steroid levels would lead to a more pronounced relationship between sex steroid levels and mammographic density in premenopausal women. Thus far, no such relationships have been observed, casting doubt on the conclusions made in the aforementioned study (73). In addition, studies have shown negative associations between plasma androgens and mammographic breast density in pre-and postmenopausal women (74, 75). Several other studies have shown a lack of association between T and mammographic density or independent breast cancer risk (Table 7) (73-81).

Table 7. Association of testosterone with mammographic density in Pre-postmenopausal women.


Relationship between testosterone therapy and breast cancer

A retrospective case-cohort study and a case-control study found no major increase in the risk of ischemic heart disease or breast cancer in women using T (62, 82, 83). Safety was assessed for a period of 52 weeks, resulting in four total breast cancer cases in the treatment group during that time (84). However, two of the cases showed symptoms before the start of the trial or had been treated with estrogen for 27 years in addition to a strong family history of breast cancer. Long-term safety of T treatment has not been assessed; however, evidence thus far does not indicate any association with increased breast cancer risk.

Studies with female to male transsexuals

The long-term safety use of T in female to male transsexuals showed no serious adverse events even at pharmacological doses. Safety outcomes of women using T therapy in clinical settings were explored with 2103 women treated with T and 6309 controls (85). There were no major differences in the rate of ischemic heart disease or breast cancer in subjects using T compared to controls and no difference in outcomes with or without HRT. There were no cases of clitorimegaly. However, there was an increase in acne and hirsutism. A review of data on androgen treatment of female to male transsexuals was performed and the authors also noted that there were no serious side effects and no increased incidence in breast cancer (86). These studies strongly suggest that androgens do not increase breast cancer risk.

Clinical studies with aromatase inhibitors

Aromatase inhibitors have been shown to improve disease-free survival among postmenopausal women with ER + early breast cancer (12-17). Aromatase inhibitors block estrogen biosynthesis by inhibiting the conversion of androgens (Δ4-Adione and T) to E1 and E2 (86). Inhibition of the aromatase is associated with increased levels of T and Δ4-Adione (12-17). Interestingly, women with hormone responsive breast cancer treated with aromatase inhibitors do not experience increased incidence of contralateral breast cancer and the breast tumor regresses with aromatase inhibitor treatment. If androgens, indeed, increase breast cancer risk, as has been proposed previously (6), then one would expect that women treated with aromatase inhibitors to have higher incidence of contralateral breast cancer and the existing cancer would not remit (6, 44-50). On the contrary, this has not been noted in the many studies with aromatase inhibitor treatment of women with breast cancer.

Studies in polycystic ovarian disease (PCOD)

PCOD is the most common endocrine disease in women of reproductive age occurring in 5-10% of women. Serum and urinary androgens were measured and authors suggested that breast cancer was more common in women with PCOD (87). On the contrary, other authors argued that T was protective against breast cancer in women with PCOD (88). A retrospective study from the Mayo Clinic showed no increased risk of breast cancer in women, but subgroup analysis of postmenopausal women with breast cancer showed a relationship; however, only five cases were analyzed (89).

More recent reviews examining the association of PCOD and breast cancer have not shown any increased risk (90). In fact a 50% reduction of breast cancer risk was noted in study subjects with PCOD, examining a large cohort of 4730 women with breast cancer and 4688 controls (91). A study utilizing the Iowa Women’s Health Study also failed to show an increase in risk of women with a self-reported diagnosis of PCOD (92). In addition, a cohort of 786 women diagnosed with PCOD by histological examination did not find an association between breast cancer and PCOD (93).

Authors believe existing data to exclude a strong association between polycystic ovarian syndrome (PCOS) and breast cancer as opposed to the established positive association of PCOD and endometrial cancer (94). Even a recently performed meta-analysis on the association between PCOD and gynecological malignancies only deemed 8 out of 15 studies were eligible for assessment (95). Women with PCOD were more likely to develop endometrial (odds ratio, OR, 2.70) and ovarian cancer (OR 2.52), but no increased risk of breast cancer (OR 0.88).

Clinical evaluation of 273 women with PCOD and 276 controls was performed (96). A significant positive family history of breast cancer was found among the control group (4.35% vs. 1.30%, p = 0.02). Patients with PCOS had three cases of breast cancer among relatives and the control group had 12 cases of breast cancer among relatives. Therefore, this study revealed that breast cancer in the relatives of infertile population (without PCOS) was significantly higher than PCOS patients. These results are inconsistent with those reported by others, which were attributed to small sample size, genetic differences and other environmental factors (97, 98).


In women, androgens are synthesized in the ovaries and adrenal glands, and obviously play an important physiological role in women’s health. In fact the concentrations of androgens in women are several-fold higher than that of estrogens, allowing utilization of androgens as substrates for aromati-zation to estrogens under physiological conditions. Androgens have a wide range of physiological activities in many tissues and AR expression has been demonstrated in such tissues. Furthermore, T therapy has been utilized in treatment of a host of endocrine and sexual disorders in women, since the late 1930s, with little or no reported serious side effects (1). Interestingly, several epidemiological studies have reported an association between T levels and increased breast cancer risk. However, considerable contradictory and often opposite associations between T levels and increased breast cancer risk were also reported. These discrepancies are attributed, in part, to lack of adjustment for estrogen levels and confounding factors associated with T assays in women, such as unreliability, imprecision and inaccuracy of T assays. It is also clear from the evidence discussed in this review that existing data do not support androgens as a risk for breast cancer in women; in fact, most data support a protective role for androgens in breast cancer.

In vitro studies with breast tumor cell lines (Figure 1 and Table 2) strongly suggest that androgens provide a protective effect, as they inhibit tumor cell growth. Closer examination of preclinical studies (Table 2) clearly highlighted the antiproliferative effects of androgens in breast cancer cell growth, despite their conversion to estrogens. Similarly, clinical and non-human primate studies suggest that androgens inhibit mammary epithelial proliferation and breast growth, whereas conventional estrogen treatment suppresses endogenous androgens (98, 99). Studies assessing tissue activity in response to serum sex steroid levels, utilizing fine needle aspiration breast biopsy, and expression of Ki-67 demonstrated a correlation with estrogens; however, no associations with androgens were found (58, 59). These observations do not corroborate the notion that androgens increase breast cancer risk.

Recently, Raynaud et al. (100) reviewed the literature concerning the role of T and other androgens in breast cancer and provided a comprehensive discussion of biotransformation of androgens, and various biological effects of androgens in normal and breast cancer. The authors also assessed the risk of breast cancer and T levels in post-and premenopausal women based on available data (100). A host of earlier epidemiological studies in pre-and postmenopausal women (Tables 3 and 4) showed no consistencies among these studies and many of the conclusions drawn are based on data that were not adjusted for estrogen levels and based on imprecise and insensitive T assays. Recent examination of data in the literature (98, 100) led to similar conclusions in that epidemiological studies have significant methodological limitations and thus provide inconclusive results. In contrast, several recent epidemiological and clinical studies have emphatically stated that androgens are not associated with increased breast cancer risk (60, 61, 101).

More importantly, data from clinical studies with exogenous androgens utilized in treatment of women with endocrine and sexual disorders did not show increased incidence of breast cancer (62, 81, 83). No adverse effects were noted on mammographic density during T therapy (62). No increase in the rate of invasive breast cancer was noted when T was used to treat reduced sexual desire (81), even when estrogens were not added to a woman’s hormonal replacement regimen (83). Furthermore, women with polycystic ovary disease and who are hyperandrogenized did not show increased incidence of breast cancer. In addition, data from studies on female to male transsexuals, who are treated with supraphysiological doses of T for a long time period prior to surgical procedures, did not report increased risk of breast cancer. Finally, women with hormone responsive primary breast cancer are treated with aromatase inhibitors, as a first line therapy. This treatment blocks conversion of androgens to estrogens, thus elevating androgen levels. These women do not experience increased incidence of contralateral breast cancer nor do they experience increased tumor growth. In conclusion, data from various studies available to date strongly suggest that no evidence exists to implicate T in increased breast cancer risk, and some data are suggestive of a protective role of androgens against breast cancer. Clearly, large prospective trials will be necessary to confirm or contradict these clinical and preclinical observations.


This work was supported solely by the Department of Biochemistry and Urology, Boston University School of Medicine. There were no study sponsor(s).


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