Abstract
Testosterone is increasingly used as part of postmenopausal HRT regimens. Unfortunately, few androgenic preparations designed specifically for use in women have been approved by regulatory authorities. Ongoing concerns exist surrounding the potential long-term effects of testosterone therapy, Here, we review the most recent data on postmenopausal testosterone therapy, focusing particularly on the effects of testosterone on breast, endometrium and cardiovascular health.
In addition to estrogen and progesterone, testosterone is increasingly used as part of HRT regimens, particularly in women suffering from symptoms of androgen deficiency such as low sexual desire and well-being. Despite increasing evidence in support of postmenopausal androgen therapy, its use remains controversial [1,2] and options for androgen replacement in women are currently very limited.
There are, at present, no androgen products licensed by the US FDA for use in women. The transdermal testosterone patch (TTP; Intrinsa®, Warner Chilcott, NJ, USA) has been approved by the EMA for use in surgically menopausal women with hypoactive sexual desire disorder (HSDD), and subcutaneous testosterone implants are licensed in the UK and Australia.
Regulatory authorities have raised concerns regarding the lack of long-term safety data [3], particularly in terms of breast, cardiovascular and endometrial safety. Here, we review the most recent and relevant data investigating the effects of postmenopausal testosterone replacement.
Androgen physiology
In women, androgens circulate at levels approximately 10–20-times lower than in men [4,5]. Testosterone is produced in women both by direct secretion from the adrenal gland and the ovaries, and through the peripheral conversion of androgen precursors, such as androstenedione, dihydroepiandrosterone and its sulfate dihydroepiandrosterone. In young women, the ovaries produce approximately three- to four-times more testosterone than estrogen per day [6].
Within the circulation, most testosterone is bound to sex hormone-binding globulin (SHBG; 66%) or albumin (33%) [7]. Only a very small amount (~2%) circulates freely. Testosterone only binds to albumin with relatively weak affinity and therefore ‘bioavailable’ testosterone (i.e., that with the ability to diffuse across cell membranes) is often considered as the free testosterone plus the albumin-bound fraction.
The level of circulating androgens declines gradually with age, owing to a reduction in adrenal production, so the levels at the age of 40 years are approximately half that of a 20 year old [8]. In contrast to estrogen, androgen levels do not appear to fall rapidly during natural menopause, although studies have demonstrated a 40–50% drop in testosterone following surgically induced menopause [9,10]. In postmenopausal women, bioavailable testosterone is primarily determined by SHBG levels and is therefore highly susceptible to the many factors that affect SHBG levels, including obesity or exogenous estrogens.
Testosterone exerts wide-ranging effects via androgen receptors, which are found throughout the body, including in brain tissue, skin, adipose tissue, the vascular tree and bone. Testosterone can also be converted into estradiol by the aromatase enzyme and so it is not entirely clear whether testosterone exerts its actions directly or through the actions of estradiol. Although the exact role of androgens in females remains poorly understood [11], they clearly have an important role in sexual desire and arousal [12]. In addition, exogenous testosterone can affect bone density [13], body composition [14], energy levels and psychological well-being [15].
Testosterone replacement
Testosterone has been used therapeutically in women for over 70 years. It was initially reported to be beneficial in the management of a wide range of gynecological disorders including menorrhagia, dysmenorrhea, mastalgia and even pelvic inflammatory disease [16]. While testosterone is no longer used for these conditions, it was through the use of testosterone in gynecology that the role of androgens in female sexual dysfunction became increasingly clear. Reports of a beneficial effect of testosterone therapy in treatment of menopausal symptoms and female sexual dysfunction were published as early as the 1950s [17]. Many of the early studies reported on the use of injectable, oral or implant therapy, often in supraphysiological doses. Over the last decade, following the development of the TTP, there has been a marked increase in the number of clinical trials investigating the effects of physiological testosterone replacement, predominantly in postmenopausal women for treatment of low libido. These studies have led to a substantial improvement in our understanding of the efficacy of postmenopausal testosterone therapy and potential adverse effects.
Benefits of testosterone therapy
Reduction in testosterone levels have been associated with reduced libido and sexual activity, fatigue and a lesser sense of physical well-being. Terms such as ‘relative androgen deficiency’ [18] or ‘female androgen insufficiency syndrome’ [19] have been suggested to characterize this constellation of symptoms
Although exogenous testosterone has been recognized for many years to play a role in improving sexual desire, until recently there has been a lack of randomized controlled data to support its use. Many older studies showed that postmenopausal testosterone use in women on estrogen replacement therapy improves desire [20–23], although these studies primarily used oral or intramuscular therapy, often in supraphysiological doses.
More recently, attention has turned towards the use of TTPs. It is thought that this route provides a more physiological and constant serum concentration of the hormone. In addition, the transdermal route avoids first-pass metabolism in the liver, which may help reduce unwanted effects on hepatic proteins. A number of randomized placebo-controlled trials investigating the use of the testosterone patch in treating HSDD have found significant improvements in sexual desire and other sexual function domains both with [24–28] and without [29,30] concurrent HRT use.
In addition to the TTP, testosterone is now most frequently administered via subcutaneous implant or transdermal gel/cream. The testosterone implants have been used for over 30 years and there are both observational and randomized controlled trial (RCT) data that women receiving estradiol and testosterone implants have a significant benefit in sexual function compared with those receiving estrogen alone [31,32]. Testosterone gel is the least well-studied route in women. There is one randomized, placebo-controlled, crossover study in 53 postmenopausal women with low libido on HRT, which showed that 10 mg daily of testosterone gel was associated with significant improvements in desire, including frequency of sexual activity, fantasies and sexual interest [33]. More extensive reviews on the use of testosterone for the management of low libido have recently been published [34,35].
In addition to the effects of exogenous testosterone on sexual function, several other beneficial effects have been reported, particularly on quality of life, mood and well-being [23,24,26,36]. A recent observational study examined the use of 75—160 mg testosterone implants, without concomitant estrogen, in 300 premenopausal and postmenopausal women reporting symptoms of androgen deficiency such as sexual problems, fatigue, mood disturbance, headaches, insomnia, memory loss and hot flushes. Testosterone implants were found to be effective for the relief of psychological, somatic and urogenital symptoms, in addition to sexual desire [37]. Furthermore, pilot data have indicated that transdermal testosterone may improve cognitive performance, particularly memory and verbal learning in postmenopausal women on transdermal HRT [38].
Androgens can also act to inhibit bone resorption and therefore it has been suggested that testosterone may play a role in the maintenance of bone density. Although no studies have examined fracture rates as a clinical end point, there are data that testosterone implants [13] and combined oral estrogen—methyltestosterone therapy may improve bone density [39,40]. However, conflicting data exist, as a further study found improvements in bone density in both estrogen- and estrogen—androgen-treated groups, with no significant difference observed between groups [41].
Symptoms of androgen deficiency.
Reduced sense of well-being
Dysphoric mood
Low energy/reduced motivation
Low sexual desire
Bone loss
Reduced muscle strength
Poor cognition and memory
Insomnia
Potential adverse effects
Although testosterone replacement can therefore have significant benefit, an ongoing concern frequently cited by regulatory authorities and consensus statements is the apparent uncertainty surrounding the long-term safety of testosterone, especially with regard to the risk of breast or endometrial cancer and cardiovascular disease [3,42]. As will be discussed, many of these concerns are unfounded, particularly when using physiological, transdermal therapy.
Androgenic side effects
Hirsutism and acne are the most common androgenic side effects observed in women receiving physiological doses of testosterone. Androgenic side effects tend to be dose dependent [29] and may take several months to become evident, but are usually mild and resolve when treatment is discontinued.
In the TTP randomized trials, hirsutism was reported by 3.0–19.9% of patients receiving the TTP, although in the majority of studies this was not significantly more frequent than in the placebo group [24–28]. Of note, hirsutism was significantly increased in testosterone users (19.9% cf. 10.5% of controls) in the sole TTP study to continue safety assessment for 52 weeks, in contrast to the other trials, which were 24 weeks in duration [29]. However, participants in this study were not on concomitant HRT, which probably contributed to the findings.
Only one study reported an increase in acne (18% cf. 13% of controls) [28]. In the other TTP trials there was no significant increase in acne, which was experienced by 4.6—7.5% of participants.
Virilization — voice deepening, clitoromegaly and frontal hair loss — is extremely rare and tends to occur only when serum testosterone levels rise significantly above the normal range for reproductive females.
Concern has been expressed that many of these clinical trials were only of relatively short duration and therefore may not reflect clinical practice. Nachtigall et al. have recently published a 4-year extended open-label follow-up data from 1094 surgically menopausal women on concomitant estrogen, using testosterone for HSDD [43]. Participants had a mean exposure of 1.1 years of testosterone therapy. They found no increase in the rates of androgenic adverse events (unwanted hair growth, acne, alopecia or voice deepening) over 4 years of treatment, and reported events to be generally mild and not associated with study discontinuation. The observed rates of all androgenic events were 28.4% (0–12 months), 14.3% (12–24 months), 10.5% (24–36 months) and 3.5% (36–48 months).
In an observational case—control study, 8412 women were followed-up for a mean of 4.4 years. The study population included 2103 testosterone users, administered through implants (72.2%), tablets (18.4%) or injections (7.9%). The rate of androgenic events was increased in the testosterone cohort (relative risk [RR]: 1.55, 95% CI: 1.21–1.97), although the overall incidence of androgenic events was only 1.2% in testosterone users compared with 0.7% of controls [44].
Cardiovascular disease
Owing to the marked gender differences in the prevalence of cardiovascular disease, it has previously been thought that androgens increase cardiovascular risk. However, recent studies in men have demonstrated that low circulating testosterone levels are associated with increased cardiovascular risk, even after adjustment for classical cardiovascular risk factors [45]. This has led to increasing speculation regarding the potential cardioprotective role of testosterone.
Unfortunately, in women, the role of androgens on the cardiovascular system is less clear. Potential mechanisms by which androgens may affect cardiovascular risk include effects on lipid profile, insulin resistance, vascular tone and fat distribution.
There have been several studies examining the effects of both endogenous and exogenous testosterone levels on cardiovascular disease, atherosclerosis and cardiovascular risk factors; however, results are frequently conflicting. Methodological limitations of testosterone assays, failure to adjust for estrogen levels, and the varying cardiovascular effects depending on route of sex-hormone administration have contributed to the inconsistent results.
Endogenous testosterone
Many studies have examined the effects of circulating testosterone levels on risk factors for cardiovascular disease. It is well established that in premenopausal women, hyperandrogenism as seen in women with polycystic ovarian syndrome is associated with an adverse cardiovascular risk profile, with increased triglycerides and low-density lipoprotein cholesterol, and reduced high-density lipoprotein (HDL) cholesterol [46,47].
In postmenopausal women, the effects of endogenous androgen levels are less well established. Raised endogenous testosterone has been linked to multiple cardiovascular risk factors including increased BMI, increased abdominal obesity and elevated blood pressure [48]. Although some studies have demonstrated that increased androgenicity is associated with adverse changes to the lipid profile including increased total cholesterol, increased low-density lipoprotein cholesterol and reduced HDL cholesterol [49,50], the majority of observational data do not support a role for endogenous testosterone and lipid metabolism [48].
Studies investigating the effects of endogenous testosterone on surrogate markers for atherosclerosis have shown conflicting results. Bernini et al. demonstrated that endogenous free testosterone levels in 44 postmenopausal women were negatively correlated with carotid intima-media thickness, suggesting a positive effect on the development of atherosclerosis [51]. Subsequent studies [52,53] have also shown an inverse relationship between endogenous testosterone levels and atherosclerosis. A case—control study found that postmenopausal women with proven carotid artery disease were found to have significantly lower levels of free testosterone compared with women with normal carotid arteries, independent of other cardiovascular risk factors [54]. By contrast, other studies have found high, free or bioavailable testosterone to be associated with subclinical atherosclerosis, even after adjustment for estradiol and other cardiovascular risk markers [55,56].
Few studies have examined the impact of endogenous testosterone levels on cardiovascular events and mortality. Patel and colleagues performed a cross-sectional study in 344 older postmenopausal women and found that women in the top quartile for total testosterone had a threefold increased risk of coronary heart disease (odds ratio: 2.95, 95% CI: 1.2–73); however, this association was not true for free testosterone [57]. In another study, the association between the Free Androgen Index and increased cardiovascular risk did not persist after adjustment for BMI and other cardiovascular risk factors [58].
A recent prospective population-based study followed 639 women, who had testosterone levels measured at baseline, for a mean of 12.3 years [59]. There were 134 cardiovascular events during the follow-up. In this study, a U-shaped cardiovascular risk curve was observed, with those in the highest and lowest quintile for bioavailable testosterone having increased cardiovascular risk. This led the authors to suggest that to optimize cardiovascular health, testosterone levels shown be within normal limits [59].
Exogenous testosterone
Therefore, although increased androgenicity is associated with an adverse cardiovascular risk factor profile in postmenopausal women, evidence for an association with cardiovascular events is lacking. Furthermore, it is uncertain whether these associations with endogenous testosterone levels have clinical implications regarding the use of postmenopausal testosterone therapy. Few studies have investigated the cardiovascular risks associated with testosterone administration and no studies have reported on cardiovascular events as a primary outcome.
In animal models, testosterone has been associated with activation of the renin and angiotensin system [60,61] and other cardiovascular risk factors, such as elevated BMI and visceral fat [62]. When looking at surrogate markers of cardiovascular risk such as endothelial function, conflicting results occur. Testosterone administration has been shown to impair endothelium-dependent vasodilatation in hyper-cholesterolemic rabbits [63], but a further study demonstrated that testosterone caused relaxation of rabbit coronary arteries and aortic rings [64]. High-dose exogenous testosterone in primate models was associated with a doubling of atherosclerosis [62] and similar results of increases in atherosclerotic plaques were observed in rabbit models [65]. Of note, physiological administration of testosterone to androgen-deficient rats led to an improvement in the vasodilator response of the endothelium [66].
Several studies have investigated the effect of exogenous testosterone on traditional cardiovascular risk factors and other surrogate markers of cardiovascular disease.
BMI/weight distribution
High-dose intramuscular testosterone in female-to-male transsexuals has been associated with reductions in subcutaneous fat, but increases in BMI and visceral fat [67–69]. Oral therapy has been associated with increases in lean body mass [23,70] but also with increases in visceral fat mass [71]. Gruber et al. examined the effect of transdermal testosterone gel or placebo on body composition in 39 postmenopausal women [72]. Testosterone gel was associated with a significant reduction in total body weight, abdominal fat and BMI. No differences in BMI were observed in a 24-week placebo-controlled study of the TTP [26].
Lipid profile
Studies examining the effects of oral testosterone therapy have consistently demonstrated a positive effect on triglyceride levels, but at the expense of reductions in HDL [22,23,39,40,71,73–76]. The mechanisms through which testosterone may influence lipid metabolism have not been fully elucidated. In contrast to oral testosterone administration, transdermal therapy does not appear to affect the lipid profile [72]. No disturbances of lipid profiles were found in 4-year follow-up data from 967 surgically menopausal patients who were also on estrogen replacement, each receiving at least one application of the TTP [43]. Thus, the effects of testosterone on lipid profile will depend on the route of administration, dosage and the presence of concomitant estrogen therapy.
Blood pressure
There are no data to suggest a detrimental effect on blood pressure from oral [71], subcutaneous [77] or transdermal therapy [26].
Surrogate cardiovascular markers
The effect of exogenous testosterone on surrogate markers for cardiovascular disease has been studied in three trials. In a trial by Hak et al., intramuscular testosterone and estrogen administration resulted in increased rates of severe aortic atherosclerosis in postmenopausal women, as demonstrated by radiographic detection of calcified aortic deposits [78]. However, this study involved the use of high-dose intramuscular testosterone in a small population and only demonstrated a small effect after 1 year of treatment. Penotti et al. examined the effects of 8 months of relatively high-dose oral testosterone undecanoate in addition to transdermal estrogen and medroxyprogesterone acetate on vascular reactivity [79]. They found a small but significant increase in the pulsatility index of the middle cerebral artery in women receiving testosterone. By contrast, Worboys et al. showed an improvement in flow-mediated and glyceryl trinitrate-induced vasodilatation following 6 weeks of 50-mg testosterone implant therapy in addition to ongoing estrogen treatment, suggesting a beneficial role for exogenous testosterone in vascular reactivity [77].
No long-term prospective studies have been sufficiently powered to examine cardiovascular risk associated with exogenous testosterone, and there are few data investigating the effect of physiological replacement using transdermal preparations on surrogate markers of cardiovascular disease. A retrospective study in female-to-male transsexuals receiving high doses of testosterone showed no increase in frequency of myocardial infarction, hypertension and no excess of cardiovascular deaths [80]. These studies have involved high dose, oral or intramuscular therapy and, therefore, whether this data can be applied to postmenopausal testosterone use remains controversial.
The recent RCTs using testosterone patches for reduced libido noted no short-term (up to 1 year) increased cardiovascular disease but did not include specific cardiovascular outcome measurements. Some of these studies took further measurements of vital signs, lipid profiles, coagulation, renal and liver function, carbohydrate metabolism and chemistry and hematology; however, no clinically relevant changes were noted in a 24-week [24–26,30] or 52-week follow-up [29].
Therefore, although high-dose parenteral or oral testosterone has been associated with some adverse cardiovascular markers, physiological transdermal replacement does not appear to be detrimental and may even have cardiovascular benefit. A large randomized, placebo-controlled trial designed to investigate cardiovascular outcomes in users of transdermal testosterone gel [81] is currently underway, and should provide useful data regarding the long-term cardiovascular effects of physiological transdermal testosterone replacement.
Glucose metabolism/insulin resistance
Insulin resistance is central in the development of the metabolic syndrome. This syndrome, consisting of insulin resistance, central obesity, hypertension and dyslipidemia [201], is a well-established risk factor for cardiovascular disease. The relationship between insulin resistance and androgens has been recognized for many years, primarily due to observations in patients with polycystic ovarian syndrome who suffer from hyperandrogensim and insulin resistance.
The mechanisms behind the complex relationship between androgens and insulin sensitivity remain a subject of debate. Insulin can promote androgen production by acting as a co-gonadotrophin with lutenizing hormone, to stimulate androgen production from ovarian theca cells. Insulin also causes a reduction in hepatic production of SHBG, resulting in higher free-androgen levels. Conversely, however, it has also been suggested that hyperandrogenism may affect glucose metabolism and insulin sensitivity. It has been shown in vitro that adipocytes exposed to testosterone have reduced insulin-mediated glucose uptake [82]. Androgens may indirectly affect insulin sensitivity via effects on lipid balance and body fat distribution. Furthermore, estradiol can affect insulin sensitivity and therefore, due to the peripheral conversion of androgens, their exact effects may be difficult to elicit.
Several clinical studies have demonstrated the relationship between supraphysiological androgen levels and hyperinsulinemia. Polycystic ovary syndrome is strongly associated with hyperinsulinemia and Type II diabetes mellitus [83]. Similar trends have been observed in postmenopausal women, as an elevated Free Androgen Index ratio has been associated with metabolic syndrome [84,85]. A further analysis from the Rancho Bernardo study found that in 233 postmenopausal women not taking estrogen, higher baseline bioavailable testosterone was associated with significantly increased insulin resistance and the risk of Type II diabetes mellitus, with a threefold increased risk of diabetes in women in the highest quartile of bioavailable testosterone (odds ratio: 2.9, 95% CI: 1.1–8.4) [86].
The implications of these findings for exogenous testosterone administration have not been fully explored. Zang et al. examined the effects of oral testosterone on insulin sensitivity in 63 postmenopausal women [70]. After 3 months, a small but significant reduction in insulin-mediated glucose disposal was observed in the testosterone groups. However, in obese postmenopausal women, treatment with an anabolic steroid with weak androgenic properties had no effect on fasting glucose or insulin sensitivity [87]. Other studies using oral testosterone therapy also failed to demonstrate any effect on glucose metabolism [71], and physiological replacement using the TTP has been shown to have no detrimental effects on glucose metabolism [25,26,29,36]. In a recent pilot study of elderly women with congestive cardiac failure, 6-month TTP therapy was associated with a significant improvement in insulin resistance [88], a finding which has also been observed in men.
Similarly to the influence on cardiovascular risk, it is possible that at physiological levels, testosterone plays an important role in glucose homeostasis. However, at supraphysiological levels it may result in adverse effects on insulin sensitivity. At present, there is insufficient evidence regarding the use of physiological transdermal testosterone in postmenopausal women to make definitive conclusions upon its effects on insulin sensitivity. Although current data are reassuring, studies are often limited by short treatment periods or small study numbers.
Endometrium
In vitro data suggest that androgens do not act directly to stimulate the endometrium [89]. However, aromatase activity has been observed in endometrial cancer cells [90,91], and so, concerns have been raised that androgens may act indirectly to simulate endometrial proliferation via estrogenic effects.
Very few clinical studies have examined the effects of exogenous testosterone on the endometrium. Only one randomized study could be found that examined the endometrial effects of postmenopausal testosterone replacement as a primary outcome. In this unblinded study, Zang and colleagues randomized 63 naturally postmenopausal women to 2 mg estradiol (n = 22), 40 mg testosterone undecanoate on alternate days (n = 21), or both estradiol and testosterone (n = 20) [92]. Endometrial thickness and proliferation was assessed after 3 months of treatment by ultrasonography and histopathology. They found that endometrial thickness was significantly increased by estrogen therapy, alone or in combination with testosterone. In those receiving testosterone-only therapy, there was no increase in endometrial thickness or proliferation.
In the APHRODITE study, Davis et al. investigated the effects of two doses of transdermal testosterone in 814 postmenopausal women with HSDD who were not using concomitant estrogen [29]. Safety outcomes were assessed over a 52-week period. Vaginal bleeding occurred more frequently in the group using 300 μg patches (10.6%) compared with the 150 μg (2.7%) or placebo groups (2.6%), but no cases of endometrial hyperplasia or carcinoma were diagnosed. Other studies using the TTP in conjunction with HRT have not demonstrated increases in vaginal bleeding [26].
In a 6-month double-blinded randomized trial of esterified estrogen, given with or without 1.25 mg methlytestosterone (but no progestogen), endometrial proliferation was observed in both groups but there was no difference in biopsy scores between groups [73]. A double-blinded randomized cross-over study in 53 naturally menopausal women found that 10 mg of testosterone gel daily was not associated with any change in endometrial thickness compared with placebo [33]. In an observational case—control study, 8412 women were followed-up for a mean of 4.4 years. Of the 2103 testosterone users, there were no cases of endometrial cancer compared with five cases in 6309 controls [44]. Finally, there is evidence that even relatively high-dose long-term testosterone therapy, as given to female-to-male transsexuals, does not result in endometrial proliferation and may even have atrophic effects [93].
Breast
The effects of testosterone on the breast and in the etiology of breast cancer remain poorly understood. Androgens may act directly on breast tissue via the androgen receptor but breast tissue also exhibits aromatase activity and therefore, again, the androgenic effects may occur due to conversion to estrogen.
Experimental data have shown that androgens can have both proliferative [94] and antiproliferative [95–97] effects on breast cancer cell lines. In addition, there is evidence that dihydrotestosterone is proapoptotic [98,99] and that androgens may inhibit estrogenic effects on mammary growth [100]. Animal studies have demonstrated that in nonhuman primates, testosterone treatment was associated with a reduction in estrogen-induced breast epithelial cell proliferation [96,101]. Based on these experimental data, it has therefore been suggested that testosterone may act to reduce the adverse effects of estrogen on breast tissue [102].
Many observational studies have examined the relationship between endogenous androgen levels and the risk of postmenopausal breast cancer. A combined analysis of nine prospective studies with 663 incidences of breast cancer cases demonstrated that higher endogenous testosterone was associated with increased risk of postmenopausal breast cancer (RR: 2.22, 95% CI: 1.59–3.10, for those in the highest testosterone quintile compared with the lowest) [103]. A more recent case—control study from the Nurses Health Study with 265 cases and 541 controls reported similar findings with a RR of 1.8 (95% CI: 1.1—2.9) for those in the highest androgen quintile compared with those in the lowest group [104]. Other observational studies have produced conflicting results with no association between endogenous androgens and breast cancer risk observed [105,106]. Methodological limitations with testosterone assays in women, differences in the testosterone fraction measured and failure to adjust for factors such as BMI, estradiol and SHBG levels may, in part, explain the conflicting results. Of note, current evidence in women with hyperandrogenism due to polycystic ovary syndrome is not suggestive of an increased risk of breast cancer [107].
There are relatively few clinical trial data examining the effect of exogenous testosterone on breast cancer risk. Trials to date are summarized in
Epidemiological studies investigating breast cancer risk with exogenous testosterone therapy.
E: Estrogen; im.: Intramuscular; MT: Methyltestosterone; MWS: Million Women Study; P: Progestogen; PM: Postmenopausal; RR: Relative risk; T: Testosterone; WHI: Women's Health Initiative.
An early case—control study suggested that the risk of breast cancer was increased in women using intramuscular testosterone in addition to estrogen or estrogen plus progestogen therapy [108]. A 24 year follow-up of the Nurses Health Study cohort, contributing 1,359,323 person years of data and 4610 incident cases, found an increased breast cancer risk in combined estrogen and testosterone users compared with never users (RR: 2.48, 95% CI: 1.53–4.04) [109]. Data from the Women's Health Initiative observational arm reported nonsignificant increases with combined estrogen and testosterone use, but significant increases in risk when Estratest® (Solvay Pharmaceuticals, GA, USA) was compared separately with other products (hazard ratio: 1.78, 95% CI: 1.05–3.01) [110]. More reassuringly, the other six studies did not find any increased risk of breast cancer associated with postmenopausal testosterone use [44,111–115].
There are no randomized data investigating breast cancer risks with testosterone replacement as a primary outcome. Randomized, placebo-controlled studies on the effects of the TTP on breast cell proliferation [116] and mammographic density [117,118] have shown no adverse effects from transdermal testosterone.
There has been a suggestion from one study that the risk of breast cancer may increase with duration of testosterone treatment [113]. Of the studies that specifically looked at treatment duration, none found an association between duration of treatment and breast cancer risk [109–112,114,115].
Therefore, currently available clinical data are reassuring, particularly regarding physiological replacement via transdermal or subcutaneous routes, although further randomized controlled trials are needed. The large randomized BLISS trial [81] will be examining incidence of invasive breast cancer as a co-primary outcome and should therefore provide much needed safety data.
Conclusion
Testosterone is increasingly used as part of postmenopausal hormone replacement regimens to improve sexual desire and other symptoms of androgen deficiency. As with estrogen therapy, clinical practice is moving more towards physiological replacement with lower dose transdermal preparations in an attempt to minimize adverse effects. Current data do not indicate that transdermal preparations are associated with any adverse cardiovascular, breast or endometrial outcomes but further large-scale randomized data are needed. Few testosterone preparations are currently licensed for use in women, and approved products must be used with concomitant estrogen therapy. More data is needed to support the use of testosterone with this population.
Future perspective
In the next 5–10 years, we will hopefully see more data in support of testosterone replacement and convince regulatory authorities that transdermal testosterone should be approved for postmenopausal women.
Despite more than 50 years of observational data and short-term RCT data, which is generally reassuring, further evidence is needed, particularly regarding the risk of breast cancer. Unfortunately, studies of sufficient length (10–20 years) and power to fully assess breast cancer risk are unlikely to happen, therefore, we must rely on shorter RCTs or epidemiological studies. Importantly, in the next few years, large randomized trials (BLISS) [81] will report on the cardiovascular and breast cancer outcomes associated with transdermal testosterone gel. In licensed products we must continue research through RCTs and postmarketing surveillance. Furthermore, the regulatory authorities must be made aware that testosterone therapy is not merely a ‘lifestyle drug’ but a drug that is essential in some postmenopausal women to restore or maintain their quality of life. As with estrogen and progestogen therapy, small risks may be accepted if significant benefit is derived.
Executive summary
Testosterone is increasingly used as part of postmenopausal HRT regimens but concerns have been raised regarding the lack of long-term safety data.
Androgens predominantly circulate bound to sex hormone-binding globulin and albumin and therefore biologically active testosterone is highly susceptible to factors that alter sex hormone-binding globulin levels, including oral estrogens and obesity.
Older methods of testosterone replacement such as parenteral or oral therapy are being increasingly replaced by transdermal or subcutaneous therapies.
Testosterone has been shown to improve sexual function, quality of life, mood, cognition and bone density.
Androgenic side effects
– Hirsutism & acne are the most common androgenic side effects.
– Androgenic effects are dose dependent but usually mild and resolve on discontinuation of therapy.
– Virilization is extremely rare with physiological replacement.
Cardiovascular disease
– Endogenous testosterone
– Both low and high levels of endogenous testosterone have been associated with cardiovascular events.
– It has been suggested to optimize cardiovascular health that testosterone should be kept within normal limits.
– Exogenous testosterone
– High dose or oral therapy can increase lean body mass but may be associated with visceral fat deposition. Transdermal therapy has either a neutral or beneficial effect on body composition.
– Oral testosterone therapy has a positive effect on triglyceride levels but causes reductions in high-density lipoprotein cholesterol. Transdermal therapy does not appear to affect lipid metabolism.
– There is currently no evidence that testosterone replacement affects blood pressure.
– There are no long-term prospective studies sufficiently powered to examine cardiovascular risk associated with exogenous testosterone.
– Data investigating the effect of testosterone on surrogate markers of cardiovascular disease show that high-dose therapy may be detrimental whereas low-dose subcutaneous therapy may have cardiovascular benefit.
Glucose metabolism/insulin resistance
– There is currently insufficient evidence to make definitive conclusions upon the effects of testosterone on insulin sensitivity but there are no data to suggest a deleterious effect from current therapies.
Available evidence does not support an increased risk of endometrial cancer with testosterone therapy.
Epidemiological studies linking elevated endogenous androgens with breast cancer have produced conflicting results.
Although current clinical data regarding the breast cancer risk with exogenous therapy are reassuring, particularly regarding physiological replacement via transdermal or subcutaneous routes, a lack of randomized trials precludes definitive conclusions.
As with estrogen therapy, clinical practice is moving more towards physiological replacement with lower dose transdermal testosterone preparations to minimize adverse effects.
Current data do not indicate that these preparations are associated with any adverse cardiovascular, breast or endometrial outcomes but further large scale randomized data are needed.
Should further reassuring long-term safety data become available we hope this would allow more products to be approved and stimulate development of new preparations to improve patient choice. The next few years are also likely to see development of novel selective androgen receptor modulators, which aim to harness the beneficial effects of androgen therapy while minimizing adverse effects.
Footnotes
The authors have been in receipt of a study grant from Warner Chilcott (NJ, USA) to purchase reagents for a testosterone patch study. N Panay has performed consultancy work for Proctor and Gamble and been involved in previous testosterone patch studies. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.