Dr. Ron’s Research Review – April 29, 2020

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This week’s research review focuses on testosterone therapy for women.

Position Statement

The North American Menopause Society published a position statement about the role of testosterone therapy in postmenopausal women. Published evidence from randomized controlled trials, although limited, indicates that exogenous testosterone, both oral and non-oral formulations, has a positive effect on sexual function, primarily desire, arousal, and orgasmic response, in women after spontaneous or surgically induced menopause. (Bachman, 2005)

Breast Cancer Risk

Testosterone and/or testosterone with anastrozole, delivered subcutaneously as a pellet implant, reduced the incidence of breast cancer in pre and postmenopausal women. Evidence supports that breast cancer is preventable by maintaining a testosterone to estrogen ratio in favor of testosterone and, in particular, by the use of continuous testosterone or, when indicated, testosterone with anastrozole. (Glaser and Dimitrakakis, 2013)
Testosterone use was not associated with a significant increase in breast cancer risk. (Davis et al., 2009a)
Transdermal testosterone patch therapy over 52 weeks appears to have no significant effect on digitally quantified absolute or percent dense mammographic area in postmenopausal women not using estrogen/progestin therapy. (Davis et al., 2009b)
At present, there are no valid randomized or observational clinical studies that provide evidence that the addition of testosterone to conventional postmenopausal hormone therapy influences breast cancer risk. (Bitzer et al., 2008)
Addition of testosterone may counteract breast cell proliferation as induced by estrogen/progestogen therapy in postmenopausal women. (Hofling et al., 2007)
Aromatase explains why testosterone increases breast cancer rate. (Friedman 2009)
The addition of testosterone to conventional hormone therapy for postmenopausal women does not increase and may indeed reduce the hormone therapy-associated breast cancer risk-thereby returning the incidence to the normal rates observed in the general, untreated population. (Dimitrakakis et al., 2004)

 

Dr. Ron


 

Articles

The role of testosterone therapy in postmenopausal women: position statement of The North American Menopause Society
            (Bachman, 2005)  Download
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.

Breast cancer risk in postmenopausal women using testosterone in combination with hormone replacement therapy
            (Bitzer, Kenemans et al. 2008) Download
OBJECTIVES: Testosterone supplementation can be considered as a treatment option for surgically postmenopausal women with a distressful low sexual desire disorder, while on oestrogen therapy with or without progestagens. The purpose of this study is to review the available clinical data on the impact of exogenous testosterone containing postmenopausal hormone therapy on breast cancer risk. METHODS: A literature search was done in MEDLINE (1969-July 2007) and in addition in EMBASE and Biosis (1990-July 2007) for original reports in English and French. Case reports and studies without a control group were excluded. RESULTS: No prospective randomized clinical trials were found. The five studies found (two case-control studies, two cohort studies and one retrospective observational study) showed inconsistent results. All studies had severe methodological limitations. Formulations and dosages used could be considered suboptimal. CONCLUSION: At present, there are no valid randomized or observational clinical studies that provide evidence that the addition of testosterone to conventional postmenopausal hormone therapy influences breast cancer risk.

The effect of transdermal testosterone on mammographic density in postmenopausal women not receiving systemic estrogen therapy.
            (Davis et al., 2009b)  Download
CONTEXT:  Greater mammographic density is associated with increased breast cancer risk and reduced diagnostic mammographic sensitivity and may be seen with estrogen/progestin therapy (EPT). The effects of testosterone therapy on mammographic density in postmenopausal women not on EPT are not known. OBJECTIVE:  Our objective was to compare effects of two doses of the testosterone transdermal patch (TTP) with placebo in postmenopausal women without concomitant EPT on mammographic density over 52 wk. DESIGN:  We conducted a randomized, double-blind, placebo-controlled, parallel-group, multinational trial. PATIENTS:  Patients included 279 postmenopausal women participating in a testosterone and sexual function study with paired mammograms for baseline and 52 wk/exit. INTERVENTIONS:  Patients were randomized to placebo, TTP 150 microg/d, or TTP 300 microg/d, stratified by menopause type (natural or surgical). MAIN OUTCOME MEASURES:  Change from baseline to wk 52 in the percentage of dense tissue (PD) on digital mammograms. RESULTS:  A total of 250 women with paired mammograms for study baseline and wk 52 were included in the primary analysis. Mean age was 54.6 yr, baseline body mass index was 27.5 kg/m(2), and 78% were naturally menopausal. There were no baseline differences between groups. Mean changes from baseline (+/-SEM) in PD for placebo, TTP 150 microg/d and TTP 300 microg/d were small (0.05 +/- 0.16, 0.06 +/- 0.19, and 0.21 +/- 0.17%) and not significantly different. There were no statistically significant differences from placebo for total dense or nondense area and no significant relationships between hormone levels and PD after adjustment for body mass index. CONCLUSION:  TTP therapy over 52 wk appears to have no significant effect on digitally quantified absolute or percent dense mammographic area in postmenopausal women not using EPT.

Testosterone for low libido in postmenopausal women not using systemic oestrogen therapy
            (Davis 2009) Download
            Results are promising but long-term safety remains uncertain.

Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy
            (Dimitrakakis, Jones et al. 2004) Download
OBJECTIVE: There is now convincing evidence that usual hormone therapy for ovarian failure increases the risk for breast cancer. We have previously shown that ovarian androgens normally protect mammary epithelial cells from excessive estrogenic stimulation, and therefore we hypothesized that the addition of testosterone to usual hormone therapy might protect women from breast cancer. DESIGN: This was a retrospective, observational study that followed 508 postmenopausal women receiving testosterone in addition to usual hormone therapy in South Australia. Breast cancer status was ascertained by mammography at the initiation of testosterone treatment and biannually thereafter. The average age at the start of follow-up was 56.4 years, and the mean duration of follow-up was 5.8 years. Breast cancer incidence in this group was compared with that of untreated women and women using usual hormone therapy reported in the medical literature and to age-specific local population rates. RESULTS: There were seven cases of invasive breast cancer in this population of testosterone users, for an incidence of 238 per 100,000 woman-years. The rate for estrogen/progestin and testosterone users was 293 per 100,000 woman-years--substantially less than women receiving estrogen/pro-gestin in the Women's Health Initiative study (380 per 100,000 woman-years) or in the "Million Women" Study (521 per 100,000 woman-years). The breast cancer rate in our testosterone users was closest to that reported for hormone therapy never-users in the latter study (283 per 100,000 woman-years), and their age-standardized rate was the same as for the general population in South Australia. CONCLUSIONS: These observations suggest that the addition of testosterone to conventional hormone therapy for postmenopausal women does not increase and may indeed reduce the hormone therapy-associated breast cancer risk-thereby returning the incidence to the normal rates observed in the general, untreated population.

 

Aromatase explains why testosterone increases breast cancer rate
            (Friedman 2009) Download


 

Reduced breast cancer incidence in women treated with subcutaneous testosterone, or testosterone with anastrozole: a prospective, observational study.
            (Glaser and Dimitrakakis, 2013) Download
OBJECTIVES: There is evidence that androgens are breast protective and that testosterone therapy treats many symptoms of hormone deficiency in both pre and postmenopausal patients. However, unlike estrogen and progestins, there is a paucity of data regarding the incidence of breast cancer in women treated with testosterone therapy. This study was designed to investigate the incidence of breast cancer in women treated with subcutaneous testosterone therapy in the absence of systemic estrogen therapy. STUDY DESIGN: This is a 5-year interim analysis of a 10-year, prospective, observational, IRB approved study investigating the incidence of breast cancer in women presenting with symptoms of hormone deficiency treated with subcutaneous testosterone (T) implants or, T combined with the aromatase inhibitor anastrozole (A), i.e., T+A implants. Breast cancer incidence was compared with that of historical controls reported in the literature, age specific Surveillance Epidemiology and End Results (SEER) incidence rates, and a representative, similar age group of our patients used as a 'control' group. The effect of adherence to T therapy was also evaluated. RESULTS: Since March 2008, 1268 pre and post menopausal women have been enrolled in the study and eligible for analysis. As of March 2013, there have been 8 cases of invasive breast cancer diagnosed in 5642 person-years of follow up for an incidence of 142 cases per 100000 person-years, substantially less than the age-specific SEER incidence rates (293/100000), placebo arm of Women's Health Initiative Study (300/100000), never users of hormone therapy from the Million Women Study (325/100000) and our control group (390/100000). Unlike adherence to estrogen therapy, adherence to T therapy further decreased the incidence of breast cancer (73/100000). CONCLUSION: T and/or T+A, delivered subcutaneously as a pellet implant, reduced the incidence of breast cancer in pre and postmenopausal women. Evidence supports that breast cancer is preventable by maintaining a T to estrogen ratio in favor of T and, in particular, by the use of continuous T or, when indicated, T+A. This hormone therapy should be further investigated for the prevention and treatment of breast cancer.

Testosterone implants in women: pharmacological dosing for a physiologic effect.
            (Glaser et al., 2013) Download
OBJECTIVES: The objectives of this study were to determine therapeutic serum testosterone (T) levels/ranges and inter-individual variance in women treated with subcutaneous T implants. STUDY DESIGN: In study group 1, T levels were measured at two separate time intervals in pre- and post-menopausal women treated with subcutaneous T for symptoms of androgen deficiency: (i) four weeks after pellet insertion, and (ii) when symptoms of androgen deficiency returned. In a separate pharmacokinetic study (study group 2), 12 previously untreated postmenopausal women each received a 100mg T implant. Serum T levels were measured at baseline, 4 weeks and 16 weeks following T pellet implantation. In study 'group' 3, serial T levels were measured throughout a 26 h period in a treated patient. RESULTS: In study group 1, serum T levels measured at 'week 4' (299.36+/-107.34 ng/dl, n=154), and when symptoms returned (171.43+/-73.01 ng/dl, n=261), were several-fold higher compared to levels of endogenous T. There was significant inter-individual variance in T levels at 'week 4' (CV 35.9%) and when symptoms returned (CV 42.6%). Even with identical dosing (study group 2), there was significant inter-individual variance in T levels at 'week 4' (CV 41.9%) and 'week 16' (CV 41.6%). In addition, there was significant intra-individual circadian variation (CV 25%). CONCLUSIONS: Pharmacologic dosing of subcutaneous T, as evidenced by serum levels on therapy, is needed to produce a physiologic effect in female patients. Safety, tolerability and clinical response should guide therapy rather than a single T measurement, which is extremely variable and inherently unreliable.

Testosterone inhibits estrogen/progestogen-induced breast cell proliferation in postmenopausal women.
            (Hofling et al., 2007)  Download
OBJECTIVE:  During the past few years serious concern has been raised about the safety of combined estrogen/progestogen hormone therapy, in particular about its effects on the breast. Several observations suggest that androgens may counteract the proliferative effects of estrogen and progestogen in the mammary gland. Thus, we aimed to study the effects of testosterone addition on breast cell proliferation during postmenopausal estrogen/progestogen therapy. DESIGN:  We conducted a 6-month prospective, randomized, double-blind, placebo-controlled study. A total of 99 postmenopausal women were given continuous combined estradiol 2 mg/norethisterone acetate 1 mg and were equally randomly assigned to receive additional treatment with either a testosterone patch releasing 300 microg/24 hours or a placebo patch. Breast cells were collected by fine needle aspiration biopsy at baseline and after 6 months, and the main outcome measure was the percentage of proliferating breast cells positively stained by the Ki-67/MIB-1 antibody. RESULTS:  A total of 88 women, 47 receiving active treatment and 41 in the placebo group, completed the study. In the placebo group there was a more than fivefold increase (P<0.001) in total breast cell proliferation from baseline (median 1.1%) to 6 months (median 6.2%). During testosterone addition, no significant increase was recorded (1.6% vs 2.0%). The different effects of the two treatments were apparent in both epithelial and stromal cells. CONCLUSIONS:  Addition of testosterone may counteract breast cell proliferation as induced by estrogen/progestogen therapy in postmenopausal women.

 


References

Bachman, E. (2005), ‘The role of testosterone therapy in postmenopausal women: position statement of The North American Menopause Society’, Menopause, 12 (5), 496-511; quiz 649. PubMed: 16145303
Bitzer, J., P. Kenemans, and A. O. Mueck (2008), ‘Breast cancer risk in postmenopausal women using testosterone in combination with hormone replacement therapy’, Maturitas, 59 (3), 209-18. PubMed: 18343056
Davis, S. R., et al. (2009a), ‘The incidence of invasive breast cancer among women prescribed testosterone for low libido’, J Sex Med, 6 (7), 1850-56. PubMed: 19453875
Davis, SR, et al. (2009b), ‘The effect of transdermal testosterone on mammographic density in postmenopausal women not receiving systemic estrogen therapy.’, J Clin Endocrinol Metab, 94 (12), 4907-13. PubMed: 19850682
Dimitrakakis, C., et al. (2004), ‘Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy’, Menopause, 11 (5), 531-35. PubMed: 15356405
Glaser, R, S Kalantaridou, and C Dimitrakakis (2013), ‘Testosterone implants in women: pharmacological dosing for a physiologic effect.’, Maturitas, 74 (2), 179-84. PubMed: 23265303
Glaser, RL and C Dimitrakakis (2013), ‘Reduced breast cancer incidence in women treated with subcutaneous testosterone, or testosterone with anastrozole: a prospective, observational study.’, Maturitas, 76 (4), 342-49. PubMed: 24028858
Hofling, M, et al. (2007), ‘Testosterone inhibits estrogen/progestogen-induced breast cell proliferation in postmenopausal women.’, Menopause, 14 (2), 183-90. PubMed: 17108847