Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance and physical function in a randomized trial

Abstract

Objective: This study aims to determine the dose-dependent effects of testosterone on sexual function, body composition, muscle performance, and physical function in hysterectomized women with or without oophorectomy.

Methods: Seventy-one postmenopausal women who previously underwent hysterectomy with or without oophorectomy and had total testosterone levels less than 31 ng/dL or free testosterone levels less than 3.5 pg/mL received a standardized transdermal estradiol regimen during the 12-week run-in period and were randomized to receive weekly intramuscular injections of placebo or 3, 6.25, 12.5, or 25 mg of testosterone enanthate for 24 weeks. Total and free testosterone levels were measured by liquid chromatography-tandem mass spectrometry and equilibrium dialysis, respectively. The primary outcome was change in sexual function measured by the Brief Index of Sexual Functioning for Women. Secondary outcomes included changes in sexual activity, sexual distress, Derogatis Interview for Sexual Functioning, lean body mass, fat mass, muscle strength and power, and physical function.

Results: Seventy-one women were randomized; five groups were similar at baseline. Sixty-two women with analyzable data for the primary outcome were included in the final analysis. The mean on-treatment total testosterone concentrations were 19, 78, 102, 128, and 210 ng/dL in the placebo, 3-mg, 6.25-mg, 12.5-mg, and 25-mg groups, respectively. Changes in composite Brief Index of Sexual Functioning for Women scores, thoughts/desire, arousal, frequency of sexual activity, lean body mass, chest-press power, and loaded stair-climb power were significantly related to increases in free testosterone concentrations; compared with placebo, changes were significantly greater in women assigned to the 25-mg group, but not in women in the lower-dose groups. Sexual activity increased by 2.7 encounters per week in the 25-mg group. The frequency of androgenic adverse events was low.

Conclusions: Testosterone administration in hysterectomized women with or without oophorectomy for 24 weeks was associated with dose and concentration-dependent gains in several domains of sexual function, lean body mass, chest-press power, and loaded stair-climb power. Long-term trials are needed to weigh improvements in these outcomes against potential long-term adverse effects.

Trial registration: ClinicalTrials.gov NCT00494208.

Conflict of interest statement

Conflict of Interest Disclosure: Dr. Bhasin has received research grant support from Abbott Pharmaceuticals and Eli Lilly and Co. for investigator-initiated research which is unrelated to this study. Dr. Bhasin has served as a consultant for Regeneron, Merck and Eli Lilly and Co. No other potential conflict of interest relevant to this article was reported.

Figures

Figure 1

Flow of Participants Through the Trial * Represents number of participants who had a baseline and at least one post-randomization visit assessment of the Brief Index of Sexual Functioning Questionnaire, the primary outcome of the trial. ^In each of these groups, one subject did not have an evaluable post-randomization assessment.

Figure 2

On−Treatment Total and Free Testosterone Concentrations. Data represents means and standard errors at baseline and on−treatment for each testosterone dose group. The reference ranges for total and free testosterone in healthy, cycling women from the Framingham Heart Study presented as the median (2.5th, 97.5th precentile range) are as follows: Total testosterone: Follicular Phase 23.7 (8.3, 48.3)ng/dl, Ovulatory Phase (10.1, 48.3) ng/dl, Luteal Phase 28.5 (11.3, 62.5) ng/dl. Free Testosterone: Follicular Phase 1.8 (0.7, 4.4) pg/ml, Ovulatory Phase 2.8 (1.1, 4.6) pg/ml, Luteal Phase 2.4 (0.9, 7.2) pg/ml.

Figure 3A

Sexual Function Outcome Measures In the bar graphs on the left, data represent absolute mean changes (± SE) from baseline for each treatment group. The * represents a significant difference between mean on treatment change in dose group vs. placebo at a 0.05 level; the significance level for the overall dose effect (by likelihood ratio test) is also shown. Scatterplots on the right display estimates and 95% confidence regions for the Generalized Additive Model (GAM) of change in sexual function outcomes as a function of free testosterone levels. The p−values displayed here are from a significance test of no association. BISF; Brief Index of Sexual Functioning

Figure 3B

Sexual Function Outcome Measures In the bar graphs on the left, data represent absolute mean changes (± SE) from baseline for each treatment group. The * represents a significant difference between mean on treatment change in dose group vs. placebo at a 0.05 level; the significance level for the overall dose effect (by likelihood ratio test) is also shown. Scatterplots on the right display estimates and 95% confidence regions for the Generalized Additive Model (GAM) of change in sexual function outcomes as a function of free testosterone levels. The p−values displayed here are from a significance test of no association. SAL, Sexual Activity Log; FSDS, Female Sexual Distress Scale; PGWBI, Psychological General Well-Being Index

Figure 4

Body Composition and Muscle Performance Measures In the bar graphs on the left, data represent absolute mean changes (± SE) from baseline for each treatment group. The * represents a significant difference between mean on treatment change in dose group vs. placebo at a 0.05 level; the significance level for the overall dose effect (by likelihood ratio test) is also shown. Scatterplots on the right display estimates and 95% confidence regions for the Generalized Additive Model (GAM) of change in body composition compartments as a function of free testosterone levels. The p−values displayed here are from a significance test of no association. Kg, kilogram; N, Newton; W, Watt.

Figure 5

Hematocrit, Hemoglobin and Metabolic Parameters The data represent absolute mean changes (± SE) of data for each treatment group. The * represents a significant difference between mean on treatment change in dose group vs. placebo at a 0.05 level. The p−value displayed is an overall F-test for significance of dose level, obtained via ANCOVA. LDL, Low Density Lipoprotein; HDL, High Density Lipoprotein.

Figure 6

Androgenic Adverse Events The data represent absolute mean changes (± SE) of data for each treatment group. The * represents a significant difference between mean on treatment change in dose group vs. placebo at a 0.05 level. The p−value displayed is an overall F-test for significance of dose level, obtained via ANCOVA.