Abstract
Background:
Testosterone treatment increases erythrocytes in men, but its effects on leukocyte and platelet counts are unknown and could affect its safety.
Objective:
To determine if testosterone affects circulating leukocytes and platelets in men.
Methods:
Secondary analyses of two randomized testosterone trials were performed: the 5α-Reductase (5aR) and OPTIMEN Trials. In 5aR trial, 102 healthy men, 21–50 years (mean age 38), received a long-acting GnRH-agonist, and 50, 125, 300, or 600 mg*week−1 testosterone enanthate (TE) plus placebo or 2.5 mg*day−1 dutasteride for 20-weeks. In OPTIMEN, 78 functionally-limited men, ≥65 years (mean age 72) with protein intake ≤0.83 g*kg−1*day−1 were randomized to controlled diets with 0.8 g*kg−1*day−1 protein or 1.3 g*kg−1*day−1 protein plus placebo or TE (100 mg*week−1) for 6 months. Changes from baseline in total and differential leukocyte count, and platelet count were evaluated.
Results:
In 5aR, testosterone administration was associated with increases in total leukocyte (estimated change from baseline 40, 490, 1230, and 1280 cells/μL, p<0.001), neutrophil (65.1, 436.1, 1177.2, and 1192.2 cells/μL, p<0.001), monocyte (−20.2, 24.5, 90.6, and 143.9 cells/μL, p<0.001), platelet (−7.3, 8.4, 8.7 and 8.9 *103cells/μL, p=0.033), and erythrocyte counts. Testosterone did not affect absolute lymphocyte count. Similar increase in total leukocyte count was observed with testosterone treatment in OPTIMEN (change 0.77*103cells/μL, P vs placebo=0.004).
Conclusions:
Testosterone administration in men differentially increases neutrophil and monocyte counts. These findings, together with its erythropoietic effects, suggest that testosterone promotes the differentiation of hematopoietic progenitors into the myeloid lineage. These findings have potential mechanistic, therapeutic and safety implications.
Trial Registration:
clinicaltrials.gov Identifiers: NCT01275365 and NCT00493987.
Keywords: hematopoiesis, androgen, white blood cell, thrombocyte, cardiovascular
Introduction
Testosterone is well known to increase circulating hemoglobin, hematocrit and erythrocyte count1–6, and erythrocytosis is a well-recognized adverse effect of testosterone treatment. Accordingly, the Endocrine Society guideline recommends monitoring of hemoglobin and hematocrit in hypogonadal men receiving testosterone therapy7. Testosterone treatment corrects anemia of inflammation8 and unexplained anemia of the elderly5,9, and testosterone and other androgens were used to treat several non-ferropenic anemic states prior to the advent of erythropoietin10. However, the mechanisms by which testosterone increases hemoglobin and hematocrit are incompletely understood. Previous studies have shown that testosterone suppresses hepcidin transcription and stimulates iron-dependent erythropoiesis9,11,12; however, testosterone administration increases hemoglobin and hematocrit even in genetically modified mice with disruption of the hepcidin gene13, indicating that suppression of hepcidin by testosterone cannot fully account for the testosterone-induced increase in erythropoiesis. Other mechanisms that have been proposed include direct effects on erythropoietic progenitors in the bone marrow, stimulation of erythropoietin, and alteration in erythropoietin sensitivity.
Suppression of endogenous testosterone secretion through androgen deprivation therapy for prostate cancer has recently been shown to be associated with a decrease in leukocyte count14. However, there are no randomized trial data on the effects of exogenous testosterone on circulating leukocytes and platelets. Because of the known association of increased leukocyte15–18 and platelet counts19–21 with cardiovascular and thromboembolic risk, these findings, if confirmed in human studies, could affect the safety of testosterone treatment. These findings could also provide important clues to the site of testosterone’s action in the bone marrow. Accordingly, secondary analyses of data from a testosterone dose-response trial in men22 were performed to determine whether testosterone affects total and differential leukocyte counts, and platelet counts. These findings were verified in another trial in which testosterone treatment was administered to functionally-limited older men23.
Methods
The randomized trials from which these data were derived have been published22,23. Both trials were approved by institutional review boards of Boston University Medical Center and Brigham and Women’s Hospital. All participants gave written informed consent.
The 5α-Reductase Trial (5aR Trial)
As described previously22, the primary aim of the 5aR Trial was to determine the role of the conversion of testosterone to 5α-dihydrotestosterone by the steroid 5α reductase enzymes in mediating testosterone’s effects on androgen-dependent outcomes. Participants were healthy men, 18 to 50 years, with normal testosterone levels (300 to 1200 ng/dL)22. Men who had a history of prostate cancer, lower urinary tract symptom (LUTS) score >20 on the International Prostate Symptom Scale, body weight ≥135kg, uncontrolled hypertension, hematocrit ≥51%, prostate-specific antigen level ≥4 ng/mL, aspartate aminotransferase or alanine aminotransferase ≥1.5 times the upper limit of normal, creatinine level ≥2 mg/dL, and those who were receiving glucocorticoids, growth hormone, androgens, or 5α-reductase inhibitors were excluded.
Participants received monthly injections of 7.5-mg leuprolide acetate to suppress endogenous testosterone production, and weekly injections of one of four graded doses of testosterone enanthate (TE) (50, 125, 300, or 600 mg*week−1) plus either placebo or 2.5 mg dutasteride daily for 20 weeks. Complete blood counts with differential leukocyte counts were measured at baseline and every 4 weeks during the 20-week intervention period.
The OPTIMEN Trial
The primary aim of the OPTIMEN Trial was to determine whether increasing protein intake to 1.3 g*kg−1*day−1 in functionally-limited, older adults with usual protein intake <0.83 g*kg−1*day−1 improves lean body mass (LBM), and augments LBM response to testosterone23.
Briefly, community-dwelling men, 65 years or older, with moderate degree of functional limitation as indicated by Short Physical Performance Battery score 3–10, whose average daily usual protein intake was ≤ 0.83 g*kg−1*day−1, were randomized for 6 months to one of four intervention arms: 0.8 g*kg−1*day−1 protein plus placebo weekly, 1.3 g*kg−1*day−1 protein plus placebo, 0.8 g*kg−1*day−1 protein plus 100 mg•week−1 TE, or 1.3 g*kg−1*day−1 protein plus TE. Men with a history of prostate cancer, severe LUTS, untreated sleep apnea, heart failure, myocardial infarction, or stroke within 6 months, as well as those having glycated hemoglobin levels > 8% or those with erythrocytosis were excluded. Complete blood counts were measured at baseline, and during months 3 and 6. Differential leukocyte counts were not available.
Laboratory Methods
Blood counts were measured using electronic cell sizing and cytometry at the Quest Diagnostics Laboratory, Cambridge, MA. Total testosterone was measured using liquid-chromatography tandem mass-spectrometry with sensitivity of 2 ng/dL24. Free testosterone was measured by equilibrium dialysis25.
Statistical Analyses
The baseline characteristics of study participants were summarized as mean and standard deviations or median and interquartile ranges for normally and non-normally distributed data, respectively. In the 5aR study, dutasteride had no significant effect on testosterone’s erythropoietic effects22; therefore, the placebo and dutasteride groups within each testosterone dose level were combined. Additional sensitivity analyses were performed to verify if dutasteride had any effect on any hematopoietic variables. Similarly, in the OPTIMEN Trial, protein intake level had no effect on hematocrit23; therefore, men who received testosterone treatment were combined and the men randomized to placebo were combined regardless of protein intake level; sensitivity analyses were performed to assess potential effect of protein level on hematopoietic variables. Participants who had baseline and at least one post-randomization complete blood count were included in the analyses.
The distributional properties of outcomes were assessed graphically. Mixed-model regression analyses with repeated measures were employed to allow for within-subject correlation of outcomes over time. Null hypotheses assumed no difference between dose groups over 20 weeks (5aR trial) and no difference in change from baseline between testosterone and placebo groups over 6 months (OPTIMEN trial). The associations between on-treatment total and free testosterone levels and blood counts were explored using linear regression analyses. Type 1 error was set at 0.05; all tests were two-tailed. Analyses were performed using SAS v.9.4 (SAS Institute, Cary, NC). Graphs were generated using GraphPad Prism version 6 (GraphPad Software, La Jolla, CA).
Results
Baseline Characteristics
The baseline characteristics of the participants were similar across the intervention groups (Table 1). In the 5aR Trial, 102 participants who completed the trial were included in the analyses. Their median age was 38 years (range 24 to 50 years) and mean BMI 26.3 kg/m2 (range 19.0 to 36.9 kg/m2). In the OPTIMEN trial, 78 participants, who completed the trial were included in the analyses. Their median age was 72 years (range 65 to 90 years) and mean body mass index 30.1 kg/m2 (range 20.1 to 40.0 kg/m2).
Table 1 –
Baseline characteristics of the participants in the 5aR and the OPTIMEN trials.
| 5aR Testosterone Enanthate Dose Groups |
OPTIMEN Treatment Groups |
|||||
|---|---|---|---|---|---|---|
| 50mg | 125mg | 300mg | 600mg | Placebo | 100mg | |
| n | 28 | 21 | 24 | 29 | 42 | 36 |
| Age, years | 39.7 ± 9.0 | 36.4 ± 8.3 | 35.9 ± 8.6 | 37.7 ± 8.8 | 72.5 ± 5.2 | 73.8 ± 6.9 |
| Body mass index, kg/m2 | 26.3 ± 4.2 | 26.9 ± 3.8 | 25.5 ± 3.6 | 26.5 ± 4.2 | 30.8 ± 4.6 | 28.9 ± 4.7 |
| Erythrocyte count, 106 cells/μL | 4.9 ± 0.4 | 4.7 ± 0.4 | 4.8 ± 0.5 | 4.9 ± 0.3 | 4.6 ± 0.4 | 4.5 ± 0.3 |
| Platelets, 103cells/μL | 249.7 ± 45.6 | 229.0 ± 50.4 | 215.7 ± 41.8 | 232.9 ± 45.3 | 219.3 ± 63.4 | 190.9 ± 44.4 |
| Leukocyte count, 103cells/μL | 6.0 ± 1.9 | 5.9 ± 2.0 | 5.7 ± 1.6 | 5.7 ± 1.4 | 6.0 ± 1.3 | 5.9 ± 1.3 |
| Neutrophils count, cells/μL | 3510.7 ± 1396.8 | 3386.0 ± 1592.5 | 3295.3 ± 947.7 | 3315.7 ± 1227.2 | ||
| Lymphocyte count, cells/μL | 1823.6 ± 510.2 | 1721.2 ± 485.8 | 1763.9 ± 594.4 | 1713.4 ± 393.9 | ||
| Monocyte count, cells/μL | 467.4 ± 163.1 | 527.3 ± 219.4 | 453.8 ± 155.7 | 468.6 ± 166.2 | ||
| Eosinophil count, cells/μL | 114.0 (54.0, 176.0) | 130.0 (79.0, 260.0) | 150.0 (110.0, 261.0) | 118.0 (81.0, 188.0) | ||
| Basophil count, cells/μL | 17.0 (0.0, 48.0) | 40.0 (0.0, 56.0) | 0.0 (0.0, 49.0) | 17.0 (0.0, 44.0) | ||
| Neutrophil, % | 57.7 ± 6.5 | 56.0 ± 8.8 | 57.4 ± 6.5 | 57.2 ± 9.4 | ||
| Lymphocyte, % | 31.0 ± 6.1 | 31.0 ± 8.1 | 30.6 ± 6.3 | 31.3 ± 8.1 | ||
| Monocyte, % | 8.0 ± 2.1 | 9.0 ± 2.3 | 7.9 ± 2.0 | 8.3 ± 1.9 | ||
| Eosinophil, % | 2.0 (1.0, 3.0) | 3.0 (1.1, 5.0) | 3.0 (2.0, 5.0) | 2.0 (1.5, 3.0) | ||
| Basophil, % | 0.3 (0.0, 1.0) | 1.0 (0.0, 1.0) | 0.0 (0.0, 1.0) | 0.3 (0.0, 1.0) | ||
Values are means ± SD or median (Q1, Q3) for normally and non-normally distributed data, respectively.
The 5-Alpha Reductase Trial
Testosterone administration was associated with an increase in total leukocyte count (p<0.001; Figure 1), absolute and percent neutrophil count (p<0.001), and absolute (p<0.001) and percent (p=0.008) monocyte count (Figure 2), all of which were numerically greater in men assigned to the higher doses. 11 men had leukocyte count >10,500 cells/μL (3 in 50 mg, 2 in 125 mg, 3 in 300 mg and 3 in 600 mg groups), and 18 men had neutrophil counts >7000 cells/μL (3 in 50 mg, 4 in 125 mg, 4 in 300 mg and 7 in 600 mg groups) at least once during the 20-week intervention period. On-treatment total testosterone concentrations were weakly associated with the change from baseline in the absolute neutrophil (p=0.024; r2=0.05) and the monocyte counts (p<0.001; r2=0.114). Similar weak associations were seen between free testosterone concentration and the changes in the neutrophil count (p=0.027; r2=0.049), and the monocyte count (p=0.001; r2=0.100).
Figure 1 –
Top panels: The bars represent the estimated changes from baseline in the leukocyte, platelet and erythrocyte counts for each testosterone dose group (50, 125, 300 or 600 mg*week−1) during the 20-week intervention period in the 5aR trial. The cell counts were measured using electronic cell sizing and cytometry. The P values derived from the mixed-effects regression model framework for difference between testosterone dose groups are shown. Error bars indicate 95% confidence intervals.
Bottom panels: The black bars represent the estimated changes from baseline in each blood cell type evaluated for each treatment group in the OPTIMEN trial, whereas gray bars represent estimated difference between treatment groups. The P values derived from the mixed-effects regression model framework for the testosterone effect (testosterone vs placebo) are shown. Error bars indicate 95% confidence intervals.
Figure 2 –
The bars represent estimated change from baseline in the circulating counts of each leukocyte subtype and their relative proportion for each testosterone dose group (50, 125, 300 or 600 mg*week−1) electronic cell sizing and cytometry. The P values derived from the mixed-effects regression framework for difference between testosterone dose groups are shown. Error bars indicate 95% confidence intervals.
As expected, testosterone treatment increased erythrocyte count (p<0.001; Figure 1; Table 2), with numerically greater increases at the higher doses. The absolute lymphocyte count did not change significantly from baseline across dose groups. However, testosterone administration was associated with a decrease in the percent lymphocyte count (p<0.001; Figure 2; Table 2), likely due to the concomitant increase in absolute neutrophil and monocyte counts.
Table 2 –
Estimated changes from baseline in the circulating numbers of total leukocytes, platelets, and erythrocytes as well as the absolute and relative counts of the leukocyte subtypes for testosterone dose groups in the 5aR trial.
| Testosterone Enanthate Dose Group | Dose-Effect | ||||
|---|---|---|---|---|---|
| 50mg | 125mg | 300mg | 600mg | P-Value | |
| Erythrocyte count, 106 cells/μL | −0.07 (−0.16, 0.02) | 0.19 (0.09, 0.29) | 0.35 (0.26, 0.45) | 0.32 (0.23, 0.40) | <0.001 |
| Platelets, 103cells/μL | −7.3 (−16.3, 1.7) | 8.4 (−1.6, 18.4) | 8.7 (−0.6, 18.1) | 8.9 (0.5, 17.4) | 0.033 |
| Leukocyte count, 103cells/μL | 0.04 (−0.33, 0.41) | 0.49 (0.07, 0.91) | 1.23 (0.83, 1.62) | 1.28 (0.92, 1.64) | <0.001 |
| Neutrophils count, cells/μL | 65.1 (−293.6, 423.9) | 436.1 (27.7, 844.4) | 1177.2 (790.1, 1564.4) | 1192.2 (849.2, 1535.1) | <0.001 |
| Lymphocyte count, cells/μL | −7.89 (−123.9, 108.1) | −14.4 (−146.1, 117.3) | 38.7 (−86.0, 163.5) | −83.7 (−194.8, 27.3) | 0.53 |
| Monocyte count, cells/μL | −20.2 (−52.7, 12.4) | 24.5 (−12.9, 61.9) | 90.6 (55.5, 125.8) | 143.9 (112.8, 175.0) | <0.001 |
| Eosinophil count, cells/μL | 0.67 (−30.3, 31.7) | 39.1 (4.1, 74.1) | −2.70 (−36.3, 30.8) | 3.1 (−26.5, 32.8) | 0.29 |
| Basophil count, cells/μL | −2.61 (−8.95, 3.73) | 0.82 (−6.48, 8.13) | 1.58 (−5.21, 8.38) | −0.36 (−6.40, 5.67) | 0.82 |
| Neutrophil, % | 0.03 (−2.09, 2.14) | 1.61 (−0.79, 4.00) | 5.98 (3.70, 8.25) | 6.79 (4.77, 8.80) | <0.001 |
| Lymphocyte, % | 0.65 (−1.15, 2.44) | −2.06 (−4.10, −0.03) | −5.21 (−7.14, −3.27) | −6.71 (−8.43, −4.99) | <0.001 |
| Monocyte, % | −0.35 (−0.82, 0.12) | −0.14 (−0.68, 0.41) | −0.19 (−0.70, 0.32) | 0.70 (0.25, 1.15) | 0.008 |
| Eosinophil, % | 0.03 (−0.44, 0.49) | 0.48 (−0.04, 1.00) | −0.56 (−1.06, −0.06) | −0.47 (−0.91, −0.03) | 0.014 |
| Basophil, % | −0.05 (−0.15, 0.05) | 0.003 (−0.11, 0.12) | −0.05 (−0.16, 0.05) | −0.07 (−0.16, 0.03) | 0.81 |
Data are expressed as estimated change from baseline (95% Confidence Intervals). P values, derived from the mixed-effects regression model with repeated measures framework for testosterone dose-effect, are also shown.
Testosterone administration was associated with a significant increase in the platelet count (p=0.033; Figure 1; Table 2), with the 3 higher doses being higher than the 50 mg dose group. No subject had any platelet count greater than 450,000 cells/μL during the intervention period.
In sensitivity analyses, accounting for dutasteride use did not significantly affect the results.
The OPTIMEN Trial
Consistent with the findings of the 5aR Trial, testosterone treatment for 6 months in the OPTIMEN Trial was associated with a significantly greater increase in the erythrocyte count (p<0.001) and total leukocyte count (p=0.004) compared to placebo treatment (Figure 1; Table 3). The platelet count increased significantly in the men randomized to the testosterone arm (p=0.019), but the change from baseline in the platelet count did not differ significantly between the intervention arms (p=0.23; Figure 1; Table 3). No testosterone-treated subject had total leukocyte count greater than 10,500 cells/μL or platelet count greater than 450,000 cells/μL.
Table 3 –
Estimated changes from baseline in circulating counts of erythrocytes, platelets and leukocytes for treatment groups in the OPTIMEN trial.
| Treatment Group | ||||
|---|---|---|---|---|
| Placebo | 100mg TE | Difference | P-value | |
| Erythrocyte count, 106 cells/μL | 0.01 (−0.05, 0.07) | 0.45 (0.38, 0.51) | 0.44 (0.35, 0.53) | <0.001 |
| Platelets, 103cells/μL | 2.64 (−4.24, 9.51) | 8.94 (1.49, 16.4) | 6.30 (−3.99, 16.6) | 0.23 |
| Leukocyte count, 103cells/μL | 0.25 (0.01, 0.48) | 0.77 (0.52, 1.03) | 0.53 (0.18, 0.88) | 0.004 |
Data are expressed as estimated change from baseline (95% Confidence Intervals). The P values, derived from the mixed-effects regression model with repeated measures framework, for the testosterone effect (testosterone vs placebo) are also shown. TE, testosterone enanthate
In sensitivity analyses, accounting for protein intake did not significantly affect results.
Discussion
The guidelines of many professional societies for testosterone treatment of hypogonadism in men recommend monitoring of hemoglobin and hematocrit during testosterone treatment7,26,27. The present study shows that testosterone treatment also increases circulating leukocytes. The effects of testosterone on leukocytes are lineage specific; testosterone treatment differentially increased the neutrophil as well as the monocyte counts but did not affect absolute lymphocyte, basophil, or eosinophil counts. The decrease in the relative proportion of lymphocytes was likely due to the increase in the absolute neutrophil and monocyte counts. The increase in platelet count observed in the 5aR Trial was not confirmed in the OPTIMEN Trial. Because erythrocytes, neutrophils, and monocytes are all derived from a common myeloid progenitor within the bone marrow, while lymphocytes are derived from a common lymphoid progenitor, the selective increase in erythrocytes, neutrophils, and monocytes, but not lymphocytes, basophils, and eosinophils suggests that testosterone likely promotes the differentiation of a multipotential hematopoietic progenitor into the myeloid lineage. This hypothesis should be tested.
These findings also have therapeutic implications for the potential use of testosterone to treat some types of myelodysplastic conditions and cytopenias. The increase in the neutrophil count, especially at supraphysiologic doses of testosterone, was similar to that reported with granulocyte-macrophage colony stimulating factor in neutropenic patients28,29.
It is surprising that testosterone-induced changes in the neutrophil and monocyte and possibly platelet counts have gone unnoticed until now even to those of us who treat hypogonadal men with testosterone in our clinical practice. This could be because the total leukocyte, neutrophil, and platelet counts typically do not rise above the normal range in testosterone-treated men; modest increases in neutrophil and monocyte counts in the normal range may be ignored. However, higher leukocyte counts, even within the normal range, are a risk-factor for ischemic heart disease, arterial thrombosis, and cardiovascular and cancer mortality16–18,30–32. Higher neutrophil counts are associated with cardiovascular disease in men15. High monocyte counts have been suggested as a risk-factor for cardiovascular mortality and coronary artery plaque formation33. The safety implications of increases in neutrophil and monocyte counts during testosterone treatment need further investigation, particularly given the ongoing controversy regarding the cardiovascular safety of testosterone therapy34. These findings raise the question whether monitoring of platelet and leukocyte counts should be considered in men receiving testosterone treatment.
The findings of increased platelet count observed in the 5aR should be further evaluated in larger trials because higher platelet counts, even within the normal range, are associated with an increased risk of ischemic stroke, and cardiovascular and all-cause death19–21. Increased platelet counts are associated with risk of venous thromboembolism during recovery from acute illness and in cancer patients35.
This study has several strengths and some limitations. The trials had attributes of good trial design: subject allocation using concealed block randomization; the masking of the intervention from the participants, the study staff, and the persons performing outcome assessments; and parallel groups. The increases in the leukocyte, neutrophil and the monocyte counts were associated with the on-treatment serum testosterone concentrations. The total leukocyte count findings were consistent across the two trials. However, the leukocyte and platelet counts were not prespecified outcomes of these trials; the substantial variability in platelet counts may have resulted in a low power to detect a treatment-effect in older men receiving testosterone compared to placebo. Differential leukocyte counts were available only in one trial. Previous studies have reported that testosterone might affect T-cell subtype differentiation36, CD4+ to CD8+ ratio, and proinflammatory as well as immunosuppressive cytokines, which were not studied.
Conclusions
Testosterone administration increases total leukocyte count, as well as the counts of neutrophils, monocytes, but not of lymphocytes, basophils, or eosinophils. These findings, together with the known effects of testosterone on erythrocyte count, suggest that testosterone likely promotes the differentiation of hematopoietic progenitors into the myeloid lineage. Safety and therapeutic implications of these findings, and the molecular mechanisms by which testosterone regulates the differentiation of hematopoietic progenitors need further investigation.
Acknowledgements
The 5aR study was supported by grant 1RO1HD043348 (to SBh) from the National Institute of Child Health and Human Development. Additional support was provided by Boston University Clinical and Translational Science Institute grant 1UL1RR025771, by the Boston Claude D. Pepper Older Americans Independence Center, and by grant 5P30AG031679 from the National Institute on Aging. Glaxo-SmithKline Inc provided dutasteride and placebo and ENDO Pharmaceuticals provided testosterone enanthate. The OPTIMEN study was funded primarily by National Institutes of Health grant R01AG037547 from the National Institute on Aging (to Drs Bhasin and Apovian). Additional support was provided by the infrastructural resources of the Boston Claude D. Pepper Older Americans Independence Center for Function Promoting Therapies, which is supported by grant P30AG031679 from the National Institute on Aging. This study was also supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Boston University Clinical Translational Science Institute grant 1UL1TR001430, and by the Boston Nutrition Obesity Research Center through grant P30DK046200. Dietary supplements were provided by Abbott Laboratories, Bariatrix Nutrition, and the National Dairy Council. Endo Pharmaceuticals provided testosterone enanthate for this trial. This study was also supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through the Harvard Catalyst, the Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1TR001102), and financial contributions from Harvard University and its affiliated academic health care centers.
Dr. Bhasin (S.Bh) has received research grant support from Abbvie Pharmaceuticals, Transition Therapeutics, Alivegen, and Metro International Biotechnology for investigator-initiated research unrelated to this study; these grants are managed by the Brigham and Women’s Hospital. S.Bh has served as a consultant to AbbVie, and OPKO, and has equity interest in Function Promoting Therapies, LLC. Dr. Basaria has served as a consultant to AbbVie Pharmaceuticals and Regeneron. Other authors report no conflicts.
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