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Gonadal steroid-dependent effects on bone turnover and bone mineral density in men
Background:
Severe gonadal steroid deficiency induces bone loss in adult men; however, the specific roles of androgen and estrogen deficiency in hypogonadal bone loss are unclear. Additionally, the threshold levels of testosterone and estradiol that initiate bone loss are uncertain.
Methods:
One hundred ninety-eight healthy men, ages 20-50, received goserelin acetate, which suppresses endogenous gonadal steroid production, and were randomized to treatment with 0, 1.25, 2.5, 5, or 10 grams of testosterone gel daily for 16 weeks. An additional cohort of 202 men was randomized to receive these treatments plus anastrozole, which suppresses conversion of androgens to estrogens. Thirty-seven men served as controls and received placebos for goserelin and testosterone. Changes in bone turnover markers, bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA), and BMD by quantitative computed tomography (QCT) were assessed in all men. Bone microarchitecture was assessed in 100 men.
Results:
As testosterone dosage decreased, the percent change in C-telopeptide increased. These increases were considerably greater when aromatization of testosterone to estradiol was also suppressed, suggesting effects of both testosterone and estradiol deficiency. Decreases in DXA BMD were observed when aromatization was suppressed but were modest in most groups. QCT spine BMD fell substantially in all testosterone-dose groups in which aromatization was also suppressed, and this decline was independent of testosterone dose. Estradiol deficiency disrupted cortical microarchitecture at peripheral sites. Estradiol levels above 10 pg/ml and testosterone levels above 200 ng/dl were generally sufficient to prevent increases in bone resorption and decreases in BMD in men.
Conclusions:
Estrogens primarily regulate bone homeostasis in adult men, and testosterone and estradiol levels must decline substantially to impact the skeleton.
Trial Registration:
ClinicalTrials.gov, NCT00114114.
Funding:
AbbVie Inc., AstraZeneca Pharmaceuticals LP, NIH.
Insights
Estrogen plays a key role in maintaining bone health in men. Both testosterone and estradiol levels must significantly decrease to negatively impact bone mineral density and microarchitecture.
Area of Science:
- Endocrinology
- Bone Biology
- Men's Health
Background:
- Bone loss in men with hypogonadism is linked to gonadal steroid deficiency.
- The distinct roles of androgen and estrogen deficiency in this bone loss remain unclear.
- Thresholds for testosterone and estradiol initiating bone loss are uncertain.
Purpose of the Study:
- To investigate the specific contributions of testosterone and estradiol deficiency to bone loss in men.
- To determine the critical levels of these hormones for maintaining bone health.
Main Methods:
- 198 healthy men (ages 20-50) received goserelin acetate to suppress steroid production.
- Participants were randomized to receive varying doses of testosterone gel.
- A subset also received anastrozole to inhibit estrogen conversion, with bone density and turnover assessed.
Main Results:
- Decreased testosterone and suppressed estradiol significantly increased bone resorption markers.
- Quantitative computed tomography (QCT) showed substantial spine bone mineral density (BMD) loss, independent of testosterone dose when aromatization was blocked.
- Estradiol deficiency impaired peripheral cortical microarchitecture; levels above 10 pg/ml and testosterone above 200 ng/dl generally preserved BMD.
Conclusions:
- Estrogen is the primary regulator of bone homeostasis in adult men.
- Significant declines in both testosterone and estradiol are required to affect the male skeleton.
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