Article - Do statins decrease testosterone in men? Systematic review and meta-analysis.

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Take home message

Continuous statin use may decrease testosterone levels which may have negative longer term effects on health, such as increased risk of osteoporosis, sexual dysfunction, depressed mood and decreased physical performance.

Evidence category

A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)

Summary review

Introduction

• The aim of this systematic review and meta-analysis was to evaluate whether chronic use of statins decreases levels of testosterone and other sex hormones in men with hypercholesterolaemia.

Methods

• Systematic review and meta-analysis of prospective and retrospective comparative studies in adult men receiving statin therapy and reporting sex hormone outcomes.

• PRISMA methodology was followed and risk of bias was assessed with the Cochrane Collaboration’s Tool, the Newcastle-Ottawa Scale and the Assess the Quality of Cross-sectional Studies (AXIS) tool, depending on study type.

• PubMed, Embase and Cochrane Central were searched in May 2023.

Results

• 21 articles were selected, including a total of 9879 patients, 5 randomised controlled trials (RCT, n=1104), 10 prospective cohorts (PC, n=712) and 6 cross-sectional studies (CSS, n=8063)

• Total testosterone (TT): In 6 CSS, TT was significantly lower in the statin compared to the control group, by 55.02ng/dL (95% CI = [39.40, 70.64], I2 = 91 %, p < 0.00001). In 5 RCTs, testosterone reduced significantly more in the statin compared to the control group (13.12ng/dL, [1.16, 25.08], I² = 0%, p=0.03). No statistically significant difference was seen in 3 of the PCs.

• Free testosterone (FT): In 5 CSS, FT was significantly lower in the statin groups (0.60 ng/dL, [0.56, 0.64], I2 = 0%, p<0.00001). No significant difference was observed in 2 of the PCs.

• Follicle stimulating hormone (FSH): In 6 of the PCs, FSH was increased after statin use (mean difference -0.39 UI/L, [-0.59, -0.19], I² = 28%, p = 0.0002). There was no significant difference in the one RCT.

• Luteinising hormone (LH): In 2 CSS, LH was higher in the statin group -0.29 UI/L, [-0.45, -0.12], I2 = 5%, p<0.0008. There were no significant differences in 5 PCs and one RCT.

• Oestradiol and sex hormone-binding globulin: Neither the 4 prospective studies nor the 3 CSS showed significant differences.

Conclusion

• The authors concluded that continuous statin use decreases levels of total testosterone but without it dropping below the normal range, defined as total serum testosterone < 300 ng/dL and free testosterone < 5 ng/dL.

Clinical practice applications

• Monitoring sex hormone levels may be prudent in clients who take statins, especially where symptoms may be suggestive of low testosterone levels. Longer term, low testosterone levels may increase the risk of chronic health issues, including osteoporosis, sexual dysfunction, depressed mood and decreased physical performance.

Considerations for future research

• As much of the evidence in this meta-analysis is based on cross-sectional and cohort studies, further RCTs would be of value to establish whether there is a causal relationship.

• Evaluating not only hormone levels but also signs and symptoms in such RCTs would be of value to establish clinical significance.

Abstract

PURPOSE

Statins are one of the most prescribed classes of drugs worldwide to treat hypercholesterolemia and dyslipidemia. By lowering the level of cholesterol, the use of statin could cause a reduction in testosterone levels. The objective was to evaluate whether the continued use of statins in patients with hypercholesterolemia causes a deficiency in testosterone and other sex hormones.

MATERIALS AND METHODS

Systematic Review with Meta-analysis, performed in Embase, Medline and Cochrane databases, until May 2023; PROSPERO CRD42021270424protocol. Selection performed by two independent authors with subsequent conference in stages. Methodology based on PRISMA statement. There were selected comparative studies, prospective cohorts (CP), randomized clinical trials (RCT) and cross-sectional studies (CSS) with comparison of testosterone levels before and after statin administration and between groups. Bias analysis were evaluated with Cochrane Tool, The Newcastle-Ottawa Scale (NOS), and using the Assess the Quality of Cross-sectional studies (AXIS) tool.

RESULTS

There were found on MedLine, Embase and Cochrane, after selected comparative studies, 10CP and 6RCT and 6CSS for the meta-analysis. In the Forrest plot with 6CSS, a correlation between patients with continuous use of statins and a reduction in total testosterone was evidenced with a statistically significant reduction of 55.02ng/dL (95%CI=[39.40,70.64],I²=91%,p<0.00001).In the analysis with 5RCT, a reduction in the mean total testosterone in patients who started continuous statin use was evidenced, with a statistical significance of 13.12ng/dL (95%CI=[1.16,25.08],I²=0%,p=0.03). Furthermore, the analysis of all prospective studies with 15 articles showed a statistically significant reduction in the mean total testosterone of 9.11 ng/dL (95%CI=[0.16,18.06],I²=37%,p=0.04). A reduction in total testosterone has been shown in most studies and in its accumulated analysis after statin use. However, this decrease was not enough to reach levels below normal.

CONCLUSION

Statins use causes a decrease in total testosterone, not enough to cause a drop below the normal range and also determines increase in FSH levels. No differences were found in LH, Estradiol, SHBG and Free Testosterone analysis.