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Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis.
Hudson, J, Cruickshank, M, Quinton, R, Aucott, L, Aceves-Martins, M, Gillies, K, Bhasin, S, Snyder, PJ, Ellenberg, SS, Grossmann, M, et al
The lancet. Healthy longevity. 2022;3(6):e381-e393
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Hypogonadism is caused by testosterone deficiency and results in diminished sexual function, muscle wastage, weakness, osteoporosis, and reduced quality of life. Testosterone supplementation is used as a therapy for hypogonadism but there is some doubt on its safety, and it may come with serious side effects such as heart attacks. This systematic review and meta-analysis aimed to determine the effect of testosterone supplementation on heart health. The results showed that heart disease risk was unaffected by testosterone supplementation and there was a trend for fewer deaths following treatment. It was concluded that testosterone did not affect short-medium-term heart attack risk, however there was a lack of evidence in the long-term. This study could be used by healthcare professionals to understand that testosterone supplementation may be of benefit to individuals who need it without increasing their risk for heart attacks.
Abstract
BACKGROUND Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD. METHODS We did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005. FINDINGS 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9·5 months) from nine different countries while 18 did not provide IPD data. Risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0·4%] of 1621) than placebo (12 [0·8%] of 1537) without significant differences between groups (odds ratio [OR] 0·46 [95% CI 0·17-1·24]; p=0·13). Cardiovascular risk was similar during testosterone treatment (120 [7·5%] of 1601 events) and placebo treatment (110 [7·2%] of 1519 events; OR 1·07 [95% CI 0·81-1·42]; p=0·62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0·97 [99% CI 0·92-1·03]; p=0·17), baseline testosterone (interaction 0·97 [0·82-1·15]; p=0·69), smoking status (interaction 1·68 [0·41-6·88]; p=0.35), or diabetes status (interaction 2·08 [0·89-4·82; p=0·025) were not associated with cardiovascular risk. INTERPRETATION We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone. FUNDING National Institute for Health Research Health Technology Assessment Programme.
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The impact of nutrition and lifestyle on male fertility.
Benatta, M, Kettache, R, Buchholz, N, Trinchieri, A
Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica. 2020;92(2)
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The impact of environmental, lifestyle and nutritional factors on unexplained male fertility has long been acknowledged. Yet, little research had been dedicated to the topic, despite declining semen quality having become a worldwide phenomena. Available studies have yielded limited, and at times conflicting, evidence. Hence this literature review sought to capture the current knowledge around unexplained male infertility and environmental, lifestyle, diet and nutrients factors. Summarized is the evidence from 69 studies, including population observations and clinical trials. The collected outcomes showed that a Western-type diet, rich in red and processed meats, refined grains, high-energy drinks and sweets, trans and saturated fats was associated with poor semen quality. Whereby higher intakes of fruits and vegetables, whole grains, omega-3 and poultry showed beneficial effects. However, as only selected groups were examined, more research is needed to project such findings onto the wider population. The reviewed evidence also included alcohol consumption, which showed high alcohol intake closely correlated to declining sperm concentrations. Whilst the verdict on caffeine consumption and the impact on sperm quality was inconclusive. In addition, several interventional studies evaluated the effect of dietary supplementation on various parameters of semen, where coenzyme Q10, L-carnitine, vitamin E, antioxidants, combined nutrient formulations and herbal blends all had positive outcomes. The review on zinc and folic acid supplementation yielded mixed results. This brief recap of the current evidence on environmental, lifestyle and nutritional influences on male infertility summarises the dietary foundations for the support of unexplained male infertility.
Abstract
BACKGROUND AND AIMS Male unexplained infertility has long been suspected to result from environmental, lifestyle and nutritional factors. However, the literature on the subject is still scarce, and clinical studies providing robust evidence are even scarcer. In addition, some similar studies come to different conclusions. Dietary pattern can influence spermatogenesis by its content of fatty acids and antioxidants. Yet, in an age of industrialized mass food production, human bodies become more exposed to the ingestion of xenobiotics, as well as chemicals used for production, preservation, transportation and taste enhancement of foods. We attempted in this paper to collect the available evidence to date on the effect of nutritional components on male fertility. MATERIAL AND METHODS A systematic search of the relevant literature published in PubMed, ScienceDirect and Cochrane Central Register of Controlled Trials Database was conducted. Literature was evaluated according to the Newcastle-Ottawa- Scale. RESULTS Epidemiological observations are concordant in demonstrating an association of low-quality sperm parameters with higher intake of red meat, processed and organ meat and fullfat dairy. On the contrary, better semen parameters were observed in subjects consuming a healthy diet, rich in fruit, vegetables, whole grains and fish. Evidences of the negative impact on male fertility of by-products of water disinfection, accumulation in food chain of persistent organochlorine pollutants, pesticides, phthalates from food and water containers and hormones used in breeding cattle have been reported. Clinical trials of the effects of micronutrients on semen parameters and outcomes of assisted fertilization are encouraging, although optimal modality of treatment should be established. CONCLUSIONS Although quality of evidence should be ameliorated, it emerges that environmental factors can influence male fertility. Some nutrients may enhance fertility whereas others will worsen it. With diagnostic analysis on a molecular or even sub-molecular level, new interactions with micronutrients or molecular components of our daily ingested foods and leisure drugs may lead to a better understanding of so far suspected but as yet unexplained effects on male spermatogenesis and fertility.