Males and females differ in their immunological responses to foreign and self-antigens and show distinctions in innate and adaptive immune responses. Certain immunological sex differences are present throughout life, whereas others are only apparent after puberty and before reproductive senescence, suggesting that both genes and hormones are involved. Furthermore, early environmental exposures influence the microbiome and have sex-dependent effects on immune function. Importantly, these sex-based immunological differences contribute to variations in the incidence of autoimmune diseases and malignancies, susceptibility to infectious diseases and responses to vaccines in males and females. Here, we discuss these differences and emphasize that sex is a biological variable that should be considered in immunological studies.

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Sex differences in immune responses

This study suggests that there are sex differences in vocational attitude maturity. In the four-school stratified sample of eleventh grade boys and girls studied, the girls scored significantly higher than the boys in vocational attitude. No sex differences in overall level of self-esteem, as measured by the Tennessee Self-Concept Scale, were found. For both sexes a significant relationship between the over all level of self-esteem and vocational attitude maturity was indicated, with the relationship being higher for males than for females. The self-concept variables of self-satisfaction, family, and moral-ethical self were found to contribute to the vocational attitude maturity of males. For females, the self-concept variables of identity and moral-ethical self contributed to their vocational attitude maturity.

Sex Differences in

Background Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied. Methods Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group. Results A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load. Conclusions In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy. (ClinicalTrials.gov number, NCT00240981.)

https://www.hormonebalance.org/images/documents/Basari%2010%20TRT%20men%20Cardiac%20events%20NEJM.pdf

Adverse Events Associated with Testosterone Administration

ContextInconsistent data suggest that endogenous sex hormones may have a role in sex-dependent etiologies of type 2 diabetes, such that hyperandrogenism may increase risk in women while decreasing risk in men.ObjectiveTo systematically assess studies evaluating the association of plasma levels of testosterone, sex hormone–binding globulin (SHBG), and estradiol with risk of type 2 diabetes.Data SourcesSystematic search of EMBASE and MEDLINE (1966-June 2005) for English-language articles using the keywords diabetes, testosterone, sex-hormone-binding-globulin, and estradiol; references of retrieved articles; and direct author contact.Study SelectionFrom 80 retrieved articles, 43 prospective and cross-sectional studies were identified, comprising 6974 women and 6427 men and presenting relative risks (RRs) or hormone levels for cases and controls.Data ExtractionInformation on study design, participant characteristics, hormone levels, and risk estimates were independently extracted by 2 investigators using a standardized protocol.Data SynthesisResults were pooled using random effects and meta-regressions. Cross-sectional studies indicated that testosterone level was significantly lower in men with type 2 diabetes (mean difference, −76.6 ng/dL; 95% confidence interval [CI], −99.4 to −53.6) and higher in women with type 2 diabetes compared with controls (mean difference, 6.1 ng/dL; 95% CI, 2.3 to 10.1) (P 60 vs ≤60 nmol/L) had an 80% lower risk of type 2 diabetes (RR, 0.20; 95% CI, 0.12 to 0.30), while men with higher SHBG levels (>28.3 vs ≤28.3 nmol/L) had a 52% lower risk (RR, 0.48; 95% CI, 0.33 to 0.69). Estradiol levels were elevated among men and postmenopausal women with diabetes compared with controls (P = .007).ConclusionsThis systematic review indicates that endogenous sex hormones may differentially modulate glycemic status and risk of type 2 diabetes in men and women. High testosterone levels are associated with higher risk of type 2 diabetes in women but with lower risk in men; the inverse association of SHBG with risk was stronger in women than in men.

https://jamanetwork.com/journals/jama/articlepdf/202548/JRV60001.pdf

Sex Differences of Endogenous Sex Hormones and Risk of Type 2 Diabetes: A Systematic Review and Meta-analysis

Aging in men is accompanied by a progressive, but individually variable decline of serum testosterone production, more than 20% of healthy men over 60 yr of age presenting with serum levels below the range for young men. Albeit the clinical picture of aging in men is reminiscent of that of hypogonadism in young men and decreased testosterone production appears to play a role in part of these clinical changes in at least some elderly men, the clinical relevancy of the age-related decline in sex steroid levels in men has not been unequivocally established. In fact, minimal androgen requirements for elderly men remain poorly defined and are likely to vary between individuals. Consequently, borderline androgen deficiency cannot be reliably diagnosed in the elderly, and strict differentiation between “substitutive” and “pharmacological” androgen administration is not possible. To date, only a few hundred elderly men have received androgen therapy in the setting of a randomized, controlled study, and many of th...

https://www.hormonebalance.org/images/documents/Kauffman%2005%20TDS%20REVIEW%20ER.pdf

The decline of androgen levels in elderly men and its clinical and therapeutic implications.

Testosterone has immune-modulating properties, and current in vitro evidence suggests that testosterone may suppress the expression of the proinflammatory cytokines TNFalpha, IL-1beta, and IL-6 and potentiate the expression of the antiinflammatory cytokine IL-10. We report a randomized, single-blind, placebo-controlled, crossover study of testosterone replacement (Sustanon 100) vs. placebo in 27 men (age, 62 +/- 9 yr) with symptomatic androgen deficiency (total testosterone, 4.4 +/- 1.2 nmol/liter; bioavailable testosterone, 2.4 +/- 1.1 nmol/liter). Compared with placebo, testosterone induced reductions in TNFalpha (-3.1 +/- 8.3 vs. 1.3 +/- 5.2 pg/ml; P = 0.01) and IL-1beta (-0.14 +/- 0.32 vs. 0.18 +/- 0.55 pg/ml; P = 0.08) and an increase in IL-10 (0.33 +/- 1.8 vs. -1.1 +/- 3.0 pg/ml; P = 0.01); the reductions of TNFalpha and IL-1beta were positively correlated (r(S) = 0.588; P = 0.003). In addition, a significant reduction in total cholesterol was recorded with testosterone therapy (-0.25 +/- 0.4 vs. -0.004 +/- 0.4 mmol/liter; P = 0.04). In conclusion, testosterone replacement shifts the cytokine balance to a state of reduced inflammation and lowers total cholesterol. Twenty of these men had established coronary disease, and because total cholesterol is a cardiovascular risk factor, and proinflammatory cytokines mediate the development and complications associated with atheromatous plaque, these properties may have particular relevance in men with overt vascular disease.

https://www.hormonebalance.org/images/documents/Malkin%2004%20TRT%20Chol%20Immune%20JCEM.pdf

The Effect of Testosterone Replacement on Endogenous Inflammatory Cytokines and Lipid Profiles in Hypogonadal Men

Aims Chronic heart failure is associated with maladaptive and prolonged neurohormonal and pro-inflammatory cytokine activation causing a metabolic shift favouring catabolism, vasodilator incapacity, and loss of skeletal muscle bulk and function. In men, androgens are important determinants of anabolic function and physical strength and also possess anti-inflammatory and vasodilatory properties.

Methods and results We conducted a randomized, double-blind, placebo-controlled parallel trial of testosterone replacement therapy (5 mg Androderm®) at physiological doses in 76 men (mean±SD, age 64±9.9) with heart failure (ejection fraction 32.5±11%) over a maximum follow-up period of 12 months. The primary endpoint was functional capacity as assessed by the incremental shuttle walk test (ISWT). At baseline, 18 (24%) had serum testosterone below the normal range and bioavailable testosterone correlated with distance walked on the initial ISWT ( r =0.3, P =0.01). Exercise capacity significantly improved with testosterone therapy compared with placebo over the full study period (mean change +25±15 m) corresponding to a 15±11% improvement from baseline ( P =0.006 ANOVA). Symptoms improved by at least one functional class on testosterone in 13 (35%) vs. 3 (8%) on placebo ( P =0.01). No significant changes were found in handgrip strength, skeletal muscle bulk by cross-sectional computed tomography, or in tumour necrosis factor levels. Testosterone therapy was safe with no excess of adverse events although the patch preparation was not well tolerated by the study patients.

Conclusion Testosterone replacement therapy improves functional capacity and symptoms in men with moderately severe heart failure.

http://www.hormonebalance.org/images/documents/Malkin%2006%20Testosterone%20Rx%20CHF%20EHJ.pdf

Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial.

Type 2 diabetes mellitus is increasing globally and is an established risk factor for the development of atherosclerotic vascular disease. Insulin resistance is the hallmark feature of type 2 diabetes and is also an important component of the metabolic syndrome. There is evidence to suggest that testosterone is an important regulator of insulin sensitivity in men. Observational studies have shown that testosterone levels are low in men with diabetes, visceral obesity (which is strongly associated with insulin resistance), coronary artery disease and metabolic syndrome. Short-term interventional studies have also demonstrated that testosterone replacement therapy produces an improvement in insulin sensitivity in men. Thus hypotestosteronaemia may have a role in the pathogenesis of insulin-resistant states and androgen replacement therapy could be a potential treatment that could be offered for improvements in glycaemic control and reduction in cardiovascular risk, particularly in diabetic men.

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Androgens, insulin resistance and vascular disease in men

Background: Low serum testosterone is associated with several cardiovascular risk factors including dyslipidaemia, adverse clotting profiles, obesity, and insulin resistance. Testosterone has been reported to improve symptoms of angina and delay time to ischaemic threshold in unselected men with coronary disease. Objective: This randomised single blind placebo controlled crossover study compared testosterone replacement therapy (Sustanon 100) with placebo in 10 men with ischaemic heart disease and hypogonadism. Results: Baseline total testosterone and bioavailable testosterone were respectively 4.2 (0.5) nmol/l and 1.7 (0.4) nmol/l. After a month of testosterone, delta value analysis between testosterone and placebo phase showed that mean (SD) trough testosterone concentrations increased significantly by 4.8 (6.6) nmol/l (total testosterone) (p  =  0.05) and 3.8 (4.5) nmol/l (bioavailable testosterone) (p  =  0.025), time to 1 mm ST segment depression assessed by Bruce protocol exercise treadmill testing increased by 74 (54) seconds (p  =  0.002), and mood scores assessed with validated questionnaires all improved. Compared with placebo, testosterone therapy was also associated with a significant reduction of total cholesterol and serum tumour necrosis factor α with delta values of −0.41 (0.54) mmol/l (p  =  0.04) and −1.8 (2.4) pg/ml (p  =  0.05) respectively. Conclusion: Testosterone replacement therapy in hypogonadal men delays time to ischaemia, improves mood, and is associated with potentially beneficial reductions of total cholesterol and serum tumour necrosis factor α.

https://heart.bmj.com/content/heartjnl/90/8/871.full.pdf

Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life.

Background To examine the effect of serum testosterone levels on survival in a consecutive series of men with confirmed coronary disease and calculate the prevalence of testosterone deficiency. Design Longitudinal follow-up study. Setting Tertiary referral cardiothoracic centre. Patients 930 consecutive men with coronary disease referred for diagnostic angiography recruited between June 2000 and June 2002 and followed up for a mean of 6.962.1 years. Outcome All-cause mortality and vascular mortality. Prevalence of testosterone deficiency. Results The overall prevalence of biochemical testosterone deficiency in the coronary disease cohort using bio-available testosterone (bio-T) <2.6 nmol/l was 20.9%, using total testosterone <8.1 nmol/l was 16.9% and using either was 24%. Excess mortality was noted in the androgen-deficient group compared with normal (41 (21%) vs 88 (12%), p¼0.002). The only parameters found to influence time to all-cause and vascular mortality (HR 6 95% CI) in multivariate analyses were the presence of left ventricular dysfunction (3.85; 1.72 to 8.33), aspirin therapy (0.63; 0.38 to 1.0), b-blocker therapy (0.45; 0.31 to 0.67) and low serum bio-T (2.27; 1.45 to 3.6). Conclusions In patients with coronary disease testosterone deficiency is common and impacts significantly negatively on survival. Prospective trials of testosterone replacement are needed to assess the effect of treatment on survival.

https://heart.bmj.com/content/heartjnl/96/22/1821.full.pdf

Chris J. Malkin

Papers

The Effect of Testosterone Replacement on Endogenous Inflammatory Cytokines and Lipid Profiles in Hypogonadal Men

Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial.

Androgens, insulin resistance and vascular disease in men

Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life.

Low serum testosterone and increased mortality in men with coronary heart disease