Testosterone Deficiency Is a Risk Factor for Severe COVID-19.

Background: Male sex is related to increased COVID-19 severity and fatality although confirmed infections are similarly distributed between men and women. The aim of this retrospective analysis was to investigate the impact of sex hormones on disease progression and immune activation in men with COVID-19. Patients and Methods: We studied for effects of sex hormones on disease severity and immune activation in 377 patients (230 men, 147 women) with PCR-confirmed SARS-CoV-2 infections hospitalized at the Innsbruck University Hospital between February and December 2020. Results: Men had more severe COVID-19 with concomitant higher immune system activation upon hospital admission when compared to women. Men with a severe course of infection had lower serum total testosterone (tT) levels whereas luteinizing hormone (LH) and estradiol (E2) levels were within the normal range. tT deficiency was associated with elevated CRP (rs = - 0.567, p < 0.001), IL-6 levels (rs = - 0.563, p < 0.001), lower cholesterol levels (rs = 0.407, p < 0.001) and an increased morbidity and mortality. Men with tT levels < 100 ng/dL had a more than eighteen-fold higher in-hospital mortality risk (OR 18.243 [95%CI 2.301 - 144.639], p = 0.006) compared to men with tT levels > 230 ng/dL. Moreover, while morbidity and mortality showed a positive correlation with E2 levels at admission, we detected a negative correlation with the tT/E2 ratio upon hospital admission. Conclusion: Hospitalized men with COVID-19 present with rather low testosterone levels linked to more advanced immune activation, severe clinical manifestations translating into an increased risk for ICU admission or death. The underlying mechanisms remain elusive but may include infection driven hypogonadism as well as inflammation mediated cholesterol reduction causing gonadotropin suppression and impaired androgen formation. Finally, in elderly late onset hypogonadism might also contribute to lower testosterone levels.

Male-Specific Metabolic Considerations Concerning the Prescription of Second-Generation Antipsychotics to Adolescents.

Objectives: Although males and females gain comparable weight when prescribed second-generation antipsychotics (SGAs), males may be uniquely vulnerable to an array of endocrinological, inflammatory, and psychosocial adverse drug effects. Methods: This opinion piece reviews work in each of these three areas for consideration. Results: Androgens may decrease both through hypothalamic-pituitary-gonadal axis dysregulation and as a consequence of increased adiposity. Testosterone has anti-inflammatory properties, and declining levels as well as many other factors may influence overall immunological functioning. Psychosocial stressors are gender specific in obesity, and SGA-induced obesity may affect males in unique and severe ways. Conclusion: This opinion piece supports the framework of the World Federation of Societies of Biological Psychiatry's Task Force on Men's Mental Health to advocate for further studies concerning the adverse drug effects of SGAs as unique manifested in male children, adolescents, and young men.

Level of sex hormones and their association with acetylsalicylic acid intolerance and nasal polyposis.

BACKGROUND: Chronic rhinosinusitis may be associated with nasal polyposis. Recurrence of disease is often observed and may be due to an intolerance of acetylsalicylic acid. Sex hormones are known to modulate allergic reactions and inflammation. Whether they may be involved in the development and progression of nasal polyposis has not been investigated yet. AIM: Examine the relationship between levels of sex hormones and nasal polyposis. METHODS: Hormonal levels (estradiol, testosterone and progesterone) in patients with nasal polyposis (n = 26) with or without acetylsalicylic acid-intolerance were determined and compared to hormonal levels in patients with septal deviation (n = 35). Cone-beam computed tomography scans were analysed by using scores as defined by Lund and Mackay and by Kennedy. RESULTS: Our results show a 5 times greater odds (p = 0.01) for developing nasal polyposis in the presence of lowered estradiol plasma levels than in the presence of normal / elevated levels. When analyzing females and males separately, a 6 times greater odds for females to develop nasal polyposis in the presence of lowered estradiol plasma levels was calculated (p = 0.02). Thus, females are more likely to develop nasal polyposis when they have lowered estradiol levels than males. In addition, female patients showed an increased risk for developing ASA intolerance (p = 0.01). CONCLUSION: Variation of sex hormones may be involved in nasal polyposis. Further studies including more patients to validate the presented results are required. SIGNIFICANCE: Retrospective clinical investigation suggesting a correlation between varying sex hormones and nasal polyposis.

Sex hormones and COVID-19: tussle between the two.

Novel coronavirus disease (COVID-19) has affected nearly 7 million individuals and claimed more than 0.4 million lives to date. There are several reports of gender differences related to infection and death due to COVID-19. This raises important questions such as "Whether there are differences based on gender in risk and severity of infection or mortality rate?" and "What are the biological explanation and mechanisms underlying these differences?" Emerging evidences have proposed sex-based immunological, genetic, and hormonal differences to explain this ambiguity. Besides biological differences, women have also faced social inequities and economic hardships due to this pandemic. Several recent studies have shown that independent of age males are at higher risk for severity and mortality in COVID-19 patients. Although susceptibility to SARS-CoV-2 was found to be similar across both genders in several disease cohorts, a disproportionate death ratio in men can be partly explained by the higher burden of pre-existing diseases and occupational exposures among men. At immunological point of view, females can engage a more active immune response, which may protect them and counter infectious diseases as compared to men. This attribute of better immune responses towards pathogens is thought to be due to high estrogen levels in females. Here we review the current knowledge about sex differences in susceptibility, the severity of infection and mortality, host immune responses, and the role of sex hormones in COVID-19 disease.

Age-associated decline in neural, endocrine, and immune responses in men and women: Involvement of intracellular signaling pathways.

The aim of this study was to investigate the alterations in the neuroendocrine-immune functions by using human peripheral blood mononuclear cells (hPBMCs) from three age groups (young, middle-aged, and old) of men and women for the analyses of lymphocyte proliferation and cytokine production, expression of cell signaling molecules, nitric oxide (NO) production, and expression of p-tyrosine hydroxylase (TH). Serum was examined for levels of testosterone in men, 17-ß-estradiol in women, and cortisol in both sexes. Lymphoproliferation, expression of p-ERK, p-CREB, p-Akt, and p-TH, and levels of serum sex steroid hormones declined with age in men and women. However, TNF-α production and serum cortisol level increased with age in men and women. mTOR expression was higher in older men while it was lower in older women. IFN-γ and IL-6 production and expression of p-TH and p-mTOR were differentially regulated in men and women. These results suggest that intracellular signaling mediators may be involved in the age-related alterations in the neuroendocrine-immune interactions in men and women.

Testosterone, cortisol, and secretory immunoglobulin-A within a single day and across two sequential days among trans- and cis-gender men.

BACKGROUND: Previous research on the association between testosterone (T) and immunity has produced conflicting results. OBJECTIVES: We address two potential reasons for these empirical inconsistencies in the present research. First, the association between T and immunity may depend on which branch of the immune system is considered. Here, we examine secretory IgA (sIgA), a measure of mucosal immunity functionally related to respiratory infection risk. Second, the association between T and immunity may depend on a third regulatory variable. Therefore, we examine the interaction between T and cortisol (CORT) as well as their independent and combined effects on mucosal immunity. To do this, we explore intra-individual associations between sIgA, CORT, and T within a single day (i.e., morning vs. evening) and across 2 sequential mornings. We target two samples of men: (1) cisgender (i.e., born and identifying as men), and (2) transgender (i.e., born female but identifying as men) undergoing T therapy for gender realignment. MATERIALS AND METHODS: One hundred and forty-eight adult men (transgender n = 29) provided saliva samples at three time points: (1) upon waking, (2) before sleep on the same day, and (3) upon waking the following day. Samples were assayed in duplicate for sIgA, T and CORT. RESULTS: For cisgender men, sIgA, T, and CORT exhibited clear circadian rhythms and were significantly related within and between samples. For transgender men, evidence for circadian change was found for sIgA and CORT, but not T. Further, sIgA was associated with CORT, but not T. DISCUSSION AND CONCLUSIONS: This study provides the first evidence that salivary T and sIgA concentrations are associated within a single day and across sequential days for cisgender men. Differences between cis- and transgender men suggest that this may only be true for T levels driven by endogenous production; however, future studies should employ a larger sample size.

Loss of testosterone impairs anti-tumor neutrophil function.

In men, the incidence of melanoma rises rapidly after age 50, and nearly two thirds of melanoma deaths are male. The immune system is known to play a key role in controlling the growth and spread of malignancies, but whether age- and sex-dependent changes in immune cell function account for this effect remains unknown. Here, we show that in castrated male mice, neutrophil maturation and function are impaired, leading to elevated metastatic burden in two models of melanoma. Replacement of testosterone effectively normalized the tumor burden in castrated male mice. Further, the aberrant neutrophil phenotype was also observed in prostate cancer patients receiving androgen deprivation therapy, highlighting the evolutionary conservation and clinical relevance of the phenotype. Taken together, these results provide a better understanding of the role of androgen signaling in neutrophil function and the impact of this biology on immune control of malignancies.

Sexual Dimorphism in Innate Immunity.

Sexual dimorphisms account for differences in clinical manifestations or incidence of infectious or autoimmune diseases and malignancy between females and males. Females develop enhanced innate and adaptive immune responses than males and are less susceptible to many infections of bacterial, viral, parasitic, and fungal origin and malignancies but in contrast, they are more prone to develop autoimmune diseases. The higher susceptibility to infections in males is observed from birth to adulthood, suggesting that sex chromosomes and not sex hormones have a major role in sexual dimorphism in innate immunity. Sex-based regulation of immune responses ultimately contributes to age-related disease development and life expectancy. Differences between males and females have been described in the expression of pattern recognition receptors of the innate immune response and in the functional responses of phagocytes and antigen presenting cells. Different factors have been shown to account for the sex-based disparity in immune responses, including genetic factors and hormonal mediators, which contribute independently to dimorphism in the innate immune response. For instance, several genes encoding for innate immune molecules are located on the X chromosome. In addition, estrogen and/or testosterone have been reported to modulate the differentiation, maturation, lifespan, and effector functions of innate immune cells, including neutrophils, macrophages, natural killer cells, and dendritic cells. In this review, we will focus on differences between males and females in innate immunity, which represents the first line of defense against pathogens and plays a fundamental role in the activation, regulation, and orientation of the adaptive immune response.

Immune-endocrine responses and physical performance of master athletes during the sports season.

The purpose of this study was to investigate the impact of a training season (approximately 7 months) on physiological and salivary immune-endocrine markers in master athletes. Nine male master athletes were evaluated at the beginning of the season (M1) and a week after the main official competition at the end of the sports season (M2). The controlled variables included Maximal oxygen consumption, anthropometric, physiological, and salivary immune-endocrine markers. Master athletes presented a reduced percentage of fat mass and increased lean body mass at the end of the season. VO2max values were similar at M1 and M2, while the maximal heart rate and lactate were lower at M2. No differences were observed in Immunoglobulin A and cortisol levels between moments, whereas testosterone levels and the testosterone/cortisol ratio were significantly lower at the end of the season. The results suggest that maintaining regular training throughout life has positive effects on body composition and improves physiological fitness. However, care should be taken to avoid fatigue as indicated by lower testosterone levels at the end of the season.

Competitive light-initiated chemiluminescent assay: using 5-α-dihydrotestosterone-BSA as competitive antigen for quantitation of total testosterone in human sera.

This paper described a homogeneous method, light-initiated chemiluminescent assay (LICA), for quantitation of total testosterone in human sera. The assay was bead based and built on a competitive-binding reaction format, in which 5-α-dihydrotestosterone (5-α-DHT) competed with the testosterone in serum samples in binding with biotinylated anti-testosterone antibody. The more testosterone in the serum sample, the less 5-α-DHT that bonded with biotinylated anti-testosterone antibodies. 5-α-DHT was coupled with emission beads (doped with thioxene derivatives and Eu(III) as a chemiluminescence emitter) via bovine serum albumin as a linker. Once streptavidin-coated sensitizer beads (modified with phthalocyanine as a photosensitizer) were added, the streptavidin/biotin reaction between 5-α-DHT-bound anti-testosterone antibody and sensitizer beads could bring emission and sensitizer beads together, which allowed energy transfer from sensitizer bead to emission bead. As such, an exciting light (680 nm) impinging on the sensitizer beads led to light emission at 520-620 nm by emission beads. The strength of the emitted light was inversely proportional to the testosterone in serum sample. The detection range of this assay was from 13.3 to 1200 ng/dL. The coefficient variation for intra- and inter-assay was lower than 15%. The recovery of this method ranged from 95.5 to 105.9% for different samples. Moreover, the LICA assay was highly specific with low cross-reactivity and interference. The concentration of testosterone from 58 serum samples analyzed by the LICA method significantly correlated (y = 0.97x + 1.87, R2 = 0.970, p < 0.001) with those obtained with the SIEMENS Centaur Xp System. Graphical abstract ᅟ.

Negative correlation between testosterone and TNF-α in umbilical cord serum favors a weakened immune milieu in the human male fetoplacental unit.

Clinical and epidemiological evidence supports that pregnancies carrying a male fetus are more vulnerable to infections and preterm birth, probably due to testosterone immunosuppressive properties. In human placentas, testosterone lowers the expression of CYP27B1, the vitamin D (VD)-activating enzyme, diminishing cathelicidin synthesis, a potent VD-dependent antimicrobial peptide (AMP). VD also stimulates other AMPs, including defensins. To get insights into the increased male vulnerability mechanisms, we investigated the relationship between fetal sex and the immunoendocrine milieu at the fetoplacental unit. For this, umbilical vein serum and placental samples were collected from healthy newborns. In males' serum, testosterone levels were significantly higher and negatively associated with TNF-α, a cytokine that strengthens the immune response. Males showed lower serum TNF-α and increased levels and gene expression of the immunosuppressive cytokine IL-10. Only in female samples there was a positive association (P < 0.05) between AMPs and both TNF-α and CYP27B1 and between 25-hydroxyvitamin D3 and IL-1ß serum levels. Accordingly, VD-metabolites (25-hydroxyvitamin D3, calcitriol) significantly stimulated IL-1ß gene expression in cultured trophoblasts. Interestingly, IL-1ß mRNA correlated positively with defensins (P < 0.05) in males, but not with cathelicidin expression, which was significantly diminished in comparison to females. Our data suggest that high umbilical serum testosterone and IL-10 in males could explain reduced TNF-α levels and lack of association between VD-dependent innate immunity markers and proinflammatory cytokines expression in the fetoplacental unit. Altogether, our observations imply a restricted basal immune milieu in males compared to females, which may help understand the higher male susceptibility to adverse perinatal outcomes.

Testosterone is an endogenous regulator of BAFF and splenic B cell number.

Testosterone deficiency in men is associated with increased risk for autoimmunity and increased B cell numbers through unknown mechanisms. Here we show that testosterone regulates the cytokine BAFF, an essential survival factor for B cells. Male mice lacking the androgen receptor have increased splenic B cell numbers, serum BAFF levels and splenic Baff mRNA. Testosterone deficiency by castration causes expansion of BAFF-producing fibroblastic reticular cells (FRCs) in spleen, which may be coupled to lower splenic noradrenaline levels in castrated males, as an α-adrenergic agonist decreases splenic FRC number in vitro. Antibody-mediated blockade of the BAFF receptor or treatment with the neurotoxin 6-hydroxydopamine revert the increased splenic B cell numbers induced by castration. Among healthy men, serum BAFF levels are higher in men with low testosterone. Our study uncovers a previously unrecognized regulation of BAFF by testosterone and raises important questions about BAFF in testosterone-mediated protection against autoimmunity.

Testicular macrophages: Guardians of fertility.

Macrophages are innate immune cells present in essentially every organ of the body with dedicated tissue specific functions. We will present in this review the unique properties and functions of macrophage populations residing in the testis, an immune-privileged organ. Testicular macrophages (tMΦ) could be seen as guardians of fertility due to their immunosuppressive functions protecting spermatogenesis from auto immune-attack. They exhibit testis specific functions with essential roles in normal testis homeostasis and fetal testicular development. Recently, two distinct testicular macrophage populations have been characterized based on different localization, morphology, gene expression profiles, developmental origin and postnatal development. We will discuss the importance of these two testicular macrophage populations for organ specific functions such as testosterone production and spermatogenesis, as well as their role in establishing immuno-privilege highlighting the contributions of macrophages to male fertility.

Testosterone-like immunoreactivity in hair measured in minute sample amounts - a competitive radioimmunoassay with an adequate limit of detection.

The concentrations of testosterone deposited in hair during hair growth may provide a retrospective reflection of the concentrations of bioactive testosterone in plasma. The objective of this study was to develop a radioimmunoassay with a sufficiently low limit of detection to measure the testosterone-like immunoreactivity in smaller hair samples (5 mg) than used in earlier studies, and to compare three different extraction procedures. The competitive radioimmunoassay consisted of a polyclonal antiserum (immunogen testosterone-7α-BSA) and a radioligand synthesised from testosterone-3-CMO-histamine. The within-assay and total coefficients of variation in the working range was 3% and 4.5%, respectively. The limit of detection was 0.87 pg/mL, which is equivalent to 0.12 pg/mg testosterone in 5 mg of hair. The concentration of testosterone-like immunoreactivity in hair samples was 1.23 (SD 0.47) pg/mg in women and 2.67 (SD 0.58) pg/mg in men (pulverised hair). Significantly improved precision was found when pulverised hair was used compared to non-pulverised hair. Our data indicate that pulverisation of the hair prior to hormone extraction is crucial. Detection limits fit for the intended purpose are achievable with 5 mg samples of hair.

Dihydrotestosterone levels at birth associate positively with higher proportions of circulating immature/naïve CD5+ B cells in boys.

Boys present with higher proportions of immature/naïve CD5+ B cells than girls up to 3 years of age. Boys also have higher fractions of regulatory T cells (Tregs) in early infancy, but the mechanisms for these sex-related differences are unknown. In the prospective FARMFLORA follow-up study of 23 boys and 25 girls, we investigated if these immunological differences remained at 8 years of age. We also examined if testosterone or dihydrotestosterone (DHT) levels at birth and at 8 years of age were associated with immune maturation. Immunological variables and androgen levels were examined and measured in blood samples obtained at birth, 3-5 days and at 8 years of age. Boys had higher proportions of CD5+ and immature/transitional CD24hiCD38hi B cells, whereas girls had higher fractions of B cells with a memory phenotype at 8 years of age. School-aged boys also presented with higher frequencies of Tregs, and a greater capacity to produce T-cell-associated cytokines. Among boys, higher cord blood DHT levels were associated with higher proportions of CD5+ B cells in early infancy and at 8 years of life. These results suggest that DHT actions in utero might be involved in the mechanism for delayed peripheral B-cell maturation in boys.

Immune Response to Native Lipoproteins Induces Visceral Obesity and Aortic Wall Injury in Rats: The Role of Testosterone.

OBJECTIVES: The underlying mechanism of atherosclerosis and visceral obesity remains unknown.The purpose of this study was to test the hypothesis that atherosclerosis and visceral obesity are caused by an immune response to native plasma lipoproteins, and the atherogenic and adipogenic effects of the antibodies to native lipoproteins stem from the androgen deficiency that is created. METHODS: Wistar rats were immunized with native human (nh) low-density (LDL) or high-density lipoproteins (HDL). Visceral fat, aortic wall structure, and testosterone levels were studied. RESULTS: Immunization with nhLDL or nhHDL induced in rats increased visceral abdominal fat and perivascular adipose tissue volume, the appearance of epicardial fat, and atherosclerosis-like changes in the aortic wall: accumulation of leucocytes, destruction of the intima, and disruption of the media structure. Immunized rats produced antibodies to native plasma lipoproteins, while there was no difference between immunized and adjuvant-injected rats with regard to the level of antibodies to oxidized LDL. The immune response to nhHDL caused testosterone disturbances, but it is not associated with visceral obesity and atherosclerosis. CONCLUSION: The immune response to native lipoproteins is atherogenic and adipogenic and testosterone is not involved in the atherogenic and adipogenic effects of antibodies to lipoproteins.

Androgen regulation of host defenses and response to inflammatory stimuli in the prostate gland.

The prostate gland is a strictly androgen-dependent organ which is also the main target of infectious and inflammatory diseases in the male reproductive tract. Host defenses and immunity of the gland have unique features to maintain a constant balance between response and tolerance to diverse antigens. In this context, the effects of reproductive hormones on the male tract are thus complex and have just started to be defined. From the classical description of "the prostatic antibacterial factor," many host defense proteins with potent microbicidal and anti-tumoral activities have been described in the organ. Indeed, it has been proposed a central role for resident cells, that is, epithelial and smooth muscle cells, in the prostatic response against injuries. However, these cells also represent the target of the inflammatory damage, leading to the development of a Proliferative Inflammatory Atrophy-like process in the epithelium and a myofibroblastic-like reactive stroma. Available data on androgen regulation of inflammation led to a model of the complex control, in which the final effect will depend on the tissue microenvironment, the cause of inflammation, and the levels of androgens among other factors. In this paper, we review the current scientific literature about the inflammatory process in the gland, the modulation of host defense proteins, and the influence of testosterone on the resolution of prostatitis.

A computational approach for studying antibody-antigen interactions without prior structural information: the anti-testosterone binding antibody as a case study.

Given the increasing exploitation of antibodies in different contexts such as molecular diagnostics and therapeutics, it would be beneficial to unravel the atomistic level properties of antibody-antigen complexes with the help of computational modeling. Thus, here we have studied the feasibility of computational tools to gather atomic scale information regarding the antibody-antigen complexes solely starting from an amino acid sequence. First, we constructed a homology model for the anti-testosterone binding antibody based on the knowledge based classification of complementary determining regions (CDRs) and implicit solvent molecular dynamics simulations. To further examine whether the generated homology model is suitable for studying antibody-antigen interactions, docking calculations were carried out followed by binding free-energy simulations. Our results indicate that with the antibody modeling approach presented here it is possible to construct accurate homology models for antibodies which correctly describes the antibody-antigen interactions, and produces absolute binding free-energies that are comparable with experimental values. In addition, our simulations suggest that the conformations of complementary determining regions (CDRs) may considerably change from the X-ray configuration upon solvation. In conclusion, here we have introduced an antibody modeling workflow that can be used in studying the interactions between antibody and antigen solely based on an amino acid sequence, which in turn provides novel opportunities to tune the properties of antibodies in different applications. Proteins 2017; 85:322-331. © 2016 Wiley Periodicals, Inc.

Identification of serum protein markers for early diagnosis of pregnancy in buffalo.

Improper or delayed pregnancy diagnosis has significant impact over animal production, particularly in buffaloes which inherently suffer from several reproductive inefficiencies. Thus the present study has undertaken to identify serum protein markers pertaining to early pregnancy diagnosis in buffaloes. Serum samples were collected from 10 pregnant Murrah Buffalo heifers at weekly intervals from days 0-35 post-artificial insemination and from 12 inseminated non-pregnant cyclic buffalo heifers on days 0, 7, 14 and 21. Two-dimensional gel electrophoresis and densitometric analysis revealed the presence of five protein spots showing average density fold change of ≥4 during early pregnancy. Mass spectrometry analysis identified these up-regulated proteins as anti-testosterone antibody light chain, apolipoprotein A-II precursor, serum amyloid A, cytokeratin type II, component IV isoform 1, which are have established roles in embryogenesis, but over-expression of the fifth identified protein immunoglobulin lambda light chain in pregnancy has been elucidated as a novel finding in the current study. Further, with bioinformatics analysis, potential antigenic B-cell epitopes were predicted for all these five proteins. An antibody cocktail-based approach involving antibodies against all these five up-regulated entire proteins or their epitopes could be developed for early detection of pregnancy in buffaloes. © 2016 Japanese Society of Animal Science.

Associations between male testosterone and immune function in a pathogenically stressed forager-horticultural population.

OBJECTIVES: Despite well-known fitness advantages to males who produce and maintain high endogenous testosterone levels, such phenotypes may be costly if testosterone-mediated investment in reproductive effort trade-off against investment in somatic maintenance. Previous studies of androgen-mediated trade-offs in human immune function find mixed results, in part because most studies either focus on a few indicators of immunity, are confounded by phenotypic correlation, or are observational. Here the association between male endogenous testosterone and 13 circulating cytokines are examined before and after ex vivo antigen stimulation with phytohemagglutinin (PHA) and lipopolysaccharides (LPS) in a high pathogen population of Bolivian forager-horticulturalists. MATERIALS AND METHODS: A Milliplex 13-plex cytokine panel measured cytokine concentration in whole blood samples from 109 Tsimane men aged 40-89 (median = 50 years) before and after antigen stimulation with PHA and LPS. Urinary testosterone was measured via enzyme immunoassay, demographic, and anthropometric data were collected as part of the Tsimane Health and Life History Project. RESULTS: Higher endogenous testosterone was associated with down-regulated responses in all cytokines after PHA stimulation (but significantly in only 2/13 cytokines), controlling for age and body mass index. In contrast, testosterone was not significantly associated with down-regulation of cytokines after LPS stimulation. MANOVAs indicate that men with higher testosterone showed reduced cytokine responses to PHA compared with LPS (p = 0.0098). DISCUSSION: Endogenous testosterone appears to be immunomodulatory rather than immunosuppressive. Potentially costlier forms of immune activation like those induced by PHA (largely T-cell biased immune activation) are down-regulated in men with higher testosterone, but testosterone has less impact on potentially less costly immune activation following LPS stimulation (largely B-cell mediated immunity).