Practice and development of male contraception: European Academy of Andrology and American Society of Andrology guidelines.

BACKGROUNDS: Despite a wide spectrum of contraceptive methods for women, the unintended pregnancy rate remains high (45% in the US), with 50% resulting in abortion. Currently, 20% of global contraceptive use is male-directed, with a wide variation among countries due to limited availability and lack of efficacy. Worldwide studies indicate that >50% of men would opt to use a reversible method, and 90% of women would rely on their partner to use a contraceptive. Additional reasons for novel male contraceptive methods to be available include the increased life expectancy, sharing the reproductive risks among partners, social issues, the lack of pharma industry involvement and the lack of opinion makers advocating for male contraception. AIM: The present guidelines aim to review the status regarding male contraception, the current state of the art to support the clinical practice, recommend minimal requirements for new male contraceptive development and provide and grade updated, evidence-based recommendations from the European Society of Andrology (EAA) and the American Society of Andrology (ASA). METHODS: An expert panel of academicians appointed by the EAA and the ASA generated a consensus guideline according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. RESULTS: Sixty evidence-based and graded recommendations were produced on couple-centered communication, behaviors, barrier methods, semen analysis and contraceptive efficacy, physical agents, surgical methods, actions before initiating male contraception, hormonal methods, non-hormonal methods, vaccines, and social and ethical considerations. CONCLUSION: As gender roles transform and gender equity is established in relationships, the male contribution to family planning must be facilitated. Efficient and safe male-directed methods must be evaluated and introduced into clinical practice, preferably reversible, either hormonal or non-hormonal. From a future perspective, identifying new hormonal combinations, suitable testicular targets, and emerging vas occlusion methods will produce novel molecules and products for male contraception.

Design of an international male contraceptive efficacy trial using a self-administered daily transdermal gel containing testosterone and segesterone acetate (Nestorone).

Injectable male hormonal contraceptives are effective for preventing pregnancy in clinical trials; however, users may prefer to avoid medical appointments and injections. A self-administered transdermal contraceptive gel may be more acceptable for long-term contraception. Transdermal testosterone gels are widely used to treat hypogonadism and transdermal administration may have utility for male contraception; however, no efficacy data from transdermal male hormonal contraceptive gel are available. We designed and are currently conducting an international, multicenter, open-label study of self-administration of a daily combined testosterone and segesterone acetate (Nestorone) gel for male contraception. The transdermal approach to male contraception raises novel considerations regarding adherence with the daily gel, as well as concern about the potential transfer of the gel and the contraceptive hormones to the female partner. Enrolled couples are in committed relationships. Male partners have baseline normal spermatogenesis and are in good health; female partners are regularly menstruating and at risk for unintended pregnancy. The study's primary outcome is the rate of pregnancy in couples during the study's 52-week efficacy phase. Secondary endpoints include the proportion of male participants suppressing sperm production and entering the efficacy phase, side effects, hormone concentrations in male participants and their female partners, sexual function, and regimen acceptability. Enrollment concluded on November 1, 2022, with 462 couples and enrollment is now closed. This report outlines the strategy and design of the first study to examine the contraceptive efficacy of a self-administered male hormonal contraceptive gel. The results will be presented in future reports. IMPLICATIONS: The development of a safe, effective, reversible male contraceptive would improve contraceptive options and may decrease rates of unintended pregnancy. This manuscript outlines the study design and analysis plan for an ongoing large international trial of a novel transdermal hormone gel for male contraception. Successful completion of this and future studies of this formulation may lead to the approval of a male contraceptive.

Latent tuberculosis is associated with heightened levels of pro-and anti-inflammatory cytokines among Kenyan men and women living with HIV on long-term antiretroviral therapy.

BACKGROUND: Persons with HIV (PWH) on antiretroviral therapy (ART) have persistent immune activation associated with increased risk for non-AIDS related diseases. Latent tuberculosis infection (LTBI), endemic in Africa, may contribute to this immune dysregulation. We evaluated the impact of HIV and TB co-infection on plasma pro- and anti-inflammatory cytokines among Kenyan adults. METHODS: We compared data from 221 PWH on long-term ART and 177 HIV-negative adults examining biomarkers of pro-[sCD14, interleukin (IL)-2, IL-6, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), IL-12p70, IL-17A] and anti(IL-4, IL-5, IL-13) inflammatory cytokines, by HIV/LTBI status (HIV+LTBI+, HIV+LTBI-, HIV-LTBI+, HIV-LTBI-). LTBI was diagnosed based on a positive QuantiFERON TB Gold-Plus test in the absence of active TB symptoms. Linear regression was used to evaluate the associations of HIV, LTBI, and HIV/LTBI status with biomarkers adjusting for clinical factors including HIV-specific factors. RESULTS: Half of the participants were women and 52% had LTBI. HIV was independently associated with higher sCD14, IL-15, IL-6, IL-4, IL-5. LTBI was independently associated with higher TNF-α, IL-12p70, IL-17A, IL-4, IL-13 in adjusted models ( P  < 0.05). LTBI status was associated with higher IL-4 and IL-12p70 only among PWH, but not HIV-negative participants ( P  < 0.05 for interactions). In multivariate analysis, only HIV+LTBI+ demonstrated elevated levels of TNF-α, IL-6, IL-12p70, IL-15, IL-17A, IL4, IL-5, IL-13 in comparison to the HIV-LTBI- ( P  < 0.05 for all). The effect of LTBI on cytokines among PWH was independent of CD4 + T-cell count and ART duration. CONCLUSIONS: Despite viral suppression, persons with HIV and LTBI exhibit abnormal cytokine production accompanied by high concentrations of pro- and anti-inflammatory cytokines.

Association of HIV, cardiovascular risk factors, and carotid intimal media thickness: A cross-sectional study in Western Kenya.

The carotid intimal media thickness (CIMT) is a validated measure of subclinical atherosclerosis. Human immunodeficiency virus (HIV) is a risk factor for cardiovascular disease (CVD) and has been associated with CIMT in North America and Europe; however, there are limited data from Sub-Saharan Africa (SSA). In this cross-sectional study, we measured CIMT in a cohort of 262 people living with HIV (PLHIV) on antiretroviral therapy (ART) for ≥6 months and HIV-negative adults in western Kenya. Using linear regression, we examined the associations between CVD risk factors and CIMT, both overall and stratified according to the HIV status. Among the PLHIV, we examined the association between CIMT and HIV-related factors. Of 262 participants, approximately half were women. The HIV-negative group had a higher prevalence of age ≥55 years (P = .002), previously diagnosed hypertension (P = .02), treatment for hypertension (P = .03), and elevated blood pressure (BP) (P = .01). Overall prevalence of carotid plaques was low (15/262 [6.0%]). HIV-positive status was not significantly associated with a greater mean CIMT (P = .19). In multivariable regression models, PLHIV with elevated blood pressure or treatment for hypertension had a greater mean CIMT (P = .002). However, the CD4 count, viral load, and ART regimen were not associated with differences in CIMT. In the HIV-negative group, older age (P = .006), high total cholesterol levels (P = .01), and diabetes (P = .02) were associated with a greater mean CIMT. In this cross-sectional study of Kenyan adults, traditional CVD risk factors were found to be more prevalent among HIV-negative participants. After multivariable regression analysis, we found no association between HIV status and CIMT, and PLHIV had fewer CVD risk factors associated with CIMT than HIV-negative participants did. HIV-specific factors were not associated with the CIMT.

The world needs better male contraceptives: What is taking so long?

Forty percent of US pregnancies are unintended despite currently available contraceptives. A substantial number of men use the currently available methods of male contraception, condoms and vasectomy, and a large majority would be interested in novel forms of male contraception if available. Research into male contraception has been ongoing for more than 50 years, with hormonal contraceptives nearing clinical utility and non-hormonal methods hopefully becoming available, albeit with a longer time frame. However, uncertainly regarding benchmarks for the efficacy and safety of male contraception continue to be an issue with development and regulatory approval. In addition, pharmaceutical industry support is minimal with the NIH and Foundations being the main research funders. Given the continuing high rates of unintended pregnancy, many of which are now occurring in areas with extremely restricted access to legal abortion, additional focus and investment in male contraceptive development is imperative.

Effect of Selective Androgen Receptor Modulator on Cholesterol Efflux Capacity, Size, and Subspecies of HDL Particles.

Context: Selective androgen receptor modulators (SARMs), because of their preferential muscle vs prostate selectivity, are being developed for muscle-wasting conditions. Oral SARMs suppress high-density lipoprotein cholesterol (HDL-C) but their effects on functional capacity and atherogenic potential of HDL particles are unknown. Objective: To determine the effects of an oral SARM (OPK-88004) on cholesterol efflux capacity, HDL particle number and size, apolipoprotein particle number and size and HDL subspecies. Methods: We measured cholesterol efflux capacity (CEC); HDL particle number and size; APOB; APOA1; and protein-defined HDL subspecies associated with coronary heart disease (CHD) risk in men, who had undergone prostatectomy for low-grade prostate cancer during 12-week treatment with placebo or 1, 5, or 15 mg of an oral SARM (OPK-88004). Results: SARM significantly suppressed HDL-C (P < .001) but HDL particle size did not change significantly. SARM had minimal effect on CEC of HDL particles (change + 0.016, -0.036, +0.070, and -0.048%/µmol-HDL/L-1 at 0, 1, 5, and 15 mg SARM, P = .045). SARM treatment suppressed APOAI (P < .001) but not APOB (P = .077), and reduced APOA1 in HDL subspecies associated with increased (subspecies containing α2-macroglobulin, complement C3, or plasminogen) as well as decreased (subspecies containing APOC1 or APOE) CHD risk; relative proportions of APOA1 in these HDL subspecies did not change. SARM increased hepatic triacylglycerol lipase (HTGL) (P < .001). Conclusion: SARM treatment suppressed HDL-C but had minimal effect on its size or cholesterol efflux function. SARM reduced APOA1 in HDL subspecies associated with increased as well as decreased CHD risk. SARM-induced increase in HTGL could contribute to HDL-C suppression. These data do not support the simplistic notion that SARM-associated suppression of HDL-C is necessarily proatherogenic; randomized trials are needed to determine SARM's effects on cardiovascular events.

Hormonal Male Contraception: Getting to Market.

Rates of unplanned pregnancies are high and stagnant globally, burdening women, families and the environment. Local limitations placed upon contraceptive access and abortion services exacerbate global disparities for women. Despite survey data suggesting men and their partners are eager for expanded male contraceptive options, efforts to develop such agents have been stymied by a paucity of monetary investment. Modern male hormonal contraception, like female hormonal methods, relies upon exogenous progestins to suppress the hypothalamic-pituitary-gonadal axis, in turn suppressing testicular testosterone production and sperm maturation. Addition of an androgen augments gonadotropin suppression, more effectively suppressing spermatogenesis in men, and provides androgenic support for male physiology. Previous contraceptive efficacy studies in couples have shown that hormonal male methods are effective and reversible. Recent efforts have been directed at addressing potential user and regulatory concerns by utilizing novel steroids and varied routes of hormone delivery. Provision of effective contraceptive options for men and women is an urgent public health need. Recognizing and addressing the gaps in our contraceptive options and engaging men in family planning will help reduce rates of unplanned pregnancies in the coming decades.

Male contraception is coming: Who do men want to prescribe their birth control?

OBJECTIVE: To assess men's preferences for healthcare provider from whom they would obtain hormonal male contraceptive (HMC) methods. STUDY DESIGN: We asked participants from 3 clinical trials of investigational HMC methods-an oral pill (11ß-Methyl-19-nortestosterone-17ß-dodecylcarbonate, 11ß-MNTDC), intramuscular or subcutaneous injection (Dimethandrolone undecanoate), and transdermal gel (Nestorone and testosterone)-to rank their top 3 preferred HMC providers from a list including: men's health doctor (urologist/andrologist), hormonal doctor (endocrinologist), reproductive health doctor (OB/GYN), family planning clinician (community health worker, midwife, nurse practitioner), regular doctor (family medicine/internal medicine), and community pharmacist. We examined preferences based on their rankings and conducted bivariate analyses. Collapsing the various specialists (men's health doctor, hormonal doctor, reproductive health doctor, and family planning clinician) into a single provider type, we examined participant demographics against provider preference (regular doctor, pharmacist, or specialist). RESULTS: Participants across the 3 trials (n = 124) ranked their regular doctor (44%) and community pharmacist (18%) as their most preferred HMC provider; these preferences did not differ significantly by trial and drug formulation. Specialists in family planning (13%), men's health (12%), reproductive health (10%), and hormones (4%) were least frequently ranked as their preferred provider. Older and higher educated participants more often preferred specialists over regular doctors and pharmacists (p = 0.02 and p = 0.01). CONCLUSIONS: Despite receiving contraceptive steroid hormones and care from endocrinologists and family planning specialists in a clinical trial, participants would prefer to obtain contraception from their regular doctor. IMPLICATIONS: As most men expect to obtain hormonal male contraceptives from their regular doctor when commercially available, primary care physicians should become familiar with HMCs and be prepared to provide counseling and options accordingly.

Androgens in male contraception.

Rates of unplanned pregnancies are high globally, burdening women and families. Efforts to develop male contraceptive agents have been thwarted by unacceptable failure rates, side effects and a dearth of pharmaceutical industry involvement. Hormonal male contraception consists of exogenous androgens which exert negative feedback on the hypothalamic-pituitary-gonadal axis and suppress gonadotropin production. This in turn suppresses testicular testosterone production and sperm maturation. Addition of a progestin suppresses spermatogenesis more effectively in men. Contraceptive efficacy studies in couples have shown male hormonal methods are effective and reversible, but also may come with side effects related to sexual desire, acne and serum cholesterol and inconvenient methods of dosing and delivery. Recently, novel androgens as potential contraceptive agents are being evaluated in early clinical trials and look to overcome these drawbacks. Here we summarize landmark studies of prototype male hormonal contraceptives, showcasing recent advances and future prospects in this important area of public health.

Increased risk of prediabetes among virally suppressed adults with HIV in Central Kenya detected using glycated haemoglobin and fasting blood glucose.

AIMS: As survival among people living with HIV (PLHIV) improves with universal HIV treatment, new strategies are needed to support management of co-morbidities like type 2 diabetes (T2D). We assessed prediabetes and T2D prevalence and risk factors using haemoglobin A1c (HbA1c) among PLHIV on antiretroviral therapy (ART) in Central Kenya. METHODS: This cross-sectional study, conducted at a rural and urban site, enrolled PLHIV aged ≥35 years on ART for at least 5 years. HbA1c was assayed using Cobas b 101® , a point-of-care device. HbA1c levels ≥6.5% were considered diagnostic of T2D. For pre-diabetic HbA1c levels (5.7%-6.4%), participants were requested to return the following day for a fasting blood glucose (FBG) to rule out T2D. Risk factors were assessed using multivariable log-binomial regression. RESULTS: Of the 600 completing study procedures, the prevalence of diabetes was 5% (30/600). Ten participants were known to have diabetes; thus, prevalence of newly diagnosed T2D was 3.4% (20/590). Prevalence of prediabetes (HbA1c 5.7%-6.4%) was 14.2% (84/590). Significant predictors of elevated HbA1c were increase in age (Prevalence ratio [PR]: 1.10, CI: 1.02, 1.18, p = .012), hypertension (PR: 1.43, CI: 1.07-2.3, p = .015), central adiposity (PR: 2.11, CI: 1.57-2.84, p < .001) and use of Efavirenz (PR: 2.09, CI: 1.48, 2.96, p < .001). CONCLUSION: There is a high prevalence of prediabetes, a significant predictor of T2D, among PLHIV in Central Kenya. Point-of-care HbA1c may help identify PLHIV with prediabetes in a single screening visit and provide an opportunity for early intervention.

Acceptability of the oral hormonal male contraceptive prototype, 11ß-methyl-19-nortestosterone dodecylcarbonate (11ß-MNTDC), in a 28-day placebo-controlled trial.

OBJECTIVE: To determine men's satisfaction with and the potential acceptability of 11ß-methyl-19-nortestosterone dodecylcarbonate (11ß-MNTDC) when used for 28 days as an experimental, once-daily, oral hormonal male contraceptive (HMC). STUDY DESIGN: We surveyed participants from a double-blind, randomized, placebo-controlled, phase 1 clinical trial, examining their experience with and willingness to use daily oral 11ß-MNTDC for male contraception. RESULTS: Of 42 trial participants, 40 (30 11ß-MNTDC, 10 placebo) completed baseline and end-of-treatment surveys. Based on a 28-day experience, few cited any baseline concerns about safety and drug adherence. Following treatment, nearly three-quarters (72.5%) of participants reported satisfaction with the study drug and nearly all (92.5%) would recommend the method to others. More than half of participants would be willing to pay for the study drug (62.5%) and indicated that the method exceeded initial expectations (53.9%). Nearly 90% reported that taking the pill was easy to remember and did not interfere with their daily routines. Approximately one-third of participants reported bothersome side effects (37% 11ß-MNTDC vs. 20% placebo, p = 0.45). Given the option, 42% of participants would prefer a daily HMC pill over injectable regimens or a daily topical gel. CONCLUSION: A majority of participants in this short-term trial of daily oral 11ß-MNTDC reported satisfaction with the regimen, would recommend it to others, and would pay to use the drug as HMC despite some bothersome side effects. IMPLICATIONS: Oral 11ß-MNTDC would be an acceptable and preferable method among men desiring reversible hormonal male contraception (HMC). These data support further trials of novel oral HMCs such as 11ß-MNTDC.

Central obesity is a contributor to systemic inflammation and monocyte activation in virally suppressed adults with chronic HIV in Kenya.

OBJECTIVES: Heightened systemic inflammation is common in obese individuals and persons with HIV (PWH) and is independently associated with an increased risk of cardiovascular diseases (CVDs). We investigated the combined effect of central obesity, a surrogate measure of visceral fat and HIV on circulating levels of inflammatory cytokines among Kenyan adults. DESIGN: A cross-sectional study. METHODS: We analysed and compared data from 287 virally suppressed PWH and 277 noninfected Kenyan adults, including biomarkers of gut epithelial dysfunction (intestinal fatty acid binding protein), monocyte activation (soluble CD163 and CD14) and inflammation [interleukin (IL)-1ß, IL-6, TNF-α and hsCRP] by HIV/central obesity status (HIV-positive/obese, HIV-negative/obese, HIV-positive/nonobese and HIV-negative/nonobese). Central obesity was defined as waist circumference more than 80 cm for women and more than 94 cm for men. We assessed the association of HIV/obesity status with elevated biomarkers (>75th percentile) using logistic regression. RESULTS: Median age for participants was 44 years and 37% were centrally obese. Levels of all biomarkers were higher among the HIV-positive/obese compared with the HIV-negative/nonobese (P < 0.05 for all comparisons). The HIV-positive/obese group had the greatest odds of having elevated inflammatory biomarkers compared with other groups even after adjustment of age, BMI and other conventional CVD risk factors (P < 0.05 for all). Additional adjustment for sCD163 in the multivariate model substantially attenuated the association for HIV-positive/obesity with IL-1ß, IL-6 and TNF-α but not hsCRP. The contribution of HIV-positive/obesity to inflammation was independent of the degree of immunosuppression. CONCLUSION: Central obesity is prevalent among virally suppressed African PWH and is associated with greater inflammation and monocyte activation independent of other comorbidities and HIV-specific factors.

Comparison of metabolic effects of the progestational androgens dimethandrolone undecanoate and 11ß-MNTDC in healthy men.

BACKGROUND: Dimethandrolone (DMA) and 11ß-methyl-19-nortestosterone (11ß-MNT) are two novel compounds with both androgenic and progestational activity that are under investigation as potential male hormonal contraceptives. Their metabolic effects have never been compared in men. OBJECTIVE: Assess for changes in insulin sensitivity and adiponectin and compare the metabolic effects of these two novel androgens. MATERIALS/METHODS: In two clinical trials of DMA undecanoate (DMAU) and 11ß-MNT dodecylcarbonate (11ß-MNTDC), oral prodrugs of DMA and 11ß-MNT, healthy men received drug, or placebo for 28 days. Insulin and adiponectin assays were performed on stored samples. Mixed model analyses were performed to compare the effects of the two drugs. Student's t test, or the non-parametric Kruskal-Wallis test as appropriate, was used to evaluate for an effect of active drug versus placebo. RESULTS: Class effects were seen, with decrease in HDL-C and SHBG, and increase in weight and hematocrit, with no statistically significant differences between the two compounds. No changes in fasting glucose, fasting insulin, or HOMA-IR were seen with either compound. There was a slight decrease in adiponectin with DMAU that was not seen with 11ß-MNTDC. An increase in LDL-C was seen with 11ß-MNTDC but not with DMAU. DISCUSSION: There were no significant changes in insulin resistance after 28 days of oral administration of these novel androgens despite a mild increase in weight. There may be subtle differences in their metabolic impacts that should be explored in future studies. CONCLUSION: Changes in metabolic parameters should be carefully monitored when investigating androgenic compounds.

Prevalence and correlates of dyslipidemia in HIV positive and negative adults in Western Kenya: A cross-sectional study.

ABSTRACT: There is increasing morbidity and mortality from cardiovascular diseases (CVD) in sub-Saharan Africa (SSA). Dyslipidemia is a well-known CVD risk factor which has been associated with human immunodeficiency virus (HIV) infection and its treatment in high-income countries. Studies in SSA that have examined the relationship between HIV and dyslipidemia have reported mixed results. In this study, we sought to determine the prevalence of dyslipidemia in HIV positive and negative adults (>=30 years old) and evaluate for association in Western Kenya with a higher prevalence expected among HIV positive individuals.HIV positive adults receiving antiretroviral therapy (ART) and HIV negative individuals seeking HIV testing and counseling services were recruited into a cross-sectional study. Demographic and behavioral data and fasting blood samples were collected. Dyslipidemia was defined according to the National Cholesterol Education Program Adult Treatment Panel III. Associations between baseline demographic and clinical variables and dyslipidemia were analyzed using logistic regression.A total of 598 participants, 300 HIV positive and 298 HIV negative adults were enrolled. Dyslipidemia data was available for 564 (94%) participants. In total, 267 (47%) had dyslipidemia. This was not significantly different between HIV positive and HIV negative individuals (46% vs 49%, P = .4). In a multivariate analysis including both HIV positive and negative individuals, adults 50 to 59 years of age had a 2-fold increased risk of dyslipidemia (Odds ratio [OR] 2.1, 95% confidence interval (1.2-3.5) when compared to 30 to 39-years-old participants. Abdominal obesity (OR 2.5), being overweight (OR 1.9), and low fruit and vegetable intake (OR 2.2) were significantly associated with dyslipidemia. Among HIV positive participants, time since HIV diagnosis, ART duration, use of (PI) protease inhibitor-based ART, viral load suppression, current cluster of differentiation (CD4) count and nadir CD4 did not have significant associations with dyslipidemia.The prevalence of dyslipidemia is high in Western Kenya, with nearly half of all participants with lipid abnormalities. Dyslipidemia was not significantly associated with HIV status, or with HIV-specific factors. Older age, being overweight, abdominal obesity, and low fruit and vegetable intake were associated with dyslipidemia and may be targets for public health interventions to lower the prevalence of dyslipidemia and CVD risk in sub-Saharan Africa.

Dimethandrolone Undecanoate, a Novel, Nonaromatizable Androgen, Increases P1NP in Healthy Men Over 28 Days.

CONTEXT: Dimethandrolone undecanoate (DMAU) is being developed as a male contraceptive. Daily oral administration of DMAU, a potent androgen that is not aromatized, markedly suppresses serum testosterone (T) and estradiol (E2) in healthy men. E2 deficiency can increase bone resorption in men. OBJECTIVE: This work aimed to assess changes in bone turnover markers with DMAU administration in a 28-day study. DESIGN: A randomized, double-blind, placebo-controlled study was conducted. SETTING: This study took place at 2 academic medical centers. PARTICIPANTS: Healthy men, age 18 to50 years (n = 81), participated. INTERVENTION: Men received 0, 100, 200, or 400 mg of oral DMAU for 28 days. Serum C-terminal telopeptide of type I collagen (CTX; bone resorption marker) and procollagen type I amino-terminal propeptide (P1NP; bone formation marker) were measured on days 1 and 28. MAIN OUTCOME MEASURES: Changes in bone turnover markers and serum hormones over the treatment period were measured. RESULTS: On day 28, median serum T and E2 were markedly suppressed in all treatment groups vs placebo (P < .001 for both). Percentage change (%) in serum P1NP significantly differed across treatment groups (P = .007): Serum P1NP significantly increased in the 200 mg (5%, interquartile range [IQR] -7% to 27%) and 400 mg (22%, IQR -1% to 40%) groups relative to placebo (-8%, IQR -20% to 0%). Change (%) in serum CTX did not differ between groups (P = .09). CONCLUSIONS: DMAU administration for 28 days to healthy men leads to marked suppression of serum T and E2, yet increases P1NP, a serum marker of bone formation. Longer-term studies of the potent androgen DMAU are warranted to determine its impact on bone health in men.

Human Immunodeficiency Virus Is Associated With Higher Levels of Systemic Inflammation Among Kenyan Adults Despite Viral Suppression.

BACKGROUND: Systemic inflammation independently predicts future cardiovascular events and is associated with a 2-fold increase in cardiovascular disease (CVD) risk among persons living with human immunodeficiency virus (PLHIV). We examined the association between inflammatory markers, HIV status, and traditional CVD risk factors. METHODS: We conducted a cross-sectional study of Kenyan adults with and without HIV seeking care at Kisumu County Hospital. Using a multiplex immunoassay, we measured interleukin (IL) 1ß, IL-6, tumor necrosis factor α (TNF-α), and high-sensitivity C-reactive protein (hsCRP) concentrations. We compared inflammatory marker concentrations by HIV status using the Wilcoxon rank-sum test. Multivariable linear regression was used to evaluate associations between inflammatory biomarkers and HIV status, adjusting for CVD risk factors. RESULTS: We enrolled 286 PLHIV and 277 HIV-negative participants. Median duration of antiretroviral therapy for PLHIV was 8 years (interquartile range, 4-10) and 96% were virally suppressed. PLHIV had a 51% higher mean IL-6 concentration (P < .001), 39% higher mean IL-1ß (P = .005), 40% higher mean TNF-α (P < .001), and 27% higher mean hsCRP (P = .008) compared with HIV-negative participants, independent of CVD risk factors. Male sex, older age, and obesity were associated with higher concentrations of inflammatory markers. Restricting to PLHIV, viral load of ≥1000 copies/mL was associated with higher TNF-α levels (P = .013). CONCLUSIONS: We found higher levels of systemic inflammatory biomarkers among PLHIV who were virally suppressed, and this was independent of traditional CVD risk factors. Further longitudinal analyses to determine whether these inflammatory markers predict future CVD events, and are possible therapeutic targets among PLHIV, are warranted.

Antiretroviral therapy reduces but does not normalize immune and vascular inflammatory markers in adults with chronic HIV infection in Kenya.

INTRODUCTION: Markers of monocyte/macrophage activation and vascular inflammation are associated with HIV-related cardiovascular diseases (CVD) and mortality. We compared these markers among African people living with HIV (PLWH) and HIV-negative adults, and examined risk factors associated with elevated biomarkers (>75th percentile) in PLWH on antiretroviral therapy (ART). DESIGN: Cross-sectional study. METHODS: We measured serum concentrations of a gut integrity biomarker (intestinal-fatty acid binding protein), monocyte/macrophage activation biomarkers (soluble CD14 and CD163), and vascular inflammation biomarkers [soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular adhesion molecule 1 (sVCAM-1)]. We assessed the relationship of these inflammatory parameters with HIV, using logistic regression adjusting for traditional CVD risk factors. RESULTS: Among the 541 participants, median age was 43 years and half were female. Among 275 PLWH, median CD4 T-cell count and duration of ART use was 509 cells/µl and 8 years, respectively. PLWH had significantly higher prevalence of elevated inflammatory biomarkers compared with HIV-negative individuals even after adjustment for traditional CVD risk factors. Compared with individuals without HIV, the prevalence of elevated biomarkers was highest among persons with detectable viral load and CD4 T-cell counts 200 cells/µl or less. In a subanalysis among PLWH, nadir CD4 T-cell count 200 cells/µl or less was associated with elevated soluble CD14 (sCD14); dyslipidemia with elevated sCD14, sICAM-1, and sVCAM-1; and overweight/obesity with reduced sCD14. Longer ART exposure (>4 years) was associated with reduced sVCAM-1 and sICAM-1. CONCLUSION: HIV and not traditional CVD risk factors is a primary contributor of monocyte/macrophage activation and inflammation despite ART. Anti-inflammatory therapies in addition to ART may be necessary to reduce these immune dysregulations and improve health outcomes of African PLWH.

Male Contraception.

Unintended pregnancy is a global public health problem. Despite a variety of female contraceptive options, male contraceptive options are limited to the condom and vasectomy. Condoms have high failure rates and surgical vasectomy is not reliably reversible. There is a global need and desire for novel male contraceptive methods. Hormonal methods have progressed the furthest in clinical development and androgen plus progestin formulations hold promise as a marketable, reversible male contraceptive over the next decade. Investigators have tested androgen plus progestin approaches using oral, transdermal, subdermal, and injectable drug formulations and demonstrated the short-term safety and reversibility of hormonal male contraception. The most commonly reported side effects associated with hormonal male contraception include weight gain, acne, slight suppression of serum high-density cholesterol, mood changes, and changes in libido. Efficacy trials of hormonal male contraceptives have demonstrated contraceptive efficacy rates greater than that of condoms. Although there has been less progression in the development of nonhormonal male contraceptives, potentially reversible vaso-occlusive methods are currently in clinical trials in some countries. Various studies have confirmed both men and women's desire for novel male contraceptives. Barriers to development include an absence of investment from pharmaceutical companies, concerns regarding side effects and spermatogenic rebound with hormonal methods, and lack of clear reversibility and proven effectiveness of nonhormonal methods. The ultimate availability of male contraceptives could have an important impact on decreasing global unintended pregnancy rates (currently 40% of all pregnancies) and will be a step towards reproductive justice and greater equity in family planning.

Postpartum metabolic syndrome and high-sensitivity C-reactive protein after gestational hypertension and pre-eclampsia.

OBJECTIVE: To evaluate the association between metabolic syndrome (MetS) and high-sensitivity C-reactive protein (hsCRP), a biomarker of chronic inflammation and an independent predictor for cardiovascular disease overall and in subgroups of women with/without pre-eclampsia and gestational hypertension (GHT). METHODS: A prospective cohort study was conducted in Nairobi, Kenya. Women with pre-eclampsia or GHT and normotensive women within 12 weeks postpartum underwent physical, anthropometric, fasting lipid profile, plasma glucose, and hsCRP measurements at 6 months postpartum. A generalized linear regression model with Poisson distribution adjusted for body mass index and age was used to estimate the association between elevated hsCRP and MetS overall and stratified by pre-eclampsia or GHT. RESULTS: In the 171 women included in the study, risk of elevated hsCRP (>3 mg/L) was greater among women with compared to those without MetS (adjusted relative risk [ARR] 1.70, 95% confidence interval [CI] 1.05-2.73, P=0.03) and was statistically significantly higher in the hypertensive (ARR 2.16 95% CI 1.01-4.62, P=0.04) but not in the normotensive (ARR 1.46, 95% CI 0.93-2.28) group. CONCLUSION: Increased risk of elevated hsCRP postpartum can guide longitudinal mechanistic and intervention studies to reduce postpartum cardiovascular morbidity in women with MetS, especially after pre-eclampsia or GHT.