Anticancer Drugs-Related Hypogonadism in Male Patients with Advanced Cancers on Active Treatment: A Systematic Review.

BACKGROUND: In male patients with cancer treated with antineoplastic drug, hypogonadism is a neglected cause of diminished quality of life. This condition may be cancer related as well as toxicity related. The role of antineoplastic drug in causing hypogonadism is poorly understood. The aim of this systematic review was to establish the prevalence, nature (primary/secondary), and impact of hypogonadism on quality of life in male patients with cancer on antineoplastic therapy. METHODS: The search strategy used PubMed, Embase, and Cochrane databases to select articles in English language that described hypogonadism in male patients with cancer. The search period was from January 1, 1945 to February 28, 2023. We included observational studies, case reports or case series and excluded studies concerning hematological malignancies, prostate cancer, female patients, and survivors. FINDINGS: Of 4488 records identified, 28 studies met inclusion criteria (17 observational studies, 11 case reports or case series). Anti-angiogenic drugs and crizotinib were found to have a role in the development of hypogonadism. Patients treated with immune checkpoint-inhibitors developed secondary hypogonadism due to immune-related hypophysitis or orchitis. As for active chemotherapy, platinum salts were often associated with hypogonadism, followed by antimetabolites and taxanes. Selected studies were heterogeneous for populations, interventions, and outcomes assessments. Thus, a generalization is difficult. Moreover, the role of concurrent etiologies cannot be excluded in most studies. CONCLUSION: Our research emphasizes the importance of evaluating the gonadal axis before treatment in patients considered at risk and testing it at regular intervals or in case of clinical suspicion.

Opioid-induced hypogonadism in opioid use disorder, its role in negative reinforcement, and implications for treatment and retention.

Hypogonadism is a highly prevalent complication of chronic opioid use associated with a constellation of affective, algesic, and cognitive symptoms as well as decreased quality of life. Given that the mainstays of pharmacologic opioid use disorder (OUD) treatment - methadone and buprenorphine - are themselves agonists or partial agonists at the mu opioid receptor, opioid-induced hypogonadism (OIH) remains an underappreciated clinical concern throughout the course of OUD treatment. Prominent theoretical frameworks for OUD emphasize the importance of negative reinforcement and hyperkatifeia, defined as the heightened salience of negative emotional and motivational states brought on by chronic opioid use. In this perspective article, we highlight the striking parallels between the symptom domains of hyperfakifeia and hypogonadism in males, who comprise the vast majority of existing clinical research on OIH. By extension we propose that future research and ultimately clinical care should focus on the identification and treatment of OIH in OUD patients to help address the longstanding paradox of poor treatment retention despite efficacious therapies, particularly in the setting of the current opioid overdose epidemic driven by high potency synthetic opioids such as fentanyl. We then review evidence from chronic pain patients that testosterone replacement provides clinically significant benefits to men with OIH. Finally, using this framework, we compare extant OUD therapeutics and discuss critical gaps in the clinical literature-including the relative dearth of data regarding hypothalamic-pituitary-gonadal function in females who use opioids-where future study should be focused.

Management of Male Fertility in Hypogonadal Patients on Testosterone Replacement Therapy.

Testosterone is crucial in regulating several body functions in men, including metabolic, sexual, and cardiovascular functions, bone and muscle mass, and mental health. Therefore, optimizing testosterone levels in men is an important step to maintaining a healthy body and mind, especially as we age. However, traditional testosterone replacement therapy has been shown to lead to male infertility, caused by negative feedback in the hypothalamic-pituitary-gonadal (HPG) axis. Recent advances in research have led to the discovery of many new methods of administration, which can have more or less suppressive effects on the HPG axis. Also, the usage of ancillary medications instead of or after testosterone administration might help maintain fertility in hypogonadal patients. The goal of this narrative review is to summarize the newest methods for optimizing fertility parameters in patients undergoing treatment for hypogonadism and to provide the necessary information for healthcare providers to make the right treatment choices.

Testosterone replacement therapy is not associated with increased prostate cancer incidence, prostate cancer-specific, or cardiovascular disease-specific mortality in Finnish men.

BACKGROUND: Concerns have been expressed over the safety of testosterone replacement therapy (TRT) in men with late-onset hypogonadism (LOH). Previous studies have shown controversial results regarding the association of TRT with the risk of cardiovascular events or prostate cancer (PCa) incidence, aggressiveness, and mortality. This study explores the overall risk of PCa and risk by tumor grade and stage, as well as mortality from PCa and cardiovascular disease (CVD), among men treated with TRT compared to men without LOH and TRT use. MATERIALS AND METHODS: The study included 78,615 men of age 55-67 years at baseline from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). Follow-up started at randomization and ended at death, emigration, or a common closing date January 1st, 2017. Cox proportional hazards regression model with time-dependent variables and adjustment for age, trial arm, use of other medications, and Charlson comorbidity index was used. Comprehensive information on TRT purchases during 1995-2015 was obtained from the Finnish National Prescription Database. PCa cases were identified from the Finnish Cancer Registry and causes of death obtained from Statistics Finland. RESULTS: Over the course of 18 years of follow-up, 2919 men were on TRT, and 285 PCa cases were diagnosed among them. TRT users did not exhibit a higher incidence or mortality rate of PCa compared to non-users. On the contrary, men using TRT had lower PCa mortality than non-users (HR = 0.52; 95% CI 0.3-0.91). Additionally, TRT users had slightly lower CVD and all-cause mortality compared to non-users (HR = 0.87; 95% CI 0.75-1.01 and HR = 0.93; 95% CI 0.87-1.0, respectively). No time- or dose-dependency of TRT use was evident in any of the analyses. CONCLUSION: Men using TRT were not associated to increased risk for PCa and did not experience increased PCa- or CVD-specific mortality compared to non-users. Further studies considering blood testosterone levels are warranted.

Exogenous Testosterone Replacement Therapy Is Associated with Increased Risk for Vascular Graft Infections Among Hypogonadal Men.

BACKGROUND: Vascular graft infections (VGIs) are a major source of morbidity following vascular bypass surgery. Hypogonadal men may be at increased risk for impaired wound healing and infections, but it is unclear if testosterone replacement therapy (TRT) mitigates this risk. We designed this study to evaluate the relationship between hypogonadism and the use of testosterone replacement therapy (TRT) with subsequent risk for developing a VGI. METHODS: We performed a retrospective analysis of claims in the MarketScan database identifying men greater than 18 years of age who underwent placement of a prosthetic graft in the peripheral arterial circulation from January 2009 to December 2020. Patients were stratified based on diagnosis of hypogonadism and use of TRT within 180 days before surgery. The primary outcome was VGI and the need for surgical excision. The association between hypogonadism and TRT use on risk of VGI was analyzed using Kaplan-Meier plots and multivariate Cox proportional hazards models. RESULTS: We identified 18,312 men who underwent a prosthetic bypass graft procedure in the upper and lower extremity during the study period, of which 802 (5%) had diagnosis of hypogonadism. Among men with hypogonadism, 251 (31%) were receiving TRT. Patients on TRT were younger, more likely to be diabetic, and more likely develop a VGI during follow-up (14% vs. 8%; P < 0.001) that was in the lower extremity. At 5 years, freedom from VGI was significantly lower for hypogonadal men on TRT than patients not on TRT or without hypogonadism (Log rank P < 0.001). In Cox regression models adjusted for age, diabetes, obesity, smoking, corticosteroid use, and procedure type, hypogonadal men on TRT were at a significantly increased risk of graft infection (hazard ratio (HR):1.94, 95% confidence interval (CI):1.4-2.7; P < 0.001) compared to controls. CONCLUSIONS: This study demonstrates TRT among hypogonadal men is associated with an increased risk of prosthetic VGIs. Temporary cessation of TRT should be considered for men undergoing prosthetic graft implants, particularly those in the lower extremity.

Effects of long-term testosterone treatment on cardiovascular outcomes in men with hypogonadism: Rationale and design of the TRAVERSE study.

BACKGROUND: Testosterone exerts some effects on the cardiovascular system that could be considered beneficial; some other effects may potentially increase the risk of cardiovascular (CV) events. Neither the long-term efficacy nor safety of testosterone treatment has been studied in an adequately-powered randomized trial. METHODS: The Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study is a randomized, double-blind, placebo-controlled, parallel group, non-inferiority, multicenter study. Eligible participants are men, 45 to 80 years, with serum testosterone concentration <300 ng/dL and hypogonadal symptoms, who have evidence pre-existing CV disease or increased risk of CV disease. Approximately 6,000 subjects will be randomized to either 1.62% transdermal testosterone gel or a matching placebo gel daily for an anticipated duration of up to 5 years. The primary outcome is CV safety defined by the major adverse CV event composite of nonfatal myocardial infarction, nonfatal stroke, or death due to CV causes. The trial will continue until at least 256 adjudicated major adverse CV event endpoints have occurred to assess whether the 95% (2-sided) upper confidence limit for a hazard ratio of 1.5 can be ruled out. Secondary endpoints include prostate safety defined as the incidence of adjudicated high grade prostate cancer and efficacy in domains of sexual function, bone fractures, depression, anemia, and diabetes. RESULTS: As of July 1, 2021, 5,076 subjects had been randomized. CONCLUSIONS: The TRAVERSE study will determine the CV safety and long-term efficacy of testosterone treatment in middle-aged and older men with hypogonadism with or at increased risk of CV disease.

Opioids and pituitary function: expert opinion.

PURPOSE: Opioids are highly addictive potent analgesics and anti-allodynics whose use has dramatically increased in recent decades. The precipitous rise in opioid dependency and opioid use disorder is an important public health challenge given the risks for severely adverse health outcomes. The long-term opioid impact on hypothalamic-pituitary axes is particularly underappreciated among both endocrinologists and primary care physicians. We review the effects of opioids on hypothalamic-pituitary-target gland function and their implications for clinical practice. METHODS: Experts in hypothalamic-pituitary disorders and opioid pharmacology reviewed recently published literature and considered strategies for diagnosing and managing these opioid-induced endocrine effects. RESULTS: Opioid suppression of hypothalamic-pituitary axes can lead to hypogonadotropic hypogonadism, central adrenal insufficiency, and hyperprolactinemia. These important clinical manifestations are often under-estimated, poorly evaluated, and typically either untreated or not optimally managed. Data on biochemical testing for diagnosis and on the effect of hormone replacement in these patients is limited and prospective randomized controlled studies for guiding clinical practice are lacking. CONCLUSIONS: Patients should be informed about risks for hypogonadism, adrenal insufficiency, and hyperprolactinemia, and encouraged to report associated symptoms. Based on currently available evidence, we recommend clinical and biochemical evaluation for potential central adrenal insufficiency, central hypogonadism, and/or hyperprolactinemia in patients chronically treated with opioids as well as the use of current expert guidelines for the diagnosis and treatment of these conditions.

Hormonal Changes after R-CHOP Chemotherapy in Patients with Diffuse Large B-Cell Lymphoma: A Prospective Study.

Background and Objectives: There is a lack of data regarding hormonal metabolic abnormalities resulting from the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone), a commonly used chemotherapy in diffuse large B-cell lymphoma (DLBCL). This study aimed to determine the incidence of hormonal and metabolic changes after R-CHOP therapy. Methods and Methods: This prospective cohort study initially included 17 DLBCL patients. Hormonal tests, including gonadal function, thyroid function, and ACTH stimulation tests for cortisol and metabolic markers, were performed before the 1st and after the 5th cycle of R-CHOP. The paired t-test was used to evaluate the changes. Statistical significance was set at p < 0.05. Results: Out of 17 patients, two died before the last follow-up, and 15 completed the study. LH levels were significantly higher in males after the 5th cycle (p = 0.04), while no significant changes were observed in other hormonal levels. After the 5th cycle, the only trend toward statistical significance was observed with higher FSH in males, higher blood glucose, and cholesterol. After the 5th cycle of chemotherapy, seven patients had at least one hormonal dysfunction, three patients had alterations in their thyroid function tests. Three patients had adrenal insufficiency (AI), one of whom also had secondary hypothyroidism concomitant with hypogonadism and AI. Additionally, two males had hypogonadism, and impaired fasting glucose was observed in three patients. Conclusions: Hormonal and metabolic abnormalities can occur in DLBCL after the 5th R-CHOP cycle. A high level of awareness and careful observation is of value in detecting these abnormalities, as some can be lethal.

Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism.

Concern has been raised over increased male reproductive disorders in the Western world, and the disruption of male endocrinology has been suggested to play a central role. Several studies have shown that mild analgesics exposure during fetal life is associated with antiandrogenic effects and congenital malformations, but the effects on the adult man remain largely unknown. Through a clinical trial with young men exposed to ibuprofen, we show that the analgesic resulted in the clinical condition named "compensated hypogonadism," a condition prevalent among elderly men and associated with reproductive and physical disorders. In the men, luteinizing hormone (LH) and ibuprofen plasma levels were positively correlated, and the testosterone/LH ratio decreased. Using adult testis explants exposed or not exposed to ibuprofen, we demonstrate that the endocrine capabilities from testicular Leydig and Sertoli cells, including testosterone production, were suppressed through transcriptional repression. This effect was also observed in a human steroidogenic cell line. Our data demonstrate that ibuprofen alters the endocrine system via selective transcriptional repression in the human testes, thereby inducing compensated hypogonadism.

Exposure to di-n-octyl phthalate during puberty induces hypergonadotropic hypogonadism caused by Leydig cell hyperplasia but reduced steroidogenic function in male rats.

Humans are exposed to phthalates ubiquitously, which may threaten health. However, whether di-n-octyl phthalate can prevent pubertal sexual maturity is still elusive. In this study, male Sprague Dawley rats (age 35 days) were treated daily by gavage with 0, 10, 100, and 1000 mg/kg body weight of di-n-octyl phthalate from day 35 to day 49 after birth. Di-n-octyl phthalate significantly reduced serum testosterone levels at doses of 100 and 1000 mg/kg, but increased serum luteinizing hormone levels of 1000 mg/kg and decreased testosterone/luteinizing hormone ratio at ≥10 mg/kg, without affecting serum follicle-stimulating hormone levels. Di-n-octyl phthalate significantly induced Leydig cell hyperplasia (increased number of CYP11A1-positive Leydig cells) at 100 and 1000 mg/kg. Di-n-octyl phthalate down-regulates the gene expression of Cyp11a1, Hsd3b1 and Insl3 in individual Leydig cells. Di-n-octyl phthalate can also reduce the number of sperm in the epididymis. Di-n-octyl phthalate increased phosphorylated AKT1/AKT2 without affecting their total proteins, but increased the total protein and phosphorylated protein of ERK1/2 and GSK-3ß. Primary immature Leydig cells isolated from 35-day-old rats were treated with 0-50 µM di-n-octyl phthalate for 3 h. This phthalate inhibited androgen production under basal, LH-stimulated, and cAMP-stimulated conditions by 5 and 50 µM in vitro via down-regulating Cyp11a1 expression but up-regulating Srd5a1 expression in vitro. In conclusion, di-n-octyl phthalate induces hypergonadotropic hypogonadism caused by Leydig cell hyperplasia but reduced steroidogenic function and prevents sperm production.

Anabolic androgenic steroid-induced hypogonadism, a reversible condition in male individuals? A systematic review.

The anabolic-androgenic steroids (AAS) are clinically used as an androgen replacement, in hypogonadism treatment, to induce puberty, and also in the treatment of chronic degenerative diseases. The AAS use out of clinical context is becoming massively, being used merely for aesthetic reasons. AAS abuse may cause severe disarrangement on the HPG axis and generate a significant decrease in testosterone synthesis and secretion by the testes. This review aims to evaluate whether the hypogonadism induced by AAS abuse is reversible and under what circumstances the reversibility is possible. For this, PRISMA guidelines and several databases are used between July and September 2020. Altogether, this systematic review identified and analysed 179 cases of AAS users. Of these, 168 cases had the hypogonadism clearly diagnosed and proven to be linked exclusively to AAS abuse. However, between these 168 cases, only 38 cases presented fully known outcomes and among these, merely in 4, the hypogonadism was completely reversible (2 based on drug therapy) with HPG axis recovery. In conclusion, this review presents evidences that AAS-induced hypogonadism is a seriously underestimated problem, and in the majority of cases, full recovery is very difficult to succeed.

Late Effects of Parasellar Lesion Treatment: Hypogonadism and Infertility.

Central hypogonadism, also defined as hypogonadotropic hypogonadism, is a recognized complication of hypothalamic-pituitary-gonadal axis damage following treatment of sellar and parasellar masses. In addition to radiotherapy and surgery, CTLA4-blocking antibodies and alkylating agents such as temozolomide can also lead to hypogonadism, through different mechanisms. Central hypogonadism in boys and girls may lead to pubertal delay or arrest, impairing full development of the genitalia and secondary sexual characteristics. Alternatively, cranial irradiation or ectopic hormone production may instead cause early puberty, affecting hypothalamic control of the gonadostat. Given the reproductive risks, discussion of fertility preservation options and referral to reproductive specialists before treatment is essential. Steroid hormone replacement can interfere with other replacement therapies and may require specific dose adjustments. Adequate gonadotropin stimulation therapy may enable patients to restore gametogenesis and conceive spontaneously. When assisted reproductive technology is needed, protocols must be tailored to account for possible long-term gonadotropin insufficiency prior to stimulation. The aim of this review was to provide an overview of the risk factors for hypogonadism and infertility in patients treated for parasellar lesions and to give a summary of the current recommendations for management and follow-up of these dysfunctions in such patients. We have also briefly summarized evidence on the physiological role of pituitary hormones during pregnancy, focusing on the management of pituitary deficiencies.

Opioid-induced hypogonadism: Pathophysiology, clinical and therapeutics review.

Opioids are pivotal therapeutics in the management of escalated chronic pain (moderate-severe). In the last two decades, the increased prescription rate and the prolonged usage of opioids shed light on opioid-induced endocrinopathy. Opioid-induced hypogonadism (OHG) results upon long-term opioid therapy. Clinically, patients with OHG are presented mainly by sexual dysfunction and infertility. Opioid clinical use in pain therapy is indispensable. However, the resultant sexual endocrinopathy cannot be overlooked and hence hormonal replacement therapy with regular monitoring of the patients represents a potential therapeutic strategy while avoiding opioids in patients with guaranteed long therapeutic exposure and switching to using low-dose naltrexone as alternative represents a possible prophylactic measure to ensure therapeutic compliance and secure a good life quality of patients.

Effects of nonsteroidal anti-inflammatory drug (NSAID) use upon male gonadal function: A national, population-based study.

Recent data have suggested that short-term NSAID use induces a state of compensated hypogonadism. Our aim was to investigate the association between chronic, regular NSAID use and compensated hypogonadism in a large, nationally representative cohort, the US National Health and Nutrition Examination Survey (NHANES) database. Men 20-80 years who answered the analgesic use questionnaire and underwent hormonal testing were included. Multivariable regression was utilised to determine the relationship between NSAID use and serum testosterone (T), anti-Mullerian hormone (AMH) and T:AMH ratio. Among 3,749 men, 505 (13.5%) reported regular NSAID use and 3,244 (86.5%) did not. Regular users had lower T (440.7 ± 27.0 vs. 557.0 ± 24.9 ng/dl, p = .005) and albumin (43.8 ± 0.2 vs. 45.1 ± 0.1, p < .001) compared to nonregular users. On multivariable analysis, only active smoking was significantly associated with T, AMH and T:AMH ratio (p < .001, p = .036 and p = .005 respectively). Regular NSAID use was not associated with T, AMH or T:AMH ratio (p = .523, p = .974, and p = .872 respectively). In this nationally representative sample of US men, regular and chronic NSAID use was not associated with alterations in T or compensated hypogonadism. These data should reassure patients and clinicians regarding the safety of NSAID use with respect to the risk of alteration in the hypothalamic-pituitary-gonadal axis.

Hormone Replacement Therapy and Opioid Tapering for Opioid-Induced Hypogonadism Among Patients with Chronic Noncancer Pain: A Systematic Review.

OBJECTIVE: To systematically review evidence addressing the efficacy of testosterone replacement therapy (TRT) and opioid tapering for opioid-induced hypogonadism among patients with chronic noncancer pain. STUDY DESIGN: Systematic review of randomized controlled trials (RCTs) and observational studies. METHODS: We searched MEDLINE, CINAHL, AMED, CENTRAL, CINAHL, DARE, EMBASE, and PsycINFO through August 2017. Eligible studies enrolled ≥10 patients with chronic noncancer pain and opioid-induced hypogonadism and reported the effect of TRT or opioid tapering on a patient-important outcome collected ≥14 days after treatment. Pairs of reviewers independently screened for eligible studies, assessed risk of bias, and extracted data. We used the GRADE approach to rate quality of evidence. RESULTS: Of 666 abstracts reviewed, five studies including one RCT (N = 84) and four observational studies (N = 157) were eligible. No studies explored the effect of opioid tapering for opioid-induced hypogonadism. Very low-quality evidence found that TRT was associated with improvements in pain (median reduction of 2 points on the 11-point numerical rating scale for pain; 95% confidence interval [CI] = -1.4 to -2.6; minimally important difference [MID] = 2 points), and emotional functioning (mean increase of 9 points on the 100-point SF-36 Mental Component Summary score; 95% CI = 4.40 to 13.60; MID = 5 points). Low-quality evidence suggested that TRT had no effect on sleep quality, sexual function, physical functioning, role functioning, or social functioning; very low-quality evidence suggested no association with depressive symptoms. CONCLUSIONS: Low-quality to very low-quality evidence suggests that TRT may improve pain and emotional functioning, but not other outcomes, in chronic noncancer pain patients with opioid-induced hypogonadism.

Hypothalamic-pituitary-gonadal axis dysfunction: An innate pathophysiology of schizophrenia?

The female hormone 17ß-estradiol is postulated to be protective against schizophrenia onset and severity. Hypoestrogenism is a common phenomenon in women with schizophrenia that has serious effects that adds to the burden of an already very onerous disease. The cause of hypoestrogenism is largely attributed to antipsychotic-induced hyperprolactinemia. Evidence suggest however that a significant portion of female schizophrenia patients develop hypoestrogenism either before antipsychotic treatment or without regard to the level of prolactin, suggesting that for a sizeable segment of female patients, gonadal abnormality may be an innate and early aspect of the disease. This review aims to summarise the available literature that examines gonadal dysfunction in schizophrenia through this prism as well as to outline some recent developments in treatment strategies that may provide feasible ways to successfully tackle hypoestrogenism in schizophrenia.

An Internet-Based Survey to Assess Clinicians' Knowledge and Attitudes Towards Opioid-Induced Hypogonadism.

BACKGROUND: Long-term opioid therapy for chronic pain management requires regularly assessing and documenting benefits and side effects. Opioid-induced sex hormone disturbances are a complication that needs to be assessed routinely and perhaps not only when suspected. There is abundant literature about its prevalence, clinical consequences, and treatment, yet routine hormone screening and appropriate treatment are seldom performed in pain clinics. Ignorance, skepticism, and/or indifference are possible reasons explaining why opioid-induced hypogonadism (OIH) remains underdiagnosed among chronic pain patients. METHODS: This was an Internet-based survey reaching out to pain clinicians to assess their knowledge and attitudes regarding OIH. RESULTS: A total of 135 responses were received, representing a 23.7% response rate. Analysis of responses showed that 47% of responders were somewhat familiar with this complication, but their knowledge about the prevalence and the time to develop varied. Screening for OIH is ordered based on suspicion of its presence (50%), but not routinely (38%). Lack of knowledge was the most frequent reason adduced for not screening for OIH. Sex-related symptoms and signs are the most relevant reasons leading to suspicion and screening of OIH. Upon laboratory confirmation, most responders refer their patients to endocrinology (82%) for further management since most (60%) believe that testosterone replacement would improve their patients' health. CONCLUSIONS: Knowledge and attitudes towards OIH varied among this population of pain clinicians invited to participate in the research. Lack of knowledge and incertitude seem to impact the attitudes towards screening and treating OIH. Better medical training at undergraduate and postgraduate levels as well as continuous medical education may contribute to raising awareness about this complication and providing early treatment.

Endotoxin-initiated inflammation reduces testosterone production in men of reproductive age.

Inflammation, both acute and chronic, is associated with testosterone deficiency, raising the possibility of a direct causal link. One potential trigger for inflammation in obese men is the passage of intestinal bacteria into the circulation due to a breakdown in mucosal barrier integrity. Recently, we hypothesized that this endotoxin exposure may cause androgen deficiency in obese men. To test this hypothesis, we analyzed the relationship between serum levels of lipopolysaccharide-binding protein (LBP), an indirect measure of endotoxin exposure, against male reproductive hormones, inflammatory markers (C-reactive protein, IL-1ß, IL-6, TNF-α), and adiposity in 75 men. Adiposity was positively correlated with endotoxin exposure (LBP) and inflammation (C-reactive protein, IL-6) and negatively correlated with testosterone. Furthermore, endotoxemia (LBP) was negatively correlated with serum testosterone but positively correlated with IL-6. Multivariate analysis revealed a significant, negative correlation between serum IL-6 and free testosterone. In a second interventional study, low-dose endotoxin challenge in lean men produced a transient inflammatory response that was followed by a decline in serum testosterone, without changes in LH or FSH, providing further evidence that endotoxin-driven inflammation may result in impaired Leydig cell function.

Structural modeling and mRNA expression of epididymal ß-defensins in GnRH immunized boars: A model for secondary hypogonadism in man.

Human secondary hypogonadism is associated with impaired testicular function, however, little is known about its impact on sperm epididymal maturation. Endocrine disruption in the epididymis could impair the secretion of key proteins, such as ß-defensins, responsible for spermatozoa maturation during epididymal transit. This study evaluated the sequence and structural similarities between porcine epididymal ß-defensins porcine ß-defensins (pBD3), pBD4, pBD125, and pEP2C and their human homologs using bioinformatics integrated with information derived from protein databanks. We then verified whether the expression of pBD3, pBD4, pBD125, and pEP2C genes in the testis and epididymis are influenced by disruption of the hypothalamic-pituitary-testicular (HPT) axis in a pig model for male human secondary hypogonadism. Upon modeling porcine ß-defensins, structural and functional analysis confirmed the presence of motifs associated with ß-defensin function, validating the models generated in silico. pBD3 and pBD4 showed acceptable structural alignments with human ß-defensins BDEF103 and BDEF110, respectively. In addition, evaluation of hormonal regulation of ß-defensins was assessed by analyzing the expression of these four ß-defensins in adult boars immunized against gonadotropin-releasing hormone (GnRH). Our results indicate that HPT axis disruption modifies the expression of pBD3, pBD4, pBD125, and pEP2C in boar testis and epididymis, suggesting an endocrine-dependent regulation of ß-defensins in swine epididymis. In conclusion, sequence and structural homology between pBD3 and pBD4 and their human homologs provide a basis for using the pig as a model for the study of human secondary hypogonadism. Further investigation of the human homologs in hypogonadal men could elucidate the connections between fertility and epididymal expression of ß-defensins.

Testosterone deficiency in non-cancer opioid-treated patients.

PURPOSE: The use of opioids in patients with chronic non-cancer pain is common and can be associated with opioid-induced androgen deficiency (OPIAD) in men. This review aims to evaluate the current literature regarding the prevalence, clinical consequence and management of OPIAD. METHODS: A database search was performed in Medline, Embase and Cochrane using terms such as "analgesics", "opioids" and "testosterone". Relevant literature from January 1969 to March 2018 was evaluated. RESULTS: The prevalence of patients with OPIAD ranges from 19 to 86%, depending on the criteria for diagnosis of hypogonadism. The opioid-induced suppression of gonadotropin-releasing and luteinizing hormones represents the main important pathogenetic mechanisms. OPIAD has significant negative clinical consequences on sexual function, mood, bone density and body composition. In addition, OPIAD can also impair pain control leading to hyperalgesia, which can contribute to sexual dysfunction and mood impairment. CONCLUSIONS: OPIAD is a common adverse effect of opioid treatment and contributes to sexual dysfunction, impairs pain relief and reduces overall quality of life. The evaluation of serum testosterone levels should be considered in male chronic opioid users and the decision to initiate testosterone treatment should be based on the clinical profile of individuals, in consultation with the patient.