Benefits Of Testosterone Replacement Therapy Research Articles

Management of male obesity-related secondary hypogonadism: A clinical update.

The global obesity pandemic has resulted in a rise in the prevalence of male obesity-related secondary hypogonadism (MOSH) with emerging evidence on the role of testosterone therapy. We aim to provide an updated and practical approach towards its management. We did a comprehensive literature search across MEDLINE (via PubMed), Scopus, and Google Scholar databases using the keywords "MOSH" OR "Obesity-related hypogonadism" OR "Testosterone replacement therapy" OR "Selective estrogen receptor modulator" OR "SERM" OR "Guidelines on male hypogonadism" as well as a manual search of references within the articles. A narrative review based on available evidence, recommendations and their practical implications was done. Although weight loss is the ideal therapeutic strategy for patients with MOSH, achievement of significant weight reduction is usually difficult with lifestyle changes alone in real-world practice. Therefore, androgen administration is often necessary in the management of hypogonadism in patients with MOSH which also improves many other comorbidities related to obesity. However, there is conflicting evidence for the appropriate use of testosterone replacement therapy (TRT), and it can also be associated with complications. This evidence-based review updates the available evidence including the very recently published results of the TRAVERSE trial and provides comprehensive clinical practice pearls for the management of patients with MOSH. Before starting testosterone replacement in functional hypogonadism of obesity, it would be desirable to initiate lifestyle modification to ensure weight reduction. TRT should be coupled with the management of other comorbidities related to obesity in MOSH patients. Balancing the risks and benefits of TRT should be considered in every patient before and during long-term management.

Impact of GH Deficiency and Excess on Men Sexual Health and Fertility.

A fair shred of evidence supports the mutual relationship between the hypothalamus-pituitary testis axis and the growth hormone (GH) pathway. Nevertheless, the role of GH on male sexual function and fertility is controversial, due to conflicting data from literature. The present review summarizes the available andrological consequences of two pathological extremes, i.e., either GH excess or deficiency. GH excess drives different disorders of male sexual health. On one hand, it indirectly favors the onset of erectile dysfunction (40.2% of cases) mostly by its detrimental vascular and metabolic effects, while testosterone levels don't appear as a key factor. On the other hand, GH excess directly impairs fertility, leading to secondary hypogonadism. Of note, compared to controls, this condition adversely affects the main sperm parameters, i.e., sperm concentration (p = 0.00), progressive motility (p = 0.03), and normal morphology (p = 0.02). Although with limited evidence, GH deficiency also fosters erectile dysfunction, while its effect on fertility is still unclear. On the whole, the available literature shows that any GH disorder plays a negative role in both male general and sexual health. Nevertheless, the potential benefit of testosterone replacement therapy in this population has not yet been explored.

남성갱년기의 치료와 기능의학적 접근

Male hypogonadism, also known as androgen deficiency syndrome, refers to age-related alterations in hormone levels and the consequent symptoms observed in middle-aged and elderly men. Testosterone, a crucial male sex hormone, plays a central role in androgen deficiency syndrome. This review aims to investigate the intricate connection between testosterone deficiency and male health. Additionally, we delve into the potential benefits of testosterone replacement therapy in enhancing metabolic function. Furthermore, we explore lifestyle habits and functional strategies for promoting intrinsic testosterone levels.

Exploring the Role of Testosterone Replacement Therapy in Benign Prostatic Hyperplasia and Prostate Cancer: A Review of Safety

Increased risk of prostate diseases triggered by testosterone replacement therapy (TRT) remains a worldwide concern. That said, we reviewed the safety of TRT in the spheres of benign prostatic hyperplasia (BPH) and prostate cancer (PCa), exploring clinical findings in this regard. Compelling evidence based on meta-analyses of randomized and observational studies indicates safety for TRT in patients suffering from prostate disorders such as BPH and PCa, at the same time improving lower tract urinary symptoms. Thus, the harmful relationship geared toward androgens and BPH seems to be overestimated as TRT has sufficient safety and, if properly prescribed, may counteract several metabolic problems. Even after PCa treatment, the benefits of TRT could outweigh the risk of recurrence, but further long-term randomized clinical trials are needed to elucidate unresolved questions.

European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males: Endorsing organization: European Society of Endocrinology.

Evidence regarding functional hypogonadism, previously referred to as 'late-onset' hypogonadism, has increased substantially during the last 10year. To update the European Academy of Andrology (EAA) guidelines on functional hypogonadism. Expert group of academicians appointed by the EAA generated a series of consensus recommendations according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. The diagnosis of functional hypogonadism should be based on both the presence of clinical symptoms supported by repeatedly low morning fasting serum total testosterone (T) measured with a well-validated assay, after exclusion of organic causes of hypogonadism. Lifestyle changes and weight reduction should be the first approach in all overweight and obese men. Whenever possible, withdrawal/modification of drugs potentially interfering with T production should be advised. Testosterone replacement therapy (TRT) is contraindicated in men with untreated prostate or breast cancer, as well as severe heart failure. Severe low urinary tract symptoms and haematocrit >48%-50% represent relative contraindications for TRT. Prostate-specific antigen and digital rectal examination of the prostate should be undertaken in men >40years of age before initiating TRT to exclude occult prostate cancer. Transdermal T should be preferred for initiation of TRT, whereas gonadotrophin therapy is only recommended when fertility is desired in men with secondary hypogonadism. TRT is able to improve sexual function in hypogonadal men. Other potential positive outcomes of TRT remain uncertain and controversial. TRT can reliably improve global sexual function in men with hypogonadism in the short term. Long-term clinical benefits, and safety of TRT in functional hypogonadism, remain to be fully documented. Clinicians should therefore explicitly discuss the uncertainties and benefits of TRT and engage them in shared management decision-making.

Is Testosterone Replacement Safe in Men with Cardiovascular Disease?

Testosterone is an anabolic hormone that is responsible for the development of male sex organs. It also increases muscle mass and fortifies bone density. In addition to being responsible for primary sexual characteristics at birth and puberty (development and changes of sexual organs such as uterus, vagina, penis, and testes), testosterone is also involved in maintaining secondary sexual characteristics. Patients with low testosterone who are symptomatic should be treated with testosterone replacement therapy (TRT) once the diagnosis has been confirmed. The goal of treatment is to improve the symptoms including the physical, sexual, and cognitive health with the aim being to keep the testosterone in the mid-normal limit of the reference range. Male hypogonadism has been increasingly diagnosed and treated in elderly males since the last decade. A proportionate increase in the prescription of testosterone has been seen as well. The relationship of testosterone levels with cardiovascular (CV) outcomes is challenging and has shown conflicting results. Moreover, in patients with established CV disease, those with high CV risk factors including diabetes, or those with significant risk factors for atherosclerotic CV disease (ASCVD), the benefits of TRT should be weighed against the risks of replacement. Risks and benefits of TRT should be discussed with every patient prior to starting or restarting the procedure.

Late-onset hypogonadism: Prostate safety.

There have always been concerns regarding testosterone replacement therapy and prostate safety because of the central role of testosterone in prostate tissue. Even though there is a body of evidence supporting that the benefits of testosterone replacement therapy outbalance the risks of prostate disease, this matter is still debatable and represents a common concern among testosterone prescribers. The aim of this article was to review the influence of testosterone on prostate pathophysiology and discuss the potential impact of testosterone replacement therapy on the most common prostate pathologies, including benign prostatic hyperplasia and prostate cancer. We have performed an extensive PubMed review of the literature examining the effects of testosterone replacement therapy on the prostate and its most common affections, especially in terms of safety. Testosterone replacement therapy has been shown to improve components of metabolic syndrome and decrease prostate inflammation, which is related to the worsening of lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia. Studies evaluating the link between testosterone replacement therapy and benign prostatic hyperplasia/LUTS have mostly demonstrated no change in symptom scores and even some benefits. There are a significant number of studies demonstrating the safety of testosterone replacement therapy in individuals with late-onset hypogonadism and a history of prostate cancer. The most recently published guidelines have already acknowledged this fact and do not recommend against T treatment in this population, particularly in non-high-risk disease. Testosterone replacement therapy could be considered for most men with late-onset hypogonadism regardless of their history of prostate disease. However, a discussion about the risks and benefits of testosterone replacement therapy is always advised, especially in men with prostate cancer. Appropriate monitoring is mandatory.

Cardiovascular benefits and risks of testosterone replacement therapy in hypogonadal men with type 2 diabetes mellitus and/or the metabolic syndrome: a systematic review

Background: Because of the paucity of large randomised controlled trials (RCTs) in men with type 2 diabetes mellitus (T2DM) and/or the metabolic syndrome (MS), the majority of evidence for use of testosterone replacement therapy (TRT) on the cardiovascular (CV) system in such men is derived from observational studies and systematic reviews.Methods: We carried out an extensive retrospective review of the literature, comparing the major comparative trials that involved TRT in hypogonadal men with T2DM and/or MS and focused on CV outcomes.Results: Of 311 studies initially identified, 25 studies (12 RCTs and 13 non-RCTs) with a total number of 729,927 participants were deemed eligible for further review. Three RCTs and one non-RCT were excluded as these had not measured all-cause mortality and CV events as primary outcomes. Benefits of TRT on myocardial infarction were observed in two RCTs which were reviewed, while the rest demonstrated a neutral effect on CV events. In the non-RCTs, seven studies observed reduced all-cause mortality and/or major adverse CV events in the TRT group compared with the placebo group.Conclusions: This retrospective and systematic review of the literature suggests protective effects of TRT against all-cause mortality and major adverse cardiac events in hypogonadal men with T2DM and/or MS, although these results need to be interpreted cautiously.

Measuring testosterone and testosterone replacement therapy in men receiving androgen deprivation therapy for prostate cancer: A survey of UK uro-oncologists' opinions and practice.

To explore the practice and attitudes of uro-oncologists in the UK regarding monitoring testosterone levels and the use of testosterone replacement therapy (TRT) in their prostate cancer patients treated with androgen deprivation therapy (ADT). An expert-devised online questionnaire was completed by the members of the British Uro-oncology Group (BUG). Of 160 uro-oncologists invited, 84 completed the questionnaire. Before initiating ADT in patients with non-metastatic prostate cancer, only 45% of respondents measured testosterone levels and 61% did not measure testosterone at all during ADT in the adjuvant or neoadjuvant setting. However, in men with metastatic prostate cancer, 71% of the uro-oncologists measured testosterone before starting ADT and the majority continued testing during treatment. Approximately two-thirds of respondents did not prescribe TRT for their patients who were in remission following neo(adjuvant) ADT and who had castration levels of testosterone. Among UK uro-oncologists, the measurement of testosterone levels before and during ADT was not typically part of routine practice in the management of patients with prostate cancer. However, testosterone levels were checked more frequently for patients with metastatic disease than disease at an earlier stage. Testing could be conducted in parallel with PSA measurement as testosterone levels are linked to biochemical failure. The majority of specialists participating in the survey did not prescribe TRT for their patients in remission following ADT. Uro-oncologists in the UK do not generally measure testosterone as part of their patient management and they remain cautious about the possible benefits of TRT in men with prostate cancer.

Management Strategies in Opioid Abuse and Sexual Dysfunction: A Review of Opioid-Induced Androgen Deficiency.

Over the last several decades, the opioid epidemic has become a national crisis, largely spurred by the spike in the use of prescription painkillers. With the epidemic came a concomitant rise in the incidence of opioid-induced androgen deficiency (OPIAD). Although OPIAD can significantly impact male sexual function and quality of life, it is an overlooked and poorly understood clinical entity that requires more attention from healthcare providers. The objectives of the current review are to highlight the increasing incidence of OPIAD and the importance of an integrated, multidisciplinary approach to identify and treat patients with the condition. This review presents the epidemiology surrounding the current opioid epidemic, with a focus on its origin, followed by a literature review surrounding the pathophysiology, diagnosis, and treatment of OPIAD. Single-center studies were used to determine the safety and efficacy of various opioid and testosterone formulations on analgesia, sexual function, and quality of life. There should be a low threshold for obtaining laboratory studies (testosterone, luteinizing hormone [LH], follicle-stimulating hormone [FSH]) on symptomatic patients who have a history of chronic opioid use. Treatment options include opioid cessation, short-acting opioids, and testosterone replacement therapy (TRT). The patient and physician should weigh the risks and benefits of TRT against more conservative approaches. Options such as clomiphene and anastrozole are available for patients who wish to preserve fertility. Because OPIAD is an underappreciated and underdiagnosed consequence of chronic opioid abuse, healthcare providers should be particularly vigilant for signs of hypogonadism in this patient population. It is reasonable for pain specialists, urologists, and primary care physicians to closely monitor patients on prescription opioids and discuss available options for treatment of hypogonadism. Hsieh A, DiGiorgio L, Fakunle M, etal. Management strategies in opioid abuse and sexual dysfunction: A review of opioid-induced androgen deficiency. Sex Med Rev 2018;6:618-623.

The role of testosterone in MS risk and course

There is significant animal model data demonstrating a benefit of testosterone on both inflammatory and neuroprotective mechanisms relevant to multiple sclerosis (MS). Several studies have demonstrated lowered testosterone levels in up to 40% of men with MS. Lower testosterone levels were correlated with worsened scores of physical and cognitive disability. There is increasing data suggesting a role of testosterone in MS risk. A pilot study has demonstrated significant benefits of testosterone replacement therapy on cognitive, radiological, and immunological outcome measures in men with MS. Larger studies in other conditions have demonstrated concerns in terms of cardiovascular risk, which indicate the need for careful monitoring upon administration to MS patients. Further studies are needed to develop safer testosterone preparations, which preserve its multiple beneficial effects, as well as multicenter clinical trials to evaluate safety, dosing, and efficacy in larger populations of men with MS. Additionally, studies are needed to further explore the role of androgens as a risk factor for MS, particularly at key life transitions.

Quality of Life and Sexual Function Benefits of Long-Term Testosterone Treatment: Longitudinal Results From the Registry of Hypogonadism in Men (RHYME)

BackgroundThe benefits and risks of long-term testosterone administration have been a topic of much scientific and regulatory interest in recent years. AimTo assess long-term quality of life (QOL) and sexual function benefits of testosterone replacement therapy (TRT) prospectively in a diverse, multinational cohort of men with hypogonadism. MethodsA multinational patient registry was used to assess long-term changes associated with TRT in middle-age and older men with hypogonadism. Comprehensive evaluations were conducted at 6, 12, 24, and 36 months after enrollment into the registry. OutcomesQOL and sexual function were evaluated by validated measures, including the Aging Males’ Symptom (AMS) Scale and the International Index of Erectile Function (IIEF). ResultsA total of 999 previously untreated men with hypogonadism were enrolled at 25 European centers, 750 of whom received TRT at at least one visit during the period of observation. Patients on TRT reported rapid and sustained improvements in QOL, with fewer sexual, psychological, and somatic symptoms. Modest improvements in QOL and sexual function, including erectile function, also were noted in RHYME patients not on TRT, although treated patients showed consistently greater benefit over time in all symptom domains compared with untreated patients. AMS total scores for patients on TRT were 32.8 (95% confidence interval = 31.3–34.4) compared with 36.6 (95% confidence interval = 34.8–38.5) for untreated patients (P < .001). Small but significant improvements in IIEF scores over time also were noted with TRT. Approximately 25% of treated and untreated men also used phosphodiesterase type 5 inhibitors, with notable differences in the frequency of phosphodiesterase type 5 inhibitor prescription use according to physician specialty and geographic site location. Clinical ImplicationsTRT-related benefits in QOL and sexual function are well maintained for up to 36 months after initiation of treatment. Strengths and LimitationsThe major strengths are the large, diverse patient population being treated in multidisciplinary clinical settings. The major limitation is the frequency of switching from one formulation to another. ConclusionOverall, we confirmed the broad and sustained benefits of TRT across major QOL dimensions, including sexual, somatic, and psychological health, which were sustained over 36 months in our treatment cohort.Rosen RC, Wu F, Behre H, et al. Quality of Life and Sexual Function Benefits Effects of Long-Term Testosterone Treatment: Longitudinal Results From the Registry of Hypogonadism in Men (RHYME). J Sex Med 2017;14:1104–1115.

Testosterone deficiency

As its symptoms are non-specific and develop progressively, testosterone deficiency is often misdiagnosed and overlooked. Symptoms may be mild and accepted as normal manifestations of ageing. Some of these symptoms can indeed occur in ageing men who do not have testosterone deficiency. Diagnosis of testosterone deficiency in ageing men can be challenging, as symptoms of testosterone deficiency overlap with those of ’normal’ physiological ageing. GPs’ prescriptions of testosterone have increased significantly over the past decade. An increased awareness among GPs, when coupled with extra demand from patients, is likely to lead to increased prescribing of testosterone. Patient demand has increased with sophisticated drug marketing and guidelines promoting testing and treatment of testosterone deficiency. This article reviews the common clinical features and diagnosis of testosterone deficiency, identifies the risk and benefits of testosterone replacement therapy, and briefly discusses the associated controversies regarding prostate cancer and cardiovascular risk.

Gaps in Patient Knowledge About Risks and Benefits of Testosterone Replacement Therapy

To assess patient knowledge of the symptoms of testosterone deficiency, and the benefits and risks associated with testosterone replacement therapy (TRT). An anonymous, 10-question multiple choice survey was administered to consecutive patients presenting for urologic evaluation at an academic medical center, from December 2015 to April 2016. The survey included questions about perceived symptoms of testosterone deficiency, perceived benefits and risks associated with TRT, whether respondents had a diagnosis of testosterone deficiency, and whether they were interested in receiving TRT. The survey response rate was 88% (97/110). The median age group was 41-50 years. Although 43% of all respondents reported an interest in TRT, only half of them had a clinical diagnosis of hypogonadism. The most commonly reported symptoms of low testosterone were "low energy" (54%), "decreased libido" (51%), "weak erections" (52%), and "decreased strength" (42%). Of the perceived benefits of TRT, the most commonly reported were "improved sexual function" (54%), "increased energy" (53%), and "feeling better" (51%). Half of the respondents were unsure of the risks of TRT. Of the respondents, 16%, 10%, and 8% acknowledged the association between TRT and heart attack, TRT and stroke, and TRT and blood clots, respectively. There is disproportionate knowledge about the benefits vs the risks associated with TRT among patients. Although 43% of the respondents were interested in receiving TRT, half of the respondents were unsure of the associated risks. These findings indicate an ongoing need for patient education regarding TRT.

Demographic and Clinical Correlates of Patient-Reported Improvement in Sex Drive, Erectile Function, and Energy With Testosterone Solution 2%

IntroductionEvidence from well-designed studies documenting the benefit of testosterone replacement therapy as a function of patient demographic and clinical characteristics is lacking. AimTo determine demographic and clinical predictors of treatment outcomes in hypogonadal men with low sex drive, low energy, and/or erectile dysfunction. MethodsPost hoc analysis of a randomized, multicenter, double-blinded, placebo-controlled, 16-week study of 715 hypogonadal men (mean age = 55.3 years, age range = 19–92 years) presenting with low sex drive and/or low energy who received placebo or testosterone solution 2% for 12 weeks. Main Outcomes and MeasuresTwo levels defined patient-reported improvement (PRI) in sex drive or energy: level 1 was at least “a little better” and level 2 was at least “much better” in energy or sex drive on the Patient Global Impression of Improvement at study end point. PRI in erectile function was stratified by erectile dysfunction severity at baseline as measured by the erectile function domain of the International Index for Erectile Function: mild at baseline (change of 2), moderate at baseline (change of 5), and severe at baseline (change of 7). Associations of demographic and clinical characteristics with PRI were calculated with stepwise forward multiple logistic regression analysis. Odds ratios represented the likelihood of PRI in symptoms among variable categories. ResultsHigher levels of end-point testosterone were associated with higher rates of PRI (at levels 1 and 2) in sex drive and energy (P < .001 for the two comparisons). Lower baseline testosterone levels were associated with higher rates of level 1 PRI in sex drive (P = .028); and classic hypogonadism (vs non-classic hypogonadism) was associated with higher rates of level 2 PRI in sex drive (P = .005) and energy (P = .006). ConclusionWhen assessing the potential for improvements in men with testosterone deficiency using patient-reported outcome questionnaires, possible predictors of treatment outcomes to consider include the etiology of hypogonadism and testosterone levels (baseline and end point).

Hypotestosteronaemia in the aging male: should we treat it?

The term male hypogonadism is defined as the failure to maintain physiological concentrations of testosterone, a physiological quantity of sperm or the combination of both. Aetiologically, androgen deficiency can originate from the testes (primary hypogonadism) or from the hypothalamic-pituitary regulation of the testicular function (secondary hypogonadism). The causes of hypogonadism are very diverse and may be genetically determined (e.g. Klinefelter's syndrome) or acquired (tumours, infections, haemochromatosis). Classical hypogonadism linked to an underlying disease, such as a pituitary tumour, is a distinct indication for androgen substitution. But how about the aging male? It is known that there is a highly variable age-related decline in testosterone levels; whether this represents a variation of normality or has a true disease value requiring therapy has been disputed over more than a decade. The key questions surrounding this debate concern not only the age-dependent threshold for serum testosterone but, more importantly, the risks and benefits of testosterone replacement therapy in the aging male. We searched the literature for randomised controlled trials of testosterone administration in aging males with a size of at least 100 patients and a follow-up of at least 6 months, and identified eight studies. These studies mostly tried to evaluate the effect of testosterone on bone density, muscle strength and body composition, rather than clinically meaningful endpoints. Moreover, these trials have provided evidence for relevant cardiovascular adverse events in elderly men. This supports the need for further studies to define the treatment threshold for testosterone levels in the aging male, as well as with regard to the long-term risks and relevant benefits of testosterone therapy in this population. Until we have more solid data in aging males, testing for testosterone deficiency and testosterone replacement should remain reserved for patients with predisposing conditions, symptoms and signs of bona fide hypogonadism.

Pharmacotherapy. Benefit of testosterone replacement therapy on CVD and mortality.

Pharmacotherapy. Benefit of testosterone replacement therapy on CVD and mortality.

Injection of testosterone may be safer and more effective than transdermal administration for combating loss of muscle and bone in older men.

The value of testosterone replacement therapy (TRT) for older men is currently a topic of intense debate. While US testosterone prescriptions have tripled in the past decade (9), debate continues over the risks and benefits of TRT. TRT is currently prescribed for older men with either low serum testosterone (T) or low T plus accompanying symptoms of hypogonadism. The normal range for serum testosterone is 300 to 1,000 ng/dl. Serum T ≤ 300 ng/dl is considered to be low, and T ≤ 250 is considered to be frank hypogonadism. Most experts support TRT for older men with frank hypogonadism and symptoms. Treatment for men who simply have low T remains somewhat controversial. TRT is most frequently administered by intramuscular (im) injection of long-acting T esters or transdermally via patch or gel preparations and infrequently via oral administration. TRT produces a number of established benefits in hypogonadal men, including increased muscle mass and strength, decreased fat mass, increased bone mineral density, and improved sexual function, and in some cases those benefits are dose dependent. For example, doses of TRT administered by im injection are typically higher than those administered transdermally, which results in greater musculoskeletal benefits. TRT also produces known risks including development of polycythemia (Hct > 50) in 6% of those treated, decrease in HDL, breast tenderness and enlargement, prostate enlargement, increases in serum PSA, and prostate-related events and may cause suppression of the hypothalamic-pituitary-gonadal axis. Importantly, TRT does not increase the risk of prostate cancer. Putative risks include edema and worsening of sleep apnea. Several recent reports have also indicated that TRT may produce cardiovascular (CV) risks, while others report no risk or even benefit. To address the potential CV risks of TRT, we have recently reported via meta-analysis that oral TRT increases CV risk and suggested that the CV risk profile for im TRT may be better than that for oral or transdermal TRT.

Cardiovascular Benefits of Testosterone Replacement Therapy in the Andropausal Male

Androgen deficiency has been receiving a lot of attention as an evolving health concern in the in-dustrialized world. With population aging, hypogonadism has become a challenging medical problem confronting practicing physicians. The importance of this increasingly prevalent disease arises from its potentially debilitating and serious consequences, such as atherosclerosis, diabetes mellitus, metabolic disorders, muscular weakness, psychiatric illness, sexual dysfunction and vascular inflammation. When left untreated, testosterone deficiency is associated with increased cardiovascular mortality.

Bone health in hypogonadal men.

To examine bone health in relation to testosterone and male hypogonadism. An emerging area of research pertains to the newly described bone-testis axis. In particular, the peptide hormone osteocalcin, which is made by bone and fat, appears to play a role in testosterone production. Inconsistent weak associations have been noted between vitamin D deficiency or insufficiency and lower testosterone levels. Although a high prevalence of hypogonadism is associated with opioid use, HIV and transfusion-dependent thalassemia, the risk of fracture in these populations is unclear. In fact, one study found that the modest increase in fractures among opioid users was attributed to central nervous system adverse effects of the medications as opposed to chronic hypogonadism. In terms of therapy, many small studies have found that testosterone replacement therapy increases bone mineral density in hypogonadal men, including men with hypopituitarism. Further research is needed on the cross-talk that occurs in the bone-testis axis. When it comes to managing men with hypogonadism, the benefit of testosterone replacement therapy on prevention of incident fractures is uncertain. Large, long-term randomized controlled trials are needed with fracture as the primary outcome.