Andropause or Male Menopause? Rationale for Testosterone Replacement Therapy in Older Men with Low Testosterone Levels

ObjectiveTo provide rationale for testosterone replacement therapy (TRT) in older men with low testosterone levels and symptoms consistent with testosterone deficiency.MethodsThe relevant literature was reviewed using PubMedResultsCross-sectional and longitudinal population-based studies indicate that total and free testosterone levels fall with aging, and they may be accompanied by symptoms consistent with androgen deficiency. Testosterone treatment of younger men with very low testosterone levels and hypothalamic, pituitary, or testicular disease is associated with improvements in symptoms, body composition, bone density, and hematocrit/hemoglobin. Studies evaluating testosterone treatment of older men with low testosterone levels are limited, but they suggest some increase in fat free mass, some decrease in fat mass, and some increase in bone density of the lumbar spine and femoral neck.ConclusionThe Testosterone Trial should provide definitive information regarding the potential benefits of TRT in men ≥ years of age. If efficacy is confirmed, we will still need more information regarding the risks of TRT in older men. (Endocr Pract. 2013;19:847-852)     

Fundamental aspects of hypogonadism in the aging male

With aging in men, serum testosterone levels decline progressively and the prevalence of hypogonadism increases; these changes are associated with alterations in androgen-regulated physiological functions. In young hypogonadal men, similar alterations improve with testosterone replacement. In older men, short-term testosterone treatment trials suggest benefits (eg, on body composition and bone mineral density), without significant adverse effects. Therefore, androgen deficiency may contribute to physiological decline with aging, and testosterone therapy is reasonable for older men with clinical manifestations of androgen deficiency and low testosterone levels. However, the long-term benefits and potential risks (eg, for prostate disease) of testosterone treatment in older men are unknown.     

Does Testosterone Therapy Increase the Risk of Prostate Cancer?

ObjectiveTo review factors affecting use of testosterone therapy for hypogonadism including the persistent controversial link between testosterone therapy and prostate cancer.MethodsWe reviewed studies investigating the relationship between testosterone therapy and prostate cancer progression and summarized strategies for hypogonadism management and prostate monitoring.ResultsTrials of up to 36 months in length and longitudinal studies consistently fail to demonstrate an increased prostate cancer risk associated with increased testosterone levels. No evidence of an associated relationship between exogenous testosterone therapy and prostate cancer has emerged from clinical trials or adverse event reports. It does not appear that exogenous testosterone accumulates in the prostate or provokes major biologic change in the prostate gland. In addition, preliminary evidence indicates that low endogenous testosterone may confer an increased risk of prostate cancer.ConclusionsMounting evidence demonstrates that there is a lack of association between testosterone therapy and prostate cancer progression. Testosterone therapy may be prescribed for men for whom it was once not considered. Careful monitoring of patients with hypogonadism who are receiving testosterone therapy is imperative. Well-designed, large-scale prospective clinical trials are necessary to adequately address prostate safety in hypogonadal men receiving testosterone therapy. (Endocr Pract. 2008;14:904-911)     

Invasive Breast Cancer After Initiation of Testosterone Replacement Therapy in A Man—A Warning To Endocrinologists

ObjectiveTo alert fellow endocrinologists of a rare side effect of testosterone therapy, for which men with hypogonadism must receive appropriate counseling and monitoring.MethodsWe present clinical features, laboratory data, and histopathologic findings in a man with hypogonadism who received testosterone replacement therapy.ResultsA 61-year-old man was referred to an endocrinologist after presenting to his general practitioner with erectile dysfunction and low libido. He had no history of hypothalamic, pituitary, or testicular disorders. There were no other illnesses or medications to account for low testosterone levels. Physical examination was unremarkable. There was no family history of malignant disease. Biochemical investigations confirmed the presence of primary hypogonadism, for which no cause (including Klinefelter syndrome) was identified. Testosterone therapy was initiated to improve sexual function and preserve bone density. Five weeks later, the patient returned to his general practitioner, complaining of a gradually enlarging lump in his right breast. When biopsy showed breast cancer, testosterone therapy was discontinued. Right mastectomy and axillary node clearance were performed. Further histologic examination revealed estrogen receptor-positive, invasive carcinoma, without nodal involvement. The patient remains on tamoxifen therapy and is undergoing follow-up in the breast clinic. After 6 months of treatment, estradiol levels were undetectable, and testosterone levels remained low.ConclusionAlthough breast cancer has been described in men with hypogonadism receiving long-term testosterone replacement therapy, to our knowledge this is the first report of breast cancer becoming clinically manifest after a short duration (5 weeks) of testosterone treatment. This case should remind clinicians that men receiving testosterone therapy should be warned of the risk of not only prostate cancer but also breast cancer. Patient self-monitoring and breast examinations by the attending physician are recommended. (Endocr Pract. 2008;14: 201-203)     

Predicting low testosterone in aging men: a systematic review

Background:Physicians diagnose and treat suspected hypogonadism in older men by extrapolating from the defined clinical entity of hypogonadism found in younger men. We conducted a systematic review to estimate the accuracy of clinical symptoms and signs for predicting low testosterone among aging men.Methods:We searched the MEDLINE and Embase databases (January 1966 to July 2014) for studies that compared clinical features with a measurement of serum testosterone in men. Three of the authors independently reviewed articles for inclusion, assessed quality and extracted data.Results:Among 6053 articles identified, 40 met the inclusion criteria. The prevalence of low testosterone ranged between 2% and 77%. Threshold testosterone levels used for reference standards also varied substantially. The summary likelihood ratio associated with decreased libido was 1.6 (95% confidence interval [CI] 1.3–1.9), and the likelihood ratio for absence of this finding was 0.72 (95% CI 0.58–0.85). The likelihood ratio associated with the presence of erectile dysfunction was 1.5 (95% CI 1.3–1.8) and with absence of erectile dysfunction was 0.83 (95% CI 0.76–0.91). Of the multiple-item instruments, the ANDROTEST showed both the most favourable positive likelihood ratio (range 1.9–2.2) and the most favourable negative likelihood ratio (range 0.37–0.49).Interpretation:We found weak correlation between signs, symptoms and testosterone levels, uncertainty about what threshold testosterone levels should be considered low for aging men and wide variation in estimated prevalence of the condition. It is therefore difficult to extrapolate the method of diagnosing pathologic hypogonadism in younger men to clinical decisions regarding age-related testosterone decline in aging men.Male hypogonadism is defined as the presence of low serum testosterone and spermatozoa levels, accompanied by clinical signs and symptoms.¹ The Endocrine Society divides the symptoms and signs of androgen deficiency into 2 groups, based on expert consensus.¹ The first group, which is considered more specific, includes incomplete or delayed sexual development; eunuchoidism; reduced sexual desire (libido); erectile dysfunction; gynecomastia; decreased axillary, facial and pubic hair; small testes (i.e., volume < 5 mL); infertility: low-trauma fracture; low bone mineral density; and hot flushes.¹ The second group includes less specific signs and symptoms, such as decreased energy and motivation, depressed mood, poor concentration and memory, sleep disturbance, mild anemia, reduced muscle bulk and strength, increased body fat or body mass index, and diminished physical performance. ¹ Similar definitions have recently been developed by the Canadian Men’s Health Foundation Multidisciplinary Guidelines Task Force on Testosterone Deficiency.²In young men, hypogonadism is more commonly characterized by signs and symptoms from the first group, such as reduced libido and erectile dysfunction. This condition is most often caused by testicular or pituitary pathology, including hyperprolactinemia, pituitary or hypothalamic disorders, testicular disease, radiation exposure or genetic diseases such as Klinefelter syndrome.³ Testosterone replacement is indicated in these cases of “classic hypogonadism,” as it ameliorates the clinical symptoms.⁴In contrast, although these entities exist in older men too, they are less frequent causes of low testosterone than age-related changes. There is evidence that testosterone levels decline with age in all men, regardless of symptoms, at an estimated rate of 1%–3% per year.^5,6 One study found that serum testosterone levels were below the normal range in 20% of men in their 60s and in close to 50% of men in their 80s.⁷ However, the prevalence of symptomatic low testosterone (hypogonadism) is estimated by some to be much lower in this population, at about 2%.⁸ Given the high prevalence of low testosterone and more limited correlation with symptoms in aging men, it is uncertain to what extent this represents a physiologic or pathologic event.^6,7 Moreover, symptoms typically associated with low testosterone are less specific in older men and may be caused by other comorbidities. For example, erectile dysfunction can be the result of vascular insufficiency, neurologic impairment, psychogenic causes or substance use.⁹ Conditions such as diabetes mellitus and atherosclerosis are more common in older men, with up to 40% of men over 50 years of age having evidence of vascular insufficiency as the primary cause of their erectile dysfunction.¹⁰ Low libido similarly can result from psychiatric or medical conditions that are more common in older men.¹¹Currently, many clinicians diagnose hypogonadism in older men on the basis of low serum testosterone levels, with or without symptoms, largely on the assumption that this is a pathologic condition requiring treatment. The purpose of this study was to systematically review the available literature to estimate the accuracy and operating characteristics of signs and symptoms for predicting low testosterone in aging men.     

Optimizing Diagnostic Accuracy and Treatment Decisions in Men With Testosterone Deficiency

ObjectiveThis narrative review offers a guideline-based approach for optimizing diagnostic evaluation and treatment decision making in men being evaluated for testosterone deficiency.MethodsA narrative review.ResultsTestosterone deficiency is a clinical syndrome that results from the inability of the testes to produce normal amounts of testosterone and is characterized by a constellation of symptoms and signs associated with consistently low testosterone concentrations. The diagnosis of testosterone deficiency is made by the ascertainment of symptoms and signs; the measurement of total and, if indicated, free testosterone levels in early-morning fasting samples on ≥2 days; the measurement of luteinizing hormone and follicular-stimulating hormone levels to distinguish primary from secondary hypogonadism; and an additional evaluation to ascertain the cause of testosterone deficiency. Nonspecificity of symptoms and signs, variations in testosterone levels over time, inaccuracy in the measurement of total and free testosterone levels, variations in binding protein concentrations, and suboptimal reference ranges contribute to diagnostic inaccuracy. Testosterone treatment is indicated for men with symptomatic testosterone deficiency. Testosterone treatment should be avoided in men with prostate or breast cancer, erythrocytosis, thrombophilia, increased risk of prostate cancer or severe lower urinary tract symptoms without prior urologic evaluation, a recent major adverse cardiovascular event, uncontrolled heart failure, or severe untreated sleep apnea. Testosterone replacement therapy should be accompanied by a standardized monitoring plan.ConclusionA shared decision of the patient and physician to treat should be guided by the consideration of the burden of symptoms, potential benefits and risks, patient’s values, and the cost and burden of long-term treatment and monitoring.     

Effects of Bisphosphonates on Bone of Osteoporotic Men With Different Androgen Levels: A Case-Control Study

ObjectiveOsteoporosis in men has been neglected despite its association with disability and mortality. We evaluated the effect of bisphosphonates (BPs) on bone mineral density (BMD) and bone turnover biomarkers of osteoporotic men with different androgen levels.MethodsThis case-control study included 136 osteoporotic men who were divided into normal group (n = 75) and hypogonadism group (n = 61) (patients treated with testosterone were excluded) according to their serum testosterone levels (cutoff value, 350 ng/dL). BMD, serum testosterone, total alkaline phosphatase, and cross-linked C-telopeptide of type I collagen were detected. The relationship between testosterone levels and BMD at baseline was evaluated. All patients were treated with BPs for 2 years. We compared the effects of BPs on BMD and bone turnover biomarkers between the 2 groups.ResultsAt baseline, there were no significant differences in BMD and bone turnover biomarkers between the 2 groups. Testosterone levels were positively correlated with BMD in the hypogonadism group. After treatment, the lumbar BMD increased by 7.65% ± 1.54% and 7.47% ± 1.88% in normal and hypogonadism groups, respectively (both P < .01 vs baseline) and hip BMD increased without significant differences between the 2 groups. Serum cross-linked C-telopeptide of type I collagen and alkaline phosphatase levels decreased without significant differences between the 2 groups (all P < .01 vs baseline).ConclusionTestosterone level is positively correlated with BMD in men with hypogonadism. In osteoporotic men, BPs significantly increase spine and hip BMD and decrease bone resorption. The efficacy of BPs is similar in men with or without hypogonadism.     

Diagnostic et traitement du déficit en androgènes des patients infectés par le virus de l’immunodéficience humaine

Androgen deficiency is frequent among men infected by the human immune deficiency virus (HIV), with an estimated prevalence of between 35% and 50%. Primary testicular damage has been described, either due to the virus itself, opportunistic agents such as CMV,Toxoplasma gondii orMycobacterium avium intracellulare, or less frequently neoplastic invasion by lymphoma or in a context of Kaposi’s sarcoma. However, secondary hypogonadism remains a more frequent cause. Hypogonadotropic hypogonadism can be secondary to opportunistic infections, malnutrition, and sometimes even certain therapeutic agents. Since the introduction of highly active antiretroviral therapies, the prevalence of hypogonadism has substantially decreased. However, it remains a significant clinical problem, particularly among patients suffering from wasting, as androgen deficiency may aggravate the loss of lean body mass observed in the wasting syndrome of HIV patients. Screening for androgen deficiency is therefore indicated in HIV patients suffering from wasting, even in the absence of specific symptoms. Androgen replacement therapy is justified in symptomatic (loss of libido, impotence) and asymptomatic patients with documented hypogonadism. We recommend replacement therapy with testosterone by subcutaneous or intramuscular injection. In the absence of specific symptoms, it should be remembered that testosterone replacement therapy of HIV-infected hypogonadic patients is associated with improvements in body composition and muscle strength, bone densitometry, quality of life and mood. Similar improvements have also been demonstrated in hypogonadic patients with wasting syndrome. Synthetic testosterone analogues such as oxandrolone or nandrolone do not seem to be more powerful than testosterone at replacement doses, and may be associated with more side effects, particularly severe hepatic dysfunction. In contrast, there is no proven benefit of androgen treatment of eugonadic HIV-infected patients, and the treatment of such patients with androgens, even in the presence of wasting, cannot be recommended.     

Prevalence of Hypogonadism in Patients with Type 2 Diabetes Mellitus in an Asian Indian Study Group

ObjectiveTo determine the prevalence of hypogonadism in Asian Indian patients with type 2 diabetes mellitus (T2DM) and to correlate it with components of the metabolic syndrome and microvascular complications of T2DM.MethodsOne hundred consecutive male patients with T2DM between 25 and 50 years of age and 50 age-matched healthy adults without diabetes underwent assessment. Calculated free testosterone was derived by using serum total testosterone and sex hormone-binding globulin. Those patients with 2 calculated free testosterone values less than 64.8 pg/mL were diagnosed as having hypogonadism.ResultsOf the 100 patients with T2DM, 15 (15%) were found to have hypogonadism—7 of 29 (24%) between 31 and 40 years of age and 8 of 67 (12%) between 41 and 50 years old. None of the 4 patients between 25 and 30 years old had hypogonadism. Eleven patients (73%) had hypogonadotropic hypogonadism, and 4 (27%) had hypergonadotropic hypogonadism. Among the control subjects, the prevalence of hypogonadism was 10%. In comparison with Western data, we found a higher prevalence of hypogonadism in patients with T2DM, especially in those in the 4th decade of life. The prevalence of hypogonadism was higher in obese patients, although it did not reach statistical significance. No statistically significant correlation was observed between hypogonadism and age, duration of diabetes, glycemic control, androgen deficiency symptoms, or microvascular complications.ConclusionThe prevalence of hypogonadism was higher in the patients with diabetes than in the control subjects, although the difference did not reach statistical significance. There was no correlation of hypogonadism with components of the metabolic syndrome or microvascular complications of diabetes mellitus. (Endocr Pract. 2009;15:513-520)     

Pharmacokinetics And Relative Bioavailability Of Absorbed Testosterone After Administration Of A 1.62% Testosterone Gel To Different Application Sites In Men With Hypogonadism

ObjectiveTo determine the pharmacokinetics, bioavailability, and safety of a new formulation (1.62%) of testosterone gel that produces eugonadal serum testosterone levels with use of a lower amount of gel than the currently available 1% gels.MethodsIn an open-label, randomized, 3-way crossover study, 36 male patients with hypogonadism applied 5 g of 1.62% testosterone gel (81 mg of testosterone) once daily to the abdomen, to the upper arms/shoulders, or alternating between both sites per an established schedule for7 days. Serum levels of testosterone, dihydrotestosterone, and estradiol were measured and used to compare the pharmacokinetics and bioavailability of the 3 treatments.ResultsEach application method produced average serum testosterone concentrations within the eugonadal range (300 to 1,000 ng/dL), and steady-state testosterone concentrations were achieved after 2 days of gel application to either the abdomen or the upper arms/shoulders. When testosterone gel was applied to the abdomen, approximately 30% to 40% lower bioavailability (based on area under the serum concentration-time curve from 0 to 24 hours) was observed in comparison with application to the upper arms/shoulders. The 1.62% testosterone gel was found to be safe and well tolerated in men with hypogonadism.ConclusionAlthough lower testosterone bioavailability was observed after abdominal application of 1.62% testosterone gel in comparison with application to the upper arms/shoulders, application to either site yielded eugonadal levels of serum testosterone. (Endocr Pract. 2011;17:574-583)     

Androgen treatment of male hypogonadism in older males

The treatment of primary and secondary hypogonadism with testosterone is well established. Recently, there has been increased awareness that low testosterone levels also occur in chronically ill persons and aging males. Because of sex hormone binding globulin changes, it is more appropriate to make the diagnosis using either free or bioavailable testosterone. A small number of controlled studies have suggested that testosterone replacement in older men improves libido, quality of erections, some aspects of cognition, muscle mass, muscles strength, and bone mineral density. It also decreases fat mass and leptin levels. A number of screening questionnaires for the andropause have been developed. Insufficient numbers of older men have been treated with testosterone to characterize the true incidence of side effects. There is a desperate need for well designed, large controlled trials to establish the value or otherwise of testosterone treatment in older males.     

Gonadopenia And Aging In Men

Objective: The decrease in testosterone levels that occurs with aging has become an important clinical issue both due to the growth of the geriatric population and patient interest in testosterone therapy. The decision to assess for testosterone deficiency and the ability to determine whether the benefits exceed the risks require a comprehensive evaluation of the aging patient. This article is part of a series of papers focused on the endocrinology of aging. This review addresses common issues needed for clinical decision making, including how to interpret test results, differential diagnosis, potential impact of testosterone treatment on insulin resistance and cardiovascular disease, and options for therapy.Methods: Papers reviewed were identified through literature searches conducted on PubMed.Results: Assessment of testosterone levels in the geriatric male requires an understanding of the limitations of the assay that is used, the symptoms associated with low testosterone, the impact of comorbid conditions on levels, and risks of therapy. Successful treatment requires setting realistic expectations of the benefits of replacement therapy.Conclusion: While the prevalence of low testosterone concentrations is increased with aging, the common comorbidities such as obesity and diabetes may contribute to changes in testosterone levels. Clinical trial evidence shows modest benefit for treatment of low testosterone in the presence of symptoms. Assessment of the geriatric male should include evaluation of their testosterone level in the context of their functional status and comorbidities.Abbreviations: CDC = Centers for Disease Control and Prevention; CI = confidence interval; CVD = cardiovascular disease; DXA = dual-energy X-ray absorptiometry; EMAS = European Male Aging Study; FDA = U.S. Food and Drug Administration; FHS = Framingham Heart Study; HDL = high-density lipoprotein; HOMA-IR = homeostasis model assessment of insulin resistance; LH = luteinizing hormone; OR = odds ratio; PSA = prostate-specific antigen; SHBG = sex hormone–binding globulin; T2DM = type 2 diabetes mellitus; vBMD = volumetric bone mineral density     

Treatment of Hypogonadism with Testosterone in Patients with Type 2 Diabetes Mellitus

ObjectiveTo investigate the effect of testosterone treatment on insulin resistance, glycemic control, and dyslipidemia in Asian Indian men with type 2 diabetes mellitus (T2DM) and hypogonadism.MethodsWe conducted a double-blind, placebo-controlled, crossover study in 22 men, 25 to 50 years old, with T2DM and hypogonadism. Patients were treated with intramuscularly administered testosterone (200 mg every 15 days) or placebo for 3 months in random order, followed by a washout period of 1 month before the alternative treatment phase. The primary outcomes were changes in fasting insulin sensitivity (as measured by homeostasis model assessment [HOMA] in those patients not receiving insulin), fasting blood glucose, and hemoglobin A1c. The secondary outcomes were changes in fasting lipids, blood pressure, body mass index, waist circumference, waist-to-hip ratio, and androgen deficiency symptoms. Statistical analysis was performed on the delta values, with the treatment effect of placebo compared with the effect of testosterone.ResultsTreatment with testosterone did not significantly influence insulin resistance measured by the HOMA index (mean treatment effect, 1.67 ± 4.29; confidence interval, -6.91 to 10.25; P > .05). Mean change in hemoglobin A1c (%) (-1.75 ± 5.35; -12.46 to 8.95) and fasting blood glucose (mg/dL) (20.20 ± 67.87; -115.54 to 155.94) also did not reach statistical significance. Testosterone treatment did not affect fasting lipids, blood pressure, and anthropometric determinations significantly.ConclusionIn this study, testosterone treatment showed a neutral effect on insulin resistance and glycemic control and failed to improve dyslipidemia, control blood pressure, or reduce visceral fat significantly in Asian Indian men with T2DM and hypogonadism. (Endocr Pract. 2010;16:570-576)     

Androgen supplementation and prostate cancer risk: strategies for pretherapy assessment and monitoring

Since in men androgen levels decrease with age and result in symptoms of hypogonadism, the use of testosterone supplementation to treat symptoms resulting from hypogonadism is increasing. One potential complication of this treatment is the possibility of an increased risk of prostate cancer. Although most authorities agree that androgen is involved in the exacerbation of existing carcinoma of the prostate, the action of androgens on the carcinogenic process is not well understood. Attempts to demonstrate a correlation between hormone levels and prostate cancer have yielded inconsistent results. No clear evidence exists that androgen supplementation to restore physiologic levels produces any deleterious effects on the prostate. It is highly doubtful that when testosterone therapy is administered to middle-aged or older men, any potential prostate cancer promotion effect will be clinically manifested in the absence of already established cancer. It is, however, imperative that existing or developing prostate cancer be ruled out before initiation and during androgen replacement therapy. As with any therapeutic regimen, careful monitoring of the patient receiving treatment is recommended and constitutes good medical care.     

Low Testosterone Levels are Frequent in Patients with Acute Respiratory Failure and Are Associated with Poor Outcomes

ObjectiveLow testosterone level is a common finding in critically ill patients with trauma, shock, and sepsis. However, its prevalence and outcomes in patients with primary acute respiratory failure is unknown; low testosterone could contribute to respiratory muscle weakness and further compromise ventilation in these patients.MethodsWe aimed to determine the prevalence, severity, and effects of hypotestosteronemia in patients with acute respiratory failure in a 16-bed single academic center medical intensive care unit (ICU). We studied 30 men who required mechanical ventilation for ≥ 24 hours for a primary diagnosis of acute respiratory failure. Blood samples were drawn on ICU day 1 and day 3 to measure serum levels of total and free testosterone.ResultsHypotestosteronemia (level below the lower reference limit) was present on day 1 in 93.1% (total testosterone) and 76.7% (free testosterone) of patients and on day 3 in 94.4% (total testosterone) and 100% (free testosterone) of patients. Sex hormone–binding globulin, dehydroepiandrosterone sulfate, follicle-stimulating hormone, luteinizing hormone, and thyroid function levels were all within stated reference ranges. Total and free testosterone levels correlated inversely with ventilator days and ICU length of stay.ConclusionHypotestosteronemia is common in mechanically ventilated patients with primary acute respiratory failure and may contribute to longer ICU stay. Further studies are needed to determine the effect of testosterone replacement on short- and long-term outcomes in these patients. (Endocr Pract. 2014;20:1057-1063)     

Déficit androgénique lié à l’âge. Que faut-il attendre de l’androgénothérapie?

With the exception of disease or drug-induced changes in Leydig cell function, aging is accompanied by specific changes of androgen status in healthy men. The level of testosterone production decreases in contrast with the rise in plasma protein testosterone binding capacity. Free testosterone, considered to be the biologically active fraction, decreases, leading to tissue androgen deficiency. The resulting clinical picture mimics hypogonadism, including physical and psychological asthenia, decreased libido and sexual behaviour, increased fat mass and decreased lean mass, gynaecomastia, osteoporosis and pro-atherogenic metabolic changes. The cut-off value for plasma testosterone below which androgen deficiency can be considered to be responsible for clinical signs is a key point which determines the therapeutic approach. In the absence of clearly validated data in healthy aging males, this cut-off value has been consensually defined as the mean plasma testosterone levels of men between 30 and 50 years of age minus two standard deviations, corresponding to the zone of hypogonadism in adult males. The association of clinical signs compatible with hypogonadism and reduced total (or preferably bioavailable) plasma testosterone level justifies initiation of hormone replacement therapy after excluding any contraindications (especially prostatic). The aim of this treatment is to reverse the consequences of age-related hypogonadism. Some benefits of this treatment have been clearly demonstrated, such as a decrease of fat mass, and an increase of lean mass and muscle strength. Similarly, bone mineral density increases, particularly in men with the lowest pretreatment plasma testosterone levels. It must be stressed that these changes are observed in truly hypogonadal aging men, but not in aging men with normal plasma testosterone levels. Testosterone replacement therapy can promote the development of gynaecomastia, while dihydrotestosterone tends to reduce gynaecomastia. Finally, androgen replacement therapy appears to improve a hypogonadism-related decrease in libido or sexual behaviour, provided other associated non-endocrine factors have been previously treated. Androgen replacement therapy improves well-being, and physical and psychological asthenia in hypogonadal men. However, this treatment has not been demonstrated to be effective in healthy aging men. Although androgen replacement therapy does not have a negative impact on lipid parameters, its possible cardiovascular protective effects have not yet been demonstrated. In conclusion, androgen replacement therapy, respecting the contraindications, is beneficial in patients of all ages with clearly demonstrated hypogonadism, but has no efficacy on symptoms in other cases.     

Estrogen Levels Do Not Rise With Testosterone Treatment For Transgender Men

Objective: Existing transgender treatment guidelines suggest that for transmasculine treatment, there is a possible need for estrogen-lowering strategies adjunct to testosterone therapy. Further, guidelines advocate consideration of prophylactic female reproductive tissue surgeries for transgender men to avoid the possibility of estrogen-related health risks. Despite the paucity of objective data, some transgender men seek conversion inhibitors. We sought to determine estradiol levels in transgender men treated with testosterone therapy and the change in those levels with treatment, if any.Methods: Estradiol levels were extracted from the electronic medical records of 34 anonymized transgender men treated with testosterone therapy at the Endocrinology Clinic at Boston Medical Center. Data were sufficient to observe 6 years of follow-up.Results: With increased testosterone levels in trans-gender men, a significant decrease in estradiol levels was noted. There was a significant negative correlation between testosterone levels and body mass index, which may serve to explain part of the mechanism for the fall in estradiol levels. Even though the fall in estradiol levels was significant statistically, the actual levels remained within the normal male range, even with 6 years of follow-up.Conclusion: These data suggest that when exogenous testosterone is used to achieve normal serum male testosterone levels for transgender men, it is converted to normal male levels of estradiol, with some decline in those estradiol levels that might be attributable to a fall in fat mass. There appears to be no role for aromatase conversion inhibitors or other estrogen-reducing strategies in trans-gender men.Abbreviation: BMI = body mass index     

Osteoporosis in male hypogonadism: responses to androgen substitution differ among men with primary and secondary hypogonadism

BACKGROUND: No randomized study exists comparing the effects of different modes of androgen substitution on bone mineral density (BMD). METHODS: We performed a prospective, randomized, trial assigning 53 hypogonadal men to the following treatment groups: mesterolone 100 mg p.o. daily, testosterone undecanoate 160 mg p.o. daily, testosterone enanthate 250 mg i.m. every 21 days, or a single subcutaneous implantation of 1,200 mg crystalline testosterone. The BMD was determined by peripheral quantitative computed tomography. RESULTS: At baseline, men with secondary hypogonadism (n = 33) had a lower BMD (-1.52 +/- 0.23 SDS; Z-scores) than men with primary hypogonadism (n = 20, -0.87 +/- 0.23 SDS, p < 0.01). In men with primary hypogonadism, the BMD increased dose dependently (crystalline testosterone +7.0 +/- 1.3%, testosterone enanthate +4.8 +/- 0.2%, testosterone undecanoate +3.4 +/- 2.5%, mesterolone +0.8 +/- 1.6%) after 6 months of therapy. Only secondary hypogonadal men treated with testosterone enanthate experienced an increase of the BMD. CONCLUSIONS: In primary hypogonadal men the BMD responds dose dependently to testosterone substitution, whereas in secondary hypogonadism only testosterone enanthate treatment significantly increased the BMD.