The effects and safety of testosterone replacement therapy for men with hypogonadism: the TestES evidence synthesis and economic evaluation.

Background: Low levels of testosterone cause male hypogonadism, which is associated with sexual dysfunction, tiredness and reduced muscle strength and quality of life. Testosterone replacement therapy is commonly used for ameliorating symptoms of male hypogonadism, but there is uncertainty about the magnitude of its effects and its cardiovascular and cerebrovascular safety. Aims of the research: The primary aim was to evaluate the safety of testosterone replacement therapy. We also assessed the clinical and cost-effectiveness of testosterone replacement therapy for men with male hypogonadism, and the existing qualitative evidence on men's experience and acceptability of testosterone replacement therapy. Design: Evidence synthesis and individual participant data meta-analysis of effectiveness and safety, qualitative evidence synthesis and model-based cost-utility analysis. Data sources: Major electronic databases were searched from 1992 to February 2021 and were restricted to English-language publications. Methods: We conducted a systematic review with meta-analysis of individual participant data according to current methodological standards. Evidence was considered from placebo-controlled randomised controlled trials assessing the effects of any formulation of testosterone replacement therapy in men with male hypogonadism. Primary outcomes were mortality and cardiovascular and cerebrovascular events. Data were extracted by one reviewer and cross-checked by a second reviewer. The risk of bias was assessed using the Cochrane Risk of Bias tool. We performed one-stage meta-analyses using the acquired individual participant data and two-stage meta-analyses to integrate the individual participant data with data extracted from eligible studies that did not provide individual participant data. A decision-analytic Markov model was developed to evaluate the cost per quality-adjusted life-years of the use of testosterone replacement therapy in cohorts of patients of different starting ages. Results: We identified 35 trials (5601 randomised participants). Of these, 17 trials (3431 participants) provided individual participant data. There were too few deaths to assess mortality. There was no difference between the testosterone replacement therapy group (120/1601, 7.5%) and placebo group (110/1519, 7.2%) in the incidence of cardiovascular and/or cerebrovascular events (13 studies, odds ratio 1.07, 95% confidence interval 0.81 to 1.42; p = 0.62). Testosterone replacement therapy improved quality of life and sexual function in almost all patient subgroups. In the testosterone replacement therapy group, serum testosterone was higher while serum cholesterol, triglycerides, haemoglobin and haematocrit were all lower. We identified several themes from five qualitative studies showing how symptoms of low testosterone affect men's lives and their experience of treatment. The cost-effectiveness of testosterone replacement therapy was dependent on whether uncertain effects on all-cause mortality were included in the model, and on the approach used to estimate the health state utility increment associated with testosterone replacement therapy, which might have been driven by improvements in symptoms such as sexual dysfunction and low mood. Limitations: A meaningful evaluation of mortality was hampered by the limited number of defined events. Definition and reporting of cardiovascular and cerebrovascular events and methods for testosterone measurement varied across trials. Conclusions: Our findings do not support a relationship between testosterone replacement therapy and cardiovascular/cerebrovascular events in the short-to-medium term. Testosterone replacement therapy improves sexual function and quality of life without adverse effects on blood pressure, serum lipids or glycaemic markers. Future work: Rigorous long-term evidence assessing the safety of testosterone replacement therapy and subgroups most benefiting from treatment is needed. Study registration: The study is registered as PROSPERO CRD42018111005. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/68/01) and is published in full in Health Technology Assessment; Vol. 28, No. 43. See the NIHR Funding and Awards website for further award information.

Testosterone is a hormone which is vital for sexual activity, bone growth and muscle development in men. Men with low testosterone levels may experience problems with erections and may suffer from brittle bones (osteoporosis), weakness, feeling down (low mood) and tiredness. The manifestations of low testosterone can be treated with testosterone replacement therapy. However, there is current uncertainty about the positive effects of testosterone replacement therapy and its safety. We brought together results from all available medical studies that looked at the use of testosterone replacement therapy in men with low testosterone and contacted the doctors who led these studies to gather further information on their participants. We found 35 studies (5601 participants) conducted in different countries, 17 of which provided additional information on their participants. We did not find any evidence to show that testosterone replacement therapy increases the risk of heart problems, or any evidence to show that some men who take testosterone replacement therapy benefit more than others. Men with low testosterone reported having low mood, poor concentration and lack of energy; however, medical studies often failed to prove that these manifestations improved with testosterone replacement therapy. Most medical studies were conducted among white men in North America using questionnaires designed specifically for them; therefore, the results may not reflect the experiences of men in other countries and from more diverse ethnic backgrounds. There is too much uncertainty about the benefits of testosterone replacement therapy to accurately estimate its value for money for the NHS. We think our findings offer some reassurance to doctors and patients that testosterone replacement therapy does not increase the risk of heart problems. New studies are needed to find out whether some groups of men (such as older or younger men) are more likely to benefit from testosterone replacement therapy more than others. It is also important to develop tools which better reflect the experience of men from a diverse range of social and ethnic backgrounds. To inform men with low testosterone about our findings, we are creating a website with dedicated YouTube video clips.

[Effect and safety of pulsatile GnRH therapy for male congenital hypogonadotropic hypogonadism].

OBJECTIVE: To investigate the efficiency and safety of the pulsatile GnRH therapy in the treatment of male congenital hypogonadotropic hypogonadism (CHH). METHODS: We retrospectively analyzed the clinical data on 45 CHH males treated by pulsatile GnRH therapy in our hospital from January 2013 to March 2023. We treated the patients with gonadorelin at 7－15 µg, one pulse/90 min, and followed them up every month in the first 3 months and then every 3 to 6 months after treatment, for an average of 19.1±4.3 months, during which we recorded the height, body weight, penile length, testis volume, Tanner stages, levels of FSH, LH and T, semen parameters and adverse reactions of the patients, followed by comparison of the data obtained with the baseline. RESULTS: The levels of FSH, LH and T of the patients were dramatically elevated after treatment (P < 0.01). The T level of the 6 cases of cryptorchidism, however, failed to reach the normal value within 18.2 ± 8.6 months of follow-up. Significant improvement was seen in the external genitalia and secondary sexual characteristics of all the patients, and spermatogenesis was observed in the semen in 33 cases (73.3%), with a mean sperm concentration of (18.2 ± 6.2) 106/ml, sperm progressive motility of (19.7 ± 6.5) %, and semen volume of (1.8 ± 0.6) ml. Eight of the cases achieved natural fertility, and another 3 achieved childbirth by assisted reproductive technology. As for adverse events, gynecomastia was observed in 8, subcutaneous induration in 6, and allergic reaction to therapeutic agent in 3 cases. CONCLUSION: Pulsatile GnRH therapy is an effective and safe strategy for male CHH. However, clinicians should choose appropriate approaches to different individual cases.

Testosterone therapy as a novel approach to the management of cytopenias in myelodysplastic neoplasms: a review of literature and case report.

PURPOSE: To explore the potential of testosterone therapy in managing cytopenias in myelodysplastic neoplasm and investigate the link between hypogonadism and hematologic malignancies. METHODS: A case of a patient with intermediate-risk myelodysplastic neoplasm and hypogonadism treated with testosterone replacement therapy is presented. Testosterone, prostate specific antigen, and erythropoietin levels were checked prior to therapy initiation and 3 months after. Blood counts were monitored over time. This is followed by a literature review of testosterone use in myelodysplastic neoplasm and the prevalence of hypogonadism in hematologic malignancies. RESULTS: The patient showed sustained improvement in anemia with testosterone therapy and reported subjective improvement in his weakness and fatigue. This improvement occurred even in the setting of an undetectable follow up erythropoietin level. His repeat prostate specific antigen levels remained low, while testosterone levels showed marked improvement. The literature review demonstrated positive response rates for testosterone in treating myelodysplastic neoplasm-related cytopenias, and showed a higher incidence of hypogonadism in hematologic malignancies. CONCLUSION: Our review suggests that the use of testosterone in low and intermediate-risk myelodysplastic neoplasm is underexplored and poses to have significant potential as a future therapeutic agent, after careful consideration of risks and benefits. In addition, the incidence of hypogonadism in myelodysplastic neoplasm and its potential impact on exacerbating cytopenias in myelodysplastic neoplasm warrants further investigation.

Testosterone replacement therapy for hypogonadism: A primer for primary care.

ABSTRACT: Testosterone replacement therapy (TRT) is a crucial intervention for men diagnosed with hypogonadism, a condition characterized by inadequate testosterone production. As primary care NPs play an essential role in managing patients with hypogonadism, they must comprehensively understand TRT. This article serves as a primer for primary care NPs, based on current guidelines, to provide evidence-based care for men with hypogonadism. It offers an overview of the etiology, clinical presentation, diagnostic criteria, and treatment options for hypogonadism, focusing on using TRT appropriately in primary care settings.

Prevention of Male Late-Onset Hypogonadism by Natural Polyphenolic Antioxidants.

Androgen production primarily occurs in Leydig cells located in the interstitial compartment of the testis. In aging males, testosterone is crucial for maintaining muscle mass and strength, bone density, sexual function, metabolic health, energy levels, cognitive function, as well as overall well-being. As men age, testosterone production by Leydig cells of the testes begins to decline at a rate of approximately 1% per year starting from their 30s. This review highlights recent findings concerning the use of natural polyphenolics compounds, such as flavonoids, resveratrol, and phenolic acids, to enhance testosterone production, thereby preventing age-related degenerative conditions associated with testosterone insufficiency. Interestingly, most of the natural polyphenolic antioxidants having beneficial effects on testosterone production tend to enhance the expression of the steroidogenic acute regulatory protein (Star) gene in Leydig cells. The STAR protein facilitates the entry of the steroid precursor cholesterol inside mitochondria, a rate-limiting step for androgen biosynthesis. Natural polyphenolic compounds can also improve the activities of steroidogenic enzymes, hypothalamus-pituitary gland axis signaling, and testosterone bioavailability. Thus, many polyphenolic compounds such as luteolin, quercetin, resveratrol, ferulic acid phenethyl ester or gigantol may be promising in delaying the initiation of late-onset hypogonadism accompanying aging in males.

Testosterone: A Review for Orthopaedic Surgeons.

¼ Testosterone replacement treatment (TRT) and anabolic androgenic steroid (AAS) use is common and possibly increasing.¼ Diagnosing and treating hypogonadism in men is controversial.¼ Hypogonadism and the use of AASs seem to have a detrimental effect on the musculoskeletal system. The current literature on TRT and the musculoskeletal system shows an increased risk of tendon injury.¼ There may be a role for testosterone supplementation in the postoperative period.

Testosterone Replacement Therapy for Male Hypogonadism.

Testosterone deficiency, or male hypogonadism, is a clinical syndrome that can be defined as persistently low serum testosterone levels in the setting of symptoms consistent with testosterone deficiency. Studies suggest that testosterone replacement therapy may improve sexual function, depressive symptoms, bone density, and lean body mass. Evidence is conflicting regarding its effect on cardiovascular events and mortality. Although prior studies suggested that testosterone replacement therapy increased the risk of cardiovascular disease, a large, randomized trial showed that it does not increase the risk of myocardial infarction or stroke, even in patients at high risk. After a detailed discussion of the potential benefits and risks through shared decision-making, testosterone replacement therapy should be considered for men with testosterone deficiency to correct selected symptoms and induce and maintain secondary sex characteristics. Treatment method should take into consideration patient preference, pharmacokinetics, potential for medication interactions, formulation-specific adverse effects, treatment burden, and cost. Clinicians should monitor men receiving testosterone replacement therapy for symptom improvement, potential adverse effects, and adherence. Serum testosterone, hematocrit, and prostate-specific antigen levels should be measured at baseline and at least annually in men 40 years or older receiving testosterone replacement therapy. (Am Fam Physician. 2024;109(6):543-549.

Pharmacological management of testosterone deficiency in men current advances and future directions.

INTRODUCTION: Testosterone deficiency (TD) is relatively common in aging men, affecting around 2% of the general population. Testosterone replacement therapy (TRT) represents the most common medical approach for subjects who are not interested in fathering. AREAS COVERED: This review summarizes advances in TRT, including approved or non-approved pharmacological options to overcome TD. When possible, a meta-analytic approach was applied to minimize subjective and biased interpretations of the available data. EXPERT OPINION: During the last decade, several new TRT formulations have been introduced on the market, including oral, transdermal, and parenteral formulations. Possible advantages and limitations have been discussed appropriately. Anti-estrogens, including selective estrogen modulators or aromatase inhibitors still represent further possible off-label options. However, long-term side effects on sexual function and bone parameters constitute major limitations. Glucagon-like peptide 1 analogues can be an alternative option in particular for massive obesity-associated TD. Weight loss obtained through lifestyle modifications including diet and physical exercise should be encouraged in all overweight and obese patients. A combination of TRT and lifestyle changes can be considered in those subjects in whom a reversal of the condition cannot be expected in a reasonable time frame.

Two livebirths achieved in cases of hypergonadotropic hypogonadism nonobstructive azoospermia, treated with GnRH agonist and gonadotrophins: a case series and review of the literature.

Non-obstructive azoospermia (NOA) is the most severe form of male factor infertility. It results form from either primary or secondary testicular failure. Here, we report cases of two patients with NOA due to maturation arrest and increased serum FSH, treated with GnRH agonist and gonadotrophins. The two NOA patients underwent a pharmacological treatment consisting of pituitary desensibilization using a GnRH agonist and testicular stimulation using menotropin. Testicular stimulation started one month after the beginning of GnRH agonist treatment. The female partner underwent controlled ovarian stimulation (COS) followed by intracytoplasmic sperm injection (ICSI). On the third day of the cycle, menotropin daily doses was administered. When at least one follicle ≥14 mm was visualized, pituitary blockage was performed using GnRH antagonist ganirelix. When three or more follicles attained a mean diameter of ≥17 mm, triptorelin acetate was administered to trigger final follicular maturation. Oocyte retrieval was performed 35 hours later. After treatment, male partner blood levels of the FSH, LH, decreased and total testosterone were increased. Spermatozoa was observed after semen collection in both cases. After COS, oocytes were retrieved and ICSI was performed. Embryos were biopsied for preimplantation genetic testing (PGT) and those considered euploidy were transferred resulting in positive implantation, ongoing pregnancy, and livebirth on both cases. In this report we present a successful strategy for hypergonadotropic hypogonadism AOA men, as an alternative approach to the surgical testicular sperm recovery. Nevertheless, prospective randomized trials are needed to confirm our findings.

Ambulatory Blood Pressure Parameters Among Men With Hypogonadism Treated With Testosterone Transdermal Therapy.

OBJECTIVE: Studies are needed to examine the effects of testosterone replacement therapy on ambulatory blood pressure (BP) parameters. This study assessed a testosterone transdermal system (TTS) using 24-hour ambulatory BP monitoring. METHODS: In a single-arm, noninferiority trial conducted at 41 US sites, 168 men (mean age: 56.2 years) with hypogonadism not receiving testosterone replacement therapy in the past 6 months were enrolled and received ≥1 study drug dose. Nightly TTS treatment was administered for 16 weeks (starting dose: 4 mg/d; min, max dose: 2, 6 mg/d) to achieve testosterone concentration of 400-930 ng/dL. The primary endpoint was mean change from baseline to week 16 in 24-hour systolic BP (SBP). Noninferiority was determined based on the upper bound of the 2-sided 95% CI <3.0 mmHg. RESULTS: Sixty-two men had ≥85% study drug compliance and a valid week 16 ambulatory BP monitoring session. Mean change from baseline to week 16 in 24-hour average SBP was 3.5 mmHg (95% CI, 1.2-5.8 mmHg; n = 62). Since the upper limit of the CI was >3 mmHg, an effect of TTS could not be ruled out. Mean changes were larger at daytime vs nighttime and in subgroups of men with vs without hypertension. Cardiovascular adverse events were rare (<2%) and nonserious; no major cardiovascular adverse events were reported. CONCLUSION: A meaningful effect of 16-week TTS treatment on 24-hour average SBP among men with hypogonadism could not be ruled out based on the study's noninferiority criterion. The magnitude of mean changes observed may not be clinically meaningful regarding cardiovascular events.

Testosterone therapy in older men: clinical implications of recent landmark trials.

Testosterone therapy for men with hypogonadism due to identifiable hypothalamic-pituitary-testicular (HPT) pathology is uncontroversial. However, the risks and benefits of testosterone for men with clinical features of hypogonadism in the absence of identifiable HPT axis pathology have been uncertain. Recent landmark placebo-controlled trials assessed the benefits and risks of testosterone therapy (≤3 years) for middle-aged and older men with symptoms and possible signs of hypogonadism or end-organ androgen deficiency, low or low-normal serum testosterone concentrations, but no HPT pathology: Testosterone therapy (1) had modest-but clinically significant-benefits on average self-reported energy and mood, sexual function, and satisfaction; (2) in conjunction with a lifestyle programme, reversed or reduced incident type 2 diabetes mellitus (T2D) in men at high risk of or newly diagnosed with T2D; (3) modestly improved objectively assessed muscle strength and timed walking distance; (4) increased bone density and strength, but did not reduce falls or typical osteoporotic fractures and surprisingly increased the risk of fractures typically attributable to trauma; and (5) did not significantly increase the risk of myocardial infarction, stroke, or prostate cancer. These landmark trials help to inform clinical decision-making about testosterone therapy for men.

Combined gonadotropin therapy to replace mini-puberty in male infants with congenital hypogonadotropic hypogonadism.

Infants born with severe central disorders of the hypothalamic-pituitary-gonadal axis leading to gonadotropin deficiency not only lack pubertal development in adolescence, but also lack infantile mini-puberty. This period of mini-puberty, where infants have gonadotropin and sex steroid concentrations up into the adult range, is vital for future reproductive capacity, particularly in boys. At present, there is no consensus on the diagnosis or management of infants with gonadotropin deficiency due to congenital hypogonadotropic hypogonadism or multiple pituitary hormone deficiency. Case series suggest that gonadotropin treatment in male infants with absent mini-puberty is effective in promoting both testicular descent in those with undescended testes and also facilitating increased penile size. Moreover, replacement with follicle-stimulating hormone increases the testicular Sertoli cell population, measurable as an increase in testicular volume and inhibin B, thus hypothetically increasing the capacity for spermatogenesis in adult life for these patients. However, long-term follow-up data is limited for both outcomes pertaining to fertility and nonreproductive sequelae, including neurodevelopment and psychological well-being. The use of international registries for patients with gonadotropin deficiency is a key element in the collection of high-quality, geographically widespread data to inform best-practice management from birth to adulthood.

Prostate Risk and Monitoring During Testosterone Replacement Therapy.

ABSTRACT: Men with hypogonadism have reduced risk of prostate cancer mortality; whether testosterone treatment increases the risk of prostate safety events in men with hypogonadism remains controversial. Several studies including 4 larger randomized trials-the Testosterone Trials, TEstosterone and Atherosclerosis Progression in Aging Men (TEAAM) trial, Testosterone for Diabetes Mellitus trial, and Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) trial-treated men with testosterone or placebo for 1 year or longer and reported prospectively ascertained prostate safety data. The TRAVERSE Trial, because of its large size, longer duration, and adjudication of prostate events, has provided comprehensive data on the risk of adverse prostate events during testosterone replacement therapy (TRT). Among men with hypogonadism, carefully screened to exclude those at high risk of prostate cancer, the incidences of high-grade or any prostate cancer, acute urinary retention, surgical procedure for benign prostatic hyperplasia, prostate biopsy, or new pharmacologic therapy for lower urinary tract symptoms were low and did not differ between the testosterone and placebo groups. Testosterone did not worsen lower urinary tract symptoms. TRT was associated with a greater increase in prostate-specific antigen than placebo in the first year of treatment. CONCLUSION: Testosterone treatment of men with hypogonadism, screened to exclude those at high risk of prostate cancer, is associated with low risk of adverse prostate events. Baseline evaluation of prostate cancer risk and a standardized monitoring plan can minimize the risk of unnecessary prostate biopsy while enabling the detection of high-grade prostate cancers in men receiving TRT.

Androgen Deprivation Therapy/Androgen Receptor Signaling Inhibitor Treatments for Prostate Cancer: Pathophysiology and Review of Effects on Cardiovascular Disease.

Androgen deprivation therapy is the cornerstone of systemic management for prostate cancer but is associated with multiple adverse effects that must be considered during treatment. These effects occur because of the profound hypogonadism that is induced from lack of testosterone or due to the medications used in the treatment or in combination with androgen receptor signaling inhibitors. This article critically reviews the associations between androgen deprivation therapy, androgen receptor signaling inhibitors, and cardiovascular complications such as prolonged QT interval, atrial fibrillation, heart failure, atherosclerosis, coronary heart disease, venous thromboembolism, and peripheral arterial occlusive disease. These unfavorable outcomes reinforce the need for regular cardiovascular screening of patients undergoing androgen deprivation for the management of prostate cancer.

Hypogonadism as a consequence of craniopharyngioma in female patients: comparison of childhood and adult onset and effects of estrogen replacement therapy.

PURPOSE: (1) to compare clinical, biochemical features in female patients with hypoestrogenism due to childhood- and adult-onset CP; (2) to reveal effects of estrogen replacement therapy in female patients with childhood-onset CP. METHODS: Thirty-seven women that received specific treatment for CP in the period from 1980 to 2019 were recruited: 21 with childhood-onset and 16 with adult-onset CP. Clinical and hormonal characteristics were evaluated. Seventeen-beta-estradiol 2 mg and dydrogesterone 10 mg in sequential regiment was used in 18 childhood-onset cases. Mean follow-up was 31 months. RESULTS: Amenorrheic women with childhood- and adult-onset CP presented with the same complaints except for lack of genital hair and breast hypoplasia, which were common in patients with childhood-onset CP. BMI was lower in childhood-onset CP group, as was the proportion of overweight patients. They had more favorable lipid profile. The levels of estradiol, testosterone and DHEA-S were low and did not differ. Uterine and ovary volumes were reduced in all patients, but the decline was noticeable in the childhood-onset group. Mineral bone density of lumbar vertebrae was diminished in childhood-onset group. Estrogen therapy in these patients led to clinical improvement: increase in BMD in lumbar spine without negative changes in BMI and/or lipid profile. CONCLUSIONS: Study showed that women with childhood-onset CP had less negative metabolic changes. However, they have more pronounced breast and uterus hypoplasia and lower BMD in lumbar spine. The estrogen replacement therapy led to clinical improvement and BMD increase in lumbar spine without increase of BMI and/or lipid profile changes.

Testosterone therapy over 60 months improves aging male symptoms scores in all men with adult-onset testosterone deficiency.

OBJECTIVE: We evaluated change (Δ) in AMSS in men with adult-onset testosterone deficiency (TD) on/not on testosterone undecanoate (TU) by analysing a registry of men with adult-onset TD. METHODS: Analyses were performed using non-parametric statistics to determine ΔAMSS at 6-12 monthly intervals in men on/not on TU and movement in AMSS. Factors predicting ΔAMSS were established via linear/multiple regression. RESULTS: TU was significantly associated with lower AMSS values compared with that at baseline/prior assessment during the initial 42 months treatment; 259 of the 260 men showed improvement. In the 361 men not on TU, AMSS values increased during 60 months of follow-up compared with that at baseline/prior assessment; improvement after 60 months was evident in 1 man, whilst AMSS remained the same or worsened in 213 and 147 men, respectively. In men on TU, baseline AMSS was inversely associated with ΔAMSS (R2 = 0.97), with no other factors reaching significance. Baseline AMSS, age, serum total testosterone (TT), waist circumference (WC), and diastolic blood pressure (BP) were associated with ΔAMSS in men not on TU. DISCUSSION: We show that TU was associated with lower AMSS in men with adult-onset TD whilst non-treatment led to increased values. Baseline AMSS values inversely predicted ΔAMSS in both groups.