Non-testosterone management of male hypogonadism: an examination of the existing literature.
ABSTRACT: Testosterone deficiency is defined as a total testosterone level <300 ng/dL confirmed on two early morning lab draws. Testosterone therapy has historically been offered to men with symptomatic testosterone deficiency in the form of injections, gels, or pellets. However, these treatments are invasive or have undesirable effects including the risk of drug transference. Additionally, testosterone therapy has been associated with increases in hematocrit and controversy remains regarding the risk of cardiovascular and thromboembolic events while on testosterone therapy. As such, much interest has recently been focused on alternative treatment options for testosterone deficiency in the form of orally-administered medications with more favorable side effect profiles. Lifestyle modifications and varicocelectomy have been shown to raise endogenous testosterone production. Similarly, SERMs and aromatase inhibitors (AIs) have been shown to raise testosterone levels safely and effectively. Human chorionic gonadotropin (hCG) remains the only FDA-approved non-testosterone treatment option for testosterone deficiency in men. However, this medication is expensive and requires patient-administered injections. Over the counter herbal supplements and designer steroids remain available though they are poorly studied and are associated with the potential for abuse as well as increased hepatic and cardiovascular risks. This review aims to discuss the existing treatment alternatives to traditional testosterone therapy, including efficacy, safety, and side effects of these options. The authors suggest that the SERM clomiphene citrate (CC) holds the greatest promise as a non-testosterone treatment option for testosterone deficiency.
Project description:The aim of this study is to review four case-based scenarios regarding the treatment of symptomatic hypogonadism in men. The article is designed as a review of published literature. We conducted a PubMed literature search for the time period of 1989-2014, concentrating on 26 studies investigating the efficacy of various therapeutic options on semen analysis, pregnancy outcomes, time to recovery of spermatogenesis, as well as serum and intratesticular testosterone levels. Our results demonstrated that exogenous testosterone suppresses intratesticular testosterone production, which is an absolute prerequisite for normal spermatogenesis. Cessation of exogenous testosterone should be recommended for men desiring to maintain their fertility. Therapies that protect the testis involve human chorionic gonadotropin (hCG) therapy or selective estrogen receptor modulators (SERMs), but may also include low dose hCG with exogenous testosterone. Off-label use of SERMs, such as clomiphene citrate, are effective for maintaining testosterone production long-term and offer the convenience of representing a safe, oral therapy. At present, routine use of aromatase inhibitors is not recommended based on a lack of long-term data. We concluded that exogenous testosterone supplementation decreases sperm production. It was determined that clomiphene citrate is a safe and effective therapy for men who desire to maintain fertility. Although less frequently used in the general population, hCG therapy with or without testosterone supplementation represents an alternative treatment.
Project description:Varicocelectomy is the most commonly performed surgical procedure for the treatment of male infertility. Although several different techniques for varicocele repair have been described in the literature, microsurgical varicocelectomy performed through a subinguinal or inguinal incision is recognized as the gold-standard approach for varicocelectomy, due to high success rates with minimal complications. Standard indications for varicocelectomy include palpable varicocele(s), with one or more abnormal semen parameters, and, for the couple trying to conceive, in the setting of normal or correctable female infertility. However, varicocele repair is often recommended and undertaken for reasons other than infertility, including low serum testosterone, testicular pain, testicular hypotrophy and poor sperm DNA quality. This article reviews the technical aspects of microsurgical varicocelectomy, and its indications in adults and adolescents.
Project description:Conventional meta-analyses have shown inconsistent results for the efficacy of various treatments of varicoceles. Therefore, we performed a multiple-treatment meta-analysis to assess the effectiveness and safety of 10 methods of varicocelectomy and embolization/sclerotherapy. We systematically reviewed 35 randomized controlled trials and observational studies, from 1966 to August 5, 2013, which compared any of the following treatments for varococeles: laparoscopic, retroperitoneal, open inguinal and subinguinal varicocelectomy, microsurgical subinguinal and inguinal varicocelectomy, percutaneous venous embolization, Tauber antegrade sclerotherapy, retrograde sclerotherapy and expectant therapy (no treatment). Inguinal and subinguinal microsurgery, open inguinal, laparoscopic varicocelectomy showed a signi?cant advantage over expectant therapy in terms of pregnancy rates (odds ratio (OR): 3.48, 2.68, 2.92 and 2.90, respectively). Compared with retroperitoneal open surgery, inguinal microsurgery showed an improvement of sperm density (mean difference (MD): 10.60, 95% confidence interval (CI): 1.92-19.60) and sperm motility (MD: 9.09, 95% CI: 4.88-13.30). Subinguinal and inguinal microsurgery outperformed retroperitoneal open surgery in terms of recurrence (OR: 0.05, 0.06 respectively). Tauber antegrade sclerotherapy and subinguinal microsurgery were associated with the lowest risk of hydrocele formation. The odds of overall complication, compared with retroperitoneal open varicocelectomy, were lowest for inguinal microsurgery (OR = 0.07, 95% CI: 0.02-0.19), followed by subinguinal microsurgery (OR = 0.09, 95% CI: 0.02-0.19). Inguinal and subinguinal micro-varicocelectomy had the highest pregnancy rates, signi?cant increases in sperm parameters, with low odds of complication. These results warrant additional properly conducted randomized controlled clinical studies with larger sample sizes.
Project description:UNLABELLED: Tendinopathy is a broad term encompassing painful conditions occurring in and around tendons in response to overuse. Recent basic science research suggests little or no inflammation is present in these conditions. Thus, traditional treatment modalities aimed at controlling inflammation such as corticosteroid injections and nonsteroidal antiinflammatory medications (NSAIDS) may not be the most effective options. We performed a systematic review of the literature to determine the best treatment options for tendinopathy. We evaluated the effectiveness of NSAIDS, corticosteroid injections, exercise-based physical therapy, physical therapy modalities, shock wave therapy, sclerotherapy, nitric oxide patches, surgery, growth factors, and stem cell treatment. NSAIDS and corticosteroids appear to provide pain relief in the short term, but their effectiveness in the long term has not been demonstrated. We identified inconsistent results with shock wave therapy and physical therapy modalities such as ultrasound, iontophoresis and low-level laser therapy. Current data support the use of eccentric strengthening protocols, sclerotherapy, and nitric oxide patches, but larger, multicenter trials are needed to confirm the early results with these treatments. Preliminary work with growth factors and stem cells is promising, but further study is required in these fields. Surgery remains the last option due to the morbidity and inconsistent outcomes. The ideal treatment for tendinopathy remains unclear. LEVEL OF EVIDENCE: Level II, systematic review.
Project description:Citrin deficiency is an autosomal recessive disorder caused by loss-of-function mutations in SLC25A13, encoding the liver-specific mitochondrial aspartate/glutamate transporter. It has a broad spectrum of clinical phenotypes, including life-threatening neurological complications. Conventional protein replacement therapy is not an option for these patients because of drug delivery hurdles, and current gene therapy approaches (e.g., AAV) have been hampered by immunogenicity and genotoxicity. Although dietary approaches have shown some benefits in managing citrin deficiency, the only curative treatment option for these patients is liver transplantation, which is high-risk and associated with long-term complications because of chronic immunosuppression. To develop a new class of therapy for citrin deficiency, codon-optimized mRNA encoding human citrin (hCitrin) was encapsulated in lipid nanoparticles (LNPs). We demonstrate the efficacy of hCitrin-mRNA-LNP therapy in cultured human cells and in a murine model of citrin deficiency that resembles the human condition. Of note, intravenous (i.v.) administration of the hCitrin-mRNA resulted in a significant reduction in (1) hepatic citrulline and blood ammonia levels following oral sucrose challenge and (2) sucrose aversion, hallmarks of hCitrin deficiency. In conclusion, mRNA-LNP therapy could have a significant therapeutic effect on the treatment of citrin deficiency and other mitochondrial enzymopathies with limited treatment options.
Project description:The effects of progesterone therapy (5 mg, administered subcutaneously daily for 6 days) on the abnormal uterus of adult anovulatory Wistar rats have been studied. These rats, rendered anovulatory by neonatal treatment with testosterone propionate or clomiphene citrate, displayed severe hyperplasia and metaplasia of the uterine luminal epithelium and a disproportionately high content of nuclear oestrogen receptor, as a result of constant oestrogen stimulation unrelieved by progesterone [White, Moore, Elder & Lim (1981) Biochem. J. 196, 557-565]. Progesterone therapy resulted in the virtual elimination of the hyperplasia and metaplasia and a corresponding decrease in the content of nuclear oestrogen receptor with the proportion of the unoccupied nuclear receptor being increased to values exhibited by normal cyclic females. There was also a decrease in the content of progestin receptors, a putative index of oestrogenic stimulation. Further, in the testosterone-treated group, progesterone therapy resulted in the restoration of oestrogen receptor translocational responses to oestradiol stimulation. Progesterone treatment of these anovulatory rats thus provides a model system for investigating the biochemical mechanisms underlying progestin antagonism and regulation of oestrogen-stimulated cell proliferation.
Project description:BACKGROUND:Fall accidents are a major cause of mortality among the elderly and the leading cause of traumatic brain injury. After a fall, many elderly people never completely recover and need help in coping with everyday life. Due to the increasing older population in the world, injuries, disabilities, and deaths caused by falls are a growing worldwide problem. Muscle weakness leads to greatly increased risk of falling, decreased quality of life, and decline in functional capacity. Muscle mass and muscle power decrease about 40% from age 20 to 80 years, and the level of testosterone decreases with age and leads to impaired muscle mass. In addition, 20% of men older than 60 years-and 50% older than 80 years-have low levels of testosterone. Treatments after a fall are significant financial burdens on health and social care, and it is important to find treatments that can enhance function in the elderly people. OBJECTIVE:The purpose of this study is to investigate whether testosterone and progressive resistance training alone or combined can improve muscle strength and reduce the risk of falls in older men. Additionally, we will examine whether such treatments can improve quality of life, functional capacity, including sexual function, and counteract depression. METHODS:This is a randomized placebo-controlled, double-blind trial in which frail older men with testosterone deficiency are treated with testosterone supplemental therapy and therapist-assisted progressive resistance training for 20 weeks, with the possibility to continue treatment for 1 year. Four study arms of 48 participants each are provided based on factorial assignment to testosterone supplemental therapy and progressive resistance training. The 4 groups are as follows: controls given placebo injections without physical exercise for 20 weeks, testosterone-alone group given testosterone injections without physical exercise for 20 weeks, training-alone group given placebo injections for 20 weeks combined with 16 weeks of progressive strength training, and combination group given testosterone injections for 20 weeks combined with 16 weeks of progressive strength training. Performance in the 30-second chair stand test to measure improvement of general strength, balance, and power in lower extremities is the primary endpoint. Secondary endpoints comprising tests of cognition, muscle strength, and quality of life are applied before and after the training. RESULTS:Funding was provided in October 2016. Results are expected to be available in 2020. Sample size was calculated to 152 participants divided into 4 equal-sized groups. Due to age, difficulty in transport, and the time-consuming intervention, up to 25% dropouts are expected; thus, we aim to include at least 192 participants. CONCLUSIONS:This investigation will evaluate the efficacy of testosterone supplemental therapy alone or combined with progressive resistance training. Additionally, improvements in quality of life and cognition are explored. TRIAL REGISTRATION:Clinicaltrials.gov NCT02873559; https://clinicaltrials.gov/ct2/show/NCT02873559 (Archived by WebCite at http://www.webcitation.org/6x0BhU2p3).
Project description:BACKGROUND:Cancer cachexia negatively impacts cancer-related treatment options, quality of life, morbidity, and mortality, yet no established therapies exist. We investigated the anabolic properties of testosterone to limit the loss of body mass in late stage cancer patients undergoing standard of care cancer treatment. METHODS:A randomized, double-blind, placebo-controlled phase II clinical trial was undertaken to assess the potential therapeutic role of adjunct testosterone to limit loss of body mass in patients with squamous cell carcinoma of the cervix or head and neck undergoing standard of care treatment including chemotherapy and chemoradiation. Patients were randomly assigned in blocks to receive weekly injections of either 100 mg testosterone enanthate or placebo for 7 weeks. The primary outcome was per cent change in lean body mass, and secondary outcomes included assessment of quality of life, tests of physical performance, muscle strength, daily activity levels, resting energy expenditure, nutritional intake, and overall survival. RESULTS:A total of 28 patients were enrolled, 22 patients were studied to completion, and 21 patients were included in the final analysis (12 placebo, nine testosterone). Adjunct testosterone increased lean body mass by 3.2% (95% confidence interval [CI], 0-7%) whereas those receiving placebo lost 3.3% (95% CI, -7% to 1%, P = 0.015). Although testosterone patients maintained more favourable body condition, sustained daily activity levels, and showed meaningful improvements in quality of life and physical performance, overall survival was similar in both treatment groups. CONCLUSIONS:In patients with advanced cancer undergoing the early phase of standard of care therapy, adjunct testosterone improved lean body mass and was also associated with increased quality of life, and physical activity compared with placebo.
Project description: To compare the effectiveness of alternative first line treatment options for women with WHO group II anovulation wishing to conceive. Systematic review and network meta-analysis. Cochrane Central Register of Controlled Trials, Medline, and Embase, up to 11 April 2016. Randomised controlled trials comparing eight ovulation induction treatments in women with WHO group II anovulation: clomiphene, letrozole, metformin, clomiphene and metformin combined, tamoxifen, gonadotropins, laparoscopic ovarian drilling, and placebo or no treatment. Study quality was measured on the basis of the methodology and categories described in the Cochrane Collaboration Handbook. Pregnancy, defined preferably as clinical pregnancy, was the primary outcome; live birth, ovulation, miscarriage, and multiple pregnancy were secondary outcomes. Of 2631 titles and abstracts initially identified, 57 trials reporting on 8082 women were included. All pharmacological treatments were superior to placebo or no intervention in terms of pregnancy and ovulation. Compared with clomiphene alone, both letrozole and the combination of clomiphene and metformin showed higher pregnancy rates (odds ratio 1.58, 95% confidence interval 1.25 to 2.00; 1.81, 1.35 to 2.42; respectively) and ovulation rates (1.99, 1.38 to 2.87; 1.55, 1.02 to 2.36; respectively). Letrozole led to higher live birth rates when compared with clomiphene alone (1.67, 1.11 to 2.49). Both letrozole and metformin led to lower multiple pregnancy rates compared with clomiphene alone (0.46, 0.23 to 0.92; 0.22, 0.05 to 0.92; respectively). In women with WHO group II anovulation, letrozole and the combination of clomiphene and metformin are superior to clomiphene alone in terms of ovulation and pregnancy. Compared with clomiphene alone, letrozole is the only treatment showing a significantly higher rate of live birth. PROSPERO CRD42015027579.
Project description:Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility in women of reproductive age. Lifestyle change is considered the first line treatment for the management of infertile anovulatory women with PCOS, and weight loss for those who are overweight or obese. First line medical ovulation induction therapy to improve fertility outcomes is letrozole, whilst other less efficacious ovulation induction agents, such as clomiphene citrate, metformin, and metformin combined with clomiphene citrate, may also be considered. Metformin combined with clomiphene citrate is more effective than clomiphene citrate alone. In obese women with PCOS, clomiphene citrate could be used in preference to metformin alone whilst clomiphene citrate could be added to metformin alone in order to improve reproductive outcome in all women with PCOS. Gonadotrophins, which are more effective than clomiphene citrate in therapy naïve women with PCOS, can be considered a first line therapy in the presence of ultrasound monitoring, following counselling on the cost and the potential risk of multiple pregnancy.