Safety and efficacy of topical testosterone in breast cancer patients receiving ovarian suppression and aromatase inhibitor therapy.

BACKGROUND: Premenopausal, high-risk, hormone receptor-positive breast cancer patients are often treated with ovarian suppression in combination with aromatase inhibitors (AI). This combination has important adverse effects, particularly in sexual function, such as vaginal dryness and loss of libido. There is no effective therapy for reduced sexual function in this setting. Our study aimed to determine the efficacy and safety, particularly regarding sexual function, of a low-dose, topical testosterone gel administration. METHODS: This is a pilot, single-center study, designed to evaluate the efficacy of topical testosterone gel (3 mg/day) in improving sexual function in 29 premenopausal patients on ovarian suppression in combination with an AI. The primary safety endpoint was to assess serum estradiol elevation. The primary efficacy endpoint was sexual function improvement, assessed by the Female Sexual Function Index questionnaire. RESULTS: We report the results on 29 patients. Twenty-two patients (75%) completed the 3-month treatment, and seven discontinued treatment before completion, mostly due to logistical difficulties related to the COVID-19 pandemic. All patients maintained the value of baseline mass spectrometry assay for estradiol of less than 2.7 pg/mL during the undertaken measurements. We observed a significant improvement in Female Sexual Function Index measures over the visits, with an increase from a mean of 11.7 at baseline to 19.1 in the third month (p < 0.001), with the greatest improvement observed between the second and third months. CONCLUSIONS: Our findings suggest that topical testosterone seems to be safe and may be effective in improving sexual function in patients on ovarian suppression and AI. TRIAL REGISTRATION: The project was submitted and approved through the hospital's SGPP platform in 11/26/2019 (Project No. SGPP 393819) and CAAE (Research Ethics Committee) (CAAE No 25609719.5.0000.007).

Assessment of parenteral estradiol and dihydroxyprogesterone use among other feminizing regimens for transgender women: insights on satisfaction with breast development from community-based healthcare services.

The practice of hormone therapy is crucial in aligning secondary sex characteristics with the gender identity of transgender adults. This study examines the effects of a commonly used injectable hormone combination, specifically estradiol enanthate with dihydroxyprogesterone acetophenide (EEn/DHPA), on serum hormonal levels and self-reported satisfaction with breast development in transwomen. Our research focused on a retrospective longitudinal study involving a large cohort of transwomen evaluated between 2020 and 2022, comprising 101 participants. We assessed serum levels of estradiol (E2), testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH), comparing the EEn/DHPA hormonal regimen with other combined estrogen-progestogen (CEP) therapies. Additionally, a subset of 43 transwomen completed a 5-question survey to evaluate self-reported satisfaction with breast development using Tanner scales. Our findings indicated that participants using the EEn/DHPA regimen exhibited significantly higher serum E2 levels (mean: 186 pg/mL ± 32 pg/mL) than those using other therapies (62 ± 7 pg/mL), along with lower FSH levels, but no significant differences in T and LH levels. Concerning satisfaction with breast development, 76% reported increased fulfillment with breast augmentation while using EEn/DHPA. These results suggest that an injectable, low-cost EEn/DHPA administered every three weeks could serve as an alternative feminizing regimen, particularly considering the extensive long-term experience of the local transgender community. Further longitudinal studies on the efficacy of feminizing-body effects and endovascular risks of various parenteral CEP types are warranted to improve primary healthcare provision for transgender persons.

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.

Addition of testosterone to endocrine care for transgender women: a dose-finding and feasibility trial.

OBJECTIVE: Transgender women who underwent gonadectomy have lower serum testosterone concentrations than cisgender women. There is uncertainty regarding the dosing and side effects of supplementation of testosterone in transgender women. This study aimed to assess the feasibility of dosing testosterone to the cisgender female physiological range in transgender women. In addition, we explored changes in cardiovascular parameters, virilizing side effects, and clinical symptoms. DESIGN: This is an open-label, single-arm feasibility study. Participants initially went through a dose-titration phase with 2-week intervals of 0.07-0.09-0.13 mL (277-318-403 µg bioavailable testosterone) testosterone 2% gel to establish a dose leading to serum testosterone concentrations between 1.5 and 2.5 nmol/L. This dose was then continued for 8 weeks. METHODS: Participants applied daily transdermal testosterone 2% gel (Tostran®) at the prescribed dosage. Testosterone was measured every 2-4 weeks. Laboratory analyses, side effects, and clinical symptoms were evaluated. RESULTS: In total, 12 participants were included. Most participants required a dose of 0.07 mL (277 µg bioavailable testosterone) or 0.09 mL (318 µg bioavailable testosterone) to reach serum testosterone concentrations of 1.5-2.5 nmol/L. Continuing this dose, testosterone concentrations remained stable throughout the study. Changes in clinical outcomes were in the desired direction, and side effects were mild. CONCLUSIONS: The use of testosterone supplementation in transgender women seems feasible and safe in the short term. Although dosing requires personalized titration, stable testosterone levels can be established. A blinded, placebo-controlled, randomized clinical trial is needed to study the clinical benefit.

Recruiting transgender men in the Southeastern United States for genital microbiome research: Lessons learned.

BACKGROUND: Transgender men (TGM) are underrepresented in genital microbiome research. Our prospective study in Birmingham, AL investigated genital microbiota changes over time in TGM initiating testosterone, including the development of incident bacterial vaginosis (iBV). Here, we present lessons learned from recruitment challenges encountered during the conduct of this study. METHODS: Inclusion criteria were assigned female sex at birth, TGM or non-binary identity, age ≥18 years, interested in injectable testosterone but willing to wait 7 days after enrollment before starting, and engaged with a testosterone-prescribing provider. Exclusion criteria were recent antibiotic use, HIV/STI infection, current vaginal infection, pregnancy, or past 6 months testosterone use. Recruitment initiatives included community advertisements via flyers, social media posts, and referrals from local gender health clinics. RESULTS: Between February 2022 and October 2023, 61 individuals contacted the study, 17 (27.9%) completed an in-person screening visit, and 10 (58.8%) of those screened were enrolled. The primary reasons for individuals failing study screening were having limited access to testosterone-prescribing providers, already being on testosterone, being unwilling to wait 7 days to initiate testosterone therapy, or desiring the use of topical testosterone. Engagement of non-White TGM was also minimal. CONCLUSION: Despite robust study inquiry by TGM, screening and enrollment challenges were faced including engagement by TGM not yet in care and specific study eligibility criteria. Excitement among TGM for research representation should be leveraged in future work by engaging transgender community stakeholders at the inception of study development, particularly regarding feasibility of study inclusion and exclusion criteria, as well as recruitment of TGM of color. These results also highlight the need for more clinical resources for prescribing gender-affirming hormone therapy, especially in the Southeastern US.

Testosterone and other treatments for transgender males and non-binary trans masculine individuals.

Testosterone therapy is the main hormonal treatment offered in transmen to alleviate somatic gender dysphoria. Testosterone can be administered via topical or injectable preparations to achieve physical changes resulting in masculinisation and improve quality of life for the treated individuals. The aim of our paper is to outline methods for testosterone replacement, their impact on main body systems of transmen, potential associated health risks and long term follow up. Androgen use in transgender medicine is safe with appropriate endocrine guidance and monitoring. Studies with longer follow-up period, including those who may prefer low dose testosterone, interested in pregnancy or older people may further improve the management of female-to-male transgender persons.

Long-term Effects of Pre-operative Testosterone and Dihydrotestosterone on Glans Width in Boys With Hypospadias.

BACKGROUND: Small glans width is a risk factor for urethroplasty complications. This study aimed to assess and compare short- and long-term effects of two pre-operative topical androgen treatment protocols on maximum glans width. Furthermore, to evaluate post-operative complications when surgery was delayed >3 months following hormonal treatment completion. METHODS: Topical 2.5% dihydrotestosterone (February 2016-July 2018) and 5% testosterone (August 2018-December 2022) treatment protocols, completed >3 months before surgery, were offered to all children with proximal hypospadias and small glans width requiring urethroplasty. Serial glans width measurements were collected prospectively pre- and post-androgen treatment. Demographic data and complications were collected retrospectively. RESULTS: A significant increase in mean glans width was observed following both dihydrotestosterone (6.1 mm [95% CI 4.3-7.9 mm] pre-dihydrotestosterone to 14.9 mm [13.2-16.6 mm, p < 0.0001] post-dihydrotestosterone in 11 children) and testosterone (10.5 mm [9.9-11.1 mm] pre-testosterone to 14.6 mm [13.7-15.5 mm, p < 0.0001] post-testosterone in 32 children). Serial post-treatment measurements showed no loss of gained width >1 year after treatment completion. Mean increase in glans width from pre-treatment measurement at 0-3 months, 4-12 months and >12 months following treatment was 7 mm (95% CI 3.8-10.2), 9 mm (7.2-10.8) and 10 mm (7.3-12.7) post-dihydrotestosterone and 4.4 mm (95% CI 3.4-5.4 mm), 4.3 mm (3.5-5.2) and 5.1 mm (4-6.2) post-testosterone respectively. Complications were noted in 4/22 patients who received topical androgen prior to initial hypospadias surgery and had completed all surgical stages. CONCLUSIONS: Both treatment protocols produced a significant, sustained increase in glans width. Delaying hypospadias surgery for >3 months following androgen application may circumvent androgen induced vascularity and poor wound healing. LEVEL OF EVIDENCE: Level IV. TYPE OF STUDY: Treatment study.

Risk of erythrocytosis in transgender individuals undergoing testosterone therapy: a systematic review.

INTRODUCTION: In transgender individuals assigned female at birth, testosterone therapy is employed for body masculinization. Guidelines recommend close monitoring for potential side effects of hormonal therapy, especially during the first year. Erythrocytosis is a common finding during testosterone therapy and has been associated with a potential risk of thrombotic and cardiovascular events. Currently, the hematologic effects of testosterone therapy are understudied, with existing data primarily derived from the cisgender male population. The aim of this study was to comprehensively examine the hematological changes induced by testosterone therapy in the transgender population. EVIDENCE ACQUISITION: A systematic search was conducted using the electronic database PubMed. EVIDENCE SYNTHESIS: Thirty-six manuscripts were retrieved. After screening for original studies, 19 articles were included. Selected articles were published between 2005 and 2023. CONCLUSIONS: In our systematic review, the prevalence of erythrocytosis varied from 0% to 29.3%, with severe erythrocytosis ranging from 0.5% to 2.3%. Testosterone therapy was associated with an increase in hemoglobin and hematocrit, particularly within the first year of therapy. Factors such as serum testosterone levels, along with the duration, doses, and formulation of testosterone therapy, were found to be associated with the development of erythrocytosis. Further research is crucial to provide specific recommendations for clinical practice.

[Efficacy of oral testosterone undecanoate in children with androgen insensitivity syndrome].

Objective: To investigate the efficacy and safety of oral testosterone therapy in individuals diagnosed with androgen insensitivity syndrome (AIS). Methods: A self-controlled study design was utilized, focusing on individuals with AIS who were genetically diagnosed at the Department of Endocrinology, Genetics, and Metabolism of Beijing Children's Hospital between 2009 and 2021. These patients underwent treatment involving the administration of testosterone. The primary observed indexes include the measurement of penis length, which should meet the minimal surgical standard (penis length≥2.5 cm) or greater than or equal to -2.5 s (lower limit of normal). Secondary observed indexes include penile length standard deviation score (PL-SDS), an increase in penis longitude (ΔPL), medication dosage, the course of therapy, and safety indicators, among others. There were 4 courses of treatment. After each course, patients were evaluated to determine whether termination of treatment was appropriate. Patients who exhibited inadequate post-treatment penile length growth were advised to continue with further treatment. The statistical methodology included t-test, and a Wilcoxon rank sum test to describe efficacy and safety. The patients were followed up until 2023. Results: The study comprised a total of 51 individuals with AIS, comprising 33 males and 18 females (gender of registered permanent residence). Among these patients, 10 were diagnosed with complete androgen insensitivity syndrome (CAIS) and 41 were diagnosed with partial androgen insensitive syndrome (PAIS). There were 2 children with CAIS were diagnosed by doctors and prescribed testosterone undecanoate, but the children did not really take medicine.The penile length of CAIS patients could not be measured (penile length<0.5 cm) before and after treatment. For PAIS patients, baseline penile length and PL-SDS were (2.3±0.6) cm and -3.7±1.3, respectively. The measurements for penile length and PL-SDS after each treatment course were recorded as follows: (2.7±0.8), (2.8±0.6), (2.6±0.4), (2.6±0.4) cm and -2.8±1.6, 2.5±1.6, 2.9±1.2, -3.2±0.9, respectively. Both penile length and PL-SDS interventions showed statistically significant gains when compared to the baseline performance of the 4 courses (t=4.05、3.56、2.55、2.23 and 3.88、3.50、2.50、2.19, all P<0.05). Before treatment, 13 PAIS patients (32%) reached 2.5 cm and seven (17%) reached greater than or equal to -2.5 s. Following the initial, subsequent, third, and fourth therapeutic interventions, 18 cases (44%), 24 cases (59%), 25 cases (61%), and 26 cases (63%) reached 2.5 cm, respectively. Additionally, A total of 12 cases (29%), 15 cases (37%), 20 cases (49%), and 21 cases (51%), respectively, were found to reach greater than or equal to -2.5 s. The study involved the longitudinal monitoring of patients with the highest recorded age being 13.7 years. The weight, height, body mass index, bone age/age, cholesterol, hemoglobin and so on were all within the normal range and the difference were not statistically significant (all P>0.05). All 49 patients were no abnormalities in blood electrolyte, liver and kidney function and thyroid function and no changes in precocious puberty, pubic hair growth, aggressive behavior, vulvar skin darkening, diarrhea or other conditions. Conclusions: Testosterone undecanote in children with CAIS was no effective. The initial course of treatment for patients with PAIS demonstrates observable enhancements in penile length and PL-SDS. For patients with inadequate penile length growth, continued treatment in subsequent courses (such as the second, third, and fourth courses) is recommended toenhance outcomes gradually. Testosterone undecanoate was safe and effective for the majority of individuals with PAIS patients, with few adverse effects and good treatment tolerance.

Gender-affirming hormone therapy for transgender and gender-diverse adults in Australia.

Gender-affirming hormone therapy (GAHT) is used by many transgender and gender-diverse adults to align physical characteristics with their gender identity, reduce gender incongruence and improve psychological functioning. This narrative review provides an overview of the initiation and monitoring of GAHT in an Australian context. Trans individuals treated with testosterone typically receive standard testosterone doses and formulations recommended for cisgender men, whereas those receiving estradiol GAHT are typically treated with estradiol in combination with an anti-androgen in those without orchidectomy. Proactive monitoring and mitigation of cardiovascular risk factors is pertinent in all transgender and gender-diverse adults and bone health is an important consideration in those using estradiol GAHT.

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.

Systemic testosterone for the treatment of female sexual interest and arousal disorder (FSIAD) in the postmenopause.

INTRODUCTION: Female sexual interest and arousal disorder (FSIAD) is the most prevalent female sexual dysfunction in the postmenopause. OBJECTIVE: The aim of this review is to provide a summary of the currently available evidence on the use of testosterone in the treatment of FSIAD in postmenopausal women. METHODS: A narrative review on the topic was performed. Only randomized controlled trials (RCTs) and systematic reviews and meta-analysis were considered. 123 articles were screened, 105 of them assessed for eligibility, and finally 9 were included in qualitative synthesis following the PRISMA declaration. RESULTS: Current evidence recommends, with moderate therapeutic benefit, the use of systemic transdermal testosterone within the premenopausal physiological range in postmenopausal women with Hypoactive Sexual Desire Disorder (HSDD), the previous entity for low desire dysfunction, not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. The available evidence is based on studies with heterogeneity on their design (different testosterone doses, routes of administration, testosterone use in combination and alone, sexual instruments of measurement). There is no data indicating severe short-term adverse effects, although long-term safety data is lacking. CONCLUSIONS: Despite having testosterone as a valuable tool, therapeutic strategies are lacking in the pharmacological field of HSDD/FSIAD. Neuroimaging studies could provide valuable information regarding the sexual desire substrate and suggest the potential application of already approved drugs for women with a good safety profile. The use of validated instruments for HSDD in postmenopausal women, considering the level of distress, is necessary to be able to draw robust conclusions on the evaluated treatments.

Short Adult Height After Rapid-tempo Puberty: When is it too Late to Treat?

A rarely reported phenomenon of rapid-tempo puberty in which the physical changes of puberty and testosterone levels increase very rapidly has not been reported outside apart from in two reviews. The resulting rapid advancement of skeletal age causes early completion of growth with shorter adult stature than expected. This appears to be genetic given its occurrence in the present report in two families, one with three brothers, one with two. We also describe potential treatments and found for the youngest that early initiation of standard therapy preserved or reclaimed adult height (AH) potential. The foreshortened AH in this situation involves rapidly advancing puberty resulting from high circulating testosterone levels leading to rapid advance in skeletal age. This was recognized earlier among younger brothers and treatment with gonadotropin-releasing analogues, growth hormone (GH) and/or aromatase inhibitor therapy (AIT) was tried. Two brothers in family A and family B were treated. Case 5 started treatment early enough so his AH was within target height (mid-parental height) range. Cases 2, 3, 4 were tried on GH and/or AIT with outcomes suggesting benefit. The prevalence and mechanism of rapid-tempo puberty requires further study. Furthermore, as illustrated by two of the current cases, this phenomenon may have a heightened prevalence, or at least may occur, in children previously diagnosed with constitutional delay of growth, underscoring the need to be cautious in assurance of a normal AH outcomes in this population, based on data from a single assessment.

In vivo effect of recombinant Fsh and Lh administered to meagre (Argyrosomus regius) at the initial stages of sex differentiation.

Recombinant gonadotropins, follicle stimulating (rFsh) and luteinizing hormone (rLh), offer the potential to induce gametogenesis in prepubertal fish. This study aimed to determine the in vivo effect of the administration of Argyrosomus regius rFsh and rLh on the reproductive development of prepubertal meagre juveniles at the initial stages of sexual differentiation. Juvenile meagre, 9-months old with mean weight of 219 ± 3.9 g (mean ± SEM) were randomly distributed into nine groups (n = 8 per group). Experimental groups were treated weekly with an acute injection of either rFsh or rLh. Control groups were injected with saline solution. In a 3-week experiment, different groups were administered with different doses 6, 12 or 18 µg kg-1 of rFsh or rLh or saline solution. In a 6-week experiment a group was administered with 12 µg kg-1 of rFsh and a second group with saline solution. The fish were held in a single 10 m3 tank with natural photoperiod (Feb. - March) and temperature 16.1 ± 0.4 °C. At the start of the experiment (n = 8) and at the end of the 3-week experiment, fish were blood sampled and sacrificed. Blood was analysed for 17ß-estradiol (E2) and 11-ketotestosterone (11-KT). Gonads and liver were dissected and weighed. Gonads were fixed in Bouins solution and processed for histological analysis. Juvenile meagre at the start of the experiment were in the initial stages of sexual differentiation, indicated by the presence of the ovarian cavity or testes duct that was surrounded by undifferentiated embryonic germ stem cells and somatic cells. At the end of the 3-week experiment, there was no significant difference in gonadosomatic index (GSI) amongst control (initial and saline treated) and the experimental groups. After three weeks of application of rFsh, rLh or saline all fish presented a similar gonadal structure as at the start of the experiment. However, the incidence of sporadic developing germ cells (principally spermatogonia, spermatocytes, spermatids, but also perinucleolar stage oocytes) generally increased in rGth treated meagre. A mean of 44 % of meagre treated with rFsh or rLh presented sporadic isolated developing germ cells, mainly male cells. Plasma steroid levels of E2 decreased significantly from the start of the experiments to the end. At the end of the experiments there were no differences in plasma E2 amongst Control fish and rGth treated fish. Plasma 11-KT showed no change from the start of the experiment to week 3. However, a significant increase was observed in a proportion of the rFsh group after six weeks of treatment compared to the start of the experiment and the saline control group on week 6. The application of rFsh or rLh to meagre at the initial stages of sex differentiation did not stimulate steroid production until week six (11-KT) and had a limited, but evident effect on the development of sporadic isolated germ cells. However, we conclude that rGth, rFsh or rLh did not stimulate large developmental changes in sexually undifferentiated meagre gonads.

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.

The Use of Injectable Estradiol in Transgender and Gender Diverse Adults: A Scoping Review of Dose and Serum Estradiol Levels.

OBJECTIVE: Feminizing gender-affirming hormone therapy is the mainstay of treatment for many transgender and gender diverse people. Injectable estradiol preparations are recommended by the World Professional Association for Transgender Health Standards of Care 8 and the Endocrine Society guidelines. Many patients prefer this route of administration, but few studies have rigorously assessed optimal dosing or route. METHODS: We performed a scoping review of the available data on estradiol levels achieved with various dosages of estradiol injections in transgender and gender diverse adults on feminizing gender-affirming hormone therapy. We also report on testosterone suppression, route (ie, subcutaneous vs intramuscular), and type of injectable estradiol ester as well as timing of blood draw relative to the most recent dose, where available. RESULTS: The data we reviewed suggest that the current guidelines, which recommend starting doses 2 to 10 mg weekly or 5 to 30 mg every 2 weeks of estradiol cypionate or valerate, are too high and likely lead to patients having supraphysiologic levels across much of their injection cycle. CONCLUSIONS: The optimal starting dose for injectable estradiol remains unclear and whether it should differ for cypionate and valerate. Based on the data available, we suggest that clinicians start injectable estradiol cypionate or valerate via subcutaneous or intramuscular injections at a dose ≤5 mg weekly and then titrate accordingly to keep levels within guideline-recommended range. Future studies should assess timing of injections and subsequent levels more precisely across the injection cycle and between esters.

Pulsatile gonadotropin releasing hormone therapy for spermatogenesis in congenital hypogonadotropic hypogonadism patients who had poor response to combined gonadotropin therapy.

Objective: Both pulsatile gonadotropin-releasing hormone (GnRH) and combined gonadotropin therapy are effective to induce spermatogenesis in men with congenital hypogonadotropic hypogonadism (CHH). This study aimed to evaluate the effect of pulsatile GnRH therapy on spermatogenesis in male patients with CHH who had poor response to combined gonadotropin therapy. Materials and methods: Patients who had poor response to combined gonadotropin therapy ≥ 6 months were recruited and shifted to pulsatile GnRH therapy. The rate of successful spermatogenesis, the median time to achieve spermatogenesis, serum gonadotropins, testosterone, and testicular volume were used for data analysis. Results: A total of 28 CHH patients who had poor response to combined gonadotropin (HCG/HMG) therapy for 12.5 (6.0, 17.75) months were recruited and switched to pulsatile GnRH therapy for 10.0 (7.25, 16.0) months. Sperm was detected in 17/28 patients (60.7%). The mean time for the appearance of sperm in semen was 12.0 (7.5, 17.5) months. Compared to those who could not achieve spermatogenesis during pulsatile GnRH therapy, the successful group had a higher level of LH60min (4.32 vs. 1.10 IU/L, P = 0.043) and FSH60min (4.28 vs. 1.90 IU/L, P = 0.021). Testicular size increased during pulsatile GnRH therapy, compared to previous HCG/ HMG therapy (P < 0.05). Conclusion: For CHH patients with prior poor response to one year of HCG/ HMG therapy, switching to pulsatile GnRH therapy may induce spermatogenesis.

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.