Guidance on the use of oral testosterone undecanoate: background, clinical considerations, and best practices.

IntroductionHormone replacement therapy (HRT) for transgender men involves various formulations of testosterone, each exhibiting unique pharmacokinetic profiles and emotional impacts. A comprehensive understanding of these variations is crucial for optimizing treatment outcomes and managing side effects effectively.ObjectivesThis study aims to elucidate the differential emotional effects associated with various testosterone formulations used in HRT for transgender men.MethodsA comprehensive literature review was conducted using databases such as PubMed, Scopus, and Web of Science. The review focused on four primary testosterone administration methods: intramuscular and subcutaneous injections, transdermal patches and gels, oral testosterone, and implantable pellets. Key metrics evaluated included pharmacokinetics, emotional effects, and nature of side effects.ResultsThe review identified distinct pharmacokinetic profiles and emotional responses associated with each testosterone formulation:Intramuscular and Subcutaneous Injections: These methods showed peak testosterone levels within 24-48 hours, followed by a decline over one to two weeks. Emotional effects included mood elevation and increased energy during the peak phase, with potential irritability or anxiety. The trough phase was marked by mood swings and depressive symptoms, particularly before the next injection. Side effects such as acne and libido changes peaked shortly after injection and decreased before the subsequent dose.Transdermal Patches and Gels: These methods maintained consistent blood testosterone levels, resulting in stable mood and emotional states with reduced mood swings. Initial therapy adaptation caused mild mood changes, and side effects were primarily localized to skin irritation at application sites.Oral Testosterone: Testosterone undecanoate offered stable testosterone levels with consistent mood regulation. Gastrointestinal side effects were common, and emotional stability varied based on absorption rates and adherence to dosing schedules.Implantable Pellets: These provided the most stable testosterone levels over several months, leading to very stable emotional states with minimal mood fluctuations. Side effects included localized reactions such as discomfort or infection at the implantation site, with minimal systemic side effects.ConclusionsThe choice of testosterone formulation significantly impacts the emotional well-being of transgender men undergoing HRT. Intramuscular and subcutaneous injections were associated with emotional fluctuations tied to hormone peaks and troughs, while transdermal, oral, and implantable methods provided more stable hormone levels and emotional states. Regular monitoring and individualized modifications are crucial to optimizing physiological and emotional outcomes and enhancing the quality of life for transgender men.Disclosure of InterestNone Declared

To evaluate the clinical efficacy of "Shibao Decoction" in the management of late-onset hypogonadism (LOH) caused by deficiency of kidney essence. Sixty male patients with late-onset hypogonadism of kidney essence deficiency type were randomly assigned to the treatment group and the control group, each with 30 cases. The patients in treatment group were treated with oral Shibao Decoction, while the control group was treated with oral Testosterone Undecanoate Capsules. The patients in both groups were treated for 12 weeks. The PADAM symptom score, TCM syndrome score, serum total testosterone (TT), serum free testosterone (FT), sex hormone binding globulin (SHBG), body mass index (BMI), total skeletal muscle mass index (SMI), appendicular skeletal muscle mass index (ASMI), FBG, FINS, and insulin resistance index (HOMA-IR) levels were compared between the two groups. After treatment, PADAM scores for each item and TCM symptoms score decreased, TT and FT increased in both groups, all with statistically significant differences from those of pre-treatment (P<0.05). The level of SHBG in the control group decreased (P<0.05), which had not changed significantly in the treatment group (P>0.05). After treatment, SMI and ASMI increased in both groups significantly (P<0.05). BMI decreased in the control group (P<0.05), which had not changed significantly in the treatment group (P>0.05). The level of FINS decreased in the control group (P<0.05), which had not changed significantly in the treatment group (P>0.05). FPG had not changed significantly in both groups (P>0.05), and the insulin resistance index (HOMA-IR) had significantly improved in both groups, all with statistically significant differences from those of pre-treatment (P<0.05). After treatment, the total effective rates of PADAM score and TCM syndrome score in the treatment group were 73.3% and 86.6% respectively, and the total effective rates in the control group were 66.7% and 76.6% respectively. The total effective rates of the two scores in the treatment group were slightly higher than those in the control group (P>0.05). There was no significant difference in the indicators between the two groups after treatment, and the treatment group is generally comparable with the control group in the therapeutic effects (P>0.05). And no adverse reactions occurred during treatment in both groups. The "Shibao Decoction" has a remarkable therapeutic effect on late-onset hypogonadism caused by deficiency of kidney essence and has good safety. It can be used as an alternative to testosterone undecanoate and is worthy of clinical promotion and application.

Erythropoiesis-stimulating agents (ESAs) achieve hematological improvement-erythroid (HIE) in only 30% of ESA-naïve lower risk myelodysplastic syndrome (LR-MDS) patients with anemia, highlighting the need for developing novel drugs or new treatment strategies to improve the outcome of these patients. We conducted this multicenter, single-arm trial to investigate the efficacy and safety of a triple regimen consisting of recombinant human erythropoietin (rhEPO), all-trans retinoic acid (ATRA) and testosterone undecanoate in patients with anemia due to lower-risk MDS based on Revised International Prognostic Scoring System. Eligible patients received rhEPO 10000 IU/day, oral ATRA 25 mg/m2/day and oral testosterone undecanoate 80 mg twice daily for 12 weeks. The primary endpoint was the proportion of patients achieving HI-E during 12 weeks of treatment. Of 52 eligible patients, 32 (61.5%, 95%CI 48.0%-73.5%) achieved HI-E, meeting the primary endpoint. Fifteen patients (65.2% [15/23]) with baseline serum erythropoietin ≤500 IU/L had HI-E versus 58.6% of those (17/29) with baseline serum erythropoietin >500 IU/L. More patients with very low or low risk had HI-E than those with intermediate risk (73.3% vs. 45.5%, P = 0.041) and fewer patients with mutated ASXL1 had HI-E than those with wildtype ASXL1 (33.3% vs. 70.0%, P = 0.040). The regimen had an acceptable safety profile compatible with individual agents. In conclusion, the triple regimen of rhEPO combined with ATRA and testosterone undecanoate attained HI-E in approximately 61.5% of patients regardless of baseline serum EPO levels, supporting further development of this regimen for LR-MDS patients with anemia. This study was registered at CHICTR.ORG.CN as ChiCTR2000032845.

Efficacy of oral testosterone undecanoate in children with androgen insensitivity syndrome

Testosterone has a pivotal role in spermatogenesis, erectile function, libido and expression of secondary sexual characteristics. The prevalence of symptomatic, laboratory-proven testosterone deficiency increases with age and is often treated with testosterone replacement therapy (TRT). Treatment with exogenous androgens suppresses gonadotropin levels, inhibits endogenous testosterone production and drastically reduces intratesticular testosterone, consequently impairing spermatogenesis. Sperm production often slowly resumes after TRT cessation. However, the rate of recovery shows highly variable kinetics that might complicate family planning. Medical therapies (including aromatase inhibitors and selective oestrogen receptor antagonists) and exogenous gonadotropins (including human chorionic gonadotropin and follicle-stimulating hormone) may be used to preserve or restore spermatogenesis in select populations receiving TRT. Exogenous testosterone is contraindicated in men trying to conceive, but new short-acting formulations, including oral testosterone undecanoate and nasal testosterone gel, might incompletely suppress the hypothalamic-pituitary-gonadal axis and partially preserve spermatogenesis.

Misconceptions about testosterone therapy are prevalent and there is an unmet need for a review of current literature that can be leveraged by physicians to deliver safe and effective care for men with hypogonadism. This review aims to address common misconceptions about testosterone therapy using current literature and synthesize practical guidance for clinicians with patients who are starting testosterone therapy. A literature search of PubMed, Embase, CINAHL was carried out to identify associations between testosterone therapy and prostate cancer, cardiovascular risk, and hepatic toxicity; definitions of hypogonadism; and practical guidance for clinician with patients starting testosterone therapy. There is no evidence to support the misconception that testosterone therapy leads to or promotes progression of prostate cancer, no evidence that testosterone therapy increases cardiovascular risk, no evidence that newer oral testosterone therapy formulations (eg, testosterone undecanoate) are associated with hepatic toxicity, and no consistent definition of hypogonadism among regulatory agencies and expert bodies. Clinicians should diagnose hypogonadism using testosterone concentrations and/or symptoms of testosterone deficiency, help patients select a testosterone therapy formulation that best fits their needs and preferences (including considerations for dose adjustment), ensure appropriate laboratory monitoring before and during treatment, and assess how patients are feeling during treatment. Testosterone therapy is not associated with increased prostate cancer or increased cardiovascular risk, newer oral testosterone therapy formulations are not associated with hepatic toxicity, and a strict definition of hypogonadism is difficult because patient individualization is required. Each patient in real-world clinical practices has unique baseline characteristics and will likely respond differently to testosterone therapy. As the primary goal of testosterone therapy is to provide relief from symptoms of hypogonadism, physicians should work with their male patients to create a comprehensive treatment plan that suits the patient's specific needs and preferences.

The detection of endogenous anabolic androgenic steroids misuse in Asian population using the Steroidal Module of the Athlete Biological Passport (ABP) is a challenge due to the high prevalence of UGT2B17 gene deletion polymorphism and low levels of testosterone (T) glucuronide. In this study, the capabilities of different approaches based on urine analysis for detecting oral T undecanoate administration were evaluated in 13 Asian volunteers, including 11 subjects with del/del genotype and 2 subjects with del/ins genotype. In this part of the work, the effect on the urinary steroid profile (SP) and the isotope ratio mass spectrometry (IRMS) markers were studied. Results showed that the 5α-androstane-3α,17β-diol/epitestosterone ratio is the most sensitive marker of the SP to detect oral T administration in Asian volunteers. All urines that led to suspicious urinary SP were concluded IRMS positive. However, for some subjects, the ABP Steroidal Module was unable to identify suspicious samples that were still detectable by IRMS. Positive IRMS samples were detected up to 24 h (n = 9), 36 h (n = 3), or 48 h (n = 1) after oral administration. Overall, the urinary SP together with IRMS allowed the detection of T administration in Asian volunteers. However, the detection windows are short, as reported for oral T administration in Caucasian volunteers. These findings highlight the need of implementing additional markers in the Steroidal Module of ABP that could enlarge detection windows.

Study question How should premature/primary ovarian insufficiency (POI) be diagnosed and managed, based on the best available evidence from published literature? Summary answer The current guideline provides 145 recommendations on symptoms, diagnosis, causation, sequelae and treatment of POI. What is known already POI presents a significant challenge to women’s health, with far-reaching implications, both physically and emotionally. The potential implications include adverse effects on quality of life, on fertility and on bone, cardiovascular and cognitive health. Although hormone therapy (HT) can mitigate some of these effects, many questions still remain regarding the optimal management of POI. Study design, size, duration The guideline was developed according to the structured methodology for development of European Society of Human Reproduction and Embryology (ESHRE) guidelines. Key questions were determined by a group of experts and informed by a scoping survey of women and healthcare professionals. Literature searches and assessment were then performed. Papers published up to 30 January 2024 and written in English were included in the guideline. An integrity review was conducted for the randomized controlled trials on POI included in the guideline. Participants/materials, setting, methods Based on the collected evidence, recommendations were formulated and discussed within the guideline development group until consensus was reached. Women with lived experience of POI informed the recommendations in general, and particularly those on provision of care. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline development group and the ESHRE Executive Committee. Main results and the role of chance New data indicate a higher prevalence of POI, 3.5%, than was previously thought. This guideline aims to help healthcare professionals apply best practice care for women with POI. The recent update of the POI guideline covers 40 clinical questions on diagnosis of the condition, the different sequelae, including bone, cardiovascular, neurological and sexual function, fertility and general well-being, and treatment options, including HT. The list of clinical questions was expanded from the previous iteration of the guideline (2015) based on the scoping survey and appreciation of emerging knowledge of POI. Questions were added on the role of anti-Müllerian hormone (AMH) in the diagnosis of POI, fertility preservation, muscle health and specific considerations for HT in iatrogenic POI. Additionally, the topic on complementary treatments was extended with specific focus on non-hormonal treatments and lifestyle management options. Significant changes from the previous 2015 guideline include the recommendations that only one elevated follicle stimulating hormone (FSH) >25 IU is required for diagnosis of POI and guidance that AMH testing, repeat FSH measurement and/or AMH may be required where there is diagnostic uncertainty. Recommendations were also updated regarding genetic testing, estrogen doses and regimens, use of the combined oral contraceptive and testosterone therapy. Women with lived experience of POI informed the recommendations on provision of care. Limitations, reasons for caution The guideline describes different management options, but it must be acknowledged that for most of these options, supporting evidence is limited for POI. Wider implications of the findings The guideline provides healthcare professionals with clear advice on best practice in POI care, based on the best evidence currently available. In addition, a list of research recommendations is provided to guide further studies in POI.

In recent years, the landscape of testosterone replacement therapy (TRT) has evolved significantly, offering new hope for hypogonadal men seeking effective and convenient treatment options. The introduction of oral testosterone undecanoate (TU) marks a pivotal advancement in this field, as highlighted in the comprehensive review by Dr. Julian Borges. This editorial aims to explore the implications of these findings and the future of oral TRT in clinical practice.

Objective: To conduct a systematic review and meta-analysis to evaluate the safety and efficacy of oral testosterone therapy in hypogonadal men. The primary outcome is the assessment of safety, focusing on cardiovascular risks, liver toxicity, and prostate safety. Secondary outcomes include evaluations of bone mass, cardiovascular benefits, cognitive function, and potential reductions in mortality. Methods: A systematic search was conducted using databases such as PubMed, Embase, and Cochrane Library, identifying peer-reviewed studies published until August 2024. The search included randomized controlled trials (RCTs), cohort studies, and large clinical trials. The studies involved a total of 3,183 hypogonadal men. Data were extracted and analyzed to assess primary and secondary outcomes. Statistical methods for meta-analysis included fixed-effects and random-effects models to calculate pooled estimates and assess heterogeneity. Results: The analysis included 11 studies, encompassing a total of 3,183 hypogonadal men. Oral testosterone therapy demonstrated a safety profile comparable to other testosterone replacement therapy (TRT). No significant increase in liver toxicity was observed, supported by studies showing no liver damage after long-term oral testosterone undecanoate (TU) administration. Cardiovascular safety results were mixed; some studies noted minor increases in systolic blood pressure (SBP), but there was no consistent evidence of a significant increase in major cardiovascular events compared to other TRT forms. The prostate safety profile was consistent with existing TRT modalities, with only minor increases in prostate-specific antigen (PSA) levels noted. Secondary outcomes were generally favorable: bone density improved, fat mass was reduced, and there were indications of cognitive benefits, although these findings varied across studies. However, the evidence for mortality reduction was inconclusive, with no strong data supporting a significant effect of oral testosterone on reducing mortality. Conclusion: Oral testosterone therapy appears to be a safe and effective treatment for hypogonadal men, with a risk profile comparable to other TRT forms. It offers potential benefits in bone health and cognitive function but requires careful monitoring of cardiovascular health and prostate safety during treatment. The findings suggest that oral testosterone therapy can be a valuable option for hypogonadal men, though long-term studies are needed to better understand its full range of effects, particularly concerning mortality and cardiovascular outcomes.

Testosterone deficiency is a clinical disorder due to either failure of the testes to produce testosterone or failure of the hypothalamus or pituitary to produce sufficient gonadotropins. Previous formulations of oral testosterone therapy, particularly methyltestosterone, have been associated with adverse liver effects. Many different routes of testosterone delivery have been developed, each with their own administrative benefits and challenges. Newer formulations of oral testosterone undecanoate (TU) provide a convenient administration option, although their use has been limited by hepatotoxicity concerns based on older methyltestosterone data, and prescribing physicians may still be concerned about adverse liver effects. In this review, we discuss the history of oral testosterone development, clarify the mechanism of action of oral TU, and describe the relevant liver safety findings. Relevant literature was allocated to present a review on the history of oral TU development and the mechanism of action of oral TU. We pooled data from individual studies of oral TU products to present a safety summary. Overall, safety results from studies of the newer formulations of oral TU showed that increased liver function test values are not generally associated with oral TU formulations and that no clinically significant liver toxicities were noted in clinical trials of oral TU. Continued research into the safety of oral TU will contribute to a better understanding of the potential risks in patients receiving this therapy, an outcome that highlights the importance of providing patient education and reassurance regarding oral TU safety.

BackgroundTestosterone deficiency results from insufficient testosterone production. Testosterone therapy may require dose titration to reach eugonadal serum testosterone concentrations.ObjectiveThe primary objective was the efficacy of oral testosterone undecanoate (TLANDO; Antares Pharma Inc.) in male patients with documented hypogonadism. Secondary objectives included a comparison of oral testosterone undecanoate safety and quality‐of‐life assessments to 1.62% topical testosterone gel (AndroGel 1.62%; AbbVie).Materials and methodsIn this phase 3 study, 315 patients were randomized 2:1 to oral testosterone undecanoate or 1.62% topical testosterone gel (NCT02081300). Patients received 225 mg oral testosterone undecanoate twice daily, and doses were adjusted by 75 mg/dose at weeks 4 and 8 based on average serum total testosterone concentration and maximum observed serum concentration. The primary endpoint was the proportion of patients receiving oral testosterone undecanoate with serum total testosterone concentration within the eugonadal reference range (300–1140 ng/dL). Secondary endpoints included the proportion of patients with maximum serum total testosterone concentrations within predetermined limits, safety parameters, and quality‐of‐life endpoints including the Short Form‐36v2 Health Survey, Psychosexual Daily Questionnaire, and International Prostate Symptom Score.ResultsOverall mean ± SD baseline testosterone was 205.7 ± 71.6 ng/dL. For patients receiving oral testosterone undecanoate, 87.4% demonstrated a 24‐h average serum total testosterone concentration within the reference range following titration. Oral testosterone undecanoate demonstrated a nominal statistically significantly greater mean change from baseline than 1.62% topical testosterone gel for Short Form‐36v2 Health Survey measures of mental health (2.91 vs. ‐0.10; p = 0.035), and mental component summary (3.82 vs. 0.55; p = 0.009); and Psychosexual Daily Questionnaire measure of weekly negative mood (‐0.57 vs. ‐0.20; p = 0.021). Safety endpoints were comparable between therapies. No deaths or treatment‐related serious adverse events were reported.Discussion and conclusionMale patients with hypogonadism receiving oral testosterone undecanoate 225 mg twice daily demonstrated improvements in libido and sexual frequency. Serum testosterone concentrations were within the reference range in 87% of patients without dose titration.

Abstract Introduction Testosterone replacement therapy (TRT) is commonly prescribed for men with hypogonadism. While injectable testosterone preparations are widely used, oral testosterone formulations have become an increasingly popular treatment option due to their ease of administration and avoidance of repeated intramuscular injections. However, the effects of oral testosterone on semen analysis (SA) parameters and male fertility potential remain understudied. Objective To evaluate changes in semen analysis parameters, including sperm concentration, motility, and morphology, among hypogonadal men receiving oral testosterone undecanoate therapy. Methods A pilot prospective study was conducted enrolling hypogonadal men. Exclusion criteria included prior TRT, use of clomiphene citrate or human chorionic gonadotropin, and azoospermia. Participants received oral testosterone undecanoate for 3 months. SA evaluating sperm concentration, motility, and volume were performed at baseline and 3 months. Concurrent biochemical assessment included measurement of reproductive hormone levels and hematocrit. An interim blood draw was made for drug titration to the therapeutic testosterone range. Baseline and follow-up semen parameters and hormonal values were compared using paired statistical tests. The primary outcome was a change in semen parameters after 3 months of oral testosterone therapy. Results At the interim analysis with 5 patients enrolled thus far, the mean age was 39.6 years (SD: 5.36). Overall, only one patient became azoospermic. When excluding him, a statistically significant increase in total testosterone levels was observed between baseline and follow-up (220.60 ± 42.54 ng/dL vs. 704.67 ± 188.83 ng/dL, p = 0.02), as well as for free testosterone (62.64 ± 9.78 ng/dL vs. 221.98 ± 43.78 ng/dL, p = 0.01). No significant differences were detected between baseline and follow-up values for estradiol, follicle-stimulating hormone, luteinizing hormone, or hematocrit levels. Semen analysis parameters, including sperm concentration, motility, and volume, did not demonstrate statistically significant changes from baseline to 3-month follow-up. These preliminary findings are summarized in Table 1. Conclusions In this pilot study expected increases in total and free testosterone levels were achieved, confirming adequate treatment. No significant changes in semen parameters or other reproductive hormones were observed after 3 months of treatment. Larger scale studies are needed to fully evaluate the effects of oral testosterone formulations on semen quality and male fertility potential. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Disclosures: Consultant for AbbVie, Marius, Tolmar, Endo, Petros, Boston Scientific, Coloplast, Halozyme Investor: Sprout.

Abstract Introduction Hypogonadism in men is commonly treated with testosterone replacement therapy. Kyzatrex (Marius Pharmaceuticals), a novel oral testosterone undecanoate (TU) formulation, is conventionally initiated at a dose of 200 mg BID. However, many patients attain greater symptomatic benefit at higher doses. In our practice we often initiate therapy at a starting dose of 400 mg BID. This retrospective chart review examines the outcomes of initiating therapy at 400 mg BID. Objective Retrospectively report the safety, efficacy, patient satisfaction, and adherence of starting hypogonadal men on oral TU at the maximum available dose of 400 mg BID. Methods This retrospective, single-center chart review included hypogonadal men treated with oral TU at 400 mg BID from August 2023 to April 2024. Medical records were reviewed for baseline and follow-up levels of serum total testosterone (TT), sex hormone binding globin (SHBG), calculated free testosterone (fT), Estradiol, Hematocrit (Hct), follicle stimulating hormone (FSH), and luteinizing hormone (LH). Satisfaction was subjectively recorded in the medical record and adherence was measured by prescription refill records. Results A total of 27 patients met the inclusion criteria and had complete data. At a mean follow up time of 6 months, patients demonstrated a significant increase in TT (263 to 798 ng/dL), drop in SHBG (32.4 to 17.83 nmol/L), and increase in calculated fT (7.24 to 26.74 ng/dL). FSH and LH, while lower, were maintained at non-zero levels (FSH from 5.7 to 2.9 mIU/mL and LH from 3.3 to 1.9 mIU/mL). Estradiol modestly increased (20.5 to 24.7 pg/mL) while hematocrit did not significantly increase (44.9% to 47.4%). No patients reported testicular atrophy or were initiated on aromatase inhibitors. One patient had a hematocrit rise above 52% (53.2%) and was reduced to 300 mg BID. Patient reported side effects were rare with 2 patients (7.4%) reporting transient GI upset. Subjective patient satisfaction was high, with 26/27 (96%) of patients reporting improvement in symptoms and continuing on therapy. One patient opted to convert to testosterone cypionate injections instead. Conclusions Initiating oral TU therapy with Kyzatrex at 400 mg BID is safe and effective in achieving therapeutic serum testosterone levels. The high dose was well-tolerated and resulted in substantial symptom improvement, high patient satisfaction, and adherence. These findings support considering a higher starting dose for hypogonadal men considering oral TU therapy. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Senior author serves as consultant for Marius Pharmaceuticals, Boston Scientific, Endo Pharmaceuticals.

Abstract Introduction Clomiphene is often used in the treatment of hypogonadal men who wish to preserve endogenous testosterone production, however symptomatic responses are often suboptimal. Exogenous testosterone replacement, while effective, typically suppress the hypothalamic–pituitary-gonadal (HPG) axis. This case series investigates the efficacy of combining clomiphene with high-dose oral testosterone undecanoate (TU) (Kyzatrex, Marius Pharmaceuticals). Objective To report the outcomes in a series of patients treated with combined clomiphene and oral TU therapy. Methods Three hypogonadal men who initially received clomiphene therapy (50 mg every other day) but did not achieve satisfactory symptomatic improvement despite numerical improvement were identified. Subsequently, they were given oral TU 400 mg once daily with lunch. Subjective symptomatic outcomes, total testosterone (TT), sex hormone binding globulin (SHBG), calculated free testosterone (fT), estradiol, hematocrit (Hct), and HPG axis markers luteinizing hormone (LH) and follicle stimulating hormone (FSH) were monitored at baseline, after 3 months of clomiphene monotherapy, and after 3 additional months of combined clomiphene and oral TU therapy. Results The patients had baseline serum testosterone levels of 303, 223, and 230 ng/dL. After 3 months of clomiphene 50 mg QoD, TT rose to 418, 680, and 667 ng/dL respectively, however these patients reported continued symptoms of hypogonadism. After adding 400 mg oral TU once daily for 3 months, TT rose to 1001, 1055, and 1120 ng/dL, and the patients reported significant improvement in symptoms such as erectile dysfunction, fatigue, libido, and exercise tolerance. Both SHBG and Estradiol levels rose with clomiphene monotherapy but subsequently decreased after adding oral TU. Hct was unchanged throughout. FSH and LH levels both rose on clomiphene and subsequently dropped after initiation of oral TU, but remained near baseline, indicating preserved HPG axis function. No significant adverse events were reported. Conclusions In these patients for whom clomiphene monotherapy failed to generate a sufficient symptomatic response, the addition of high-dose oral TU therapy (Kyzatrex 400 mg) at a once-daily dosing resulted in substantial symptomatic improvement while maintaining endogenous FSH and LH levels at baseline. These findings suggest a novel approach to hypogonadism management, balancing effective symptom relief with preservation of endogenous testosterone production, with potential downstream ramifications on fertility preservation. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Senior author serves as consultant for Marius Pharmaceuticals, Boston Scientific, Endo Pharmaceuticals.

Abstract Introduction Over 2.4 million US men have hypogonadism, defined as serum testosterone (T) levels &amp;lt;300 ng/dL and/or symptoms of T deficiency. Negative effects associated with hypogonadism include development of metabolic syndrome, increased risk of coronary artery disease, decreased libido, low bone mineral density, and muscle loss. Oral T replacement therapies provide a route of administration that may be more appropriate for some patients’ needs. Objective We present secondary analyses of T data from a phase 3 study of oral testosterone undecanoate (TU) which is approved in 158, 198, 237, 316, and 396 mg doses, with the goal of demonstrating that the starting oral TU dose quickly and effective achieves normal serum T concentrations in a large proportion of men. Methods A phase 3, randomized, active controlled, open-label study was conducted to assess the safety and efficacy of oral TU in 222 hypogonadal men. Men ≥18 to ≤75 years with morning serum T ≤ 300 ng/dL twice in one week were eligible. Eligible patients were randomized to oral TU or transdermal T-gel from Days 0 to 42. The initial oral TU dose was 237 mg TU twice a day (BID). For men treated with the initial oral TU dose, serum T concentrations were evaluated at Day 21, 4 hours after the dose. Results 165 men had serum T data. 85% of men achieved serum T concentrations ≥300 ng/dL on Day 21 at 4 hours after the first oral TU dose with no dose titrations. (Figure 1) For these 85%, the mean T concentration was 679 ng/dL. Conclusions Overall, the starting dose of 237 mg TU BID quickly and effectively increased serum T concentrations ≥300 ng/dL in 85% of hypogonadal men. The wide distribution of serum T concentrations for the same dose (e.g., 15% &amp;lt;300 ng/d and 12% ≥1000 ng/dL) suggests that men likely respond differently to T replacement therapy. Therefore, an oral T replacement therapy that allows for dose titration would likely be preferable to a fixed dose. Future studies and investigations should evaluate patient factors that impact the magnitude of T increases allowing for more individualized titrations. Disclosure Yes, this is sponsored by industry/sponsor: Tolmar, Inc. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Tolmar, Inc.

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.

Abstract Introduction Testosterone therapy has gained popularity in recent decades, with various methods of administration available, such as oral, topical, injection, and implantable routes. As a wider variety of treatment options arise, knowledge regarding the public interest in varying modalities may give providers an insight to patient preferences and assist in the counseling of patients seeking to initiate testosterone replacement therapy. Objective To examine public interest in the different methods of testosterone administration across the United States and compare their relative popularity to intramuscular injections. Methods Utilizing Google Trends, data pertaining to searches related to diverse testosterone administration methods were collected over a ten-year duration. The categories under analysis encompassed 1) testosterone injections, 2) implanted testosterone, 3) oral testosterone, and 4) topical testosterone. Controlled search terms, including news and weather queries, were employed. Search term trends were quantified in arbitrary units (a.u.) and plotted against the corresponding time period. Results Testosterone injection had the highest average search intent from Google Trends during the past 10 years (63.08 +/- 12.7 a.u.), followed by testosterone pills (60.56 +/- 13.4 a.u.), testosterone pellets (53.14 +/- 19.4 a.u.), testosterone patches (51.03 +/- 16.2 a.u.), and lastly testosterone gel (17.29 +/- 21.5 a.u.) A notable upward trend was recorded for all searches, with the highest increase in searches seen for implanted testosterone (m = 0.433), testosterone injections (m = 0.297), oral testosterone (m = 0.222), and lastly topical testosterone (m = 0.050) (Figure 1). Conclusions This study provides compelling evidence that all modes of testosterone administration had increasing search trends, most notably implantable testosterone therapies followed by testosterone injections, and oral testosterone, which may be in line with recent FDA approvals since 2019 for newer oral (Jatenzo, Tlando, Kyzatrex) and implantable (ex: Xyosted) options. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Antares Pharma, Clarus Therapeutics, Coloplast.

For antidoping laboratories, the determination of an illicit testosterone (T) administration in urine samples remains a difficult process as it requires the determination of the exogenous origin by carbon isotope ratios (CIRs) of testosterone and its metabolites. As a complement to the urinary analysis, targeting testosterone esters (e.g. testosterone undecanoate [TU]) in serum samples by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) could represent a simpler approach compared with isotope ratio mass spectrometry (IRMS). These two approaches both lead to the direct detection of the administration of exogenous T but with a difference in effort and complexity of the analysis. To compare the detection window obtained with the two strategies, serum and the corresponding urine samples collected from an administration study with oral TU were analysed. Results showed that, at all timepoints where the intact TU was detected in serum, the CIRs of urinary steroids were also not in agreement with an endogenous origin. IRMS analysis required more effort but resulted in slightly longer detection windows than the ester analysis. Finally, this comparison study showed that, in the presence of a suspicious urinary steroid profile, the LC-MS/MS steroid esters analysis in the corresponding serum samples can be very helpful. If steroid esters are not detected, the IRMS analysis can then be conducted on the urine sample afterwards. Overall, the combination of matrices might facilitate the detection of prohibited T administration in sports, especially for athletes with naturally low T/E ratios.