Testosterone Pellets Research Articles

B Cell Maturation Antigen Inhibits an Inflammatory Role of Testosterone in Experimental Autoimmune Encephalomyelitis in C57BL/6 mice.

Abstract Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Sex influences both the incidence and prognosis of MS, with the disease more prevalent in women than men. Yet, men experience a more severe disease compared to women. The interplay of immune cells, hormones, and genetics may contribute to these phenomena. In experimental autoimmune encephalomyelitis (EAE) model of MS, there are no discernible effects of sex hormones in C57BL/6 mice. However, we now report an unexpected role of BCMA in controlling an inflammatory function of testosterone in C57BL/6 mice during EAE. BCMA, a cytokine receptor with established effects on B cells, was previously shown to attenuate EAE. We now show sex differences in EAE in BCMA-deficient C57BL/6 mice. Like other reports, we show no differences in the severity of EAE in male and female BCMA+/+ mice. However, the BCMA-/- males had significantly increased paralysis and CNS inflammation compared to BCMA-/- females. Remarkably, castration of BCMA-/- males significantly reduced EAE compared to sham controls, which was not observed in the BCMA+/+ males. In addition, we found that administration of testosterone pellets elevated EAE in male and female BCMA-/- mice. Previous EAE studies have shown a protective effect of testosterone in mice with genetic backgrounds other than C57BL/6. We now show a novel function for BCMA, where it inhibits a paradoxical inflammatory role for testosterone during EAE in C57BL/6 mice.

(334) Worldwide Interest in Testosterone Replacement Therapy

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.

Therapeutic Potential of Bipolar Androgen Therapy for Castration-Resistant Prostate Cancer: In Vitro and In Vivo Studies.

Androgen deprivation therapy (ADT) is a primary treatment for advanced prostate cancer (PCa), but resistance often leads to castration-resistant PCa (CRPC). CRPC remains androgen receptor (AR)-dependent, and AR overexpression causes vulnerability to high doses of androgen in CRPC. Bipolar androgen therapy (BAT) refers to the periodic administration of testosterone, resulting in oscillation between supraphysiologic and near-castrate serum testosterone levels. In this study, we evaluated the efficacy of BAT against CRPC in a preclinical setting. To emulate CRPC characteristics, PCa cell lines (LNCaP, VCaP, and 22Rv1) were cultured in phenol red-free RPMI-1640 medium supplemented with 10% dextran-coated charcoal treated FBS (A- cell line). Cell viability, AR, and AR-V7 expression were evaluated using the Cell Counting Kit-8 and Western blotting. In vivo studies involved 12 castrated NOG mice injected with LNCaP/A- cells, treated with testosterone pellets or controls in 2-week cycles. Tumor sizes were measured post a 6-week treatment cycle. Bicalutamide inhibited PCa cell viability but not in the adapted cell lines. Supraphysiologic androgen levels suppressed AR-expressing PCa cell growth in vitro. In vivo, high AR-expressing LNCaP cells proliferated under castrate conditions, while BAT-treated xenografts exhibited significant growth inhibition with low Ki-67 and mitotic indexes and a high cell death index. This study provides preliminary evidence that BAT is effective for the treatment of CRPC through rapid cycling between supraphysiologic and near-castrate serum testosterone levels, inducing an anti-tumor effect.

Effect of Testosterone Pellet Therapy on Bone Mineral Density in Postmenopausal Women

Effect of Testosterone Pellet Therapy on Bone Mineral Density in Postmenopausal Women

(009) Testosterone Management in Women with Hypoactive Sexual Desire Disorder Who Have Reduced 5α-Reductase Activity: A Unique Population

Abstract Introduction According to the Global Consensus Position Statement on the Use of Testosterone Therapy for Women, testosterone can significantly improve desire in menopausal women with hypoactive sexual desire disorder. Based on safety and efficacy of different formulations, the recommended treatment is 1/10th of a man’s dose, using a government approved topical testosterone gel or solution, or AndroFeme which is approved for use in menopausal women in Australia. There are, however, a subset of women without significant improvement in desire with this dose who experience improvement using higher doses of testosterone. These women have low or lower tertile dihydrotestosterone blood test values despite their total testosterone being above normal range or even in the upper tertile. The enzyme 5α-reductase converts testosterone to the more active form, dihydrotestosterone, that has a higher affinity for the androgen receptor than testosterone. 5α-reductase activity varies in different individuals. It is postulated that there are menopausal women with HSDD who have reduced 5α- reductase activity and therefore require a higher dose of testosterone from the gel or solution, or need a different testosterone formulation to realize clinical benefit. This subset of women do not appear to experience the usual adverse side effects of elevated testosterone (acne, thinning scalp hair, facial hair, aggressive behavior), in part because of low levels of dihydrotestosterone. Objectives This study examines the efficacy and safety of higher doses of testosterone using products government approved for men. Methods This is a retrospective chart review of menopausal women who were provided menopause management at our clinic focusing on women for whom 1/10th of a man’s dose of gel or solution did not provide symptom relief. Options included increasing the dose of gel or solution, or administration of an alternative delivery system of FDA approved (for men) testosterone including insertion of one or two 75 mg testosterone pellets (Testopel) or weekly intramuscular injection of testosterone cypionate (100 mg/ml – 0.1 ml or 10 mg). Results A total of 11 women (mean age 58 +/− 6 years) failed the usual 1/10th dose of topical testosterone gel for treatment of HSDD. Using testosterone pellet therapy, with 1-2 pellets implanted every 4-6 months, 6 patients had excellent desire as well as energy and self-confidence; 4 patients had excellent clinical response to weekly IM testosterone administration; 1 had improved symptoms by increasing the gel to 1 tube/4 days. While these treatments resulted in systemic levels of total testosterone outside the normal range for women (100 – 200 ng/dl), dihydrotestosterone values remained low or in the lower tertile (mean value 36 +/− 8 ng/dl; normal range 30 – 80 ng/dl). In general, side effects to be expected with higher doses of testosterone were not experienced despite elevated testosterone values. No patient complained of side effects consistent with excess testosterone other than mild facial hair. Conclusions In some women with reduced 5α-reductase activity, higher testosterone levels result in improved quality of life without expected negative side effects from higher physiologic levels of testosterone. Disclosure No.

(064) Pharmacokinetics and Safety Outcomes of Compounded Versus Branded Testosterone Pellets in Men with Testosterone Deficiency: A Single-Center, Open-Label, Randomized Trial

Abstract Introduction Testosterone deficiency (TD) is a prevalent condition, especially in men ≥ 45 years old, and testosterone therapy (TTh) can improve quality of life in these patients. Objective In this abstract, we aim to evaluate the safety profile of compounded subcutaneous testosterone pellets and to compare the pharmacokinetics between compounded and FDA approved testosterone pellets (Testopel®) for TTh. Methods This was a prospective, Phase 3, randomized, non-inferiority clinical trial. We enrolled 75 men diagnosed with TD and randomized them 1:1 ratio to Testopel® and a 100mg compounded pellet group. The patients were implanted with their respective treatment: Testopel® (10 pellets of 75mg) or compounded testosterone pellets (8 pellets of 100mg). Results After randomization, there were 35 participants enrolled in the Testopel® 75mg arm and 40 participants in E100 arm. Serum T levels were similar between the groups at 2, 4 and 6 months, with most men (82%) dropping below 300 ng/dL by the end of the trial. Adverse events such as elevations in prostate specific antigen, estrogen and hematocrit in each group were similar. Most dropouts were related to persistent TD symptoms and serum T < 300ng/dL, with similar rates between the two groups in the study. Conclusions Men treated with Testopel® and compounded pellets had comparable serum testosterone levels and similar adverse events rates. Compounded testosterone pellets can provide an effective choice of long term TTh among men with TD comparable to Testopel®. Disclosure Yes, this is sponsored by industry/sponsor: Empower Pharmaceuticals. Clarification Industry funding only - investigator initiated and executed study. Any of the authors act as a consultant, employee or shareholder of an industry for: Empower Pharmacy.

(046) Long-term Testosterone Pellet Insertion in Women with Low Libido Shows No Evidence of Erythrocytosis and a Minimal Side Effect Profile

Abstract Introduction Testosterone therapy for low libido in women has become more prevalent over recent years. While numerous testosterone formulations exist and have been studied in women, there has been little data assessing the safety and efficacy of subcutaneous testosterone pellet use in this population. Objective The aim of this study was to understand the biochemical effects and side effect profile of female patients who underwent testosterone pellet insertion by a single provider at an academic institution. Methods An Institutional Review Board approved retrospective chart review of all female patients undergoing testosterone pellet insertion from 2009-2022 was undertaken. Women taking 75 mg and 100 mg testosterone pellets were identified, and separately analyzed for biochemical and clinical data. Analysis of variance was performed to determine statistical significance of laboratory values over duration of testosterone pellet insertion. Results A total of 220 separate pellet insertion sessions were undertaken amongst the two cohorts. In the 75 mg cohort, the average number of pellets inserted per session was one. The average time between pellet insertion was 4.7 months (Standard error (SE) 0.1) over a five year period. There was no statistically significant change in testosterone trough levels over the duration of treatment (P=0.5105). There was also no statistically significant change in hematocrit levels from baseline (P=0.9696). In addition, no statistically significant change in systolic blood pressure was noted (P=0.8798). None of the patients in this cohort reported new or worsening acne. One patient reported mild increased facial hair growth. Two out of 19 (10.5%) patients reported vaginal bleeding during the study period, but both were also on systemic estrogen therapy at the time. In the 100 mg cohort, the average number of pellets inserted per session was one. The average time between pellet insertion was 4.3 months (SE 0.1) over an 18 month period. There was a statistically significant rise in testosterone trough levels over the duration of treatment (P=0.0168). There was no statistically significant change in hematocrit levels from baseline (P=0.7805). There was no statistically significant change in systolic blood pressure (P=0.7030). Two patients in this cohort were started on new blood pressure medications during the treatment course. None of the patients in this group reported new or worsening acne, changes in facial hair growth, or vaginal bleeding. Conclusions In both the 75 mg and 100 mg cohorts, testosterone pellet insertion lead to steady testosterone levels based on trough data, with a statistically significant rise amongst the 100mg cohort, and without any statistically significant rise in erythrocytosis rates, which is commonly seen with exogenous testosterone administration in the male population. In addition, no statistically significant changes in systolic blood pressure were noted in either cohort, along with minimal other side effects. This data suggests a relatively safe biochemical profile for regulated testosterone pellet administration in women with low libido, with a minimal side effect profile. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Boston Scientific

Allometric Scaling of Testosterone Enanthate Pharmacokinetics to Adolescent Hypogonadal Males (IM and SC Administration).

Intramuscular (IM) testosterone enanthate (TE) and testosterone pellets were US Food and Drug Administration approved before 1962 for pediatric use but not studied in controlled trials in adolescents. An analysis using nonlinear mixed effect (NLME) modeling was designed to evaluate the adult pharmacokinetics (PK) of subcutaneous (SC) and IM TE. This model was used to simulate SC and IM TE administration in adolescents of different weight groups. Data from adult male patients in a phase 2 trial were used to characterize the PK of TE using population PK modeling for SC and IM administration: Allometry was used to scale PK parameters from the adult model to simulate adolescent (aged 12 to < 18 years) serum testosterone levels at body weights of 30, 40, 50, and 60 kg after weekly, every-other-week (EOW), and monthly SC and IM administration of 12.5, 25, 50, 75, and 100 mg TE regimens. The final data set included 714 samples from 15 patients receiving 100 mg SC TE and 123 samples from 10 patients receiving 200 mg IM TE. In simulated populations, average serum concentration SC:IM ratios were 0.783, 0.776, and 0.757 at steady state for weekly, EOW, and monthly dosing groups, respectively. Simulated regimens of 12.5 mg SC TE monthly produced serum testosterone levels representative of early puberty and simulated pubertal stage progression following multiple subsequent testosterone dose increases. SC TE administration achieved a testosterone exposure-response relationship similar to IM TE in simulated adolescent hypogonadal males, which may reduce size of fluctuations in serum T and related symptoms.

A Short Review Based on the Article Entitled “Subcutaneous Testosterone Pellet Therapy for Reversal of Male Osteoporosis: A Review and Case Report”

Consistent levels of 943 were achieved, the patient also experienced improvements in quality of life and sleep apnea.

Prevalence of secondary erythrocytosis in men receiving testosterone therapy: A matched-cohort analysis of intranasal gel, injections, and pellets.

Increased hematocrit (HCT) is a common adverse effect in men on testosterone therapy (TTh). We aimed to uncover differences in HCT changes among men receiving different forms of TTh, namely intranasal gels, intramuscular injections, and subcutaneous pellets. We conducted a single-center, retrospective, matched-cohort study of patients treated for testosterone deficiency (TD) to investigate the effect of three TTh regimens on HCT. We included men who received intranasal testosterone (NT), intramuscular testosterone (TC), or subcutaneous testosterone pellet (TP) regimens between January 2011 and December 2020. We matched treatment cohorts 1:1:1 for age, body mass index (BMI), and history of obstructive sleep apnea. Those taking TTh for less than 16 weeks were excluded. Comparison between groups was performed with U-Mann Whitney test, Student t-test, ANOVA, or Kruskal Wallis test as appropriate. Seventy-eight matched-cohort individuals with testosterone deficiency (TD) received either NT, TC, or TP. The most common TD symptoms prior to initiation of TTh were erectile dysfunction (38%), low libido (22%), and lack of energy (17%). Baseline serum testosterone and HCT were higher in NT (p<0.05) recipients. As expected, all men receiving TTh were found to have increased serum testosterone levels at followup (p<0.001). Relative to their respective baselines, men receiving TC experienced the greatest increase in serum testosterone (240.8 ng/dL to 585.5 ng/dL), followed by NT (230.3 ng/dL to 493.5 ng/dL) and TP (210.8 ng/dL to 360.5 ng/dL) (all p<0.001). TC and TP were associated with significant increases in HCT (4.4% and 1.7%), while NT was associated with a decrease in HCT (-0.8%) at 16-week followup. When controlled for age, BMI, and OSA, men receiving NT experienced decreased HCT compared to TC or TP at 16-week followup. Intranasal testosterone, while able to increase serum testosterone levels to reference range, does not appear to have a significant impact on HCT compared to the longer-acting forms of TTh.

MP79-02 PHARMACOKINETICS AND SAFETY OUTCOMES OF COMPOUNDED VERSUS BRANDED TESTOSTERONE PELLETS IN MEN WITH TESTOSTERONE DEFICIENCY: A SINGLE-CENTER, OPEN-LABEL, RANDOMIZED TRIAL

You have accessJournal of UrologyCME1 Apr 2023MP79-02 PHARMACOKINETICS AND SAFETY OUTCOMES OF COMPOUNDED VERSUS BRANDED TESTOSTERONE PELLETS IN MEN WITH TESTOSTERONE DEFICIENCY: A SINGLE-CENTER, OPEN-LABEL, RANDOMIZED TRIAL Nicholas Deebel, Eliyahu Kresch, Thiago Fernandes Negris Lima, Manuel Molina, Rohit Reddy, Mehul Patel, Justin Loloi, Chase Carto, Daniel Gonzalez, Jesse Ory, Halifax Canada, and Ranjith Ramasamy Nicholas DeebelNicholas Deebel More articles by this author , Eliyahu KreschEliyahu Kresch More articles by this author , Thiago Fernandes Negris LimaThiago Fernandes Negris Lima More articles by this author , Manuel MolinaManuel Molina More articles by this author , Rohit ReddyRohit Reddy More articles by this author , Mehul PatelMehul Patel More articles by this author , Justin LoloiJustin Loloi More articles by this author , Chase CartoChase Carto More articles by this author , Daniel GonzalezDaniel Gonzalez More articles by this author , Jesse OryJesse Ory More articles by this author , Halifax CanadaHalifax Canada More articles by this author , and Ranjith RamasamyRanjith Ramasamy More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003356.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Testosterone deficiency (TD) is a prevalent condition, especially in men ≥45 years old. Treatment of TD with testosterone therapy (TTh) carries numerous metabolic benefits. Subcutaneous Testopel® pellets are FDA approved for the treatment of TD however can impose a significant financial burden to the patient. The objective was to evaluate the safety profile of compounded subcutaneous testosterone pellets and compare the pharmacokinetics between compounded and FDA approved testosterone pellets (Testopel®) for TTh. METHODS: This was a prospective, randomized, non-inferiority clinical trial. We enrolled 75 men diagnosed with TD and randomized them 1:1 ratio to Testopel® and a 100mg compounded pellet group from Empower Pharmaceuticals, an FDA-registered-facility. The patients were implanted with their respective treatment: Testopel® (10 pellets of 75mg) or compounded testosterone pellets (8 pellets of 100mg). Patients were monitored for adverse events with morning laboratory assessment (serum Testosterone, estradiol, 17-hydroxyprogesterone (17-OHP), hematocrit & prostate specific antigen) at 2, 4 and 6 months. RESULTS: After randomization, 34 participants enrolled in the Testopel® 75mg arm and 42 participants in E100 arm. Serum T levels were similar between the groups at 2, 4 and 6 months, with most men (82%) dropping below 300 ng/dL by the end of the trial. The only adverse event was pellet extrusion (n=1). Most dropouts were related to persistent TD symptoms and serum T < 300ng/dL, with similar rates between the two groups in the study. The mean E levels for Testopel® and E100 at 2 months were 29.1 (IQR: 21.3-35.4) and 42.7±17.3 (IQR: 42.1-48.4) pg/mL respectively (p=0.0006). However, levels were not statistically different at the 4 (p=0.53) and 6-month (p=0.17) time points. Other lab values were similar (Figure 1). CONCLUSIONS: Compounded testosterone pellets are clinically efficacious and safe in the treatment of TD. Compounded pellets may represent an economic alternative to Testopel®. This pilot study may provide the practicing urologist with the support to offer compounded testosterone pellets as TTh. Source of Funding: Investigator-initiated grant by Empower Pharmaceuticals SupportNIH Grant R01 DK130991 and Clinician Scientist Development Grant from the ACS to RR © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1141 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nicholas Deebel More articles by this author Eliyahu Kresch More articles by this author Thiago Fernandes Negris Lima More articles by this author Manuel Molina More articles by this author Rohit Reddy More articles by this author Mehul Patel More articles by this author Justin Loloi More articles by this author Chase Carto More articles by this author Daniel Gonzalez More articles by this author Jesse Ory More articles by this author Halifax Canada More articles by this author Ranjith Ramasamy More articles by this author Expand All Advertisement PDF downloadLoading ...

Comparative RNA-sequencing analysis of the prostate in a mouse model of benign prostatic hyperplasia with bladder outlet obstruction

In ageing men, benign prostatic hyperplasia (BPH) is a chronic disease that leads to progressive lower urinary tract symptoms (LUTS) caused by obstruction of the bladder outlet (BOO). Patients with LUTS (such as increased frequency and urgency of urination) and complications of BOO (such as hydronephrosis and bladder stones) are at risk of serious health problems. BPH causes a rapidly rising burden of LUTS far exceeding that of other urological conditions. Treatment outcomes are unsatisfactory for BPH largely due to the lacking of fully understanding of the pathogenesis. Hormonal imbalances related to androgen and oestrogen can cause BPH, but the exact mechanism is still unknown, even the animal model is not fully understood. Additionally, there are no large-scale data to explain this mechanism. A BPH mouse model was established using mixed slow-release pellets of testosterone (T) and estradiol (E2), and we measured gene expression in mouse prostate tissue using RNA-seq, verified the results using qRT‒PCR, and used bioinformatics methods to analyse the differentially expressed genes (DEGs).

Efficacy and safety outcomes of a compounded testosterone pellet versus a branded testosterone pellet in men with testosterone deficiency: a single-center, open-label, randomized trial.

Testosterone deficiency (TD) is a prevalent condition, especially in men ≥45years old, and testosterone therapy (TTh) can improve the quality of life in these patients. To evaluate the safety profile of compounded subcutaneous testosterone pellets and to compare the efficacy between compounded and market brand testosterone pellets for TTh: E100 (Empower Pharmacy) and Testopel (Food and Drug Administration approved), respectively. This was a prospective, phase 3, randomized, noninferiority clinical trial. We enrolled 75 men diagnosed with TD and randomized them 1:1 to a market brand group and a compounded pellet group. The patients were implanted with their respective testosterone pellets: Testopel (10 pellets of 75mg) and E100 (8 pellets of 100mg). We evaluated adverse events after implantation and followed men at 2, 4, and 6months for morning laboratory levels (prior to 10am): serum testosterone, estradiol, hematocrit, and prostate-specific antigen. After randomization, 33 participants were enrolled in the Testopel arm and 42 in the E100 arm. Serum testosterone levels were similar between the groups at 2, 4, and 6months, with most men (82%) dropping to <300ng/dL by the end of the trial. Adverse events were also similar, such as elevations in prostate-specific antigen, estradiol, and hematocrit. Most dropouts were related to persistent TD symptoms and serum testosterone <300ng/dL, with similar rates between the groups in the study. Men treated with Testopel and E100 pellets had comparable serum testosterone levels and similar adverse event rates, providing an effective choice of long-term TTh among men with TD. Strengths include the prospective, randomized, single-blinded study design and adequate follow-up. Limitations include the lack of external validity and the single-institution cohort. E100 compounded testosterone pellets are a noninferior option of TTh as compared with Testopel for men presenting with TD.

Testosterone does not shorten action potential duration in Langendorff-perfused rabbit ventricles.

Women have longer baseline QT intervals than men. Because previous studies showed that testosterone and 5α-dihydrotestosterone shorten the ventricular action potential duration (APD) in animal models, differential testosterone concentrations may account for the sex differences in QT interval. The purpose of this study was to test the hypothesis that testosterone shortens the APD in Langendorff-perfused rabbit ventricles. We performed optical mapping studies in hearts with or without testosterone administration. Acute studies included 26 hearts using 2 different protocols, including 17 without and 9 with atrioventricular (AV) block. For chronic studies, we implanted testosterone pellets subcutaneously in 7 female rabbits for 2-3 weeks before optical mapping studies during complete AV block. Six rabbits without pellet implantation served as controls. The hearts in the acute studies were paced with a pacing cycle length (PCL) of 200-300 ms and mapped at baseline and after administration of 1 nM, 10 nM, 100 nM, and 3 μM of testosterone. There was no shortening of APD80 at any PCL. Instead, a lengthening of APD80 was noted at higher concentrations. There were no sex differences in testosterone responses. In chronic studies, heart rates were 136 ± 5 bpm before and 148 ± 9 bpm after (P = .10) while QTc intervals were 314 ± 9 ms before and 317 ± 99 ms after (P= .69) testosterone pellet implantation, respectively. Overall, ventricular APD80 in the pellet group was longer than in the control group at 300- to 700-ms PCL. Testosterone does not shorten ventricular repolarization in rabbit hearts.

Testosterone Pellet Use in Transgender Men.

We assessed the efficacy and short-term adverse effects of testosterone pellet use in transgender men to broaden therapeutic options. We conducted a retrospective study of 30 transgender men who started testosterone pellets between 2018 and 2020. Testosterone pellets were started at dosages 675-825 mg per cycle and dose was adjusted according to testosterone levels obtained 1 to 6 months post-testosterone pellet insertion. Pharmacokinetics of testosterone pellet in transgender men was similar to those in cisgender men. Total testosterone levels reached a peak in 1 month and remained in the therapeutic range for ∼4 months in the range of 300-800 ng/dL. After switching over to testosterone pellets, 100% of patients continued to achieve amenorrhea and deepening of their voice. Most of the patients noticed increased hair growth in androgen-dependent regions (96.3%) and improved libido (70%). Adverse events were notable for a rate of polycythemia that was unexpectedly high at 46.67%. Pellet extrusion was found in 13.33% of patients. There was a low rate of pellet site hematoma (6.67%) and cellulitis (3.33%). No thromboembolic or cardiovascular events occurred in any of the patients. This study reveals that testosterone pellets are a reasonable alternative to other testosterone modalities in transgender men but would use caution in patients with a history of polycythemia or higher risk for thromboembolic events.

OPTIMIZED TREATMENT OF MEN’S HYPOHONADISM

Aim: to study the effectiveness of different treatment options for male hypogonadism. Material and methods: the paper investigates outcomes in treating male hypogonadism (86 patients with secondary male hypogonadism). Scientific literature was reviewed to single out the following methods: androgen replacement therapy subcutaneous testosterone pellet implants use of long-acting subcutaneous testosterone tablets (the use of subcutaneous long-acting testosterone tablets as replacement therapy), a combination of traction therapy and medication Testosterone undecanoate. Results: androgen replacement therapy promotes the development of a number of beneficial effects in terms of physique, metabolic control, psychological and sexual indicators. The use of long-acting subcutaneous testosterone pellets can enhance the androgenic effect at the receptor level. The combined method of treatment traction therapy and medication Testosterone undecanoate is relevant for men with concomitant micropenia. The surgical method of subcutaneous testosterone pellet implants is recommended for patients with contraindications to testosterone replacement therapy. The determination of sexual constitution’s indicators testified to persistent sexual rehabilitation in the long term after transplantation of testicle. Conclusions: Each clinical case should be approached individually and optimized in case of concomitant pathologies. According to the scientific literature, androgen replacement therapy is optimized as an application of long-acting subcutaneous testosterone tablets, which shows good results in case of concomitant pathologies. For men with concomitant micropenia, it is suggested to apply the combined treatment of traction therapy and medication Testosterone undecanoate. In case of contraindication to hormone therapy, subcutaneous testosterone pellet implants are the optimal option.

Comparison of Intratesticular Testosterone between Men Receiving Nasal, Intramuscular, and Subcutaneous Pellet Testosterone Therapy: Evaluation of Data from Two Single-Center Randomized Clinical Trials.

Testosterone replacement therapy (TRT) can potentially cause decreased spermatogenesis and subsequent infertility. Recent studies have suggested that 17-hydroxyprogesterone (17-OHP) is a reliable surrogate for intratesticular testosterone (ITT) that is essential for spermatogenesis. We evaluated data from two ongoing open-label, randomized, two-arm clinical trials amongst different treatment preparations (Trial I) subcutaneous testosterone pellets (TP) and (Trial II) intranasal testosterone (NT) or intramuscular testosterone cypionate (TC). Seventy-five symptomatic hypogonadal men (2 serum testosterone <300 ng/dL) were randomized into open label randomized clinical trials. Eligible subjects received 800 mg TP, 11 mg TID NT or 200 mg ×2 weeks TC. 17-OHP and Serum testosterone were evaluated at baseline and follow-up. The primary outcome was changes in 17-OHP. Secondary outcome was changes in serum testosterone. Data was analyzed by two-sample and single-sample t-tests, and determination of equal or unequal variances was computed using F-tests. Median participant age was 45 years old, with overall baseline 17-OHP of 46 and serum testosterone of 223.5 ng/dL. 17-OHP significantly decreased in subjects prescribed long-acting TP or TC. The 4-month change in 17-OHP in the NT group (-33.3% from baseline) was less than the change seen in TC (-65.3% from baseline) or TP (-44% from baseline) (p=0.005). All testosterone formulations increased serum testosterone levels at follow-up, with the largest increase seen in TC (+157.6%), followed by NT (+114.3%) and TP (+79.6%) (p=0.005). Short-acting nasal testosterone appear to have no impact on serum 17-OHP especially in comparison to long-acting testosterone formulations. All modalities saw significant increases in serum testosterone levels at follow-up. NT and other short acting testosterone formulations may better preserve ITT and be beneficial for hypogonadal men seeking to maintain fertility potential while on TRT.

Maturity induction and extended spawning kinetics of milkfish (Chanos chanos) administered with combined GnRHa and 17α- methyl testosterone pellet at varied frequencies

Inclusion of sustained-release androgen-gonadotrophin releasing hormone analogue implants into fertility treatment regimes of male and female milkfish has been proposed to benefit artificial maturation outcomes. This study aimed to investigate scope of co-administration of the androgen, 17α –methyl testosterone (17 α -MT) in combination with GnRHa as a single hormone pellet at varied frequencies in male and female milkfish to affect maturation, egg quality, spawning and subsequent larval fitness. Cholesterol pellet combined with GnRHa and 17 α–MT in equal amount was found superior to individual treatment in breeding responses (Experiment-1, 2015). In second experiment during 2016–2019 we evaluated effectiveness of chronic (10 implantations/year- December, January–September) and assisted (04 implantation/year- Dec, Jan, April, July) implantation of combined hormone pellet to compare breeding responses during trimester of implantation/breeding period divided as early (January–March), maximum (April–June) and extended (July–September) phase. Assisted hormone implantation helped to achieve desired percentage of unimodal distribution of mature oocytes (650–750 μm) reaching final oocyte maturation (FOM) stage in milkfish along with higher spawning frequency. On the contrary, chronic implantation caused an increased percentage of vitellogenic oocytes with bimodal distribution (250–500 μm and 500–600 μm) in ovary with reduced spawning events. Application of combined hormone implants, both assisted and chronic facilitated sustained release of both gonadotropin releasing hormone analogue (GnRHa) and androgen (17 α – MT) together and thereby induced entire reproductive axis resulting in extended spawning frequency for seven months (February–September). We also observed that milkfish breeding was aligned with abiotic factors such as higher water temperature and salinity along with synchrony to full moon or new moon. We conclude that assisted type of implantation pattern significantly improved maturation, milting male %, average fecundity, egg diameter, fertilization rate, hatching rate and larval length compared to that of chronic implantation with added benefit of reduced handling stress. This study represents the first report of milkfish captive maturation and hatchery seed production in tropical climate using combined hormone pellet administration.

Impact of Short-Acting vs Long-Acting Testosterone Therapy on Intratesticular Testosterone Using Data From Two Open-Label Randomized Clinical Trials of Testosterone Pellets, Injections, and Intranasal Gel in Hypogonadal Men

Introduction & Objective: Exogenous testosterone (T) replacement therapy (TRT) is typically long-acting and can potentially cause infertility in a majority of men due to suppression of HPG axis. Intratesticular testosterone is vital for spermatogenesis and can be reliably evaluated with serum 17-hydroxyprogesterone (17-OHP). Based on this observation, we hypothesized that we used serum 17-OHP as a serum biomarker for evaluating intratesticular T in men receiving TRT. We hypothesized that long-acting TRT will have a significant impact on suppressing HPG axis as compared to short-acting preparations. We evaluated data from two simultaneous open-label, randomized, two-arm clinical trials amongst different treatment preparations (Trial I) subcutaneous T pellets and (Trial II) Intranasal Testosterone (Natesto) or Intramuscular Testosterone cypionate (TC).Subject & Methods: Hypogonadal men (2 AM serum T < 300 ng/dL assayed by LC-MS/MS) aged 18-65 years were randomized into open-label randomized clinical trials. Eligible subjects received: 800mg subcutaneous Testopel T pellets (n=47); or 11mg TID Intranasal testosterone (Natesto) (n=10) or 200mg x 2 weeks TC (n=10) for 2 months. Serum T and 17-OHP were collected at baseline and after 2 months of therapy. Data are presented as a post-hoc analysis of the two randomized clinical trials and reported as the median and interquartile range [25th-75th], paired sample analysis (baseline versus follow-up) was performed with the Wilcoxon test to determine change during time within the different TRT modalities, with p<0.05 considered significant. Results: Median change for serum T between baseline and 2mo follow-up to subcutaneous T pellets was 542 [454-757] ng/dL, Intranasal Testosterone 706 [517-1010] ng/dL, and TC 525 [280-712]ng/dL.; 96% of subjects in each trial achieved mean T concentrations in the eugonadal range. We demonstrated that serum T levels were within normal range among men receiving the various therapies. As expected, we found a statistically significant decrease amongst the different T preparations in serum 17-OHP. Longer acting T preparations such as T pellets and TC demonstrated the greatest decrease in 17-OHP, from 41 [20.3-65.6] to 14 [10.3-20.8] ng/dL and 80 [48-121] ng/dL to 20 [17-36] ng/dL (p<0.001), respectively. Shorter acting T preparations such as Natesto demonstrated a statistically significant decrease in 17-OHP, from 52.5 [26-67] ng/dL to 26.5 [18-39.8]ng/dL (p=0.007), but to a lesser extent as compared to the longer-acting preparations.Conclusions: Natesto, and other short acting forms of TRT may help hyogonadal men maintain Intratesticular T that is critical for maintaining spermatogenesis. The differential effects of TRT on intratesticular T based on their half-lives is novel and should be considered during the decision making for hypogondal men who wish to preserve fertility and / or testis size.

Salivary Estrogens Androgens and Aromatase Inhibitors by LC-MS/MS in Breast Cancer Patients Treated With Testosterone Pellets Combined With Aromatase Inhibitors

Introduction: High dose testosterone (T) has been used for treating hormone-sensitive breast cancers for many years. However, a drawback to T therapy is its propensity to convert to estradiol (E2) via aromatase, which can override the growth inhibitory effects of T and stimulate estrogen sensitive tumors. Aromatase is higher in some women than others, particularly those with active tumors, truncal obesity, and inflammatory conditions contributing to and caused by cancer. Oral aromatase inhibitors (AI) have been used to prevent conversion of T to E2. While this effectively reduces E2 burden, systemic oral AI require higher dosing, which often leads to severe side effects. As an alternative to oral AI therapy, researchers have found that T combined with a much lower dose of AI in a solitary pellet implant placed in the subcutaneous (SC) tissue, or alternatively, into the breast adjacent to a primary tumor, is effective in reducing tumor burden and maintaining a low systemic level of E2, while reducing the adverse side effects of very low E2. Study Design: In this case study we report on the use of an LC-MS/MS method to monitor salivary levels of E2, Estrone (E1), T, and the AIs Letrozole (LET) and Anastrozole (ANZ) following T + AI therapy in a breast cancer patient (intolerant of oral LET) with active (measurable) tumor in the breast and metastatic disease. Steroids and AIs were measured in saliva at baseline, 1 week, and 4 weeks after insertion of subcutaneous pellets containing ‘60 mg T + 4 mg ANZ’ and ‘60 mg T + 6 mg LET’. Results: LC-MS/MS (range values-pg/ml) for postmenopausal women, and baseline, week 1 and week 4 post treatment values for each steroid and AI were: E2: (range 0.3-0.9), 0.4, < 0.3, < 0.3; E1: (range 0.9-3.1), 1.0, <0.4, <0.4; T: (range 7-22), 6, 96, 48; ANZ: (range <4), < 4, 2063, 24; LET: (range <4), < 4, 744, 175. Self-reported (Pre/Post Therapy) estrogen deficiency symptoms such as hot flashes, night sweats, vaginal dryness, joint pain, and sleep disturbances were significantly improved post T+AI therapy. In addition, the intramammary tumor decreased in size > 95% by month 5. Summary: These results show that low-dose SC AI therapy (4-6 mg/2-3 months = 0.1 mg/day) with T (120 mg/2-3 months = 1-2 mg/day) increases T to supra-physiological levels, prevents T metabolism to estrogens E2 and E1, reduces estrogen deficiency symptoms, and has beneficial effects on tumor growth inhibition. Simultaneous testing of sex-steroids E2, E1, T, and aromatase inhibitors LET and ANZ by LC-MS/MS provides a convenient means to monitor the bioavailable levels of these analytes and adjust them as necessary to optimize therapeutic efficacy and reduce adverse side effects.