Topical Testosterone Research Articles

Association of testosterone replacement therapy with atrial fibrillation and acute kidney injury.

Secondary analyses of the Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial revealed significantly higher rates of new-onset atrial fibrillation (AF) and acute kidney injury (AKI) in the testosterone replacement therapy (TRT) cohort. To validate the secondary findings of the TRAVERSE trial. We utilized the TriNetX Research Network to identify a cohort of men ages 45-80years old who met similar inclusion criteria to the TRAVERSE trial. We compared hypogonadal men (testosterone 100-300ng/dL) who had a prescription for topical testosterone therapy and men who did not. Propensity score matching was used to match patient populations. Kaplan Meier survival analysis was used to determine the relative risk of new-onset AF and AKI within 3years. New-onset AF and AKI within 3years. There were 2134 men included in each cohort after propensity score matching. Men on TRT had significantly lower testosterone (T) at the time of diagnosis compared to men not prescribed TRT (207 ± 66ng/dL vs 246 ± 140ng/dL, P< 0.001). Kaplan-Meier survival analysis showed a significantly increased risk of AKI among men on TRT (RR 1.53, 95% CI 1.07-2.18). However, TRT was not associated with a significantly increased risk of new-onset AF (RR 1.48, 95% CI 0.93-2.37). Hypogonadal men with underlying cardiovascular risk factors or pre-existing cardiovascular disease who receive TRT may be at increased risk of AKI after starting therapy. We evaluated a large global research database and utilized similar inclusion and exclusion to the TRAVERSE trial. However, our results are limited by the retrospective study design and reliance on documented claims data. Similar to the TRAVERSE trial, our study demonstrated an increased risk of AKI among men on TRT, but did not find increased risk of AF. However, further studies are required to validate these results.

Safety, efficacy, and pharmacokinetics of oral testosterone undecanoate in males with hypogonadism.

Testosterone deficiency results from insufficient testosterone production. Testosterone therapy may require dose titration to reach eugonadal serum testosterone concentrations. The 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). In this phase 3 study, 315 patients were randomized 2:1 to oral testosterone undecanoate or 1.62% topical testosterone gel (NCT02081300). Patients received 225mg oral testosterone undecanoate twice daily, and doses were adjusted by 75mg/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 (300-1140ng/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. Overall mean±SD baseline testosterone was 205.7±71.6ng/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 (2.91vs. -0.10; p=0.035), and mental component summary (3.82vs. 0.55; p=0.009); and Psychosexual Daily Questionnaire measure of weekly negative mood (-0.57vs. -0.20; p=0.021). Safety endpoints were comparable between therapies. No deaths or treatment-related serious adverse events were reported. Male patients with hypogonadism receiving oral testosterone undecanoate 225mg twice daily demonstrated improvements in libido and sexual frequency. Serum testosterone concentrations were within the reference range in 87% of patients without dose titration.

(081) ACCESSIBILITY AND PRESCRIBING PATTERNS OF HORMONE THERAPIES AMONGST ISSWSH PROVIDERS

Abstract Introduction Vaginal estrogen is a common topical therapy used to treat vulvovaginal disorders and genitourinary syndrome of menopause (GSM). Systemic hormone replacement therapy (HRT) is an evidence based treatment for menopause and female sexual dysfunction. Insurance coverage for topical estrogen and HRT is highly variable and may be inaccessible for many patients. Compounded medications are an alternative that some prescribers turn to despite inconsistency in quality, safety, and prices. Objective To examine prescribing patterns of ISSWSH providers of various hormonal and non-hormonal topical therapies, HRT, and strategies of increasing patient access to these medications. Methods A fourteen-item survey was distributed to ISSWSH providers via online platforms including social media. Participants were asked about medical education background and specialty, practice location, topical hormone replacement therapy (i.e., estrogen, estrogen and testosterone) and non-hormonal therapy (i.e., capsaicin, gabapentin) prescription practices, the most common diagnoses for which they prescribe these medications, systemic hormone therapy prescription practices, and counseling on cost-saving programs. All data was de-identified prior to analysis. Descriptive statistics were performed in SPSS. Results Fifty-five responses were collected. Of these, a majority of participants (51%) are ob-gyn providers and 22% are urology providers. The remaining participants are providers of internal medicine, family medicine, midwifery, urogynecology, and functional medicine. A majority are designated MD, DO, or equivalent (49%) and 45.5% are advanced practice providers (NP or PA). Interestingly, 100% of participating family medicine providers (n=8) report prescribing estrogen-containing systemic therapies, compared to ob-gyns (89%) and urologists (58%). Systemic testosterone was prescribed most often by urologists. Numerous providers report prescribing topical estrogen and testosterone: 50% being family medicine, 67% urologists, 67% midwives, 71% ob-gyns, and 100% of urogynecologists. Prescribing patterns for non-hormonal topicals vary. Gabapentin and valium appear to be most common in ob-gyn practices (43% each). Valium is also commonly prescribed by urologists, family medicine providers, and urogynecologists. According to the results, internal medicine providers rarely prescribe non-hormonal options. Additionally, our data reveals that 91% of participants report counseling patients on cost-saving programs like GoodRx, Mark Cuban Cost Plus Drugs, and others. Conclusions In conclusion, topical and systemic hormone therapies are prescribed at high rates by family medicine, ob-gyn, urogynecology, and urology providers within the ISSWSH community. However, the types of therapies prescribed vary greatly. Counseling regarding cost-saving methods shows to be promising, suggesting that patients are receiving these therapies at the most affordable rate. Further examination of pharmacy-level practices, patient refill trends, and direct medication costs will help to better describe and address patients’ barriers in acquiring treatment options. Disclosure No.

Testosterone maintains male longevity and female reproduction in Chrysopa pallens

Vertebrate testosterone, an androgen present in the testes, is essential for male fertility. Vertebrate-type steroid hormones have been identified in insects, but their function remains unknown. Insect vitellogenin (Vg) is usually a female-specific protein involved in reproductive processes. However, males of some species, such as the green lacewing Chrysopa pallens, have Vg. Here, we demonstrated that the knockdown of C. pallens male Vg by RNAi significantly shortened the lifespan of males, suppressed the reproduction of post-mating females, and strikingly reduced the abundance of several immune-related compounds, including testosterone. LC-MS/MS revealed that C. pallens male testosterone had the same structure and molecular mass as vertebrate testosterone. Topical testosterone application partially restored the lifespan of Vg-deficient males and the reproduction of post-mating females. These results suggest that vertebrate-type testosterone maintains male longevity and female reproduction under the control of the male Vg in C. pallens.

Testosterone Therapy for Late-Onset Hypogonadism: A Clinical, Biological, and Analytical Approach Using Compounded Testosterone 0.5-20% Topical Gels.

Testosterone is integral to men's sexual and overall health, but there is a gradual decline in the ageing male. The topical administration of testosterone is a valuable option as a supplement (replacement) therapy to alleviate hypogonadal symptoms. The clinical efficacy of a compounded testosterone 5% topical gel was assessed retrospectively in a male patient in his seventies by evaluating the laboratory testing of the serum total testosterone and the results of a validated androgen deficiency questionnaire. After treatment, the patient's hypogonadal symptoms improved and the serum total testosterone level achieved was considered clinically optimal. The skin permeation of the testosterone topical gel (biological testing) was evaluated in vitro using the Franz finite dose model and human cadaver skin, and it is shown that testosterone can penetrate into and through ex vivo human skin. Testosterone therapy is often prescribed for extended periods, and consequently, it is crucial to determine the beyond-use date of the compounded formulations. The analytical testing involved a valid, stability-indicating assay method for compounded testosterone 0.5% and 20% topical gels. This multidisciplinary study shows evidence supporting topically applied testosterone's clinical efficacy and the compounded formulations' extended stability. Personalized, topical testosterone therapy is a promising alternative in current therapeutics for hypogonadal patients.

Reflex strategy to ensure accurate total testosterone results from consumer initiated, self-collected capillary samples

BackgroundSelf-collected capillary samples are convenient for direct access testing (DAT), but exogenous testosterone use may cause falsely elevated total testosterone (TT) results.We designed a quality assurance workflow to differentiate between accurate or erroneous supraphysiological TT concentrations. MethodsClinical samples with TT > 1500 ng/dL were reflexed to luteinizing hormone (LH) and follicle stimulating hormone (FSH) and screened for exogenous testosterone use. Samples (n = 120) with normal TT were reflexed to LH/FSH as a control. ResultsA total of 8572 TT samples were evaluated, of which 533 (6.2 %) had TT > 1500 ng/dL and were reflexed. Of these, 441 (82.7 %) had significantly decreased LH/FSH (<0.85/<0.7mIU/mL, respectively), 72 (13.5 %) had normal or borderline normal LH/FSH, and 20 (3.8 %) had insufficient plasma volume. In patients with TT > 1500 ng/dL, injectable exogenous testosterone use was most commonly accompanied by significantly decreased LH/FSH, while topical testosterone use was most commonly accompanied by detectable LH/FSH. Control samples were almost all (99.2 %) within or above the LH/FSH reference intervals. Unique patients ordered 351 TT tests where at least one TT result was > 1500 ng/dL. Based on TT and LH/FSH results, we hypothesized that patients were intermittently or consistently overusing exogenous testosterone, resolved elevated TT with recollection, or repeatedly contaminated their sample. ConclusionSelf-collected capillary specimens are acceptable for TT testing. A quality assurance reflex to LH/FSH can determine the validity of supraphysiological TT results in a consumer initiated/DAT population.

Is topical testosterone less likely to cause polycythemia than IM testosterone in patients on testosterone replacement therapy?

Is topical testosterone less likely to cause polycythemia than IM testosterone in patients on testosterone replacement therapy?

(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.

Evaluation of sulfate metabolites as markers of topical testosterone administration in Caucasian and Asian populations.

Sulfate metabolites of endogenous anabolic androgenic steroids (EAAS) have been shown to prolong the detection times compared with the conventional urinary markers of the steroid profile for oral and intramuscular administrations of testosterone (T). In this work, the sensitivity of sulfate EAAS markers for the detection of T gel administration has been evaluated in six Caucasian and six Asian male volunteers. Fourteen sulfate metabolites were measured in basal and post-administration samples after multiple doses of T gel (100 mg/day, three consecutive days), and the detection times based on individual thresholds for each volunteer were evaluated. Sulfate concentrations did not show adequate sensitivity, but the results of sulfate ratios were much more promising. Androsterone sulfate/testosterone sulfate (A-S/T-S), epiandrosterone sulfate/epitestosterone sulfate (epiA-S/E-S), epiA-S/T-S, and etiocholanolone sulfate/epitestosterone sulfate (Etio-S/E-S) provided the most consistent detectability for all volunteers and populations, with detection times ranging from 60 to 96 h since the first dose. Additional ratios improved detectability to up to 7days, but only in particular volunteers. In general, sensitivity was similar to or better than the conventional testosterone/epitestosterone ratio (T/E) of the steroid profile, which further reinforces the conclusion that sulfate EAAS metabolites can be a good complement for the current steroid profile.

Falsely elevated serum testosterone measurements resulting from testosterone topical gel contamination of the venipuncture site: Case Series and retrospective review

Testosterone as replacement therapy for male hypogonadism or as gender-affirming hormone therapy for transgender and non-binary patients has increased worldwide. Commonly used formulations of testosterone include intramuscular, transdermal patch, and topical gel, each of which has differing pharmacokinetics and practical challenges. In monitoring testosterone serum concentrations, contamination of the phlebotomy site by testosterone topical gel can lead to supraphysiologic (>1000 ng/dL or 34.7 nmol/L) serum concentrations of testosterone, as demonstrated in a few published case reports. The frequency of this issue is currently not known. The present study involves a retrospective search over a 13-year period across all clinical sites at an academic medical center. Out of 578 unique patients using testosterone topical gel, a total of 48 patients had at least 1 testosterone serum concentration exceed 1000 ng/dL. Documentation in the electronic health record revealed 7 patients where contamination of the phlebotomy site by topical gel was strongly supported as the cause of supraphysiologic testosterone serum concentrations. These included 5 males with primary hypogonadism, 1 male with panhypopituitarism, and a non-binary patient with gender dysphoria. The high testosterone concentrations prompted further work-up, including retesting and endocrinology consultation. There were additional cases of high testosterone serum concentration that may have been falsely elevated due to gel contamination but without sufficient supporting evidence available in the health record. Overall, we present 7 cases of spuriously high testosterone concentrations strongly suspected to be due to venipuncture performed near or at the location of prior testosterone gel application. Gel contamination should be considered as a possible cause of otherwise unexplained high testosterone serum concentration in patients receiving topical testosterone gel formulations. Patient counseling and provider awareness of this potential cause of spuriously high testosterone serum concentrations is important.

FRI403 The Unintended Consequences Of Applying Topical Testosterone Directly To The Scrotum

Abstract Disclosure: J.G. Melendez-Rivera: None. S.J. Steven: None. Background: Topical testosterone is commonly used to treat hypogonadism in men. A concern associated with its use is the unintentional transfer to partners and children by direct contact with the application site. While prior studies and case reports have demonstrated the effects of direct skin contact with traditional application sites including the axillary regions and the abdomen, scarce data is available regarding the effects of transfer from application to the scrotum. Clinical Case: A 44-year-old woman presented with gradually worsening hirsutism and deepening voice over the past two years along with sudden cessation of menses. Initial laboratory studies revealed elevated testosterone of 1,776 ng/dL [10-55 ng/dL], elevated free testosterone of 14.4 pg/mL [0-4.2 pg/mL], normal androstenedione of 80 ng/dL [41-262 ng/dL) and normal DHEA-S of 57.7 ug/dL [57.3-279.2 ug/dL]. Transvaginal ultrasound revealed no ovarian masses or hyperplasia and CT abdomen and pelvis with and without contrast revealed no adrenal masses or hyperplasia. Ovarian and adrenal vein sampling were unremarkable. Anabolic steroid panel demonstrated a significantly elevated testosterone-to-epitestosterone ratio of 83.5 [&amp;lt;4] confirming an exogenous source of testosterone. Although the woman initially reported that her husband was applying topical testosterone, she reported that he was “obsessive” about being sure to wash the area of application prior to intimacy. Further questioning revealed that her husband was actually applying high concentration topical testosterone directly to his scrotum with sexual intercourse occurring up to five times daily. Conclusion: This case illustrates the dangers of applying topical testosterone directly to the scrotum. Prior studies have demonstrated that it may result in higher levels of serum testosterone in a shorter period of time which makes it seem like an attractive option for men desiring rapid resolution of their hypogonadal symptoms. Despite these perceived benefits, it can be detrimental to the health of their female partners who may experience extraordinarily elevated testosterone levels as a result of direct intravaginal absorption of topical testosterone. Presentation: Friday, June 16, 2023

THU646 Postmenopausal Hyperandrogenism Secondary To Ovarian Leydig Cell Tumor

Abstract Disclosure: J.T. Batch: None. G.Y. Gandhi: None. Introduction: Hirsutism is typically the initial presentation of virilization, including male pattern balding, deepening of the voice, and clitoromegaly. Postmenopausal hyperandrogenism can originate from adrenal or ovarian causes. This report describes marked hirsutism and scalp hair loss in a patient, leading to significant negative psychological and social impacts. Case Report: A 73-year-old female presented to the clinic complaining of scalp hair loss and increased facial hair in the upper lip and chin. She has hypertension (treated with amlodipine, losartan, metoprolol tartrate, and hydrochlorothiazide), dyslipidemia (treated with omega-3 fatty acids), hypothyroidism (treated with levothyroxine), and transvaginal hysterectomy without oophorectomy in 1994 for menorrhagia (no hormonal replacement therapy after surgery). The patient reported regular menstrual periods before the hysterectomy but developed menorrhagia during her early 50s. For the past five years, she noted bitemporal scalp hair loss that progressed significantly and created recession of the hairline and thinning of hair in her crown area. She developed dark pigmented hair on her upper lip and chin area, lower abdomen, and chest. Due to the significant impact of these physical changes, she became socially withdrawn and admitted to only leaving home to attend doctors’ appointments. She denied using supplements or physical contact with anyone using topical testosterone. She denied enlargement of her clitoris. She did note a deepening of her voice, although she is a chronic smoker. A hormonal work-up revealed a significantly high total testosterone of 511 ng/dL (normal range 2-45 ng/dL). DHEA-sulfate was normal at 62 mcg/dL (4-157 mcg/dL), and 17-hydroxyprogesterone was not significantly high at 192 ng/dL. MRI abdominal and pelvis with and without contrast revealed a 1.8 cm avidly enhancing left ovarian nodule. The patient underwent bilateral salpingo-oophorectomy. Pathology showed tumor cells with eosinophilic cytoplasm, central nucleus, and prominent nucleolus, consistent with a Leydig cell tumor measuring 1 cm and was confined to the left ovary. Four weeks after surgery, a repeat hormonal work-up revealed a normal total testosterone level of 23 ng/dL (normal range 2-45 ng/dL). Discussion: Hyperandrogenism with rapidly progressing hirsutism indicates a tumoral etiology. Leydig cell ovarian tumors are uncommon neoplasms arising from the gonadal stroma, accounting for &amp;lt;0.1% of all primary ovarian tumors. The diagnosis is based mainly on clinical and laboratory data since imaging studies may not show the small androgen-producing lesion. Bilateral oophorectomy should be recommended in postmenopausal women when an ovarian source is suspected. Most ovarian virilizing tumors are benign, and bilateral salpingo-oophorectomy results in a cure. Presentation: Thursday, June 15, 2023

FRI429 Association Between Nonalcoholic Fatty Liver Disease And Fib-4 In Patients With Hypogonadism

Abstract Disclosure: C.M. Godar: None. K.F. Brown: None. A.J. Spiro: None. N.O. Vietor: None. T.D. Hoang: None. M.K. Shakir: None. Introduction: Recent studies have reported a strong bidirectional association between non-alcoholic fatty liver disease (NAFLD) and hypogonadism in both genders. Men with hypogonadism may have higher noninvasive indices of NAFLD via hepatic steatosis index (HSI, reference range &amp;lt;36) and hepatic fibrosis via FIB-4 (reference range &amp;lt;1.3). However, there is limited clinical data on the association between serum testosterone concentrations and NAFLD in men. We report here HSI and FIB-4 in 3 men with hypogonadism. Case #1: 56-year-old male with a 20-year history of idiopathic hypogonadism, hypertension on telmisartan and amlodipine, and obstructive sleep apnea with regular CPAP use. Pituitary MRI is normal. He uses 3 pumps of topical testosterone gel daily. Vital signs: BP 139/83mmHg, HR 59bpm and BMI 36.2. Examination of heart and lungs is normal, testes are 15cc bilaterally. Serum testosterone is 400-500 ng/dL, alanine aminotransferase (ALT) 88 U/L (0-50), aspartate aminotransferase (AST) 71 U/L (17-59), alkaline phosphatase (ALP) 78 U/L (38-126), iron saturation 43.1% (20-55), ferritin 452 ng/mL (30-400). Calculated FIB-4: 2.3, HSI: 46. Case #2: 71-year-old male with 46XX phenotype with hypogonadism and gynecomastia on 2 pumps of transdermal testosterone gel daily. Vital signs: BP 150/79 mmHg, HR 67/min, BMI 36.8. Examination of heart and lungs is normal, and testes are 5cc bilaterally. Serum testosterone is 416 ng/dL, ferritin 509 ng/mL, iron saturation 41.3%, ALT 19 U/L, AST 22 U/L, ALP 136 U/L. Liver ultrasound demonstrated diffuse hepatic steatosis with borderline hepatomegaly. Calculated FIB-4: 1.38, HSI: 48.4. Case #3: 48-year-old male with central hypogonadism currently taking testosterone 100 mg IM every week. Evaluation for central hypogonadism was unrevealing for pituitary lesion. Vital signs of BP 130/91, HR 76/min, BMI 27.2. Examination of heart and lungs is normal, and testes are 20cc bilaterally. ALT 201U/L, AST 80U/L, ALP 136U/L, serum testosterone 241 ng/dL. Liver ultrasound is consistent with hepatic steatosis. Calculated FIB-4: 1.22, HSI 59.2. Conclusion: Patients with a combination of hypogonadism, high BMI, mild or moderate elevations of AST/ALT/ALP, elevated serum ferritin or transferrin saturation should undergo screening for NAFLD. In this series, all 3 patients had high HSI, an early indicator of fibrosis although only 1 patient had a high FIB-4 level. As fibrosis is the strongest predictor for long-term clinical outcomes among patients with NAFLD there is growing interest in employing non-invasive methods such as HSI, FIB-4, NFS and APRI for risk stratification. In conclusion, it is recommended that high risk patients with hypogonadism need to be screened for NAFLD and hepatic fibrosis with these simple tools. Presentation: Friday, June 16, 2023

FRI241 Late Diagnosis Of Non-classical CAH In An Elderly Male Previously Diagnosed With Estrogen Producing Adrenal Tumor

Abstract Disclosure: R. Kaval: None. J. Subauste: None. In 2013 a 66-year-old Caucasian male presented to the VA outpatient endocrinology clinic to establish care; the patient carried a diagnosis of estrogen producing left adrenal tumor in 1989 at the age of 42 at an outside facility. On review of records the patient was initially worked up for hypogonadism and was noted to have an elevated estrogen level and a “left adrenal tumor”. He subsequently underwent an unilateral left adrenalectomy for treatment and pathology reported with benign tumor findings. Following surgery, the patient was started on steroid and mineralocorticoid replacement for primary adrenal insufficiency (PAI) and topical testosterone gel for hypogonadism. The question was raised as to why this patient had PAI as he had an intact right adrenal gland on CT scan. On laboratory work-up in 2006 the patient had baseline cortisol of 3.4 ug/dl, ACTH was elevated at 99 pg/ml [7.2- 63.3], and adrenal antibodies (21-OH antibody] were negative. Renin was 2.35 ng/ml/hr [0.167-5.380], Estradiol was 41.8 pg/ml [7.6 - 42.6], LH was low at 0.20 mIU/ml [1.2-8.6] and total testosterone was low at 2.2 ng/ml [1.8-7.8]. Repeat testing yielded ACTH that was elevated at 686.7 pg/ml [7.2- 63.3], electrolytes including sodium and potassium were normal. On physical examination the patient had hyperpigmented skin, normal height, weight and otherwise unremarkable. On CT scan of the abdomen the right adrenal gland was mildly diffusely enlarged. In 2019, 30 years after his initial diagnosis the team questioned whether the adrenal tumor was truly an estrogen producing tumor. As a result, 17-OH progesterone was obtained, and the unstimulated value resulted as 3522 ng/dl [27-199]. With the elevated 17 OH &amp;gt;1000 ng/dL this was diagnostic for Non-classical CAH. The unilateral adrenalectomy likely unmasked the underlying impairment of cortisol production leading to primary AI that is seen with Non-classical CAH patients. The patient was lost to follow up during the pandemic, hence we were not able to perform and further testing. Presentation: Friday, June 16, 2023

(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.

Successful non-surgical treatment of priapism in a breeding stallion.

Priapism is an abnormally prolonged erection of the penis normally not associated with sexual desire. It can occur in horses following phenothiazine tranquilizer administration. In general, priapism therapy consists of slings, massage, diuretics, cholinergic blockade and surgery. A 17-year-old, 538-kg KWPN breeding stallion was referred with priapism of > 4 days duration. Priapism occurred on the farm after a single IM injection of 15 ml imidocarb for treatment of suspected piroplasmosis (Babesia PCR positive). The horse was referred to a clinic where he was treated with 12ml flunixin meglumine IV, 30ml dexamethasone IV, 5ml furosemide IM and nadroparine calcique SC. Hematology and biochemistry were within normal limits except for a slight elevation of ASAT, LHD and total bilirubin. He was correctly vaccinated against influenza/tetanus/equine herpes virus and negative for all equine venereal diseases. On arrival the body score was 7/9 and a completely normal systemic and reproductive exam except for a non-painful erect penis, which he was unable to retract. Surgical creation of a vascular shunt between the corpus cavernosum penis (CCP) and the corpus spongiosum (CS) was proposed but rejected. After sedation with detomidine and butorphanol IV,10 mg phenylephrine diluted in 5ml NaCl 0.9% was injected twice in the CCP in 24 hours, at 1cm dorso-caudal to the corona glandis of the penis. After the second injection, permanent detumescence was achieved.Paralysis/paraphimosis necessitated 2 months of meloxicam treatment and use of a penile suspensory device to keep the penis in position. An initial 4-week intense acupuncture treatment did not resolve the paraphimosis. During a 2-month period, 3 cold showers of 30 minutes each were applied daily, each time resulting in partial retraction. He also received 60 ml Vitamin B per os daily for 3 months. Seven months post-injury, semen could only be collected via pharmacologically induced ejaculation (100%). Despite his excellent libido, regular trials to collect semen on the dummy, using three different AVs and with the aid of systemic gabapentin, clomipramine, oxytocin, phenylbutazone, xylazine, gonadotropin, topical testosterone gel and hot compresses at the root of the penis never resulted in effective ejaculation. Ultrasonographic examination revealed multiple distinct hyperechogenic areas in the CC. Twenty months post injury the stallion, ejaculated for the first time on the dummy in a hot and tight Colorado AV while under clomipramine, oxytocin, phenylbutazone and xylazine medication. All medication was gradually discontinued over the ensuing month. Until today he has remained active as a fertile breeding stallion without using any medication. This case shows that non-surgical treatment for priapism can be a valid alternative for the stallion to return to a normal full-time breeding activity on the dummy.

(393) Pooled Safety Analysis of Ten Clinical Studies Evaluating Fixed-Dose Oral Testosterone Undecanoate in Male Patients With Testosterone Deficiency

Abstract Introduction Oral testosterone undecanoate (TU) was approved outside the United States 50 years ago and is currently used in several countries for the treatment of men with testosterone deficiency. The efficacy of prior oral TU is limited by a short half-life, requiring frequent dosing and administration with meals. A novel formulation of fixed-dose TU is now indicated for the treatment of testosterone deficiency (FDA approved March 2022). In a phase 3 study (NCT03242590: 1021-16-002) evaluating the efficacy and safety of fixed-dose oral TU 225 mg twice daily in adult men with testosterone deficiency, oral TU was well tolerated and restored testosterone levels to eugonadal ranges in most patients. Objective The objective of this pooled analysis of ten clinical studies (LPCN 1021-09-001, S361.1.001, M12-778, M13-298, 1021-14-001, LPCN 1021-16-002, LPCN 1021-16-003, LPCN 1021-13-001, LPCN 1021-18-001, LPCN 1021-18-003) was to further evaluate the safety of fixed-dose TU administered to adult men with testosterone deficiency. Methods This pooled analysis included men with testosterone deficiency who were enrolled or randomized in one of ten clinical studies and received at least one dose of study drug, which included fixed-dose TU, dose-adjusted TU, or topical testosterone gel. Data from separate studies were allocated to defined treatment groups, and these data were pooled to present a safety summary of patients treated with fixed-dose TU. Treatment groups were defined as follows: all fixed-dose TU patients, active control patients (dose-adjusted TU or topical testosterone gel), and placebo patients. Participants in a crossover study of various fixed-dose TU doses were counted once overall for analysis, and data relating to the highest dose were used. Results Overall, 777 patients were included in this pooled analysis: 654 received fixed-dose TU, 104 received topical testosterone gel, 34 received dose-adjusted TU, and 18 received placebo. Baseline characteristics are available on Table 1. Among 654 patients who received fixed-dose TU, 549 (83.9%) patients completed their respective study, and 15 (2.3%) patients discontinued because of an AE. The most frequently occurring treatment-emergent related adverse events (AEs) for patients treated with fixed-dose TU included headache (10 [1.5]), hematocrit increase (8 [1.2]), and acne (6 [0.9]) (Table 2). Three (0.5%) patients receiving fixed-dose TU experienced a blood pressure increase and 13 (2.0%) exhibited hypertension. No patients receiving fixed-dose TU experienced an increase in hepatic enzymes. The mean change from baseline (SD) in hematocrit (HCT) for patients receiving fixed-dose TU was 0.003% (0.029); three patients receiving fixed-dose TU discontinued because of HCT &amp;gt;54%. No patients in this pooled analysis experienced a serious AE (SAE) related to study treatment, and no deaths occurred. Conclusions In this pooled analysis of ten clinical studies in male patients with testosterone deficiency, fixed-dose TU was well tolerated with no hepatic adverse events, no drug-related SAEs, and no deaths. Disclosure Yes, this is sponsored by industry/sponsor: Halozyme (previously Antares) Clarification Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Halozyme (previously Antares)

(014) Testosterone Therapy in Females Is Not Associated with Increased Cardiovascular Risk – A US Claims Database Analysis

Abstract Introduction Testosterone therapy (TT) has been shown to improve libido in females with sexual dysfunction; however, utilization of TT has been limited in part due to concern for increased cardiovascular risk. Objective Our objective was to assess the association of TT in females with major adverse cardiac events (MACE) using a large claims database. Methods A US-based claims database (TriNetX Diamond Network) of over 200 million patients was queried from 2009 to 2022. Our study cohort included adult (18+) females with three or more injectable or topical testosterone prescriptions excluding those with heart failure (ICD-10 I50), unstable angina (I20.0), intersex surgery female to male (CPT 55980), personal history of sex reassignment (Z87.890), and gender identity disorders (F64). Our control cohort excluded females with any testosterone prescriptions, heart failure, intersex surgery female to male, personal history of sex reassignment, gender identity disorder, unstable angina, polycystic ovary syndrome (E28.2), or androgen excess (E28.1). Propensity-matching between the cohorts was performed for age, ethnicity, race, estrogen usage (HS300), family history of cardiovascular disease (Z82.4), tobacco usage (Z72.0), type 2 diabetes (E11), hyperlipidemia (E78), hypertensive diseases (I10-16), and utilization of outpatient (1013626), inpatient (1013659), or emergency department services (1013711). MACE was defined as heart attack (I21, I22), stroke (I60, I61, I62, I63), or death within three years of the index event. We evaluated the association of TT to MACE, upper or lower emboli or DVT (I82.4, I82.6), pulmonary embolism (PE) (I26), breast neoplasm (C50), and hirsutism (L68.0). A sub-analysis by age-based stratification (18-55-year-old and &amp;gt;55-year-old) was also conducted. Results Adult females with ≥3 testosterone prescriptions (n=8,457) were compared to an equivalent number of propensity-score matched controls (Table 1). Compared to matched controls, those with testosterone prescriptions had similar odds of MACE (odds ratio (OR) 0.80 [95% CI 0.60, 1.07]) and PE (OR 0.77 [0.41, 1.46]); significantly lower odds of upper or lower emboli or DVT (OR 0.59 [0.35, 0.99]) and breast neoplasm (OR 0.43 [0.32, 0.59]); and higher odds of hirsutism (OR 2.34 [1.28, 4.29]). This trend remained in the age 18-55 years group (n=5,951): MACE (OR 0.67 [0.37, 1.21]), breast neoplasm (OR 0.41 [0.24, 0.70]), and hirsutism (OR 1.45 [0.79, 2.64]) (Table 2). A similar trend was observed amongst &amp;gt;55-year-olds (n=2,582): MACE (OR 1.18 [0.81, 1.72]), upper or lower emboli or DVT (OR 0.89 [0.45, 1.75]), and breast neoplasm (OR 0.49 [0.33, 0.72]) (Table 2). Odds ratios could not be calculated for any patient counts less than 10 (Table 2). Conclusions In this large claims-based analysis, we showed systemic TT in women does not increase the odds of MACE or PE, and is protective against upper and lower emboli or DVTs and breast neoplasm. Our results suggest that TT in women may be safe, enabling physicians to provide appropriate therapy to women with sexual dysfunction. Disclosure No

Micropenis.

Micropenis, i.e., a structurally normal but abnormally small penis is defined as stretched penile length (SPL) 2.5 SD below the mean for age and sexual stage. Several studies worldwide have published country-specific normative data on SPL; an appropriate cutoff for evaluation of micropenis as per international standards would be below 2cm at birth and below 4cm after 5 y of age. Testosterone production by fetal testes, its conversion to dihydrotestosterone (DHT) and its action on the androgen receptor is necessary for normal penile development. Hypothalamo-pituitary disorders (gonadotropin or growth hormone deficiencies), genetic syndromes, partial gonadal dysgenesis, testicular regression, disorders of testosterone biosynthesis and action constitute the various etiologies of micropenis. Associated hypospadias, incomplete scrotal fusion, and cryptorchidism are suggestive of disorders of sex development (DSD). Along with basal and human chorionic gonadotropins (HCG)-stimulated gonadotropins, testosterone, DHT, and androstenedione levels, karyotype assessment is equally important. Treatment aims at attaining penile length sufficient enough for urination and to perform sexual function. Hormonal therapy with intramuscular or topical testosterone, topical DHT or recombinant follicle stimulating hormone (FSH) and luteinizing hormone (LH) should be attempted in the neonatal or infancy period. The role of surgery for micropenis is limited and has variable patient satisfaction and complication outcomes. There is a need for long-term studies on the adult SPL achieved following treatment for micropenis in infancy and childhood.

Reversibility in male idiopathic osteoporosis possible.

A 44-year-old athletic man presented in 2009 with severe low back pain. Dual-energy x-ray absorptiometry revealed severe osteoporosis; serum testosterone was 189 ng/dL while serum estradiol (E2) measured by liquid chromatography/mass spectrometry was 8 pg/mL. DNA was extracted and sequenced from a blood sample from the patient since his maternal first cousin also had low bone mass and both patients were screened for aromatase dysfunction by PCR analysis for the CYP19A1 gene, which encodes aromatase. No known pathologic mutations were observed in the coding exons, but novel single nucleotide polymorphisms were detected both in the proband and in his cousin. Treatment with topical testosterone started in August 2010. Over the next 8 years, testosterone dosage was varied and switched from topical gel to injections and maintained on depo-injections of testosterone at about 60 mg once per week. Re-examination in March 2012 included a brain MRI to exclude pituitary lesions; hyperparathyroidism was ruled out (normal serum parathyroid hormone, calcium, and calcium to phosphorous ratio) and celiac disease was excluded (negative transglutaminase antibodies). Follow-up in October 2018 showed improved bone mineral density of the lumbar spine by 29% and of the left femoral hip by 15% compared to baseline measurements. This reveals the importance of measuring serum E2 for making the correct diagnosis, as well as for monitoring a therapeutic effect. Herein, we propose treatment of male osteoporosis where serum E2 levels are below about 20 pg/mL with testosterone to reverse osteoporosis. Estrogen deficiency in the diagnosis of male idiopathic osteoporosis. Importance of serum estradiol in male osteoporosis. Role of polymorphisms in aromatase gene on bone health. Reversal of osteoporosis. Tailored testosterone treatment for bone health.