Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic study (n = 544,513), we expand the number of genetic loci from 16 to 29, and additionally identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to an increased oocyte number and/or availability across the lifespan. Hormonal regulation in the etiology of this condition, through metabolic and reproductive features, was emphasized. The proteomic analysis highlighted metabolic biology known to be related to PCOS. A polygenic risk score (PRS) was associated with adverse cardiometabolic outcomes, with differing relevance of testosterone and body mass index in women and men. Finally, while oligo-anovulation and anovulatory infertility are features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.

Context:A rare cause of hypocalcemia, autosomal dominant hypocalcemia type 1 (ADH1) arises from a gain-of-function variant of the calcium-sensing receptor gene (CASR). Objective:Three patients from 2 unrelated families, presenting with hypocalcemia and other biochemical parameters consistent with ADH1, were examined for variants in the CASR with the aim to functionally assess any variant detected to confirm the ADH1 diagnosis. Methods:Sanger sequencing of the coding region of the CASR from the 3 patients identified a single CASR variant that was generated by site-directed-mutagenesis in the CASR as a FLAG-tagged construct in the mammalian expression vector pcDNA3.1. The variant's expression in HEK293 cells (compared to FLAG-tagged wild-type [WT] receptor) was assessed by Western blot analysis and its activity measured following calcium dosing experiments using an IP-One enzyme-linked immunosorbent assay. Results:Sequence analysis revealed the presence of a heterozygous missense variant in the CASR, an adenine to guanine transition at nucleotide 1256 causing an asparagine to serine substitution at amino acid 419 (N419S) in the CaSR's Venus flytrap domain in all 3 patients. The N419S variant showed a modest increase in expression compared to the WT receptor. Significantly, the IP-One assay demonstrated that the variant is constitutively active in the absence of Ca++ ions and that this gain-of-function is maintained at physiologically relevant Ca++ ion concentrations. Conclusion:The N419S CASR variant affecting 2 separate families is constitutively activating and therefore causative of ADH1. This is the first report of a constitutively active variant affecting the extracellular domain of the CaSR.

BACKGROUND:Lower testosterone concentrations in older men are associated with poorer health outcomes. OBJECTIVE:We examined whether, on a background of lifestyle intervention, testosterone treatment modulates leucocyte telomere length, a postulated marker of biological ageing, in overweight men with impaired glucose tolerance (IGT) or newly diagnosed type 2 diabetes (T2D). PARTICIPANTS AND METHODS:We conducted a secondary analysis of a randomised, placebo-controlled trial in 50- to 74-year-old men with waist circumference ≥ 95 cm and dysglycaemia (ACTRN12612000287831). All men received a background lifestyle program, and were randomised to 2 years treatment with intramuscular testosterone undecanoate (1000 mg) every 3 months or placebo. Leucocyte telomere length was assayed by multiplex quantitative polymerase chain reaction and expressed as relative telomere length (rTL), a ratio of telomeric DNA to β-globin, a single-copy control gene (T/S ratio). RESULTS:There were 720 participants, aged 60 ± 6 years (mean ± SD), 38% had BMI 30-34.99 kg/m2 and 44% ≥ 35 kg/m2. Mean rTL at baseline was 1.63 ± 0.27 in testosterone-treated men (N = 375) and 1.61 ± 0.28 in placebo-treated men (N = 345). At 2 years, mean rTL was 1.61 ± 0.28 and 1.58 ± 0.29, respectively. Change in rTL after 2 years treatment was -0.02 ± 0.15 in testosterone-treated and -0.03 ± 0.12 in placebo-treated men. Adjusting for baseline values there was no effect of testosterone treatment on rTL at 2 years (mean difference 0.01 [95% CI, -0.01 to 0.03], p = 0.24). Results were similar for rTL change at 2 years from baseline. CONCLUSIONS:There was no effect of testosterone treatment on telomere length in this group of men. Larger studies with longer treatment durations are merited.

A 53-year-old female patient was incidentally found to have asymptomatic hypercalcemia, later diagnosed due to primary hyperparathyroidism (PHPT): ionized calcium 6.48 mg/dL (SI: 1.62 mmol/L) (reference range, 4.48-5.28 mg/dL [SI: 1.12-1.32 mmol/L]); total calcium 12.08 mg/dL (SI: 3.02 mmol/L) (reference range, 8.8-10.4 mg/dL [SI: 2.20-2.60 mmol/L]); and parathyroid hormone (PTH) 184.8 pg/mL (SI: 19.6 pmol/L) (reference range, 15-85 pg/mL [SI: 1.6-9.0 pmol/L]). Preoperatively, standard imaging modalities, including ultrasound (US), four-dimensional computed tomography (4DCT) and dual radiolabeled technetium-99 pertechnetate and sesta-methoxyisobutylisonitrile with single photon emission computed tomography (99mTc-MIBI SPECT/CT), failed to localize a parathyroid adenoma. The patient underwent cervical exploration and parathyroidectomy where 4 orthotopic glands were identified, removing 2 mildly enlarged right-sided parathyroid glands and marking the 2 left-sided parathyroids with clip and suture; however, postoperative hypercalcemia persisted. Subsequent 18F-fluorocholine positron emission tomography/computed tomography (18F-FCH PET/CT) localized an intrathyroidal parathyroid adenoma. Fine needle aspiration (FNA) confirmed parathyroid tissue, and the patient underwent a right hemithyroidectomy, with biochemical cure. This case highlights the diagnostic and management challenges of an intrathyroidal fifth parathyroid adenoma causing PHPT, underscores potential pitfalls localizing parathyroid adenomas, and discusses the usefulness of 18F-FCH PET/CT imaging in challenging cases.

IntroductionPolycystic ovary syndrome (PCOS) is a common, but clinically heterogeneous, condition. This study explores PCOS subtypes using two orthogonal statistical analyses of biochemical and anthropometric data.MethodsUnsupervised hierarchical cluster analysis and principal component analysis (PCA) of hormonal and metabolic parameters were performed in a cohort of PCOS-affected women, diagnosed based on the NIH criteria. Data collected included body mass index (BMI), blood pressure (BP), fasting insulin and glucose (HOMA-IR), gonadotropins, androgens, and lipids. Subtypes were explored using unsupervised hierarchical cluster analysis, grouping both phenotypic variables and patients into clusters. PCA resolved correlated variables (excluding BMI) into independent factors, and the influence of BMI on the components was then explored.ResultsOne thousand and thirty-five women with PCOS were included in the study, with 975 assessed using cluster analysis and PCA. Two main clusters of variables were evident: one characterized by BP, BMI, HOMA-IR, and lipids (triglycerides/cholesterol/LDL) and the second by LH: FSH, androgens, SHBG, and HDL. Three separate patient clusters emerged: cluster A (29.6% of women) showed higher BP, BMI, HOMA-IR, and lipids (triglycerides/cholesterol/LDL) and lower LH: FSH, SHBG, and HDL. Cluster C (43.3%) showed lower BP, BMI, HOMA-IR, triglycerides, testosterone, and FAI and higher LH: FSH, DHEAS, androstenedione, 17-hydroxyprogesterone, SHBG, and HDL. Cluster B (27.1%) was intermediate. Two components aligned with the cluster analysis: principal component (PC) 1, including HOMA-IR, systolic and diastolic BP, triglycerides, LDL, FAI, and SHBG, was positively correlated with BMI (R2= 0.32, p-value < 0.0001) and aligned with cluster A. PC2, influenced by testosterone, LH: FSH, FAI, DHEAS, androstenedione, and 17-hydroxyprogesterone, with loadings in the opposite direction from LDL and cholesterol, aligned with cluster C, with little relationship with BMI (R2= 0.0067, p-value = 0.0107).DiscussionDifferent metabolic and reproductive PCOS subtypes are evident. Androstenedione and 17-hydroxyprogesterone are important in the reproductive phenotype, highlighting the importance of these hormones in diagnosis and subtype identification and emphasizing their significance in understanding PCOS biology as a predominantly hyperandrogenic disorder. BMI influences and exacerbates the metabolic subtype; in the reproductive group and in lean/normal BMI patients, there is little relationship between weight and other PCOS-related characteristics. Accordingly, traditional treatment paradigms cannot be generalized to all women, and these subtypes may ultimately be viewed as separate disorders

Context The combined effects of testosterone treatment and lifestyle intervention on sexual function in men at high risk of type 2 diabetes are unclear.Objective To assess the effect of testosterone treatment with a lifestyle intervention in men aged 50 to 74 years at high risk of, or newly diagnosed with, type 2 diabetes (via oral glucose tolerance test).Design A secondary analysis of the Testosterone for the Prevention of Type 2 Diabetes trial, a double-blind, placebo-controlled trial conducted across 6 Australian centers.Interventions Intramuscular testosterone undecanoate (1000 mg) or placebo, 3 monthly for 2 years alongside a community-based lifestyle program.Main outcomes Sexual function measured using the International Index of Erectile Function (IIEF)-15 questionnaire.Results Of 1007 participants, 792 (79%) had complete International Index of Erectile Function-15 data. Baseline domain scores were inversely related to age and waist circumference, but unrelated to serum testosterone or estradiol levels. Testosterone treatment improved all 5 International Index of Erectile Function-15 domain scores, with stronger effects on sexual desire and orgasmic function in older men, and sexual desire in men with higher depression scores. Testosterone had no impact on depression. Independent of treatment, reductions in waist circumference were associated with improved erectile function, and reductions in depression scores correlated with better sexual function. Clinically significant improvement in erectile function and sexual desire occurred in 3% and 10% of men, respectively, and was inversely related to baseline function. Clinically significant improvement improvements in erectile function and sexual desire were greater in younger and older men respectively.Conclusion Testosterone treatment enhanced sexual desire and, to a lesser extent, erectile function, particularly in older men and those with higher waist circumference or depressive symptoms. Reduced waist circumference and depression independently improved sexual function.

Objective We have shown that men aged 50 years+ at high risk of type 2 diabetes treated with testosterone together with a lifestyle program reduced the risk of type 2 diabetes at 2 years by 40% compared to a lifestyle program alone. To develop a personalized approach to treatment, we aimed to explore a prognostic model for incident type 2 diabetes at 2 years and investigate biomarkers predictive of the testosterone effect.Design Model development in 783 men with impaired glucose tolerance but not type 2 diabetes from Testosterone for Prevention of Type 2 Diabetes; a multicenter, 2-year trial of Testosterone vs placebo. External validation performed in 236 men from the Examining Outcomes in Chronic Disease in the 45 and Up Study (EXTEND-45, n = 267 357).Methods Type 2 diabetes at 2 years defined as 2-h fasting glucose by oral glucose tolerance test (OGTT) >= 11.1 mmol/L. Risk factors, including predictive biomarkers of testosterone treatment, were assessed using penalized logistic regression.Results Baseline HbA1c and 2-h OGTT glucose were dominant predictors, together with testosterone, age, and an interaction between testosterone and HbA1c (P = .035, greater benefit with HbA1c >= 5.6%, 38 mmol/mol). The final model identified men who developed type 2 diabetes, with C-statistics 0.827 in development and 0.798 in validation. After recalibration, the model accurately predicted a participant's absolute risk of type 2 diabetes.Conclusions Baseline HbA1c and 2-h OGTT glucose predict incident type 2 diabetes at 2 years in high-risk men, with risk modified independently by testosterone treatment. Men with HbA1c >= 5.6% (38 mmol/mol) benefit most from testosterone treatment, beyond a lifestyle program.

OBJECTIVE:To determine the effect of testosterone vs placebo treatment on health-related quality of life (HR-QOL) and psychosocial function in men without pathologic hypogonadism in the context of a lifestyle intervention. DESIGN, SETTING, PARTICIPANTS:Secondary analysis of a 2-year randomized controlled testosterone therapy trial for prevention or reversal of newly diagnosed type 2 diabetes, enrolling men ≥ 50 years at high risk for type 2 diabetes from 6 Australian centers. INTERVENTIONS:Injectable testosterone undecanoate or matching placebo on the background of a community-based lifestyle program. MAIN OUTCOMES:Self-reported measures of HR-QOL/psychosocial function. RESULTS:Of 1007 participants randomized into the Testosterone for Type 2 Diabetes Mellitus (T4DM) trial, 648 (64%) had complete data available for all HR-QOL/psychosocial function assessments at baseline and 2 years. Over 24 months, while most measures were not different between treatment arms, testosterone treatment, compared with placebo, improved subjective social status and sense of coherence. Baseline HR-QOL/psychosocial function measures did not predict the effect of testosterone treatment on glycemic outcomes, primary endpoints of T4DM. Irrespective of treatment allocation, larger decreases in body weight were associated with improved mental quality of life, mastery, and subjective social status. Men with better baseline physical function, greater sense of coherence, and fewer depressive symptoms experienced greater associated decreases in body weight, with similar effects on waist circumference. CONCLUSION:In this diabetes prevention trial, weight loss induced by a lifestyle intervention improved HR-QOL and psychosocial function in more domains than testosterone treatment. The magnitude of weight and waist circumference reduction were predicted by baseline physical function, depressive symptomology, and sense of coherence.

Breast cancer survivorship is increasing, due to earlier diagnosis of the disease and more effective therapies. Long-term endocrine sequelae, including early menopause, bone health, fertility implications and menopausal symptoms, are important survivorship issues. Ovarian failure is common with chemotherapy and options for preserving fertility in young women include ovarian suppression during chemotherapy and oocyte or embryo cryopreservation before chemotherapy. Tamoxifen as adjunct therapy in premenopausal women leads to ovarian stimulation, sometimes ovulation and occasionally pregnancy with important teratogenic implications. Aromatase inhibitor therapy with or without gonadotrophin releasing hormone (GnRH) agonist leads to profound bone loss and anti-resorptive therapy is advised to prevent fracture. Tamoxifen acts to preserve bone in postmenopausal women but not premenopausal women. Pregnancy is not discouraged in young women with early breast cancer, even to the point of pausing adjunct therapy in order to conceive. However, menopausal hormone therapy is discouraged even years later. Non-hormonal therapy for menopausal symptoms in breast cancer survivors is available but, in some cases, estrogen-containing therapy may be worthy of consideration for quality of life in the informed patient.

Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic and proteomic study, we expand the number of genetic loci from 19 to 29, and identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to a larger functional ovarian reserve. Hormonal regulation in the aetiology of this condition, through metabolic and reproductive features, was emphasised. The proteomic analysis highlighted perturbations of metabolically-related biology that are typical in women with PCOS. A PCOS polygenic risk score was associated with adverse cardio-metabolic outcomes, with differing contributions of testosterone and BMI in women and men. Finally, while oligo- and anovulatory infertility are characteristic features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.

We present the case of a 20-year-old woman with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, with uncontrolled hyperandrogenemia despite supraphysiological glucocorticoid therapy. We used abiraterone acetate, an inhibitor of the 17-hydroxylase/17,20-lyase enzyme, to suppress adrenal androgen synthesis and allow physiological glucocorticoid and mineralocorticoid therapy, as a proof-of-concept, before proceeding to bilateral adrenalectomy. We report the patient's clinical course, the changes in adrenal steroids, and the immunohistochemistry of the adrenals.

Background Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case–control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes. Results The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m 2 ). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A ( P = 1.55 × 10 –12 ) and rs2228260 within XBP1 ( P = 3.68 × 10 –8 ). One additional locus, LINC02905 , was highlighted as significantly associated with lean PCOS through gene-based analyses ( P = 1.76 × 10 –6 ). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance ( P = 3.22 × 10 –9 ) and a gene-based association was identified with ERBB4 ( P = 1.59 × 10 –6 ). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata. Conclusions Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.

Context The T4DM study randomized 1007 men with impaired glucose tolerance or newly diagnosed diabetes to testosterone undecanoate (TU, 1000 mg) or matching placebo (P) injections every 12 weeks for 24 months with a lifestyle program with testosterone (T) treatment reducing diabetes diagnosis by 40%.Background The long-term effects on new diagnosis of diabetes, cardiovascular and prostate disease, sleep apnea, weight maintenance trajectory and androgen dependence were not yet described.Methods A follow-up email survey after a median of 5.1 years since last injection obtained 599 (59%) completed surveys (316 T, 283 P), with participants in the follow-up survey compared with nonparticipants in 23 anthropometric and demographic variables.Results Randomization to was TU associated with stronger belief in study benefits during (64% vs 49%, P < .001) but not after the study (44% vs 40%, P = .07); there is high interest in future studies. At T4DM entry, 25% had sleep apnea with a new diagnosis more frequent on TU (3.0% vs 0.4%, P = .03) during, but not after, the study. Poststudy, resuming prescribed T treatment was more frequent among TU-treated men (6% vs 2.8%, P = .03). Five years after cessation of TU treatment there was no difference in self-reported rates of new diagnosis of diabetes, and prostate or cardiovascular disease, nor change in weight maintenance or weight loss behaviors.Conclusion We conclude that randomized T treatment for 24 months in men with impaired glucose tolerance or new diabetes but without pathological hypogonadism was associated with higher levels of self-reported benefits and diagnosis of sleep apnea during, but not after, the study as well as more frequent prescribed poststudy T treatment consistent with androgen dependence in some men receiving prolonged injectable TU.

Over the last 70years, oestrogen therapy for the management of menopausal symptoms has undergone a metamorphosis from perceived cardiovascular protection to perceived cardiovascular risk. The former perception is based on the convincing evidence from the Nurses' Health Study cohorts and the epidemiological data surrounding early menopause. The latter, and later, perception is based on the disquieting results from two randomised controlled studies, the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women's Health Initiative study (WHI). The reality is probably more nuanced than the conclusions presented by any of these studies. When face to face with a patient, the clinician must negotiate the appropriate decision pathway around the interaction between cardiovascular risk, cardiovascular disease, menopause, and oestrogen +/-progestogen-containing hormone therapy.

A 28-year-old man with congenital hypogonadotropic hypogonadism (CHH) was found to be heterozygous for the GNRH1 p.R31C mutation, reported in the literature as pathogenic and dominant. The same mutation was found in his son at birth, but the testing of the infant at 64 days confirmed the hormonal changes associated with minipuberty. This led to further genetic sequencing of the patient and his son, which found a second variant, AMHR2 p.G445_L453del, in the heterozygous form, reported as pathogenic in the patient but not in his son. This suggests a digenic cause of the patient's CHH. Together, these mutations are postulated to contribute to CHH by the lack of anti-Müllerian hormone (AMH) signalling, leading to the impaired migration of gonadotrophin releasing hormone (GnRH) neurons, the lack of the AMH effect on GnRH secretion, and altered GnRH decapeptide with reduced binding to GnRH receptors. This led us to the conclusion that the observed GNRH1 mutation in the heterozygous state is not certain to be dominant or, at least, exhibits incomplete penetrance and variable expressivity. This report also emphasises the opportunity afforded by the time window of minipuberty in assessing the inherited genetic disorders of hypothalamic function.

Abstract Disclosure: G.A. Wittert: Advisory Board Member; Self; Bayer Schering Pharma. Speaker; Self; Bayer Schering Pharma, Besin. K. Robledo: None. M. Grossmann: None. B.B. Yeap: Advisory Board Member; Self; Bayer Schering Pharma. Grant Recipient; Self; Bayer Schering Pharma, Lawley. B.G. Stuckey: None. W.J. Inder: None. K. Bracken: None. D.R. Jesudason: None. C.A. Allan: None. D.J. Handelsman: None. Background: In T4DM (men aged 50 – 74 yrs., waist circumference (WC) ≥95cm cm, prediabetes, or newly diagnosed type 2 diabetes (T2D) and serum testosterone (T) ≤ 14 nmol/L), 2 years treatment with T-undecanoate (1000 mg IM 3 monthly) vs placebo while enrolled in a lifestyle weight management program, decreased fat mass, and reduced the risk of T2D by 40%. Aim: To determine baseline predictors and T treatment effects on sexual function (SF) over time, including interactions with changes in waist circumference (WC), blood pressure (BP), glucose and mood. Methods: Adjusting for baseline sociodemographic, clinical parameters and serum sex steroid (LCMS) concentrations, linear mixed effects models were fitted to assess T treatment effects on measures of SF (erectile function (EF), sexual desire (SD), orgasmic function (OF), intercourse satisfaction (IS) and overall satisfaction (OS) via questionnaire (IIEF)) completed by each participant at baseline and weeks 30, 54, 78, and 102, together with WC, BP, glucose, trough T, estradiol (E), T:E ratio and mood (Center for Epidemiologic Studies Depression Scale (CES-D) at weeks 0, 54 and 102. Results Among men on T (504) or placebo (503) at baseline, age was inversely associated with all SF scales (p <0.001), and WC and CES-D score inversely associated with EF (p=0.041) and SD (p=0.029). There was no effect of baseline T, E or T:E ratio on SF. T treatment improved all SF measures (p<0.001) peaking at 30-54 weeks). The T treatment effect on SD and OF (both p-int=0.014) was greater in older men. Increasing WC over time was inversely associated with EF (p=0.036) and SD (p=0.043) scores, with no interaction with T treatment. SF scores were unaffected by changes in glucose, BP, or trough T, E or T:E ratio. Increase in depression scores corresponded to decreases in all SF scores (p <0.001). T treatment increased SD more in those with higher depression scores (p int=0.026) while not affecting the CES-D scores. Conclusion: Baseline age, WC, and depression scores, but not T were inversely associated with SF measures which improved with T treatment regardless of baseline T, E, or T:E ratio. T treatment improved SD and OF more in older men, and SD in those with more depressive symptoms. Change in WC was inversely associated with EF and SD, independent of T treatment. A pharmacological effect of T treatment to improve SF, particularly in older and depressed men, coexists with benefits from reduced central adiposity. Presentation: Thursday, June 15, 2023

Summary:With rising rates of adoption and surrogacy, induced lactation is likely to become increasingly relevant, allowing women who did not undergo pregnancy to breastfeed. We describe the case of a woman with complete androgen insensitivity syndrome (CAIS) on conventional oestrogen therapy who was expecting a child via surrogacy and who wished to breastfeed. The woman was commenced on supplementary oestrogen therapy, domperidone and breast stimulation by mechanical breast pump 8 weeks prior to the delivery of her child. Following delivery, the patient produced a small, unquantified amount of milk, allowing her to suckle the infant for a short period of time. Induced lactation is possible in chromosomally XY individuals. It has been most successful in cis-women and transwomen, both of whom have had progesterone/progestogen exposure to the breast. We suggest that the addition of a progestogen to our patient's treatment regimen, either as part of her original hormone therapy or part of the lactation induction program, would have improved her changes of establishing successful lactation.Learning points:Induced lactation is possible in chromosomally XY individuals with the use of pharmacological and non-pharmacological therapies. There are no standardised guidelines regarding the optimal regimen for induced lactation. Progesterone exposure to the breast is essential for ductal branching and alveolar maturation. In the published literature, induced lactation is more successful in transwomen and other XY individuals who have had prior progesterone exposure. The addition of progestogen to our patient's treatment regimen would have improved her chances of establishing successful lactation.

Summary A 33-year-old man with Kallmann syndrome had received pulsatile GnRH as an infant for the treatment of cryptorchidism. As an adult, his treatment for fertility with gonadotrophins was unusually rapid compared with expectations, with a total sperm count of 25 million after only 12 months of gonadotrophin therapy. We propose that pulsatile GnRH treatment as an infant induced minipuberty and facilitated his successful, rapid response to therapy. We also propose that identification of the absence of minipuberty in infants with clinical signs suggesting congenital hypogonadotrophic hypogonadism (CHH) is an opportunity for intervention with pulsatile GnRH yielding benefits for fertility decades later. Learning points Absence of minipuberty in males with CHH results in low Sertoli cell numbers and delayed response to induction of spermatogenesis in adulthood. Presentation with 'red flags' for androgen deficiency including cryptorchidism at birth, with or without micropenis, should prompt screening for CHH and minipuberty by measurement of gonadotrophins and testosterone in the first 2 months after birth. Pulsatile GnRH therapy in patients with CHH, given prior to age of attainment of Sertoli cell maturation, can replicate the normal physiology of minipuberty, thereby priming the testis for future fertility.

Abstract Disclosure: D.J. Handelsman: None. M. Grossmann: None. B.B. Yeap: Consulting Fee; Self; Bayer, Inc., Lawley. Research Investigator; Self; Lawley. B.G. Stuckey: Speaker; Self; Lawley. N. Shankara-Narayana: None. A.J. Conway: None. W. Inder: None. R.I. McLachlan: None. C.A. Allan: None. A. Jenkins: None. D.R. Jesudason: None. K. Bracken: None. K. Robledo: None. G.A. Wittert: Research Investigator; Self; Bayer, Inc., Lilly USA, LLC. The T4DM study randomized 1007 men (age 50-74 yr, waist ≥95 cm, serum T ≤14.0 nmol/L, no pathological hypogonadism) with impaired glucose tolerance or newly diagnosed type 2 diabetes to T undecanoate (1000 mg) or matching placebo injections every 12 weeks for 24 months with a lifestyle program. At study’s end, T treatment reduced OGTT diabetes diagnosis by 40% without change in HbA1C. After a median of 5 years since last injection, a follow-up email survey obtained 705 responses (70%) comprising 599 completed surveys (316 T, 283 P, 10 deceased, 95 declining). Participants in follow-up survey were similar to non-participants in 23 anthropometric and demographic variables at entry to T4DM, but more in follow-up study were randomized to T (53 vs 46%%, p=0.038), had lower entry weight (107 vs 109 kg, p=0.026) and older school leaving age (16.7 vs 16.5 years, p=0.026) but remaining well matched for work status (46% retired, 35% full-time work, p=0.60), alcohol intake (69% nil or light, 3% heavy; p=0.12) and smoking (3% smoking, p=0.61). At long-term follow-up, randomization to T treatment was associated with stronger belief in benefits during study (64% vs 49%, p<0.001) with less for post-study benefits (44% vs 40%, p=0.07) but overall high interest in future studies (surveys 93%, clinical 76%). At entry, 35% had sleep apnea, most (71%) diagnosed pre-study, with new diagnosis more frequent on T during (9% vs 1%, p=0.03), but not before or after, the study. After study, T treatment was prescribed at a higher rate for men who had study T treatment (6% vs 2.8%, p=0.03), mostly using T injections with 81% continuing at 24 months (median) on post-study T treatment. In the long-term, study T treatment did not influence self-reported new post-T4DM study diagnosis of diabetes (19%, p=0.65) or diabetes drug treatments (22%, p=0.31; oral 18%, injectable 2%, both 2%), prostate disease (p=0.49; cancer 3%, non-cancer 8%) or cardiovascular disease (p=0.95; heart disease 13%, stroke 1%). Both groups had similar weight maintenance (maintained 24%, lost 22%, gain 24%, up/down 30%, p=0.91) and further attempts to lose weight (76%, p=0.29; diet 68%, exercise 57%, drugs 6%, surgery 2%). We conclude that randomized T (vs placebo) treatment for 24 months in men with impaired glucose tolerance or new diabetes but without pathological hypogonadism, was associated with higher rates of (a) self-reported benefits during, but not after the study, (b) of resuming T treatment after the study, consistent with androgen dependence due to withdrawal (androgen deficiency) symptoms and/or recalling perceived benefits of study T treatment, and (c) of sleep apnea diagnosis during, but not before or after the study. Five years after T treatment stopped, there was no difference in the long-term rates of self-reported new diagnosis of diabetes, prostate or cardiovascular disease nor change in weight maintenance or weight loss behaviors. Presentation: Friday, June 16, 2023