Keogh Institute for Medical Research

Abstract Scalar order parameters are widely used to describe critical transitions in nonlinear systems, yet their structural validity is rarely stated explicitly. This paper identifies a sharp obstruction to scalar diagnostics that arises when regime boundaries are generated by interacting degeneracies. We show that if the reduced boundary ideal is non-principal, then the boundary-induced comparability structure necessarily contains incomparabilities, and no scalar index can be faithful (even up to monotone transformation) to the underlying boundary constraints. Our analysis yields a boundary-first classification. In the codimension-one principal regime, the boundary is a hypersurface with a canonical generator Δred (unique up to units and admissible reparametrizations), and scalar crisis diagnostics are structurally pinned down to a single channel. Beyond this regime, scalarization fails intrinsically: the failure is ideal-theoretic rather than a calibration artifact. We illustrate the mechanism by a minimal two-fold construction producing a non-principal boundary, and introduce the positive-degree Betti Profile Index BPI∗ as a minimal cohomological gatekeeper that becomes informative exactly when the scalar paradigm is no longer defensible.

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

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

The exploratory objectives of this study were to evaluate the usability and acceptability and to conduct a preliminary evaluation of the efficacy of DARE-HRT1. DARE-HRT1 is an intravaginal ring (IVR) that releases 17β2-estradiol (E2) with progesterone (P4) over 28 days. It is the first combination E2 and P4 IVR being developed for the treatment of vasomotor symptoms (VMS) in healthy postmenopausal women with an intact uterus. This was a randomized, open-label, 2-arm, parallel group study in 21 healthy postmenopausal women. Women were randomized (1:1) to either DARE-HRT1 IVR1 (E2 80 μg/d with P4 4 mg/d) or DARE-HRT1 IVR2 (E2 160 μg/d with P4 8 mg/d). They used the assigned IVR for three 28-day cycles, inserting a new IVR monthly. Preliminary genitourinary syndrome of menopause (GSM) treatment efficacy was estimated by measuring changes from baseline in vaginal pH, vaginal maturation index (VMI), and changes in the severity of GSM symptoms. Preliminary systemic VMS efficacy was measured by changes in responses to the Menopause-Specific Quality of Life (MENQOL) questionnaire. Acceptability was assessed by product experience surveys. Preliminary local GSM treatment efficacy was supported by significant decreases in vaginal pH and % parabasal cells, and significant increases in the overall VMI and % superficial cells for both IVR groups (all P values <0.01). Preliminary VMS efficacy was supported by significant decreases in all domains of the MENQOL questionnaire from baseline for both dosing groups (all P values <0.01). Data from this study support further development of DARE-HRT1 for the treatment of menopausal symptoms.