Development of a minimum clinical dataset for preoperative comprehensive geriatric assessment using a modified Delphi technique.

OBJECTIVE: To construct a standardised, consensus-guided minimum clinical dataset (MCDS) for preoperative comprehensive geriatric assessment and optimisation (CGA) in Australia and Aotearoa New Zealand. METHODS: We conducted a review of the international perioperative literature to identify CGA domains and tools for potential inclusion in the MCDS. We invited members of the Australian and New Zealand Society for Geriatric Medicine to participate in a Delphi study to obtain consensus on MCDS tools. Participants were asked to rate proposed tools using Likert scales (when >2 tools) or make a binary choice between two proposed tools. Consensus was considered to be achieved when there was at least 75% concordance between the two rounds amongst the participants, and at least one variable attaining over 50% of participants' votes. Domains that did not achieve consensus in Round 1 were carried over to Round 2. RESULTS: There were 73 participants in Round 1 of the Delphi study and 47 participants in Round 2. Consensus was achieved on tool/s recommended for every MCDS domain: Clinical Frailty Scale (frailty); sMMSE, RUDAS, MoCA (cognition); 4AT (delirium); timed-up-and-go (physical function); GDS-15 (mood); Barthel Index (functional status); and MUST (malnutrition). CONCLUSIONS: We recommend clinicians delivering preoperative CGA consider the use of the MCDS we have constructed when assessing older people contemplating surgery, as part of a multicomponent and multidisciplinary approach to optimising perioperative outcomes.

Anti-Müllerian hormone level in older women: detection of granulosa cell tumor recurrence.

OBJECTIVE: To determine whether anti-Müllerian hormone (AMH) production resumes during normal late menopausal aging. Anti-Müllerian hormone has been proposed as a specific serum marker for adult granulosa cell tumors. MATERIALS AND METHODS: Serum AMH from 21 elderly postmenopausal women (mean age, 77 years) and 9 young women (mean age, 22 years) were measured by ultrasensitive immunoassay. RESULTS: Both median (0 pmol/L) and mean (0.48 pmol/L) serum AMH values for the elderly women were below the level of detection for the immunoassay kit. Three of the 21 participants had minimally detectable level of AMH (1.13-2.76 pmol/L). The cohort of young women had expected normal values of AMH as measurable by the same immunoassay kit. CONCLUSIONS: Serum AMH values were negligible for postmenopausal women older than 65 years. This extends the normative data for AMH to 108 years old, providing a reference range for the detection of granulosa cell tumors in postmenopausal women.

Introducing and Implementing a Universally Accepted, Readily Accessible, and Actionable End-of-Life Planning Tool for Patients with Advanced Serious Illness or Frailty in Southern New Zealand.

Background: Each health provider/agency in Southland, New Zealand, previously had its own forms and processes to document and communicate the planned scope of treatment; this project attempted to consolidate and streamline these variable processes into one actionable medical order that is valid in all settings. Aim: The hypothesis was that the intervention would reduce unnecessary hospitalizations in the final year of life. Design: The Clinical Order Articulating Scope of Treatment (COAST) form was a single-page medical order designed to document and communicate the resuscitation status and scope of medical treatment for adult patients believed to be in the final year of life, as evidenced by a "no" response to the Surprise Question. This three-phase initiative piloted the use of the COAST form in Southland from May 2019 to January 2020. Results: One hundred eighty-three patients with COAST forms consented to study participation. Sixty-one percent had a malignant primary diagnosis. The average number of emergency department (ED) presentations in the 12 months before COAST form implementation was 1.5 per person, and the average number of hospital admissions per person was 2.2. This was reduced to 0.5 and 0.5, respectively, in the 12 months following COAST implementation (p = 0.00). Three patients had no ED presentations/hospital admissions in the 12 months before COAST implementation, compared with 29 following COAST implementation, and 66.7% of patients died between May 2019 and February 2021. Conclusions: Patients with a COAST form had significantly fewer ED presentations and hospital admissions in the 12 months following implementation.

Electronic FRAIL score may predict treatment outcomes in older adults with myeloma.

INTRODUCTION: Frailty is a known risk factor for older patients with myeloma. Here we present realworld data using a computer-generated frailty assessment score (FRAIL score), based on 5 clinically derived parameters, in predicting patient outcomes. METHODS: Older patients with newly diagnosed multiple myeloma who received frontline treatment with cyclophosphamide-bortezomib-dexamethasone had their FRAIL score retrospectively assessed. Treatment outcomes were assessed using standard IMWG criteria, and event free survival and overall survival determined. RESULTS: 155 patients were analysed. Compared to those who were assessed as non-frail (FRAIL score 0-1) likely-frail patients (score ≥ 2) were less likely to complete the full course of treatment (24.3% vs 53.4%, p = 0.002), and more likely to terminate treatment due to toxicities (35.1% vs 22.0%, p = 0.109), as well as having a greater number of patients stop treatment early for reasons other than toxicity or progression (27.0% vs 10.2%, p = 0.010). After a median follow up of 42.5 months, likely-frail patients were found to have a trend for shorter event-free survival (median EFS, 8.7 vs 17.9 months, p = 0.064) and statistically inferior overall survival (median OS, 30.2 vs 49.8 months, p < 0.001). After adjusting for age, stage, and Charlson comorbidity index, FRAIL score was prognostic for OS (HR = 3.47, 95% CI 1.88-6.4), but not EFS (HR = 1.28, 95%CI 0.79-2.06). CONCLUSION: The FRAIL score is independently predictive of overall survival in older patients with myeloma receiving bortezomib-based induction chemotherapy and can help identify those patients more likely to experience treatment toxicity.

Exploratory analysis of serum concentrations of oocyte biomarkers growth differentiation factor 9 and bone morphogenetic protein 15 in ovulatory women across the menstrual cycle.

OBJECTIVE: To characterize and evaluate the variation in serum concentrations of oocyte-secreted growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) throughout the menstrual cycle in women from young to advanced reproductive ages. DESIGN: Cross-sectional, observational, and exploratory study. SETTING: Multicenter university-based clinical practices and laboratories. PATIENT(S): Serum was collected every 1-3 days throughout the menstrual cycle from 3 cohorts of healthy, ovulatory women: menses to late luteal phase (21-29 years of age; n = 16; University of Otago) and across one interovulatory interval (18-35 years of age; n = 10; and 45-50 years of age; n = 15; University of Saskatchewan). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): To detect the changes in serum GDF9 and BMP15 across the cycle, mean concentration and variance were statistically modeled using a generalized additive model of location, shape and scale (GAMLSS). Follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, and anti-Müllerian hormone were also assessed. RESULT(S): GDF9 and BMP15 were detectable in 54% and 73% of women and varied 236-fold and 52-fold between women, respectively. Across the menstrual cycle, there were minimal changes in GDF9 or BMP15 within a woman for all cohorts, with no significant differences detected in the modeled mean concentrations. However, modeled variances were highest in the luteal phases of all women for BMP15 immediately after ovulation, regardless of age. CONCLUSION(S): Serial changes in GDF9 or BMP15 concentrations across the cycle were not statistically detected and are likewise similar across the reproductive lifespan. Further research is required to fully elucidate the utility of these oocyte biomarkers at diagnosing fertility potential and/or disease.

The Testicular Hormones AMH, InhB, INSL3, and Testosterone Can Be Independently Deficient in Older Men.

BACKGROUND: Late-onset hypogonadism is symptomatically diverse and not fully explained by circulating testosterone level. The adult testes secrete four distinct hormones (testosterone, AMH, INSL3, and InhB) into the circulation. Testosterone and InhB have proven dynamic regulation, with limited information available for AMH and INSL3. During aging, there is cellular senescence, which may underlie the diversity of hypogonadism. This leads to the postulate that the relative levels (profile) of the four testicular hormones in older men are variable and cannot be evaluated by the measurement of one hormone. METHODS: 111 men aged 19-50 years and 98 men aged 70-90 years were examined. The circulating levels of the testicular hormones were measured using ELISAs, and the variation in the levels of hormones was analyzed by various correlative analyses. RESULTS: All four hormones were largely or totally independent. Some men were deficient in multiple hormones, but no man had multiple elevated hormones. The average hormonal levels were lower in older men, with diverse profiles of the four testicular hormones. Hence, some men had one or more hormones below the reference range, with testosterone the most conserved. Consequently, testosterone levels were not indicative of the complete state of the endocrine testes. CONCLUSIONS: The four hormones vary independently of each other, in younger and older men. This indicates that they are regulated dynamically rather than influenced by endocrine cell number. Older men exhibited diverse profiles of low levels of testicular hormones, suggesting that the testes age differently between men. Testosterone alone inadequately describes gonadal states.

Testosterone in advance age: a New Zealand longitudinal cohort study: Life and Living in Advanced Age (Te Puawaitanga o Nga Tapuwae Kia Ora Tonu).

OBJECTIVES: Serum testosterone (T) levels in men decline with age. Low T levels are associated with sarcopenia and frailty in men aged >80 years. T levels have not previously been directly associated with disability in older men. We explored associations between T levels, frailty and disability in a cohort of octogenarian men. SETTING: Data from all men from Life and Living in Advanced Age Cohort Study in New Zealand, a longitudinal cohort study in community-dwelling older adults. PARTICIPANTS: Community-dwelling (>80 years) adult men excluding those receiving T treatment or with prostatic carcinoma. OUTCOMES MEASURES: Associations between baseline total testosterone (TT) and calculated free testosterone (fT), frailty (Fried scale) and disability (Nottingham Extended Activities of Daily Living scale (NEADL)) (baseline and 24 months) were examined using multivariate regression and Wald's χ2 techniques. Subjects with the lowest quartile of baseline TT and fT values were compared with those in the upper three quartiles. RESULTS: Participants: 243 men, mean (SD) age 83.7 (2.0) years. Mean (SD) TT=17.6 (6.8) nmol/L and fT=225.3 (85.4) pmol/L. On multivariate analyses, lower TT levels were associated with frailty: ß=0.41, p=0.017, coefficient of determination (R2)=0.10 and disability (NEADL) (ß=-1.27, p=0.017, R2=0.11), low haemoglobin (ß=-7.38, p=0.0016, R2=0.05), high fasting glucose (ß=0.38, p=0.038, R2=0.04) and high C reactive protein (CRP) (ß=3.57, p=0.01, R2=0.06). Low fT levels were associated with frailty (ß=0.39, p=0.024, R2=0.09) but not baseline NEADL (ß=-1.29, p=0.09, R2=0.09). Low fT was associated with low haemoglobin (ß=-7.83, p=0.0008, R2=0.05) and high CRP (ß=2.86, p=0.04, R2=0.05). Relationships between baseline TT and fT, and 24-month outcomes of disability and frailty were not significant. CONCLUSIONS: In men over 80 years, we confirm an association between T levels and baseline frailty scores. The new finding of association between T levels and disability is potentially relevant to debates on T supplementation in older men, though, as associations were not present at 24 months, further work is needed.

Variation in circulating antimüllerian hormone precursor during the periovulatory and acute postovulatory phases of the human ovarian cycle.

OBJECTIVE: To determine whether the relative quantity of circulating AMH precursor (proAMH) declines relative to levels of the active form (AMHN,C) in the periovulatory phase of the ovarian cycle. DESIGN: Longitudinal study. SETTING: Local community. PATIENT(S): Sixteen women aged between 18 to 30 years with regular menstrual cycles between 25 to 35 days long. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum concentrations of proAMH and total AMH (proAMH and AMHN,C combined) measured by immunoassay, with relative levels of proAMH expressed as the AMH prohormone index (API = [ProAMH]/[Total AMH] × 100). RESULT(S): The mean API in the 11 eligible women fell from 20.7 during the luteinizing hormone (LH) surge period to 18.7 during the acute postsurge period. No statistically significant differences in the API were observed among samples taken at single time points in the early follicular, midfollicular, midluteal, and late luteal phases. CONCLUSION(S): This study suggests that activation of AMH by proteolytic enzymes is largely stable throughout the ovarian cycle. However, there is a subtle but robust decrease in the level of proAMH relative to AMHN,C in the acute postovulatory period. This may indicate that periovulatory increases in prohormone convertases cause increases in proAMH cleavage rates. Alternatively, rapid changes in the hierarchy of follicle developmental stages during ovulation may result in changes in the relative ratios of proAMH and AMHN,C.

Relative levels of the proprotein and cleavage-activated form of circulating human anti-Müllerian hormone are sexually dimorphic and variable during the life cycle.

Anti-Müllerian hormone (AMH) is a gonadal hormone, which induces aspects of the male phenotype, and influences ovarian follicular recruitment. AMH is synthesized as a proprotein (proAMH), which is incompletely cleaved to the receptor-competent AMHN ,C AMH ELISAs have not distinguished between proAMH and AMHN ,C; consequently, the physiological ranges of circulating proAMH and AMHN ,C are unknown. A novel proAMH ELISA has been used to assay serum proAMH in humans. Total AMH was also measured, enabling the AMHN ,C concentration to be calculated. Stored serum from 131 boys, 80 younger, and 106 older men were examined, with serum from 14 girls and 18 women included for comparison. The mean levels of proAMH and AMHN ,C in pM were respectively: boys (253, 526), men (7.7, 36), elderly men (5.7, 19), girls (3.3, 15), and women (5.2, 27) (boys vs. men, P < 0.001; girls vs. women, P = 0.032). The proportion of proAMH as a percentage of total AMH (API) was approximately twofold higher in boys than men (P < 0.001) with little overlap between the ranges, with girls also exhibiting lesser cleavage of their AMH than women (P < 0.001). The API varied within each population group. In young men, the API did not correlate with circulating levels of the other testicular hormones (testosterone, InhB, and INSL3). In conclusion, the cleavage of circulating AMH varies extensively within the human population, with most individuals having significant levels of proAMH The physiological and clinical relevance of circulating proAMH needs to be established.

Topical dihydrotestosterone to treat micropenis secondary to partial androgen insensitivity syndrome (PAIS) before, during, and after puberty - a case series.

BACKGROUND: X-linked partial androgen insensitivity syndrome (PAIS) causes under-virilization at all stages of development. In two thirds of males, this results in micropenis. Dihydrotestosterone (DHT) is a potent androgen that is critical for male genital development, which when applied topically, has been shown to increase penile length with micropenis of varying etiologies. We present the first case series using topical DHT gel to treat micropenis in 46,XY males with PAIS, before, during, and after puberty. METHODS: Three related 46,XY males with confirmed p.L712F androgen receptor mutations exhibited varying degrees of micropenis post-surgical correction. They were of pre-pubertal, peri-pubertal and adult ages, respectively. Following baseline clinical and laboratory assessments all completed a 4-month course of daily DHT gel 2.5% (androstanolone) topically to penis (0.3 mg/kg body weight), with monitoring for adverse effects. Primary outcome was change in stretched penile length (SPL) following treatment. RESULTS: Mixed results were obtained following topical DHT therapy. In the pre- and peri- pubertal patients, SPL changed from 2.5 cm to 3.5 cm (+40%), and 3.5 cm to 5.7 cm (+63%), respectively. In the adult patient with 1 year of prior high-dose weekly testosterone therapy, no additional change in SPL was seen. No adverse effects of topical DHT were reported or observed throughout the 4 months of treatment. CONCLUSIONS: Topical DHT treatment appears to be a safe and well-tolerated method of virilising micropenis both prior to and during puberty in children with PAIS. Questions remain about long-term outcomes into adulthood, and efficacy in adults with prior lengthy exposure to high-dose testosterone.

The Daily Profiles of Circulating AMH and INSL3 in Men are Distinct from the Other Testicular Hormones, Inhibin B and Testosterone.

The testes secrete four hormones (anti-Müllerian hormone, insulin-like peptide 3, Inhibin B and testosterone) from two endocrine cell types. It is unknown whether anti-Müllerian hormone and insulin-like peptide 3 levels have a diurnal variation, and if so, whether they covary during the day with testosterone and InhB. Sera were obtained from 13 men at 00:00, 06:00, 09:00, 12:00, 14:00, 17:00 and 19:00 hours and the levels of their testicular hormones measured by ELISA. A second cohort of 20 men was similarly examined with blood drawn at 19:00 and the following 06:00. Anti-Müllerian hormone levels exhibited a subtle diurnal pattern with a 19:00 peak that was 4.9% higher on average than the 06:00 nadir (p = 0.004). The decrease in anti-Müllerian hormone coincided with a rise in testosterone and InhB, but there was no association between the person-to-person variation in the diurnal patterns of anti-Müllerian hormone and testosterone or Inhibin B. Insulin-like peptide 3 had no diurnal pattern, with only minor sporadic variation between time points being observed in some men. In conclusion, the diurnal and sporadic variation of each testicular hormone is distinct, indicating that the major regulation is at the level of the hormone rather than at the endocrine cell type. Consequently, the balance of the hormones being released by the testes has complex variation during the day. The physiological significance of this will vary depending on which combinations of testicular hormones that the target cells respond to.

Enzyme-linked immunosorbent assay measurements of antimüllerian hormone (AMH) in human blood are a composite of the uncleaved and bioactive cleaved forms of AMH.

OBJECTIVE: To determine whether the Beckman Coulter antimüllerian hormone (AMH) Gen II enzyme-linked immunosorbent assay (ELISA) detects the uncleaved precursor (proAMH) and/or the active cleaved form (AMHN,C) of AMH. DESIGN: Technical investigation. SETTING: Community study. PATIENT(S): Healthy boys and male and female adult volunteers. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Assay of AMH and Western blot analysis of captured forms of AMH. RESULT(S): In blood, AMH in blood consists of both proAMH, the inactive uncleaved precursor, and AMHN,C, the enzyme-cleaved, receptor-competent form. The Gen II AMH ELISA detected both recombinant proAMH and AMHN,C. The noncovalent association of the two cleavage fragments of AMHN,C appears to be necessary for ELISA detection because recombinant free AMHC and AMHN were undetectable. Spike-recovery experiments showed that proAMH was not completely recovered from serum unless it was prediluted 1 hour before the assay. CONCLUSION(S): The leading ELISA for AMH provides a composite value of two biologically distinct forms of AMH. It is not known whether proAMH and AMHN,C have identical relationships to ovarian reserve, antral follicle counts, or other aspects of ovarian function. Hence, future research into the physiology and clinical utility of AMH should consider the two forms separately.

Renal manifestations of severe Rabson-Mendenhall syndrome: a case report.

INTRODUCTION: Rabson-Mendenhall Syndrome (RMS) is a rare form of severe insulin resistance due to a recessive mutation of the insulin receptor. Associated manifestations include facial dysmorphism, skin abnormalities, and renal anomalies. CASE PRESENTATION: We report a case of a 13 year old African female with RMS, severe insulin resistance, and a cluster of renal pathologies including nephromegaly, nephrolithiasis, hydronephrosis, and medullary sponge kidney. CONCLUSION: This is the first case of severe insulin resistance associated with the collection of renal conditions described. We postulate that renal conditions present in RMS may be under recognised, and recommend screening for the above conditions. This case adds to the scarce body of literature of associated renal manifestations with RMS, including medullary sponge kidney, across the spectrum of insulin resistance.

Serum anti-Mullerian hormone (AMH) levels correlate with infrarenal aortic diameter in healthy older men: is AMH a cardiovascular hormone?

Anti-Müllerian hormone (AMH) is a gonadal hormone present in the blood in men and pre-menopausal women. AMH regulates male sexual differentiation but has no putative function in adulthood. In recent studies, high AMH levels are associated with absence of cardiovascular disease in men and smaller atherosclerotic burden in monkeys. Mechanistically, AMH has downstream convergence with known regulators of the cardiovascular system, while the specific receptor for AMH is present in murine aorta and the human heart. Our primary objective was to examine whether AMH levels in healthy men correlated with the physical characteristics of their aorta. Our secondary aim was to document whether men with distinct vascular disorders expressed different levels of AMH. Serum AMH assayed by ELISA in 153 men (54-93 years) free from vascular disease inversely correlated with the ultrasonographic diameters of the distal- (r=-0.22, P=0.006) and mid-infrarenal aorta (r=-0.26, P=0.008). This association was similar in magnitude but opposite to that of body surface area (largest known determinant of aortic diameter) and independent of known cardiovascular risk factors. This relationship is specific to AMH, as inhibin B, a Sertoli cell hormone-like AMH, did not correlate with aortic diameter (r=-0.04, P=0.66) despite partially correlating with AMH. Among men with known vascular disease, higher AMH levels were associated with varicose vein disease, while men with higher levels of AMH were under-represented in the abdominal aortic aneurysm relative to the healthy cohort. These findings identify AMH as a novel putative regulator of the cardiovascular system.

Elderly men have low levels of anti-Müllerian hormone and inhibin B, but with high interpersonal variation: a cross-sectional study of the sertoli cell hormones in 615 community-dwelling men.

The Sertoli cells of the testes secrete anti-Müllerian hormone (Müllerian inhibiting Substance, AMH) and inhibin B (InhB). AMH triggers the degeneration of the uterine precursor in male embryos, whereas InhB is part of the gonadal-pituitary axis for the regulation of sperm production in adults. However, both hormones are also putative regulators of homeostasis, and age-related changes in these hormones may therefore be important to the health status of elderly men. The levels of AMH in elderly men are unknown, with limited information being available about age-related changes in InhB. We have therefore used ELISAs to measure Sertoli cell hormone levels in 3 cohorts of community-dwelling men in New Zealand. In total, 615 men were examined, 493 of which were aged 65 or older. Serum AMH and InhB levels inversely correlated with age in men older than 50 years (p<0.001) but not in the younger men. A minority of elderly men had undetectable levels of AMH and InhB. The variation in hormone levels between similarly aged men increased with the age of men. AMH and InhB partially correlated with each other as expected (r = 0.48, p<0.001). However, the ratio of the two Sertoli hormones varied significantly between men, with this variation increasing with age. Elderly men selected for the absence of cardiovascular disease had AMH levels similar to those of young men whereas their InhB levels did not differ from aged-matched controls. These data suggests that Sertoli cell number and function changes with age, but with the extent and nature of the changes varying between men.