bluuebunny/crossref_metadata_2025 huggingface dataset:
Thyroid Hormone Resistance Syndrome Presenting as Exercise Induced Asthma
Authors: Umscheid Joshua D , Mitre Naim , Muhaisen Fadi Jamil Odeh Al
Published: May 2021

Background: Pathogenic variants in the thyroid hormone receptor (THRB) gene are associated with thyroid hormone resistance. Over 85% of the genetic mutations are in the beta TR gene. The disorder is characterized mainly by elevated thyroid hormone levels, unsuppressed levels of TSH, and goiter.

Clinical case: An 11-year-old male initially seen at the PCP office for tachycardia and chest discomfort, especially during school exercise. He reported shortness of breath. His symptoms will resolve at rest. He was diagnosed initially with asthma and was put on Singular, Pulmicort, and albuterol as needed. His symptoms did not improve with this treatment, and he reported symptoms worsened with albuterol. He had a normal Echocardiogram and chest X-ray. A mild goiter was noted on his physical exam. Thyroid ultrasound showed an enlarged thyroid gland. An ovoid echogenic focus in the inferior thyroid lobe measuring 4 X 7 X 8mm was identified. The nodule was wider than tall, with a solid appearance with no internal color flow. Evaluation in our clinic showed normal TSH at 1.624mcIU/mL (0.35-5.5). FT4 was high at 1.54ng/dL (0.82-1.40), and FT3 elevated at 6.3pg/mL (3.3-4.8). Thyroid antibodies and thyroid-stimulating immunoglobulin (TSI) were normal. A 24 hour I-123 thyroid uptake was approximately 55% (10-30%) with no focal increased or decreased uptake. Given his elevated thyroid hormone levels with unsuppressed TSH in the context of goiter and tachycardia, genetic testing for the Thyroid receptor gene was done. He was found to be heterozygous for a pathogenic variant in THRB, c.1286G>A (p.Arg429Gln). This genotype is consistent with a diagnosis of autosomal dominant Thyroid hormone resistance. The patient was started on Atenolol, given his elevated heart rate, and he reported improvement in his symptoms during exercise.

Conclusion: Thyroid hormone resistance was first described as a clinical entity in 1967. The phenotype can vary among individuals. It is characterized by a reduced responsiveness of target tissue to thyroid hormone and binding affinity. The disease can present with goiter, behavioral issues, abnormal growth, and tachycardia. Affected individuals may have attention deficit-hyperactivity disorders (ADHD) and language difficulties. Thyroid hormone resistance can be misdiagnosed, as in our patient. He was diagnosed with asthma and was put on unnecessary medications that worsened his symptoms. Thyroid hormone resistance can also be misdiagnosed with Graves’ disease, given the elevated thyroid hormone. It is essential to highlight the importance of genetic testing in these cases, as an accurate diagnosis will prevent unnecessary treatments with potentially serious side effects.
Variable Clinical Presentation of Children With Hereditary Hypophosphatemic Rickets With Hypercalciuria: A Case Series
Authors: Christensen Stephanie , Tebben Peter J , Sas David , Creo Ana
Published: May 2021

Background: Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) is a rare condition of phosphate wasting due to variants in the SLC34A3 gene, encoding the sodium-phosphate cotransporter 2c (NaPi2c) at the brush border of proximal renal tubular cells (1). While labs are characterized by low serum phosphorus, high 1,25 dihydroxyvitamin D and inappropriately high levels of urine phosphate and calcium, the presenting symptoms can vary widely. Little remains known about specific phenotype-genotype correlations, especially in children. Clinical Cases: We report three new cases of HHRH in an unrelated 12 year-old male, 9 year-old female and 14 year-old male. All three patients were found to have low serum phosphorus for age (2.9-3.2 mg/dL), normocalcemia (9.4-9.9 mg/dL), low to low-normal parathyroid hormone (7-15 pg/mL), elevated 1,25 dihydroxyvitamin D (91-178 pg/mL), and hypercalciuria (4.5-7.6 mg/kg/day). Urine phosphorus was inappropriately elevated given the degree of their hypophosphatemia. Despite having similar lab findings, however, their clinical presentations were varied. The 12 year-old male presented with lower extremity pain, which was previously ascribed to patellofemoral pain syndrome. He had no history of renal symptoms, though a renal ultrasound later identified stones bilaterally. Conversely, the 9 year-old female and 14 year-old male presented with recurrent urinary stones and no bone symptoms. Genetic analyses identified 4 novel SLC34A3 gene mutations. Of interest, the 12 year-old male and 9 year-old female each shared a variant (c.575C-T (p.Ser192Leu)) despite having disparate symptoms. All three patients were treated with phosphorus supplementation and were advised to discontinue Vitamin D, if this had previously been prescribed. Conclusion: These three cases highlight the variability of presenting signs and symptoms among individuals with HHRH. Obtaining an accurate diagnosis is critical, as the addition of Vitamin D can seriously worsen symptoms in HHRH though it is a commonly used treatment for other disorders of phosphate wasting and bone demineralization. To aid in clinical decision making, we present a stepwise approach to the diagnosis of hypophosphatemic diseases. References: (1) Lorenz-Depiereux, B., Benet-Pages, A., Eckstein, G., Tenenbaum-Rakover, Y., Wagenstaller, J., Tiosano, D., Gershoni-Baruch, R., Albers, N., Lichtner, P., Schnabel, D., Hochberg, Z., Strom, T. Hereditary Hypophosphatemic Rickets with Hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am. J. Hum. Genetic. 2006;78:193-201.
Brain Tumours Involving the Areas of the Circadian System Result in Disturbances in Melatonin Secretion, Fatigue and Poor Quality of Life
Authors: Pickering Line , Main Katharina M , Sehested Astrid , Mathiasen René , Feldt-Rasmussen Ulla , Klose Marianne C , Jennum Poul
Published: May 2021

Background: Sleep disturbances, circadian abnormalities and poor health are often reported in children with brain tumours. The objective of this study was to examine circadian function, sleep pattern, fatigue and mental health in these children. We hypothesized that children with tumours involving the areas of the circadian system have altered melatonin secretion.

Design: Cross-sectional study.

Methods: 309 children diagnosed with a tumour in the brain or cervical medulla and aged ≤18 years were identified, 174 met the inclusion criteria, and 68 consented to participate. They were divided according to their tumour location into 1) location involving the areas of the circadian system, i.e. diencephalon, pineal gland, brain stem and cervical medulla and 2) other areas. Sleep-wake patterns were assessed by two weeks of sleep diary recordings and actigraphy in 66 and 61 children, respectively. Diurnal saliva-melatonin levels were measured in 51 children. Sleep quality, fatigue and mental health were assessed in 65 children by Children’s Sleep Habits Questionnaire, Strengths and Difficulties Questionnaire and Pediatric Quality of Life Inventory, Multidimensional Fatigue Scale and Generic Core Scale.

Results: All children had normal sleep-wake patterns without significant between-group differences. The children with tumours involving the areas of the circadian system had lower melatonin peak levels (p=0.03) and a tendency of lower levels at 00 h and 04 h (all p=0.06). Three patterns of diurnal melatonin profiles were observed: Normal, low peak and phase-shifted peak. In comparison of the two patient groups, more children with tumours involving the areas of the circadian system had melatonin profiles with low peak values (29% vs 13%) and one had phase-shifted peak (3% vs 0%), although not significant. These children were more affected by mental problems (p<0.01), more cognitive fatigued (p=0.03) and had poorer quality of life (p=0.01) than children with tumours located elsewhere.

Conclusion: Children with tumours affecting the areas of the circadian system including the diencephalon, pineal gland, brain stem and cervical medulla have altered melatonin secretion, are fatigued, have poor mental health and poor quality of life. Circadian disturbances may adversely affect health and have negative psychological impact.
Design of the ACcomplisH Trial: A Phase 2, Multicenter, Placebo-Controlled, Dose Escalation Trial Evaluating Safety, Efficacy, and Pharmacokinetics of Weekly TransCon CNP in Children With Achondroplasia
Authors: Savririyan Ravi , Zarate Yuri , Legare Janet M , Decker Carl , Giwa Adebola , Zhang Ying , Charlton R William , Beckert Michael
Published: May 2021

Background: Achondroplasia (ACH) is the most common skeletal dysplasia and the most frequent form of dwarfism. ACH is caused by a gain-of-function mutation in the fibroblast growth factor receptor 3 (FGFR3) gene and results in impairment of the endochondral ossification processes. C-type natriuretic peptide (CNP) promotes chondrocyte development through inhibition of the FGFR3 pathway, specifically through activation of NPRB. CNP is a desirable target as it is known to increase chondrocyte development without off-target effects (Bocciardi, 2007).

TransCon CNP is a long-acting prodrug of CNP designed to optimize safety and efficacy with a once-weekly dose. The Phase 1 clinical trial with TransCon CNP demonstrated that doses up to 150 μg CNP/kg were well-tolerated in healthy adult male volunteers, with no clinically significant trends observed in clinical laboratory assessments, vital sign measurements, ECG parameters, or physical examination findings.

Methods: The phase 2 ACcomplisH trial will be conducted at over 35 sites worldwide. The primary objective of the trial will be to evaluate the safety and efficacy of once-weekly TransCon CNP compared to placebo at 12 months in prepubertal children, aged 2-10 years old, with ACH. Approximately 60 subjects will be randomized 3:1 to receive either weekly TransCon CNP or placebo. Following screening and verification of clinical ACH with genetic confirmation, subjects will remain within the dose cohort for 52 weeks of treatment. TransCon CNP will be dosed 6 to 100 μg CNP/kg/week across 4 cohorts, with an optional 5th cohort at up to 200 μg CNP/kg/week. An independent Data Monitoring Committee will review safety data prior to initiation of a higher dose cohort.

The primary endpoint will evaluate annualized height velocity at 52 weeks of TransCon CNP or placebo. Key secondary endpoints will examine change in upper to lower body segment ratio at week 52, safety, pharmacokinetics (PK), and quality of life associated with weekly TransCon CNP.

Conclusion: CNP is targeted specifically to the underlying pathology of ACH through inhibition FGFR3. No effective medicinal product is currently available for the treatment of ACH. TransCon CNP is designed to provide sustained exposure of CNP. This ongoing Phase 2 ACcomplisH trial is designed to assess the efficacy, safety, and PK of TransCon CNP by weekly administration compared to placebo.
Evaluation of Methods That Estimate Glomerular Filtration Rate in Patients With Prader-Willi Syndrome
Authors: Ko Paul Jihoon , Ballal Shaila , Hirano Patricia , Cowen Neil
Published: May 2021

Background: Prader-Willi syndrome (PWS) is a rare, complex, multisystem disorder caused by the loss of multiple paternally expressed genes on chromosome 15q11-13 and is present in 1/15,000-30,000 individuals. Characteristics of PWS include low muscle mass and hypotonia, accumulation of excess body fat, short stature, hyperphagia, behavioral problems, cognitive disabilities, developmental delays, and hypogonadism. In these patients, serum creatinine (SCr)-based methods to calculate estimated glomerular filtration rate (eGFR) can lead to inaccurate results. eGFR is reported to be negatively correlated to muscle mass and PWS-associated low lean body mass may contribute to low SCr levels. Therefore, eGFR calculations may not accurately reflect PWS patient’s renal function. A more accurate, non-invasive, inexpensive means to monitor renal function for this patient population is desirable. Objective: To assess methods of estimating renal function in pediatric PWS patients and summarize the relationship between eGFR and patient-specific factors. Methods: The pre-treatment data of patients ≥4 years old with genetically confirmed PWS participating in an investigational study of DCCR (diazoxide choline) were evaluated. Lean body mass was measured using dual X-ray absorptiometry. Lean body mass and age were correlated to eGFR/creatinine clearance (CrCl) values calculated using four different equations: Bedside Schwartz (BS), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD), and Cockcroft-Gault (C-G). Results: Of the 124 patients enrolled in the study, 99 were <18 years old and 103 were taking growth hormone (GH). Mean SCr was below normal range at 0.52 mg/dL, with only two subjects (1.6%) having SCr in the normal range (0.84 to 1.21 mg/dL). eGFR calculated using BS was 120±22 mL/min/1.73m2; CKD-EPI 154±23 mL/min/1.73m2; MDRD 211±77 mL/min/1.73m2; and CrCl by C-G 191±80 mL/min. Among the three eGFR equations, CKD-EPI presented with the most reasonable eGFR values <200 mL/min/1.73m2. When stratified by different age groups, SCr increased with age while eGFR decreased (and surprisingly CrCl by C-G increased). When correlating the eGFR values to various parameters, lean mass and age showed significant negative correlations with eGFR for BS, CKD-EPI, and MDRD. In contrast, for C-G there were significant positive correlations between CrCl and both lean mass and age. Conclusion: In PWS, the combination of low SCr and excess accumulation of body fat results in eGFR values that likely overestimate actual renal function in PWS patients. The inconsistent trends in correlation values between eGFR or CrCl by C-G and both lean mass and age indicate current SCr-based methods to estimate renal function in PWS may be inadequate. The use of CKD-EPI or other non-SCr-based methods to monitor renal function should be considered in PWS.
Prevalence Trends of Metabolic Syndrome Among Korean Children and Adolescents From 2007 to 2018
Authors: Kim Jihyun , Lim Jungsub
Published: May 2021

Background: The prevalence of metabolic syndrome (MetS) in adults is increasing worldwide. The change of cardiovascular structure associated with metabolic syndrome appears from childhood, it is crucial to detect MetS early, and control associated risk factors to protect future health. Methods: We used data of children and adolescents (8,718 subjects aged 10-18) from the National Health and Nutrition Survey IV-VII (KNHANES 2007-2018) to estimate the recent prevalence of MetS, and identify related nutritional factors. The definition of MetS used modified NCEP-ATP III and IDF criteria. Results: The prevalence of MetS among Korean adolescents in 2007-2018 was 4.6% using the modified NCEP-ATP III criteria, and the trend of MetS increased significantly (P trend=0.02). In the overweight and obese groups, the risk of MetS increased 7.079 (95% CI, 5.188-9.793) and 27.131 (95% CI, 20.896-35.240) compared to the normal-weight group. During KNHANES IV-VII, overall caloric intake increased, carbohydrate and sodium intake decreased, but fat intake increased (KNHANE-IV; 21.3% to VII; 24.0%, P <0.001). These fat intakes were significantly correlated with an increase in systolic blood pressure, fasting blood glucose, and waist circumference. Conclusion: The prevalence of MetS is also increasing in Korean adolescents, and changes in dietary habits are related. In the future, it is also necessary to study the relationship with lifestyle.
The Effects of Conditioning Regimen on Thyroid Function After Hematopoietic Stem Cell Transplantation in Children: 2-Year Short Term Follow Up
Authors: Lee Nayeong , Kim Sungeun , Kim Seulki , Ahn Moon Bae , Kim Shin-Hee , Won-Kyoung Cho , Jung Min-Ho , Suh Byung-Kyu
Published: May 2021

Background: Long term effect of conditioning regimen such as Total body irradiation (TBI) and chemotherapy has been studied. However short term effect of conditioning regimen on endocrinologic system was not well known. Purpose. Our study aimed to evaluate the effect of conditioning regimen on thyroid function in children who had HSCT after 2 years. Methods:. Date was obtained from retrospective review of medical records who treated malignant hematologic disease and transplanted hematopoietic stem cell in Seoul St. Mary’s hospital from January 1, 2010 to August 31, 2018. Among 563 patients who underwent HSCT for about 9 years, we studied 150 patients who conforming to inclusion criteria of this study. Thyroid function was tested before HSCT and follow 12 and 24 months. Anthropometric date, duration of chemotherapy, history of relapse, graft versus host disease (GVHD) were also analyzed. Results: In patient’s characteristics, median age at HSCT was 10.49 (0.89 - 19.29) years. Out of 150 patients, male was 92 and female was 58. Acute lymphoid leukemia (ALL) was 74, acute myeloid leukemia (AML) was 76. Among them, busulfan based conditioning was done in 53 patients, TBI based conditioning regimen used in 72 and 25 patients had done TBI with busulfan based conditioning regimen. Fifteen patients (12.5%) had thyroid dysfunction after 2 years of HSCT (4 euthyroid sick syndrome, 11 subclinical hypothyroidism and 1 high T4 syndrome). Incidence of thyroid dysfunction by conditioning regimen was different at 2 years after HSCT, higher in TBI with busulfan based group (p = 0.033). In univariate regression analysis, using conditioning regimen, by TBI with busulfan was risk factor of thyroid dysfunction at 2 years after HSCT. Conclusions: TBI with busulfan based group showed higher incidence of thyroid dysfunction and conditioning regimen was risk factor of thyroid dysfunction at 2 years after HSCT.
Peripubertal Anti-Mullerian Hormone Levels Are Associated With Hyperandrogenemia During Adolescence: The Avon Longitudinal Study of Parents and Children
Authors: Dieguez Abigayil , Yeh Chen , Rasmussen-Torvik Laura , Torchen Laura Christine
Published: May 2021

Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders in women and is associated with negative reproductive and metabolic outcomes including subfertility, pregnancy complications, metabolic syndrome, and type 2 diabetes. The diagnosis of PCOS cannot be made until reproductive maturity, when the diagnostic criteria of hyperandrogenemia and oligomenorrhea develop. However, studies have described early metabolic and reproductive characteristics of the disorder in girls at increased risk, suggesting the pathogenesis starts much earlier. Indeed, studies in animal models suggest that exposure to excessive androgen or anti-Mullerian hormone (AMH) levels during critical developmental periods can program the offspring to develop the metabolic and reproductive features of PCOS during reproductive maturity.

We investigated early maternal or peripubertal factors associated with hyperandrogenemia during adolescence using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a United Kingdom birth cohort which has been ongoing since 1991. We performed linear regression to test for an association of testosterone levels at 15 years with peripubertal reproductive and metabolic phenotypes and with maternal measures of insulin sensitivity. Peripubertal phenotypes included AMH levels at 7, 9, and 11 years, and androstenedione, DHEAS, SHBG, IGF-1, fasting insulin, QUICKI, post-glucose insulin, leptin and adiponectin at age 8 years. Maternal phenotypes included fasting insulin levels and QUICKI at a post-partum visit. Unadjusted and adjusted analyses including the covariates pubertal stage, ethnicity, maternal and daughter BMI were performed.

Testosterone levels at age 15 years were significantly positively associated with AMH levels at ages 7(N=299), 9(N=295), and 11(N=300) years in both the adjusted and unadjusted models (Age 7 unadjusted P<0.0001, adjusted P=0.01; Age 9 unadjusted P<0.0001, adjusted P=0.003; Age 11 unadjusted P<0.0001, adjusted P=0.02). Testosterone at age 15 years was also associated with DHEAS at age 8 years using the unadjusted (P<0.0001) but not the adjusted model. There was no significant association between any of the other peripubertal metabolic and reproductive phenotypes or the maternal metabolic phenotypes of fasting insulin and QUICKI with testosterone level at age 15 years.

We have found a persistent and significant positive association of AMH levels at pre- or peri-pubertal ages with testosterone levels during adolescence, a developmental stage at which a clinical diagnosis of PCOS can be made. It remains unclear if this early elevation in AMH contributes to the pathogenesis of hyperandrogenemia or is an early marker of PCOS. Nonetheless, these findings suggest there are early differences in the reproductive phenotype in girls with hyperandrogenemia, even before the onset of puberty.
Recovery of Male Reproductive Endocrine Function Following Prolonged Injectable Testosterone Undecanoate Treatment
Authors: Shankara-Narayana Nandini , Desai Reena , Conway Ann , Stuckey Bronwyn Gwenneth Ann , Inder Warrick John , Grossmann Mathis , Yeap Bu Beng , McLachlan Robert Ian , Lam Ly P , Bracken Karen , Wittert Gary Allen , Handelsman David J
Published: May 2021

Background: Exogenous androgen treatment suppresses the hypothalamo-pituitary testicular (HPT) axis causing reduced serum LH, FSH and testosterone (T). Recovery of male reproductive endocrine function in past androgen abusers takes 9-18 months with persistent mild lowering of serum T. The natural history of recovery of HPT axis following prolonged injectable testosterone undecanoate (TU) treatment at standard dose is not known. Therefore, the Runoff Study investigated the rate and extent of reproductive hormone recovery over 12 months following cessation of 2 years of TU treatment in the Testosterone for Diabetes Mellitus (T4DM) Study, while men remain blinded to treatment allocation. Methods: T4DM participants without pathological hypogonadism (n=1007) were randomised to TU or Placebo (P) injections every 3 months for 2 years with 303 subsequently volunteering to enter the Runoff study at 12 weeks after last injection. Before T4DM study unblinding, they provided blood samples and validated sexual function questionnaires (PDQ, IIEF-15) at entry (3 months after last injection), 6, 12, 18, 24, 40 and 52 weeks later. Serum steroid profile (T, DHT, E2, E1) was measured batchwise by LCMS and serum LH, FSH and SHBG by immunoassays. Results: Runoff study participants in both groups were similar and did not differ from all T4DM participants. As expected, at entry to Runoff serum T was higher in TU-treated men but at all timepoints from 12 weeks onwards serum T and SHBG remained consistently 11% and 13%, respectively, lower in TU-treated than in P-treated men. Similarly, at entry sexual function scores were higher in TU-treated men but subsequently no different from P-treated men. Serum LH and FSH recovered slowly with the median time to reach their own pre-treatment baseline of serum LH was 51.1 weeks [95% CI 50.4 – 53.0 weeks] and for serum FSH was 52.7 weeks [51.0 – 60.9 weeks]. Conclusion: After stopping 2 years of standard dose injectable TU treatment in men without pathological hypogonadism, recovery of testicular endocrine function is eventually complete but slow with serum gonadotropin recovery taking on 12 months since the last dose. Persistent mild, proportionate reduction in serum SHBG and T reflects lasting exogenous T effects on hepatic SHBG secretion rather than signifying androgen deficiency. This suggests that recovery from androgen-induced HPT axis suppression depends primarily on time since cessation rather than dose or duration of androgen exposure.
The Hypothalamic-Pituitary-Testicular Axis in Exceptionally Old Men
Authors: Aleksic Sandra , Desai Dimpi , Ye Kenny , Duran Sally , Gao Tina , Crandall Jill P , Atzmon Gil , Barzilai Nir , Milman Sofiya
Published: May 2021

Introduction: As life expectancy continues to increase and more men reach the extremes of age, it is important to understand the physiology of the aging hypothalamic-pituitary-testicular (HPT) axis and its role in health. While prior studies primarily focused on men younger than age ninety, we studied a unique cohort enriched for men with exceptional longevity to characterize the age-related trends in male sex-hormones, the etiology of the observed changes in the HPT axis, and its relationship with metabolic dysfunction and survival at the extremes of age. Methods: This is a cross-sectional study of community-dwelling Ashkenazi Jewish men (n = 427), age range 50-106 years. Longitudinal follow-up for vital status was conducted for men age ≥ 88 at enrollment (n = 86). Measurements included serum total testosterone (TT) by LC/MS, LH, SHBG, lipids, glucose and BMI. Free testosterone (FT) was calculated according to Vermeulen et. al. A change-point linear regression model was applied to describe the age trend of TT. Multivariable linear regression adjusted for comorbidities tested the associations between metabolic parameters and TT. The association between survival and TT was evaluated with the age-adjusted Cox proportional hazards model. Age-specific cutoffs for TT and LH were used to define primary and secondary hypogonadism. Results: The change point model was a significantly better fit for the data compared to the straight-line model (p = 0.004), indicating that TT significantly declines after age 88 years. Men age < 88 years had higher average TT (401 ± 162 vs. 278 ± 178 ng/dL, p < 0.001), FT (6.3 ± 2.0 vs. 3.3± 2.1 pg/mL, p < 0.001), and lower LH (4.3 [3.0 - 6.1] vs. 14.6 [7.2 - 25.5] mIU/mL, p < 0.001), compared to men age ≥ 88 years. The prevalence of primary and secondary hypogonadism was 2% and 11%, respectively, in men age < 88 years, and 30% and 11%, among men age ≥ 88 years (p < 0.001). A multivariable linear regression analysis revealed interactions between age, dichotomized at the change-point of 88 years, and metabolic parameters. Models stratified at age 88 demonstrated an inverse association between TT and BMI (p = 0.02), serum triglycerides (p = 0.007), and random glucose levels (p = 0.02) among men age < 88; whereas a positive association was noted between TT and HDL cholesterol (p = 0.009) in this group. In men age ≥ 88 years, TT was not associated with any of the metabolic parameters or overall survival. Conclusions: Low testosterone in men with exceptional longevity is largely a result of primary testicular failure that occurs around age 88 and is accompanied by preserved hypothalamic-pituitary response with no associated metabolic dysfunction or effect on survival. This is in contrast to younger men, whose low T typically results from hypothalamic-pituitary dysfunction and is associated with metabolic derangements.
An Oral Contraceptive Containing Estetrol 15 MG and Drospirenone 3 MG Has Limited Effects on Endocrine and Metabolic Parameters
Authors: Klipping Christine , Duijkers Ingrid J M , Jost Maud , Bastidas Adriana , Foidart Jean Michel F
Published: May 2021

Background: Most combined oral contraceptives (COCs) contain ethinylestradiol (EE), an estrogen component known to increase the risk of venous thromboembolic events. Previous phase 2 trials have shown that Estetrol (E4), a naturally-occurring estrogen produced by the human fetal liver, in combination with Drospirenone (DRSP), inhibits ovulation and is associated with favorable vaginal bleeding, safety and tolerability profiles and high user satisfaction. When administered in doses up to 10 mg for less than 3 months, E4 either alone or in combination with DRSP showed limited effects on liver function as well as on metabolic and endocrine parameters. However, the impact of E4 15 mg/DRSP 3 mg, the selected dose for pregnancy prevention (hereafter referred to as E4/DRSP), on metabolic and endocrine parameters was never investigated. Methods: A randomized, open-label, controlled, three-arm parallel study was conducted in 101 healthy volunteers aged 18-50 years with a body mass index between 18.0 and 30.0 kg/m2. Of the randomized individuals, 98 subjects received either E4/DRSP (n=38), EE 30 µg/levonorgestrel (LNG) 150 µg (n=29) or EE 20 µg/DRSP 3 mg (n=31) COCs for six consecutive treatment cycles of 28 days. Endocrine and metabolic parameters were measured at baseline, cycle 3 and cycle 6. Results: FSH and LH decreased with both EE/LNG (-84% and -92%, respectively) and EE/DRSP (-64% and -90%, respectively), whereas E4/DRSP slightly increased FSH (31%) and had minor effect on LH (-8%). Total cortisol increased by more than 100% during treatment with EE/LNG (109%) and EE/DRSP (107%), while E4/DRSP only slightly increased total cortisol (26%). The effects of E4/DRSP, EE/LNG and EE/DRSP on other endocrine parameters including androstenedione (-31%, -49% and -40%) and free testosterone (-50%, -50% and -71%) were similar. Liver proteins, except CRP, increased from baseline in all treatment groups. The increase in angiotensinogen, CBG, and TBG levels was significantly lower for E4/DRSP (75%, 40% and 17%) in comparison with EE/LNG (170%, 152% and 37%) and EE/DRSP (207%, 140% and 70%). SHBG substantially increased for EE/DRSP (251%), while EE/LNG and E4/DRSP had limited effects on SHBG (74% and 55%, respectively). Triglycerides changed to a lesser extent for E4/DRSP (24%) compared to EE/DRSP (66%); EE/LNG increased triglycerides levels by 28%. Moreover, E4/DRSP had minimal impact on lipid parameters including HDL (4%), Apolipoprotein A1 (5%) and Apolipoprotein B (4%) compared to baseline, and no effects on carbohydrate metabolism. Conclusion: These data confirm that E4/DRSP has limited effects on liver proteins, lipid and carbohydrate metabolism, cortisol, and gonadotropins. The effect on other endocrine parameters, including suppression of ovarian steroids, was typical for a COC. In conclusion, combining E4 15 mg with DRSP 3 mg resulted in a different and potentially favorable metabolic profile.
Effect of Diet on Mental Health on Those Suffering With Premenstrual Syndrome
Authors: Ramirez Francisco E , Hunter Jennifer
Published: May 2021

Objective: This study documents the effects that various dietary factors have on mental health among those suffering with premenstrual syndrome (PMS). DESIGN/Methods: N=3231 participants from around the world took an 85 question questionnaire that assessed depression and anxiety using the DSM-5 [The Diagnostic and Statistical Manual of Mental Disorders Volume 5] criteria, as well as various dietary patterns. Depression was classified as: Less than 7 none, 7 to 10 mild, 11 to 19 moderate and more than 20 severe.

Results: From n=3231 that took the test, n=1330 reported suffering from PMS. The average age from the n=1330 group was 35.1 ST 12.2.

Regarding meat n=1002 reported not eating meat twice a week, they had an average depression of 12 and SD of 7.7, n=328 eating meat twice a week they had a depression of 13.6 and SD of 7.3.

Regarding cheese n=720 reported not eating cheese more than twice a week, they had an average depression of 11 and SD 7.6, n=610 were eating cheese twice a week and had a depression of 14 and SD 7.5.

Regarding folate N=597 were eating folate rich foods at least 3 times a week, they had an average depression of 10.1 SD 7.5, n=356 were eating irregularly folate rich food less than 3 times a week they had a depression of 13.1 SD 7.2, n=377 did not eat folate eat rich food at least 3 times a week they had a depression of 15.2 and SD 7.3.

Regarding fish n=134 were eating fish more than twice a week they had an average depression of 12.6 and SD 7.4, n=1196 were not eating fish twice a week they had a depression of 12.3 SD 7.7

Regarding whole foods n=225 were eating more than 5 portions of fruits, vegetables and whole grain each day had an average depression of 9.6 SD 7.6, those that were eating 3 to 4 portions (n=453) had a depression of 10.8 SD 7.6, those eating 1 or 2 portions (n=512) had a depression of 14.1 SD 7.6, those eating less than 1 portion daily (n=140) had a depression of 15.2 SD 6.9. Regarding alcohol n=132 were drinking alcohol more than twice a week they had an average depression of 16.5 SD 7.2, n=1198 were not drinking alcohol more than twice a week they had a depression of 11.9 SD 7.6.

Conclusions: It seems that among those suffering from PMS eating fruits, vegetables, whole grains, and folate rich foods was related to less depression symptoms while alcohol, meat and cheese consumption was related to worse depression maybe due to a hormonal effect. It seems fish didn’t have an effect.
Wnt2b Is Essential for Adrenocortical Progenitor Cell Fate and Zona Glomerulosa Identity in Vivo
Authors: Little Donald W , Borges Kleiton S , Basham Kaitlin J , O’Connell Amy E , LaPensee Christopher R , Breault David T , Hammer Gary D
Published: May 2021

Dysregulation of normal adrenal structure and function contributes to a spectrum of diseases from hypoplasia to cancer. Peripheral adrenocortical progenitor cells in the zona glomerulosa (zG) centripetally migrate and differentiate to replenish steroidogenic cells of the zG and the inner cortex over time. Both the fate of progenitor cells and aldosterone production by steroidogenic cells in the zG are regulated by Wnt/β-catenin signaling, but the cell-specific effects of individual WNT ligands in the adrenal cortex are not fully understood. To further characterize Wnt signaling components crucial for progenitor cell fate and zG identity, we analyzed mouse adrenals using single molecule in situ hybridization, which revealed the previously unknown expression of Wnt2b exclusively in the adrenal capsule. Wnt2b is co-expressed in the capsule with the Wnt signaling potentiator Rspo3, the loss of which causes zG depletion and reduced adrenal size in mice. Therefore, we hypothesized that capsular WNT2B activates Wnt signaling in the underlying zG to maintain the undifferentiated state of progenitor cells. To define the role of WNT2B in these processes, we first generated whole body Wnt2b knockout (KO) mice, which exhibit complete zG loss, as defined by known markers of zG identity (β-catenin and DAB2). To more fully determine the mechanism by which Wnt2b deletion results in zG loss, we crossed Wnt2b-floxed and capsule-specific Gli1-CreERT2 mice to generate a Wnt2b conditional knockout (cKO) model and study the effects of Wnt2b loss on the zG during homeostasis of the adult adrenal cortex. Gli1-CreERT2 activation by tamoxifen in 6-week-old mice significantly decreased Wnt2b expression and resulted in a lower adrenal-to-body weight ratio in Wnt2b cKOs compared to controls four weeks later. Adrenocortical proliferation (Ki67) was also significantly decreased in Wnt2b cKO mice, suggesting that WNT2B may promote progenitor cell self-renewal. To characterize the consequences of WNT2B loss on canonical Wnt signaling, we assessed activation of β-catenin, the primary Wnt signaling effector. High β-catenin activity in the zG observed in wild-type mice was disrupted in Wnt2b cKO mice, together with markedly reduced expression of adrenocortical Wnt target genes Axin2 and Wnt4. In addition, Wnt2b loss resulted in downregulation of steroidogenic genes Cyp11b2 and Hsd3b6. Together, these data reveal that capsule-derived WNT2B is required for zG differentiation and maintenance, potentially through activating adrenocortical Wnt/β-catenin signaling and downstream target gene expression involved in both progenitor cell fate and steroid-producing cell function. Studies to more fully elucidate the dynamic effects of WNT2B on the adrenal zG are ongoing as they have important implications for adrenal homeostasis and disease, including both primary adrenal failure and neoplasia.
The Effect of Estetrol/Drospirenone on Ovarian Function Is Similar to a Well-Established Combined Oral Contraceptive: Results From a Phase 2 Study
Authors: Duijkers Ingrid J M , Klipping Christine , Jost Maud , Bastidas Adriana , Foidart Jean Michel F
Published: May 2021

Background: Combined oral contraceptives (COCs) often contain ethinylestradiol (EE), an estrogen known to be associated with several side effects including venous thromboembolism. Estetrol (E4) is a native estrogen synthesized by the human fetal liver during pregnancy. Results from a phase 2 dose-finding study showed that E4 15 mg in combination with drospirenone 3 mg (E4/DRSP) resulted in a good bleeding profile and cycle control. Here, we present phase 2 results showing the effect of E4/DRSP on ovarian function. Study Design: A single-center, randomized, open-label, parallel study was conducted in healthy young volunteers with proven ovulatory cycles. Study subjects received either E4 15 mg/DRSP 3 mg (n=41) or EE 20 µg/DRSP 3 mg (n=41) in a 24/4-day regimen for three consecutive cycles. Both in cycle 1 and 3, serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH), estradiol and progesterone levels were determined, and follicular size and endometrial thickness were measured every three days using transvaginal ultrasound. Ovarian function was assessed using the Hoogland score, which considers follicular size and estradiol/progesterone levels. Return of ovulation was determined after treatment cessation. Safety and tolerability were assessed by monitoring adverse events (AEs), vital signs, physical and gynecological examination, clinical laboratory parameters, 12-lead electrocardiogram and echocardiogram. Results: No ovulations were reported during the use of E4/DRSP, while three ovulations occurred in two subjects in the EE/DRSP group. In both groups, most participants had no ovarian activity according to the Hoogland score. In cycle 1, Hoogland scores and follicular diameters were similar in both groups. In cycle 3, these parameters were slightly less suppressed in the E4/DRSP group when compared to EE/DRSP. While mean FSH and LH concentrations were less inhibited by E4/DRSP, mean estradiol and progesterone concentrations and endometrial thickness were similarly suppressed in both groups. Return of ovulation occurred on average 15.5 days after discontinuation of E4/DRSP intake. The number of frequently reported AEs considered to be related to study medication was similar for both treatment groups except for breast pain (11 subjects in the E4/DRSP group versus 4 subjects with EE/DRSP). Most related AEs were of mild or moderate intensity. Three subjects discontinued due to an AE, one with E4/DRSP (severe stress, emotional lability), and two with EE/DRSP (emotional lability, depressed mood). Other safety assessments did not show significant abnormalities. No serious AEs were reported. Conclusions: The combination of E4 15 mg and DRSP 3 mg results in adequate ovulation inhibition and ovarian function suppression, which is similar to a well-established COC containing EE/DRSP. E4/DRSP is considered safe and well-tolerated.
The Impact of the Covid-19 Pandemic on Women’s Reproductive Health
Authors: Owens Lisa A , Phelan Niamh , Behan Lucy Ann A
Published: May 2021

Background: The Covid-19 pandemic has profoundly affected the lives of the global population. It is known that periods of stress and psychological distress can affect women’s menstrual cycles. We, therefore, performed an observational study of women’s reproductive health over the course of the pandemic. Materials & Methods: An anonymous digital survey was shared by the authors via social media in September 2020. All women of reproductive age were invited to complete the survey. Results: 1031 women completed the survey. The mean age was 36.7 ± 6.6 years. 693/70% reported recording their cycles using an app or diary. 233/23% were using hormonal contraception. 441/46% reported a change in their menstrual cycle since the beginning of the pandemic. 483/53% reported worsening premenstrual symptoms, 100/18% reported new menorrhagia (p=0.003) and 173/30% new dysmenorrhea (p<0.0001) compared to before the pandemic. 72/9% reported missed periods who not previously missed periods (p=0.003) and the median number of missed periods was 2 (IQR 1-3). 17/21% of those who ‘occasionally’ missed periods pre-pandemic missed periods ‘often’ during the pandemic. 467/45% reported a reduced libido. There was no change in the median cycle length (28 days) or days of bleeding (5) but there was a wider variability of cycle length (p=0.01) and a 1-day median decrease in the minimum (p<0.0001) and maximum (p=0.009) cycle length. Women reported a median 2kg increase in self-reported weight and a 30-minute increase in median weekly exercise. 517/50% of women stated that their diet was worse and 232/23% that it was better than before the pandemic. 407/40% reported working more and 169/16% were working less. Women related a significant increase in low mood (p<0.0001), poor appetite (p<0.0001), binge eating (p<0.0001), poor concentration (p<0.0001), anxiety (p<0.0001), poor sleep (p<0.0001), loneliness (p<0.0001) and excess alcohol use (p<0.0001). Specific stressors reported included work stress (499/48%), difficulty accessing healthcare (254/25%), change in financial (201/19%) and living (169/16%) situation, difficulties with homeschooling children (191/19%), family or partner conflict (170/16%), family illness or bereavement (156/15%), and difficulties accessing or providing childcare (99/10%). Conclusions: The Covid-19 pandemic has significantly impacted the reproductive health of women. The long term health implications of this are yet to be determined and future studies should address this.
Vitamin D and TSH: Do Their Level Impact on IVF outcomes?
Authors: Negreiros Ricardo , Negreiros Luis , Rosado Victor , Cavalcanti Leonardo , Rosado Bernardo , Machado Breno , Bianco Bianca , Assunção Viviane
Published: May 2021

Abstract: There is a positive correlation between serum 25 (OH) Vit D concentrations below 30 ng/ml and the incidence of preterm delivery, while higher levels can bring benefits to pregnancy. Although studies agree that TSH levels affect fertility, in euthyroid women (0.5<TSH<4.5), the serum concentration of this hormone still has a dubious effect on gestational outcomes. In order to study the relationship between vitamin D, TSH levels and pregnancy endpoint, a retrospective cohort study was conducted that considered 520 women who had undergone In-Vitro Fertilization (IVF). Patients were grouped regarding TSH values in mIU/L: 0.5-2.49 (Group 1) (n=416) and 2.5-4.5 (Group 2) (n=104), the serum levels of 25 (OH) Vit D within them were dichotomized in subgroups: <30 ng/mL (Group 1, n=212; Group 2, n=49) and >30 ng/mL (Group 1, n=204; Group 2, n=55). Primary endpoint was clinical pregnancy (the presence of the gestational sac and fetal heartbeat by ultrasound) and secondary outcomes were miscarriage and gestacional age (preterm or full-term pregnancy). The rate of clinical pregnancy in group 1 was significantly higher in patients with 25 (OH) Vit D <30 ng/ml (51.9%) than 25 (OH) Vit D >30 ng/ml (42.2%) according to the chi-square test and Fisher’s exact test (p<0.05 all). There was no significant difference in group 2 (p=0.35), with percentages of 49% and 40% in the respective subgroups. Moreover, no statistical difference between the abortion rates was seen in 25 (OH) Vit D subgroups in groups 1 (p=0.71) and 2 (p=0.52). When gestational age rates were measured, the percentage of full-term pregnancies was lower in patients with 25 (OH) Vit D <30 ng/ml (Group 1=62.6%; Group 2=57.9%), compared to those with 25 (OH) Vit D >30 ng/ml (Group 1=77.6%; Group 2=78.9%), however, only the subgroups in the TSH category between 0.5-2.49 mUI/L showed a statistically significant difference (p<0,05). The Spearman test identified a weak positive correlation between 25 (OH) Vit D and gestational age (ρ=0.218; p<0.05). The findings indicate lower frequency of clinical pregnancy in patients with TSH between 0.5-2.49 mIU/L and 25 (OH) Vit D >30 ng/ml. In addition, variations in 25 (OH) Vit D, in both TSH groups, do not suggest interference in miscarriage rates. Furthermore, higher serum concentrations of 25 (OH) Vit D seem to be involved with an increase in the prevalence of full-term births, an important finding to guide the procedures for IVF.
A Prospective Cross-Over Study of Tissue Glucocorticoid Metabolism in Patients With Adrenal Insufficiency: The Effects of Dual-Release Hydrocortisone Therapy
Authors: Dineen Rosemary Anne , Martin-Grace Julie , Saeed Ahmed Khalid Mohamed , Taylor Angela Elizabeth , Shaheen Fozia , Schiffer Lina , Gilligan Lorna , Frizelle Isolda Mary , Gunness Anjuli , Garrahy Aoife , Hannon Anne marie , O’Reilly Michael William , Smith Diarmuid , McDermott John , Marie-Louise Healy , Agha Amar , Pazderska Agnieszka , Gibney James , Behan Lucy-Ann , Arlt Wiebke , Thompson Chris John , Sherlock Mark
Published: May 2021

Background: Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). We hypothesize that GC metabolism is altered in patients with AI due to the non-physiological pattern of current immediate-release hydrocortisone (IR-HC) replacement therapy. The use of once-daily dual-release hydrocortisone (DR-HC) preparation (Plenadren®) offers a more physiological cortisol profile and may alter GC metabolism in vivo.Study Design and Methods: Prospective cross-over study assessing impact of 12 weeks of DR-HC on tissue GC metabolism (using urinary steroid metabolomics, serum cortisol generation curves and adipose tissue biopsies) in 51 patients with AI (primary and secondary) and compared to age-and BMI-matched controls. Results: Patients with AI (n=51) receiving immediate-release HC (IR-HC) had a higher median 24-hour excretion of urinary cortisol compared to healthy controls [72.1µg/24hrs (IQR 43.6–124.2) vs 51.85 (35.5–72.3), p=0.02],with a lower global activity of 11β-HSD2 and higher activity of 5-alpha reductase. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary F and total GC metabolite excretion, which was most significant in the evening on diurnal urine sampling. There was an increase in global 11β-HSD2 activity. Hepatic 11β-HSD1 activity was not significantly altered post-DR-HC but there was a significant reduction in gene expression of 11β-HSD1 in subcutaneous adipose tissue. Conclusion: Using comprehensive in-vivo techniques we have demonstrated significant abnormalities in glucocorticoid metabolism in patients with AI. This is driven by dysregulation in the pre-receptor enzyme activity controlling tissue-specific GC availability, which can be improved following treatment with DR-HC.