Janet E. Hall

Objective: Short-term dieting has gained popularity in women. We studied thyroid hormone change after short-term, moderate energy restriction. Methods: Nineteen, healthy women aged 23.36 ± 2.08 yr (mean ± SD) without obesity and thyroidal disease underwent a neutral (NEA, ±0%) and a deficient (DEA, −55%) diet for 5 days each in the early follicular phases of successive menstrual cycles. Blood was sampled every 10 min between 8 AM and 4 PM and analyzed for TSH, GH, and cortisol every 30 min, total T3 (TT3), reverse T3 (rT3), and total T4 (TT4) hourly and free T3 (fT3), free T4 (fT4), and TBG at the beginning and end of the studies. Liquid chromatography-tandem mass spectrometry (LCMS) assessed all thyroid hormones except TSH and TBG. Data shown as mean difference or least squared (ls) mean (±SEM). Results: There was a small decrease in body mass index and body weight after DEA (0.4 ± 0.08 kg/m2; P < .001 and 1.1 ± 0.21 kg; P < .001, respectively), with unchanged fat mass. Compared to NEA, TT3 (ls mean ± SEM; 95.55 ± 2.89 ng/dL vs. 89.15 ± 2.89; P < .0001), and TSH (1.03 ± 0.07 vs. 0.92 ± 0.07 μIU/mL; P < .0001) declined while TT4 (6.06 ± 0.25 vs. 6.26 ± 0.25 μg/dL; P = .005), fT4 (1.71 ± 0.07 vs. 1.83 ± 0.07 ng/dL; P = .0052) and rT3 (9.02 ± 0.56 vs. 12.04 ± 0.56 ng/dL; P < .0001) increased after DEA with no change in TBG, GH and cortisol. Conclusion: Adaptive central and peripheral changes in thyroid hormones occur after short-term, moderate dieting in young women without obesity. ClinicalTrials.gov: NCT02858336

Introduction: Short-term caloric restriction is a common practice even in lean and underweight women. We studied the impact of dietary restriction on sleep and its interplay with reproductive hormones across the menstrual cycle in women without obesity. Methods: Seventeen healthy women without obesity, aged 23.6 ± 2.3 years (mean ± SD) underwent a neutral (± 0%) and deficient energy availability diet (−55%) in the early follicular phase of 2 menstrual cycles. Actigraphic data and urinary LH, estrone-3-glucuronide (E1G), and pregnanediol-3-glucuronide (PDG) were collected daily. Blood orexin and leptin were collected on the fifth day of each diet. Sleep was analyzed in relation to menstrual cycle phase, diet, and hormones. Results: Decreased energy availability and menstrual cycle phase independently affected wake after sleep onset (WASO; P = .004, P = .007 for diet and cycle phase, respectively) and number of awakenings (NOA; P = .03, P = .0006, respectively) with the greatest sleep disruption in the late luteal phase. Sleep efficiency (SE) was lower and duration of awakenings was longer in association with dietary restriction. Orexin was positively associated with WASO (P = .02), the sleep fragmentation index (P = .001), and NOA (P = .009) and inversely related to SE (P = .02). Increasing PDG was associated with WASO (P < .05) and duration of awakenings (P < .05) and inversely associated with SE (P < .01). Increasing E1G was positively associated with WASO (P < .05) and NOA (P < .01). Conclusion: Short-term modest caloric restriction independently disrupts sleep and exacerbates changes in sleep that occur across the menstrual cycle in healthy, young women without obesity.

Context Hypogonadism may be caused by Cushing syndrome (CS) and may intensify its adverse consequences. Objective To determine the frequency of male hypogonadism before and after curative surgery for CS, and its cause. Design Post-hoc analyses of prospective cohort studies Setting Clinical research center Patients Men with ACTH-dependent CS. Cohort 1 (C1) (n=8, age 32.5±12 y; studied 1985-1989); Cohort 2 (C2) (n=44, 42.7 ± 15.1 y; studied 1989-2021). Interventions C1: Every 20-minute blood sampling for 24h before and 1–40 months after surgical cure. Three subjects underwent GnRH stimulation tests pre- and post-surgery. C2: Hormone measurements at baseline and 6 and 12 months (M) post-cure. Main Outcome Measures C1: LH, FSH, LH pulse frequency and LH response to GnRH. C2: LH, FSH, testosterone (T), free T, fT4, T3, TSH and UFC levels and frequency of hypogonadism pre- and post-surgery. Results C1: mean LH and LH pulse frequency increased after surgery (p < 0.05) without changes in LH pulse amplitude, mean FSH, or peak gonadotropin response to GnRH. C2: 82% had baseline hypogonadism (total T 205 ± 28 ng/dL). Thyroid hormone levels varied inversely with UFC and cortisol. LH, total and free T, and SHBG increased at 6M and 12M post surgery, but hypogonadism persisted in 51% at 6M and in 26% at 12M. Conclusion Hypogonadism in men with CS is widely prevalent but reversible in ∼75% of patients one year after surgical cure and appears to be mediated through suppression of hypothalamic GnRH secretion, and modulated by thyroid hormones.

Objective: Female reproductive disorders (FRDs) are common health conditions that may present with significant symptoms. Diet and environment are potential areas for FRD interventions. We utilized a knowledge graph (KG) method to predict factors associated with common FRDs (e.g., endometriosis, ovarian cyst, and uterine fibroids). Materials and Methods: We harmonized survey data from the Personalized Environment and Genes Study on internal and external environmental exposures and health conditions with biomedical ontology content. We merged the harmonized data and ontologies with supplemental nutrient and agricultural chemical data to create a KG. We analyzed the KG by embedding edges and applying a random forest for edge prediction to identify variables potentially associated with FRDs. We also conducted logistic regression analysis for comparison. Results: Across 9765 PEGS respondents, the KG analysis resulted in 8535 significant predicted links between FRDs and chemicals, phenotypes, and diseases. Amongst these links, 32 were exact matches when compared with the logistic regression results, including comorbidities, medications, foods, and occupational exposures. Discussion: Mechanistic underpinnings of predicted links documented in the literature may support some of our findings. Our KG methods are useful for predicting possible associations in large, survey-based datasets with added information on directionality and magnitude of effect from logistic regression. These results should not be construed as causal, but can support hypothesis generation. Conclusion: This investigation enabled the generation of hypotheses on a variety of potential links between FRDs and exposures. Future investigations should prospectively evaluate the variables hypothesized to impact FRDs.

Context The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown. Objective This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH). Methods We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice-breaking in the UK Biobank cohort. Results MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 [2.2%]; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 [0.6%]; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07). Conclusion We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.

Thyroid function affects multiple sites of the female hypothalamic-pituitary gonadal (HPG) axis. Disruption of thyroid function has been linked to reproductive dysfunction in women and is associated with menstrual irregularity, infertility, poor pregnancy outcomes, and gynecological conditions such as premature ovarian insufficiency and polycystic ovarian syndrome. Thus, the complex molecular interplay between hormones involved in thyroid and reproductive functions is further compounded by the association of certain common autoimmune states with disorders of the thyroid and the HPG axes. Furthermore, in prepartum and intrapartum states, even relatively minor disruptions have been shown to adversely impact maternal and fetal outcomes, with some differences of opinion in the management of these conditions. In this review, we provide readers with a foundational understanding of the physiology and pathophysiology of thyroid hormone interactions with the female HPG axis. We also share clinical insights into the management of thyroid dysfunction in reproductive-aged women.

Endocrine disrupting chemicals are widely distributed in our environment. Humans are exposed to these compounds not only through their occupations, but also through dietary consumption and exposure to contaminated water, personal care products and textiles. Chemicals that are persistent in the body and in our environment include dioxins and polychlorinated biphenyls. Non-persistent chemicals including bisphenol A, phthalates and parabens are equally as important because they are ubiquitous in our environment. Heavy metals, including lead and cadmium, can also have endocrine disrupting properties. Although difficult to study due to their variety of sources of exposures and mechanisms of action, these chemicals have been associated with early menopause, increased frequency of vasomotor symptoms, altered steroid hormone levels and markers of diminished ovarian reserve. Understanding the impacts of these exposures is important given the potential for epigenetic modification, which can alter gene function and result in multi-generational effects. This review summarizes findings in humans and animals or cell-based models from the past decade of research. Continued research is needed to assess the effects of mixtures of chemicals, chronic exposures and new compounds that are continuously being developed as replacements for toxic chemicals that are being phased out.

The hOGG1 gene encodes the DNA glycosylase that removes the mutagenic lesion 7,8-dihyro-8-oxoguanine (8-oxoG) from DNA. A frequently found polymorphism resulting in a serine to cysteine substitution at position 326 of the OGG1 protein has been associated in several molecular epidemiologic studies with cancer development. To investigate whether the variant allele encodes a protein with altered OGG1 function, we compared the 8-oxoG repair activity, both in vivo and in cell extracts, of lymphoblastoid cell lines established from individuals carrying either Ser/Ser or Cys/Cys genotypes. We show that cells homozygous for the Cys variant display increased genetic instability and reduced in vivo 8-oxoG repair rates. Consistently, their extracts have an almost 2-fold lower basal 8-oxoG DNA glycosylase activity when compared with the Ser variant. Treatment with reducing agents of either the Cys variant cells directly or of protein extracts from these cells increases the repair capacity to the level of the Ser variant, whereas it does not affect the activity in cells or extracts from the latter. Furthermore, the DNA glycosylase activity of cells carrying the Cys/Cys alleles is more sensitive to inactivation by oxidizing agents when compared with that of the Ser/Ser cells. Analysis of the redox status of the OGG1 protein in the cells confirms that the lower activity of OGG1-Cys326 is associated with the oxidation of Cys326 to form a disulfide bond. Our findings support the idea that individuals homozygous for the OGG1-Cys variant could more readily accumulate mutations under conditions of oxidative stress. [Cancer Res 2009;69(8):3642–9]

Pathogenic SRY-box transcription factor 2 ( SOX2 ) variants typically cause severe ocular defects within a SOX2 disorder spectrum that includes hypogonadotropic hypogonadism. We examined exome-sequencing data from a large, well-phenotyped cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH) for pathogenic SOX2 variants to investigate the underlying pathogenic SOX2 spectrum and its associated phenotypes. We identified 8 IHH individuals harboring heterozygous pathogenic SOX2 variants with variable ocular phenotypes. These variant proteins were tested in vitro to determine whether a causal relationship between IHH and SOX2 exists. We found that Sox 2 was highly expressed in the hypothalamus of adult mice and colocalized with kisspeptin 1 (KISS1) expression in the anteroventral periventricular nucleus of adult female mice. In vitro, shRNA suppression of mouse SOX2 protein in Kiss-expressing cell lines increased the levels of human kisspeptin luciferase (hKiss-luc) transcription, while SOX2 overexpression repressed hKiss-luc transcription. Further, 4 of the identified SOX2 variants prevented this SOX2 - mediated repression of hKiss-luc. Together, these data suggest that pathogenic SOX2 variants contribute to both anosmic and normosmic forms of IHH, attesting to hypothalamic defects in the SOX2 disorder spectrum. Our study describes potentially novel mechanisms contributing to SOX2 -related disease and highlights the necessity of SOX2 screening in IHH genetic evaluation irrespective of associated ocular defects.