Digit ratios and their asymmetries as risk factors of developmental instability and hospitalization for COVID-19.

COVID-19 presents with mild symptoms in the majority of patients but in a minority it progresses to acute illness and hospitalization. Here we consider whether markers for prenatal sex hormones and postnatal stressors on developmental instability, i.e. digit ratios and their directional and unsigned asymmetries, are predictive of hospitalization. We focus on six ratios: 2D:3D; 2D:4D; 2D:5D; 3D:4D; 3D:5D; 4D:5D and compare hospitalized patient and control means for right, and left ratios, directional asymmetries (right-left) and unsigned asymmetries [|(right-left)|]. There were 54 patients and 100 controls. We found (i) patients differed in their digit ratios from controls (patients > controls) in all three ratios that included 5D (2D:5D, 3D:5D and 4D:5D) with small to medium effect sizes (d = 0.3 to 0.64), (ii) they did not differ in their directional asymmetries, and (iii) patients had greater |(right-left)| asymmetry than controls for 2D:4D (d = .74) , and all ratios that included 5D; 2D:5D (d = 0.66), 3D:5D (d = .79), 4D:5D (d = 0.47). The Composite Asymmetry of the two largest effects (2D:4D + 3D:5D) gave a patient and control difference with effect size d = 1.04. All patient versus control differences were independent of sex. We conclude that digit ratio patterns differ between patients and controls and this was most evident in ratios that included 5D. Large |(right-left)| asymmetries in the patients are likely to be a marker for postnatal stressors resulting in developmental perturbations and for potential severity of COVID-19.

Identification of a duplication within the GDF9 gene and novel candidate genes for primary ovarian insufficiency (POI) by a customized high-resolution array comparative genomic hybridization platform.

STUDY QUESTION: Can high-resolution array comparative genomic hybridization (CGH) analysis of DNA samples from women with primary ovarian insufficiency (POI) improve the diagnosis of the condition and identify novel candidate genes for POI? SUMMARY ANSWER: A mutation affecting the regulatory region of growth differentiation factor 9 (GDF9) was identified for the first time together with several novel candidate genes for POI. WHAT IS KNOWN ALREADY: Most patients with POI do not receive a molecular diagnosis despite a significant genetic component in the pathogenesis. STUDY DESIGN, SIZE, DURATION: We performed a case-control study. Twenty-six patients were analyzed by array CGH for identification of copy number variants. Novel changes were investigated in 95 controls and in a separate population of 28 additional patients with POI. The experimental procedures were performed during a 1-year period. PARTICIPANTS/MATERIALS, SETTING, METHODS: DNA samples from 26 patients with POI were analyzed by a customized 1M array-CGH platform with whole genome coverage and probe enrichment targeting 78 genes in sex development. By PCR amplification and sequencing, the breakpoint of an identified partial GDF9 gene duplication was characterized. A multiplex ligation-dependent probe amplification (MLPA) probe set for specific identification of deletions/duplications affecting GDF9 was developed. An MLPA probe set for the identification of additional cases or controls carrying novel candidate regions identified by array-CGH was developed. Sequencing of three candidate genes was performed. MAIN RESULTS AND THE ROLE OF CHANCE: Eleven unique copy number changes were identified in a total of 11 patients, including a tandem duplication of 475 bp, containing part of the GDF9 gene promoter region. The duplicated region contains three NOBOX-binding elements and an E-box, important for GDF9 gene regulation. This aberration is likely causative of POI. Fifty-four patients were investigated for copy number changes within GDF9, but no additional cases were found. Ten aberrations constituting novel candidate regions were detected, including a second DNAH6 deletion in a patient with POI. Other identified candidate genes were TSPYL6, SMARCC1, CSPG5 and ZFR2. LIMITATIONS, REASONS FOR CAUTION: This is a descriptive study and no functional experiments were performed. WIDER IMPLICATIONS OF THE FINDINGS: The study illustrates the importance of analyzing small copy number changes in addition to sequence alterations in the genetic investigation of patients with POI. Also, promoter regions should be included in the investigation. STUDY FUNDING/COMPETING INTERESTS: The study was supported by grants from the Swedish Research council (project no 12198 to A.W. and project no 20324 to A.L.H.), Stockholm County Council (E.I., A.W. and K.R.W.), Foundation Frimurare Barnhuset (A.N., A.W. and M.B.), Karolinska Institutet (A.N., A.L.H., E.I., A.W. and M.B.), Novo Nordic Foundation (A.W.) and Svenska Läkaresällskapet (M.B.). The funding sources had no involvement in the design or analysis of the study. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Lifestyle intervention up-regulates gene and protein levels of molecules involved in insulin signaling in the endometrium of overweight/obese women with polycystic ovary syndrome.

STUDY QUESTION: Does lifestyle intervention aiming at weight loss influence endometrial insulin signaling in overweight/obese women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Lifestyle intervention up-regulates, both at the mRNA and protein levels, components of insulin signaling in the endometrium of overweight/obese PCOS women, in relation to an improved menstrual pattern. WHAT IS KNOWN ALREADY: PCOS is a multifactorial endocrine disorder diagnosed by two of the following three criteria: chronic anovulation, hyperandrogenism and polycystic ovaries. Many women with PCOS also have insulin resistance and obesity. The syndrome is furthermore associated with endometrial cancer and possible alterations in endometrial function and receptivity. STUDY DESIGN, SIZE, DURATION: This study assessed the effects of a combined diet and exercise lifestyle intervention for 3 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: A group of 20 overweight/obese PCOS women with anovulation, hyperandrogenism and polycystic ovaries were subjected to a combined diet and exercise program for 3 months. Ten body mass index (BMI)-matched regularly menstruating overweight/obese controls, nine normal-weight PCOS women and ten normal-weight controls were also included in the study. In an academic clinical setting, women were examined in mid-follicular phase for endocrine assessment and determination of endometrial levels of mRNA and immunohistochemical staining of insulin signaling molecules (the insulin receptor, insulin receptor substrate-1 (IRS1) and glucose transporter (GLUT) 1 and 4). MAIN RESULTS AND THE ROLE OF CHANCE: Women with PCOS exhibited lower levels of IRS1 (P < 0.01) and GLUT4 (P < 0.01) mRNA in their proliferative endometrium than BMI-matched controls. After lifestyle intervention, weight loss averaged 4.7% and the menstrual pattern improved in 65% of the overweight/obese women with PCOS. Levels of IRS1 (P < 0.01) and GLUT1 (P < 0.05) mRNA were significantly up-regulated in the endometrium of those women with improved menstrual function, as were the protein expression levels of pY612IRS1 (the activated IRS1 form, P < 0.05), pS312IRS1 (the inhibitory form of IRS1, P < 0.05) and GLUT1 (P < 0.05). Improvement in the menstrual function of women in the obese/overweight group following the lifestyle intervention was positively correlated with the increase in the endometrial level of IRS1 mRNA (r = 0.63, P < 0.01) and negatively correlated with the change in BMI (r = -0.50, P < 0.05). LIMITATIONS, REASONS FOR CAUTION: The number of women in each group was limited, although the power calculation indicated that the number of patients subjected to the lifestyle intervention was sufficient. WIDER IMPLICATIONS OF THE FINDINGS: We propose that up-regulation of endometrial IRS1 and GLUT1 in overweight/obese women with PCOS following lifestyle intervention improves the glucose homeostasis and thereby restores the functioning of the endometrium in these women. STUDY FUNDING/COMPETING INTEREST(S): This study was supported financially by the Swedish Research Council (A.L.H., 20324), Karolinska Institutet and the Stockholm County Council. None of the authors has any conflict of interest to declare.

No mutations in the PSMC3IP gene identified in a Swedish cohort of women with primary ovarian insufficiency.

Ovarian dysfunction before the age of 40 years, characterized by hypergonadotropic hypogonadism and presenting with either primary or secondary amenorrhea, is called primary ovarian insufficiency (POI). POI has a significant genetic component, but the specific genetic cause is often unknown. A novel candidate gene for POI, PSMC3IP, has recently been identified. The aim of this study was to investigate a group of patients with POI for possible PSMC3IP mutations. Therefore, DNA samples from 50 patients with POI of primarily Swedish origin were used in the study, 27 with secondary amenorrhea (median age of diagnosis 23 years) and 23 with primary amenorrhea. Control material consisting of DNA samples from 95 women without POI was used for investigation of novel sequence variants. All exons and intron/exon boundaries of the PSMC3IP gene were analyzed by PCR and sequencing. As a result, no pathogenic mutation in the PSMC3IP gene was detected in the cohort. A previously unreported variant, NM_016556.3:c.337+33A>G, was detected in heterozygous form in 1 patient with secondary amenorrhea, likely constituting a normal variant. Two reported single nucleotide polymorphisms were detected in the cohort at the expected frequency. In conclusion, PSMC3IP gene mutations are not common causes of POI in this Swedish cohort.

Suboptimal psychosocial outcomes in patients with congenital adrenal hyperplasia: epidemiological studies in a nonbiased national cohort in Sweden.

CONTEXT: Congenital adrenal hyperplasia (CAH), CYP21A2 deficiency, results in cortisol and aldosterone deficiency and increased production of androgens, with a good genotype phenotype correlation. OBJECTIVE: The objective of the investigation was to study psychosocial outcomes in relation to clinical severity, CYP21A2 genotype, in men and women. DESIGN: This was an epidemiological study with a matched case control design. SETTING: The setting of the study was all known CAH patients in Sweden. PARTICIPANTS: Five hundred eighty-eight patients, more than 80% with known severity of CAH, and 100 controls per patient matched for sex, year, and place of birth participated in the study. MAIN OUTCOME AND MEASURES: Proxies for quality of life were selected: level of education, employment, income, sick leave, disability pension, marriage, and children. RESULTS: Women with salt-wasting (SW) CAH had completed primary education less often [odds ratio (OR) 0.3], not explained by neonatal salt crisis or hypoglycemia because the men did not differ from controls. Men and women in the less severe I172N genotype group were more likely to have an academic education (OR 1.8). SW women were more likely to have an income in the top 20th percentile (OR 2.0). Both men and women had more disability pension (OR 1.5) and sick leave (OR 1.7). The men more often had long-lasting employment (OR 3.1). Men were more often (OR 1.6) and women were less often married (OR 0.7). Patients had children less often (OR 0.3). CONCLUSIONS: This study shows important outcome differences regarding education; employment; marriage and fertility, depending on sex; and severity of CAH. The mechanisms behind this and the increased risk for sick leave or disability pension in both men and women should be identified to improve medical and psychological care.

Retarded head growth and neurocognitive development in infants of mothers with a history of eating disorders: longitudinal cohort study.

OBJECTIVE: To characterise early growth and neurocognitive development in children of mothers with a history of eating disorders (ED). DESIGN: A longitudinal cohort study. SETTING: Child-care centres in Stockholm, Sweden. POPULATION: Children born to mothers with previous ED (n = 47) (24 anorexia nervosa, 20 bulimia nervosa, 3 unspecified ED), and controls (n = 65). METHODS: Mean values and standard deviation scores of weight and height from birth to 5 years of age and head circumference up to 18 months of age were compared between groups. Neurocognitive development was studied at the age of 5 years by the validated parent questionnaire Five to Fifteen. MAIN OUTCOME MEASURES: Head growth and neurocognitive development. RESULTS: We previously reported that mothers with a history of ED conceived infants with lower birthweight and head circumference than controls. At 3 months of age, body mass index (BMI) was no longer reduced but mean head circumferences of the children born to mothers with ED were smaller throughout the observation period. Similarly, the longitudinal results of the standard deviation scores of head circumference showed a significant overall group effect with lower levels in both subgroups of ED (anorexia nervosa and bulimia nervosa). The children of the ED mothers also had significantly higher Five to Fifteen scores than controls, reflecting difficulties in language skills. Head circumference at birth correlated with language skills in the children of mothers with ED. CONCLUSION: Children of mothers with previous ED demonstrated an early catch-up in BMI, but the average head circumference continued to be delayed until at least 18 months of age. The reduced head growth was related to delayed neurocognitive development.

Digitized assessment of mammographic breast density--effects of continuous combined hormone therapy, tibolone and black cohosh compared to placebo.

OBJECTIVES: To determine the effects of continuous combined hormone therapy, tibolone, black cohosh, and placebo on digitized mammographic breast density in postmenopausal women. STUDY DESIGN: A prospective, double-blind, placebo-controlled study of 154 postmenopausal women randomized to estradiol 2 mg/norethisterone acetate 1 mg (E2/NETA), tibolone 2.5 mg or placebo and a prospective, open, uncontrolled drug safety study, of which 65 postmenopausal women were treated with black cohosh. Mammograms, at baseline and after six months of treatment, were previously classified according to visual quantification scales. MAIN OUTCOME MEASURES: Reanalysis of assessable mammograms by digitized quantification of breast density. RESULTS: Treatment groups were comparable at baseline. During treatment, both E2/NETA and tibolone significantly increased breast density (mean increase 14.3%, p<0.001 and 2.3%, p<0.001, respectively), while black cohosh and placebo did not. Twenty-four out of the 43 women on E2/NETA had an increase in density exceeding 10% and 6 women had an increase of 30% or more. In the tibolone group, only one woman had an increase in density of more than 10%. The difference in increase in breast density between E2/NETA on the one hand and tibolone, black cohosh and placebo on the other was highly significant (p<0.0001). CONCLUSIONS: Digitized mammographic breast density is a highly sensitive method confirming significant increase in density by standard E2/NETA treatment and to a lesser extent by tibolone, whereas black cohosh does not influence mammographic breast density during six months treatment. Digitized assessment also yields data on individual variation and small increases left undetectable by visual classification.

Peak bone mineral density in Vietnamese women.

SUMMARY: This cross-sectional study showed that peak bone mineral density in Vietnamese women is comparable to that in Caucasian women; however, the prevalence of osteoporosis in post-menopausal Vietnamese women was slightly higher than in Caucasian women. The age of achieving peak bone mass in Vietnamese women was between 26 and 30 years. INTRODUCTION: While peak bone mass and its determinants have been well-documented in Caucasian populations, little has been studied in Asian populations. The present study was designed to estimate the peak bone mineral density (BMD), age of its attainment, and to examine the prevalence of osteoporosis in Vietnamese women aged 50+. METHODS: The study was designed as a cross-sectional study with 328 women aged between 10 and 65 years (average age: 41) who were randomly selected from two districts around Hanoi city according to a stratified sampling scheme. BMD at the lumbar spine, femoral neck and total hip was measured by a DXA instrument (GE Lunar Prodigy, WI, USA). BMD was modeled as a cubic function of age, from which peak BMD and age at peak BMD were estimated. Bootstrap method was utilized to estimate the 95% confidence interval of peak BMD and age at peak BMD. From the peak BMD, T-score was calculated for each woman, and using the World Health Organization criteria, any woman with femoral neck BMD T-score

The influence of premenstrual symptoms on postural balance and kinesthesia during the menstrual cycle.

Recent studies have indicated an increased incidence of female athletic injuries during the luteal phase and the first days of the menstrual period. The purpose of this study was to investigate whether postural sway and knee-joint kinesthesia very during the menstrual cycle, and whether premenstrual syndrome (PMS) influences postural balance and kinesthesia. A total of 13 subjects with regular menstrual cycles participated in the study. Postural sway and kinesthesia were measured in the early follicular phase, in the ovulation phase and in the mid-luteal phase. Postural sway was measured with an ankle disc placed on a Statometer, and kinesthesia was measured with a specially designed device. Menstrual cycle phases were determined by sex hormone analyses in serum and by luteinizing hormone (LH) detection in urine. The diagnosis of PMS was made prospectively using validated daily symptom ratings. Eight of 13 women were classified as having PMS. These women had a significantly greater postural sway (p = 0.002) and a greater threshold for detection of passive motion in the knee joints (p = 0.05) than women without PMS. A tendency (p = 0.06) towards greater postural sway in the mid-luteal phase was detected among women with PMS. This may explain the finding of an increased incidence of athletic injuries in the luteal phase, reported previously.

Hormonal regulation of appetite and food intake.

Several clinical disorders are strongly influenced by hormones involved in appetite and weight regulation. Obesity and eating disorders are of major importance, because they are associated with severe morbidity and considered to be among the greatest health problems in the Western world today. This review describes recent findings in hormonal regulation of food intake by substances acting both centrally, such as corticotropin-releasing factor, neuropeptide Y and leptin, and peripherally, such as cholecystokinin and somatostatin. Sex hormones and glucocorticoids play an important role in long-term regulation of metabolism. The role of these hormones in appetite and weight changes during life as well as during pregnancy and lactation is discussed. Furthermore, the development of obesity and eating disorders is influenced, in particular, by steroid hormones. Treatment with sex hormones, as in hormone replacement therapy, affects appetite and weight and may have beneficial effects in preventing android obesity. Currently, there is great effort in developing endogenous neurohumoral substances into effective drugs for the treatment of obesity and eating disorders. Leptin and neuropeptide Y analogues are of interest as potential antiobesity agents.

[Athletic amenorrhea and its consequences. Hard physical training at an early age can cause serious bone damage]. / Idrottsamenorré och dess konsekvenser. Hård fysisk träning i unga år kan ge allvarliga skelettskador.

Strenuous exercise in women is associated with a high incidence of menstrual dysfunction, including amenorrhoea. Athletic amenorrhoea is most common among long-distance runners and ballet dancers, with a prevalence of up to 66 per cent. It is of hypothalamic origin, the pulsatile release of GnRH (gonadotrophin-releasing hormone) being disturbed during exercise, resulting in low gonadotrophin and oestrogen levels. Accumulated evidence suggests athletic amenorrhoea to be related to energy deficiency or to the eating disorders that are prevalent among athletes. The long-term consequences of amenorrhoea are premature osteoporosis and increased risk of musculoskeletal injury. Elite training in young girls tends to delay pubertal development, resulting in decreased bone mass accumulation and reduced growth potential.

Reduced serum cholecystokinin and increase in body fat during oral contraception.

This investigation was undertaken to explore a possible role of the "satiety peptide" cholecystokinin and some other gastrointestinal hormones for changes in appetite and weight during oral contraception. Ten young healthy women attending a youth health care center for contraceptive counseling volunteered for the study. A standardized meal test was used for recordings of appetite and gastrointestinal hormone response before and after 5 months of treatment with a monophasic combined oral contraceptive. Body fat was calculated from measurements of skin-fold thickness. Oral contraceptives caused a suppression of basal levels of serum cholecystokinin, which was correlated to an increase in body fat. Meal-related response of cholecystokinin and appetite were not affected. Serum levels of gastrin and insulin were also unchanged, whereas triglycerides and postprandial glucose levels were elevated. The results suggest a role of cholecystokinin in regulation of body composition. Cholecystokinin stimulates the release of insulin and stimulates lipolysis in adipose tissue. Reduced cholecystokinin levels may, therefore, be related to mild impairment of glucose tolerance and promote body fat storage during oral contraception.

Altered adrenal steroid metabolism underlying hypercortisolism in female endurance athletes.

OBJECTIVE: To explore possible changes in adrenal steroid metabolism and androgenic-anabolic status in female endurance athletes as a mechanism for their hypercortisolism. DESIGN: Adrenal steroids and androgenic-anabolic factors were studied during basal conditions and in response to ACTH stimulation related to menstrual status. SETTING: Department of Obstetrics and Gynecology, Karolinska Hospital, Stockholm, Sweden. PARTICIPANTS: Thirteen female elite middle to long distance runners (six eumenorrheic, seven oligoamenorrheic) and seven regularly menstruating controls. INTERVENTIONS: Blood samples were collected before and after an injection of 250 micrograms IV synthetic ACTH 1-24. Body weight, height, and body fat were measured. MAIN OUTCOME MEASURES: Basal serum concentrations of cortisol, androstenedione (A), DHEA, DHEAS, 17 alpha-hydroxyprogesterone (17-OHP), T, steroid-binding proteins, and insulin-like growth factor I and ACTH-induced response (area under the curve) of cortisol, DHEA, and 17-OHP. RESULTS: Oligoamenorrheic athletes had higher basal cortisol and A concentrations compared with healthy controls, whereas basal levels of DHEA and DHEAS were normal. Important findings in the oligoamenorrheic athletes were a significantly lower ratio between the ACTH-induced increments of DHEA and 17-OHP and an increased ratio between basal A and DHEAS. Insulin-like growth factor I was correlated negatively to sex hormone-binding globulin and to the amount of body fat in the combined material. CONCLUSIONS: The results indicate a redistribution of adrenal steroid metabolism in favor of glucocorticoid production in female endurance athletes. We suggest that hypercortisolism in female endurance athletes is a physiological adaptation to maintain adequate blood glucose levels during a condition of energy deficiency.

Reduced serum cholecystokinin response to food intake in female athletes.

Strenuous training in women has been shown to cause menstrual dysfunction and decreased bone mineral density. These endocrine and metabolic complications are associated with an insufficient dietary intake and decreased body fat content in female athletes. The present investigation was undertaken to study serum levels of cholecystokinin (CCK), insulin, gastrin, and cortisol in 14 female long-distance runners and 15 sex- and age-matched control subjects during intake of a standardized meal (500 kcal). The athletes showed a decreased response of the "satiety peptide" CCK to the meal and reported increased hunger compared with the control group. Meal-related insulin response was also decreased in the athletes, whereas gastrin levels were comparable to those of controls. Basal levels of glucose were increased in the athletes, but there was no difference in postprandial levels between the groups. Cortisol levels were clearly elevated in the female runners. We conclude that insufficient food intake in female athletes cannot be explained by increased CCK secretion and satiety. Since the athletes reported a larger caloric intake of a normal daily breakfast than the control subjects, the decreased CCK response may instead be explained by an adaptation to increased food intake. The decreased meal-related insulin response may be a reflection of increased insulin sensitivity as an adaptation to physical exercise. However, an impaired peptide secretion cannot be excluded. The role of elevated cortisol levels in the gastrointestinal hormone response needs further investigation.

Hormone anabolic/catabolic balance in female endurance athletes.

The anabolic/catabolic hormone balance in 13 female endurance athletes was studied during basal conditions by comparing their serum concentrations of androgenic and catabolic steroids, growth hormone, insulin-like growth factor 1 (IGF-1) and insulin with corresponding values in 15 matched sedentary controls. Higher cortisol and lower levels sex hormone-binding globulin (SHBG) were found in the athletes, and these differences were enhanced depending on the degree of menstrual disorders. There was a negative correlation between cortisol and SHBG levels. No differences were found in concentrations of androgens, IGF-1 and insulin. The results indicate a normal anabolic activity in oligomenorrheic athletes, but due to their distinct hypercortisolism, the anabolic/catabolic hormone balance is changed to a predominantly catabolic state.