The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10(-8)) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.
Perimenopausal period refers to the interval when women’s menstrual cycles become irregular and is characterized by an increased risk of depression. Use of homeopathy to treat depression is widespread but there is a lack of clinical trials about its efficacy in depression in peri- and postmenopausal women. The aim of this study was to assess efficacy and safety of individualized homeopathic treatment versus placebo and fluoxetine versus placebo in peri- and postmenopausal women with moderate to severe depression.
Adolescent girls aged 15-19 bear a disproportionate burden of negative sexual and reproductive health outcomes in low- and middle-income countries. Research from several high-income countries suggests that early age at menarche is an important determinant of sexual and reproductive health. We conducted this systematic review to better understand whether and how early menarche is associated with various negative sexual and reproductive health outcomes in low- and middle-income countries and the implications of such associations.
Spontaneous dizygotic (DZ) twinning occurs in 1%-4% of women, with familial clustering and unknown physiological pathways and genetic origin. DZ twinning might index increased fertility and has distinct health implications for mother and child. We performed a GWAS in 1,980 mothers of spontaneous DZ twins and 12,953 control subjects. Findings were replicated in a large Icelandic cohort and tested for association across a broad range of fertility traits in women. Two SNPs were identified (rs11031006 near FSHB, p = 1.54 × 10(-9), and rs17293443 in SMAD3, p = 1.57 × 10(-8)) and replicated (p = 3 × 10(-3) and p = 1.44 × 10(-4), respectively). Based on ∼90,000 births in Iceland, the risk of a mother delivering twins increased by 18% for each copy of allele rs11031006-G and 9% for rs17293443-C. A higher polygenic risk score (PRS) for DZ twinning, calculated based on the results of the DZ twinning GWAS, was significantly associated with DZ twinning in Iceland (p = 0.001). A higher PRS was also associated with having children (p = 0.01), greater lifetime parity (p = 0.03), and earlier age at first child (p = 0.02). Allele rs11031006-G was associated with higher serum FSH levels, earlier age at menarche, earlier age at first child, higher lifetime parity, lower PCOS risk, and earlier age at menopause. Conversely, rs17293443-C was associated with later age at last child. We identified robust genetic risk variants for DZ twinning: one near FSHB and a second within SMAD3, the product of which plays an important role in gonadal responsiveness to FSH. These loci contribute to crucial aspects of reproductive capacity and health.
Is sugar-sweetened beverage (SSB) consumption associated with age at menarche?
: Many athletes are beginning intense training before puberty, a time of increased bone accrual when up to 25% of total bone mineral accrual occurs. Female athletes experiencing late or delayed pubertal onset may have open epiphyseal plates that are vulnerable to injury. This investigation’s purpose was to determine whether a delay in puberty (primary amenorrhea) affects the growth plate immediately postpuberty and at maturity.
Given the ambiguity surrounding the source of the continuing trend toward earlier menarche observed in Westernized nations, several competing explanatory models have emerged regarding variation in pubertal timing. While a biomedical model proposes that predominantly constitutional characteristics shape the maturation timetable, an alternative framework derived from Life History Theory (LHT) evolutionary principles emphasizes the influence of psychosocial factors on development. Working with a sample of women 19-25 years of age (N = 103) drawn from two Southeastern U.S. colleges, we combined cultural consensus analysis with retrospective self-report regarding childhood stress and menarcheal timing to investigate whether reported developmental experiences align with cultural models regarding factors that should drive pubertal timing. Results suggest a robust cultural model consistent with a biomedical framework concentrating principally on constitutional characteristics. However, participants' personal developmental recollections support an association between higher childhood stress and earlier menarche. These findings support LHT predictions that early reproductive maturation is an evolutionary adaptive response to chronic childhood stress as well as clarify the extent to which cultural models of factors contributing to puberty concord with developmental experiences.
BACKGROUND: Changes during puberty may influence final adult height. Height is related to multiple health conditions, including lung function. We investigated the association between the age of onset of five puberty events and height at age 18 years, analyzing boys and girls separately. METHODS: Of 1456 children recruited into the Isle of Wight birth cohort (1989-1990), 1313 were followed up at age 18 years. Height was measured, and age of pubertal onset was collected at age 18 years. Cluster analysis was performed on the five puberty events in boys and girls and linear regression was applied with the clusters predicting height at age 18 years. Individual linear regression analyses assessed the age of onset of each pubertal event as a potential predictor for height at age 18 years. RESULTS: Of the 1313 children followed up at age 18 years, 653 were males and 660 were females. All puberty variables had high internal consistency. In girls, earlier age of menarche, breast development, and growth spurt were related to shorter height. In boys, earlier age of growth spurt and slower progression through puberty were related to taller height at age 18 years. CONCLUSIONS: Given that boys and girls may have opposing associations between pubertal timing and adult height and that height is an important predictor of lung function, the effect of pubertal timing on respiratory health should be explored.
Circulating MKRN3 Levels Decline Prior to Pubertal Onset and Through Puberty: A Longitudinal Study of Healthy Girls
- The Journal of clinical endocrinology and metabolism
- Published over 3 years ago
Context: Puberty is initiated by a complex interaction of suppressing and stimulating factors. Genetic studies of familial central precocious puberty have suggested makorin RING-finger protein 3 (MKRN3) as a major inhibitor of GnRH secretion during childhood. Furthermore, genetic variation near MKRN3 (rs12148769) affects age at menarche in healthy girls. Objective: To evaluate if serum levels of MKRN3 declined prior to pubertal onset in healthy girls. Design: 1) Population-based longitudinal study of healthy Danish girls; 2) Cohort study of early maturing girls. Setting: 1) General community; 2) Tertiary referral centre for pediatric endocrinology. Patients or Other Participants: Healthy girls (n=38) aged 9.3 (5.9-11.3) years at baseline followed for 6.0 (2.7-7.6) years (2006-2014) with blood sampling every 6 months. Early maturing girls (n=13) with breast development < 8.3 years of age. Interventions: None Main outcome Measures: Serum levels of MKRN3: 354 samples (median 9, range 2 - 14 per girl). Genotyping of variants near MKRN3 (rs12148769 and rs12439354). Results: MKRN3 concentrations declined preceding pubertal onset; geometric mean (95% CI) 3 years prior to pubertal onset vs. last visit before pubertal onset: 304 (264-350) vs. 257 (243-273) pg/mL, corresponding to a reduction of 15% (1-27%) (p=0.033). In prepubertal girls, circulating MKRN3 correlated negatively with gonadotropin levels; FSH: r = -0.262 (p=0.015) and LH: r = -0.226 (p=0.037). After adjustment, MKRN3 levels were lower in early maturing girls compared to age-matched prepubertal girls: 171 (< 25-333) vs. 262 (94-624) pg/mL, p=0.051. Genetic variants near MKRN3 did not correlate with serum levels of MKRN3. Conclusions: Declining levels of circulating MKRN3 preceded pubertal onset. The negative correlation between MKRN3 and gonadotropins further support MKRN3 as a major regulator of hypothalamic GnRH secretion during childhood. Undetectable or low MKRN3 levels were observed in a subgroup of patients with early onset of puberty.