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This article provides an approach to amenorrhea and is intended for pre-clinical and clerkship medical students. Primary amenorrhea refers to the absence of menarche by 15 years or 3 years post thelarche while secondary amenorrhea is the cessation of menses for 3 months in women with a previously regular cycle or for 6 months in women with previously irregular menses. While amenorrhea can be physiological it can also reflect an anatomical or more complex hormonal problem that students must learn to identify and investigate.

Background Pelvic ultrasonography (PUS) of the uterus and ovaries allows the diagnosis of changes in sexual development. However, the reference values used in Spain originate from old studies conducted in other countries. Objective To determine reference uterine and ovarian measurements by PUS and according to pubertal status and bone age in a Spanish population of healthy girls aged between 6 and 12 years. Materials and methods Descriptive cross‐sectional study performed on 221 healthy girls from 2017 to 2019. Ovarian and uterine measurements were described and associated with chronological age, bone age, and Tanner stage. ROC curves were used to assess the predictive value of tests for Tanner stage II. Results We described reference values for all PUS uterine and ovarian measurements assessed. Subjects in Tanner II (thelarche) had a mean age of 9.7 years (SD = 1.1) and mean BMI of 19.2 kg/m2. Fundal–cervical ratio changed from 1:1 to 2:1 at 12 years of chronological age (62.5% with 1:1 ratio; p, The study provides updated pelvic ultrasound reference values for uterine and ovarian measurements. According to our findings, a significant change in uterine length (p = 0.0020), ovarian transverse diameter (p

Introduction: Current health literature suggests that there has been a decline in the age of pubertal onset and that pubertal onset/duration of puberty may, besides weight status, be influenced by socioeconomic context. Objective: The goal of this study was to determine whether pubertal onset/duration and puberty-triggering hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH) vary according to socioeconomic status (SES). Moreover, we aimed to propose cutoff values of serum LH and FSH for predicting gonadarche in boys. Methods: 2,657 apparently healthy children and adolescents between 5.5 and 18 years from the area of Leipzig were recruited from the LIFE Child study. Age at pubertal onset/end of puberty was given in 738/573 children, respectively. Anthropometric parameters of puberty, blood measurements of LH and FSH, and questionnaires assessing SES were evaluated. Results: Lower SES was associated with earlier thelarche and longer duration of puberty in overweight/obese girls, whereas age of menarche was not affected. In boys with low SES, a trend versus earlier puberty onset can be seen. Lower SES was significantly associated with boys’ age at mutation. No significant differences in boys’ and girls’ serum levels of LH and FSH during puberty according to SES were observed. Serum LH levels of 0.56 IU/L and serum FSH levels of 1.74 IU/L showed the best prediction of gonadarche in boys. Conclusion: Puberty onset/duration and boys’ age at mutation is affected by SES. The proposed cutoff levels for serum LH and FSH could provide a serological tool to determine gonadarche in boys.

The objective of this systematic review was to evaluate the association between a soy-based infant diet and the onset of puberty. We included studies in which children were fed a soy-based diet, and we compared them with those who were not. The primary outcomes were the onset of puberty in girls (thelarche, pubarche, and menarche age), boys (pubarche, voice change, testicular and penis enlargement age), and both (risk of delayed and precocious puberty [PP]). Search strategies were performed in PubMed, Embase, LILACS, and CENTRAL databases. Two reviewers selected eligible studies, assessed the risk of bias, and extracted data from the included studies. The odds ratio (OR) and mean difference (MD) were calculated with a 95% confidence interval (CI) as a measure of the association between soy consumption and outcomes. We used a random-effects model to pool results across studies and the Grading of Recommendations Assessment, Development, and Evaluation to evaluate the certainty of evidence. We included eight studies in which 598 children consumed a soy-based diet but 2957 did not. The primary outcomes that could be plotted in the meta-analysis were the risk of PP and age at menarche. There was no statistical difference between groups for PP (OR: 0.51, 95% CI: 0.09 to 2.94, 3 studies, 206 participants, low certainty of evidence). No between-group difference was observed in menarche age (MD 0.14 years, 95% CI -0.16 to 0.45, 3 studies, 605 children, low certainty of evidence). One study presented this outcome in terms of median and interquartile range, and although the onset of menarche was marginally increased in girls who received a soy-based diet, the reported age was within the normal age range for menarche. We did not find any association between a soy-based infant diet and the onset of puberty in boys or girls. Trial Registration: PROSPERO registration: CRD42018088902.

Puberty is the period of transition from childhood to adulthood characterized by the attainment of adult height and body composition, accrual of bone strength and the acquisition of secondary sexual characteristics, psychosocial maturation and reproductive capacity. In girls, menarche is a late marker of puberty. Primary amenorrhea is defined as the absence of menarche in ≥ 15-year-old females with developed secondary sexual characteristics and normal growth or in ≥13-year-old females without signs of pubertal development. Furthermore, evaluation for primary amenorrhea should be considered in the absence of menarche 3 years after thelarche (start of breast development) or 5 years after thelarche, if that occurred before the age of 10 years. A variety of disorders in the hypothalamus–pituitary–ovarian axis can lead to primary amenorrhea with delayed, arrested or normal pubertal development. Etiologies can be categorized as hypothalamic or pituitary disorders causing hypogonadotropic hypogonadism, gonadal disorders causing hypergonadotropic hypogonadism, disorders of other endocrine glands, and congenital utero–vaginal anomalies. This article gives a comprehensive review of the etiologies, diagnostics and management of primary amenorrhea from the perspective of pediatric endocrinologists and gynecologists. The goals of treatment vary depending on both the etiology and the patient; with timely etiological diagnostics fertility may be attained even in those situations where no curable treatment exists.

Objectives Pubertal assessment is crucial as puberty is the transition from childhood to adulthood. Pubertal assessment, growth, and secular trend in puberty need to be explored further in India. The objectives were to assess Sexual Maturity Rating (SMR) among children and establish normative data of puberty from western India. We also compared age of attainment of various stages of puberty with BMI and secular trend in menarche. Methods A cross-sectional observational study was undertaken at a tertiary care pediatric center. The study population were healthy girls and boys between 6 and 18 years. Demographic data was noted. Anthropometry and SMR assessment (Tanner staging) were performed. The age of menarche was noted among the girls and their mothers. Data were analyzed using SPSS 21. Results In girls, median age of thelarche, pubarche, and menarche was 9.37 (8.5–10.2), 10.18 (9.87–10.49), and 12.55 years (12.41–12.75) respectively. There was an early appearance of thelarche but menarche was delayed in overweight-obese girls (statistically not significant). Age of menarche showed a shift to left in girls as compared to their mothers (p=0.036). In boys, median age of testicular stage 2 and pubarche was 10.7 (9.9–11.8) and 11.6 years (11.1–12.1) respectively. In overweight-obese boys the pubertal milestones were achieved earlier (statistically not significant). Conclusions Normative data on pubertal assessment from western India is presented. Age of menarche shows a shift to left in girls as compared to their mothers. Pubertal milestones were observed at a younger age in overweight obese children which was not significant.

Background: Polybrominated diphenyl ethers (PBDEs) are flame retardants, exposing humans primarily though diet, dust and inhalation. Higher levels of PBDEs have been associated with adverse health ...

Background Girls who experience early-life familial stress may have heightened risk of early puberty, which has adverse implications for adolescent and adult health. We assessed the association between household intactness and pubertal onset using a racially/ethnically diverse cohort of girls from Northern California. Methods A prospective cohort study of 26,044 girls born in 2003-10. Girls living with both parents from birth up to 6 years were considered to come from “intact” households while others constituted “non-intact” households. Pubertal development was measured using pediatrician-assessed Tanner staging for breast and pubic hair. Pubertal onset was defined as the transition from Tanner Stage 1 to 2+ for breast (thelarche) and pubic hair (pubarche). Menarche data was collected from routine well-child questionnaires. Weibull regression models accommodating left, right, and interval censoring were used to determine risk of earlier thelarche and pubarche, and logistic regressions were used to assess the risk of early menarche (age Results Girls exposed to non-intact households before age 2 years were at increased risk for earlier thelarche and pubarche with significant effect modification by race/ethnicity, compared with girls from intact households. The associations were strongest among Black girls (adjusted hazard ratio [HR]: 1.60, 95% confidence interval [CI]: 1.29,1.98; HR: 1.42, 95%CI: 1.15,1.77 for thelarche and pubarche, respectively). There were no significant associations among Asian/Pacific Islanders. Girls who lived in non-intact households before age 2 years were also at increased risk for earlier menarche, but without race/ethnic interaction. Adjustment for prepubertal obesity did not change these associations. Associations between living in non-intact households after age 2 years and early puberty were weaker but still significant. Conclusions Exposure to a non-intact household early in life may increase the risk of early puberty in girls. Future psychosocial interventions focused on improving family cohesiveness and efforts to reduce childhood stress among families that are non-intact may mitigate these negative associations, thereby preventing future adverse health effects of early puberty and health disparities.

Key Points Question Are there dimension- and sex-specific longitudinal associations between early-life adversity and accelerated biological aging in children with specific genetic backgrounds? Findings This cohort study of 997 youths found that both threat- and deprivation-related early-life adversity were associated with earlier age of pubertal onset in boys and girls among those with a low polygenic susceptibility for early puberty. Greater exposure to threat, but not deprivation, was associated with greater telomere attrition among children with low and moderate polygenic profiles. Meaning The findings suggest that the accelerating association of early adversity with biological aging might occur at a younger age and act in a genetic background–dependent and dimension-specific manner., Importance A growing body of literature suggests that exposure to early-life adversity (ELA) is associated with accelerated biological aging, offering 1 mechanism through which ELA may be associated with an increased risk for age-related disease. These investigations, however, have been predominantly cross-sectional and focused on adults and females. Objective To evaluate associations of threat-related (ie, physical abuse) and deprivation-related (ie, emotional neglect) ELA exposure with cellular and reproductive strategy metrics of biological aging among boys and girls with specific genetic backgrounds around the period of pubertal onset. Design, Setting, and Participants In this cohort study, 997 boys and girls in grade 1 to grade 3 from 3 large elementary schools were recruited from Bengbu, Anhui Province, China, and were followed up from March 21, 2016 (baseline; wave 1), for 4 consecutive years, through March 25, 2019. Main Outcomes and Measures The outcome was accelerated biological aging in both cellular and reproductive strategy metrics: telomere attrition and age at thelarche (for girls) and testicular maturation (for boys). Multi-informant assessment of exposure to threat-related and deprivation-related ELA was done at baseline (wave 1) and 1-year follow-up (wave 2). The polygenic risk score (PRS) was computed based on 17 single-nucleotide variations for early pubertal timing. Results Of the 997 participants (579 girls [58.1%]; mean [SD] age at baseline, 8.0 [0.8] years), 550 (55.2%) reported exposure to threat-related ELA and 443 (44.4%) reported exposure to deprivation-related ELA. Threat-related ELA was associated with onset of thelarche 2.6 months earlier and deprivation-related ELA with onset of thelarche 3.3 months earlier in exposed girls than in unexposed peers; these associations were observed only among girls with a low PRS. Among boys, a similar pattern was found. Threat-related ELA was associated with testicular volume of 4 mL or more 1.4 months earlier and deprivation-related ELA was associated with testicular volume of 4 mL or more 2.3 months earlier than in unexposed peers but only among those with a low PRS. Boys and girls with greater exposure to threats showed a significantly higher percentage of telomere length change during 1-year follow-up, but only among those with low PRS (boys: β = 1.50; 95% CI, 0.80-2.21; P, This cohort study evaluates the association of exposure to threat-related and deprivation-related early-life adversity with metrics of biological aging among boys and girls with specific genetic backgrounds around the period of pubertal onset.

Objective: To assess whether the presence of high DHEAS (HD) at 7 years determines different timing, sequence, and rate of pubertal events, and whether it is associated with adrenal and/or ovarian hyperandrogenism and changes in ovarian morphology throughout puberty. Methods: In a longitudinal study of 504 girls, clinical evaluation was performed every 6 months after 7 years of age to detect Tanner stages; hormonal and anthropometric measurements were conducted at thelarche (B2), breast Tanner 4 (B4), and 1 year after menarche; ultrasonographic evaluation was also performed after menarche. The girls were classified as HD if their DHEAS level was >42.1 µg/dL (>75th percentile) around 7 years. Results: HD around 7 years is associated with a younger age at thelarche, pubarche, and menarche. Girls with HD had higher androstenedione and total testosterone levels, and a higher free androgen index (FAI), and lower levels of antimüllerian hormone (AMH) at B2, and higher levels of androstenedione and FAI at B4 and after menarche. All these results were significant even after adjusting for body mass index, age at first DHEAS determination, and birth weight. One year after menarche, polycystic ovarian morphology was detected in 7.6 and 7.3% of the HD and the normal DHEAS group, respectively. Ovarian volume was correlated with AMH, testosterone, androstenedione, and LH but not with DHEAS around 7 years. Conclusion: Prepubertal HD in normal girls was associated with earlier thelarche, pubarche, and menarche, and a mild androgen increase throughout puberty. We believe continuous follow-up of this cohort is important to prospectively address the interrelationships between biochemical adrenarche and early growth as determinants of ovarian function.

Author(s): Smith, Meghan B; Ho, Jacqueline; Ma, Lihong; Lee, Miryoung; Czerwinski, Stefan A; Glenn, Tanya L; Cool, David R; Gagneux, Pascal; Stanczyk, Frank Z; McGinnis, Lynda K; Lindheim, Steven R | Abstract: ObjectiveTo examine the changes in AMH levels longitudinally over time and their relationship with both body composition, particularly abdominal adiposity, and milestones of pubertal development in female children.DesignSecondary analysis of a prospective, longitudinal study.SettingUniversity affiliated research center and laboratories.PatientsEighty-nine females were examined between 1990 and 2015 to study child growth and development.InterventionsDemographic, anthropometric, growth, and pubertal milestone data with serum samples stored and subsequently analyzed for AMH.Main outcome measuresLongitudinal change in AMH and predicted AMH levels based on body composition, age, and pubertal milestones including, pubarche, thelarche, and menarche.ResultsNatural log-transformed AMH (AMHlog) levels appeared to have a nonlinear relationship with age, decreasing between 10 and 14 years of age, increasing until 16 years. A mixed effect linear model demonstrated that increased abdominal adiposity (waist/height ratio, WHtR) was significantly associated with the predicted increased AMHlog levels (β=1.37). As females progressed through the Tanner stages, the model predicted decreasing AMHlog values when adjusting for age and WHtR.ConclusionsDeclining AMH levels during puberty may not be reflective of diminished ovarian reserve as observed in adults, but may suggest a permissive role of AMH in the activation of the hypothalamic-pituitary-ovarian axis.

Most of the problems of the female reproductive system in fertile age are a direct consequence of those pathologies that have arisen in puberty age, in the period of the establishment of its functions. Therefore, the formation of the normal physical and sexual development of adolescent girls depends on the formation of reproductive capacity, the improvement of the demographic situation and the health of future generations. The aim of the study — detection of the relationship between the features of sexual development in healthy and girls with primary dysmenorrhea of puberty age. The results of researches of 306 girls of puberty age of different somatotypes are analyzed, defined by the Hit-Carter method. Statistical processing of the results obtained was carried out in a licensed package “Statistica 6.1”. The study group included 76 girls with primary dysmenorrhea, and the control group consisted of 230 healthy girls (data were taken from the database of the SRC National Pirogov Memorial Medical University, Vinnytsya). We investigated the peculiarities of the development of the reproductive system of girls of pubertal age with primary dysmenorrhea of different somatotypes. The results of our research show that there is a connection between the age-depending dynamics of sexual development: the thelarche, axillary hair growth, the formation of menstrual function in girls of pubertal age who suffer from primary dysmenorrhea in comparison with healthy girls. The results of our study should be taken for the diagnosing of primary dysmenorrhea of girls of pubertal age in order to reduce clinical manifestations and further development of complications in reproductive age.

Background : Adiposity may play a role as a potential trigger for adrenarche. The purpose of this study was to evaluate the association between body mass index (BMI) and serum dehydroepiandrosterone sulfate (DHEAS) level. Methods : The medical records of 8-year-old girls who presented to our clinic between 2014 and 2016 with concerns regarding pubertal changes were retrospectively reviewed. The 192 girls were divided into two groups depending on activation of the hypothalamic-pituitary-gonadal (HPG) axis. Group I included 77 subjects with a breast Tanner stage 1 with unknown HPG axis or thelarche without activated HPG axis. Group II included 115 subjects with activated HPG axis. Serum DHEAS level ≥1.1 μmol/L was regarded as biochemical adrenarche. Results : Based on correlation analyses, BMI standard deviation score (SDS) was positively correlated with height SDS, bone age divided by chronological age (BA/CA), and DHEAS level in all subjects (r=0.269, r=0.270, r=0.298; all P

Purpose This study aimed to investigate associations of central obesity with sexual maturation and metabolic parameters in Korean girls with precocious puberty. Methods This retrospective study evaluated data from 72 girls under 8 years of age with a chief complaint of early breast development. The patients were categorized as central precocious puberty (CPP) subjects or non-CPP subjects based on their gonadotropin-releasing hormone stimulation test results. Visceral fat thickness (VFT) was measured using ultrasonography and defined as the distance from the linea alba to the aorta. Patient anthropometric, metabolic, and hormonal parameters were also evaluated. Results Increased VFT was correlated with an earlier onset of thelarche among all study subjects (r=-0.307, P=0.034). Overweight CPP subjects showed higher insulin resistance than normal weight CPP subjects. Insulin resistance was not significantly different between overweight and normal weight non-CPP subjects. VFT was not significantly different between CPP and non-CPP subjects (2.22±0.79 cm vs. 2.74±1.47 cm, P=0.169). However, overweight and obese CPP subjects (body mass index percentile>85%) had lower VFT than non-CPP obese subjects. Conclusion Central obesity, defined using ultrasonography-measured VFT, might be associated with early pubertal development in Korean girls. However, VFT was not higher in CPP than non-CPP patients and was not significantly correlated with insulin resistance. Further longitudinal studies with a larger cohort are needed.

Pediatric gynecologists of all types of disorders of sexual development most often diagnose an incomplete form of premature puberty in girls of the isosexual type – isolated thelarche against the background of an elevated prolactin levels. Aim of the research: to study the effect of the drug Cyclodynon® on girls with an isolated thelarche on the background of increased prolactin levels. Materials and methods. Study include 30 girls aged from 1 to 5 years with isolated premature thelarche. Ultrasound and hormonal studies were conducted. All patients were examined by the endocrinologist, neurologist and pediatrician. Girls with isolated thelarche and a high prolactin level were prescribed the drug Cyclodynon® depending on the age and prolactin level at a dose of 1/8 to 1 tablet (or 5 to 40 drops) in the morning on an empty stomach once a day. Results. Study included 30 girls with isolated thelarche revealed a stable increase in the prolactin level (up to 680 mIU/l while normal values is 110–400 mIU/l) with relatively normal gonadotropins and estradiol levels. The use of a special extract of Vitex Agnus Castus Cyclodуnon® contributed to a gradual over 3 months reducing the prolactin level to normal from 680 to 396 mIU/l. Decrease in prolactin level correlated with regression of clinical signs of thelarche. Adverse or desirable effects when Cyclodynon® use for 3 months were noted. Conclusion. Increased prolactin level played significant role in children during the first five years of life in the isolated thelarche genesis. The use of standardized herbal drug Cyclodynon® with dopaminergic effect led to normalization of the prolactin level in treatment girls with isolated thelarche on the background of elevated prolactin levels and is an effective and pathogenetically justified. This is confirmed by the results of clinical and hormonal studies.

Purpose: Early age at breast development (thelarche) has been associated with increased breast cancer risk. Average age at thelarche has declined over time, but there are few established risk factors for early thelarche. We examined associations between pre- and postnatal exposures and age at thelarche in a U.S. cohort of women born between 1928 and 1974. Methods: Breast cancer-free women ages 35–74 years who had a sister diagnosed with breast cancer were enrolled in the Sister Study from 2003–2009 (N = 50,884). At enrollment, participants reported their age at thelarche, which we categorized as early (≤10 years), average (11–13 years), and late (≥14 years), as well as information on early-life exposures. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for early and late thelarche relative to average age at thelarche using polytomous logistic regression for each early-life exposure, adjusted for birth cohort, race/ethnicity and family income level in childhood. We examined modification by birth cohort, race/ethnicity, family income, relative weight at age 10, and extent of breast cancer family history through stratification. Results: Early thelarche was more common in recent birth cohorts and among non-Hispanic Black and Hispanic women. Early thelarche (≤10 years) was associated with multiple prenatal exposures: gestational hypertensive disorder (OR = 1.25, 95% CI, 1.09–1.43), maternal diethylstilbestrol (DES) use (OR = 1.23, 95% CI, 1.04–1.45), maternal smoking during pregnancy (OR = 1.20, 95% CI, 1.13–1.27), and young maternal age (OR 1.30, 95% CI, 1.16–1.47 for

Background Over 95% of girls with Turner syndrome (TS) who lack all or part of the X chromosome will experience premature ovarian insufficiency and will require estrogen replacement therapy to initiate and maintain puberty. However, the optimal protocol that mimics physiologic puberty while preserving growth potential is not yet known. Current recommendations to start with low dose estrogen increased incrementally over two to three years will typically result in thelarche within six months and menarche after an average of two years. Here we present three patients with TS who experienced rapid progression of puberty, with menarche occurring shortly after initiating the lowest dose of transdermal estrogen. Our institutional review board deemed this retrospective case series exempt from the need for IRB approval. Case Three 12-year-old females with mosaic TS (Table 1) presented for pubertal induction. On exam, the patients had tanner stage I breasts and pubic hair. Labs were consistent with ovarian insufficiency with elevated levels of follicle stimulating hormone (FSH) and undetectable levels of estradiol. They were each started on estradiol 14 ucg transdermal patch weekly for pubertal induction and experienced menarche within five months. Breast and pubic hair progressed to tanner stage II and III. Cases 1 and 2 subsequently had regular monthly menses with moderate flow. The dose of their transdermal estradiol patch was decreased by half to 7 ucg weekly. Case 3 developed heavy, irregular bleeding, which caused her to stop using the transdermal estrogen patch. Four months later, she reinstated estrogen use with half of her prior dose at 7 ucg weekly. At one year follow up, all three cases continued with the ultra low dose estradiol 7 ucg transdermal patch weekly without further episodes of vaginal bleeding. On imaging bone age was within normal limits. Comments These cases highlight the importance of starting estrogen replacement therapy at the lowest available dose in girls with Turner syndrome. Given the possible advancement of bone age with pubertal levels of estrogen, rapid progression to menarche could further impair the final growth potential in these patients who are already susceptible to short stature. Thus girls with TS should be monitored closely when initiating estrogen therapy and should be re-evaluated if they experience vaginal bleeding with low dose therapy.

Increasing evidence indicates that early onset endometriosis (EOE), starting around menarche or early adolescence, may have an origin different from the adult variant, originating from neonatal uterine bleeding (NUB). This implies seeding of naïve endometrial progenitor cells into the pelvic cavity with NUB; these can then activate around thelarche. It has its own pathophysiology, symptomatology and risk factors, warranting critical management re-evaluation. It can also be progressive, endangering future reproductive capacity. This variant seems to be characterized by the presence of ovarian endometrioma. Today, the diagnosis of endometriosis in young patients is often delayed for years; if rapidly progressive, it can severely affect pelvic organs, even in the absence of serious symptoms. Given the predicament, great attention must be paid to symptomatology that is often non-specific, justifying a search for new, simple, non-invasive markers of increased risk. Better use of modern imaging techniques will aid considerably in screening for the presence of EOE. Traditional laparoscopy should be limited to cases in which imaging gives rise to suspicion of severity and a stepwise, minimally invasive approach should be used, followed by medical treatment to prevent recurrence. In conclusion, EOE represents a condition necessitating early diagnosis and stepwise management, including medical treatment.

Objective To evaluate the clinical features of Chinese women with idiopathic hypogonadotropic hypogonadism (IHH). Methods We retrospectively reviewed the clinical characteristics, laboratory and imaging findings, therapeutic management and fertility outcomes of 138 women with IHH. All patients had been treated and followed up at an academic medical centre during 1990–2016. Results Among the 138 patients, 82 patients (59.4%) were diagnosed with normosmic IHH and 56 patients (40.6%) were diagnosed with Kallmann syndrome (KS). The patients with IHH experienced occasional menses (4.3%), spontaneous thelarche (45.7%) or spontaneous pubarche (50.7%). Women with thelarche had a higher percentage of pubarche (P < 0.001) and higher gonadotropin concentrations (P < 0.01). Olfactory bulb/sulci abnormalities were found during the magnetic resonance imaging (MRI) of all patients with KS. Most patients with IHH had osteopenia and low bone age. Among the 16 women who received gonadotropin-releasing hormone treatment, ovulation induction or assisted reproductive technology, the clinical pregnancy rate was 81.3% and the live birth rate was 68.8%. Conclusions The present study revealed that the phenotypic spectrum of women with IHH is broader than typical primary amenorrhoea with no secondary sexual development, including occasional menses, spontaneous thelarche or pubarche. MRI of the olfactory system can facilitate the diagnosis of KS. Pregnancy can be achieved after receiving appropriate treatment.

Timing of breast development (or thelarche) and its endogenous and exogenous determinants may underlie global variation in breast cancer incidence. The study objectives were to characterize endogenous estrogen levels and bisphenol A (BPA) exposure using a migrant study of adolescent girls and test whether concentrations explained differences in thelarche by birthplace and growth environment. Estrogen metabolites (EM) and BPA-glucuronide (BPA-G) were quantified in urine spot samples using liquid chromatography tandem mass spectrometry (LC-MS/MS) from a cross-sectional study of Bangladeshi, first- and second-generation Bangladeshi migrants to the UK, and white British girls aged 5&ndash, 16 years (n = 348). Thelarche status at the time of interview was self-reported and defined equivalent to Tanner Stage &ge, 2. We compared geometric means (and 95% confidence interval (CIs)) of EM and BPA-G using linear regression and assessed whether EM and BPA-G explained any of the association between exposure to the UK and the age at thelarche using hazard ratios and 95% confidence intervals. Average EM decreased with exposure to the UK, whereas BPA-G increased and was significantly higher among white British (0.007 ng/mL, 95% CI: 0.0024&ndash, 0.0217) and second-generation British-Bangladeshi girls (0.009 ng/mL, 95% CI: 0.0040&ndash, 0.0187) compared to Bangladeshi girls (0.002 ng/mL, 95% CI: 0.0018&ndash, 0.0034). Two of four EM ratios (16-pathway/parent and parent/all pathways) were significantly associated with thelarche. The relationship between exposure to the UK and thelarche did not change appreciably after adding EM and BPA-G to the models. While BPA-G is often considered a ubiquitous exposure, our findings suggest it can vary based on birthplace and growth environment, with increasing levels for girls who were born in or moved to the UK. Our study did not provide statistically significant evidence that BPA-G or EM concentrations explained earlier thelarche among girls who were born or raised in the UK.

Importance The initial clinical sign of pubertal onset in girls is breast gland development (thelarche). Although numerous studies have used recalled age at menarche (first menstruation) to assess secular trends of pubertal timing, no systematic review has been conducted of secular trends of thelarche. Objectives To systematically evaluate published data on pubertal timing based on age at thelarche and evaluate the change in pubertal onset in healthy girls around the world. Data Sources A systematic literature search was performed in PubMed and Embase of all original peer-reviewed articles published in English before June 20, 2019. Study Selection Included studies used clinical assessment of breast development in healthy girls and used adequate statistical methods, including the reporting of SEs or CIs. The quality of the articles was evaluated by assessing study design, potential sources of bias, main characteristics of the study population, and methods of statistical analysis. Data Extraction and Synthesis In accordance with PRISMA guidelines, all articles were assessed for eligibility independently by 2 authors. Weighted regression analysis was performed using a random-effects model. Main Outcomes and Measures Studies examining age at thelarche (development of Tanner breast stage 2) in healthy girls. Results The literature search resulted in a total of 3602 studies, of which 30 studies fulfilled the eligibility criteria. There was a secular trend in ages at thelarche according to race/ethnicity and geography. Overall, the age at thelarche decreased 0.24 years (95% CI, −0.44 to −0.04) (almost 3 months) per decade from 1977 to 2013 (P = .02). Conclusions and Relevance The age at thelarche has decreased a mean of almost 3 months per decade from 1977 to 2013. A younger age at pubertal onset may change current diagnostic decision-making. The medical community needs current and relevant data to redefine “precocious puberty,” because the traditional definition may be outdated, at least in some regions of the world.

Objective Pubertal timing is highly heritable. Observational studies were inconclusive concerning a potential sex-specific difference in the parental contribution, while genome-wide association studies highlighted a heterogeneity in the genetic architecture of pubertal timing between sexes. Our objectives were to evaluate the association of timing of pubertal milestones in offspring with parental pubertal timing and to identify the genetic basis of the heterogeneity. Design (1.) Population-based mixed cross-sectional/longitudinal cohort (2006–2014, COPENHAGEN Puberty Study) comprising 1381 healthy Danish children including their parents. (2.) UK Biobank-based summary statistics of genetic data on timing of menarche (n = 188 644), voice-break (n = 154 459) and facial hair (n = 161 470). Methods (1.) Participants underwent clinical examination(s) including blood sampling. Parental pubertal timing was obtained by questionnaire. Timing of milestones were analyzed using SAS-lifereg. (2.) Genetic correlations between pubertal outcomes were estimated using LD Score regression. Genetic heterogeneity was analyzed using METAL. Results We observed significant associations of relative parental pubertal timing with timing of pubertal milestones in offspring of concordant sex, that is, fathers/sons (e.g. testicular enlargement: P = 0.004, β = 0.34 years per relative category) and mothers/daughters (e.g. thelarche: P P −4). Conclusion Our results highlight a distinct genetic heterogeneity of pubertal timing between sexes.

The term thelarche refers to the onset of normal pubertal phase of breast development in females.

Context Application of ultrasound (US) to evaluate attainment and morphology of glandular tissue provides a new rationale for evaluating onset and progression of female puberty, but currently no hormone references complement this method. Furthermore, previous studies have not explored the predictive value of endocrine profiling to determine female puberty onset. Objective To integrate US breast staging with hypothalamic-pituitary-gonadal hormone references and test the predictive value of an endocrine profile to determine thelarche. Design Setting and Participants Cross-sectional sample of 601 healthy Norwegian girls, ages 6 to 16 years. Main Outcome Measures Clinical and ultrasound breast evaluations were performed for all included girls. Blood samples were analyzed by immunoassay and ultrasensitive liquid chromatography–tandem mass spectrometry (LC-MS/MS) to quantify estradiol (E2) and estrone (E1) from the subpicomolar range. Results References for E2, E1, luteinizing hormone, follicle-stimulating hormone, and sex hormone–binding globulin were constructed in relation to chronological age, Tanner stages, and US breast stages. An endocrine profile index score derived from principal component analysis of these analytes was a better marker of puberty onset than age or any individual hormone, with receiver-operating characteristic area under the curve 0.91 (P Conclusions We provide the first hormone references for use with US breast staging and demonstrate the application of endocrine profiling to improve detection of female puberty onset.

Context Discriminating adipose and glandular tissue is challenging when clinically assessing breast development. Ultrasound facilitates staging of pubertal breast maturation (US B), but has not been systematically compared to Tanner breast (Tanner B) staging, and no normative data have been reported. Objective To present normative references for US B along with references for Tanner B, pubic hair (PH), and menarche. Design, Setting, and Participants A cross-sectional sample of 703 healthy girls aged 6 to 16 years were examined. Main Outcome Measures Breast development was determined with US B and Tanner B staging. Tanner PH and menarcheal status were recorded. The age distributions of entry in US B, Tanner B, and PH stages and menarche were estimated with generalized linear and generalized additive models with a probit link. Method agreement was tested with weighted Cohen’s kappa. Results The median (±2SD) ages for thelarche, US B2 and Tanner B2, were 10.2 (7.7, 12.8) and 10.4 (8.0, 12.7) years. The median (±2SD) ages at Tanner PH2 and menarche were 10.9 (8.5, 13.3) and 12.7 (11.0, 16.2) years. Cohen’s kappa of agreement (95% confidence interval) between US B and Tanner B was 0.87 (0.85–0.88). When the methods disagreed, US B was usually more advanced. Conclusion Thelarche occurred at a slightly younger age when assessed with ultrasound compared to clinical Tanner staging, although the 2 methods had a very good agreement when determining pubertal breast maturation. A significant decrease of 2.8 months in age at menarche was observed during the past decade in Norwegian girls.