Minipuberty Of Infancy Research Articles

12212 A Rare Case Of Central Precocious Puberty In A Male Infant With Adrenal Hypoplasia Congenita

Abstract Disclosure: A. Mastoropoulou: None. A.H. Lane: None. Introduction: We describe a male with Adrenal Hypoplasia Congenita (AHC) caused by a novel mutation in NR0B1, who was noted at 9 months of age to have central precocious puberty (CPP). Clinical case: A 3 week-old full-term male presented with hypothermia and lethargy, and a 0.3 kg weight loss since birth. Labs were consistent with adrenal crisis: Na 109 mmol/L, K 10.4 mmol/L, Ca 12.2 mg/dL, glucose 43 mg/dL. He was stabilized with stress dose hydrocortisone (HC), insulin and antibiotics, and was admitted. Subsequent labs revealed cortisol 3.5 ug/dL (4.6-23), ACTH 1,123 pg/mL (7.2-63), 17OHP 181 ng/dL (<199), and a renin of 180 ng/mL/h (1.7-11.2) with aldosterone 14.9 ng/dL (6-179). Abdominal ultrasound was remarkable for non-visualization of the adrenal glands. The patient was discharged with HC, fludrocortisone and sodium supplementation with good tolerance and interval weight gain and normal electrolytes. Genetic testing identified a novel pathogenic c.707G>A [p.Trp236Ter] nonsense variant in the DNA-binding domain of NR0B1 (DAX-1). At 9 months of age, penile enlargement with prepubertal testes was noted. Testosterone was 318 ng/dL (Tanner stage I: 0-18), LH 3.2 mIU/mL (prepubertal: 0-0.3), DHEA-S 2 ug/dL (0-33), FSH 1.1 mIU/mL (prepubertal: 0-1), consistent with hypothalamic pituitary gonadal (HPG) axis activation. Given previous reports of prolonged but self-resolving “mini-puberty of infancy” in AHC, observation was initially chosen. At 12 months of age the bone age was consistent with the Greulich and Pyle 17 months standard. At 13 months of age testosterone remained elevated, therefore based on others’ reported experiences we increased HC from 8 to 15 mg/m2/day and noted a decrease in testosterone to 104 ng/dL within 5 days. HC was further increased to 18 mg/m2/day for 15 days, however testosterone increased to 270 ng/dL, therefore decision was made to treat with Lupron Depot. Conclusions: Historically, hypogonadotropic hypogonadism has been observed in 76% of adolescent patients with AHC who have alterations in NR0B1. CPP has been infrequently described in AHC, and the natural history and management of CPP in this setting is not established. CPP in AHC does not seem to correlate with any particular functional domain of DAX1, because previously reported NR0B1 variants associated with CPP, and this case’s, are dispersed across the gene. The course of our patient suggests multiple underlying mechanisms, including early HPG axis activation as well as the possibility of ACTH dependent precocious puberty. Our observations may contribute to the understanding of factors influencing normal and abnormal puberty in infants. Increased awareness of the possibility of CPP in AHC will aid clinicians in the earlier clinical and laboratory detection of this complication. Presentation: 6/1/2024

Anti-Mullerian hormone and spontaneous puberty in a diverse US Turner syndrome clinic cohort: A cross-sectional study.

Serum Anti-Mullerian Hormone (AMH) concentrations have been proposed as a marker of spontaneous puberty and future fertility in Turner syndrome (TS). Gonadotropins during minipuberty may also provide a clue to ovarian function but there is insufficient data to inform utility in the routine clinical management of TS. Our objective was to describe the distribution of AMH in a cross-sectional cohort of patients in a TS specialty clinic, and correlate with spontaneous puberty and karyotype, as well as gonadotropins during the minipuberty of infancy in a smaller subset of patients aged 2-9 months. Retrospective chart review of patients seen in the TS clinic at Children's National Hospital from 1/1/2019 to 8/24/2022, to assess AMH and correlate with karyotype and spontaneous puberty. Among 114 patients (median age 9.6 year, 0.08-22 year), AMH values were detectable in only (40/104) 38%, and higher mean AMH (2.7 ± 0.95 ng/mL) was seen in mosaic 45,X/46,XX karyotype compared to 45,X (0.03 ± 0.14 ng/mL) (p < .001), and structurally abnormal-X karyotype (0.11 ± 0.5) (p = .0003). Mean AMH was higher (1.4 ± 1.6 ng/mL) among those with spontaneous menarche compared with spontaneous thelarche but no menarche. AMH was detectable in 2/10 during minipuberty in those with the lowest luteinizing hormone (LH). Our institutional data reflects a diverse cohort of patients seen in a TS specialty clinic in the United States, showing correlation of AMH with karyotype and spontaneous menarche, as well as description of gonadotropins during minipuberty highlighting their clinical relevance. Studies in larger, prospective longitudinal cohorts will help determine their predictive value and role in the care of TS.

Deciphering the Roles & Regulation of Estradiol Signaling during Female Mini-Puberty: Insights from Mouse Models.

Mini-puberty of infancy is a short developmental phase occurring in humans and other mammals after birth. In females, it corresponds to transient and robust activation of the hypothalamo-pituitary-ovarian (HPO) axis revealed by high levels of gonadotropin hormones, follicular growth, and increased estradiol production by the ovary. The roles of estradiol signaling during this intriguing developmental phase are not yet well known, but accumulating data support the idea that it aids in the implementation of reproductive function. This review aims to provide in-depth information on HPO activity during this particular developmental phase in several mammal species, including humans, and to propose emerging hypotheses on the putative effect of estradiol signaling on the development and function of organs involved in female reproduction.

Characterization of ovarian development in girls from birth to 9months.

The minipuberty of infancy is a period of increased reproductive axis activity. Changes in reproductive hormone concentrations and organ size occur during this period, but longitudinal changes have not been well described. The objective of this study was to characterize ovarian growth trajectories and ovarian follicle development during the first 9months of life in a large longitudinal cohort of healthy girls. Data from the Infant Feeding and Early Development Study, a longitudinal cohort study of oestrogen-responsive outcomes in healthy infants, were used to estimate ovarian growth trajectories and describe the presence of ovarian antral follicles in girls 0-9months old. Ovarian ultrasound evaluations were performed on the infants within 72hours of birth (newborn visit) and at 4, 8, 16, 24, and 32weeks of age. Mixed-effects regression splines were used to characterize changes in ovarian volume during infancy and assess the association between the presence of ovarian follicles at the newborn visit and ovarian growth. This analysis included 163 girls with two or more ovarian ultrasounds in the study. Results from the estimated overall ovarian growth trajectory show that ovarian volume increases more than sixfold during the first 16weeks after birth and then remains relatively stable in the later weeks of infancy. Among girls with observable ovaries at the newborn visit (n=133), girls with at least one visible ovarian follicle showed more rapid initial ovarian growth compared with girls without visible follicles. Infant ovarian volume increased to a peak at 16weeks, which was influenced by the number and size of developing follicles. This research contributes to future development of reference ranges for postnatal ovarian growth in healthy, term infants.

Treatment of gonadotropin deficiency during the first year of life: long-term observation and outcome in five boys.

STUDY QUESTIONWhat is the peripubertal outcome of recombinant human FSH (r-hFSH) treatment during minipuberty in boys with congenital hypogonadotropic hypogonadism (CHH)?SUMMARY ANSWERSertoli-cell response to r-hFSH, given during the minipuberty of infancy, appears insufficient to maintain Sertoli cell function throughout childhood, as evaluated by inhibin B measurements.WHAT IS KNOWN ALREADYSevere CHH in boys can be diagnosed during the minipuberty of infancy. Combined gonadotropin treatment at that age is suggested to improve testicular endocrine function and future fertility, yet long-term evidence is lacking.STUDY DESIGN, SIZE, DURATIONIn this retrospective cohort study, we describe five CHH boys treated with r-hFSH in Helsinki University Hospital or Kuopio University Hospital between 2004 and 2018. Immediate follow-up data (0.1–1.4 months after cessation of the gonadotropin therapy) was available for four boys and long-term observations (at the age of 10.0–12.8 years) was available for three boys. As a retrospective control cohort, we provide inhibin B values of eight untreated CHH boys at the age of 12.7–17.8 years.PARTICIPANTS/MATERIALS, SETTING, METHODSFour patients had combined pituitary hormone deficiency, and one had CHARGE syndrome due to a CHD7 mutation. The patients were treated at the age of 0.7–4.2 months with r-hFSH (3.4 IU/kg–7.5 IU/kg per week in 2 or 3 s.c. doses for 3–4.5 months) combined with T (25 mg i.m. monthly for three months for the treatment of micropenis). Inhibin B was chosen as the primary outcome measure.MAIN RESULTS AND THE ROLE OF CHANCEDuring the r-hFSH + T treatment, inhibin B increased from 76 ± 18 ng/l to 176 ± 80 ng/l (P = 0.04) and penile length increased by 81 ± 50% (P = 0.04). Unexpectedly, two boys with robust inhibin B responses in infancy demonstrated low inhibin B values in peripuberty: declining from 290 ng/l (4 months) to 16 ng/l (12.4 years), and from 207 ng/l (6 months) to 21 ng/l (12.8 years). All boys underwent orchiopexy at 2.0 ± 0.7 years of age. Inhibin B values in long-term follow-up, available for the three boys, did not significantly differ from the untreated CHH controls.LIMITATIONS, REASONS FOR CAUTIONLimitations of this retrospective study are the small number and heterogeneity of the patients and their treatment schemes.WIDER IMPLICATIONS OF THE FINDINGSWe describe the first long-term follow-up data on CHH boys treated with r-hFSH and T as infants. The results from this small patient series suggest that the effects of infant r-hFSH treatment may be transient, and further longitudinal studies are required to determine the efficacy of this treatment approach to optimise the fertility potential in this patient population.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by the Finnish foundation for Pediatric Research, the Academy of Finland and the Emil Aaltonen Foundation. The authors have no competing interests.TRIAL REGISTRATION NUMBERNon-applicable.

MON-246 Long-Term Impact of Recombinant Follicle Stimulating Hormone Treatment in Five Infants with Hypogonadotropic Hypogonadism

Background Severe congenital hypogonadotropic hypogonadism (CHH) in boys can be diagnosed during the minipuberty of infancy. Combined gonadotrophin treatment at that age is suggested to improve testicular function, yet long-term evidence is lacking. We describe the first long-term follow-up data on CHH boys treated with recombinant human follicle stimulating hormone [r-hFSH] as infants. Patients and Methods This is a retrospective patient chart review of five boys from two pediatric tertiary centers in Finland (2004-2016). Four patients had panhypopituitarism of yet unknown etiology, one had CHARGE syndrome due to a CHD7 mutation. The patients were treated at the age of 0.7 to 4.2 months with r-hFSH (from 16.6 IU to 33.4 IU s.c. per week for 3 to 4.3 months) combined with testosterone [T] (25 mg i.m. monthly for three months). Inhibin B levels and testicular development were followed for 1.9 to 12.2 years after the treatment. Results During the r-hFSH + T treatment, inhibin B increased from 76 ± 18 ng/L to 176 ± 80 ng/L (p = 0.04) and penile length increased by 81 ± 50% (p = 0.04). All boys underwent orchidopexy at 2.0 ± 0.7 years of age; one boy had testicular regression. Unexpectedly, two boys with robust inhibin B responses in infancy demonstrated low inhibin B values in peripuberty: from 290 ng/L (4 months) to 16 ng/L (12.4 years), and from 207 ng/L (6 months) to 21 ng/L (12.8 years). Conclusions This is the first report of the long-term effects of r-hFSH-treatment given during minipuberty. The data suggest that Sertoli-cell response to r-hFSH is transient and that testosterone, given concomitantly with r-hFSH at infancy, does not inhibit Sertoli cell activity. Our observations require confirmation from larger longitudinal patient series.

Postnatal Changes in Testicular Position Are Associated With IGF-I and Function of Sertoli and Leydig Cells.

Despite clinical guidelines calling for repetitive examination of testicular position during childhood, little is known of normal changes in testicular position during childhood, let alone factors that control it. To assess changes in and factors associated with testicular position during childhood. Testicular position (the distance from the pubic bone to the upper pole of the testes) at birth, 3 months, 18 months, 36 months, and 7 years and reproductive hormones at 3 months were measured. Prenatally recruited, prospective longitudinal birth cohort. A total of 2545 boys were recruited prenatally in a Danish-Finnish birth cohort and had a testicular position examination available. A subset of 680 Danish and 362 Finnish boys had serum reproductive hormone concentrations and insulin-like growth factor I (IGF-I) determined at 3 months. Testicular distance to pubic bone (TDP), serum reproductive hormone, and IGF-I concentrations. TDP increased from birth to 3 months and decreased thereafter. Length, gestational age, weight for gestational age, and penile length were positively associated with larger TDP and thus lower testicular position in a linear mixed-effect model. Furthermore, IGF-I concentration, inhibin B/follicle-stimulating hormone ratio, and testosterone/luteinizing hormone ratio were all independently and positively associated with longer TDP. We provide longitudinal data on postnatal changes in TDP. TDP is dynamic and associated with Leydig and Sertoli cell function as well as with IGF-I levels during the first months of life at mini-puberty of infancy. TDP may thus be a useful biomarker of postnatal testicular function.

Mini-Puberty of Infancy in Extreme Prematurity

Mini-Puberty of Infancy in Extreme Prematurity

Salivary Testosterone during the Minipuberty of Infancy

Background: The hypothalamic-pituitary-gonadal axis is transiently activated during the postnatal months in boys, a phenomenon termed “minipuberty” of infancy, when serum testosterone (T) increases to pubertal levels. Despite high circulating T there are no signs of virilization. We hypothesize that free T as measured in saliva is low, which would explain the absence of virilization. Methods: We measured serum total T and free T in saliva using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 30 infant boys, aged 1–6 months, and in 12 adolescents, aged 11–17 years. Results: Total serum T in all infants was, as expected, high (172 ± 78 ng/dL) while salivary T was low (7.7 ± 4 pg/mL or 0.45 ± 0.20%). In contrast, salivary T in the adolescents was much higher (41 ± 18 pg/mL or 1.3 ± 0.36%) in relation to their total serum T (323 ± 117 ng/dL). We provide for the first time reference data for salivary T in infants. Conclusion: Measurement of salivary T by LC-MS/MS is a promising noninvasive technique to reflect free T in infants. The low free T explains the absence of virilization. The minipuberty of infancy is more likely of intragonadal than peripheral significance.

Childhood growth of females with Kallmann syndrome and FGFR1 mutations.

In search of phenotypic cues that would allow early detection of Kallmann syndrome (KS), we evaluated the paediatric phenotypes in a series of females with KS. In this retrospective cohort study, we investigated childhood growth in six females with KS due to mutations in FGFR1 and evaluated their reproductive phenotypes later in life. While growth during early infancy and childhood was within normal limits, a decreasing trend in height SDS already from mid-childhood occurred in most patients. The lowest height SDS (mean, -1·2 SDS) occurred between 14 and 15 years of age, before the start of hormone replacement therapy. As adults, these women required assisted reproductive techniques for fertility. One of the probands passed on her G48S mutation to her son, who showed normal reproductive hormone levels during the minipuberty of infancy. Early diagnosis of female KS remains a challenge as early phenotypic signs, apart from anosmia, are scarce. Females with KS exhibit a slight reduction in growth rate during mid-childhood, but normal growth rate during the minipuberty of infancy, despite congenital lack of ovarian oestrogen. Women harbouring FGFR1 mutations will have 50% chance of passing on the gene defect to their offspring. We recommend genetic counselling to all females with KS to be carried out as a part of family planning.

Endocrinology of male puberty

To review recent information leading to a better understanding of the endocrinology of male puberty, including information from earlier stages of life. Differences in relative levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the neonatal period have been further described, as well as changes in inhibin B and anti-Müllerian hormone levels. Studies among men with congenital hypogonadotropic hypogonadism suggest a role for the 'minipuberty of infancy' in inhibin B levels. Gonadotropin-releasing hormone analog-stimulated LH levels at the age of puberty may be useful in diagnosing hypogonadotropic hypogonadism. Inhibin B levels are likewise useful in monitoring spermatogenic activity. Data from fetal life (men born small for gestational age with evidence of a defect in steroidogenesis, relatively high LH:FSH ratio among very premature boys), neonatal period (attenuated rise of inhibin B after rFSH stimulation among men with congenital hypogonadotropic hypogonadism), and puberty (often demonstrable by LH levels alone, progressive rise of insulin-like factor 3 levels, and decrease of anti-Müllerian hormone levels as a consequence of FSH and LH stimulation), all enhance the understanding of the physiology of puberty.