Normal Pubertal Development Research Articles

Diagnosis and management of pituitary adenomas in children and adolescents.

Pituitary adenomas (PAs)-also now called pituitary neuroendocrine tumours or Pit-NETS-are rare in children and adolescents and exceptional below the age of 10. Most evidence-based high-quality data are derived from larger studies in adult patients. We will review recent knowledge on the epidemiology, clinical features, diagnosis, and treatment modalities of the different types of pituitary adenomas diagnosed in children and adolescents, emphasizing the many reasons why these cases should be discussed within pituitary-specific multidisciplinary teams with experts from both paediatric and adult practice. Paediatric PA presents multiple peculiarities that may challenge their adequate management. They are overall proportionally larger and more aggressive than in adults, with potential mass effects including hypopituitarism. Hormonal hypersecretion is frequent, resulting in clinical syndromes affecting normal growth and pubertal development. Prolactinomas represent the most frequent subtype of PA found during childhood, followed by adrenocorticotropin (ACTH) and growth hormone (GH)-secreting adenomas, while clinically non-functioning adenomas are exceptionally diagnosed before the age of 16. The occurrence of a pituitary tumour in a young individual should also prompt genetic testing in each case, searching for either germline mutations in one of the known genes that may drive inherited/familial PA (such as the multiple endocrine neoplasia type 1 or MEN1 gene, or the aryl hydrocarbon receptor interacting protein or AIP gene), or for a mosaic activating mutation of GNAS as found in the McCune-Albright syndrome.

Genetic and non-genetic factors in prediction of early pubertal development in Chinese girls.

The objective of this study is to develop a combined predictive model for early pubertal development (EPD) in girls based on both non-genetic and genetic factors. The case-control study encompassed 147 girls diagnosed with EPD and 256 girls who exhibited normal pubertal development. The non-genetic risk score (NGRS) was calculated based on 6 independent biochemical predictors screened by multivariate logistic regressions, and the genetic risk score (GRS) was constructed using 28 EPD related single-nucleotide polymorphisms (SNPs). Area under receiver operator characteristic curve (AROC), net reclassification optimization index (NRI) and integration differentiation index (IDI) were used to evaluate the improvement of adding genetic variants to the non-genetic risk model. Overweight (OR=2.74), longer electronic screen time (OR=1.79) and higher ratio of plastic bottled water (OR=1.01) were potential risk factors, and longer exercise time (OR=0.51) and longer day sleeping time (OR=0.97) were protective factors for EPD, and the AROC of NGRS model was 83.6% (79.3-87.9%). The GRS showed a significant association with EPD (OR=1.90), and the AROC of GRS model was 65.3% (59.7-70.8%). After adding GRS to the NGRS model, the AROC significantly increased to 85.7% (81.7-89.6%) (P=0.020), and the reclassification significantly improved, with NRI of 8.19% (P= 0.023) and IDI of 4.22% (P <0.001). We established a combined prediction model of EPD in girls. Adding genetic variants to the non-genetic risk model brought modest improvement. However, the non-genetic factors such as overweight and living habits have higher predictive utility.

Pubertal Delay Secondary to Hashimoto's Disease in the Hypothyroid Phase: About a Case in the Internal Medicine Department of the Gabriel Touré University Hospital in Bamako, Mali

Introduction: Pubertal delay is defined by the absence of development of secondary sexual characteristics beyond the age of 13 in girls or 14 years in boys. In children of puberty age, delayed puberty is common in long-standing, untreated hypothyroidism. We report a case of delayed puberty revealed by Hashimoto's disease in the hypothyroid phase diagnosed in the Internal Medicine department of the Gabriel Touré University Hospital in Bamako, Mali. Observation: This was a female patient, aged 20 years old, without any particular medico-surgical ATCD or notion of taking medication, who had consulted at the end of 2021, in the Internal Medicine department of the University Hospital Gabriel Touré from Bamako for primary amenorrhea and delayed puberty. At the end of the clinical and paraclinical examination, a hypometabolism syndrome and pubertal delay were noted. On an evolutionary level, development of secondary sexual characteristics (From T1 to T3, and appearance of menstruation) after one year of treatment. Conclusion: Delayed puberty may be the consequence of hypothyroidism. Opotherapy with L Thyroxine helps restore normal pubertal development.

Total osteocalcin levels are independently associated with worse testicular function and a higher degree of hypothalamic-pituitary-gonadal axis activation in Klinefelter syndrome.

The role of osteocalcin (OCN) in pubertal development, male hypogonadism, and the effect of testosterone (Te) replacement therapy (TRT) remains unclear. We aimed to investigate the total OCN (tOCN) concentrations in male patients with Klinefelter syndrome (KS), a model of adult hypergonadotropic hypogonadism. This retrospective longitudinal study investigated 254 male patients with KS (47,XXY) between 2007 and 2021 at an academic referral center, categorized as (1) prepubertal, (2) pubertal, and (3) adults. All prepubertal patients were Te-naïve. Adult patients were subcategorized as (1) eugonadal, (2) hypogonadal, and (3) receiving TRT. We also analyzed 18 adult patients withavailable tOCN levels before and 3months after TRT commencement. The tOCN levels varied throughout the lifespan according to pubertal status, were highest in eugonadal and significantly lower in TRT subjects, correlated with both LH (p = 0.017) and FSH levels (p = 0.004) in adults, and significantly declined after 3months of TRT (p = 0.006) in the adult KS cohort. HPG-axis hormones levels demonstrated no correlation in prepubertal boys. Adjustment for age and body mass index confirmed previous results and revealed significant inverse correlations with total Te (p = 0.004), calculated free Te (p = 0.016), the Te/LH (p = 0.010), and calculated free Te/LH ratios (p = 0.031). In KS, a model of male hypergonadotropic hypogonadism, tOCN levels were not associated with gonadal function during normal prepuberty and pubertal development but were associated with worse testicular function and a higher degree of HPG stimulation in adults. TRT acutelyreduced tOCN levels in adults.

Single-cell insights into mouse testicular toxicity under peripubertal exposure to di(2-ethylhexyl) phthalate.

Male fertility depends on normal pubertal development. Di-(2-ethylhexyl) phthalate (DEHP) is a potent antiandrogen chemical, and exposure to DEHP during peripuberty can damage the developing male reproductive system, especially the testis. However, the specific cellular targets and differentiation processes affected by DEHP, which lead to testicular toxicity, remain poorly defined. Herein, we presented the first single-cell transcriptomic profile of the pubertal mouse testis following DEHP exposure. To carry out the experiment, 2 groups (n = 8 each) of 3-week-old male mice were orally administered 0.5% carboxymethylcellulose sodium salt or 100 mg/kg body weight DEHP daily from postnatal day 21-48, respectively. Using single-cell RNA sequencing, a total of 31 distinct cell populations were identified, notably, Sertoli and Leydig cells emerged as important targets of DEHP. DEHP exposure significantly decreased the proportions of Sertoli cell clusters expressing mature Sertoli markers (Sox9 and Ar), and selectively reduced the expression of testosterone synthesis genes in fetal Leydig cells. Through cell-cell interaction analyses, we observed changed numbers of interactions in Sertoli cells 1 (SCs1), Leydig cells 1 (LCs1), and interstitial macrophages, and we also identified cell-specific ligand gene expressions in these clusters, such as Inha, Fyn, Vcam1, and Apoe. Complementary in vitro assays confirmed that DEHP directly reduced the expression of genes related to Sertoli cell adhesion and intercellular communication. In conclusion, peripubertal DEHP exposure reduced the number of mature Sertoli cells and may disrupt testicular steroidogenesis by affecting the testosterone synthesis genes in fetal Leydig cells rather than adult Leydig cells.

Joint association of overweight/obesity, high electronic screen time, and low physical activity time with early pubertal development in girls: a case–control study

To examine the joint association of electronic screen time (EST), moderate-to-vigorous physical activity time (MVPA) and overweight/obesity with early pubertal development (EPD) in girls. A case–control study of 177 EPD girls and 354 girls with normal pubertal development was conducted between October 2019 and August 2022. Overweight/obesity was defined as body mass index ≥ 85th percentiles for age and sex. We found a non-significant increase of EPD risk among girls with high EST alone [OR: 2.75 (0.65–11.58)] or low MVPA alone [OR: 2.54 (0.74–8.69)], but a significant increase of EPD risk among girls with overweight/obesity alone [OR: 4.91 (1.01–23.92)], compared to girls without any of the three risk factors (low MVPA, high EST and overweight/obesity). Girls with any two of the three risk factors faced increased risk of EPD, and girls with all three risk factors faced the highest risk of EPD [OR and 95% CI: 26.10 (6.40–106.45)]. Being overweight/obesity might be more important than having low MVPA or high EST as a correlate of EPD compared to girls without any of the three risk factors, but the co-presence of low MVPA, high EST and overweight/obesity would largely increase the risk of EPD in girls.

Correlation of pelvic ultrasonography with pubertal development in girls.

This study aims to correlate pelvic ultrasound with female puberty and evaluate the usual ultrasound parameters as diagnostic tests for the onset of puberty and, in particular, a less studied parameter: the Doppler evaluation of the uterine arteries. Cross-sectional study with girls aged from one to less than eighteen years old, with normal pubertal development, who underwent pelvic ultrasound examination from November 2020 to December 2021. The presence of thelarche was the clinical criterion to distinguish pubescent from non-pubescent girls. The sonographic parameters were evaluated using the ROC curve and the cutoff point defined through the Youden index (J). 60 girls were included in the study. Uterine volume ≥ 2.45mL had a sensitivity of 93%, specificity of 90%, PPV of 90%, NPV of 93% and accuracy of 91% (AUC 0.972) for predicting the onset of puberty. Mean ovarian volume ≥ 1.48mL had a sensitivity of 96%, specificity of 90%, PPV of 90%, NPV of 97% and accuracy of 93% (AUC 0.966). Mean PI ≤ 2.75 had 100% sensitivity, 48% specificity, 62% PPV, 100% NPV and 72% accuracy (AUC 0.756) for predicting the onset of puberty. Pelvic ultrasound proved to be an excellent tool for female pubertal assessment and uterine and ovarian volume, the best ultrasound parameters for detecting the onset of puberty. The PI of the uterine arteries, in this study, although useful in the pubertal evaluation, showed lower accuracy in relation to the uterine and ovarian volume.

FRI430 A Case Of Elevated Sex Hormone-binding Globulin Secondary To Variegate Porphyria In A Patient With Hypogonadotropic Hypogonadism

Abstract Disclosure: J. Law: None. C. Yip: Research Investigator; Self; Eli Lilly &amp; Company. Background: Acute porphyria is a group of disorders characterized by enzymatic defects in the heme biosynthetic pathway. The liver is the source of both acute intermittent porphyria (AIP) and variegate porphyria. AIP is known to cause an elevation in sex hormone-binding globulin (SHBG) levels, likely secondary to impaired hepatic function and hepatocyte abnormalities1. We describe a case of elevated SHBG secondary to variegate porphyria, in a male with hypogonadotropic hypogonadism. Case Report: A 44-year-old male presented with an elevated SHBG and symptoms of hypogonadism with low libido, weakness, and fatigue. Fasting morning bloodwork revealed an elevated SHBG at 89 nmol/l (13.5- 71.0), a normal total testosterone level at 12.95 nmol/l (8-32), and a low bioavailable testosterone at 0.82 nmol/l (2.5-10), with confirmatory repeat blood work. His history was significant for longstanding variegate porphyria, manifesting as frequent attacks of abdominal pain. He was on opioids for greater then 10 years for his chronic pain, as well as metoclopramide. On assessment of causes for his elevated SHBG, his TSH was normal at 1.49 mIU/L (0.35-4.30). He did not have cirrhosis, hepatitis, hereditary hemochromatosis, and was not on anticonvulsants. No other cause was found, and his elevated SHBG was deemed secondary to his variegate porphyria. His normal total testosterone level was due to his elevated SHBG, but as mentioned, his bioavailable testosterone was low. His LH and FSH were both inappropriately normal, with his LH being 4.67 IU/L (0.6-12.0) and his FSH 4.7 IU/L (1.0-12.0), in keeping with hypogonadotropic hypogonadism. He went through normal pubertal development and had no anosmia. Workup revealed an elevated prolactin level of 73.8 ug/l (3.5-19.4). He had no galactorrhea or gynecomastia and an MRI sella revealed a normal pituitary gland. His elevated prolactin level was determined to be secondary to his opioid medication and/or metoclopramide use. His hypogonadotropic hypogonadism was deemed secondary to his opioid medications and/or hyperprolactinemia. Conclusion: This case demonstrated variegate porphyria as a likely cause of elevated SHBG, similar to AIP. In patients with variegate porphyria and symptoms of hypogonadism, the SHBG should be measured and if it is elevated, the bioavailable or free testosterone levels should be used in assess instead of relying on the total testosterone levels. As has been previously shown, this case also illustrated the use of opioid medications as a cause of hypogonadotropic hypogonadism.

Familial central precocious puberty due to DLK1 deficiency: novel genetic findings and relevance of serum DLK1 levels.

Several rare loss-of-function mutations of delta-like noncanonical notch ligand 1 (DLK1) have been described in non-syndromic children with familial central precocious puberty (CPP). We investigated genetic abnormalities of DLK1 gene in a French cohort of children with idiopathic CPP. Additionally, we explored the pattern of DLK1 serum levels in patients with CPP and in healthy children at puberty, as well as in wild-type female mice. Genomic DNA was obtained from 121 French index cases with CPP. Automated sequencing of the coding region of the DLK1 gene was performed in all cases. Serum DLK1 levels were measured by enzyme linked immunosorbent assay (ELISA) in 209 individuals, including 191 with normal pubertal development and in female mice during postnatal pubertal maturation. We identified 2 rare pathogenic DLK1 allelic variants: A stop gain variant (c.372C>A; p.Cys124X) and a start loss variant (c.2T>G; p.Met1?, or p.0) in 2 French girls with CPP. Mean serum DLK1 levels were similar between healthy children and idiopathic CPP children. In healthy individuals, DLK1 levels correlated with pubertal stage: In girls, DLK1 decreased between Tanner stages III and V, whereas in boys, DLK1 decreased between Tanner stages II and V (P = .008 and .016, respectively). Serum levels of Dlk1 also decreased in wild-type female mice. Novel loss-of-function mutations in DLK1 gene were identified in 2 French girls with CPP. Additionally, we demonstrated a pattern of dynamic changes in circulating DLK1 serum levels in humans and mice during pubertal stages, reinforcing the role of this factor in pubertal timing.

New therapies towards a better glycemic control in youths with type 1 diabetes

Type 1 diabetes (T1D) is the most frequent form of diabetes in pediatric age, affecting more than 1.5 million people younger than age 20 years worldwide. Early and intensive control of diabetes provides continued protection against both microvascular and macrovascular complications, enhances growth, and ensures normal pubertal development. In the absence of definitive reversal therapy for this disease, achieving and maintaining the recommended glycemic targets is crucial. In the last 30 years, enormous progress has been made using technology to better treat T1D. In spite of this progress, the majority of children, adolescents and young adults do not reach the recommended targets for glycemic control and assume a considerable burden each day. The development of promising new therapeutic advances, such as more physiologic insulin analogues, pioneering diabetes technology including continuous glucose monitoring and closed loop systems as well as new adjuvant drugs, anticipate a new paradigm in T1D management over the next few years. This review presents insights into current management of T1D in youths.

Polycystic Ovarian Syndrome In Some Sample Of Iraqi Adolescents: Implementation Of Consensus Guidelines

Background: The diagnosis of polycystic ovarian syndrome (PCOS) in adolescent girls can be difficult because symptoms are shared with normal pubertal development. The updated consensus guideline for PCOS diagnosis in adolescents sought to encourage accurate and timely diagnosis, optimize therapy, and improve health outcomes. Aim: the present study aims to implement an updated consensus criteria in the diagnosis of PCOS in adolescents complaining of clinical features of hyperandrogenism or menstrual abnormalities. Methods: A total of 60 patients with clinical features of hyperandrogenism and/or menstrual abnormalities were studied. A detailed history followed by clinical examination was taken. Serum Thyroid Stimulating Hormone, Cortisol, Total Testosterone, Dehydroepiandrosterone, Luteinizing Hormone (LH), and Prolactin were performed for all patients. Consensus criteria were used for PCOS diagnosis. Results: Menstrual irregularity was reported by 20 (33.3%) and hyperandrogenism features in 21(35%) of the participants. PCOS was confirmed in 14 (23%) participants. Patients diagnosed with PCOS were shown to have substantially higher rates of menstrual irregularity, hirsutism, elevated serum testosterone, and LH (P0.001, P0.001, P=0.002, and P0.002 respectively). Seven patients (50%) had both clinical and biochemical hyperandrogenism. Association between testosterone rise was more significant with hirsutism (P&lt;0.001) than with acne (P=0.001). Morbid obesity was observed in 21% of patients, 7% had their diastolic blood pressure 90mm Hg, and 39% had and fasting blood sugar ≥100 mg/dL. Conclusion: PCOS was diagnosed in 23% of adolescent girls who had features of hyperandrogenism and menstrual irregularities. Obesity and family history were more frequent in PCOS adolescents. Concordant clinical and biochemical hyperandrogenism was confirmed in only half of PCOS patients. PCOS patients may be at higher risk of metabolic syndrome.

The Role of MCM9 in the Etiology of Sertoli Cell-Only Syndrome and Premature Ovarian Insufficiency.

Infertility in couples is a common problem, with both female and male factors contributing to similar extents. Severe, congenital disorders affecting fertility are, however, rare. While folliculogenesis and spermatogenesis are generally orchestrated via different mechanisms, some genetic anomalies can impair both female and male gametogenesis. Minichromosome maintenance complex component 9 (MCM9) is involved in DNA repair and mutations of the MCM9 gene have been previously reported in females with premature ovarian insufficiency (POI). MCM9 is also an emerging cancer risk gene. We performed next-generation and Sanger sequencing of fertility and related genes and hormonal and imaging studies in a kindred whose members had POI and disordered spermatogenesis. We identified a homozygous pathogenic MCM9 variant, c.394C>T (p.Arg132*) in three sisters affected by POI due to ovarian dysgenesis and their brother who had normal pubertal development but suffered from non-obstructive azoospermia. Testicular biopsy revealed Sertoli cell-only testicular histopathology. No evidence of early onset cancer was found in the homozygotic family members, but they were all young (<30 years) at the time of the study. In the male patient the homozygous MCM9 variant led to normal pubertal development and hormonal levels but caused a Sertoli-cell-only syndrome with non-obstructive azoospermia. In the homozygous females studied, the clinical, hormonal, and gonadal phenotypes revealed ovarian dysgenesis consistent with previous reports. Active screening for potential colorectal and other cancer risks in the homozygotic MCM9 subjects has been instigated.

ODP402 Adult height and reproductive outcome of Klinefelter men with a 46,XX/47,XXY mosaicism

Abstract Background Mosaicism in Klinefelter Syndrome (KS) is reported in 15–20%, but 46,XX/47,XXY mosaicismis extremely rare and presents either during infancy with ambiguous genitalia or during adolescence with gynecomastia or microorchidism. In view of the scarce data on adult outcomes (1,2), we here comprehensively report the skeletal and reproductive health outcome in two individuals with 46,XX/47,XXY KS. Clinical cases The first case was born at 40 weeks after a spontaneous conception with a birth length of 49 cm. At birth right cryptorchidism, but a normally developed penis and scrotum was present. Surgical intervention at the age of 1 year, showed a right abdominal testicular nubbin. He was investigated at the age of 17 years for left microorchidism (6ml) contrasting with a normal genital development (Tanner G5). Hormonal investigation showed hypergonadotropinemia with a normal serum testosterone. Peripheral blood karyotype showed mosaicism 46,XX (60%)/47,XXY (40%). At the age of 18 years, standing height was 164.5 cm (mid-parental height (MPH) 173.5 cm). BMI was 19 kg/m2. Hormonal evaluation showed an unmeasurable serum inhibin B, elevated gonadotropins (LH 43 IU/L and FSH 65 IU/L), but a normal testosterone and estradiol. Ultrasound of the left testis showed a normal echo pattern. Azoospermia was documented. Lumbar spine bone mineral density (LS-BMD) was -1 SDS. The second case was born at 37 weeks after ICSI with a birth length of 49 cm. External genitalia at birth were normal. However, routine karyotyping after ICSI conception showed a mosaicism 46,XX (50)/ 47,XXY (50). A normal pubertal development apart from an arrest in testicular development at the age of 15 years was documented. At the age of 18 years, his height was 176.8 cm (MPH 184 cm), BMI 26 kg/m2, Tanner stage G5 and testes volumes 8/8 ml. Hormonal evaluation showed low inhibin B (43.4 ng/l), slightly elevated gonadotropins (LH 16.1 IU/L and FSH 12.5 IU/L), and normal testosterone and estradiol. Ultrasonography of the scrotum showed normal testicular structure. LS-BMD SDS was 1. Conclusion 46,XX/47,XXY KS men, who present with normal male genitals at birth, can have a normal pubertal progression with the exception of a mid-pubertal testicular regression, but in contrast to men with a 46,XY/ 47,XXY constitution, appear at risk for a shorter stature than expected for parental height. References Velissariou V et al., European Journal of Medical Genetics (2006) 49, 331-337Matsuki S, Journal of Urology (1999) 161 (5), 1573-74 Presentation: No date and time listed

LBMON274 Total Osteocalcin Levels Are Independently Associated With Worse Testicular Function And A Higher Degree Of HPG Axis Activation In Klinefelter Syndrome

Abstract Context. Osteocalcin (OCN) is an osteoblast-produced polypeptide, emerging as the core element of the bone-testicular axis toghether with its undercarboxylated form (uOCN), proposed to increase testosterone (Te) levels in healthy men, by binding the Gpcr6a receptor on Leydig cells and modulating the GnRH pulse frequency and amplitude. However little is known with regards to its role in pubertal development and male hypogonadism. Objective and Design We investigated OCN concentrations in 47,XXY men affected by Klinefelter syndrome (KS), a model of adult hypergonadotropic hypogonadism, in a retrospective longitudinal study between 2007 and 2021 at an academic referral center. Patients and Methods 254 KS subjects, divided into the following groups: 1) pre-pubertal (n = 48, from 1 year of age until Tanner stage II), 2) pubertal (n = 46, Tanner stages II through V, &amp;lt;18 years), and 3) adults (n = 160, Tanner stage V, ≥18 years). All (pre-)pubertal patients were Te-naïve. Adult patients were categorized as: 1) eugonadal (total Te &amp;gt; 10.4 nmol/L; n = 47), 2) hypogonadal (Te &amp;lt; 10.4 nmol/L; n = 39), and 3) receiving testosterone replacement therapy (TRT) (n = 74). Data are presented as means ± SD, were tested with Brown-Forsythe and Welch ANOVA tests for unequal variances, corrected for multiple comparisons (Dunnett T3), and with partial correlations, after bootstrapping on 2000 samples. Main outcomes. Total serum OCN, hypothalamic-pituitary-gonadal (HPG) axis hormones (LH, FSH, total Te, 11β-estradiol, SHBG), and derived indexes. Results OCN levels varied throughout the life span, with a mean of 85.9±30.4 ng/mL in pre-pubertal infants, peaking at 130. 0±77.2 ng/mL in pubertal children (p = 0.243 vs pre-pubertal) and then declining to 22.9±9. 0 ng/mL in adults (p &amp;lt; 0. 001 vs pre-pubertal and pubertal). In (pre-)pubertal boys no correlation with HPG axis hormones was found. When comparing adult KS, OCN values were highest in eugonadal (26.5±10.4 ng/mL), slightly lower in hypogonadal (24.5±8.1 ng/mL, p = 0.268 vs eugonadal) and significantly lower in TRT subjects (20.4±8. 0 ng/mL, p = 0. 008 vs. eugonadal and = 0. 013 vs. hypogonadal). In adults, OCN correlated with both LH (r = 0.23, p = 0. 017) and FSH levels (r = 0.28, p = 0. 004). These significancies were maintained after the exclusion of subjects on TRT. Surprisingly, adjusting for age and BMI revealed significant inverse correlations with total Te (r = -0.44, p = 0. 004), calculated free Te (r = -0.37, p = 0. 016), the Te/LH (r = -0.40, p = 0. 010) and the calculated free Te/LH ratios (r = -0.33, p = 0. 031). These results were confirmed on a smaller sample with available uOCN levels. Conclusions In an experimental model of hypergonadotropic hypogonadism, OCN showed no association with gonadal function during normal pre-puberty and pubertal development. In adults, OCN levels were unexpectedly associated with worse testicular function and a higher degree of HPG stimulation. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

In vitro fertilization and preimplantation genetic diagnosis outcomes in mosaic Turner's syndrome: A retrospective cohort study from a single referral center experience

Background: Patients with mosaic Turner syndrome who have normal phenotype and pubertal development may be diagnosed based on karyotype examination which is performed due to recurrent abortion or recurrent implantation failure; but according to the literature review, reproductive and obstetric consequences of these cases are based on case reports. There are contradictory publications on this subject recommending pre-implantation genetic testing (PGT) may be a solution to reduce the high risk for the fetus and perform normal embryo transfer. Aim: In this study, our aim was to evaluate the results of in vitro fertilization and preimplantation genetic diagnosis in patients with low-grade and high-grade mosaic Turner syndrome. Methods: We collected data of patients between 2012 and 2018 from a single center retrospectively. The study analyzed 36 mosaic Turner syndrome patients, of whom, 10 patients were evaluated as high, 26 patients were evaluated as low-grade mosaic pattern for Turner syndrome. Results: Mean age (35,46±0,87 vs. 36,2 ± 1,85) body mass index (25,26±0,74 vs. 30,8 ± 0,63) baseline follicle stimulating hormone (5,73±0,74 vs. 6,70±1,17) basal luteinizing hormone (4,78±0,43 vs. 4,92±0,99) were similar between two groups. In the high-grade mosaic Turner Syndrome patients, duration of stimulation (7,60±0,16 vs. 8,0 ± 0,28, p<0,001), total gonadotrophin dose (1540,0 ± 165,12 vs. 2046,15± 111,47, p<0,001) and the number of normal karyotype embryos was statistically significantly higher (1,58±0,17 vs. 2,00±0,55, p<0,001). The Pregnancy rates in the low-grade and high-grade mosaic Turner syndrome patients’ cycles were 30,8% versus 30%, (p = 0.76) respectively. IVF results were also evaluated by the presence of triploidy were accompanying Turner syndrome or not. In the presence of one or 2 X chromosomes, none of the included in the study could achieve live birth. The most common abnormality in the embryos was monosomy and trisomy of the chromosome13. In 30% of the cases, there were 2 or 3 abnormalities present together. In embryos with 2 abnormal chromosomes, the most common 2 abnormalities were monosomy 13 and trisomy 21, while trisomy 13, trisomy X and monosomy 18 were found in 3 or more abnormalities, respectively. Conclusion: In vitro fertilization and Preimplantation genetic diagnose should be considered in the infertility treatment of the patient with mosaic Turner Syndrome.

Investigation of Laboratory Values and Ultrasonographic Characteristics in Adolescent Girls with Polycystic Ovarian Syndrome

Background: Polycystic ovarian syndrome (PCOS) is a complex disease linked with adverse cardiovascular, metabolic, and reproductive health outcomes. Early diagnosis of this disease in adolescence is important for treatment optimization. However, there are multiple sets of PCOS diagnostic criteria and the physiological and anatomical changes during normal pubertal development make diagnosis of adolescent PCOS difficult. Recent guidelines for PCOS in adolescents endorse the Rotterdam criteria, recommend against using ultrasound (US) imaging, and call for further investigation of potentially diagnostic biomarkers.

Polycystic Ovary Syndrome in Adolescence: Challenges in Diagnosis and Management.

Diagnosing polycystic ovary syndrome (PCOS) during adolescence is challenging since normal pubertal development overlap typical features of this syndrome. The authors aim to summarize the existing evidence concerning PCOS in adolescence, particularly its diagnostic criteria and therapeutic options. A search throughout medical databases such as PubMed and MedScape was performed. Diagnostic criteria include irregular menstrual cycles according to time postmenarche and evidence of clinical hyperandrogenism and/or biochemical hyperandrogenism, provided other causes have been excluded. Polycystic ovarian morphology ought not to be used as a diagnostic criterion. Treatment should target manifestations and/or comorbidities, even in the absence of a definite diagnosis. Lifestyle interventions are the first-line treatment. Combined oral contraceptives, metformin or antiandrogens may also be considered as adjuvants. Screening for PCOS in adolescence is crucial as it allows an early intervention on the symptoms and comorbidities presented leading to better long-term reproductive and metabolic outcomes.

Testicular ultrasound in a patient with Kallmann syndrome: A case report

Introduction. Kallmann syndrome is a genetic disorder marked by hypogonadotropic hypogonadism and anosmia. Patients with Kallmann syndrome have low circulating testosterone levels and low gonadotropin levels, whereas other pituitary hormones are normal. The treatment is based on sex steroid replacement with the aim to restore normal pubertal development and includes attempts to restore fertility by using gonadotropin-releasing hormones. Ultrasound examination of the testicles is a very useful complement to determine and monitor the precise testicular volume, which is an important prognostic factor for future fertility. Case Report. At the age of 18, the patient was suspected of having Kallmann syndrome and was referred to an endocrinologist. After three months of testosterone therapy, the patient was sent for an ultrasound of the testicles. The right testicle measured 16 x 6 mm, the left testicle 10 x 5 mm, both with a discrete marginal circular dichroism signal. One year after the first testicular ultrasound, the patient came for a checkup. The right testicle measured 14 x 5 mm, the left testicle 11 x 5 mm, stationary structure. Conclusion. The diagnosis of Kallmann syndrome is often delayed, because hypogonadotropic hypogonadism is usually not apparent until puberty, and individuals with anosmia are often unaware of this sensory deficit. In this case, late recognition of the syndrome, as well as late initiation of therapy, did not give satisfactory results.

Accuracy of Doppler assessment of the uterine arteries in healthy girls for the diagnosis of pubertal onset.

To evaluate the accuracy of the uterine artery pulsatility index (PI) for the diagnosis of pubertal onset in girls. Cross-sectional study of girls with normal pubertal development. Puberty was diagnosed by the presence of Tanner breast development score ≥2. All girls underwent pelvic ultrasound and Doppler imaging of the uterine arteries. We evaluated the uterine artery PI and uterine, endometrial, and ovarian measurements. We used ROC curves with cutoffs determined by Youden index for data analysis. We included 169 girls aged 5-16 years who underwent 202 pelvic ultrasound examinations. Prepubertal girls had a significantly higher mean PI (6.70 ± 2.15) than girls in initial puberty (4.14 ± 1.55) and in late puberty (2.81 ± 1.05) (P < 0.001 for all comparisons), which reflects a progressive increase in blood flow to the uterus with the progression of puberty. ROC curve analysis showed that the PI was able to identify the onset of puberty with a mean area under the curve of 0.838 ± 0.04 (P < 0.001), and the PI cutoff point of 5.05 had a sensitivity of 77%, specificity of 85%, positive predictive value (PPV) of 92%, and accuracy of 79%. The combination of PI < 5.05 plus uterine volume >3.75 cm³ had a sensitivity of 73%, specificity of 95%, PPV of 97%, and accuracy of 79% to detect initial puberty. We found a significant reduction in the PI during pubertal development, which can possibly be a valuable noninvasive tool in the evaluation of pubertal disorders, alone or in combination with uterine and ovarian volumes.

Heavy Menstrual Bleeding in Adolescent: Normal or a Sign of an Underlying Disease?

Heavy, and often irregular, menstrual bleeding (HMB) is a common gynecologic complaint among adolescents. During the first few post-menarcheal years, anovulatory cycles related to immaturity of the hypothalamic-pituitary-ovarian axis are the most common etiology for abnormal uterine bleeding and should be considered as a part of normal pubertal development rather than a disease. If an already regular menstrual cycle becomes irregular, secondary causes of anovulation should be ruled out. Inherited and acquired bleeding disorders, such as von Willebrand disease, and quantitative and qualitative abnormalities of platelets are relatively common findings in adolescents with HMB from menarche. History of excessive bleeding or a diagnosed bleeding disorder in the family supports this etiology, warranting specialized laboratory testing. First-line treatment of HMB among adolescents is medical management with hormonal therapy or nonhormonal options. Levonorgestrel-releasing intrauterine device is an effective tool also for all adolescents with menstrual needs.