Pubertal Induction Research Articles

Abnormal Uterine Bleeding during Pubertal Induction with Transdermal Estrogen in Individuals with Turner Syndrome

Study ObjectiveIncidence of abnormal uterine bleeding (AUB) during pubertal induction among individuals with Turner syndrome (TS) has not been described previously. We estimated the incidence and characterized factors associated with AUB among individuals with TS. A secondary objective was to evaluate the management of AUB among this patient population. Design, Setting, Participants, and InterventionWe conducted a retrospective chart review to evaluate individuals with TS undergoing hormone replacement therapy (HRT) for pubertal induction with transdermal estrogen. A total of 45 participants were identified between January 2007 and June 2019. ResultsOf the 45 individuals with TS included, 16 (35%) experienced AUB. Individuals with AUB most commonly experienced prolonged (44%), prolonged and heavy (25%), and intermenstrual (19%) bleeding. Individuals who experienced AUB were more likely to experience spontaneous bleeding (69% vs 28%) and a duration of unopposed estrogen greater than 18 months (63% vs 41%), undergo progestin cycling less often than monthly (69% vs 0%), use a micronized progestin dose of less than 200 mg (25% vs 14%), and be noncompliant with HRT (19% vs 0%) compared with those who did not experience AUB. ConclusionThere is a relatively high incidence of AUB among individuals with TS undergoing pubertal induction with transdermal estrogen. Care providers should consider the clinical factors examined to guide monitoring and management of individuals with TS on HRT.

Ovarian Function and Spontaneous Pregnancy After Hematopoietic Stem Cell Transplantation for Leukemia Before Puberty: An L.E.A. Cohort Study

Ovarian function impairment and infertility are among the most frequent late effects after hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate ovarian function, occurrence of premature ovarian insufficiency (POI), and spontaneous pregnancy in a large cohort of adult survivor women who had undergone HSCT for leukemia before puberty. We conducted a retrospective observational study in women from the national cohort L.E.A., the long-term French follow-up program after childhood leukemia. The median follow-up duration was 18 years (14.2-23.3) after HSCT. Among 178 women, 106 (60%) needed pubertal induction with hormone substitution treatment, whereas 72 (40%) had spontaneous menarche. After spontaneous menarche, 33 (46%) developed POI, mostly within 5 years of HSCT. Older age at time of HSCT and cryopreservation of ovarian tissue appeared as significant risk factors for POI. More than 65% of patients who underwent HSCT before the age of 4.8 years had spontaneous menarche, and almost 50% didn't have POI at last evaluation, whereas more than 85% with HSCT after the age of 10.9 years didn't have spontaneous menarche and needed induction of puberty with hormone replacement therapy. Twenty-two women (12%) had at least one spontaneous pregnancy, with 17 live-births, 14 miscarriages, 4 legal abortions, and 2 therapeutic abortions. These results add supplementary data to better counsel patients and their families on the chances of ovarian residual function and pregnancy after HSCT, as well as on the potential interest of fertility preservation.

Adult Height in Indian Girls with Turner Syndrome Treated with Long-Term Growth Hormone Therapy - A Western India Tertiary Centre Experience.

Owing to paucity of data on adult height in Indian girls with Turner syndrome treated with growth hormone (GH), this study was conducted to assess improvement in height following GH therapy and adult height achieved with long-term GH therapy in Indian girls with Turner syndrome and to assess relationship between achieved and predicted height. Retrospective analysis was performed on 12 girls with karyotype-proven Turner syndrome, who had attained adult height following mean duration of GH therapy of 4.8 years (range: 2.7-7.6). Adult height predictions were performed using index of responsiveness (IOR) and Ranke's prediction model. Mean age at starting GH was 10.2 ± 1.9 years; Pubertal induction was between 11 and 15 years. Mean height gain was 29.3 ± 9.8 cm (range: 14-39.5) from onset of treatment to adult height. Significant improvement in height Z scores (IAP 2015 and Indian Turner reference data) following GH therapy (p = 0.002 and 0.012, respectively) was noted. Using Indian Turner reference data, the height Z score improved from pre-treatment 0.8 ± 0.8 to 2.0 ± 0.9 on stopping GH and adult height Z score of 1.3 ± 0.7. Using Ranke's equation for prediction of near adult height, predicted and achieved adult height showed a strong positive correlation (Spearman correlation coefficient = 0.827, significant at 0.01 level). At a dose in the lower range (40-50 mcg/kg/day) of recommendation and duration of 5 years, Indian girls with Turner syndrome can achieve adult height within the healthy Indian reference range. Dose individualization based on IOR would help in optimizing GH dosage and would turn out to be economically sustainable without compromising on height outcomes.

Clinical Profile of Turner Syndrome: A Tertiary Center Experience

Background: Turner syndrome (TS) is the commonest chromosomal abnormality in females with an incidence of 25–50 per 100,000 females. Girls with TS universally have short stature (95%), along with gonadal failure (>90%) and infertility (99%); however, the ethnic differences are not well elaborated. Objectives: This study has been planned to evaluate the presentation and course of Indian girls with TS. Methods: Patients with TS presenting to our referral endocrinology clinic were included in this study. Diagnosis of TS was done by karyotyping. A retrospective chart review of these patients formed the basis of this study. Results: A total of 55 patients with TS karyotype were seen, and the mean age at diagnosis was 12.3 years. The commonest presenting features were short stature alone seen in 37 (65.45%) and short stature with delayed puberty in 18 (32.72%). The earliest age at presentation was 4.5 years who presented with short stature. The mean height was 124.17 cm and mean BMI 17.54 kg/m². The most common karyotype was 45, XO found in 34 (61.6%) of the cases. 15 (27.27%) the cases were started on growth hormone therapy. 26 cases (47.27%) required pubertal induction. Conclusion: A vast number of cases with TS in India remain undiagnosed until puberty or present very late. A high degree of clinical suspicion can help us diagnose these children earlier. If TS is diagnosed earlier, growth can be achieved up to their maximum potential. Early identification and management will help us provide multidisciplinary care and hence prevent complications.

Reproductive health in Turner syndrome: A narrative review.

Turner syndrome (TS), a common chromosomal abnormality affecting females, is associated with partial or complete loss of the second sex chromosome. Although the classic karyotype is 45, X, the detection of mosaic TS is increasing. TS is a multi-system disorder with significant endocrine, cardiovascular and reproductive impacts. Accelerated ovarian follicular loss leads to primary amenorrhoea or premature ovarian insufficiency and infertility. Early diagnosis and counselling regarding hormone replacement therapy and future reproductive capacity, including fertility preservation, are essential to improve reproductive outcomes. Pubertal induction or estrogen replacement is usually required to optimise long-term health outcomes; however, initiation may be delayed due to delayed diagnosis. Spontaneous pregnancy occurs in a small number of women; however, many require donor oocytes and assisted reproductive technology to achieve a pregnancy. Pregnancy is a high risk especially when associated with congenital heart disease. Prepregnancy counselling by the multidisciplinary team (MDT) to identify contraindications and optimise pre-existing health issues is essential. Pregnancy management should be led by a maternal-fetal medicine unit with input from the MDT. This review examines reproductive health outcomes in women with TS and how best to manage them to reduce health risks and improve maternal and neonatal outcomes.

OR08-5 Associations Between Signal Transducer and Activator of Transcription (STAT) Mutations and Galactorrhea

Abstract Background Prolactin (PRL) is responsible for the development of mammary glands and milk production. STAT1 and STAT3 are genes that express transcription factors that mediate PRL's intracellular signaling, but an association between their function and galactorrhea has not yet been identified. Here we describe three patients with somatic STAT mutations and galactorrhea. A 27-year-old woman with hyper-IgE syndrome (Job's Syndrome) due to a STAT3 deletion mutation (p.Val463del) associated with recurrent infections reported thin, white, bilateral discharge with breast manipulation beginning in adolescence. She did not have spontaneous leakage or pain. At presentation, PRL was slightly elevated to 27.9 (ref. 2.0-25.0 mcg/L) with otherwise normal levels of anterior pituitary hormones. She was not on any drugs known to cause hyperprolactinemia. MRI showed a 5×4 mm microadenoma without any mass effect. A 32-year-old woman also with Job's syndrome due to a heterozygous loss-of-function STAT3 mutation (p.R382Q) associated with recurrent infections and papillary thyroid cancer described unilateral, chronic, thin, white nipple discharge with light touch of her right breast for "as long as she could remember." She had a history of breast abscesses, but at presentation there was no evidence of abscess or infection. PRL was 15.1 mcg/L, and other anterior pituitary hormones were normal. MRI showed a structurally normal pituitary. A 22-year-old woman with a STAT1 activating mutation (p.E235A) associated with recurrent infections, autoimmune hypothyroidism, T1DM, and hypogonadotropic hypogonadism requiring pubertal induction at age 12y reported bilateral galactorrhea starting at age 18y. A white, milky discharge could be expressed with light manipulation, but no discharge was produced spontaneously. PRL was 16.2 mcg/L with serial dilution and has consistently been in the reference range. Anterior pituitary evaluation was normal except for elevated TSH of 12.5 (ref. 0.27-4.2) consistent with autoimmune hypothyroidism. MRI revealed a diffusely enlarged pituitary gland (12mm in the cranio-caudal dimension) without focal hypo-enhancement. Conclusions It is known that PRL signaling involves the JAK/STAT pathway, and an analysis of human milk cells showed upregulated STAT3 and downregulated STAT1 during lactation (PMID 26909879). These three cases provide clinical evidence for a mechanistic connection between STAT signaling and galactorrhea and suggest that STAT3 and STAT1 function in opposite directions to regulate lactation. In our cases, increased STAT1 or decreased STAT3 activity are associated with normal-PRL, inducible galactorrhea. Beyond understanding the specific intracellular signaling pathways leading to galactorrhea, these observations may be utilized for developing therapies for those with impaired lactation. Presentation: Saturday, June 11, 2022 12:30 p.m. - 12:45 p.m.

45,X male – rare case of unbalanced translocation of Y chromosome to chromosome 2 presenting with developmental delay, learning difficulty and obesity

A male phenotype accompanied by a 45,X karyotype is rare. It may occur due to Y chromosomal translocation or insertion to X/autosome. Clinical presentation may vary depending on the presence of the Y chromosomal locus and the degree of loss of autosome material. 45,X males can present with short stature and Turner syndrome phenotype due to haploinsufficiency of genes which are normally expressed in both X and Y chromosomes. The presence of the sex-determining region Y (SRY) gene leads to the differentiation of bipotential gonads to testis. Most individuals go through puberty normally, but some may need pubertal induction for delayed puberty. Rarely some can have a pubertal arrest. The risk of gonadoblastoma is minimal in these individuals due to functioning testicular tissue. The azoospermia factor (AZF) region is found on the long arm of the Yq chromosome and is needed for spermatogenesis. In a 45,X male with unbalanced translocation of Y chromosome, spermatogenesis can be affected due to the lack of AZF leading to Sertoli cell-only syndrome. This will have an implication on fertility in adult life. We present a 14-year-old boy with developmental delay, learning difficulties and subtle dysmorphic features who was diagnosed with 45,X,der(2)t(Y:2)(?:p25). Fluorescence in situ hybridisation analysis revealed translocation of SRY (Yp11.3) to the terminal part of the short arm of chromosome 2 resulting in the deletion of most of the Y chromosome (Yp11.2-q12) and part of chromosome 2(2p25.3). This is the first case where SRY translocation to chromosome 2 presents with the above clinical presentation. 45,X karyotype is rare in male. It may occur due to SRY translocation or an insertion to X/autosome. SRY gene translocation to chromosome 2 has been not reported in the literature. Clinical presentation can be varied due to degree of loss of chromosomal material. Due to loss of AZF region found on the long arm of the Yq, spermatogenesis can be affected. Loss of 2p25 leads to learning difficulty and obesity.

Hypogonadism in adolescent girls: treatment and long-term effects.

Hypogonadism in adolescent females presents as delayed puberty or primary amenorrhea. Constitutional delay of growth and puberty, hypogonadotropic hypogonadism and hypergonadotropic hypogonadism represent the principal differential diagnosis of delayed puberty. Girls with hypogonadism require hormone replacement therapy to initiate and sustain puberty. We aimed to provide a brief review concerning treatment for female adolescents with hypogonadism and further to focus on current data regarding long-term effects of therapy. The published studies and articles of the international literature were used regarding the approach to adolescent girls with hypogonadism. The aim of therapy is the development of secondary sexual characteristics and achievement of target height, body composition and bone mass, to promote psychosexual health and, finally, to maximize the potential for fertility. Hypogonadal females need long-term HRT, so it is of great importance to fully define risks and benefits of therapy. The optimal pubertal induction in women contains both estrogens and progesterone regimens. Different therapeutic options have been described over the years in the literature, but larger randomized trials are required in order to define the ideal approach. The latest acquisitions in the field seem to propose that transdermal 17β-estradiol and micronized progesterone present the most physiological formulations available for this purpose. Further studies and follow up are needed concerning the long-term effects of HRT in adolescents.

Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline

Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline

A single-centre study on predictors and determinants of pubertal delay and growth impairment in Epidermolysis Bullosa.

BackgroundDelayed puberty is a possible complication of Epidermolysis Bullosa (EB), though the actual incidence is still unknown. In chronic illnesses delayed puberty should be correctly managed since, if untreated, can have detrimental effects on adult height attainment, peak bone mass achievement and psychological health.Aims and methodsThis is a single-centre study on pubertal development, growth and bone status in EB. Auxological, densitometric (areal Bone Mineral Density-aBMD Z-score, Bone Mineral Apparent Density-BMAD Z-score, Trabecular Bone Score-TBS and Bone Strain Index-BSI at Lumbar spine) and body composition data (Total Body DXA scans) were collected. Disease severity was defined according to Birmingham Epidermolysis Bullosa Severity (BEBS) score.ResultsTwenty-one patients (12 Recessive Dystrophic EB-RDEB, 3 Dominant Dystrophic EB, 3 Junctional EB-JEB, 2 EB Simplex and one Kindler EB) aged 13 years (females) or 14 years (males) and above were enrolled (age 16.2±2.5 years, M/F 11/10). Short stature was highly prevalent (57%, mean height -2.12±2.05 SDS) with 55% patients with height <-2SD their mid-parental height. 7/21 patients (33%, 6 RDEB and 1 JEB) had delayed puberty with a median BEBS of 50 (range 29 to 63), a height SDS of -2.59 SDS (range -5.95 to -2.22) and a median lumbar BMAD Z-score of -4.0 SDS (range -5.42 to -0.63 SDS). Pubertal status was negatively associated with BEBS, skin involvement, inflammatory state and positively with height SDS and BMI SDS.ConclusionsPubertal delay is highly prevalent in EB, especially in patients with RDEB and JEB, high severity score and inflammatory state. Moreover, pubertal delay worsens growth impairment and bone health. A study on pubertal induction is ongoing to enlighten possible beneficial effects on adult height attainment and peak bone mass accrual.

The effects of estrogen induction therapy on pubertal presentations in turner syndrome patients

ObjectiveIn this study, we investigated various pubertal presentations and progressions before and after estrogen induction therapy and the correlations with Turner syndrome karyotypes. Materials and methodsWe reviewed the medical records of patients with Turner syndrome diagnosed before the age of 18 years between 2000 and 2019. Sixty-six patients were enrolled and distributed into 45,X monosomy group, X chromosome structural abnormalities group and X mosaicism group. The pubertal presentations were classified into spontaneous puberty, arrested puberty and no spontaneous puberty. All patients’ karyotypes, pubertal progressions and laboratory data were collected and analyzed. ResultsThe karyotypes were highly correlated with pubertal presentations. No spontaneous puberty was noticed in 58.3% 45,X monosomy patients, 50% patients with X chromosome structural abnormalities had arrested puberty, whereas 70% patients with X mosaicism had spontaneous puberty. Estrogen induction therapy in patients with no spontaneous puberty could induce puberty and the tempo of puberty may approximate to the spontaneous puberty group (median, 2.3 vs. 2.2 years, P = 0.95). In both interventional groups, the FSH level was distinguishable before treatment (median, 65.1 vs. 100.4 mIU/mL, P = 0.02). After long term estrogen therapy, the FSH could be suppressed to similar level in both interventional groups (median, 37.5 vs 34.5 mIU/mL, P = 0.84). Neither LH nor E2 level provided valuable information before and after treatment. ConclusionThe karyotypes were highly correlated with pubertal presentations at Turner syndrome patients. The integrity of 2nd X chromosome plays an important role. Low dose estrogen could mimic the tempo of puberty even delay induction age at Taiwan. The FSH data could provide predictive information of pubertal induction for both interventional groups.

Efficacy of short-term induction therapy with low-dose testosterone as a diagnostic tool in the workup of delayed growth and puberty in boys

Constitutional delay of growth and puberty (CDGP) represents the most frequent cause of delayed puberty in males, sharing some clinical features with growth hormone deficiency (GHD) and isolated hypogonadotropic hypogonadism (IHH). Short-term induction therapy (SIT) has been approved for the induction of puberty in CDGP. We aim to investigate the efficacy of SIT with transcutaneous testosterone gel (TTG) or intramuscular testosterone therapy (IMTT) in a cohort of CDGP subjects, compared to clinical observation. Furthermore, we aim to evaluate the role of SIT as a diagnostic tool to differentiate CDGP from GHD and IHH subjects. The retrospective study included 246 male subjects with delayed puberty. The study population was divided into three groups: TTG, IMTT, and control group (CNT). At 6months observation, height velocity (HV) was significantly increased in both treated groups compared to CNT group, particularly higher in TTG than IMTT group. A significant testicular enlargement was revealed in both CNT and TTG group compared to IMTT group. Furthermore, LH value was significantly greater in TTG compared to IMTT group. IGF-1 values after SIT rose significantly in both treated groups compared to CNT group. Moreover, almost all GH provocative tests performed after SIT showed a normal GH response. SIT with TTG appears to be more effective to induce growth spurt, better tolerated and with a more physiological effect on pubertal induction compared to IMTT in CDGP population. Finally, TTG might be a useful tool in the diagnostic work up to discriminate CDGP from GHD or IHH.

Management of a Girl With Delayed Puberty and Elevated Gonadotropins.

A girl presenting with delayed puberty and elevated gonadotropins may have a range of conditions such as Turner syndrome (TS), primary ovarian insufficiency (POI), and 46,XY disorders of sexual development (DSD). An organized and measured approach to investigation can help reach a timely diagnosis. Management of young people often requires specialist multidisciplinary input to address the endocrine and nonendocrine features of these complex conditions, as well as the psychological challenges posed by their diagnosis. Next-generation sequencing within the research setting has revealed several genetic causes of POI and 46,XY DSD, which may further facilitate an individualized approach to care of these young people in the future. Pubertal induction is required in many and the timing of this may need to be balanced with other issues specific to the condition (eg, allowing time for information-sharing in 46,XY DSD, optimizing growth in TS). Shared decision-making and sign-posting to relevant support groups from the outset can help empower young people and their families to manage these conditions. We describe 3 clinical vignettes of girls presenting with delayed puberty and hypergonadotropic amenorrhea and discuss their clinical management in the context of current literature and guidelines.

Breast satisfaction in adult women with Turner syndrome-An international survey employing the BREAST-Q questionnaire.

Turner syndrome (TS) is associated with short stature, delayed puberty, primary ovarian insufficiency, and other features. Most girls with TS require oestrogen replacement for pubertal induction. There is paucity of data in adult TS on pubertal outcomes, including breast satisfaction. Here, we assess breast satisfaction in TS with the BREAST-Q questionnaire, a well-validated patient-related outcome measure (PROM). International survey distributed online through TS support groups. Adult women aged 18-45 years with TS (self-reported). The questionnaire contained demographics, health history and the four domains of the BREAST-Q. BREAST-Q scores were matched on a one-to-one basis for age, body mass index(BMI) and educational background to a normative data set derived from the 'Army of Women', an online community of healthy volunteers. Of 97 total responses, 74 could be matched to the control cohort. Median age was 32 years (18-45 years) and 97% were White Caucasian. Median age at menarche was 15.5 years (12-34 years), 86% had received pubertal induction therapy as teenagers. We found significantly lower BREAST-Q scores in TS in the domains 'Satisfaction with Breast' (p = .021), 'Psychosocial Wellbeing' (p < .0001) and 'Sexual Wellbeing' (p < .0001). TS who had received oestrogen replacement therapy reported lower scores compared to TS who had not received oestrogen therapy (p < .0001). Lower BMI and previous growth hormone therapy were associated with lower breast satisfaction. TS women who received oestrogen replacement for pubertal induction self-report lower breast satisfaction scores and late menarche, suggesting that type, mode of delivery, dose and timing of hormone supplements merit prospective study.

Pubertal induction in girls with hypogonadism: insight into estrogen replacement therapy outcomes and optimization of progesterone introduction

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Puberty induction with recombinant gonadotropin: What impact on future fertility?

Congenital hypogonadotropic hypogonadism (CHH) is a group of rare diseases characterized by inadequate secretion of the gonadotropins LH (luteinizing hormone) and FSH (follicle stimulating hormone) during the physiological activation periods of the gonadotropic axis. The disease? (anomaly) is present from fetal life and usually persists throughout life. Clinically, hypogonadotropic hypogonadism is associated with neonatal clinical signs (micropenis, cryptorchidism in boys in about half of the cases). The diagnosis is sometimes only evoked in the presence of an absence or arrest of pubertal maturation in the adolescent, which is often poorly tolerated physically and psychologically. Different therapeutic options for pubertal induction have been described, but we lack the necessary larger randomized trials to define the best approaches for both sexes. Historically, congenital hypogonadotropic hypogonadism diagnosed at puberty is treated with testosterone injections. These injections allow the development of secondary sexual characteristics, without an increase in testicular volume in severe forms (FSH deficiency), and a pubertal statural peak. During the last twenty years, studies have underlined the beneficial role of recombinant gonadotropins to induce puberty in this population for future fertility. This is what we will develop.

Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline

An Endo-European Reference Network guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult and 2 patient representatives. The guideline was endorsed by the European Society for Pediatric Endocrinology, the European Society for Endocrinology and the European Academy of Andrology. The aim was to create practice guidelines for clinical assessment and puberty induction in individuals with congenital pituitary or gonadal hormone deficiency. A systematic literature search was conducted, and the evidence was graded according to the Grading of Recommendations, Assessment, Development and Evaluation system. If the evidence was insufficient or lacking, then the conclusions were based on expert opinion. The guideline includes recommendations for puberty induction with oestrogen or testosterone. Publications on the induction of puberty with follicle-stimulation hormone and human chorionic gonadotrophin in hypogonadotropic hypogonadism are reviewed. Specific issues in individuals with Klinefelter syndrome or androgen insensitivity syndrome are considered. The expert panel recommends that pubertal induction or sex hormone replacement to sustain puberty should be cared for by a multidisciplinary team. Children with a known condition should be followed from the age of 8 years for girls and 9 years for boys. Puberty induction should be individualised but considered at 11 years in girls and 12 years in boys. Psychological aspects of puberty and fertility issues are especially important to address in individuals with sex development disorders or congenital pituitary deficiencies. The transition of these young adults highlights the importance of a multidisciplinary approach, to discuss both medical issues and social and psychological issues that arise in the context of these chronic conditions.

Oral Hormone replacement treatment and uterine volume in Korean adolescent with Turner syndrome: retrospective case-control study.

Background: For girls diagnosed Turner syndrome (TS) before puberty, pubertal induction by hormone replacement treatment (HRT) is a generalized treatment of choice. A few studies conducted in TS patients reported that uterine volume (UV) has been significantly smaller in pubertal induction group with HRT. In current study, we aimed to investigate UV among pubertal induction (PI) versus natural menarche (NM) group in TS, and normal control group. In detail, we ought to elucidate the factors that affect uterine development during HRT.

Pubertal induction in girls with Turner Syndrome.

Turner Syndrome (TS) is the most common female sex chromosome aneuploidy in females, and patients may present with hypergonadotropic hypogonadism due to gonadal dysgenesis. Timing and modalities of pubertal induction in these patients is still a matter of debate. Aim of this review was to focus on the latest update on pubertal induction in TS. Based on literature data, the following practical approach to this issue is recommended. Pubertal induction should begin between 11 and 12 years of age, starting with low doses of estradiol to preserve height potential. Transdermal 17β-Estradiol (17β-E2) could represent the first-choice induction regimen as it is more physiologic compared to an oral regimen and avoids the first-pass mechanism in the liver. In the case of poor compliance, administration of oral 17β-E2 or ethinyl estradiol could be offered. Incremental dose increases, approximately every 6 months, can contribute to mimic normal pubertal progression until adult dosing is reached over a 2- to 3-year period. Progestin should be added once breakthrough bleeding occurs or after 2 to 3 years of estrogen therapy or if ultrasound shows a mature uterus with thick endometrium. Treatment needs to be individualized and monitored by clinical assessment in relation to patient compliance and satisfaction. Well-designed prospective randomized clinical trials aimed to identify the best estrogen regimen for pubertal induction in TS girls are needed.

New and Consolidated Therapeutic Options for Pubertal Induction in Hypogonadism: In-depth Review of the Literature.

Delayed puberty (DP) defines a retardation of onset/progression of sexual maturation beyond the expected age from either a lack/delay of the hypothalamo-pituitary-gonadal axis activation or a gonadal failure. DP usually gives rise to concern and uncertainty in patients and their families, potentially affecting their immediate psychosocial well-being and also creating longer term psychosexual sequelae. The most frequent form of DP in younger teenagers is self-limiting and may not need any intervention. Conversely, DP from hypogonadism requires prompt and specific treatment that we summarize in this review. Hormone therapy primarily targets genital maturation, development of secondary sexual characteristics, and the achievement of target height in line with genetic potential, but other key standards of care include body composition and bone mass. Finally, pubertal induction should promote psychosexual development and mitigate both short- and long-term impairments comprising low self-esteem, social withdrawal, depression, and psychosexual difficulties. Different therapeutic options for pubertal induction have been described for both males and females, but we lack the necessary larger randomized trials to define the best approaches for both sexes. We provide an in-depth and updated literature review regarding therapeutic options for inducing puberty in males and females, particularly focusing on recent therapeutic refinements that better encompass the heterogeneity of this population, and underlining key differences in therapeutic timing and goals. We also highlight persistent shortcomings in clinical practice, wherein strategies directed at "the child with delayed puberty of uncertain etiology" risk being misapplied to older adolescents likely to have permanent hypogonadism.