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Endocrine Reviews Sep 2022Delayed puberty (DP) defines a retardation of onset/progression of sexual maturation beyond the expected age from either a lack/delay of the... (Review)
Review
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.
Topics: Adolescent; Child; Female; Gonadotropins; Humans; Hypogonadism; Male; Puberty; Puberty, Delayed; Testosterone
PubMed: 34864951
DOI: 10.1210/endrev/bnab043 -
The Angle Orthodontist Mar 2021To evaluate whether the success of miniscrew-assisted rapid palatal expansion (MARPE), performed in patients with advanced bone maturation is related to factors such as...
OBJECTIVES
To evaluate whether the success of miniscrew-assisted rapid palatal expansion (MARPE), performed in patients with advanced bone maturation is related to factors such as midpalatal suture (MPS) maturation, age, sex, or bicortical mini-implant anchorage.
MATERIALS AND METHODS
Twenty-eight cone beam computed tomography (CBCT) scans of adults and post-pubertal adolescents treated by MARPE were included in the sample. CBCT images before (T0) and after expansion (T1) were used to evaluate the skeletal changes and the success or failure of MARPE. Axial images of MPS were extracted from T0 and classified into one of the five maturation stages. The correlation between MARPE success and the factors of age, sex, MPS maturation, and bicortical mini-implant anchorage was investigated.
RESULTS
Only the age showed a statistically significant negative correlation with MARPE success and all the skeletal measures. There was an 83.3% success rate among individuals aged 15 to 19 years, 81.8% from 20 to 29 years, and 20% from 30 to 37 years. MPS maturation showed a negative correlation with the expansion effect. Subjects with stages B or C of MPS maturation showed a 100% success rate, followed by stage D (62.5%) and stage E (58.3%).
CONCLUSIONS
As age increased, there was a decrease in MARPE success and the skeletal effects of maxillary expansion. Sex and bicortical mini-implant anchorage were not shown to be relevant factors. There was no correlation between MPS maturation and MARPE success; however, it was observed that all cases of MARPE failure were classified as stage D or E of MPS maturation.
Topics: Adolescent; Adult; Cone-Beam Computed Tomography; Cranial Sutures; Humans; Maxilla; Palatal Expansion Technique; Palate; Young Adult
PubMed: 33351888
DOI: 10.2319/051420-436.1 -
Endocrine Reviews Jan 2024Kisspeptin (KP) and neurokinin B (NKB) are neuropeptides that govern the reproductive endocrine axis through regulating hypothalamic gonadotropin-releasing hormone... (Review)
Review
Kisspeptin (KP) and neurokinin B (NKB) are neuropeptides that govern the reproductive endocrine axis through regulating hypothalamic gonadotropin-releasing hormone (GnRH) neuronal activity and pulsatile GnRH secretion. Their critical role in reproductive health was first identified after inactivating variants in genes encoding for KP or NKB signaling were shown to result in congenital hypogonadotropic hypogonadism and a failure of pubertal development. Over the past 2 decades since their discovery, a wealth of evidence from both basic and translational research has laid the foundation for potential therapeutic applications. Beyond KP's function in the hypothalamus, it is also expressed in the placenta, liver, pancreas, adipose tissue, bone, and limbic regions, giving rise to several avenues of research for use in the diagnosis and treatment of pregnancy, metabolic, liver, bone, and behavioral disorders. The role played by NKB in stimulating the hypothalamic thermoregulatory center to mediate menopausal hot flashes has led to the development of medications that antagonize its action as a novel nonsteroidal therapeutic agent for this indication. Furthermore, the ability of NKB antagonism to partially suppress (but not abolish) the reproductive endocrine axis has supported its potential use for the treatment of various reproductive disorders including polycystic ovary syndrome, uterine fibroids, and endometriosis. This review will provide a comprehensive up-to-date overview of the preclinical and clinical data that have paved the way for the development of diagnostic and therapeutic applications of KP and NKB.
Topics: Pregnancy; Female; Humans; Neurokinin B; Kisspeptins; Gonadotropin-Releasing Hormone; Reproduction; Hypothalamus
PubMed: 37467734
DOI: 10.1210/endrev/bnad023 -
Cell Reports. Medicine Nov 2022Leydig cell failure (LCF) caused by gene mutation results in testosterone deficiency and infertility. Serum testosterone levels can be recovered via testosterone...
Leydig cell failure (LCF) caused by gene mutation results in testosterone deficiency and infertility. Serum testosterone levels can be recovered via testosterone replacement; however, established therapies have shown limited success in restoring fertility. Here, we use a luteinizing hormone/choriogonadotrophin receptor (Lhcgr)-deficient mouse model of LCF to investigate the feasibility of gene therapy for restoring testosterone production and fertility. We screen several adeno-associated virus (AAV) serotypes and identify AAV8 as an efficient vector to drive exogenous Lhcgr expression in progenitor Leydig cells through interstitial injection. We observe considerable testosterone recovery and Leydig cell maturation after AAV8-Lhcgr treatment in pubertal Lhcgr mice. Of note, this gene therapy partially recovers sexual development, substantially restores spermatogenesis, and effectively produces fertile offspring. Furthermore, these favorable effects can be reproduced in adult Lhcgr mice. Our proof-of-concept experiments in the mouse model demonstrate that AAV-mediated gene therapy may represent a promising therapeutic approach for patients with LCF.
Topics: Male; Mice; Animals; Leydig Cells; Receptors, LH; Dependovirus; Chorionic Gonadotropin; Testosterone; Fertility; Disease Models, Animal; Genetic Therapy
PubMed: 36270285
DOI: 10.1016/j.xcrm.2022.100792 -
Pediatric Clinics of North America Dec 2020Gonadal dysfunction and infertility after cancer treatment are major concerns for childhood cancer survivors and their parents. Uncertainty about fertility or being... (Review)
Review
Gonadal dysfunction and infertility after cancer treatment are major concerns for childhood cancer survivors and their parents. Uncertainty about fertility or being diagnosed with infertility has a negative impact on quality of survival. In this article, determinants of gonadal damage are reviewed and consequences for fertility and pregnancies are discussed. Recommendations for screening and treatment of gonadal function are provided. These should enable timely treatment of gonadal insufficiency aiming to improve linear growth, pubertal development, and sexual functioning. Options for fertility preservation are discussed.
Topics: Antineoplastic Agents; Cancer Survivors; Child; Child Development; Drug-Related Side Effects and Adverse Reactions; Female; Genital Diseases, Female; Genital Diseases, Male; Humans; Male; Neoplasms; Radiotherapy
PubMed: 33131541
DOI: 10.1016/j.pcl.2020.08.003 -
Nature Communications Aug 2022Kiss1 neurons, producing kisspeptins, are essential for puberty and fertility, but their molecular regulatory mechanisms remain unfolded. Here, we report that congenital...
Kiss1 neurons, producing kisspeptins, are essential for puberty and fertility, but their molecular regulatory mechanisms remain unfolded. Here, we report that congenital ablation of the microRNA-synthesizing enzyme, Dicer, in Kiss1 cells, causes late-onset hypogonadotropic hypogonadism in both sexes, but is compatible with pubertal initiation and preserved Kiss1 neuronal populations at the infantile/juvenile period. Yet, failure to complete puberty and attain fertility is observed only in females. Kiss1-specific ablation of Dicer evokes disparate changes of Kiss1-cell numbers and Kiss1/kisspeptin expression between hypothalamic subpopulations during the pubertal-transition, with a predominant decline in arcuate-nucleus Kiss1 levels, linked to enhanced expression of its repressors, Mkrn3, Cbx7 and Eap1. Our data unveil that miRNA-biosynthesis in Kiss1 neurons is essential for pubertal completion and fertility, especially in females, but dispensable for initial reproductive maturation and neuronal survival in both sexes. Our results disclose a predominant miRNA-mediated inhibitory program of repressive signals that is key for precise regulation of Kiss1 expression and, thereby, reproductive function.
Topics: Animals; DEAD-box RNA Helicases; Female; Fertility; Kisspeptins; Male; Mice; MicroRNAs; Neurons; Ribonuclease III; Sexual Maturation
PubMed: 35945211
DOI: 10.1038/s41467-022-32347-4