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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 -
Current Opinion in Endocrinology,... Dec 2014This review focuses on the pathogenesis, diagnosis, management and long-term outcomes of disorders of sex development, specifically women with Swyer syndrome (46,XY... (Review)
Review
PURPOSE OF REVIEW
This review focuses on the pathogenesis, diagnosis, management and long-term outcomes of disorders of sex development, specifically women with Swyer syndrome (46,XY complete gonadal dysgenesis).
RECENT FINDINGS
Recent discoveries have broadened our understanding of the complex pathways involved in normal and abnormal sex development. In 46,XY gonadal dysgenesis, lack of testis development may be triggered by sex determining region Y, NR5A1, DHH or testis-determining gene loss-of-function mutations, DAX1 or WNT4 duplication or MAP3K1 gain-of-function mutations. The diagnosis and management of patients with Swyer syndrome is complex, and optimal care requires an experienced multidisciplinary team. Early diagnosis is vital because of the significant risk of germ cell tumour, and bilateral gonadectomy should be performed. Furthermore, early sex hormone treatment is necessary to induce and maintain typical pubertal development and to achieve optimal bone mineral accumulation. Pregnancy is possible via ova donation, and outcomes are similar to women with 46,XX ovarian failure.
SUMMARY
Further pathogenic gene mutations are likely to be identified, and the function, interaction and phenotypic effects of new and existing mutations will be further defined. Patients require long-term follow-up in specialist centres.
Topics: Bone Density; Early Diagnosis; Female; Fertility Preservation; Gonadal Dysgenesis, 46,XY; Gonadal Steroid Hormones; Hormone Replacement Therapy; Humans; Neoplasms, Germ Cell and Embryonal; Ovarian Neoplasms; Prognosis; Sexual Development
PubMed: 25314337
DOI: 10.1097/MED.0000000000000113 -
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 -
Pediatric Nephrology (Berlin, Germany) May 2016Renal transplantation (RTx) has become an accepted mode of therapy in infants with severe renal failure. The major indications are structural abnormalities of the... (Review)
Review
Renal transplantation (RTx) has become an accepted mode of therapy in infants with severe renal failure. The major indications are structural abnormalities of the urinary tract, congenital nephrotic syndrome, polycystic diseases, and neonatal kidney injury. Assessment of these infants needs expertise and time as well as active treatment before RTx to ensure optimal growth and development, and to avoid complications that could lead to permanent neurological defects. RTx can be performed already in infants weighing around 5 kg, but most operations occur in infants with a weight of 10 kg or more. Perioperative management focuses on adequate perfusion of the allograft and avoidance of thrombotic and other surgical complications. Important long-term issues include rejections, infections, graft function, growth, bone health, metabolic problems, neurocognitive development, adherence to medication, pubertal maturation, and quality of life. The overall outcome of infant RTx has dramatically improved, with long-term patient and graft survivals of over 90 and 80 %, respectively.
Topics: Age Factors; Body Weight; Child Development; Donor Selection; Graft Survival; Humans; Infant; Infant, Newborn; Intraoperative Care; Kidney Transplantation; Postoperative Complications; Renal Insufficiency; Risk Factors; Severity of Illness Index; Time Factors; Time-to-Treatment; Treatment Outcome
PubMed: 26115617
DOI: 10.1007/s00467-015-3144-0 -
Current Opinion in HIV and AIDS May 2018We present an overview of recent research in the inter-related areas of growth and pubertal development among adolescents with HIV. Growth deficits early in childhood... (Review)
Review
PURPOSE OF REVIEW
We present an overview of recent research in the inter-related areas of growth and pubertal development among adolescents with HIV. Growth deficits early in childhood can lead to delayed puberty, with subsequent effects on pubertal growth spurts and bone health.
RECENT FINDINGS
Impaired growth remains a critical concern, particularly in low-resource settings, where stunting, wasting and underweight remain pervasive. Antiretroviral treatment (ART) initiation results in improved growth, with greatest growth recovery in the first years and more improvement in weight than in height. However, even years after ART initiation, growth deficits persist in low-resource settings (LRS), and adolescents appear at particularly increased risk. The high prevalence of stunting translates to delays in pubertal onset and sexual maturity. In contrast, HIV-infected adolescents in developed countries do not demonstrate persistent wasting, yet still have delayed pubertal development. Impaired growth increases the risk for mortality, virologic failure, and abnormal bone health, as well as increased depression and stigma.
SUMMARY
Early initiation of ART across all age groups regardless of immunological status is essential for restoring growth. Coordination of ART initiation, nutritional supplementation programs, and concurrent prophylaxis is required to ameliorate growth deficits and pubertal delays, particularly in LRS.
Topics: Adolescent; Adolescent Development; Adolescent Health; Anti-HIV Agents; HIV; HIV Infections; Humans; Puberty
PubMed: 29432228
DOI: 10.1097/COH.0000000000000450 -
Pediatric Endocrinology Reviews : PER Sep 2018Growth failure is nearly universal in individuals with Turner syndrome (TS). It is a consequence of haploinsufficiency of the short stature homeobox gene located on the... (Review)
Review
Growth failure is nearly universal in individuals with Turner syndrome (TS). It is a consequence of haploinsufficiency of the short stature homeobox gene located on the short arm of the X chromosome (SHOX). Without treatment, individuals with TS are expected to be on average 20 cm shorter than unaffected adult females. Short stature is cited by patients as one of their biggest burdens and may have an adverse impact on psychosocial well-being, pubertal timing, and ability to complete a variety of daily living activities. The routine use of recombinant human growth hormone (rhGH) treatment has increased height outcomes. Clinical evidence has strongly supported the efficacy and safety of this treatment. In this article we review the rationale for rhGH treatment in TS, the factors that affect treatment response, safety and monitoring considerations, and potential changes in the way rhGH may be utilized in TS care in the future.
Topics: Body Height; Growth Disorders; Growth Hormone; Homeodomain Proteins; Human Growth Hormone; Humans; Short Stature Homeobox Protein; Turner Syndrome
PubMed: 30378785
DOI: 10.17458/per.vol16.2018.bnb.ghtherapyturnersyndrome -
Current Opinion in Pediatrics Feb 2016Crouch gait is defined as excessive ankle dorsiflexion, knee and hip flexion during the stance phase. This gait disorder is common among patients with cerebral palsy.... (Review)
Review
PURPOSE OF REVIEW
Crouch gait is defined as excessive ankle dorsiflexion, knee and hip flexion during the stance phase. This gait disorder is common among patients with cerebral palsy. The present article brings an up-to-date literature review on the pathoanatomy, natural history, and treatment of this frequent gait abnormality.
RECENT FINDINGS
Hamstrings are often not shortened in patients with crouch. Patella alta must be addressed if surgery is performed. Surgical correction of joint contractures and lever arm dysfunction can be effectively achieved through a single-event multilevel surgery.
SUMMARY
Crouch gait is a common gait deviation, often seen among ambulatory diplegic and quadriplegic patients, once they reach the pubertal spurt, when weak muscles can no longer support a toe walking pattern because of rapidly increased weight. This form of gait is highly ineffective and might compromise walking ability over time. The anterior knee is overloaded; pain, extensor mechanism failure, and arthritis might develop. Its progressive nature often requires surgical intervention. The cause of crouch gait is multifactorial, and surgery should be tailored to meet the individual's specific anatomic and physiologic abnormalities.
Topics: Cerebral Palsy; Child; Disease Progression; Gait; Gait Disorders, Neurologic; Humans
PubMed: 26709688
DOI: 10.1097/MOP.0000000000000316