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Hormone Research in Paediatrics 2024Recombinant human growth hormone (rhGH) therapy effectively increases height in various disorders of childhood growth. However, whether rhGH affects pubertal timing is... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Recombinant human growth hormone (rhGH) therapy effectively increases height in various disorders of childhood growth. However, whether rhGH affects pubertal timing is unclear. We aimed to review systematically published evidence on the effect of rhGH on pubertal timing.
METHODS
Embase, MEDLINE, and Cochrane Library databases were searched until December 2021 on randomized and non-randomized controlled studies of rhGH in children.
RESULTS
Twenty-five articles (n = 1,433 children) were identified, describing 12 randomized and 13 non-randomized controlled studies in children with idiopathic short stature (ISS; 15 studies), small for gestational age (n = 6 studies), chronic renal failure (n = 3), Noonan syndrome (n = 1), and growth hormone deficiency (n = 1). Significant differences in the effects of rhGH on pubertal timing were found by clinical indication. Only among children with ISS, rhGH promoted earlier age at pubertal timing (mean difference = -0.46 years; 95% CI, -0.90 to -0.03; 9 studies; n total = 397) or higher relative risk for pubertal onset during study follow-up (1.26; 95% CI, 1.03 to 1.54; 6 studies; n total = 284).
CONCLUSIONS
Treatment with rhGH appears to promote earlier pubertal timing among children with ISS. Evidence was lacking in children with growth hormone deficiency due to the absence of studies with untreated controls.
Topics: Child; Humans; Human Growth Hormone; Growth Hormone; Body Height; Growth Disorders; Dwarfism, Pituitary; Recombinant Proteins
PubMed: 37075730
DOI: 10.1159/000530578 -
Transplantation and Cellular Therapy Aug 2022Male gonadal dysfunction is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT) that can lead to disturbances in pubertal development,...
Male gonadal dysfunction is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT) that can lead to disturbances in pubertal development, sexual dysfunction, and infertility. However, no systematic review exists regarding prevalence and risk factors in relation to different treatment regimens. We aimed to systematically evaluate the current evidence regarding the prevalence of male gonadal dysfunction after pediatric HSCT, related risk factors, and the diagnostic value of surrogate markers of spermatogenesis in this patient group. We searched PubMed and Embase using a combination of text words and subject terms. The eligibility screening was conducted using predefined criteria. Data were extracted corresponding to the Leydig cell compartment involved in testosterone production and the germ cell compartment involved in spermatogenesis, respectively. Subsequently, data synthesis was performed. Of 2369 identified records, 25 studies were eligible. The studies were heterogeneous in terms of included diagnoses, gonadotoxic therapy, follow-up time, and definitions of gonadal dysfunction. The data synthesis revealed a preserved Leydig cell function in patients treated with non-total body irradiation (TBI) regimens, whereas the evidence regarding the impact of TBI conditioning on Leydig cell function was conflicting. Based on surrogate markers of spermatogenesis and only limited data on semen quality, the germ cell compartment was affected in half of the patients treated with non-TBI regimens and in nearly all patients treated with TBI conditioning. Testicular irradiation as part of front-line therapy before referral to HSCT led to complete Leydig cell failure and germ cell failure. Evidence regarding the impact of diagnosis, pubertal stage at HSCT, and chronic graft-versus-host disease is limited, as is the evidence of the diagnostic value of surrogate markers of spermatogenesis. Testicular irradiation as part of front-line therapy and TBI conditioning are the main risk factors associated with male gonadal dysfunction after pediatric HSCT; however, impaired spermatogenesis is also observed in half of the patients treated with non-TBI regimens. Methodological shortcomings limit existing evidence, and future studies should include semen quality analyses, follow-up into late adulthood, and evaluation of the cumulative exposure to gonadotoxic therapy.
Topics: Adult; Child; Gonadal Disorders; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Semen Analysis; Transplantation Conditioning; Whole-Body Irradiation
PubMed: 35644480
DOI: 10.1016/j.jtct.2022.05.036 -
The Cochrane Database of Systematic... Mar 2019This is an update of the original review published in the Cochrane Database of Systematic Reviews 2011, Issue 11, and updated in 2015, Issue 4.Chemotherapy has... (Meta-Analysis)
Meta-Analysis
BACKGROUND
This is an update of the original review published in the Cochrane Database of Systematic Reviews 2011, Issue 11, and updated in 2015, Issue 4.Chemotherapy has significantly improved prognosis for women with malignant and some non-malignant conditions. This treatment, however, is associated with ovarian toxicity. The use of gonadotropin-releasing hormone (GnRH) analogues, both agonists and antagonists, may have a protective effect on the ovaries. The primary mechanism of action of GnRH analogues is to suppress the gonadotropin levels to simulate pre-pubertal hormonal milieu and subsequently prevent primordial follicles from maturation and therefore decrease the number of follicles that are more vulnerable to chemotherapy.
OBJECTIVES
To assess the efficacy and safety of GnRH analogues given before or in parallel to chemotherapy to prevent chemotherapy-related ovarian damage in premenopausal women with malignant or non-malignant conditions.
SEARCH METHODS
The search was run for the original review in July 2011, and for the first update in July 2014. For this update we searched the following databases in November 2018: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and the Chinese Biomedicine Database (CBM).
SELECTION CRITERIA
Randomised controlled trials (RCTs), in all languages, which examined the effect of GnRH analogues for chemotherapy-induced ovarian failure in premenopausal women, were eligible for inclusion in the review.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data and assessed trial quality using the Cochrane 'Risk of bias' tool. We analysed binary data using risk ratios (RRs) with 95% confidence intervals (CI) and for continuous data, we used the standardized mean difference (SMD) to combine trials. We applied the random-effects model in our analyses. We used the GRADE approach to produce a 'Summary of findings' table for our main outcomes of interest.
MAIN RESULTS
We included 12 RCTs involving 1369 women between the ages of 12 and 51.1 years. Participants were diagnosed with breast malignancy, ovarian malignancy, or Hodgkin's lymphoma, and most of them received alkylating, or platinum complexes, based chemotherapy. The included studies were funded by a university (n = 1), research centres (n = 4), and pharmaceutical companies (n = 1). Trials were at high or unclear risk of bias.Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy aloneThe incidence of menstruation recovery or maintenance was 178 of 239 (74.5%) in the GnRH agonist group and 110 of 221 (50.0%) in the control group during a follow-up period no longer than 12 months (RR 1.60, 95% CI 1.14 to 2.24; 5 studies, 460 participants; I = 79%; low-certainty evidence), with an overall effect favouring treatment with GnRH agonist (P = 0.006). However, we observed no difference during a follow-up period longer than 12 months between these two groups (P = 0.24). In the GnRH agonist group, 326 of 447 participants had menstruation recovery or maintenance (72.9%) in comparison to the control group, in which 276 of 422 participants had menstruation recovery or maintenance (65.4%) during a follow-up period longer than 12 months (RR 1.08, 95% CI 0.95 to 1.22; 8 studies, 869 participants; I = 56%; low-certainty evidence).The incidence of premature ovarian failure was 43 of 401 (10.7%) in the GnRH agonist group and 96 of 379 (25.3%) in the control group (RR 0.44, 95% CI 0.31 to 0.61; 4 studies, 780 participants; I = 0%; moderate-certainty evidence), with an overall effect favouring treatment with GnRH agonist (P < 0.00001).The incidence of pregnancy was 32 of 356 (9.0%) in the GnRH agonist group and 22 of 347 (6.3%) in the control group (RR 1.59, 95% CI 0.93 to 2.70; 7 studies, 703 participants; I = 0%; low-certainty evidence), with no difference between groups (P = 0.09). However, we are cautious about this conclusion because there were insufficient data about whether the participants intended to become pregnant.The incidence of ovulation was 29 of 47 (61.7%) in the GnRH agonist group and 12 of 48 (25.0%) in the control group (RR 2.47, 95% CI 1.43 to 4.26; 2 studies, 95 participants; I = 0%; low-certainty evidence) with an overall effect favouring treatment with GnRH (P = 0.001).The most common adverse effects of GnRH analogues included hot flushes, vaginal dryness, urogenital symptoms, and mood swings. The pooled analysis of safety data showed no difference in adverse effects between GnRH agonist group and control group.Comparison 2: GnRH agonist-antagonist cotreatment plus chemotherapy versus chemotherapy aloneOnly one RCT discussed GnRH agonist-antagonist cotreatment. The limited evidence showed the incidence of menstruation recovery or maintenance was 20 of 25 (80%) in both cotreatment group and control group during a 12-month follow-up period (RR 1.00, 95% CI 0.76 to 1.32; 50 participants; very low-certainty evidence), with no difference between groups (P = 1.00). In the cotreatment group, 13 of 25 participants had menstruation recovery or maintenance (52.0%) in comparison to the control group, in which 14 of 25 participants had menstruation recovery or maintenance (56.0%) during a follow-up period longer than 12 months (RR 0.93, 95% CI 0.56 to 1.55; 50 participants; very low-certainty evidence), with no difference between groups (P = 0.78). The incidence of pregnancy was 1 of 25 (4.0%) in the cotreatment group and 0 of 25 (0%) in the control group (RR 3.00, 95% CI 0.13 to 70.30; 50 participants; very low-certainty evidence), with no difference between groups (P = 0.49).
AUTHORS' CONCLUSIONS
GnRH agonist appears to be effective in protecting the ovaries during chemotherapy, in terms of maintenance and resumption of menstruation, treatment-related premature ovarian failure and ovulation. Evidence for protection of fertility was insufficient and needs further investigation. Evidence was also insufficient to assess the effect of GnRH agonist and GnRH antagonist cotreatment on ovarian protection against chemotherapy. The included studies differed in some important aspects of design, and most of these studies had no age-determined subgroup analysis. Large and well-designed RCTs with longer follow-up duration should be conducted to clarify the effects of GnRH analogues in preventing chemotherapy-induced ovarian failure, especially on different age groups or different chemotherapy regimens. Furthermore, studies should address the effects on pregnancy rates and anti-tumour therapy.
Topics: Administration, Intranasal; Adolescent; Adult; Antineoplastic Agents; Child; Female; Gonadotropin-Releasing Hormone; Humans; Injections, Intramuscular; Injections, Subcutaneous; Menstruation; Middle Aged; Ovulation; Pregnancy; Pregnancy Rate; Premenopause; Primary Ovarian Insufficiency; Randomized Controlled Trials as Topic; Recovery of Function; Young Adult
PubMed: 30827035
DOI: 10.1002/14651858.CD008018.pub3 -
Transplantation Apr 2017A number of corticosteroid minimization and avoidance protocols for post-solid organ transplant have been developed. The study objective was to examine the effect of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A number of corticosteroid minimization and avoidance protocols for post-solid organ transplant have been developed. The study objective was to examine the effect of corticosteroid withdrawal/avoidance on growth and safety parameters in pediatric solid organ transplant recipients.
METHODS
A systematic review using Medline and Embase was performed. All randomized controlled trials (RCT) and observational studies comparing corticosteroid withdrawal/avoidance to controls receiving corticosteroids in pediatric transplant recipients which reported growth as change in height or final height were included. Two reviewers independently abstracted study data and assessed quality.
RESULTS
The search yielded 930 records, 14 separate studies involving 1146 patients. Renal RCTs (n = 5) showed that corticosteroid withdrawal/avoidance was associated with a significant increase in growth (mean difference in height standard deviation score [SDS], 0.18; 95% confidence interval [95% CI], 0.07-0.29; P = 0.001) compared with those remaining on steroids. In liver RCTs (n = 2), mean difference in height SDS was -0.20 (95% CI, -1.08 to 0.68; P = 0.66). Results for renal observational studies (n = 5) was 0.34 (95% CI, 0.03-0.65; P = 0.03). The most pronounced effect was seen in prepubertal children with SDS of 0.28 (95% CI, 0.14-0.41; P < 0.0001). In pubertal participants this was not observed (SDS, 0.06; 95% CI, -0.04 to 0.15; P = 0.24). Corticosteroid withdrawal/avoidance was not associated with acute rejection (odds ratio [OR], 0.87; P = 0.63), graft failure (OR, 0.45; P = 0.08), or death (OR, 0.34; P = 0.16) in renal trials.
CONCLUSIONS
Corticosteroid withdrawal/avoidance in pediatric renal transplantation is associated with a significant improvement in height. Prepubertal patients appeared to have the greatest benefit. Importantly, the improvement in growth was not accompanied by increased rejection or worsening patient/allograft survival in the short term.
Topics: Adolescent; Adolescent Development; Adrenal Cortex Hormones; Age Factors; Body Height; Chi-Square Distribution; Child; Child Development; Child, Preschool; Graft Rejection; Graft Survival; Growth Disorders; Humans; Immunosuppressive Agents; Infant; Odds Ratio; Organ Transplantation; Puberty; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome
PubMed: 27736823
DOI: 10.1097/TP.0000000000001320