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EClinicalMedicine Sep 2023Anti-androgens and combined oral contraceptive pills (COCPs) may mitigate hyperandrogenism-related symptoms of polycystic ovary syndrome (PCOS). However, their efficacy...
BACKGROUND
Anti-androgens and combined oral contraceptive pills (COCPs) may mitigate hyperandrogenism-related symptoms of polycystic ovary syndrome (PCOS). However, their efficacy and safety in PCOS remain unclear as previous reviews have focused on non-PCOS populations. To inform the 2023 International Evidence-based Guideline in PCOS, we conducted the first systematic review and meta-analysis investigating the efficacy and safety of anti-androgens in the management of hormonal and clinical features of PCOS.
METHODS
We systematically searched MEDLINE, Embase, PsycInfo, All EBM reviews, and CINAHL up to 28th June 2023 for randomised controlled trials (RCTs) examining oral anti-androgen use, alone or in combination with metformin, COCPs, lifestyle, or other interventions, in women of any age, with PCOS diagnosed by Rotterdam, National Institutes of Health or Androgen Excess & PCOS Society criteria, and using a form of contraception. Non-English studies and studies of less than 6 months duration or which used the same anti-androgen regimen in both/all groups were excluded in order to establish efficacy for the clinical outcomes of interest. Three authors screened articles against selection criteria and assessed risk of bias and quality using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. Critical outcomes (prioritised during guideline development for GRADE purposes) included weight, body mass index (BMI), irregular cycles, hirsutism, liver function, and quality of life. Random effects meta-analyses were conducted where appropriate. This study is registered with PROSPERO, CRD42022345640.
FINDINGS
From 1660 studies identified in the search, 27 articles comprising 20 unique studies were included. Of these, 13 studies (n = 961) were pooled in meta-analysis. Seven studies had a high risk of bias, nine moderate and four low. Anti-androgens included finasteride, flutamide, spironolactone, or bicalutamide. In meta-analysis, anti-androgens + lifestyle were superior to metformin + lifestyle for hirsutism (weighted mean difference [WMD] [95% CI]: -1.59 [-3.06, -0.12], p = 0.03; = 74%), SHBG (7.70 nmol/l [0.75, 14.66], p = 0.03; = 0%), fasting insulin and fasting insulin: glucose ratio (-2.11 μU/ml [-3.97, -0.26], p = 0.03; = 0% and -1.12 [-1.44, -0.79], p < 0.0001, = 0%, respectively), but were not superior to placebo + lifestyle for hirsutism (-0.93, [-3.37, 1.51], p = 0.45; = 76%) or SHBG (9.72 nmol/l [-0.71, 20.14], p = 0.07; = 31%). Daily use was more effective for hirsutism than use every three days (-3.48 [-4.58, -2.39], p < 0.0001, = 1%), and resulted in lower androstenedione levels (-0.30 ng/ml [-0.50, -0.10], p = 0.004; = 0%). Combination treatment with anti-androgens + metformin + lifestyle resulted in lower testosterone compared with metformin + lifestyle (-0.29 nmol/l [-0.52, -0.06], p = 0.01; = 61%), but there were no differences in hirsutism when anti-androgens + metformin + lifestyle were compared with either anti-androgens + lifestyle or metformin + lifestyle. In limited meta-analyses (n = 2 trials), combining anti-androgens with COCP resulted in poorer lipid profiles compared with COCP ± placebo, with no differences in other outcomes.
INTERPRETATION
Current evidence does not support the use of anti-androgens preferentially to COCPs to treat hyperandrogenism in PCOS. Anti-androgens could be considered to treat hirsutism in PCOS, where COCPs are contraindicated, poorly tolerated, or present a sub-optimal response after a minimum 6-month period, with consideration of clinical context and individual risk factors and characteristics.
FUNDING
National Health and Medical Research Council (NHMRC) of Australia Monash University.
PubMed: 37583655
DOI: 10.1016/j.eclinm.2023.102162 -
Reproductive Biology and Endocrinology... Jan 2023Metformin is the gold standard insulin sensitizer, which is widely used to treat insulin resistance in polycystic ovary syndrome (PCOS). However, metformin may induce... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Metformin is the gold standard insulin sensitizer, which is widely used to treat insulin resistance in polycystic ovary syndrome (PCOS). However, metformin may induce gastrointestinal side effects.
OBJECTIVE
Inositols have long been debated as a potential alternative for metformin in treating PCOS. Therefore, the present systematic review aimed to evaluate the efficacy and safety of inositols in treating PCOS.
METHODS
The present systematic search was performed in CENTRAL, MEDLINE, and Embase from the inception until October 20th, 2021. Eligible randomized controlled trials (RCTs) included women diagnosed with PCOS and compared any inositols with metformin or placebo. Our primary outcome was cycle normalization, whereas secondary outcomes were body mass index (BMI), parameters of carbohydrate metabolism and clinical and laboratory hyperandrogenism. Results are reported as risk ratios or mean differences (MDs) with 95% confidence intervals (CIs).
RESULTS
Twenty-six RCTs were identified, including data of 1691 patients (806 inositol, 311 with placebo, and 509 metformin groups). In patients treated with inositols, the risk (CI: 1.13; 2.85) of having a regular menstrual cycle was found by 1.79 higher than in the case of placebo. Moreover, the inositols showed non-inferiority compared to metformin in this outcome. In the case of BMI (MD = -0.45; CI: -0.89; -0.02), free testosterone (MD = -0,41, CI: -0.69; -0.13), total testosterone (MD = -20.39, CI: -40.12; -0.66), androstenedione (MD = -0.69, CI: -1,16; -0.22), glucose (MD = -3.14; CI: -5.75; -0.54) levels and AUC insulin (MD = -2081.05, CI: -2745.32; -1416.78) inositol treatment induced greater decrease compared to placebo. Inositol increased sex-hormone-binding globulin significantly compared to placebo (MD = 32.06, CI:1.27; 62.85).
CONCLUSION
Inositol is an effective and safe treatment in PCOS. Moreover, inositols showed non-inferiority in most outcomes compared to the gold standard treatment; metformin.
TRIAL REGISTRATION
PROSPERO registration number: CRD42021283275.
Topics: Female; Humans; Polycystic Ovary Syndrome; Inositol; Hypoglycemic Agents; Randomized Controlled Trials as Topic; Metformin; Testosterone; Insulins
PubMed: 36703143
DOI: 10.1186/s12958-023-01055-z -
Life (Basel, Switzerland) Jan 2023Exposure to endocrine disrupting chemicals (EDCs) can result in alterations of the female reproductive system, including polycystic ovary syndrome (PCOS). The aim of... (Review)
Review
Exposure to endocrine disrupting chemicals (EDCs) can result in alterations of the female reproductive system, including polycystic ovary syndrome (PCOS). The aim of this review was to summarize the knowledge about the association of EDCs (bisphenols, parabens, and triclosan) with PCOS. We conducted an electronic literature search using PubMed for studies published between January 2007 and October 2022 on EDCs related to PCOS, and evaluated the association of PCOS with bisphenols, parabens and triclosan in 15 articles. Most studies revealed significantly higher plasma, urinary or follicular fluid levels of bisphenol A (BPA) in women with PCOS, and some showed a positive correlation of BPA with insulin resistance, polycystic morphology on ultrasound, hepatic steatosis, bilirubin levels, as well as free androgen index, androstenedione and testosterone serum levels, and markers of low-grade chronic inflammation. There was a negative correlation of BPA with markers of ovarian reserve, sex hormone binding globulin and vitamin D-binding protein. Parabens and triclosan have been studied in only one study each, with no significant associations with PCOS observed. Our review revealed an association of BPA with PCOS and negative effects of BPA on human ovaries; more research is needed to assess the potential associations of parabens and triclosan with PCOS.
PubMed: 36676087
DOI: 10.3390/life13010138 -
Therapeutic Advances in Endocrinology... 2022Polycystic ovary syndrome (PCOS) is one of the commonest endocrine disorders affecting women of reproductive age, and metformin is a widely used medication in managing... (Review)
Review
Impact of metformin on the clinical and metabolic parameters of women with polycystic ovary syndrome: a systematic review and meta-analysis of randomised controlled trials.
CONTEXT
Polycystic ovary syndrome (PCOS) is one of the commonest endocrine disorders affecting women of reproductive age, and metformin is a widely used medication in managing this condition.
AIM
To review the available literature comprehensively on the therapeutic impact of metformin on the clinical and metabolic parameters of women with PCOS.
DATA SOURCE
We searched PubMed, MEDLINE, Scopus, Embase, Cochrane Library and the Web of Science and selected sources for grey literature from their inception to April 2020. An updated search in PubMed was performed in June 2022.
DATA SYNTHESIS
Two reviewers selected eligible studies and extracted data, and the review is reported following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
RESULTS
In 24 eligible randomised controlled trials (RCTs) involving 564 participants who received metformin therapy, metformin was associated with significant reduction in body weight by 3.13 kg (95% CI: -5.33, -0.93), body mass index (BMI) by 0.82 kg/m² (95% CI: -1.22, -0.41), fasting blood glucose [standardised mean difference (SMD): -0.23; 95% CI: -0.40, -0.06], low-density lipoprotein cholesterol (LDL-C) (SMD: -0.41; 95% CI: -0.85, 0.03), total testosterone (SMD: -0.33; 95% CI: -0.49, -0.17), androstenedione (SMD: -0.45; 95% CI: -0.70, -0.20), 17-hydroxyprogesterone (17-OHP) (SMD: -0.58; 95% CI: -1.16, 0.00) and increase the likelihood of clinical pregnancy rate [odds ratio (OR): 3.00; 95% CI: 1.95, 4.59] compared with placebo.
CONCLUSION
In women with PCOS, metformin use has shown a positive impact in reducing body weight, BMI, total testosterone, androstenedione, 17-OHP, LDL-C, fasting blood glucose and increasing the likelihood of pregnancy in women with PCOS.
PubMed: 36225721
DOI: 10.1177/20420188221127142 -
Archives of Endocrinology and Metabolism Mar 2022The fundamental objective of military field training exercises (FTX) is to prepare military personnel for real-life operations through simulated scenarios. These... (Review)
Review
The fundamental objective of military field training exercises (FTX) is to prepare military personnel for real-life operations through simulated scenarios. These training sessions often require extreme physical efforts with prolonged, high-intensity exercises that can be combined with food restrictions and partial, or total, sleep deprivation. Such conditions can compromise an individual's physical performance and cause tissue damage, thus affecting their health. This study aimed to perform a systematic review of the literature to identify studies that measured the changes in hormone levels and biomarkers of cellular injury and oxidative stress resulting from FTX with high levels of energy expenditure combined with food and sleep restrictions. PubMed and the Scopus database were searched for articles that combined physical effort/food restriction/sleep deprivation with military training. The initial database search identified 158 articles that were reduced to 18 after confirmation. Significant reductions were reported in thyroid hormones, T3, T4, and anabolic hormones such as testosterone, insulin and androstenedione. An exception for GH was found, which increased throughout FTX. Less distinct responses to FTX were observed with cortisol, TSH and LH. The presence of biomarkers for cellular damage (myoglobin, TNF, and CRP) and increased immune response activities were also described. The scarcity of information on oxidative stress, analyses of cellular injury and biomarkers of inflammatory responses warrants the future study of these topics, which could be helpful in facilitating the safe and effective physical preparations of the members of the armed forces.
PubMed: 35289515
DOI: 10.20945/2359-3997000000443 -
International Journal of Molecular... Nov 2021There is increasing evidence that steroid hormone levels and, especially, androgen levels are elevated in autism. An overactivity of 17, 20-lyase with a higher... (Meta-Analysis)
Meta-Analysis
There is increasing evidence that steroid hormone levels and, especially, androgen levels are elevated in autism. An overactivity of 17, 20-lyase with a higher production of the testosterone precursors dehydroepiandrosterone (DHEA) and androstenedione/androstenediol seems especially present in autism. An encompassing literature analysis was performed, searching for altered androgens in children with autism and using preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. Included were all studies published before 31 March 2021 found using the following electronic databases: PubMed, Google Scholar, Cochrane Library, Scopus, and TRIP. Eight studies with boys and three studies with girls where steroid hormone measurements were performed from either plasma, urine, or saliva were found and analyzed. Analyses were performed for DHEA(-S/-C), androstenedione/androstenediol, and testosterone. Effect sizes were calculated for each parameter between mean concentrations for children with autism versus healthy controls. Higher levels of androgens in autism were detected, with the majority of calculated effect sizes being larger than one. We found higher levels of the main testosterone precursors DHEA, androstenedione, and androstenediol, likely causing an additionally higher level of testosterone, and an increased 17, 20-lyase activity is therefore implied. Medications already used in PCOS such as metformin might be considered to treat hyperandrogenism in autism following further research.
Topics: Androgens; Androstenediol; Androstenedione; Autistic Disorder; Child; Child, Preschool; Dehydroepiandrosterone; Female; Humans; Hyperandrogenism; Lyases; Male; Saliva; Testosterone
PubMed: 34830216
DOI: 10.3390/ijms222212324 -
The Cochrane Database of Systematic... Jan 2021Statins are one of the most prescribed classes of drugs worldwide. Atorvastatin, the most prescribed statin, is currently used to treat conditions such as... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Statins are one of the most prescribed classes of drugs worldwide. Atorvastatin, the most prescribed statin, is currently used to treat conditions such as hypercholesterolaemia and dyslipidaemia. By reducing the level of cholesterol, which is the precursor of the steroidogenesis pathway, atorvastatin may cause a reduction in levels of testosterone and other androgens. Testosterone and other androgens play important roles in biological functions. A potential reduction in androgen levels, caused by atorvastatin might cause negative effects in most settings. In contrast, in the setting of polycystic ovary syndrome (PCOS), reducing excessive levels of androgens with atorvastatin could be beneficial.
OBJECTIVES
Primary objective To quantify the magnitude of the effect of atorvastatin on total testosterone in both males and females, compared to placebo or no treatment. Secondary objectives To quantify the magnitude of the effects of atorvastatin on free testosterone, sex hormone binding globin (SHBG), androstenedione, dehydroepiandrosterone sulphate (DHEAS) concentrations, free androgen index (FAI), and withdrawal due to adverse effects (WDAEs) in both males and females, compared to placebo or no treatment.
SEARCH METHODS
The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to 9 November 2020: the Cochrane Hypertension Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; ;two international trials registries, and the websites of the US Food and Drug Administration, the European Patent Office and the Pfizer pharmaceutical corporation. These searches had no language restrictions. We also contacted authors of relevant articles regarding further published and unpublished work.
SELECTION CRITERIA
RCTs of daily atorvastatin for at least three weeks, compared with placebo or no treatment, and assessing change in testosterone levels in males or females.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the citations, extracted the data and assessed the risk of bias of the included studies. We used the mean difference (MD) with associated 95% confidence intervals (CI) to report the effect size of continuous outcomes,and the risk ratio (RR) to report effect sizes of the sole dichotomous outcome (WDAEs). We used a fixed-effect meta-analytic model to combine effect estimates across studies, and risk ratio to report effect size of the dichotomous outcomes. We used GRADE to assess the certainty of the evidence.
MAIN RESULTS
We included six RCTs involving 265 participants who completed the study and their data was reported. Participants in two of the studies were male with normal lipid profile or mild dyslipidaemia (N = 140); the mean age of participants was 68 years. Participants in four of the studies were female with PCOS (N = 125); the mean age of participants was 32 years. We found no significant difference in testosterone levels in males between atorvastatin and placebo, MD -0.20 nmol/L (95% CI -0.77 to 0.37). In females, atorvastatin may reduce total testosterone by -0.27 nmol/L (95% CI -0.50 to -0.04), FAI by -2.59 nmol/L (95% CI -3.62 to -1.57), androstenedione by -1.37 nmol/L (95% CI -2.26 to -0.49), and DHEAS by -0.63 μmol/l (95% CI -1.12 to -0.15). Furthermore, compared to placebo, atorvastatin increased SHBG concentrations in females by 3.11 nmol/L (95% CI 0.23 to 5.99). We identified no studies in healthy females (i.e. females with normal testosterone levels) or children (under age 18). Importantly, no study reported on free testosterone levels.
AUTHORS' CONCLUSIONS
We found no significant difference between atorvastatin and placebo on the levels of total testosterone in males. In females with PCOS, atorvastatin lowered the total testosterone, FAI, androstenedione, and DHEAS. The certainty of evidence ranged from low to very low for both comparisons. More RCTs studying the effect of atorvastatin on testosterone are needed.
Topics: Aged; Androgens; Androstenedione; Atorvastatin; Bias; Dehydroepiandrosterone Sulfate; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Placebos; Polycystic Ovary Syndrome; Randomized Controlled Trials as Topic; Sex Factors; Sex Hormone-Binding Globulin; Testosterone
PubMed: 33482034
DOI: 10.1002/14651858.CD013211.pub2 -
International Journal of Endocrinology 2020Metformin is an important component of PCOS treatment. At present, the effect of metformin in overweight women with PCOS has not been evaluated. Therefore, we conducted... (Review)
Review
OBJECTIVE
Metformin is an important component of PCOS treatment. At present, the effect of metformin in overweight women with PCOS has not been evaluated. Therefore, we conducted a systematic review to assess the effects of metformin in overweight women with PCOS and to analyze the effects of metformin in overweight women with PCOS.
METHODS
We searched the PubMed, Cochrane Library, Embase, CNKI, VIP, and Wanfang databases for studies published before March 2020. Randomized controlled trials were identified to study the effects of metformin in overweight women with PCOS. Data from studies including body mass index (BMI), waist circumference (WC), follicle-stimulating hormone (FSH), homeostasis model assessment of insulin resistance (HOMA-IR), luteinizing hormone (LH), sex hormone-binding globulin (SHBG), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol (TC), triglycerides (TG), fasting blood glucose (FBG), fasting insulin, testosterone, and androstenedione were pooled. Qualified trials were selected, and methodological quality was strictly assessed. Two reviewers chose the studies independently of each other.
RESULTS
Twelve trials were included. The intervention group and the control group had significant differences in the changes in body mass index (BMI) (WMD = -1.25, 95% CI (-1.60, -0.91), < 0.00001) and waist circumference (WC) (WMD = -1.41, 95% CI (-2.46, -0.37), =0.008) after metformin. The comprehensive results show that, in all studies, overweight women with polycystic ovary syndrome treated with metformin had significantly improved endocrine and metabolic indicators, including testosterone, follicle-stimulating hormone, luteinizing hormone, and low-density lipoprotein cholesterol. However, metformin did not regulate the secretion indexes of fasting insulin, homeostasis model assessment of insulin resistance, sex hormone-binding globulin, high-density lipoprotein cholesterol, total cholesterol, triglycerides, fasting blood glucose, and androstenedione.
CONCLUSIONS
Compared with control interventions, metformin appears to be an effective intervention for overweight women with PCOS.
PubMed: 33014044
DOI: 10.1155/2020/5150684 -
Reproductive Biology and Endocrinology... Aug 2020Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive-aged women. It is reported that intrauterine exposure to hyperandrogenism... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive-aged women. It is reported that intrauterine exposure to hyperandrogenism may induce the development of PCOS and associated complications in later life. To analyze the intrauterine androgen levels in infants born to PCOS mothers, we evaluated the androgen levels in fetal cord blood through a meta-analysis of observational studies.
MATERIAL AND METHODS
The following online databases were systematically searched: PubMed, EMBASE, Cochrane library databases and Web of Science up to December 2019. Human studies compared cord blood androgen levels, including testosterone (T) and androstenedione (ADION), in fetal cord blood of mothers with and without PCOS. Statistical analysis was performed in Review Manager, Version 5.3, with the inverse variance method based on a random-effects model.
RESULTS
A total of 7 articles were scrutinized and a total of 570 samples including 268 female and 222 male infants were qualified for review. In the mass spectrograph (MS) subgroup, PCOS mothers showed no signs of increased T concentration in umbilical cord blood at birth (4 studies; hazard ratio [HR] = - 0.05; 95% confidence interval [CI] = [- 0.33,0.24]; I = 7%; P = 0.75; fixed-effects model). ADION level tends to be lower in daughters' cord blood of PCOS mothers (3 studies; HR = -0.59; 95%CI = [- 1.00, - 0.19]; I = 0%; P = 0.004; fixed-effects model).
CONCLUSIONS
Fetal cord blood T level is not related to PCOS, while ADION levels tend to be lower in the cord blood of daughters born to mothers with PCOS.
Topics: Adult; Androgens; Child; Child of Impaired Parents; Female; Fetal Blood; Humans; Infant, Newborn; Observational Studies as Topic; Polycystic Ovary Syndrome; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 32782029
DOI: 10.1186/s12958-020-00634-8 -
The Cochrane Database of Systematic... Mar 2020Congenital adrenal hyperplasia (CAH) is an autosomal recessive condition which leads to glucocorticoid deficiency and is the most common cause of adrenal insufficiency... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Congenital adrenal hyperplasia (CAH) is an autosomal recessive condition which leads to glucocorticoid deficiency and is the most common cause of adrenal insufficiency in children. In over 90% of cases, 21-hydroxylase enzyme deficiency is found which is caused by mutations in the 21-hydroxylase gene. Managing individuals with CAH due to 21-hydroxylase deficiency involves replacing glucocorticoids with oral glucocorticoids (including prednisolone and hydrocortisone), suppressing adrenocorticotrophic hormones and replacing mineralocorticoids to prevent salt wasting. During childhood, the main aims of treatment are to prevent adrenal crises and to achieve normal stature, optimal adult height and to undergo normal puberty. In adults, treatment aims to prevent adrenal crises, ensure normal fertility and to avoid the long-term consequences of glucocorticoid use. Current glucocorticoid treatment regimens can not optimally replicate the normal physiological cortisol level and over-treatment or under-treatment is often reported.
OBJECTIVES
To compare and determine the efficacy and safety of different glucocorticoid replacement regimens in the treatment of CAH due to 21-hydroxylase deficiency in children and adults.
SEARCH METHODS
We searched the Cochrane Inborn Errors of Metabolism Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews, and trial registries (ClinicalTrials.gov and WHO ICTRP). Date of last search of trials register: 24 June 2019.
SELECTION CRITERIA
Randomised controlled trials (RCTs) or quasi-RCTs comparing different glucocorticoid replacement regimens for treating CAH due to 21-hydroxylase deficiency in children and adults.
DATA COLLECTION AND ANALYSIS
The authors independently extracted and analysed the data from different interventions. They undertook the comparisons separately and used GRADE to assess the quality of the evidence.
MAIN RESULTS
Searches identified 1729 records with 43 records subject to further examination. After screening, we included five RCTs (six references) with a total of 101 participants and identified a further six ongoing RCTs. The number of participants in each trial varied from six to 44, with participants' ages ranging from 3.6 months to 21 years. Four trials were of cross-over design and one was of parallel design. Duration of treatment ranged from two weeks to six months per treatment arm with an overall follow-up between six and 12 months for all trials. Overall, we judged the quality of the trials to be at moderate to high risk of bias; with lack of methodological detail leading to unclear or high risk of bias judgements across many of the domains. All trials employed an oral glucocorticoid replacement therapy, but with different daily schedules and dose levels. Three trials compared different dose schedules of hydrocortisone (HC), one three-arm trial compared HC to prednisolone (PD) and dexamethasone (DXA) and one trial compared HC with fludrocortisone to PD with fludrocortisone. Due to the heterogeneity of the trials and the limited amount of evidence, we were unable to perform any meta-analyses. No trials reported on quality of life, prevention of adrenal crisis, presence of osteopenia, presence of testicular or ovarian adrenal rest tumours, subfertility or final adult height. Five trials (101 participants) reported androgen normalisation but using different measurements (very low-quality evidence for all measurements). Five trials reported 17 hydroxyprogesterone (17 OHP) levels, four trials reported androstenedione, three trials reported testosterone and one trial reported dehydroepiandrosterone sulphate (DHEAS). After four weeks, results from one trial (15 participants) showed a high morning dose of HC or a high evening dose made little or no difference in 17 OHP, testosterone, androstenedione and DHEAS. One trial (27 participants) found that HC and DXA treatment suppressed 17 OHP and androstenedione more than PD treatment after six weeks and a further trial (eight participants) reported no difference in 17 OHP between the five different dosing schedules of HC at between four and six weeks. One trial (44 participants) comparing HC and PD found no differences in the values of 17 OHP, androstenedione and testosterone at one year. One trial (26 participants) of HC versus HC plus fludrocortisone found that at six months 17 OHP and androstenedione levels were more suppressed on HC alone, but there were no differences noted in testosterone levels. While no trials reported on absolute final adult height, we reported some surrogate markers. Three trials reported on growth and bone maturation and two trials reported on height velocity. One trial found height velocity was reduced at six months in 26 participants given once daily HC 25 mg/m²/day compared to once daily HC 15 mg/m²/day (both groups also received fludrocortisone 0.1 mg/day), but as the quality of the evidence was very low we are unsure whether the variation in HC dose caused the difference. There were no differences noted in growth hormone or IGF1 levels. The results from another trial (44 participants) indicate no difference in growth velocity between HC and PD at one year (very low-quality evidence), but this trial did report that once daily PD treatment may lead to better control of bone maturation compared to HC in prepubertal children and that the absolute change in bone age/chronological age ratio was higher in the HC group compared to the PD group.
AUTHORS' CONCLUSIONS
There are currently limited trials comparing the efficacy and safety of different glucocorticoid replacement regimens for treating 21-hydroxylase deficiency CAH in children and adults and we were unable to draw any firm conclusions based on the evidence that was presented in the included trials. No trials included long-term outcomes such as quality of life, prevention of adrenal crisis, presence of osteopenia, presence of testicular or ovarian adrenal rest tumours, subfertility and final adult height. There were no trials examining a modified-release formulation of HC or use of 24-hour circadian continuous subcutaneous infusion of hydrocortisone. As a consequence, uncertainty remains about the most effective form of glucocorticoid replacement therapy in CAH for children and adults. Future trials should include both children and adults with CAH. A longer duration of follow-up is required to monitor biochemical and clinical outcomes.
Topics: Adolescent; Adrenal Hyperplasia, Congenital; Child; Child, Preschool; Dexamethasone; Glucocorticoids; Humans; Infant; Prednisolone; Quality of Life; Randomized Controlled Trials as Topic; Young Adult
PubMed: 32190901
DOI: 10.1002/14651858.CD012517.pub2