The dosing regimen for 17-hydroxyprogesterone caproate was suboptimal: lessons for future pharmacotherapy for pregnant women.

BACKGROUND: Makena (17-hydroxyprogesterone caproate) was approved by the United States Food and Drug Administration for the prevention of recurrent spontaneous preterm birth in 2011 under the accelerated approval pathway, but fundamental pharmacokinetic or pharmacodynamic (Phase 1 and Phase 2) studies were not performed. At the time, there were no dose-response or concentration-response data. The therapeutic concentration was not known. The lack of such data brings into question the dosing regimen for 17-hydroxyprogesterone caproate and if it was optimized. OBJECTIVE: The purpose of this study was to evaluate the dosing regimen for 17-hydroxyprogesterone by analyzing 3 data sets in which the 17-hydroxyprogesterone caproate pharmacology was evaluated, namely the Maternal-Fetal Medicine Omega 3 study, the Obstetric-Fetal Pharmacology Research Units study, and the Obstetrical-Fetal Pharmacology Research Centers study. If an inappropriate dosing regimen could be identified, such information could inform future studies of pharmacotherapy in pregnancy. STUDY DESIGN: Data from the Omega 3 study were used to determine if plasma concentration was related to spontaneous preterm birth risk and if a threshold concentration could be identified. Data from the Obstetric-Fetal Pharmacology Research Units study were used to determine the half-life of 17-hydroxyprogesterone caproate and to develop a model to simulate drug concentrations with various dosing regimens. Data from the Obstetrical-Fetal Pharmacology Research Centers study were used to determine the relationship between dose and safety outcomes. RESULTS: Analysis of the Omega 3 data set indicated that the risk for spontaneous preterm birth decreased as the log concentration of 17-hydroxyprogesterone caproate increased (odds ratio, 0.04; 95% confidence interval, 0.00-0.90). A steady state concentration of >9 ng/mL (equivalent to >8 ng/mL at 25-28 weeks) was associated with the lowest risk for spontaneous preterm birth (hazard ratio, 0.52; 95% confidence interval, 0.27-0.98; P=.04); this concentration was not achieved in 25% of subjects who received the 250 mg weekly dose. In the Obstetrical-Fetal Pharmacology Research Units study, the adjusted half-life (median and interquartile range) of 17-hydroxyprogesterone caproate was 14.0 (11.5-17.2) days. Simulations indicated that with the 250 mg weekly dose, >5 weekly injections were required to reach the 9 ng/mL target; however, those with the shortest half-life (corresponding to higher clearance), never reached the targeted 9 ng/mL concentration. In 75% of subjects, a loading dose of 500 mg weekly for 2 weeks followed by 250 mg weekly achieved and maintained the 9 ng/mL concentration within 2 weeks but in those 25% with the shortest half-life, concentrations exceeded the 9 ng/mL target for only 3 weeks. In the Obstetrical-Fetal Pharmacology Research Centers study, all 65 subjects who received a weekly dose of 500 mg exceeded the 9 ng/mL steady state. CONCLUSION: The dosing regimen for 17-hydroxyprogesterone caproate was inadequate. There is a significant inverse relationship between drug concentration and spontaneous preterm birth. The risk was lowest when the concentration exceeded 9 ng/mL, but 25% of women who received the 250 mg weekly dose never reached or maintained this concentration. The drug's long half-life necessitates a loading dose to achieve therapeutic concentrations rapidly. The omission of basic pharmacologic studies to determine the proper dosing may have compromised the effectiveness of 17-hydroxyprogesterone caproate. Future pharmacotherapy trials in pregnancy must first complete fundamental pharmacology studies.

Mineralocorticoid replacement therapy in salt-wasting congenital adrenal hyperplasia.

Patients with salt-wasting congenital adrenal hyperplasia (SW-CAH) usually show pronounced impairment of aldosterone secretion and, therefore, also require mineralocorticoid replacement. While a lot of research and discussion focusses on the glucocorticoid therapy in SW-CAH to replace the missing cortisol and to control adrenal androgen excess, very little research is dealing with mineralocorticoid replacement. However, recent data demonstrated an increased cardiovascular risk in adult CAH patients urging to reflect also on the current mineralocorticoid replacement therapy. In this review, we explain the role and function of the mineralocorticoid receptor, its ligands and inhibitors and its relevance for the therapy of patients with SW-CAH. We performed an extensive literature search and present data on mineralocorticoid therapy in SW-CAH patients as well as clinical advice how to monitor and optimise mineralocorticoid replacement therapy.

Cardiovascular risk in Cuban adolescents and young adults with congenital adrenal hyperplasia.

BACKGROUND: Hyperandrogenism and supraphysiologic glucocorticoid replacement may lead to subclinical atherosclerosis in people with congenital adrenal hyperplasia (CAH) and predispose the development of cardiovascular diseases from an early age. OBJECTIVES: To determine if cardiometabolic risk factors and subclinical atherosclerosis are more frequent in patients with CAH due to 21-hydroxylase deficiency (21OHD) and if there is an association with clinical, hormonal and treatment of 21OHD. MATERIAL AND METHODS: A descriptive prospective cross-sectional study exploring clinical variables, biochemical, hormonal variables, endothelial dysfunction (flow-mediated dilation < 5%) and carotid intima media thickness (≥ 95 percentile in adolescents and ≥ 75 percentile in adults) and epicardial fat. Adolescents and young patients with 21OHD were compared with controls matched by age, sex, body mass index and Tanner stage. RESULTS: Forty four subjects (22 with CAH), 36 (82%) females, with a mean age of 17.1 ± 5.5 years (range 10-30 years) were included. Family history revealed diabetes, hypertension, and hypercholesterolemia with high frequencies in both groups. The blood pressure was similar in both groups. Blood glucose levels were lower and triglycerides higher in patient (both p < 0.01). Epicardial fat was similar between groups and in patients with CAH it was related to cholesterol levels ​​(r = 0.679, p < 0.01), time since CAH diagnosis (r = 0.462, p = 0.03) and glucocorticoid dose (r = 0.499, p = 0.04). Carotid intima media thickness (CIMT) had a tendency to be increased in patients (p = 0.07) and was directly related to 17-hydroxyprogesterone (r = 0.510, p = 0.018), diastolic blood pressure (r = 0.444, p = 0.04) and the homeostatic model assessment (HOMA) index (r = 0.507, p = 0.01). Endothelial dysfunction was not different between groups. CONCLUSIONS: Some cardiometabolic risk factors were increased in patients with CAH and were associated with clinical, hormonal and treatment parameters of CAH. Cardiometabolic risk should be evaluated regularly in patients with CAH.

Clinical analysis of 78 patients with nonclassical 21-hydroxylase deficiency.

PURPOSE: Retrospectively analyze the clinical characteristics of patients with nonclassical 21-hydroxylase deficiency (NC21OHD) as well as the relationship between the gene mutations and endocrine hormones. In addition, the relationship between different basal 17-hydroxyprogesterone (17OHP) levels and patients' glucolipid metabolism, hormone levels, pregnancy, and treatment outcomes were examined. METHODS: Clinical data of 78 females with NC21OHD from January 2012 to July 2022 in the Department of Endocrinology and Metabolism of the Third Affiliated Hospital of Guangzhou Medical University were retrospectively analyzed. Diagnosis was based on the 17OHP level combined with clinical manifestations, imaging, and other endocrine hormones and the cytochrome P450 c21, steroid 21-hydroxylase (CYP21A2) gene. RESULTS: The age at diagnosis of the 78 patients was 29.1 ± 4.2 years; 83.3% (65/78) of the patients had menstrual abnormalities, 70 patients were of childbearing age, and 97.1% (68/70) had a history of infertility with a median time of infertility of 3.6 years. Moreover, 71.8% (56/78) of the patients had polycystic ovaries, 26.9% (21/78) had hyperandrogenemia manifestations on physical examination, 66.7% (52/78) had adrenal hyperplasia, 32.1% (25/78) had combined dyslipidemia, and 41.0% (32/78) had combined insulin resistance. Pathogenic mutations were detected in 78.2% (61/78) of the patients with both CYP21A2 alleles; 14.1% (11/78) of the patients had only one allele and 7.7% (6/78) had no pathogenic mutations. The levels of total testosterone (TT), progesterone (P) (0 min, 30 min), and 17-OHP (0 min, 30 min, 60 min) in the adrenocorticotropic hormone (ACTH) stimulation test varied between the groups. Furthermore, patients with NC21OHD were divided into 17OHP < 2 ng/ml, 2 ng/ml < 17OHP < 10 ng/ml, and 17OHP ≥ 10 ng/ml groups according to their different basal 17OHP levels. The 17OHP ≥ 10 ng/ml group had significantly higher TT, FT4, basal and post-stimulation progesterone, and 17OHP, net value added of 17-hydroxyprogesterone (△17OHP), net value added of 17-hydroxyprogesterone/net value added of cortisol ratio (△17OHP/△F), the incidence of adrenal hyperplasia, and number of gene mutations compared to those of the 17OHP < 2 ng/ml group (P < 0.05). NC21OHD infertile patients who received low-dose glucocorticoids showed a significant increase in pregnancy and live birth rates, and a significant decrease in miscarriage rate (all P < 0.05). CONCLUSION: Comprehensive analysis is important as NCCAH diagnoses may be false positive or false negative based on clinical characteristics, hormone levels, and gene detection. Females with NC21OHD showed varying degrees of fertility decline; thus, low doses of glucocorticoid treatment for infertile females with NC21OHD can improve fertility and fertility outcomes.

21-Deoxycortisol is a Key Screening Marker for 21-Hydroxylase Deficiency.

OBJECTIVES: To assess whether 21-deoxycortisol (21deoxy) can be used to predict 21-hydroxylase deficiency (21OHD) in newborns and to evaluate the influence of gestational age and the timing of collection on 21deoxy concentrations. STUDY DESIGN: 17-hydroxyprogesterone (17OHP) and 21deoxy levels were measured in 906 newborn screening specimens (851 unaffected newborns, 55 confirmed cases of 21OHD) to compare their ability to identify babies with 21OHD. In addition, these 2 steroids were assessed in the unaffected cohort to determine the influence of gestational age (ranging from 23 to 42 weeks) and the timing of specimen collection on the measured concentrations. RESULTS: The gestational age of the newborn impacted both 17OHP and 21deoxy concentrations, but the degree of influence was more substantial for 17OHP. Timing of collection did not affect 21deoxy concentration. Moreover, 21deoxy was a better predictor of 21OHD status compared with 17OHP, with little overlap in concentrations between the unaffected population and confirmed cases of 21OHD. A streamlined decision tree using solely 21deoxy (cutoff value, 0.85 ng/mL) yielded a 91.7% positive predictive value for 21OHD screening. CONCLUSIONS: Our findings demonstrate that 21deoxy is a key disease marker of 21OHD and can be used to improve the accuracy of newborn screening for this disorder.

Diurnal salivary androstenedione and 17-hydroxyprogesterone levels in healthy volunteers for monitoring treatment efficacy of patients with congenital adrenal hyperplasia.

OBJECTIVE: Treatment of congenital adrenal hyperplasia (CAH) patients with glucocorticoids is often challenging since there is a delicate balance between over- and undertreatment. Treatment can be monitored noninvasively by measuring salivary androstenedione (A4) and 17-hydroxyprogesterone (17-OHP). Optimal treatment monitoring requires the establishment of reference values in saliva. DESIGN: A descriptive study. PATIENTS: For this study saliva of 255 healthy paediatric and adult volunteers with an age range of 4-75 years old was used. MEASUREMENTS: We developed a sensitive liquid chromatography-tandem mass spectrometry method, assessed salivary A4 and 17-OHP stability, and measured A4 and 17-OHP concentrations in saliva collected in the morning, afternoon, and evening. RESULTS: We quantified A4 and 17-OHP concentrations in the morning, afternoon, and evening and demonstrated that there is a significant rhythm with the highest levels in the morning and decreasing levels over the day. A4 and 17-OHP concentrations display an age-dependent pattern. These steroids remain stable in saliva at ambient temperature for up to 5 days. CONCLUSIONS: Good stability of the steroids in saliva enables saliva collection by the patient at home. Since salivary A4 and 17-OHP display a diurnal rhythm and age-dependent pattern, we established reference values for both children and adults at three time points during the day. These reference values support treatment monitoring of children and adults with CAH.

Vaginal progesterone vs intramuscular 17-hydroxyprogesterone caproate for prevention of recurrent preterm birth: a randomized controlled trial.

BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality, and previous preterm birth is one of the strongest risk factors for preterm birth. National and international obstetrical societies have different recommendations regarding progesterone formulation for the prevention of recurrent preterm birth. OBJECTIVE: This study aimed to determine whether vaginal progesterone is superior to 17-hydroxyprogesterone caproate in the prevention of recurrent preterm birth in patients with singleton pregnancies who had a previous spontaneous preterm birth. STUDY DESIGN: This was an open-label multicenter pragmatic randomized controlled trial at 5 US centers of patients with singleton pregnancies at <24 weeks of gestation who had a previous spontaneous preterm birth randomized 1:1 to either 200 mg vaginal progesterone suppository nightly or 250 mg intramuscular 17-hydroxyprogesterone caproate weekly from 16 to 36 weeks of gestation. Based on the estimated recurrent preterm birth rate of 36% with 17-hydroxyprogesterone caproate, 95 participants were needed in each arm to detect a 50% reduction in preterm birth rate with vaginal progesterone, with 80% power and 2-sided alpha of 0.05. The primary outcome was preterm birth at <37 weeks of gestation. Prespecified secondary outcomes included preterm birth at <34 and <28 weeks of gestation, mean gestational age at delivery, neonatal morbidity and mortality, and measures of adherence. Analysis was by intention to treat. The chi-square test and Student t test were used as appropriate. P<.05 was considered significant. RESULTS: Overall, 205 participants were randomized; 94 participants in the vaginal progesterone group and 94 participants in 17-hydroxyprogesterone caproate group were included. Although gestational age at enrollment was similar, those assigned to vaginal progesterone initiated therapy earlier (16.9±1.4 vs 17.8±2.5 weeks; P=.001). Overall continuation of assigned formulation until delivery was similar (73% vs 69%; P=.61). There was no significant difference in preterm birth at <37 (31% vs 38%; P=.28; relative risk, 0.81 [95% confidence interval, 0.54-1.20]), <34 (9.6% vs 14.9%; P=.26; relative risk, 0.64 [95% confidence interval, 0.29-1.41]), or <28 (1.1% vs 4.3%; P=.37; relative risk, 0.25 [95% confidence interval, 0.03-2.20]) weeks of gestation. Participants in the vaginal progesterone group had a later mean gestational age at delivery than participants in the 17-hydroxyprogesterone caproate group (37.36±2.72 vs 36.34±4.10 weeks; mean difference, 1.02 [95% confidence interval, 0.01-2.01]; P=.047). CONCLUSION: Vaginal progesterone did not reduce the risk of recurrent preterm birth by 50% compared with 17-OHPC; however, vaginal progesterone may lead to increased latency to delivery. This trial was underpowered to detect a smaller, but still clinically significant, difference in the efficacy of preterm birth prevention. Patient factors that impact adherence and ability to obtain medication in a timely fashion should be included in counseling on progesterone selection.

Reassessment of predictive values of ACTH-stimulated serum 21-deoxycortisol and 17-hydroxyprogesterone to identify CYP21A2 heterozygote carriers and nonclassic subjects.

INTRODUCTION: Heterozygotes (HZs) for 21-hydroxylase deficiency (21OHD) are highly prevalent, ranging from 1:60 to 1:11 for classic and nonclassic (NC) forms, respectively. Detection of HZ and asymptomatic NC by CYP21A2 genotyping is valuable for genetic counselling, but costly, complex and narrowly available. Adrenocorticotropic hormone (ACTH)-stimulated serum 17-hydroxyprogesterone (17P) and 21-deoxycortisol (21DF) discriminate 21OHD phenotypes effectively, notably if measured simultaneously by liquid chromatography-tandem mass spectrometry (LC-MS/MS). OBJECTIVE: This study was performed to reassess former LC-MS/MS-defined post-ACTH 21DF, 17P and cortisol (F) cutoffs in family members at risk for 21OHD. DESIGN AND PATIENTS: Prospective study in which we screened 58 asymptomatic relatives from families with 21OHD patients and compared post-ACTH steroid phenotypes with subsequent genotypes. RESULTS: Post-ACTH 21DF, 17P, F and (21DF + 17P)/F ratio segregate NC, HZ and wild-type (WT) phenotypes (subsequently genotyped) with some overlap. New receiver operating characteristic curve-defined cutoffs for post-ACTH 21DF, 17P and (21DF + 17P)/F ratio are 60 ng/dl, 310 ng/dl and 12 (unitless). Twenty-six of 33 HZ and all 6 NC (82.1%) had post-ACTH 21DF > 60 and 17P > 310 ng/dl, whereas 17/19 WT (89.5%) had values below cutoffs. Post-ACTH 21DF and 17P had a strong positive correlation (r = .9558; p < .001). A (21DF + 17P)/F ratio > 12 correctly identified 36 of 39 HZ plus NC (92.3% sensitivity) with 84.2% specificity (16 of 19 WT). Given the high frequency of 21OHD HZ, the negative prediction of ratio values below 12 excludes heterozygosity in 99.8% and 99.1% for classic and NC mutations, respectively. CONCLUSIONS: Reassessed ACTH-stimulated 21DF and 17P cutoffs by LC-MS/MS (60 and 310 ng/dl, respectively) correctly recognised 82.5% HZ plus NC, but combined precursor-to-product ratio ([21DF + 17P]/F) cutoff of 12 was superior, identifying 92.3% HZ plus NC. Since one WT subject is an outlier (potential HZ), these values would be somewhat better reinforcing their utility for screening asymptomatic relatives at risk for 21OHD.

Prescription medications for use in pregnancy-perspective from the US Food and Drug Administration.

Obstetrical healthcare providers frequently field questions about the safety of medications recommended or prescribed to their pregnant patients. Most women use as least 1 medication during pregnancy; however, there is little information about the safety or appropriate dosing of many medications during this phase of life. In addition, the development of drugs for use in pregnant women trails behind the development of drugs intended for other sectors of the population. Our goal is to inform the obstetrics community about the US Food and Drug Administration authority and their role in approving drugs for marketing. We begin with the statutes that led to the creation of the Food and Drug Administration and its current organization. We then cover drug development and the Food and Drug Administration review process, including the role of the advisory committee. The different types of drug approvals are discussed, with some specific examples. Finally, we enumerate the drugs specifically approved for use in obstetrics and contrast them with drugs commonly used by pregnant women and drugs used "off-label" during pregnancy. The Food and Drug Administration is committed to protecting and advancing the public health of pregnant women by guiding the development and ensuring the availability of effective and safe therapeutics for obstetrical indications and for medical conditions during pregnancy. We hope this review will inspire more research addressing drug use during pregnancy.

Measurement of serum 17-hydroxyprogesterone using isotope dilution liquid chromatography-tandem mass spectrometry candidate reference method and evaluation of the performance for three routine methods.

OBJECTIVES: Accurate measurements of serum 17-hydroxyprogesterone (17OHP) are essential for diagnosis and treatment monitoring for congenital adrenal hyperplasia patients. The performance of serum 17OHP routine methods remains highly variable that calls for a candidate reference measurement procedure (cRMP) to improve the standardization of serum 17OHP measurements. METHODS: Serum samples spiked with internal standards were extracted with a combination of solid-phase extraction and liquid-liquid extraction. The 17OHP was quantified by the isotope dilution coupled with liquid chromatography/tandem mass spectrometry (ID-LC/MS/MS) with electrospray ionization in positive ion mode. Nine structural analogs of 17OHP were evaluated for interferences. The precision and analytical recovery were assessed. Twenty native and 40 spiked serum for performance evaluation were measured by the cRMP and two clinical LC/MS routine methods. RESULTS: No apparent interferences were found with the 17OHP measurement. The within-run, between-run, and total precision for our method were 0.4-0.8%, 0.6-2.0%, and 1.0-2.1% for four pooled serum (2.46-102.72 nmol/L), respectively. The recoveries of added 17OHP were 100.0-100.2%. For the performance of two LC/MS routine methods, they showed relative deviation ranges of -22.1 to 1.1% and -6.7 to 12.8%, respectively. CONCLUSIONS: We developed and validated a reliable serum 17OHP method using ID-LC/MS/MS. The desirable accuracy and precision of this method enable it to serve as a promising cRMP to improve the standardization for serum 17OHP routine measurements.

Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency.

21-Hydroxylase deficiency (21OHD) is a rare genetic disorder in which salt-wasting syndrome occurs in 75% of cases, due to inability to synthesize cortisol and aldosterone. Recent mass spectrometry progress allowed identification of 21-deoxysteroids, i.e., 17-hydroxyprogesterone (17OHP), 21-deoxycortisol (21DF), and 21-deoxycorticosterone (21DB). We hypothesized that they may interfere with mineralocorticoid signaling and fludrocortisone therapy in patients with congenital adrenal hyperplasia (CAH) without effective glucocorticoid replacement and ACTH suppression. Our goal was to quantify circulating 21-deoxysteroids in a pediatric cohort with CAH related to 21OHD and to examine their impact on mineralocorticoid receptor (MR) activation. Twenty-nine patients with salt-wasting phenotype were classified in two groups according to their therapeutic control. During routine follow-up, 17OHP, 21DF, 21DB, and cortisol levels were quantified by liquid chromatography with tandem mass spectrometry before hydrocortisone intake and 1 and 2.5 h following treatment administration. Luciferase reporter gene assays were performed on transfected HEK293T cells while in silico modeling examined structural interactions between these steroids within ligand-binding domain of MR. Plasma 17OHP, 21DF, and 21DB accumulate in uncontrolled patients reaching micromolar concentrations even after hydrocortisone intake. 21DF and 21DB act as partial MR agonists with antagonist features similar to 17OHP, consistent with altered anchoring to Asn770 and unfavorable contact with Ala773 in ligand-binding pocket of MR. Our results demonstrate a complex interaction between all accumulating 21-deoxysteroids in uncontrolled 21OHD patients and mineralocorticoid signaling and suggest that appropriate steroid profiling should optimize management and follow-up of such patients, as keeping those steroids to low plasma levels should attest therapeutic efficacy and prevent interference with MR signaling.

Serum 17-Hydroxyprogesterone is a Potential Biomarker for Evaluating Intratesticular Testosterone.

PURPOSE: Intratesticular testosterone is essential for spermatogenesis and can only be reliably measured with invasive testicular sampling. Previous studies have demonstrated good correlation between intratesticular testosterone and serum 17-hydroxyprogesterone (17-OHP) in men treated with human chorionic gonadotropin. Based on this observation we hypothesized that we can use serum 17-OHP as a serum biomarker for evaluating intratesticular testosterone in men receiving medications that alter serum testosterone. MATERIALS AND METHODS: Initially, we conducted a cross-sectional analysis of men with a single serum 17-OHP evaluation from July 2018 to March 2019. We followed this with a prospective analysis from July 2018 to October 2019 with evaluation of 140 men including fertile controls, and those receiving treatments that alter serum testosterone at baseline and after 3 months of therapy. According to the data distribution, we reported the median and interquartile ranges, and used the Mann Whitney U or Wilcoxon tests. RESULTS: In the initial cross-sectional analysis of 93 men, a total of 30 men received treatments that increase or maintain intratesticular testosterone concentrations, such as clomiphene citrate and/or human chorionic gonadotropin; 21 men received treatments that suppress intratesticular testosterone concentrations (various exogenous testosterone replacement therapy formulations) and 42 fertile men with normal serum testosterone (greater than 300 ng/dl) were used as control. We demonstrated that serum testosterone levels were within normal range among men receiving the various therapies. In contrast, we found that serum 17-OHP was undetectable in men who received exogenous testosterone replacement therapy, as opposed to men receiving human chorionic gonadotropin and/or clomiphene citrate or fertile controls (p <0.05). In the prospective evaluation that ensued, 17-OHP values decreased in the 21 men who received testosterone replacement therapy (47.5 [21-70] to 13.5 [10-23] ng/dl, p <0.05). Conversely, 17-OHP increased in the 55 men who received human chorionic gonadotropin and/or clomiphene citrate when compared to their baseline levels (42 [24-72] to 88 [61-135] ng/dl, p <0.05). CONCLUSIONS: Serum 17-OHP appears to be a reliable serum marker for intratesticular testosterone levels and could potentially be used to titrate or change medications that alter intratesticular testosterone.

Liquid chromatography-tandem mass spectrometry analysis of 17-hydroxyprogesterone in dried blood spots revealed matrix effect on immunoassay.

Immunoassays for measuring 17-hydroxyprogesterone (17-OHP) produce high rates of false positives that impact the identification of congenital adrenal hyperplasia (CAH) in neonates. A confirmatory test with high analytical specificity employing liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology is needed in newborn screening for CAH. 17-OHP and cortisol were extracted from dried blood spot (DBS) samples, resolved on a C18 column, and measured using tandem mass spectrometry. The results were compared with those determined using the AutoDELFIA immunoassay. The LC-MS/MS method had a limit of quantitation of 10.0 and 5.0 ng/mL for 17-OHP and cortisol, respectively. The method characteristics showed coefficient variation (%CV) ≤ 11.9% for both 17-OHP and cortisol, recoveries ranging from 83.1 to 101.5% for 17-OHP and from 95.1 to 102.8% for cortisol, and linearity with R2 = 0.9994 for 17-OHP and R2 = 0.9996 for cortisol, clinical sensitivity of 100.0% and a specificity of 96.4% as obtained by receiver operating characteristic analysis on 45 patient samples when 17-OHP > 39.1 ng/mL was selected as the cutoff value. Comparison between the LC-MS/MS and the AutoDELFIA immunoassay methods revealed a poor correlation for patient DBS samples (R2 = 0.6784); however, an excellent correlation was obtained for QC and proficiency test (PT) DBS samples (R2 = 0.9797). The LC-MS/MS method produced reliable results for 17-OHP and cortisol for the diagnosis of CAH. The AutoDELFIA immunoassay appears to be subject to matrix effects in the analysis for 17-OHP in DBS patient samples. The DBS samples of non-patient origin may not be suitable for assessing analytical accuracy of immunoassays.

Adjuvant 17-hydroxyprogesterone caproate in women with history-indicated cerclage: A systematic review and meta-analysis.

INTRODUCTION: The purpose of this study was to evaluate whether there are additional benefits of 17-hydroxyprogesterone caproate (17-OHPC) supplementation in preventing recurrent spontaneous preterm birth in women with a prophylactic cerclage. MATERIAL AND METHODS: Electronic databases (MEDLINE, Scopus, ClinicalTrials.gov, PROSPERO, EMBASE, Scielo and the Cochrane Central Register of Controlled Trials) were searched for studies published before June 2018. Keywords included "preterm birth", "prophylactic cerclage", "history-indicated cerclage", "pregnancy" and "17-hydroxyprogesterone caproate". Studies comparing history-indicated cerclage alone with cerclage+17-OHPC were included. The primary outcome measure was preterm birth at <24 weeks of gestation. Secondary outcome measures include preterm birth at <28 weeks, <32 weeks and <37 weeks of gestation, respiratory distress syndrome, necrotizing enterocolitis, fetal birthweight, neonatal intensive care unit stay, mean gestational age at delivery, fetal/neonatal death, neurological morbidity (intraventricular hemorrhage plus periventricular leukomalacia), neonatal sepsis and a composite of severe neonatal morbidity. Severe neonatal morbidity was defined as a composite measure of periventricular leukomalacia, intraventricular hemorrhage (grades III and IV), necrotizing enterocolitis or respiratory distress syndrome. Meta-analysis was performed using the random-effects model of DerSimonian and Laird. Risk of bias and quality assessment were performed using the ROBINS-I and GRADE tools, respectively. PROSPERO Registration Number: CRD42018094559. RESULTS: Five studies met the inclusion criteria and were included in the final analysis. Of the 546 women, 357 (75%) received history-indicated cerclage alone and 189 (35%) received adjuvant 17-OHPC. The composite endpoint, severe neonatal morbidity, was present in 84 of 1515 neonates. Though there was a trend toward a reduced risk of preterm birth, the summary estimate of effect was not statistically significant when comparing cerclage alone with cerclage+17-OHPC at <24 weeks (relative risk [RR] .86, 95% confidence interval [CI] .45-1.65). Similarly, we found no differences in preterm birth at <37 weeks (RR .90, 95% CI .70-1.17) and <28 weeks (RR .85, 95% CI .54-1.32) when comparing cerclage alone with cerclage+17-OHPC. There were no differences in fetal birthweight, respiratory distress syndrome or necrotizing enterocolitis comparing cerclage alone with cerclage+17-OHPC. CONCLUSIONS: Intramuscular 17-OHPC in combination with prophylactic cerclage in women with prior preterm birth had no synergistic effect in reducing spontaneous recurrent preterm birth or improving perinatal outcomes.

Androgen profile in young females with insulin resistance; the importance of 17-HydroxyprogesteroneAndrogens in young insulin resistant females.

Considerable researches on sex steroids and insulin action have suggested a mutual interaction between hyperandrogenemia and insulin resistance (IR). The objective of present study was to evaluate the androgens levels in young females with emphasis on the association of 17OHP with IR. Serum concentrations of glucose, insulin, and androgens in 80 young females were measured by standard routine procedures. Total testosterone (TT), dihydrotestosterone (DHT), dehydroepiandrosterone sulfate (DHEAS), androstenedione (ASD), and 17-hydroxyprogesterone (17OHP) levels were higher in patients with IR compared to healthy controls (p < .05). 17OHP was associated with IR and other androgens tested in young females. According to the results, androgen excess was associated with IR in young females and TT appeared to be independent predictor of IR in these patients. These data may suggest that simultaneous quantification of an androgen profile including at least TT, DHT, and 17OHP can present useful clinical information for assessment of androgen excess.

Neonatal screening for congenital adrenal hyperplasia in Southern Brazil: a population based study with 108,409 infants.

BACKGROUND: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder associated with inborn errors of steroid metabolism. 21-hydroxylase enzyme deficiency occurs in 90 to 95% of all cases of CAH, with accumulation of 17 hydroxyprogesterone (17-OHP). Early diagnosis of CAH based on newborn screening is possible before the development of symptoms and allows proper treatment, correct sex assignment, and reduced mortality rates. This study describes the results obtained in the first year of a public CAH screening program in the state of Rio Grande do Sul, Brazil. METHODS: We reviewed the screening database in search of babies with suspected CAH, that is, altered birth-weight adjusted 17-OHP values at screening. The following data were analyzed for this population: screening 17-OHP values, retest 17-OHP values, serum 17-OHP values for those with confirmed CAH on retest, maternal and newborn data, and family history of CAH. For the screening program, 17-OHP levels are determined on dried blood spots obtained in filter paper with GSP solid phase time-resolved immunofluorescence. RESULTS: Of 108,409 newborns screened, eight were diagnosed with CAH (four males, four females). The incidence of CAH in the state was 1:13,551. Six cases were identified as classic salt-wasting CAH and two were cases of virilizing CAH. The positive predictive value (PPV) of the initial screening (before diagnostic confirmation) was 1.6%. The overall rate of false positive results was 0.47%. The number of false positive results was higher among newborns with birth weight < 2000 g. CONCLUSION: The present results support the need for CAH screening by the public health care system in the state, and show that the strategy adopted is adequate. PPV and false positive results were similar to those reported for other states of Brazil with similar ethnic backgrounds.

Basal 17-hydroxyprogesterone cannot accurately predict nonclassical congenital adrenal hyperplasia in children and adolescents.

AIM: This study explored whether using the suggested diagnostic serum basal level of 17-hydroxyprogesterone (6.0 nmol/L) would lead to underdiagnosis of nonclassical congenital adrenal hyperplasia. METHODS: We retrospectively studied 123 patients with nonclassical congenital adrenal hyperplasia, defined as an adrenocorticotropic hormone-stimulated 17-hydroxyprogesterone level of more than 45 nmol/L. Of these 13 had basal 17-hydroxyprogesterone levels of less than 6.0 nmol/L and 110 exceeded that level. The 42 controls had idiopathic premature pubarche. Clinical and laboratory data were reviewed and compared. RESULTS: There were no differences between patients with 17-hydroxyprogesterone levels of <6.0 nmol/L or ≥6.0 nmol/L based on age at presentation, gender, anthropometric measurements, bone age advancement, age at glucocorticoid initiation and hydrocortisone dosage. Patients with basal 17-hydroxyprogesterone <6.0 nmol/L had significantly lower stimulated 17-hydroxyprogesterone levels (p = 0.02) and higher stimulated serum cortisol levels (p < 0.008). Children with nonclassical congenital adrenal hyperplasia and premature pubarche were clinically indistinguishable from controls with idiopathic premature pubarche. Androgen levels were significantly higher in the nonclassical congenital adrenal hyperplasia group. CONCLUSION: A basal 17-hydroxyprogesterone threshold of 6.0 nmol/L was not a sensitive predictive marker for diagnosing nonclassical congenital adrenal hyperplasia. Children whose clinical presentation suggests nonclassical congenital adrenal hyperplasia should undergo diagnostic adrenocorticotropic hormone stimulation testing.

Gestational dating by metabolic profile at birth: a California cohort study.

BACKGROUND: Accurate gestational dating is a critical component of obstetric and newborn care. In the absence of early ultrasound, many clinicians rely on less accurate measures, such as last menstrual period or symphysis-fundal height during pregnancy, or Dubowitz scoring or the Ballard (or New Ballard) method at birth. These measures often underestimate or overestimate gestational age and can lead to misclassification of babies as born preterm, which has both short- and long-term clinical care and public health implications. OBJECTIVE: We sought to evaluate whether metabolic markers in newborns measured as part of routine screening for treatable inborn errors of metabolism can be used to develop a population-level metabolic gestational dating algorithm that is robust despite intrauterine growth restriction and can be used when fetal ultrasound dating is not available. We focused specifically on the ability of these markers to differentiate preterm births (PTBs) (<37 weeks) from term births and to assign a specific gestational age in the PTB group. STUDY DESIGN: We evaluated a cohort of 729,503 singleton newborns with a California birth in 2005 through 2011 who had routine newborn metabolic screening and fetal ultrasound dating at 11-20 weeks' gestation. Using training and testing subsets (divided in a ratio of 3:1) we evaluated the association among PTB, target newborn characteristics, acylcarnitines, amino acids, thyroid-stimulating hormone, 17-hydroxyprogesterone, and galactose-1-phosphate-uridyl-transferase. We used multivariate backward stepwise regression to test for associations and linear discriminate analyses to create a linear function for PTB and to assign a specific week of gestation. We used sensitivity, specificity, and positive predictive value to evaluate the performance of linear functions. RESULTS: Along with birthweight and infant age at test, we included 35 of the 51 metabolic markers measured in the final multivariate model comparing PTBs and term births. Using a linear discriminate analyses-derived linear function, we were able to sort PTBs and term births accurately with sensitivities and specificities of ≥95% in both the training and testing subsets. Assignment of a specific week of gestation in those identified as PTBs resulted in the correct assignment of week ±2 weeks in 89.8% of all newborns in the training and 91.7% of those in the testing subset. When PTB rates were modeled using the metabolic dating algorithm compared to fetal ultrasound, PTB rates were 7.15% vs 6.11% in the training subset and 7.31% vs 6.25% in the testing subset. CONCLUSION: When considered in combination with birthweight and hours of age at test, metabolic profile evaluated within 8 days of birth appears to be a useful measure of PTB and, among those born preterm, of specific week of gestation ±2 weeks. Dating by metabolic profile may be useful in instances where there is no fetal ultrasound due to lack of availability or late entry into care.

17-Hydroxyprogesterone caproate in triplet pregnancy: an individual patient data meta-analysis.

BACKGROUND: Preterm birth complicates almost all triplet pregnancies and no preventive strategy has proven effective. OBJECTIVE: To determine, using individual patient data (IPD) meta-analysis, whether the outcome of triplet pregnancy is affected by prophylactic administration of 17-hydroxyprogesterone caproate (17OHPc). SEARCH STRATEGY: We searched literature databases, trial registries and references in published articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) of progestogens versus control that included women with triplet pregnancies. DATA COLLECTION AND ANALYSIS: Investigators from identified RCTs collaborated on the protocol and contributed their IPD. The primary outcome was a composite measure of adverse perinatal outcome. The secondary outcome was the rate of birth before 32 weeks of gestation. Other pre-specified outcomes included randomisation-to-delivery interval and rates of birth at <24, <28 and <34 weeks of gestation. MAIN RESULTS: Three RCTs of 17OHPc versus placebo included 232 mothers with triplet pregnancies and their 696 offspring. Risk-of-bias scores and between-study heterogeneity were low. Baseline characteristics were comparable between 17OHPc and placebo groups. The rate of the composite adverse perinatal outcome was similar among those treated with 17OHPc and those treated with placebo (34 and 35%, respectively; risk ratio [RR] 0.98, 95% confidence interval [95% CI] 0.79-1.2). The rate of birth at <32 weeks was also similar in the two groups (35 and 38%, respectively; RR 0.92, 95% CI 0.55-1.56). There were no significant between-group differences in perinatal mortality rate, randomisation-to-delivery interval, or other specified outcomes. CONCLUSION: Prophylactic 17OHPc given to mothers with triplet pregnancies had no significant impact on perinatal outcome or pregnancy duration. TWEETABLE ABSTRACT: 17-Hydroxyprogesterone caproate had no significant impact on the outcome or duration of triplet pregnancy.