Progesterone and 17-hydroxy-progesterone concentrations in follicular fluid and serum reflect their production in granulosa and theca cells.

RESEARCH QUESTION: How is the production of progesterone (P4) and 17-hydroxy-P4 (17-OH-P4) regulated between theca cells and granulosa cells during the follicular phase, during ovulation and after transformation into a corpus luteum? DESIGN: Three cohorts were examined: (i) 31 women undergoing natural and stimulated cycles, with serum hormone measurements taken every 3 days; (ii) 50 women undergoing ovarian stimulation, with hormone concentrations in serum and follicular fluid assessed at five time points during final follicle maturation; and (iii) 12 women undergoing fertility preservation, with hormone concentrations evaluated via the follicular fluid of small antral follicles. RESULTS: In the early follicular phase, theca cells primarily synthesized 17-OH-P4 while granulosa cells produced limited P4, maintaining the P4:17-OH-P4 ratio <1. As follicles reached follicle selection at a diameter of approximately 10 mm, P4 synthesis in granulosa cells was up-regulated, but P4 was mainly accumulated in follicular fluid. During final maturation, enhanced activity of the enzyme HSD3B2 in granulosa cells enhanced P4 production, with the P4:17-OH-P4 ratio increasing to >1. The concentration of 17-OH-P4 in the luteal phase was similar to that in the follicular phase, but P4 production increased in the luteal phase, yielding a P4:17-OH-P4 ratio significantly >1. CONCLUSIONS: The P4:17-OH-P4 ratio reflects the activity of granulosa cells and theca cells during the follicular phase and following luteinization in the corpus luteum. Managing the function of granulosa cells is key for reducing the concentration of P4 during ovarian stimulation, but the concerted action of FSH and LH on granulosa cells during the second half of the follicular phase makes this complex.

Sertoli-Leydig Cell Tumor as a Cause of Elevated 17-OH Progesterone.

Virilizing ovarian tumors are rare but a clinically important diagnosis in a patient presenting with hyperandrogenism. Workup of hyperandrogenism is challenging with a broad range of differentials, including adrenal and ovarian pathology, tumoral or nontumoral in nature. Baseline follicular-phase 17-hydroxyprogesterone (17OHP) measurement is part of the investigation algorithm, and elevated levels are often associated with nonclassic congenital adrenal hyperplasia (NCCAH), which can have its first presentation in adolescence or adulthood. This case describes a young adult woman of reproductive age presenting with menstrual irregularity, raised testosterone, and 17OHP. After extensive workup and serial follow-up, she was found to have a Sertoli-Leydig cell tumor of the left ovary and underwent successful laparoscopic salpingo-oophorectomy with normalization of her menstrual irregularity and biochemical resolution of her testosterone and 17OHP levels.

Quality of Life in Children and Young People With Congenital Adrenal Hyperplasia-UK Nationwide Multicenter Assessment.

CONTEXT: Quality of life (QoL) has been inconsistently reported in children and young people (CYP) with congenital adrenal hyperplasia (CAH). OBJECTIVE: Assess QoL in CYP with CAH in the UK alongside biometric and androgen profiles. DESIGN: To define the evidence base for health care delivery, we conducted a cross-sectional study in CYP with CAH in the UK. Questionnaire results were compared with normative data and between groups, and modelled for association with sex, height, weight, body mass index, or steroid biomarkers of CAH control. SETTING: Tertiary care in 14 UK centers. PATIENTS: Results from 104 patients, 55% female, mean age 12.7 years (SD 3.0), paired responses from parents. INTERVENTIONS: Strengths and Difficulties questionnaire (SDQ) and pediatric QoL questionnaire. MAIN OUTCOME MEASURE: Total QoL scores as assessed by SDQ and a pediatric QoL questionnaire in comparison to normative data. RESULTS: Total scores were worse in parents than normative data, but similar in patients. Patient QoL was rated better in social functioning but worse in emotional, school, and peer domains by patients, and worse in total scores and domains of peer problems, and psychosocial, emotional, and school functioning by parents. Parents consistently scored QoL of their children lower than their child. Larger height-SD score and lower weight-SD score were associated with better QoL. Girls with lower steroid biomarkers had worse SDQ scores. CONCLUSIONS: In CYP with CAH, reduced height, increased weight, and hormonal biomarkers consistent with overtreatment were associated with worse QoL; addressing these problems should be prioritized in clinical management.Clinical Trials Registration Number: SCH/15/088.

Premature Pubarche: Time to Revise the Diagnostic Approach?

Premature pubarche (PP) could represent the first manifestation of non-classic congenital adrenal hyperplasia caused by 21 hydroxylase deficiency (NC21OHD) (10-30% of cases). In the last 20 years, the necessity of performing an ACTH test to diagnose NC21OHD in all cases with PP has been questioned, with conflicting results. This study aims to retrospectively evaluate the predictive value of the basal androgens, 17-OHP levels, and auxological features in suggesting the presence of NC21OHD and, thus, the need for a standard ACTH test to confirm the diagnosis. In all, 111 consecutive patients (87 females) with PP and advanced bone age underwent an ACTH test. Of these, 6/111 cases (1 male) were diagnosed with NC21OHD. The mean baseline 17 hydroxyprogesterone (17-OHP), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), delta 4 androstenedione (Δ4A), and testosterone serum levels were higher in NC21OHD patients than in the others (p < 0.05). We found three predictive features for NC21OHD: basal 17 OHP of >200 ng/mL, bone age advance of >2 years, and DHEA-S levels of >228 ng/mL with sensitivity and specificity of 83.3% and 97.1%, 83.3% and 65.7%, and 83.3% and 96.2%, respectively. Our data confirm that the prevalence of NC21OHD is low among patients with PP. Serum 17-OHP of >200 ng/mL could be helpful to decide, in most cases, which patients should undergo the ACTH test. Bone age advance represented an inadequately specific predictive marker of NC21OHD.

Maternal opioid addiction: A potential cause of elevated 17-OH progesterone in neonatal screening.

BACKGROUND: Congenital adrenal hyperplasia (CAH) is a disease that is part of neonatal screening. There are many causes of false-positive results on neonatal screening, and maternal opioid consumption during pregnancy is suspected to increase 17-hydroxyprogesterone (17-OHP) levels at birth. The aim of this study was to determine the effect of maternal drug consumption on 17-OHP values on neonatal screening. MATERIAL AND METHODS: We studied 17-OHP levels of term newborns with reported maternal drug consumption born at the Maternity Hospital of Nancy between 2002 and 2018. These infants were matched with newborns of mothers without drug addiction. The 17-OHP levels, withdrawal syndromes, birth parameters, and maternal characteristics were compared between the two groups. RESULTS: The study included 241 patients (121 in the drug-exposed group, 120 in the control group). The mean 17-OHP levels in newborns of mothers with substance addiction were 9.83 nmol/L compared to 4.90 nmol/L (p=0.0001) in the control group. Newborns exposed to drugs were smaller (p=0.0001), lighter (p=0.0001), had smaller head circumference (p=0.0001), and had lower Apgar scores (p=0.004 at 1 min and p=0.0001 at 5 min). The 17-OHP level did not differ in cases of withdrawal syndrome in drug-exposed newborn (p=0.911). CONCLUSION: A significant increase in 17-OHP levels was observed in newborns exposed to drugs, with no influence of withdrawal syndrome on 17-OHP levels. Maternal substance addiction may be associated with moderately increased 17-OHP levels during neonatal screening.

Diverse effects of α-/ß-estradiol on catalytic activities of human UDP-glucuronosyltransferases (UGT).

ß-estradiol (ß-E2) and α-estradiol (α-E2) act as an endo- and an exon-estrogen in humans, respectively. There is a structural variation in C17-OH configuration of the two estrogens. UDP-glucuronosyltransferases (UGT) are responsible for termination of activities of a variety of endogenous hormones, clinical drugs, and environmental toxicants. The current study was conducted to investigate the effects of the two estrogens towards catalytic activities of UGTs. It was found that ß-E2 could decrease activities of UGT1A9, - 2B4 and - 2B7, with Ki values of a few micro-molars. ß-E2 could additionally accelerate the activity of UGT2B17 via promoting enzyme-substrate binding and increasing the turn over number. Comparatively, α-E2 displayed much stronger inhibitory potentials towards UGT2B7 and - 2B4, but showed little influence to UGT1A9 and - 2B17. The Ki values for inhibition of UGT2B7 in glucuronidation of different substrates by α-E2 were in a nanomolar range that is only about 1/100-1/50 of ß-E2. UGT2B7 structural model was fatherly constructed to explore the mechanism underlying dramatically different inhibition selectivity of the two estrogens. Compared to ß-E2, α-E2 formed more hydrophobic and hydrogen-bonded interactions with the residues in the active pocket. It is concluded that the configuration of E2-17-OH determines the inhibitory potentials towards UGTs. The results are useful in better understanding ligand selectivity of UGTs, as well as in further development of α-E2 in health protection.

17α-Hydroxylase/17,20-Lyase Deficiency in 46,XY: Our Experience and Review of Literature.

CONTEXT: There are more than 100 pathogenic variants in CYP17A1 that have been identified in patients with 17α-hydroxylase/17,20-lyase deficiency (17OHD). OBJECTIVE: We aimed to describe 46,XY patients with 17OHD from our center and review the literature. METHODS: We retrospectively analyzed genetically proven index cases of 17OHD from our 46,XY disorders of sex development cohort and reviewed similar cases from the literature (n = 150). Based on the phenotype, 17OHD probands were classified into combined severe deficiency (n = 128) and combined partial deficiency (n = 16). Additionally, patients with the apparent isolated 17,20-lyase deficiency (n = 7, from 6 families) were noted. Residual enzyme activities with the observed mutant enzymes were divided in 2 categories as < 1% and ≥ 1%, each for hydroxylase and lyase. RESULTS: We present 4 index cases of 46,XY 17OHD with a complete spectrum of undervirilization and 2 novel variants in CYP17A1. In the review, the combined severe deficiency was the most common form, with more frequent female sex of rearing, hypertension, hypokalemia, suppressed renin, higher plasma corticotropin, lower serum cortisol, and androgens. Immunoassay-measured serum aldosterone was frequently (68.2%) unsuppressed (>5 ng/dL). Elevated serum progesterone had high sensitivity for diagnosis of combined 17OHD, even in combined partial deficiency (83.3%). Among patients with clinical phenotype of combined severe deficiency, 11.5% had partial 17α-hydroxylase and complete 17,20-lyase deficiency (>1%/<1%) and had significantly higher serum cortisol than those with < 1%/<1% activity. CONCLUSION: We report the first monocentric case series of Asian Indian 46,XY patients with 17OHD. We propose that a phenotype of severe undervirilization with milder cortisol deficiency may represent a distinct subtype of combined severe 17OHD with residual 17α-hydroxylase activity but severe 17,20-lyase deficiency (>1%/<1%), which needs further validation.

Report from the HarmoSter study: impact of calibration on comparability of LC-MS/MS measurement of circulating cortisol, 17OH-progesterone and aldosterone.

OBJECTIVES: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is recommended for measuring circulating steroids. However, assays display technical heterogeneity. So far, reproducibility of corticosteroid LC-MS/MS measurements has received scant attention. The aim of the study was to compare LC-MS/MS measurements of cortisol, 17OH-progesterone and aldosterone from nine European centers and assess performance according to external quality assessment (EQA) materials and calibration. METHODS: Seventy-eight patient samples, EQA materials and two commercial calibration sets were measured twice by laboratory-specific procedures. Results were obtained by in-house (CAL1) and external calibrations (CAL2 and CAL3). We evaluated intra and inter-laboratory imprecision, correlation and agreement in patient samples, and trueness, bias and commutability in EQA materials. RESULTS: Using CAL1, intra-laboratory CVs ranged between 2.8-7.4%, 4.4-18.0% and 5.2-22.2%, for cortisol, 17OH-progesterone and aldosterone, respectively. Trueness and bias in EQA materials were mostly acceptable, however, inappropriate commutability and target value assignment were highlighted in some cases. CAL2 showed suboptimal accuracy. Median inter-laboratory CVs for cortisol, 17OH-progesterone and aldosterone were 4.9, 11.8 and 13.8% with CAL1 and 3.6, 10.3 and 8.6% with CAL3 (all p<0.001), respectively. Using CAL1, median bias vs. all laboratory-medians ranged from -6.6 to 6.9%, -17.2 to 7.8% and -12.0 to 16.8% for cortisol, 17OH-progesterone and aldosterone, respectively. Regression lines significantly deviated from the best fit for most laboratories. Using CAL3 improved cortisol and 17OH-progesterone between-method bias and correlation. CONCLUSIONS: Intra-laboratory imprecision and performance with EQA materials were variable. Inter-laboratory performance was mostly within specifications. Although residual variability persists, adopting common traceable calibrators and RMP-determined EQA materials is beneficial for standardization of LC-MS/MS steroid measurements.

Comprehensive Genetic Testing of CYP21A2: A Retrospective Analysis in Patients with Suspected Congenital Adrenal Hyperplasia.

The most common form of congenital adrenal hyperplasia (CAH) results from a deficiency of the 21-hydroxylase enzyme (21-OHD), presenting with a broad spectrum of clinical phenotypes according to the CYP21A2 gene mutations. Of the 59 patients with suspected CAH, 62.7% presented a positive genetic result. Of them, 78.4% and 18.9% presented with non-classical and classical forms, respectively. An overall phenotype-genotype correlation of 88.9% was observed. Biochemically, 17-hydroxiprogesterone concentrations were significantly higher in genetically confirmed patients. Genetically, 36 patients presented with previously reported pathogenic variants, and one presented a new variant in homozygosis. Among the 74 alleles tested, point mutations were found in 89.2% and large rearrangements were found in the rest. The most prevalent pathogenic variant was p.(Val282Leu). The inclusion of relatives revealed one further case. Interestingly, 87.5% of relatives were carriers of a pathogenic variant, including two siblings initially classified as genetically positive. In addition, the study of male partners with gestational desire identified several carriers of mild mutations. Studying the allelic distribution of the variants also allowed for reclassifying one patient. In conclusion, a genetic approach including Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA) analysis, and allelic distribution of the pathogenic variants represents a beneficial tool for better classifying patients with 21-OHD.

In vitro activity of itraconazole against SARS-CoV-2.

Although vaccination campaigns are currently being rolled out to prevent coronavirus disease (COVID-19), antivirals will remain an important adjunct to vaccination. Antivirals against coronaviruses do not exist, hence global drug repurposing efforts have been carried out to identify agents that may provide clinical benefit to patients with COVID-19. Itraconazole, an antifungal agent, has been reported to have activity against animal coronaviruses. Using cell-based phenotypic assays, the in vitro antiviral activity of itraconazole and 17-OH itraconazole was assessed against clinical isolates from a German and Belgian patient infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Itraconazole demonstrated antiviral activity in human Caco-2 cells (EC50 = 2.3 µM; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay). Similarly, its primary metabolite, 17-OH itraconazole, showed inhibition of SARS-CoV-2 activity (EC50 = 3.6 µM). Remdesivir inhibited viral replication with an EC50 = 0.4 µM. Itraconazole and 17-OH itraconazole resulted in a viral yield reduction in vitro of approximately 2-log10 and approximately 1-log10 , as measured in both Caco-2 cells and VeroE6-eGFP cells, respectively. The viral yield reduction brought about by remdesivir or GS-441524 (parent nucleoside of the antiviral prodrug remdesivir; positive control) was more pronounced, with an approximately 3-log10 drop and >4-log10 drop in Caco-2 cells and VeroE6-eGFP cells, respectively. Itraconazole and 17-OH itraconazole exert in vitro low micromolar activity against SARS-CoV-2. Despite the in vitro antiviral activity, itraconazole did not result in a beneficial effect in hospitalized COVID-19 patients in a clinical study (EudraCT Number: 2020-001243-15).

Programa cubano de pesquisa neonatal de la hiperplasia suprarrenal congénita: una realidad. 2005-2014 / Cuban neonatal screening program for congenital adrenal hyperplasia: a reality. 2005­2014

Introducción: la hiperplasia suprarrenal congénita (HSC) es el desorden adrenal más común en la infancia y la causa más frecuente de ambigüedad sexual. La forma clásica, que representa los casos más severos de este déficit, se asocia en un 75 % con pérdida de sal. Por otra parte, en los recién nacidos (RN) del sexo femenino se pueden presentar grados severos de virilización de genitales. Objetivo: presentar los resultados (durante diez años), del Programa Cubano de Pesquisa Neonatal (PN) de la HSC, soportado en un procedimiento inmunoenzimático desarrollado en Cuba. Resultados: en el período de enero 2005 a diciembre 2014, se han estudiado 1 140 882 RN y se detectaron 56 niños con HSC, para una incidencia de 1:20 373 RN. La cobertura del programa se ha incrementado hasta llegar en el año 2013 al 99.34 % de todos los RN cubanos. Conclusiones: la existencia del Programa Cubano de PN de HSC, ha permitido estimar la incidencia e incrementar el conocimiento de esta enfermedad. La PN ha posibilitado el diagnóstico precoz en la variedad perdedora de sal, contribuyendo a la disminución de la mortalidad infantil. El Programa ha favorecido a pacientes con formas virilizantes de la enfermedad, mediante la asignación correcta del sexo

Introduction: Congenital Adrenal Hyperplasia (HSC) is the most common adrenal disorder in childhood and the most frequent cause of sexual ambiguity. The classic form, which represents the most severe causes of this deficit, is associated in 75 % with loss of salt. On the other hand, in the NB of the female sex that present severe degrees of virilization of the genitals. Objective: To present result of the application for ten years of the Cuban Neonatal Research Program of the HSC, supported by an inmmunoenzymatic procedure developed in Cuba. Result: In the period from January 2005 to December 2014, using the UMELISA 17 OH PROGESTERONA NEONATAL, 1 140882 RN were detected, for an incidence of 1:20373 RN. The coverage of the program has been increasing until2013 reaching 99.34 % of all Cuban RN. Conclusion: The existence of the Cuban HSC PN Program, has allowed estimating the incidence and increase knowledge of this disease in our country. PN has made possible the early diagnosis of patients with the salt losing variety, contributing to decrease in infant mortality nationwide. The Program has favored patients with virilizing form of the disease, through the correct assignment of sex

The role and importance of auxiliary tests in differential diagnosis in patients with mildly high basal 17-OH-progesterone levels in the evaluation of hirsutism

Background/aim: In the differential diagnosis of hirsutism, early follicular basal 17-OH-progesterone levels sometimes overlap with the diagnosis of late onset congenital adrenal hyperplasia (LOCAH) and other causes of hyperandrogenism. This study aims to investigate the role of some common tests and clinical findings in differential diagnosis in such cases. Materials and methods: One hundred seventy-five female patients with hirsutism and mildly high initial 17-OH-progesterone levels (2-10 ng/mL) were included in the study. The cases were divided into three groups according to their diagnosis: LOCAH (n = 16, mean age = 26.1 ± 6.9), polycystic ovary syndrome (PCOS) (n = 122, mean age = 23.9 ± 5.1), and intracranial hypertension (IH) (n = 37, mean age = 25.2 ± 7.3). Clinical signs and symptoms, such as menstrual irregularity and hirsutism score, and hormone levels including total testosterone and dehydroepiandrosterone sulfate (DHEAS), were compared between the groups. Results: There was no difference between the groups with PCOS, LOCAH, and IH for total testosterone level results (P = 0.461). The DHEAS level was higher in the PCOS group than in the LOCAH group (449.6 ± 151.14 vs. 360.31 ± 152.40, P = 0.044). While there was no difference between the PCOS and LOCAH groups in terms of menstrual irregularity (P = 0.316), the hirsutism score for IH was significantly lower than those of PCOS and LOCAH (9.2 vs. 12.2 and 11.1, respectively; P < 0.001). Basal 17-OH-progesterone levels were higher in the LOCAH group than in the other groups (P = 0.016). Conclusion: While DHEAS level was lower in LOCAH than in PCOS, it was not different from that in IH. While the severity of hirsutism was higher in LOCAH than in IH, it was not different from that in PCOS. Menstrual irregularity was similar between PCOS and LOCAH. According to these results, although the auxiliary tests and clinical findings for the diagnosis of LOCAH contribute to the clinical interpretation, they are not superior to the 17-OH-progesterone level for diagnosis.

Steroid Screening Tools Differentiating Nonclassical Congenital Adrenal Hyperplasia and Polycystic Ovary Syndrome.

PURPOSE: To analyze the performance of basal 17OH-progesterone (17OHP) levels versus the basal 17OHP/cortisol ratio in nonclassical congenital adrenal hyperplasia (NCAH) and polycystic ovary syndrome (PCOS) differential diagnosis. Basal 17OHP levels >10 ng/mL have been used to confirm NCAH diagnosis without the adrenocorticotropic hormone (ACTH) test; however, the optimal cutoff value is a matter of debate. METHODS: A cross-sectional study was performed at the endocrinology and gynecological endocrinology outpatient clinics of a tertiary hospital. A total of 361 patients with PCOS (age 25.0 ± 5.3 years) and 113 (age 19.0 ± 13.6 years) patients with NCAH were enrolled. Basal and ACTH-17OHP levels were measured by radioimmunoassay, and CYP21A2 molecular analysis was performed to confirm hormonal NCAH diagnosis. Receiver operating characteristic curve analysis compared basal 17OHP levels and the 17OHP/cortisol ratio between NCAH and PCOS patients. RESULTS: Basal 17OHP levels were higher in NCAH patients than in those with PCOS (8.85 [4.20-17.30] vs 1.00 [0.70-1.50] ng/mL; P < 0.0001), along with 17OHP/cortisol ratio (0.86 [0.47-1.5]) vs 0.12 [0.07-0.19]; P < 0.0001, respectively). Basal 17OHP levels and the 17OHP/cortisol ratio were strongly correlated in both groups (rho = 0.82; P < 0.0001). Areas under the curves for basal 17OHP levels (0.9528) and the 17OHP/cortisol ratio (0.9455) were not different to discriminate NCAH and PCOS (P > 0.05). Basal 17OHP level >5.4 ng/mL and 17OHP/cortisol ratio >2.90 had 100% specificity to identify NCAH. MAIN CONCLUSIONS: Basal 17OHP levels >5.4 ng/mL can be used to perform differential diagnoses between NCAH and PCOS, dismissing the ACTH test. The basal 17OHP/cortisol ratio was not superior to basal 17OHP levels in this scenario.

Management of the Female With Non-classical Congenital Adrenal Hyperplasia (NCCAH): A Patient-Oriented Approach.

Non-classical congenital adrenal hyperplasia (NCCAH) is considered to be a common monogenic inherited disease, with an incidence range from 1:500 to 1:100 births worldwide. However, despite the high incidence, there is a low genotype-phenotype correlation, which explains why NCCAH diagnosis is usually delayed or even never carried out, since many patients remain asymptomatic or are misdiagnosed as suffering from other hyperandrogenic disorders. For affected adolescent and adult women, it is crucial to investigate any suspicion of NCCAH and determine a firm and accurate diagnosis. The Synacthen test is a prerequisite in the event of clinical suspicion, and molecular testing will establish the diagnosis. In most cases occurring under 8 years of age, the first symptom is premature pubarche. In some cases, due to advanced bone age and/or severe signs of hyperandrogenism, initiation of hydrocortisone treatment prepubertally may be considered. Our unifying theory of the hyperandrogenic signs system and its regulation by internal (hormones, enzymes, tissue sensitivity) and external (stress, insulin resistance, epigenetic, endocrine disruptors) factors is presented in an attempt to elucidate both the prominent genotype-phenotype heterogeneity of this disease and the resultant wide variation of clinical findings. Treatment should be initiated not only to address the main cause of the patient's visit but additionally to decrease abnormally elevated hormone concentrations. Goals of treatment include restoration of regular menstrual cyclicity, slowing the progression of hirsutism and acne, and improvement of fertility. Hydrocortisone supplementation, though not dexamethasone administration, could, as a general rule, be helpful, however, at minimum doses, and also for a short period of time and, most likely, not lifelong. On the other hand, in cases where severe hirsutism and/or acne are present, prescription of oral contraceptives and/or antiandrogens may be advisable. Furthermore, women with NCCAH commonly experience subfertility, therefore, there will be analysis of the appropriate approach for these patients, including during pregnancy, based mainly on genotype. Besides, we should keep in mind that since the same patient will have changing requirements through the years, the attending physician should undertake a tailor-made approach in order to cover her specific needs at different stages of life.

Pharmacokinetics of 17 alpha hydroxyprogesterone caproate in singleton pregnancy and its influence of maternal body size measures.

BACKGROUND: Reducing spontaneous preterm deliveries is a worldwide public health priority. Although many interventions have been studied, 1 of the most effective treatments to decrease recurrent preterm birth is the use of weekly 17 alpha hydroxy progesterone caproate. Previous studies on the influence of excessive adipose tissue and obesity on the use of 17 alpha hydroxyprogesterone caproate for the prevention of recurrent spontaneous preterm deliveries have shown conflicting findings. OBJECTIVE: To estimate the pharmacokinetics of weekly17 alpha hydroxyprogesterone caproate in singleton and to evaluate the effect of maternal body size on the pharmacokinetics parameters. STUDY DESIGN: A prospective, open-label, longitudinal design was implemented for this population pharmacokinetic study. Plasma samples and clinical variables were collected in pregnant women between 16 and 36 weeks' gestational age, carrying a singleton pregnancy and receiving 17 alpha hydroxyprogesterone caproate, 250 mg intramuscularly weekly for the prevention of recurrent spontaneous preterm birth. Pharmacokinetics parameters and significant clinical covariates were estimated using mixed effect modeling. Four body size indicators were used in the model to predict pharmacokinetics parameters: lean body weight, total body weight, body mass index, and body surface area. RESULTS: A total of 56 pregnant women, aged 18-44 years with body mass index of 14.5-54.6 kg/m2, provided 114 17 alpha hydroxyprogesterone caproate plasma samples concentration for analysis. A 1-compartment model with first-order absorption satisfactorily described 17 alpha hydroxyprogesterone caproate pharmacokinetics. Compared to other body size indicators, lean body weight best explained intersubject variability. Age, race, and gestational age did not influence 17 alpha hydroxyprogesterone caproate pharmacokinetics. Lean body weight was the best descriptor for the influence of body size on 17 alpha hydroxyprogesterone caproate apparent clearance. Simulations showed that administration of a standard fixed dose of 250 mg intramuscularly produced substantially lower 17 alpha hydroxyprogesterone caproate plasma concentrations in pregnant women with body mass index >30 kg/m2 compared to those with body mass index <30 kg/m2. Conversely, adjustment of the standard dose for differences in total body weight among women resulted in markedly higher 17 alpha hydroxyprogesterone caproate concentrations in women with body mass index >30 kg/m2 compared to women with lower body mass index. Administration of doses adjusted for lean body weight produced nearly identical 117 alpha hydroxyprogesterone caproate plasma concentrations in both the low- and high-body mass index groups. CONCLUSION: Population pharmacokinetics analysis indicates the clearance significantly increases with increasing lean body mass. Higher 17 alpha hydroxyprogesterone caproate doses, adjusted by maternal lean body mass, may be required in patients with a body mass index >30 to achieve equivalent plasma concentrations in pregnant women with a body mass index <30. Adjustment of 17 alpha hydroxyprogesterone caproate doses for lean body weight produces equivalent systemic 17 alpha hydroxyprogesterone caproate exposure in pregnant women regardless of body size.

Mid-Luteal 17-OH Progesterone Levels in 614 Women Undergoing IVF-Treatment and Fresh Embryo Transfer-Daytime Variation and Impact on Live Birth Rates.

Introduction: Corpus luteum (CL) produces progesterone (P4) and 17-OH progesterone (17-OH P4) during the luteal phase. Contrary to P4, 17-OH P4 is not supplied as part of the luteal phase support following IVF-treatment. Therefore, measuring endogenous serum 17-OH P4 levels may more accurately reflect the CL function compared to monitoring serum P4 concentrations. Objective: To explore the correlation between mid-luteal serum 17-OH P4 levels and live birth rates and to explore the possible daytime variations in mid-luteal serum 17-OH P4. Design: Prospective cohort study. Patients: 614 women undergoing IVF-treatment and fresh embryo transfer. Intervention: All patients had serum 17-OH P4 measured 7 days after oocyte pick-up (OPU+7). Furthermore, on OPU+7, seven patients underwent repeated blood sampling during daytime to clarify the endogenous daytime secretory pattern of 17-OH P4. Outcome measure: Live birth rate. Secondary outcome measure: Daytime variation in serum 17-OH P4 levels. Results: The highest chance of a live birth was seen with mid-luteal 17-OH P4 between 6.0 and 14.0 nmol/l. The chance of a live birth was reduced below (RD -10%, p = 0.07), but also above the optimal range for 17-OH P4 (RD -12%, p = 0.04). Patients with diminished CL-function (17-OH P4 < 6 nmol/l) displayed clinically stable 17-OH P4 values, whereas patients with 17-OH P4 levels >6 nmol/l showed random 17-OH P4 fluctuations during daytime. Conclusion: The association between 17-OH P4 and reproductive outcomes is non-linear, and the negative effect of excessive CL-secretion seems to be just as strong as the negative effect of a reduced CL-function during the peri-implantation period.

Hiperplasia adrenal congénita en forma clásica virilizante simple / Congenital adrenal hyperplasia in simple classical virilizing form

El déficit de 21-hidroxilasa es la forma más frecuente de hiperplasia adrenal congénita, que forma parte de los desórdenes de la diferenciación sexual. Se presentan 3 casos. El primero, un recién nacido de 19 días que es llevado a consulta por presentar desórdenes de los genitales externos. Al examen físico presentaba un clítoris aumentado de tamaño, con orificio uretral en su base y engrosamiento de los rodetes labioescrotales. El diagnóstico se realizó por ultrasonido ginecológico, cromatina sexual, estudios hormonales y cariotipo. El segundo caso, un recién nacido de 15 días que también es llevado a consulta por desórdenes de los genitales externos, con examen físico similar al primer caso, y se le realizaron los mismos complementarios para su diagnóstico. El tercer caso, un lactante de 2 meses de edad, que es llevado a consulta por igual motivo, y que al examen físico se encontró hiperplasia del clítoris, con orificio en su base, y engrosamiento de los labios mayores que estaban fusionados en la línea media. Se le indicaron iguales complementarios. Se diagnosticó en los 3 casos una hiperplasia adrenal virilizante, y se realizó tratamiento sustitutivo hormonal y cirugía reconstructiva de los genitales externos.

Steroid 21-hydroxylase is the most frequent form of congenital adrenal hyperplasia that is part of the sexual differentiation disorders. This article reported 3 cases. The first one was a 19 days-old infant who was taken to the doctor´s because of external genitalia disorders. The physical exam revealed augmented clitoris with urethral orifice in its basis and thickening of the labioscrotal swellings. The patient was diagnosed by means of gynecological ultrasound, sexual chromatin, hormonal studies and karyotype. The second case was a 15 days-old newborn, who was also taken to the doctor´s for external genitalia disorders. The physical exam was similar to that of the first case and the same complementary tests were performed for diagnosis. The third case was a 2 months-old infant who was taken to the medical service for the same reasons, and his physical exam showed clitoris hyperplasia, orifice in its base and thickening of labia majora that fused in the midline. The same complementary tests were indicated. The final diagnosis in these three cases was virilizing adrenal hyperplasia. They were all treated with hormone replacement therapy and reconstructive surgery of their external genitalia.

Hiperplasia adrenal congénita en forma clásica virilizante simple / Congenital adrenal hyperplasia in simple classical virilizing form

El déficit de 21-hidroxilasa es la forma más frecuente de hiperplasia adrenal congénita, que forma parte de los desórdenes de la diferenciación sexual. Se presentan 3 casos. El primero, un recién nacido de 19 días que es llevado a consulta por presentar desórdenes de los genitales externos. Al examen físico presentaba un clítoris aumentado de tamaño, con orificio uretral en su base y engrosamiento de los rodetes labioescrotales. El diagnóstico se realizó por ultrasonido ginecológico, cromatina sexual, estudios hormonales y cariotipo. El segundo caso, un recién nacido de 15 días que también es llevado a consulta por desórdenes de los genitales externos, con examen físico similar al primer caso, y se le realizaron los mismos complementarios para su diagnóstico. El tercer caso, un lactante de 2 meses de edad, que es llevado a consulta por igual motivo, y que al examen físico se encontró hiperplasia del clítoris, con orificio en su base, y engrosamiento de los labios mayores que estaban fusionados en la línea media. Se le indicaron iguales complementarios. Se diagnosticó en los 3 casos una hiperplasia adrenal virilizante, y se realizó tratamiento sustitutivo hormonal y cirugía reconstructiva de los genitales externos(AU)

Steroid 21-hydroxylase is the most frequent form of congenital adrenal hyperplasia that is part of the sexual differentiation disorders. This article reported 3 cases. The first one was a 19 days-old infant who was taken to the doctor´s because of external genitalia disorders. The physical exam revealed augmented clitoris with urethral orifice in its basis and thickening of the labioscrotal swellings. The patient was diagnosed by means of gynecological ultrasound, sexual chromatin, hormonal studies and karyotype. The second case was a 15 days-old newborn, who was also taken to the doctor´s for external genitalia disorders. The physical exam was similar to that of the first case and the same complementary tests were performed for diagnosis. The third case was a 2 months-old infant who was taken to the medical service for the same reasons, and his physical exam showed clitoris hyperplasia, orifice in its base and thickening of labia majora that fused in the midline. The same complementary tests were indicated. The final diagnosis in these three cases was virilizing adrenal hyperplasia. They were all treated with hormone replacement therapy and reconstructive surgery of their external genitalia(AU)

Pathways and genes involved in steroid hormone metabolism in male pigs: a review and update.

This paper reviews state-of-the-art knowledge on steroid biosynthesis pathways in the pig and provides an updated characterization of the porcine genes involved in these pathways with particular focus on androgens, estrogens, and 16-androstenes. At least 21 different enzymes appear to be involved in these pathways in porcine tissues together with at least five cofactors. Until now, data on several porcine genes were scarce or confusing. We characterized the complete genomic and transcript sequences of the single porcine CYP11B gene. We analyzed the porcine AKR1 gene cluster and identified four AKR1C, one AKR1C like genes and one AKR1E2 gene. We provide evidence that porcine AKR1C genes are not orthologous to human AKR1C. A new nomenclature is thus needed for this gene family in the pig. Thirty-two genes are now described: transcript (30+2 characterized in this study) and genomic (complete: 18+1 and partial: 12+1) sequences are identified. However, despite increasing knowledge on steroid metabolism in the pig, there is still no explanation of why porcine testes can produce androstenone and epiandrosterone, but not dihydrotestosterone (DHT), which is also a reduced steroid.

Assessment of steroidogenesis and steroidogenic enzyme functions.

There is some confusion in the literature about steroidogenesis in endocrine glands and steroidogenesis in peripheral intracrine tissues. The objective of the present review is to bring some clarifications and better understanding about steroidogenesis in these two types of tissues. Concerns about substrate specificity, kinetic constants and place of enzymes in the pathway have been discussed. The role of 17α-hydroxylase/17-20 lyase (CYP17A1) in the production of dehydroepiandrosterone and back-door pathways of dihydrotestosterone biosynthesis is also analyzed. This article is part of a Special Issue entitled "Synthesis and biological testing of steroid derivatives as inhibitors".