17-hydroxyprogesterone Levels Research Articles

Classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OHD) in adult males: Clinical presentation, hormone function and the detection of adrenal and testicular adrenal rest tumors (TARTs)

Introduction21-hydroxylase deficiency (21-OHD) is the most common form of congenital adrenal hyperplasia (CAH). In adulthood, most studies are reported in females. By contrast, data on adult males are scarce. ObjectiveTo describe a series of adult males with classic 21-OHD and to assess the presence of adrenal masses and testicular adrenal rest tumors (TARTs). Material and MethodsEight males (21–42 years) were included. We evaluated clinical presentation, 17-Hydroxyprogesterone (17-OHP), Testosterone (T), Δ4Androstenedione (Δ4A) ACTH, LH, FSH and plasma renin activitiy (PRA) levels at consultation. Molecular studies of the CYP21A2 gene, testicular ultrasound (US), semen analysis and adrenal computed tomography (CT) scan were performed. Treatment and compliance were assessed. ResultsBasal 17-OHP levels were >20ng/ml in all patients. At consultation, median 17OH-P was 11.5 (2.3–81) ng/ml, FSH: 3 (0.3–4) mUI/ml, LH: 1.1 (0.1–6) mUI/ml, T: 4.3 (1.7–8) ng/ml, Δ4A: 5.7 (1.4–16) ng/ml, ACTH: 86.4 (76–334) pg/ml, PRA: 9.5 (1.3–23.6) ng/ml/h. Semen analysis was performed in 5/8 patients, showing azoospermia in two. Molecular genetic analysis was performed in 4/8 patients. TARTs were found in 5/6, being bilateral in four. Adrenal masses were found in 4/6. In the 7 patients diagnosed in childhood, their follow-up was referred to as irregular, both in their attendance at consultations and in compliance with the indicated treatment. ConclusionsTo our knowledge, this is the first series on adult males with classic 21-OHD which concomitantly assesses clinical presentation, molecular biology, adrenal and testicular imaging studies, semen analysis and compliance to treatment. A high prevalence of adrenal masses and TARTs was observed, possibly associated with poor treatment compliance leading to elevated ACTH and increased proliferation. Our findings on TARTs agree with reports in international publications of CAH in males, with adrenal imaging being added in our group. Although we are aware that further studies with a larger sample size and more data are needed, we consider that our findings contribute to the clinical management of classical 21-OHD in the male population.

Adiposity is Associated with Decreased Serum 17-Hydroxyprogesterone Levels in Non-Diabetic Obese Men Aged 18-49: A Cross-Sectional Study.

Obesity is associated with decreased circulating testosterone levels, the main male sex hormone. However, there are a number of different male sex hormones whose dynamics remain poorly understood regarding this pathology. In this regard, 17 hydroxyprogesterone (17-OH progesterone), as an important precursor of testosterone synthetized in testes and adrenal glands, could play an essential role in testosterone deficiency in male obesity. Moreover, similarly to testosterone, 17-OH progesterone could be closely associated with visceral fat distribution and metabolic dysfunction. Thus, the aim of this study was to assess serum 17-OH progesterone levels in non-diabetic obese young men and to evaluate their relationship with clinical, analytical, and anthropometric parameters. We conducted a cross-sectional study including 266 non-diabetic men with obesity (BMI ≥ 30 kg/m2) aged 18–49 years; 17-OH progesterone and total testosterone (TT) were determined by high-performance liquid chromatography mass spectrometry. 17-OH progesterone levels were significantly lower in tertile 3 of body fat percentage in comparison with tertile 1 (0.74 ng/mL vs. 0.94 ng/mL, p < 0.01; Bonferroni correction) and in comparison with tertile 2 (0.74 ng/mL vs. 0.89 ng/mL, p = 0.02; Bonferroni correction). 17-OH progesterone levels correlated negatively with weight, BMI, waist circumference, insulin, homeostatic model assessment of insulin resistance (HOMA-IR), and visceral fat, and positively with TT, free testosterone (FT), luteinizing hormone, and fat-free mass percentage. Multivariate linear-regression analysis showed that body fat percentage and HOMA-IR were inversely associated with 17-OH progesterone levels, while FT and ACTH were positively linked to circulating 17-OH progesterone levels. In conclusion, in a population of non-diabetic obese young men, 17-OH progesterone levels were inversely associated with adiposity. Body fat percentage and insulin resistance were negatively related to 17-OH progesterone levels, whereas FT and ACTH levels were positively associated with 17-OH progesterone levels.

The effect of metformin treatment on the basal and gonadotropin-stimulated steroidogenesis in male rats with type 2 diabetes mellitus.

Type 2 diabetes mellitus impairs reproductive functions in men, and important tasks are deciphering the mechanisms of testicular dysfunctions in diabetes and the search of effective approaches to their correction. The purpose was to study the effect of four-week metformin treatment (120mgkg-1 day-1 ) of male Wistar rats with high-fat diet/low-dose streptozotocin-induced type 2 diabetes on basal and gonadotropin-stimulated steroidogenesis, intratesticular content of leptin and the leptin and luteinising hormone receptors and on spermatogenesis. Diabetic rats had hyperleptinaemia, androgen deficiency and reduced sperm count and quality, and in the testes, they had the increased leptin level and the decreased content of the leptin and luteinising hormone receptors and 17-hydroxyprogesterone. The stimulating effects of chorionic gonadotropin on testosterone production and expression of steroidogenic genes (Star, Cyp11a1) were decreased. Metformin restored basal and gonadotropin-stimulated blood testosterone levels. In the testes, it restored gonadotropin-stimulated 17-hydroxyprogesterone, androstenedione and testosterone levels, Star expression and the content of leptin and the leptin and luteinising hormone receptors. Metformin also improved epididymal sperm count and morphology. We concluded that metformin treatment normalises the testicular steroidogenesis in diabetic rats, which is due to restoration of the gonadotropin and leptin systems in the testes and is associated with an improvement in spermatogenesis.

The relationship between prolactin and adipose tissue and metabolic parameters in patients with polycystic ovary syndrome

Objectives: Polycystic ovary syndrome is a reproductive endocrinopathy, predominantly accompanied by insulin resistance, obesity, and metabolic disorder. In this study, we aimed to investigate the possible relationship between prolactin and adipose tissue and metabolic parameters in patients with polycystic ovary syndrome (PCOS). Methods: A total of 58 patients with PCOS and 34 body mass index (BMI)-matched healthy controls between September 2018 and March 2019 were included in the study. Visceral and subcutaneous adipose tissues were measured using ultrasonography. Serum prolactin, fasting blood glucose, insulin, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride, total cholesterol, luteinizing hormone (LH), total testosterone, dehydroepiandrosterone sulfate (DHEA-S), and 17-hydroxyprogesterone (17-OHP) levels were measured. Results: The median BMI (p = 0.001), waist circumference (p = 0.002), hip circumference (p = 0.003), waist-to-hip ratio (p = 0.013), LH (p = 0.012), total testosterone (p = 0.004), DHEA-S (p = 0.049), 17-OHP (p = 0.001), insulin (p = 0.001), minimum preperitoneal fat thickness (p = 0.001), maximum preperitoneal fat thickness (p = 0.048), and intraperitoneal fat thickness (p = 0.018) were significantly higher in the PCOS group compared to the control group. However, there was no significant correlation between prolactin levels and adipose tissue parameters and insulin levels in the patients with PCOS. Conclusions: Although there was an increase in the preperitoneal and intraperitoneal fat thickness in the PCOS group compared to the control group, no significant correlation was observed between prolactin and visceral and subcutaneous adipose tissues and metabolic parameters.

Establishment of Clinical and Lab Algorithms for the Identification of Carriers of Mutations in CYP21A2 - A Study of 365 Children and Adolescents.

Mutations of CYP21A2 encoding 21-hydroxylase are the most frequent cause of congenital adrenal hyperplasia (CAH) and are associated either with elevated basal or ACTH-stimulated levels of 17-hydroxyprogesterone (17OHP) in blood. The study objective was to identify the most suitable of 12 different test algorithms and appropriate cut-off levels for that test to recognize patients with non-classical congenital adrenal hyperplasia (NCCAH) and carriers of clinically relevant mutations in CYP21A2. Between July 2006 and July 2015 ACTH-tests were conducted in 365 children and adolescents (Age 1-20 y) suspected to have NCCAH. As a reference, results from subsequent gene sequencing of CYP21A2 was used. Inclusion criteria that were used were premature pubarche with accelerated bone age, hyperandrogenism, hirsutism, or menstrual irregularities. Receiver operating characteristics (ROC) were plotted. Evaluated test algorithms were composed around 17OHP measurements by radioimmunoassays. The most suitable test was identified by the greatest area under the curve (AUC). Among the 12 tested algorithms, the sum of 30 min and 60 min stimulated 17OHP values (sum17OHPstim) showed the highest AUC of 0.774 for identifying heterozygous and bi-allelic mutations. A cut-off of 10.1 μg/l was advisable. Bi-allelic mutations only were best identified calculating the difference between 30 min and basal 17OHP values (Δ17OHP30). A cut-off of 9.4 μg/l was most effective. Alternatively to the above mentioned cut-offs the difference of 60 min after stimulation to basal 17OHP (Δ17OHP60) can be used for the benefit of a combined test to identify both heterozygotes and bi-allelic patients. There are minimal decreases in sensitivity and specificity compared to an approach that applies two tests. However, it denotes a simpler approach in the clinical routine.

30 Predicting gestational age improves newborn screening for congenital adrenal hyperplasia

Abstract Background Newborn screening for congenital adrenal hyperplasia is performed using a two-tier approach. The first tier involves comparison of neonate 17-hydroxyprogesterone levels to gestational age (GA)-based thresholds. When GA is unreported, which occurs in approximately 5% of births, birth weight (BW)-based thresholds are the only available option. However, these have a lower specificity and result in more false positive results. Recently, a predictive model was developed to estimate GA based on newborn demographics and the screening analytes measured in a blood sample. Objectives The objective of this study was to determine whether supplying a predicted GA to newborns with unreported GA, and subsequent GA-based screening, has a higher positive predictive value than BW-based screening. Design/Methods Screening data was obtained for approximately 700,000 births that occurred in Canada between 2011 and 2015. Predicted GA was calculated using a model composed of demographic and screening analyte factors. The positive predictive values of BW- and predicted GA-based screening were calculated for newborns with unreported GA. A sequential approach was then developed whereby newborns with unreported GA were first screened by BW-based screening. Newborns that screened positive were then supplied with their predicted GA and screened using GA-based thresholds. Results First-tier CAH screening using GA-based 17-hydroxyprogesterone thresholds had a higher positive predictive value than using BW-based thresholds (1.30% vs. 0.82%). In the study time period, 3.61% of newborns had an unreported GA. For these newborns, predicted GA-based screening had a higher positive predictive value than BW-based screening (0.83% vs. 0.76%) and correctly identified the 2 infants with CAH whose GA was unreported. A sequential screening approach was then used: BW-based screening and, for the screen positive population, predicted GA-based screening. This further increased the positive predictive value compared to BW-based screening (0.95% vs. 0.76%), reduced the false positive rate, and correctly identified true positive cases. Conclusion Reducing the false positive rate of CAH screening is important to prevent unnecessary second-tier screening and referrals. For newborns with unreported GA (4-5% of all births), BW-based screening is the only currently available approach. However, this approach has a poor specificity and a high false positive rate compared to GA-based screening. This study is the first to demonstrate an alternative screening strategy with a higher positive predictive value for newborns with unreported GA.

Primary Adrenocortical Insufficiency Case Series in the Neonatal Period: Genetic Etiologies Are More Common Than Expected.

Primary adrenocortical insufficiency (PAI) is an important cause of morbidity in neonates. The most common cause of PAI in neonates is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). Other rarer monogenic cases, for example, adrenal hypoplasia congenita (AHC) or familial glucocorticoid deficiency, also simulate clinical manifestation of 21-OHD, leading to misdiagnosis. The therapies and prognosis of these monogenic cases of PAI are entirely different. This study aimed to compare the differences of clinical data and identify genetic etiologies of PAI cases in the neonatal period. All 7 neonates initially presented with hyperpigmentation, hyponatremia, hyperkalemia, and high serum adrenocorticotropic hormone levels. Only CAH patients showed hyperandrogenism and remarkably elevated serum 17-hydroxyprogesterone levels. All the pathogenic mutations found in CYP21A2 were well known, except c.1069C>T (exon 8). The male patient with AHC had a novel hemizygous deletion of exon 2 in DAX1. The other one with familial glucocorticoid deficiency type 1 had two novel heterozygous mutations in the gene coding melanocortin 2 receptor, c.701C>T (exon 2) and c.119delT (exon 2). Glucocorticoid and/or mineralocorticoid replacement therapy depends on the cause of PAI. Genetic testing can be performed as a alternative diagnostic approach to provide information about therapy, prognosis, and genetic counseling.

Changes in Adrenal Androgens and Steroidogenic Enzyme Activities From Ages 2, 4, to 6 Years: A Prospective Cohort Study.

The levels of adrenal androgens are increased through the action of steroidogenic enzymes with morphological changes in the adrenal zona reticularis. We investigated longitudinal changes in androgen levels and steroidogenic enzyme activities during early childhood. From a prospective children's cohort, the Environment and Development of Children cohort, 114 boys and 86 girls with available blood samples from ages 2, 4, and 6 years were included. Serum concentrations of adrenal androgens using liquid chromatography-tandem mass spectrometry and steroidogenic enzyme activity calculated by the precursor/product ratio. During ages 2 to 4 years, 17,20-lyase and dehydroepiandrosterone (DHEA) sulfotransferase activities increased (P < 0.01 for both in boys). During ages 4 to 6 years, 17,20-lyase activity persistently increased, but 3β-hydroxysteroid dehydrogenase (HSD) and 17β-HSD activities decreased (P < 0.01 for all). Serum DHEA sulfate (DHEA-S) levels persistently increased from 2, 4, to 6 years, and DHEA, 17-hydroxyprogesterone, and androstenedione levels increased during ages 4 to 6 years (P < 0.01 for all). Serum DHEA-S levels during early childhood were associated with body mass index z-scores (P = 0.001 in only boys). This study supports in vivo human evidence of increased 17,20-lyase and DHEA sulfotransferase activities and decreased 3β-HSD activity during early childhood.

Outcome of Newborn Screening for Congenital Adrenal Hyperplasia at Two Time Points

Background/Aims: Screening newborns for congenital adrenal hyperplasia (CAH) is problematic owing to the dynamic changes in serum 17-hydroxyprogesterone (17-OHP) levels following birth. Our study objectives were to determine the accuracy of screening, severity of CAH, and biochemical and clinical outcomes of cases detected by our program which collects specimens at 2 time periods following birth. Methods: We reviewed all CAH cases detected in the Northwest Regional Newborn Screening Program from 2003 through 2017. Comparison was made of screening and confirmatory serum 17-OHP, neonatal, maternal, and follow-up auxologic data, steroid treatment doses, and 21-hydroxylase genotype in cases detected on the first versus second test. Results: Out of 164 cases of CAH, 25% were detected on the second screen. Infants detected on the second test had a lower screening 17-OHP (147 vs. 294 ng/mL), lower confirmatory serum 17-OHP (7,772 vs. 14,622 ng/dL), and were more likely to have simple virilizing CAH. There were no identifiable neonatal or maternal factors associated with detection on the second test. 21-Hydroxylase genotypes overlapped in first versus second screen cases. Conclusion: Early collection of specimens necessitated by early discharge resulted in milder CAH cases falling below the screening 17-OHP cutoff. In our program 25% of cases were detected on a routine second screen.

Sexual function in women with androgen excess disorders: classic forms of congenital adrenal hyperplasia and polycystic ovary syndrome

PurposeWe compared the sexual function in women with classic forms of congenital adrenal hyperplasia (CAH) and polycystic ovary syndrome (PCOS) to find if the cause of androgen excess determines sexual functioning.MethodsHundred and four women (21 with CAH, 63 with PCOS and 20 healthy controls) aged 18–40 years were included into the study. All participants completed a questionnaire regarding their sociodemographic background and underwent anthropometric and basic biochemical measurements. Plasma levels of total testosterone, androstenedione, and 17-hydroxyprogesterone were measured with immunoassay. To assess the sexual functions, the Female Sexual Function Index (FSFI) questionnaire was applied.ResultsApart from the higher physical activity in PCOS patients (P = 0.017), we found no significant sociodemographic differences between the studied groups. In clinical assessment, women with CAH had a lower incidence of acne (P = 0.006). Their plasma levels of 17OHP (P = 0.005) and insulin resistance index (P = 0.0248) were higher, while total testosterone (P = 0.0495) and glucose (P = 0.0061) was lower compared to the PCOS group. Significantly more women with CAH were homosexual (P = 0.003) and bisexual (P = 0.006). CAH group showed a lower total FSFI score (P = 0.0043) and lower scores in three domains: lubrication (P = 0.0131), sexual satisfaction (P = 0.0006), and dyspareunia (P < 0.0001). Higher physical activity was associated in all women with higher total FSFI score (P = 0.009) and scores in the domain of desire (P = 0.034) and sexual satisfaction (P = 0.01), while in CAH women apart from the total score (P = 0.03) and sexual satisfaction (P = 0.002) also in the domains of orgasm (P = 0.005), and pain (P = 0.03).ConclusionsCAH women present more often homosexual and bisexual orientation, while their sexual functions are impaired compared to PCOS patients.

SAT-010 Non-Classic POR Deficiency as a Cause of Menstrual Disorders &amp; Infertility

P450 oxidoreductase deficiency (PORD) is an autosomal recessive disease caused by bi-allelic mutations of the POR gene. It is responsible for decreased activity of several P450 enzymes including CYP21A2, CYP17A1 and CYP19A1 that are involved in adrenal and/or gonadal steroidogenesis. PORD is typically diagnosed in neonates and children with ambiguous genitalia and/or skeletal abnormalities. Adult-onset PORD has been very seldom reported and little is known about the optimal way to investigate and treat such patients. In this series, we report five women aged 19-38 years, who were referred for unexplained oligo-/amenorrhea and/or infertility. Genetic testing excluded 21-hydroxylase deficiency (21OH-D), initially suspected due to increased 17-hydroxyprogesterone (17-OHP) levels. Extensive phenotyping, steroid profile by mass spectrometry, pelvic imaging and next-generation sequencing of 84 genes involved in gonadal and adrenal disorders were performed in all patients. In Vitro Fertilization (IVF) followed by frozen embryo transfer under glucocorticoid suppression therapy was performed in two patients. All patients had oligomenorrhea or amenorrhea. None had hyperandrogenism. Low-normal serum estradiol (E2) and testosterone levels contrasted with chronically increased serum progesterone (P) and 17-OHP levels, which further increased after ACTH administration. Despite excessive P, 17OH-P and 21-deoxycortisol rises after ACTH stimulation suggesting non-classic 21-hydroxylase deficiency, CYP21A2 sequencing did not support this hypothesis. Basal serum cortisol levels were low to normal, with inadequate response to ACTH in some women, suggesting partial adrenal insufficiency. Pelvic imaging revealed bilateral ovarian macrocysts in all women. All patients were found to harbor rare bi-allelic POR mutations classified as pathogenic according to American College of Medical Genetics standards. IVF was performed in two women after retrieval of a normal oocyte number despite very low E2 levels during controlled ovarian hyperstimulation. Frozen embryo transfer under glucorticoid suppression therapy led to successful pregnancies. These observations suggest that diagnosis of PORD must be considered in infertile women with chronically elevated P and 17OH-P levels and ovarian macrocysts. Differentiation of this entity from non-classic 21-hydroxylase deficiency is important, as the multiple enzyme deficiency requires a specific management. Successful fertility induction is possible by IVF, providing that P levels be sufficiently suppressed by glucocorticoid therapy prior to implantation.

SUN-LB16 Clitoromegaly in Premature Infants: Is It Truly Pathologic?

Background: Normative data for clitoral size in premature infants are limited. Consequently, the potential for over-diagnosis is high; leading to unnecessary investigations, increased healthcare costs and parental stress. Several proposed mechanisms, e.g., persistence of fetal adrenal zone activity to term gestation, point to the transient physiologic nature of clitoromegaly in premature infants. Studies of normative data have shown a negative correlation between birth weight and clitoral size. We hypothesized that 1) the majority of clitoromegaly in premature infants is not associated with hormonal dysfunction and 2) lower birth weight and lower gestational age increase the likelihood of a formal consult in premature infants with perceived clitoromegaly. Methods: A retrospective chart review of female infants born at our institution from January 2012 to December 2018 with perceived clitoromegaly was conducted. Birth history, demographic and laboratory data were collected. Patients were divided into two groups: ‘formal consult’ and ‘no formal consult’ for clitoromegaly. True clitoromegaly was defined as clitoral length >9 mm or clitoral width >6 mm. Patients not meeting these criteria or those with clitoral edema, prominent clitoral hood were classified under false clitoromegaly. In the ‘no formal consult’ group, the documented discharge examination was used to assess persistence of clitoromegaly. Uni- and multi-variable logistic regression were used to determine factors that increased the likelihood of a formal consult. Results: 29 patients met inclusion criteria; 15 in the ‘formal consult’ group and 14 in the ‘no formal consult’ group. No significant differences were found between the groups in terms of birth weight, gestational age, race, ethnicity and maternal factors. History of IUGR (intrauterine growth restriction) was more common in the ‘formal consult’ group (60%) vs. ‘no formal consult’ group (21%) (p=0.04). Only 3/15 patients in the ‘formal consult’ group had true clitoromegaly; all 3 had normal 17-hydroxyprogesterone levels, and only 1 patient had transient elevation in androgen levels (androstenedione, deoxycortisol and testosterone). Of the ‘no formal consult’ group, only 3/14 patients had clitoromegaly noted on discharge; outcome was unknown for 1. Multi-variable logistic regression showed that lower gestational age (p=0.04) and history of IUGR (p=0.03), even after adjusting for birth weight, increased the likelihood of a formal consult. Conclusion: In summary, the majority of perceived clitoromegaly in premature infants is not associated with hormonal dysfunction. Lower gestational age and a history of IUGR increase the likelihood of a formal consult for clitoromegaly in these patients. Approximately half of the patients were noted to have false clitoromegaly indicating inconsistencies in examination technique and need for provider education.

Differential diagnosis of nonclassical 21-hydroxylase deficiency and polycystic ovary syndrome

Objective To explore the differential diagnosis methods between nonclassical 21-hydroxylase deficiency(NC21-OHD) and polycystic ovary syndrome(PCOS). Methods The clinical data of 31 women with NC21-OHD were compared with those of 29 women with PCOS. Results Women with NC21-OHD showed a higher prevalence of adrenal hyperplasia and lower likelihood of polycystic ovary(PCO) than those with PCOS(P<0.05), with lower height(P<0.05). The levels of adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone(17-OHP), androstenedione(AD), total testosterone(TT), and progesterone were higher in women with NC21-OHD compared with those with PCOS(P<0.05). Women with PCOS had higher levels of luteinizing hormone(LH) and higher ratio of LH to follicle stimulating hormone(FSH) than those with NC21-OHD(P<0.05). The best two identification indexes for the two diseases were 17-OHP and progesterone, with the optimal cut-off points 3.34 ng/ml(sensitivity 89.7%, specificity 93.1%) and 0.64 ng/ml(sensitivity 90.0%, specificity 75.9%), respectively. During the 1-day mid-dose dexamethasone suppression test(DST), women with NC21-OHD had higher inhibition rates of 17-OHP, progesterone, AD, and TT(P<0.01) than those with PCOS. Their optimal cut-off values of suppression rates were 73.5%(sensitivity 95.2%, specificity 100.0%), 55.5%(sensitivity 100%, specificity 88.9%), 61.4%(sensitivity 84.2%, specificity 100.0%), 68.3%(sensitivity 65.0%, specificity 100.0%), respectively. Conclusion The clinical manifestations of women with NC21-OHD are similar to those with PCOS. 17-OHP is the best differential indicator and the 1-day mid-dose DST plays an important role in the identification of the two diseases. Genetic analysis is the gold standard for distinguishing the two diseases. Key words: Nonclassical 21-hydroxylase deficiency; Polycystic ovary syndrome; 17-hydroxyprogesterone; Progesterone; Dexamethasone suppression test

Neglected congenital adrenal hyperplasia presenting as recurrent abdominal pain

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder with the incidence of the classic type being 1:15,000 births worldwide. It results from defective synthesis of steroid hormones because of deficiency of one of the five enzymes required for synthesis of cortisol. Cases of severe forms of CAH are often missed in developing countries where there is no program for newborn screening with many of them dying in neonatal periods. Management of the mild forms are also hindered or delayed because of superstitions, ignorance and poverty. We present an 11years old girl who presented with abnormal genital since birth and recurrent monthly lower abdominal pain of eight month duration. She had Tanner stage 4 breasts, normal female pubic hair distribution, clitoromegaly, fused scrotalized labia with urogenital sinus and absent vaginal opening. Abdominal ultrasound showed normal female reproductive organs; she had advanced bone age of 16years and elevated serum 17-hydroxyprogesterone level. She’s being worked up for possible genitoplasty.

Non-classic cytochrome P450 oxidoreductase deficiency strongly linked with menstrual cycle disorders and female infertility as primary manifestations.

Can cytochrome P450 oxidoreductase deficiency (PORD) be revealed in adult women with menstrual disorders and/or infertility? PORD was biologically and genetically confirmed in five adult women with chronically elevated serum progesterone (P) who were referred for oligo-/amenorrhea and/or infertility. PORD is an autosomal recessive disease typically diagnosed in neonates and children with ambiguous genitalia and/or skeletal abnormalities. It is responsible for the decreased activity of several P450 enzymes, including CYP21A2, CYP17A1 and CYP19A1, that are involved in adrenal and/or gonadal steroidogenesis. Little is known about the optimal way to investigate and treat patients with adult-onset PORD. In this series, we report five adult females who were evaluated in three tertiary endocrine reproductive departments between March 2015 and September 2018. Five women aged 19-38years were referred for unexplained oligo-/amenorrhea and/or infertility. Genetic testing excluded 21-hydroxylase deficiency (21OH-D), initially suspected due to the increased 17-hydroxyprogesterone (17-OHP) levels. Extensive phenotyping, steroid profiling by mass spectrometry, pelvic imaging and next-generation sequencing of 84 genes involved in gonadal and adrenal disorders were performed in all patients. IVF followed by frozen embryo transfer (ET) under glucocorticoid suppression therapy was performed for two patients. All patients had oligomenorrhea or amenorrhea. None had hyperandrogenism. Low-normal serum estradiol (E2) and testosterone levels contrasted with chronically increased serum P and 17-OHP levels, which further increased after adrenocorticotrophic hormone (ACTH) administration. Despite excessive P, 17OH-P and 21-deoxycortisol rise after ACTH stimulation suggesting non-classic 21OH-D, CYP21A2 sequencing did not support this hypothesis. Basal serum cortisol levels were low to normal, with inadequate response to ACTH in some women, suggesting partial adrenal insufficiency. All patients harbored rare biallelic POR mutations classified as pathogenic or likely pathogenic according to the American College of Medical Genetics and Genomics standards. Pelvic imaging revealed bilateral ovarian macrocysts in all women. IVF was performed for two women after retrieval of a normal oocyte number despite very low E2 levels during ovarian stimulation. Frozen ET under glucocorticoid suppression therapy led to successful pregnancies. The number of patients described here is limited and these data need to be confirmed on a larger number of women with non-classic PORD. The diagnosis of PORD must be considered in infertile women with chronically elevated P and 17OH-P levels and ovarian macrocysts. Differentiation of this entity from non-classic 21OH-D is important, as the multiple enzyme deficiency requires a specific management. Successful fertility induction is possible by IVF, providing that P levels be sufficiently suppressed by glucocorticoid therapy prior to implantation. No specific funding was used for this study. There are no potential conflicts of interest. N/A.

Evaluation of fetal stress in preeclamptic patients

Objective Previous studies have established the association between preeclampsia (PE)-induced stress on fetus and elevated 17-hydroxyprogesterone levels (17-OHP) of which known as a stress markers. The aim of our study was to evaluate the relationship between these markers that were analyzed via cord blood with the severity of PE. Methods Consecutive PE women who were admitted to Dr. Lütfi Kırdar Training and Research Hospital Obstetrics and Gynecology Clinics from August 2009 to December 2009 were recruited. Uncomplicated pregnant women admitted at the same period consisted the control group. Umbilical blood samples were collected from umbilical artery immediately after birth and 17-OHP analyzed. Results The study group consisted of 40 mild PE (n=12) and severe PE patients (n=28) and the control group consisted of 35 patients. Maternal age and body mass index were similar between the study groups, but the fetuses in the severe PE group had a smaller mean gestational age and mean birth weight (p=0.001). Umbilical cord 17-OHP levels were statistically significantly lower in the severe PE patients than the controls [Control group=12.5±4.6 (n=35); mild PE=10.3±6 (n=12, p=0.24), severe PE=9.6±5.2 (n=28, p=0.019)]. Although the patients with mild PE had lower 17-OHP levels, they were not statistically significant (p=0.827). Conclusion In our study, it is found that there is no association between PE severity and the cord blood levels of 17-OHP. The effect of early intervention that prevent feto-maternal complications may lead to normal or low levels of these markers of which was found increased in cord blood of preeclamptic patients in previous studies.

Glucocorticoid replacement regimens for treating congenital adrenal hyperplasia.

Glucocorticoid replacement regimens for treating congenital adrenal hyperplasia.

Yenidoğanlarda skrotal pigmentasyonun spektrometre ile değerlendirilmesi ve 17-hidroksiprogesteron kan düzeyi ile korelasyonunun incelenmesi

Aim: To evaluate the scrotal melanin density in infants using spectrometry and to determine the correlation between spectrometric evaluations, physical examinations and blood 17-hydroxyprogesterone levels.Material and methods: A total of 40 infants were enrolled to the study, 22 of whom were diagnosed by a physician as having scrotal hyperpigmentation and 18 with normal scrotal pigmentation, who were admitted for the evaluation of prolonged jaundice. Age, gestational week, birth weight and scrotal pigmentation noted by the physician were recorded. Spectral data were acquired from scrotum and thigh. A correlation between the spectral measurements and the blood 17-hydroxyprogesterone level was determined by comparing spectral value in the wavelength range of 620-800 nm and 17-hydroxyprogesterone levels. Results: No statistically significant difference was observed between the groups who were categorized by the physician as having “hyperpigmented” or “normal” scrotal color in terms of the infant’s age, gestational week, birth weight, 17-hydroxyprogesterone level or spectrometric values. We observed a strong correlation between 17-hydroxyprogesterone levels and spectrometric values in all groups.Conclusion: This preliminary study is the first one in the literature which evaluates scrotal pigmentation with an objective spectrometric method and determines its relationship with 17-hydroxyprogesterone levels. Further studies are needed to employ this method as a non-invasive, indirect screening test for the screening of congenital adrenal hyperplasia in male infants.

Increased Sympathetic Cardiac Autonomic Modulation after Two Consecutive Tilt Tests in Women with Polycystic Ovary Syndrome.

The present study aimed to analyze cardiac autonomic modulation via spectral and symbolic analysis of heart rate variability (HRV) in women with polycystic ovary syndrome (PCOS) who were subjected to two consecutive tilt tests. A total of 64 women were selected and divided into 2 groups: control (without PCOS), and PCOS. Concentrations of follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, homocysteine, sex hormone-binding globulin, thyroid stimulating hormone, fasting insulin, testosterone, androstenedione, and 17-hydroxyprogesterone levels, triglycerides, free androgen index (FAI), and homeostasis assessment model (HOMA-IR) were assessed. Cardiac autonomic modulation was evaluated by spectral and symbolic analyses during two consecutive tilt tests (two moments) and supine moments before, between and after (three moments) the tilt tests. Women with PCOS had higher fasting insulin, HOMA-IR indexes, testosterone and FAI. Additionally, we observed that the PCOS group had greater sympathetic autonomic cardiac modulation in supine 2, tilt 1, and supine 3 moments compared with controls. Women with PCOS had higher autonomic sympathetic cardiac modulation even after a second tilt test. No adaptation to this provocative test was observed. Spectral analysis was more sensitive for identifying differences between groups than the symbolic analysis.

Timing of hyponatremia development in patients with salt-wasting-type 21-hydroxylase deficiency.

.Newborn screening (NBS) can detect 21-hydroxylase deficiency (21-OHD), allowing for early treatment initiation. However, many patients present with adrenal crises or hyponatremia at their first visit. Age (in days) of hyponatremia development in infants with salt-wasting (SW)-type 21-OHD remains unclear. Therefore, we determined the earliest age of hyponatremia diagnosis in this retrospective observational study using medical records of 40 patients with classic 21-OHD in Niigata Prefecture, Japan, from April 1989 to March 2019. We determined the earliest diagnosis of hyponatremia (serum sodium levels < 130 mEq/L) and created a sodium decrease rate model to estimate hyponatremia development age. Of 23 patients with SW-type 21-OHD, 10 (43.5%) were identified during NBS; the earliest case to present with hyponatremia was at day 7. Serum sodium levels were significantly and negatively correlated with age in days, and hyponatremia was estimated to develop at 6.6 d after birth. Genotype or serum 17-hydroxyprogesterone levels were not associated with sodium decrease rate. Thus, hyponatremia development age is earlier (within 7 d) than the previously described time-point (10–14 d) in infants with SW-type 21-OHD. Efforts to reduce the time lag from obtaining results to consultation may be required in patients with high 17-hydroxyprogesterone levels on NBS.