Women's response regarding timing of genital surgery in congenital adrenal hyperplasia.

PURPOSE: To study what adult women with congenital adrenal hyperplasia (CAH) thought about the timing of genital surgery. METHODS: As part of a larger follow-up study performed between the years 2002-2005 there were questionnaires concerning genital surgery, type of surgery, their thoughts about timing of genital surgery and experience of information about surgery. Early surgery was defined as ≤4 years of age and late ≥10 years. The medical and surgical files were reviewed. RESULTS: 62 women with CAH due to 21-hydroxylase deficiency, mean age 28 years (18-63) were included. The age at first genital surgery was 3 years (0-28 years) in the 52 patients (84%) who had had genital surgery, with 60% had early surgery (≤4 years) and 29% late (≥10 years). Almost half of the cohort had a positive experience of the information about surgery, a third had no opinion and a fifth had a negative experience. Of the women 39% thought that early surgery was good, while 19% thought it should be done during or after puberty and 42% had no opinion. Of those preferring early surgery 70% had early surgery themselves. Vaginal surgery was less common among those favoring early surgery. Age, phenotype, genotype, decade of surgery and experience of the information about surgery did not differ significantly between the three groups. CONCLUSION: Equal numbers of women had no opinion regarding age at surgery or preferred early surgery while 19% thought it would be preferred to have surgery during or after puberty.

Clinical and Hormonal Profile of Classical 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia: Experience from a Tertiary Centre In India.

Introduction: Congenital adrenal hyperplasia (CAH) is a rare autosomal recessive disorder requiring treatment with steroids. Both over and under-treatment can have an impact on growth outcomes. Aims: The aim of this study was to study the clinical and hormonal profile of a cohort of individuals with classical 21-hydroxylase CAH and to assess the factors influencing growth outcomes in these individuals. Methods: In this cross-sectional study, individuals with classical CAH were included. Baseline data were obtained from electronic medical records. Anthropometric measurements and hormonal profiles were assessed. Quantitative variables were expressed as mean ± standard deviation or median (interquartile range) and qualitative variables as percentages. To measure the correlation between variables, Spearman's rank correlation was used. Results: Of the 27 patients with classical 21-hydroxylase CAH, 13 had salt wasting and 14 had simple virilizing phenotype. The median height standard deviation score (SDS) of the cohort was -1 SDS (-2.00 to 0.2) with 24% having short stature (height < -2 SDS). There was no significant difference in height SDS depending on the age, gender, type of CAH or onset of central precocious puberty. There was no significant correlation between glucocorticoid dose and height SDS (r = 0.104). Obesity was a common finding (40% adults, 41.1% children). However, there was no significant correlation between BMI and glucocorticoid dose (r = 0.419). Conclusions: Short stature was a significant finding as noted in earlier studies. However, the high prevalence of obesity was a new finding that could not be explained by the dose of steroids alone.

Demonstrating Synergistic Activity of Magnetic Iron Oxide Nano Photocatalyst for C-H Activation in Heterogeneous Phase.

This report describes a dual catalytic approach for the versatile C‒H arylation of arenes under photo-excitation at room temperature. The cooperative catalysis utilizes iron oxide magnetic nanoparticles (which mostly contain Fe3O4 along with some γ-Fe2O3) as the potential photocatalyst, which merges with the Pd-catalyzed C‒H activation cycle for the reductive generation of aryl radical from aryl diazonium salt, revealing its photocatalytic activities. The method is applicable to a wide range of aryl coupling partners and different directing groups, demonstrating excellent productivity, nice co-operativity and recyclability. Adequate control experiments and mechanistic studies assisted in establishing the radical-based mechanism for the C‒H arylation occurring in the heterogeneous phase.

Oxidative Amidation of Ferrocenyl aldehydes with Amines Catalyzed by Chalcogenised Fe3Se2(CO)9 Cluster: Direct Transformation of Aldehyde to Amides.

With the interest and knowing the importance of ferrocenyl conjugates, a direct amidation of ferrocenyl aldehyde has been developed under feasible conditions. Varieties of amines has been oxidatively coupled with ferrocene aldehyde in the presence of highly economical and robustly stable iron chalcogenide ironcarbonyl clusters [Fe3E2(CO)9, E= S, Se, and Te] and TBHP. The reaction worked in greener solvent water at a moderate temperature of 70 °C and synthesized the ferrocenyl-amides in just 30 minutes. All the varieties of amines were found to be well tolerated for the present method, and due to the high medicinal importance of ferrocenyl-amides, sole focus of this report was concentrate on the synthesis of various new ferrocenyl-amides in good to excellent amounts.

Effects of Congenital Adrenal Hyperplasia (CAH) and Biological Sex on Brain Size.

Congenital Adrenal Hyperplasia (CAH) has been reported to involve structural alterations in some brain regions. However, it remains to be established whether there is also an impact on the size of the brain as a whole. Here, we compiled the largest CAH sample to date (n = 53), matched pair-wise to a control group (n = 53) on sex, age, and verbal intelligence. Using T1-weighted brain scans, we calculated intracranial volume (ICV) as well as total brain volume (TBV), which are both common estimates for brain size. The statistical analysis was performed using a general linear model assessing the effects of CAH (CAH vs. controls), sex (women vs. men), and any CAH-by-sex interaction. The outcomes were comparable for ICV and TBV, i.e., there was no significant main effect of CAH and no significant CAH-by-sex interaction. However, there was a significant main effect of sex, with larger ICVs and TBVs in men than in women. Our findings contribute to an understudied field of research exploring brain anatomy in CAH. In contrast to some existing studies suggesting a smaller brain size in CAH, we did not observe such an effect. In other words, ICV and TBV in women and men with CAH did not differ significantly from those in controls. Notwithstanding, we observed the well-known sex difference in brain size (12.69% for ICV and 12.50% for TBV), with larger volumes in men than in women, which is in agreement with the existing literature.

Bone mineral density determinants in adolescents and young adults with congenital adrenal hyperplasia.

Background: The effects of long-term glucocorticoid (GC) treatment on bone mineral density (BMD) in patients with congenital adrenal hyperplasia (CAH) remain controversial. Objectives: This cross-sectional study aimed to evaluate BMD in relation to genotype, growth, vitamin D status, cumulative GC doses, and other relevant factors in youths with CAH. Methods: Thirty-two patients with classical CAH (13 males; mean age 26.0 ± 7.1 years) were compared with 32 healthy controls matched by age and sex. BMD was measured using dual-energy x-ray absorptiometry, and statistical analyses, including the Mann-Whitney U-test and Spearman's correlation coefficient, were performed to evaluate differences and associations. Results: Median whole-body and lumbar BMD Z-scores were similar between CAH patients and controls (p = 0.27 and 0.15, respectively). Low bone density was observed in 12.5% of CAH patients and 18.75% of controls (p = 0.5), and osteoporosis was confirmed in 12.5% of CAH patients and 0% of controls (p = 0.04). BMD did not correlate with cumulative GC doses, estradiol, renin, phosphate, sodium levels, or anthropometric parameters in CAH patients. There was no significant difference in BMD between severe and non-severe genotypes of CAH. However, a positive correlation was found between the whole-body BMD Z-score and growth velocity during infancy (r = 0.776, p = 0.021) in CAH patients. Vitamin D deficiency was noted in 56.25% of CAH patients, although vitamin D levels did not correlate with BMD or genotype. No history of bone fractures was reported among study participants. Conclusions: CAH patients are at risk of developing osteoporosis, but in this study, BMD Z-scores were not associated with cumulative GC doses. The study did not identify an association between genotype and BMD. Poor growth during infancy was linked to decreased BMD in adulthood.

Selective Monoborylation of Methane by a Mono Bipyridyl-Nickel(II) Hydride Catalyst.

We report the development of an earth-abundant metal catalyst for methane C‒H borylation. The post-synthetic metalation of bipyridine-functionalized zirconium metal-organic framework (MOF) with NiBr2, followed by treatment of NaEt3BH affords MOF-supported monomeric bipyridyl-nickel(II) dihydride species via active site isolation. The heterogeneous and recyclable nickel catalyst selectively borylates methane at 200 ºC using pinacolborane (HBpin) to afford CH3Bpin in 61% yield with a turnover number (TON) up to 1388. The confinement of the active NiH2-species within the uniformly porous MOF allows selective monoborylation of methane via shape-selective catalysis by preventing the formation of sterically encumbered overborylated products. Unlike MOF-Ni catalyst,  its homogeneous control is almost inactive in methane borylation due to its intermolecular decomposition. Our mechanistic investigation, including spectroscopic, kinetic, and control experiments, as well as DFT calculations, revealed that stabilizing mononuclear bipyridyl-nickel dihydride and diboryl species by MOF is crucial for achieving efficient methane borylation via turnover-limiting σ-bond metathesis. This work shows promise in designing MOF-based abundant metal catalysts for the chemoselective functionalization of methane and other inert molecules into valuable chemicals.

Evaluation of 3ß-hydroxysteroid dehydrogenase activity using progesterone and androgen receptors-mediated transactivation.

3ß-Hydroxysteroid dehydrogenases (3ß-HSDs) catalyze the oxidative conversion of delta (5)-ene-3-beta-hydroxy steroids and ketosteroids. Human 3ß-HSD type 2 (HSD3B2) is predominantly expressed in gonadal and adrenal steroidogenic cells for producing all classes of active steroid hormones. Mutations in HSD3B2 gene cause a rare form of congenital adrenal hyperplasia with varying degree of salt wasting and incomplete masculinization, resulting from reduced production of corticoids and androgens. Therefore, evaluation of the HSD3B2 enzymatic activity in both pathways for each steroid hormone production is important for accurately understanding and diagnosing this disorder. Using progesterone receptor (PR)- and androgen receptor (AR)-mediated transactivation, we adapted a method that easily evaluates enzymatic activity of HSD3B2 by quantifying the conversion from substrates [pregnenolone (P5) and dehydroepiandrosterone (DHEA)] to (progesterone and androstenedione). HEK293 cells were transduced to express human HSD3B2, and incubated medium containing P5 or DHEA. Depending on the incubation time with HSD3B2-expressing cells, the culture media progressively increased luciferase activities in CV-1 cells, transfected with the PR/AR expression vector and progesterone-/androgen-responsive reporter. Culture media from human and other mammalian HSD3B1-expressing cells also increased the luciferase activities. HEK293 cells expressing various missense mutations in the HSD3B2 gene revealed the potential of this system to evaluate the relationship between the enzymatic activities of mutant proteins and patient phenotype.

Prevalence of adrenal rest tumors and course of gonadal dysfunction in a clinical sample of men with congenital adrenal hyperplasia: a longitudinal analysis over 10 years.

BACKGROUND: Subfertility is prevalent in men with classic 21-hydroxylase deficiency (21OHD). We sought to characterize the long-term evolution of their gonadal function. METHODS: Retrospective longitudinal single-center study in 27 men (11 with testicular adrenal rest tissue [TART]), median observation period 12 years, testosterone (T), 11-oxygenated androgens, gonadotropins, and inhibin B measurement at each time point. RESULTS: T concentrations were below the normal range (n.s.) in 43.2% (no TART) and 54.6% (TART) per patient. After accounting for body mass index, sex hormone-binding globulin, and age, men with TART exhibited higher T (14.0 ± 0.80 nmol/L) than those without (11.9 ± 0.71 nmol/L). During the observation period, T levels rose in both groups but more in men with TART (from 10.1 ± 1.1 to 17.3 ± 1.9 nmol/L vs 10.3 ± 1.0 to 12.8 ± 1.9 nmol/L); this was accompanied by rising luteinizing hormone and diminishing hydrocortisone equivalent dosages (TART: from 38.1 ± 3.2 to 35.1 ± 1.8 mg/d; vs no TART: 28.8 ± 2.7 to 28.1 ± 1.6 mg/d) without correlation with any markers of adrenal androgen control. Inhibin B declined in men with large TART over time while TART status remained stable. CONCLUSION: T levels below the normal range are frequent in men with 21OHD, regardless of TART, but change little over time. Besides adrenal androgen control gonadal axis suppression from supraphysiological glucocorticoid dosages needs to be considered. While our results do not endorse regular screening for alterations in TART status among adults, Sertoli cell function should be monitored in men with large TART.

Remote C─H Bond Activation via Enantioselective Carbopalladation and 1,4-Pd Migration Cascade Process.

Carbopalladation-initiated cascade reaction involving 1,4-Pd migration is a straightforward and powerful approach to activate remote C─H bond, forging versatile fused polycyclic compounds containing fluorene fragment which are highly valuable synthetic targets. However, its asymmetric variants pose considerable challenges and have not been explored. Here the first asymmetric palladium-catalyzed tandem carbopalladation is reported, 1,4-Pd migration reaction of ortho-iodophenol-derived allyl ether under mild conditions, allowing the transformation of a wide range of substrates in good to excellent enantioselectivities, and providing a facile and straight forward access to tetracyclic dihydroindeno[1,2,3-de]chromene bearing a chiral fluorene skeleton. A good functional group tolerance, high stereoselectivity, as well as the good chiroptical properties (high fluorescence quantum yields, circular dichroism) of the products make this approach highly attractive. Moreover, density functional theory (DFT) calculations indicate that the protonation of five-membered palladacycle intermediate is more favorable rather than its direct reductive elimination process.

Relationship between adipokines and androgens in children and young adults with congenital adrenal hyperplasia.

Introduction: Children and young adults with congenital adrenal hyperplasia (CAH) are at increased risk of obesity and insulin resistance. There is evidence that children with CAH have increased visceral adiposity, which has been linked to metabolic syndrome and cardiovascular disease (CVD). The adipokine adiponectin has been shown to correlate with reduced metabolic risk, whereas the adipokines visfatin and leptin have been linked to visceral fat and adipocyte inflammation and can serve as biomarkers of increased metabolic risk. Few studies to date have characterized adipokine levels in children and young adults with congenital adrenal hyperplasia. We sought to investigate the relationship between adiponectin, leptin and visfatin levels to metabolic risk factors and androgen levels in children and young adults with CAH. Methods: Fasting blood was obtained for visfatin, leptin, adiponectin, glucose, insulin, CRP, lipid panel, total cholesterol (TC), triglycerides (TG) and HbA1c, as well as standard laboratory tests to assess adrenal control, from children with CAH due to 21-hydroxylase deficiency. HOMA-IR was calculated based on fasting glucose and insulin. Anthropomorphic measurements of BMI and waist-to-hip ratio were also obtained. Results: Adiponectin and androstenedione were inversely correlated (R = -0.57, p =0.016). There was a positive correlation between leptin and BMI percentile (R = 0.63, p <0.001) as well as leptin and HOMA-IR (R = 0.63, p <0.01). Glucocorticoid dose had a positive correlation with HOMA-IR (R=0.56, p = 0.021). Visfatin was inversely correlated with HDL cholesterol (R = -0.54, p = 0.026) and total cholesterol (R = -0.49, p <0.05). Overweight children and young adults had a significantly higher leptin (p = 0.02) and HOMA-IR (p=0.001) than non-overweight children and young adults. Conclusion: The inverse relationship between adiponectin and androstenedione suggests that better CAH control can reduce the risk of insulin resistance and metabolic syndrome. However, a high glucocorticoid dose appears to increase the risk of insulin resistance, underscoring the delicate balance required when treating CAH.

Design, Synthesis, and Biological Evaluations of Novel Thiazolo[4,5-d]pyrimidine Corticotropin Releasing Factor (CRF) Receptor Antagonists as Potential Treatments for Stress Related Disorders and Congenital Adrenal Hyperplasia (CAH).

Corticotropin-releasing factor (CRF) is a key neuropeptide hormone that is secreted from the hypothalamus. It is the master hormone of the HPA axis, which orchestrates the physiological and behavioral responses to stress. Many disorders, including anxiety, depression, addiction relapse, and others, are related to over-activation of this system. Thus, new molecules that may interfere with CRF receptor binding may be of value to treat neuropsychiatric stress-related disorders. Also, CRF1R antagonists have recently emerged as potential treatment options for congenital adrenal hyperplasia. Previously, several series of CRF1 receptor antagonists were developed by our group. In continuation of our efforts in this direction, herein we report the synthesis and biological evaluation of a new series of CRF1R antagonists. Representative compounds were evaluated for their binding affinities compared to antalarmin. Four compounds (2, 5, 20, and 21) showed log IC50 values of -8.22, -7.95, -8.04, and -7.88, respectively, compared to -7.78 for antalarmin. This result indicates that these four compounds are superior to antalarmin by 2.5, 1.4, 1.7, and 1.25 times, respectively. It is worth mentioning that compound 2, in terms of IC50, is among the best CRF1R antagonists ever developed in the last 40 years. The in silico physicochemical properties of the lead compounds showed good drug-like properties. Thus, further research in this direction may lead to better and safer CRF receptor antagonists that may have clinical applications, particularly for stress-related disorders and the treatment of congenital adrenal hyperplasia.

Free cortisol and free 21-deoxycortisol in the clinical evaluation of congenital adrenal hyperplasia.

CONTEXT: Some patients with classic congenital adrenal hyperplasia (CAH) survive without glucocorticoid treatment. Increased precursor concentrations in these patients might lead to higher free (biological active) cortisol concentrations by influencing the cortisol-protein binding. In 21-hydroxylase deficiency (21OHD), the most common CAH form, accumulated 21-deoxycortisol (21DF) may further increase glucocorticoid activity. Both mechanisms could explain the low occurrence of symptoms in some untreated classic CAH patients. OBJECTIVE: Develop and validate an LC-MS/MS method for free cortisol and free 21DF to quantify these steroids in untreated patients with classic CAH (n=29), non-classic CAH (NCCAH, n=5), other forms of adrenal insufficiency (AI, n=3), and controls (n=11) before and 60 minutes after Synacthen® administration. RESULTS: Unstimulated total cortisol concentrations of untreated classic CAH patients (median 109 nmol/L) were lower than in untreated NCCAH patients (249 nmol/L, p=0.010) and controls (202 nmol/L, p=0.016), but free cortisol concentrations were similar. Basal free 21DF concentrations were high in 21OHD patients (median 5.32 nmol/L) and undetectable in AI patients and controls (<0.19 nmol/L). After Synacthen® administration, free 21DF concentrations increased in 21OHD patients, while free cortisol concentrations did not change. CONCLUSIONS: Free cortisol concentrations in classic CAH patients were similar to those in controls and NCCAH patients, indicating comparable cortisol availability. Additionally, 21OHD patients produce high concentrations of 21DF, possibly explaining the low occurrence of symptoms in some classic 21OHD patients. Free cortisol and 21DF levels should be considered in evaluating adrenal insufficiency in patients with CAH.

Iron Corrole-Catalyzed Intramolecular Amination Reactions of Alkyl Azides. Spectroscopic Characterization and Reactivity of [FeV(Cor)(NAd)].

As nitrogen analogues of iron-oxo species, high-valent iron-imido species have attracted great interest in the past decades. FeV-alkylimido species are generally considered to be key reaction intermediates in Fe(III)-catalyzed C(sp3)─H bond aminations of alkyl azides but remain underexplored. Here, it is reported that iron-corrole (Cor) complexes can catalyze a wide range of intramolecular C─H amination reactions of alkyl azides to afford a variety of 5-, 6- and 7-membered N-heterocycles, including alkaloids and natural product derivatives, with up to 3880 turnover numbers (TONs) and excellent diastereoselectivity (>99:1 d.r.). Mechanistic studies including density functional theory (DFT) calculations and intermolecular hydrogen atom abstraction (HAA) reactions reveal key reactive FeV-alkylimido intermediates. The [FeV(Cor)(NAd)] (Ad = adamantyl) complex is independently prepared and characterized through electron paramagnetic resonance (EPR), resonance Raman (rR) measurement, and X-ray photoelectron spectroscopy (XPS). This complex is reactive toward HAA reactions with kinetic isotope effects (KIEs) similar to [Fe(Cor)]-catalyzed intramolecular C─H amination of alkyl azides.

Modifying Parallel Excitations into One Framework for C(sp3)─H Bond Activation with Energy Combined More Than Two Photons.

Natural photosynthesis enzymes utilize energies of several photons for challenging oxidation of water, whereas artificial photo-catalysis typically involves only single-photon excitation. Herein, a multiphoton excitation strategy is reported that combines parallel photo-excitations with a photoinduced electron transfer process for the activation of C(sp3)─H bonds, including methane. The metal-organic framework Fe3-MOF is designed to consolidate 4,4',4″-nitrilotrisbenzoic units for the photoactivation of dioxygen and trinuclear iron clusters as the HAT precursor for photoactivating alkanes. Under visible light irradiation, the dyes and iron clusters absorbed parallel photons simultaneously to reach their excited states, respectively, generating 1O2 via energy transfer and chlorine radical via ligand-to-metal charge transfer. The further excitation of organic dyes leads to the reduction of 1O2 into O2 •- through a photoinduced electron transfer, guaranteeing an extra multiphoton oxygen activation manner. The chlorine radical abstracts a hydrogen atom from alkanes, generating the carbon radical for further oxidation transformation. Accordingly, the total oxidation conversion of alkane utilizing three photoexcitation processes combines the energies of more than two photons. This new platform synergistically combines a consecutive excited photoredox organic dye and a HAT catalyst to combine the energies of more than two photons, providing a promising multiphoton catalysis strategy under energy saving, and high efficiency.

An ultra-sensitive and rapid immunosensor for the onsite detection of circulating tumor DNA in breast cancer.

Breast cancer currently stands as the most prevalent form of cancer worldwide and the primary cause of cancer-related deaths among women. However, the current diagnostic methods for breast cancer exhibit several limitations, including invasiveness, high costs, and limited sensitivity and specificity. The detection of the PIK3CA-H1047R variant is of paramount importance due to its close association with tumor growth and treatment resistance. Consequently, developing a straightforward, rapid, and highly sensitive approach for detecting PIK3CA-H1047R is of utmost importance. We have been working on the development of a rapid and ultrasensitive biosensor, leveraging the alternating current (AC) electrokinetic (ACEK) capacitive sensing method. This biosensor involves modifying the surface of interdigital electrodes with antibodies, facilitating the antibody-antigen-binding process through AC electrokinetic techniques. Our sensor strategy directly measures the interface capacitance, and the rate of change serves as a quantitative marker for event identification. Remarkably, our biosensor successfully detects the PIK3CA-H1047R antigen within a concentration range of 1 ng/mL to 1 µg/mL. In conclusion, this study proposes a fast and highly sensitive biosensor for the detection of a key breast cancer marker, the PIK3CA-H1047R variant. This technology is expected to improve breast cancer diagnosis, address the limitations of current methods, and provide patients with better treatment options. This detection method offers a promising avenue for on-site and real-time sensitive detection of the PIK3CA-H1047R antigen, potentially revolutionizing breast cancer diagnosis.

When Diagnosis Takes a Turn: A Case Series on Testicular Adrenal Rest Tumor/Leydig Cell Tumor.

Testicular adrenal rest tumor (TART) is a known complication of congenital adrenal hyperplasia (CAH) that simulates testicular germ cell tumors to the extent that they can pose a diagnostic challenge to treating physicians. In this case series, we have presented four patients with different clinical scenarios but all of them presented with a common symptom of bilateral testicular masses. Their clinical histories were strongly suggestive of CAH. Most of them were treated initially as cases of germ cell tumor (Leydig) as their clinical features were overlapping, posing a diagnostic challenge. The histopathological features of CAH and Leydig cell tumors overlap considerably. Diagnosis of CAH must always be kept in mind as a differential diagnosis in patients presenting with bilateral testicular swellings. Timely diagnosis of TARTs and CAH can help preserve testicular functions. Careful histopathological analysis can add to the clinical features of CAH and Leydig tumors to correctly diagnose these patients. Here, we discuss this diagnostic challenge in our four patients.

Massive Uterine Leiomyoma in a Phenotypic Male.

We present a case report of a 55-year-old male patient with congenital adrenal hyperplasia (CAH) and a large neoplastic mass in the abdomen. The patient presented with an abdominal mass and discomfort, along with a bilateral empty scrotum since birth. A diagnostic workup revealed the mass to be a uterine leiomyoma associated with CAH, a simple virilizing type. Treatment involved an exploratory laparotomy and excision of the mass, including the removal of the entire uterus. Complete removal of the mass and uterus was ensured. The patient's response to treatment was satisfactory. This case highlights how pre-operative and post-operative diagnoses can vary, along with the importance of early diagnosis of CAH and disorders of sexual differentiation (DSD), emphasizing the significance of unusual presentations and resultant complications, as they might go unnoticed. CAH in XX females may have unusual presentations, such as short stature and a male phenotype (Prader 5). The patient exhibited a normal pattern of male sexual function. This condition might go unnoticed, resulting in leiomyoma, adrenal tumors, prostate tumors if prostate tissue is present, and so on. Healthcare providers must watch out for such rare presentations.

CYP21A2 Intron 2 Genetic Variants Might Be Associated with the Clinical Characteristics of Women with PCOS.

AIMS: Pathogenic variants in the CYP21A2 gene are related to the classic and non-classic forms of congenital adrenal hyperplasia (CAH). However, the role of CAH carrier status in the clinical presentation of polycystic ovarian syndrome (PCOS) is still unclear. Moreover, the possible associations of different CYP21A2 gene polymorphisms with metabolic and reproductive abnormalities in PCOS have not been investigated. Therefore, the present study aims to examine the prevalence of the most common CYP21A2 pathogenic variant IVS2-13A/C>G (c.293-13A/C>G) in Eastern European women with PCOS and to evaluate the associations between common intron 2 genetic polymorphisms and the clinical symptoms of the patients. METHODS: Sixty consecutively recruited women with PCOS were genotyped for the CYP21A2 intron 2 IVS2-13A/C>G genetic variant. Additionally, CYP21A2 intron 2 polymorphic variants rs6453 (c.293-44G>T), rs6451 (c.293-67C>A/G), rs369651496 (c.293-104del), and rs6474 (c.308G>A/p.R103L) were tested and described. The clinical and hormonal characteristics were compared in women with PCOS and with polymorphic and wild-type genotypes. RESULTS: The heterozygous CYP21A2 pathogenic variant IVS2-13A/C>G was found in one of the investigated PCOS patients (1.67%) with a non-hyperandrogenic type of PCOS. The presence of the rs6453 (c.293-44G>T) T-allele was associated with increased levels of DHEAS (15.18 vs. 9.14 µmol/L, p = 0.003) compared to the wild-type genotype in the investigated group. The rs6451 (c.293-67C>A/G) minor alleles were associated with an earlier age of menarche in the patients (12.0 vs. 13.0 years, p = 0.007). The polymorphic rs369651496 minor 6G allele was related to a better lipid profile in the women with PCOS, while the rs6474 variant modulated the blood pressure of the patients. CONCLUSIONS: The presence of CYP21A2 genetic minor alleles of rs6467 (IVS2-13A/C, c.293-13A/C), rs6453 (c.293-44G>T), rs6451 (c.293-67C>A/G), rs369651496 (c.293-104del), and rs6474 (c.308G>A/p.R103L) might modulate the adrenal androgens, age of menarche, and metabolic features in women with PCOS. Further studies on 21-hydroxylase genetic variants (pathogenic and polymorphisms) in different ethnic groups might help reveal the influence of adrenal steroidogenesis on PCOS development, clinical manifestations, and lifelong cardiovascular risks.

A differential expression of an identical mutation in CYP17A1 gene in two infertility patients: a case report.

BACKGROUND: 17-Hydroxylase deficiency is the rarest form of congenital adrenal hyperplasia, a disorder that affects steroidogenesis, causing abnormal hormone levels. Studies have shown a clear association between 17-hydroxylase deficiency and primary infertility, but a definite protocol to treat the disorder has not been determined yet. CASE PRESENTATION: Case I presents a 24-year-old Caucasian Israeli-Arab female who experienced 6 years of infertility. Before her initial visit to our clinic, she underwent three laparoscopic ovarian cystectomies, had an unsuccessful in vitro fertilization cycle, and was treated with combined oral contraceptives. Her hormonal profile was tested, and the results led to genetic counseling and the diagnosis of non-classical congenital adrenal hyperplasia. She was treated with estradiol, glucocorticoids, and transdermal testosterone. After hormonal levels were lowered, in vitro fertilization cycles were initiated, and the patient had a spontaneous ovulation. In case II, a 20-year-old Caucasian Israeli-Arab female presented for infertility evaluation owing to her oligomenorrhea. Her vitals and physical examination had normal results. The investigation of her abnormal hormonal profile led her to be referred to genetic testing, where the results showed the same genetic mutation as seen in case I. CONCLUSION: Both cases highlight the distinctiveness of the condition, where an identical mutation in the gene responsible for the same enzyme can bring about diverse phenotypes. Case I offers a potential treatment protocol for this rare disorder.