P450 Oxidoreductase Deficiency Research Articles

Exploring Novel Variants of the Cytochrome P450 Reductase Gene (POR) from the Genome Aggregation Database by Integrating Bioinformatic Tools and Functional Assays.

Cytochrome P450 oxidoreductase (POR) is an essential redox partner for steroid and drug-metabolizing cytochromes P450 located in the endoplasmic reticulum. Mutations in POR lead to metabolic disorders, including congenital adrenal hyperplasia, and affect the metabolism of steroids, drugs, and xenobiotics. In this study, we examined approximately 450 missense variants of the POR gene listed in the Genome Aggregation Database (gnomAD) using eleven different in silico prediction tools. We found that 64 novel variants were consistently predicted to be disease-causing by most tools. To validate our findings, we conducted a population analysis and selected two variations in POR for further investigation. The human POR wild type and the R268W and L577P variants were expressed in bacteria and subjected to enzyme kinetic assays using a model substrate. We also examined the activities of several cytochrome P450 proteins in the presence of POR (WT or variants) by combining P450 and reductase proteins in liposomes. We observed a decrease in enzymatic activities (ranging from 35% to 85%) of key drug-metabolizing enzymes, supported by POR variants R288W and L577P compared to WT-POR. These results validate our approach of curating a vast amount of data from genome projects and provide an updated and reliable reference for diagnosing POR deficiency.

SAT336 A Successful Ovulation Induction And Embryo Generation In A Woman With P450-oxidoreductase Deficiency From Mutation G539R, Which Preferentially Impairs 17,20-lyase Activity

Abstract Disclosure: S. Charoensri: None. M. Thakur: None. R.J. Auchus: None. Introduction: Cytochrome P450 oxidoreductase (POR) deficiency is an autosomal recessive disorder causing decreased activity of several P450 enzymes, including CYP21A2, CYP17A1, and CYP19A1 that are essential for steroidogenesis in the adrenals and gonads. Female POR deficiency patients are typically manifested with genital ambiguity, abnormal menstruation, and infertility. Very few pregnancies have been documented from these patients. Case presentation: During an evaluation for infertility, a 35-year-old woman with late menarche, irregular cycles, and unruptured ovarian follicles was diagnosed with POR deficiency due to compound heterozygous pathogenic variant c.1615G>C (G539R) and a large deletion c.1669+5_1669+32del in the POR gene. Because mutation G539R preferentially impairs the 17,20-lyase activity of CYP17A1, she underwent in-vitro fertilization (IVF) with the protocol that has been used successfully to achieve pregnancy in incomplete 17-hydroxylase deficiency. Oral dexamethasone of 0.5 mg/day was given to suppress the adrenal-derived progesterone. After one menstrual cycle induced with estradiol and progesterone priming, leuprolide acetate was used to down-regulate endogenous gonadotropin secretion, then the oocyte maturation was induced with recombinant follicle-stimulating hormone (rFSH) and highly purified menotrophin. In the first cycle, 6 eggs were retrieved, 2 that were mature and fertilized with intracytoplasmic sperm injection (ICSI); however, none advanced to the blastocyst stage. She underwent the same protocol in a second IVF cycle with higher rFSH dosing. Despite increasing dexamethasone to 1.5 mg/day, progesterone rose to 4.9 ng/mL, while estradiol peaked at 120 pg/mL, consistent with progesterone accumulation in the developing ovarian follicles due to POR deficiency. From 6 eggs retrieved, 5 eggs were mature and all fertilized, and 3 developed past day 3. On day 6, one embryo (grading 5BB) was biopsied for preimplantation genetic testing and frozen. The second phase of the treatment plan is to lower adrenal-derived progesterone with a combination of hydrocortisone and prednisolone, prepare the endometrium with estradiol followed by progesterone, and perform embryo transfer. Conclusions: Very few examples of pregnancy in women with POR deficiency have been reported, and we describe the first example of successful ovulation induction and embryo generation in a woman with POR deficiency caused by the G539R mutation, which preferentially impairs 17,20-lyase activity. The complex array of steroid excess and deficiencies, from both adrenal and ovarian origin, must be systematically managed during assisted reproduction treatment for these women. Presentation: Saturday, June 17, 2023

THU210 A Single-center Retrospective Study Of Brazilian Subjects With Differences In Sex Development (DSD) From Infancy To Adulthood

Abstract Disclosure: R.L. Batista: None. N.L. Gomes: None. T.A. Bachega: None. G. Madureira: None. M.C. Miranda: None. R.T. dallago: None. M.M. Ferrari: None. L.M. Lousada: None. F.L. Craveiro: None. J.P. Batatinha: None. R.D. Scalco: None. E.F. Costa: None. M.P. Sircili: None. F.T. Denes: None. M. Inacio: None. M.Y. Nishi: None. S. Domenice: None. B.B. Mendonca: None. Context: DSD represent a wide range of conditions presenting at different ages to many health professionals with several backgrounds. Establishing a correct diagnosis is essential for appropriate management. Objective: To amplify the understanding of the first clinical presentation, prevalence, and gender change of Brazilian DSD subjects. Design: A retrospective, observational cohort study of all DSD subjects referred to a DSD multi-professional team over 41 years (from 1980 to 2021). Participants: 696 subjects.Outcome Measures: Data included DSD diagnosis, sex assignment, age at diagnosis, gender change, clinical presentation, and phenotypic features. Results: Subjects presented at prepubertal, post-pubertal, and adult age, usually with atypical genitalia, undescended testes, or primary amenorrhea. Amongst the three major DSD categories, sex chromosome DSD was diagnosed in 264 subjects (135 with 45,X karyotype); 101 are mosaics (45,X/46,Xi(Xq) and three chimerism (all ovotesticular DSD). Among the 4 ovotesticular DSD subjects, 3 were raised as females and 1 as male, no gender changes occurred in this group. Thirteen chromosome DSD patients with Y material were assigned as male and two female-assigned patients changed their gender. 258 subjects have 46,XY DSD (69 unknown DSD, 64 gonadal dysgenesis, 36 5-αRD2 deficiency, 18 17β-HSD3 deficiency, 11 17α-hydroxylase deficiency, 9 Leydig cell hypoplasia, 25 CAIS, 18 PAIS, 8 AMH defects). Among the 192 XY subjects with atypical genitalia, the sex of rearing was female in 89 (46%) and gender change from female to male occurred in 13%, most in 5 αRD2 (45%) followed by 17β-HSD3 (33%) deficiency. Among those reared as male, only 2.9% changed their gender. 46,XX DSD was diagnosed in 178 patients. Congenital adrenal hyperplasia-CAH (most 21-hydroxylase deficiency) was diagnosed in 123 (115 female-assigned). Among CAH, gender change from female to male occurred in 6 cases, of which most have VS form (5/6; p=.004), a late beginning of treatment (>2 ys old), and poor compliance. In the remaining 55 with 46,XX DSD, 24 have ovotesticular DSD (all with atypical genitalia), 16 have 46,XX testicular DSD (seven with atypical genitalia). Among the ovotesticular subjects, 14 were reared as male and ten as female, and gender change occurred in 4 cases (3 from female to male). The diagnosis was not established in twelve 46,XX DSD patients (all with atypical genitalia, three with syndromic features). One patient has aromatase deficiency, one POR deficiency, and one glucocorticoid resistance syndrome. Conclusion: gender change from female to male mainly occurred among subjects with 46,XY DSD, particularly in those with 5 αRD2 and 17β-HSD3 deficiency, suggesting that male sex assignment is desirable in patients with these diagnoses. Among 46,XX DSD, the VS form of CAH, a late start of treatment, and poor compliance were implicated in female-to-male gender change. Presentation: Thursday, June 15, 2023

Diagnostic challenges and management advances in cytochrome P450 oxidoreductase deficiency, a rare form of congenital adrenal hyperplasia, with 46, XX karyotype.

Cytochrome P450 oxidoreductase deficiency (PORD) is a rare form of congenital adrenal hyperplasia that can manifest with skeletal malformations, ambiguous genitalia, and menstrual disorders caused by cytochrome P450 oxidoreductase (POR) mutations affecting electron transfer to all microsomal cytochrome P450 and some non-P450 enzymes involved in cholesterol, sterol, and drug metabolism. With the advancement of molecular biology and medical genetics, increasing numbers of PORD cases were reported, and the clinical spectrum of PORD was extended with studies on underlying mechanisms of phenotype-genotype correlations and optimum treatment. However, diagnostic challenges and management dilemma still exists because of unawareness of the condition, the overlapping manifestations with other disorders, and no clear guidelines for treatment. Delayed diagnosis and management may result in improper sex assignment, loss of reproductive capacity because of surgical removal of ruptured ovarian macro-cysts, and life-threatening conditions such as airway obstruction and adrenal crisis. The clinical outcomes and prognosis, which are influenced by specific POR mutations, the presence of additional genetic or environmental factors, and management, include early death due to developmental malformations or adrenal crisis, bilateral oophorectomies after spontaneous rupture of ovarian macro-cysts, genital ambiguity, abnormal pubertal development, and nearly normal phenotype with successful pregnancy outcomes by assisted reproduction. Thus, timely diagnosis including prenatal diagnosis with invasive and non-invasive techniques and appropriate management is essential to improve patients' outcomes. However, even in cases with conclusive diagnosis, comprehensive assessment is needed to avoid severe complications, such as chromosomal test to help sex assignment and evaluation of adrenal function to detect partial adrenal insufficiency. In recent years, it has been noted that proper hormone replacement therapy can lead to decrease or resolve of ovarian macro-cysts, and healthy babies can be delivered by in vitro fertilization and frozen embryo transfer following adequate control of multiple hormonal imbalances. Treatment may be complicated with adverse effects on drug metabolism caused by POR mutations. Unique challenges occur in female PORD patients such as ovarian macro-cysts prone to spontaneous rupture, masculinized genitalia without progression after birth, more frequently affected pubertal development, and impaired fertility. Thus, this review focuses only on 46, XX PORD patients to summarize the potential molecular pathogenesis, differential diagnosis of classic and non-classic PORD, and tailoring therapy to maintain health, avoid severe complications, and promote fertility.

Infertility treatment for Chinese women with P450 oxidoreductase deficiency: Prospect on clinical management from IVF to FET.

Cytochrome P450 oxidoreductase deficiency (PORD) is a rare recessive disease with multiple clinical manifestations, which is usually diagnosed in neonates and children because of ambiguous genitalia or skeletal malformations. Moreover, the paucity of studies does not allow us to establish whether adult-onset PORD is associated with infertility. Here, we report clinical and laboratory findings in two phenotypically normal women diagnosed with PORD who underwent in vitro fertilization (IVF) and frozen embryo transfer (FET). We modified the gonadotropin stimulation protocol during controlled ovarian hyperstimulation (COH) and suggest the use of the vaginal 17β-estradiol route for endometrium preparation in hormone replacement therapy (HRT) cycles. We presume that PORD may be associated with infertility in several aspects, including disordered steroidogenesis, endometrium impairment, attenuation of drug metabolism, and the high risk of miscarriage. Our observations will help the early diagnosis and make a tailored approach to infertility management in adult-onset PORD.

P450 oxidoreductase regulates barrier maturation by mediating retinoic acid metabolism in a model of the human BBB.

SummaryThe blood-brain barrier (BBB) selectively regulates the entry of molecules into the central nervous system (CNS). A crosstalk between brain microvascular endothelial cells (BMECs) and resident CNS cells promotes the acquisition of functional tight junctions (TJs). Retinoic acid (RA), a key signaling molecule during embryonic development, is used to enhance in vitro BBB models’ functional barrier properties. However, its physiological relevance and affected pathways are not fully understood. P450 oxidoreductase (POR) regulates the enzymatic activity of microsomal cytochromes. POR-deficient (PORD) patients display impaired steroid homeostasis and cognitive disabilities. Here, we used both patient-specific POR-deficient and CRISPR-Cas9-mediated POR-depleted induced pluripotent stem cell (iPSC)-derived BMECs (iBMECs) to study the role of POR in the acquisition of functional barrier properties. We demonstrate that POR regulates cellular RA homeostasis and that POR deficiency leads to the accumulation of RA within iBMECs, resulting in the impaired acquisition of TJs and, consequently, to dysfunctional development of barrier properties.

In Silico Analysis of PORD Mutations on the 3D Structure of P450 Oxidoreductase.

Cytochrome P450 oxidoreductase (POR) is a membrane-bound flavoprotein that helps in transferring electrons from its NADPH domain to all cytochrome P450 (CYP450) enzymes. Mutations in the POR gene could severely affect the metabolism of steroid hormones and the development of skeletal muscles, a condition known as Cytochrome P450 oxidoreductase deficiency (PORD). PORD is associated with clinical presentations of disorders of sex development, Antley and Bixler’s syndrome (ABS), as well as an abnormal steroid hormone profile. We have performed an in silico analysis of POR 3D X-ray protein crystal structure to study the effects of reported mutations on the POR enzyme structure. A total of 32 missense mutations were identified, from 170 PORD patients, and mapped on the 3D crystal structure of the POR enzyme. In addition, five of the missense mutations (R457H, A287P, D210G, Y181D and Y607C) were further selected for an in-depth in silico analysis to correlate the observed changes in POR protein structure with the clinical phenotypes observed in PORD patients. Overall, missense mutations found in the binding sites of POR cofactors could lead to a severe form of PORD, emphasizing the importance of POR cofactor binding domains in transferring electrons to the CYP450 enzyme family.

Classic and backdoor pathways of androgen biosynthesis in human sexual development.

Both genes and hormones regulate human sexual development. Although ovarian hormones are not essential for female external genitalia development, male sexual development requires the action of testicular testosterone and dihydrotestosterone (DHT). DHT is the most active endogenous androgen formed by the conversion of testosterone in genital skin. This synthesis route from cholesterol to DHT is called the conventional classic pathway. Recent investigations have reported an alternative ("backdoor") route for DHT formation that bypasses fetal testicular testosterone. This alternative route plays a crucial role in human hyperandrogenic disorders like congenital adrenal hyperplasia caused by P450c21 deficiency, polycystic ovary syndrome, and P450 oxidoreductase deficiency. In addition, mutations in AKR1C2 and AKR1C4, genes encoding 3α-reductases, have been implicated in disorders of sexual development, indicating that both the classic and backdoor routes are required for normal human male sexual development. More recently, androsterone was found to be the primary androgen of the human backdoor route. Androsterone and steroidal substrates specific to the backdoor route are predominantly found in the placenta, liver, and adrenal glands rather than in the testes. These findings are essential to understanding human sexual development.

The uncommon forms of congenital adrenal hyperplasia.

Clinicians recognize 21-hydroxylase deficiency as the most common form of congenital adrenal hyperplasia (CAH), and many papers have been published on this condition. In contrast, much less awareness has been addressed to the other, rare forms of CAH. The second most common form of CAH varies with country and ethnic background. In Brazil, 17-hydroxylase/17,20-lyase deficiency is the second most common, whereas 11-hydroxylase deficiency is most common in the Middle East. In Japan and Korea, both congenital lipoid adrenal hyperplasia and P450-oxidoreductase deficiency are more common than in the rest of the world. Finally, 3β-hydroxysteroid dehydrogenase/isomerase deficiency is rare worldwide, but pockets of affected populations, such as the Amish in Lancaster County, Pennsylvania are found. The treatment of each form varies by both the nature of steroids produced in excess above the enzymatic block and the deficiencies of steroids other than cortisol past these blocks. This article summarizes the pathophysiology, diagnosis, and management of rare forms of CAH.

Steroid profile in dried blood spots by liquid chromatography tandem mass spectrometry: Application to newborn screening for congenital adrenal hyperplasia in China

BackgroundNewborn screening for congenital adrenal hyperplasia (CAH) using 17-hydroxyprogesterone dissociation-enhanced, lanthanide fluorescence immunoassay (DELFIA) generates a large number of false-positive results. The present study aimed to improve the sensitivity of the CAH neonatal screening by including second-tier steroid profiling in dried blood spots (DBS) using liquid chromatography tandem mass spectrometry (LC-MS/MS). MethodsWe developed and validated a LC-MS/MS method for simultaneous determination of six steroids in DBS, including androstenedione, testosterone, 17-hydroxyprogesterone, 11-deoxycortisol, 21-deoxycortisol, and cortisol. Two 5-mm blood spots were eluted by internal standard working solution. We analyzed 1170 DBS samples from neonates to determine gestational age-specific reference intervals. In order to test the specificity of the second-tier method, we analyzed 707 cards with a positive screening by DELFIA. ResultsValues of intra- and inter-day precision coefficients of variance and accuracy were 2.0%–13.3% and 85.8%–114.5%, respectively. Recovery ranged from 85.0% to 106.9%. The lower limit of quantification was 0.5 ng/mL for 21-deoxycortisol, 0.25 ng/mL for 17-hydroxyprogesterone and cortisol, and 0.1 ng/mL for testosterone, androstenedione, and 11-deoxycortisol. In addition, the linearity range was 0.25–50 ng/mL (R2 > 0.99). According to the 17-hydroxyprogesterone levels and ratios of (androstenedione + 17-hydroxyprogesterone)/cortisol in the 707 positive screening samples, 77 neonates should receive recall visit. The number of false-positive results reduced by 89.1%. Totally, 18 newborns were diagnosed with 21-hydroxylase deficiency, one with P450 oxidoreductase deficiency and one with 11β-hydroxylase deficiency. With two-tier screening, the positive predictive value increased to 26.0%. ConclusionsThe second-tier steroid profiling by LC-MS/MS reduced the false-positive rate and improved the positive predictive value of CAH screening. We suggest applying this steroid profiling assay as a second-tier test for CAH screening in China.

Clinical applications of genetic analysis and liquid chromatography tandem-mass spectrometry in rare types of congenital adrenal hyperplasia

BackgroundOur study aims to summarize the clinical characteristics of rare types of congenital adrenal hyperplasia (CAH) other than 21-hydroxylase deficiency (21-OHD), and to explore the clinical applications of genetic analysis and liquid chromatography tandem-mass spectrometry (LC-MS/MS) in rare CAH.MethodsWe retrospectively analysed the clinical data of 5 rare cases of CAH admitted to our hospital and summarized their clinical manifestations, auxiliary examinations, diagnosis and mutational spectrum.ResultsAfter gene sequencing, complex heterozygous variants were detected in all patients (2 cases were lipoid congenital adrenal hyperplasia (LCAH), 11β-hydroxylase deficiency (11β-OHD), 3β-hydroxysteroid dehydrogenase deficiency (3β-HSD deficiency) and P450 oxidoreductase deficiency (PORD) each accounted for 1 case), which were consistent with their clinical manifestations. Among them, 4 novel variants were detected, including c.650 + 2 T > A of the StAR gene, c.1145 T > C (p. L382P) of the CYP11B1 gene, c.1622C > T (p. A541V) and c.1804C > T (p. Q602 *) of the POR gene. The LC-MS/MS results for steroid hormones in patients were also consistent with their genetic variants: 2 patients with LCAH showed a decrease in all steroid hormones; 11β-OHD patient showed a significant increase in 11-deoxycortisol and 11-deoxycorticosterone; patient with 3β-HSD deficiency showed a significant increase in DHEA; and PORD patient was mainly characterized by elevated 17OHP, progesterone and impaired synthesis of androgen levels.ConclusionsThe clinical manifestations and classification of CAH are complicated, and there are cases of missed diagnosis or misdiagnosis. It’s necessary to combine the analysis of clinical manifestations and auxiliary examinations for diagnosis; if necessary, LC-MS/MS analysis of steroid hormones or gene sequencing is recommended for confirming diagnosis and typing.

Steroidogenic electron-transfer factors and their diseases.

Most steroidogenesis disorders are caused by mutations in genes encoding the steroidogenic enzymes, but work in the past 20 years has identified related disorders caused by mutations in the genes encoding the cofactors that transport electrons from NADPH to P450 enzymes. Most P450s are microsomal and require electron donation by P450 oxidoreductase (POR); by contrast, mitochondrial P450s require electron donation via ferredoxin reductase (FdxR) and ferredoxin (Fdx). POR deficiency is the most common and best-described of these new forms of congenital adrenal hyperplasia. Severe POR deficiency is characterized by the Antley-Bixler skeletal malformation syndrome and genital ambiguity in both sexes, and hence is easily recognized, but mild forms may present only with infertility and subtle disorders of steroidogenesis. The common POR polymorphism A503V reduces catalysis by P450c17 (17-hydroxylase/17,20-lyase) and the principal drugmetabolizing P450 enzymes. The 17,20-lyase activity of P450c17 requires the allosteric action of cytochrome b5, which promotes interaction of P450c17 with POR, with consequent electron transfer. Rare b5 mutations are one of several causes of 17,20-lyase deficiency. In addition to their roles with steroidogenic mitochondrial P450s, Fdx and FdxR participate in the synthesis of iron-sulfur clusters used by many enzymes. Disruptions in the assembly of Fe-S clusters is associated with Friedreich ataxia and Parkinson disease. Recent work has identified mutations in FdxR in patients with neuropathic hearing loss and visual impairment, somewhat resembling the global neurologic disorders seen with mitochondrial diseases. Impaired steroidogenesis is to be expected in such individuals, but this has not yet been studied.

Disorders of Sex Development.

Disorders of Sex Development.

Two cases of cytochrome P450 oxidoreductase deficiency with severe scoliosis and surgery requirement.

Two cases of cytochrome P450 oxidoreductase deficiency with severe scoliosis and surgery requirement.

Targeted gene panel sequencing for molecular diagnosis of congenital adrenal hyperplasia

ContextCongenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic diseases caused by genetic deficiency in nine genes encoding steroidogenesis enzymes and cofactors. ObjectiveTo establish a targeted next-generation sequencing (NGS) assay for all nine CAH candidate genes. MethodsWe developed a customized targeted NGS assay of CAH candidate genes (CYP21A2, CYP17A1, CYP11B1, StAR, CYP11A1, POR, HSD3B2, H6PD, CYP11B2) and apply this assay plus MLPA of CYP21A2 in a total of 469 patients with CAH like signs and symptoms. ResultsWe totally identified 125 variants with seven variant types in eight genes. Variant types included missense variant (46.8 %), splicing variant (21.5 %), small indel (12.5 %), large structure variation (11.8 %), nonsense variant (4.1 %), UTR variant (2.9 %), synonymous variant (0.3 %). Successful genotyping, defined as biallelic pathogenic or likely pathogenic variants, was achieved in 98.5 % (336/341) of cases, including biallelic variants in CYP21A2 (n = 254), CYP17A1 (n = 45), CYP11B1 (n = 23), StAR (n = 7), HSD3B2 (n = 4), POR (n = 1), CYP11A1 (n = 1) and CYP11B2 (n = 1) gene. Importantly, the assay found one patient with CYP11B1 deficiency, one patient with non-classic POR deficiency and two patients with non-classic CYP17A1 deficiency while clinically diagnosed differently. ConclusionsOur NGS-based assay plus MLPA of CYP21A2 is a useful tool to genotype all subtypes of CAH. The test successfully achieved genotype in 98.5 % of patients with clinically determined CAH. It also efficiently facilitated the diagnosis of CAH in patients with rare subtypes as well as non-classic phenotypes.

Successful live birth in a Chinese woman with P450 oxidoreductase deficiency through frozen-thawed embryo transfer: a case report with review of the literature

BackgroundCongenital adrenal hyperplasia (CAH) caused by P450 oxidoreductase deficiency (PORD) in 46, XX patients is characterized by genital ambiguity, primary amenorrhea, absent or incomplete sexual maturation, infertility, skeletal malformations and so on. But few pregnancies have been reported from these female patients with PORD.Case descriptionA 29-year-old Chinese woman with PORD due to the compound heterozygous mutation (c.1370G > A/c.1196_1204del) in the P450 oxidoreductase (POR) gene had suffered from primary amenorrhea and infertility. She had one cancelled cycle of ovulation induction due to low serum estradiol(E2), high progesterone(P) levels and thin endometrium, then in vitro fertilization (IVF) was recommended. At the first IVF cycle, 4 oocytes were retrieved and 4 viable embryos were cryopreserved due to thin endometrium associated with low E2 and prematurely elevated P after ovarian stimulation, even though oral dexamethasone were used to control adrenal P overproduction at the same time. When basal P fell to < 1.5 ng/ml after the therapy of oral dexamethasone, artificial endometrial preparation and frozen embryo transfer were performed, resulting in a twin pregnancy. She delivered a healthy boy and a healthy girl by caesarean section at 37 weeks and 2 days of gestation. After the literature search in PORD women, no spontaneous pregnancy has been reported and only two previous case reports of 3 successful pregnancies through IVF were summarized.ConclusionsIt is the third report that successful pregnancy was achieved in a CAH woman caused by a compound heterozygous POR mutation, with primary amenorrhea and disorders of steroidogenesis. It seemed that disorders of steroidogenesis caused by PORD didn’t impair the developmental potential of oocytes. IVF and frozen embryo transfer after adequate hormonal control and endometrial preparation should be an effective infertility treatment for PORD women.

Prenatal diagnosis of cytochrome P450 oxidoreductase deficiency（PORD）with 3DCT and maternal urinary steroid profile: A case report

Prenatal diagnosis of cytochrome P450 oxidoreductase deficiency（PORD）with 3DCT and maternal urinary steroid profile: A case report

The pediatric case of ossicular malformation with PORD (Cytochrome P450 Oxidoreductase Deficiency)

The pediatric case of ossicular malformation with PORD (Cytochrome P450 Oxidoreductase Deficiency)

P450 oxidoreductase deficiency: A systematic review and meta-analysis of genotypes, phenotypes, and their relationships

P450 oxidoreductase deficiency: A systematic review and meta-analysis of genotypes, phenotypes, and their relationships

Alternative pathway androgen biosynthesis and human fetal female virilization

Androgen biosynthesis in the human fetus proceeds through the adrenal sex steroid precursor dehydroepiandrosterone (DHEA), which is converted to testosterone in the gonads, followed by further activation to 5α-dihydrotestosterone (DHT) in genital skin, thereby facilitating male external genital differentiation (1). Congenital adrenal hyperplasia (CAH) due to P450 oxidoreductase deficiency (PORD) is an inborn disorder that results in disrupted DHEA biosynthesis, leading to undervirilization of affected boys. However, some affected girls present with severe genital virilization at birth, despite low circulating androgen concentrations (2-4). Here, Reisch et al. hypothesized that this might be explained by a prenatally active, alternative biosynthesis pathway to 5α-DHT. They investigated the presence of an alternative androgen-producing pathway in human fetuses.