High carrier frequency of a nonsense p.Trp230* variant in HSD3B2 gene in Ossetians.

Background: Congenital adrenal hyperplasia (CAH) caused by 3ß-HSD deficiency is a rare form of congenital adrenal deficiency with an autosomal recessive type of inheritance. Previously we have demonstrated that a single nucleotide variant (SNV) p.Trp230* in the homozygous state is a frequent cause of CAH among the indigenous population of North Ossetia-Alania represented by Ossetians. Methods: Genotyping of the NM_000198.3:c.690G>A p.Trp230* variant was performed by Real-time PCR. 339 healthy individuals of Ossetian origin were included in the study. Allele frequencies, Fisher's confidence intervals (CI) were calculated using the WinPepi v. 11.65 software. Comparison of allele frequencies was performed with the z-score test for two proportions. Results: Eight heterozygous carriers of c.690G>A variant in HSD3B2 gene were detected in 339 samples investigated. The total allele frequency of p.Trp230* variant was 0.0118 (n=8/678, 95% CI=0.0051-0.0231). Accordingly, the heterozygous carrier rate was 0.0236 (n=8/339). The frequency of CAH caused by p.Trp230* variant in HSD3B2 in Ossetian population was 1:7183 or 13.9 per 100,000 (95% CI: 1:1874-1:38447 or 3-53 per 100,000). Conclusion: The results demonstrate high frequency of p.Trp230* variant in Ossetians, which is most likely attributed to a founder effect.

Co-Occurrence of a Pathogenic HSD3B2 Variant and a Duplication on 10q22.3-q23.2 Detected in Newborn Twins with Salt-Wasting Congenital Adrenal Hyperplasia.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by enzyme deficiencies required for cortisol biosynthesis in the adrenal cortex. The majority of CAH are due to the deficiency of the 21-hydroxylase enzyme, while 3ß-hydroxysteroid dehydrogenase type 2 deficiency accounts for less than five percent of all CAH cases. We report two Moroccan twins from a spontaneous triplet pregnancy. The 46,XY newborn exhibited a disorder of sexual differentiation (DSD) with hypo virilization, while the 46,XX newborn had normal female external genitalia. In the first week of life, they showed hyponatremia and primary adrenal insufficiency with a slight 17OHP elevation and increased DHEAS and renin levels. The aCGH-SNP analysis disclosed a 8.36 Mb long contiguous stretch of homozygosity (LCSH) on chromosome 1p13.2-p11.2 including the candidate HSD3B2 gene, a LCSH of 7.3 Mb on 14q31.1-q32.11, and a 7 Mb duplication on 10q22.3-q23.2. Clinical exome sequencing revealed the biallelic c.969T > G (p.Asn323Lys) HSD3B2, likely pathogenic, variant in both of the affected twins. This case emphasizes the importance of a prompt molecular diagnosis performed through the combination of aCGH and clinical exome, both for establishment of correct therapy and for follow-up, as the newborns also carry a genomic rearrangement with possible clinical implications.

Association Between Adrenal-Restrictive HSD3B1 Inheritance and Hormone-Independent Subtypes of Endometrial and Breast Cancer.

BACKGROUND: The germline variant rs1047303 (HSD3B1[1245A/C]), restricting or enabling production of potent androgens and estrogens from adrenal precursors, affects outcomes of castration-resistant prostate cancer and is associated with estrogen receptor positivity in postmenopausal breast cancer. Like breast cancer, endometrial cancer is another malignancy with hormone-dependent and hormone-independent subtypes. We hypothesized that adrenal-restrictive HSD3B1 genotype would associate with hormone-independent cancer subtypes. METHODS: We employed a previously described classification of tumors in The Cancer Genome Atlas into genomic clusters. We determined HSD3B1 genotype frequencies by endometrial cancer genomic cluster and calculated the odds per adrenal-restrictive A allele for the largely hormone-independent copy-number (CN) high subtype vs other subtypes. An equivalent analysis was performed for the genomically similar, hormone-independent basal breast cancer subtype. Last, we performed survival analyses for UK Biobank participants with endometrial cancer by HSD3B1 genotype. All statistical tests were 2-sided. RESULTS: The adrenal-restrictive HSD3B1(1245A) allele was associated with the CN-high endometrial cancer subtype (odds ratio [OR] = 1.63, 95% confidence interval [CI] = 1.14 to 2.32; P = .007). Similarly, HSD3B1(1245A) was associated with the basal breast cancer subtype (OR = 1.54, 95% CI = 1.13 to 2.08; P = .006). In the UK Biobank, endometrial cancer patients homozygous for HSD3B1(1245A) had worse overall (hazard ratio [HR] = 1.39, 95% CI = 1.16 to 1.68; P < .001) and cancer-specific (HR = 1.39, 95% CI = 1.14 to 1.70; P = .001) survival, consistent with the A allele being enriched in the more aggressive CN-high subtype. CONCLUSIONS: These findings suggest roles for adrenal-restrictive vs adrenal-permissive steroidogenesis, by way of rs1047303 genotype, in the development of and/or outcomes from at least 3 commonly hormone-associated types of cancer: prostate, breast, and endometrial.

Role of single nucleotide polymorphisms of the HSD3B1 gene (rs6203 and rs33937873) in the prediction of prostate cancer risk.

3­ß­hydroxysteroid dehydrogenase 1 (HSD3B1) is shown to affect dihydrotestosterone level in prostatic tissue which is a risk factor for prostate cancer (PC). The present study aimed to determine whether rs33937873 (G313A) and rs6203 (C338T) single nucleotide polymorphisms (SNP) in HSD3B1 gene was a potential risk factor for PC susceptibility and can predict the recurrence of PC in Egyptian patients. A total of 186 Egyptian patients were selected with incident primary PC and compared with 180 age healthy controls. The frequencies and the main effect of rs33937873 and rs6203 in HSD3B1 were compared and investigated between the patients and control using genotyping technique and statistical analysis. The mutant GA genotype of G313A in rs33937873 SNP was considered as an independent risk for PC in the multivariate regression analysis [odds ratio (OR)=2.7, 95% confidence intervals (CI): 1.2­5.5, P=0.01] together with positive history of hypertension (HTN) (OR=6.2, 95% CI: 3.2­12.1, P=0.0001) and begin prostatic hyperplasia (BPH; OR=8.9, 95% CI: 4.5­17.5, P=0.0001). Conversely, in rs6203 (C338T), C allele is considered as major risk allele in the development of PC (OR=1.8, 95% CI: 1.3­2.4, P=0.0003). The univariate logistic regression analyses indicated that CC genotype of rs6203 was a PC risk factor (OR=1.9, 95% CI: 1.3­2.9, P=0.002). In addition, the frequency of the A­C haplotype established by rs33937873­rs6203 was also significantly higher for PC (P=0.013). The predication of PC recurrence was associated only with positive family history (OR=7.7, 95% CI: 2.3­25.9, P=0.001) and not for The G313A and C338T SNPs. These results suggested that the two HSD3B1 polymorphisms rs33937873 and rs6203 may modify the risk of PC, particularly among patients with HTN and history of BPH, suggesting them as prominent future markers for prediction of PC risk.

Association of HSD3B1 Genotype and Clinical Outcomes in Postmenopausal Estrogen-Receptor-Positive Breast Cancer.

BACKGROUND: Homozygous inheritance of a single-nucleotide polymorphism (1245A > C) in HSD3B1 results in an adrenal permissive phenotype of increased adrenal steroid precursor conversion to potent androgens. This is associated with poor outcomes in prostate cancer. We hypothesized that inheritance of the HSD3B1 adrenal permissive genotype would similarly negatively impact breast cancer outcomes. PATIENTS AND METHODS: Germline HSD3B1 was sequenced in 644 postmenopausal women diagnosed between 2004 and 2015 with stage I-III estrogen receptor-positive (ER+), HER2/neu-negative (HER2-) breast cancer enrolled in a population-based study in western Washington. Primary endpoint was distant metastatic recurrence according to genotype. Secondary endpoint was breast cancer-specific survival. Hazard ratios (HR) were calculated using cause-specific Cox regression accounting for competing risks. RESULTS: Adrenal restrictive genotype (homozygous wild type) was most prevalent (47%), followed by heterozygous (44%) and adrenal permissive (9%). There were no significant differences comparing demographic, tumor, or treatment characteristics apart from higher frequency of adrenal permissive genotype among non-Hispanic white participants (p = 0.04). After accounting for competing risks, the cumulative incidence of distant metastatic recurrence (15 events) was significantly higher among participants with adrenal permissive compared with the adrenal restrictive genotype (HR 4.9, 95% CI 1.32-18.4, p = 0.02). The adrenal permissive genotype was also predictive of breast cancer-specific mortality (HR 3.5, 95% CI 1.27-9.59, p = 0.02). CONCLUSIONS: Inheritance of the HSD3B1 adrenal permissive genotype is associated with increased incidence of distant metastasis and higher cause-specific mortality in postmenopausal ER+/HER2- breast cancer. Further research is necessary to understand the effect of excess adrenal androgen metabolism in promoting breast cancer growth and progression.

A Testis-Specific Long Noncoding RNA, Start, Is a Regulator of Steroidogenesis in Mouse Leydig Cells.

The testis expresses many long noncoding RNAs (lncRNAs), but their functions and overview of lncRNA variety are not well understood. The mouse Prss/Tessp locus contains six serine protease genes and two lncRNAs that have been suggested to play important roles in spermatogenesis. Here, we found a novel testis-specific lncRNA, Start (Steroidogenesis activating lncRNA in testis), in this locus. Start is 1822 nucleotides in length and was found to be localized mostly in the cytosol of germ cells and Leydig cells, although nuclear localization was also observed. Start-knockout (KO) mice generated by the CRISPR/Cas9 system were fertile and showed no morphological abnormality in adults. However, in adult Start-KO testes, RNA-seq and qRT-PCR analyses revealed an increase in the expression of steroidogenic genes such as Star and Hsd3b1, while ELISA analysis revealed that the testosterone levels in serum and testis were significantly low. Interestingly, at 8 days postpartum, both steroidogenic gene expression and testosterone level were decreased in Start-KO mice. Since overexpression of Start in two Leydig-derived cell lines resulted in elevation of the expression of steroidogenic genes including Star and Hsd3b1, Start is likely to be involved in their upregulation. The increase in expression of steroidogenic genes in adult Start-KO testes might be caused by a secondary effect via the androgen receptor autocrine pathway or the hypothalamus-pituitary-gonadal axis. Additionally, we observed a reduced number of Leydig cells at 8 days postpartum. Collectively, our results strongly suggest that Start is a regulator of steroidogenesis in Leydig cells. The current study provides an insight into the overall picture of the function of testis lncRNAs.

The association between missense polymorphisms in SRD5A2 and HSD3B1 and treatment failure with abiraterone for castration-resistant prostate cancer.

Missense polymorphism in HSD3B1, encoding 3ß-hydroxysteroid dehydrogenase-1, was associated with outcome after abiraterone treatment. Other androgen-metabolizing enzymes may be involved in therapeutic effect in abiraterone. In this study, we investigated the significance of polymorphisms in genes involved in androgen and abiraterone metabolisms in prostate cancer patients treated with abiraterone. A total of 99 Japanese male castration-resistant prostate cancer patients treated with abiraterone between 2014 and 2018 were included. Genomic DNA was obtained from whole blood samples, and genotyping on SRD5A2 (rs523349), CYP17A1 (rs743572), CYP17A1 (rs2486758), and AKR1C3 (rs12529) was performed by PCR-based technique. Among the 99 patients, 32 (32.3%), 49 (49.5%), and 18 patients (18.2%) carried GG, GC, and CC alleles in SRD5A2, respectively. CC allele was associated with lower risk of treatment failure (hazard ratio, 0.43; 95% confidence interval, 0.20-0.87; P = 0.017) on multivariate analyses, compared with GG/GC alleles. In the combination model using HSD3B1 and SRD5A2 polymorphisms, compared with the combination of AA in HSD3B1 and GG/GC in SRD5A2, other combinations were associated with lower risk of treatment failure (hazard ratio, 0.34; 95% confidence interval, 0.17-0.62; P = 0.0003) on multivariate analyses. This study showed that SRD5A2 genetic variation was associated with the risk of treatment failure in abiraterone. Combinational use of genetic variation in HSD3B1 with SRD5A2 genetic variation augmented the ability of prognostic stratification.

Progesterone dose during synchronization treatment alters luteinizing hormone receptor and steroidogenic enzyme mRNA abundances in granulosa cells of Nellore heifers.

The objective was to investigate effects of progesterone (P4) dose on abundance of luteinizing hormone receptor (LHCGR), aromatase (CYP19A1), 3ß-hydroxysteroid dehydrogenase (HSD3B1), and other steroidogenic mRNA transcripts in granulosa cells from dominant follicles. Nellore heifers were assigned to one of six groups: new, first-use controlled internal drug release device (CIDR1) inserted for 5 days (Large-P4-dose-D5; n = 7) or 6 days (Large-P4-dose-D6; n = 8), prostaglandin (PG)F2α administered on D0 and 1 previously-used CIDR (CIDR3) inserted for 5 days (Small- P4-dose-D5; n = 8) or 6 days (Small-P4-dose-D6; n = 8), CIDR1 inserted on D0 and removed plus PGF2α on D5 (Large-P4-dose-proestrus (PE); n = 7), and CIDR3 and PGF2α on D0 and 1, CIDR3 removed plus PGF2α on D5 (Small-P4-dose-PE; n = 7). Duration of P4 treatment (D5 compared to D6) affected abundances of CYP19A1 mRNA transcripts, with there being greater abundances on D6 than D5 (P ≤ 0.05). Heifers treated with the large dose of P4 had a smaller dominant follicle, less serum and intra-follicular estradiol (E2) concentrations (P ≤ 0.05) and lesser LHCGR, CYP19A1, and HSD3B1 transcript abundances (P ≤ 0.05). Heifers treated to induce PE had a larger follicle diameter (P = 0.09), greater intra-follicular E2 concentrations and larger abundances of CYP19A1 mRNA transcript (P ≤ 0.05) than heifers of the D6 group. Overall, treatment with larger doses of P4 resulted in lesser abundances of LHCGR, HSD3B1, and CYP19A1 mRNA transcripts; thus, potentially leading to development of smaller dominant follicles and lesser E2 concentrations.

A large cohort of disorders of sex development and their genetic characteristics: 6 novel mutations in known genes.

INTRODUCTION: Disorders of sex development (DSD) constitutes a group of congenital conditions that affect urogenital differentiation and are associated with chromosomal, gonadal and phenotypic sex abnormalities. OBJECTIVE: To evaluate the clinical and genetic features of childhood DSD cases. MATERIALS AND METHODS: DSD patients followed up between the years of 2002-2018 were evaluated in terms of their complaints, demographic, clinical features and genetic diagnoses. RESULTS: Out of 289 patients, 143(49.5%) were classified as 46XY DSD, 62(21.5%) as 46XX DSD and 84(29%) as sex chromosomal DSD. Genetic diagnosis was achieved in 150 patients (51.9%). The distribution of the molecular diagnosis of the 46XY DSD patients were; 12 (26.6%) SRD5A2, 10 (22.2%) AR, 7 (15.5%) HSD17B3, 3 (6.6%) WT-1, 2 (4.4%) AMHR2, 2 (4.4%) AMH, 2 (4.4%) LHCGR, 2 (4.4%) HSD3B2, 1 (2.2%) NR5A1, 1 (2.2%) CYP17A1 and 1 (2.2%) SRY mutation. Fifty (80.6%) of the 46XX DSD patients received a diagnosis with clinical and laboratory findings. Twenty-four (38.7%) of them were 21-hydroxylase deficiency, 9(14.5%) Rokitansky-Küster-Hauser Syndrome, 4 (6.5%) 11-ß hydroxylase deficiency, 3 (4.8%) gonadal dysgenesis and 2 (3.2%) aromatase deficiency. In 46XX group pathogenic mutations were detected in 21(33.8%) of the patients. Eighty-four (29%) patients were diagnosed as sex chromosomal disorder. Of these 66 (78.5%) were Turner Syndrome, 6 (7.2%) Klinefelter Syndrome and 10 (11.9%) mix gonadal dysgenesis. Gender re-assignment was decided in 11 patients. Malignant and pre-invasive lesions was diagnosed in 8 (2.7%) patients. CONCLUSION: Many of DSD's are clinically similar and etiology of numerous of them still cannot be established. A multi-disciplinary approach and new rapid genetic diagnostic methods are needed in the process from diagnosis to gender assignment and follow-up.

Effects of electromagnetic field (EMF) radiation on androgen synthesis and release from the pig endometrium during the fetal peri-implantation period.

An electromagnetic field (EMF) may have effects on female reproduction. This study was conducted to determine whether EMF [50 and 120 Hz, 2 and 4 h of incubation in the presence or absence of progesterone (P4, 10-5 M)] affects androgen synthesis and release from the pig endometrium. Endometrial slices were collected from pigs (n = 5) during the fetal peri-implantation period (i.e., days 15-16 of gestation) and treated in vitro with EMF. The selected endometrial slices were treated with P4 to determine whether this hormone has effects on protection of the tissue from EMF radiation. The CYP17A1 and HSD3B1 mRNA transcript abundance, steroid 17αhydroxylase/17, 20-lyase (cytochrome P450c17) and hydroxyΔ5steroid dehydrogenase/3ß and steroidΔisomerase (3ßHSD) protein abundance were examined using Real-Time PCR and Western Blot procedures, respectively. In media collected after incubation, the concentrations of androstenedione (A4) and testosterone (T) were quantified used a RIA. When P4 was added to the culture medium, EMF radiation had suppressive effects on endometrial T release after 2 and 4 h of incubation when the EMF treatment was occurring and increased A4 release after 4 h of incubation with EMF at 120 Hz. When there was no inclusion of P4, release of A4 was decreased after 2 h of EMF treatment at 120 Hz and after 4 h of EMF treatment at 50 and 120 Hz. Progesterone did not have functions that protected the pig endometrium against EMF radiation during the fetal peri-implantation period.

Late diagnosis of 3ß-Hydroxysteroid dehydrogenase deficiency: the pivotal role of gas chromatography-mass spectrometry urinary steroid metabolome analysis and a novel homozygous nonsense mutation in the HSD3B2 gene.

OBJECTIVES: 3ß-Hydroxysteroid dehydrogenase (3ß-HSD) deficiency is a rare type of congenital adrenal hyperplasia caused by recessive loss-of-function mutations in HSD3B2 gene. CASE PRESENTATION: We report an 8.5-year-old, 46XY, Roma boy with advanced adrenarche signs born to consanguineous parents. He was born at term with ambiguous genitalia. At 15 days of age, he underwent replacement therapy with hydrocortisone and fludrocortisone due to a salt wasting (SW) crisis and adrenal insufficiency. At 3.5 years, he was admitted again with SW crisis attributed to the low - unadjusted to body surface area - hydrocortisone dose and presented with bilateral gynecomastia and adrenarche. At 8.5 years, his bone age was four years more advanced than his chronological age and he was prepubertal, with very high testosterone levels. Gas chromatography-mass spectrometry (GC-MS) urinary steroid metabolome analysis revealed the typical steroid metabolic fingerprint of 3ß-HSD deficiency. Sequencing of the HSD3B2 gene identified in homozygosity the novel p.Lys36Ter nonsense mutation. Furthermore, this patient was found to be heterozygous for p.Val281Leu in the CYP21A2 gene. Both parents were identified as carriers of the p.Lys36Ter in HSD3B2. CONCLUSIONS: A novel nonsense p.Lys36Ter mutation in HSD3B2 was identified in a male patient with hypospadias. 3ß-HSD deficiency due to mutations in the HSD3B2 gene is extremely rare and the finding of a patient with this rare type of disorders of sex development (DSD) is one of the very few reported to date. The complexity of such diseases requires a multidisciplinary team approach regarding the diagnosis and follow-up.

Prostate Cancer Foundation Hormone-Sensitive Prostate Cancer Biomarker Working Group Meeting Summary.

Androgen deprivation therapy remains the backbone therapy for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC). In recent years, several treatments, including docetaxel, abiraterone + prednisone, enzalutamide, and apalutamide, have each been shown to demonstrate survival benefit when used upfront along with androgen deprivation therapy. However, treatment selection for an individual patient remains a challenge. There is no high level clinical evidence for treatment selection among these choices based on biological drivers of clinical disease. In August 2020, the Prostate Cancer Foundation convened a working group to meet and discuss biomarkers for hormone-sensitive prostate cancer, the proceedings of which are summarized here. This meeting covered the state of clinical and biological evidence for systemic therapies in the mHSPC space, with emphasis on charting a course for the generation, interrogation, and clinical implementation of biomarkers for treatment selection.

Molecular genetics of disorders of sex development in a highly consanguineous population.

Consanguinity increases the risk of hereditary diseases including disorders of sex development (DSD). There are minimal data on DSD in the highly consanguineous population of Saudi Arabia. This study reports the molecular genetics of a series of patients with different types of DSD. METHODS: We enrolled 77 patients from 47 families with DSD. DNA was isolated from peripheral leucocytes. Genes of interest were amplified by polymerase chain reaction and subsequently sequenced. RESULTS: Overall, 77 patients from 47 families (44 of them are consanguineous) had a total of 29 mutations; 16 of them were described before and 13 were novel mutations. The most common condition was 5-α reductase (SRD5A2) deficiency (25 patients from 18 families) and the most common mutation was a splice site mutation in intron 1 (c.282-2A>G). The next most common condition was 11-ß hydroxylase (CYP11B1) deficiency where 19 patients from 10 families had 8 mutations (7 of them are novel). Other mutations affected CYP17A1 with 2 novel and 2 known mutations in 7 patients; HSD3B2 with 2 known mutations in 11 patients of 4 families; StAR with 1 novel and 1 known mutations in 4 patients; NR0B1 with 1 novel mutation in 2 siblings; HSD17B3 with 1 known mutation in 3 siblings; LHCGR with 1 novel mutation in 2 siblings; and AR with 1 novel and 3 known mutations in 4 unrelated patients. CONCLUSION: In the highly consanguineous and homogeneous population of Saudi Arabia, SRD5A2 and CYP11B1 deficiencies are common causes of DSDs. Other DSDs occur less frequently but often with novel mutations.

Transcriptome analysis of sheep follicular development during prerecruitment, dominant, and mature stages after FSH superstimulation.

Sheep is usually a monovular animal; superovulation technology is used to increase the number of offspring per individual and shorten generation intervals. To date, mature FSH superstimulatory treatments have been successfully used in sheep breeding, but much remains unknown about genes, pathways, and biological functions involved in follicular development. Therefore, in this study, we performed transcriptome profiling of small follicles (SFs; 2-2.5 mm), medium follicles (MFs; 3.5-4.5 mm), and large follicles (LFs; > 6 mm) in Mongolian ewes after FSH superstimulation. Furthermore, we identified differentially expressed genes and performed Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology enrichment analyses in 3 separate pairwise comparisons. We found that ovarian steroidogenesis was significantly enriched in the SFs versus MFs analysis; the associated genes, cytochrome P450 family 19 (CYP19) and Hydroxy-delta-5-steroid dehydrogenase 3 beta- and steroid delta-isomerase 1 (HSD3B1), were significantly upregulated. Moreover, proline metabolism, glutathione metabolism, and PPAR signaling pathways were significantly enriched in the LFs versus SFs analysis; the associated genes, glutamate-cysteine ligase modifier subunit (GCLM) and cystathionine gamma-lyase (CTH), were significantly upregulated, whereas peroxisome proliferator-activated receptor gamma (PPARγ) was significantly downregulated. In summary, our study provides basic data and possible biological direction to further explore the molecular mechanism of sheep follicular development after FSH superstimulation.

Novel role of CXCL14 in modulating STAR expression in luteinized granulosa cells: implication for progesterone synthesis in PCOS patients.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive-age women. Reduced progesterone levels are associated with luteal phase deficiency in women with PCOS. The levels of C-X-C motif chemokine ligand-14 (CXCL14) were previously reported to be decreased in human-luteinized granulosa (hGL) cells derived from PCOS patients. However, the function of CXCL14 in hGL cells and whether CXCL14 affects the synthesis of progesterone in hGL cells remain unclear. In the present study, the levels of CXCL14 were reduced in follicular fluid and hGL cells in PCOS patients, accompanied by decreased progesterone levels in follicular fluid and decreased steroidogenic acute regulatory (STAR) expression in hGL cells. CXCL14 administration partially reversed the low progesterone production and STAR expression in hGL cells obtained from PCOS patients. In primary hGL cells, CXCL14 upregulated STAR expression and progesterone production. CXCL14 activated the phosphorylation of cyclic adenosine monophosphate response element-binding protein (CREB) and CREB inhibitor attenuated the modulation of StAR expression by CXCL14. P38 and Jun N-terminal kinase (JNK) pathways were also activated by CXCL14 and inhibition of p38 and JNK attenuated the increase of phosphorylation of CREB, STAR expression and progesterone production caused by CXCL14. Our findings revealed the novel role of CXCL14 in upregulation of STAR expression and progesterone synthesis through CREB phosphorylation via activation of p38 and JNK pathways in hGL cells. This is likely contributing to the dysfunction in steroidogenesis in granulosa cells from PCOS patients.

HSD3B1 variant and androgen-deprivation therapy outcome in prostate cancer.

OBJECTIVE: Rate-limiting enzyme 3b-hydroxysteroid dehydrogenase type 1 (3ßHSD1) encoded by HSD3B1 catalyzes the transition of dehydroepiandrosterone (DHEA) to dihydrotestosterone (DHT). The HSD3B1 (1245C) variant renders 3bHSD1 of resistant to ubiquitination and degradation, leading to a large amount of protein accumulation in the cell. Multiple clinical studies have shown that this mutation was correlated with resistance to androgen-deprivation therapy in prostate cancer. However, the results were not consistent depending on different treatment strategy and in some researches, the number of observed cases was relatively small. METHODS: To determine the effects of HSD3B1 (1245C) variant on resistance to androgen-deprivation therapy in prostate cancer, we performed a meta-analysis of the available literature. Electronic database searches identified appropriately designed studies that detected HSD3B1 in prostate cancer. We conducted a systematic search of studies in the following databases: PubMed, and EMBASE published until August 10, 2020 using the following search terms: (HSD3B1 AND ((((prostate cancer) OR prostatic neoplasm) OR prostatic carcinoma) OR prostatic cancer). RESULTS: Eight researches were included in this research. The result validated that the HSD3B1 (1245C) variant allele was associated with a shorter PFS (HR, 1.97; 95% CI, 1.39-2.79; P = 0.0001) (homozygous wild-type group) in men with prostate cancer when treated with ADT, however, a higher PFS (HR, 0.68; 95% CI, 0.48-0.96; P = 0.03) when treated with ADT and CYP17A1 inhibitor. CONCLUSION: The HSD3B1 (1245C) variant is a predictor of ADT plus CYP17A1 inhibitor response in prostate cancer.

Germline HSD3B1 Genetics and Prostate Cancer Outcomes.

Dihydrotestosterone synthesis in prostate cancer from adrenal DHEA/DHEA-sulfate requires enzymatic conversion in tumor tissues. 3ß-hydroxysteroid dehydrogenase-1 is an absolutely necessary enzyme for such dihydrotestosterone synthesis and is encoded by the gene HSD3B1 which comes in 2 functional inherited forms described in 2013. The adrenal-permissive HSD3B1(1245C) allele allows for rapid dihydrotestosterone synthesis. The adrenal-restrictive HSD3B1(1245A) allele limits androgen synthesis. Studies from multiple cohorts show that adrenal-permissive allele inheritance confers worse outcomes and shorter survival after castration in low-volume prostate cancer and poor outcomes after abiraterone or enzalutamide treatment for castration-resistant prostate cancer. Here, we review the clinical data and implications.

Dysregulated expression of androgen metabolism genes and genetic analysis in hypospadias.

BACKGROUND: The aberrant expression of genes involved in androgen metabolism and genetic contribution are unclear in hypospadias. METHODS: We compared gene expression profiles by RNA sequencing from five non-hypospadiac foreskins, five mild hypospadiac foreskins, and five severe hypospadiac foreskins. In addition, to identify rare coding variants with large effects on hypospadias risk, we carried out whole exome sequencing in three patients in a hypospadias family. RESULTS: The average expression of androgen receptor (AR) and CYP19A1 were significantly decreased in severe hypospadias (p < .01) and mild hypospadias (p < .05), whereas expression of several other androgen metabolism enzymes, including CYP3A4, HSD17B14, HSD3B7, HSD17B7, CYP11A1 were exclusively significantly expressed in severe hypospadias (p < .05). Compound rare damaging mutants of AR gene with HSD3B1 and SLC25A5 genes were identified in the different severe hypospadias. CONCLUSIONS: In conclusion, our findings demonstrated that dysregulation of AR and CYP19A1 could play a crucial role in the development of hypospadias. Inconsistent AR expression may be caused by the feedback loop of ESR1 signaling or combined genetic effects with other risk genes. This findings complement the possible role of AR triggered mechanism in the development of hypospadias.

Through the Looking-Glass: Reevaluating DHEA Metabolism Through HSD3B1 Genetics.

Dehydroepiandrosterone (DHEA) and DHEA sulfate together are abundant adrenal steroids whose physiological effects are mediated through their conversion to potent downstream androgens. 3ß-Hydroxysteroid dehydrogenase isotype 1 (3ßHSD1) facilitates the rate-limiting step of DHEA metabolism and gates the flux of substrate into the distal portion of the androgen synthesis pathway. Notably, a germline, missense-encoding change, HSD3B1(1245C), results in expression of 3ßHSD1 protein that is resistant to degradation, yielding greater potent androgen production in the periphery. In contrast, HSD3B1(1245A) encodes 3ßHSD1 protein that is easily degraded, limiting peripheral androgen synthesis. These adrenal-permissive (AP) and adrenal-restrictive (AR) alleles have recently been associated with divergent outcomes in androgen-sensitive disease states, underscoring the need to reevaluate DHEA metabolism using HSD3B1 genetics.