Female ; Humans ; Breast Neoplasms ; Testosterone ; Prolactin ; Estradiol ; Testosterone Congeners ; China

Background: Metformin has been studied for its anti-proliferative effects on endometrial cells, and it is hypothesized to have a synergistic effect with progestin therapy in suppressing endometrial cell proliferation. This systematic review and meta-analysis aimed to determine the efficacy of adjunctive metformin in the clinical regression of endometrial hyperplasia and early-stage endometrial carcinoma. Methodology: This meta-analysis followed the Cochrane methodology and adhered to the PRISMA 2020 guidelines. Randomized controlled trials (RCTs) were included if they enrolled reproductive-aged women with endometrial hyperplasia (with and without atypia) and endometrial carcinoma who were treated with progestin and metformin. The primary outcome was the complete response rate at 12-16 weeks, and secondary outcomes included relapse rate, clinical pregnancy rate, and live birth rate. Odds ratios (ORs) and 95% confidence intervals (CIs) were used for dichotomous data. Results: Six RCTs were included. The addition of metformin to progestin therapy may increase the complete response rate of endometrial hyperplasia without atypia (OR 5.12, 95% CI 1.17 to 22.41; n=102) and live birth rates (OR 2.51, 95% CI 1.34 to 4.69; n=188) compared to progestin therapy alone, but the certainty of the evidence is low. Metformin did not have a significant effect on the clinical response of endometrial hyperplasia with atypia and endometrial carcinoma, relapse rates, and clinical pregnancy rates. Conclusion Current evidence is uncertain on the potential benefit of metformin with progestin in endometrial hyperplasia and carcinoma. Future high-quality randomized controlled trials with larger sample sizes and longer follow-up periods are needed to support practice recommendations.
Endometrial Hyperplasia ; Endometrial Neoplasms ; Metformin ; Progesterone

Humans ; Female ; Receptors, Estrogen/metabolism* ; Breast Neoplasms/metabolism* ; Receptors, Progesterone/metabolism* ; Immunohistochemistry ; Estrogen Receptor alpha

BACKGROUND: Steroid receptor-associated and regulated protein (SRARP) suppresses tumor progression and modulates steroid receptor signaling by interacting with estrogen receptors and androgen receptors in breast cancer. In endometrial cancer (EC), progesterone receptor (PR) signaling is crucial for responsiveness to progestin therapy. The aim of this study was to investigate the role of SRARP in tumor progression and PR signaling in EC. METHODS: Ribonucleic acid sequencing data from the Cancer Genome Atlas, Clinical Proteomic Tumor Analysis Consortium, and Gene Expression Omnibus were used to analyze the clinical significance of SRARP and its correlation with PR expression in EC. The correlation between SRARP and PR expression was validated in EC samples obtained from Peking University People's Hospital. SRARP function was investigated by lentivirus-mediated overexpression in Ishikawa and HEC-50B cells. Cell Counting Kit-8 assays, cell cycle analyses, wound healing assays, and Transwell assays were used to evaluate cell proliferation, migration, and invasion. Western blotting and quantitative real-time polymerase chain reaction were used to evaluate gene expression. The effects of SRARP on the regulation of PR signaling were determined by co-immunoprecipitation, PR response element (PRE) luciferase reporter assay, and PR downstream gene detection. RESULTS: Higher SRARP expression was significantly associated with better overall survival and disease-free survival and less aggressive EC types. SRARP overexpression suppressed growth, migration, and invasion in EC cells, increased E-cadherin expression, and decreased N-cadherin and Wnt family member 7A ( WNT7A ) expression. SRARP expression was positively correlated with PR expression in EC tissues. In SRARP -overexpressing cells, PR isoform B (PRB) was upregulated and SRARP bound to PRB. Significant increases in PRE-based luciferase activity and expression levels of PR target genes were observed in response to medroxyprogesterone acetate. CONCLUSIONS This study illustrates that SRARP exerts a tumor-suppressive effect by inhibiting the epithelial-mesenchymal transition via Wnt signaling in EC. In addition, SRARP positively modulates PR expression and interacts with PR to regulate PR downstream target genes.
Female ; Humans ; Receptors, Progesterone/metabolism* ; Proteomics ; Cell Line, Tumor ; Endometrial Neoplasms/metabolism* ; Cell Proliferation/genetics* ; Luciferases/pharmacology* ; Gene Expression Regulation, Neoplastic/genetics*

BACKGROUND: In light of the significant clinical benefits of antibody-drug conjugates in clinical trials, the human epidermal growth factor receptor 2 (HER2)-low category in breast cancers has gained increasing attention. Therefore, we studied the clinicopathological characteristics of Chinese patients with hormone receptor (HR)-positive/HER2-low early-stage breast cancer and developed a recurrence risk prediction model. METHODS: Female patients with HR-positive/HER2-low early-stage breast cancer treated in 29 hospitals of the Chinese Society of Breast Surgery (CSBrS) from Jan 2015 to Dec 2016 were enrolled. Their clinicopathological data and prognostic information were collected, and machine learning methods were used to analyze the prognostic factors. RESULTS: In total, 25,096 patients were diagnosed with breast cancer in 29 hospitals of CSBrS from Jan 2015 to Dec 2016, and clinicopathological data for 6486 patients with HER2-low early-stage breast cancer were collected. Among them, 5629 patients (86.79%) were HR-positive. The median follow-up time was 57 months (4, 76 months); the 5-year disease-free survival (DFS) rate was 92.7%, and the 5-year overall survival (OS) rate was 97.7%. In total, 412 cases (7.31%) of metastasis were observed, and 124 (2.20%) patients died. Multivariate Cox regression analysis revealed that T stage, N stage, lymphovascular thrombosis, Ki-67 index, and prognostic stage were associated with recurrence and metastasis ( P <0.05). A recurrence risk prediction model was established using the random forest method and exhibited a sensitivity of 81.1%, specificity of 71.7%, positive predictive value of 74.1%, and negative predictive value of 79.2%. CONCLUSION: Most of patients with HER2-low early-stage breast cancer were HR-positive, and patients had favorable outcome; tumor N stage, lymphovascular thrombosis, Ki-67 index, and tumor prognostic stage were prognostic factors. The HR-positive/HER2-low early-stage breast cancer recurrence prediction model established based on the random forest method has a good reference value for predicting 5-year recurrence events. REGISTRITATION ChiCTR.org.cn, ChiCTR2100046766.
Humans ; Female ; Breast Neoplasms/diagnosis* ; Ki-67 Antigen ; Receptor, ErbB-2 ; Prognosis ; Thrombosis ; Receptors, Progesterone

OBJECTIVE: This study aimed to compare 9 perfluoroalkyl sulfonic acids (PFSA) with carbon chain lengths (C4-C12) to inhibit human placental 3β-hydroxysteroid dehydrogenase 1 (3β-HSD1), aromatase, and rat 3β-HSD4 activities. METHODS: Human and rat placental 3β-HSDs activities were determined by converting pregnenolone to progesterone and progesterone secretion in JEG-3 cells was determined using HPLC/MS-MS, and human aromatase activity was determined by radioimmunoassay. RESULTS: PFSA inhibited human 3β-HSD1 structure-dependently in the order: perfluorooctanesulfonic acid (PFOS, half-maximum inhibitory concentration, IC ₅₀: 9.03 ± 4.83 μmol/L) > perfluorodecanesulfonic acid (PFDS, 42.52 ± 8.99 μmol/L) > perfluoroheptanesulfonic acid (PFHpS, 112.6 ± 29.39 μmol/L) > perfluorobutanesulfonic acid (PFBS) = perfluoropentanesulfonic acid (PFPS) = perfluorohexanesulfonic acid (PFHxS) = perfluorododecanesulfonic acid (PFDoS) (ineffective at 100 μmol/L). 6:2FTS (1H, 1H, 2H, 2H-perfluorooctanesulfonic acid) and 8:2FTS (1H, 1H, 2H, 2H-perfluorodecanesulfonic acid) did not inhibit human 3β-HSD1. PFOS and PFHpS are mixed inhibitors, whereas PFDS is a competitive inhibitor. Moreover, 1-10 μmol/L PFOS and PFDS significantly reduced progesterone biosynthesis in JEG-3 cells. Docking analysis revealed that PFSA binds to the steroid-binding site of human 3β-HSD1 in a carbon chain length-dependent manner. All 100 μmol/L PFSA solutions did not affect rat 3β-HSD4 and human placental aromatase activity. CONCLUSION Carbon chain length determines inhibitory potency of PFSA on human placental 3β-HSD1 in a V-shaped transition at PFOS (C8), with inhibitory potency of PFOS > PFDS > PFHpS > PFBS = PFPS = PFHxS = PFDoS = 6:2FTS = 8:2FTS.
Humans ; Pregnancy ; Female ; Rats ; Animals ; Placenta ; Progesterone/pharmacology* ; Aromatase/pharmacology* ; Cell Line, Tumor ; Fluorocarbons ; Alkanesulfonic Acids ; Structure-Activity Relationship ; Hydroxysteroid Dehydrogenases/pharmacology*

17α hydroxylase is a key enzyme for the conversion of progesterone to prepare various progestational drug intermediates. To improve the specific hydroxylation capability of this enzyme in steroid biocatalysis, the CYP260A1 derived from cellulose-mucilaginous bacteria Sorangium cellulosum Soce56 and the Fpr and bovine adrenal-derived Adx_4-108 derived from Escherichia coli str. K-12 were used to construct a new electron transfer system for the conversion of progesterone. Selective mutation of CYP260A1 resulted in a mutant S276I with significantly enhanced 17α hydroxylase activity, and the yield of 17α-OH progesterone reached 58% after optimization of the catalytic system in vitro. In addition, the effect of phosphorylation of the ferredoxin Adx_4-108 on 17α hydroxyl activity was evaluated using a targeted mutation technique, and the results showed that the mutation Adx_4-108T69E transferred electrons to S276I more efficiently, which further enhanced the catalytic specificity in the C17 position of progesterone, and the yield of 17α-OH progesterone was eventually increased to 74%. This study provides a new option for the production of 17α-OH progesterone by specific transformation of bacterial-derived 17α hydroxylase, and lays a theoretical foundation for the industrial production of progesterone analogs using biotransformation method.
Animals ; Cattle ; Progesterone/metabolism* ; Hydroxylation ; Biocatalysis ; Electron Transport ; Mixed Function Oxygenases/metabolism*

To investigate the factors affecting the sperm retrieval rate of microdissection testicular sperm extraction (micro-TESE) in patients with nonmosaic Klinefelter syndrome (KS), 64 patients with nonmosaic KS who underwent micro-TESE in the Center for Reproductive Medicine of Peking University Third Hospital (Beijing, China) between January 2016 and December 2017 were included in the study. Data on medical history, physical examination and laboratory examination results, and micro-TESE outcomes were collected. Patients were divided into two groups according to micro-TESE outcomes. The following factors were compared between the two groups by the Mann‒Whitney U test or Student's t-test based on the distribution (nonnormal or normal) of the factors: age, testicular size, follicle-stimulating hormone level, luteinizing hormone level, testosterone level, and anti-Müllerian hormone level. The overall success rate of sperm retrieval was 50.0%. Correlation analysis showed that testicular volume was positively correlated with testosterone level. Using a logistic regression model, age and anti-Müllerian hormone levels were found to be better predictors for the sperm retrieval rate than the other parameters.
Humans ; Male ; Sperm Retrieval ; Klinefelter Syndrome ; Microdissection ; Anti-Mullerian Hormone ; Semen ; Testis ; Spermatozoa ; Testosterone ; Azoospermia ; Retrospective Studies

To compare the impact of the scrotal vs inguinal orchidopexy approach on the testicular function of infants with cryptorchidism, a randomized controlled trial was conducted involving boys who were 6-12 months old at surgery and were diagnosed with clinically palpable, inguinal undescended testis. Between June 2021 and December 2021, these boys at Fujian Maternity and Child Health Hospital (Fuzhou, China) and Fujian Children's Hospital (Fuzhou, China) were enrolled. Block randomization with a 1:1 allocation ratio was employed. The primary outcome was testicular function assessed by testicular volume, serum testosterone, anti-Müllerian hormone (AMH), and inhibin B (InhB) levels. Secondary outcomes included operative time, amount of intraoperative bleeding, and postoperative complications. Among 577 screened patients, 100 (17.3%) were considered eligible and enrolled in the study. Of the 100 children who completed the 1-year follow-up, 50 underwent scrotal orchidopexy and 50 underwent inguinal orchidopexy. The testicular volume, serum testosterone, AMH, and InhB levels in both groups increased markedly after surgery (all P < 0.05), but there were no apparent differences between groups at 6 months and 12 months after operation (all P > 0.05). No differences between the scrotal and inguinal groups were noted regarding the operative time ( P = 0.987) and amount of intraoperative bleeding ( P = 0.746). The overall complication rate (2.0%) of the scrotal group was slightly lower than that of the inguinal group (8.0%), although this difference was not statistically significant ( P > 0.05). Both scrotal and inguinal orchiopexy exerted protective effects on testicular function in children with cryptorchidism, with similar operative status and postoperative complications. Scrotal orchiopexy is an effective alternative to inguinal orchiopexy in children with cryptorchidism.
Female ; Pregnancy ; Male ; Infant ; Humans ; Child ; Cryptorchidism/surgery* ; Orchiopexy ; Scrotum/surgery* ; Postoperative Complications ; Anti-Mullerian Hormone ; Testosterone

A 13-year and 6-month-old girl attended the Hunan Children's Hospital due to delayed menarche. The laboratory test results indicated increased follicle-stimulating hormone and luteinizing hormone, decreased anti-Mullerian hormone, and pelvic ultrasound showed a cord-like uterus and absence of bilateral ovaries. Her 11-year and 5-month-old younger sister had the same laboratory and imaging findings, and both girls were diagnosed with primary ovarian insufficiency. Whole exome sequencing and Sanger sequencing confirmed that the proband and her sister carried heterozygous variants of HROB gene c.718C>T (p.Arg240*) and c.1351C>T (p.Arg451*), which were inherited from their parents respectively and consistent with autosomal recessive inheritance. Oral estradiol valerate at an initial dose of 0.125 mg/d was given to the proband, and the secondary sexual characteristics began to develop after 6 months.
Humans ; Female ; Child ; Infant ; Primary Ovarian Insufficiency/genetics* ; Luteinizing Hormone ; Estradiol