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Frontiers in Endocrinology 2024A reduction in anti-müllerian hormone (AMH) levels at short-term after bariatric surgery (BS) has been previously described. However, an assessment of ovarian reserve...
INTRODUCTION
A reduction in anti-müllerian hormone (AMH) levels at short-term after bariatric surgery (BS) has been previously described. However, an assessment of ovarian reserve at longer-follow up, and a comprehensive evaluation of the potentially implicated factors has not been reported.
DESIGN
Prospective cohort study.
MATERIALS AND METHODS
Twenty women aged 18-40 years with BMI 43.95 kg/m2 undergoing BS were studied at baseline (BS0), and at 1 month (BS1), 4 months (BS2), 12 months (BS3), and 24-36 months (BS4) after the surgery. Anthropometrics, reproductive hormones (AMH, FSH, LH, estradiol, testosterone, SHBG, androstenedione), metabolic parameters (adiponectin, leptin, ghrelin, insulin), and nutritional blood parameters (markers of nutritional status, vitamins, and minerals) were obtained at each study time point. Antral follicular count (AFC) was assessed by ultrasonography at BS0, BS3, and BS4. Mixed models were used for analysis of longitudinal data.
RESULTS
The mean AMH level was 3.88 ng/mL at BS0, decreased at BS3 (mean= 2.59 ng/mL; p=0.009), and remained stable between BS3 and BS4 (mean= 2.96 ng/mL; p=0.409). We also observed a non-significant decrease in AFC at BS3 (mean=26.14 at BS0, mean 16.81 at BS3; p=0.088) that remained stable at BS4 (mean= 17.86; p=0.731). Mixed models analysis showed: (a) a decrease in 10 kg of body weight was associated with an average decrease of 0.357 ng/mL in AMH (p=0.014); (b) a decrease in 1 BMI point was associated with an average decrease of 0.109 ng/mL in AMH (p=0.005); (c) an increase in 1 µg/mL of adiponectin was associated with an average decrease of 0.091 ng/ml in AMH (p=0.041) Significant positive correlations were found between the AMH levels after BS and plasma concentrations of testosterone, free androgen index, insulin and HOMA index. No significant correlations were detected between AMH levels and nutritional parameters.
CONCLUSIONS
Our results were in line with previous observations, showing that AMH levels decreased significantly at 12 months after bariatric surgery, in parallel with a non-significant reduction in AFC. Both ovarian reserve markers showed a later stabilization up to the end of the study. Of note, postoperative AMH levels were positively correlated with key androgen and insulin resistance-related parameters.
Topics: Female; Humans; Ovarian Reserve; Adipokines; Prospective Studies; Adiponectin; Androgens; Bariatric Surgery; Testosterone; Insulins; Anti-Mullerian Hormone
PubMed: 38559698
DOI: 10.3389/fendo.2024.1284576 -
International Journal of Molecular... Mar 2024C19 steroids and C22 steroids are vital intermediates for the synthesis of steroid drugs. Compared with C19 steroids, C22 steroids are more suitable for synthesizing...
C19 steroids and C22 steroids are vital intermediates for the synthesis of steroid drugs. Compared with C19 steroids, C22 steroids are more suitable for synthesizing progesterone and adrenocortical hormones, albeit less developed. 9,22-dihydroxy-23,24-bisnorchol-4-ene-3-one(9-OHBA), due to its substituents at positions C-9 and C-22, is a beneficial and innovative steroid derivative for synthesizing corticosteroids. We focused on the C22 pathway in ATCC 35855, aiming to develop a productive strain that produces 9-OHBA. We used a mutant strain, MFΔ, that knocked out from ATCC 35855 named MFKD in this study as the original strain. Hsd4A and FadA5 are key enzymes in controlling the C19 metabolic pathway of steroids in ATCC 35855. After knocking out , MFKDΔ accumulated 81.47% 9-OHBA compared with 4.13% 9-OHBA in the strain MFKD. The double mutant MFKDΔΔ further improved the selectivity of 9-OHBA to 95.13%, and 9α-hydroxy-4-androstenedione (9-OHAD) decreased to 0.90% from 4.19%. In the end, we obtained 6.81 g/L 9-OHBA from 10 g/L phytosterols with a molar yield of 80.33%, which showed the best performance compared with formerly reported strains.
Topics: Mycobacterium fortuitum; Androstenedione; Molar; Phytosterols; Progesterone
PubMed: 38612391
DOI: 10.3390/ijms25073579 -
Nutrients Jun 2024Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease which seriously affects public health. Gut microbiota remains a dynamic balance state in healthy...
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease which seriously affects public health. Gut microbiota remains a dynamic balance state in healthy individuals, and its disorder may affect health status and even results in metabolic diseases. Quercetin, a natural flavonoid, has been shown to have biological activities that can be used in the prevention and treatment of metabolic diseases. This study aimed to explore the mechanism of quercetin in alleviating T2DM based on gut microbiota. / mice were adopted as the model for T2DM in this study. After 10 weeks of administration, quercetin could significantly decrease the levels of body weight, fasting blood glucose (FBG), serum insulin (INS), the homeostasis model assessment of insulin resistance (HOMA-IR), monocyte chemoattractant protein-1 (MCP-1), D-lactic acid (D-LA), and lipopolysaccharide (LPS) in / mice. 16S rRNA gene sequencing and untargeted metabolomics analysis were performed to compare the differences of gut microbiota and metabolites among the groups. The results demonstrated that quercetin decreased the abundance of Proteobacteria, , and . Moreover, metabolomics analysis showed that the levels of L-Dopa and S-Adenosyl-L-methionine (SAM) were significantly increased, but 3-Methoxytyramine (3-MET), L-Aspartic acid, L-Glutamic acid, and Androstenedione were significantly decreased under quercetin intervention. Taken together, quercetin could exert its hypoglycemic effect, alleviate insulin resistance, repair the intestinal barrier, remodel the intestinal microbiota, and alter the metabolites of / mice.
Topics: Animals; Gastrointestinal Microbiome; Quercetin; Insulin Resistance; Mice; Diabetes Mellitus, Type 2; Male; Intestinal Mucosa; Blood Glucose; Disease Models, Animal; Insulin
PubMed: 38931226
DOI: 10.3390/nu16121870 -
Frontiers in Microbiology 2023Limited numbers of CYPs have been reported to work naturally as peroxygenases. The peroxide shunt pathway can be efficiently used as an alternative for the NAD(P)H and...
Limited numbers of CYPs have been reported to work naturally as peroxygenases. The peroxide shunt pathway can be efficiently used as an alternative for the NAD(P)H and reductase systems, particularly in high hydrogen peroxide (HO) resistance CYPs. We reported the structural and biochemical features of CYP105D18 peroxygenase for its high HO tolerance capacity. Q348 was a crucial residue for the stability of CYP105D18 during the exposure to HO. In addition, the role of the hydrophilic amino acid T239 from the I helix for peroxygenation and regiospecificity toward testosterone was investigated. Interestingly, T239E differs in product formation from wild type, catalyzing testosterone to androstenedione in the presence of HO. The other variant, T239A, worked with the Pdx/Pdr system and was unable to catalyze testosterone conversion in the presence of HO, suggesting the transformation of peroxygenase into monooxygenase. CYP105D18 supported the alternative method of HO used for the catalysis of testosterone. The use of the same concentration of urea hydrogen peroxide adducts in place of direct HO was more efficient for 2β-hydroxytestosterone conversion. Furthermore, HO generation using GOx/glucose system enhanced the catalytic efficiency (/) for wild type and F184A by 1.3- and 1.9-fold, respectively, compared to direct use of HO The engineering of CYP105D18, its improved peroxygenase activity, and alteration in the product oxidation facilitate CYP105D18 as a potential candidate for biotechnological applications.
PubMed: 38149268
DOI: 10.3389/fmicb.2023.1296202 -
Dermal repeated dose toxicity study of the anti-breast cancer drug Formestane cream in Bama minipig.Food and Chemical Toxicology : An... Aug 2023Formestane (4-OHA) has been proven to be highly effective with high systemic tolerability in treating ER breast cancer. However, its intramuscular administration and...
Formestane (4-OHA) has been proven to be highly effective with high systemic tolerability in treating ER breast cancer. However, its intramuscular administration and associated side effects make it unsuitable for adjuvant treatment, leading to its withdrawal from the market. In contrast, Formestane cream may offer a solution by providing a more convenient route of administration and retaining its tumor-shrinking effects. This suggests that 4-OHA cream could have promising clinical applications. However, before clinical application, it is necessary to evaluate the potential toxicity of the cream in animals. This study evaluated the toxicity of 4-OHA cream on female Bama minipigs in vivo by analyzing hematology, biochemistry, and histopathology. The results showed that there was no significant difference between the cream-treated group and the control normal group for each parameter analyzed, indicating that 4-OHA cream was non-dermal toxic to minipigs. This finding provides a basis for the safe clinical use of the cream.
Topics: Animals; Female; Swine; Swine, Miniature; Androstenedione; Antineoplastic Agents; Neoplasms
PubMed: 37406756
DOI: 10.1016/j.fct.2023.113927 -
The Journal of Clinical Endocrinology... Apr 2024Pubertal girls with higher total body fat (TBF) demonstrate higher androgen levels. The cause of this association is unknown but is hypothesized to relate to insulin...
CONTEXT
Pubertal girls with higher total body fat (TBF) demonstrate higher androgen levels. The cause of this association is unknown but is hypothesized to relate to insulin resistance.
OBJECTIVE
This work aimed to investigate the association between higher TBF and higher androgens in pubertal girls using untargeted metabolomics.
METHODS
Serum androgens were determined using a quantitative mass spectrometry (MS)-based assay. Metabolomic samples were analyzed using liquid chromatography high-resolution MS. Associations between TBF or body mass index (BMI) z score (exposure) and metabolomic features (outcome) and between metabolomic features (exposure) and serum hormones (outcome) were examined using gaussian generalized estimating equation models with the outcome lagged by one study visit. Benjamini-Hochberg false discovery rate (FDR) adjusted P values were calculated to account for multiple testing. RaMP-DB (relational database of metabolomic pathways) was used to conduct enriched pathway analyses among features nominally associated with body composition or hormones.
RESULTS
Sixty-six pubertal, premenarchal girls (aged 10.9 ± 1.39 SD years; 60% White, 24% Black, 16% other; 63% normal weight, 37% overweight/obese) contributed an average of 2.29 blood samples. BMI and TBF were negatively associated with most features including raffinose (a plant trisaccharide) and several bile acids. For BMI, RaMP-DB identified many enriched pathways related to bile acids. Androstenedione also showed strong negative associations with raffinose and bile acids.
CONCLUSION
Metabolomic analyses of samples from pubertal girls did not identify an insulin resistance signature to explain the association between higher TBF and androgens. Instead, we identified potential novel signaling pathways that may involve raffinose or bile acid action at the adrenal gland.
Topics: Female; Humans; Overweight; Androgens; Insulin Resistance; Raffinose; Puberty; Obesity; Body Mass Index; Bile Acids and Salts
PubMed: 37978828
DOI: 10.1210/clinem/dgad675 -
Cells Aug 2023In the liver, phase-1 biotransformation of drugs and other xenobiotics is largely facilitated by enzyme complexes consisting of cytochrome P450 oxidoreductase (CPR) and...
Stable Chinese Hamster Ovary Suspension Cell Lines Harboring Recombinant Human Cytochrome P450 Oxidoreductase and Human Cytochrome P450 Monooxygenases as Platform for In Vitro Biotransformation Studies.
In the liver, phase-1 biotransformation of drugs and other xenobiotics is largely facilitated by enzyme complexes consisting of cytochrome P450 oxidoreductase (CPR) and cytochrome P450 monooxygenases (CYPs). Generated from human liver-derived cell lines, recombinant in vitro cell systems with overexpression of defined phase-1 enzymes are widely used for pharmacological and toxicological drug assessment and laboratory-scale production of drug-specific reference metabolites. Most, if not all, of these cell lines, however, display some background activity of several CYPs, making it difficult to attribute effects to defined CYPs. The aim of this study was to generate cell lines with stable overexpression of human phase-1 enzymes based on Chinese hamster ovary (CHO) suspension cells. Cells were sequentially modified with cDNAs for human CPR in combination with CYP1A2, CYP2B6, or CYP3A4, using lentiviral gene transfer. In parallel, CYP-overexpressing cell lines without recombinant CPR were generated. Successful recombinant expression was demonstrated by mRNA and protein analyses. Using prototypical CYP-substrates, generated cell lines proved to display specific enzyme activities of each overexpressed CYP while we did not find any endogenous activity of those CYPs in parental CHO cells. Interestingly, cell lines revealed some evidence that the dependence of CYP activity on CPR could vary between CYPs. This needs to be confirmed in further studies. Recombinant expression of CPR was also shown to enhance CYP3A4-independent metabolisation of testosterone to androstenedione in CHO cells. We propose the novel serum-free CHO suspension cell lines with enhanced CPR and/or defined CYP activity as a promising "humanised" in vitro model to study the specific effects of those human CYPs. This could be relevant for toxicology and/or pharmacology studies in the pharmaceutical industry or medicine.
Topics: Animals; Cricetinae; Humans; CHO Cells; Cricetulus; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Biotransformation
PubMed: 37681872
DOI: 10.3390/cells12172140 -
Cureus Mar 2024Hyperandrogenism in postmenopausal females may arise from either ovarian or adrenal sources and can pose a challenging diagnostic dilemma. We present the case of a...
Hyperandrogenism in postmenopausal females may arise from either ovarian or adrenal sources and can pose a challenging diagnostic dilemma. We present the case of a 66-year-old female with postmenopausal hyperandrogenism with virilization, adrenal incidentaloma, and concurrent finding of two extremely rare ovarian tumors, including bilateral Leydig cell tumor and Brenner tumor. Laboratory tests showed elevated testosterone and androstenedione and normal dehydroepiandrosterone sulfate (DHEAS). Response to 1 mg overnight dexamethasone suppression test demonstrated persistently elevated testosterone and incomplete suppression of androstenedione. Computed tomography (CT) scan showed a left adrenal nodule and an unremarkable appearance of the ovaries. The pelvic ultrasound did not show an ovarian tumor on the right ovary, and the left ovary was not seen. Adrenal and ovarian vein sampling suggested the ovaries as the source of the testosterone. Given the ovarian vein sampling results, a multidisciplinary discussion between endocrinology and gynecologic oncology concluded that bilateral salpingo-oophorectomy (BSO) was the next best step for diagnosis and management. Laparoscopic BSO was performed. Histopathology showed bilateral Leydig cell tumors and a left ovarian Brenner tumor. At one-year postoperative follow-up, alopecia improved, and testosterone level normalized. This case highlights the importance of diagnostic pathways and interdisciplinary collaboration in managing rare clinical scenarios of hyperandrogenism in postmenopausal females. As in our case, surgeons may be hesitant to remove normal-appearing ovaries. While the three presented tumor types in this case arise from distinct tissues and exhibit different histological characteristics, the presence of such a unique triad prompts consideration of potential unifying pathogenic mechanisms.
PubMed: 38559537
DOI: 10.7759/cureus.55334 -
Physical Chemistry Chemical Physics :... Jun 2024The human steroidogenic cytochrome P450 CYP17A1 catalyzes two types of reactions in the biosynthetic pathway leading from pregnenolone to testosterone and several other...
The human steroidogenic cytochrome P450 CYP17A1 catalyzes two types of reactions in the biosynthetic pathway leading from pregnenolone to testosterone and several other steroid hormones. The first is the hydroxylation of pregnenolone or progesterone to the corresponding 17α-hydroxy steroid, followed by a lyase reaction that converts these 17α-hydroxy intermediates to the androgens dehydroepiandrosterone and androstenedione, respectively. cytochrome (cyt) is known to act as both an effector and electron donor for the lyase oxidations, markedly stimulating the rate of the lyase reaction in its presence relative to the rate in its absence. Extensive sequential backbone H,N and C nuclear magnetic resonance assignments have now been made for oxidized CYP17A1 bound to the prostate cancer drug and inhibitor abiraterone. This is the first eukaryotic P450 for which such assignments are now available. These assignments allow more complete interpretation of the structural perturbations observed upon cyt addition. Possible mechanism(s) for the effector activity of cyt are discussed in light of this new information.
Topics: Steroid 17-alpha-Hydroxylase; Cytochromes b5; Humans; Nuclear Magnetic Resonance, Biomolecular; Protein Binding; Androstenes; Protein Conformation; Oxidation-Reduction; Magnetic Resonance Spectroscopy
PubMed: 38842434
DOI: 10.1039/d4cp01268b -
Cell Communication and Signaling : CCS Jun 2024Sex-specific gonadal differentiation is directed by complex signalling promoting development in either male or female direction, while simultaneously inhibiting the...
Sex-specific gonadal differentiation is directed by complex signalling promoting development in either male or female direction, while simultaneously inhibiting the opposite pathway. In mice, the WNT/β-catenin pathway promotes ovarian development and the importance of actively inhibiting this pathway to ensure normal testis development has been recognised. However, the implications of alterations in the tightly regulated WNT/β-catenin signalling during human fetal gonad development has not yet been examined in detail. Thus, the aim of this study was to examine the consequences of dysregulating the WNT/β-catenin signalling pathway in the supporting cell lineage during sex-specific human fetal gonad development using an established and extensively validated ex vivo culture model. Inhibition of WNT/β-catenin signalling in human fetal ovary cultures resulted in only minor effects, including reduced secretion of RSPO1 and reduced cell proliferation although this was not consistently found in all treatment groups. In contrast, promotion of WNT/β-catenin signalling in testes severely affected development and function. This included disrupted seminiferous cord structures, reduced cell proliferation, reduced expression of SOX9/AMH, reduced secretion of Inhibin B and AMH as well as loss of the germ cell population. Additionally, Leydig cell function was markedly impaired with reduced secretion of testosterone, androstenedione and INSL3. Together, this study suggests that dysregulated WNT/β-catenin signalling during human fetal gonad development severely impairs testicular development and function. Importantly, our study highlights the notion that sufficient inhibition of the opposite pathway during sex-specific gonadal differentiation is essential to ensure normal development and function also applies to human fetal gonads.
Topics: Humans; Male; Wnt Signaling Pathway; Testis; Female; Sex Differentiation; Fetus; Cell Differentiation; Cell Proliferation; beta Catenin; Leydig Cells; Ovary
PubMed: 38879537
DOI: 10.1186/s12964-024-01704-9