scholarly journals Regulation of Androgen Receptor Expression Alters AMPK Phosphorylation in the Endometrium: In Vivo and In Vitro Studies in Women with Polycystic Ovary Syndrome

2015 ◽  
Vol 11 (12) ◽  
pp. 1376-1389 ◽  
Author(s):  
Xin Li ◽  
Bano Pishdari ◽  
Peng Cui ◽  
Min Hu ◽  
Hong-Ping Yang ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Receptor Expression ◽  
In Vitro Studies ◽  
Androgen Receptor Expression ◽  
Ovary Syndrome ◽  
Ampk Phosphorylation

scholarly journals PAPSS2 Deficiency Causes Androgen Excess via Impaired DHEA Sulfation—In Vitro and in Vivo Studies in a Family Harboring Two Novel PAPSS2 Mutations

2015 ◽  
Vol 100 (4) ◽  
pp. E672-E680 ◽  
Author(s):  
Wilma Oostdijk ◽  
Jan Idkowiak ◽  
Jonathan W. Mueller ◽  
Philip J. House ◽  
Angela E. Taylor ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Challenge Test ◽  
Compound Heterozygous ◽  
Androgen Excess ◽  
Ovary Syndrome ◽  
Functional Impact ◽  
Low Serum

Context: PAPSS2 (PAPS synthase 2) provides the universal sulfate donor PAPS (3′-phospho-adenosine-5′-phosphosulfate) to all human sulfotransferases, including SULT2A1, responsible for sulfation of the crucial androgen precursor dehydroepiandrosterone (DHEA). Impaired DHEA sulfation is thought to increase the conversion of DHEA toward active androgens, a proposition supported by the previous report of a girl with inactivating PAPSS2 mutations who presented with low serum DHEA sulfate and androgen excess, clinically manifesting with premature pubarche and early-onset polycystic ovary syndrome. Patients and Methods: We investigated a family harboring two novel PAPSS2 mutations, including two compound heterozygous brothers presenting with disproportionate short stature, low serum DHEA sulfate, but normal serum androgens. Patients and parents underwent a DHEA challenge test comprising frequent blood sampling and urine collection before and after 100 mg DHEA orally, with subsequent analysis of DHEA sulfation and androgen metabolism by mass spectrometry. The functional impact of the mutations was investigated in silico and in vitro. Results: We identified a novel PAPSS2 frameshift mutation, c.1371del, p.W462Cfs*3, resulting in complete disruption, and a novel missense mutation, c.809G>A, p.G270D, causing partial disruption of DHEA sulfation. Both patients and their mother, who was heterozygous for p.W462Cfs*3, showed increased 5α-reductase activity at baseline and significantly increased production of active androgens after DHEA intake. The mother had a history of oligomenorrhea and chronic anovulation that required clomiphene for ovulation induction. Conclusions: We provide direct in vivo evidence for the significant functional impact of mutant PAPSS2 on DHEA sulfation and androgen activation. Heterozygosity for PAPSS2 mutations can be associated with a phenotype resembling polycystic ovary syndrome.

scholarly journals Enhanced Thecal Androgen Production Is Prenatally Programmed in an Ovine Model of Polycystic Ovary Syndrome

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 450-461 ◽  
Author(s):  
Kirsten Hogg ◽  
Julia M. Young ◽  
Elizabeth M. Oliver ◽  
Carlos J. Souza ◽  
Alan S. McNeilly ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Female Offspring ◽  
Fetal Life ◽  
Ovary Syndrome ◽  
Androgen Synthesis ◽  
Basal Expression ◽  
Thecal Cells

One of the hallmarks of polycystic ovary syndrome (PCOS) is increased ovarian androgen secretion that contributes to the ovarian, hormonal, and metabolic features of this condition. Thecal cells from women with PCOS have an enhanced capacity for androgen synthesis. To investigate whether this propensity is a potential cause, rather than a consequence, of PCOS, we used an ovine prenatal androgenization model of PCOS and assessed ewes at 11 months of age. Pregnant Scottish Greyface ewes were administered 100 mg testosterone propionate (TP) or vehicle control twice weekly from d 62 to 102 of gestation, and female offspring (TP = 9, control = 5) were studied. Prenatal TP exposure did not alter ovarian morphology or cyclicity, or plasma androgen, estrogen, and gonadotropin concentrations, at this stage. However, follicle function was reprogrammed in vivo with increased proportions of estrogenic follicles (P < 0.05) in the TP-exposed cohort. Furthermore, in vitro the thecal cells of follicles (>4 mm) secreted more LH-stimulated androstenedione after prenatal androgenization (P < 0.05), associated with increased basal expression of thecal StAR (P < 0.01), CYP11A (P < 0.05), HSD3B1 (P < 0.01), CYP17 (P < 0.05), and LHR (P < 0.05). This provides the first evidence of increased thecal androgenic capacity in the absence of a PCOS phenotype, suggesting a thecal defect induced during fetal life.

scholarly journals Metformin reduces androgen receptor and upregulates homeobox A10 expression in uterine endometrium in women with polycystic ovary syndrome

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Miki Ohara ◽  
Hiromi Yoshida-Komiya ◽  
Miho Ono-Okutsu ◽  
Akiko Yamaguchi-Ito ◽  
Toshifumi Takahashi ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Polycystic Ovary Syndrome ◽  
Stromal Cells ◽  
Hormone Receptors ◽  
Polycystic Ovary ◽  
Steroid Hormone Receptors ◽  
Metformin Treatment ◽  
Ovary Syndrome ◽  
Aberrant Expression

Abstract Background Polycystic ovary syndrome (PCOS) causes anovulation and is associated with a reduced clinical pregnancy rate. Metformin, which is widely used for treating PCOS, can lead to successful pregnancy by restoring the ovulation cycle and possibly improving endometrial abnormality during the implantation period. However, the mechanism by which metformin improves endometrial abnormality remains unknown. Women with PCOS have an aberrant expression of steroid hormone receptors and homeobox A10 (HOXA10), which is essential for embryo implantation in the endometrium. Methods In this study, we examined whether metformin affects androgen receptor (AR) and HOXA10 expression in PCOS endometrium in vivo and in human endometrial cell lines in vitro. Expression of AR and HOXA10 was evaluated by immunohistochemistry, fluorescent immunocytochemistry, and western blot analysis. Results AR expression was localized in both epithelial and stromal cells; however, HOXA10 expression was limited to only stromal cells in this study. In women with PCOS, 3 months after metformin treatment, the expression of AR was reduced in epithelial and stromal cells in comparison to their levels before treatment. In contrast, HOXA10 expression in the stromal cells with metformin treatment increased in comparison to its level before treatment. Further, we showed that metformin counteracted the testosterone-induced AR expression in both Ishikawa cells and human endometrial stromal cells (HESCs); whereas, metformin partly restored the testosterone-reduced HOXA10 expression in HESCs in vitro. Conclusions Our results suggest that metformin may have a direct effect on the abnormal endometrial environment of androgen excess in women with PCOS. Trial registration The study was approved by the Ethical Committee of Fukushima Medical University (approval no. 504, approval date. July 6, 2006), and written informed consent was obtained from all patients. https://www.fmu.ac.jp/univ/sangaku/rinri.html

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