scholarly journals Polycystic ovary syndrome as a plausible evolutionary outcome of metabolic adaptation

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Daniel A. Dumesic ◽  
Vasantha Padmanabhan ◽  
Gregorio D. Chazenbalk ◽  
David H. Abbott
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Abdominal Fat ◽  
Normal Weight ◽  
Metabolic Adaptation ◽  
Acid Oxidation ◽  
Fetal Life ◽  
Ovary Syndrome

AbstractAs a common endocrinopathy of reproductive-aged women, polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology. It is linked with insulin resistance through preferential abdominal fat accumulation that is worsened by obesity. Over the past two millennia, menstrual irregularity, male-type habitus and sub-infertility have been described in women and confirm that these clinical features of PCOS were common in antiquity. Recent findings in normal-weight hyperandrogenic PCOS women show that exaggerated lipid accumulation by subcutaneous (SC) abdominal stem cells during development to adipocytes in vitro occurs in combination with reduced insulin sensitivity and preferential accumulation of highly-lipolytic intra-abdominal fat in vivo. This PCOS phenotype may be an evolutionary metabolic adaptation to balance energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction. This review integrates fundamental endocrine-metabolic changes in healthy, normal-weight PCOS women with similar PCOS-like traits present in animal models in which tissue differentiation is completed during fetal life as in humans to support the evolutionary concept that PCOS has common ancestral and developmental origins.

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 Serum Testosterone to Androstenedione Ratio Predicts Metabolic Health in Normal-Weight Polycystic Ovary Syndrome Women

2021 ◽  
Author(s):  
Daniel A Dumesic ◽  
Ayli Tulberg ◽  
Megan McNamara ◽  
Tristan R Grogan ◽  
David H Abbott ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Elevated Serum ◽  
Normal Weight ◽  
Model Assessment ◽  
Metabolic Function ◽  
Ovary Syndrome ◽  
Intravenous Glucose

Abstract Context Increased aldo-keto reductase 1C3 (AKR1C3)-mediated conversion of androstenedione (A4) to testosterone (T) promotes lipid storage in subcutaneous (SC) abdominal adipose in overweight/obese polycystic ovary syndrome (PCOS) women. Objective To examine whether an elevated serum T/A4 ratio, as a marker of enhanced AKR1C3 activity in SC abdominal adipose, predicts metabolic function in normal-weight PCOS women. Design Prospective cohort study. Setting Academic center. Patients Nineteen normal-weight PCOS women; 21 age- and body mass index-matched controls. Intervention(s) Circulating hormone/metabolic determinations, intravenous glucose tolerance testing, total body dual-energy x-ray absorptiometry, SC abdominal fat biopsy. Main Outcome Measure(s) Serum T/A4 ratios, hormone/metabolic measures and AKR1C3 expression of adipocytes matured in vitro were compared between female types; serum T/A4 ratios were correlated with serum lipids, adipose insulin resistance (adipose-IR), homeostatic model assessment of insulin resistance (HOMA-IR) and insulin sensitivity (Si). Results Increased serum T/A4 ratios (P=0.040) and log adipose-IR values (P=0.002) in PCOS women versus controls were accompanied by AKR1C3 mRNA overexpression of PCOS adipocytes matured in vitro (P=0.016). Serum T/A4 ratios in PCOS women, but not controls, negatively correlated with log triglycerides (TG: R=-0.65, P=0.002) and the TG index (R=-0.57, P=0.011). Adjusting for serum free T, serum T/A4 ratios in PCOS women remained negatively correlated with log TG (R=-0.57, P=0.013) and TG index (R=-0.50, P=0.036), respectively, without significant relationships with other metabolic measures. Conclusion An elevated serum T/A4 ratio, as a marker of enhanced AKR1C3 activity in SC abdominal adipose, predicts healthy metabolic function in normal-weight PCOS women.

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 Influence of body mass index on in vitro fertilization outcome in women with polycystic ovary syndrome

2016 ◽  
Vol 69 (7-8) ◽  
pp. 230-236
Author(s):  
Milan Trenkic ◽  
Jasmina Popovic ◽  
Artur Bjelica ◽  
Vesna Kopitovic ◽  
Marija Trenkic-Bozinovic ◽  
...  
Keyword(s):  
Body Mass Index ◽  
In Vitro Fertilization ◽  
Polycystic Ovary Syndrome ◽  
Body Mass ◽  
Polycystic Ovary ◽  
Normal Weight ◽  
Ovary Syndrome ◽  
Vitro Fertilization ◽  
Gonadotrophin Releasing Hormone

Introduction. The purpose of this study was to investigate the influence of the body mass index on the outcome of in vitro fertilization in patients with polycystic ovary syndrome. Material and Methods. The study sample consisted of 123 patients with polycystic ovary syndrome who completed their in vitro fertilization treatment at the Department of Gynecology and Obstetrics, Clinical Center Nis, Republic of Serbia, and they were retrospectively analyzed. The patients were divided by body mass index into two groups for the comparison of the findings. One group (normal weight) consisted of women with body mass index ? 25 kg/m2 (mean 22.08?1.90), and the other group (overweight) included women with body mass index > 25 kg/m2 (mean 27.65?1.47). The patients underwent either the standard long gonadotrophin-releasing hormone agonist protocol or flexible multidose gonadotrophin-releasing hormone antagonist protocol. Results. The normal-weight patients had a higher number of mature oocytes, significantly higher fertilization rate (p<0.001) and significantly higher number of the obtained embryos class I (p<0.01) than the overweight patients. However, the implantation rate and clinical pregnancy rate were the same in both groups. Conclusion. In the group of overweight women the numbers of mature oocytes and good quality embryos were lower. However, since this study dealt with the patients with polycystic ovary syndrome who generally had a higher number of the obtained oocytes and embryos, this shortfall did not affect clinical pregnancy rates, which were the same in both groups. Certainly, before starting the in vitro fertilization, each infertile patient should be informed about the possible negative effect of her high body mass index on the treatment outcome.

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