Obesity and polycystic ovary syndrome Barber, Thomas M.; Franks, Stephen
Clinical endocrinology (Oxford),
October 2021, Letnik:
95, Številka:
4
Journal Article
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The increased global prevalence of obesity over the last 40‐years has driven a rise in prevalence of obesity‐related co‐morbidities, including polycystic ovary syndrome (PCOS). On a background of ...genetic susceptibility, PCOS often becomes clinically manifest following weight gain, commonly during adolescence. A common endocrinopathy affecting between 6%‐10% of reproductive‐age women, PCOS presents with the cardinal features of hyperandrogenism, reproductive and metabolic dysfunction. PCOS associates with insulin resistance, independently of (but amplified by) obesity. Insulin resistance in PCOS is characterized by abnormal post‐receptor signalling within the phosphatidylinositol‐kinase (PI3‐K) pathway. Multiple factors (including most notably, weight gain) contribute towards the severity of insulin resistance in PCOS. Compensatory hyperinsulinaemia ensues, resulting in over‐stimulation of the (intact) post‐receptor mitogen‐activated protein kinase (MAP‐K) insulin pathway, with consequent implications for steroidogenesis and ovarian function. In this concise review, we explore the effects of weight gain and obesity on the pathogenesis of PCOS from the perspective of its three cardinal features of hyperandrogenism, reproductive and metabolic dysfunction, with a focus on the central mediating role of the insulin pathway. We also consider key lifestyle strategies for the effective management of obese and overweight women with PCOS.
Context: Polycystic ovary syndrome (PCOS) is a very common endocrinopathy with a heterogeneous presentation whose etiology is still uncertain. Not surprisingly, therefore, the definition of, and ...diagnostic criteria for, PCOS remain controversial.
Objective: The objective of the study was to review and justify the basis for the recently revised definition of PCOS arising from the joint European Society for Human Reproduction & Embryology/American Society for Reproductive Medicine (ESHRE/ASRM) Rotterdam workshop in 2003.
Intervention(s): The Rotterdam criteria take account of the broad spectrum of presenting features of PCOS, including women with hyperandrogenism but regular menses and, more controversially, those with menstrual disturbance without overt androgen excess.
Positions: The Rotterdam criteria for definition and diagnosis of PCOS, in the opinion of this author, represent a significant advance in recognizing the broad spectrum of presentation of the syndrome and acknowledge that the clinical and biochemical features may vary with time within individuals. The important refinements when compared to the 1990 NIH definition of PCOS are: 1) inclusion of polycystic ovarian morphology; and 2) inclusion of subjects with hirsutism and regular menses.
Conclusions: These new diagnostic criteria for PCOS reflect the significant advances, particularly from studies of familial PCOS, in understanding of the etiology of the syndrome and the basis for its heterogeneity. Under the revised diagnostic criteria, the inclusion of women with hyperandrogenism and regular cycles has met with general agreement. The inclusion of women with oligomenorrhea and polycystic ovaries who do not have clear evidence of androgen excess is, in the opinion of this author, also justified but remains a contentious issue and one that requires further investigation.
Androgen Action in the Ovary Franks, Stephen; Hardy, Kate
Frontiers in endocrinology (Lausanne),
08/2018, Letnik:
9
Journal Article
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Androgen production by the ovary is an essential requirement for normal cyclical secretion of estradiol but its physiological role extends to important actions on both preantral and antral follicle ...development, including promotion of granulosa cell proliferation. It is likely only in mature antral follicles that androgens encourage apoptosis and consequent follicle atresia, and this may be an important mechanism to ensure mono-follicular ovulation in primates, including humans. Recent studies have provided new insight into the mechanism of androgen signaling in the ovary which involves both genomic and non-genomic effects that are complementary in effecting a cellular response. In polycystic ovary syndrome, a condition characterized by intra-ovarian androgen excess, aberrant development of both preantral and antral follicles is a salient feature. We present evidence that local action of androgens plays a part in such abnormalities. Finally, we review the role of androgens in follicle atresia and conclude that the effects are part of the normal physiology of follicle maturation.
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in females, with a high prevalence. The etiology of this heterogeneous condition remains obscure, and its phenotype expression ...varies. Two widely cited previous ESHRE/ASRM sponsored PCOS consensus workshops focused on diagnosis (published in 2004) and infertility management (published in 2008), respectively. The present third PCOS consensus report summarizes current knowledge and identifies knowledge gaps regarding various women’s health aspects of PCOS. Relevant topics addressed—all dealt with in a systematic fashion—include adolescence, hirsutism and acne, contraception, menstrual cycle abnormalities, quality of life, ethnicity, pregnancy complications, long-term metabolic and cardiovascular health, and finally cancer risk. Additional, comprehensive background information is provided separately in an extended online publication.
Polycystic ovary syndrome (PCOS) is the most common ovarian disorder associated with androgen excess in women, which justifies the growing interest of endocrinologists. Great efforts have been made ...in the last 2 decades to define the syndrome. The presence of three different definitions for the diagnosis of PCOS reflects the phenotypic heterogeneity of the syndrome. Major criteria are required for the diagnosis, which in turn identifies different phenotypes according to the combination of different criteria. In addition, the relevant impact of metabolic issues, specifically insulin resistance and obesity, on the pathogenesis of PCOS, and the susceptibility to develop earlier than expected glucose intolerance states, including type 2 diabetes, has supported the notion that these aspects should be considered when defining the PCOS phenotype and planning potential therapeutic strategies in an affected subject. This paper offers a critical endocrine and European perspective on the debate on the definition of PCOS and summarises all major aspects related to aetiological factors, including early life events, potentially involved in the development of the disorder. Diagnostic tools of PCOS are also discussed, with emphasis on the laboratory evaluation of androgens and other potential biomarkers of ovarian and metabolic dysfunctions. We have also paid specific attention to the role of obesity, sleep disorders and neuropsychological aspects of PCOS and on the relevant pathogenetic aspects of cardiovascular risk factors. In addition, we have discussed how to target treatment choices based according to the phenotype and individual patient's needs. Finally, we have suggested potential areas of translational and clinical research for the future with specific emphasis on hormonal and metabolic aspects of PCOS.
Polycystic ovary syndrome (PCOS), characterized by ovarian androgen excess, is the commonest endocrine disorder in women. Obesity increases androgen synthesis, a phenomenon attributed to the ...accompanying hyperinsulinemia. Our hypothesis was that adipokines, fat cell-derived hormones, play a direct role in modulating ovarian androgen secretion. Therefore, the aims of this study were to explore the effects of adipokines (in particular, adiponectin) on ovarian steroidogenesis and compare the expression of adiponectin receptors in ovaries from women with and without PCO. Sections of archived human ovaries (nine from women with normal ovaries and 16 with PCOS, classified histologically, with reference to menstrual history and ultrasound) were analysed by quantitative morphometry and the proportion of positive-labelling cells compared. In addition, studies of androgen production in relation to adipokine function in primary bovine theca cell culture were also performed. A significantly lower proportion of theca cells expressed adiponectin receptors 1 and 2 (AdipoR1, AdipoR2) in polycystic ovaries than in normal ovaries. In cultured theca cells, adiponectin suppressed androstenedione production and gene expression of LH receptor and key enzymes in the androgen synthesis pathway. Moreover, knockdown of genes for AdipoR1 and AdipoR2 was associated with increased androstenedione secretion by bovine theca cells. These results provide evidence for a direct link between fat cell metabolism and ovarian steroidogenesis, suggesting that disruption of adiponectin and/or its receptors plays a key role in pathogenesis of hyperandrogenism in PCOS.
Polycystic ovary syndrome (PCOS) is a common endocrinopathy that is associated with an adverse metabolic profile including reduced postprandial thermogenesis. Although abnormalities in adipose tissue ...function have been widely reported in women with PCOS, less is known about direct effects of androgen on white and, particularly, brown adipocytes. The purpose of this study was to investigate the effect of the nonaromatizable androgen dihydrotestosterone (DHT) on (1) lipid accumulation and expression of adipogenic markers in immortalized mouse brown adipose cell lines (IMBATs), (2) mitochondrial respiration in IMBATs, (3) mitochondrial DNA content and gene expression, (4) expression of brown adipose tissue (BAT) markers and thermogenic activation. In addition, we profiled the relative levels of 38 adipokines secreted from BAT explants and looked at androgen effects on adipokine gene expression in both IMBATs and immortalized mouse white adipose (IMWATs) cell lines. Androgen treatment inhibited IMBAT differentiation in a dose-dependent manner, reduced markers of adipogenesis, and attenuated the β-adrenoceptor-stimulated increase in uncoupling protein-1 (UCP1) expression. In explants of mouse interscapular BAT, androgen reduced expression of UCP1, peroxisome proliferator-activated receptor-γ coactivator-1 (PCG-1) and Cidea. Significantly, as well as affecting genes involved in thermogenesis in BAT, androgen treatment reduced mitochondrial respiration in IMBATs, as measured by the Seahorse XF method. The results of this study suggest a role for excess androgen in inhibiting brown adipogenesis, attenuating the activation of thermogenesis and reducing mitochondrial respiration in BAT. Together, these data provide a plausible molecular mechanism that may contribute to reduced postprandial thermogenesis and the tendency to obesity in women with PCOS.
Does PCOS have developmental origins? Franks, Stephen, M.D., F.Med.Sci; Berga, Sarah L., M.D
Fertility and sterility,
2012, 2012-Jan, 2012-01-00, 20120101, Letnik:
97, Številka:
1
Journal Article
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PRO —The similarity of reproductive and metabolic phenotype between prenatally androgenized sheep, or monkeys, and women with PCOS provides strong supportive evidence for developmental programming ...being important in the etiology of PCOS. CON —While one would not exclude altogether developmental determinants of PCOS, it is difficult to view PCOS as purely developmental or resulting only from intrauterine exposures or simply an adaptation gone astray.
The oocyte-secreted factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) play essential roles in follicle development and oocyte maturation, and aberrant ...regulation might contribute to the pathogenesis of polycystic ovary syndrome.
Are there measurable differences in concentrations of GDF9, BMP15, and the GDF9/BMP15 heterodimer in small antral follicle fluids from women with and without polycystic ovaries (PCO)?
Follicle fluids (n = 356) were collected from 4- to 11-mm follicles in unstimulated ovaries of 87 women undergoing ovarian tissue cryopreservation for fertility preservation.
Twenty-seven women with PCO were identified and 60 women without PCO-like characteristics (non-PCO women) were matched according to age and follicle size.
Intrafollicular concentrations of GDF9, BMP15, GDF9/BMP15 heterodimer, anti-Mullerian hormone (AMH), inhibin-A and -B, total inhibin, activin-B and -AB, and follistatin were measured using enzyme-linked immunosorbent assays.
The detectability of GDF9, BMP15, and the GDF9/BMP15 heterodimer were 100%, 94.4%, and 91.5%, respectively, and concentrations were significantly negatively correlated with increasing follicle size (P < 0.0001). GDF9 was significantly higher in women with PCO (PCO: 4230 ± 189 pg/mL mean ± SEM, n = 188; non-PCO: 3498 ± 199 pg/mL, n = 168; P < 0.03), whereas BMP15 was lower in women with PCO (PCO: 431 ± 40 pg/mL, n = 125; non-PCO: 573 ± 55 pg/mL, n = 109; P = 0.10), leading to a significantly higher GDF9:BMP15 ratio in women with PCO (P < 0.01). Significant positive associations between BMP15 and AMH, activins, and inhibins in non-PCO women switched to negative associations in women with PCO.
Intrafollicular concentrations of GDF9 and BMP15 varied inversely in women with PCO reflecting an aberrant endocrine environment. An increased GDF9:BMP15 ratio may be a new biomarker for PCO.
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