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.
The deficiency of 21-hydroxylase due to
pathogenic variants is a rather frequent disease with serious consequences, going from a real mortality risk to infertility and to milder symptoms, ...nevertheless important for affecting the patients' self-esteem. In the most severe cases life-threatening adrenal salt wasting crises may occur. Significant morbidity including the possibility of mistaken gender determination, precocious puberty, infertility and growth arrest with consequent short stature may also affect these patients. In the less severe cases milder symptoms like hirsutism will likely affect the image of the self with strong psychological consequences. Its diagnosis is confirmed by 17OH-progesterone dosages exceeding the cut-off value of 10/15 ng/ml but genotyping is progressively assuming an essential role in the study of these patients particularly in confirming difficult cases, determining some aspects of the prognosis and allowing a correct genetic counseling. Genotyping is a difficult process due to the occurrence of both a gene and a highly homologous pseudo gene. However, new tools are opening new possibilities to this analysis and improving the chances of a correct diagnosis and better understanding of the underlying mechanisms of the disease. Beyond the 10 classic pathogenic variants usually searched for in most laboratories, a correct analysis of 21OH-deficiency cases implies completely sequencing of the entire gene and the determination of gene duplications. These are now recognized to occur frequently and can be responsible for some false positive cases. And finally, because gene conversions can include several pathogenic variants one cannot be certain of identifying that both alleles are affected without studying parental DNA samples. A complete genotype characterization should be considered essential in the preparation for pregnancy, even in the case of parents with milder forms of the disease, or even just carriers, since it has been reported that giving birth to progeny with the severe classic forms occurs with a much higher frequency than expected.
Early activation of the adrenal zona reticularis, leading to adrenal androgen secretion, mainly dehydroepiandrosterone sulfate (DHEAS), is called premature adrenarche (PA). The fact that adrenal ...hyperandrogenism in females has been linked to a cluster of cardiovascular (CV) risk factors, even in prepubertal children, warrants investigation. Controversial results have been obtained in this field, probably due to genetic, constitutional, and environmental factors or differences in the characteristics of participants. In an attempt to understand, in depth, the impact of PA as a potential activator of CV risk, we critically present available data stratified according to pubertal status. It seems that prepubertally, CV risk is increased in these girls, but is somewhat attenuated during their second decade of life. Furthermore, different entities associated with PA, such as polycystic ovary syndrome, non-classical congenital adrenal hyperplasia, heterozygosity of CYP21A2 mutations, and the impact of DHEAS on CV risk, are reviewed. At present, firm and definitive conclusions cannot be drawn. However, it may be speculated that girls with a history of PA display a hyperandrogenic hormonal milieu that may lead to increased CV risk. Accordingly, appropriate long-term follow-up and early intervention employing a patient-oriented approach are recommended.
•Postmenopausal hypoestrogenism increases the risk of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.•Perplexing hormonal, metabolic and inflammatory factors promote the ...postmenopausal development and progression of fatty liver disease.•The risk of non-alcoholic fatty liver disease and the influence of menopausal hormonal therapy on its development and progression should be estimated separately in specific estrogen-deficient groups of patients, including those with premature ovarian failure and surgical menopause.•Levels of sex hormone-binding globulin depend on estrogen, androgen and insulin levels, and may be an important tool for predicting the development of non-alcoholic fatty liver disease in postmenopausal patients.•The postmenopausal influence of polycystic ovarian syndrome and long-lasting hyperandrogenism on liver steatosis needs to be elucidated.
The hypoestrogenic period after menopause and associated metabolic imbalance might facilitate the onset of non-alcoholic fatty liver disease (NAFLD) and its progression. The prevalence of NAFLD increases in patients experiencing premature ovarian insufficiency, as well as surgical or natural menopause. The postmenopausal period is characterized by dyslipidemia and insulin resistance associated with an increased influx of free fatty acids to the liver with consequent steatosis and further progression of NAFLD. More than half of postmenopausal women with diabetes mellitus type 2 suffer from NAFLD. It is suggested that estrogens slow the progression of chronic liver diseases by suppression of inflammation, improvement of mitochondrial function, alleviation of oxidative stress, insulin resistance, and fibrogenesis. The hyperandrogenic state of polycystic ovary syndrome (PCOS) is associated with the development of NAFLD in women of reproductive age, but it is difficult to extend these findings to menopause due to inappropriate diagnosis of PCOS after menopause. Lifestyle intervention, including physical activity and dietary regimens, remains the first-line preventive and therapeutic option for NAFLD. There are contradictory reports on the use of menopausal hormonal therapy (MHT) and NAFLD. It is necessary to investigate the potential effects of estradiol dose, progesterone type, selective estrogen receptor modulators and tissue-selective estrogen complex compounds on NAFLD development and progression in postmenopausal women. The present review aims to explore the pathophysiological and clinical aspects of liver metabolic disturbances in women after menopause, focusing on the possible preventive and therapeutic strategies in NAFLD, including the potential role of MHT.
For the past 80 years, the effect of the Mediterranean diet on overall health has been a constant topic of interest among medical and scientific researchers. Parallel with the persistent global rise ...of cases of type 2 diabetes, many studies conducted in the past 20 years have shown the benefits of the Mediterranean lifestyle for people with, or at risk of developing, type 2 diabetes mellitus. However, despite the large body of evidence, concerns exist amongst scientists regarding the reliability of the data related to this topic. This review offers a glimpse of the onset of the Mediterranean diet and follows its significant impact on the prevention and treatment of type 2 diabetes. There is a constant rise in type 2 diabetes cases on the Balkan Peninsula and North Macedonia in particular. Having in mind that North Macedonia, as well as most of the countries on the Balkans have low to middle income, there is a need for a certain affordable dietary pattern to ameliorate the rise in diabetes incidence, as well as improve the glycemic control. We did a review based on the available literature regarding Mediterranean diet and people with or at risk of developing type 2 diabetes mellitus, its effects on glycemic control, lipid profile and metabolic outcome.
The complex mechanisms, which are related to the pathophysiology and the development of autoimmune thyroid diseases, involve transforming growth factor beta (TGF-β) and its interplay with the immune ...system. The aim of this review is to examine the role of TGF-β regarding thyroid autoimmunity and explore the potent role of this molecule either as a diagnostic or prognostic marker or a therapeutic target regarding autoimmune thyroid diseases. TGF-β is clearly a master regulator of the immune response, exerting either inhibitory or facilitatory effects on cells of the immune system. Thus, this molecule is involved in the pathogenesis and development of autoimmune thyroid diseases. Recent research has revealed the involvement of TGF-β in the pathophysiology of autoimmune thyroid diseases. The role of TGF-β in the development of autoimmune thyroid diseases varies, depending on its concentrations, the type of the activated TGF-β signalling pathway, the genetic predisposition of the patient and the pathophysiologic stage of the disease. TGF-β could emerge as a useful diagnostic or prognostic marker for the evolution of thyroid autoimmunity. Promising perspectives for the effective therapeutic use of TGF-β regarding thyroid autoimmunity exist. The main treatment approaches incorporate either enhancement of the immunosuppressive role of TGF-β or inhibition of its facilitatory role in the autoimmune thyroid diseases. Further research towards deeper understanding of TGF-β physiology and clinical application of its possible therapeutic role regarding thyroid autoimmunity is needed.
Introduction
Pregnancy represents a fragile period in the life of a woman, vulnerable to hazardous environmental substances which might affect maternal and fetal metabolism. The possible influence of ...environmental factors, including endocrine disrupting chemicals (EDCs), upon the mother and the fetus before and/or during pregnancy might be associated directly and/or indirectly to deleterious pregnancy outcomes. Because the existence of such associations would be, to our view, of major importance to the scientific community, their investigation is the scope of this critical review.
Methods
This critical review includes in vivo animal and human studies regarding the role of environmental factors, including EDCs, on pregnancy outcomes complying with the SANRA (a scale for the quality assessment of narrative review articles) questions for narrative reviews. Studies were identified by searching the MEDLINE (PubMed and PubMed Central), the Cochrane library and the Google Scholar databases till October 2022 with the combinations of the appropriate key words (detailed environmental factors including EDCs AND detailed negative pregnancy outcomes) as well as by scanning references from already included articles and relevant reviews manually. Because environmental factors and EDCs have been associated to epigenetic alterations, special care has been given to EDC-induced transgenerational effects on pregnancy outcomes.
Results
The existing evidence suggests positive associations between specific environmental factors and negative pregnancy outcomes such as ectopic pregnancies, pregnancy losses, gestational diabetes, hypertensive disorders of pregnancy, preterm births, birth defects, intrauterine growth restriction, and small or large for gestational age babies.
Conclusion
Environmental factors and EDCs may have a catalytic effect on the course and the outcomes of pregnancy.
Polycystic ovary syndrome (PCOS) is associated with altered lipid profile and increased small, dense LDL particles (sdLDL). Considering that paraoxonase 1 (PON1) is an antioxidative enzyme located on ...HDL particles, the aim of this study was to investigate the connection between oxidative stress (OS) and PON1 activity with lipoprotein subclasses in PCOS depending on obesity. In 115 PCOS patients, lipoprotein subclasses distributions were determined by gradient gel electrophoresis. OS status was assessed by total oxidative status (TOS), advanced oxidation protein products, malondialdehyde (MDA), prooxidant-antioxidant balance (PAB), total antioxidative status (TAS) and superoxide dismutase (SOD) and PON1 activity. Overweight/obese PCOS patients (
55) had increased OS compared with normal weight patients (
60). In addition, overweight/obese group had lower HDL size and higher proportion of HDL 3a subclasses (
< 0·05). PAB was in negative correlation with HDL 2a (
< 0·001), whereas MDA and SOD correlated positively with HDL 3 subclasses (
< 0·05). Serum PON1 activity was positively associated with proportions of PON1 activity on HDL 2b (
< 0·05) and 2a (
< 0·01), but negatively with the proportion on HDL 3 particles (
< 0·01). LDL B phenotype patients had increased TAS, SOD and PON1 activity on HDL 2b, but decreased PON1 activity on HDL 3 subclasses. OS is associated with altered lipoprotein subclasses distribution in PCOS patients. Obesity in PCOS affects the profile of HDL subclasses, reflected through the reduced proportion of PON1 activity on HDL 3 subclasses in the presence of sdLDL particles.
Obesity is the best described risk factor for the development of non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction associated steatotic liver disease (MASLD) and polycystic ovary ...syndrome (PCOS) while the major pathogenic mechanism linking these entities is insulin resistance (IR). IR is primarily caused by increased secretion of proinflammatory cytokines, adipokines, and lipids from visceral adipose tissue. Increased fatty acid mobilization results in ectopic fat deposition in the liver which causes endoplasmic reticulum stress, mitochondrial dysfunction, and oxidative stress resulting in increased cytokine production and subsequent inflammation. Similarly, IR with hyperinsulinemia cause hyperandrogenism, the hallmark of PCOS, and inflammation in the ovaries. Proinflammatory cytokines from both liver and ovaries aggravate IR thus providing a complex interaction between adipose tissue, liver, and ovaries in inducing metabolic abnormalities in obese subjects. Although many pathogenic mechanisms of IR, NAFLD/MASLD, and PCOS are known, there is still no effective therapy for these entities suggesting the need for further evaluation of their pathogenesis. Extracellular vesicles (EVs) represent a novel cross-talk mechanism between organs and include membrane-bound vesicles containing proteins, lipids, and nucleic acids that may change the phenotype and function of target cells. Adipose tissue releases EVs that promote IR, the development of all stages of NAFLD/MASLD and PCOS, while mesenchymal stem cell-derived AVs may alleviate metabolic abnormalities and may represent a novel therapeutic device in NAFLD/MASLD, and PCOS. The purpose of this review is to summarize the current knowledge on the role of adipose tissue-derived EVs in the pathogenesis of IR, NAFLD/MASLD, and PCOS.
Purpose
The exact risk of type 2 diabetes mellitus (T2DM) in women with polycystic ovary syndrome (PCOS) is unknown. It is also unclear if obesity independently increases T2DM risk in this ...population. The aim of this study was to systematically review and synthesize the best available evidence regarding the association between PCOS and T2DM, stratified according to obesity status.
Methods
A comprehensive search was conducted in PubMed, CENTRAL and Scopus databases up to October 31, 2020. Data are expressed as relative risk (RR) with 95% confidence interval (CI). The
I
2
index was employed for heterogeneity.
Results
The eligibility criteria were fulfilled by 23 studies (319,780 participants; 60,336 PCOS and 8847 type 2 diabetes cases). Women with PCOS demonstrated a higher risk of T2DM than those without PCOS (RR 3.45, 95% CI, 2.95–4.05,
p
< 0.001;
I
2
81.6%). This risk remained significant both in studies matched or unmatched for participants’ age. With regard to body mass index (BMI), the RR for developing T2DM in obese and non-obese PCOS women compared with their non-PCOS counterparts was 3.24 (95% CI 2.25–4.65;
p
< 0.001;
I
2
30.9%) and 1.62 (95% CI 0.14–18.50;
p
= 0.70;
I
2
89.9%), respectively. The RR for developing T2DM was 3.85 (95% CI 1.99–7.43;
p
< 0.001;
I
2
46.2%) in obese compared with non-obese women with PCOS. This was also the case for overweight compared with lean women with PCOS.
Conclusions
Women with PCOS present an increased risk of T2DM compared with non-PCOS women only if they are obese/overweight.
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