Adolescents' polycystic ovary syndrome health-related quality of life questionnaire (APQ-20): development and psychometric properties.

Several health-related quality of life (HRQOL) questionnaires for adults with polycystic ovary syndrome (PCOS) have been developed so far. However, an adolescent-specific HRQOL questionnaire for PCOS patients is still lacking. Hence, this study aimed to develop and validate a questionnaire to assess HRQOL in adolescents with PCOS. This mixed-method study was conducted in Tehran, Iran, from 2018 to 2020. The qualitative phase was conducted on 18 target participants, and in the quantitative phase, exploratory factor analysis (EFA) was performed on 200 adolescents with PCOS and confirmatory factor analyses (CFA) on the other 200 ones. The item-developing process was finalized with 77 questions. Concerning the optimum cutoff of content validity ratio, content validity index, kappa statistic coefficient, and item impact score, a draft with 55 items was finalized. Then, piloting scale was performed on 40 participants and considering the interitem correlation < 0.3, fifteen items were excluded. Based on the EFA, 20 items in six components (emotion and mood, loss of attractiveness due to the hirsutism, loss of attractiveness due to the acne, self-care, support, and menstrual cycle problem) that explain 60.3% of the variance were extracted. The CFA with acceptable values of goodness-of-fit statistics supports this construct validity. Results of reliability, floor, and ceiling effect were acceptable.  Conclusion: Our study showed that the short questionnaire of APQ-20 is valid and reliable for assessment of the HRQOL of adolescents with PCOS. Further studies are needed to assess the feasibility and reliability of APQ-20 for assessing the HRQOL of adolescents with PCOS. It constitutes a significant step forward in the measurement of HRQOL of adolescents with PCOS. What is Known: • There is no disease-specific questionnaire for assessment of the health-related quality of life (HRQOL) of adolescents with polycystic ovary syndrome (PCOS). What is New: • The short questionnaire of APQ-20 is easy to use, valid, and reliable for the assessment of the HRQOL of adolescents with PCOS. • APQ-20 constitutes a significant step forward in the measurement of HRQOL of adolescents with PCOS.

Declining muscle NAD+ in a hyperandrogenism PCOS mouse model: Possible role in metabolic dysregulation.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder, defined by reproductive and endocrine abnormalities, with metabolic dysregulation including obesity, insulin resistance and hepatic steatosis. Recently, it was found that skeletal muscle insulin sensitivity could be improved in obese, post-menopausal, pre-diabetic women through treatment with nicotinamide mononucleotide (NMN), a precursor to the prominent redox cofactor nicotinamide adenine dinucleotide (NAD+). Given that PCOS patients have a similar endocrine profile to these patients, we hypothesised that declining NAD levels in muscle might play a role in the pathogenesis of the metabolic syndrome associated with PCOS, and that this could be normalized through NMN treatment. Here, we tested the impact of NMN treatment on the metabolic syndrome of the dihydrotestosterone (DHT) induced mouse model of PCOS. We observed lower NAD levels in the muscle of PCOS mice, which was normalized by NMN treatment. PCOS mice were hyperinsulinaemic, resulting in increased adiposity and hepatic lipid deposition. Strikingly, NMN treatment completely normalized these aspects of metabolic dysfunction. We propose that addressing the decline in skeletal muscle NAD levels associated with PCOS can normalize insulin sensitivity, preventing compensatory hyperinsulinaemia, which drives obesity and hepatic lipid deposition, though we cannot discount an impact of NMN on other tissues to mediate these effects. These findings support further investigation into NMN treatment as a new therapy for normalizing the aberrant metabolic features of PCOS.

The interplay between PCOS pathology and diet on gut microbiota in a mouse model.

The gut microbiome has been implicated in polycystic ovary syndrome (PCOS) pathophysiology. PCOS is a disorder with reproductive, endocrine and metabolic irregularities, and several studies report that PCOS is associated with a decrease in microbial diversity and composition. Diet is an important regulator of the gut microbiome, as alterations in macronutrient composition impact the balance of gut microbial communities. This study investigated the interplay between macronutrient balance and PCOS on the gut microbiome of control and dihydrotestosterone (DHT)-induced PCOS-like mice exposed to diets that varied in protein (P), carbohydrate (C) and fat (F) content. The amount of dietary P, C and F consumed significantly altered alpha (α) and beta (ß) diversity of the gut microbiota of control and PCOS-like mice. However, α-diversity between control and PCOS-like mice on the same diet did not differ significantly. In contrast, ß-diversity was significantly altered by PCOS pathology. Further analysis identified an operational taxonomic unit (OTU) within Bacteroides (OTU3) with 99.2% similarity to Bacteroides acidifaciens, which is inversely associated with obesity, to be significantly decreased in PCOS-like mice. Additionally, this study investigated the role of the gut microbiome in the development of PCOS traits, whereby PCOS-like mice were transplanted with healthy fecal microbiota from control mice. Although the PCOS gut microbiome shifted toward that of control mice, PCOS traits were not ameliorated. Overall, these findings demonstrate that while diet exerts a stronger influence over gut microbiota diversity than PCOS pathology, overall gut microbiota composition is affected by PCOS pathology.

Maternal metabolic factors and the association with gestational diabetes: A systematic review and meta-analysis.

Gestational diabetes (GDM) is associated with several adverse outcomes for the mother and child. Higher levels of individual lipids are associated with risk of GDM and metabolic syndrome (MetS), a clustering of risk factors also increases risk for GDM. Metabolic factors can be modified by diet and lifestyle. This review comprehensively evaluates the association between MetS and its components, measured in early pregnancy, and risk for GDM. Databases (Cumulative Index to Nursing and Allied Health Literature, PubMed, Embase, and Cochrane Library) were searched from inception to 5 May 2021. Eligible studies included ≥1 metabolic factor (waist circumference, blood pressure, fasting plasma glucose (FPG), triglycerides, and high-density lipoprotein cholesterol), measured at <16 weeks' gestation. At least two authors independently screened potentially eligible studies. Heterogeneity was quantified using I2 . Data were pooled by random-effects models and expressed as odds ratio and 95% confidence intervals (CIs). Of 7213 articles identified, 40 unique articles were included in meta-analysis. In analyses adjusting for maternal age and body mass index, GDM was increased with increasing FPG (odds ratios [OR] 1.92; 95% CI 1.39-2.64, k = 7 studies) or having MetS (OR 2.52; 1.65, 3.84, k = 3). Women with overweight (OR 2.17; 95% CI 1.89, 2.50, k = 12) or obesity (OR 4.34; 95% CI 2.79-6.74, k = 9) also were at increased risk for GDM. Early pregnancy assessment of glucose or the MetS, offers a potential opportunity to detect and treat individual risk factors as an approach towards GDM prevention; weight loss for pregnant women with overweight or obesity is not recommended. Systematic review registration: PROSPERO CRD42020199225.

Does Adding Adverse Pregnancy Outcomes Improve the Framingham Cardiovascular Risk Score in Women? Data from the Tehran Lipid and Glucose Study.

Background Limited and conflicting evidence is available regarding the predictive value of adding adverse pregnancy outcomes (APOs) to established cardiovascular disease (CVD) risk factors. Hence, the objective of this study was to determine whether adding APOs to the Framingham risk score improves the prediction of CVD events in women. Methods and Results Out of 5413 women who participated in the Tehran Lipid and Glucose Study, 4013 women met the eligibility criteria included for the present study. The exposure and the outcome variables were collected based on the standard protocol. Cox proportional hazard model was used to evaluate the association of APOs and CVDs. The variant of C-statistic for survivals and reclassification of subjects into Framingham risk score categories after adding APOs was reported. Out of the 4013 eligible subjects, a total of 1484 (36.98%) women reported 1 APO, while 395 (9.84%) of the cases reported multiple APOs. Univariate proportional hazard Cox models showed the significant relations between CVD events and APOs. The enhanced model had a higher C-statistic indicating more acceptable discrimination as well as a slight improvement in discrimination (C-statistic differences: 0.0053). Moreover, we observed a greater risk of experiencing a CVD event in women with a history of multiple APOs compared with cases with only 1 APO (1 APO: hazard ratio [HR] = 1.22; 2 APOs: HR; 1.94; ≥3 APOs: HR = 2.48). Conclusions Beyond the established risk factors, re-estimated CVDs risk by adding APOs to the Framingham risk score may improve the accurate risk estimation of CVD. Further observational studies are needed to confirm our findings.

Pathogenesis of Reproductive and Metabolic PCOS Traits in a Mouse Model.

Polycystic ovary syndrome (PCOS) is a common and heterogeneous disorder; however, the etiology and pathogenesis of PCOS are poorly understood and current management is symptom-based. Defining the pathogenesis of PCOS traits is important for developing early PCOS detection markers and new treatment strategies. Hyperandrogenism is a defining characteristic of PCOS, and studies support a role for androgen-driven actions in the development of PCOS. Therefore, we aimed to determine the temporal pattern of development of PCOS features in a well-characterized dihydrotestosterone (DHT)-induced PCOS mouse model after 2, 4, and 8 weeks of DHT exposure. Following 2 weeks of treatment, DHT induced the key PCOS reproductive features of acyclicity, anovulation, and multifollicular ovaries as well as a decrease in large antral follicle health. DHT-treated mice displayed the metabolic PCOS characteristics of increased body weight and exhibited increased visceral adiposity after 8 weeks of DHT treatment. DHT treatment also led to an increase in circulating cholesterol after 2 weeks of exposure and had an overall effect on fasting glucose levels, but not triglycerides, aspartate transaminase (AST) and alanine transaminase (ALT) levels, or hepatic steatosis. These data reveal that in this experimental PCOS mouse model, acyclicity, anovulation, and increased body weight are early features of a developing PCOS phenotype whereas adiposity, impaired glucose tolerance, dyslipidemia, and hepatic steatosis are later developing features of PCOS. These findings provide insights into the likely sequence of PCOS trait development and support the addition of body weight criteria to the early diagnosis of PCOS.

Chronic niacin administration ameliorates ovulation, histological changes in the ovary and adiponectin concentrations in a rat model of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common ovarian diseases among women of reproductive age. The reproductive and metabolic traits of PCOS are underpinned by adipocyte dysfunction, especially diminished adiponectin secretion. Based on evidence that niacin stimulates adiponectin secretion, this study evaluated the effects of niacin on adiponectin concentrations and reproductive traits in a rat model of PCOS. PCOS was induced by single injection of 4mg kg-1 oestradiol valerate (i.m.), and PCOS groups were administered orally with saline or niacin (10 or 25mg kg-1) daily for 30 days after PCOS induction. The control group received 0.2mL sesame oil (i.m.) only. At the end of the experimental period, serum samples and ovaries were collected for adiponectin, histological and molecular analyses. Niacin reduced the bodyweight gain and increased ovary weights in PCOS rats. Niacin also increased the number of normal antral follicles and corpora lutea while reducing the number of cystic follicles and the thickness of theca interna. Moreover, niacin significantly increased serum adiponectin concentration and the gene expression of adiponectin and its type 1 receptor. In conclusion, this study indicates that niacin reduces cystic follicles and improves ovulation in PCOS rats. Adiponectin signalling may have contributed, in part, to the beneficial effects.

Neurokinin 3 Receptor Antagonism Ameliorates Key Metabolic Features in a Hyperandrogenic PCOS Mouse Model.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition characterized by a range of endocrine, reproductive, and metabolic abnormalities. At present, management of women with PCOS is suboptimal as treatment is only symptomatic. Clinical and experimental advances in our understanding of PCOS etiology support a pivotal role for androgen neuroendocrine actions in PCOS pathogenesis. Hyperandrogenism is a key PCOS trait and androgen actions play a role in regulating the kisspeptin-/neurokinin B-/dynorphin (KNDy) system. This study aimed to investigate if targeted antagonism of neurokinin B signaling through the neurokinin 3 receptor (NK3R) would reverse PCOS traits in a dihydrotestosterone (DHT)-induced mouse model of PCOS. After 3 months, DHT exposure induced key reproductive PCOS traits of cycle irregularity and ovulatory dysfunction, and PCOS-like metabolic traits including increased body weight; white and brown fat pad weights; fasting serum triglyceride and glucose levels, and blood glucose incremental area under the curve. Treatment with a NK3R antagonist (MLE4901) did not impact the observed reproductive defects. In contrast, following NK3R antagonist treatment, PCOS-like females displayed decreased total body weight, adiposity, and adipocyte hypertrophy, but increased respiratory exchange ratio, suggesting NK3R antagonism altered the metabolic status of the PCOS-like females. NK3R antagonism did not improve circulating serum triglyceride or fasted glucose levels. Collectively, these findings demonstrate that NK3R antagonism may be beneficial in the treatment of adverse metabolic features associated with PCOS and support neuroendocrine targeting in the development of novel therapeutic strategies for PCOS.

Androgen Action in Adipose Tissue and the Brain are Key Mediators in the Development of PCOS Traits in a Mouse Model.

Polycystic ovary syndrome (PCOS) is a complex disorder characterized by endocrine, reproductive, and metabolic abnormalities. Despite PCOS being the most common endocrinopathy affecting women of reproductive age, the etiology of PCOS is poorly understood, so there is no cure and symptomatic treatment is suboptimal. Hyperandrogenism is the most consistent feature observed in PCOS patients, and recently aberrant neuroendocrine signaling and adipose tissue function have been proposed as playing a role in the development of PCOS. To investigate the role of adipose tissue and the brain as key sites for androgen receptor (AR)-mediated development of PCOS, we combined a white and brown adipose and brain-specific AR knockout (AdBARKO) mouse model with a dihydrotestosterone (DHT)-induced mouse model of PCOS. As expected, in wildtype (WT) control females, DHT exposure induced the reproductive PCOS traits of cycle irregularity, ovulatory dysfunction, and reduced follicle health, whereas in AdBARKO females, DHT did not produce the reproductive features of PCOS. The metabolic PCOS characteristics of increased adiposity, adipocyte hypertrophy, and hepatic steatosis induced by DHT in WT females were not evident in DHT-treated AdBARKO females, which displayed normal white adipose tissue weight and no adipocyte hypertrophy or liver steatosis. Dihydrotestosterone treatment induced increased fasting glucose levels in both WT and AdBARKO females. These findings demonstrate that adipose tissue and the brain are key loci of androgen-mediated actions involved in the developmental origins of PCOS. These data support targeting adipocyte and neuroendocrine AR-driven pathways in the future development of novel therapeutic strategies for PCOS.

Androgen signaling pathways driving reproductive and metabolic phenotypes in a PCOS mouse model.

As the mechanistic basis of polycystic ovary syndrome (PCOS) remains unknown, current management relies on symptomatic treatment. Hyperandrogenism is a major PCOS characteristic and evidence supports it playing a key role in PCOS pathogenesis. Classically, androgens can act directly through the androgen receptor (AR) or, indirectly, following aromatization, via the estrogen receptor (ER). We investigated the mechanism of androgenic actions driving PCOS by comparing the capacity of non-aromatizable dihydrotestosterone (DHT) and aromatizable testosterone to induce PCOS traits in WT and Ar-knockout (ARKO) mice. DHT and testosterone induced the reproductive PCOS-like features of acyclicity and anovulation in WT females. In ARKO mice, DHT did not cause reproductive dysfunction; however, testosterone treatment induced irregular cycles and ovulatory disruption. These findings indicate that direct AR actions and indirect, likely ER, actions of androgens are important mediators of PCOS reproductive traits. DHT, but not testosterone, induced an increase in body weight, body fat, serum cholesterol and adipocyte hypertrophy in WT mice, but neither androgen induced these metabolic features in ARKO mice. These data infer that direct AR-driven mechanisms are key in driving the development of PCOS metabolic traits. Overall, these findings demonstrate that differing PCOS traits can be mediated via different steroid signaling pathways and indicate that a phenotype-based treatment approach would ensure effective targeting of the underlying mechanisms.