Maternal obesity: A potential disruptor of female fertility and current interventions to reduce associated risks

Currently, obesity has achieved epidemic levels in reproductive-aged women with a myriad of consequences. Obesity is susceptible to several reproductive complications that eventually affect fertility rates. These complications originate from the deteriorated quality of oocytes from mothers with obesity, which increases the probability of chromosomal aneuploidy, elevated reactive oxygen species production, compromised embryonic developmental competency, and eventually reduced fertility. Maternal obesity is linked to pregnancy complications such as implantation error, abortion, miscarriage, and early pregnancy loss. This review highlights the adverse effects of maternal obesity on female fertility, with a focus on the mechanistic link between maternal obesity and oocyte quality and discusses possible measures to reduce its associated risks.     

肥胖对动脉粥样硬化的影响

肥胖是一种由多种因素引起的慢性代谢性疾病,表现为体内脂肪堆积过多和(或)脂肪分布异常。动脉粥样硬化的主要病变特征是动脉内膜下脂质沉积,伴有平滑肌细胞和胶原纤维增多,逐步发展形成动脉粥样硬化性斑块。大量的基础和临床研究表明,肥胖能够加剧动脉粥样硬化的发生危险,其可能的机制包括脂代谢异常、胰岛素抵抗、炎症、内皮功能障碍等,但是迄今为止肥胖对动脉粥样硬化的影响机制尚未完全清楚。本文将重点从心外膜及血管周围的异位脂肪沉积、新型脂肪因子、脂肪组织相关外泌体、脂肪棕色化等新的观点阐述肥胖对动脉粥样硬化的影响,为肥胖致动脉粥样硬化的防治提供一些新的思路。     

The impact of childhood obesity on musculoskeletal form

Despite the greater prevalence of musculoskeletal disorders in obese adults, the consequences of childhood obesity on the development and function of the musculoskeletal system have received comparatively little attention within the literature. Of the limited number of studies performed to date, the majority have focused on the impact of childhood obesity on skeletal structure and alignment, and to a lesser extent its influence on clinical tests of motor performance including muscular strength, balance and locomotion. Although collectively these studies imply that the functional and structural limitations imposed by obesity may result in aberrant lower limb mechanics and the potential for musculoskeletal injury, empirical verification is currently lacking. The delineation of the effects of childhood obesity on musculoskeletal structure in terms of mass, adiposity, anthropometry, metabolic effects and physical inactivity, or their combination, has not been established. More specifically, there is a lack of research regarding the effect of childhood obesity on the properties of connective tissue structures, such as tendons and ligaments. Given the global increase in childhood obesity, there is a need to ascertain the consequences of persistent obesity on musculoskeletal structure and function. A better understanding of the implications of childhood obesity on the development and function of the musculoskeletal system would assist in the provision of more meaningful support in the prevention, treatment and management of the musculoskeletal consequences of the condition.     

Adipokines and dietary interventions in human obesity

Obesity is a multisystem disorder associated with cardiovascular and metabolic complications. According to recent studies, it is characterized as a condition of low‐grade inflammation with altered adipose tissue function and secretion of various adipokines. One of the strategies in obesity treatment is dietary intervention (DI) that could modulate cytokine levels in a favourable way. The aim of this review was to summarize the results of studies performed in the last 13 years investigating DI programmes accompanied with weight loss in relation to profile of adipokines at different level (adipose tissue mRNA, adipose tissue secretion and circulating level) and identify whether modulations of adipokines are implicated in the positive effects of DIs. The overall finding is that DIs leading to 5–10% weight loss modulate production of certain adipokines and generally induce improvement of clinical parameters, e.g. insulin sensitivity, but the amelioration of obesity complications is not coherent with the pattern of adipokine regulation, except maybe for leptin. Global analysis of the adipose tissue secretome and measurement of panels of adipokines may prove more informative than studies on individual molecules.     

The influence of obesity on hyperandrogenism and infertility in the female

Although a critical mass of adipose tissue is essential for the normal development of female reproductive function, obesity has been shown to produce menstrual disturbances and subfertility. The severity of obesity and the distribution of fat tissue are important factors that influence the female reproductive system. The pathogenetic mechanistic links between them aren’t clearly elucidated. Obese women, especially those with upper body obesity, have insulin resistance and hyperinsulinaemia, hyperandrogenaemia, increased peripheral aromatization of androgens to oestrogens, altered gonadotrophin secretion, decreased sex hormone binding globulin, decreased growth hormone (GH) and insulin like growth factor binding proteins (IGFBPs), increased leptin levels and altered neuroregulation of the hypothalamic‐pituitary‐gonadal axis. These have been considered as some of the links in the sequence of events of the disrupted ovulatory process. The mechanisms of these actions and their influence on female reproductive function are discussed below.     

Mechanisms linking obesity,inflammation and altered metabolism to colon carcinogenesis

Due to its prevalence, obesity is now considered a global epidemic. It is linked to increased risk of colorectal cancer, the third most common cancer and the second leading cause of death among adults in Western countries. Obese adipose tissue differs from lean adipose tissue in its immunogenic profile, body fat distribution and metabolic profile. Obese adipose tissue releases free fatty acids, adipokines and many pro‐inflammatory chemokines. These factors are known to play a key role in regulating malignant transformation and cancer progression. Obese adipose tissue is infiltrated by macrophages that participate in inflammatory pathways activated within the tissue. Adipose tissue macrophages consist of two different phenotypes. M1 macrophages reside in obese adipose tissue and produce pro‐inflammatory cytokines, and M2 macrophages reside in lean adipose tissue and produce anti‐inflammatory cytokines, such as interleukin‐10 (IL‐10). The metabolic networks that confer tumour cells with their oncogenic properties, such as increased proliferation and the ability to avoid apoptosis are still not well understood. We review the interactions between adipocytes and immune cells that may alter the metabolism towards promotion of colorectal cancer.     

The link between abdominal obesity, metabolic syndrome and cardiovascular disease

AimThe prevalence of metabolic syndrome has increased dramatically in recent years, and the cluster of metabolic abnormalities it encompasses results in increased cardiovascular morbidity and mortality. The role of abdominal (visceral) obesity and the underlying molecular and cellular mechanisms central to this association have been the subject of intensive research in recent times. The aim of this review is to correlate data in this area, highlighting the central role of excess visceral fat and its secreted adipokines, and to review existing and emerging therapies.Data synthesisData were generated from a search of the PubMed database using the terms ‘abdominal obesity’, ‘metabolic syndrome’, ‘insulin resistance’, ‘adipokines’, ‘interleukin-6 (IL-6)’, ‘adiponectin’, ‘tumour necrosis factor-alpha (TNF-α)’ and ‘cardiovascular disease’.ConclusionMetabolic syndrome is associated with a pro-inflammatory state, and the role of visceral obesity is thought to be central to this. Visceral obesity leads to alteration of the normal physiological balance of adipokines, insulin resistance, endothelial dysfunction and a pro-atherogenic state. In association with this, the presence of conventional cardiovascular risk factors such as hypertension, dyslipidaemia and smoking results in a significantly elevated cardiovascular and metabolic (cardiometabolic) risk. Better understanding of the molecular mechanisms central to this association has led to the development of potential therapeutic agents.     

Critical roles of the guanylyl cyclase B receptor in endochondral ossification and development of female reproductive organs

Guanylyl cyclase B is the receptor for a small peptide (C-type natriuretic peptide) produced locally in many different tissues. To unravel the functions of the receptor, we generated mice lacking guanylyl cyclase B through gene targeting. Expression of the receptor mRNA in tissues such as bone and female reproductive organs was evident, and significant phenotypes associated with each of these tissues were apparent in null mice. A dramatic impairment of endochondral ossification and an attenuation of longitudinal vertebra or limb-bone growth were seen in null animals. C-type natriuretic peptide-dependent increases of guanylyl cyclase B activity, but not basal enzyme activity, appeared to be required for the progression of endochondral ossification. Female mice were infertile, but male mice were not. This result was due to the failure of the female reproductive tract to develop. Thus, the guanylyl cyclase B receptor is critical for the development of both bone and female reproductive organs.     

Renin in the female reproductive system

Summary The female reproductive system is characterized by the presence of local renin-angiotensin systems within the evary and within the uterine lining. In the human ovary, renin arises from theca cells. In the uterus, the endometrium (uterine lining in the nonpregnant state) and the decidua (uterine lining in the pregnant state) are the major sources of renin. The primary form of renin produced by these extrarenal sources is prorenin. Angiotensin II, the active component of the renin cascade has a number of potential roles in the ovary and uterus. A key observation is that the human ovum and fetus is bathed in fluids rich in prorenin and angiotensin II.     

Increased plasma levels of retinol‐binding protein 4 with visceral obesity is associated with cardiovascular risk factors

Aims/Introduction: Visceral obesity has been suggested to be an independent risk factor for cardiovascular disease (CVD); the role of adipokines in the risk for CVD is less clear. Aim of this study was to investigate the relationship between parameters of visceral obesity and index of CVD risk factors. Materials and Methods: A cross‐sectional analysis of healthy males (n = 116) and females (n = 175) for evaluation of clinical, laboratory and anthropometric parameters were undertaken. Abdominal subcutaneous (SAT) and visceral adipose tissues (VAT) were measured by computed tomography. Adipokines, including retinol‐binding protein 4 (RBP4) and adiponectin, were determined. The risk for CVD was estimated using the 10‐year Framingham Coronary Heart Disease Risk Point scale (Framingham score). Results: The Framingham score was increased in subjects with metabolic syndrome, and significantly increased with various indices of obesity, traditional risk factors of CVD, C‐reactive protein (CRP) and RBP4, but decreased with adiponectin. With multiple linear regression analysis, the Framingham score independently associated with age, smoking status, body mass index, triglyceride and RBP4. The magnitude of the Framingham score showed a linear trend of increase with CRP, VAT and RBP4 (all P < 0.001), but of decrease with SAT and adiponectin (all P < 0.05) at stratified levels of obesity. Conclusions: RBP4 is increased with visceral fat accumulation and associated with CVD risk factors independent of obesity or traditional risk factors. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00213.x , 2012)     

Optimizing respiratory function assessments to elucidate the impact of obesity on respiratory health

There is an increasing prevalence of obesity worldwide and its impact on respiratory health is of significant concern. Obesity affects the respiratory system by several mechanisms, including by direct mechanical changes due to fat deposition in the chest wall, abdomen and upper airway, as well as via systemic inflammation. The increased mechanical load in obese individuals leads to reduced chest wall and lung compliance and increased work of breathing. While there is generally minimal effect on spirometric values, as body mass index increases, the expiratory reserve volume, and hence functional residual capacity, reduces, often approaching residual volume in more severe obesity. The majority of evidence however suggests that obese individuals free from lung disease have relatively normal gas exchange. The link between asthma and obesity, while initially unclear, is now recognized as being a distinct asthma phenotype. While studies investigating objective markers of asthma have shown that there is no association between obesity and airway hyper‐responsiveness, a recent working group identified obesity as a major risk factor for the development of asthma in all demographic groups. Although the temptation may be to attribute obesity as the cause of dyspnoea in symptomatic obese patients, accurate respiratory assessment of these individuals is necessary. Lung function tests can confirm that any altered physiology are the known respiratory consequences of obesity. However, given that obesity causes minimal changes in lung function, significant abnormalities warrant further investigation. An important consideration is the knowledge that many of the respiratory physiology consequences of obesity are reversible by weight loss.     

Effects of overactive bladder syndrome on female sexual function

This study was to evaluate the impact of the symptoms of overactive bladder (OAB) syndrome on female sexual function. Seventy nine patients with OAB (OAB group) and 79 healthy women (control group) underwent physical examination at our center, and had their sexual function evaluated using the female sexual function index (FSFI). In accordance with the presence or absence of urge incontinence, the OAB group was further divided into the wet and dry groups. The sexual function was evaluated again after 3 months of pharmacotherapy. We investigate the difference of sexual function between OAB and control group. The effect of OAB severity and OAB pharmacotherapy on sexual function was also explored. There were no significant differences between OAB group and control group, including age, body mass index (BMI), education, occupation, fertility, parity, childbirth, and menopause. Compared with the control group, the OAB group had significantly lower FSFI scores. The respective mean ± standard error FSFI scores in the control group and the OAB group were 2.98 ± 1.07 and 2.27 ± 0.96 for desire, 3.48 ± 1.16 and 2.32 ± 1.44 for arousal, 4.60 ± 1.13 and 3.10 ± 1.95 for lubrication, 3.37 ± 0.87 and 2.63 ± 1.04 for orgasm, 3.58 ± 1.02 and 2.41 ± 1.35 for sexual satisfaction, 3.58 ± 1.02 and 2.41 ± 1.35 for sexual pain, and 22.24 ± 5.29 and 15.59 ± 7.47 for the total score (P < .05 for all comparisons). The scores for desire, lubrication, orgasm, sexual satisfaction, pain, and total FSFI between the OAB-dry and OAB-wet subgroup were similar while score of arousal in OAB-wet subgroup was significantly increased compared with that of OAB-dry. OABSS score was commonly used in the assessment of OAB severity. The difference of the FSFI scores among mild OAB group, moderate OAB group, and severe OAB group was statistically significant (P < .05). Female FSFI sexual function scores were significantly improved after OAB pharmacotherapy (P < .05). Women with OAB syndrome have poorer sexual function than healthy women. Patients with more serious OAB experience more disturbing sexual dysfunction. Female sexual function scores were significantly improved after OAB pharmacotherapy.     

Endocrine disorders & female infertility

Female infertility occurs in about 37% of all infertile couples and ovulatory disorders account for more than half of these. The ovaries are in continuous interaction with the other endocrine organs. The interplay may account for infertility occurring at different levels and may render the diagnosis of infertility a difficult exercise for the involved physician. A hypothalamic cause of female infertility should be considered in an appropriate clinical context, with tests pointing to a hypogonadotropic hypogonadism. It can be functional, physiological or related to organic causes. Hyperprolactinemia has well characterized effects on the normal gonadal function and treatment is well established. Acromegaly and Cushing's disease may impair fertility at different levels, mechanisms involved however remain ill defined. Thyroid disorders, both hyperthyroidism and hypothyroidism, can interact with the ovaries, through a direct effect on ovarian function, but autoimmunity may be involved, as well as alterations of the sex hormone binding protein levels. Primary ovarian disorders, such as the polycystic ovary syndrome and primary ovarian insufficiency are frequent diseases, for which novel treatments are currently being developed and discussed. We will propose an algorithm for the diagnosis and approach of the female patient presenting with infertility on the basis of the available evidence in literature.     

Impact of obesity on respiratory function

Obesity has long been recognized as having significant effects on respiratory function. The topic has been studied for at least the last half century, and some clear patterns have emerged. Obese patients tend to have higher respiratory rates and lower tidal volumes. Total respiratory system compliance is reduced for a variety of reasons, which will be discussed. Lung volumes tend to be decreased, especially expiratory reserve volume. Spirometry, gas exchange and airway resistance all tend to be relatively well preserved when adjusted for lung volumes. Patients may be mildly hypoxaemic, possibly due to ventilation-perfusion mismatching at the base of the lungs, where microatelectasis is likely to occur. Weight loss leads to a reversal of these changes. For all of these changes, the distribution of fat, that is, upper versus lower body, may be more important than body mass index.     

The effect of obesity on pulmonary lung function of school aged children in Greece

Obesity impacts on many issues of pulmonary medicine, where it is debated if obesity is linked to asthma, atopy or altered lung function tests. Our study aimed to investigate primarily the effect of obesity on the lung function tests and secondary the possible link of obesity with atopy and asthma in a large cohort of children in Greece. Body mass index (BMI) and data from a questionnaire for lung health, atopy, nutritional habits and family history were obtained from 2,715 children aged 6–11 years. Six hundred fifty‐seven children with BMI>85th percentile (357 overweight, 300 obese) and a group of 196 normal weight children underwent spirometry. The % expected FVC, FEV₁, FEF_25–75, and FEV1/FVC were significantly reduced in overweight or obese children compared to children with normal weight (P = 0.007, P < 0.001, P < 0.001, and P < 0.001, respectively). Reported atopy was significantly higher in overweight or obese children compared to normal weight children (P = 0.008). High BMI remained a strong independent risk factor for asthma (OR = 2.17, 95% CI = 1.22–3.87, P = 0.009) and for atopy (OR = 2.06, 95% CI = 1.32–3.22, P = 0.002). The effect of increased BMI on asthma was significant in girls, but not in boys (OR = 2.73, 95% CI = 1.09–6.85, P = 0.032; OR = 1.74, 95% CI = 0.83–3.73, P = 0.137, respectively). In conclusion we have shown that high BMI remains an important determinant of reduced spirometric parameters, a risk factor for atopy in both genders and for asthma in girls. Pediatr Pulmonol. 2009; 44:273–280. © 2009 Wiley‐Liss, Inc.