Obesity is defined as an abnormal accumulation of body fat, usually 20% or more over an individual's ideal body weight. This is often described as a body mass index (BMI) over 30. However, BMI does not account for whether the excess weight is fat or muscle, and is not a measure of body composition. For most people, however, BMI is an indication used worldwide to estimate nutritional status. Obesity is usually the result of consuming more calories than the body needs and not expending that energy by doing exercise. There are genetic causes and hormonal disorders that cause people to gain significant amounts of weight but this is rare. People in the obese category are much more likely to suffer from fertility problems than people of normal healthy weight.
A report carried out by the Nurses Health Study demonstrated an increased risk of anovulation in women with an increasing BMI value. Its major effects include a reduction in ovulation rate, a decline in oocyte quality, menstrual irregularities, a decreased pregnancy rate and a rise in miscarriages. Obesity can have particularly damaging effects in young women as they begin menstruating earlier than non-obese girls, essentially enhancing the defects associated with obesity and fertility. Obesity also affects fertility in men.
Epidemiology
On a global scale, there are more people who are obese than underweight. This finding occurs in every region worldwide with the exception of parts of sub-Saharan Africa and Asia.
Previously, obesity and overweight were considered problems nearly exclusive to high-income countries; however, the prevalence of these health problems is now rising in low- and middle- income countries. Moreover, obesity and overweight are health issues which are more prevalent in urban areas compared to rural areas.
Since 1975, obesity rates have tripled worldwide.
As of 2016, 1.9 billion adults (aged 18 years or older) were classified as being overweight, and within these adults, 650 million were classified as obese. This translates to 39% of adults (39% of men and 40% of women) being overweight and 13% of the adult population worldwide (11% of men and 15% of women) being obese in 2016.
An estimated 38.2 million under 5 years of age were either overweight or obese as of 2019. In Africa, the number of overweight children under 5 years of age has increased by 24% percent since 2000. Almost half of the children under 5 who were overweight or obese in 2019 lived in Asia.
In 2016, over 340 million children and adolescents from ages 5–19 were overweight or obese. 124 million children and adolescents aged 5–19 (6% of girls and 8% of boys) were obese in 2016, as compared to 1975 where obesity affected just under 1% of children and adolescents in this age range. The prevalence of obesity and overweight amongst children and adolescents in this age group has significantly risen from 4% in 1975 to just above 18% in 2016. This marked increase in the rate among children has occurred similarly in both boys and girls, reflected in the 2016 statistic where 18% of girls and 19% of boys were overweight.
24.5% of reproductive age women (age 20–44 years) are estimated to be overweight and 23.0% of reproductive age women are estimated to be obese. It has also been shown that the risk of infertility amongst obese women due to disrupted ovulation is 2.7%. For adult women who are obese and are reproductively active, each unit increase in BMI over a BMI of 32 kg/m2 is associated with a reduction of spontaneous conception rate by 5%.
Obesity and overweight among women of reproductive age have been associated with reduced success of conception and a higher risk of complications during pregnancy. Individuals who are obese are at an increased risk of death compared to individuals who are classified as normal weight. This increased risk persists for those who are classified as class 2 and 3 obese.
Women Higher weights have been shown to impair fertility by inhibiting reproductive hormones. Obesity disrupts normal endocrine function, leading to irregularities in ovulation, endometrial development, and embryo development. Adipocytes (fat cells) secrete proteins and signaling molecules known as adipokines. Certain adipokines have been implicated in reducing fertility in women.
Hormonal disruption In women with non-disrupted reproduction function, they hypothalamic-pituitary-ovarian (HPO) axis facilitates proper ovulation and egg implantation. Through producing gonadotropic and steroid hormones, the HPO is responsible for follicular and oocyte development. However, the regulatory functions of the HPO can be disrupted due to the up or down regulation of certain hormones in the setting of obesity.
Insulin One such disruptor of proper HPO function is insulin. Obesity, particularly the presence of visceral fat (fat around the abdomen), is associated with an increased risk of insulin resistance. Insulin resistance refers to cell's reduced sensitivity to insulin, leading to the reduced ability to uptake glucose from the blood and high levels of circulation insulin. The elevated blood insulin levels can disrupt gonadotropin release. Insulin has been shown to increase androgen production, leading to hyperandrogenism. These androgens are converted to estrogen which exert negative feedback on the HPO, leading to down regulation of the HPO and limiting gonadotropin production. This hyperinsulinemia and resulting hyperandrogenism have been associated with disruptions in ovulation.
Adiponectin, the protein secreted in greatest amounts from adipocytes, functions to increase the sensitivity of cells to insulin. Circulating adiponectin levels have been shown to be reduced in obese women. These reduced levels of adiponectin have also been associated with insulin resistance.
Leptin Leptin is a satiety adipokine released from adipocytes. Normally, leptin interacts with leptin receptors (LEPRs) in the brain in order to decrease hunger and facilitate energy expenditure. In obesity, the greater number of adipocytes release greater amounts of leptin. These higher levels of leptin have been implicated in disrupted endometrial maturation and embryo implantation in to the endometrium. Leptin may also inhibit the production of certain steroids, such as progesterone, which is also necessary for proper endometrial development.
Leptin is also a product of the ob gene. Due to leptin's interaction with the hypothalamus to decrease appetite, therefore a mutation in the obese gene would result in an increased appetite, leading to obesity. Leptin has been found to be linked to the HPG axis as it can induce the release of gonadotrophin-releasing hormone (GnRH) by the hypothalamus and subsequently follicle stimulating hormone (FSH) and leutinising hormone (LH) by the anterior pituitary. Pre-pubertal individuals that lack leptin fail to reach the pubertal stage. If given leptin administratively, the mutation would be reversed and puberty resumed. Leptin is further expressed in mature follicles produced by the ovary, suggesting it plays a role in oocyte maturation, hence embryo development.
Inflammation and Oxidative Stress Obesity has been associated with higher levels of circulating triglycerides and inflammatory markers. Pro-inflammatory adipokines secreted by adipocytes have been demonstrated to stimulate fatty acid accumulation. Fatty acids are normally stored in adipocytes as triglycerides. However, as triglycerides accumulate in adipocytes, fatty acids can deposit in other tissues. These fatty acids can create oxidative stress, disrupting the functions of mitochondria and endoplasmic reticula, leading to apoptosis. This process is known as lipotoxicity. Lipotoxicity can impair follicular development, lead to errors in meiotic divisions, and disrupt the implantation of the trophoblast in the endometrium. Lipotoxicity can further contribute to insulin resistance in the setting of an inflammatory state.
Polyendocrine metabolic ovarian syndrome
Increasing body weight is also thought to be linked to the development of polyendocrine metabolic ovarian syndrome (PMOS). PMOS is a very common endocrine disorder among women who are reproductively active with a prevalence of 5-10%. Many women who have PMOS are also obese, and it is estimated that the prevalence of obesity in women with PMOS is 35 - 63%.
PMOS diagnosis is defined by the Rotterdam criteria of having at least two of the following: polycystic ovaries, hyperandrogenism, and ovulatory dysfunction. Polycystic ovaries can be viewed by the ultrasound, and it will show multiple, small cysts in the ovaries. Some symptoms that people may experience with PMOS are irregular periods, acne, infertility, and excessive hair growth.
PMOS is associated with excess levels of male hormones (androgens) or hyperandrogenism. Studies have shown that hyperandrogenism could be caused by a reaction between ovarian theca cells and reactive oxygen species. Hyperandrogenism in women results in menstrual abnormalities, insulin resistance, and ovarian dysfunction in the body. Obesity interferes with the Hypothalamic-Pituitary-Ovarian (HPO) Axis. The HPO Axis is a tightly regulated cycle of female hormones that control female reproduction. In a female with the absence of PMOS, gonadotropin and other steroid hormone are tightly regulated for follicular development. The ovary also plays a vital role in releasing steroid hormones for follicular maturation and oocyte development. After the oocyte develops into an egg, the egg is released and implanted into the lining of the uterus (endometrium). In the absence of fertilization of a sperm, the endometrium lining will shed, and menstruation will occur in a 28-day cycle. Hyperandrogenism can disrupt this cycle and decrease follicular maturation, leading to irregular menstrual cycles (anovulatory cycles) and decreasing fertility.
Obesity in PMOS women amplifies hormonal and metabolic decline, therefore decreasing fertility and oocyte quality in women. In obese women, there is an increased level of insulin circulating the body because of the inability of the body to respond to insulin (insulin resistance). Increased insulin in the blood stimulates the ovaries to produce more androgens increasing the risk of hyperandrogenism that can interfere with the HPO Axis and result with the pathway mentioned previously. In addition, pregnant women with a history of insulin resistance caused by PMOS have an increased risk of gestational diabetes. Obese women tend to have increased abdominal fat deposits, which is correlated with reduced menstrual frequency and fertility and increased insulin resistance.
PMOS and obesity can have an effect on assisted reproductive technology (ART) outcomes. Some studies reported women undergoing in vitro fertilization (IVF) treatment tend to have smaller oocytes that can decrease their chances of a successful conception. Some studies have further indicated that even if conception is successful through ART, there is still an increase in miscarriage rates.
Currently, therapy is aimed at improving insulin resistance so that hyperinsulinemia is reduced and ovulatory features in women are improved. According to recent studies, insulin-sensitiser drugs are the main type of therapy for women with irregular cycles that want to improve their fertility, although weight loss is normally the first step in overweight women with PMOS.
Stigma