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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open  Access   Full Text Article                                                                                                                                                                                Review Article 

Female Obesity: A Probable Cause of Infertility

Nayana B Nair¹ , Minnu Skaria²* , R. Sambath Kumar³ 

¹ Post Graduate Student, Department of Pharmacy Practice, J.K.K. Nattraja College of Pharmacy, Namakkal (Dt), Kumarapalayam- 638 183, Tamil Nadu, India

² Assistant Professor, Department of Pharmacy Practice, J.K.K. Nattraja College of Pharmacy, Namakkal (Dt), Kumarapalayam- 638 183, Tamil Nadu, India

³ Professor, Department of Pharmaceutics, J.K.K. Nattraja College of Pharmacy, Namakkal (Dt), Kumarapalayam- 638 183, Tamil Nadu, India

INTRODUCTION                                                                                                                                                  

Obesity is a worldwide problem. Obesity continues to rise worldwide, despite efforts to combat it ¹. Overweight persons account for around one billion people in the globe, with over 300 million of these being obese. ²

The most accessible measure of obesity is the body mass index (BMI), or overall body size adjusted for height, because the methods for measuring BMI are widely available. Adiposity (regional or total body fat), adipokine production, and lifestyle factors, on the other hand, may all have a role in the overall obesity-related health risk. ³

The link between obesity and cardiometabolic disease is generally understood by both the medical community and the general public. Obesity also appears to play a significant role in the development of female-specific reproductive health disorders, which have a considerable public health impact. ⁴ Obesity has been linked to a higher risk of breast ⁵ and endometrial cancer. ^{6, 7}

Obesity is linked to a number of interconnected diseases, including insulin resistance/diabetes, hypertension, dyslipidemia, and sleep apnea, all of which contribute to the diagnosis of a metabolic syndrome, which shortens life expectancy. ⁸ Obesity-related metabolic alterations may have an impact on reproduction. Obese women undergoing infertility therapy, on the other hand, may experience additional issues such as the requirement for larger dosages of medicines to induce/stimulate ovulation, oocyte morphological alterations, decreased fertilization and implantation rates, and embryo quality. Obese women undergoing IVF may have lower rates of clinical pregnancy and live births, as well as a higher rate of abortion, as compared to women of normal body weight. ⁹ Obese pregnant women are also more likely to experience maternal and foetal problems like gestational diabetes, hypertensive disorders of pregnancy, and increased neonatal morbidity and death. ¹⁰

The link between obesity and infertility was first discovered in 1934, when Irving Stein and Micheal Leventhal described the ‘Stein–Leventhal Syndrome,' which included obesity, hirsutism, and infertility. ¹¹

Infertility is an illness that is commonly described as inability to conceive after twelve or more months of natural fertilization attempts, according to the American Society of Reproductive Medicine Practice Committee, ¹² and it is a growing concern in our society today. According to the World Health Organization, this disease affects up to 50–80 million women worldwide, with a fluctuating incidence that can reach up to 50% of all women in some cases. ¹³

Skin fold thickness, underwater weighing, dual energy x-ray absorptiometry (DEXA), MRI, and infrared spectroscopy can all be used to precisely estimate total body fat, ¹⁴ but their use is restricted to research. Simpler measurements of obesity, such as BMI, waist circumference (WC), and waist–hip ratio, are employed in daily clinical practice to assess the degree of obesity (WHR). ²

A WHR of more than 0.9 for males and higher than 0.8 for women is generally considered to indicate an elevated risk of cardiovascular disease. It was also discovered that in women with a WHR greater than 0.8, the RRs of irregular menstruation and oligomenorrhea were 1.56 and 2.29, respectively. ¹⁵

We examine the impact of a changed metabolic state on women's reproductive health, with an emphasis on the consequences of obesity on fertility and the treatment of infertility in obese and overweight women.

LIFESTYLE: DIETARY FACTORS 

Inadequate diets, such as those with low calories and protein content or, conversely, those based on a habitual hypercaloric dietary assumption, which result in severe thinness or overweight, have a significant impact on ovarian function and raise the risk of infertility in women. In this regard, it has been observed that women with a BMI of more than 25 kg/m2 take longer to conceive than women with a BMI of less than 19 kg/m2, and that obesity and overweight are related with lower pregnancy rates, higher gonadotrophin requirements, and more miscarriage events. Premature labour, gestational diabetes, and hypertension are all linked to having a high BMI during pregnancy. ¹⁷

One way through which fat intake can affect reproductive tissues is lipotoxicity. ^18-22 Excess circulating long-chains saturated fatty acids, which are produced by adipocytes and are received through the food, characterize this process. When adipocytes can no longer retain these fatty acids, fat is stored by non-adipose cell types. This causes an increase in reactive oxygen species generation, which leads to mitochondrial malfunction, endoplasmic reticulum stress, and cell death. ²³ Granulosa cells and oocytes are among the reproductive tissues damaged, resulting in delayed oocyte maturation and low oocyte quality. ^{22, 24}

ADIPOKINES AND INFERTILITY

Adipokines are signalling molecules produced by adipose cells, and the amount produced depends on the amount of adipose tissue present. Leptin, tumour necrosis factor alpha (TNF), interleukin 6 (IL-6), free fatty acids, and adiponectin are adipokines that may play a role in obesity-related illness. ^25-27 Adipokine imbalances can cause inflammation and a disruption in cell communication, affecting cellular metabolism and function. ³

Leptin, for example, may influence reproductive function at the hypothalamic level, delivering both the signal to induce reproductive maturation and the signal to keep the hypothalamic-pituitary-ovarian axis signaling normal. ^{25, 28, 29}

The levels of leptin and tumour necrosis factor (TNF) differ between the follicular and luteal phases of the menstrual cycle. ²⁵ Although the significance of these differences in adipokines between menstrual cycle phases is unknown, they could influence signalling within the hypothalamic-pituitary-ovarian axis, which is essential for optimal oocyte recruitment and ovulation. ³

Figure 1 Functional property of adipocites

LH Luteinizing hormone, FSH Follicle stimulating Hormone, E2 Estradiol

OBESITY, PHYSICAL ACTIVITY AND INFERTILITY

Physical inactivity reduces energy expenditure and contributes to the development and maintenance of obesity. It's uncertain if inactivity and exercise play a role in the pathophysiologic mechanisms that relate obesity to disease. ³⁰ Another study using NHSII data that adjusted for BMI found that women with the highest levels of physical activity were less likely to experience ovulatory infertility than those with low levels of physical activity. ³¹ Another recent study of physical activity and pregnancy time found that higher levels of physical exercise were linked to a shorter pregnant time. ^[32] Obesity is caused and maintained by a combination of poor dietary choices and a lack of physical activity, ³⁰ and therefore physical activity may be a key component in improving reproductive function in obese people. ³

ENHANCING REPRODUCTIVE FUNCTION IN OBESE WOMEN WITH INFERTILITY

Obese infertile women should first try to lose weight before turning to ovulation-inducing medicines or artificial insemination. Improved menstrual function and fertility, as well as a reduction in metabolic risks, should follow from reducing fat and abdominal fat. Restoration of ovulation, an 11 percent reduction in belly fat, a 4 cm reduction in WC, and a 71 percent increase in insulin sensitivity were all linked to a 2–5% drop in body weight. ³³ Weight loss leads to an increase in SHBG (sex-hormone binding globulin), a decrease in testosterone, improved menstrual function, a higher rate of conception, and a lower chance of miscarriage. Abdominal fat removal is crucial in recovering ovulation since central adiposity is linked to menstrual problems and infertility. ²

DIETARY MANAGEMENT

Calorie restriction, rather than the diet's composition, should be the focus of attention. Obesity diets should strive for gradual weight loss by reduced calorie intake and increased physical activity, with the overall goal of energy expenditure exceeding energy intake. ²

BARIATRIC SURGERY AND WEIGHT LOSS

For some women, clinically meaningful weight loss with lifestyle changes may be challenging. Bariatric surgery may result in more significant and long-term weight loss. ³

Laparoscopic adjustable gastric banding and laparoscopic Roux-en-Y gastric bypass are the two most popular bariatric procedures performed today. Both of these procedures have outstanding results, ^35,36 with the majority of patients losing more than half of their excess weight and the majority of obesity-related comorbidities, such as diabetes and hypertension, being reversed or avoided. ³⁷

After bariatric surgery, menstrual cycle abnormalities may go completely. Menstrual issues and PCOS-related fertility improve significantly after gastric bypass surgery and subsequent weight loss. Infertility caused by anovulation in morbidly obese women could thus be considered an additional rationale for bariatric surgery if other less invasive methods have failed. ²

COMPLICATIONS OF BARIATRIC SURGERY

Simple post-operative tachycardia in obese patients is a WARNING SIGNAL and should be treated seriously. Dehydration is the most prevalent cause; however pulmonary embolism or a surgical complication like an anastomotic fistula should also be investigated. ³⁸

Peritonitis from anastomotic fistula formation is the most prevalent post-surgery complication. This is a common early complication that occurs within the first 10 days following surgery, with a 1-6 percent ^39,40 incidence after gastric bypass and 3-7 percent after sleeve gastrectomy. ⁴¹

With a predicted frequency of 2% and a fatality rate of 20-30%, deep vein thrombosis and pulmonary embolism are the second largest cause of post-operative death following gastric surgery. ^{[15, 16]} They may appear a few days after surgery, but the risk remains for several months afterward.

Obese people are more likely to have gallstones, which appear to be exacerbated following bariatric surgery (3-30 percent). To try to avoid this problem, urso-deoxycholic acid is frequently administered post-operatively (for 6 months). ⁴⁴

Gastric ulcers can arise in as many as 15% of people who have bypass surgery. The exact reason of this has yet to be determined. These symptoms usually appear during the first 90 days after surgery and include severe dyspepsia, dysphagia, retrosternal discomfort, and/or vomiting. ^{45, 46}

PHARMACOLOGICAL TREATMENT 

Thyroid hormone, phenylpropanolamine (PPA), a sympathomimetic agent (25mg orally 3 times a day), mazindol, a sympathomimetic amine (3mg/day orally in divided doses), fenfluramines, a serotonergic agonist (0.2mg/kg/day) and more recently, sibutramine, a schedule-IV controlled substance (10mg once daily) and orlistat, a lipase inhibitor (60mg orally 3 times a day) have all been used to treat obesity, with the primary goals of weight loss, weight maintenance, and risk reduction. These substances suppress hunger, reduce fat absorption, and enhance energy expenditure. However, research on the long-term efficacy of anti-obesity drugs is few. ²

CONCLUSION

With the global obesity rate rising, study in this field will undoubtedly continue. Time limits female fertility, the reproductive phenotype of obesity varies, and existing obesity measurements are not accurate predictors of these phenotypes. Finally, while the search for a "magic bullet" to cure obesity will undoubtedly continue, the importance of food, exercise, and lifestyle adjustment must remain at the forefront of obesity management.

ACKNOWLEDGEMENT

We would like to express our thanks to the head, Department of Pharmacy Practice and our Department staffs to their valuable suggestions and recommendations.

CONFLICTS OF INTEREST

Authors declare that they have no conflicts of interest.

FUNDING STATEMENT

This review did not receive any funding.

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