Medical therapy to treat obesity and optimize fertility in women of reproductive age: a narrative review

Abstract

Background: Overweight and obesity-chronic illnesses in which an increase in body fat promotes adipose tissue dysfunction and abnormal fat mass resulting in adverse metabolic, biomechanical, and psychosocial health consequences-negatively impact female fertility. Adverse conception outcomes are multifactorial, ranging from poor oocyte quality and implantation issues to miscarriages and fetal health issues. However, with the advent of novel pharmacologic agents, significant weight loss can be achieved, improving the chances of healthy pregnancies, and their use should be considered during periconceptual counseling. There are currently 6 FDA-approved medications for weight loss: 2 GLP1-receptor agonists (GLP1-RAs) liraglutide and semaglutide, 1 dual GLP-1 and gastric inhibitory peptide agonist (GLP1-GIP) tirzepatide, Contrave (naltrexone/bupropion), Qsymia (phentermine/Topamax), and Xenical (orlistat). GLP1-RAs reduce food cravings, appetite, and "food noise" and improve insulin sensitivity and satiety, all of which lead to significant weight loss, ranging from 6 to 30% of starting total body weight or greater, depending on the specific agent used. Their efficacy and relative safety should make them first-line options for women seeking to lose weight in the year before trying to conceive. Contrave, the combination of naltrexone and bupropion, seems to work most significantly for weight loss by inhibiting the rewarding and reinforcing effects of food consumption. Clinical trials report ~ 6% loss of starting total body weight with use of Contrave, as well as improvement in metabolic health factors. It may also improve a woman's ability to conceive by mitigating the effects of PCOS and endometriosis and reducing the drive for alcohol and smoking. Qsymia, the combination of phentermine and topiramate, results in more weight loss than Contrave but cannot be used in the acute preconception period, as its topiramate component is a known teratogen. Orlistat is another FDA-approved medication for weight loss; however, it is currently used much less often than other anti-obesity drugs because of its relatively lower efficacy and significant side effects. Bariatric surgery, which can lead to significant weight loss (25-50%), was previously regarded as the most durable method for weight loss, before the advent of GLP1-RAs. Given the inherent risks of surgery, the development of vitamin (i.e. B12, folate, vitamin D) and mineral (i.e. iron, copper, zinc) deficiencies, that may impact the health of the mother and fetus, as well as the recommended delay of 1-2 years prior to attempting pregnancy, bariatric surgery should not be considered first-line therapy for obesity management in women of reproductive age, especially for women who are hoping to conceive quickly or are nearing advanced maternal age.

Conclusion: Clinically significant and meaningful weight loss is achievable with pharmacotherapy to help enhance fertility in women of reproductive age who are overweight or obese. Current research supports the use of weight loss medications for enhancing spontaneous conception and response to ovulation induction. Further research on the effects upon live birth rates are warranted. For meaningful weight loss, GLP1-RAs can be considered for use in the preconception period, as long as they are stopped at least 2 months before conception. Contrave can be considered as well, though resulting in less weight loss. Phentermine and Qsymia are teratogenic but can be used with contraception for weight loss before trying to get pregnant.

Keywords: GLP1-RAs; Infertility; Obesity; Overweight; Weight loss pharmacotherapy.