By Alicia Loucks
Editor’s Note: This piece by Alicia Loucks summarizes the narrative review by Lei R. and colleagues, “Advances in the study of the correlation between insulin resistance and infertility,” which explores how insulin resistance contributes to infertility through hormonal dysregulation, impaired endometrial receptivity, oxidative stress, and downstream effects on pregnancy and neonatal outcomes. As a narrative review, the article synthesizes current evidence across different patient populations, highlighting both established mechanisms and areas for further research.
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Introduction
“Advances in the study of the correlation between insulin resistance and infertility” examines current evidence on the relationship between insulin resistance (IR) and infertility.[1] Insulin resistance is commonly discussed in the context of polycystic ovary syndrome (PCOS). This article, however, expands the conversation to include infertility in the general population, patients receiving artificial reproduction treatments (ART), and neonatal and postpartum outcomes.
Overview of Insulin Resistance and Fertility
First, insulin resistance may be intricately related to, and perhaps the root cause of, the hyperandrogenism seen in PCOS patients. Second, its effects on metabolism may affect endometrial receptivity, oocyte quality, and oocyte development even in patients without PCOS, thus influencing the likelihood of successful implantation and embryonic survival. Third, it significantly increases the occurrence of chronic diseases such as diabetes and hypertension in both neonatal and postpartum populations.
Insulin resistance’s effects on metabolism may affect endometrial receptivity, oocyte quality, and oocyte development even in patients without PCOS, thus influencing the likelihood of successful implantation and embryonic survival.
Insulin resistance and hyperandrogenism are key factors in PCOS pathophysiology. However, current research suggests that these are not two separate entities but may be intimately related. Insulin seems to enhance the effect of LH on the ovaries and acts synergistically to promote androgen production. It further elevates androgen levels via the adrenal glands, where it appears to enhance the effect of ACTH stimulation. Lastly, it reduces the liver’s ability to produce sex hormone-binding globulin (SHBG), leading to elevated androgens in the blood. In patients who are insulin resistant, the body tries to maintain normal blood glucose levels by producing excess insulin. Thus, all the previously mentioned effects of insulin would be increased by its elevated concentration in these patients. This begs the question of whether insulin resistance is a symptom of PCOS or perhaps the root cause.
Insulin resistance … reduces the liver’s ability to produce sex hormone–binding globulin (SHBG), leading to elevated androgens in the blood.
Mechanisms Linking Insulin Resistance to Infertility
Even in patients without PCOS, insulin resistance can affect fertility. Insulin usually stimulates the production of GLUT4 receptors that facilitate the transport of glucose from the blood into metabolizing tissues. In cells that are resistant to insulin’s effects, these receptors are deficient, and the tissue’s supply of nutrients is blunted. This impaired metabolism limits the endometrium’s ability to differentiate properly and may contribute to failed implantation.
High insulin levels also increase the concentration of free fatty acids (FFAs) in the blood. Blood concentrations of FFAs have been shown to correlate with their levels in oocyte follicular fluid. These elevated FFAs damage oocytes and disrupt their growth and development. Finally, the most damaging effect of insulin resistance appears to be the general state of oxidative stress that it induces in the body. The state of hyperinsulinemia tilts the body’s metabolic balance too far toward catabolism, and reactive oxygen species are created in overabundance. They damage cellular proteins and activate inflammatory pathways that worsen insulin resistance. The cycle persists, affecting even the reproductive organs.
Patients undergoing ART may experience reduced success due to insulin resistance. The damage to the endometrium previously mentioned affects this population as well and potentially contributes to patients experiencing “repeated implantation failure.”[1] In addition, patients seeking ART are often older and have a greater susceptibility to oxidative stress. Reactive oxidative species (ROS) generated by insulin resistance (IR) can damage telomeres and the spindle apparatus of oocytes, leading to defective DNA separation and a higher prevalence of aneuploid or polyploid eggs. It is suggested that supplementing antioxidants prior to ART may mitigate some of these effects and hopefully increase the likelihood of successful implantation and embryo development.
Even if a healthy conception and implantation occur, insulin resistance has the potential to affect pregnancy, postpartum, and neonatal course. Through mechanisms such as decreased nitric oxide synthesis and endothelial cell dysfunction, it may increase hypertensive disorders of pregnancy. Insulin resistance may also contribute to recurrent miscarriage. Lupus anticoagulant levels are elevated in patients with recurrent miscarriage and insulin resistance compared with recurrent miscarriage alone, and the persistent activation of inflammatory pathways may impair endometrial angiogenesis and alter blood supply to the fetus. Patients with insulin resistance are also much more likely to develop gestational diabetes. This consequently increases the risk for type 2 diabetes in postpartum mothers and the development of diabetes and hypertension in newborns born to these GDM mothers.
Even if a healthy conception and implantation occur, insulin resistance has the potential to affect pregnancy, postpartum, and neonatal course… (and) may also contribute to recurrent miscarriage.
Discussion
This research underscores the importance of healthy lifestyle choices for women who hope to conceive. While medications and supplements that help with insulin resistance exist, other treatment options focus on healthy eating, exercise, and good sleep. Patients are aware of the risks to organs such as their heart, lungs, and brain if they develop insulin resistance and other chronic diseases, but many do not consider the toll it also takes on their reproductive system. This article provided an eye-opening summary of the many ways in which chronic inflammation can affect fertility. This directly relates to the importance of overall health for fertility and the idea of a woman’s cycle and fertility as a sign of her overall health. This research also serves as a reminder to include insulin resistance on the differential for unexplained infertility. Insulin resistance is often mentioned with PCOS. But as metabolic syndrome becomes more widespread, it should also be considered in other patient populations.
The strengths of this research were the number of patient populations considered and the patient-relevant outcomes discussed. The authors included data on patients with PCOS, the general population, pregnant patients, postpartum patients, and neonates. They discussed outcomes such as recurrent miscarriage, implantation success rates, and chronic disease development that would be important to an actual patient. The biggest weakness of this article was the lack of certainty in the data presented. Many pathologic cellular mechanisms were mentioned that “potentially” could be caused by insulin resistance. This is less a reflection of the authors and more a reflection of the current state of research on insulin resistance. Evidence is needed to establish definitively whether harmful inflammatory effects are a direct result of insulin resistance or whether they are coincidental. Further research opportunities include establishing the threshold of insulin resistance necessary to impact fertility, assessing the duration required for damage to occur, and evaluating the potential reversibility of its effects.
References
[1] Lei R, Chen S, Li W. Advances in the study of the correlation between insulin resistance and infertility. Frontiers in Endocrinology. 2024;15:1288326. doi:10.3389/fendo.2024.1288326
ABOUT THE AUTHOR
Alicia Loucks is a fourth-year medical student at Liberty University College of Osteopathic Medicine in Lynchburg, VA. She is pursuing residency in family medicine and is passionate about education and accompanying patients through every stage of life. She enrolled in the FACTS elective to understand the uses of cycle tracking and plans to use this knowledge to help her patients understand their body better. In her free time, she loves engaging in all outdoor activities and spending time with her family in the West Coast mountains whenever she can!
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