During the last year, dominated by one topic, the COVID-19 pandemic, obesity has been discussed mainly as a risk factor for more severe courses of this infection. At the same time, obesity itself represents a pandemic, with a prevalence that has doubled since 1980, reaching 12% among adults (1Afshin A. Forouzanfar M.H. Reitsma M.B. Sur P. Estep K. et al.GBD 2015 Obesity Collaborators
Health effects of overweight and obesity in 195 countries over 25 years.). It often is associated with hypertension, low levels of high-density lipoprotein, hypertriglyceridemia, elevated fasting glucose, and/or abdominal obesity. The concomitant presence of ≥3 of these factors has been termed “metabolic syndrome” and is associated with a particularly high risk of cardiovascular diseases.In women, obesity has been implicated further in menstrual disorders, infertility, and adverse pregnancy outcomes. Obese women have been reported to suffer more often from irregular cycles and anovulation than lean women. They not only have a higher risk of suffering from infertility, but also face complications resulting from infertility treatments. Once they do achieve pregnancy, obese women demonstrate higher rates of miscarriage, gestational diabetes, and hypertensive pregnancy disorders as well as birth complications and cesarean sections (2Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child.). Therefore, the increased prevalence of obesity has important implications for gynecologists and obstetricians. The most obvious solution (weight loss) is extremely hard to achieve for most patients, as we all know from our clinical practice. Moreover, studies evaluating the effect of weight reduction on fertility and pregnancy outcomes report conflicting results. Particularly regarding fertility, some investigators have described a reduction in the time to pregnancy after weight reduction, while others have not found any beneficial effect.Therefore, it is extremely important to elucidate the underlying pathophysiology responsible for the association between high body mass index and impaired reproductive function. Many previous studies have concentrated on obese women with polycystic ovary syndrome (PCOS), but this population represents only a subgroup of obese women in which the two conditions may be confounding. While women with PCOS almost universally show high luteinizing hormone (LH) levels and elevated LH-to-follicle stimulating hormone (LH: FSH) ratio, in obese women without PCOS, low gonadotropin levels have been observed. This may be seen as unexpected, especially in light that obese patients additionally have been reported to present with lower levels of antimüllerian hormone, inhibin B, and estradiol (3De Pergola G. Maldera S. Tartagni M. Pannacciulli N. Loverro G. Giorgino R. Inhibitory effect of obesity on gonadotropin, estradiol, and inhibin B levels in fertile women.). As these three ovarian hormones exert a negative feed-back on pituitary FSH secretion, we would expect higher FSH levels when the inhibition exerted by them is lacking. Therefore, it is not fully understood yet how obesity causes an impairment of the hypothalamic-pituitary-ovarian axis resulting in hypogonadotropic hypogonadism and infertility.In studies evaluating the metabolic and endocrine profile of obese women, the coexistence of decreased FSH and LH secretion with hyperlipidemia and hyperinsulinemia has been observed (4Chosich J. Bradford A.P. Allshouse A.A. Reusch J.E.B. Santoro N. Schauer I.E. Acute recapitulation of the hyperinsulinemia and hyperlipidemia characteristic of metabolic syndrome suppresses gonadotropins.). Therefore, the term “reprometabolic syndrome” has been coined by Santoro et al. (4Chosich J. Bradford A.P. Allshouse A.A. Reusch J.E.B. Santoro N. Schauer I.E. Acute recapitulation of the hyperinsulinemia and hyperlipidemia characteristic of metabolic syndrome suppresses gonadotropins.) to characterize this condition and emphasize the profound impact of obesity on female reproductive function. However, are the observed metabolic change merely associated with a low concentration of gonadotropins or is there a causal link?To better elucidate this correlation, Santoro et al. (4Chosich J. Bradford A.P. Allshouse A.A. Reusch J.E.B. Santoro N. Schauer I.E. Acute recapitulation of the hyperinsulinemia and hyperlipidemia characteristic of metabolic syndrome suppresses gonadotropins.) published a previous study in 2017, in which they aimed to reproduce the metabolic changes typically observed in obese patients – more precisely, hyperlipidemia combined with hyperinsulinemia – in lean regularly cycling women and in lean men. Using a crossover study design, they administered infusions of saline (control), lipid solution alone, insulin alone (while maintaining euglycemia), and the combination of lipid solution and insulin over 6 hours, respectively, in a random order over four separate study visits. They measured LH and FSH twice-hourly and found these to be significantly decreased in women and men after the combined lipid and insulin solution compared to saline-control. In contrast, neither lipid nor insulin alone led to significant changes in gonadotropin levels. The investigators concluded that hyperinsulinemia combined with elevated lipid levels suppresses gonadotropin secretion in the short term and hypothesized that this might be the pathophysiologic mechanism underlying hypogonadotropic hypogonadism in obese women.In this month’s issue of Fertility and Sterility, Santoro et al. (5Santoro N. Schauer I.E. Kuhn K. Fought A.J. Babcock-Gilbert S. Bradford A.P. Gonadotropin response to insulin and lipid infusion reproduces the reprometabolic syndrome of obesity in eumenorrheic lean women: a randomized crossover trial.) report the results of a subsequent and expanded study, again using a randomized crossover design, evaluating the short term induction of the reprometabolic syndrome in lean women. Accounting for their previous results, they compared only two scenarios: infusion of lipid plus insulin vs. infusion of saline-control. The study included 15 eumenorrheic, normal-weight women who underwent one 6-hour infusion with each of these two solutions in a random order. Blood sampling was performed every 10 minutes, to better characterize the time course of gonadotropin secretion and examine secretion patterns in response to the two interventions. Consequently, the investigators were able to analyze LH pulse amplitude and frequency in addition to mean FSH and LH levels, as reported previously in their earlier study. They found a reduced LH pulse amplitude after infusion of lipid plus insulin (mean pulse amplitude 1.49 IU/L) compared to saline infusion (2.33 IU/L, P = .14). LH pulse frequency did not differ significantly. In addition, as obese women have been reported to show a reduced responsiveness to exogenous gonadotropin releasing hormone (GnRH), this study further examined the LH response to an exogenous GnRH bolus. LH response was reduced significantly after infusion of lipid plus insulin (P = .02), when one participant with very high LH and antimüllerian levels was excluded, indicating a reduced pituitary sensitivity because of the metabolic changes induced.

Although most of the results of this study are at marginal statistical significance – likely because of the small sample size and underpowering – it is nonetheless quite interesting, detailing the likely pathophysiology of hypogonadotropic hypogonadism in obese women. In particular, the investigators showed decreased LH pulse amplitude and a reduced response to GnRH induced by hyperinsulinemia combined with hyperlipidemia, implicating a pituitary origin of the low gonadotropin levels. It is striking how rapidly the endocrine effects of a short term administration of insulin and lipid infusion appeared in the lean women included in this study. This indirectly implies that specific and reversible dietary factors, especially those foods with a high glycemic index which rapidly raise glucose and insulin, may have a significant role for the reprometabolic syndrome. If this is indeed true, then the consistency of one’s diet is of critical importance and could be explored as a potential target for the development of new therapeutic strategies.

Future studies should investigate whether an improvement of insulin and lipid levels really leads to an improvement of the reproductive outcomes of obese women, to confirm the causal relationship of these metabolic changes with infertility. In the meantime, when counseling obese patients wishing to conceive, we clinicians should keep in mind that a modification of the consistency of the diet and lifestyle might be more important than the number of kilograms lost.

ReferencesAfshin A. Forouzanfar M.H. Reitsma M.B. Sur P. Estep K. et al.GBD 2015 Obesity Collaborators

Health effects of overweight and obesity in 195 countries over 25 years.

N Engl J Med. 377: 13-27

Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child.

BMJ. 356: j1De Pergola G. Maldera S. Tartagni M. Pannacciulli N. Loverro G. Giorgino R.

Inhibitory effect of obesity on gonadotropin, estradiol, and inhibin B levels in fertile women.

Obesity. 14: 1954-1960Chosich J. Bradford A.P. Allshouse A.A. Reusch J.E.B. Santoro N. Schauer I.E.

Acute recapitulation of the hyperinsulinemia and hyperlipidemia characteristic of metabolic syndrome suppresses gonadotropins.

Obesity. 25: 553-560Santoro N. Schauer I.E. Kuhn K. Fought A.J. Babcock-Gilbert S. Bradford A.P.

Gonadotropin response to insulin and lipid infusion reproduces the reprometabolic syndrome of obesity in eumenorrheic lean women: a randomized crossover trial.

Fertil Steril. ()Article InfoPublication History

Published online: July 04, 2021

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DOI: https://doi.org/10.1016/j.fertnstert.2021.06.002

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©2021 American Society for Reproductive Medicine, Published by Elsevier Inc.

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