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

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Authors:

Nanette Santoro, M.D., Irene E. Schauer, M.D., Ph.D., Katherine Kuhn, M.S., Angela J. Fought, M.S., Sara Babcock-Gilbert, M.D., Andrew P. Bradford, Ph.D.

Abstract:

Objective

To study the reprometabolic syndrome in normal-weight, eumenorrheic women by infusing a combination of insulin and lipid. Women with obesity have been shown to have reduced gonadotropins and impaired luteinizing hormone (LH) and follicle-stimulating hormone (FSH) response to gonadotropin-releasing hormone (GnRH).


Design

Randomized crossover.


Setting

Academic medical center.


Participant(s)

Fifteen women, median age 32 (interquartile ranged [IQR] 26, 36) years and body mass index 21.9 (IQR 20.2, 22.9) kg/m2 were recruited.


Intervention(s)

Early follicular phase, 6-hour infusions of insulin (20–40 mU/m2 per minute) and lipid (Intralipid)—insulin/lipid infusion; or saline infusion (controls). The first 4 hours of each study assessed endogenous gonadotropins; at 4 hours, GnRH (75 ng/kg) bolus was administered and sampling continued until 6 hours.


Main Outcome Measure(s)

Linear mixed model analysis was used to determine differences between insulin/lipid and saline influence on endogenous LH pulse amplitude (primary outcome), mean FSH, and area under the curve (AUC) response to GnRH (secondary outcomes).


Result(s)

Twelve women completed both intended studies and an additional 3 women completed only 1 of the 2 studies. LH pulse amplitude, mean FSH, and both AUC responses to GnRH were reduced by insulin/lipid, mean FSH and AUC for LH were at or near statistical significance. LH response to GnRH was significantly reduced when 1 participant with very high LH and antimullerian hormone levels was excluded.


Conclusion(s)

Acute infusion of insulin/lipid to eumenorrheic, normal-weight women recapitulated the reprometabolic syndrome of obesity. These findings imply that specific circulating factors in obese women contribute to their subfertility and thus may be amenable to discovery and treatment.


Clinical Trial Registration Number

NCT02653092.

Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders.