Reprometabolic Syndrome Mediates Subfertility in Obesity
Condition: Obesity; Infertility; Hypogonadotropic Hypogonadotropism; Hyperinsulinemia
MeSH terms: Infertility; Obesity; Hyperinsulinism; Hypogonadism
Study type: Interventional

Summary: 
      Obesity plays an adverse role at every stage of conception and pregnancy and mounting
      evidence implicates relative hypogonadotropic hypogonadism, and reduced menstrual cycle
      hormone secretion as likely contributors to the subfertility phenotype and possible
      contributors to complications of pregnancy and the developmental origin of adult diseases
      such as diabetes and cardiovascular disease. This study will be the first comprehensive
      investigation to tie together the patterns of hyperinsulinemia, hyperlipidemia and
      inflammation, characteristic of obesity and obesity-caused relative hypogonadotropic
      hypogonadotropism and its potential adverse reproductive outcomes. The investigators findings
      will be used to inform a subsequent clinical intervention to optimize reproductive outcomes
      for obese women and their offspring.
    

Detailed description: 
      Before any of the well-known adverse effects in pregnancy2,3, obesity causes a relatively
      hypogonadotropic hypogonadal phenotype. Reduced LH, FSH, estradiol (E2) and progesterone
      secretion are well documented during the menstrual cycles of obese women compared to normal
      weight women (NWW).4,5. Decreased gonadotropin secretion associated with obesity is related
      to reduced pituitary sensitivity to GnRH6. This reduction in pituitary sensitivity suggests
      mediation by circulating factors such as cytokines, insulin, or other pro-inflammatory
      signals known to be elevated in obesity. We have recently discovered that the combination of
      hyperinsulinemia and circulating free fatty acids (FFAs), but neither agent alone, can
      acutely decrease gonadotropin secretion in NWW as well as men, establishing a direct causal
      linkage for the central hypothesis of this proposal: that chronic pituitary suppression
      partially mediates obesity related subfertility. Our working model is that the combination of
      excess, possibly pro-inflammatory (omega-6) circulating FFAs and insulin resistance
      associated with obesity, cause decreased pituitary sensitivity to GnRH, with a resulting
      relative sex steroid deficit that further exacerbates the obese phenotype. We have named this
      phenotype the reprometabolic syndrome. We propose to examine the interrelationships among
      obesity, reproductive dysfunction and metabolic dysfunction in a mechanistic fashion. We will
      induce the hypogonadotropic hypogonadal phenotype of obesity in NWW, who will be primed with
      a high-fat diet (HFD) designed to increase circulating FFAs and produce short-term insulin
      resistance and higher insulin levels.1,7-11 Before and after priming, we will test the
      additive effects of lipid excess, insulin, and inflammation on the reproductive and metabolic
      axes.
    

Intervention name(s): Insulin; Intralipid; Dextrose; Heparin; GnRH; Hyperinsulinemic Euglycemic Clamp
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Procedure
Other intervention name(s): Humulin; Free Fatty Acid; d-glucose; anticoagulant; gonadorelin acetate; HEC
Intervention MeSH terms: Heparin; Anticoagulants; Soybean oil, phospholipid emulsion
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science