The objective of this K99/R00 award is to complete further training in female reproductive endocrinology, particularly translational studies in primary cell muscle cultures from women with polycystic ovary syndrome (PCOS), analyze, publish and present data collected during 2 pilot studies and complete the coursework required for the Masters of Science in Clinical Research program at Tulane University. During the R00 (independent phase) the PI will conduct a randomized controlled trial in obese women with PCOS to determine the effect of: a) exercise training, b) 25% dietary restriction, c) metformin and d) no intervention (control group) on neuroendocrine function (pulsatile LH secretion), reproductive function (ovulation rate), ovarian morphology/function and insulin sensitivity. PCOS, an endocrinopathy characterized by excessive androgen production and reproductive dysfunction is the most common reproductive disorder in women of reproductive age. The etiology of PCOS is unclear;however, abnormal neuroendocrine function and hyperinsulinemia are considered primary candidates involved in the development in PCOS. Weight loss is regarded as the choice treatment of infertility in overweight women with the condition. However, it is not known if reproductive function is improved as a result of improving insulin sensitivity and/or reducing body weight. Preliminary studies conducted by the PI indicate that exercise, independent of weight loss, induces menstrual cyclicity in women with PCOS. Since exercise did not cause weight loss, we now hypothesize that the observed increase in insulin sensitivity may mediate the improvement in reproductive function rather than weight loss. In support of this hypothesis, our 16-week aerobic exercise study reduced fasting insulin and increased insulin-stimulated glucose disposal during a hyperinsulinemic euglycemic clamp. Furthermore, treatment of PCOS patients with insulin sensitizers improves both androgen excess and ovulatory function without weight change. The proposed randomized controlled trial will provide data to indicate possible mechanisms by which lifestyle modification can influence reproductive function in women with PCOS. It is hoped that further studies will then lead to the development of evidence based treatment programs for infertility in overweight women with PCOS.

Public Health Relevance

Polycystic ovary syndrome (PCOS) is the most common reproductive abnormality in premenopausal women. The prevalence of PCOS in the community is increasing in parallel with the rise in obesity. Weight loss by regular exercise and dieting is currently recommended in the treatment of the syndrome. The ability of these treatments to restore menstrual function and fertility in some women is not known.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Career Transition Award (K99)
Project #
5K99HD060762-02
Application #
8019048
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Eisenberg, Esther
Project Start
2010-02-01
Project End
2011-08-31
Budget Start
2011-02-01
Budget End
2011-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$61,008
Indirect Cost
Name
Lsu Pennington Biomedical Research Center
Department
Type
Organized Research Units
DUNS #
611012324
City
Baton Rouge
State
LA
Country
United States
Zip Code
70808
Covington, Jeffrey D; Bajpeyi, Sudip; Moro, Cedric et al. (2015) Potential effects of aerobic exercise on the expression of perilipin 3 in the adipose tissue of women with polycystic ovary syndrome: a pilot study. Eur J Endocrinol 172:47-58
Apolzan, John W; Bray, George A; Smith, Steven R et al. (2014) Effects of weight gain induced by controlled overfeeding on physical activity. Am J Physiol Endocrinol Metab 307:E1030-7
Tam, Charmaine S; Redman, Leanne M (2013) Adipose tissue inflammation and metabolic dysfunction: a clinical perspective. Horm Mol Biol Clin Investig 15:19-24
Heymsfield, Steven B; Thomas, Diana; Martin, Corby K et al. (2012) Energy content of weight loss: kinetic features during voluntary caloric restriction. Metabolism 61:937-43
Tam, Charmaine S; Covington, Jeffrey D; Ravussin, Eric et al. (2012) Little evidence of systemic and adipose tissue inflammation in overweight individuals(†). Front Genet 3:58
Thomas, Diana M; Navarro-Barrientos, Jesus E; Rivera, Daniel E et al. (2012) Dynamic energy-balance model predicting gestational weight gain. Am J Clin Nutr 95:115-22
Redman, Leanne M; Elkind-Hirsch, Karen; Ravussin, Eric (2011) Aerobic exercise in women with polycystic ovary syndrome improves ovarian morphology independent of changes in body composition. Fertil Steril 95:2696-9
Redman, Leanne M; Huffman, Kim M; Landerman, Lawrence R et al. (2011) Effect of caloric restriction with and without exercise on metabolic intermediates in nonobese men and women. J Clin Endocrinol Metab 96:E312-21
Lecoultre, Virgile; Ravussin, Eric; Redman, Leanne M (2011) The fall in leptin concentration is a major determinant of the metabolic adaptation induced by caloric restriction independently of the changes in leptin circadian rhythms. J Clin Endocrinol Metab 96:E1512-6
Pieper, Carl; Redman, Leanne; Racette, Susan et al. (2011) Development of adherence metrics for caloric restriction interventions. Clin Trials 8:155-64

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