Insulin resistance in the menopause

The menopause is accompanied by a transition from a gynoid to an android pattern of body fat distribution and an increase in total body fat without a significant change in total percent body fat1. Increases are seen in both truncal and subcutaneous abdominal fat mass, with the greatest change seen in intra-abdominal fat mass. This has been reported to increase by as much as 20% to 44%1, 2. The accumulation of central abdominal fat in women at this time is associated with a decline in circulating adiponectin. Adiponectin, an adipokine produced by fat, increases insulin sensitivity by promoting fat oxidation distally in liver and muscle. Low serum adiponectin levels are associated with insulin resistance (IR) and the metabolic syndrome such that the decline in adiponectin with intra-abdominal weight gain at menopause is believed to have an important role in the development of IR after menopause.

Whether these metabolic changes are due to the abrupt decline in oestrogen production at menopause or a direct consequence of ageing merits consideration. In rodents, oophorectomy increases food intake and body and fat mass, and these effects are reversed by oestrogen therapy. Mice rendered oestrogen deficient by a targeted mutation in the aromatase gene, which is required for oestrogen biosynthesis, are obese and insulin resistant. Similarly, the rare event of a mutation in the aromatase gene, and hence inability to biosynthesize oestrogen, results in IR, T2DM, acanthosis nigricans, hepatic steatosis and signs of precocious atherogenesis3. A key observation has been that treatment of a man with an aromatase gene mutation with oestradiol resulted in an improvement of his acanthosis nigricans and hepatic steatosis, improved glycaemic control and the resolution of carotid plaques3.

Consistent with these unique models of menopausal oestrogen deficiency, treatment of postmenopausal women with oral oestrogen plus progestin or oestrogen alone is associated with a significant decline in IR over the first year of therapy4, 5. Oestrogen plus progestin therapy has also been associated with a significant reduction in the cumulative incidence of treated diabetes (hazard ratio 0.79, 95% CI 0.67-0.93, p=0.004)5 , whereas the effect of oestrogen alone versus placebo in the Women's Health Initiative randomised controlled trial approached statistical significance (hazard ratio 0.88, 95% CI 0.77-1.01, p=0.072)4. In a 24 month study we also observed a reduction in central abdominal fat in women treated with oestradiol implants.

An important recent observation is the link between obesity, IR and breast cancer risk indicating that factors produced by adipose tissue not only influence metabolic pathways involved in IR but also pathways involved in BC development. Thus accumulation of intra-abdominal fat after menopause may contribute to the increase in risk of breast cancer, an oestrogen dependent malignancy, in the postmenopausal years, when circulating oestradiol levels are low. In a prospective cohort study of non-diabetic women with early stage breast cancer, women with the highest fasting insulin levels had three times the risk of recurrence and death compared with women with the lowest insulin levels. Other studies have since indicated that the use of metformin is associated with decreased breast cancer risk.

Together, the available data provides strong evidence that the decline in oestrogen production by the ovaries at menopause contributes to the increase in intra-abdominal fat and IR which can be ameliorated with oestrogen therapy. Furthermore, the development of IR after menopause not only has serious health implications in terms of increased risks of T2DM and cardiovascular disease, but may also contribute to pathogenesis of breast cancer.

References

  1. Lee CG, Carr MC, Murdoch SJ, et al. Adipokines, inflammation, and visceral adiposity across the menopausal transition: a prospective study. J Clin Endocrinol Metab 2009;94:1104-10.
  2. Franklin RM, Ploutz-Snyder L, Kanaley JA. Longitudinal changes in abdominal fat distribution with menopause. Metabolism 2009;58:311-5.
  3. Maffei L, Murata Y, Rochera V, et al. Dysmetabolic Syndrome in a Man with a Novel Mutation of the Aromatase Gene: Effects of Testosterone, Alendronate, and Estradiol. J Clin Endocrinol Metab 2004;89:61-70.
  4. Bonds DE, Lasser N, Qi L, et al. The effect of conjugated equine oestrogen on diabetes incidence: the Women's Health Initiative randomised trial. Diabetologia 2006;49:459-68.
  5. Margolis KL, Bonds DE, Rodabough RJ, et al. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women's Health Initiative Hormone Trial. Diabetologia 2004;47:1175-87.