The midlife transition and the risk of cardiovascular disease and cancer Part I: magnitude and mechanisms

Nathan G. Kase, Elissa Gretz Friedman, Michael Brodman, Chifei Kang, Emily J. Gallagher, Derek LeRoith

Research output: Contribution to journalReview articlepeer-review

15 Scopus citations


Heart disease and cancer are the leading causes of death in the United States. In women, the clinical appearance of both entities—coronary heart disease and cancer (breast, endometrium, and ovary)—escalate during the decades of the midlife transition encompassing the menopause. In addition to the impact of aging, during the interval between the age of 40 and 65 years, the pathophysiologic components of metabolic syndrome also emerge and accelerate. These include visceral adiposity (measured as waist circumference), hypertension, diabetes, and dyslipidemia. Osteoporosis, osteoarthritis, sarcopenia, depression, and even cognitive decline and dementia appear, and most, if not all, are considered functionally related. Two clinical reports confirm the interaction linking the emergence of disease: endometrial cancer and metabolic syndrome. One describes the discovery of unsuspected endometrial cancer in a large series of elective hysterectomies performed in aged and metabolically susceptible populations. The other is from the Women's Health Initiative Observational Study, which found a positive interaction between endometrial cancer and metabolic syndrome regardless of the presence or absence of visceral adiposity. Both provide additional statistical support for the long-suspected causal interaction among the parallel but variable occurrence of these common entities—visceral obesity, heart disease, diabetes, cancer, and the prevalence of metabolic syndrome. Therefore, 2 critical clinical questions require analysis and answers: 1: Why do chronic diseases of adulthood—metabolic, cardiovascular, endocrine—and, in women, cancers of the breast and endometrium (tissues and tumors replete with estrogen receptors) emerge and their incidence trajectories accelerate during the postmenopausal period when little or no endogenous estradiol is available, and yet the therapeutic application of estrogen stimulates their appearance? 2: To what extent should identification of these etiologic driving forces require modification of the gynecologist's responsibilities in the care of our patients in the postreproductive decades of the female life cycle? Part l of this 2-part set of “expert reviews” defines the dimensions, gravity, and interactive synergy of each clinical challenge gynecologists face while caring for their midlife (primarily postmenopausal) patients. It describes the clinically identifiable, potentially treatable, pathogenic mechanisms driving these threats to quality of life and longevity. Part 2 (accepted, American Journal of Obstetrics & Gynecology) identifies 7 objectives of successful clinical care, offers “triage” prioritization targets, and provides feasible opportunities for insertion of primary preventive care initiatives. To implement these goals, a reprogrammed, repurposed office visit is described.

Original languageEnglish
Pages (from-to)820-833
Number of pages14
JournalAmerican Journal of Obstetrics and Gynecology
Issue number6
StatePublished - Dec 2020


  • aging
  • cancer
  • coronary artery disease
  • diabetes type 2
  • dyslipidemia
  • estradiol
  • hormone therapy
  • insulin resistance
  • menopause
  • metabolic syndrome
  • midlife transition
  • steroid and insulin receptors
  • systemic inflammatory state
  • visceral adiposity
  • waist circumference
  • window of opportunity


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