Perimenopause as an obesogenic sensitive period: Contributions to elevated cardiovascular risk

Perimenopause, encompassing the period of progressive menstrual irregularity preceding a woman's final menstrual cycle and extending 12 months thereafter, is associated with an acceleration in atherosclerotic cardiovascular disease (CVD) risk, attributable in part to redistribution of body fat. During perimenopause, even in the context of minimal-to-modest weight gain, women experience an expansion of visceral adipose tissue. Concomitantly, women often experience a reduction in gluteofemoral subcutaneous adipose tissue. This pattern of fat redistribution is associated with a greater prevalence of CVD risk factors and a higher incidence of CVD events. Here we present a case of disproportionate weight gain and fat redistribution in a woman newly initiating a long-acting injectable antipsychotic medication with mild-to-moderate obesogenic effects during perimenopause.

A 46-year-old woman with schizoaffective disorder and primary hypothyroidism on levothyroxine presented to her endocrinologist with concerns of weight gain. She also reported vasomotor symptoms and oligomenorrhea. For management of schizoaffective disorder, she was engaged in psychiatric counseling and had initiated a monthly, extended-release aripiprazole lauroxil injectable, within the year. On physical examination, her weight had increased by 9.2 kilograms, shifting her to an overweight body mass index. Fat distribution was notably centripetal, but there was no other Cushing's stigmata. Laboratory evaluation revealed thyroid stimulating hormone within normal limits, an elevated follicle stimulating hormone level, and an undetectable antimullerian hormone level. Human chorionic gonadotropin test was negative, and neither prolactin nor 24-hour urine free cortisol levels were elevated. Ultimately, her psychiatrist discontinued the long-acting aripiprazole therapy while continuing counseling. Greater than two years post medication discontinuation, she has not achieved significant weight loss, despite augmented physical activity and implementation of dietary changes.

In a perimenopausal woman, initiation of a medication with mild-to-moderate obesogenic effects potentially precipitated a dramatic weight gain (10x above the potential magnitude described in package insert), and despite medication discontinuation and lifestyle interventions, excess weight was not shed. While the menopausal transition is not typically associated with significant weight gain, the clinical case described suggests that perimenopausal factors may have contributed to medication-induced weight gain, which was predominantly centrally distributed. As metabolic memory in adipocytes can impede meaningful weight loss, this case highlights perimenopause as a critical period of heightened metabolic sensitivity to pharmacologic insult. Clinicians of perimenopausal patients should exercise caution in initiating medications with obesogenic side effects. When such medications are necessary, ongoing evaluation of cardiometabolic risk indices and support for concomitant salutary lifestyle modifications are advised.