Menopause, Weight Gain and Mood
“Weight gain, mood changes, and insomnia”. Jackie, a beautiful 49-year-old lawyer, sits down across the desk from me and asks me if I see a lot of women suffering from these symptoms. A better question might have been, “Do I see any perimenopausal women NOT experiencing the classic trifecta?”
First, I need to reassure her that what she is experiencing is a result of hormonal changes rather than a character flaw or inherent weakness. I review the following data with her:
The truth about menopausal weight gain
During the menopausal transition, women typically gain up to 1 pound per year. Unfortunately, this weight typically doesn’t disappear when menopause ends.
As circulating estrogen levels drop, the body often becomes less responsive to insulin, the hormone that lowers blood sugars. The body produces excess insulin to overcome the systemic resistance. Insulin is an example of an anabolic hormone which means that higher levels of insulin translate to weight gain.
Insulin resistance is closely associated with a phenomenon called incretin resistance. Incretins are hormones produced by the gut which regular hunger and satiety. Resistance to these hormones, including GLP-1 and GIP (the active hormones in medications like semaglutide and tirzepatide), can contribute to weight gain during the menopausal years by altering women’s “set points” for weight and modifying hunger and satiety signals.
Independent of the fall in estrogen, the corresponding rise in a pituitary hormone called FSH may be involved in weight gain. [1]
The decrease in lean mass characteristic of the perimenopausal years changes metabolism. One pound of muscle burns 6 calories per day while one pound of fat only burns four calories per day. A decrease in lean mass logically translates to slowing of metabolism.
The decline in estrogen at the end of the reproductive years leads to fat deposition in the midsection. This type of fat is known as visceral fat and can raise the risk for a host of medical conditions including heart disease, asthma, breast cancer and dementia.
The link between menopause and mood
Estrogen affects the production of serotonin, a neurotransmitter in the brain involved in boosting happiness. When estrogen levels drop, this can trigger anxiety and depression.
In one eight year study, a diagnosis of depression was 2.5 times more likely during the perimenopausal transition vs the premenopausal years. [2]
Premenopausal-range testosterone levels may also protect again anxiety and depression (although this is still a controversial point), and this key hormone typically drops to a nearly undetectable levels during menopause.
In addition, recent studies have shown that menopause may lead to the shrinking of grey and white matter in the brain. These MRI findings may be predictive of susceptibility to depression during menopause. [3]
Perimenopausal women tend to experience sleep disturbances even in the absence of hot flashes. Estimates of difficulty sleeping are upwards of 40% in the perimenopausal population. [4] If you’ve ever suffered from chronic insomnia, you understand how sleep deprivation factors into worsening depression and anxiety.
Next, I need to develop an evidence-based plan to tackle these issues:
The most pressing question is really what did I do to help Jackie? It is important not to overstate the role of estrogen as a panacea. Unfortunately, while estrogen therapy may help preserve muscle mass and prevent the build up of visceral fat, estrogen has not been shown to prevent fat gain or lead to weight loss. In the Women’s Health Initiative trial, women who received estrogen and progesterone lost less lean muscle and experience decreased redistribution of fat than women receiving placebo. [5] However, they did not lose any significant weight.
The key to weight loss during menopause, beyond healthy eating and regular exercise, likely involves incretin therapy to overcome systemic insulin and incretin resistance. Medications like semaglutide and tirzepatide help restore insulin sensitivity, allowing for weight loss and a simultaneous reduction in cardiovascular risk factors.
Mood changes, including anxiety, depression and brain fog, respond quickly to hormone replacement therapy. My personal favorite treatment regimen involves estrogen patches with a progesterone containing intrauterine device (IUD) for uterine protection. A little SSRI on the side can be beneficial during those tough transitional years to raise serotonin and boost morale.
Sleep disturbances also respond quickly to estrogen therapy but women who have contraindications to estrogen can also try fezolinetant, a non-hormonal treatment for hot flashes. Since insomnia is often linked to hot flashes, fezolinetant can often improve sleep quality. In patients with severe insomnia, I sometimes recommend bedtime progesterone in the place of the progesterone containing IUD since progesterone causes sleepiness. Other sleeping aids include magnesium, melatonin, trazodone or even low doses of benzodiazepines (used with restraint).
Nothing makes me feel as much like a sorceress as treating a woman like Jackie with the menopausal trifecta. I gave Jackie a little incretin and estrogen magic with a sprinkling of short-term SSRI therapy and watched as her misery evaporated into thin air. While menopausal treatment is certainly not a one size fits all answer, the menopausal trifecta should be recognized as the sequelae of hormonal shifts rather than personal shortcomings and should be treated with appropriate pharmaceutical interventions.
[1] Kohrt WM, Wierman ME. Preventing Fat Gain by Blocking Follicle-Stimulating Hormone. N Engl J Med 2017; 377:293.
[2] Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry 2006; 63:375.
[3] Lu W , Guo W , Hou K , et al. : Grey matter differences associated with age and sex hormone levels between premenopausal and perimenopausal women: a voxel-based morphometry study . J Neuroendocrinol 2018. ; 30 : e12655
[5] Chen Z, Bassford T, Green SB, et al. Postmenopausal hormone therapy and body composition--a substudy of the estrogen plus progestin trial of the Women's Health Initiative. Am J Clin Nutr 2005; 82:651.
