After three nights of disturbed sleep, as well as after estrogen suppression with normal or disturbed sleep, women burned significantly less fat, which could explain why menopausal women have increased rates of obesity, according to a study presented in March at ENDO 2021.
Leilah Grant, PhD, of Brigham and Women’s Hospital in Boston, Mass., spoke on the effects of sleep fragmentation and estradiol withdrawal on metabolism in menopausal women. “Although weight tends to increase with age in both men and women,” she says, “in women specifically we see a marked increase in obesity prevalence around the age of menopause. One of the factors thought to contribute to this is the withdrawal of the female hormone estradiol.”
However, the withdrawal of estradiol is universal in menopausal women, yet only about half of women tend to gain weight, so these researchers sought to find other potentially contributing factors. Knowing that significant sleep fragmentation caused by hot flashes is highly prevalent in the menopausal population, the team examined both estradiol withdrawal and sleep disturbance on changes in metabolism that might be underlying body fat gain associated with menopause. They conducted two study visits on 21 healthy premenopausal women, one in a high-estradiol state (during a part of the menstrual cycle when levels are naturally high) and the other in a low-estradiol state achieved naturally as well as through suppression with leuprolide, a gonadotropin-releasing hormone agonist, in a subset of participants.
During each of the visits, participants had two nights of normal unfragmented sleep followed by three nights of fragmented sleep, a protocol that mimics the type of sleep disruption seen in menopause — an increase in nocturnal nighttime awakenings but no overall change in sleep duration.
“Although weight tends to increase with age in both men and women, in women specifically we see a marked increase in obesity prevalence around the age of menopause. One of the factors thought to contribute to this is the withdrawal of the female hormone estradiol.”– Leilah Grant, PhD, Brigham and Women’s Hospital, Boston, Mass.
The primary outcome measure was nutrient utilization using indirect calorimetry conducted at the start and end of each study visit to calculate the respiratory quotient, which indicates the level of breakdown of fats or carbohydrate to produce energy.
On fragmentation night, participants were awoken every 15 minutes with an alarm and kept awake for two minutes with alarms throughout that interval. Over the course of the night, this led to just over an hour of wakefulness. To compensate for the fragmented sleep, participants were given an extra hour in bed.
“In terms of the results, when we fragmented sleep, we saw an increase in the respiratory quotient, which means there was a greater reliance by the body on the breakdown of carbohydrates for energy,” explained Grant. “To put the respiratory quotient into context, if you are eating a mixed diet of carbohydrates, fats, and proteins, we would expect your respiratory quotient to fall somewhere in the range of 0.8 to 0.85, which was true for the women after they had normal sleep.”
With fragmented sleep, the respiratory quotient increased outside of the healthy range. In addition, they also saw a change in the rate of oxidation of fats, meaning that participants were burning less fat, which ultimately would lead to greater fat storage. Estradiol suppression alone induced the same response.
“When we combined the two interventions of sleep fragmentation and hypo-estradiol state, the same outcomes were observed, but I will point out that under these circumstances, we didn’t see an additive effect, so the combination of the interventions was no worse than either intervention on its own,” says Grant.
Thus, their menopausal model of sleep fragmentation and estradiol suppression led to changes in nutrient utilization that if someone was to maintain the same diet might ultimately lead to body fat gain. “Importantly, our sleep fragmentation protocol shows that healthy sleep cannot just be defined by sleep duration since we see the negative effects on metabolism in sleep fragmentation even when we maintain sleep duration.”
These results suggest that some of the metabolic responses seen in menopause are independent of age since they can be replicated with estradiol suppression in young, healthy women. From a clinical perspective, these results show that sleep may be a modifiable risk factor that we can target therapeutically to try to reduce the risk of weight gain and associated health problems like diabetes and cardiovascular disease in menopausal women.
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