For young women, missed periods from intense stress could signal heart health risk (2024)

Key takeaways:

• Signs of functional hypothalamic amenorrhea include early estrogen loss and anovulation.
• The condition is often diagnosed in young female athletes and may increase CV risk.

PHILADELPHIA — Consistently missed periods brought on by intense exercise, disordered eating or stress in young women can lead to multiple consequences, including endothelial dysfunction and increased CVD risk, according to a speaker.

Estrogen loss at key stages in a woman’s reproductive life span may impact the trajectory of CVD risk, Chrisandra L. Shufelt, MD, MS, FACP, MSCP, professor and chair of the division of internal medicine at Mayo Clinic in Jacksonville, Florida, and associate director of the Center for Women’s Health Research, said during a presentation at the Heart in Diabetes CME Conference. CVD is the leading cause of death among premenopausal women and traditional CV risk factors, such as hypertension or dyslipidemia, do not capture this risk for women at age 26 years — the average age of diagnosis for functional hypothalamic amenorrhea, a condition in which “the ovary is shutting off,” Shufelt said.

When regular periods ‘abruptly halt’

Functional hypothalamic amenorrhea (FHA), a condition similar to but distinct from polycystic ovary syndrome, results from low energy availability due to decreased caloric intake or disordered eating, increased or excessive physical activity or stress, Shufelt said. A key feature of FHA is regular menstrual cycles that “abruptly halt.” FHA is defined as the absence of regular menses for 3 or more months, decreased energy and a low BMI.

“In the crossover between PCOS and FHA, women with FHA predominantly have a BMI of less than 21 kg/m²,” Shufelt said. “These women look physically fit; they are very thin and our society is set up to think that thin equals physically healthy. But they actually have decreased luteinizing hormone (LH) pulsatility as opposed to elevated LH seen in PCOS. It remains unknown if this form of premature ovarian insufficiency is actually a risk factor for future CV health in these young, 26-year-old women.”

Estrogen levels are typically very low in FHA; women will often have estradiol levels that are only usually seen during menopause, Shufelt said. However, LH and follicle-stimulating hormone levels are also very low, distinguishing FHA from forms of early or premature menopause.

“This is a reversible form, which is good news, unlike premature ovarian insufficiency,” Shufelt said.

‘Silent pandemic’ of stress

FHA is responsible for approximately 30% to 35% of cases of secondary amenorrhea, equivalent to the prevalence of lupus, Shufelt said. Stress is likely playing a role in the prevalence of FHA, Shufelt said.

Questionnaire data from the American Psychological Association in 2023 show nearly one in three people aged 18 to 34 years reported their mental health is worse today than last year. Additionally, almost 80% of young adults reported changing their behavior in the past month as a result of stress.

“We are in a silent pandemic of stress,” Shufelt said.

In surveys, women consistently experienced higher levels of stress compared with men. In the 2023 American Psychological Association report, women were more likely than men to report stress levels of eight out of 10 or higher, Shufelt said. Social media only compounds stress levels, Shufelt said, with worldwide events such as natural disasters, wars and pandemics instantly accessible.

“We also know social media platforms negatively induce self and social perception in the younger generations,” Shufelt said. “There is now a new psychiatric term: doomscrolling. This is a term that relates to the habit of obsessively scrolling through your social media to search negative information. This underscores this very problematic behavior that goes back to the role of stress.”

Impact beyond the menstrual cycle

FHA is a complex endocrinopathy occurring at the hypothalamic level in which ultimately low estrogen levels and high cortisol levels “shut off” the hypothalamic-pituitary-ovarian axis and upregulate the hypothalamic-pituitary-adrenal axis, creating an inflammatory state.

“Unlike natural menopause, premature menopause or early menopause where it is just impacting ovarian production of estrogen, [FHA] is upregulating other areas, including dysfunction at the thyroid level and even dysfunction at the leptin level and the relationship with insulin,” Shufelt said.

This inflammatory state is associated with outcomes including cognitive impairment, depression, anxiety and decreased vasodilation, as well as infertility, hypoestrogenism and low bone mineral density that increase fracture risk.

Endothelial dysfunction seen in women with FHA, a subclinical marker for CVD, is often “the first domino in the cascade” that leads to obstructive coronary disease, Shufelt said.

Management of FHA

Given FHA’s multifactorial etiology, management involves accurately identifying and reversing the underlying causes, Shufelt said.

Research shows cognitive behavioral therapy aimed at identifying unhealthy eating patterns and maladaptive attitudes to improve stress coping mechanisms restored ovulatory and neuroendocrine function after 20 weeks for most women. The Endocrine Society does not recommend the use of oral contraceptives for the sole purpose of restoring the menstrual cycle. Shufelt said estrogen patches combined with oral progesterone can be used for women who do not gain their menstrual cycles after a reasonable trial of psychological, nutritional and modified exercise interventions. However, estrogen is not associated with an improvement in vascular health.

Shufelt said more research is needed to identify specific phenotypes of FHA and treatment targets for CVD prevention.

“Endothelial dysfunction is a signal we have seen in FHA and it is not attributed to just estrogen alone,” Shufelt said. “So, are these women with high cortisol levels at future risk for CVD? We need to work to understand more. Is it over-exercise, it is disordered eating? Or is it stress?”