Adverse Impact of Early-Onset Menopause or Symptom Severity

The average age of menopause in the United States is 51 years.

Premature menopause describes a woman who enters menopause under age 40.

Early-onset menopause is typically diagnosed when women enter menopause at age 40-45 years.

Late-onset menopause occurs when women enter menopause after 55 years of age.

A menopausal woman is no longer ovulating, her sex hormone levels have plummeted, and she may struggle for years with menopausal miseries such as sleep deprivation, memory loss, and unwanted weight gain.

Over the decades, we've published many articles about how maturing women can offset the miseries and health risks inflicted by menopause.

We were among the first to identify the potential cancer and cardiovascular risks posed by some types of oral synthetic progestogens (also called progestins) that were often combined with various forms of conjugated equine estrogen (i.e., estrogen derived from horses).

A potentially better option for most women and their treating physicians contemplating hormone replacement therapy is the use of transdermal bioidentical estrogen and oral micronized progesterone that are available at most pharmacies today.

Dangers of Severe Menopause Symptoms

In a huge observational cohort of around 80,000 postmenopausal women from the famous Women's Health Initiative study, the severity of menopausal symptoms correlated with increased risk of cardiovascular disease and shorter lifespans.¹

The women in this study had no known cardiovascular disease at baseline.

The severity and medical outcomes were assessed during a median of 8.2 years of follow-up.

Greater cardiovascular disease risk was observed with increased severity of the following menopausal symptoms:

• night sweats,
• waking up several times at night,
• joint pain or stiffness,
• heart racing or skipping beats,
• dizziness,
• feeling tired,
• forgetfulness,
• mood swings,
• being restless or fidgety, and
• difficulty concentrating

Each of the above menopausal miseries was significantly associated with cardiovascular disease events.

The largest risk was for "moderate or severe heart racing or skipping beats." This menopausal symptom increased cardiovascular events by 55%.

Increased all-cause mortality was associated with individual severities of:

• heart racing or skipping beats,
• dizziness,
• tremors,
• feeling tired,
• forgetfulness,
• mood swings,
• being restless or fidgety, and
• difficulty concentrating.

These data sets garnered some publicity in 2023, but little has been done to improve standard of care as it relates to use of more preventative cardiovascular interventions in women with a history of severe menopausal symptoms.

Alleviating severe symptoms with the hormones (estrogen, progesterone, others) lost to menopause might reduce the adverse health outcomes.

Dangers of Early Menopause

Data from 12 independent studies were extracted to assess if the length of reproductive life span is associated with future risk of cardiovascular disease.²

Reproductive lifespan can be defined as the years between the age of first menstrual bleeding (menarche) to the onset of menopause (or perimenopause in some cases).

This pooled analysis consisted of over 307,000 participants and found that women with short reproductive lifespan (under 30 years) were at a 71% higher risk of heart attack, stroke, or nonfatal coronary event compared to those with longer reproductive lifespans of 36-38 years.

Said differently, a female who enters menarche at age 10 and menopause at age 40 has a short reproductive lifespan (30 years) and in this study, greater cardiovascular disease hazards.

Younger age at menarche remained a significant uncontrolled factor, but delayed menopause was found to reduce cardiovascular risks.

Health consequences of Premature Menopause

A data review from the Mayo Clinic Cohort Study of Oophorectomy and Aging study further identified the adverse impact of premature menopause, be it naturally occurring or caused by a medical procedure.³

The researchers found that women who experience premature menopause (before age 40 years) or early- onset menopause (between ages 40 and 45 years) experience increased risks of:

• overall mortality,
• cardiovascular diseases,
• psychiatric disorders,
• osteoporosis, and
• other health issues.

The researchers found the risk of adverse health outcomes increases with earlier age of menopause onset.

These researchers noted that some of the adverse outcomes may be prevented by estrogen treatment initiated after the onset of menopause. They cautioned that estrogen alone does not prevent all long-term consequences and other hormonal mechanisms are likely involved.

The authors of this study concluded:³

"… women who experience hormonal menopause and estrogen deficiency before reaching the median age of natural menopause are at increased risk for morbidity and mortality."

Early Menopause Associated with Type II Diabetes and Reduced Life Expectancy

Researchers conducted a population-based prospective cohort study of 3,650 postmenopausal women over age 45 years to compare the association of age of natural menopause onset with total life expectancy and the number of years alive with and without type II diabetes.⁴

The study found that women with early-onset menopause (defined as under 44 years old) have a shorter overall life expectancy and are at increased risk of developing type II diabetes earlier in life.

Compared with late-onset menopause (defined as ≥55 years old), early-onset menopause was associated with a 42% increased risk of death in women without diabetes.

Women with type II diabetes and early-onset menopause were at a 64% associated increased risk of death compared with those with late-onset menopause. This high mortality rate was not found in women who undergo menopause at typical ages.

These researchers found that total life expectancy at age 50 years was shorter in women who had early menopause and significantly longer in those with late menopause.

Early Menopause = Heart Attack and Early Death

A study conducted in The Netherlands found that women who enter menopause before age 45 are more likely to have cardiovascular problems and to die younger than women who enter menopause later in life.⁵

Comparing women who had their last period before age 45 to those who entered menopause at age 45 or older, women with earlier menopause had a 50% higher risk of coronary heart disease.

Women who entered menopause before age 45 were about 20% more likely to die from cardiovascular disease (including heart attack and stroke) than women with later-onset menopause.

Women who entered menopause early were also 12% more likely to die of any cause.

These European findings corroborate other studies described in this article showing that age at menopause may help predict women's risk for future health issues. In an interview, the lead researcher stated:⁶

"Our results indicate that menopause might be a critical period to evaluate women's risk for future cardiovascular events and that it may be an appropriate time to introduce interventions to reduce the risk…women who enter menopause early may want to work on controlling their blood pressure, cholesterol, blood sugar and other factors affecting their heart health."

Estrogen-Progesterone Replacement Options

The data conveyed in this editorial should alter medical practice in ways that encourage recognition of early-menopause onset or severe menopausal symptoms as indicators of increased disease risk.

Compared to prior decades when synthetic progestogens and conjugated equine estrogens in oral form were widely used, women have many options including transdermal application of bioidentical estrogen and progesterone drugs prescribed by a physician.

Fenugreek is a plant-derived estrogen that boosted estradiol blood levels and reduced menopausal symptoms in a placebo-controlled clinical trial.

References

1. Nudy M, Aragaki AK, Jiang X, et al. The severity of individual menopausal symptoms, cardiovascular disease, and all-cause mortality in the Women's Health Initiative Observational Cohort. Menopause. 2022 Dec 1;29(12):1365-74.
2. Mishra SR, Chung HF, Waller M, et al. Association Between Reproductive Life Span and Incident Nonfatal Cardiovascular Disease: A Pooled Analysis of Individual Patient Data From 12 Studies. JAMA Cardiol. 2020 Dec 1;5(12):1410-8.
3. Shuster LT, Rhodes DJ, Gostout BS, et al. Premature menopause or early menopause: long-term health consequences. Maturitas. 2010 Feb;65(2):161-6.
4. Asllanaj E, Bano A, Glisic M, et al. Age at natural menopause and life expectancy with and without type 2 diabetes. Menopause. 2019 Apr;26(4):387-94.
5. Muka T, Oliver-Williams C, Kunutsor S, et al. Association of Age at Onset of Menopause and Time Since Onset of Menopause With Cardiovascular Outcomes, Intermediate Vascular Traits, and All- Cause Mortality: A Systematic Review and Meta-analysis. JAMA Cardiol. 2016 Oct 1;1(7):767-76.
6. Available at: https://www.reuters.com/article/idUSKCN11L2K1/. Accessed July 8, 2024.
7. Available at: https://www.nhs.uk/conditions/hysterectomy/consider- ations/. Accessed August 5, 2024.
8. Rocca WA, Gazzuola Rocca L, Smith CY, et al. Loss of Ovarian Hormones and Accelerated Somatic and Mental Aging. Physiology (Bethesda). 2018 Nov 1;33(6):374-83.
9. Faubion SS, Kuhle CL, Shuster LT, Rocca WA. Long-term health consequences of premature or early menopause and considerations for management. Climacteric. 2015;18(4):483-91.
10. Price MA, Alvarado BE, Rosendaal NTA, et al. Early and surgical menopause associated with higher Framingham Risk Scores for cardiovascular disease in the Canadian Longitudinal Study on Aging. Menopause. 2021 Jan 4;28(5):484-90.
11. Bove R, Secor E, Chibnik LB, et al. Age at surgical menopause influ- ences cognitive decline and Alzheimer pathology in older women. Neurology. 2014 Jan 21;82(3):222-9.
12. Kuck MJ, Hogervorst E. Stress, depression, and anxiety: psycho- logical complaints across menopausal stages. Front Psychiatry. 2024;15:1323743.
13. Lephart ED, Naftolin F. Factors Influencing Skin Aging and the Im- portant Role of Estrogens and Selective Estrogen Receptor Modula- tors (SERMs). Clin Cosmet Investig Dermatol. 2022;15:1695-709.