Premature menopause and early menopause, whether spontaneous or induced, are associated with long-term health risks which may include premature death, cardiovascular disease, neurologic disease, osteoporosis, psychosexual dysfunction, and mood disorders. Estrogen mitigates some but not all of these consequences.
The most common interpretation of these findings is that premature or early menopause is the first step in a chain of causality leading to tissue or organ dysfunctions and lesions via hormonal mechanisms [2
]. However, before discussing this interpretation more extensively, we also mention the alternative hypothesis that premature or early menopause is the result of an accelerated aging process determined by genetic or non-genetic causes and involving all tissues and organs throughout the body, including the ovaries [46
]. Under this hypothesis, the hormonal changes following premature or early menopause have no causal role in the development of premature death, cardiovascular disease, neurologic disease, osteoporosis, psychosexual dysfunction, and mood disorders. The evidence in support of this hypothesis is limited.
Whether different types of premature menopause or early menopause result in different long-term health consequences remains unknown. Their hormonal milieus differ because the postmenopausal ovary is hormonally active, producing small amounts of estradiol and estrone, as well as androgens including testosterone, androstenedione, and dehydroepiandrosterone [47
]. Following bilateral oophorectomy in premenopausal women, estradiol levels drop, testosterone levels drop by 40–50%, and follicle-stimulating hormone levels rise abruptly. Women undergoing bilateral oophorectomy continue to have lower levels of androgens than naturally menopausal women even beyond 65 years of age [48
With POF, follicle-stimulating hormone levels are elevated and estradiol levels are low, but sporadic increases in estradiol may occur [49
]. Ovarian androgens remain age-appropriate in these women [50
]. Ovarian failure caused by cancer therapy, when permanent, is associated with elevated follicle-stimulating hormone levels and reduced estradiol levels similar to natural menopause; androgen function has not been well-characterized. Overall, different consequences from the different types of menopause may relate to the extent of disruption of the hypothalamic-pituitary-ovarian axis as much as to the reduced levels of circulating sex steroid hormones [2
Concern about the risks of hormone therapy following publication of results from the Women’s Health Initiative clinical trials may be inappropriate if applied to women with premature menopause or early menopause who typically need estrogen in adequate replacement doses for a duration of time long enough to reduce the consequences of prolonged estrogen deficiency. It is important that clinicians not withhold health-promoting estrogen replacement for these women.
Professional organizations including the North American Menopause Society, the British Menopause Society, and the International Menopause Society recommend estrogen replacement therapy for women with premature menopause or premature ovarian failure [51
]. There is some evidence, although not from randomized controlled clinical trials, that restoring pathologically low estrogen levels will reduce the later development of cardiovascular disease, osteoporosis, and possibly dementia. This leads to the general recommendation that estrogen be continued in women who experience premature menopause or early menopause until at least around the median age of natural menopause (approximately age 51 years).
The health benefits of prophylactic bilateral oophorectomy for reducing the risk of breast, ovarian, and fallopian tube cancers in women known to be at increased risk, such as BRCA1
mutation carriers, is well-established [54
]. However, for those women not known to be at increased risk of cancer, early spontaneous menopause or early induced menopause may result in more risks than benefits, and should be accompanied by estrogen replacement. Even in women with BRCA1
mutations who undergo risk-reducing prophylactic bilateral oophorectomy before age 45 years, short-term estrogen replacement is an option [54
]. The age of onset of estrogen deficiency appears to be an important determinant of long-term health [2