Analysis of 300 million laboratory tests from women in the US and Israel: US data show abrupt changes in 52 of 90 measures at the final menstrual period, with hormonal changes beginning 12 to 15 years earlier
Analysis of 300 million laboratory tests from women in the US and Israel: US data show abrupt changes in 52 of 90 measures at the final menstrual period, with hormonal changes beginning 12 to 15 years earlier
On October 12, Nature Medicine published a study by Uri Alon's group at the Weizmann Institute of Science. The authors used laboratory results from the US National Health and Nutrition Examination Survey (NHANES) and the Israeli health insurer Clalit to mathematically reconstruct how these measures change around the final menstrual period.
Large laboratory databases rarely record the date of the final menstrual period, and the age at menopause varies: half of American women reach it between ages 45 and 53. If a measure changes abruptly at each woman's final menstrual period, but those periods occur at different ages, the curve averaged by age appears as a gradual slope. The US longitudinal study SWAN records the date precisely, but the authors say it has relatively few participants (3302), laboratory tests, and years of observation before the final menstrual period. In that study, menopause appeared to be a gradual transition.
The method draws on an idea from astronomy: a telescope blurs an image, but a known distortion can be corrected mathematically. Here, the blurring comes from variation in the age at menopause, whose distribution is known from surveys. The method removes this blurring to reconstruct an average profile for each measure as though the date were known for every woman.
The abrupt changes range from 0.1 to 1.4 standard deviations, measured against the usual variation among nonpregnant women aged 25 to 45. They are particularly pronounced in measures of sex hormones, bone health, liver function, and blood lipids. Most changes are in a direction associated with greater disease risk, and after the final menstrual period, the proportion of women with osteoporosis, heart attack, and stroke begins to rise faster. Iron and hemoglobin are exceptions: their levels improve, probably because menstrual blood loss has stopped.
Applying the same calculation to men, with a hypothetical “menopause” at age 50, produced no abrupt changes. The Clalit data showed abrupt changes similar in magnitude to those in the US data.
Sex hormone receptors are present in almost all tissues, but the authors estimate that the magnitude of an abrupt change partly reflects the system's sensitivity to estrogen. Free thyroid hormones and folic acid, which have weak associations with estrogen, showed no abrupt change.
On average, anti-Müllerian hormone, which is used to assess ovarian reserve, begins to decline more rapidly 15 years before the final menstrual period. Follicle-stimulating hormone, produced by the pituitary gland, begins to rise 14 years before it, and estradiol, the main estrogen, begins to fall 12 years before it. In SWAN, hormonal changes began approximately seven years before menopause.
If estrogen loss causes the abrupt changes, they should be smaller in women using menopausal hormone therapy (medicines containing estrogen). In the US data, these women differ from comparable women without therapy on 39 of the 80 measures compared. Their abrupt changes are generally smaller, and the larger the change, the greater the difference between the groups.
Martha Hickey, who heads the menopause service at the Royal Women's Hospital in Melbourne, told ABC that the authors' description of a “cliff” was unnecessarily alarming for women:
“A physiological cliff is neither a scientific nor a medical term.”
She said that studies based on previously collected data are of low quality and that healthy women are more likely to use hormone therapy.
Alon told ABC:
“Bone density is currently checked at around age 60. This study would support checking it at around age 40 or 45 and then considering menopausal hormone therapy for prevention.”
He added that all of this should be done with medical advice. The group plans a trial involving women who begin therapy before their periods stop.