By Jeffrey T. Jensen, MD, MPH

Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland

Dr. Jensen reports he is a consultant for Teva Pharmaceuticals, Microchips, and Evofem; and is a consultant for and receives grant research support from Bayer Healthcare, Merck, Agile Pharm, Population Council, AbbVie, ContraMed, and FHI360; and receives grant/research support from HRA Pharma and Medicines 360.

SYNOPSIS: A population-based study found that premenopausal women with low ovarian reserve, as determined by low levels of anti-Müllerian hormone, have unfavorable cardiovascular disease profiles.

SOURCE: de Kat AC, Verschuren WMM, Eijkemans MJC, et al. The association of low ovarian reserve with cardiovascular disease risk: A cross-sectional population-based study. Hum Reprod 2016;31:1866-1874.

The available literature suggests that early initiation of hormone replacement therapy (HRT) may reduce cardiovascular disease (CVD).1 Since age is also a risk factor for CVD, the critical window for early intervention is a hot topic. The Doetinchem Cohort Study is a population-based cohort study from the Netherlands established to study risk factors for chronic disease. Participants answered questions about lifestyle determinants, reproductive characteristics, and general health, and also underwent biometric and laboratory assessments. To determine whether anti-Müllerian hormone (AMH) levels were associated with other risk factors for CVD, the authors evaluated premenopausal women (one or more menstruations in the past year) who participated in the cohort between 1993 to 1997 (n = 2,729). Of these, 2,338 had stored serum samples available for analysis. The lower limit of quantification of AMH in the ELISA assay used by the investigators was 0.16 ng/mL. The investigators assessed CVD risk using the metabolic risk score (total number of risk factors present: waist circumference 80 cm, hypertension, HDL cholesterol < 39 mg/mL, total cholesterol > 217 mg/mL, use of lipid-lowering drugs). Baseline characteristics included a number of potential confounders: age, current oral contraceptive use, current smoking, body mass index, parity, cycle regularity, socioeconomic status, estrogen use (at the time of follow-up), and pregnancy (at the time of follow-up). The presence of polycystic ovary syndrome was considered a potential effect modifier and defined as a self-report of irregular cycles in combination with an AMH > 4.7 ng/mL.

The age range of the study population was 20-57 years. Overall, the relationship between AMH levels and CVD risk factors was nonlinear. Women with AMH levels at or below the limit of quantification (0.16 ng/mL) had more metabolic risk factors (relative risk, 0.11; 95% confidence interval, 0.01-0.21) than women with AMH 0.16 ng/mL. Individual CVD risk factor levels were not associated with low AMH levels.

COMMENTARY

Is a high-risk cardiovascular profile determined during perimenopause? Evidence is accumulating that the key failure of the Women’s Health Initiative study was the recruitment of an asymptomatic and older (approximately 10 years postmenopausal) cohort of women with baseline CVD. Early initiation of HRT may prevent the development of atherosclerotic plaque while later administration may exacerbate risk by introducing a prothrombotic effect in women with existing plaque. Evidence in support of this conclusion include the Estrogen in Prevention of Atherosclerosis Trial (EPAT), which showed a reduction of atherosclerosis progression in postmenopausal women without coronary heart disease who were treated with oral estradiol, and the Women’s Estrogen Lipid-Lowering Hormone Atherosclerosis Regression Trial (WELL-HART), which found no benefit of estrogen therapy in women with existing coronary lesions.2 The Early versus Late Intervention Trial with Estradiol (ELITE) study found that initiation of oral estradiol and vaginal micronized progesterone within six years of onset of menopause reduced the progression of atherosclerosis, an effect not seen when therapy was initiated after 10 years.3

Moving this discussion forward to women in the perimenopause is hazardous. First, the perimenopause is difficult to rigorously define. Ovarian reserve and estrogen levels may not correlate. Henry et al followed markers of ovarian function in premenopausal women before and following chemotherapy.4 Although AMH declined from 1.95 to 0.23 ng/mL and follicle-stimulating hormone (FSH) increased (7.6 to 32.6 mIU/mL) one year post-chemotherapy, estradiol levels remained stable (baseline 79.1 to 92.5 pg/mL post-treatment). With the court of public opinion still profiling hormonal therapy as risky, expanding the discussion of early initiation of HRT into the premenopausal years will require a convincing argument.

Although the Doetinchem Cohort Study demonstrates a modest increase in the metabolic risk score for perimenopausal women with very low AMH levels, the results should be evaluated with caution. First, the overall magnitude of the effect is small, about one-tenth of a risk factor point measured on a five-point scale. Although the authors stated that the effect size was larger in the youngest women with low AMH, this was not statistically significant and the data are not shown. Also, no single CVD risk factor was associated with low AMH levels, suggesting weaknesses in the methodology to elucidate a causal pathway using this outcome. Whether these small differences in the metabolic risk score affect long-term health have not been validated.

On a positive note, the results do follow on other studies that have identified unfavorable lipid profiles in premenopausal women with low AMH levels5 or elevated FSH and low antral follicle counts.6

While we wait for the science to settle, these preliminary results provide an opportunity to consider estrogen effects across a woman’s life. Estrogens exert a favorable effect on vascular endothelium, which reduces the risk of atherosclerotic plaque formation.7 As estrogen levels decline, this protection diminishes, and plaque accumulates, particularly in women with unfavorable lipid profiles and other cardiovascular risk factors. Consider also that the ovarian follicle represents a net lipid-consuming organ. During a natural cycle, steroid hormone production contributes to a net drop in circulating lipid levels; about a 5% decline occurs in the luteal phase during the massive synthesis of progesterone.8 All of this changes as cycles become irregular and then stop. So the effect on lipids is complicated, and represents ovarian and extra-ovarian metabolism, and direct hormonal effects.

The current data do not support a recommendation to treat perimenopausal women with hormonal therapy. Demonstrating that premenopausal initiation of HRT reduces CVD will require a large, prospective clinical trial, so don’t hold your breath awaiting the results. However, many women who present with symptoms of hot flashes or estrogen withdrawal headache benefit from estrogen therapy. Given that studies of early menopausal treatment women with HRT demonstrate benefit, extending treatment to symptomatic perimenopausal women may provide a secondary cardiovascular health benefit as well.

REFERENCES

  1. Harman SM, Vittinghoff E, Brinton EA, et al. Timing and duration of menopausal hormone treatment may affect cardiovascular outcomes. Am J Med 2011;124:199-205.
  2. Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135:939-953.
  3. Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med 2016;374:1221-1231.
  4. Henry NL, Xia R, Schott AF, et al. Prediction of postchemotherapy ovarian function using markers of ovarian reserve. Oncologist 2014;19:68-74.
  5. Tehrani FR, Erfani H, Cheraghi L, et al. Lipid profiles and ovarian reserve status: A longitudinal study. Hum Reprod 2014;29:2522-2529.
  6. Verit FF, Keskin S, Omer B, et al. Is there any relationship between cardiovascular risk markers and young women with diminished ovarian reserve? Gynecol Endocrinol 2014;30:697-700.
  7. Miller VM, Clarkson TB, Harman SM, et al. Women, hormones, and clinical trials: A beginning, not an end. J Appl Physiol 2005;99:381-383.
  8. Barnett JB, Woods MN, Lamon-Fava S, et al. Plasma lipid and lipoprotein levels during the follicular and luteal phases of the menstrual cycle. J Clin Endocrinol Metab 2004;89:776-782.