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In September 2019, The North American Menopause Society (NAMS) organized a Workshop on Normal Ranges for Estradiol in Postmenopausal Women. The workshop aimed to review existing analytical methodologies for measuring estradiol in postmenopausal women and establish normal postmenopausal ranges.

The use of established ranges of normal estradiol and estrone levels could be a valuable instrument to harmonize data on the associations of exogenous and endogenous estrogens with important health risks such as endometrial and breast cancers, cognitive decline, bone fracture.

First, it was established that liquid chromatography with tandem mass spectrometry assays is the state-of-the-art technology for the determination of postmenopausal estradiol and estrone levels. Second, a consensus was reached to use the term reference range instead of normal range as some normal persons may fall out of this range, such that being outside the reference range does not automatically indicate pathology.

Based on large databases of healthy postmenopausal women, which used gas chromatography/tandem mass spectrometry estradiol assay, it was established that a postmenopausal reference range for estradiol is that from below the limit of detection up to 10 pg/ mL. This range considers the effect of age and BMI and a minimal effect of ethnicity, smoking, and duration of menopause on estradiol levels. An important point of discussion was the physiological importance of estrone in postmenopausal women, and that blood estrone concentrations in postmenopausal women do not differ greatly than concentrations in premenopausal; women.

One of the goals of this workshop was to provide evidence-based education for women, providers, and insurers about the safety of vaginal estrogen, the most effective treatment for the invalidating genitourinary syndrome. Low-dose vaginal hormone options that have shown minimal detectable systemic absorption and are FDA approved include vaginal 10-µg estradiol tablet, estradiol 7.5-mg ring, 4 and 10 mg vaginal soft gel inserts, vaginal conjugated estrogen or estradiol creams dosed at 0.5 g, and the intravaginal dehydroepiandrosterone 6.5 mg/d suppositories. Low-dose vaginal hormones that do not determine circulating estradiol levels above the upper limit of the reference range will unlikely cause breast cancer, coronary artery disease, stroke, deep venous thrombosis, pulmonary embolism, and probable dementia, all risks listed in the package insert boxed warning.

In this respect, NAMS and the Working Group on Women’s Health and Well-Being in Menopause wanted to address the need for more appropriate and evidence-based labelling of low-dose vaginal hormone therapies.

  1. Santen RJ, Pinkerton JV, Liu JH, et al. Workshop on normal reference ranges for estradiol in postmenopausal women, September 2019, Chicago, Illinois. Menopause. 2020;27(6):614‐624.
    https://pubmed.ncbi.nlm.nih.gov/32379215/
  2. Workshop on Normal Reference Ranges for Estradiol in Postmenopausal Women: Commentary From The North American Menopause Society on Low-Dose Vaginal Estrogen Therapy Labeling
    https://pubmed.ncbi.nlm.nih.gov/32459749/
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