Hormone Biomarkers: Estradiol, Postmenopausal

Optimal Takeaways

Circulating estradiol levels decrease substantially following menopause, resulting in a loss of its beneficial effects on physiology and metabolism, including its protective effects on the cardiovascular system, bone health, and vasomotor stability. Decreased estradiol may be associated with impaired cognitive function as well.

However, elevated estradiol may increase the risk of breast cancer and other gynecological cancers, especially in high-risk individuals.

Standard Range (Quest Diagnostics): < or = 31 pg/mL (114 pmol/L)

Low estradiol levels in menopause are associated with hot flashes, dysuria, dyspareunia, vaginal dryness, and increased risk of atherosclerosis, hyperlipidemia, cardiovascular disease, and osteoporosis (Hariri 2023).

High levels of estradiol in menopause may be associated with increased breast cancer risk (Ketha 2015, Zhang 2013), endometrial cancer, ovarian cancer, CVD events, coronary artery disease, and venous thromboembolism (Hariri 2023).

Overview

Ovarian estradiol production decreases in the peri- and postmenopausal period as it is no longer needed to regulate the menstrual cycle. However, it can still be produced to some extent in peripheral sites, including the brain, bone, vascular endothelium, and adipose tissue. However, the overall reduction in estrogen during menopause contributes to classic symptoms, especially hot flashes. Women also lose the benefit of estradiol’s protective effects on the bones and cardiovascular system in the postmenopausal period. Research also suggests that estradiol may reduce the effects of stress by promoting an increase in corticosteroid-binding globulin and decreasing free cortisol in circulation (Hariri 2023).

Serum estradiol drops below 54.48 pg/mL (200 pmol/L) as menstruation ceases and can be typically maintained at 2.7-7.4 pg/mL (9.8-27.1 pmol/L) in the postmenopausal period (Honour 2018). Research using the liquid chromatography tandem mass spectrometry (LC-MS/MS) method confirmed a reference interval of below 7.08 pg/mL (26 pmol/L) in menopause (Verdonk 2019).

Some research suggests that estradiol influences cognitive function, and decreased levels may be associated with mild cognitive impairment. In one cross-sectional study of 209 healthy postmenopausal women, a lower Montreal Cognitive Assessment score of 26 or less was associated with a mean estradiol level of 14.92 pg/mL (54.8 pmol/L) versus 21.67 pg/mL (79.6 pmol/L) in those with a score above 26. The upper value for estradiol in the higher cognition group was 36.59 pg/mL (134.32 pmol/L) (Gholizadeh 2018).

A cross-sectional evaluation of hormone replacement therapy (HRT) in 344 postmenopausal women revealed that serum estradiol of 60.1-65.8 pg/mL (220.63-241.55 pmol/L) can be achieved with 1 mg/day of estradiol and a level of 107.6 pg/mL (395.00 pmol/L) can be achieved with 2 mg/day. Results were consistent with past research, achieving a serum estradiol of 30-50 pg/mL (110-184 pmol/L) with 1 mg/day and 60-110 pg/mL (220-404 pmol/L) with 2 mg/day. Researchers note that an estradiol level of at least 60 pg/mL (220 pmol/L) was needed to decrease osteoporosis risk and reduce 50% of hot flashes (Kim 2021).

However, higher estradiol levels may be associated with increased breast cancer risk. A nested case-control study of postmenopausal women from the Nurses’ Health Study found that higher estradiol levels were associated with hormone receptor-positive breast cancer risk during a 20-year follow-up, especially in those with a history of benign breast disease or a family history of breast cancer. Women with serum estradiol above 9 pg/mL (33.04 pmol/L) had a significantly greater risk of breast cancer than those with the lowest estradiol levels of 4 pg/mL (14.68 pmol/L) or below. The study used both immunoassay and LC-MS for estradiol measurement, and the study subjects were not on hormone replacement therapy (Zhang 2013).

FDA warnings regarding postmenopausal HRT include (Hariri 2023):

• Women who take estrogen plus progestin therapy are at increased risk for breast cancer.
• Women with increased exposure to estrogen are at risk for endometrial cancer. Estrogen stimulates endometrial growth, which results in endometrial hyperplasia, which could result in endometrial cancer.
• Other risk factors associated with increased exposure to estrogen HRT are cerebrovascular events, coronary artery disease, and venous thromboembolism. There have also been reports of ovarian cancer with estrogen use. 

References

Gholizadeh, Soheila et al. “The association between estradiol levels and cognitive function in postmenopausal women.” International journal of reproductive biomedicine vol. 16,7 (2018): 455-458.

Hariri, Lana. and Anis Rehman. “Estradiol.” StatPearls, StatPearls Publishing, 28 June 2023. This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) (http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Honour, John W. “Biochemistry of the menopause.” Annals of clinical biochemistry vol. 55,1 (2018): 18-33. doi:10.1177/0004563217739930

Ketha, Hemamalini et al. “Estradiol assays--The path ahead.” Steroids vol. 99,Pt A (2015): 39-44. doi:10.1016/j.steroids.2014.08.009

Kim, Soo-Min et al. “Serum estradiol level according to dose and formulation of oral estrogens in postmenopausal women.” Scientific reports vol. 11,1 3585. 11 Feb. 2021, doi:10.1038/s41598-021-81201-y

Verdonk, Sara J E et al. “Estradiol reference intervals in women during the menstrual cycle, postmenopausal women and men using an LC-MS/MS method.” Clinica chimica acta; international journal of clinical chemistry vol. 495 (2019): 198-204. doi:10.1016/j.cca.2019.04.062

Zhang, Xuehong et al. “Postmenopausal plasma sex hormone levels and breast cancer risk over 20 years of follow-up.” Breast cancer research and treatment vol. 137,3 (2013): 883-92. doi:10.1007/s10549-012-2391-z