During menopause, a decline in estrogen accelerates bone loss and raises osteoporosis risk. Estrogen replacement therapy (ERT) can help prevent this, but only if estradiol levels reach a certain minimum threshold. While the ERT doses needed for bone protection are known for women on average, the actual estradiol level a woman gets from a given dose cannot be known unless it’s verified through hormone testing for that individual. Recent research shows that estradiol levels achieved by ERT vary widely between different transdermal forms of ERT as well as between women in how the body absorbs it. Because of this variability, average group data may not be reliable for making clinical decisions about which dose will optimize treatment outcomes (including bone protection) for a given woman. Instead, individual-level hormone testing to check each woman’s response to ERT would ensure that her estradiol levels are adequate not only for vasomotor symptom relief but also for osteoporosis prevention.  

Estrogen’s role in women’s bone health

Over a woman’s life span, bone health follows a natural trajectory where bones reach peak density in early adulthood and then plateau for several decades. Estrogen is a crucial player in the normal bone turnover cycle — promoting bone formation and inhibiting bone breakdown — ultimately helping to maintain healthy bone mineral density (BMD). However, around the time of menopause, a significant drop in estrogen precipitates a decline in BMD, increasing the risk of osteoporosis, a progressive condition where bones become structurally weak and more prone to fractures. The good news is that women can still proactively support their bone health during and after the menopausal transition through adequate nutrient intake, weight-bearing exercise, and hormone optimization. When appropriate, estrogen replacement therapy (ERT) can be a useful tool to maintain estrogen’s effects on BMD during this time. ERT is FDA-approved for the prevention of bone loss and fractures from osteoporosis in postmenopausal women. 

How much estrogen is needed for bone protection?

The doses used for ERT are typically based on management of menopausal symptoms, especially vasomotor symptoms (e.g., hot flashes). When a woman experiences relief of these symptoms with ERT, it’s often presumed that the ERT dose being used is effectively providing her with enough estrogen needed to experience all benefits of ERT. But what about the benefit of bone protection? The ERT dose adequate to resolve vasomotor symptoms may not necessarily be high enough to protect bone. Relying on subjective improvement of vasomotor symptoms to determine dosing for bone protection could be misleading because of the substantial placebo effect associated with ERT.¹ In order for ERT to be effective for bone preservation, the dose needs to achieve certain minimum threshold levels of estradiol and anything below those levels might be insufficient to fully prevent bone loss.^2–4  For blood (serum) testing, estradiol levels of at least 20-60pg/mL may be needed; for dried urine testing, this correlates with an approximate value of 0.7-2.4ng/mg.⁵  Even though the specific ERT doses effective for increasing BMD have been identified for women on average,⁶ what is not known is the actual estradiol level delivered by any given dose in an individual patient, unless it’s verified through hormone testing for that patient. 

New research continues to emerge supporting the value of individual-level testing of estradiol levels for women on ERT. For example, a recent peer-reviewed study by Precision Analytical, published in Menopause in 2023, revealed that some women on ERT will have lower levels of estradiol than other women, depending on the form that they’re using.⁵ The study compared estradiol levels achieved by different commonly used transdermal forms of ERT (FDA-approved gels and patches versus compounded estrogen therapy) within a large sample of postmenopausal women. The researchers measured urinary estradiol with the dried urinary sampling method used in DUTCH Tests (where four urine samples are collected within a 24-hour period), providing a reliable estimate of the average hormone exposure over 24 hours. The results showed that compounded estrogen creams effectively delivered estradiol to the circulation, proportional to the dose used. However, FDA-approved gels and patches provided significantly higher estradiol levels with similar doses, suggesting that gels and patches might be more easily absorbed. Essentially, women using compounded creams had significantly lower estrogen exposure than women using FDA-approved gels and patches. This doesn’t necessarily mean that creams shouldn’t be used; it does, however, underscore the importance of testing estradiol levels in women using compounded creams (especially low-mid doses) and adjusting the dose accordingly to meet known bone-protective thresholds.

Newman et al (2023), Menopause

Reinforcing this point are independent findings from a 2025 Menopause study led by Sarah Glynne (The Portland Hospital, London), showing that a surprisingly large number of perimenopausal and postmenopausal women had low estradiol levels despite ERT use (in a sample of 1,508 women total).⁷ In fact, one in four women (25%) using the highest licensed dose of transdermal ERT (a 100mcg patch twice weekly or 4 pumps gel daily) had low, subtherapeutic estradiol levels, as did around 1 in 6 women using high off-label doses. These findings suggest that the prevalence of women who are “poor absorbers” of transdermal ERT is higher than previously thought. The results from these studies echo those of smaller pharmacokinetic studies demonstrating significant variability in absorption patterns between women. They reported up to 10-fold differences in estradiol levels between women using the same dose of estradiol patch or gel.^4,8

Collectively, these studies show that the amount of estrogen exposure from ERT varies not only from one form of transdermal ERT to another but also between women using the same form and dose of transdermal ERT. Because estradiol levels with transdermal ERT can vary so much from one woman to the next, relying on data from average group-level responses to ERT could be misleading when making clinical decisions about which dose will optimize treatment outcomes (including bone protection) for a given woman. Instead, paying attention to individual-level responses to ERT for each woman would ensure that the estradiol levels achieved with ERT are adequate for osteoporosis prevention.  

Hormone testing allows optimization of estrogen therapy for bone protection 

The wide variability in estradiol levels with ERT makes a compelling case for implementing regular hormone testing to verify that the patient is on the right dose for her — a dose that actually provides enough estrogen to protect her bones, not just relieve hot flashes. Although hormone testing is not currently part of the standard of care for women on ERT, tailoring ERT according to each woman’s individual treatment goals is.^9,10 In line with this, hormone testing allows healthcare providers to tailor ERT to the woman’s treatment goals, especially if one of the treatment goals is osteoporosis prevention. 

One reason why routine hormone testing during ERT may not be recommended at this time is because of the limitations of the testing medium typically used for measuring estradiol (serum testing). When serum testing of estradiol is done at a single time point, as it almost always is in clinical settings, it fails to accurately represent estradiol’s fluctuating, up-and-down pharmacokinetic pattern observed when ERT is applied on the skin.⁸ While serum might be a suitable method to monitor estradiol in women on a steady-state dose such as patches, it could be more challenging for transdermal applications with periodic applications such as gels and creams. Measuring estradiol in dried urine, especially with validated 4-spot collection within a 24-hour period,⁵ may help to average out the daily fluctuation patterns seen in serum after the application of ERT creams and gels. 

To truly safeguard bone health in menopausal women on transdermal ERT, hormone testing should be embraced as a critical tool to move beyond guesswork and ensure that each woman receives the ERT dose she genuinely needs for protection against bone loss and prevention of osteoporosis.

References

1. Zhou T. Estimation of placebo effect in randomized placebo-controlled trials for moderate or severe vasomotor symptoms: a meta-analysis. Menopause. 2023;30(1):5-10. doi:10.1097/GME.0000000000002094

2. Reginster JY, Sarlet N, Deroisy R, Albert A, Gaspard U, Franchimont P. Minimal levels of serum estradiol prevent postmenopausal bone loss. Calcif Tissue Int. 1992;51(5):340-343. doi:10.1007/BF00316876

3. de Lignieres B. Hormone replacement therapy: clinical benefits and side-effects. Maturitas. 1996;23 Suppl:S31-36. doi:10.1016/s0378-5122(96)90012-2

4. Armston A, Wood P. Hormone replacement therapy (oestradiol-only preparations): can the laboratory recommend a concentration of plasma oestradiol to protect against osteoporosis? Ann Clin Biochem. 2002;39(Pt 3):184-193. doi:10.1258/0004563021902107

5. Newman MS, Saltiel D, Smeaton J, Stanczyk FZ. Comparative estrogen exposure from compounded transdermal estradiol creams and Food and Drug Administration-approved transdermal estradiol gels and patches. Menopause. Published online October 18, 2023. doi:10.1097/GME.0000000000002266

6. Weiss SR, Ellman H, Dolker M. A randomized controlled trial of four doses of transdermal estradiol for preventing postmenopausal bone loss. Transdermal Estradiol Investigator Group. Obstet Gynecol. 1999;94(3):330-336. doi:10.1016/s0029-7844(99)00313-0

7. Glynne S, Reisel D, Kamal A, et al. The range and variation in serum estradiol concentration in perimenopausal and postmenopausal women treated with transdermal estradiol in a real-world setting: a cross-sectional study. Menopause. 2025;32(2):103-111. doi:10.1097/GME.0000000000002459

8. Järvinen A, Bäckström A, Elfström C, Viitanen A. Comparative absorption and variability in absorption of estradiol from a transdermal gel and a novel matrix-type transdermal patch. Maturitas. 2001;38(2):189-196. doi:10.1016/s0378-5122(00)00222-x

9. Stuenkel CA, Davis SR, Gompel A, et al. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(11):3975-4011. doi:10.1210/jc.2015-2236

10. “The 2022 Hormone Therapy Position  Statement of The North American Menopause Society” Advisory  Panel. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29(7):767-794. doi:10.1097/GME.0000000000002028