Our special thanks to Hans Casteels, Ruth Langley, and Duncan Gilbert for helping write these FAQ’s!
1. Can transdermal estradiol (tE2) ADT reduce testosterone (T)?
Yes. The PATCH/STAMPEDE team reported that more than 80% of men using tE2 for ADT had suppressed their T < 50 ng/dl after 4 weeks, indicating a rapid decline in T.
Note: Additional details will be provided soon.
2. Can tE2 ADT reduce PSA?
Yes. The PATCH/STAMPEDE trial reported that more than 80% of men using tE2 for ADT had their baseline PSA reduced by at least 90% after 12 weeks.
Note: Additional details will be provided soon.
3. Can tE2 ADT provide equivalent cancer control as standard ADT drugs?
Yes. In a head-to-head comparison, the 14-year, Phase-III PATCH/STAMPEDE randomized controlled trial conclusively demonstrated that using tE2 for ADT was non-inferior compared to standard ADT drugs, in terms of a Metastasis-Free Survival (MFS) end point.
Note: These survival results were limited to locally advanced PCa patients who were hormone-sensitive, had no distant metastasis at diagnosis, and who did not use Androgen Receptor Pathway Inhibitor drugs (ARPI’s) or Orgovyx™ (relugolix) pills.
4. Does tE2 ADT have an increased risk of blood clots or other cardiovascular problems compared to standard ADT drugs?
No. The PATCH/STAMPEDE trials found no increased risk of blood clots or other cardiovascular events when tE2 ADT was used, following the PATCH trial protocol, as compared to standard ADT drugs.
Background: From the 1940’s through the early 1980’s, the oral estrogen, diethylstilbestrol (DES), was successfully used to treat PCa by suppressing T to castrate levels. However, because the oral route caused a surge of estrogen in the liver where clotting factors are produced, many DES users experienced increased incidences of thromboembolic events (TEEs). Oral DES was discontinued when Leuprolide (e.g., Lupron™) was adopted for ADT in 1985, because it reduces the risk of TEEs.
5. Are tE2 products FDA approved or a Standard-of-Care for men?
Generally, No.Most tE2 products are not currently FDA approved, nor is their use a Standard-of-Care for men. However, they are FDA approved for postmenopausal women. The tE2 products approved for women can be prescribed off-label for men, with their informed consent. Nevertheless, some injectable forms of E2 (e.g., estradiol valerate) are currently FDA approved for palliative care of men with advanced prostate cancer.
6. How many patches should I prescribe for tE2 ADT?
The PATCH trial protocol initially specified four FEM7 or Progynova patches, each delivering 0.1 mg/24hrs, changed twice weekly. Then, after the T level had dropped below 50 ng/dl, the number of patches was reduced to three (or two) at a time. However, the average serum E2 levels generated by 13 different patch brands having the same nominal strength (0.1 mg E2/24hrs) varies greatly by a factor of 2.6 X.
For this reason, if using a patch brand other than FEM7 or Progynova, we recommend that you start patients on one patch (changed twice weekly) and then monitor monthly the patient’s T for 2-3 months (Note: T normally drops significantly over 1-2 weeks). Then, gradually increase the number of patches until a desired level of suppressed T has been reached (e.g., T < 20 ng/dl).
The general guideline is to use the lowest dose of tE2 that maintains a suppressed level of T.
7. Is tE2 ADT recommended for all patients with prostate cancer?
No. The use of tE2 ADT may be a good alternative to standard ADT in most men, but it may not be suitable for everyone, including:
- Men with a history of thromboembolic events (TEEs).
- Men with localized, low-risk prostate cancer who are candidates for active surveillance. For these men, ADT (with standard agents or tE2) is typically not recommended nor needed.
- Men unable to comply with patch or gel application routines. Consistent application is important for successfully suppressing T.
- Men who have BRCA gene mutations generally have a higher risk of having breast cancer. However, the absolute risk of breast cancer in healthy, BRCA-positive men is relatively low compared to rates for women. Long-term data from the PATCH/STAMPEDE trial has not shown an increase in breast cancers with tE2 ADT. Men considering using tE2 products may want to determine their BRCA 1/2 gene status prior to starting tE2 treatment. (prostatecancerpromise.org).
8. What is the relationship between tE2 dose and a patient’s serum E2 level?
The relationship between tE2 dose and average serum E2 level is approximately linear, for both number and strength of patches, and for both volume or concentration of tE2 gel/cream.
9. What is the best way to determine an optimum dose of tE2 for ADT?
There is an inverse, hyperbolic relationship between T and serum E2 levels. A recommended approach to achieving sub-castrate levels of T (i.e., T < 20 ng/dL) is to start your patient on a lower dose of tE2 and then measure monthly T over 2-3 months. Then, gradually increase the tE2 dose until a castrate level of T is reached—traditionally, T < 50 ng/dL, but preferably T < 20 ng/dL.
The general guideline is to use the lowest dose of tE2 that maintains a suppressed level of T.
10. What was the median serum E2 level observed in the PATCH trials?
The median serum E2 level reported in the PATCH trials was 230 pg/ml (5%-95% Range: 100 – 600 pg/ml).
11. What factors influence serum E2 level?
Your patient’s serum E2 level depends on many variables, which puts dosing into the category of “personalized medicine”. This includes: 1) the brand of patch, 2) how long the patient wears each patch, 3) the location of the patches on their body, 4) if they change the patches once or twice a week, 5) when they take their blood draws, and 6) likely their overall amount of body fat. To accurately track serum E2 levels, patients should have blood draws done at the same number of hours after applying a new E2 patch or gel product, or just before applying a new patch or gel product (i.e., trough value).
12. Is there a specific target serum E2 level that will prevent hot flashes caused by standard ADT drugs?
No. We don’t have enough data to accurately answer this question for men using standard ADT drugs. However, data from postmenopausal women indicates a serum E2 level of about 60 pg/ml may reduce the frequency of hot flashes by about 50%. Also, a higher serum E2 level, such as E2 > 120 pg/ml, may completely eliminate hot flashes in most patients. Your patient’s best strategy is to start by using a low dose of tE2 and then determine if they have had some relief. However, if symptoms persist, then gradually increase their tE2 dose until hot flashes diminish in frequency and/or intensity, or even disappear completely.
13. What are the best locations to apply E2 patches?
In general, the best locations to apply E2 patches are where the fat layer underneath the skin is relatively thin. Applying patches to the upper buttocks or hips typically generates higher serum E2 levels than the abdomen.
14. Are E2 gels or creams as effective as E2 patches for ADT?
Yes. While E2 patches have been the most extensively studied, E2 gels/creams are just as capable of suppressing T. E2 gel/cream products are applied daily, are odorless, and the alcohol-based gel products dry quickly. In a recent survey of n=>800 patients, they preferred daily gels/creams over patches by about 3X. Both patches and gel products are more comfortable than getting depot injections of LHRH drugs. Patches and gels can be discontinued at any time, whereas depot injections can last several months.
15. How much E2 gel or cream should your patient use for tE2 ADT?
There is no recommended amount of E2 gel or cream that your patient should apply for tE2 ADT, because different gel products use different concentrations of E2 (ranging from 0.06% to 0.1% E2, or even greater for compounded products). The goal is to suppress T to castrate levels (ideally to T < 20 ng/dL).
16. What is the best location to apply E2 gels or creams?
The best locations of rapid uptake of E2 are body surfaces with the least amount of underlying fat, such as the thumb side of the forearm, the jawline, or the scrotum (which has no underlying fat). These surfaces, however, are not commonly recommended for the various tE2 products on the market, which strive to reach a more prolonged and stable serum E2 concentration
17. For E2 gels or creams, should the material be spread out over as large an area as possible?
No. A study of postmenopausal women showed that E2 gels (and, presumably, creams) should be applied to as small an area as possible if the goal is to maximize E2 absorption efficiency.
18. How should I transition a patient from standard ADT to tE2 ADT?
Although there is no official protocol for transitioning from standard ADT to tE2 ADT, your patient may want to start using tE2 sooner, rather than later, in order to reduce side effects such as hot flashes, fatigue, and osteoporosis (among others). Regular monitoring of T and E2 levels can help to guide a full switchover.
19. Can patients switch back to standard ADT after using tE2 ADT?
Yes. One can revert back to standard ADT after using tE2 for ADT with no wash-out period.
20. What should I tell patients about the risks of gynecomastia and mastalgia?
About 80% of men who use tE2 for ADT will experience some mild gynecomastia (compared to 40% incidence with standard ADT drugs). However, breast growth is typically less than what patients might imagine. Studies of genetic males who take high-dose estrogen report that their breasts are typically smaller than an A-cup size. Larger breast growth is rare and is generally worse with obesity. Gynecomastia is primarily a cosmetic concern, and it does not have adverse health consequences. Nerve ablation can be used to treat painful mastalgia, and plastic surgery can be used to treat distressing breast growth.
21. Can prophylactic Radiation Therapy prevent gynecomastia from tE2 ADT?
Yes, in many men. Prophylactic electron beam Radiation Therapy (RT) has been shown to reduce the incidence of gynecomastia caused by first generation anti-androgen monotherapy (e.g. bicalutamide or flutamide) by about 50-65%, compared to controls without RT. The dose of radiation used (~10 Gy) is about 10% of the dose used to irradiate the prostate, and only 1-2 sessions of e-beam RT are generally needed.
22. Is Tamoxifen recommended to treat gynecomastia caused by tE2 ADT?
No. Tamoxifen is not recommended for use with tE2 ADT because it may counteract the ability of tE2 to suppress T. It also may not suppress hot flashes, and it may increase the risk for TEEs.
23. What are some additional ways of administering E2?
There are many different ways of administering E2 other than the oral route, which is not recommended because of the increased risk of TEEs. These modalities include patches, gels, creams, body sprays, sub-cutaneous implanted pellets, intramuscular (IM) and sub-cutaneous (Sub-Q) injections, intravenous (IV) delivery, nasal spray, buccal delivery, sub-lingual delivery, and rectal suppositories. Many of these methods have been studied for women, but they have varying degrees of clinical evidence documenting efficacy. Most have not been tested in men, and many are not commercially available. Most of these alternatives are not FDA approved. However, IM injection of E2 (e.g., estradiol valerate) is currently FDA approved for palliative care of men with advanced prostate cancer.
24. What’s the Bottom Line?
Safety and cancer survival rates for patients who use tE2 for ADT are equally as good as standard ADT drugs. tE2 ADT significantly reduces hot flashes and can reverse osteoporosis caused by standard ADT drugs. Sleep quality, fatigue, brain fog, insulin resistance and cholesterol levels may also be improved. The primary side effects of tE2 ADT are mild gynecomastia and transient mastalgia.
The bottom line is that using tE2 for ADT is not experimental. Rather, it is equally safe, rigorously tested and can provide patients a better quality of life compared to standard ADT drugs.
References:
Gilbert DC, Nankivell M, Sehjal J, Rush H, Mangar S, Gale J, et al. A0474 – Androgen suppression, PSA response, toxicity and longer-term outcomes with transdermal oestradiol (tE2) patches compared with LHRH analogues for the treatment of locally advanced prostate cancer, the phase III PATCH (NCT00303784) and STAMPEDE (NCT00268476) trials. Conference presentation at: Annual European Association of Urology Congress; 2025 March 21-24; Madrid, Spain.
Gilbert, D., Duong, T., Kynaston, H., Alhasso, A., Cafferty, F., Rosen, S., Kanaga-Sundaram, S., Dixit, S., Laniado, M., Madaan, S., Collins, G., Pope, A., Welland, A., Nankivell, M., Wassersug, R., Parmar, M., Langley, R., & Abel, P. (2017). Quality-of-life outcomes from the Prostate Adenocarcinoma: TransCutaneous Hormones (PATCH) trial evaluating luteinising hormone-releasing hormone agonists versus transdermal oestradiol for androgen suppression in advanced prostate cancer. BJU International, 119(5), 667-675. https://doi.org/10.1111/bju.13687
Gilbert, D., Nankivell, M., Rush, H., Clarke, N., Mangar, S., Al-hasso, A., Rosen, S., Kockelbergh, R., Sundaram, S., Dixit, S., Laniado, M., McPhail, N., Shaheen, A., Brown, S., Gale, J., Deighan, J., Marshall, J., Duong, T., Macnair, A., Griffiths, A., Amos, C., Sydes, M., James, N., Parmar, M., & Langley, R. (2024). A repurposing programme evaluating transdermal oestradiol patches for the treatment of prostate cancer within the PATCH and STAMPEDE trials: Current results and adapting trial design. Clinical Oncology, 36(1), E11-E19. https://doi.org/10.1016/j.clon.2023.10.054
James ND, Rush H, Nankivell MG, Sehjal J, Mangar SA, McPhail N et al. 21 Transdermal oestradiol (tE2) patches as androgen deprivation therapy (ADT): Efficacy and safety of combining with androgen receptor pathway inhibitors (ARPIs) in metastatic (M1) prostate cancer—Randomised comparison from the STAMPEDE trial platform. J Clin Oncol. 2025;43(5 suppl), 21-21. DOI:10.1200/JCO.2025.43.5_suppl.21
Langley RE, Nankivell M, Gilbert D, Bourmpaki E, Mangar S, Rush HL, Rosen S, Alhasso A, Kockelbergh R, Marshall J, Griffiths A, Chan KHY, Mohamed WM, Dallas NL, Brown SJ, Clarke N, James N, Parmar M. LBA69 Prostate cancer efficacy results from a randomised phase III evaluation of transdermal oestradiol (tE2) versus luteinising hormone releasing hormone agonists (LHRHa) for androgen suppression in non-metastatic (M0) prostate cancer. Ann Oncol. 2024;35. S1258. DOI: 10.1016/j.annonc.2024.08.2312
Langley, R. (2024). Prostate Cancer Efficacy Results from a Randomized Phase 3 Evaluation of Transdermal Estradiol Versus LHRH Agonists for Androgen Suppression in M0 Prostate Cancer. European Society of Medical Oncology (ESMO) Annual Congress.
Langley, R., Cafferty, F., & Abel, P. (2013). Extending the case for oestradiol in androgen-sensitive prostate cancer – Authors’ reply. In The Lancet Oncology, 14(7). https://doi.org/10.1016/S1470-2045(13)70203-1
Langley, R., Duong, T., Godsland, I., Kynaston, H., Kockelbergh, R., Rosen, S., Alhasso, A., Dearnaley, D., Clarke, N., Jovic, G., Carpenter, R., Bara, A., Welland, A., Parmar, M., & Abel, P. (2015). Oestrogen patches (OP) to treat prostate cancer (PC) – Are different commercial brands interchangeable? Maturitas, 81(1) 210-211. https://doi.org/10.1016/j.maturitas.2015.02.320
Langley, R., Gilbert, D., Duong, T., Clarke, N., Nankivell, M., Rosen, S., Mangar, S., Macnair, A., Sundaram, S., Laniado, M., Dixit, S., Madaan, S., Manetta, C., Pope, A., Scrase, C. D., Mckay, S., Muazzam, I., Collins, G., Worlding, J., Williams, S., Paez, E., Robinson, A., McFarlane, J., Deighan, J., Marshall, J., Forcat, S., Weiss, M., Kockelbergh, R., Alhasso, A., Kynaston, H., & Parmar, M. (2021). Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme. The Lancet, 397(10274), 581-591. https://doi.org/10.1016/S0140-6736(21)00100-8
Langley, R., Godsland, I., Kynaston, H., Clarke, N., Rosen, S., Morgan, R., Pollock, P., Kockelbergh, R., Lalani, E., Dearnaley, D., Parmar, M., & Abel, P. (2008). Early hormonal data from a multicentre phase II trial using transdermal oestrogen patches as first-line hormonal therapy in patients with locally advanced or metastatic prostate cancer. BJU International, 102(4), 442-445. https://doi.org/10.1111/j.1464-410X.2008.07583.x
Langley, R., Kynaston, H., Alhasso, A., Duong, T., Paez, E., Jovic, G., Scrase, C., Robertson, A., Cafferty, F., Welland, A., Carpenter, R., Honeyfield, L., Abel, R., Stone, M., Parmar, M., & Abel, P. (2016). A randomised comparison evaluating changes in bone mineral density in advanced prostate cancer: Luteinising hormone-releasing hormone agonists versus transdermal oestradiol. European Urology, 69(6), 1016-1025. https://doi.org/10.1016/j.eururo.2015.11.030
Ockrim, J., Lalani, E., Laniado, M., Carter, S., & Abel, P. (2003). Transdermal estradiol therapy for advanced prostate cancer – Forward to the past? Journal of Urology, 169(5), 1735-1737. https://doi.org/10.1097/01.ju.0000061024.75334.40
Rush, H. L., Merrick, S., Marshall, J., Deighan, J., Abdel-Aty, H., Alhasso, A., Clarke, N. W., Kockelbergh, R., Mangar, S., Rosen, S. D., James, N. D., Gilbert, D. C., South, A., & Langley, R. E. (2025, July 30). Preferences between three options for androgen deprivation therapy: A focus group study. BJU International. https://doi.org/10.1111/bju.16863
Russell, N., Cheung, A., & Grossmann, M. (2017). Estradiol for the mitigation of adverse effects of androgen deprivation therapy. In Endocrine-Related Cancer, 24(8), 297-313. https://doi.org/10.1530/ERC-17-0153
Russell, N., Ghasem-Zadeh, A., Hoermann, R., Cheung, A., Zajac, J., Shore-Lorenti, C., Ebeling, P., Handelsman, D., & Grossmann, M. (2022). Effects of estradiol on bone in men undergoing androgen deprivation therapy: a randomized placebo-controlled trial. European Journal of Endocrinology, 187(2), 241-256. https://doi.org/10.1530/EJE-22-0227
Russell, N., & Grossmann, M. (2019). Mechanisms in endocrinology: Estradiol as a male hormone. European Journal of Endocrinology, 181(1), R23-R43. https://doi.org/10.1530/eje-18-1000
Russell, N., Hoermann, R., Cheung, A., Ching, M., Zajac, J., Handelsman, D., & Grossmann, M. (2018). Short-term effects of transdermal estradiol in men undergoing androgen deprivation therapy for prostate cancer: A randomized placebo-controlled trial. European Journal of Endocrinology, 178(5), 565-576. https://doi.org/10.1530/EJE-17-1072