By Aly W. | First published March 29, 2019 | Last modified October 9, 2020
Transdermal estradiol patches applied to scrotal or neolabial skin are absorbed much better than conventional skin sites and result in approximately 5-fold higher estradiol levels in comparison.
I recently came upon the following study on scrotal transdermal estradiol patches as a form of hormonal chemotherapy for men with prostate cancer:
- Re, I., Asenjo, G., Maximino, G., & Micheletti, L. (2005). Tratamiento del Cáncer de Próstata Avanzado con Estrógenos Transdérmicos Escrotales (ETE). [Transdermal Scrotal Estrogen Patches (TSEP) in the Treatment of Advanced Prostate Cancer.] Revista Argentina de, 70(4), 231. [PDF] [Translation]
Before I discuss the findings of the study, I’ll give a little background on the concept of scrotal transdermal estradiol and the reasoning for it. If you’d prefer to just know what the researchers found, you can just skip to the Study Findings section below.
Estrogens are used at high doses in the treatment of prostate cancer in men due to their powerful functional antiandrogenic effects. They have comparable effectiveness to surgical castration and GnRH agonists/antagonists for this use but have some advantages and disadvantages in comparison. Advantages of estrogens include no hot flashes, preservation of bone density, preservation of some sexual interest, better quality of life, and far lower cost. Disadvantages include feminization and gynecomastia (undesirable for cisgender men of course), and, in the case of oral and non-bioidentical/synthetic estrogens (e.g., diethylstilbestrol, ethinylestradiol, conjugated estrogens), cardiovascular toxicity. Parenteral bioidentical estradiol (e.g., injected estradiol esters, transdermal estradiol) is preferred over other forms of estrogen due to its far better side-effect profile—namely, minimal to no cardiovascular toxicity.
For prostate cancer, injections of estradiol esters are very effective, but the long-acting estradiol esters like polyestradiol phosphate and estradiol undecylate that have traditionally been used to treat prostate cancer have unfortunately been discontinued. Shorter-acting estradiol esters like estradiol valerate and estradiol cypionate can be used but need to be injected frequently (e.g., weekly) and have limited availability in many places. Injections are also inconvenient and can be anxiety-inducing and painful. Transdermal estradiol patches are very effective, but generally about four large 100 μg/day patches are required for full testosterone suppression (Ockrim, Lalani, & Abel, 2006; Langley et al., 2008). Using so many patches can be both uncomfortable and expensive. Transdermal estradiol gel has been used as well, but very high doses are required (6 mg/day+), and even then, only modestly high estradiol levels and incomplete suppression of testosterone levels have been observed (Aly W., 2019).
Transdermal medications are absorbed through the skin. The absorption capacity of human skin is not homogeneous; we’ve known for a while now that scrotal skin has a far higher capacity for absorption than do most other skin sites (Wiki). Indeed, the first transdermal testosterone patches were scrotal patches, due to the high amounts of hormone that needed to be delivered in men; non-scrotal testosterone patches were only introduced later, and had to be larger in size in comparison (Behre & Nieschlag, 2012; Khera, 2012). As such, there is basis that transdermal estradiol could be much more potent than it is normally if applied instead to scrotal skin.
Re and colleagues (cited study up top) assessed the use of a single transdermal estradiol patch worn on the scrotum to treat prostate cancer. These researchers are from Argentina, a country in which poverty is high. Many people have considerable difficulty affording medications in this part of the world. In addition to the advantages of estrogen therapy over conventional antiandrogen therapy, the economic aspect was the motivation for their research. Essentially, their goal was to achieve, via a parenteral and hence non-toxic route, high levels of estradiol that could fully suppress testosterone levels and hence treat prostate cancer. And as cheaply and conveniently as feasible. Aside from the prostate cancer part, this is precisely what many transgender women seek as well. Particularly transgender women who are do-it-yourself. Hence, transgender women serve to benefit from any such therapy as well.
Currently, the sublingual route serves the purpose of achieving high estradiol levels and testosterone suppression for many transgender women. But sublingual administration of estradiol has some drawbacks, namely a short duration and extremely erratic estradiol levels. Hence, the development of a longer-duration therapy with more constant, steady, and consistently high estradiol levels would be favorable.
First, Re et al. conducted a crossover pilot study with two men to assess whether scrotal transdermal estradiol is absorbed better than non-scrotal transdermal estradiol. One man used a 50 μg/day estradiol patch on the forearm first and subsequently on the scrotum, while the other man used a 100 μg/day estradiol patch on the forearm first and subsequently on the scrotum. The researchers found that, indeed, maximal estradiol levels were much higher with scrotal application compared to the forearm:
- Forearm 50 μg/day patch: 55 pg/mL (patient #1)
- Scrotum 50 μg/day patch: 200 pg/mL (patient #1)
- Forearm 100 μg/day patch: 180 pg/mL (patient #2)
- Scrotum 100 μg/day patch: 500 pg/mL (patient #2)
Here is a graph of the results of the initial pilot “mini study” (n = 2, crossover design):
|Figure: Estradiol levels with transdermal estradiol patches applied to the scrotum in two men (Re et al., 2005).|
After the pilot “mini study”, Re et al. conducted a full prostate cancer study with 35 patients, each patient wearing one 100 μg/day transdermal estradiol patch on the scrotum. As with the pilot study, estradiol levels of around 500 pg/mL were produced on average in the full sample of men, with a range of estradiol levels across patients of about 125 to 1,200 pg/mL. This wide range is consistent with the high interindividual variability in estradiol levels achieved with estradiol by the transdermal route in general (Wiki). With application to conventional skin sites, a single 100 μg/day estradiol patch will only achieve estradiol levels of about 100 pg/mL (Wiki; Wiki-Graphs). In addition, two to six estradiol patches were reported in one study to achieve mean estradiol levels of only about 200 to 400 pg/mL (Wiki-Graph; Ockrim, Lalani, & Abel, 2006). Taken together, it seems that scrotal application of transdermal estradiol patches may result in at least about 5-fold or greater bioavailability compared to placement of the patches on non-scrotal skin. This marked increase in bioavailability is rather analogous to the increase in potency afforded by taking oral estradiol tablets sublingually (about 2- to 5-fold increase; Wiki).
The mean levels of estradiol observed in the study (i.e., 500 pg/mL) are known to be sufficient for strong suppression of gonadal testosterone production and by extension circulating testosterone levels (Wiki). Levels of estradiol of 200 to 300 pg/mL are known to suppress testosterone levels by about 90%, to around 50 ng/dL, while estradiol levels of 500 pg/mL suppress testosterone levels by about 95%, to around 20 ng/dL (Wiki). Unfortunately, Re and colleagues were not able to obtain data on testosterone suppression in most of the men in their study because almost all of them already had low pre-treatment testosterone levels (mean 28 ng/dL, range 10 to 90 ng/dL) at the start of the study. This was due to concomitant surgical/medical castration via conventional androgen deprivation therapy. In any case, the researchers reported that in two men who were not on conventional androgen deprivation therapy and had male-range initial testosterone levels, treatment with intermittent scrotal transdermal estradiol patches resulted in testosterone levels that were 10 to 30 ng/dL during the “on” periods and 200 to 600 ng/dL during the “off” periods. This, of course, is consistent with strong suppression of testosterone levels by high estradiol levels.
The findings of Re et al. are important because they provide yet another highly efficacious and cost-effective option for high-dose parenteral estradiol therapy, which transgender women can use to suppress testosterone levels whilst minimizing risks. Moreover, this route may be advantageous relative to other alternatives (e.g., sublingual or rectal estradiol; Wiki) in terms of maintenance or stability of estradiol levels and convenience.
On another note, estradiol patches might not be required for scrotal transdermal use—it’s entirely possible that transdermal estradiol gel would be much more potent by the scrotal route compared to conventional skin sites similarly. Also, it’s notable here that it might not be necessary to apply estradiol gel to a large area of skin; a study of transdermal estradiol gel found that the smaller the area of application, the greater the estradiol levels achieved (Wiki-Graph). Higher effectiveness of estradiol gel by the scrotal/neolabial route still remains to be tested and confirmed however.
If scrotal/neolabial estradiol gel does work well, it has a major advantage of only needing to be applied once a day instead of having to be worn 24/7, unlike patches. It’s notable that 100 μg/day estradiol patches can be quite large (Wiki-Table). Scrotal testosterone patches were discontinued because they were too large and irritating, and I can totally imagine how that could be in practice. Lower-dose estradiol patches like 50 or 75 μg/day (or even less) are smaller in size and may be more tolerable than higher-dose patches though—while still potentially achieving quite high levels of estradiol.
One other interesting thought relates to transdermal progesterone. Very low but nonetheless significant circulating levels of progesterone (~0.75 ng/mL) have been observed with over-the-counter transdermal progesterone creams (Wiki). Transdermal progesterone could potentially be made more potent by the scrotal route, similarly to estradiol and testosterone. Whether this would translate into therapeutic usefulness of transdermal progesterone is unknown and possibly unlikely though—the circulating levels of progesterone that occur with transdermal progesterone are very low and may just be too low still even with scrotal application. Another issue is the high expression of 5α-reductase—a major metabolizing enzyme of progesterone—in scrotal/genital-area skin. With that said though, I do think that it would be quite interesting to look into scrotal transdermal progesterone cream or gel nonetheless.
Taken together, this study has shown that scrotal application of transdermal estradiol achieves higher estradiol levels than non-scrotal application. We knew that this was the case for testosterone, but prior to this study we had no published data on the question for estradiol.
There are widely different sizes of transdermal estradiol patches in terms of brands (e.g., Climara, Vivelle, Vivelle-Dot, etc.), doses (i.e., 14 to 100 μg/day), and durations (i.e., designed for once weekly or twice weekly use) (Wiki-Table). Estradiol patches range in size from smaller than a U.S. dime (1.65 cm2) to almost as large as a typical coffee mug base (44 cm2). This is a more than 25-fold range in size! In the case of 50 μg/day estradiol patches, sizes range from 3.3 to 22 cm2. And in the case of 100 μg/day patches, sizes range from 6.6 to 44 cm2. Wearing very large transdermal estradiol patches on the scrotum is obviously not going to be easy nor comfortable. I would recommend checking the table linked just above to see what the best patch brand and dose for a given person and their personal circumstances would be. It’s also possible to cut transdermal matrix patches and hold them in place. See the Supplementary Material section for more information.
Penile skin apparently has similar absorption characteristics to scrotal skin and hence may allow for improved absorption similarly, so it could be a supplement or alternative to scrotal application of estradiol. See the Supplementary Material section for more information.
See the page here for supplementary material to this article. This includes the most important excerpts from the paper (translated from Spanish to English); information on cutting estradiol patches and holding them in place; information on application to the penis instead of scrotum or neolabia; and anecdotes (blood test results of scrotal/neolabial administration).
See here for an article on transdermal scrotal/neolabial application specifically for gel/cream.