Insights on Genital Application of Transdermal Estradiol Gel in Transfeminine People from Scrotal Application of Testosterone in Men
By Aly W. | First published June 28, 2019 | Last modified July 15, 2021
Transdermal testosterone gel/cream applied to scrotal skin is absorbed much better and results in approximately 5- to 8-fold higher testosterone levels than when applied to conventional skin sites. The same is likely also true for estradiol.
In a previous article, I described how scrotal application of transdermal estradiol patches achieves far greater estradiol levels (~5-fold) than application of estradiol patches to conventional skin sites. Whereas a single 100 μg/day estradiol patch applied to non-scrotal skin results in estradiol levels of around 100 pg/mL on average, a single 100 μg/day estradiol patch applied to scrotal skin produces mean estradiol levels of around 500 pg/mL. Scrotal testosterone patches were previously marketed and are likewise known to achieve much greater testosterone levels (~5-fold) than non-scrotally-applied testosterone patches. In my previous article, I speculated that scrotal/neolabial application of transdermal estradiol gel might have greater efficacy than application to conventional skin sites similarly to scrotal application of transdermal estradiol patches. However, I cautioned that this hadn’t been studied or verified yet.
While browsing the literature today, I discovered these two studies on scrotal testosterone gel and cream in men:
- Iyer, R., Mok, S. F., Savkovic, S., Turner, L., Fraser, G., Desai, R., … & Handelsman, D. J. (2017). Pharmacokinetics of testosterone cream applied to scrotal skin. Andrology, 5(4), 725–731. [DOI:10.1111/andr.12357]
- Kuhnert, B., Byrne, M., Simoni, M., Kopcke, W., Gerss, J., Lemmnitz, G., & Nieschlag, E. (2005). Testosterone substitution with a new transdermal, hydroalcoholic gel applied to scrotal or non-scrotal skin: a multicentre trial. European Journal of Endocrinology, 153(2), 317–326. [DOI]:10.1530/eje.1.01964]
First I’ll discuss the findings with testosterone gel/cream and then I’ll discuss their relevance to estradiol gel/cream.
Here are some relevant excerpts from the first paper (which also briefly describe the findings of the second paper):
Scrotal skin is thin and has high steroid permeability, but the pharmacokinetics of testosterone via the scrotal skin route has not been studied in detail. The aim of this study was to define the pharmacokinetics of testosterone [cream] delivered via the scrotal skin route. The study was a single‐center, three‐phase cross‐over pharmacokinetic study of three single doses (12.5, 25, 50 mg) of testosterone cream administered in random sequence on different days with at least 2 days between doses to healthy eugonadal volunteers with endogenous testosterone suppressed by administration of nandrolone decanoate.
The bioavailability of testosterone via the scrotal skin is striking[ly] higher than for abdominal skin. Using the same testosterone cream and steroid LC-MS assay measurements, in this study a Cmax (4.6 ng/mL, 16.0 nM) was achieved with the lowest dose (12.5 mg) applied to the scrotal skin whereas applying 100 mg testosterone cream to the abdominal skin produced a Cmax of 16.3 nmol/L (4.7 ng/mL). This suggests an about eightfold increase in testosterone bioavailability, using the scrotal compared with abdominal skin routes.
One previous study has reported that the pharmacokinetics of scrotal application of testosterone gel was similar to that of a scrotal testosterone patch or a fivefold larger dose of non-scrotal testosterone gel, consistent with at least a fivefold higher transdermal bioavailability of testosterone (Kuhnert et al., 2005). Other studies assessing pharmacokinetics of testosterone application to non-scrotal skin have yielded variable time of peak concentration (Tmax) ranging from 6–16 h (Marbury et al., 2003; Miller et al., 2011; Olsson et al., 2014) but similar peak concentration (Cmax) as scrotal skin application (Rolf et al., 2002; Bouloux, 2005; Olsson et al., 2014).
We conclude that the scrotal administration of testosterone in a cream formulation provides high bioavailability, dose-dependent peak serum testosterone concentration, and tolerability with a much lower dose relative to the non-scrotal transdermal route.
In summary, maximal testosterone levels with scrotal application of testosterone gel or cream were 5- to 8-fold higher than with application to conventional skin sites (e.g., abdomen). This is analogous to the 5-fold higher testosterone levels that have been achieved with scrotal testosterone patches compared to non-scrotal testosterone patches.
Estradiol is very similar to testosterone in chemical structure and chemical properties (e.g., lipophilicity and likely absorption characteristics). Hence, although there is currently no research assessing scrotal/neolabial application of transdermal estradiol gel or cream, or showing definitively that it achieves greater estradiol levels than conventional transdermal application, we can infer that because this has been demonstrated for testosterone, it’s likely to be the case with estradiol as well. This is particularly true considering that far higher estradiol levels have already been shown with scrotal application of transdermal estradiol patches compared to non-scrotal application of such patches.
Consequently, scrotal/neolabial administration of transdermal estradiol gel or cream is likely to be a powerful alternative option for achieving high estradiol levels similarly to scrotal/neolabial application of transdermal estradiol patches. Scrotal/neolabial application of transdermal estradiol preparations may allow for greater efficacy and considerably reduced cost compared to conventional transdermal application of such formulations. In addition, whereas patches must be worn constantly and scrotal/neolabial application of such patches may be uncomfortable and inconvenient compared to conventional transdermal application, gels and creams are applied once per day and dry rapidly. Scrotal/neolabial application of patches also requires hair removal and can leave difficult-to-remove adhesive residues as well as cause local skin reactions. In contrast, this is not the case with gels or creams either. As such, estradiol preparations like gel or cream may be the preferred type of transdermal formulation for scrotal/neolabial use.
One possible caveat to scrotal/neolabial application is that transdermal estradiol gels are hydroalcoholic gels and consequently have the potential to irritate the skin and burn or sting when applied to the genital region. A potential solution to this is the use of transdermal estradiol preparations containing less or no alcohol, such as creams (e.g., compounded and over-the-counter products) and emulsions (e.g., Estrasorb), instead of hydroalcoholic gels. There is also a transdermal estradiol aerosol spray product (brand name Evamist) that may be another alternative option.