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Supplement: Genital Application of Estradiol as a Powerful Transdermal Route for Transfeminine People

By Aly W. | First published March 29, 2019 | Last modified June 10, 2021

This article is for supplemental material to the main article here.

Paper Excerpts

Here are some of the most relevant excerpts from the study paper (translated from Spanish into English):

Thirty-five, age 68.9 years ± 8.2 (mean ± sd) consenting advanced prostate cancer (APC) patients, 33 D3 stage, and two D1 stage, […] [received treatment (Tx)] with one 17β-estradiol long acting transdermal system loaded with 7.5 mg of E2 [(100 μg/day)] applied to the scrotum and changed twice per week. […] Thirty-two D3 patients received continuous Tx (CTx), one D3-stage [intermittent Tx (ITx)], and two D1-stage patients ITx with “on” periods lasting 9 months and “off” periods […]

The goal of orchiectomy, surgical or hormonal, is to lower plasma testosterone (T) below the castration level (≤50 ng/dL). Ninety-percent to 95% of a man’s T comes from the testicles that secrete approximately 6 to 7 mg daily and the half-life is 45 minutes. The level of castration is reached with surgical orchiectomy in about 8 hours; with estrogen (E) in about 38 days (21 to 60) and approximately the same time with GnRH analogues.4

Arguments for the treatment of prostate cancer with estradiol (E2) transdermal: […] The transdermal absorption of E2 varies according to the different parts of the body. In men, the absorption through the skin of the scrotum is 3 to 8 times greater than in the forearm, abdomen, or back, and this is due to the large number of hair and sebaceous follicles, to the permeability to alcoholic substances, to vascularity, temperature, and thickness of the skin, not allowing substances, as occurs with androgens with 5α-reductase, which facilitates their metabolism.54–55

In a pilot study E2 absorption by forearm skin and scrotal skin was compared. One volunteer applied a patch on the skin of the left forearm that releases 50 μg/day of 17β-E2 and another one that releases 100 μg/day and measured E2 with IRMA technology with the following results: in the first, basal, 24, 48, 72, and 120 hours, obtaining 20, 42, 55, 50, and 18 pg/mL, and in the second, basal, 24, 48, 72, and 96 hours, registering 14, 70, 65, 180, and 60 pg/mL, respectively.

The scrotal absorption was checked in two volunteers (one, the first of the previous example), to which a patch of 17β-E2 was applied to the skin of the scrotum and dosed with the same baseline E2 technology and every 24 hours. In the first one a patch that releases 50 μg of E2 daily, obtaining the following values: basal, 24, 48, 72, 96, 120, 144, and 168 hours: 12, 220, 190, 140, 100, 105, 75, and 65 pg/mL, respectively, and in the second a patch that releases 100 μg E2 daily with the following result: baseline, 24, 48, 72, 96, 120, and 192 hours; 27, 300, 500, 350, 200, 150, and 40 pg/mL, respectively. (Table 1.)56

Table 1. Transdermal absorption of estradiol in forearm and scrotum.

Steg in 1979 first used transdermal E2 in topical form in 21 men with [prostate cancer (PCa)]. Between 3 and 6 months, they lost T and LH, without changes in triglycerides or LDL.59

In 2001, we presented the excellent results obtained with transdermal scrotal estradiol patches (TSEP) in the treatment of “localized” prostate cancer,60 and in 2003 the results with TSEP intermittently.61

Ockrim in a pilot study dealt with E2 patches located in areas of the body other than the scrotum, […] They used six patches changed every day achieving castration levels in 21 days for LH, FSH, and T […] Bland treated 24 […] patients with six patches of 100 μg/day changed every day […] with a mean plasma E2 value of 460.7 pg/mL.63 Ockrim confirmed that transdermal E2 reduces […] These three communications in no case used the scrotal passage as the gateway for E2, since they used six patches changed daily located outside the scrotum.

In January 1997, patients with PCa were treated with TSEP. A patch loaded with 7.5 mg of long-acting 17β-E2 that releases 100 μg of E2 per day located on the skin of the scrotum was used.

We treated 35 patients between 52 to 82 years – 68.9 ± 8.2 (mean ± SD) of age with advanced PCa, two clinical stage D1, and 33 D3 stage, 10 D3 stage orchiectomized previously. The baseline PSA in the range between 4.8 and 4200 ng/mL, the baseline T in stage D3 – 33 ± 39 ng/dL, the physical state (Performance Score ECOG)65 – 1.71 ± 1.31 (Table 2).

The patches were applied permanently on the scrotum and were changed twice a week (every 3 or 4 days).

The baseline E2 varied between 12 and 43 pg/mL (44 and 157 pmol/L) and during treatment ranged between 123 and 1200 pg/mL (451 and 4405 pmol/L), most of the determinations being found around 500 pg/mL (1835 pmol/L).

In two stage D1 patients, […] intermittent treatment with TSEP was applied with “on” periods of 9 months duration and “off” until PSA reached the baseline level or exceeded 20 ng/mL. […]

In two patients, treatment with intermittent TSEP was performed (Table 3). [In the first patient, T] at the beginning of the “on” periods was 334, 480, 360, and 190 ng/dL, and T at the beginning of the “off” periods was 0.3, 20, 10, and 10 ng/dL. In the second [patient], [T] at the beginning of the “on” periods was 340, 600, and 560 ng/dL and at the beginning of the “off” periods PSA was 0.3 and 0.6 ng/mL and T 10 and 10 ng/dL.

Table 3. Intermittent Transdermal Estrogens in Stage D1 Prostate Cancer.

This communication tries to contribute to position E again in the role that should never have been lost, lamenting that if many of the resources that were used in non-estrogenic therapies had been dedicated to research in this field, it would probably have been possible to reach treatments more effective for PCa.

The administration of E2 through the scrotum proposed in this work started more than 9 years ago and that in our knowledge does not record antecedents has provided very satisfactory results.

The transdermal scrotal route obtains high levels of E2, higher than those obtained with other dermal locations, which decreases the number of patches used and exerts a positive effect on PCa and its symptoms. […] In the PCa D1 stage the intermittent treatment […] maintained castration levels of T, […]

There were no undesirable [cardiovascular] effects, hot flashes, or sweating, and gynecomastia was prevented with previous irradiation of the gland. In those who did not do it, it was not an important problem.

Cutting and Adhesing Patches

Some (but not all) transdermal estradiol patches can be cut into smaller portions. As many estradiol patches are pretty large, the ability to cut them could potentially be useful in the context of scrotal/neolabial application.

See the following literature excerpts regarding cutting estradiol patches:

Matrix patches are self-adhesive and release approximately 25 µg 17β-oestradiol/24 hours. Since the oestradiol is evenly distributed throughout the patch, the patches can be cut to provide the required dose. Practically, patches are cut into half or quarter as more complex divisions would be prone to inaccuracies and impracticable. Unused patch fractions may be stored in their packaging in the fridge for up to 1 week. The patch (or patch fraction) should be applied to clean dry skin over the buttocks or hips using Opsite® (a transparent adhesive film) if necessary to ensure good adhesion. […] Transdermal patches may be more difficult to use particularly when cutting patches to small sizes as they may fall off and require tape support. (Matthews et al., 2016)

Currently, the lowest-dose patch commercially available delivers 14 μg/d E2, and the most widely used low-dose patches deliver 25 μg/d. One method to deliver lower doses is to cut the patch in smaller pieces. Patches with a matrix design can be easily cut, whereas patches with a reservoir technology should not be cut. The disadvantages of cutting patches are that handling the smaller pieces may be difficult and cutting the patches is not recommended by the products’ labels. However, there is clinical experience with this, especially in Scandinavia. There, a group showed that a fractionated patch dose (one-quarter patch of a 25-μg dose approximately equals 6.2 μg or even less) applied overnight mimicked the normal, early-morning serum E2 peak and fell back to baseline within a few hours of patch removal (17). (Klein et al., 2018)

For transdermal administration, gel and patches are available; dosing by cutting patches is more reliable when titrating the E2 serum level, and the delivery can be stopped in the morning by just taking the patch away when mimicking the circadian rhythm seen in early spontaneous puberty (Fig. 1). […] Our present recommendation is to use E2 matrix patches when available. Matrix patches are stable and have a homogenous E2 layer over the total surface and can therefore be cut into individualized doses. However, matrix patches are available with different patch areas for the same dose from different brands. The larger the patch area, the easier to cut the patch into smaller pieces for the target dose.

This is to be compared to the reservoir patches which have a separate drug layer with a liquid compartment containing a drug solution or suspension separated by the adhesive layer. By cutting such a patch, the liquid compartment will be destroyed and the drug will leak out. (Norjavaara, Ankarberg-Lindgren, & Kriström, 2016)

It is unknown how to best deliver estradiol doses below 14 μg daily. While a European matrix patch can apparently be cut into quarters so the estrogen can be delivered overnight, the US manufacturers recommend against this and our limited experience has yielded erratic plasma estradiol levels, which suggests that these patches may not be uniformly impregnated with estradiol. (Rosenfield, Kiess, & Keizer-Schramad, 2006)

Almost all estradiol patches available nowadays are matrix patches. Estraderm (an estradiol reservoir patch) is one of the only exceptions. It’s discontinued in the United States but I think is still used in the United Kingdom.

Tegaderm is another option for helping to hold patches in place; see here.

Penile Skin Application

[…] topical penile therapy has a unique set of anatomic and physiological issues that must be considered. There are several anatomic/fascial layers between the penile skin and the corpora cavernosa. The tunica albuginea is presumed to be difficult to penetrate because of its thick layers of collagen. Therefore, topical treatment trials have emphasized exposure to the glans penis because it has direct venous communication to the corpora cavernosa (40,41). The skin itself is a relatively impermeable tissue because of the stratum corneum. The horny cells at the stratum corneum are bonded with a very tight intercellular lipid matrix bilayer that makes the passage of drugs challenging (42). To overcome this barrier, investigators have used penetration enhancers that permeate this layer and reach the subdermis. Fortunately, the penis and scrotum are unique in that their stratum corneum is the most permeable of all anatomic locations tested. Depending on the molecular structure of the agent tested, there can be nearly 100% absorption of topical agents applied to these areas. Exposure to the glans affords a more easily “breached” layer. Other skin regions (e.g., back and palms) are particularly impermeable (43). An additional factor confounding efficient delivery of drug is the rich vasculature of the deep dermis that may “steal” the drugs to the systemic circulation. (Hairston, Becher, & McVary, 2007)

Basically, application to penile skin, particularly the glans penis, may result in improved absorption too. So if you want more skin area to put estradiol gel or patches, using penile skin could potentially work as well. This may notably also be relevant to vaginal administration for most post-op MTFs (i.e., SRS via penile inversion technique) as the neovaginal lining is penile skin. However, no studies exist on the absorptive effectiveness of neovaginal administration.

Anecdotes (Blood Test Results)

Since the relevant article was first posted, a number of people have opted to try scrotal transdermal estradiol (gel or patches) and have provided their blood work results. These results are quite promising and can be found at the following links: #1 (Alt), #2 (Alt), #3, #4, #5, #6, #7, #8, #9, #10, #11, #12, #13, #14 (as well as three more below). Note that there is high (10-fold) variation in estradiol levels achieved both with scrotal and non-scrotal transdermal estradiol, so while most people will fall around an average, some will achieve only low levels and some quite high levels. Hence, individual cases should always be interpreted with this fact taken into consideration.

If you have blood work results to contribute, please let me know and I will link them here!

Additional Anecdote #1

Redditor u/KaySOS has shared that application of 4 pumps of EstroGel, which has 0.75 mg estradiol per pump (3.0 mg total), to her body, plus approximately 0.25 pumps of EstroGel (~0.2 mg estradiol) (“very rough estimate”) to her neolabia, resulted in estradiol levels of about 200 pg/mL 12 to 18 hours later. Normally, a single pump of EstroGel (again 0.75 mg estradiol per pump) results on average in estradiol levels of around 30 pg/mL (not baseline-corrected) (Wiki-Graph).

Additional Anecdote #2

Someone shared these blood work results with me by private message and wanted to stay anonymous for personal reasons, so I’m posting the results for them:

Medication Regimen at Time of Blood Test

  • Estradiol patches (Estradot) 100 μg/day 2x/3.5 days on thighs
  • Estradiol gel (Sandrena) 1.0 mg 2x/day (once in the morning and once in the evening) on thighs
  • Estradiol gel (Sandrena) 1.0 mg 2x/day (once in the morning and once in the evening) on scrotum
  • Progesterone (Utrogestan) 100 mg in evenings cycled, days 14 to 28 (initially oral then rectal)

Blood Test Results (Blood Draw at 15:00 Hours; Midpoint for Gels)

  • Estradiol: 519 pg/mL (1906 pmol/L)
  • Testosterone: 17.3 ng/dL (0.6 nmol/L)

Previous Non-Scrotal Blood Test Results

They also provided the following from earlier in their transition:

  • Estradiol gel (Sandrena) 3.0 mg 1x/day non-scrotally ->
  • Estradiol: ~160 pg/mL (~600 pmol/L)
  • Estradiol gel (Sandrena) 2.0 mg 1x/day non-scrotally + Estradiol patches (Estradot) 100 μg/day 2x/3.5 days ->
  • Estradiol: ~150 pg/mL (~550 pmol/L)

Additional Anecdote #3

Another blood-work anecdote (Facebook):

I got my blood test to confirm the scrotal gel application. It works for me! With 3 mg of gel I was in the range of 160 pg after 13/14 hours… Using only 1 mg in the scrotum for a month I got 214 pg after 14 and an half hour with ONLY 1 mg of sandrena!!! The gel thing on scrotum work… Originally I wanted to test after 12 h with an higher result but I can’t due to lab opening. But for me it work. Generally people on 1 mg get 50 60 pg ml of e2 (me only 30 pg) max after 14 15 hours. So on me the scrotal application it’s 4 times the normal other skin application!!!