YES! Urine Testing Can be Used to Monitor Transdermal Estrogen Creams or Gels

Precision Analytical DUTCH test – a lot of us clinicians have adopted this easy-to-do urine test wholesale. Sometimes to the exclusion of any other sex hormone testing, including serum, which is the gold standard specimen. The question is: can we use the DUTCH in place of serum or saliva to accurately track HRT therapy? DUTCH says “yes.” Check out this month’s sponsored blog with Precision Analytical to get the details. ~DrKF

There has long been confusion about how to best monitor estrogen creams and gels. We have also shared in this confusion, but fortunately the data has now made the situation much clearer. In this blog, you will see the data that has led us to the following conclusions about monitoring transdermal estrogen:

• Serum and urine (DUTCH) testing can be used to monitor transdermal creams and gels.
• Clinical parameters tested in the research (bone loss, vasomotor symptoms, FSH suppression) parallel urine and serum results, not saliva.
• Salivary estradiol results following transdermal creams/gels are elevated dramatically and lack clinical utility.
• Estradiol doses of 0.25-1.0mg result in improved bone density, vasomotor symptoms, and serum or DUTCH results lifted out of the postmenopausal range thru the bottom part of the premenopausal range, making this range (between the top of the postmenopausal range and the bottom third of the premenopausal range) a reasonable target for patients on this type of therapy.

NOTE: This blog post is educational and not an endorsement for a particular HRT dose or route of administration.

Before establishing what data is generated when women are on transdermal creams or gels, let’s establish what we know about a less confusing, but related delivery system, transdermal patches:

• In women who use estrogen patches, serum, urine and saliva values move from below the premenopausal range to within the premenopausal range in a dose-dependent manner, when doses increase from none to higher doses used (0.1mg is the highest common dose when using a patch).
• This FDA study data shows that all estrogen-patch doses (even the very lowest – 0.025mg) help to relieve vasomotor symptoms (hot flashes) and increase bone density. This is important! We will show later that 0.5-1.5mg doses of creams or gels work similarly.

Now, let’s see how the same data is presented when we switch the delivery to a transdermal gel or cream:

• Serum and urine results behave similarly after treatment with a gel or cream compared to a transdermal patch. As therapy increases (from none to 1.5mg), serum and urine values increase in a dose-dependent manner from postmenopausal levels to within (or very near) premenopausal levels. [Urine data is essentially equivalent when comparing transdermal gels and creams. This data comes from more than 1,300 patients taking these products and completing the DUTCH test.
• The serum data for transdermal gel is from the data provided to the FDA from the makers of Divigel.] The FDA data does not list the reference ranges for the specific method used for the serum data. We chose Lab Corp ranges to display the FDA data relative to expected ranges. The serum data for patches is slightly higher compared to gels. The two studies likely used different analytical methods (notice the results of women not on therapy is slightly higher for patches. Given that they are from different studies, the results are very similar. Common low doses of patches give similar results compared to low dose transdermal gels. The higher patch dose gives a significantly higher serum value in a similar fashion as the higher dose of transdermal gel.

As we have shown in the above data, commonly used transdermal creams and gels result in similar concentrations compared to commonly used doses of estradiol patches. This is true in both serum and urine; however, salivary testing tells a VERY different story.

• Saliva data for transdermal creams and gels dramatically deviates from serum and urine. Results increase far above premenopausal levels with relatively small doses. The data shown (ZRT data published online, 2012 for testing 12 hours after application) shows results far above premenopausal levels.

WHAT CLINICAL MESSAGE DO SERUM & URINE PROVIDE?

Common doses of estradiol creams and gels deliver comparable hormone levels to common doses of patches. Serum and urine results for 1.0mg of transdermal cream or gel are approximately equivalent to the highest dose of hormone patches.

WHAT CLINICAL MESSAGE DOES SALIVA PROVIDE?

Estradiol creams and gels deliver far more hormone to cells than hormone patches. At 12 hours after application, saliva results for 1.0mg transdermal cream or gel are more than 10x higher than the highest dose of hormone patches.

This leads us to the big question…

WHICH RESULTS PARALLEL THE CLINICAL PICTURE MORE ACCURATELY?

ARE COMMON DOSES (0.25-1.0MG) OF A TRANSDERMAL ESTRADIOL CREAM OR GEL SUPRA-PHYSIOLOGICAL (AS SALIVA TESTING IMPLIES) OR A RELATIVELY MODEST DOSE (AS SERUM AND URINE TESTING IMPLY)?

This question has been one of intense debate over the past decade, but we have the clinical data to help find the answer.

• The lowest dose of transdermal estradiol gel (0.25mg) did NOT significantly reduce vasomotor symptoms four weeks after beginning therapy but did reduce symptoms after five weeks. A higher dose was effective at all time points. When using a patch, even the lowest dose (0.025mg) was effective at each time point.
  • https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022038s000_CLINPHARMR.pdf
• The lowest dose of a transdermal estradiol gel did NOT significantly improve bone mineral density six months after beginning therapy, but it did improve after being used for 12 months. A higher dose was effective at six and 12 months. Patches were effective for all doses at both 6 and 12 months.
  • http://www.jcma-online.com/article/S1726-4901(09)70358-2/pdf

CONCLUSION: While all doses of patches were able to improve bone health and vasomotor symptoms at all doses and time points, transdermal gels required a second level of dosing or longer therapy time to match the clinical effect. This tells us that these “low” doses are likely delivering low hormone levels at the tissue level, as serum and urine results imply. If all tissue in the body were exposed to the amount of hormone that saliva testing implies, (remember 1.0mg elevated levels 10 times higher than a high dose patch) one would expect 0.25mg to be more than enough to match the efficacy of a hormone patch.

ARE THERE ANY FSH (FOLLICLE STIMULATING HORMONE) SUPPRESSION DATA TO SUPPORT THE ABOVE CONCLUSION?

Postmenopausal women typically have elevated FSH values. Estrogen therapy will suppress FSH. The more estrogen the brain sees, the more FSH is suppressed.

• Two studies (Andersson, Pedersen) showed patches (0.05mg) suppressed FSH 40%, on average.
• Three studies (Osorio-Wender, Taechakraichana, Callejon) showed that estradiol gels (1.0-1.5mg) also suppressed FSH 40%, on average.
• If 1.0-1.5mg of transdermal estradiol was truly a monster dose of estradiol (as saliva testing implies), we would expect FSH suppression to exceed that of a patch.
• Transdermal patches of 0.05mg and estradiol gels of 1.0-1.5mg result in similar DUTCH results and similar FSH suppression. Note: One study in each group used progestins, which may suppress FSH additionally.

For me personally, the topic of transdermal hormones has been somewhat of a black box over the past 10 years. My understanding has changed over time and as research has clarified the clinical reality. It is important to know that progesterone behaves differently, and the above is not entirely representative of transdermal progesterone. While Precision Analytical, Inc. chooses not to take an official position regarding what doses or routes of administration should be used, the data in this post can be helpful in deciding the optimal approach for your patients.

The data also shows that if patients are taking estrogen by transdermal patches, creams, or gels, the resulting concentration shift in the DUTCH test is meaningful and helpful for providers. We encourage providers using these products to monitor estradiol levels, along with the downstream estrogen metabolites (2-OH, 4-OH, 16-OH, 2-Methoxy estrogens), to optimize therapy. We have historically taken a less-confident stance on this scenario because we needed the data to support a conclusion. All lab tests (saliva, urine, serum) have HRT-monitoring scenarios where they are not effective for monitoring therapy. It is our goal to be your continual source of objective and transparent information on how to best help patients achieve optimal health. For this very popular type of treatment, we are now more confident to endorse using the DUTCH test.