Heather Hydzik, ND (Naturopathic Dr)  for The Insight Newsletter online of Doctors Data.

There is ongoing debate in the functional medicine community over transdermal hormone applications and their ability to be absorbed by the tissues and measured in various testing media.

For example, providers might hesitate to prescribe transdermal progesterone for women with a uterus on estrogen due to uncertainty over whether this route of administration provides adequate endometrial protection, as most large-scale studies have involved oral supplementation.

Another common concern is that transdermal progesterone does not increase progesterone levels in serum, the testing medium with which providers are most familiar. This causes some to question whether transdermal hormones reach various tissue sites.

After reviewing the literature, providers can have more confidence in the efficacy of this mode of BHRT delivery.

Serum is not the best medium for monitoring transdermal hormones, especially progesterone. Why? Typically, physiologic (replacement) doses of transdermal progesterone do not increase serum levels 2, 6.

Salivary testing, on the other hand, has been shown to reflect this transdermal progesterone delivery. Therefore, testing serum to monitor transdermal hormone dosing can result in excessive hormone dosing.

In a case example, 20 mg of progesterone dosed BID and stopped 12 hours prior to testing resulted in serum below the luteal range, blood spot levels in the upper luteal range, and saliva about 50x higher than the capillary levels 1.

What’s the best way to measure hormones?

The reason underlying these differences involves the unique transport of transdermal hormones in the body.

Topical hormones bypass liver and gut metabolism. It is believed that transdermal hormones may circulate via lymphatic vessels (rather than via the vascular system) as lymphatic flow is slow, taking hours, similar to the lag time before topical application increases salivary levels.

The lymphatic system parallels capillaries and there is exchange between lymph and capillaries. This theory would explain how transdermal hormones increase levels in both capillary blood and saliva.

It is also thought that much of the transdermal hormones are carried by capillary red blood cell membranes, delivering the hormones to cellular sites via free diffusion, but never traveling via venous circulation.

Why progesterone is not best measured in blood

Another issue with testing sex hormones in serum is that these steroid hormones all have a cholesterol backbone and are hydrophobic (not soluble in water) and lipophilic (fat soluble), especially progesterone.

When these hydrophobic hormones are in watery environments such as serum, they must be bound to a carrier protein or conjugated ((reversibly combined with another molecule).

The hormones measured in serum are not biologically active and do not reliably represent the patient’s clinical presentation.

Saliva is more favorable to lipids and only contains the free, unbound portion of hormones. The results correlate better to the clinical picture because they are not skewed by inactive bound hormones.

This makes saliva testing a better choice to measure baseline endogenous levels and it is also the best option to monitor topically supplemented hormones.

Oral versus skin effectiveness for hormone use

More importantly, do those topical hormones, specifically progesterone, have the intended clinical impact? When compared to oral medroxyprogesterone acetate, transdermal progesterone cream was equivalent in preventing endometrial hyperplasia among 26 women supplementing with conjugated equine estrogens for 6 months 5.

Transdermal progesterone has also been shown to reach breast tissue and reduce acinar cell proliferation2 while failing to increase serum levels of progesterone 3.

These results suggest that progesterone cream is effective, but serum does not reflect tissue levels of transdermal progesterone, nor does it correlate with clinical improvement. More large-scale studies are needed to confirm these results.

Why skin absorption of progesterone is more effective

The last question to address is why salivary progesterone increases to supraphysiological levels following physiological transdermal dosing. This is theorized to be due to the unique physiology of the salivary gland, which receives more blood flow than most other tissues – 10 times as much as skeletal muscle during exercise.

Salivary progesterone levels increase about 3 hours after topical progesterone application 4 and peak at about 8 hours. Between 12 and 24 hours following physiologic doses of hormone creams, salivary levels reach a more predictable range, which is why labs recommend this dosage interval to prepare for testing.

Supplementation ranges for saliva have been developed based on levels seen when physiologic dosing is used. This is a standard practice for salivary testing labs, as it accounts for the increased capillary blood flow to the salivary glands.

In conclusion

Topical hormones have been shown (in small studies) to reach the target tissues and to be clinically efficacious in protecting the breast and endometrium.

Due to the unique transport of this mode of delivery, saliva testing can monitor therapy better than serum. Saliva testing can also provide a baseline assessment of pre-treatment endogenous levels of bioavailable hormones, since only the unbound fraction of steroid hormones reaches this fluid.

References

1 – Burry KA, Patton PE, Hermsmeyer K. Percutaneous absorption of progesterone in postmenopausal women treated with transdermal estrogen. Am J Obstet        Gynecol. 1999;180(6 pt 1):1504-1511.

2 – Chang KJ, Lee TT, Linares-Cruz G, Fournier S, de Lignieres B. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil Steril 1995; 63:785-91.

3 – De Boever J, Verheugen C Van Maele G, Vandekerckhove D. Steroid concentrations in serum, glandular breast tissue, and breast cyst fluid of control and progesterone-treated patients. In: Endocrinology of Cystic Breast Disease, Ed. A. Angeli, Raven Press, New York, 1983 pp. 93-99.

4 – Du JY, Sanchez P, Kim L, Azen CG, Zava DT, Stanczyk FZ. Percutaneous progesterone delivery via cream or gel application in perimenopausal women: a randomized cross-over study of progesterone levels in serum, whole blood, saliva, and capillary blood. Menopause 2013; 20:1169-75.

5 – Leonetti HB, Landes J, Steinberg D, Anasti JN. Topical progesterone cream as an alternative progestin in hormone therapy. Altern Ther Health Med 2005;11(6):36-38.

6 – O’Leary P, et al. Salivary, but not serum or urinary levels of progesterone are elevated after topical application of progesterone cream to pre-and postmenopausal women. ClinEndocrinol. 2000; 53: 615-20.

Helpful information: 

As the effectiveness of bioidentical hormones is often questioned, I felt it was necessary to include the references from the original article in case you wish to investigate further.

If you are not sure what hormone you may need to supplement, then this article will be helpful.

https://anna.blog.wellsprings-health.com/which-hormone-or-hormones-might-you-need/