Topical Progesterone Delivery and Levels in Serum, Saliva, Capillary Blood, and Tissues
David T. Zava, PhD, ZRT Laboratory
Have you been frustrated with the use of topical progesterone because serum progesterone never rises to a healthy luteal level, and at the same time, salivary progesterone increases beyond the luteal level? Don’t feel alone, this problem has plagued many pharmacists and practioners for years.
Those who strictly rely on serum testing will claim that something is wrong with saliva testing results, but offer no clear explanation why - just that it’s wrong. On the other side, saliva advocates claim that the salivary testing is accurately reflecting the bioavailable fraction of hormone in the body, but can’t explain why such a high level of progesterone causes no adverse side effects. Which is correct?
Recent development of finger stick capillary blood spot testing for progesterone has helped shed light on this perplexing and confusing issue. Before discussing the intriguing findings with blood spot testing, let’s first take a look at what we know about the delivery of progesterone through the skin and how much of it shows up in different body fluids.
When progesterone is delivered through the skin with a topical cream at a physiological dose of about 20-30 mg (typical dose many practioners use) salivary levels of progesterone rise from a baseline of about 25-50 pg/mL (0.025-0.050 ng/mL) to about 10,000-30,000 pg/mL (10-30 ng/mL) at 3 hr and then decline steadily to about 300-3000 pg/mL (0.3-3 ng/mL) between 12 and 24 hr1,2,3. This represents about a 40-fold increase in salivary progesterone. In sharp contrast, serum levels of progesterone increase from a baseline of about 0.25-0.5 ng/mL to about 2-3 ng/mL at 12-24 hr, only about a 4 fold increase. This is certainly not considered a healthy luteal level4, which is in the range of 10-30 ng/mL.
The question of why salivary progesterone rises so dramatically to levels ABOVE (300-3000 pg/mL) those seen in the luteal phase (100-300 pg/mL)1,2, whereas serum progesterone does not increase so dramatically2, and does not reach healthy luteal levels4, has been difficult to reconcile since salivary progesterone is thought to be derived from blood. Which is more clinically relevant, saliva or serum progesterone? And which of these results, saliva or serum, are accurately reflecting tissue uptake and clinical response to progesterone?
Serum advocates say that topical progesterone does not increase the blood level of progesterone high enough to protect reproductive tissues such as the uterus and breasts from estrogen stimulation. They are correct in saying that topical progesterone does not increase serum levels of progesterone when the serum is prepared from blood drawn from the arm by conventional venipuncture. They are NOT correct in saying that the topical progesterone does not protect the uterus and breasts from estrogen stimulation. Let’s review why this is so.
Several clinical studies clearly show that a physiological dose of progesterone in the 20-30 mg range, while it does not raise the serum progesterone to luteal levels2,3, does accumulate in target tissues and protects these tissues from estrogen stimulation.
One such study was published by Leonetti and colleagues5 who showed that both progesterone and the synthetic progestin, medroxyprogesterone acetate (MPA) are equally protective of the endometrium (uterine lining) by preventing Premarin (0.625) from stimulating uterine hyperplasia. Another French/Tawanese study6, shows the protective role of progesterone. Biopsies of breast tissue were removed 10-13 days following topical application of progesterone, estradiol, or a combination of both directly to the breasts. Topical creams contained no hormones, 25 mg progesterone, 1 mg estradiol, or the combination of estradiol and progesterone. Tissue hormone levels and breast cell proliferation rates were measured directly in the biopsied tissues, and serum was drawn to test for blood levels of these hormones. Breast tissue levels of progesterone and estradiol increased, respectively, about 100- and 200-fold with topical delivery of these hormones, and the proliferation of the normal breast cells was decreased with progesterone (relative to placebo), increased with estradiol, and decreased with the combination of estradiol and progesterone. Serum hormone testing revealed that there was NO statistically significant difference in any of the hormone levels, regardless of treatment.
A similar study was published by a Belgium group 12 years earlier, showing that a physiological dose of progesterone (20 mg) topically applied to the breasts raises progesterone in the breast tissue to a level higher than seen in the luteal phase of the menstrual cycle7.
Another study, done in rats8 shows that topically applied progesterone is found in many different tissues throughout the body, but not in serum or urine. Radioactive progesterone was applied to the shaven bellies of rats, which were then sacrificed several hours after allowing the progesterone to enter the body. Body parts were then removed and the amount of progesterone entering the different tissues measured. Significant increases in progesterone occurred in every tissue, from the uterus and salivary glands to the kidney, liver, and lungs. While every tissue tested had taken up large amounts of progesterone, serum and urine contained relatively very little. These results were consistent with the human studies showing that topically applied progesterone enters tissues; this is not seen in serum.
Because topically delivered progesterone increases salivary and tissue (breast) levels of progesterone, and invokes a bioresponse (lowers cell proliferation caused by estrogen), one could reasonably conclude that serum testing for progesterone, which does NOT increase significantly under the same conditions, does NOT accurately reflect tissue uptake or bioresponse of the topically delivered progesterone. The sum of these results certainly points to the fact that serum grossly underestimates the amount of progesterone that is being delivered to tissues when progesterone is applied topically to the skin.
Until the development of finger stick blood spot testing there was no logical explanation for why saliva progesterone levels rise so dramatically with topical progesterone supplementation without a concomitant increase in serum progesterone. With the development of steroid hormone testing in dried blood spots at ZRT Laboratory9 a different picture began to emerge that provided a rationale explanation for this. As mentioned earlier, physiological dosing with topical progesterone in the 20-30 mg range raises the salivary and tissue levels of progesterone, but has little effect on serum progesterone levels1,2,3. Although progesterone does not rise significantly in venipuncture serum, we discovered that levels in capillary blood from the finger tip are upwards of 10 times higher (2-3 ng/mL in serum vs 20-30 pg/mL in blood spots). This marked difference in finger stick blood spot and serum was NOT seen when we measured progesterone levels in women making their own progesterone endogenously during the luteal phase of the menstrual cycle9. In fact, fingerstick blood spot and conventional serum progesterone levels are nearly identical, which we recently co-published with a group of doctors from the Oregon Health Science University (OHSU).
So why would women using topical progesterone have 10 times the level of progesterone in blood drawn from the end of the finger than in blood drawn at the same time from the arm? The important difference is that blood drawn from the end of the finger represents capillary blood, or blood and contents thereof such as oxygen being "delivered to" tissues, whereas venous blood is returning to the heart depleted of its oxygen.
Progesterone and other non-polar steroids bind loosely within the red cell membrane10,11,12. In fact, research studies have shown that when bound to red cells the off-rate of steroids such as progesterone and testosterone from the red cell to tissue within the capillary beds is extremely rap (milliseconds). Progesterone transferred from the skin into the circulation would bind rapidly to red cells and be carried to capillary beds, where progesterone would offload into tissues. This would include the salivary glands, finger tip, and all other tissues throughout the body. Blood draining from these capillary beds (venous) would be depleted of its progesterone payload, which is why serum prepared from venous blood (venipuncture), would not show significant levels of progesterone. This would explain why salivary, finger stick blood, and tissue levels of progesterone increase without a concomitant and equivalent increase in venous serum progesterone when progesterone is applied topically to the skin.
To summarize, topically delivered progesterone increases salivary, tissue, and capillary blood (finger stick) progesterone levels, but NOT serum progesterone levels to the same extent. What does this mean? It means that serum monitoring of topically delivered progesterone grossly underestimates the amount of progesterone entering tissues. It also means that a physiological dose of progesterone (10-30 mg) applied topically to the skin delivers a high luteal level of progesterone (20-50 ng/mL) directly to tissues. It also means that those practioners striving to achieve a serum luteal level of progesterone using topical progesterone will never achieve their goal and may dose the patient with more progesterone than needed.
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1. ZRT database
2. 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.
3. Dollbaum CM, Duwe GF. Absorption of progesterone after topical applications: serum and saliva levels. Presented at the 7th Annual Meeting of the American Menopause Society.
4. Sitruk-Ware R, Sterkers N, Mowszowicz I, Mauvais-Javis P. Inadequate corpus luteum function in women with benign breast diseases. J. Clin. Endocrinol. Metabol. 1977: 44: 771-774.
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. Chang K-J, Lee TTY, Linares-Cruz G, Fournier S, de Lignieres B. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertility and Sterility 1995;63:785-791.
7. 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. Endocrinology of Cystic Breast Disease, ed. A.Angeli, Raven Press, New York, 1983; 93-99.
8. Waddell BJ, O’Leary PC. Distribution and metabolism of topically applied progesterone in a rat model. J Steroid Biochemistry & Molecular Biology 2002; 80; 449-455.
9. Edelman A, Stouffer R, Zava DT, Jensen JT. A comparison of blood spot vs. plasma analysis of gonadotropin and ovarian steroid hormone levels in reproductive-age women. Fertility and Sterility 2007; 88(5); 1404-1407.
10. Johnson ME, et al. Permeation of steroids through human skin. J Pharmaceutical Sci 84: 1144-1146, 1995.
11. Devenuto F, et al. Human erythrocyte membrane. Uptake of progesterone and chemical alterations. Biochim Biophys Acta 193: 36-47, 1969.
12. Koefoed P, Brahm J. The permeability of the human red cell membrane to steroid sex hormones. Biochim Biophys Acta 1195: 55-62, 1994.
