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In a pilot clinical study published in Menopause, we addressed some of these pressing questions regarding topical progesterone supplementation and body fluid distribution.2 In the study, women used 80 mg of topical progesterone gel or cream daily for several weeks to allow for tissue equilibration, and then levels were followed in venipuncture serum and whole blood, capillary blood from the fingertip, and saliva over a 24-hour time course after morning application. What we found is that, as expected from our clinical testing of tens of thousands of patients, very high levels of progesterone in saliva and capillary blood, but not in venous serum or venous whole blood. Whole venous blood, in addition to venous serum, was tested to exclude the possibility that progesterone was residing on erythrocytes and thereby excluded from analysis with serum testing. We found that venous whole blood contained even less progesterone per unit volume than venous serum, which suggests that nearly all of the progesterone in venous blood is present in the serum, and not on the surface of blood cells. This did not exclude the possibility, however, that arterial blood entering the capillaries might have a higher concentration of bioavailable progesterone that off-loads into capillary beds, where it enters and is retained by interstitial tissues and target cells.
As an alternative explanation to erythrocyte transport and delivery of progesterone, we also speculated that progesterone might be present in and around capillary beds due to its uptake, retention, and presence in lymphatics, which form a weblike structure with blood capillaries in all tissues except the brain. The lag from time of use to presence in saliva and capillary blood, about 4 to 6 hours, is not consistent with blood transport, which is rapid, but suggests instead that transport of topical progesterone and other topically delivered hormones could in fact be transported via lymphatics. Lymphatic flow is slow and depends on movement and muscle contractions, and therefore delivery to tissues from the lymphatics could depend on one's degree of physical activity.
What we have also discovered about topical hormone delivery is that very little of the hormone, or its downstream metabolites, is delivered into the urine as determined by GC-MS/MS testing. Therefore, urine testing, like serum testing, is not reflective of tissue uptake or bioresponse to topically delivered hormones. All other forms of hormone delivery that we have evaluated (oral, intramuscular/subcutaneous injections, subcutaneous pellets, sublingual/troche) result in dose-dependent increases in salivary, venipuncture serum, capillary blood, and urine levels of supplemented hormones. Topically delivered hormones are uniquely different in that saliva and capillary blood levels rise in proportion to dose, but venipuncture serum and urine levels increase very little and rarely reach optimal physiological levels with physiological dosing.
Conclusion
To summarize, topical delivery of sex-steroid hormones can be monitored effectively with saliva and capillary blood, but not venipuncture serum or urine. Endogenously produced hormones, and all other forms of delivery (exception topical) can be effectively monitored with all of the commonly used body fluids (saliva, venipuncture serum, capillary blood, urine). Use of venipuncture serum or urine hormone levels following topical hormone delivery may lead to underestimation of tissue hormone delivery and consequent overdosing in attempts to achieve physiological levels.
Notes
1. Zava DT. Saliva hormone testing. Townsend Lett. 2004 January:120–124.
2. Du JY, Sanchez P, Kim L, Azen CG, Zava DT, Stanczyk FZ. Percutaneous progesterone delivery via cream or gel application in postmenopausal women: a randomized cross-over study of progesterone levels in serum, whole blood, saliva, and capillary blood. Menopause. Epub 2013 May 6.
3. Sitruk-Ware R, Seradour B, Lafeye C. Treatment of benign breast diseases by progesterone applied topically. In: Mauvais-Jarvis P, Vickers CF, Wepierre J, eds. Percutaneous Absorption of Steroids. Academic Press; 1980:219–229.
4. Leonetti HB, Landes J, Steinberg D, Anasti JN. Transdermal progesterone cream as an alternative progestin in hormone therapy. Altern Ther Health Med. 2005;11:36–38.
5. Burry KA, Patton PE, Hermsmeyer K. Percutaneous absorption of progesterone in postmenopausal women treated with transdermal estrogen. Am J Obstet Gynecol. 1999;180:1504–1511.
6. Wren BG, McFarland K, Edwards L, et al. Effect of sequential transdermal progesterone cream on endometrium, bleeding pattern, and plasma progesterone and salivary progesterone levels in postmenopausal women. Climacteric. 2000;3:155–160.
7. 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;63:785–791.
8. 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: Angeli A, ed. Endocrinology of Cystic Breast Disease. New York: Raven Press; 1983:93–99.
9. Cicinelli E, Cignarelli M, Resta L, Scorcia P, Petruzzi D, Santoro G. Effects of the repetitive administration of progesterone by nasal spray in postmenopausal women. Fertil Steril. 1993;60:1020–1024.
10. Leonetti HB, Wilson KJ, Anasti JN. Topical progesterone cream has an antiproliferative effect on estrogen-stimulated endometrium. Fertil Steril. 2003;79:221–222.
11. Rossouw JE, Anderson GL, Prentice RL, et al. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321–333.
12. Beral V, Million Women Study Collaborators. Breast cancer and hormone replacement therapy in the Million Women Study. Lancet. 2003;362:419–427. Erratum in Lancet 2003;362:1160.
13. Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapelon F. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005;114:448–454.
14. Hargrove JT, Maxson WS, Wentz AC, Burnett LS. Menopausal hormone replacement therapy with continuous daily oral micronized estradiol and progesterone. Obstet Gynecol. 1989;73:606–612.
15. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA. 1996;275:370–375.
16. 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. Fertil Steril. 2007;88:1404–1407.
 Dr. David Zava has devoted his 40-year professional career to exploring the role of hormones in aging and disease. After completing his PhD in biochemistry at the University of Tennessee in 1974, Dr. Zava spent much of his time researching hormones and breast cancer in Switzerland, Texas, California, and Oregon. In 1998, he established ZRT Laboratory, a CLIA-certified laboratory that is a front-runner in the innovative development of test methods to identify hormonal imbalances that can lead to debilitating symptoms, diminished quality of life, and increased risk for cancers and many of the diseases of aging, such as diabetes, cardiovascular disease, and senile dementia. ZRT Laboratory was one of the first laboratories to develop and commercialize noninvasive saliva and dried urine and semi-invasive dried blood spot methods for testing hormones as an alternative to conventional serum testing. Using these unique methods of body fluid collection, ZRT is actively engaged in hormone research studies with universities, government agencies such as the NIH and CDC, military agencies, private physicians, and professional sports teams.
In addition to his innovations in clinical laboratory testing and development, and numerous scientific publications, Dr. Zava coauthored a landmark book, What Your Doctor May Not Tell You About Breast Cancer: How Hormone Balance Can Help Save Your Life. In this book, Dr. Zava and coauthors describe how breast cancer can be caused by hormonal imbalances that occur naturally as we age, but can be prevented if the types of hormonal imbalances are identified with testing and restored to optimal healthy levels with bioidentical hormone replacement therapy and improved lifestyle.
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