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Percutaneous administration of progesterone: blood levels and endometrial protection

Stanczyk FZ, et al. Menopause (2005), 12(2): 232-237.


A very good review of the issues related to the effectiveness of topical administration of progesterone on the endometrium and the disparity between saliva and serum levels. The RBC carrier theory is validated.

Salivary, but not serum or urinary levels of progesterone are elevated after topical application of progesterone cream to pre- and postmeopausal woman.

O’Leary P, et al. Clin Endo (2005) 53: 615-620.


Researchers applied 64mg of progesterone topically to 6 each pre- and postmenopausal women. The continuous 3hr serum and 24hr urine (including pregnanediol-3-glucuronide metabolite) samples showed no significant level changes; whereas, remarkable elevations were noted in the saliva. Authors question clinical organ response without a measurable serum level, though organ delivery was obvious. They also suggest that the lymphatic system delivers the hormones rather than RBCs.

A study to evaluate serum and urinary hormone levesl following short and long term administration of two regimes of proesterome cream in postmenopausal woman.

Carey BJ, et al. British J Obstetrics and Gynecology (2000) 107:722-726.


Authors evaluated serum and urine levels in 24 pre and postmenopausal women following the topical application of 40mg of progesterone either bid divided dosage or qd. Conclusion: "Transdermal progesterone (40mg) per day for 42 days causes a small increase in serum progesterone concentration, although there is wide variation. Whether such levels are of clinical benefit remain to be seen." There was no change in the metabolite.

Topical progesterone cream has an antiproliferative effect on estorgen-stimulated endometrium

Leonetti HB, et al. Fertility and Sterility (2003) 79:221-2.


Authors monitored endometrial biopsies proliferative activity in 32 postmenopausal women following 0.625 CEE and given either bid daily 0, 1.5% or 4% progesterone topically. Endometrial biopsy evaluation after 2 weeks of progesterone clearly showed an antiproliferative effect of topical progesterone. The antiproliferative effect was essentially the same for the 1.5% and 4% dosages. Regarding serum testing, the authors comment: "The plasma concentrations of progesterone were low and varied greatly among individuals. However, elevated serum levels are irrelevant, provided one obtains the desired clinical outcome."

Micronized transdermal progesterone and endometrial response.

Wren BG, et al. Lancet (1999) 354: 1447-8.


Authors randomized 27 estradiol exposed (Climara 100 weekly) postmenopausal women into 16mg, 32mg or 64mg groups. Serum levels and endometrial biopsies were monitored. Summary: The use of transdermal progesterone for 14 days over three cycles, even at concentrations as high as 64 mg daily, did not increase circulation blood progesterone concentrations sufficiently to induce any evidence of secretory effect in the endometrium.

Hormones in Saliva

Vining RF and McGinley RA. Critical Reviews in Clinical Laboratory Sciences. (1986) 23(2):95-146.


An excellent review article looking at the constituents of saliva. Conclusion: "Saliva flow rate does affect saliva pH and the concentration of many salivary ions. This has led many clinicians to assume that it would also affect all salivary steroid levels. This is not the case—a number of clinically important steroids, such as cortisol, testosterone, estriol and progesterone, have salivary concentrations which are not appreciably affected by saliva flow rate. However, the conjugated steroids (e.g., DHEAS) and some unconjugated (e.g., cortisone) may exhibit marked flow rate dependence."

Salivary cortisol: a bette measure of adrenal cortical function than serum

Vining RF, et al. Ann Clin Biochem (1983) 20:329-35.

Influences of percutaneous administration of estradiol and progesterone on human breast epithilial cell cycle in vivo

Chang KJ, et al. Fertil Steril (1995) 63(4):785-91.


Randomized placebo controlled study of 40 Premenopausal women scheduled for excisional biopsy of benign lesions. Study groups were given either Pg 25mg or E2 1.5mg or both topically qd to the surgical breast (10-13 days before surgery. Findings: Both E2 and progesterone readily penetrated the skin, increasing the progesterone level x100. Progesterone induced a major reduction in the acinar cell proliferation rate whether used alone or in combination with E2. The serum levels did not reflect the topical hormone supplementation.


Prospective study: three groups (ages 24-32) consisting of 7 healthy men and women and 10 third trimester pregnant women). Advantages of saliva: reflects bio-available cortisol and unaffected by CBG level, which rises with BCP and during pregnancy. Stress free and easy to collect. Lends itself to multiple samples. IV cortisol injection shows salivary rise within 5 mins. Routine serum samples at 0900 and 1700 do not accurately reflect adrenal dysfunction.

Salivary cortisol determined by enzyme immunoassay is preferable to serum total cortisol for assessment of dynamic hypothalamic-pituitary-adrenal axis activity

Gozansky WS, et al. Clin Endocrin (2005) 63:336-341.


Author compared salivary and serum cortisol levels between 12 individuals under various conditions: exercise stress, dexamethasone suppression or CRH stimulation. EIA was the salivary test method compared to serum RIA. Conclusion: "Therefore, assessment of salivary cortisol should be considered over serum total cortisol because more physiologically relevant data are obtained, particularly when the cortisol response to an HPA axis stimulus exceeds.

Direct assay for progesterone in saliva: comparison with a direct serum assay

Webley GE, Edwards R. Ann Clin Biochem (1985) 22:579-585.


Study compares direct serum and saliva assays for sensitivity, precision and recovery. Twenty women in various stages of their menstrual cycle were compared using serum and saliva. Conclusion: Saliva showed a significant correlation (r=0.71, P<0.001) compared to serum with the added advantages of convenience and reduced stress (no needles).

Human Erythrocyte Membrane Uptake of Progesterone and Chemical Alterations

Devenuto F, et al. Biochem. Biophys. Acta (1969) 193:36-47

Saliva as a Medium for Investigating Intra-and Interindividual Differences in Sex Hormone Levels in Premenopausal Woman

Peter H. Gann, Susan Giovanazzi, Linda Van Horn, Amy Branning, and Robert T. Chatterton, Jr. Cancer Epidemiology, Biomarkers and Prevention. Vol. 10, 59-64, January 2001.


Authors describe saliva's advantages: "Saliva has several advantages over blood as a sampling medium: it can be easily collected by subjects themselves at repeated intervals; it requires no special storage or collection equipment; and the steroid concentrations measured exclude the fraction tightly bound to serum proteins and thus unavailable for biological action. Most importantly, consecutive samples can be grouped for analysis after the length of the menstrual cycle is known.

Validation of salivary testosterone as a screening test for male hypogonadism

Morley, J et al. The Aging Male. September 2006; 9(3): 165-169.

Salivary cortisol and DHEA levels in the Korean population: age-related differences, diurnal rhythm, and correlations with serum levels

Ahn RS, Lee YJ, Choi JY, Kwon HB, Chun SI. Yonsei Med J. 2007 Jun 30;48(3):379-88.

Salivary cortisol and dehydroepiandrosterone in relation to puberty and gender

>Netherton C, Goodyer I, Tamplin A, Herbert J. Psychoneuroendocrinology. 2004 Feb;29(2):125-40.

Salivary Sex Hormone Measurement in a National, Population-based Study of Older Adults

Gavrilova N, Lindau ST. J Gerontol B Psychol Sci Soc Sci. 2009 Nov; 64 Suppl 1:i94-105.


A large study that measured salivary levels of estradiol, progesterone, DHEA and testosterone in both men and women and found them to be a reliable, minimally invasive way of adding a physiological component to in-home, population-based studies.