The following references are articles
found by searching the peer reviewed literature that address the benefits of saliva over
serum. Percutaneous administration of
progesterone: blood levels and endometrial protection.
Stanczyk FZ, et al. Menopause (2005), 12(2):
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
Salivary, but not serum or urinary levels
of progesterone are elevated after topical application of progesterone one cream to pre- and postmenopausal
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 levels following short and
long term administration of two regimens of progesterone cream in postmenopausal women.
Carey BJ, et al. British J Obstetrics and Gynecology
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 estrogen-stimulated endometrium.
Leonetti HB, et al. Fertility and Sterility (2003)
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
Wren BG, et al. Lancet (1999) 354:
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 better measure of
adrenal cortical function than serum.
Vining RF, et al. Ann Clin Biochem (1983)
Prospective study: three groups (ages
24-32) consisting of 7 healthy men and woman and 10 third trimester pregnant woman). 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.
Influences of percutaneous administration
of estradiol and progesterone on human breast epithelial cell cycle in vivo.
Chang KJ, et al. Fertil Steril
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
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.
Salivary cortisol determined by enzyme
immunoassay is preferable to serum total cortisol for assessment of dynamic hypothalamic-pituitary-adrenal axis
Gozansky WS, et al. Clin Endocrin (2005)
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
Direct assay for progesterone in saliva:
comparison with a direct serum assay.
Webley GE, Edwards R. Ann Clin Biochem (1985)
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)
Study RBC membrane uptake to progesterone, corticosterone and cortisol in fresh and 42 day stored (blood bank)
blood. Findings: progesterone showed a much greater affinity for RBC constituents (6 to 8 times greater) than the
glucocorticoid hormones. Furthermore, there is a likely direct relationship with the amount of bound progesterone
and the viability of RBCs in storage, e.g., female blood may be more stable in storage. Also, indirectly this data
supports the RBC as a carrier medium for topical applied progesterone.