Progesterone Dominance

Long-term progesterone dominance.  

An insidious problem. 

By Bent Formby, PhD.


Bent Formby, PhD“Studies investigating the effect of topical cream on the endometrium should not be based on serum progesterone levels, but on histologic examination of the endometrium.”


As discussed in details on the Rhythmicliving website long-term topical  use of progesterone in doses advocated by the Wiley protocol of 8,200 mg/28 days represents a severe and insidious problem because the women are ending up having overdoses of progesterone accumulated in their tissues. A young and healthy menstrual cycling woman secrete 208 mg progesterone during a 28 days cycle (1) which is equivalent to 2,496 mg per year. Hence, the Wiley protocol recommends more progesterone in a single 28 days period than a normal women secrete during a period of 40 months. Even after women quit application overdosed progesterone is released from various lipophilic depot (intra-abdominal and subcutaneous) in the body into the blood circulatory system at a relative fast rate over periods of months or even years. Prenanediol glucuronide is the major metabolite of progesterone produced by the liver and excreted in the urine, but it is important to emphasize that the metabolic capacity of the liver for this process is linked to normal physiological concentrations of progesterone. Surplus from overdosing can only accumulate in other tissues as described for e.g. toxic substances like PCB.


Absorption of progesterone from topical creams.  Topical creams consist of a variety of lipid-soluble ingredients with different characteristics blended with progesterone, which is highly lipophilic (does not dissolve in water, but in lipid solving agents). After the topical administration of a progesterone cream, the lipophilic substances in the cream, including progesterone, undergo absorption by passive diffusion through the different layers of the skin and its appendages. A resorption process thereafter occurs by which progesterone enters the cutaneous microcirculation and eventually the systemic circulation of blood and lymph. Note that especially women have a relative high volume of subcutaneous fat which can function as a depot for progesterone. The extent of progesterone absorption differs between various sites of application. Krause et al (2) found a significant increase in serum levels of progesterone levels 30 to 120 min after applying a progesterone cream on the breast. But no increase was observed after application of the same cream to other regions like thighs or abdomen.


Serum levels of progesterone after topical administration of the hormone. In a recent study published by Carey et al. (3) the pharmacokinetics of a progesterone cream following long and short term dermal administration of 40 mg daily or 20 mg, twice daily, was determined in twenty-four healthy post menopausal women aged between 40 and 65 years. Blood samples were obtained at 0, 2, 4, 6, 12 and 24 hours on days 1 and 42 of treatment. No significant difference was observed in serum progesterone levels between the once and twice daily dosage regimens. Calculated mean values for the peak progesterone concentration (C max) and area under the progesterone concentration-time curve from 0 to 24 hours (AUC (area under curve) 0-24h) were 0.22 ng/ml and 1.48 ng/ml/min, respectively on day one of treatment. These values increased to 1.67 ng/ml and 16.4 ng/ml/min, respectively on day 42. Quantified levels of pregnanediol glucuronide, the major metabolite of progesterone in urine, remained relative low and did not reflect the increased plasma levels of progesterone (vide supra). We learn from the study that only a certain amount of the 40 mg progesterone cream per day is metabolized and excreted by the urine. What is not metabolized is to be regarded as surplus or overdose of progesterone and accumulates in the body – most probably in lipophilic adipose tissues.

Mircioiu C et al. (4) also studied the pharmacokinetics of progesterone in postmenopausal women following transdermal administration. Mean plasma concentration was 2.26 ng/ml. The elimination was slow, with a half-life in the range of 3,040 hours or 127 days – a value much higher than those after administration of progesterone via vaginal suppositories. Half-life is the time it takes to eliminate 50% of a substance accumulated in a body.

In several other studies to evaluate serum and urinary hormone levels following topical administration of progesterone cream in menopausal women at daily progesterone doses of 30 to 80 mg, the average progesterone levels did not exceed 3.5 ng/ml (5-9). Now, it is a general held assumption that serum progesterone levels > 5ng/ml must be achieved to inhibit endometrial mitosis. How then to explain the study by Leonetti et al (10) that the use of low-dose topical progesterone has an antiproliferative effect on the endometrium? Since progesterone concentrations in the endometrial tissue were sufficiently high enough to produce a biologic effect (10) it therefore stands to reason that circulating levels of progesterone does not reflect its concentration in a particular tissue. Additional evidence demonstrating that progesterone levels in serum may not reflect those measured in tissues is found in studies showing that progesterone levels in saliva are very high after topical progesterone cream administration even though serum progesterone levels are low (7,8). These findings are consistent with rapid uptake of progesterone by salivary glands. Presumably there is also rapid uptake of progesterone by other tissues, eg. the endometrium, fat, liver, skin, lungs, kidneys and brain.


How is progesterone transported in the blood? In comparison to other steroids progesterone has low binding affinity to SHBG, CBG and albumin. But red blood cells play an important role in transporting progesterone to salivary glands and other tissues throughout the body. Binding and release of progesterone from red blood cells is a very fast process and progesterone may be delivered directly to tissues via red blood cells without having a chance to equilibrate with the systemic blood (11).  Because progesterone is lipophilic high quantities may be released from red blood cells and directly accumulate in fat tissue and then slowly being released over long periods of time after a woman quits application. Such occult and relative high levels of released progesterone may be involved in symptoms of hair loss, muscle pain and depression.


Conclusive remarks. To me it is obvious that substantial more long-term randomized, placebo-controlled trials are required to demonstrate the beneficial effects of topical progesterone cream administered together with low-dose 17beta-estradiol in HRT. Administration of progesterone via vaginal suppositories is an important alternative pathway and should be investigated. Studies investigating the effect of topical cream on the endometrium should not be based on serum progesterone levels, but on histologic examination of the endometrium. It appears that saliva testing in some studies is reliable (12). Other investigators found saliva levels were not of significant value (7). Nobody has reported progesterone levels in whole blood i.e. plasma plus blood cells.

Only transdermal progesterone <20 mg should be applied daily during the last two weeks of a 4 weeks cycle.



1      in Review of Medical Physiology, table 23-7. McGrawHill 2003

2      Krause W et al. Geburtshilfe Frauenheilkunde 1987; 47:562-64

3      Carrey BJ et al BJOG 2000; 107:722-26

4      Mircioiu C et al. Eur J Drug Metab Pharmacokinet 1998;23:397-402

5      Burry KA et al. Am J Obstet Gynecol 1999; 180:1504-11

6      Cooper A et al. Lancet 1998; 354:1255-56

7      Wren BG et al. Lancet 1999; 354:1447-48

8      Lewis JG et al. Maturitas 2002; 41:1-6

9      O’Leary et al. Clin Endo 2000; 53:615-20

10   Leonetti HB et al. Fertil Steril 2003; 79:221-22

11   Koefod P et al. Biochim Biophys Acta 1994; 1195:55-62

12   Dr.David Zava Laboratory (


Bent Formby, PhD.