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These include uptake by the red blood cells, rapid conversion to 5-alpha-reduced progestin, and rapid clearance from the serum by salivary and hepatic excretion, combined with slow transdermal absorption. Studies in animals are limited. In a study conducted in rats, topical progesterone was found to be effectively and biologically actively absorbed. A similar distribution in tissues was found following intramuscular administration.

Metabolism was also similar. Debate exists about the relevance of plasma and salivary progesterone as surrogate indicators of clinical efficacy. In an open-label study, topical progesterone 40 mg daily applied for over 1 year did not provide adequate opposition to endometrial hyperplasia as determined by endometrial histology and bleeding patterns in 41 postmenopausal women.

Dosages of progesterone 5, 20, 40, and 60 mg daily were tested. A string placebo effect was observed. No histological effect of topical progesterone on the endometrium was demonstrated. However, an improvement in vasomotor symptoms was recorded. Topical progesterone was no better than placebo for the management of cyclic breast pain in a small clinical trial.

Commercial progesterone creams vary in concentration but are generally in the range of 1. Most trials evaluated progesterone 40 mg daily either as a single dose or 20 mg twice daily for menopausal symptoms. While progesterone cream may be helpful for women with proven low progesterone levels, for women experiencing symptoms due to relative progesterone deficits, meaning more or less normal progesterone levels but with estrogen excess, progesterone cream may increase the hormonal load in the body.

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