There is controversy about the beneficial effects of topical progesterone creams used by postmenopausal women. A major concern is that serum progesterone levels achieved with progesterone creams are too low to have a secretory effect on the endometrium. However, antiproliferative effects on the endometrium have been demonstrated with progesterone creams when circulating levels of progesterone are low. Thus, effects of topical progesterone creams on the endometrium should not be based on serum progesterone levels, but on histologic examination of the endometrium. Despite the low serum progesterone levels achieved with the creams, salivary progesterone levels are very high, indicating that progesterone levels in serum do not necessarily reflect those in tissues. The mechanism by which the serum progesterone levels remain low is not known. However, one explanation is that after absorption through the skin, the lipophilic ingredients of creams, including progesterone, may have a preference for saturating the fatty layer below the dermis. Because there appears to be rapid uptake and release of steroids by red blood cells passing through capillaries, these cells may play an important role in transporting progesterone to salivary glands and other tissues. In contrast to progesterone creams, progesterone gels are water-soluble and appear to enter the microcirculation rapidly, thus giving rise to elevated serum progesterone levels with progesterone doses comparable to those used in creams.