Topical progesterone, also known as transdermal or percutaneous progesterone, is a formulation and route of administration of progesterone in which the hormone is supplied in the form of a cream or gel that is applied to the skin. It is not approved by the FDA in the United States but is available through custom compounding pharmacies and is also notably available over-the-counter without a prescription in the United States. It is used by thousands of women as a component of hormone replacement therapy (HRT) for menopausal symptoms in the United States and Europe. However, these topical formulations of progesterone are not regulated and have not been adequately clinically tested, with often little being known about their pharmacokinetics. In addition, absorption of topical progesterone may differ significantly from formulation to formulation due to widely varying ingredients. Moreover, the effectiveness of topical progesterone in conferring therapeutically relevant progestogenic effects and in particular sufficient endometrial protection from unopposed estrogen is controversial.
Topical application of progesterone with the intention of systemic therapy should not be equated with local treatment. Although it is not approved for use in menopausal HRT, topical progesterone is registered in some countries under the brand name Progestogel as a 1% gel for direct application to the breasts to treat premenstrual mastodynia (breast pain). It has been found in clinical studies to inhibit estrogen-induced proliferation of breast epithelial cells and to abolish breast pain and tenderness in women with the condition.
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Circulating levels and effectiveness
Creams and water-based gels
At least seven studies have assessed topical progesterone. In these studies, different formulations of topical progesterone including creams and water-based gels (brand names Pro-Gest, Progestelle, and Pro-Femme, as well as compounded) were used, with different sample sizes (n = 6 to 40), at different dosages (15 to 80 mg per day), and for different durations of treatment (1.4 to 24 weeks). Venous blood progesterone levels were assessed and reported in five of the studies and in all cases were low and found not to exceed 3.5 ng/mL. It is generally accepted that progesterone levels of 5 ng/mL are necessary to inhibit mitosis and induce secretory changes in the endometrium, although some researchers have been disputed this contention. Effects on the endometrium of topical progesterone were assessed in three of the studies via endometrial biopsy and the results were mixed. In one study, there was no effect; in another, antiproliferative effects were observed; and in the last study, an atrophic state was observed but only in 28 of 40 (70%) of the women. Circulating progesterone levels were reported as less than 3.5 ng/mL in the first study, low and widely variable in the second study, and were not given in the third study. Moreover, the duration of the study in which no effect was observed was short at only 2 weeks, and a longer treatment period of 4 to 6 weeks is necessary to produce endometrial changes. It has also been suggested that the dosage of estrogen used may have been insufficient to allow for proper priming of the endometrium for progesterone to act. Taken together, further studies are required to adequately establish a protective effect of topical progesterone on the endometrium.
The site of application of topical progesterone may significantly influence absorption. A study observed a significant increase in serum levels of progesterone shortly after administration when it was applied as a topical ointment to the breasts but not when it was applied to other areas like the thigh or abdomen.
Alcohol-based gels
Although studies of topical progesterone that delivered the hormone in the form of a cream or water-based gel found only very low levels of progesterone in circulation, a preliminary study of 100 mg/day topical progesterone formulated in an alcohol-based gel observed luteal-phase levels of progesterone with peak concentrations of 8 ng/mL. Though based on limited data, these findings suggest that alcohol-based progesterone gels may yield relatively high levels of circulating progesterone. One possible explanation for the difference is that progesterone creams are more lipophilic and may have a preference for uptake into the fatty layer under the skin whereas alcohol-based gels are more water-soluble and may rapidly distribute into the microcirculation of the skin and then into the general circulation.
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Levels in saliva, capillary blood, and tissues
On the basis of the very low levels of progesterone observed in venous blood with topical progesterone creams and water-based gels, some authors have concluded that progesterone via this route of administration is not well-absorbed and will not allow for sufficient endometrial protection. However, in spite of very low levels of progesterone in circulation with these formulations, studies that have assessed levels of progesterone in saliva and/or capillary blood have found that they are dramatically elevated and in fact greatly supraphysiological. In one study that used an oil-based cream or water-based gel, salivary and fingertip capillary blood levels of progesterone were respectively found to be approximately 10-fold and 100-fold greater than venous blood levels. The exact levels of progesterone were 4-12 ng/mL in saliva and 62-96 ng/mL in capillary blood; the reference ranges of progesterone in saliva and capillary blood from a referenced laboratory were 0.75-2.5 ng/mL and 3.3-22.5 ng/mL for premenopausal women in the luteal phase and 0.12-1.0 ng/mL and 0.1-0.8 ng/mL in postmenopausal women, respectively. As such, these data confirm distribution of progesterone to at least certain tissues with topical progesterone in spite of very low levels of progesterone in circulation and indicate that progesterone levels in venous blood cannot necessarily be used as an index of tissue exposure to progesterone with this route of administration. These findings provide a possible explanation for how some studies found antiproliferative and atrophic changes in the endometrium with topical progesterone. However, elevated levels of progesterone in the endometrium with topical progesterone have not yet been demonstrated.
Concern has been raised regarding topical progesterone in that the effects of such supraphysiological levels of progesterone in tissues are unknown and hence the potential for harmful effects has not been ruled out. Salivary monitoring of progesterone levels in women using topical progesterone and adjustment of dosage as necessary has been suggested as a possible means to help prevent potential adverse effects.
Mechanism of systemic distribution
The mechanism by which topical progesterone in cream and water-based gel forms distributes to tissues throughout the body resulting in very high salivary and capillary blood levels in spite of low circulating levels is not well understood. However, at least one hypothesis has been put forward. Steroid hormones including progesterone have been found to be transported by red blood cells in addition to serum carrier proteins like albumin, SHBG, and CBG, and as much as 15 to 35% of total steroid hormone content in whole blood may be confined to red blood cells. In the hypothesis, very high local concentrations of progesterone occur in skin capillaries after topical application and this progesterone is taken up by red blood cells. The transit time of red blood cells from capillaries and the release of steroid hormones from red blood cells are both very rapid, so it is suggested that progesterone is delivered through circulation to tissues via red blood cells without having time to equilibrate with the systemic blood. This could potentially explain the low levels of progesterone in venous blood in spite of very high levels in capillary blood and saliva. However, one study assessed progesterone levels in red blood cells with topical progesterone and found that they were significantly increased but still very low. Nonetheless, according to other authors, "[a]lthough the investigators of that study concluded that the progesterone levels in red blood cells were too low to be important in the delivery of progesterone to target tissues, it should be realized that even small amounts of progesterone taken up by red blood cells might be important because the transit time of red blood cells from capillaries is very rapid. [...] However, the role of red blood cells in steroid hormone transport has not been studied thoroughly, and such studies are warranted."
An in vitro study using porcine skin and several formulations of topical progesterone found that only minute quantities of progesterone penetrated through the skin but that there was significant partitioning of progesterone in the skin tissues. According to the authors, these results suggested that the lymphatic circulation in the skin might account for the systemic distribution of topical progesterone that has been observed clinically.
Local metabolism in the skin
5?-Reductase is an important and major enzyme involved in the metabolism of progesterone, and the skin is known to express high levels of this enzyme. As such, it has been suggested that rapid metabolism of progesterone by 5?-reductase could account for the low levels of circulating progesterone produced by topical application with creams or water-based gels. However, doubt has been cast on this hypothesis for several reasons. For instance, topical progesterone in an alcohol-based gel has been found to produce high levels of circulating progesterone. In addition, a study assessed urinary levels of pregnanediol glucuronide, a 5?-reduced metabolite of progesterone and the major metabolite of progesterone in urine, and found that although urinary levels of the metabolite increased after treatment with topical progesterone (similarly to circulating levels of progesterone), the levels nonetheless remained in the range of the follicular phase and hence very low. Moreover, a case report found that the 5?-reductase inhibitor finasteride did not increase the circulating progesterone levels or urinary pregnanediol glucuronide levels produced by topical progesterone. Finally, 5?-reductase is also a major enzyme involved in the metabolism of testosterone, yet topical testosterone in the form of creams, gels, and patches is approved for use as a pharmaceutical drug and is well-established as effective in raising circulating testosterone levels.
Time to peak levels and terminal half-life
A study that investigated the pharmacokinetics of topical progesterone using a hydrophilic (gel), lipophilic, or emulsion-type base found that in all three cases the time to peak concentrations was around 4 hours and the elimination half-life was in the range of 30 to 40 hours. The venous blood levels observed were very low.
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