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JOBNAME: meno 12#2 2005 PAGE: 1 OUTPUT: Tue February 22 18:09:19 2005lww/meno/82367/GME149345Prod#: GME149345 Menopause: The Journal of The North American Menopause SocietyVol. 12, No. 2, pp. 232-237DOI: 10.1097/01.GME.0000130927.03993.5CÓ 2005 The North American Menopause Society s Text printed on acid-free paper.
Percutaneous administration of progesterone: blood levelsand endometrial protection Frank Z. Stanczyk, PhD, Richard J. Paulson, MD, and Subir Roy, MD There is controversy about the beneficial effects of topical progesterone creams used by post- menopausal women. A major concern is that serum progesterone levels achieved with progesteronecreams are too low to have a secretory effect on the endometrium. However, antiproliferative effectson the endometrium have been demonstrated with progesterone creams when circulating levels ofprogesterone are low. Thus, effects of topical progesterone creams on the endometrium should notbe based on serum progesterone levels, but on histologic examination of the endometrium. Despitethe low serum progesterone levels achieved with the creams, salivary progesterone levels are veryhigh, indicating that progesterone levels in serum do not necessarily reflect those in tissues. Themechanism by which the serum progesterone levels remain low is not known. However, oneexplanation is that after absorption through the skin, the lipophilic ingredients of creams, includingprogesterone, may have a preference for saturating the fatty layer below the dermis. Because thereappears 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 othertissues. In contrast to progesterone creams, progesterone gels are water-soluble and appear to enterthe microcirculation rapidly, thus giving rise to elevated serum progesterone levels withprogesterone doses comparable to those used in creams.
Key Words: Progesterone cream – Progesterone gel – Endometrium – Serum progesterone levels – Postmenopausal women – Skin.
The recent editorial by Dr. Gambrell1 and levels are achieved, with limited symptom relief.
accompanying article by Wren et al2 in the Dr. Gambrell also pointed out that none of the studies January–February 2003 issue of Menopause revealed any improvement in parameters such as endo- has generated considerable controversy about metrial protection, bone mineral density, or cardiovas- the clinical effectiveness of topical progesterone creams in postmenopausal women. In his editorial, Dr.
Gambrell discussed several studies using those creams.
He concluded that, although progesterone in creams can be absorbed through the skin, low serum progesterone Topical creams consist of a variety of lipid-soluble ingredients with different characteristics. The ingre-dients include agents that penetrate, moisturize, and Received December 3, 2003; revised and accepted April 13, 2004.
lubricate the skin, and/or act as emulsifiers. Topical From the Department of Obstetrics and Gynecology, University of progesterone creams contain a blend of those agents Southern California Keck School of Medicine, Los Angeles, CA.
with progesterone, which is also lipophilic. After Address correspondence to: Frank Z. Stanczyk, PhD, Department of topical administration of a progesterone cream, the Obstetrics and Gynecology, WomenÕs & ChildrenÕs Hospital, Room lipophilic substances in the cream, including pro- 1M2, 1240 N. Mission Rd, Los Angeles, CA 90033. E-mail:[email protected] gesterone, undergo absorption by passive diffusion JOBNAME: meno 12#2 2005 PAGE: 2 OUTPUT: Tue February 22 18:09:21 2005lww/meno/82367/GME149345 PERCUTANEOUS ADMINISTRATION OF PROGESTERONE through the different layers of the skin and its append- Medicine Company, Burwash, UK) to a specific area of ages. Thereafter, a resorption process occurs by which the medial aspect of the dominant forearm, using a pro- progesterone enters the cutaneous microcirculation and gesterone dose of 40 mg once daily or 20 mg twice daily eventually the systemic circulation.
for a duration of 6 weeks. Blood was obtained at 0, 2, 4, A number of factors can influence the percutaneous 6, 12, and 24 hours on days 1 and 42 of treatment. No absorption of a drug, eg, progesterone, from a vehicle significant difference was observed in serum pro- such as a cream3-5; they include progesterone concen- gesterone levels between the once and twice daily tration, physical and chemical properties of ingredients dosage regimens. Calculated mean values for the peak in the cream, solubility of progesterone in the cream, the progesterone concentration (Cmax) and area under extent to which the cream ingredients can change the the progesterone concentration-time curve from 0 to integrity of the skin, and the site and surface area of 24 hours (AUC0-24h) in the combined groups were cream application. Because progesterone creams can 0.22 ng/mL and 1.48 ngÁhÁmL21, respectively, on day 1 vary widely with respect to the types and characteristics of treatment. These values increased to 1.67 ng/mL of ingredients that they contain, and their site of appli- and 16.4 ngÁhÁmL21, respectively, on treatment day 42.
cation, the extent of progesterone absorption will also Urinary pregnanediol glucuronide, the major metabo- vary widely. The importance of differences in percu- lite of progesterone in urine, was also quantified in this taneous progesterone absorption at different sites of study. Although its levels were shown to increase after application in women is evident in a study by Krause progesterone treatment, they remained in the follicular et al.6 They showed a significant increase in serum progesterone levels 30 to 120 minutes after applying In the studies by Burry et al7 and Carey et al,8 as well a progesterone ointment on the breast, but no increase as other studies,9-14 of topical progesterone cream was observed after application of the same ointment on administered to postmenopausal women, the average serum progesterone levels did not exceed 3.5 ng/mL(Table 1). The progesterone doses used in those studies One of the most important beneficial effects of progesterone creams should be the protection of theendometrium in postmenopausal women using estrogen It is a widely held assumption that serum pro- treatment. However, a major concern in studies of gesterone levels greater than 5 ng/mL must be achieved topical progesterone creams is that serum or plasma to inhibit endometrial mitosis and to induce a secretory progesterone levels achieved with these formulations change. This threshold level is based on the observation are too low to have an antiproliferative effect on the that during a normal menstrual cycle, the corpus luteum endometrium. In a study by Burry et al,7 six post- produces circulating progesterone levels that are in the menopausal women applied the topical cream, Pro-Gest range of approximately 5 to 20 ng/mL. Wren et al10 (Transitions For Health, Inc., Portland, OR), containing showed no evidence of a secretory endometrium in pos- 30 mg progesterone, on the arms, legs, or chest daily for tmenopausal women using a topical cream (Pro-Feme 2 weeks and then twice daily for another 2 weeks.
Cream, Lawley Pharmaceuticals, Perth, Australia) During the progesterone treatment, the women were containing 16, 32, or 64 mg of progesterone, which also treated daily with 50 mg estradiol administered was administered daily for 14 continuous days (days transdermally by patch. The patch was changed twice 15-28) in each of three 28-day cycles, during which weekly. Blood samples were obtained at 0, 1, 2, 3, 4, 6, a weekly 0.05 mg transdermal estradiol patch was 8, 12, and 24 hours on days 1, 8, 15, 22, and 29. After used. Endometrial biopsies were taken pretreatment treatment, serum progesterone levels increased signif- on day 14 of cycle 1 and during treatment on days 27 icantly from baseline values (, 0.2 ng/mL) and peak levels were obtained at variable times in all subjects.
Although serum progesterone levels (, 3.5 ng/mL) Average progesterone concentrations measured in found in studies of topical progesterone creams are serum samples obtained at each of the 8 sampling generally considered too low to cause a secretory times on the 5 days of frequent sampling ranged from endometrium (Table 1), two reports contradict this gen- 1.0 to 3.3 ng/mL. In a similar study performed by erality. In one of the studies, Leonetti et al13 randomly Carey et al,8 24 postmenopausal women were random- placed postmenopausal women on either a 0% (control, ized to apply progesterone cream (Progestelle, Natural N = 10), 1.5% (15 mg, N = 11), or 4.0% (40 mg, N = 11) JOBNAME: meno 12#2 2005 PAGE: 3 OUTPUT: Tue February 22 18:09:22 2005lww/meno/82367/GME149345 TABLE 1. Summary of studies showing circulating progesterone (P) levels and effects on endometrium, after administration of topical P cream in postmenopausal women aMaximum levels achieved in serum or plasma.
b32 indicates twice daily treatment.
cNot determined.
dRandomized to treatment groups.
eA progesterone-free week was included after the first 3 weeks.
fActual values not stated.
dose of the topical progesterone cream, Pro-Gest, which of egg donation exhibit a lack of secretory changes on was administered twice daily (total daily dose 0, 30, and endometrial biopsy, even after 14 days of treatment with 80 mg, respectively). The cream was used in conjunc- 4 mg of oral micronized estradiol daily followed by tion with an oral 0.625 mg dose of conjugated equine 7 days of 200 mg of vaginal progesterone given three estrogens (CEE) daily for 28 days. Biopsies were times daily. In all of these instances, an increase in the obtained at pretreatment and on day 28 of progesterone estradiol dose in a subsequent cycle has resulted in the treatment. They were reviewed blindly by two pathol- attainment of an appropriately secretory endometrium.
ogists using numerical endometrial proliferation scores Thus, the antiproliferative effect described by Leonetti (EPS) from 0 (inactive) to 4 (highly proliferative). The et al13 and Landes et al14 may be all that can be observed results show that the scores decreased significantly at at the low levels of estradiol priming, and may very well the end of treatment (0.0-0.2), as compared to the pre- correlate with the avoidance of endometrial hyperplasia.
treatment and placebo scores (2.1 to 2.2 and 1.8 to 1.9, Although several factors can be proposed to explain respectively). Although no progesterone values were why antiproliferative endometrium was not found in the reported by the investigators, they did state that plasma study by Wren et al,10 one possible deficiency in their progesterone concentrations were low and varied study appears to be the short duration of progesterone treatment during each cycle. In their study, the inves- The demonstration of antiproliferative endometrium tigators used the Pro-Feme Cream, manufactured by with use of topical progesterone cream is also supported Lawley Pharmaceuticals (Perth, Australia). The product by preliminary data presented by Landes et al.14 In their information sheet that accompanies the cream contains study, postmenopausal women received a pretreatment the following statement: ‘‘In general most significant endometrial biopsy and were randomized to receive physiologic results are not experienced by patients until either 0.625 mg of CEE and 2.5 mg of medroxypro- the fourth to sixth week of usage.’’ Because the women gesterone acetate orally, or the same oral estrogen and in the study by Wren et al10 applied the cream topically 20 mg of progesterone in the topical cream, Pro-gest, for only 2 weeks of each cycle, the duration of treatment daily for 6 months. Of the 40 women who received may not have been sufficient to cause a biologic effect a posttreatment endometrial biopsy, the endometrium on the endometrium. This is important because it is well was atrophic in 28 subjects and proliferative in 6 recognized that, with respect to endometrial protection, subjects in each of the oral and transdermal progestin- length of progestin treatment is more important than treated groups. No information was given about serum In the studies by Leonetti et al13 and Landes et al,14 it may very well be that the reason for not observingsecretory changes in the endometrium after topical The demonstration by Leonetti et al13 and Landes cream progesterone therapy is the low level of estradiol et al14 that topical progesterone cream has an anti- that is typically achieved with menopausal estrogen proliferative effect on estrogen-stimulated endometrium therapy. It has been our experience that some recipients when circulating progesterone levels are low indicates JOBNAME: meno 12#2 2005 PAGE: 4 OUTPUT: Tue February 22 18:09:23 2005lww/meno/82367/GME149345 PERCUTANEOUS ADMINISTRATION OF PROGESTERONE that the endometrial progesterone concentrations were It is now well recognized that salivary progesterone sufficiently high enough to produce a biologic effect in levels can increase from baseline levels by at least two most of the study subjects. These findings are consistent orders of magnitude after topical cream application, with data from other studies, which show that circulating depending on dose and time of saliva sampling. These levels of a steroid may not reflect its concentration in findings are consistent with rapid uptake of pro- a particular tissue. In one of our studies,15 we found gesterone by salivary glands. Presumably there is also a conspicuous variability between serum and secretory rapid uptake of progesterone by other tissues, eg, the endometrial progesterone concentrations after vaginal endometrium, after topical cream administration; how- or intramuscular administration of progesterone to pre- ever, this has not yet been demonstrated.
menopausal women. After 6 days of dosing, peak serum progesterone levels were considerably lower after vaginal administration of 200 mg progesterone every6 hours compared to intramuscular injection of 50 mg It has been proposed that red blood cells may play an progesterone twice daily (11.9 vs 69.8 ng/mL, re- important role in transporting progesterone to salivary spectively). Endometrial concentrations of progester- glands and other tissues throughout the body. The one, however, were significantly greater after vaginal binding of steroids to red blood cells was first administration than after intramuscular administration demonstrated in 1969.21 More recently, Koefoed and (11.5 vs 1.4 ng/g protein, respectively). Our results were Brahm22 studied the in vitro release rates of several subsequently confirmed by Cicinelli et al16 in a study 3H-labeled sex steroids, including progesterone, from similar to ours, except that endometrial tissue specimens human red blood cells. Their results showed that as were obtained from hysterectomy specimens. The much as 15% to 35% of the total hormone content in findings in the two studies not only demonstrate that whole blood may be confined to red blood cells. These serum progesterone levels may not reflect progesterone findings are compatible with a model of rapid transition levels in a particular tissue, but also lend support to the of hormone through the red blood cell membrane and hypothesis that there is preferential distribution of intracellular binding. The authors concluded that the vaginally administered progesterone to the uterus (‘‘first release of steroid hormones from red blood cells is a very fast process, and that these cells may be regarded In another study by Cicinelli et al,19 the investigators as transporters of steroid hormones in a manner similar showed a marginal increase in mean serum pro- to that of albumin, which has a low affinity but high gesterone levels from baseline to end of treatment (0.6 to 3.9 ng/mL), following repetitive administration When progesterone cream is applied to skin, the red of a nasal progesterone spray during the last 10 days of blood cells passing through capillaries in that skin are a 1 month cycle in which 8 postmenopausal women exposed to very high concentrations of progesterone.
ingested CEE daily. However, histologic examination of Because the transit time of red blood cells from the endometrium in each subject showed secretory capillaries has been shown to be very rapid (%1 s),22 changes at the end of treatment from the proliferative progesterone may be delivered directly to tissues via red cells without having a chance to equilibrate with the Additional evidence demonstrating that progesterone systemic blood. In the study by Lewis et al12 that levels in serum may not reflect those measured in tissues showed high salivary progesterone levels in conjunction is found in studies showing that progesterone levels in with low levels of progesterone in plasma after saliva are very high after topical progesterone cream treatment with a topical progesterone cream (Pharma- application, even though serum progesterone levels ceutical Compounding NZ Ltd., Auckland, New are low.11,12,20 OÕLeary et al20 measured progesterone in Zealand) in postmenopausal women, the investigators saliva samples obtained at 0, 0.5, 1, 2, 4, 16, and 24 also quantified progesterone in red blood cells from hours after a single application of a cream containing these subjects. The subjects were randomized to receive 64 mg of progesterone (Pro-Feme Cream) on an inner one of three different progesterone doses: 0 (placebo), 20, arm of each of 6 postmenopausal women. Mean or 40 mg. Treatment was performed daily for 3 weeks, salivary progesterone levels were found to increase followed by a treatment-free week and an additional from baseline levels of 0.09 ng/mL to peak values of 3 weeks of treatment. Blood samples were obtained at 18 ng/mL at 1 hour after treatment, but serum proges- 0, 1, 3, 4, 7, and 8 weeks after treatment. The results terone levels did not change significantly. The salivary show that after progesterone treatment there was large progesterone levels fell to baseline values by 24 hours.
intersubject variability in red blood cell progesterone JOBNAME: meno 12#2 2005 PAGE: 5 OUTPUT: Tue February 22 18:09:24 2005lww/meno/82367/GME149345 levels, which did not exceed 0.27 ng/mL (vs 1.1 and 25.8 ng/mL in plasma and saliva, respectively). The It has been suggested that because transdermally highest increases (23% and 45%) in red blood cell delivered progesterone is a substrate for 5a-reductase in progesterone levels in each treatment group were skin,25 conversion of progesterone to 5a-reduced metab- observed after 1 week. Although the investigators of olites may be a significant factor contributing to low that study concluded that the progesterone levels in red serum progesterone levels and urinary pregnanediol blood cells were too low to be important in the delivery glucuronide excretion. However, one would expect to of progesterone to target tissues, it should be realized find low serum progesterone levels after topical admin- that even small amounts of progesterone taken up by red istration not only of creams but also of gels containing blood cells might be important because the transit time progesterone. Our study23,24 showed that elevated serum of red blood cells from capillaries is very rapid. The progesterone levels are obtained with progesterone gel traditional view is that albumin, SHBG, and CBG are administration. In the study by Lewis et al12 described the important transporters of steroid hormones. However, earlier, the investigators also concluded that conversion the role of red blood cells in steroid hormone transport of progesterone by 5a-reductase is an unlikely mech- has not been studied thoroughly, and such studies are anism to account for low systemic progesterone levels.
They found that serum progesterone levels and urinary pregnanediol glucuronide excretion were not increasedafter treatment of a single subject with the 5a-reductase Although progesterone levels in salivary glands are high after topical progesterone cream application, theconcomitant low progesterone levels found in serum may best be explained by the characteristics of proges- It is obvious that long-term randomized, placebo- terone creams. In our preliminary study23,24 with a controlled trials are required to demonstrate the bene- progesterone gel, we found that serum progesterone ficial effects of topical progesterone creams conclusively.
levels increased by 50% to 100% from baseline levels Studies investigating the effect of topical cream on the and remained in the follicular phase range (, 0.5 ng/mL) endometrium should not be based on serum progesterone after administration of a 30-mg progesterone dose.
levels but on histologic examination of the endometrium.
However, with 100-mg progesterone doses, peak serum Also, conclusions cannot be made about potential progesterone levels of 5.9 to 8.0 ng/mL were found at 2 beneficial effects of topical progesterone creams on to 3 hours after dosing, and thereafter, similar levels other parameters, such as vasomotor symptoms, uro- were achieved at 1, 2, and 4 weeks of treatment.
genital atrophy, bone mineral density, cardiovascular No studies have been performed in which direct markers, cognitive function, and mood, until a wide comparisons of absorption rates were made between range of progesterone doses, eg, 50, 100, and 150 mg, progesterone creams and gels. However, it appears that and different formulations of progesterone creams are steroidal compounds are generally absorbed better from investigated. Finally, an alternate approach that should be gels. One possible explanation for this is that after considered is the use of a progesterone gel instead of absorption through the skin the lipophilic ingredients of a progesterone cream for studying beneficial effects of creams, which include progesterone, may have a prefer- progesterone on the endometrium and other parameters.
ence for saturating the fatty layer below the dermis Progesterone gels are rapidly absorbed, show a dose instead of resorption into the cutaneous microcircula- response of progesterone, and yield relatively high levels tion. Because topical progesterone creams contain of serum progesterone. The argument that therapeutic relatively high doses of the steroid (16- to 80-mg doses creams are preferred over gels by postmenopausal have been studied), even a small portion of the dose women for cosmetic reasons will be weakened if the entering the microcirculation in the skin could account progesterone gel is shown to be more reliable and for the high salivary progesterone concentrations found clinically more effective than the cream.
soon after application of the cream. In contrast toprogesterone creams, progesterone gels are generallyprepared by dissolving the steroid in alcohol, and mixing the alcoholic solution with hydroxypropyl methylcellu-lose and water. This mixture is water-soluble and appears 1. Gambrell RD Jr. Progesterone skin cream and measurements of to enter the microcirculation rapidly after its absorption 2. Wren BG, Champion SM, Willetts K, Manga RZ, Eden JA.
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trial tissue levels of progesterone after administration by in- 3. Wester RC, Maibach HI. Cutaneous pharmacokinetics: 10 steps to tramuscular and vaginal routes: a comparative study. Fertil Steril percutaneous absorption. Drug Metab Rev 1983;14:169-205.
4. Idson B. Vehicle effects in percutaneous absorption. Drug Metab 16. Cicinelli E, Schonauer LM, Galantino P, Matteo MG, Cassetta R, Pinto V. Mechanisms of uterine specificity of vaginal progesterone.
5. Zhai H, Maibach HI. Effects of skin occlusion on percutaneous Hum Reprod 2000;15(suppl 1);159-163.
absorption: an overview. Skin Pharmacol Appl Skin Physiol 2001; 17. Buletti C, de Ziegler D, Flamigni C. Targeted drug delivery in gynecology: the first uterine pass effect. Hum Reprod 1997;12: 6. Krause W, Wichmann U, Horn W. Resorption of progesterone through the intact skin of the breast in comparison with other body 18. Cicinelli E, de Ziegler D, Bulletti C, Matteo MG, Schonauer LM, regions. Geburtshilfe Frauenheilkunde 1987;47:562-564.
Galantino P. Direct transport of progesterone vagina to uterus.
7. Burry KA, Patton PE, Hermsmeyer K. Percutaneous absorption of progesterone in postmenopausal women treated with transdermal 19. Cicinelli E, Cignarelli M, Resta L, Scorcia P, Petruzzi D, Santoro estrogen. Am J Obstet Gynecol 1999;180:1504-1511.
G. Effects of the repetitive administration of progesterone by 8. Carey BJ, Carey AH, Patel S, Carter G, Studd JW. A study to nasal spray in postmenopausal women. Fertil Steril 1993;60:1020- evaluate serum and urinary hormone levels following short and long term administration of two regimens of progesterone cream in 20. OÕLeary P, Feddema P, Chan K, Taranto M, Smith M, Evans postmenopausal women. BJOG 2000;107:722-726.
S. Salivary, but not serum or urinary levels of progesterone are 9. Cooper A, Spencer C, Whitehead MI, Ross D, Barnard GJ, Collins elevated after topical application of progesterone cream to pre- and WP. Systemic absorption of progesterone from Progest cream in postmenopausal women. Clin Endo 2000;53:615-620.
postmenopausal women. Lancet 1998;351:1255-1256.
21. Devenuto F, Ligon DF, Friedrichsen DH, Wilson HL. Human 10. Wren BG, McFarland K, Edwards L. Micronised transdermal pro- erythrocyte membrane uptake of progesterone and chemical gesterone and endometrial response. Lancet 1999;354:1447-1448.
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11. Wren BG, McFarland K, Edwards L, et al. Effect of sequential 22. Koefoed P, Brahm J. The permeability of the human red cell transdermal progesterone cream on endometrium, bleeding pattern, membrane to steroid sex hormones. Biochim Biophys Acta 1994; and plasma progesterone and salivary progesterone levels in postmenopausal women. Climacteric 2000;3:155-160.
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