CLIMACTERIC 2014;17(Suppl 2):8–11
Treatment of postmenopausal women with topical progesterone creams and gels: are they effective? F. Z. Stanczyk Departments of Obstetrics and Gynecology, and Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA Key words: PROGESTERONE, CREAM, GEL, POSTMENOPAUSAL WOMEN, SERUM, PLASMA, SALIVA, CAPILLARY BLOOD, ENDOMETRIUM
ABSTRACT Topical progesterone creams and gels can be obtained over the counter and/or by prescription from customcompounding pharmacies and are used by thousands of postmenopausal women for hormonal treatment. However, the effectiveness of these preparations for protecting the endometrium from unopposed estrogen is controversial, due largely to the very low serum progesterone levels that are achieved. Despite these low serum levels, salivary and capillary blood levels are very high and a protective endometrium has been reported in a limited number of studies. Topical alcohol-based, but not water-based, gels appear to yield luteal-phase serum progesterone levels but studies with these preparations are scant. Long-term studies with percutaneous progesterone creams and gels are likely to provide valuable information for treatment of postmenopausal women with this popular route of administration.
INTRODUCTION Progestogens are commonly prescribed for postmenopausal women with a uterus, who are using estrogen therapy to treat symptoms of menopause, to prevent estrogen-induced endometrial hyperplasia and endometrial cancer. The progestogens used for hormonal therapy include the natural progestogen, progesterone, and several different progestins (synthetic progestogens), e.g. medroxyprogesterone acetate and norethindrone acetate. They are available in different doses and can be administered either orally and/or parenterally. A widely used route of parenteral progestogen administration is percutaneous delivery via topical progesterone cream and gel preparations. These preparations are available by prescription at compounding pharmacies, and the creams are also available over the counter. They are used by thousands of postmenopausal women in the United States and Europe and have received wide publicity in the lay press as possible alternatives to conventional estrogen–progestogen hormonal therapy. In addition, it has been suggested that topical progesterone creams and gels may have a number of beneficial effects, not only for protection of the endometrium when used with estrogen, but also
when used alone for the treatment of endometrial hyperplasia, relief of menopausal symptoms, and bone conservation. However, there is little evidence to support these claims. During the past two decades, a major concern and controversy regarding topical progesterone creams and gels pertain to protection of the endometrium in postmenopausal women. In 2003, a position statement by the North American Menopause Society cautioned clinicians that topical progesterone cream or gel preparations obtained over the counter or custom-compounded by prescription may not exert sufficient activity to protect the endometrium from unopposed estrogen1,2. The objective of the present article is to provide an overview on the controversy and problems associated with treatment of postmenopausal women with topical progesterone creams and gels.
EFFECT ON CIRCULATING PROGESTERONE LEVELS AND ENDOMETRIAL PROTECTION Several studies have concluded that serum progesterone levels following application of cream formulations are too low
Correspondence: Professor F. Z. Stanczyk, Departments of Obstetrics and Gynecology, and Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA; E-mail: [email protected] REVIEW © 2014 International Menopause Society DOI: 10.3109/13697137.2014.944496
Received 04-07-2014 Accepted 10-07-2014
Treatment with topical progesterone creams and gels
Stanczyk
to have an antiproliferative effect on the endometrium3. It is generally accepted that serum progesterone levels must be ⬎ 5 ng/ml to inhibit endometrial mitosis and induce secretory change. Table 1 shows that, in five studies in which circulating progesterone levels were measured following topical administration of progesterone creams in postmenopausal women (n ⫽ 6–40), the levels did not exceed 3.5 ng/ml4-8. In a sixth study9, progesterone levels were low, but no values were given, and, in a seventh study10, progesterone levels were not measured. In these studies, the administered progesterone dose ranged from 16 to 80 mg and the duration of treatment was 1.4 to 24 weeks. Table 1 also shows that four of the seven studies did not determine effects on the endometrium. In the three studies in which the endometrium was biopsied and examined, an antiproliferative effect was found in all subjects in the study by Leonetti and colleagues9, whereas no effect was observed in the study by Wren and colleagues7. In the latter study, the duration of treatment was 2 weeks. In the package insert that accompanied the cream used in the study by Wren and colleagues7, the manufacturer of the cream stated that significant physiologic results are not experienced by patients until the 4th to 6th week of usage. In the study by Landes and colleagues10, the endometrium was reported to be atrophic in 28 of the subjects. Although the results from two studies show a protective effect on the endometrium with topical progesterone creams9,10, there are insufficient data to draw reliable conclusions regarding endometrial protection with these preparations. In addition, in one of the studies10 not all subjects showed an atrophic endometrium (28 out of 40 subjects). Also, the number of subjects used in these studies is relatively small (n ⫽ 37–40). From these considerations, it is obvious that long-term, randomized, placebo-controlled trials are required to demonstrate a protective effect of topical progesterone cream on the endometrium. In a more recent study11, we measured progesterone levels in serum, whole blood, saliva and capillary blood following application of topical progesterone cream or gel
in postmenopausal women. Ten women were randomized to receive 80 mg of progesterone in an oil-based cream or water-based gel applied daily for 14 days, crossing over after a 14-day washout. On the last day of each treatment period, venous blood, saliva and fingertip capillary blood were sampled at frequent intervals over a 24-h period after the final application. The results show that, after application of either topical progesterone cream or gel, salivary and capillary blood levels were approximately 10-fold and 100fold greater, respectively, than those seen in serum or whole blood. High salivary progesterone in conjunction with low circulating progesterone levels have been reported in other studies8,12. The salivary and capillary blood progesterone levels observed in the studies just described are in the supraphysiologic range. These levels are well in excess of the salivary and capillary blood progesterone normal ranges for both postmenopausal and premenopausal women. The reference ranges at the ZRT Laboratory for salivary and capillary blood progesterone are 0.75–2.5 ng/ml and 3.3– 22.5 ng/ml in the luteal phase and 0.12–1.0 ng/ml and ⬍ 0.1–0.8 ng/ml in the postmenopause, respectively. The corresponding progesterone levels in the study by Du and colleagues11, which were also measured at the ZRT Laboratory, were 4–12 ng/ml and 62–96 ng/ml, respectively. Thus, our data confirm the distribution of progesterone to tissues despite very low serum progesterone levels. The mechanism by which this occurs is poorly understood. Although the above observations show that serum or plasma progesterone levels cannot be used as an index of tissue exposure to progesterone following topical progesterone cream or gel therapy, this may not apply to topical progesterone gels that are alcohol-based. In a preliminary study13, we showed that luteal-phase plasma progesterone levels were achieved with an alcohol-based, topical progesterone gel containing 100 mg of progesterone in postmenopausal women; the peak progesterone levels were approximately 8 ng/ml. In the study by Du and colleagues11, in which a water-based, topical progesterone gel was used, the serum progesterone levels did not exceed 1.5 ng/ml.
Table 1 Summary of studies showing circulating progesterone (P) levels and effects on the endometrium following administration of topical progesterone cream in postmenopausal women
Reference
n
Type of cream
4 5 6 7 8 9 10
6 24 10 27 24 37 40
Pro-Gest Progestelle Pro-Gest Pro-Feme compounded Pro-Gest Pro-Gest
Daily P dose (mg)
Duration of treatment (weeks)
Mean P levels (ng/ml)
Effect on endometrium
30 or 60 40 or 20 40–80 16, 32 or 64 0, 40 or 80 0, 15 or 40 20
2 6 1.4 2 6 4 24
3.3 1.67 2.9 ⬍ 3.5 3.5 low not given
ND ND ND no effect ND antiproliferative atrophic (in 28)
ND, not determined
Climacteric
9
Treatment with topical progesterone creams and gels
CONCERNS REGARDING CIRCULATING PROGESTERONE LEVELS ACHIEVED WITH TOPICAL PROGESTERONE CREAM AND GELS Another major concern in women using topical progesterone creams or water-based gels is that serum progesterone levels do not reflect the corresponding supraphysiologic levels in tissues, which potentially may cause harmful effects. Minor side-effects of topical progesterone creams or gels may be exacerbated. Oversaturation of tissues and cellular progesterone receptors with progesterone may eventually compromise clinical responses due to persistent progesterone receptors or estrogen receptor down-regulation and/or over-production of downstream progesterone metabolites with agonist or antagonist bioactivities. Thus, it is essential to monitor progesterone levels in women using topical progesterone creams or waterbased gels. Since serum levels obtained with these preparations do not reflect tissue levels, testing progesterone levels in saliva in a well-established laboratory, where reference ranges are available, may prevent harmful effects in postmenopausal women using these preparations.
COMPARISON OF WATER-BASED VERSUS ALCOHOL-BASED GELS We have focused on data pertaining to circulating, salivary and capillary blood levels obtained with topical progesterone creams because these preparations are widely available over the counter and used by thousands of postmenopausal women. Based on the study by Du and colleagues11, it appears that topical progesterone gels which are water-based, and not alcohol-based, also yield low serum progesterone levels accompanied by very high salivary and capillary blood progesterone levels. In contrast, alcohol-based, progesterone gels appear to yield relatively high serum progesterone levels, based on limited data; however, there are no studies comparing serum, salivary and capillary blood progesterone levels in postmenopausal women treated with these preparations. A similar situation exists with topical estradiol and testosterone creams and gels, which are also used by thousands of postmenopausal women. However, unlike topical progesterone creams, topical estradiol and testosterone creams are not available over the counter and are usually prepared by compounding pharmacies. Topical estradiol and testosterone gels are also usually prepared by compounding pharmacies.
CONCERNS REGARDING CUSTOMCOMPOUNDED TOPICAL PROGESTERONE CREAMS AND GELS Because topical progesterone creams and gels are often prepared by custom-compounding pharmacies, it is important to realize that postmenopausal women using these preparations may be subject to overdosing or underdosing of progesterone because there is no strict regulation and oversight of compounded medicines14. Thus, steroid doses of
10
Stanczyk products prepared by custom-compounding pharmacies are not regulated, and most often little is known about the pharmacokinetics of the products. The doses can be based on a physician’s prescription, using information either reported in the literature or not evidence-based. In addition, in most instances, the physician does not send serum and/or salivary samples to a diagnostic laboratory to determine steroid levels achieved by a particular custom-compounded steroid hormone preparation. Furthermore, overthe-counter hormonal preparations can be used by women with no oversight by physicians as to the medical history of the patient, potential presence of risk factors, or circulating and/or salivary levels of active hormones attained with these products.
SUMMARY AND CONCLUSIONS In summary, on the basis of our studies and those of others on absorption of progesterone from topical creams in postmenopausal women, it appears that progesterone absorption from these creams is much more efficient than has been reported. Several studies have concluded that progesterone is not well absorbed following topical application of a progesterone cream and will not protect the endometrium from estrogen stimulation. However, the conclusions from these studies are predominantly based solely on measurement of progesterone in venous serum or plasma levels and findings that the progesterone levels are very low. Our findings that salivary and capillary blood levels of progesterone increase dramatically with topical progesterone creams, in addition to some published observations showing therapeutic effects on the endometrium, confirm the distribution of progesterone to tissues despite very low serum or plasma progesterone levels. Thus, serum or plasma progesterone levels cannot be used as an index of tissue exposure to progesterone following topical progesterone cream therapy. Although topical progesterone gels are also widely used by postmenopausal women, there is a paucity of data on the absorption of progesterone from these gels. Based on our preliminary data, it appears that serum progesterone levels achieved with alcohol-based, topical progesterone gels can reach elevated progesterone values found during the luteal phase. In contrast, serum progesterone levels achieved in our study with a waterbased, topical progesterone gel were very low and similar to those achieved with a topical progesterone cream. Obviously, much more research is required to demonstrate a protective effect of topical progesterone creams and gels on the endometrium. Long-term studies with a sufficient number of postmenopausal women and different doses of progesterone are essential. In addition, studies should be performed to resolve the question of why serum progesterone levels are so low with topical progesterone creams and gels when salivary and capillary blood progesterone levels are so high. Such information should provide valuable information that may be useful in percutaneous treatment of postmenopausal women, not only with progesterone preparations but also other hormonal preparations.
Climacteric
Treatment with topical progesterone creams and gels
ACKNOWLEDGEMENTS I thank Margaret N. Groves, MPhil, ELS and Mary Stanczyk for their help in the preparation of the manuscript.
Stanczyk Conflict of interest The author reports no confl ict of interest. The author alone is responsible for the content and writing of this paper. Source of funding
Nil.
References 1. Position Statement: Role of progestogen in hormone therapy for postmenopausal women: position statement of the North American Menopause Society. Menopause 2003;10:113–32 2. Position Statement: The 2012 hormone therapy position statement of the North American Menopause Society. Menopause 2012;19:257–71 3. Stanczyk FZ, Paulson RJ, Roy S. Percutaneous administration of progesterone: blood levels and endometrial protection. Menopause 2005;12:232–7 4. Burry KA, Patton PE, Hermsmeyer K. Percutaneous absorption of progesterone in postmenopausal women treated with transdermal estrogen. Am J Obstet Gynecol 1999;180:1504–11 5. Carey BJ, Carey AH, Patel S, Carter G, Studd JW. A study to evaluate serum and urinary hormone levels following short and long term administration of two regimens of progesterone cream in postmenopausal women. BJOG 2000;107:722–6 6. Cooper A, Spencer C, Whitehead MI, Ross D, Bernard GJ, Collins WP. Systemic absorption of progesterone from Progest cream in postmenopausal women. Lancet 1998;31:1255–6 7. Wren BG, McFarland K, Edwards L, et al. Effect of sequential transdermal progesterone cream on endometrium, bleeding pattern, and plasma progesterone and salivary progesterone levels in postmenopausal women. Climacteric 2000;3:155–60 8. Lewis JG, McGill H, Patton VM, Elder PA. Caution on the use of saliva measurements to monitor absorption of progesterone
Climacteric
9.
10.
11.
12.
13.
14.
from transdermal creams in postmenopausal women. Maturitas 2002;41:1–6 Leonetti HB, Wilson KJ, Anasti JN. Topical progesterone cream has an anti proliferative effect on estrogen-stimulated endometrium. Fertil Steril 2003;79:221–2 Landes J, Leonetti HB. Topical progesterone cream: An alternative progestin in hormone replacement therapy. Obstet Gynecol 2003;101(Suppl 1):56 Du JY, Sanchez P, Kim L, Azen CG, Zava DT, Stanczyk FZ. Percutaneous progesterone delivery via cream or gel application in postmenopausal women: a randomized cross-over study of progesterone levels in serum, whole blood, saliva, and capillary blood. Menopause 2013;20:1169–75 O’Leary P, Feddema P, Chan K, Taranto M, Smith M, Evans S. Salivary, but not serum or urinary, levels of progesterone are elevated after topical application of progesterone cream to pre- and postmenopausal women. Clin Endocrinol (Oxf) 2000;53:615–20 Bello SM, Mezrow G, Shoupe D, Winer SA, Stanczyk FZ. Administration of progesterone by use of a percutaneous gel in postmenopausal women. Presented at the 45th Annual Meeting of the Pacific Coast Fertility Society, Indian Wells, CA, USA, April 10–13, 1997 Bhavnani BR, Stanczyk FZ. Misconception and concerns about bioidentical hormones used for custom-compounded hormone therapy. JCEM 2012;97:756–9
11
Copyright of Climacteric is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Treatment of postmenopausal women with topical progesterone creams and gels: are they effective? F. Z. Stanczyk Departments of Obstetrics and Gynecology, and Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA Key words: PROGESTERONE, CREAM, GEL, POSTMENOPAUSAL WOMEN, SERUM, PLASMA, SALIVA, CAPILLARY BLOOD, ENDOMETRIUM
ABSTRACT Topical progesterone creams and gels can be obtained over the counter and/or by prescription from customcompounding pharmacies and are used by thousands of postmenopausal women for hormonal treatment. However, the effectiveness of these preparations for protecting the endometrium from unopposed estrogen is controversial, due largely to the very low serum progesterone levels that are achieved. Despite these low serum levels, salivary and capillary blood levels are very high and a protective endometrium has been reported in a limited number of studies. Topical alcohol-based, but not water-based, gels appear to yield luteal-phase serum progesterone levels but studies with these preparations are scant. Long-term studies with percutaneous progesterone creams and gels are likely to provide valuable information for treatment of postmenopausal women with this popular route of administration.
INTRODUCTION Progestogens are commonly prescribed for postmenopausal women with a uterus, who are using estrogen therapy to treat symptoms of menopause, to prevent estrogen-induced endometrial hyperplasia and endometrial cancer. The progestogens used for hormonal therapy include the natural progestogen, progesterone, and several different progestins (synthetic progestogens), e.g. medroxyprogesterone acetate and norethindrone acetate. They are available in different doses and can be administered either orally and/or parenterally. A widely used route of parenteral progestogen administration is percutaneous delivery via topical progesterone cream and gel preparations. These preparations are available by prescription at compounding pharmacies, and the creams are also available over the counter. They are used by thousands of postmenopausal women in the United States and Europe and have received wide publicity in the lay press as possible alternatives to conventional estrogen–progestogen hormonal therapy. In addition, it has been suggested that topical progesterone creams and gels may have a number of beneficial effects, not only for protection of the endometrium when used with estrogen, but also
when used alone for the treatment of endometrial hyperplasia, relief of menopausal symptoms, and bone conservation. However, there is little evidence to support these claims. During the past two decades, a major concern and controversy regarding topical progesterone creams and gels pertain to protection of the endometrium in postmenopausal women. In 2003, a position statement by the North American Menopause Society cautioned clinicians that topical progesterone cream or gel preparations obtained over the counter or custom-compounded by prescription may not exert sufficient activity to protect the endometrium from unopposed estrogen1,2. The objective of the present article is to provide an overview on the controversy and problems associated with treatment of postmenopausal women with topical progesterone creams and gels.
EFFECT ON CIRCULATING PROGESTERONE LEVELS AND ENDOMETRIAL PROTECTION Several studies have concluded that serum progesterone levels following application of cream formulations are too low
Correspondence: Professor F. Z. Stanczyk, Departments of Obstetrics and Gynecology, and Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA; E-mail: [email protected] REVIEW © 2014 International Menopause Society DOI: 10.3109/13697137.2014.944496
Received 04-07-2014 Accepted 10-07-2014
Treatment with topical progesterone creams and gels
Stanczyk
to have an antiproliferative effect on the endometrium3. It is generally accepted that serum progesterone levels must be ⬎ 5 ng/ml to inhibit endometrial mitosis and induce secretory change. Table 1 shows that, in five studies in which circulating progesterone levels were measured following topical administration of progesterone creams in postmenopausal women (n ⫽ 6–40), the levels did not exceed 3.5 ng/ml4-8. In a sixth study9, progesterone levels were low, but no values were given, and, in a seventh study10, progesterone levels were not measured. In these studies, the administered progesterone dose ranged from 16 to 80 mg and the duration of treatment was 1.4 to 24 weeks. Table 1 also shows that four of the seven studies did not determine effects on the endometrium. In the three studies in which the endometrium was biopsied and examined, an antiproliferative effect was found in all subjects in the study by Leonetti and colleagues9, whereas no effect was observed in the study by Wren and colleagues7. In the latter study, the duration of treatment was 2 weeks. In the package insert that accompanied the cream used in the study by Wren and colleagues7, the manufacturer of the cream stated that significant physiologic results are not experienced by patients until the 4th to 6th week of usage. In the study by Landes and colleagues10, the endometrium was reported to be atrophic in 28 of the subjects. Although the results from two studies show a protective effect on the endometrium with topical progesterone creams9,10, there are insufficient data to draw reliable conclusions regarding endometrial protection with these preparations. In addition, in one of the studies10 not all subjects showed an atrophic endometrium (28 out of 40 subjects). Also, the number of subjects used in these studies is relatively small (n ⫽ 37–40). From these considerations, it is obvious that long-term, randomized, placebo-controlled trials are required to demonstrate a protective effect of topical progesterone cream on the endometrium. In a more recent study11, we measured progesterone levels in serum, whole blood, saliva and capillary blood following application of topical progesterone cream or gel
in postmenopausal women. Ten women were randomized to receive 80 mg of progesterone in an oil-based cream or water-based gel applied daily for 14 days, crossing over after a 14-day washout. On the last day of each treatment period, venous blood, saliva and fingertip capillary blood were sampled at frequent intervals over a 24-h period after the final application. The results show that, after application of either topical progesterone cream or gel, salivary and capillary blood levels were approximately 10-fold and 100fold greater, respectively, than those seen in serum or whole blood. High salivary progesterone in conjunction with low circulating progesterone levels have been reported in other studies8,12. The salivary and capillary blood progesterone levels observed in the studies just described are in the supraphysiologic range. These levels are well in excess of the salivary and capillary blood progesterone normal ranges for both postmenopausal and premenopausal women. The reference ranges at the ZRT Laboratory for salivary and capillary blood progesterone are 0.75–2.5 ng/ml and 3.3– 22.5 ng/ml in the luteal phase and 0.12–1.0 ng/ml and ⬍ 0.1–0.8 ng/ml in the postmenopause, respectively. The corresponding progesterone levels in the study by Du and colleagues11, which were also measured at the ZRT Laboratory, were 4–12 ng/ml and 62–96 ng/ml, respectively. Thus, our data confirm the distribution of progesterone to tissues despite very low serum progesterone levels. The mechanism by which this occurs is poorly understood. Although the above observations show that serum or plasma progesterone levels cannot be used as an index of tissue exposure to progesterone following topical progesterone cream or gel therapy, this may not apply to topical progesterone gels that are alcohol-based. In a preliminary study13, we showed that luteal-phase plasma progesterone levels were achieved with an alcohol-based, topical progesterone gel containing 100 mg of progesterone in postmenopausal women; the peak progesterone levels were approximately 8 ng/ml. In the study by Du and colleagues11, in which a water-based, topical progesterone gel was used, the serum progesterone levels did not exceed 1.5 ng/ml.
Table 1 Summary of studies showing circulating progesterone (P) levels and effects on the endometrium following administration of topical progesterone cream in postmenopausal women
Reference
n
Type of cream
4 5 6 7 8 9 10
6 24 10 27 24 37 40
Pro-Gest Progestelle Pro-Gest Pro-Feme compounded Pro-Gest Pro-Gest
Daily P dose (mg)
Duration of treatment (weeks)
Mean P levels (ng/ml)
Effect on endometrium
30 or 60 40 or 20 40–80 16, 32 or 64 0, 40 or 80 0, 15 or 40 20
2 6 1.4 2 6 4 24
3.3 1.67 2.9 ⬍ 3.5 3.5 low not given
ND ND ND no effect ND antiproliferative atrophic (in 28)
ND, not determined
Climacteric
9
Treatment with topical progesterone creams and gels
CONCERNS REGARDING CIRCULATING PROGESTERONE LEVELS ACHIEVED WITH TOPICAL PROGESTERONE CREAM AND GELS Another major concern in women using topical progesterone creams or water-based gels is that serum progesterone levels do not reflect the corresponding supraphysiologic levels in tissues, which potentially may cause harmful effects. Minor side-effects of topical progesterone creams or gels may be exacerbated. Oversaturation of tissues and cellular progesterone receptors with progesterone may eventually compromise clinical responses due to persistent progesterone receptors or estrogen receptor down-regulation and/or over-production of downstream progesterone metabolites with agonist or antagonist bioactivities. Thus, it is essential to monitor progesterone levels in women using topical progesterone creams or waterbased gels. Since serum levels obtained with these preparations do not reflect tissue levels, testing progesterone levels in saliva in a well-established laboratory, where reference ranges are available, may prevent harmful effects in postmenopausal women using these preparations.
COMPARISON OF WATER-BASED VERSUS ALCOHOL-BASED GELS We have focused on data pertaining to circulating, salivary and capillary blood levels obtained with topical progesterone creams because these preparations are widely available over the counter and used by thousands of postmenopausal women. Based on the study by Du and colleagues11, it appears that topical progesterone gels which are water-based, and not alcohol-based, also yield low serum progesterone levels accompanied by very high salivary and capillary blood progesterone levels. In contrast, alcohol-based, progesterone gels appear to yield relatively high serum progesterone levels, based on limited data; however, there are no studies comparing serum, salivary and capillary blood progesterone levels in postmenopausal women treated with these preparations. A similar situation exists with topical estradiol and testosterone creams and gels, which are also used by thousands of postmenopausal women. However, unlike topical progesterone creams, topical estradiol and testosterone creams are not available over the counter and are usually prepared by compounding pharmacies. Topical estradiol and testosterone gels are also usually prepared by compounding pharmacies.
CONCERNS REGARDING CUSTOMCOMPOUNDED TOPICAL PROGESTERONE CREAMS AND GELS Because topical progesterone creams and gels are often prepared by custom-compounding pharmacies, it is important to realize that postmenopausal women using these preparations may be subject to overdosing or underdosing of progesterone because there is no strict regulation and oversight of compounded medicines14. Thus, steroid doses of
10
Stanczyk products prepared by custom-compounding pharmacies are not regulated, and most often little is known about the pharmacokinetics of the products. The doses can be based on a physician’s prescription, using information either reported in the literature or not evidence-based. In addition, in most instances, the physician does not send serum and/or salivary samples to a diagnostic laboratory to determine steroid levels achieved by a particular custom-compounded steroid hormone preparation. Furthermore, overthe-counter hormonal preparations can be used by women with no oversight by physicians as to the medical history of the patient, potential presence of risk factors, or circulating and/or salivary levels of active hormones attained with these products.
SUMMARY AND CONCLUSIONS In summary, on the basis of our studies and those of others on absorption of progesterone from topical creams in postmenopausal women, it appears that progesterone absorption from these creams is much more efficient than has been reported. Several studies have concluded that progesterone is not well absorbed following topical application of a progesterone cream and will not protect the endometrium from estrogen stimulation. However, the conclusions from these studies are predominantly based solely on measurement of progesterone in venous serum or plasma levels and findings that the progesterone levels are very low. Our findings that salivary and capillary blood levels of progesterone increase dramatically with topical progesterone creams, in addition to some published observations showing therapeutic effects on the endometrium, confirm the distribution of progesterone to tissues despite very low serum or plasma progesterone levels. Thus, serum or plasma progesterone levels cannot be used as an index of tissue exposure to progesterone following topical progesterone cream therapy. Although topical progesterone gels are also widely used by postmenopausal women, there is a paucity of data on the absorption of progesterone from these gels. Based on our preliminary data, it appears that serum progesterone levels achieved with alcohol-based, topical progesterone gels can reach elevated progesterone values found during the luteal phase. In contrast, serum progesterone levels achieved in our study with a waterbased, topical progesterone gel were very low and similar to those achieved with a topical progesterone cream. Obviously, much more research is required to demonstrate a protective effect of topical progesterone creams and gels on the endometrium. Long-term studies with a sufficient number of postmenopausal women and different doses of progesterone are essential. In addition, studies should be performed to resolve the question of why serum progesterone levels are so low with topical progesterone creams and gels when salivary and capillary blood progesterone levels are so high. Such information should provide valuable information that may be useful in percutaneous treatment of postmenopausal women, not only with progesterone preparations but also other hormonal preparations.
Climacteric
Treatment with topical progesterone creams and gels
ACKNOWLEDGEMENTS I thank Margaret N. Groves, MPhil, ELS and Mary Stanczyk for their help in the preparation of the manuscript.
Stanczyk Conflict of interest The author reports no confl ict of interest. The author alone is responsible for the content and writing of this paper. Source of funding
Nil.
References 1. Position Statement: Role of progestogen in hormone therapy for postmenopausal women: position statement of the North American Menopause Society. Menopause 2003;10:113–32 2. Position Statement: The 2012 hormone therapy position statement of the North American Menopause Society. Menopause 2012;19:257–71 3. Stanczyk FZ, Paulson RJ, Roy S. Percutaneous administration of progesterone: blood levels and endometrial protection. Menopause 2005;12:232–7 4. Burry KA, Patton PE, Hermsmeyer K. Percutaneous absorption of progesterone in postmenopausal women treated with transdermal estrogen. Am J Obstet Gynecol 1999;180:1504–11 5. Carey BJ, Carey AH, Patel S, Carter G, Studd JW. A study to evaluate serum and urinary hormone levels following short and long term administration of two regimens of progesterone cream in postmenopausal women. BJOG 2000;107:722–6 6. Cooper A, Spencer C, Whitehead MI, Ross D, Bernard GJ, Collins WP. Systemic absorption of progesterone from Progest cream in postmenopausal women. Lancet 1998;31:1255–6 7. Wren BG, McFarland K, Edwards L, et al. Effect of sequential transdermal progesterone cream on endometrium, bleeding pattern, and plasma progesterone and salivary progesterone levels in postmenopausal women. Climacteric 2000;3:155–60 8. Lewis JG, McGill H, Patton VM, Elder PA. Caution on the use of saliva measurements to monitor absorption of progesterone
Climacteric
9.
10.
11.
12.
13.
14.
from transdermal creams in postmenopausal women. Maturitas 2002;41:1–6 Leonetti HB, Wilson KJ, Anasti JN. Topical progesterone cream has an anti proliferative effect on estrogen-stimulated endometrium. Fertil Steril 2003;79:221–2 Landes J, Leonetti HB. Topical progesterone cream: An alternative progestin in hormone replacement therapy. Obstet Gynecol 2003;101(Suppl 1):56 Du JY, Sanchez P, Kim L, Azen CG, Zava DT, Stanczyk FZ. Percutaneous progesterone delivery via cream or gel application in postmenopausal women: a randomized cross-over study of progesterone levels in serum, whole blood, saliva, and capillary blood. Menopause 2013;20:1169–75 O’Leary P, Feddema P, Chan K, Taranto M, Smith M, Evans S. Salivary, but not serum or urinary, levels of progesterone are elevated after topical application of progesterone cream to pre- and postmenopausal women. Clin Endocrinol (Oxf) 2000;53:615–20 Bello SM, Mezrow G, Shoupe D, Winer SA, Stanczyk FZ. Administration of progesterone by use of a percutaneous gel in postmenopausal women. Presented at the 45th Annual Meeting of the Pacific Coast Fertility Society, Indian Wells, CA, USA, April 10–13, 1997 Bhavnani BR, Stanczyk FZ. Misconception and concerns about bioidentical hormones used for custom-compounded hormone therapy. JCEM 2012;97:756–9
11
Copyright of Climacteric is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
