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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

Du, Joanna Y. MD; Sanchez, Puy MD; Kim, Lila BS; Azen, Colleen G. MS; Zava, David T. PhD; Stanczyk, Frank Z. PhD

doi: 10.1097/GME.0b013e31828d39a2
Original Study

Objective This study aims to investigate the distribution of progesterone in venous whole blood, venous serum, fingertip capillary blood, and saliva after its topical application in both cream and gel formulations.

Methods Ten postmenopausal women were randomized to receive 80 mg of progesterone cream or gel applied daily for 14 days, crossing over after a 14-day washout. On the last day of each treatment period, venous blood, fingertip capillary blood, and saliva were sampled frequently for 24 hours after the final application.

Results After progesterone cream or gel application, serum progesterone levels rose gradually, reaching a peak at 9 and 8 hours, respectively; AUC0-24 h was significantly higher with cream (12.39 vs 8.32 ng h mL−1, P = 0.0391). Whole venous blood levels followed a pattern similar to that of serum but were considerably lower. Saliva progesterone showed a peak at 1 and 6 hours after cream and gel application, respectively, and C max was comparable with cream and gel. Saliva AUC0-24 h was substantially higher than the corresponding area under the curve for serum or whole blood but did not differ significantly by delivery method (39.02 and 58.37 ng h mL−1, P = 0.69). In capillary blood, C max was reached at the same time (8 h) and was similar with both formulations; AUC0-24 h was also similar with both formulations (1,056 ng h mL−1 for cream and 999 ng h mL−1 for gel) but was dramatically higher than the corresponding areas under the curve for venous serum and whole blood.

Conclusions After application of topical progesterone, saliva and capillary blood levels are approximately 10-fold and 100-fold greater, respectively, than those seen in serum or whole blood. High capillary blood and saliva levels indicate high absorption and transport of progesterone to tissues. Reliance on serum levels of progesterone for monitoring topical dose could lead to underestimation of tissue levels and consequent overdose.

From the 1Department of Obstetrics and Gynecology and 2Southern California Clinical and Translational Science Institute, University of Southern California Keck School of Medicine, Los Angeles, CA; and 3ZRT Laboratory, Beaverton, OR; and 4Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA.

Received August 16, 2012; revised and accepted February 12, 2013.

Present address of P.S.: Department of Obstetrics and Gynecology, Hospital La Zarzuela, Madrid, Spain.

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

Funding/support: This publication was supported by grant UL1 RR031986 from the National Institutes of Health/National Center for Research Resources Southern California Clinical and Translational Science Institute.

Financial disclosure/conflicts of interest: D.T.Z. is the owner/president of ZRT Laboratory.

Address correspondence to: Frank Z. Stanczyk, PhD, Reproductive Endocrine Research Laboratory, Room 207, Livingston Research Building, 1321 North Mission Road, Los Angeles, CA 90033. E-mail:

© 2013 by The North American Menopause Society.