Historically dosed via injection, suppository, or troche, progesterone is now available in several additional delivery modes.  Of interest is the increase over the last decade in the delivery of hormones through the skin, with various effective modes of application including patches, creams, and gels. Transdermal delivery of hormones has been found to be effective and well tolerated, with the additional benefit of bypassing the first-pass effect of the liver, allowing for reduced dosages as more of the hormone is directly available for its therapeutic effect rather than being mostly metabolized (see Hermann, below).  Micronization of progesterone in oral formulations has also benefited absorption, and some doctors prefer to prescribe oral micronized progesterone because of its tendency to induce drowsiness and thus aid sleep, which may help women who are troubled with night-time menopausal symptoms.  

Further references in the section on “progesterone and the uterus” confirm the effectiveness of topical progesterone preparations in protecting the endometrium from proliferation, which may otherwise lead to the development of uterine cancer, in women using estrogen therapy for menopausal symptoms. 

• Hermann AC, Nafziger AN, Victory J, Kulawy R, Rocci ML Jr, Bertino JS Jr.  Over-the-counter progesterone cream produces significant drug exposure compared to a food and drug administration-approved oral progesterone product.  J Clin Pharmacol 2005; 5(6):614-9. 
  
  In 12 healthy, postmenopausal women, steady state levels of progesterone in the blood were measured in a randomized crossover study comparing topical progesterone cream (Pro-gest®, 40 mg twice daily x 12 days ) with oral micronized progesterone (Prometrium®, 200 mg daily x 12 days). There was no significant difference noted in mean steady state levels between the two products as measured by area under the curve (AUC) of progesterone levels in whole blood. This indicates that equivalent blood levels of progesterone can be achieved with substantially lower doses of topical progesterone cream than with oral micronized progesterone.
  
  
• Waddell BJ, O'Leary PC. Distribution and metabolism of topically applied progesterone in a rat model. J Steroid Biochem Mol Biol 2002 Apr; 80(4-5):449-55.
  
  Following topical application of a commercially available progesterone cream, concentrations of fat and water-soluble metabolites of progesterone were measured in various tissues (uterus, kidney, salivary gland, liver) as well as plasma and urine. The topically applied progesterone was demonstrated to be well absorbed and had distribution and metabolism patterns similar to that seen with intravascular progesterone delivery.
  
  
• Kleinstein J, Schlegelmilch R, Mazur D, Vens-Cappell B. [Pharmacokinetic comparison of progesterone capsules with a progesterone gel after vaginal administration] Arzneimittelforschung 2002; 52(8):615-21[Article in German]
  
  Twenty-four women participated in this randomized controlled, crossover study comparing the bioavailability and pharmacokinetics of a vaginal progesterone capsule (200 mg/dose) vs a progesterone vaginal gel (90 mg/dose). Both were well tolerated, and no differences were noted with respect to safety. The vaginal capsule delivered more progesterone, however peak concentrations between the two preparations didn’t differ.
  
  
• de Ziegler D, Fanchin R. Progesterone and progestins: applications in gynecology. Steroids 2000 Oct-Nov;65(10-11):671-9.
  
  This paper reviews the use of a transvaginal progesterone gel as a viable option to other routes of application of natural progesterone (intramuscular, oral micronized), and offered it as a viable option to synthetic progestins given the low incidence of side effects noted in existing studies.
  
  
• 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 Nov;53(5):615-20.
  
  Absorption of progesterone as provided in a topical preparation of “natural” progesterone cream to 6 premenopausal and 6 postmenopausal women was demonstrated via salivary hormone levels. Salivary progesterone concentrations reached their peak 1-4 hrs after application. A five-fold increase in mean levels was seen in the premenopausal group. Serum progesterone levels were not significantly different from baseline in either group, and serum progesterone was not seen as an effective measure of absorption of topically applied progesterone.
  
  
• Burry KA, Patton PE, Hermsmeyer K. Percutaneous absorption of progesterone in postmenopausal women treated with transdermal estrogen. Am J Obstet Gynecol 1999 Jun;180(6 Pt 1):1504-11.
  
  This pilot study demonstrated a significant increase in serum progesterone levels in 6 women receiving topical progesterone cream (Pro-gest®; 30-60 mg P4/day) and 17beta estradiol (0.05mg patch). The absorption of progesterone via a topical cream correlated well with estrogen absorption (p< 0.001). They concluded that progesterone cream appeared to be a safe and effective route of application.
  
  
• Fanchin R, De Ziegler D, Bergeron C, et al. Transvaginal administration of progesterone. Obstet Gynecol 1997;90:396-401.
  
  Three different doses of transvaginal progesterone gel were administered to 40 estrogen-deprived women aged 25-41 years. Estradiol was administered orally for 28 days, with progesterone added vaginally on alternate days from days 15-27. Plasma gonadotropins, estriol, estradiol and progesterone were measured, and an endometrial biopsy was obtained to assess endometrial status and estrogen and progesterone receptor determinations. Transvaginal progesterone induced normal secretory transformation despite low serum progesterone levels, suggesting a direct transit of progesterone into the uterus, or “first uterine pass effect.”
  
  
• Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol 1997 Nov; 17(11): 3071-8.
  
  Oral hormone replacement therapy postmenopausally has been associated with an increased risk of stoke due to thromboembolism. This randomized, placebo-controlled study evaluated the differing effects of oral and transdermal estrogen/progesterone therapy or placebo on hemostasis. Oral, but not transdermal therapy was seen to increase the susceptibility of clotting in healthy post-menopausal women 45-64 years. The authors concluded that route of administration of hormones can affect the incidence of clotting, with oral hormone replacement increasing risk, and transdermal hormone replacement demonstrating no negative effect on clotting.
  
  
• Kimzey LM, et al. Absorption of micronized progesterone from a nonliquefying vaginal cream. Fertility and Sterility 1991; 56:995-996.
  
  The pharmacokinetics are compared between orally administered micronized progesterone, and that administered through a vaginal cream. Oral progesterone is extensively metabolized prior to reaching the target tissues, and progesterone metabolites may comprise a significant amount of progesterone measured in the serum. When compared, vaginal application sustained progesterone levels over a longer period of time than orally administered progesterone.
  
  
• Hargrove JH, Maxson WS, Wentz AC. Absorption of oral progesterone is influenced by vehicle and particle size. Am J Obstet Gynecol 1989;161:948-51.
  
  This small sample study shows that significant serum progesterone levels can be achieved by oral administration of progesterone. Efficacy of absorption is improved using micronization in oil formulations.
  
  
• Sitruk-Ware R. Transdermal delivery of steroids. Contraception 1989 Jan; 39(1): 1-20.
  
  This review summarizes the advantages of delivering steroids through the skin, as well as reviews skin biology. The authors make a strong case for the choice of transdermal delivery of hormones (especially estrogen, progesterone, and testosterone) for both male and female patients with respect to safety, efficacy, and ease of use and predict this delivery method to make a significant impact on the quality of care for both male and female patients.
  
  
• Nillius SV, Johansson EDB. Plasma levels of progesterone after vaginal, rectal or intramuscular administration of progesterone. Am J Obstet Gynecol 1971;110:470-77.
  
  Plasma levels of progesterone equivalent to normal luteal phase levels were obtained using 25 mg of injected progesterone or 100 mg via rectal or vaginal administration at 8 hours after administration.

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