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From the Townsend Letter
January 2014

The Trouble with Topical Progesterone and Testing
by Dr. David Zava
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Historically, topical progesterone delivery has been much maligned because, regardless of dose, it fails to raise serum progesterone to the levels known to counter estrogen-activated cell proliferation. Oddly, the results of serum progesterone testing, suggesting poor progesterone absorption, have trumped multiple studies showing the clinical benefits of topical progesterone used at physiological doses. Nearly 10 years ago, I wrote an article in the Townsend Letter explaining why topical progesterone is more beneficial than the serum levels might suggest.1 I based this on saliva progesterone testing and published clinical studies, which showed that progesterone applied to the skin results in a dramatic increase in salivary progesterone, as well as tissues, without showing much increase in serum. Since that time, studies have continued to show that topical progesterone does absorb through the skin extremely efficiently, contrary to low venipuncture serum levels, and distributes systemically to other tissues, where it has biological effects. With the advent of capillary blood spot testing for steroid hormones in 2007, we also discovered, serendipitously, that topically delivered progesterone can be found in much higher amounts in capillary blood than in venipuncture serum, adding further support to the concept that topically delivered progesterone enters tissues other than the salivary gland and increases in capillary blood to a level high enough to affect estrogen-activated cell proliferation. In this report I briefly review studies relevant to topical progesterone delivery and include a recent publication in Menopause reporting on the distribution of progesterone in different body fluids following topical progesterone treatment.2 

Optimal Endogenous Progesterone Production in Premenopausal Women and Progesterone Measurement in Serum and Saliva
In premenopausal women, the ovaries optimally produce about 30 mg of progesterone daily during the peak of the luteal phase, which occurs around days 19 to 22 of the menstrual cycle. This peak production of progesterone results in steady state blood serum levels of about 10 to 25 ng/mL, rising from a baseline follicular level of <1 ng/mL. Under these conditions, luteal salivary progesterone ranges from about 100 to 300 pg/mL, or 1% to 2% of serum levels (ZRT Laboratory data), with follicular levels usually <25 pg/mL.

While most laboratories report that serum progesterone ranges from about 3 to 25 ng/mL during the luteal phase of the menstrual cycle, it is well appreciated that >10 ng/mL is required to inhibit estrogen-activated proliferation of estrogen target tissues such as the breasts and uterus.3,4 This is particularly true when the serum estradiol levels are within the high range of normal (100–300 pg/mL). Estradiol within this physiological range seen during the luteal phase of the menstrual cycle requires at least 100 times more progesterone (10,000–30,000 pg/mL; i.e., 10–30 ng/mL, the optimal luteal level) to prevent estradiol from causing excessive tissue hypertrophy and proliferation, which can increase risk for uterine cancer if such proliferation persists for multiple menstrual cycles

Exogenous Topical Progesterone Therapy: Low Serum Progesterone Inconsistent with Clinical Efficacy
When progesterone is applied topically to the skin in physiological amounts (about 30 mg) in the form of a cream or gel, serum levels increase slightly to <1–3 ng/mL, which is considered inadequate to counter the actions of estradiol when it is present at optimal physiological concentrations and higher (>100 pg/mL).5,6 Based on serum progesterone levels, it is assumed that only about 10% of topically applied progesterone is absorbed into the systemic circulation, which accounts for the low serum progesterone (1–3 ng/mL) with physiological (20–30 mg) topical progesterone dosing. Because topically delivered progesterone is assumed to have such poor absorption kinetics, little emphasis has been placed on its potential clinical efficacy, despite evidence to the contrary. This assumption has also led to much higher pharmacological dosing (common dosing with topical progesterone 100–300 mg) in an attempt to raise serum progesterone levels. However, even with pharmacological dosing optimal luteal serum progesterone levels (10–30 ng/mL) are never achieved.5,6
A large body of evidence has been accumulating over the past 30 years to suggest that topically delivered progesterone is indeed clinically effective even though it does not raise serum progesterone levels to optimal luteal levels (10–30 ng/mL). What clinical research studies have shown repeatedly is that topical progesterone at physiological dosing (20–30 mg) has many beneficial effects to reverse symptoms associated with excessive estrogen exposure. It also lowers estradiol-activated cell proliferation in target tissues such as the breasts and uterus. Several pilot studies have explored what effect topically applied progesterone has on estrogen-activated breast cell proliferation.3,7,8 The study by Chang and colleagues showed that when a physiological dose (25 mg) of progesterone gel was applied topically to the breasts for 10 to 13 days, progesterone increased 100-fold in breast tissue biopsies to supraphysiological levels (about 60 ng/g tissue).7 Even though the study clearly showed breast tissue uptake and a biological response to progesterone, serum progesterone levels did not change significantly from placebo-treated patients. Very similar studies have been done by others showing that near-physiological (50 mg) topical progesterone increases breast tissue levels of progesterone and evokes a measurable bioresponse, but does not raise serum levels significantly.8 Similarly, nasal progesterone spray at physiological dosing (11.2 mg 3 times daily) has been shown to lower estrogen-stimulated uterine hyperplasia without increasing serum levels of progesterone to optimal physiological levels (>10–30 ng/ml).9 Similar studies and outcomes have been reported looking at the effects of topical progesterone on estrogen-activated endometrium. Leonetti and colleagues have demonstrated that progesterone applied topically to the skin at physiological dosing (30 mg) inhibits cell proliferation caused by conjugated estrogens, which alone can cause excessive proliferation of the endometrium and increase risk for uterine cancer.4,10 In one of these studies, topical progesterone was as effective as the synthetic progestin, medroxyprogesterone acetate, in inhibiting the stimulating effects of conjugated estrogens.4 

Women's Health Initiative Study Shifts Emphasis from Synthetic Progestins to Natural Progesterone
The landmark series of reports on large clinical trials of postmenopausal hormone replacement therapy all concurred that synthetic progestins increase risk for breast cancer and are associated with more adverse side effects than natural progesterone.11-13 This resulted in a trend toward replacement of the synthetic progestins with natural progesterone for treating women using estrogen replacement for menopausal symptoms.
Despite the demonstrable clinical efficacy of topical progesterone shown in the studies listed above, and the widespread and anecdotal successful use of topical progesterone as an OTC cream and as compounded creams and gels, this form of therapy is not FDA approved and therefore has not received widespread acceptance by most conventional allopathic physicians. Because topical progesterone does not raise venipuncture serum progesterone levels, it has been given little consideration as a treatment option for women endogenously producing estrogens without adequate luteal progesterone (mostly perimenopausal women) or postmenopausal women supplementing with exogenous estrogens.
Because oral progesterone is FDA approved in the form of a capsule containing 100 mg of progesterone in peanut oil, it is widely used as treatment of choice by most physicians. At 200 to 300 mg dosing, it has been shown to be clinically effective at suppressing estrogen-activated cell proliferation of the endometrium, and not to increase risk for developing breast cancer, as seen with synthetic progestins such as medroxyprogesterone acetate.11-15

The obvious question arises as to why topical progesterone is clinically effective, but cannot be found in significant amounts in serum. Testing of progesterone in different body fluids has helped shed some light on this apparent paradox.
Saliva and Capillary Blood Testing for Progesterone Show that Topical Progesterone Absorbs Well and is Systemically Available
As a saliva testing lab, ZRT Laboratory first noticed that women using topical progesterone, as well as other topical steroid hormones (estrogens, androgens, glucocorticoids), had unusually high levels of the topically delivered hormone in their saliva. In fact, physiological dosing of topical progesterone, which most physicians found to be clinically effective (i.e., improved symptoms and signs typical of estrogen excess such as fibrocystic breasts, and prevention of endometrial hyperplasia caused by estrogens) resulted in salivary progesterone levels that were about 10 times the physiological level seen in women at peak of the luteal phase (i.e., 300–3000 pg/mL vs. 100 –300 pg/mL luteal, respectively). Some saliva testing laboratories interpreted this to mean that treating women with a physiological dose of progesterone was an overdose. Serum testing laboratories, which were the majority, had the opposite interpretation. Based on the very low serum progesterone results, their interpretation was that topical progesterone is poorly absorbed and therefore could not be clinically effective. Both views were inconsistent with research studies showing that 10-30 mg of topical progesterone is neither an excessive nor an insufficient dose, since it is clinically effective in many tissues throughout the body.

Capillary Blood Testing Shows that Topical Progesterone is Effectively Transported to Tissues
The advent of capillary blood spot testing, using blood drops from a finger-prick, began to shed some light on this paradox. We developed sex-steroid testing in dried blood spot samples as an alternative to conventional serum testing because, like saliva, it allowed individuals to collect a sample at any time at their convenience.16 Capillary blood spot testing was also a good alternative to saliva for those individuals who had trouble collecting enough saliva and those using hormones in the form of a troche or sublingual drops, which causes false-high hormone levels in saliva due to supersaturation of the oral mucosa.
Our early work with capillary blood spot testing, which was published in Fertility and Sterility, showed that dried blood spot estradiol and progesterone, as well as LH and FSH, levels were quantitatively comparable to conventional venipuncture serum levels in premenopausal cycling women.16 Once we expanded the testing from endogenously produced hormones into the realm of exogenous hormone delivery by various routes of administration (topical, oral, vaginal, sublingual/troche, subcutaneous injections and pellets), we serendipitously discovered that capillary blood levels of progesterone, with physiological topical progesterone dosing (10–30 mg), rose to physiological luteal levels of progesterone (20–40 ng/mL). Venipuncture serum levels under the same conditions rose very little (<3 ng/ml), as elaborated above. We also found that with topical progesterone the capillary blood, progesterone levels increased proportionally to dose, which more closely reflects what others have found with tissue uptake of progesterone, as well as clinical response.3,4,7-10
What we discovered with capillary blood testing of progesterone, following topical progesterone delivery, holds true also for topical delivery of estrogens (estradiol, estriol, estrone) and androgens (testosterone, DHEA) in that physiological dosing with these hormones results in little increase in venipuncture serum levels but a physiological level of hormone in capillary blood. Topical estradiol, even at doses as high as 5 mg (100 times the 25 to 50 µg of estradiol produced by the ovaries daily), does not increase serum estradiol beyond about 50 pg/mL, which would be low range for a premenopausal woman; serum and capillary blood levels of estradiol are about 80 to 150 pg/mL in the luteal phase of premenopausal women.16 Commercially available, FDA-approved topical estrogen sprays and gels deliver estradiol at doses from about 1 to 5 mg but raise serum estradiol levels very little (usually <50 pg/mL). In sharp contrast, this same dosing shows a significant and dose-dependent increase in capillary blood and salivary estradiol that is 50 to 100 times higher than serum levels.
The obvious question that arises is, how could levels of hormone in capillary blood, or blood-feeding tissues, be so much higher than levels in blood returning to the heart (venous blood)?

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