Topical Delivery of Sex Steroid Hormones and Distribution in Different Body Fluids
Table 2
Saliva, DBS, Serum, Urine with Topical Estradiol (E2)
plasma levels), and urine pregnanediol, a surrogate for Pg, about 500-2000 ug/g Cr (Table 3). To achieve premenopausal luteal physiological ranges in postmenopausal women with topical Pg therapy only requires physiological dosing when measuring saliva and capillary whole blood (i.e. about 10-50 mg topical Pg)(Du JY, 2013, Zava DT, 2014), but at least 10x higher dosing (100-300 mg topical progesterone) when measuring venipuncture serum/plasma. Urine pregnanediol increases very little with increasing doses of Pg (O’Leary P, 2000).
Table 3
Saliva, DBS, Serum, Urine Progesterone (Pg) with Topical Progesterone Therapy
In men, topical T distributes into the same body fluids similar to topical E2 and Pg in women. In healthy young males, the testes produce about 5-7 mg of testosterone daily and the morning and testosterone levels range from about 500-1200 ng/dL in serum/plasma and capillary blood, 100250 pg/ml in saliva, and 1-4 ug/g Cr in urine (Table 4). To achieve physiological ranges of a healthy young male in the body fluids of hypogonadal men with topical T therapy only requires physiological dosing for saliva and capillary whole blood (i.e. about 5-10 mg topical T), but at least 10x higher dosing (50-200 mg topical T) for venipuncture serum/plasma or urine levels.
Table 4
Saliva, DBS, Serum, and Urine Testosterone (T) with Topical Testosterone Therapy
The lack of increase in serum and urine levels of topically delivered hormones at physiological dosing (i.e. 50-200 ug E2 and 10-30 mg Pg in women and 5-10 mg T in men)(Tables 2-4), has resulted in justification of dose escalation of FDAapproved and compounded products to amounts that are 10 to 20-fold higher (i.e. 500-5000 ug E2 and 100-300 mg Pg in women and 50-200 mg T in men) than levels of these hormones that are produced by the gonads of healthy young women and men over a 24 hr period (Table 1). Justification for these 10x pharmacological topical doses is based more on serum and urine levels than clinical response. Only a handful of studies have evaluated the clinical efficacy of lower physiological topical hormone dosing relative to the more allopathic acceptance of pharmacological dosing. However, some studies have clearly shown that more physiological dosing with topical E2 and progesterone are clinically effective for increasing bone mass (Prestwood KM, 2003) and protecting the breasts (Chang KJ, 1995) and endometrium (Leonetti HB, 2003) at physiological dosing of E2 and Pg applied topically. The advent of monitoring steroid hormones in body fluids that more closely reflect tissue levels of hormones, namely saliva and capillary whole blood derived from the fingertip (Dried Blood Spot-DBS), has serendipitously shed light on why such high pharmacological dosing is required to achieve even suboptimal physiological levels of hormones in serum and urine. More recent studies over the past 20 years has revealed that while salivary and capillary blood levels of endogenously produced steroids quantitatively parallel levels of parent hormones (E2, Pg, T) seen in serum and their metabolites in urine, these quantitative equivalencies no longer hold when these sex-steroid hormones are delivered percutaneously through the skin as gels or creams. Instead, salivary and capillary blood levels rise in a more linear fashion with dosing and achieve physiological levels in these body fluids at 10x lower physiological dosing (Tables 2-4); in stark contrast serum and urine levels increase very little at physiological doses. This has raised the interesting question of why salivary and capillary blood levels, which are equivalent to free serum levels with endogenously produced hormones, are so much higher (10-100 x) than levels seen in serum and urine when hormones are delivered topically through the skin. The obvious question arises as to which one of these categories of body fluids (serum and urine vs saliva and capillary whole blood) more closely reflect tissue levels of the hormone and the optimal dose that is needed for optimal physiological response. As a lab that tests all four of these body fluids, and is involved in many IRB-approved clinical research projects related to topical BHRT, we have had the opportunity to evaluate levels of endogenous steroids in women and men at different stages of life and supplementing with different hormone delivery systems (oral, occluded patch, topical, vaginal, subcutaneousinjections and pellets, troche, etc.) and doses at different time points following hormone application. From these tests and evaluation of symptom relief, or not, we have come to the conclusion that the bioavailable fractions of topically delivered hormones are not accurately quantified by testing serum or urine and that saliva and capillary whole blood levels of the
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• SPRING 2019
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