Delivery of the bioidentical hormones estradiol (E2), progesterone (Pg), and testosterone (T) through the skin as a cream or gel (topically) has become a mainstay of bioidentical hormone replacement therapy (BHRT) for women and men. A plethora of FDA-approved pharmaceuticals, compounded, and even over-the-counter topical BHRT products are available. The popularity of these products lies not only in their ease of use, but in proven clinical efficacy1-5 in treating hormonal deficiencies mostly brought on by aging of the female (menopause) and male (andropause) reproductive systems.
Dosing for Optimal Clinical Benefit
Over the past 30 or so years, higher FDA-approved topical BHRT dosing has dominated allopathic acceptance. However, more practitioners are opening their thinking to alternative views of much lower dosing as being optimal, based on clinical observations coupled with scientific discovery. It also is becoming more evident that while serum and urine testing work fine for detecting endogenously produced hormones, or hormones supplemented by nearly all other forms of delivery (e.g., transdermal patch, oral, vaginal, troche/sublingual, injections and pellets) these body fluids grossly underestimate hormone delivery to capillary beds and hence, tissues, relative to topical delivery.6 Attempts to achieve physiological levels of E2, Pg, and T in serum with topical BHRT has met with little success, resulting in use of pharmacological dosing to raise serum levels to physiological ranges.6,7
Despite the clear clinical efficacy of topical natural estrogens (mostly E2 and estriol – E3) and Pg in women and T in men, controversy still encircles the dose needed to achieve optimal clinical benefit. This controversy has arisen out of attempts to explain why topical BHRT results in very little increase in venipuncture serum or urine levels of the hormone delivered through the skin6-8 despite use of topical hormone doses that usually are more than 10x higher than daily endogenous production of these hormones in women and men (see Table 1).
How Does Testing in the Wrong Body Fluid Lead to Overdosing?
Justification for higher dosing of both FDA-approved pharmaceutical and compounded products comes from pharmacokinetic studies showing that pharmacological dosing is necessary to increase serum and urine levels of the dosed hormones to physiological levels. But even with supra-high pharmacological BHRT dosing serum and urine levels of some of the hormones rarely increase to even within low physiological ranges. This is most notable for Pg6,7,9 and less so for E2 and T5,10,11 which only increase to physiological levels in serum/plasma and urine with pharmacological dosing.
Daily ovarian production of E2 during peak luteal phase of the menstrual cycle is about 100-300 µg12 when serum and capillary blood levels of E2 are quantitatively equivalent at about 80-200 pg/mL, saliva ranges from about 1.5-4 pg/mL (approximately 2% of serum/plasma levels), and urine levels range from about 0.8-2.0 µg/g Cr (see Tables 2-4). For postmenopausal women to achieve physiological ranges seen in mid-luteal phase of premenopausal women, topical E2 therapy only requires physiological dosing to achieve physiological levels in saliva and capillary whole blood (about 100-300 µg E2), but at least 10x higher dosing (1000-3000 µg = 1-3 mg) to achieve physiological levels in venipuncture serum/plasma and urine (Table 2).
A similar distribution of Pg is seen during peak of the luteal phase of the menstrual cycle where daily Pg production by the ovaries is about 10-40 mg, and the Pg in serum and capillary blood are quantitatively equivalent at about 10-30 ng/mL, saliva about 100-300 pg/mL (approximately 1% of serum/plasma levels), and urine pregnanediol, a surrogate for Pg, about 500-2000 µg/g Cr (Table 3). To achieve premenopausal luteal ranges in postmenopausal women with topical Pg therapy only requires physiological dosing when measuring saliva and capillary whole blood (about 10-50 mg topical Pg),6,7 but at least 10x higher dosing (100-300 mg topical Pg) when measuring venipuncture serum/plasma. Urine pregnanediol increases very little with increasing doses of Pg.8
In men, topical T distributes into the same body fluids as topical E2 and Pg in women. In healthy young males, the testes produce about 5-7 mg of T daily and the morning T levels range from about 500-1200 ng/dL in serum/plasma and capillary blood, 100-250 pg/mL in saliva, and 1-4 µg/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 (about 5-10 mg topical T), but at least 10x higher dosing (50-200 mg topical T) for venipuncture serum/plasma or urine levels.
The lack of increase in serum and urine levels of topically delivered hormones at physiological dosing (50-200 µg 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 FDA-approved and compounded products to amounts that are 10 to 20-fold higher (500-5000 µg 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-hour 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 mass3 and protecting the breasts13 and endometrium4 at physiological dosing of E2 and Pg applied topically.
Saliva and Capillary Whole Blood Testing More Closely Reflect Tissue Levels
The advent of monitoring steroid hormones in body fluids that more closely reflect tissue levels, 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. Studies over the past 20 years have 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 equivalencies no longer hold when these steroid hormones are delivered percutaneously as gels or creams. Instead, salivary and DBS 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.
- Basdevant A and de Lignieres B. Treatment of menopause by topical administration of oestradiol. In: Percutaneous Absorption of Steroids, Mauvais-Jarvis P, Vickers, CFH., and Wepierre J, Eds., Academic Press (London), 1980; pp. 249-258.
- Egras AM, Umland EM. The role of transdermal estrogen sprays and estradiol topical emulsion in the management of menopause-associated vasomotor symptoms. Int J Gen Med. 2010;3:147-51.
- Prestwood KM, Kenny AM, Kleppinger A, Kulldorff M. Ultralow-dose micronized 17beta-estradiol and bone density and bone metabolism in older women: a randomized controlled trial. JAMA. 2003;290:1042-8.
- Leonetti HB, Wilson KJ, Anasti JN. Topical progesterone cream has an antiproliferative effect on estrogen-stimulated endometrium. Fertil Steril. 2003;79:221-2.
- Bhasin S, Woodhouse L, Casaburi R, Singh AB, Mac RP, Lee M, Yarasheski KE, Sinha-Hikim I, Dzekov C, Dzekov J, Magliano L, Storer TW. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab. 2005;90:678-88.
- Zava DT, Groves MN, Stanczyk FZ. Percutaneous absorption of progesterone. Maturitas. 2014;77:91-2.
- 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 post-menopausal women. Clin Endocrinol. 2000;53:615-620.
- 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.
- Place VA, Powers M, Darley PE, Schenkel L, Good WR. A double-blind comparative study of Estraderm and Premarin in the amelioration of postmenopausal symptoms. Am J Obstet Gynecol.1985;152:1092-9.
- Powers MS, Schenkel L, Darley PE, Good WR, Balestra JC, Place VA. Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17 beta-estradiol: comparison with conventional oral estrogens used for hormone replacement. Am J Obstet Gynecol. 1985;152:1099-106.
- Williams Textbook of Endocrinology, Larsen PR, Kronenberg HM, Melmed S, and Polonsky KS, Eds., 10th Ed., Elsevier Health Services (Saunders), Philadelphia, 2003.
- Chang KU, Lee TT, Linares-Cruz G, Fournier S, de Lignieres B. Influence of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil Steril. 1995;63:785-91.