Multiple studies have demonstrated the efficacy of a vaginal tablet (which is commercially available in Europe and Asia) containing an ultra-low-dose vaginal of estriol 0.03 mg in combination with viable Lactobacillus acidophilus KS400 as short-term therapy and long-term maintenance in the treatment of vaginal atrophy. A double-blind, randomized, placebo-controlled study followed by an open-label follow-up included postmenopausal women with vaginal atrophy symptoms and Vaginal Maturation Index (VMI) of ≤ 40%. The method of treatment was one vaginal tablet daily for 12 days, followed by maintenance therapy of one tablet on two consecutive days weekly for 12 weeks. 87 women completed the study. The Control phase results for a change in VMI demonstrated superiority of the 0.03 mg estriol-lactobacilli combination to placebo. In the test group, the positive change in VMI was 35.2%, compared to 9.9% in the placebo group. In the Open phase after the initial therapy, the VMI was increased to 55.4% and, during maintenance therapy, it stayed at a comparable level (52.8-49.4%). The maturation of epithelium was followed by improvement of clinical symptoms and normalization of the vaginal ecosystem. The study concluded that an ultra-low-dose vaginal 0.03 mg estriol-lactobacilli combination was superior to placebo with respect to changes in VMI after the 12-day initial therapy, and the maintenance therapy of two tablets weekly was sufficient to prevent the relapse of vaginal atrophy.

   In a pharmacokinetic study, compared with baseline, serum E1 and E2 did not increase in any of the women at any time following vaginal application. Serum E3 transiently increased after the first application in 15 of 16 women, with a maximum of 168 pg/ml 2-3 hours post-insertion. After 4 weeks, serum E3 was slightly increased in 8 women with a maximum of 44 pg/ml. The vaginal atrophy resolved or improved in all women. The product was well tolerated, and discontinuation of therapy was not observed.

Estrogens are steroid hormones present in both men and women, but present at significantly higher levels in women of reproductive age. There are three naturally occurring estrogens in women: estrone (E1), estradiol (E2) and estriol (E3). E3 is not interconvertible and hence, does not result in an increase in the levels of either of the other two estrogens.

   Estriol, coined the "weaker" of the three endogenous estrogens, has significant therapeutic effects, some of which are not commonly known by clinicians. Estriol is commonly used to treat hot flashes, insomnia, and vaginal atrophy; to reduce the frequency of urinary tract infections; and for skin enhancement. Recently, estriol has shown the potential to treat individuals with Th1-mediated autoimmune illnesses, including multiple sclerosis and rheumatoid arthritis.

   Due to the well-known and documented risks associated with estradiol (E2), estriol (E3) has long piqued the interest of researchers and clinicians. E3, for its protective and clinically beneficial actions, is considered a cornerstone of bio-identical hormone therapies (BHT). Estradiaol (E2), the well-known, well-studied, and most prescribed form of estrogen, is usually referred to synonymously with estrogen, due to its stronger actions and ubiquitous familiarity as the common estrogen-replacement therapy (ERT). However, E3 is unique as an "estrogen" due to its antagonistic effects on E2 in breast tissue. Dr. H. M. Lemon, University of Nebraska Medical Center in Omaha, noted throughout his extensive investigative career that women who developed breast cancer had significantly lower levels of E3 than women who did not develop breast cancer. Lemon clarified that E3 had a place in both the treatment of menopausal women and for the prevention of mammary carcinoma. These findings and others have become even more important and relevant following the release of the Women's Health Initiative (WHI) in 2002, which revealed significant and dangerous health risks associated with hormone replacement therapy (HRT). This raised concerns with conventional ERT and HRT, and resulted in a dramatically raised consciousness and increased awareness in patients with breast cancer and for women in general.

   Researchers have explored the potential of endometrial hyperplasia (a known risk of E2 supplementation) with E3 use. In all of the studies reviewed, the use of E3 as a therapeutic agent did not increase the risk of endometrial or ovarian cancers, nor did it cause endometrial hyperplasia. Of additional note, E3 has been reported to lower blood pressure and improve lipid metabolism. A further application of E3 that needs more exploration is for the treatment of uterine prolapsed due to loss of pelvic floor integrity. One study revealed promising beneficial results when E3 was added to the rehabilitation protocol.

   A study comparing E3 to conjugated equine estrogens (CEE) for bone loss and lipid metabolism revealed equal benefits from E3 and CEE, with both demonstrating a clear effect of increasing bone mass density (BMD). However, E3 produced fewer adverse events of uterine bleeding and, unlike CEE, did not elevate triglycerides.

   In 2009, the FDA clarified its position stating the FDA "respects a healthcare provider's decision that his or her patient should receive estriol." E3 has a USP monograph it is consistent with USP Chapters 795 and 1075 to compound E3 pursuant to a valid prescription. E3 has been commercially available in Europe and Asia for many years and its use is well supported in the medical literature. In the US, E3 is available by prescription through compounding pharmacies.

Journal of Restorative Medicine 2013; 2: page 45-52

  Patients with several stress-associated neuropsychiatric disorders, notably posttraumatic stress disorder and chronic pain and fatigue syndromes, paradoxically exhibit somewhat low plasma levels of the stress hormone cortisol. The effects appear greatest in those initially traumatized in early life, according to Yehuda and Seckl ofMount Sinai School of Medicine, Department of Psychiatry, Traumatology and Stress Studies Division, in NY, NY. In these conditions, lowered cortisol is not due to any adrenal or pituitary insufficiency. Instead, two processes appear involved. First, there is increased target cell sensitivity to glucocorticoid action, notably negative feedback upon the hypothalamic-pituitary-adrenal (stress) axis. Altered density of the glucocorticoid receptor is inferred, squaring with much preclinical data showing early life challenges can permanently program glucocorticoid receptors in a tissue-specific manner. These effects involve epigenetic mechanisms. Second, early life trauma/starvation induces long-lasting lowering of glucocorticoid catabolism, specifically by 5α-reductase type 1 (predominantly a liver enzyme) and 11β-hydroxysteroid dehydrogenase type 2 (in kidney), an effect also seen in model systems. These changes reflect a plausible early-life adaptation to increase the persistence of active cortisol in liver (to maximize fuel output) and kidney (to increase salt retention) without elevation of circulating levels, thus avoiding their deleterious effects on brain and muscle. Modestly lowered circulating cortisol and increased vulnerability to stress-associated disorders may be the outcome. This notion implies a vulnerable early-life phenotype may be discernable and indicates potential therapy by modest glucocorticoid replacement. Indeed, early clinical trials with cortisol have shown a modicum of promise.

While cortisol levels are typically tested in fatigued or chronically stressed patients, it can also be useful to test cortisol in those suffering from chronic allergies. If saliva testing determines that cortisol levels are low, and supplementation is needed, we can compound cortisol in a titratable dosage form and also recommend supplements to help restore adrenal function.