This week’s research review focuses on an article on aromatase and prostate cancer, with excerpts from an article entitled: The dual, opposing roles of estrogen in the prostate. Of interest is the testosterone to estrogen ratio. (Ellem and Risbridger 2009)
The second article is entitled Celiac Disease: The Great Masquerader, which was in the Clinical Research E-mail Update that is written exclusively for Emerson Ecologics by Dr. Steve Austin and Dr. Alan Gaby. Download
Elevated testosterone in the absence of estrogen leads to the development of hypertrophy and hyperplasia, but not malignancy. In contrast, high estrogen and low testosterone has been shown to lead to the development of inﬂammation upon aging and the emergence of pre-malignant lesions.
Epidemiological evidence provides further support for the relationship between a shift in the T:E ratio and the development of PCa. This ratio is signiﬁcantly lower in African-American men (who have the highest incidence of PCa in the USA), due to higher levels of serum estrogens, compared to Caucasian-American men. Conversely, the T:E ratio is higher in Japanese men (who are known to have a low risk of PCa), due to lower levels of serum estrogens, compared to Caucasian-Dutchmen
The activation of ER-alpha that leads to aberrant proliferation, inﬂammation and the development of pre-malignant lesions, whilst, in contrast, the activation of ER-beta mediates anti-proliferative, anti-inﬂammatory and, potentially, anti-carcinogenic effects that balance the actions of ER-alpha as well as those of androgens.
The dual, opposing roles of estrogen in the prostate
(Ellem and Risbridger 2009) Download
Both androgens and estrogens play a significant role in the prostate and are critical for normal prostate growth and development. The role of androgens in the prostate and in prostate disease is well known, however, the role for estrogens in the prostate and in prostate disease is complex and is still only just beginning to be appreciated. Our understanding of the role and action of estrogens in the prostate has advanced significantly recently due to important discoveries, including the discovery of a second estrogen receptor subtype (ER-beta), the detection of aromatase in the prostate, and the identification of rapid nongenomic estrogen signaling. We now know that estrogens are essential for normal tissue homeostasis within the prostate and that too little or too much leads to perturbation of the glands growth and the emergence of disease. We are also beginning to recognize the importance and differential roles of the estrogen receptors ER-alpha and ER-beta. Specifically, the activation of ER-alpha leads to aberrant proliferation, inflammation, and the development of premalignant lesions, while, in contrast, the activation of ER-beta is critical in prostatic stromal-epithelial cell signaling and mediating antiproliferative effects that balance the proliferative action of androgens on the epithelia. These data have established the importance and complexity of estrogen action. We now know that estrogens have the capacity to exert both beneficial and adverse effects in the prostate via ER-beta and ER-alpha, respectively. Based on this, the selective targeting of estrogen action may form the basis of new therapies for prostate disease.
Ellem, S. J. and G. P. Risbridger (2009). "The dual, opposing roles of estrogen in the prostate." Ann N Y Acad Sci 1155: 174-86.
Clinical Research Update, 24 May 2010. The Clinical Research E-mail Update is written exclusively for Emerson Ecologics, by Dr. Steve Austin and Dr. Alan Gaby.
I recently saw a woman in her fifties who consulted me because she had osteopenia despite eating a good diet and engaging in regular vigorous physical exercise. She had also been found on routine screening to have a monoclonal gammopathy that was suggestive of multiple myeloma; however, a bone marrow biopsy and full body scan were negative for multiple myeloma. Laboratory work had also demonstrated iron deficiency, which could not be explained by typical factors such as menstruation, use of nonsteroidal anti-inflammatory drugs, or vegetarianism. She had been experiencing low-level depression and had tried a selective-serotonin reuptake inhibitor, but had discontinued it when it caused side effects and did not relieve the depression.
I hypothesized that she might have celiac disease, which can present as either unexplained osteoporosis or unexplained iron deficiency. In addition, it was conceivable that the immunoglobulin spike found on her blood test was simply a high titer of tissue transglutaminase antibody (TTG), the antibody that is elevated in people with celiac disease and that is used as a diagnostic test for the disease. Although the patient denied having any gastrointestinal symptoms, it is not uncommon to encounter "silent" celiac disease (i.e., celiac disease in the absence of gastrointestinal symptoms). She was therefore advised to have a blood test for TTG and for antiendomysium antibodies (another blood test for celiac disease). Both tests were positive, and the TTG titer was above the maximum level that could be quantified by the laboratory. Although she did not undergo a small-bowel biopsy to confirm the diagnosis, the probability that a person has celiac disease if he/she is positive for both antiendomysium antibodies and TTG is virtually 100%.
Based on the results of the blood tests, the patient went on a gluten-free diet. Within a week or two, her depression had resolved. Her fairly constant intestinal bloating, which had been present nearly her entire life, also disappeared rapidly after she started the diet (she had originally denied having intestinal symptoms, because she thought intestinal bloating was normal). In addition, her mental concentration improved considerably. Six months after starting the diet, the monoclonal antibody titer had fallen by more than 50% (it takes 9-24 months for TTG to become negative on a gluten-free diet). It is still too soon to retest the patient's bone mineral density. However, consumption of a gluten-free diet typically has a positive influence on bone mineral density in patients with celiac disease, often reversing bone loss.1,2,3,4,5
Celiac disease (also called gluten-sensitive enteropathy) is a chronic gastrointestinal disease caused by intolerance to gluten. Ingestion of gluten by a person with celiac disease causes gastrointestinal damage, which results in malabsorption and multiple nutritional deficiencies. Manifestations of celiac disease may include diarrhea and other gastrointestinal symptoms, failure to thrive, weight loss, fatigue, anemia, epilepsy or other neurological disorders, defective gallbladder emptying, liver disease (including hepatic steatosis and progressive hepatitis), and infertility. Celiac disease is a relatively common cause of osteoporosis. The prevalence of celiac disease in people with osteoporosis has ranged from 3.4% to 10.1% in different studies. 6,7,8
Conditions less commonly associated with celiac disease include arthritis, asthma, schizophrenia, psoriasis, alopecia, premature graying of the hair, chronic urticaria, oral lichen planus, erythema nodosum, dental anomalies, recurrent pericarditis, reversible insensitivity to androgens, and immune system abnormalities (a decreased proportion and a decreased absolute number of circulating T lymphocytes). Many of the manifestations of celiac disease may be due in whole or in part to nutritional deficiencies, whereas other celiac disease-associated conditions may result from gluten-induced autoimmune damage to various tissues.
While most patients with celiac disease have gastrointestinal symptoms, some do not, and the disease is not detected until the patient presents with anemia, osteoporosis, infertility, or other extra-intestinal manifestations. Therefore, celiac disease should be considered in the differential diagnosis of a wide range of medical conditions, whether or not the patient presents with classical intestinal symptoms.
The most reliable diagnostic test for celiac disease is the demonstration of villous atrophy on small-intestinal biopsy. However, two different blood tests (antiendomysium antibodies and TTG) are also used to diagnose or screen for the disease. Both of these blood tests have a fairly high degree of sensitivity and specificity, but the TTG test costs less. Genetic testing can be used to confirm the antibody tests, since celiac disease is strongly associated with human lymphocyte antigen (HLA) types DR3 and DQw2. The availability of these noninvasive tests in recent years has made it possible to diagnose more cases of celiac disease.
Celiac disease affects about 1 in 130 people living in the United States and about 1 in 50 people who have symptoms consistent with the disease. While these numbers might seem small, it is important to maintain a high index of suspicion that a person has the disease, because diagnosing and properly treating celiac disease can be a life-changing event for many people.
1 Mustalahti K, Collin P, Sievanen H, et al. Osteopenia in patients with clinically silent coeliac disease warrants screening. Lancet 1999;354:744-745.
2 Mora S, Barera G, Ricotti A, et al. Reversal of low bone density with a gluten-free diet in children and adolescents with celiac disease. Am J Clin Nutr 1998;67:477-481.
3 Kemppainen T, Kroger H, Janatuinen E, et al. Bone recovery after a gluten-free diet: a 5-year follow-up study. Bone 1999;25:355-360.
4 Mora S, Weber G, Barera G, et al. Effect of gluten-free diet on bone mineral content in growing patients with celiac disease. Am J Clin Nutr 1993;57:224-228.
5 McFarlane XA, Bhalla AK, Robertson DAF. Effect of a gluten free diet on osteopenia in adults with newly diagnosed coeliac disease. Gut 1996;39:180-184.
6 Armagan O, Uz T, Tascioglu F, et al. Serological screening for celiac disease in premenopausal women with idiopathic osteoporosis. Clin Rheumatol 2005;24:239-243.
7 Shah S, Stone MD, Woodhouse KW. Latent coeliac disease in post menopausal osteoporosis. Age Ageing 2000;29(Suppl 2):46.
8 Stenson WF, Newberry R, Lorenz R, et al. Increased prevalence of celiac disease and need for routine screening among patients with osteoporosis. Arch Intern Med 2005;165:393-399.