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Menopause Live - IMS Updates
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Date of release: 22 March, 2010

Menopausal hormone therapy and risk of invasive colon cancer


A recently published paper by DeLellis Henderson and colleagues [1] evaluated the risk of colon cancer associated with the duration and recency of specific menopausal hormone therapy formulations: unopposed estrogen versus estrogen combined with progestin among 56,864 peri- and postmenopausal women who were participating in the California Teachers Study, a prospective study during 1995–2006 (mean age at recruitment around 62 years; 76% reported ever using hormone therapy (HT), 61% were current users). Altogether, 442 incident invasive colon cancer cases were diagnosed. The paper confirmed a number of observations that have been previously reported in the literature. First, a 36% reduced risk was documented among baseline (recent) hormone users compared with baseline never-users (hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.51–0.80). Results did not differ by formulation of HT. Sub-analyses showed the following: 


 


1. The highest reduction in risk was seen in women reporting on 5–15 years of recent HT use at baseline (HR 0.49, 95% CI 0.35–0.68).When hormonal treatment was used for more than 15 years, attenuation of protection against developing colon cancer was stronger in the recent-user groups of combined estrogen + progestin than in the recent users of estrogen-only therapy.


2. Women with a family history of colon cancer gain a greater protection against the disease compared to women who do not have such family history.


3. Estrogen-only therapy confers more protection than estrogen combined with a progestin.

Comment

Carcinogenesis is a complex and multi-step process that involves a number of genes. The interaction with environmental insults will ultimately result in dysregulation of cell proliferation. In order to understand why estrogen protects and the addition of progestin attenuates such protection, basic cellular and molecular events need to be addressed.
 
Estradiol induces the synthesis of its cognate receptors (ERα and ERβ) and the synthesis of progesterone receptors. Progesterone, upon binding to its cognate receptors, down-regulates the synthesis of its own receptors as well as estrogen receptors, and progesterone increases the activity of 17β-hydroxysteroid dehydrogenase (17βHSD), thereby counteracting estrogen activity. Synthetic progestins, particularly medroxyprogesterone acetate (MPA), exhibit a higher binding capacity to bind a glucocorticoid response element (GRE) in the promoter start site of the glucocorticoid receptor and as such may be responsible for added adverse features of these progestins.
 
The characteristics of colon cancer tissue include loss of immunohistochemical expression of ERα protein [2] and very low levels of ERα protein in Western blot analysis. These are combined with a selective loss of ERβ protein expression, in males and in females, when compared to the normal colon tissue in the same patient [3, 4]. All these findings point to impairment of post-transcriptional mechanisms upon malignant transformation of colon tissue that suggests loss of estrogen effects, when compared to normal colon tissue. Estrogen acts either on a single major transformation step in the oncogenetic process or is involved in multiple events that avert the course of this transformation.  
 
An important clinical feature of women treated with estrogen and progestin is that they have retained their ovaries until natural menopause and therefore benefited from the protective effects of their endogenous estrogen for longer than women who have used unopposed estrogen. For this reason, women on estrogen + progestin are, at least theoretically, more advantaged than those who have lost their ovaries. Nonetheless, the steroidogenic actions within cells are more complex than ligands’ interactions with their cognate receptors. Conversion of androstenedione into testosterone and inter-conversions of estrone to estradiol are governed by 17βHSD. The enzyme 17βHSD and its six isoenzymes are differentially expressed in various tissues and 17βHSD isoenzyme types 2 and 4 are over-expressed in colonic cancer cells. This may be responsible for the high capacity for inactivation of estrogens in colon cancer cells [5, 6]. This local conversion to estrogens may play a role in the non-receptor-mediated effect of estrogen in the pathophysiology of cell growth. These data illustrate clearly a cell context-specific concentration of these gonadal steroids.  
 
This is the time to reflect on an established dogma and to refute the benign role of progestins. Endogenous estrogen is the default safe hormone for women and its administration in physiologically equivalent doses when indicated should extend its safety to the treatment period. In the management of menopausal symptoms, estrogen dose and route of administration should be optimized to cure these symptoms. However, in order to protect the endometrium, the minimum effective dose of progestin should be administered and for the shortest duration. This means the re-establishment of withdrawal bleeding, which, if predictable and of short duration, may become acceptable to the majority of women. This inconvenience may be acceptable in the interest of safety of the long-term administration of hormonal treatment after the menopause.

Comentario

Farook Al-Azzawi
Menopause Research Unit, University Hospitals of Leicester, Leicester, UK

    References

  1. Delellis Henderson K, Duan L, Sullivan-Halley J, et al. Menopausal hormone therapy use and risk of invasive colon cancer: the California Teachers Study. Am J Epidemiol 2010;171:415-25. Published February 15, 2010.
    http://www.ncbi.nlm.nih.gov/pubmed/20067917

  2. Slattery ML, Samowitz WS, Holden JA. Estrogen and progesterone receptors in colon tumors. Am J Clin Pathol 2000;113:364-8
    http://www.ncbi.nlm.nih.gov/pubmed/10705816

  3. Castiglione F, Taddei A, DeglInnocenti DR, et al. Expression of estrogen receptor beta in colon cancer progression. Diagn Mol Pathol 2008;17:231-6.
    http://www.ncbi.nlm.nih.gov/pubmed/19034156

  4. Foley EF, Jazaeri AA, Shupnik MA, et al. Selective loss of estrogen receptor beta in malignant human colon. Cancer Res 2000;60:245-8.
    http://www.ncbi.nlm.nih.gov/pubmed/10667568

  5. English MA, Hughes SV, Kane KF, et al. Oestrogen inactivation in the colon: analysis of the expression and regulation of 17beta-hydroxysteroid dehydrogenase isozymes in normal colon and colonic cancer. Br J Cancer 2000;83:550-8.
    http://www.ncbi.nlm.nih.gov/pubmed/10945506

  6. English MA, Kane KF, Cruickshank N, et al. Loss of estrogen inactivation in colonic cancer. J Clin Endocrinol Metab 1999;84:2080-5.
    http://www.ncbi.nlm.nih.gov/pubmed/10372714