Dr. Ron’s Research Review – August 18, 2010

This week’s research review focuses on the current controversy over conventional Hormone Replacement Therapy - the WHI, E3N and EPIC Studies. The results of the EPIC study are big news with most stating that all forms of HRT increase the risk of breast cancer.

Women's Health Initiative (WHI) (Rossouw, Anderson et al. 2002)

E3N is the French component of EPIC (Fournier, Berrino et al. 2008)

The European prospective investigation into cancer and nutrition (EPIC) (Bakken, Fournier et al. 2010)

A summary article is now in the handbook - Link

Thyroid

Thyroid disruption: mechanism and clinical implications in human health (Patrick 2009)

Thyroid hormone replacement: an iatrogenic problem

(O'Reilly 2010)

Dr. Ron


Articles

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial

            (Rossouw, Anderson et al. 2002) Download

CONTEXT: Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain. OBJECTIVE: To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States. DESIGN: Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998. INTERVENTIONS: Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). MAIN OUTCOMES MEASURES: The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. RESULTS: On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years. CONCLUSIONS: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.

Menopausal hormone therapy and breast cancer risk: Impact of different treatments. The European prospective investigation into cancer and nutrition (EPIC)

            (Bakken, Fournier et al. 2010) Download

BACKGROUND: Menopausal hormone therapy (MHT) is characterized by use of different constituents, regimens and routes of administration. We investigated the association between the use of different types of MHT and breast cancer risk in the EPIC cohort study. METHODS: 133,744 postmenopausal women contributed to this analysis. Information on MHT was derived from country-specific self-administered questionnaires with a single baseline assessment. Incident breast cancers were identified through population cancer registries or by active follow-up (mean 8.6 years). Overall relative risks (RR) and 95 % confidence interval (CI) were derived from country-specific Cox proportional hazard models estimates. RESULTS: A total of 4,312 primary breast cancers were diagnosed during 1,153,747 person-years of follow-up. Compared to MHT never-users, breast cancer risk was higher among current users of estrogen-only (RR 1.42, 95 % CI 1.23-1.64) and higher still among current users of combined MHT (RR 1.77, 95 % CI 1.40-2.24; p=0.02 for combined vs. estrogen-only). Continuous combined regimens conferred a 43 % (95 % CI 19%-72 %) greater risk compared to sequential regimens. There was no significant difference between progesterone- and testosterone-derivatives in sequential regimens. There was no significant variation in risk linked to the estrogenic component of MHT, neither for oral vs. cutaneous administration, nor for estradiol compounds vs. conjugated equine estrogens. CONCLUSIONS: Estrogen-only and combined MHT were associated with increased breast cancer risk. Continuous combined preparations were associated with the highest risk. Further studies are needed to disentangle the effects of the regimen and the progestin component. (c) 2010 UICC.

Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study

            (Fournier, Berrino et al. 2008) Download

Large numbers of hormone replacement therapies (HRTs) are available for the treatment of menopausal symptoms. It is still unclear whether some are more deleterious than others regarding breast cancer risk. The goal of this study was to assess and compare the association between different HRTs and breast cancer risk, using data from the French E3N cohort study. Invasive breast cancer cases were identified through biennial self-administered questionnaires completed from 1990 to 2002. During follow-up (mean duration 8.1 postmenopausal years), 2,354 cases of invasive breast cancer occurred among 80,377 postmenopausal women. Compared with HRT never-use, use of estrogen alone was associated with a significant 1.29-fold increased risk (95% confidence interval 1.02-1.65). The association of estrogen-progestagen combinations with breast cancer risk varied significantly according to the type of progestagen: the relative risk was 1.00 (0.83-1.22) for estrogen-progesterone, 1.16 (0.94-1.43) for estrogen-dydrogesterone, and 1.69 (1.50-1.91) for estrogen combined with other progestagens. This latter category involves progestins with different physiologic activities (androgenic, nonandrogenic, antiandrogenic), but their associations with breast cancer risk did not differ significantly from one another. This study found no evidence of an association with risk according to the route of estrogen administration (oral or transdermal/percutaneous). These findings suggest that the choice of the progestagen component in combined HRT is of importance regarding breast cancer risk; it could be preferable to use progesterone or dydrogesterone.

Thyroid disruption: mechanism and clinical implications in human health

(Patrick 2009) Download

Exposure to specific environmental toxins, including polychlorinated biphenyls, dioxins, phthalates, polybrominated diphenyl ethers (PBDEs), and other halogenated organochlorines, has been shown to interfere with the production, transportation, and metabolism of thyroid hormones by a variety of mechanisms. A broad range of chemicals, with structural similarity to thyroid hormone, have been shown to bind to thyroid receptors with both agonist and antagonist effects on thyroid hormone signaling. The incidence of thyroid disease in the United States, particularly for thyroid cancer and thyroid autoimmune disease, is increasing substantially. The evidence for the significant effects of background levels of thyroid-disrupting chemicals, the known pathways for thyroid disruptors, and the evidence and implications for neurodevelopmental damage due to thyroid-disrupting chemicals is reviewed.

Thyroid hormone replacement: an iatrogenic problem

            (O'Reilly 2010) Download

Thyroid hormone replacement is one of the very few medical treatments devised in the 19th century that still survive. It is safe, very effective and hailed as a major success by patients and clinicians. Currently, it is arguably the most contentious issue in clinical endocrinology. The current controversy and patient disquiet began in the early 1970s, when on theoretical grounds and without proper assessment, the serum thyrotropin (TSH) concentration was adopted as the means of assessing the adequacy of thyroxine replacement. The published literature shows that the serum TSH concentration is a poor indicator of clinical status in patients on thyroxine. The adequacy of thyroxine replacement should be assessed clinically with the serum T3 being measured, when required, to detect over-replacement.


References

Bakken, K., A. Fournier, et al. (2010). "Menopausal hormone therapy and breast cancer risk: Impact of different treatments. The European prospective investigation into cancer and nutrition (EPIC)." Int J Cancer.

Fournier, A., F. Berrino, et al. (2008). "Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study." Breast Cancer Res Treat 107(1): 103-11.

O'Reilly, D. S. (2010). "Thyroid hormone replacement: an iatrogenic problem." Int J Clin Pract 64(7): 991-4.

Patrick, L. (2009). "Thyroid disruption: mechanism and clinical implications in human health." Altern Med Rev 14(4): 326-46.

Rossouw, J. E., G. L. Anderson, et al. (2002). "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial." JAMA 288(3): 321-33.