Dr. Ron’s Research Review – October 28, 2015

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This week’s research review focuses on breast cancer risk and HRT.

A study published in the International Journal of Cancer included 133,744 postmenopausal women from the European prospective investigation into cancer and nutrition (EPIC) cohort found increased breast cancer risk with estrogen-only (RR 1.42, 95 % CI 1.23-1.64) and combined (with progestin) menopausal hormone therapy (MHT) HT (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. The most frequently used estrogen was estradiol, except for Germany and the United Kingdom, where CEE dominated. The majority of women in most countries used a combination of estrogen plus progestin MHT.  (Bakken et al., 2010)

A study found that conventional oral doses of estradiol result in excessive exposure to estrone. 24-hour urinary steroid hormone profiles were conducted for 35 postmenopausal women receiving oral estradiol at doses from 0.025-2.0 mg/day. The recommended oral dose of estradiol (1-2 mg/day) resulted in urinary excretion of estrone at values 5-10 times the upper limit of the reference range for premenopausal women. Retrospective studies associating oral estradiol with increased risk of breast cancer may reflect overdose conditions. (Friel et al., 2005)

A case-control study published in the Annals of Oncology studied 466 women with incident breast cancer, 704 women with BBD and 244 healthy women. Compared with healthy women, breast cancer patients tended to have higher levels of steroid hormones. The evidence was strong for estrone (difference 21.5%, P < 0.001), weaker for testosterone (difference 15.8%, P = 0.07) and weaker still for estradiol (difference 12.0%, P = 0.18). (Lagiou et al., 2013)

Dr. Ron


 

Articles

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

Hormone replacement with estradiol: conventional oral doses result in excessive exposure to estrone.
            (Friel et al., 2005) Download
BACKGROUND: There is a lack of consensus about the safety of estrogen replacement therapy, especially with regard to its impact on a woman's risk for breast cancer. Elevated urinary or serum estrone and estradiol concentrations in postmenopausal women are associated with a moderately elevated risk of breast cancer. METHODS: Twenty-four-hour urinary steroid hormone profiles, including the measurement of estrone, estradiol, and estriol, were conducted for 35 postmenopausal women receiving oral estradiol at doses from 0.025-2.0 mg/day. RESULTS: Urinary excretion of estradiol exceeded premenopausal reference range values in women taking estradiol at doses greater than 0.5 mg/day. Urinary estrone excretion exceeded premenopausal reference range values in women taking estradiol doses of 0.25 mg/day or higher. Literature data indicate serum estrone concentrations also markedly exceed premenopausal reference ranges when estradiol is administered orally at a dose of 1 mg/day. CONCLUSIONS: The previously recommended oral dose of estradiol (1-2 mg/day) results in urinary excretion of estrone at values 5-10 times the upper limit of the reference range for premenopausal women. Retrospective studies associating oral estradiol with increased risk of breast cancer may reflect overdose conditions. Based on current knowledge, a prudent dose ceiling for oral estradiol replacement therapy of 0.25 mg/day is proposed.

A comparison of hormonal profiles between breast cancer and benign breast disease: a case-control study.
            (Lagiou et al., 2013) Download
BACKGROUND:  Benign breast disease (BBD), particularly proliferative BBD, is an established breast cancer risk factor. However, there has been no systematic attempt to compare the hormonal profiles of the two conditions. In a case-control investigation in Athens, Greece, we compared levels of estrogens, testosterone and insulin-like growth factor-1 (IGF-1), as well as their principal binding proteins, between breast cancer patients, women with BBD by histological type (proliferative and nonproliferative) and women with no breast pathology. PATIENTS AND METHODS:  We studied 466 women with incident breast cancer, 704 women with BBD and 244 healthy women. We used multiple regression to compare log-transformed serum hormone levels of breast cancer patients with those of healthy women and women with BBD by histological type (proliferative and nonproliferative BBD). RESULTS:  The hormonal profile of breast cancer in our study was in line with the generally accepted hormonal profile of this disease, as reported from large cohort studies. Compared with healthy women, breast cancer patients tended to have higher levels of steroid hormones. The evidence was strong for estrone (difference 21.5%, P < 0.001), weaker for testosterone (difference 15.8%, P = 0.07) and weaker still for estradiol (difference 12.0%, P = 0.18). Also compared with healthy women, breast cancer patients had barely higher levels of IGF-1 (difference 2.0%, P = 0.51), but had significantly lower levels of IGF binding protein 3 (IGFBP-3) (difference -6.7%, P = 0.001). Compared with women with BBD, breast cancer patients had nonstatistically significantly lower levels of steroid hormones, but they had higher levels of IGF-1 [difference 5.5%, 95% confidence interval (CI) 0.7% to 10.6%] and lower levels of IGFBP-3 (difference -3.7%, 95% CI -6.7% to -0.7%). Differences were more pronounced when breast cancer patients were contrasted to women with proliferative BBD. CONCLUSIONS:  Our findings suggest that high levels of IGF-1 may be an important factor toward the evolution of BBD to breast cancer.

 

References

Bakken, K., 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, PubMedID: 20232395
Friel, PN, C Hinchcliffe, and JV Wright (2005), ‘Hormone replacement with estradiol: conventional oral doses result in excessive exposure to estrone.’, Altern Med Rev, 10 (1), 36-41. PubMedID: 15771561
Lagiou, P, et al. (2013), ‘A comparison of hormonal profiles between breast cancer and benign breast disease: a case-control study.’, Ann Oncol, 24 (10), 2527-33. PubMedID: 23723293