Levothyroxine use and the risk of breast cancer: a nation-wide population-based case–control study

[helvella]

Partly due to a specific question, I have decided to post this abstract despite misgivings. The very last thing I want to do is cause any panic. At the same time, the question was entirely reasonable and it is certainly not my role to censor access to research in any way.

The abstract claims that those women who take levothyroxine have a higher rate of breast cancer diagnosis. On the positive side, it is a large study.

On the negative side, it appears simply to associate the taking of levothyroxine with breast cancer diagnosis. It does not go further than making a suggestion that levothyroxine might cause breast cancer.

We have one immediately obvious issue, those who take levothyroxine will have been diagnosed hypothyroid (or, perhaps, have had a thyroidectomy). I think this is a major difference between the cases and the controls.

We can then launch into questions such as:

● Is it inappropriate dosing with levothyroxine rather than the substance itself? That is, we see so many who are on too little or too much.

● Or that so many will have gone through periods, sometimes of many years, in which they were hypothyroid before starting levothyroxine?

● Is it taking levothyroxine-only - hence the issue being lack of T3 rather than levothyroxine itself?

● Is it related to the autoimmune processes which are surely going on in many of those diagnosed hypothyroid?

● Is it the active ingredient, levothyroxine sodium, or the other constituents (excipients and breakdown/degradation products)? This could mean that the actual products available in Taiwan need to be looked at separately to those in, say, the UK.

● Although the paper does acknowledge length of time that levothyroxine has been taken (identifying the 2 month to 1 year group), it really is unclear how the duration of taking levothyroxine might affect anything. Yes - over-65 has a higher Odds ratio, but we have no indication as to how long they had been taking levothyroxine. If, for example, the over-65s had been taking for forty years, what rate would have been predicted?

Archives of Gynecology and Obstetrics

Levothyroxine use and the risk of breast cancer: a nation-wide population-based case–control study

Authors and affiliations

Chieh-Chen Wu 1 4

Ya-Yu Yu 2

Hsuan-Chia Yang 3 4

Phung Anh Nguyen 4 5

Tahmina Nasrin Poly 1

Md. Mohaimenul Islam 1 4

Usman Iqbal 4 7

Hafash Arshed Ali Khan 4

Yao-Chin Wang 1 8

Yung-Tzu Cheng 1 9

Yu-Chuan Li 1 4

Wen-Shan Jian 4 6

1.Graduate Institute of Biomedical Informatics, College of Medicine Science and TechnologyTaipei Medical UniversityTaipeiTaiwan

2.Tri-Service General Hospital, Songshan Branch Taipei Taiwan

3.College of Medicine Science and TechnologyTaipei Medical University Taipei Taiwan

4.International Center for Health Information Technology (ICHIT) Taipei Medical University Taipei Taiwan

5.Department of Population and Quantitative Health Sciences Case Western Reserve University Cleveland USA

6.School of Health Care Administration Taipei Medical University (TMU) Taipei Taiwan

7.Master’s Program in Global Health and Development Department, College of Public Health Taipei Medical University Taipei Taiwan

8.Department of Emergency Min-Sheng General Hospital Taoyuan Taiwan

9.Department of Laboratory Medicine Cathay General Hospital Taipei Taiwan

Gynecologic Oncology

First Online: 30 June 2018

Abstract

Purpose

To investigate whether the use of levothyroxine was associated with breast cancer risk.

Methods

We conducted a population-based case–control study in Taiwan. Cases consisted of all patients who were aged 20 years and older, and had a first-time diagnosis of breast cancer for the period between 2001 and 2011. The controls were matched to the cases by age, sex, year, and month of diagnosis. Adjusted odd ratios (ORs) and 95% confidence intervals (CIs) were estimated by a conditional logistic regression.

Results

We examined 65,491 breast cancer cases and 261,964 controls. We found that use of levothyroxine was associated with a significant increase in breast cancer risk (OR 1.24, 95% CI 1.15–1.33; P < 0.001). Compared with no use levothyroxine, the adjusted odd ratio was 1.22 (95% CI 1.11–1.35; P = 0.01) for the group having been prescribed levothyroxine 2 months to 1 year, and 1.26 (95% CI 1.12–1.41; P < 0.01) for the group with more than 1 year. When stratified by age, the adjusted odd ratio was 1.45 (95% CI 1.23–1.71; P < 0.01) for the patients aged 65 years or more and 1.19 (95% CI 1.09–1.29, P < 0.01) for the patients aged less than 65 years.

Conclusion

The results of the present study are the first to suggest that levothyroxine use increased the risk of breast cancer. However, a larger long-term prospective randomized-controlled trial specifically designed to assess the effect of levothyroxine use on the risk of developing breast cancer is needed.

link.springer.com/article/1...

[shaws Administrator]

Thanks for posting helvella along with your common-sense statements.

[diogenes Remembering]

Cause and effect or mere unconnected association? Trouble with these studies is that so many links are accidental and not causative.

[helvella Administrator in reply to diogenes]

Absolutely agree.

I'd like to think that the full paper says rather more and clearly identifies its obvious limitations and inadequacies. The call for a larger long-term prospective randomized-controlled trial is all very well, but do we have to wait for many years to do that? (With the obvious consequences of delay.) Or is there already data which, with careful analysis, could produce rather more soundly based conclusions?

[Laundretta]

Thanks Helvella. The holes in this ‘research’ are so deep I feel I can see all the way to China via the core of the earth.

[jimh111]

This is interesting, there is another recent study that shows similar increased risks with both hyperthyroidism and hypothyroidism bmjopen.bmj.com/content/8/3... . I have an interest in the effects of hormone disrupting chemicals (EDCs), particularly polybrominated diphenyl ethers (PBDEs). PBDEs are ubiquitous flame retardants introduced in the 1970s which were banned in 2004 but are still around in the environment and food chain. The human burden started to decline a few years ago but will remain high for many decades. PBDEs are thyroid hormone mimics that disrupt thyroid hormone action but have little or no effect on TFTs. They are also oestrogenic and are thought to cause breast and thyroid cancer although the evidence so far is weak.

Interestingly the Weng study found that there was no association between thyroid autoimmunity and breast cancer along with no association between thyroid disorders and breast cancer in subjects over 55 years old. It is thought this might be because women over 55 were not exposed to PBDEs during their youth. It’s also possible that the menopause reduces the relative risk. My thoughts are that many of these breast cancer patients were (mis)diagnosed with primary hypothyroidism after presenting with hypothyroid signs and symptoms caused by EDCs. Most patients with hypothyroidism caused by endocrine disruption will have normal blood tests and not be diagnosed. It’s interesting that the incidence of CFS/ME (aka yuppie ‘flu) increased dramatically during the 1980s when the human burden of PBDEs was increasing rapidly. If this increased risk is caused by EDCs, the link between EDC induced hypothyroidism and breast cancer will be substantially underestimated by these studies because most patients suffering from thyroid hormone disruption are not diagnosed and so will fall into the control group.

I have just added a post healthunlocked.com/thyroidu... about breast cancer risk and vitamin D status. This is one risk we can control to some extent, so enjoy the good weather!

[helvella Administrator in reply to jimh111]

Thanks Jim.

The vitamin D issue is interesting but we have seen several members who cannot tolerate supplementation. (And there are well-known limits to sun bathing in the UK. )

[Angel_of_the_North]

I reckoned on reading this that it was gut problems caused by hashis (the main cause of hypo) leading to low vit D, which is associated with breast cancer, plus a generally stressed immune system. That covers most women taking levo.

[crimple]

Thanks for posting helvella, food for thought. Angel of the north's theory is interesting.

[Aurealis]

The only people taking Levothyroxine are those diagnosed hypothyroid for whatever reason. Not sure the study goes beyond this. They are just reporting the already known increased incidence of breast cancer in those who are hypothyroid aren’t they? But instead of using the diagnosis in the title they use ‘Levothyroxine use’. And no cause and effect established as Diogenes points out.

I look forward with anticipation to the ‘Liothyronine use’ paper to come ... now that would be very interesting ....

[helvella Administrator in reply to Aurealis]

I think I did say that in my intro?

Wholeheartedly agree about looking forward to the Liothyronine version. No idea if it is used significantly in Taiwan.

[Aurealis in reply to helvella]

Yes I think so, I read it as a subtle implication but wanted to make it more explicit, no offence intended.

[helvella Administrator in reply to Aurealis]

None taken.