HRT increases ovarian cancer risk by small amount

“HRT nearly doubles the risk of ovarian cancer,” The Daily Telegraph reports. While this may sound alarming, the actual increase in risk for individual women is small, because ovarian cancer is rare.

Hormone replacement therapy (HRT) uses synthetic versions of hormones to relieve symptoms of the menopause, such as hot flushes. Concerns have been raised that HRT could also increase the risk of cancers associated with hormones, such as breast cancer and ovarian cancer.

A new detailed review looking at the result of 52 previous studies did find a statistically significant higher risk (43%) in current HRT users compared with HRT non-users, even in those with less than five years of HRT use.

It is important to put the risk in context; in real terms, for every 1,000 women using HRT for five years, there will be just one additional ovarian cancer diagnosis. And if prognosis is typical, there will be one additional ovarian cancer death for every 1,700 users.

In ex-HRT users, risks decreased the longer ago HRT use had stopped, but risks during the first few years after stopping remained significant.

Women should not suddenly stop taking HRT without consulting their doctor. The risks and benefits associated with HRT need to be weighed up on an individual basis and in agreement between you and your doctor.

Where did the story come from?

The study was carried out by researchers from a Collaborative Group on Epidemiological Studies of Ovarian Cancer based in Oxford and funded by the Medical Research Council and Cancer Research UK.

The study was published in the peer-reviewed medical journal The Lancet on an open-access basis, so is free to read online or download as a PDF.

Refreshingly, most of the UK media resisted running the study as a scare story by just talking about the relative risk increase of 43%, and also included information on absolute risk increase at an individual level.

Including this information is a marked improvement on the usual reporting style used by the UK press, especially when it comes to “HRT and cancer” stories.

An unfortunate reminder of the poorer standard of coverage was shown in the Daily Express. It seemed to pump up the scare factor of the story, leading with: “Alert” as HRT “doubles risk of ovarian cancer”. It didn’t mention that this doubling of risk (actually around a 43% increase) was a relative risk. The absolute risk increase was smaller, as ovarian cancer is quite rare.
 

What kind of research was this?

This was a systematic review and meta-analysis looking at the effect of HRT on ovarian cancer risk.

HRT is a treatment used to relieve symptoms of the menopause. It uses either oestrogen only, or a combination of oestrogen and progestogen, known as combination therapy. Symptoms of the menopause include hot flushes, night sweats, mood swings and trouble concentrating. Long-term effects of reduced levels of oestrogen include bone thinning, which increases the risk of fractures, and cardiovascular disease.

HRT is known to be an effective method of controlling menopausal symptoms, and it can make a significant difference to a woman’s quality of life and wellbeing. HRT can also reduce a woman’s risk of developing osteoporosis and cancer of the colon and rectum. Long-term use is rarely recommended, and bone density will decrease rapidly after HRT is stopped.

However, there are risks alongside these benefits. There is evidence that combined HRT slightly increases the risk of developing breast cancer, womb cancer, ovarian cancer and having a stroke. Systemic HRT also increases your risks of deep vein thrombosis (DVT) and pulmonary embolism (blockage in the pulmonary artery). Other medicines are available to treat osteoporosis that do not carry the same level of associated risk.

This study sought to take a closer look at the link between HRT and ovarian cancer.

What did the research involve?

The study team identified all relevant research (published and unpublished) assessing hormone therapy use and ovarian cancer risk since 1998. They found 52 relevant studies containing individual participant information and combined the results – called a meta-analysis.

The meta-analysis looked at how different durations of HRT use (more or less than five years) affected ovarian cancer risk, and whether this risk reduced back to normal levels after HRT was stopped. Other information collected included: ever-use, current use, age at first and last use, and constituents of each preparation.

The main analysis compared ovarian cancer risk in women using HRT (current users, ex-users, short-term, long-term users etc.) with those that had never used HRT. The main analysis focused on data from prospective studies only, to avoid possible biases of participation and recall. Sensitivity analysis used both retrospective and prospective studies to check the robustness of the main results. 

What were the basic results?

Overall, information was available on 21,488 postmenopausal women with ovarian cancer (cases) from 52 studies (17 prospective and 35 retrospective). The prospective studies contributed more than half of the cases (12,110), with an average (mean) diagnosis year of 2001, 55% (6,601) of whom had used HRT for an average (median) of six years.

Women currently using HRT

Ovarian cancer risk was strongly related to how long ago women used HRT. In prospective studies, risk was greatest in women who, when last asked, had been current HRT users (relative risk (RR) 1.41, 95% confidence interval (CI) 1.32-1.50). Among them, risk was significantly increased even in those who, at diagnosis, had less than five years (median duration three years) of hormone therapy use (RR 1.43, 95% CI 1.31-1.56). This means that women currently using HRT when last asked were 43% more likely to develop ovarian cancer than women who had never used HRT, even if they’d been using HRT for less than five years – the previously generally accepted safe time period. This is the figure that made the news, and was described in some places as almost doubling the risk. This increases the previously known risk from less than one per 1,000 women to one per 1,000 women.

Women who’d used HRT in the past, but had now stopped

Ovarian cancer risk was significantly higher in women who had been recent ex-users and would, at the time of cancer diagnosis, have still been within five years of last use (RR 1.23, 95% CI 1.09-1.37). Risk decreased the longer ago hormone therapy had last been used.

However, women who had used hormone therapy for at least five years (median duration nine years) and then stopped were still at significantly increased risk more than five years later (RR 1.10, 95% CI 1.01-1.20). The median time since last use was 10 years. This suggested that long-term use might have a small but significant lingering effect on increasing ovarian cancer risk.

Type of ovarian tumour

In prospective studies, risks in current or recent users were increased only for the two most common ovarian tumour types: serous (RR 1.53, 95% CI 1.40-1.66) and endometrioid (1.42, 95% CI 1.201.67).

Type of HRT

In current or recent users, ovarian cancer risk was significantly increased with use of both oestrogen-only and oestrogen-progestogen types, with little variation between the risks. Both preparations raised the risk by 37% relative to non-HRT users in the prospective studies (RR 1.37, 95% CI 1.29 to 1.46).

Sensitivity analysis

For prospective and retrospective studies combined, the risks were similar to those in prospective studies alone, except that the risks in current users seemed to be somewhat smaller. Other sensitivity analyses left the main findings in prospective studies largely unchanged. This took account of any changes due to variation in year of birth, ethnic origin, education, age at menarche, height, alcohol consumption, smoking, and family history of ovarian or breast cancer.

How did the researchers interpret the results?

The researchers concluded that: “The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for five years from around the age of 50 have about one extra ovarian cancer per 1,000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1,700 users.”

They say: “At present, the World Health Organization, European and US guidelines about hormone therapy do not mention ovarian cancer, and the UK guidelines (which are due to be revised) state only that risk may be increased with long-term use. The definite risk of ovarian cancer that is observed, even with less than five years of use, starting at around the age of 50, is directly relevant to current patterns of hormone therapy use, and hence directly relevant to medical advice, personal choices, and the current efforts to revise UK and worldwide guidelines.”

Conclusion

This systematic review and meta-analysis showed that ovarian cancer risk was significantly increased in current HRT users, even in those with less than five years of HRT use (the average was three years). In ex-users, risks decreased the longer ago HRT use had stopped, but risks during the first few years after stopping remained significant. Furthermore, about a decade after stopping, long-duration hormone therapy use (average nine years of HRT use), there still seemed to be a small excess risk.

The review has a few limitations, however. The main one is that the review was heavily influenced by just two of the 52 included studies. These represented about 75% of the people studied, and neither corrected for use of oral contraceptives.

However, overall this review is robust enough for us to be relatively confident that these findings are generally applicable to women in the UK and are broadly reliable, given the available evidence.

The risk of HRT raising ovarian risk is not new, but this study seems to firm up the knowledge base and suggests the risk may come into play with shorter HRT use than previously thought. For example, current UK guidelines state that ovarian cancer risk may be increased with long-term use. These guidelines are regularly updated and this evidence will be considered when their recommendations are reviewed.

Prof Rod Baber, President of the International Menopause Society, said via the Science Media Centre that: “… this risk in absolute terms then comes down to one excess case of ovarian cancer per 2,000 users after five years of use means that for women using HRT this risk is very very low in absolute terms.”

As much of the UK media pointed out, while the risk increase found here is worth noting and investigating further, women should not stop taking HRT without consulting their doctor. What often gets lost in the mix when the media discuss HRT is that it brings very real benefits to the quality of life, which should not be discounted. Most experts agree that if HRT is used on a short-term basis (no more than five years), the benefits usually outweigh the risks.

The benefits and risks associated with HRT need to be weighed up on an individual basis and in agreement between you and your doctor.

You can read more about the benefits and risks of using HRT.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.

Links To The Headlines

HRT increases ovarian cancer risk. BBC News, February 13 2015

HRT nearly doubles the risk of ovarian cancer, experts warn. The Daily Telegraph, February 13 2015

HRT can increase a woman’s chances of developing ovarian cancer, research shows. The Independent, February 13 2015

‘Long-term HRT use raises risk of ovarian cancer’: Chance increases by 40% after using treatment for five years. Mail Online, February 13 2015

HRT treatment raises risk of ovarian cancer, says study. The Guardian, February 13 2015

Alert as hormone replacement therapy ‘doubles risk’ of ovarian cancer. Daily Express, February 13 2015

Links To Science

Collaborative Group on Epidemiological Studies of Ovarian Cancer. Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies. The Lancet. Published online February 12 2015