Hormone replacement in menopause and ovarian cancer risk

Hormone replacement in menopause must be evaluated thoroughly on an individual basis with careful attention to the important benefits and risks. This includes of course objective measurements of bioactive hormone levels before and during hormone replacement at appropriate intervals, including analysis of benign versus troublesome estrogen metabolites. Regarding adverse effects that must be weighed, an important study just published in The Lancet brings to light a significant risk for ovarian cancer in current and past users of hormone replacement. This is particularly important because regulatory decisions concerning hormone replace were based mainly on the Women's Health Initiative trial which did not consider ovarian cancer. The authors state:

"Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on ovarian cancer risk."

The authors examined data on individuals from 52 epidemiological studies on hormone replacement collected by the Collaborative Group on Epidemiological Studies of Ovarian Cancer that was established in 1998 to assess the risks associated with hormonal and other factors. This included 21,488 postmenopausal women with ovarian cancer. This enabled them to evaluate the association of ovarian cancer with just a few years of hormone replacement therapy, or past use, with minimal bias.

Hormone replacement significantly increased risk

With even less than 5 years of use the risk for ovarian cancer was significantly increased and, although declining gradually with time after hormone replacement was stopped, still persisted:

"During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 years of use (RR 1·43). Combining current-or-recent use (any duration, but stopped <5 years before diagnosis) resulted in an RR of 1·37; this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the four main tumour types, being definitely increased only for the two most common types, serous (RR 1·53) and endometrioid (1·42). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours."

Alcohol use, smoking, body size, oral contraceptive use, age when hormone replacement started, hysterectomy, and family history of breast or ovarian cancer did not account for the increased risk. The authors commented on these findings:

"Ovarian cancer risk was significantly increased in current users, even in those with less than 5 years hormone therapy use. In ex-users, risks decreased the longer ago hormone therapy use had ceased, but risks during the first few years after stopping remained appreciable. Furthermore, about a decade after ceasing long-duration hormone therapy use, there still seemed to be a small excess risk...In current-or-recent users (all of whom had used hormone therapy within the past 5 years), the RRs did not differ significantly between users of oestrogen-only and of oestrogen-progestagen preparations, or between women who had started hormone therapy before the age of 50 years or during their 50s."

In other words, women who used hormone replacement for even a short time were approximately 20% more likely to have developed ovarian cancer than women who never used HRT, and the more recent the therapy, the greater the risk. Among those women who were taking hormone replacement when last asked the relative risk was 41%. Those who had stopped but were within 5 years of last use at the time of their cancer diagnoses had a 23% increased relative risk. Although risk was lower as more time passed, having used HRT for at least 5 years was still associated with a 10% increased relative risk more than 5 years later.

 Mortality reduction by avoiding hormone replacement

Quoted in Medscape Family Medicine, the lead authors note:

"The findings of the meta-analysis "support the addition of ovarian cancer to the list of adverse effects associated with hormone therapy use," Dr Wentzensen and Dr Trabert write...Avoidance of HRT could reduce ovarian cancer mortality because of the effect on the serous subtype, they conclude."

The authors of an editorial comment in the same issue of The Lancet state:

"...very few risk factors have emerged for serous ovarian cancer, the most common and most lethal subtype; therefore, any reduction in risk, for example by avoidance of hormone therapy use, could lead to relevant reductions in ovarian cancer mortality."

The crucial matter of dosage and protocol

Another statement by the editorial authors brings up a key consideration:

"The present study did not evaluate dose, and median year of diagnosis was 2001 for the cohort studies—slightly before the widespread change in use patterns occurred. In view of recommendations to use the lowest dose possible for the shortest duration, the study findings did show significant increases in ovarian cancer risk even among current short-term users (median duration 3 years), but a few years after stopping short-term use (after, however, a median of only 1 year of use) the risks were no longer increased. It is unclear to what extent the differences in median duration of use between current and previous users are responsible for these disparate findings. Further, it remains to be explored to what extent risk is reduced for low-dose regimens and non-oral formulations."

Most women coming to my practice already on hormone replacement have almost always  been given hormones with disturbingly incomplete initial tests—if any tests have even been done at all—and I have seen almost universally a lack of follow-up tests to determine whether the hormone levels on replacement were being maintained at healthy and safe normal physiological levels. Many patients were given transdermal creams that commonly build up to hazardous supra-physiological levels as seen when follow-up tests are properly done. Moreover, hardly any had ever been tested for estrogen metabolites and their ratio of safe versus tumor-promoting.

Is there a safe way?

The principles that emerge here are the same for all the other possible adverse outcomes of hormone replacement including breast and endometrial cancers and cardiovascular disease. Considering that due to lack of appropriate testing and customization of hormone replacement to the unique needs of each patient with proper follow-up to ensure normal, physiological levels of all the major steroid hormones it's no surprise that there are too many regrettable outcomes, including ovarian cancer. Estrogen and progesterone are important for much more than hot flashes and bone health. In fact, adequate amounts are a necessary part of a strategy for healthy brain aging. But this is no place for 'try this, try that' and 'one size fits all'. As patients improve in other ways their capacity to produce more of their own hormones often increases as shown on follow-up tests, requiring hormone replacement doses to be lowered. Thorough testing at appropriate intervals in the context of a comprehensive assessment and case management that encompasses the whole picture can minimize the risk for adverse effects from hormone replacement while securing the benefits.The authors of the study conclude:

"The findings that ovarian cancer risk is greatest in current users of hormone therapy, falls after use ceases, and varies by tumour type, strongly suggest a causal relationship—ie, that among otherwise similar women, use of hormone therapy increases the probability of developing the two most common types of ovarian cancer, and hence ovarian cancer as a whole. There are still some 6 million users of hormone therapy in the USA and the UK, in addition to a comparable number in other high-income countries. At present, the WHO, 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 5 years of use starting at around age 50 years 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."

The authors of the editorial conclude:

"The available data for breast cancer and cardiovascular outcomes from clinical trials and observational data dictate caution in the use of hormone therapy. In the context of the observational data presented in this study, it is still not clear whether the current recommendation to use hormone therapy for the shortest duration possible is appropriate for women who are concerned about an increased risk of ovarian cancer. The current report underlines the importance and limitations of observational data for rare and long-term outcomes, especially for the complex associations between regimen, dose, duration, route of administration, and timing of hormone therapy use with ovarian, breast, and endometrial cancers."