All hormone therapy—regardless of the formulation, estrogen dose, progestin type, dose regimen, route of administration, or duration of use—appears to raise the risk of ovarian cancer, according to a report.
If the association between HT and ovarian cancer proves to be causal, it would mean that as many as 5% of such malignancies could be attributable to the treatment. “Even though this share seems low, ovarian cancer remains highly fatal, so accordingly this risk warrants consideration when deciding whether to use [HT],” said Lina Steinrud Mørch of Copenhagen University and her associates.
They assessed ovarian cancer using data from the Danish Sex Hormone Register Study, a national 10-year cohort study of nearly 1 million Danish women. Ms. Mørch and her colleagues restricted their analysis to the 909,946 women who were perimenopausal or postmenopausal at baseline in 1995.
This included 575,883 women who had never used HT and 334,063 who had. Among the current users of HT, nearly half had been taking the hormones for more than 7 years.
A total of 3,068 incident ovarian cancers developed in the study period, including 2,681 that were epithelial tumors.
Compared with women who had never taken HT, those who had showed a relative increase of 30%-58% in their risk of developing ovarian cancer, according to Ms. Mørch and her colleagues (JAMA 2009;302:298-305).
The risk did not differ significantly by duration of use, with women who took HT for up to 4 years showing similarly increased risk as those who took it for 5 years or more. Similarly, women who took estrogen alone had about the same risk as did those who took combined estrogen plus progestin.
Women who took cyclic HT had increased risk similar to that in women who took continuous HT. And ovarian cancer risk was elevated regardless of HT dosage and regardless of whether HT was delivered by oral tablet, patch, or gel.
“If the difference in risk between never users and current users is due to hormone therapy, these results imply that use of HT resulted in about 1 extra case of ovarian cancer for roughly every 8,300 women taking HT each year,” the investigators wrote.
In commenting on the study, Dr. Wulf H. Utian, executive director of the North American Menopause Society, said, “The possibility of a very slight increase in ovarian cancer risk [with HT] should be added to the risk-benefit discussion” between physicians and patients. Women who have severe vasomotor symptoms negatively affecting their quality of life are likely to take the risk, he added.
Although Dr. Utian said the Scandinavian figures are probably “as reliable as you can get in a public health system,” he said he had concerns about the study's methodology. In evaluating different HT regimens, the investigators included in the progestin category drugs that are not progestins such as cyproterone acetate, an antiandrogen, and raloxifene, a selective estrogen receptor modulator (SERM).
“What they've got here is fruit salad. They've got all different kinds of products lumped together, and they haven't adequately broken them out,” he said. Of the progestins that were specified, norethisterone acetate, the one most widely used in the study, was significantly associated with an increased risk of ovarian cancer; however, medroxyprogesterone acetate and levonorgestrel were not associated with an increased risk of ovarian cancer.
In addition, the investigators did not specify the type of estrogen used in their study, he noted. This contrasts with the Women's Health Initiative, a randomized, controlled study that found that Premarin (conjugated estrogens) does not increase ovarian cancer risk. The conjugated estrogen formulation is not used in Denmark, he said, so it's unlikely that it was part of the current study.
Dr. Utian reported no conflicts of interest relevant to the European drugs used in the study, but said he has consulted for several pharmaceutical companies that make estrogen products, including transdermal estrogen and SERMs. He reported being an investigator in a study of a SERM manufactured by Wyeth Pharmaceuticals.
Ms. Mørch reported no conflicts of interest. Dr. Øjvind Lidegaard, an associate in the Danish study, reported receiving a grant from Schering AG, Berlin, to cover research expenses and has received fees for speeches from Schering Denmark and Novo Nordisk. This study was supported by a grant from the Danish Cancer Society.
Felicia Rosenblatt Black contributed to this report.
'What they've got here is fruit salad. They've got all different kinds of products lumped together.'
Source DR. UTIAN