Doctor Mizutani’s lecture on Women’s Health and pregnant Women’s Health and Mother-To-Be series No.18.


One of the most concerned matters for women with themselves is cancer, the Breast Cancer. They may wonder why such a malicious event occurs and even the victims are increasing. Certainly, the aging of women’s population speaks, as most of the type of cancer is aging-related, no wonder with the cancer of breast.



What comes next is the family history, in other words, genetic disposition. Another risk factor known is environmental factor, such as often claimed as smoking and lung cancer.



You may be aware of the fact that female hormones are indispensable for a woman’s health across her lifecycle. For example, pregnancy, child bearing, adolescence, menopause, as well as menstruation problems or uterine fibroid, a benign neoplasm, during her reproductive age. As an obstetrician and gynecologist of myself, we are specialized physicians taking care of these hormones,they are estrogen or follicular hormone, and, progesterone or luteinizing hormonethe way they support a woman’s body function and health maintenance throughout her life. Management of the optimal level or status of female hormones is therefore the base of ob-gyn medicine, thus, they are indispensable medication.



Both, hormone replacement therapy (HRT) for postmenopausal women and oral contraceptives (OCs) are the composites of female hormones, so in principle, associated side effects are similar. Then, the question comes. Are HRT and OCs can be the factors for elevating the risk of breast cancer?



These was a large-scale epidemiological study (WHI) conducted in the U.S. with a prime objective to determine HRT if it has preventive effects against cardiovascular diseases. In the interim analysis of the study, the incidence of breast cancer events in the HRT arm was found to be higher than that of the control arm, compelling the whole study to discontinue. Since then the news prevailed towards a doubtless fact that HRT is the serious risk factor for breast cancer.



On the contrary, the British Medical Journal (BMJ) published three times, the results of surveillance on the pill by British family physicians and midwives in 2007, 2010, and 2014. All of these reports clearly explained out   shortcomings in the WHI’s interim analysis. In the BMJ reports the authors concluded that no relation between pill use and breast cancer deaths was indicated after a very long follow-up of a large number of women participated.



In the introduction of the OC (pill) Prescription Guideline 2015 issued by Japan Society of Obstetrics and Gynecology, it reads, “the incidence of breast cancer increases shortly after the prescription of OCs”. If it is true or not, this statement lingers on ob-gyn physicians mind. As mentioned earlier, following to the WHI interim analysis, substantial reduction in hormone prescription was witnessed worldwide including Japan since after 2002.



On the other hand, the literature published in 2003 in the American medical journal JAMA reported as follows. When postmenopausal women get prescribed hormones with HRT, the incidence of invasive breast cancer (progressive cancer) increases approximately at fourth year after starting medication compared to non-users, however, that of early-stage breast cancer (intraepithelial cancer) did not show any difference at all.



As I said, after the WHI’s interim analysis, hormone prescriptions have been refrained worldwide. Then what happened to the outbreak of breast cancer? The line of thinking may be that if its incidence has changed, it might give answers to, “are hormones (HRT or OCs) indeed risk-elevating factors for breast cancer?”



The answers can be extracted from French cohort study between 1990 and 2010, analyzed breast cancer patient records from two registered cancer sites. It showed both types of breast cancer, invasive and intraepithelial, increased from 1990 to 2003. However, from 2003, the year after WHI, early-stage type (intraepithelial) continued to increase, whereas invasive type decreased. The results were exactly in line with the conclusion of the report in 2003 in JAMA.



May be we could say female hormone is a causal factor for increasing invasive breast cancer incidence but not for all breast cancer. Perversely saying, HRT or OCs may have heightened the chances of the detection of difficult-to-diagnose type of breast cancer.



Recently, British Journal of Cancer (BJC) published a report showing two to three-fold risk of HRT for breast cancer. Their rather jumping conclusion was, “the risk was proved to be much higher than ever estimated.” Period.



This straight-forward literature does not argue if HRT is the only cause of events and if it should be refrained in the clinical settings. The authors were British group of epidemiology. I have not encountered such kind of literatures ever before in our realm of obstetrics and gynecology.



The epidemiologists mixed a natural type and synthesized types of hormone preparations as “the hormone.” Detailed genetic history was not mentioned. Self-questionnaires sent three times over 10 years follow-up, then found high risk in women on HRT for more than fifteen years. Was the fifteen-year adequately monitored and prescribed?



The epidemiologists excluded women who do not have accurate year of their menopause because the study focused on “how long” was HRT continuation. The results were obvious, the longer the higher the risk.  Years until the events were diagnosed in ten years on three collections of questionnaire. Actually, we do care, type of hormone, dose, combination of estrogen and progesteronedaily or with intervals, or without combination. These information were missing.



If we look at actual number of patients, five hundred and fifty-three cases were identified out of thirty-nine thousand menopausal women followed up. Of these cases, five hundred women answered never used HRT, and fifty-two answered they were on HRT. As these number suggests, majority of breast cancer events are regardless of HRT. Indicating a lot of other risk factors exist behind the victims of breast cancer. Without HRT, free from breast cancer, clearly it is NOT.





文献Jones ME et al. www.bjcancer.com?DOI:10.1038/bjc.2016.231

Daubisse-Marliac L. et al. Annals of Oncology 22: 329–334, 2011