Elsevier

Maturitas

Volume 77, Issue 4, April 2014, Pages 311-317
Maturitas

Review
Progestogens in postmenopausal hormone therapy and the risk of breast cancer

https://doi.org/10.1016/j.maturitas.2014.01.001Get rights and content

Abstract

Hormone therapy is the treatment of choice for the alleviation of menopausal symptoms and the treatment of urogenital atrophy. In women with an intact uterus a progestogen must be added to estrogen therapy to prevent endometrial hyperplasia and cancer. There is a wide variety of marketed progestogens which differ in their pharmacological properties according to their structure. Convincing evidence from both clinical trials and epidemiological studies indicates that combined estrogen–progestogen therapy confers a higher risk of breast cancer compared to estrogen monotherapy. Concerning the different types of progestogens, data from large observational studies suggest that natural progesterone and dydrogesterone are associated with a lower risk of breast cancer compared with the other progestins. Observational studies, furthermore, indicate that sequential estrogen–progestogen regimens may lead to a lower risk elevation compared to continuous regimens. The effect of tibolone on breast cancer is unclear. Concluding, both the type of the progestogen and the mode of HT administration may have an impact on breast cancer risk.

Introduction

Hormone therapy (HT) is the treatment of choice for the management of bothersome menopausal symptoms and of urogenital atrophy [1]. Since the majority of menopausal complaints are attributed to estrogen deficiency, HT consisted originally of estrogen monotherapy. The increase, however, of endometrial hyperplasia and cancer has mandated the addition of a progestogen to the HT regimen for endometrial protection [2]. Beyond its effect on quality of life, HT increases bone mineral density, decreases the risk of both vertebral and hip fractures as well as the risk of colon cancer in postmenopausal women [3]. HT, furthermore, has a beneficial effect on the postmenopausal cardiometabolic risk by improving the lipid profile [4], by inhibiting abdominal fat accumulation [5] and by improving insulin sensitivity [6]. If administered early after menopause, HT may reduce the risk of ischemic heart disease [7].

During the past decades HT had been widely prescribed with the expectation of both osteoporosis and cardiovascular disease prevention. The results of the Women's Health Initiative (WHI) trial, however, indicated that long-term HT use is associated with a small but significant increase of cardiovascular events and breast cancer [3]. Whereas the increase in ischemic heart disease risk is probably confined in older women, in whom HT is not usually prescribed, breast cancer risk increase applies to younger women initiating HT soon after menopause [2].

Due to concerns about breast cancer, many clinicians are hesitant to prescribe HT, depriving thus their patients from multiple beneficial HT effects. On clinical grounds, however, this small risk may be modified by several factors dependent both on the patient profile and the characteristics of the HT regimen. The customization of treatment, therefore, according to the individual needs and risks ensures efficacy and safety of HT. In this review, the available evidence is summarized on how the progestogens used in HT may affect breast cancer risk.

Section snippets

Classification of progestogens (Fig. 1)

Progestogens are compounds with progestational activity, meaning the capacity to induce secretory endometrium and support gestation. Progestogens are divided into natural progesterone, which is produced by the human ovary and to synthetic progestogens which are also called progestins. Progestins are classified into those structurally related to progesterone and those structurally related to testosterone. Progestins related to progesterone are sub-classified into pregnane and 19-norpregnane

Breast cancer risk and hormone therapy in postmenopausal women

Breast cancer is the most common malignancy in women and the second commonest malignancy after prostate cancer. The lifetime risk of developing breast cancer is around 12%. Nearly half of the cases will be diagnosed between 45–65 years of age [11], a time point at which hormone therapy is usually prescribed. The most important risk factor of breast cancer is age, followed by a history of benign proliferative breast disease, especially if atypia is present, increased mammographic density and a

Estrogen alone versus estrogen–progestogen regimens (Table 1)

Estrogen monotherapy (ET) has since long been associated with a lower breast cancer risk compared to estrogen–progestogen combined therapy (EPT). A large meta-analysis published in 1997 indicated that long term (≥5 years) current users of ET had 1.34 relative risk of breast cancer as opposed to 1.53 for current users of EPT [19]. At that time, however, most women were receiving higher doses of estrogen-only preparations regardless of the presence of a uterus, so meaningful comparisons cannot be

Conclusions

Progestogens are steroids with divergent pharmacologic properties according to their structure. There is consistent evidence that the addition of a progestogen to estrogen in postmenopausal hormone therapy increases the risk of breast cancer. Direct comparisons of different progestogens in RCTs are not available, but large epidemiological studies indicate that natural progesterone and dydrogesterone may be associated with a more favorable risk profile with respect to breast cancer risk,

Contributors and their role

Irene Lambrinoudaki reviewed the literature and drafted the manuscript.

Competing interest

The author declares no conflict of interest.

Funding

The author has received no funding for this article.

Provenance and peer review

Commissioned and externally peer reviewed.

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