br Benefits and risks of traditional

Benefits and risks of traditional combined oestrogen–progestogen HRT regimens Combined oestrogen–progestogen regimens were developed to reproduce the short- and long-term benefits of oestrogen replacement therapy (ERT) and to simultaneously provide appropriate protection against oestrogen-related endometrial hyperplasia and neoplasia. Combined regimens are effective in relieving many menopausal symptoms [9], [10], [11]. Importantly, the oestrogen-related protection from osteoporosis is not lost with the addition of progestogens [8], [10], [12], [13]. Progestogens have a protective effect on the caspofungin and suppress endometrial growth induced by oestrogen, thereby reducing the risk of developing endometrial hyperplasia and cancer [14], [15], [16]. There has been some concern that the addition of a progestogen may attenuate or even reverse the reduction in risk of cardiovascular disease seen with ERT by altering the beneficial effects of oestrogen on lipids, most notably by suppressing the increase in high-density lipoprotein (HDL) cholesterol and the decrease in low-density lipoprotein (LDL) cholesterol concentrations. This progestogenic effect on lipids has been seen in some studies [9], [17], [18], which may be related to the specific progestogen used (MPA), but has not been seen in other studies [10]. The disadvantages of combination HRT relate primarily to troublesome progestogenic side effects. Secretory effects of progestogens on the endometrium can result in uterine bleeding, which can be heavy and prolonged [4], [5]. This effect is a frequent reason given by postmenopausal women for dissatisfaction, reduced compliance, and early discontinuation of combined HRT [3], [4], [5], [19]. Side effects related to the steroidal structure of the specific progestogen in the HRT regimen can also be significant. Fluid retention, breast tenderness, abdominal bloating, headaches, and mood effects are some of the most frequently reported side effects. The adverse event profile and severity of effects may differ depending on the (anti-)androgenic, (anti-)oestrogenic, mineralocorticoid, and/or glucocorticoid properties of the chosen progestogen [5]. Some studies report that up to 20% of women experience significant progestogen intolerance [5] and approximately 40% have side effects that prevent them from continuing treatment [6].
Constant oestrogen, intermittent progestogen HRT
Summary
Introduction Breast cancer is a hormone-responsive cancer that accounts for about one fourth of all female cancers, and is the leading cause of cancer-related death among women worldwide (Torre et al., 2015). It is a highly heterogeneous disease thought to be due to the variable histological subtypes as well as differences in response to therapy and clinical outcome amongst patients (reviewed in Song et al., 2016). Breast tumours are classified as either luminal (estrogen receptor (ERα), progesterone receptor (PR)-positive), basal (ERα-negative), human epidermal growth factor receptor 2 (HER2)-overexpression (ERα and PR negative, HER2-positive) or triple negative breast cancer (TNBC) (ERα, PR, HER2-negative) (Cheang et al., 2009, Dai et al., 2015). Luminal cancer is subdivided into luminal A (low Ki67 index, slow tumour growth) and B (high Ki67 index, high tumour growth) (Yanagawa et al., 2012). Prognosis and choice of therapy thus depend on the breast cancer subtype. Breast cancer, like prostate cancer, can be driven by active steroid hormones found in circulation. Given that estrogen acting via ERα is considered to be the major etiological factor in breast cancer, current therapies include inhibitors of the ER and the estrogen producing enzyme, cytochrome P450 19A1 (CYP19A1; aromatase) (Platet et al., 2004, Zhao and Ramaswamy, 2014). However, the importance of steroid receptors such as the PR and androgen receptor (AR), and their ligands, in different breast cancer subtypes are increasingly being recognized, and thus new therapeutic strategies are now also targetting these receptors (reviewed in Lim et al., 2016). In terms of estrogen, however, there is no shortage in the supply of estrogen in circulation in premenopausal women, while in postmenopausal women the levels of circulating estrogens are significantly reduced (Simpson, 2003). A similar scenario is observed in prostate cancer, where the levels of the primary androgen testosterone (T) are decreased significantly following androgen deprivation therapy (Heidenreich et al., 2014). Yet in both cases the cancers remain hormone-dependent and express an assortment of steroid metabolising enzymes which can convert inactive steroid precursors found in circulation into active steroids. Thus, although it is well-established that the biological behaviours of breast cancers are dependent on circulating levels of steroids binding to their cognate steroid receptors, it is clear that the intracrinology of breast cancer is vitally important to our understanding of disease mechanism as well as mechanism of treatment resistance. This is particularly relevant in patients that are ER and/or PR-negative, and thus lack response to adjuvant hormone therapy. However, the intracrine metabolism of steroid hormones in the breast, and their subsequent intracrine actions, is not straightforward, but rather an intricate system influenced by factors such as the availability of circulating hormone precursors, and the expression levels of specific steroidogenic enzymes and steroid receptors. While many reviews have already highlighted the major pathways involved in the intracrinology of breast cancer (Labrie et al., 2003, McNamara and Sasano, 2015b, Capper et al., 2016), here we describe the classical steroid hormone production in the adrenal and ovary, and provide an overview of the known pathways involved in the intracrinology of breast cancer, while suggesting alternate pathways which may be equally important.