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Hormone Molecular Biology and Clinical Investigation

Editor-in-Chief: Chetrite, Gérard S.

Editorial Board: Alexis, Michael N. / Baniahmad, Aria / Beato, Miguel / Bouillon, Roger / Brodie, Angela / Carruba, Giuseppe / Chen, Shiuan / Cidlowski, John A. / Clarke, Robert / Coelingh Bennink, Herjan J.T. / Darbre, Philippa D. / Drouin, Jacques / Dufau, Maria L. / Edwards, Dean P. / Falany, Charles N. / Fernandez-Perez, Leandro / Ferroud, Clotilde / Feve, Bruno / Flores-Morales, Amilcar / Foster, Michelle T. / Garcia-Segura, Luis M. / Gastaldelli, Amalia / Gee, Julia M.W. / Genazzani, Andrea R. / Greene, Geoffrey L. / Groner, Bernd / Hampl, Richard / Hilakivi-Clarke, Leena / Hubalek, Michael / Iwase, Hirotaka / Jordan, V. Craig / Klocker, Helmut / Kloet, Ronald / Labrie, Fernand / Mendelson, Carole R. / Mück, Alfred O. / Nicola, Alejandro F. / O'Malley, Bert W. / Raynaud, Jean-Pierre / Ruan, Xiangyan / Russo, Jose / Saad, Farid / Sanchez, Edwin R. / Schally, Andrew V. / Schillaci, Roxana / Schindler, Adolf E. / Söderqvist, Gunnar / Speirs, Valerie / Stanczyk, Frank Z. / Starka, Luboslav / Sutter, Thomas R. / Tresguerres, Jesús A. / Wahli, Walter / Wildt, Ludwig / Yang, Kaiping / Yu, Qi

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Volume 25, Issue 2

Issues

Hormones and endometrial carcinogenesis

Areege Kamal
  • Institute of Translational Medicine, Department of Women’s and Children’s Health, University of Liverpool, Liverpool, UK
  • The National Center for Early Detection of Cancer, Oncology Teaching Hospital, Baghdad Medical City, Baghdad, Iraq
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/ Nicola Tempest
  • Institute of Translational Medicine, Department of Women’s and Children’s Health, University of Liverpool, Liverpool, UK
  • Liverpool Women’s Hospital NHS Foundation Trust, Liverpool, UK
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  • De Gruyter OnlineGoogle Scholar
/ Christina Parkes
  • Institute of Translational Medicine, Department of Women’s and Children’s Health, University of Liverpool, Liverpool, UK
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/ Rafah Alnafakh
  • Institute of Translational Medicine, Department of Women’s and Children’s Health, University of Liverpool, Liverpool, UK
  • Department of Pathology, Al-Hilla Teaching Hospital, Babil, Iraq
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/ Sofia Makrydima / Meera Adishesh / Dharani K. Hapangama
  • Corresponding author
  • Institute of Translational Medicine, Department of Women’s and Children’s Health, University of Liverpool, Liverpool, UK
  • Liverpool Women’s Hospital NHS Foundation Trust, Liverpool, UK
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Published Online: 2016-03-11 | DOI: https://doi.org/10.1515/hmbci-2016-0005

Abstract

Endometrial cancer (EC) is the commonest gynaecological cancer in the Western World with an alarmingly increasing incidence related to longevity and obesity. Ovarian hormones regulate normal human endometrial cell proliferation, regeneration and function therefore are implicated in endometrial carcinogenesis directly or via influencing other hormones and metabolic pathways. Although the role of unopposed oestrogen in the pathogenesis of EC has received considerable attention, the emerging role of other hormones in this process, such as androgens and gonadotropin-releasing hormones (GnRH) is less well recognised. This review aims to consolidate the current knowledge of the involvement of the three main endogenous ovarian hormones (oestrogens, progesterone and androgens) as well as the other hormones in endometrial carcinogenesis, to identify important avenues for future research.

Keywords: androgens; endometrial cancer; gonadotropin-releasing hormones; oestrogen; polycystic ovarian syndrome; progesterone

Introduction

Endometrial cancer (EC) is the commonest gynaecological cancer in Europe and has an alarmingly increasing incidence related to longevity and obesity [1, 2]. The European estimates suggest, by 2025, an incidence increase of EC in the range of 50%–100% will occur, relative to the observed incidence in 2005 [3]. Many women with EC are postmenopausal (PM) and not suitable for standard surgical treatment because of other commonly coexisting medical problems, such as obesity, hypertension and diabetes. Latest national figures in the UK show that one in four women undergoing major gynaecological surgery for cancer experience serious surgical complications [4]. The 5-year survival rates for advanced EC are 23%, worse than for other common gynaecological cancers, and similar to that of ovarian cancer [5]. Current therapeutics fail to treat late stage disease, and preventing advanced disease and distant metastasis needs early diagnosis of ECs. Identification of those ECs likely to metastasise and treating them with adjuvant therapies is imperative to tackle the impending economic and social burden caused by the increasing incidence of EC predicted over the next decade [3].

Ovarian hormones regulate normal human endometrial cell proliferation, regeneration and function, therefore are implicated in endometrial carcinogenesis. Furthermore, recent evidence suggests that all types of ECs may share common etiological factors, including their response to/stimulation by oestrogen and other ovarian steroid hormones [6]. Although many reviews previously describe the role of oestrogen and progesterone in endometrial carcinogenesis, they have largely disregarded the involvement of androgens and other hormones. Recent reports however, describe a role for androgens and its receptor [7, 8], gonadotropin-releasing hormone (GnRH) and luteinizing hormones (LH) in EC [9, 10]. This review aims to explore the current knowledge on how endogenous and exogenous hormones, influence endometrial carcinogenesis.

Method

We carried out PubMed (Medline) and Ovid searches systematically for publications from November 2000 until November 2015. Keywords used included: EC with hormones, risk factors for EC, obesity, adipose, polycystic ovarian syndrome (PCOS), lynch syndrome (LS), diabetes, Parkinson’s disease (PD), pregnancy, menarche, menopause, combined oral contraceptive pills (COCPs), oestrogens, progestogens, selective oestrogen receptor modulators (SERMs), tamoxifen, selective progesterone receptor modulators (SPRMs), aromatase inhibitors, fulvestrant, hormone replacement therapy (HRT), GnRH analogues/antagonists, LH, danazol and androgens. All studies investigating hormonal influences in EC in women, animals and endometrial cell lines, either primary cells or tissue explants in culture were considered. Further manuscripts published before November 2000 were also reviewed for specific topic areas and included as appropriate.

Human endometrium as a hormone receptive organ

Anatomy/histology

Embryonic Mullerian ducts fuse in the midline to form the human uterus and the inner layer of its mesenchyme forms the endometrium. Initially, the superficial endometrial glands originate from the fetal undifferentiated, single columnar epithelial cells in utero. The histological architecture of the endometrium at birth is analogous to the PM endometrium yet the glands remain to be shallow and superficial [11]. Humans (and other upper order primates) menstruate, and have two distinct layers of the endometrium, making them unique, amongst other mammals. The transient superficial stratum functionalis exists only during the reproductive life of the woman whilst the structurally permanent deeper stratum basalis adjacent to the myometrium remains throughout life [12]. Endometrium consists of a variety of cell types including epithelial, stromal, endothelial and leucocyte cell populations. As most ECs are carcinomas, in the context of carcinogenesis, the critical endometrial cell type is the epithelial cells. Endometrial epithelium is also organised into distinct groups of cells (i) luminal epithelium, that lines the superficial surface of the uterine cavity, (ii) the hormone responsive, fully differentiated functionalis glands and (iii) the deeper SSEA-1 expressing basalis glandular epithelium [13]. Presumably, a new functionalis layer is generated each month from the remaining basalis after menstrual shedding, hence the basalis is proposed to harbour stem/progenitor cells (SPCs) [12]. ECs commonly occur in the PM endometrium, which is essentially the retained luminal and basalis epithelium. SPCs are thought to play a role in carcinogenesis and these epithelial layers are also their postulated location [14]. The particular endometrial epithelial cell group(s) that gives rise to ECs is not yet known. However, we can conclude that either luminal or basalis glandular compartments are likely to be the common epithelial origin of ECs.

Overview of normal endometrial endocrinology

Endometrium is the primary recipient organ for ovarian steroid hormonal signal and is intricately responsive to these hormones. The three main classical ovarian steroid hormones, oestrogens, progesterone and androgens exert their effects in the endometrial cells mainly via their cognate receptors [12, 15, 16]. Endometrium expresses both subtypes of classical nuclear oestrogen receptors (ERα and ERβ). Progesterone, acts via the progesterone receptor subtypes PRA and PRB. Androgens operate via androgen receptor (AR) and all these receptors belong to the Class I nuclear hormone receptor superfamily of ligand-inducible transcription factors that share the common, evolutionarily conserved structural and functionally distinct domains of other superfamily members [12]. These classical hormone receptors are activated upon ligand binding and may exert effects involving the classical hormone-signalling pathway [12, 15]. This involves steroid receptor dimerising, translocating to the nucleus, binding to the respective hormone responsive element located in the relevant gene promoters to initiate recruitment of co-activators, co-repressors and chromatin remodelling factors to either activate or repress transcription of target genes. Post-translational modifications of the steroid hormone receptors will also affect gene promoter targeting and subsequent target gene transcription.

The general consensus is that oestrogen induces the expression of all endometrial steroid receptor types via the action of ERα whilst progesterone may downregulate them via PR (except for ERβ) [12, 17] (Figure 1). Androgens acting via AR induce their own receptor expression [18, 19] but AR-mediated effect on the other hormone receptors in the endometrium is not yet known. The expression profile of these different steroid receptors and the levels of respective hormones at the cellular level are therefore important to ascertain the full impact of hormones on the endometrium (Figure 1).

Correlation of typical hormonal changes of pituitary/ovarian axis with the consequential endometrial morphology and steroid hormone expression in women. Pituitary and ovarian hormones show typical cyclical variations during the premenopausal period and these change at menopause. The correspondent endometrial morphology and epithelial steroid receptors expression in normal [pre and postmenopausal (PM)], premalignant [endometrial hyperplasia (EH) with atypia] and malignant (low-grade endometrial cancer, LGEC and high-grade endometrial cancer, HGEC) endometrium is shown in the panels.
Figure 1:

Correlation of typical hormonal changes of pituitary/ovarian axis with the consequential endometrial morphology and steroid hormone expression in women.

Pituitary and ovarian hormones show typical cyclical variations during the premenopausal period and these change at menopause. The correspondent endometrial morphology and epithelial steroid receptors expression in normal [pre and postmenopausal (PM)], premalignant [endometrial hyperplasia (EH) with atypia] and malignant (low-grade endometrial cancer, LGEC and high-grade endometrial cancer, HGEC) endometrium is shown in the panels.

The intra-cellular levels of steroid hormone metabolising or activating enzymes may also play a pivotal role in regulating the final effect of these hormones [20]. To add another layer of complexity, some hormone receptors make heterodimers upon hormone/ligand binding. For example, ERα dimerise with ERβ and the effect of oestrogen displayed by cells expressing equal amount of both receptors will be different to another expressing more of a particular subtype of these receptors [12]. Furthermore, most class I hormone receptors can bind to the other ovarian steroid hormones with a lower affinity due to the significant homology between their ligand binding domains [21]. Therefore, when some steroid hormones are abundant, they may also exert some effects via a different steroid receptor, as well as acting through their specific cognate receptor.

Hormonal milieu of premenopausal endometrium

The prepubertal ovary is inactive, hence, the thin endometrium grows very slowly from birth until puberty due to the lack of ovarian hormonal (mainly oestrogenic) signal [12]. In response to the increasing levels in ovarian oestrogen and adrenal androgens observed at puberty, endometrium acquires the typical adult histo-anatomical configuration, and with the oestrogenic stimuli in the proliferative phase grows a functionalis layer that differentiates with the subsequent exposure to progesterone produced by the corpus luteum [22]. At the end of an infertile cycle, with luteolysis, the drop in progesterone (and oestrogen) initiates an inflammatory cascade, vasoactive and hypoxic events result in shedding of the functionalis as menstruation, followed by epithelialisation and regrowth of the functionalis to begin the next endometrial cycle [23] (Figure 1). Ovarian production of androgens is also reported to follow a cyclical pattern, yet the exact function of androgens in the normal endometrial function and regeneration is not fully described.

Hormonal milieu of PM endometrium

Similar to the prepubertal endometrium, the main histological characteristic of the PM endometrium is the complete loss of stratum functionalis. It is composed of inactive glands lying in compact stroma that morphologically resembles the stratum basalis of premenopausal endometrium [13, 24]. The PM hormonal milieu is characterised by the absence of progesterone and oestradiol production by the ovaries, persisting levels of androgens from the adrenals and the presence of low levels of circulating oestrone produced by the extra-ovarian aromatisation of adrenal androgens [20] (Figure 1). This low level of oestrogenic signal supports the maintenance of hormone receptor expression observed in the PM endometrium hence the hormone responsiveness [25].

Hormonal aberrations associated with EC

Oestrogen and insulin in excess and lack of progesterone have been proposed as the main hormonal aberrations to affect endometrial proliferation and cell survival that can result in increasing the risk of epithelial cell transformation/carcinogenesis. This section considers these hormonal aberrations in detail in the context of EC (Figure 2).

Different hormonal and metabolic pathways associated with disturbed steroid hormones homeostasis in favour of oestrogen pro-oncogenic pathway. The figure illustrates how the aberrations associated with three major ovarian hormones, oestrogen, progesterone and androgens are involved in endometrial carcinogenesis. AKR1C, aldoketoreductase1C; DHT, dihydrotestosterone; GPER, G protein coupled oestrogen receptor; IGF-1, insulin-like growth factor 1; IGFBP, insulin-like growth factor binding protein; LH, luteinising hormone; SHBG, sex hormone binding protein.
Figure 2:

Different hormonal and metabolic pathways associated with disturbed steroid hormones homeostasis in favour of oestrogen pro-oncogenic pathway.

The figure illustrates how the aberrations associated with three major ovarian hormones, oestrogen, progesterone and androgens are involved in endometrial carcinogenesis.

AKR1C, aldoketoreductase1C; DHT, dihydrotestosterone; GPER, G protein coupled oestrogen receptor; IGF-1, insulin-like growth factor 1; IGFBP, insulin-like growth factor binding protein; LH, luteinising hormone; SHBG, sex hormone binding protein.

Unopposed oestrogens

As previously mentioned, oestrogen mediates endometrial cell growth, proliferation, apotosis inhibiton and angiogenesis in vitro and in vivo reviewed in [12]. ERβ may have opposing action on the classical ERα activity and is thought to play an antiproliferative role in endometrial proliferation [12]. Although not completely decoded, several pathways have been identified to exert oestrogenic action in endometrium, these include:

  1. Genetic pathway: An activated ER induces gene transcription either directly by binding to oestrogen response element (ERE), hence via “classical oestrogen response ERE dependent” route or indirectly “non-classical, ERE independent” path via interacting with transcriptional factors such as SP-1 [26], insulin-like growth factor (IGF-1) receptor [27], epidermal growth factor (EGF) receptor [28], PA-1 [29], NF-κB [30]. ER gene transcription can also be induced through downstream factors such as EGF or IGF-I via the “ligand independent pathways” [31, 32].

  2. Non-genetic pathways: Oestrogen activation of ERK1/2 signalling pathway [33] or MEK/ERK, MAPK pathway [34] has also been demonstrated via calcium influx and membrane located non-classical ER (GPR30), respectively, in the absence of nuclear ER expression.

  3. Epigenetic: Hypermethylation of ESR1 and PRB promoters has been reported in 90% of the EC [35–37]. Furthermore, hypomethylation with subsequent activation of oestrogen downstream PAX2 has been described in EC and associated with increased tumour growth in vivo [38].

  4. Mutagenetic: Several lines of evidence have shown that 4-hydroxylated oestrogen (catechol-oestrogens), catalysed by cytochrome P450 1B1, is able to induce DNA damage [39]. Accumulation of catechol oestrogens is observed with prolonged unopposed oestrogen exposure. Interestingly, catechol oestrogens have been associated with DNA damage at a specific DNA region (codon 130/131) on PTEN gene which is frequently mutated in type 1 ECs [40].

It is clear that there is an overlap in the pathways that derive oestrogen pro-oncogenic environment and we can conclude that unopposed oestrogenic stimuli, even with low levels of oestrogen may adversely affect the endometrium.

Progesterone insufficiency

Progesterone counteracts the above-mentioned trophic drive of oestrogen, therefore anovulation, or lack of synthesis of endogenous progesterone by the ovary that can occur without a perturbation of oestradiol production, is associated with an excessive and prolonged proliferation of the endometrial cells and thickening/hyperplasia of the glandular epithelium. For example, telomerase enzyme is pertinent for endometrial epithelial proliferation, is highly active in endometrial hyperplasia [EH] and in cancer and is induced by oestrogen and inhibited by progesterone [41].

The antiproliferative action of progesterone in the endometrial epithelial cells is exerted directly and indirectly via the stroma. Apart from the progesterone receptor, androgen and glucocorticoid receptors are also postulated to be involved in progesterone action in the endometrium [42]. The evidence for the stromal involvement in the antiproliferative action of progesterone comes from a tissue recombination study utilising PR knockout (PRKO) mice [43], and by selective inactivation of endometrial epithelial PR [44].

Thus, three possible mechanisms were proposed to explain progesterone-oestrogen antagonism (Figure 2) (i) via inhibiting ERα expression, (ii) via preventing stromal production of growth factors and subsequent transcription factor activation [45, 46] and (iii) via inducing apoptosis of endometrial epithelial cells through PR action in stromal cells [47].

Therefore, the deficiency of endogenous progesterone levels or diminished length of lifetime progesterone exposure (anovulation and lack of full-term pregnancy), are associated with the development of EH and increased risk of EC [48].

Hyperinsulinism

Hyperinsulinism, associated with either diabetes mellitus or PCOS, plays an important role in carcinogenesis as it potentiates mitotic activity in the glands and stroma by increasing the activity of IGF-1 [49, 50]. Insulin excess stimulates theca cell androgen activity, elevates serum free testosterone levels through decreased hepatic sex hormone-binding globulin (SHBG) production, amplifies LH and IGF-I-stimulated androgen production, and enhances serum IGF-I bioactivity through suppressed IGF-binding protein production [51, 52]. Insulin binding sites are also expressed in the endometrial stroma of women with EC [53] (Figure 2). Therefore, evidently, an excess in insulin signalling can result in endometrial changes with a pro-proliferative, pro-survival phenotype and inflammatory changes akin to unopposed oestrogen as mentioned above.

Hyperandrogenism

Although hyperandrogenism has been debated as a cause for the increased EC risk in women with PCOS, the in vitro and in vivo evidence to support carcinogenesis effect of androgens in the endometrium is weak [54].

Several studies have shown an increase in circulating androgen levels in EC patients nonetheless these studies have not ratified the EC risk after adjusting for the oestrogen levels. There are two androgen regulatory pathways active in the endometrium (Figure 2) (i) androgenic pathway via androgen receptor and (ii) oestrogenic pathway via ERs when androgens (androstendione and testosterone) are aromatised locally to oestrogenic compounds. Unlike in the normal endometrium, dominance of the second pathway in EC can be explained by the abundance of aromatase [55, 56] and aldo-keto reductase (AKR1C) [57] enzymes in the neoplastic endometrial cells, that increase the local availability of oestrogenic ligand. This is further exagerated by the relatively higher affinity of oestrogens to their cognate receptors, compared with that of androgens to AR [58]. Interestingly, the expression of aromatase observed to be higher in type II EC compared to type I, which will allow this subtype of EC to increase local oestrogen biosynthesis [59]. Emerging evidence also show AR to be a positive prognostic indicator and that its loss is associated with shorter disease-free survival [8, 25], therefore, androgenic pathway as a therapeutic target for EC requires further investigation.

Other hormones

GnRH

Altered or high levels of GnRH is known to have antiproliferative effect on the endometrium indirectly via its suppression of gonadotropin secretion and inhibition of ovarian oestradiol synthesis as well as working directly on the endometrium via GnRH receptor (GnRH-R). In vitro, GnRH has been shown to stimulate apoptosis in normal endometrial cells [60]. GnRH-R are expressed in breast and gynaecological tumours, wherein their activation by agonists results in antiproliferative, antimetastatic and antiangiogenic effect [9].

Luteinizing hormone/human chorionic gonadotropin

LH/hCG receptors (LH-R) are expressed in 80% of ECs [10, 61] in a grade-specific manner and may regulate the invasiveness of EC cells [62]. The overexpression of the LH-R increases the ability of EC cells to undergo local invasion and metastatic spread in animal models. Likewise, LH withdrawal strongly inhibits local and distant metastatic spread of tumors [63]. LH upregulates its own receptor, therefore it is an important target in relation to the PM period where the levels of LH remains elevated (Figure 1).

Prolactin (PRL) and thyroid stimulating hormone (TSH)

Pituitary hormones PRL and TSH may influence ovarian production of sex hormones. These hormones may have a potential to be used as serum biomarkers to detect EC patients from healthy controls with 98.3% sensitivity and 98% specificity [64]. When combined in a five marker panel (including PRL, growth hormone, eotaxin, E-selectin and TSH) it was possible to discriminate EC from ovarian and breast cancers [65]. Hyperprolactinemia is induced by the use of antipsychotics in premenopausal women, and antipsychotics have been proposed as an independent variable for risk of EC [66]. Further studies are needed to confirm these preliminary reports.

Melatonin

Melatonin (N-acetyl-5-methoxytryptamine), is a hormone produced primarily by the pineal gland, appears to protect against cancer development in general. Melatonin production is under regulation of the hypothalamus, with highest levels of melatonin secreted during the night and when sleeping. It is known to exert antioxidant, antimitotic, antiangiogenic activity in tissues, as well as being an immune modulator and a regulator of fat metabolism [67]. Melatonin interacts with membrane and nuclear receptors, and may be linked to the regulation of tumour growth [68, 69]. It is of particular relevance to EC as it may also block ERα and affect the activity of aromatase. Women with EC were found to have lower melatonin levels and a significantly increased relative risk of developing EC was reported in overweight night shift workers compared to lean women [70]. Melatonin administration in addition to HRT was associated with reduced body mass, intraperitoneal fat, reduced endometrial proliferation and prevented the appearance of histological atypia of the endometrium in an ovariectomised rat model, indicating melatonin may have a prophylactic role in preventing EC in PM women [71].

Endometrial cancer

Classification

Histological classification

The dualist model of EC proposed by several researchers has been widely accepted over the last three decades [72, 73]. Based on endocrine, clinical and histopathological characteristics, it categorises EC to type I oestrogen-dependent adenocarcinoma, associated with favourable outcome and endometrioid morphology and type II non-oestrogen-dependent EC, with worst outcome and serous papillary or clear cell morphology. Although this model was broadly supported by the reported specific molecular aberrations in each type (Table 1) [74, 75], it failed to define high grade type I endometrioid EC which showed a molecular pattern and outcome that blends between type I and type II EC [76]. Moreover, the persistent expression of steroid receptors, ER and to lesser extent PR in these so-called non-oestrogen-dependent EC [76–78] suggests hormonal regulation of Type II EC.

Table 1:

Common molecular alterations differentially associated with dualistic EC classification.

Molecular classification

The heterogeneity and overlap of the reported morphological and molecular abnormalities between different groups of ECs have restricted the traditional postsurgical risk group stratification (low, intermediate and high-risk group) and limited its prognostic and predictive value [79]. The recent emergence of a large cohort of endometrioid, serous and mixed ECs and subsequent reports of integrated proteomic and transcriptomic profile of them has added a new perspective to EC taxonomy [80]. The Cancer Genome Atlas (TCGA) study identified four genomic subgroups: POLE ultramutated (favourable outcome), microsatellite instability, copy number low (both medium risk/outcome) and copy number high (the worst outcome). This classification is in harmony with the dualistic model whereby POLE ultramutated, microsatellite instability and copy number low groups comprise 97% of type I EC while the copy number high group encompasses 94% serous EC. Nonetheless, 24% of grade 3 endometrioid were also resolved to the worst outcome, high copy number group confirming the previously predicted overlap between the subtypes [80]. This warrants integration of clinic-pathological, molecular and genomic parameters and a more holistic approach in the future to improve postsurgical stratification and tailoring personalised adjuvant therapy for women with EC to improve outcome [81].

Hormonal influence of the established risk factors of EC

The role of steroid hormones, principally oestrogen, in the aetiology of EC has been confirmed by experimental, clinical and epidemiological studies. Risk factors such as early menarche, late menopause, nulliparity (particularly when associated with ovulatory dysfunction) are directly linked to prolonged unopposed oestrogen exposure [82] yet indirect involvement of steroid hormone and imbalance that occur with other known risk factors has also been reported. This section highlights the possible contributions of steroid hormones to these widely accepted EC risk factors (Figure 3).

Endogenous and exogenous factors that affect steroid hormone signalling and contribute to endometrial carcinogenesis in the human endometrium. COCP, combined oral contraceptive pills; DHEA, dehydroepiandrosterone; GnRHa, gonadotrophic-releasing hormone analogues; HRT, hormone replacement therapy; LNG-IUS, levonorgestrel-releasing intrauterine system; MPA, medroxyprogesterone acetate; PCOS, polycystic ovarian syndrome; POP, progestogen only pills; SREMs, selective oestrogen receptor modulators; SPRMS, selective progesterone receptor modulators.
Figure 3:

Endogenous and exogenous factors that affect steroid hormone signalling and contribute to endometrial carcinogenesis in the human endometrium.

COCP, combined oral contraceptive pills; DHEA, dehydroepiandrosterone; GnRHa, gonadotrophic-releasing hormone analogues; HRT, hormone replacement therapy; LNG-IUS, levonorgestrel-releasing intrauterine system; MPA, medroxyprogesterone acetate; PCOS, polycystic ovarian syndrome; POP, progestogen only pills; SREMs, selective oestrogen receptor modulators; SPRMS, selective progesterone receptor modulators.

Polycystic ovarian syndrome

The first report proposing a possible association between PCOS and EC appeared in 1949 [49]. Women with PCOS appear to have a three to four-fold increased risk for EC [83, 84], which translates to a lifetime risk of 9%, given the background lifetime risk of 3% in the general population [85].

PCOS is a heterogeneous hormone-imbalance disorder [86] and the commonest endocrine disease of women of reproductive age, affecting 5%–10% [87]. The pathogenesis of PCOS is multifactorial and is far from being fully understood [53]. It is a leading cause of anovulatory infertility and therefore is associated with the primary hormonal aberrations of unopposed oestrogen action, insulin resistance, hyperandrogenism and clinical features of diabetes and obesity [88, 89]. For the purpose of this review, we focused on the PCOS associated hormonal changes that have shown a causative relationship with EC, except the hormonal disturbances associated with obesity (which are independent risk factors of EC and discussed in detail in a later section).

In women with PCOS, the endometrium tends to remain in an oestrogen-mediated proliferative state due to chronic anovulation [53]. ERα and steroid receptor co-activators are overexpressed, signifying a reduced effectiveness of progesterone [90] and possibly contributing to a high sensitivity to oestrogen action [91].

The molecular mechanisms underlying endometrial progesterone resistance or sensitivity in these patients are not completely understood [86]. Impaired follicle maturation and consequent anovulation cause a chronic progesterone deficient state that affects the endometrial milieu. Alterations in the expression or function of PR co-activators, chaperones and co-chaperones that are bound to PR before activation and changes in gene expression are implicated in progesterone resistance [86, 90]. However, the classic progesterone resistance is proposed to describe the pathogenesis of endometriosis [92], and endometriosis is not associated with an increased risk of EC. Therefore, the contribution of progesterone resistance phenomenon in the pathogenesis of PCOS associated EC is debatable.

Hyperinsulinemia, a common finding in patients with PCOS regardless of body mass index (BMI) [51, 86] and anti-diabetic medications such as metformin have been used to normalise the hyperinsulinism in PCOS.

Hypersecretion of LH is also a frequent feature of PCOS and a modulator of endometrial growth, as evidenced by the ability of LH to promote growth of human EC cells in vitro. Endometrial LH receptors are overexpressed in anovulatory PCOS women with EH or EC [51].

Hyperandrogenism, as a cardinal feature of PCOS, is a common finding in EC [51]. Pituitary LH hypersecretion results in excessive theca cell stimulation and PCOS patients tend to have genetically impaired theca cell functional defect. Consequent hyperandrogenism [93] results in increased bioavailability of unopposed oestrogens due to the increased peripheral conversion [53, 94]. Peripheral aromatisation of androgens occurs preferentially in the adipose tissue and high BMI is a common feature of PCOS. This makes PCOS a self-propagating, oestrogen driven, hypermitotic condition of the endometrium. Therefore, it is obvious how all the above-mentioned hormonal changes associated with PCOS may increase the risk of EC. Normalising the hormonal aberrations with life style changes, limiting calorie intake, increasing exercise, weight loss and progesterone therapy to prevent EH may reduce the risk of EC.

Endometrial hyperplasia (EH)

EH is a pathologically heterogeneous diagnosis that ranges from histologically subtle and spontaneously reversible proliferative lesions to premalignant changes [95, 96]. It virtually always results from prolonged oestrogen stimulation, unopposed by progesterone. EH with cytological atypia is recognised as the precursor for the endometrioid type of EC, with significantly increased EC risk (RR=14, 95% CI, 5–38) [97]. Altered circulatory hormone levels are reported in EH patients, particularly in those with metabolic syndrome with elevated oestrogen, testosterone, insulin, leptin, LH and LH/FSH ratio [98, 99]. Additionally, increased oestrogen bioavailability as a consequence of increased local aromatase expression and activity, in hyperplastic endometrium has also been postulated [100]. Likewise, a significant change in AKR1C3, an enzyme catalyses progesterone, oestradiol and androstenedione, has been shown in EH compared with normal control and this is suggested to increase oestrogen signalling. However, there are conflicting reports of AKR1C3 expression profiles needing future clarification [57, 101]. Insulin resistance and carbohydrate metabolism disturbances are also common findings in EH [102], which demonstrated an increase in the mitogenic effect of oestradiol through EGF and activated IGF-1 [98] (Figure 2). Recently, reduced serum melatonin level has been described to predict EH transformation to the premalignant atypical phenotype [103].

Obesity

Excess weight has been shown to be causative for at least 40% of ECs in the UK [104, 105] and rather than BMI as a risk factor, the adult weight gain has been proposed as a better measure [106, 107]. The distribution of the excess adipose tissue within the body, specifically in visceral fat, is an independent EC risk factor [108].

There are three main theories linking obesity to EC (i) oestrogen, (ii) insulin and other growth factor production and (iii) excess production of inflammatory cytokines, adipokines in the visceral adipose tissue [109]. The most prominent out of these is the effects of unopposed oestrogen, due to aromatisation of adrenal androgens [107, 110]. Aromatase promoter in the adipose tissue is also under the influence of glucocorticoids and oestrogen-induced class 1 cytokines and TNFα [111].

Adipocytes produce adipokines such as adiponection and leptin. The serum leptin-adiponectin ratio is independently associated with increased EC development risk [112]. Adipokines may influence EC through mechanisms dependent/independent of oestrogen [113–115]. Adiponectin levels have shown to be inversely correlated with EC [116, 117] which might be due to polymorphisms in the adiponectin coding gene ADIPOQ [118]. Leptin is regulated by various hormones including insulin, glucocorticoids, TNFα and reproductive hormones [119]. Intentional weight loss has shown a decrease in several adipokines including leptin [120] and therefore it is expected to reduce EC risk.

Diabetes mellitus

There is a plethora of recent evidence suggesting that diabetes constitutes an independent risk factor for EC [121]. In addition to oestrogen-progesterone imbalance, which associates with obesity, the observed risk in type II diabetes can also be explained by the compensatory increase in the insulin production. This, consequently results in an increase in the circulating IGF-1 level [122] which acts as a mitogenic stimuli via non-classical oestrogen pathway, resulting in increasing the risk of EC [123].

Lynch syndrome (LS)

Approximately, 2%–5% of ECs may be due to inherited susceptibility, of which LS is the most common with an increased lifetime risk of EC 27%–70%. MLH1 mutations are frequent in EC but compared to colorectal cancers there is a five-fold increase in the prevalence of MSH6 mutations in EC [124–126]. Pathogenesis of LS is considered to be due to mutations of genes in the DNA mismatch repair (MMR) pathway [127]. An interesting theory proposes that MMR deficiency to be the most important abnormality in early stage EC [128]. High premenopausal level of oestradiol has shown to increase the MMR activity in vitro, which explains the lower incidence of EC in premenopausal women, whereas cells dividing in a low-oestrogen environment (such as in PM obese women) are more likely to accumulate genetic errors due to low DNA repair activity and they may be at high-risk for carcinogenesis [128]. Patients with defective MMR pathways are prone to microsatellite instability (MSI) and almost all LS-associated cancers have MSI due to MMR, but in some cases, it can also result from methylation of MLH1 promoter [129]. A later age of menarche, increased parity and the use of hormonal contraceptives may be protective against EC in LS women with MMR mutation [130]. As high levels of oestrogen may increase MMR proteins and thereby may play a protective role, combined pill in particular may be a useful chemo-preventive agent in these women at high-risk of developing EC.

Smoking

The inverse relationship between cigarette smoking and EC risk is well established [131]. According to a recent study, reduced EC risk was evident among former (RR=0.89, 95% CI 0.80, 1.00) and current (RR=0.65, 95% CI 0.55, 0.78) smokers compared with non-smokers [132]. This protective effect is independent of other EC risk factors and is fully explained via hormonal modulation affecting the function of hormone-producing organs, including adrenals and ovaries. Anti-oestrogenic mechanisms have been suggested through (i) increasing hepatic metabolism of oestrogen into minimally active 2-hydroxyoestrogens [133], (ii) reducing ovarian oestrogen production which associates with a shorter follicular phase and early menopause [134, 135] and (iii) reducing aromatisation of androgens by the adipose tissue considering the positive association between smoking and lower BMI [132]. Adrenal androgen production in smokers is higher than in non-smokers [136] and smoking is associated with higher circulating androstenedione and testosterone levels [137, 138]. PM smokers with high BMI maintained a lower risk for EC [139]. Serum oestrogen level for these women were not measured in that particular study, but it is tempting to speculate that aromatisation of adrenal androgen in the adipose tissue of women who smoke may be impaired, which needs confirmation in future studies.

Parkinson’s disease (PD)

Oestrogens are implicated in neurodegenerative diseases and PM HRT has been associated with lower risk of PD [140, 141]. Contrasting with EC, women with short menstrual span (late menarche, early menopause) seem to have higher risk of developing PD [142]. Furthermore, menstruation and pregnancy was associated with worsening of the symptoms and rapid progression of the disease. Consistent with this observation, reports from murine models have also shown that oestrogen and progesterone (but not testosterone) rescue substantia nigra from induced toxicity [143, 144]. Although this may suggest a protective effect of PD in EC, conversely, a recent report suggests that patients with PD have an increased risk in developing EC. This was accompanied by an overall reduction in risk of developing other cancers in general [145]. This association was not maintained after adjusting for multiple testing, therefore further studies will be required to confirm the causative relationship.

Role of common hormonal pharmacological agents in endometrial carcinogenesis

Pharmacological agents that operate via altering the hormonal activity in the body are considered here for their utility as preventative and treatments strategies or due to the role, they play in altering the risk of developing EC (Figure 3).

In support of that, the recent integrated genomic study [80] has identified a subset of hormonally responsive ECs that demonstrate alterations in hormonal pathways. Interestingly, the highest expression of ESR1 and PGR was found in copy number low and microsatellite instability groups rather than the favourable outcome POLE ultramutated group [80]. This further advocates personalised endocrine therapy in EC management. In this section, we discuss the therapeutic, preventative role of hormones as well as many of the commonly used hormonal agents in EC.

Oestrogen and progesterone based therapeutic modalities

As contraceptives

Since hormonal contraceptives are used by premenopausal women, yet EC is mainly a PM disease, any influence of hormonal contraceptives on endometrial carcinogenesis in general may be regarded as a delayed consequence.

Combined Oral Contraceptive pill (COCP): The protective effect in regards to EC has been well-documented [146]. The risk reduction appears to be proportionally related to the duration of use, and every 5 years of use is associated with a relative risk of 0.76 [147]. This favourable outcome may persist up to 30 years after cessation of COCPs, though it may be amplified as time after discontinuation elapses [148]. The similar protective effect observed in high and low dose oestrogen-containing pills [147] may suggest that the protective effect seen with COCP may be due to the increase in lifetime exposure to progesterone. In support of this finding, a higher progestin-potency COCP seem to be required for women with larger BMIs [149].

Progesterone only preparations: The use of progestogen only contraceptive agents such as depot medroxyprogesterone acetate (MPA) have been associated with a reduction in the risk of developing EC [150]. Likewise, the use of levonorgestrel-releasing intrauterine system (LNG-IUS) was found to be significantly protective with prolonged use up to 10 years [151].

High-dose systemic Depo-Provera preparation will induce hypoestrogenic state with profound ovarian suppression and has a direct endometrial effect with high progestogen levels in the endometrium [150]. There are no conclusive studies examining the differential risk associated with low dose systemic regimens such as progestogen only pill and implants. Furthermore, the protective effect of the other newer combined hormonal contraceptive methods remain to be investigated.

As postmenopausal hormonal replacement therapy

Menopausal HRT is required by millions of women for climacteric symptom management and for the prevention of osteoporosis throughout the world [152]. Studies consistently find a substantial increase in EC incidence with oestrogen alone use [152, 153], which is more marked with prolonged duration of use and persists for several years after treatment discontinuation [154]. As a result, combined oestrogen-progestin therapy is the standard, to counteract the proliferative effects of oestrogen on the endometrium [153]. Results from the Women’s Health Initiative study concluded that oestrogen plus progestin use was associated with a 37% reduction in type I EC incidence [152], whilst, oestrogen therapy was found to have little impact on the risk of type II EC [153]. Continuous combined oestrogen-progestin therapy was the only HRT regimen associated with an apparent decline in risk whereas long-term (10 years) sequential regimens were associated with an increased risk of EC [153]. Furthermore, the type of synthetic progestogen does not affect the risk reduction [154]. The use of topical vaginal oestrogen preparations has not shown to significantly increase the risk of EC [154].

As hormonal replacement after endometrial cancer treatment

HRT after treatment of EC remains controversial but studies have specifically looked into this group of patients and shown no significant increase in the risk of recurrence in EC survivors using HRT relative to the control group (OR=0.53; 95% CI, 0.30–0.96) [155]. However, personalising HRT to patient with ER negative EC may be considered to reduce any potential adverse effect.

Progestogens as treatment for hyperplasia

As hyperplasia is due to excess or unopposed oestrogenic effect in the endometrium, prophylactic treatment with high dose oral progestogens such as MPA and local administration with LNG-IUS is used to prevent progression of hyperplasia to EC [156]. Systemic administration of high dose progestogens are associated with an exceptionally poor side effect profile, low compliance and lower remission rates (60%) [157] compared with the LNG-IUS [158, 159]. The local endometrial LNG levels achieved with IUS exceeds that of oral administration by over 1000 folds with higher remission rates (100%) and the additional benefit of a more beneficial side effect profile [157], hence it is the preferable method of delivery. Progestogen treatment using LNG-IUS is also commonly used in women with obesity and other high-risk conditions (e.g. PCOS, tamoxifen treatment) mentioned above as part of a risk reduction strategy.

Progestogens as treatment for endometrial cancer

Synthetic progestogens have been used to treat EC for over 60 years, and they remain to be the main hormonal pharmaceutical agent used in EC. High dose progestogens, in the form of oral MPA and megestrol acetate have been licensed for fertility-sparing treatment of carefully chosen individuals with early stage, low-grade endometrial disease [160]. They are also routinely used as an adjuvant therapy in advanced, metastatic and recurrent ECs as well as in endometrial stromal cell cancers [161]. However, the efficacy of progestogens as an adjuvant treatment in high-risk ECs has been poor or modest at its best [162]. This observed inconsistent response to progestogens in clinical studies that can be explained by the fact that treatment is not tailored according to ECs with PR expression/progestogen responsive.

When considering hormonal modulators, one striking feature specific to EC is that presently, there is no consensus in routinely assessing ECs for their hormone responsiveness (assessing the expression of steroid hormone receptors like in other hormone responsive cancers e.g. breast cancer). Due to the distinct alterations of the steroid receptor expression observed in EC subtypes and with tumour progression (Figure 1), this is an important deficiency in current practise. We have recently proposed a validated scoring system to quantify PR (and other hormone receptor expression) in ECs, as an endeavour to provide means to identify potential responders [25]. Prolonged therapy with progestogens can render the endometrial cells unresponsive to hormone treatment by downregulating most (if not all) ovarian steroid hormone receptors. Considering this complex interplay of hormonal actions in the endometrium, a suitable sequential regimen of hormonal agents (progesterone, followed by anti-oestrogens) [157] and personalising/tailoring treatment according to sequential assessment of the tumour for hormone responsiveness is envisaged to increase the therapeutic potential of endocrine therapy in EC.

Selective progesterone receptor modulators (SPRMs)

Mifepristone is the first SPRM, and has partial agonist/antagonist activity with significant affinity to AR and GR. Therefore, the observed endometrial effect depends on the availability of progesterone, and at least some of the observed effects of mifepristone may be via the AR [163]. Long-term use of high-dose mifepristone thickens the endometrium, although the associated histology shows cystic glandular atrophy with reduction in glandular mitosis. Nevertheless, concerns have been raised regarding a potential trophic effect of SPRMs on the endometrium [164]. Ullipristol, a 2nd generation SPRM, is also licenced to be used for fibroid-associated symptoms and has been reported to have lower endometrial trophic effects. There are reports of hyperplasia without atypia and polyps after 13 weeks of Ullipristol treatment, yet the endometrium reverted to normal, 6 months after treatment [165]. In a small Phase II study, high-dose mifepristone as a single agent therapy in women with either advanced or recurrent EC, revealed very limited stabilisation of the disease, and no partial or complete response [166]. Therefore, until further conclusive data are available, clinicians using high dose prolonged therapy with SPRMs in women need to be aware of possible endometrial changes similar to that occur with tamoxifen [166, 167].

Selective oestrogen receptor modulators (SERMs)

SERMs represent a group of non-steroidal non-hormonal compounds that bind to the ER, each inducing a distinct set of tissue-specific effects. The agonistic or antagonistic effect of SERMs depend on the availability of oestrogen [168].

Tamoxifen, the first clinically applicable SERM is used as an adjuvant treatment and as a chemoprevention agent in breast cancer. Tamoxifen therapy, is associated with subsequent endometrial proliferation in PM women, with the development of a spectrum of endometrial lesions, ranging from hyperplasia and polyps to invasive carcinomas and sarcomas due to its ER agonist activity in the uterus [169]. The increased risk of EC with tamoxifen use seems to be proportionally related to longer duration, accumulative usage, and increased BMI. A recent opinion paper suggested that premenopausal women treated with tamoxifen require no additional monitoring beyond routine gynaecologic care due to lack of evidence of an increased risk of EC [170].

Conversely, the newer SERMs, such as Raloxifene, Bazedoxifene and Ospemifene, seem to have neutral effects on the endometrium [171–173]. Lasofoxifene, on the other hand, may increase endometrial thickness but the early studies have not confirmed a higher risk of hyperplasia or EC after 5 years of follow-up [174].

Tibolone, a synthetic steroid with oestrogenic, (and some progestogenic and androgenic) properties, is commonly used for climacteric symptoms and prevention of osteoporosis. It has also been recently reported to increase the risk of EC [153], however, a previous RCT suggested that tibolone use has no concerns on endometrial safety [175]. Therefore, further research is necessary to conclude on the effects of SERMs and tibolone on endometrial carcinogenesis.

Antioestrogens

Fulvestrant is a full ERα and ERβ antagonist used as a second line drug for the treatment of breast cancer. Prospective endometrial assessment of breast cancer patients treated with fulvestrant showed a significant decrease in endometrial growth without the development of new endometrial pathologies [176]. Phase II studies have shown modest activity in advanced or recurrent EC patients with ER and/or PR positive tumours [177, 178]. The effectiveness of fulvestrant in EH and fertility-sparing EC management has not yet been assessed.

Aromatase inhibitors (AI)

Third generation AIs (letrozole and anastrozole) are non-steroidal competitive inhibitors of the aromatase enzyme that act to decrease systemic and intra-tumoral oestrogen levels. Prospective endometrial assessment of breast cancer patients treated with AI show no effect on endometrial thickening and possible regression of baseline endometrial proliferation [179]. Further studies also confirm that EH respond to AI, and the efficacy is comparable to progestogens [180–182]. Likewise, regression in response to combined AI and MPA was reported for fertility-sparing low-grade EC, whereas AI monotherapy failed to show any benefit for advanced or recurrent EC patients [183, 184]. Collectively, these results suggest a potential role for AI in early EC stages, requiring further investigation to identify synergistic pathways.

Androgens

Testosterone transdermal patch and subcutaneous preparations are used as part of some HRT regimens, particularly in women suffering from symptoms of androgen deficiency, such as low sexual desire and well-being. Current data does not indicate any adverse endometrial, cardiovascular or breast effects with transdermal preparations, although data on long-term risks and benefits of testosterone therapy after the diagnosis of EC are lacking [185, 186]. Endometrial atrophy is the common finding in transgender women on supraphysiological doses of testosterone (Testoviron Depot), instead of hyperplasia [187].

Oral and transvaginal dehydroepiandrosterone (DHEA) has been used for controlling PM symptoms. Although significant benefit remains to be determined, reports have shown a persistent atrophic phenotype in PM endometria after 52 weeks of this treatment [188].

Local danazol therapy which is used to improve symptoms associated with endometriosis has shown to act on endometrial epithelial and stromal cells directly through AR (also binds PR) by reducing cell survival [189] and cell proliferation [190, 191]. Data from a murine model shows a protective effect of long-term danazol against oestrogen induced carcinogenesis [192]. Likewise, clinical trials have also confirmed the effectiveness of danazol in the management of EH with and without cytological atypia with very low incidence of recurrence [193, 194]. By contrast, minimal response to danazol was reported in advanced, recurrent or persistent EC [195], yet sample size and lack of data on AR expression status limits the results of this particular trial.

Cyproterone acetate, an AR antagonist, has been used in HRT combined with cyclic oestradiol. Studies have shown an increased risk of EC for patients on this regimen compared with non-users [153]. Therefore, androgens are likely to play an important role in the pathogenesis of EC and the emerging evidence suggests that pharmaceutical agents with AR modulatory activity may have a potential therapeutic effect. Further studies on the effects of androgen on endometrial cell proliferation and function are therefore needed to identify the potential therapeutic strategies.

GnRH agonists and antagonists

Due to differences in the intracellular signalling cascades, the effect observed with GnRH agonists and antagonists is tissue-specific [196–198]. The clinical effects of the GnRH analogues seen after sustained administration, leads to desensitisation of receptors, suppression of gonadotropin secretion and finally inhibits the gonadal steroid synthesis.

The GnRH-R are currently being targeted successfully in the treatment of many hormonal dependent tumours using GnRH agonists and antagonists. Preparations with pharmacological properties of GnRH agonists, antagonists, GnRH agonist-based cytotoxic hybrids, GnRH-R targeted nanoparticles delivering anti-cancer medications act through GnRH-R are being explored in this respect. GnRH agonists show promise in treating advanced, and metastatic prostatic and breast cancer treatment. Unlike the 1st and 2nd generation antagonists with limited solubility and anaphylactic reactions due to histamine release [199], the currently available 3rd and 4th generation antagonists like cetrorelix and ganirelix have a more favourable side effect profile and for example, have immensely improved prostate cancer therapy. Although some in vitro studies have suggested a possible anti-tumour effect with GnRH analogues in EC, there are no clinical studies reported to date evaluating their efficacy in EC. Therefore, further research is urgently needed to assess if GnRH has a therapeutic role in EC.

Summary/Conclusion

Hormones intricately influence the carcinogenesis process in endometrium. Whilst oestrogen is the most conspicuous driver of this, many other hormones also appear to play an important role. Most known risk factors for EC are associated with alteration of the endometrial hormonal milieu, with many routinely used pharmacological hormonal agents impinging on the endometrial carcinogenesis process. Routine assessment of ECs for their hormone responsiveness (assessing the expression of steroid hormone receptors as in other hormone responsive cancers), using a validated scoring system, personalisation of treatment according to sequential assessment of the tumours and further evaluation of interplay between all hormones in the endometrium are envisaged to unlock novel, therapeutic avenues, based on hormones, for this increasingly common malignancy.

Acknowledgements

The authors would like to acknowledge the support from Wellbeing of Women project grant RG1487 (DKH), Higher Committee for Education Development in Iraq (AK and RA), Wellbeing of Women Clinical Training Fellowship RTF510 (NT), Liverpool Women’s Hospital (CP, SM, MA) and Institute of Translational medicine, University of Liverpool (CP, AK, RA). All authors declare that there is no conflict of interest.

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About the article

Corresponding author: Dharani K. Hapangama, Institute of Translational Medicine, Department of Women’s and Children’s Health, University of Liverpool, Liverpool, L7 8SS, UK, Phone: +44 151 7959559, Fax: +44 151 795 9599, E-mail: ; and Liverpool Women’s Hospital NHS Foundation Trust, Liverpool, UK


Received: 2016-01-12

Accepted: 2016-02-05

Published Online: 2016-03-11

Published in Print: 2016-02-01


Citation Information: Hormone Molecular Biology and Clinical Investigation, Volume 25, Issue 2, Pages 129–148, ISSN (Online) 1868-1891, ISSN (Print) 1868-1883, DOI: https://doi.org/10.1515/hmbci-2016-0005.

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