Abstract
Rapid advance in oncology leads to increasing survival of oncologic patients. More and more of them live long enough to reach either the natural age of menopause or, as a side effect of their oncotherapy, experience the cessation of gonadal function, leading to premature ovarian insufficiency, with disturbing vasomotor symtoms and long-term negative cardiovascular and skeletal effects. Thus, an ever increasing number of cancer survivors search endocrinologic help in the form of hormone replacement therapy (HRT). The misinterpretation of the WHI (Women's Health Initiative) Study has lead to an irrational fear of female hormone replacement, both by the general population and medical professionals. It has seemed the logical and safe conclusion to many physicians to avoid HRT, supposing that this attitude definitely causes no harm, whereas the decision of prescribing estrogen alone or with progestins might bear oncologic and thromboembolic risks and may even lead to litigation in case of a potentially related complication. However, it was known even before the WHI results that premature menopause and hypogonadism decreases the life expectancy of women by years through its skeletal and cardiovascular effects, and this negative effect correlates with the length of the hypoestrogenaemic period. Therefore, the denial of HRT also needs to be supported by evidence and should be weighed againts the risks of HRT. Yet, the oncologic risk of HRT is extremely difficult to assess. In this work we review the latest evidence from in vitro experiments to clinical studies, regarding HRT in survivors of gynecologic and non-gynecologic cancers. Based on our literature research, we group tumours regarding the oncologic risk of properly chosen female hormone replacement therapy in cancer survivors as follows: ’HRT is advanageous’ (e.g. endometrial cancer type I, cervical adenocarcinoma, haematologic malignancies, local cutaneous malignant melanoma, colorectal cancer, hepatocellular cancer); ’HRT is neutral’ (e.g. BRCA 1/2 mutation carriers without cancer, endometrial cancer type II, uterinal carcinosarcoma and adenosarcoma, certain types of ovarian cancer, cervical, vaginal and vulvar squamous cell carcinoma, prolactinoma, kidney cancer, pancreatic cancer, thyroid cancer); ’HRT is relatively contraindicated’ for various reasons (e.g. leiomyosarcoma, certain types of ovarian tumours, brain tumours, advanced metastatic malignant melanoma, lung cancer, gastric cancer, bladder cancer); ’HRT is diasadvantageous and thus contraindicated’ (e.g. breast cancer, endometrial stroma sarcoma, meningioma, glioma, hormone receptor positive gastric and bladder cancer).
Highlights
Hormone replacement therapy (HRT; known as menopausal hormone therapy, MHT) means substituting estrogen
Lymphocyte precursors are regulated by sex steroids [92]; myeloid leukaemia cells express estrogen receptors [93] and their methylation is related to patient survival [94]; pregnancy is protective against the development of Hodgkin lymphoma[95]; former hormone replacement therapy (HRT) decreases the risk of B-cell non-Hodgkin lymphomas in postmenopausal women[96]; estrogen influences the proliferation, differentiation and survival of B-linage precursors [97] and by decreasing local IL-6 production, improves the disease-free and overall survival in diffuse large-cell lymphomas [98, 99]
Inconsistent results of studies indicate various relationship between the different forms of HRT and brain tumours: MHT increases the risk of meningioma by 30-80 %, but not that of glioma [106]; meningiomas can grow as a result of progesterone, estrogen and androgen stimulus [107]; estrogen-only HRT, but not E+P HRT increased the risk of brain tumours, glioma and meningioma in a large UK database of women aged 50-79 [108]; HRT but not oral contraceptive use was associated with an increased meningioma risk [109]; progesterone-only contraception is associated with a shorter progression-free survival in premenopausal women with WHO Grade I meningioma [110]
Summary
Hormone replacement therapy (HRT; known as menopausal hormone therapy, MHT) means substituting estrogen & and the oncologically relevant endocrine caracteristics of the tumour, e.g. hormone receptor status (presence of hormone receptors, receptor subtypes, receptor splice variants, or estrogen-related receptors), former or current endocrine oncotherapy (aromatase inhibitors, selective estrogen receptor modulators, selective estrogen receptor degrader, GnRH analogues) or the effect of female hormones on the given tissue in general, or on the specific tumour type in particular It is even possible, that in vivo HRT exerts its effect on tumour recurrence and progression (even contradicting in vitro results on isolated cells or tumour tissues) not by affecting the malignant cells themselves, but rather influencing for example the surrounding stromal tissue, the immune response of the body, or cells and structures participating in metastatization. When trying to find relevant data, depending on the prevalence of the tumour type, papers from preclinical research, case reports, retrospective studies, randomized controlled trials and meta-analyses can be found Their strength to predict the risks and benefits of MHT in the given clinical setting is varied, yet, these may be the only source of information for the clinician. In this review we try to summarize the data regarding the advantages and disadvantages of HRT in the most common tumour types
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