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• Les inhibiteurs de l'aromatase ont été associés à la survenue de maladies auto-immunes. • Nos cas suggèrent qu'il existe un lien entre inhibiteurs de l'aromatase et myopathies inflammatoires. • L'arrêt de l'inhibiteur de l'aromatase devrait être envisagé devant l'apparition d'une myopathie. Les inhibiteurs de l'aromatase (IA) sont couramment utilisés en traitement adjuvant des cancers du sein positifs pour les récepteurs d'œstrogènes. Des effets indésirables rhumatologiques ont été signalés avec les IA, notamment perte osseuse, arthralgie, myalgie et ténosynovite. De nouveaux éléments mettent en évidence un lien entre IA et développement de maladies auto-immunes. Nous décrivons ici trois cas de myopathie inflammatoire apparaissant au cours d'une thérapie par IA. Trois patientes présentant une myopathie inflammatoire dans le contexte d'une thérapie par IA ont été traitées dans le service de rhumatologie du Centre médical MD Anderson. Les trois dossiers médicaux ont été examinés de façon rétrospective. Nous avons recueilli le consentement verbal des patientes pour utiliser leurs données aux fins d'enseignement et de publication et nous n'avons utilisé que des données dépersonnalisées. Aucune de nos patientes n'avait d'antécédent de maladie auto-immune et toutes avaient subi récemment un dépistage de cancer ne montrant ni récidive de cancer du sein, ni signe de nouveau cancer. La fin ou l'arrêt de la thérapie par IA a été associé à la résolution de la myopathie dans les trois cas. Cette série de cas suggère l'existence d'un lien entre les IA et l'apparition d'une myopathie inflammatoire. En cas de survenue d'une myopathie inflammatoire chez une patiente sous IA, ce traitement devrait être considéré comme un possible facteur déclencheur. Si la myopathie n'est pas contrôlée par l'immunosuppression, alors l'arrêt de la thérapie par IA pourrait être envisagé. [ABSTRACT FROM AUTHOR]

Besides its interest for diagnosis, the finding of an elevated serum AMH level in PCOS has open major pathophysiological issues. This review addresses the three most important issues: 1) the role of AMH in the disturbed folliculogenesis of PCOS; 2) the role of AMH in the gonadotropin dysregulation of PCOS and 3) the role of AMH in the trans-generational transmission of PCOS. For each of those issues, the clinical and experimental evidences currently available are discussed and pathophysiological hypothesis are proposed. [ABSTRACT FROM AUTHOR]

Acquired endocrine resistance remains one of the main obstacles in the treatment of estrogen receptor (ER) positive, HER2 negative advanced breast cancer. Recently, activating ESR1 gene mutations affecting the ligand-binding domain have been identified as a keymechanismin aromatase inhibitor (AI) resistance. These mutations can be detected on histological samples or circulating tumour DNA, using PCRbased assays or next-generation sequencing. They induce a constitutive activation of ER, leading to acquired resistance to AI; tamoxifen, fulvestrant and targeted therapies against mTOR or CDK4/6 retain their efficacy. The use of monitoring ESR1 mutations in clinical practice is still to be defined. [ABSTRACT FROM AUTHOR]

After a decade of endocrine adjuvant treatment with AI (Aromatase inhibitors), it is documented that they are somewhat superior to tamoxifen, in postmenopausal women with hormone receptor-positive breast cancer. However, compared with tamoxifen, an elevated incidence of arthralgia (pain in one or more joints), has been observed during AI treatment, symptoms more important and problematic than anticipated. The potential mechanisms behind AI-induced arthralgia are not well understood, even if estrogen withdrawal may probably play a role. The frequency is not well-established within the population and clinical predictors of these related arthralgia remain unclear, but this adverse event may result in poor adherence to treatment; interventions to ameliorate are often not efficient and at least, patients and physicians can be dissuading from completing the full AI treatment. Patient educations about some management of arthralgia symptoms can helping patients adhere to AI treatment and improve breast cancer outcomes. For some authors, the occurrence of joint or vasomotor symptoms might be a predictor of treatment effectiveness and might be useful when reassuring patients who present with them, but nevertheless in reality, this opinion is insufficient to avoid adherence. The association between emergent musculoskeletal symptoms and improved outcomes have not been described as consistent in most of experiences. [ABSTRACT FROM AUTHOR]

Abstract: The use of aromatase inhibitors is frequent in adjuvant therapy of postmenopausal women with hormone-responsive breast cancer. Estrogen deprivation caused by administration of aromatase inhibitors may lead to a decrease in bone mineral density and, according to some studies, to an increased risk of fractures. LH-RH agonists can be used in premenopausal women with breast cancer, or for other indications such as endometriosis. They are more frequently prescribed for men with prostate cancer so as to carry out a chemical castration; in this setting LH-RH agonists are responsible for a rapid bone loss which is greater at the beginning of treatment, and for an increased risk of fractures. Patients being treated for cancer should receive adequate bone health monitoring. Prevention of bone adverse events observed with aromatase inhibitors in women and with LHRH agonists in men depends on detection of other fracture risk factors, bone mineral density measurement, lifestyle modifications with correction of calcium and vitamin D deficiency, and treatment, notably using bisphosphonates, when patients have past history of fracture or low bone mineral density. [Copyright &y& Elsevier]

Abstract: The recent demonstration that aromatase is expressed at higher levels in endometriosis implants than in normal endometrium has led to pilot studies using inhibitor aromatasis in patients with endometriosis. We conducted a systematic review of the literature and studied the efficacy of aromatase inhibitors on endometriosis. There were seventeen studies (case reports/series) evaluating outcomes of aromatase inhibitors. Studies suggest that aromatase inhibitors alone or co-administered with progestins, oral contraceptives or gonadotrophin releasing hormone (GnRH) agonist could reduce pain and endometriosis. There is only one randomized controlled trial comparing aromatase inhibitor+GnRH agonist and GnRH agonist and one study with eighty patients. Side-effects profiles of aromatase inhibitor regimens are favorable; it does not appear a significant bone loss. Aromatase inhibitors seem to have a promising effect on endometriosis but randomized controlled trials are needed to prove their effects and their safety. [Copyright &y& Elsevier]

A descriptive analysis of available data on reported cases of uterine carcinosarcomas associated with tamoxifen therapy is undertaken. The role of aromatase inhibitors as alternative to tamoxifen therapy in the adjuvant setting of breast cancer is discussed. The eventual implications of the presumed association of uterine carcinosarcoma and tamoxifen therapy on the choice of the therapeutic agent in the adjuvant setting of hormone-sensitive breast cancer are discussed. [Copyright &y& Elsevier]

The use of hormonal deprivation therapy in the management of breast and prostate cancers is associated with an increased risk of fracture and accelerated bone loss. In women with breast cancer, large adjuvant trials showed that all third-generation AIs (anastrozole, letrozole and exemestane) have been associated with an increased risk of fractures and bone loss. The hypogonadism induced by GnRH agonists increases the risk of osteoporosis; the risk of fracture was shown to be correlated with the duration of therapy and bone loss is maximal in the first year after initiation of the treatment and increases with time. The measurement of bone mineral density is necessary before initiating any hormonal deprivation therapy. The use of bisphosphonates in patients with osteoporosis (defined by a T-score <- −2.5) and or fracture is useful to prevent bone loss. [ABSTRACT FROM AUTHOR]

Aromatase inhibitors (AIs) are widely used as adjuvant endocrine treatment in postmenopausal women with a breast cancer at early stage, with the presence of estrogen receptor. However an elevated incidence of musculoskeletal symptoms has been observed as associated with AIs treatment. Musculoskeletal symptoms can be observed with every AI and are considered a class effect of AIs. These manifestations are related to the effect of estrogen deprivation on cartilage and periarticular tissues. Patient education regarding the possibility of experiencing arthralgia, and effective management of potential symptoms are important to promote patients’ adherence to AI treatment. [ABSTRACT FROM AUTHOR]

A case of a menopausal woman known for a chronic diffuse pain syndrome and breast cancer positive for estrogen receptors is presented. She developed an increase of her diffuse pain syndrome and joint aches after the introduction of an aromatase inhibitor. Soreness quickly improved after the interruption of the drug. We emphasize some etiological hypotheses concerning the painful symptoms, especially the role of aromatase and estrogens. [ABSTRACT FROM AUTHOR]

The use of aromatase inhibitors in postmenopausal patients with breast cancer have modified the pronostic and may prove to be the agents of choice in this setting. However this treatment is associated with an increased rate of short-term symptoms: articulary and muscle pain and long-term symptoms: bone loss and fractures. The decision making process is driven by the existence of these complications. With the continuation of the life expectation, the prevention of the osseous iatrogenic complications must not be neglected in the care of these patients. [ABSTRACT FROM AUTHOR]

Ovarian stimulation during GnRH agonists treatment can sometimes result in hyperstimulation with the risk of serious complication. Therefore, other protocols, associating antagonists, have been set out in the search for more effective ovarian stimulation resulting in satisfactory implantation with fewer complications. Still, these protocols need confirmation of their efficiency, which most other series have not reported yet; while a higher rate of unsuccessful egg retrieval and a reduction in the number of satisfactory transfers have been observed in the absence of stimulation. Currently, new molecules and personalized treatments offer a new perspective in ovulation induction with the aim of optimizing results and reducing complications. [Copyright &y& Elsevier]

For decades, ovariectomy and tamoxifen have been the mainstays of hormonal manipulation in metastatic breast cancer patients receiving adjuvant therapy. Interest in learning more about the mechanisms involved in resistance to endocrine therapy has increasingly expanded as new compounds have become available to clinicians. In this brief review article, we will focus on the major mechanisms of resistance that clearly impact the new treatment strategies used for hormone-dependent breast cancer patients. [ABSTRACT FROM AUTHOR]

For endocrine therapy of hormono-sensitive breast cancer in postmenopausal women, the third-generation aromatase inhibitor, letrozole, is effective in all clinical settings (metastatic disease, neoadjuvant therapy, and adjuvant treatment). Compared with tamoxifen, letrozole showed superiority in all primary endpoints and greater tolerability. The search for biomarkers that predict response or resistance to endocrine therapy is currently under investigation, mainly in the neoadjuvant setting. Letrozole is being tested in combination with signal transduction inhibitors and as chemopreventive agents. [ABSTRACT FROM AUTHOR]

Résumé: Les estrogènes jouent un rôle primordial dans le contrôle de la minéralisation du tissu osseux qui possède tous les éléments nécessaires au métabolisme (systèmes enzymatiques) et à la réponse (récepteurs Erα, ERß) aux estrogènes. Après la ménopause, la production endocrine, ovarienne, des estrogènes est remplacée dans un délai très court, par une production intracrine, tissulaire, basée principalement sur la conversion des androgènes d''origine surrénale. Du fait de son rôle pivot dans la production intracrine des estrogènes, l''activité aromatase constitue un des déterminants majeurs de l''imprégnation estrogénique tissulaire en postménopause. Ses mécanismes d''action sur le remodelage osseux commencent à être mieux élucidés. [Copyright 2006 Elsevier]

Abstract: Aromatase inhibitors (AI) block the last enzymatic step of estrogen production, the aromatization of the A-cycle of aromatizable androgens and particularly, androstenedione (D4) and testosterone (T). Molecules designed for interfering with aromatase activity have existed for many years. Yet the activity of products of the aminogluthetimide era was too unspecific and these substances carried too many side effects for being used clinically. Today, howewer, 3rd generation AIs have become available that are highly specific and essentially devoid of side effects. These molecules have recently been approved for treating breast cancer in post-menopausal women, either in advanced forms, or as part of adjuvant therapy. In women whose ovaries are active, a temporary inhibition of E2 production will activate gonadotropins and in turn, stimulate follicular growth. In cancer patients, this property precludes the use of AIs in women whose ovaries are still active, unless gonadotropins are blocked. In infertile patients, this property of AIs has been put to play for inducing ovulation. AIs have been used both in women who do not ovulate but whose hypothalamo-pituitary-gonadal (HPG) axis is active (oligo-anovulators of PCOD type) and in those who ovulate regularly but in whom multiple ovulation is sought for treating infertility or as part of IVF. Like CC, AIs are not usable in women whose gonadotropins are suppressed, as in the case of hypothalamic amenorrhea. The sum of data available on the use of AI for inducing ovulation remains however meager to this date and is mainly constituted of pilot and non-randomized trials. Yet mounting evidence tends to support AIs'' advantages over CC for induction of ovulation. Hence, we think that these drugs will play a key role for the induction of ovulation in the future. [Copyright &y& Elsevier]

The standard indication of neo-adjuvant treatment depends on the desire to carry out traditional surgery and if possible avoid a mutilating act on the patient whose tumour is too large. Several random clinical trials have shown that this approach indeed brings about a reduction of the size of the tumour and consequently increases the level of partial exeresis. Two neo-adjuvant methods of treatment are used -- chemotherapy and/or hormone therapy. Neo-adjuvant chemotherapy was designed to avoid total mastectomy, whereas neo-adjuvant hormone therapy is recommended to patients whose general health is precarious or who are too advanced in age to accept or tolerate a surgical act. The first neo-adjuvant hormone therapies were exclusively made up of tamoxifen. Nowadays, third generation aromatase inhibitors are taking a more and more important place in the treatment of breast cancers. [ABSTRACT FROM AUTHOR]

At present, the optimal duration of adjuvant hormonal therapy for early breast cancer is unknown. In premenopausal patients, it is uncertain that temporary ovarian ablation, alone or with tamoxifen, is as efficient as definite removal through surgery or radiation. In postmenopausal women, the standard treatment is tamoxifen, with a 20 mg dose per day for five years. However, major prospective trials are ongoing to study indefinite therapy, and recent data, using aromatase inhibitors, may modify this schedule. [ABSTRACT FROM AUTHOR]

Today, palliative endocrine treatment comprises five to six means which have to be used advisedly. Before starting an endocrine treatment, the physician has to take into account initial and metastatic breast tumour characteristics, those of the patient and her hormonal status. Thus after ovarian function suppression, progestins and anti-oestrogens (SERMs or Specific Estrogen Receptor Regulator), type I and II aromatase inhibitors are currently prescribed and pure anti-oestrogen soon after. It is important, therefore, to adequately use all these endocrine treatments since all of them will be probably used during the patient's life. [ABSTRACT FROM AUTHOR]

Breast cancer is certainly not preventable at the same degree as lung cancer is by avoiding cigarette smoking or bladder cancer by avoiding exposure to some specific professional carcinogens. Despite the increased availability of screening mammography and the use of adjuvant chemotherapy, breast cancer remains a major cause of morbidity and mortality in women. Chemoprevention could be one of the possible weapons to decrease the morbidity and the mortality due to breast cancer. Experimental, epidemiological and clinical data suggest that one can prevent occurrence of breast cancer. The results of five trials including more than 25,000 patients comparing the effectiveness of tamoxifen with a placebo were published. The results of these trials, at first sight, do not agree. Only in the USA, the results of the five trials have led to licence tamoxifen for chemoprevention of breast cancer. But the Food and Drug Administration stresses the fact that the noxious side effects are too numerous for this molecule to be prescribed with all the patients. It must be reserved for the women presenting an increased risk. The means of identifying the women at increased risk are not yet perfect. [ABSTRACT FROM AUTHOR]

Abstract: Purpose. —: The pathophysiology of osteoporosis has seen many recent progress especially with the use of genetically modified animalmodels. Current knowledge and key points. —: Among many discoveries, one can notice the crucial role of LRP5, GH, IGF-1 and the sex hormones receptors in the acquisition of the peak bone mass, the control of bone remodeling by the sympathetic nervous system and his implication as a transmitter of mechanical loading in bone. Also, the role of estrogen and androgen receptors as well as the aromatase is specified according to sexes. The role of growth plate''s chondrocytes in the installation of the trabecular bone network is better and better demonstrated. The greater periosteal apposition in men, mediated by androgens receptor, seems to explain the greatest radial growth and so the greatest bone resistance to mechanical strains like a lower fracture rate in men compared to women. The bone microarchitecture and quality explain an important part of the mechanical properties of bones and why considering the same bone mass one bone is breaking and another one not. Future prospects and projects. —: Many therapeutic applications should finalize the discovery of these new bone cells signalisation pathways. [Copyright &y& Elsevier]