Histone deacetylase 7 (HDAC7) is a member of the class IIa family of classical HDACs with important roles in cell development, differentiation, and activation, including in macrophages and other innate immune cells. HDAC7 and other class IIa HDACs act as transcriptional repressors in the nucleus but, in some cell types, they can also act in the cytoplasm to modify non-nuclear proteins and/or scaffold signalling complexes. In macrophages, HDAC7 is a cytoplasmic protein with both pro- and anti-inflammatory functions, with the latter activity involving activation of the pentose phosphate pathway (PPP) enzyme 6-phosphogluconate dehydrogenase (6PGD) and the generation of anti-inflammatory metabolite ribulose-5-phosphate. Here, we used ectopic expression systems and biochemical approaches to investigate the mechanism by which HDAC7 promotes 6PGD enzyme activity. We reveal that HDAC7 enzyme activity is not required for its activation of 6PGD and that the N-terminal protein-protein interaction domain of HDAC7 is sufficient to initiate this response. Mechanistically, the N-terminus of HDAC7 increases the affinity of 6PGD for NADP+, promotes the generation of a shorter form of 6PGD, and enhances the formation of higher order protein complexes, implicating its scaffolding function in engagement of the PPP. This contrasts with the pro-inflammatory function of HDAC7 in macrophages, in which it promotes deacetylation of the glycolytic enzyme pyruvate kinase M2 for inflammatory cytokine production.

Introduction: Estrogens used in women's healthcare have been associated with increased risks of venous thromboembolism (VTE) and breast cancer. Estetrol (E4), an estrogen produced by the human fetal liver, has recently been approved for the first time as a new estrogenic component of a novel combined oral contraceptive (E4/drospirenone [DRSP]) for over a decade. In phase 3 studies, E4/DRSP showed good contraceptive efficacy, a predictable bleeding pattern, and a favorable safety and tolerability profile. Areas covered: This narrative review discusses E4MODIFIER LETTER PRIMEs pharmacological characteristics, mode of action, and the results of preclinical and clinical studies for contraception, as well as for menopause and oncology. Expert opinion: Extensive studies have elucidated the properties of E4 that underlie its favorable safety profile. While classical estrogens (such as estradiol) exert their actions via both activation of nuclear and membrane estrogen receptor alpha (ER alpha), E4 presents a specific profile of ER alpha activation: E4 binds and activates nuclear ER alpha but does not induce the activation of membrane ER alpha signaling pathways in specific tissues. E4 has a small effect on normal breast tissue proliferation and minimally affects hepatic parameters. This distinct profile of ER alpha activation, uncoupling nuclear and membrane activation, is unique.

Homologous recombination (HR), a principal cellular pathway for double-strand break (DSB) repair, is linked to changes in chromosome movement. Although increased chromosome mobility in response to a DSB has been observed in a variety of species, its precise role in HR remains controversial. Here, we find that end resection, the recruitment of recombination proteins, increased chromosome mobility, the pairing of homologs and gene conversion are temporally linked in response to a DSB. In mre11Δ mutant cells, which exhibit a delay in the initial processing of a DSB, chromosome mobility and all subsequent recombination events are also delayed. Overexpression of the Dna2 nuclease suppresses the mre11Δ delay in end resection and restores the original timing of chromosome mobility and all subsequent downstream HR events. Thus, changing the timing of chromosome mobility results in a corresponding change in essential downstream HR events, reinforcing its mechanistic role in the DNA repair process.

Malaria, caused by Plasmodium parasites, results in >400,000 deaths annually. There is no effective vaccine, and new drugs with novel modes of action are needed because of increasing parasite resistance to current antimalarials. Histone deacetylases (HDACs) are epigenetic regulatory enzymes that catalyze post-translational protein deacetylation and are promising malaria drug targets. Here, we describe quantitative structure-activity relationship models to predict the antiplasmodial activity of hydroxamate-based HDAC inhibitors. The models incorporate P. falciparum in vitro activity data for 385 compounds containing a hydroxamic acid and were subject to internal and external validation. When used to screen 22 new hydroxamate-based HDAC inhibitors for antiplasmodial activity, model A7 (external accuracy 91%) identified three hits that were subsequently verified as having potent in vitro activity against P. falciparum parasites (IC50 = 6, 71, and 84 nM), with 8 to 51-fold selectivity for P. falciparum versus human cells.

Malaria is caused by infection with Plasmodium parasites and results in significant health and economic impacts. Malaria eradication is hampered by parasite resistance to current drugs and the lack of a widely effective vaccine. Compounds that target epigenetic regulatory proteins, such as histone deacetylases (HDACs), may lead to new therapeutic agents with a different mechanism of action, thereby avoiding resistance mechanisms to current antimalarial drugs. The anticancer HDAC inhibitor AR-42, as its racemate (rac-AR-42), and 36 analogues were investigated for in vitro activity against P. falciparum. Rac-AR-42 and selected compounds were assessed for cytotoxicity against human cells, histone hyperacetylation, human HDAC1 inhibition and oral activity in a murine malaria model. Rac-AR-42 was tested for ex vivo asexual and in vitro exoerythrocytic stage activity against P. berghei murine malaria parasites. Rac-AR-42 and 13 achiral analogues were potent inhibitors of asexual intraerythrocytic stage P. falciparum 3D7 growth in vitro (IC50 5-50 nM), with four of these compounds having >50-fold selectivity for P. falciparum versus human cells (selectivity index 56-118). Rac-AR-42 induced in situ hyperacetylation of P. falciparum histone H4, consistent with PfHDAC(s) inhibition. Furthermore, rac-AR-42 potently inhibited P. berghei infected erythrocyte growth ex vivo (IC50 40 nM) and P. berghei exoerythrocytic forms in hepatocytes (IC50 1 nM). Oral administration of rac-AR-42 and two achiral analogues inhibited P. berghei growth in mice, with rac-AR-42 (50 mg/kg/day single dose for four days) curing all infections. These findings demonstrate curative properties for HDAC inhibitors in the oral treatment of experimental mouse malaria.

TLRs reprogram macrophage metabolism, enhancing glycolysis and promoting flux through the tricarboxylic acid cycle to enable histone acetylation and inflammatory gene expression. The histone deacetylase (HDAC) family of lysine deacetylases regulates both TLR-inducible glycolysis and inflammatory responses. Here, we show that the TLR4 agonist LPS, as well as agonists of other TLRs, rapidly increase enzymatic activity of the class IIa HDAC family (HDAC4, 5, 7, 9) in both primary human and murine macrophages. This response was abrogated in murine macrophages deficient in histone deacetylase 7 (Hdac7), highlighting a selective role for this specific lysine deacetylase during immediate macrophage activation. With the exception of the TLR3 agonist polyI:C, TLR-inducible activation of Hdac7 enzymatic activity required the MyD88 adaptor protein. The rapid glycolysis response, as assessed by extracellular acidification rate, was attenuated in Hdac7-deficient mouse macrophages responding to submaximal LPS concentrations. Surprisingly however, reconstitution of these cells with either wild-type or an enzyme-dead mutant of Hdac7 enhanced LPS-inducible glycolysis, whereas only the former promoted production of the inflammatory mediators Il-1β and Ccl2. Thus, Hdac7 enzymatic activity is required for TLR-inducible production of specific inflammatory mediators, whereas it acts in an enzyme-independent fashion to reprogram metabolism in macrophages responding to submaximal LPS concentrations. Hdac7 is thus a bifurcation point for regulated metabolism and inflammatory responses in macrophages. Taken together with existing literature, our findings support a model in which submaximal and maximal activation of macrophages via TLR4 instruct glycolysis through distinct mechanisms, leading to divergent biological responses.

AR-42 is an orally active inhibitor of histone deacetylases (HDACs) in clinical trials for multiple myeloma, leukemia, and lymphoma. It has few hydrogen bond donors and acceptors but is a chiral 2-arylbutyrate and potentially prone to racemization. We report achiral AR-42 analogues incorporating a cycloalkyl group linked via a quaternary carbon atom, with up to 40-fold increased potency against human class I HDACs (e.g., JT86, IC50 0.7 nM, HDAC1), 25-fold increased cytotoxicity against five human cancer cell lines, and up to 70-fold less toxicity in normal human cells. JT86 was ninefold more potent than racAR-42 in promoting accumulation of acetylated histone H4 in MM96L melanoma cells. Molecular modeling and structure-activity relationships support binding to HDAC1 with tetrahydropyran acting as a hydrophobic shield from water at the enzyme surface. Such potent inhibitors of class I HDACs may show benefits in diseases (cancers, parasitic infections, inflammatory conditions) where AR-42 is active.

Structure-activity relationships for a series of small-molecule thiophenes resulted in potent and selective antagonism of human Complement C3a receptor. The compounds are about 100-fold more potent than the most reported antagonist SB290157. A new compound JR14a was among the most potent of the new antagonists in vitro, assessed by (a) inhibition of intracellular calcium release (IC50 10 nM) induced in human monocyte-derived macrophages by 100 nM C3a, (b) inhibition of β-hexosaminidase secretion (IC50 8 nM) from human LAD2 mast cells degranulated by 100 nM C3a, and (c) selectivity for human C3aR over C5aR. JR14a was metabolically stable in rat plasma and in rat liver microsomes and efficacious in rats when given orally to suppress rat paw inflammation, macrophage and mast cell activation, and histopathology induced by intraplantar paw administration of a C3aR agonist. Potent C3aR antagonists are now available for interrogating C3a receptor activation and suppressing C3aR-mediated inflammation in mammalian physiology and disease.

Vulvovaginal atrophy (VVA) resulting from estrogen deprivation at menopause often results in distressing vaginal dryness and dyspareunia. Fewer than 25% of affected women seek help for this condition citing embarrassment, cultural values, an aging or unavailable partner and concerns about use of estrogens following the Women's Health Initiative. Available non-hormonal treatments, such as moisturizers, while affording some relief can be messy to apply and do not prevent disease progression. A new oral selective estrogen receptor modulator, ospemifene, has been found to have strong estrogenic activity in vaginal tissues without adverse estrogenic effects at other sites.

Abstract The postreplication repair gene, HLTF, is often amplified and overexpressed in cancer. Here we model HLTF dysregulation through the functionally conserved Saccharomyces cerevisiae ortholog, RAD5. Genetic interaction profiling and landscape enrichment analysis of RAD5 overexpression (RAD5OE) reveals requirements for genes involved in recombination, crossover resolution, and DNA replication. While RAD5OE and rad5Δ both cause cisplatin sensitivity and share many genetic interactions, RAD5OE specifically requires crossover resolving genes and drives recombination in a region of repetitive DNA. Remarkably, RAD5OE induced recombination does not require other post-replication repair pathway members, or the PCNA modification sites involved in regulation of this pathway. Instead, the RAD5OE phenotype depends on a conserved domain necessary for binding 3′ DNA ends. Analysis of DNA replication intermediates supports a model in which dysregulated Rad5 causes aberrant template switching at replication forks. The direct effect of Rad5 on replication forks in vivo, increased recombination, and cisplatin sensitivity predicts similar consequences for dysregulated HLTF in cancer.

BACKGROUND AND PURPOSE:Chronic liver diseases feature excessive collagen and matrix protein deposition or crosslinking that characterises fibrosis, leads to scar tissue, and disrupts liver functions. There is no effective treatment. This study investigated whether treatment with selective histone deacetylase (HDAC) inhibitors might specifically reduce type 2 inflammation in the injured liver, thereby attenuating fibrogenesis in mice. EXPERIMENTAL APPROACH:Thioacetamide (TAA) was used to induce hepatic inflammation, fibrosis, and liver damage in female C57BL/6 mice, similar to the clinical features of chronic human liver disease. We used eight inhibitors of different human HDAC enzymes to probe histological (IHC and TUNEL), biochemical and immunological changes (flow cytometry, qPCR, Legendplex, and ELISA) in pathology, fibrosis, hepatic immune cell flux, and inflammatory cytokine expression. KEY RESULTS:Inhibitors of class I, but not class II, HDAC enzymes potently suppressed chronic hepatic inflammation and fibrosis in mice, attenuating accumulation and activation of IL-33-dependent, but not IL-25-dependent, group 2 innate lymphoid cells (ILC2) and inhibiting type 2 inflammation that drives hepatic stellate cells to secrete excessive collagen and matrix proteins. CONCLUSIONS AND IMPLICATIONS:The results show that potent and selective inhibitors of class I only HDAC enzymes profoundly inhibit hepatocyte death and type 2 inflammation to prevent TAA-induced liver fibrosis in mice. The specific HDAC enzymes identified here may be key promoters of inflammation in chronic liver fibrosis.

To determine whether age modifies the effect of the number of motile spermatozoa inseminated (NMSI) as a predictor of success in Intrauterine Insemination (IUI). This retrospective cohort study included all patients who underwent IUI at an academic infertility center between October 2004 and June 2018. The primary outcome was clinical pregnancy (CP; a gestational sac and fetal heartbeat on ultrasound). Results were analyzed by patient factors including age, NMSI, duration of infertility, and cause of infertility, along with treatment factors such as number of follicles and ovulation induction protocol. Factors associated with the odds of achieving a clinical pregnancy were analyzed using binary logistic generalized estimating equations to control for clustering effects by couple. Female age was categorized as <35 years vs. ≥35 years. Seven hundred thirty-seven couples that underwent 2062 IUI cycles for heterogeneous indications were included. The overall CP rate was 15.1% per cycle, and the cumulative CP rate per couple was 35.9%. For females < 35 years, the odds of CP per cycle were reduced for NMSI categories (× 106) of < 5.0 vs. ≥10.0 (OR = 0.49; 95% CI 0.29–0.83); the odds of CP per cycle did not differ for NMSI 5.0–9.9 vs. ≥10.0 (OR = 0.66; 0.37–1.18). For those ≥35 years, no difference was seen in the odds of CP per cycle for NMSI categories < 5.0 vs. ≥10.0 (OR = 1.55; 95% CI 0.72–3.31) or 5.0–9.9 vs. ≥10.0 (OR = 1.04; 95% CI 0.48–2.27). These results suggest that the NMSI can be used as a predictor of success in IUI in couples with women who are < 35 years of age; these patients should be counselled about their lower pregnancy rates when the NMSI is < 5.0 × 106. In patients ≥35 years, the NMSI does not appear to be a useful predictor of success. Further studies with larger sample size should be conducted.

Many factors are considered when a woman estimates her personal risk of breast cancer. Common to most decisions are four separate influences that have convinced the public and many health-care providers that breast cancer is the greatest concern for menopausal women and that menopausal hormone therapy (MHT) is generally responsible. Historically there have been well-documented situations in which big pharma and doctors have not put patient interests first. Conflicting reports about the safety of MHT and the media imperative to always increase readership by presenting a compelling scary story have created an underlying distrust of science, doctors, and MHT. Numerical and statistical illiteracy in the general population creates a situation where lotteries succeed despite astronomical odds and the risks of medical interventions are exaggerated by their description using relative, rather than absolute, risks. Finally, mammographic overdiagnosis contributing to improved breast cancer survival has contributed to the popularity paradox' (more screening - more enthusiasm) especially among survivors and advocacy groups. As a result, worry about breast cancer has overshadowed concern about cardiovascular diseases as the major cause of death and disability in the later years. The ongoing challenge for clinicians dealing with menopausal women is to bridge the gap in risk perception with evidence-based common-sense advice.

In the 2019 (second) edition of this text by Schulz and Grimes, physicians and allied health professionals will find a concise and insightful guide to the design and implementation of clinical research. Strengths and weaknesses of various research strategies are highlighted, with emphasis on how these may limit the interpretation of findings. Topics include observational studies, screening tests, randomized controlled trials, and guidelines for reporting in medical journals. Clearly written in short, easy-to-digest chapters, this text differs from other similar publications by providing practical clinical examples from the medical literature that highlight the concepts discussed. Physicians, pharmacists, and other allied health professionals will find the insights offered by these authors to be invaluable in interpreting medical literature, and established researchers will better understand how to optimize their conduct and interpretation of clinical research.

C'est un médecin français qui, en 1821, a utilisé le terme « ménopause » pour la première fois. Le Dr Archie Cameron, gynécologue canadien à l'Hôpital général de Montréal, a été le premier à recourir à l’œstrogénothérapie en 1930 en utilisant un extrait placentaire humain (Emmenin) découvert par James Collip1Baskett TF. Eponyms and names in obstetrics and gynaecology.3rd ed. Cambridge University Press, London2019Google Scholar. Dans les années qui ont suivi, la demande pour cette hormonothérapie était telle que la production d'extraits placentaires s'est avérée insuffisante. Ayerst, McKenna & Harrison, la petite entreprise pharmaceutique qui approvisionnait le marché en Emmenin, est ainsi passée à la production de composés œstrogéniques à base d'urine de jument gravide. Le médicament Premarin, homologué au Canada en 1941 puis aux États-Unis l'année suivante, a été le traitement de la ménopause le plus prescrit 60 années durant. Jusqu'au milieu des années 1970, la recherche sur la ménopause reposait uniquement sur l'observation, et les traitements reposaient largement sur l'expérience et les opinions des médecins2Barlow DH A long and winding road: reflections on the evolution of menopause medicine over a professional lifetime.Menopause. 2018; 25: 1395-1400Google Scholar. Lors du premier congrès international de 1976 sur la ménopause à Montpellier, en France, des inquiétudes commençaient à être soulevées au sujet du cancer de l'endomètre provoqué par les œstrogènes. Le traitement au progestatif concomitant est alors devenu le traitement habituel au début des années 1980 pour les femmes ayant un utérus. La thrombose provoquée par les œstrogènes a aussi suscité des inquiétudes. Le rôle de l’œstrogène dans le cancer du sein était flou, et les débats persistaient à savoir si les progestatifs augmenteraient les risques2Barlow DH A long and winding road: reflections on the evolution of menopause medicine over a professional lifetime.Menopause. 2018; 25: 1395-1400Google Scholar. Les attitudes sur l'efficacité et l'innocuité de l'hormonothérapie sont passées de la confiance au début des années 1990 à la prudence au tournant du siècle, puis à la peur pure et simple après la parution en 2002 des premiers rapports alarmants de l’étude Women's Health Initiative (WHI). Dans les dix années suivantes, les rapports de la WHI ont largement fait les manchettes. Le compte rendu initial des effets défavorables de l'hormonothérapie ménopausique (HTM) a reçu une forte attention médiatique, sans compter que la couverture unilatérale constante était encouragée par les messages négatifs constants du groupe de rédaction de la WHI3Langer RD. The evidence base for HRT: what can we believe?.Climacteric. 2017; 20: 91-96Google Scholar. En raison de son envergure impressionnante, de son format d'essai clinique randomisé et de ses conclusions inquiétantes, la WHI a éclipsé bon nombre d'autres observations de moindre proportion, quoiqu'importantes, sur les effets de l'HTM au cours des dix années qui ont suivi. Les rapports de la WHI où l'on affirme que l'hormonothérapie substitutive augmente le risque de maladie cardiovasculaire, d'accident vasculaire cérébral et de cancer ont créé un effet domino qui a donné lieu à des conséquences défavorables, à la fois nombreuses et variées, sur la santé des femmes en périménopause. Les prescriptions d'hormonothérapie ont chuté lorsque les femmes et leurs fournisseurs de soins de santé ont commencé à craindre l'HTM. Plusieurs femmes se sont fait dire qu'elles devaient simplement endurer les symptômes ou essayer un traitement parallèle. Les prescriptions d'inhibiteurs du recaptage de la sérotonine ont monté en flèche, révélant une relation inversement proportionnelle à la chute des prescriptions d'HTM. Les entreprises faisant la promotion de la médecine non conventionnelle étaient très peu réglementées et n'avaient aucune obligation de démontrer l'efficacité de leurs produits au moyen d'essais cliniques randomisés rigoureux. Les étagères des pharmacies débordaient de produits de médecine non conventionnelle prétendant soulager les symptômes vasomoteurs (SVM) et autres troubles ménopausiques. Un marché florissant a alors émergé. Forts d'une commercialisation persuasive et de l'appui de célébrités comme Oprah et Suzanne Somers, les « traitements personnalisés » d'après un bilan hormonal salivaire et l'utilisation d'hormones bio-identiques « naturelles et sécuritaires » ont renforcé la croyance répandue voulant que l'HTM traditionnelle soit dangereuse et doive être évitée. Il a depuis été déterminé que la plupart de ces produits ne procuraient rien de plus qu'un simple effet placebo. Qui plus est, les normes relatives aux médicaments composés d'hormones bio-identiques étaient déficientes, et rien ne prouvait leur efficacité ni leur innocuité4Nedrow A Miller J Walker M et al.Complementary and alternative therapies for management of menopause-related symptoms: a systematic evidence review.Arch Intern Med. 2006; 166: 1453-1465Crossref PubMed Scopus (194) Google Scholar, 5Santoro N Braunstein GD Butts CL et al.Compounded bioidentical hormones in endocrinology practice: an Endocrine Society scientific statement.J Clin Endocrinol Metab. 2016; 101: 1318-1343Crossref Scopus (35) Google Scholar. Par conséquent, les symptômes ménopausiques ont empiré au sein de la population. De plus en plus de femmes rapportaient qu'elles souffraient de symptômes pénibles et persistants, tels que les SVM, la sécheresse vaginale et la dyspareunie. On ignorait en grande partie les conséquences importantes des symptômes ménopausiques non traités sur la qualité de vie et la participation au marché du travail6Pinkerton JV Money talks: untreated hot flashes cost women, the workplace, and society.Menopause. 2015; 22: 254-255Crossref PubMed Scopus (13) Google Scholar. Les grandes organisations de soins de santé intégrés constataient une hausse du taux de fractures ostéoporotiques en plus de taux de maladies cardiovasculaires et d'accidents vasculaires cérébraux (AVC) plus élevés chez les femmes ayant cessé la HTM que chez celles l'ayant poursuivie7Lobo RA Pickar JH Stevenson JC et al.Back to the future: hormone replacement therapy as part of a prevention strategy for women at the onset of menopause.Atherosclerosis. 2016; 254: 282-290Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar. De nos jours, près de 20 ans après le premier rapport de la WHI, le retour du pendule fait en sorte que l'hormonothérapie substitutive est privilégiée pour la plupart des femmes symptomatiques nouvellement en périménopause. Non seulement l'HTM a été clairement établie comme traitement le plus efficace des SVM, elle soulage aussi le syndrome génito-urinaire de la ménopause chez de nombreuses femmes. Les études observationnelles et analyses secondaires des données tirées de la WHI fournissent des données probantes sur l'effet cardioprotecteur de l'HTM lorsqu'elle est amorcée en début de ménopause8Langer RD Simon JA Pines A et al.Menopausal hormone therapy for primary prevention: why the USPSTF is wrong.Menopause. 2017; 24: 1101-1112Google Scholar. Une analyse Cochrane conclut que, par comparaison aux femmes du groupe placebo, celles qui ont amorcé la HTM dans les 10 premières années de la ménopause présentaient 30 % moins de risques de mortalité (RR : 0,70; IC de 95 % : 0,52–0,95) et 48 % moins de risques de cardiopathies (RR : 0,52; IC de 95 % : 0,29–0,96), quoiqu'aucune incidence sur le risque d'AVC n'ait été trouvée9Boardman HM Hartley L Eisinga A et al.Hormone therapy for preventing cardiovascular disease in post-menopausal women.Cochrane Database Syst Rev. 2015; CD002229PubMed Google Scholar. La peur du cancer du sein a longtemps été un facteur déterminant dans la prescription de l'HTM et l'adhésion des femmes. Bien qu'elle soit présentée comme outil de dépistage idéal du cancer du sein, la mammographie est en fait un instrument assez grossier qui mène fréquemment au surdiagnostic et au surtraitement. Le « danger » apparent de l'HTM combinée qu'a rapporté l’étude WHI a été exagéré8Langer RD Simon JA Pines A et al.Menopausal hormone therapy for primary prevention: why the USPSTF is wrong.Menopause. 2017; 24: 1101-1112Google Scholar, 10Reid RL Hormone therapy and breast cancer: risk communication and the perfect storm.Climacteric. 2019; 22: 13-16Google Scholar, 11Hodis HN Sarrel PM Menopausal hormone therapy and breast cancer: what is the evidence from randomized trials?.Climacteric. 2018; 21: 521-528Google Scholar. Dans l’étude, l'HTM n'a entraîné aucune augmentation du risque de cancer du sein chez les nouvelles utilisatrices. La légère augmentation du risque de cancer du sein (8 cas annuels par 10 000 utilisatrices) observée chez les anciennes utilisatrices de l'HTM dans l'essai sur l'hormonothérapie combinée semble s'expliquer par une diminution inexpliquée des diagnostics de cancer du sein chez les femmes du groupe placebo. Le taux annuel de cancer du sein chez les femmes sous HTM combinée n'est pas différent de celui des deux volets de l’étude à grande échelle de la WHI sur la modification de l'alimentation8Langer RD Simon JA Pines A et al.Menopausal hormone therapy for primary prevention: why the USPSTF is wrong.Menopause. 2017; 24: 1101-1112Google Scholar. Les conclusions d'une analyse des données de l'essai clinique randomisé sont les suivantes :Après cinquante années d’études, aucune donnée concluante, y compris les données tirées de l'essai de la WHI sur l'hormonothérapie combinée EEC-AMPR (œstrogènes équins conjugués et acétate de médroxyprogestérone), ne prouve que l'HTM cause le cancer du sein. En fait, la vaste majorité des données, notamment celles de l'essai de la WHI sur la combinaison EEC-AMPR, indique que l'hormonothérapie œstrogène-progestatif n'a aucune incidence sur le risque de cancer du sein11Hodis HN Sarrel PM Menopausal hormone therapy and breast cancer: what is the evidence from randomized trials?.Climacteric. 2018; 21: 521-528Google Scholar. Il ne fait aucun doute que certains contesteront cette déclaration en citant la plausibilité biologique et les données probantes accumulées au fil des études observationnelles. Néanmoins, l'incidence de l'HTM sur le risque de cancer du sein, s'il existe, est petite; les bénéfices potentiels sur le plan de la prévention des maladies cardiovasculaires sont quant à eux considérables. De nouvelles approches en matière d'HTM seront requises pour aborder les frustrations cliniques des femmes et de leurs fournisseurs de soins de santé. Les saignements et les douleurs aux seins figurent en tête de liste des raisons de l'arrêt de l'HTM, même lorsqu'elle atténue les SVM. La diminution des doses, le changement du mode d'administration (c.-à-d. continue par rapport à cyclique) et les produits novateurs, comme les complexes œstrogéniques à action tissulaire sélective (TSEC) qui combinent un œstrogène à un modulateur sélectif des récepteurs d’œstrogènes, s'annoncent prometteurs pour soulager les SVM et limiter les effets défavorables de l'HTM traditionnelle12Pinkerton JV. Tissue selective estrogen complex for menopausal hormone therapy.Clin Obstet Gynecol. 2018; 61: 463-469Google Scholar. Bien qu'elle soit un événement défavorable rare chez les femmes sous HTM de 45 à 60 ans, la thromboembolie veineuse demeure une inquiétude pouvant être atténuée grâce à une meilleure sensibilisation aux facteurs de risque concomitants (p. ex. immobilité, thrombophilie, antécédents familiaux), à l'administration par voie non orale et à de nouvelles préparations au potentiel thrombogène moindre, contenant de l'estradiol, de l'estetrol ou des TSEC. Non seulement l'HTM soulage les SVM, elle pourrait aussi apporter d'autres bienfaits aux femmes. L'HTM peut atténuer les douleurs somatiques nouvellement apparues et, chez certaines femmes, améliorer le sommeil, l'humeur et la lucidité. Pour les femmes qui se sentent mieux sous HTM, l'utilisation prolongée pourrait être adéquate après une évaluation des avantages et risques individuels13Kaunitz AM. Extended duration use of menopausal hormone therapy.Menopause. 2014; 21: 679-681Crossref PubMed Scopus (21) Google Scholar. La courte durée de l'HTM dans la WHI (moyenne de 5,2 ans pour une HTM combinée et 6,8 ans pour l'hormonothérapie aux œstrogènes seulement) ne permet pas de déterminer si le commencement précoce d'une HTM à long terme offre une cardioprotection. Bien que des données probantes indiquent que l'aspirine, les statines et les inhibiteurs d'enzyme de conversion de l'angiotensine peuvent diminuer les risques de maladies cardiovasculaires chez les hommes, on ne dispose d'aucune donnée probante en ce sens pour les femmes7Lobo RA Pickar JH Stevenson JC et al.Back to the future: hormone replacement therapy as part of a prevention strategy for women at the onset of menopause.Atherosclerosis. 2016; 254: 282-290Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar. Les craintes du passé relativement à l'HTM et le manque de données issues d'essais cliniques sur l'incidence à long terme du commencement précoce de l'HTM sur les résultats cliniques cardiovasculaires ont laissé la plupart des cardiologues et organismes nationaux réticents à appuyer le recours à l'HTM pour prévenir les maladies cardiaques chez les femmes. D'autres ont contesté cette position en soulignant le fait que, mis à part les changements apportés au mode de vie, l'HTM pourrait être la meilleure option pour maintenir la santé cardiovasculaire des femmes âgées7Lobo RA Pickar JH Stevenson JC et al.Back to the future: hormone replacement therapy as part of a prevention strategy for women at the onset of menopause.Atherosclerosis. 2016; 254: 282-290Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 8Langer RD Simon JA Pines A et al.Menopausal hormone therapy for primary prevention: why the USPSTF is wrong.Menopause. 2017; 24: 1101-1112Google Scholar. Le risque de diabète sucré, autre important enjeu de santé mondial, diminue de 15 % à 20 % chez les femmes sous HTM14Mauvais-Jarvis F Manson JE Stevenson JC et al.Menopausal hormone therapy and type 2 diabetes prevention: evidence, mechanisms, and clinical implications.Endocr Rev. 2017; 38: 173-188Crossref PubMed Scopus (170) Google Scholar. Les fractures ostéoporotiques entraînent une augmentation importante des risques de morbidité et de mortalité. L'Organisation mondiale de la Santé les considère comme l'une des principales priorités en matière de santé publique15Levin VA Jiang X Kagan R Estrogen therapy for osteoporosis in the modern era.Osteoporos Int. 2018; 29: 1049-1055Crossref PubMed Scopus (123) Google Scholar. Après la publication des rapports de la WHI, les craintes sur l'HTM ont incité les organismes et les experts en ostéoporose à recommander les bisphosphonates comme traitement de première intention pour la prévention primaire de l'ostéoporose. Depuis la sortie d'un rapport avantages-risques bien plus rassurant au sujet de l'HTM, certains affirment désormais que cette position devrait changer afin que l'HTM devienne le traitement de première intention, puisque seuls les œstrogènes équins conjugués oraux se sont avérés réduire le risque de fracture chez les femmes ostéoporotiques et non ostéoporotiques15Levin VA Jiang X Kagan R Estrogen therapy for osteoporosis in the modern era.Osteoporos Int. 2018; 29: 1049-1055Crossref PubMed Scopus (123) Google Scholar. L’éducation et la clarté par rapport à l'incidence réelle de l'HTM sur le risque de cancer du sein sont essentielles à l'acceptation à grande échelle du traitement à long terme. La combinaison d’œstrogène avec un modulateur sélectif des récepteurs d’œstrogènes dans le TSEC pourrait un jour s'avérer réduire le risque de cancer du sein; cependant, les données dont on dispose actuellement sont insuffisantes pour étayer cette théorie. Dans leur ensemble, ces observations sur la possibilité que l'HTM puisse prévenir ou retarder plusieurs maladies graves qui touchent les femmes lorsqu'elles vieillissent suggèrent que le temps est venu, une fois encore, d’évaluer le rôle de l'HTM en tant que traitement préventif. Menopause Medicine: Past, Present, and FutureJournal of Obstetrics and Gynaecology Canada Vol. 41PreviewThe term “menopause” was coined by a French physician in 1821. A Canadian gynaecologist, Archie Cameron at Montréal General Hospital, was the first to use estrogen therapy, in 1930, using a human placental extract (Emmenin) discovered by James Collip.1 The demand for this hormone therapy was such in the ensuing years that placental extracts proved insufficient, and the small pharmaceutical company providing Emmenin to the market (Ayerst, McKenna, and Harrison) switched to producing estrogenic compounds from pregnant mare's urine. Full-Text PDF

The term "menopause" was coined by a French physician in 1821. A Canadian gynaecologist, Archie Cameron at Montréal General Hospital, was the first to use estrogen therapy, in 1930, using a human placental extract (Emmenin) discovered by James Collip.1Baskett TF Eponyms and names in obstetrics and gynaecology.3rd ed. Cambridge University Press, London2019Google Scholar The demand for this hormone therapy was such in the ensuing years that placental extracts proved insufficient, and the small pharmaceutical company providing Emmenin to the market (Ayerst, McKenna, and Harrison) switched to producing estrogenic compounds from pregnant mare's urine. Premarin, approved in Canada in 1941 and in the United States the following year, was the most widely prescribed menopausal therapy for the next 60 years. Until the mid-1970s research on menopause was exclusively observational, and therapies were largely based on the experience and opinions of clinicians.2Barlow DH A long and winding road: reflections on the evolution of menopause medicine over a professional lifetime.Menopause. 2018; 25: 1395-1400Google Scholar At the first International Conference on the Menopause in Montpellier, France in 1976, concerns about estrogen-induced endometrial cancer were emerging, and these led to concomitant progestin therapy becoming the standard of care for women with a uterus by the early 1980s. Estrogen-induced thrombosis was also identified as a concern. The role of estrogen in breast cancer was unclear, and whether progestin would ameliorate any risk was still being debated.2Barlow DH A long and winding road: reflections on the evolution of menopause medicine over a professional lifetime.Menopause. 2018; 25: 1395-1400Google Scholar Attitudes about the effectiveness and safety of hormone therapy shifted from a position of confidence in the early 1990s to one of caution at the turn of the century and then to outright fear following the alarming first reports from the Women's Health Initiative (WHI) in 2002. Over the next decade, reports from the WHI dominated the news. The initial reporting of adverse effects of menopausal hormone treatment (MHT) generated enormous media attention, and the ongoing one-sided coverage was fostered by consistent negative messaging from the WHI writing group.3Langer RD The evidence base for HRT: what can we believe?.Climacteric. 2017; 20: 91-96Google Scholar Because of its enormous size, its randomized clinical trial design, and the worrisome findings, the WHI overshadowed many smaller, yet important, observations about the effects of MHT in the next decade. Reports from the WHI claiming that hormone replacement therapy would promote cardiovascular disease, stroke, and cancer had a domino effect with a broad range of adverse consequences on the health of menopausal women. Prescriptions for hormone therapy plummeted as both women and their health care providers became fearful of MHT. Many women were told either to just "put up with symptoms" or to try alternative therapies. Prescriptions for serotonin reuptake inhibitors soared, showing an inverse relationship with the fall in MHT prescribing. Companies promoting complementary and alternative medicine (CAM) were largely unregulated and were under no obligation to demonstrate efficacy of their products through rigorous randomized clinical trials. The shelves of pharmacies were flooded with CAM products purporting to relieve vasomotor symptoms (VMS) and other menopausal concerns, and a burgeoning market emerged. Aggressive marketing with celebrity endorsement by celebrities such as Oprah and Suzanne Somers of "individualized therapy" based on salivary hormone testing and the use of "more natural and safer" compounded bioidentical hormones reinforced the prevailing belief that traditional MHT was dangerous and something to be avoided. Most CAM products were found to function merely as placebos, and compounded bioidentical hormones lack standardization as well as proof of efficacy and safety.4Nedrow A Miller J Walker M et al.Complementary and alternative therapies for management of menopause-related symptoms: a systematic evidence review.Arch Intern Med. 2006; 166: 1453-1465Crossref PubMed Scopus (194) Google Scholar,5Santoro N Braunstein GD Butts CL et al.Compounded bioidentical hormones in endocrinology practice: an Endocrine Society scientific statement.J Clin Endocrinol Metab. 2016; 101: 1318-1343Crossref Scopus (35) Google Scholar Consequently, menopausal symptoms in the population worsened, with more women reporting persistent distressing VMS, vaginal dryness, and dyspareunia. Largely ignored was the significant impact of untreated menopausal symptoms on quality of life and participation in the workforce.6Pinkerton JV Money talks: untreated hot flashes cost women, the workplace, and society.Menopause. 2015; 22: 254-255Crossref PubMed Scopus (13) Google Scholar Rates of osteoporotic fractures in large health maintenance organizations were seen to rise, and rates of cardiovascular disease and stroke increased in women who discontinued MHT compared with women who did not.7Lobo RA Pickar JH Stevenson JC et al.Back to the future: hormone replacement therapy as part of a prevention strategy for women at the onset of menopause.Atherosclerosis. 2016; 254: 282-290Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar Now, almost 20 years after the first WHI report, the pendulum has swung back in favour of hormone replacement therapy for most symptomatic newly menopausal women. Not only has MHT been clearly established as the most effective treatment for VMS, it also ameliorates the genitourinary syndrome of menopause for many women. Observational studies and secondary analyses of WHI data provided evidence that MHT is cardioprotective when it is started close to the time of menopause.8Langer RD Simon JA Pines A et al.Menopausal hormone therapy for primary prevention: why the USPSTF is wrong.Menopause. 2017; 24: 1101-1112Crossref PubMed Scopus (12) Google Scholar A Cochrane analysis concluded that women who started MHT within 10 years of menopause had 30% lower mortality (relative risk (RR) 0.70; 95% CI 0.52–0.95) and 48% lower coronary heart disease (RR 0.52; 95% CI 0.29 015–0.96), and no effect on risk of stroke relative to placebo was found.9Boardman HM Hartley L Eisinga A et al.Hormone therapy for preventing cardiovascular disease in post-menopausal women.Cochrane Database Syst Rev. 2015; CD002229PubMed Google Scholar Fear of breast cancer has long been a deciding factor in prescription and uptake of MHT. Mammography, although promoted as an ideal screening tool for breast cancer, is really a blunt instrument that leads to frequent overdiagnosis and overtreatment. The apparent "harm" reported for combined MHT in the WHI has been overstated.8Langer RD Simon JA Pines A et al.Menopausal hormone therapy for primary prevention: why the USPSTF is wrong.Menopause. 2017; 24: 1101-1112Crossref PubMed Scopus (12) Google Scholar,10Reid RL Hormone therapy and breast cancer: risk communication and the perfect storm.Climacteric. 2019; 22: 13-16Google Scholar,11Hodis HN Sarrel PM Menopausal hormone therapy and breast cancer: what is the evidence from randomized trials?.Climacteric. 2018; 21: 521-528Google Scholar In the WHI, MHT caused no increase in breast cancer among first-time users. The small increase in breast cancer rates (8/10,000 users per year) seen in former MHT users in the combined estrogen-progestin trial appears to have resulted from an unexplained decrease in breast cancer diagnoses among women assigned to placebo. The annualized rate of breast cancer in women taking combined MHT was no different from the annualized rate of breast cancer in both arms of the much larger WHI diet modification trial.8Langer RD Simon JA Pines A et al.Menopausal hormone therapy for primary prevention: why the USPSTF is wrong.Menopause. 2017; 24: 1101-1112Crossref PubMed Scopus (12) Google Scholar Findings of a review of randomized clinical trial data were as follows:After five decades of study, no conclusive evidence, including the WHI combined CEE/MPA (conjugated equine estrogen/ medroxyprogesterone acetate) trial, proves that MHT causes breast cancer and, in fact, the overwhelming preponderance of data, including the WHI combined CEE/MPA trial, show that estrogen/progestogen therapy has a null effect on breast cancer.11Hodis HN Sarrel PM Menopausal hormone therapy and breast cancer: what is the evidence from randomized trials?.Climacteric. 2018; 21: 521-528Google Scholar Undoubtedly, some will challenge this assertion by citing biological plausibility and the accumulated evidence from observational studies. Nevertheless, the impact of MHT on breast cancer, if any, is small, and the potential preventive benefits for cardiovascular disease are enormous. New MHT approaches will be needed to address the clinical frustrations of women and their health care providers. Bleeding and breast pain rank high on the list of reasons why MHT is discontinued even when it is relieving VMS. Lower doses, different formulations (i.e., continuous vs. cyclic), and innovative products, such as the tissue-selective estrogen complex (TSEC) that combines an estrogen with a selective estrogen receptor modulator, all hold promise for relieving VMS while minimizing the nuisance adverse effects of traditional MHT.12Pinkerton JV Tissue selective estrogen complex for menopausal hormone therapy.Clin Obstet Gynecol. 2018; 61: 463-469Google Scholar Venous thromboembolism, although a rare adverse event in MHT users between the ages of 45 and 60, remains a concern that may be reduced by greater awareness of concomitant risk factors (e.g., immobility, thrombophilia, family history), non-oral delivery, and newer formulations with less thrombogenic potential containing estradiol, estetrol, or TSEC. Not only does MHT relieve VMS, it also may afford other benefits to individual women. MHT can reduce new-onset somatic pain and, for some women, improve sleep, mood, and mental clarity. For women who feel better while on MHT, extended use may be appropriate after a review of individual benefits and risks.13Kaunitz AM Extended duration use of menopausal hormone therapy.Menopause. 2014; 21: 679-681Crossref PubMed Scopus (21) Google Scholar The short duration of MHT treatment in the WHI (mean of 5.2 years for combined MHT and 6.8 years for estrogen alone) leaves unanswered the question of whether early initiation and longer-term treatment with MHT would afford cardioprotection. Although there is evidence that aspirin, statins, and angiotensin-converting enzyme inhibitors can reduce cardiovascular disease in men, no such evidence exists for women.7Lobo RA Pickar JH Stevenson JC et al.Back to the future: hormone replacement therapy as part of a prevention strategy for women at the onset of menopause.Atherosclerosis. 2016; 254: 282-290Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar The MHT scares of the past and a lack of clinical trial data on the long-term impact of early initiation of MHT on cardiovascular end points have left most cardiologists and national organizations reluctant to support MHT for cardiac prevention in women. Others have challenged this position, pointing out that, other than lifestyle changes, MHT may be the best option to maintain cardiovascular health in aging women.7Lobo RA Pickar JH Stevenson JC et al.Back to the future: hormone replacement therapy as part of a prevention strategy for women at the onset of menopause.Atherosclerosis. 2016; 254: 282-290Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar,8Langer RD Simon JA Pines A et al.Menopausal hormone therapy for primary prevention: why the USPSTF is wrong.Menopause. 2017; 24: 1101-1112Crossref PubMed Scopus (12) Google Scholar The risk of diabetes mellitus, another significant global health concern, is reduced by 15% to 20% in women taking MHT.14Mauvais-Jarvis F Manson JE Stevenson JC et al.Menopausal hormone therapy and type 2 diabetes prevention: evidence, mechanisms, and clinical implications.Endocr Rev. 2017; 38: 173-188Crossref PubMed Scopus (170) Google Scholar Osteoporotic fractures lead to substantial morbidity and mortality and are considered one of the largest public health priorities by the World Health Organization.15Levin VA Jiang X Kagan R Estrogen therapy for osteoporosis in the modern era.Osteoporos Int. 2018; 29: 1049-1055Google Scholar Fears about MHT after the WHI reports led osteoporosis experts and organizations to recommend bisphosphonates as first-line treatment for primary prevention of osteoporosis. With the emergence of a much more reassuring benefit-to-risk profile for MHT, there are now arguments that this position should change, with MHT becoming first-line therapy—only oral conjugated equine estrogen has been proven to reduce the risk of fracture in both osteoporotic and non-osteoporotic women.15Levin VA Jiang X Kagan R Estrogen therapy for osteoporosis in the modern era.Osteoporos Int. 2018; 29: 1049-1055Google Scholar Education and clarity about the true impact of MHT on breast cancer remain critical to the wider acceptance of long-term therapy. The combination of estrogen with a selective estrogen receptor modulator in the TSEC may ultimately prove to reduce the risk of breast cancer; however, there is currently insufficient evidence to establish this. Taken together, these observations about the potential for MHT to prevent or delay several of the most serious conditions affecting women as they age suggest that it is time, once again, to evaluate the role of MHT as preventive therapy. Traitement de la ménopause : passé, présent et futurJournal of Obstetrics and Gynaecology Canada Vol. 41PreviewC'est un médecin français qui, en 1821, a utilisé le terme « ménopause » pour la première fois. Le Dr Archie Cameron, gynécologue canadien à l'Hôpital général de Montréal, a été le premier à recourir à l'œstrogénothérapie en 1930 en utilisant un extrait placentaire humain (Emmenin) découvert par James Collip1. Dans les années qui ont suivi, la demande pour cette hormonothérapie était telle que la production d'extraits placentaires s'est avérée insuffisante. Ayerst, McKenna & Harrison, la petite entreprise pharmaceutique qui approvisionnait le marché en Emmenin, est ainsi passée à la production de composés œstrogéniques à base d'urine de jument gravide. Full-Text PDF

Endometriosis is a common gynecologic condition that has variable clinical findings. Typical signs and symptoms include dysmenorrhea, pelvic pain, and infertility. However, when endometrial deposits are located outside the pelvis, patients may present in a more unusual fashion. We report a case of extra-pelvic endometriosis that was identified following treatment for recurrent pneumothorax. A 28-year-old nulliparous female presented with recurrent pneumothorax associated with her menstrual cycle. Initial thoracoscopic surgery identified a suspicious apical bleb. Following its resection however, her symptoms persisted. Ovarian suppression using a GnRH-agonist resulted in significant symptomatic control. This prompted a second-look thoracoscopy with a gynecologist in attendance. A right diaphragmatic deposit of ectopic endometriosis was resected with resolution of the problem. We discuss current pathogenic theories of endometriosis and catamenial pneumothorax. Additionally, we review the spectrum of presentation, dilemma of diagnosis, and available therapies used in the treatment of endometrial-associated pneumothorax. We speculate on efficacy of novel therapies (e.g., dienogest) in the treatment of extrapelvic endometriosis. This case study demonstrates the benefit of empiric treatment with ovulation suppression when other diagnostic modalities proved inconclusive. Furthermore, it highlights the importance of interdisciplinary care and stresses the need for increased awareness of endometriosis in non-gynecologic specialties.

Women and health care providers are often fearful of using hormone therapy to deal with distressing menopausal symptoms in circumstances where there is a perceived or real increased risk of breast cancer. This paper examines the evidence for and against hormone therapy use in 3 common clinical situations: the woman with a positive family history in a first-degree relative, the woman who has undergone risk-reducing salpingo-oophorectomy due to a known genetic mutation, and the woman in whom treatment of breast cancer has induced premature menopause.