Neoadjuvant endocrine therapy in primary breast cancer: indications and use as a research tool

Neoadjuvant endocrine therapy has been increasingly employed in clinical practice to improve surgical options for postmenopausal women with bulky hormone receptor-positive breast cancer. Recent studies indicate that tumour response in this setting may predict long-term outcome of patients on adjuvant endocrine therapy, which argues for its broader application in treating hormone receptor-positive disease. From the research perspective, neoadjuvant endocrine therapy provides a unique opportunity for studies of endocrine responsiveness and the development of novel therapeutic agents

The Role of Interferon Regulatory Factor-1 (IRF1) in Overcoming Antiestrogen Resistance in the Treatment of Breast Cancer

Resistance to endocrine therapy is common among breast cancer patients with estrogen receptor alpha-positive (ER+) tumors and limits the success of this therapeutic strategy. While the mechanisms that regulate endocrine responsiveness and cell fate are not fully understood, interferon regulatory factor-1 (IRF1) is strongly implicated as a key regulatory node in the underlying signaling network. IRF1 is a tumor suppressor that mediates cell fate by facilitating apoptosis and can do so with or without functional p53. Expression of IRF1 is downregulated in endocrine-resistant breast cancer cells, protecting these cells from IRF1-induced inhibition of proliferation and/or induction of cell death. Nonetheless, when IRF1 expression is induced following IFNγ treatment, antiestrogen sensitivity is restored by a process that includes the inhibition of prosurvival BCL2 family members and caspase activation. These data suggest that a combination of endocrine therapy and compounds that effectively induce IRF1 expression may be useful for the treatment of many ER+ breast cancers. By understanding IRF1 signaling in the context of endocrine responsiveness, we may be able to develop novel therapeutic strategies and better predict how patients will respond to endocrine therapy

Hypotalamus-hypofys-binjurebarksaxeln och perinatal behandling av prematurföl

The danger and vulnerability associated with a preterm birth seem to be closely correlated with a dysfunction of the fetal hypothalamic-pituitary-adrenal (HPA) axis, whose maturation in the foal is without a doubt as delicate as it is important. Not only is this endocrine cascade vital for the foal in order to cope with neonatal stress, it also appears to be fundamental for the final fetal intrauterine maturation, as well as for the onset of foaling. Equine gestation exhibits some rather unique features, indicating a somewhat different significance of the endocrine changes associated with HPA maturation, compared to many other species. This hormonal cascade is rapid and confined to a narrow time during late gestation in the horse, and the risk of the foal completely missing it therefore becomes prominent. Induced parturition in the mare may be operated through uterotonic agents, which occasionally bring about premature foals. Desirable seems the ability to initiate equine labour while simultaneously enhancing fetal HPA maturation, as in humans and ruminants through perinatal glucocorticoid administration. However, similar treatment in the horse has resulted in various, sometimes fatal, outcomes. In the light of the distinctive features of equine gestation, difficulties are encountered following such administration of glucocorticoids and ACTH. Favourable results have however also been displayed in the horse, motivating attempts to overcome the associated obstacles. To ensure a successful therapy, increased knowledge about the endocrinology of equine gestation will be necessary.En för tidig födsel innebär en väldig fara för den nyfödda individen. En bidragande orsak är ofta en bristfällig hypotalamus-hypofys-binjurebarksaxel, vars utveckling ter sig lika känslig som betydelsefull för ett föl. Utöver förmågan att hantera neonatal stress, förefaller denna endokrina kaskad vara av yttersta vikt för den slutliga intrauterina fetala utvecklingen, liksom för initieringen av fölning. Hästens dräktighet skiljer sig något från många andra djurslags, och betydelsen av de endokrina förändringarna associerade med HPA-axelns mognad förefaller något annorlunda. Den hormonella kaskaden är hastig och begränsad till en kort tidsperiod sent under hästens dräktighet, vilket ökar risken för att fölet helt missar denna. Fölning kan sättas igång artificiellt med hjälp av uterotona preparat, vilka dock kan associeras med födseln av underutvecklade individer. Fördelaktigt vore således att parallellt kunna initiera fölning och stimulera den fetala HPA-utvecklingen, vilket hos idisslare och människa kan åstadkommas med hjälp av perinatal administrering av glukokortikoider. Liknande behandling av häst har undersökts men med varierande, ibland fatala, resultat. Då hästens dräktighet innefattar dessa specifika karaktärsdrag, uppstår svårigheter vid administrering av glukokortikoider och ACTH. Vissa studier har dock uppvisat lyckade resultat hos häst, vilket motiverar eventuella försök till att lösa dessa problem. Nödvändig är således utökad kunskap om endokrinologin bakom ekvin dräktighet, innan dylik behandling kan bli aktuell

Individual 17-Hydroxyprogesterone Responses to hCG Are Not Correlated With Follicle Size in Polycystic Ovary Syndrome.

Context:In women with polycystic ovary syndrome (PCOS), 17-hydroxyprogesterone (17-OHP) responses to gonadotropin stimulation vary from increased to indistinguishable compared with normal controls. Objective:To determine whether 17-OHP responses to recombinant-human chorionic gonadotropin (r-hCG) are individually correlated to the size of antral follicles among women with PCOS. Design Setting and Participants:A prospective study conducted in 19 women with PCOS and 20 normal controls at an academic medical center. Interventions:Blood samples were obtained before and 24 hours after administration of 25 μg of r-hCG. Ovarian imaging was conducted with three-dimensional pelvic ultrasonography. Each subject underwent a 2-hour oral glucose tolerance test. Main Outcome Measures:Basal and stimulated levels of 17-OHP, androgens, estradiol, progesterone, anti-Mullerian hormone (AMH), insulin, glucose, follicle number, and size. Results:In women with PCOS, mean antral follicle count (AFC) was greater than that of controls, although the size of cohort follicles within individual subjects was not correlated to 17-OHP responses. The numbers of 2- to 3-mm and 3- to 4-mm follicles in PCOS were significantly greater than in controls, whereas differences between larger follicles were not observed. Increased AMH in PCOS was correlated to AFC, but not 17-OHP responses. Insulin sensitivity did not correlate to r-hCG‒stimulated 17-OHP after adjustment for body mass index. Conclusions:17-OHP responses to hCG in individuals with PCOS were not correlated to the distribution of antral follicles. Greater numbers of small antral follicles in women with PCOS than in controls suggest an extension of accelerated growth from the preantral stage

LSD1-mediated enhancer silencing attenuates retinoic acid signalling during pancreatic endocrine cell development.

Developmental progression depends on temporally defined changes in gene expression mediated by transient exposure of lineage intermediates to signals in the progenitor niche. To determine whether cell-intrinsic epigenetic mechanisms contribute to signal-induced transcriptional responses, here we manipulate the signalling environment and activity of the histone demethylase LSD1 during differentiation of hESC-gut tube intermediates into pancreatic endocrine cells. We identify a transient requirement for LSD1 in endocrine cell differentiation spanning a short time-window early in pancreas development, a phenotype we reproduced in mice. Examination of enhancer and transcriptome landscapes revealed that LSD1 silences transiently active retinoic acid (RA)-induced enhancers and their target genes. Furthermore, prolonged RA exposure phenocopies LSD1 inhibition, suggesting that LSD1 regulates endocrine cell differentiation by limiting the duration of RA signalling. Our findings identify LSD1-mediated enhancer silencing as a cell-intrinsic epigenetic feedback mechanism by which the duration of the transcriptional response to a developmental signal is limited

Ultradian, circadian and seasonal rhythms in cortisol secretion and adrenal responsiveness to ACTH and yarding in unrestrained red deer (Cervus elaphus) stags

Seasonal changes in the activity and responsiveness of the adrenal gland in red deer (Cervus elaphus) stags were quantified by measuring 24 h endogenous cortisol secretory profiles and plasma cortisol responses to either administration of exogenous ACTH or a standardised stressor during November (period of velvet growth), February (pre-rut), April (mid-rut) and July (post-rut) (southern hemisphere) using a remote blood sampling device (DracPac). Ultradian rhythms in the concentration of plasma cortisol were observed resulting from the episodic secretion of cortisol from the adrenal cortex at a mean rate of 0.8 pulses/h. Circadian rhythms in plasma cortisol concentrations were also found in 11 out of the 20 complete 24 h profiles (mean amplitude, 3.8+/-1.4 ng/ml). Seasonal rhythms in mean 24 h plasma cortisol concentrations and cortisol pulse parameters were also observed. Mean 24 h plasma cortisol concentrations were higher in November (12.5+/-1.0 ng/ml) than in February (6.3+/-1.0 ng/ml), April (4.0+/-1.0 ng/ml) or July (4.2+/-1. 0 ng/ml). Cortisol pulse height, nadir and amplitude were all significantly higher in November than at other times of the year (P<0.01). Peak cortisol concentrations following infusion of ACTH(1-24) (0.04 IU kg(-1)) were higher (P<0.05) in November (55.8+/-2.7 ng/ml) and lower (P<0.001) in April (33.7+/-1.8 ng/ml) than those in February and July (48.7+/-2.0 ng/ml and 45.4+/-2.0 ng/ml respectively). The area under the cortisol response curve was significantly smaller (P<0.05) in April (266.6+/-15.3 ng/ml/190 min) than at other times of the year (February, 366.1+/-15.3 ng/ml/190 min; July, 340.7+/-15.3 ng/ml/190 min and November, 387.8+/-21.2 ng/ml/190 min). These data demonstrate that the adrenal gland of the red deer stag exhibits ultradian, circadian and seasonal rhythms in activity, and that its responsiveness to ACTH varies with season. November, a period of reproductive quiescence in the southern hemisphere, with new antler growth and rapid weight gain, is associated with higher mean plasma cortisol concentrations and a greater responsiveness to exogenous ACTH. In contrast, the breeding season is associated with lower adrenal activity and responsiveness

Prenatal programming of neuroendocrine reproductive function

It is now well recognized that the gestational environment can have long-lasting effects not only on the life span and health span of an individual but also, through potential epigenetic changes, on future generations. This article reviews the “prenatal programming” of the neuroendocrine systems that regulate reproduction, with a specific focus on the lessons learned using ovine models. The review examines the critical roles played by steroids in normal reproductive development before considering the effects of prenatal exposure to exogenous steroid hormones including androgens and estrogens, the effects of maternal nutrition and stress during gestation, and the effects of exogenous chemicals such as alcohol and environment chemicals. In so doing, it becomes evident that, to maximize fitness, the regulation of reproduction has evolved to be responsive to many different internal and external cues and that the GnRH neurosecretory system expresses a degree of plasticity throughout life. During fetal life, however, the system is particularly sensitive to change and at this time, the GnRH neurosecretory system can be “shaped” both to achieve normal sexually differentiated function but also in ways that may adversely affect or even prevent “normal function”. The exact mechanisms through which these programmed changes are brought about remain largely uncharacterized but are likely to differ depending on the factor, the timing of exposure to that factor, and the species. It would appear, however, that some afferent systems to the GnRH neurons such as kisspeptin, may be critical in this regard as it would appear to be sensitive to a wide variety of factors that can program reproductive function. Finally, it has been noted that the prenatal programming of neuroendocrine reproductive function can be associated with epigenetic changes, which would suggest that in addition to direct effects on the exposed offspring, prenatal programming could have transgenerational effects on reproductive potential

Circadian Entrainment Triggers Maturation of Human In Vitro Islets

Stem-cell-derived tissues could transform disease research and therapy, yet most methods generate functionally immature products. We investigate how human pluripotent stem cells (hPSCs) differentiate into pancreatic islets in vitro by profiling DNA methylation, chromatin accessibility, and histone modification changes. We find that enhancer potential is reset upon lineage commitment and show how pervasive epigenetic priming steers endocrine cell fates. Modeling islet differentiation and maturation regulatory circuits reveals genes critical for generating endocrine cells and identifies circadian control as limiting for in vitro islet function. Entrainment to circadian feeding/fasting cycles triggers islet metabolic maturation by inducing cyclic synthesis of energy metabolism and insulin secretion effectors, including antiphasic insulin and glucagon pulses. Following entrainment, hPSC-derived islets gain persistent chromatin changes and rhythmic insulin responses with a raised glucose threshold, a hallmark of functional maturity, and function within days of transplantation. Thus, hPSC-derived tissues are amenable to functional improvement by circadian modulation

Regulation of reproduction via tight control of gonadotropin hormone levels.

Mammalian reproduction is controlled by the hypothalamic-pituitary-gonadal axis. GnRH from the hypothalamus regulates synthesis and secretion of gonadotropins, LH and FSH, which then control steroidogenesis and gametogenesis. In females, serum LH and FSH levels exhibit rhythmic changes throughout the menstrual or estrous cycle that are correlated with pulse frequency of GnRH. Lack of gonadotropins leads to infertility or amenorrhea. Dysfunctions in the tightly controlled ratio due to levels slightly outside the normal range occur in a larger number of women and are correlated with polycystic ovaries and premature ovarian failure. Since the etiology of these disorders is largely unknown, studies in cell and mouse models may provide novel candidates for investigations in human population. Hence, understanding the mechanisms whereby GnRH regulates gonadotropin hormone levels will provide insight into the physiology and pathophysiology of the reproductive system. This review discusses recent advances in our understanding of GnRH regulation of gonadotropin synthesis