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The molecular biology of sporadic acromegaly 散发性肢端肥大症的分子生物学研究
IF 7.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-05-01 DOI: 10.1016/j.beem.2024.101895
Daniel Marrero-Rodríguez (Associate Researcher), Alberto Moscona-Nissan, Jessica Sidauy-Adissi, Fabian Haidenberg-David, Esbeydi Jonguitud-Zumaya, Leonel de Jesus Chávez-Vera, Florencia Martinez-Mendoza, Keiko Taniguchi-Ponciano (Associate Researcher), Moises Mercado (Endocrinologist, Full Professor)

GH-secreting tumors represent 15 % to 20 % of all pituitary neuroendocrine tumors (pitNETs), of which 95 % occur in a sporadic context, without an identifiable inherited cause. Recent multi-omic approaches have characterized the epigenomic, genomic, transcriptomic, proteomic and kynomic landscape of pituitary tumors. Transcriptomic analysis has allowed us to discover specific transcription factors driving the differentiation of pituitary tumors and gene expression patterns. GH-secreting, along with PRL- and TSH-secreting pitNETs are driven by POU1F1; ACTH-secreting tumors are determined by TBX19; and non-functioning tumors, which are predominantly of gonadotrope differentiation are conditioned by NR5A1. Upregulation of certain miRNAs, such as miR-107, is associated with tumor progression, while downregulation of others, like miR-15a and miR-16–1, correlates with tumor size reduction. Additionally, miRNA expression profiles are linked to treatment resistance and clinical outcomes, providing insights into potential therapeutic targets. Specific somatic mutations in GNAS, PTTG1, GIPR, HGMA2, MAST and somatic variants associated with cAMP, calcium signaling, and ATP pathways have also been associated with the development of acromegaly. This review focuses on the oncogenic mechanisms by which sporadic acromegaly can develop, covering a complex series of molecular alterations that ultimately alter the balance between proliferation and apoptosis, and dysregulated hormonal secretion.

分泌 GH 的肿瘤占所有垂体神经内分泌肿瘤(pitNETs)的 15% 至 20%,其中 95% 为散发性,无可辨认的遗传原因。最近的多组学方法描述了垂体瘤的表观基因组、基因组、转录组、蛋白质组和基因组特征。转录组分析使我们能够发现驱动垂体瘤分化的特定转录因子和基因表达模式。分泌 GH、PRL 和 TSH 的垂体瘤由 POU1F1 驱动;分泌 ACTH 的肿瘤由 TBX19 决定;而主要由促性腺激素分化的无功能肿瘤则由 NR5A1 决定。某些 miRNA(如 miR-107)的上调与肿瘤进展有关,而其他 miRNA(如 miR-15a 和 miR-16-1)的下调则与肿瘤缩小有关。此外,miRNA 的表达谱与治疗耐药性和临床结果有关,为潜在的治疗靶点提供了洞察力。、、、和与 cAMP、钙信号转导和 ATP 通路相关的体细胞突变也与肢端肥大症的发生有关。本综述重点探讨散发性肢端肥大症的致癌机制,包括一系列复杂的分子改变,这些改变最终改变了增殖和凋亡之间的平衡,以及激素分泌失调。
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引用次数: 0
The clinical and biochemical spectrum of ectopic acromegaly 异位肢端肥大症的临床和生化谱系
IF 7.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-05-01 DOI: 10.1016/j.beem.2024.101877
Patricia Fainstein-Day (Associate Physician, Professor and Investigator) , Tamara Estefanía Ullmann (Associate Physician) , Mercedes Corina Liliana Dalurzo (Associate Physician) , Gustavo Emilio Sevlever (Director, Teaching, Investigator) , David Eduardo Smith (Staff Surgeon)

Ectopic acromegaly is a rare condition caused by extrapituitary central or peripheral neuroendocrine tumours (NET) that hypersecrete GH or, more commonly, GHRH. It affects less than 1% of acromegaly patients and a misdiagnosis of classic acromegaly can lead to an inappropriate pituitary surgery. Four types of ectopic acromegaly have been described: 1) Central ectopic GH-secretion: Careful cross-sectional imaging is required to exclude ectopic pituitary adenomas. 2) Peripheral GH secretion: Extremely rare. 3) Central ectopic GHRH secretion: Sellar gangliocytomas immunohistochemically positive for GHRH are found after pituitary surgery. 4) Peripheral GHRH secretion: The most common type of ectopic acromegaly is due to peripheral GHRH-secreting NETs. Tumours are large and usually located in the lungs or pancreas. Pituitary hyperplasia resulting from chronic GHRH stimulation is difficult to detect or can be misinterpreted as pituitary adenoma in the MRI. Measurement of serum GHRH levels is a specific and useful diagnostic tool. Surgery of GHRH-secreting NETs is often curative.

异位肢端肥大症是一种罕见的疾病,由垂体外中枢或外周神经内分泌肿瘤(NET)引起,可分泌过多 GH 或更常见的 GHRH。它影响不到1%的肢端肥大症患者,典型肢端肥大症的误诊可能导致不适当的垂体手术。异位肢端肥大症有四种类型:1)中枢异位 GH 分泌:需要进行仔细的横断面成像以排除异位垂体腺瘤。2)外周性 GH 分泌:极为罕见。3) 中枢异位 GHRH 分泌:垂体手术后发现ellar神经节细胞瘤,免疫组化对GHRH呈阳性反应。4) 外周 GHRH 分泌:最常见的异位肢端肥大症是由外周分泌 GHRH 的 NETs 引起的。肿瘤较大,通常位于肺部或胰腺。慢性 GHRH 刺激导致的垂体增生很难被发现,或在核磁共振成像中被误诊为垂体腺瘤。测量血清 GHRH 水平是一种特异而有用的诊断工具。分泌GHRH的NET手术通常可以治愈。
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引用次数: 0
Vitamin D deficiency or resistance and hypophosphatemia 维生素 D 缺乏或抵抗力低下和低磷血症
IF 7.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-01-30 DOI: 10.1016/j.beem.2024.101876
Vijaya Sarathi , Melkunte Shanthaiah Dhananjaya , Manjiri Karlekar , Anurag Ranjan Lila

Vitamin D is mainly produced in the skin (cholecalciferol) by sun exposure while a fraction of it is obtained from dietary sources (ergocalciferol). Vitamin D is further processed to 25-hydroxyvitamin D and 1,25-dihydroxy vitamin D (calcitriol) in the liver and kidneys, respectively. Calcitriol is the active form which mediates the actions of vitamin D via vitamin D receptor (VDR) which is present ubiquitously. Defect at any level in this pathway leads to vitamin D deficient or resistant rickets. Nutritional vitamin D deficiency is the leading cause of rickets and osteomalacia worldwide and responds well to vitamin D supplementation. Inherited disorders of vitamin D metabolism (vitamin D-dependent rickets, VDDR) account for a small proportion of calcipenic rickets/osteomalacia. Defective 1α hydroxylation of vitamin D, 25 hydroxylation of vitamin D, and vitamin D receptor result in VDDR1A, VDDR1B and VDDR2A, respectively whereas defective binding of vitamin D to vitamin D response element due to overexpression of heterogeneous nuclear ribonucleoprotein and accelerated vitamin D metabolism cause VDDR2B and VDDR3, respectively. Impaired dietary calcium absorption and consequent calcium deficiency increases parathyroid hormone in these disorders resulting in phosphaturia and hypophosphatemia. Hypophosphatemia is a common feature of all these disorders, though not a sine-qua-non and leads to hypomineralisation of the bone and myopathy. Improvement in hypophosphatemia is one of the earliest markers of response to vitamin D supplementation in nutritional rickets/osteomalacia and the lack of such a response should prompt evaluation for inherited forms of rickets/osteomalacia.

维生素 D 主要通过日晒在皮肤中产生(胆钙化醇),也有一部分从膳食中获取(麦角钙化醇)。维生素 D 在肝脏和肾脏中分别进一步加工成 25-羟基维生素 D 和 1,25-二羟基维生素 D(降钙素三醇)。降钙三醇是通过维生素 D 受体(VDR)介导维生素 D 作用的活性形式,而维生素 D 受体无处不在。这一途径中任何一个环节的缺陷都会导致维生素 D 缺乏症或抗性佝偻病。营养性维生素 D 缺乏症是全球佝偻病和骨软化症的主要病因,对维生素 D 补充剂反应良好。遗传性维生素 D 代谢紊乱(维生素 D 依赖性佝偻病,VDDR)占钙源性佝偻病/骨软化症的一小部分。维生素 D 的 1α 羟基化、维生素 D 的 25 羟基化和维生素 D 受体的功能缺陷分别导致 VDDR1A、VDDR1B 和 VDDR2A,而异质核核糖核蛋白的过度表达导致维生素 D 与维生素 D 反应元件的结合缺陷以及维生素 D 代谢加速则分别导致 VDDR2B 和 VDDR3。在这些疾病中,膳食钙吸收障碍和随之而来的钙缺乏会增加甲状旁腺激素,从而导致磷酸盐血症和低磷酸盐血症。低磷酸盐血症是所有这些疾病的共同特征,但并不是必要条件,它会导致骨骼矿化不足和肌病。低磷血症的改善是营养性佝偻病/骨软化症患者对维生素 D 补充剂反应的最早标志之一,如果缺乏这种反应,则应及时评估是否存在遗传性佝偻病/骨软化症。
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引用次数: 0
Revisiting hypophosphatemic rickets/osteomalacia 重温低磷酸盐血症佝偻病/骨软化症
IF 7.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-01-06 DOI: 10.1016/j.beem.2024.101859
Tushar Bandgar, Nalini Shah
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引用次数: 0
Premature ovarian insufficiency, early menopause, and induced menopause 卵巢早衰、更年期提前、诱发更年期。
IF 7.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-01-01 DOI: 10.1016/j.beem.2023.101823
Haitham Hamoda Consultant Gynaecologist, Subspecialist in Reproductive Medicine and Surgery , Angela Sharma BMS Menopause Specialist, Co-founder and Director of Spiced Pear Health, Clinical Sexologist

Premature ovarian insufficiency (POI) is a condition in which there is a decline in ovarian function in women who are younger than 40 years resulting in a hypo-oestrogenic state with elevated gonadotrophins and oligomenorrhoea/amenorrhoea. This leads to short term complications of menopausal symptoms and long-term effects on bone and cardiovascular health, cognition as well as the impact of reduced fertility and sexual function associated with this condition. It is managed by sex steroid replacement either with HRT or combined hormonal contraception until the age of natural menopause (51) and this can provide a beneficial role with both symptom control and minimising the long-term adverse effects associated with this condition. Women who undergo a menopause between 40 and 45 years are deemed to have an “early menopause”. The limited data available for this group suggest that they also have an increased morbidity if not adequately treated with hormone therapy. As such, women who have an early menopause should be managed in a similar way to those with POI, with the recommendation that they should take HRT at least until the natural age of menopause. This is the same for induced menopause that is caused by medical or surgical treatment that impacts the ovaries. It is important to ensure early diagnosis and access to specialist care to help support and manage these patients to reduce the symptoms and risks of long-term complications. This review looks at the diagnosis, causes, short and long-term complications and management of POI, early and induced menopause.

卵巢早搏功能不全(POI)是指40岁以下女性的卵巢功能下降,导致促性腺激素升高和月经过少/闭经的低雌激素状态。这会导致更年期症状的短期并发症,对骨骼和心血管健康、认知的长期影响,以及与这种情况相关的生育能力和性功能下降的影响。它是通过性类固醇替代激素替代疗法或联合激素避孕来控制的,直到自然更年期(51岁),这可以在控制症状和最大限度地减少与这种情况相关的长期不良影响方面发挥有益作用。更年期在40到45岁之间的女性被认为是“提前更年期”。该组可用的有限数据表明,如果没有充分的激素治疗,他们的发病率也会增加。因此,绝经早期的女性应该以与POI患者类似的方式进行管理,建议她们至少在自然绝经年龄之前服用激素替代疗法。对于由影响卵巢的药物或手术治疗引起的诱导性更年期也是如此。重要的是要确保早期诊断和获得专业护理,以帮助支持和管理这些患者,从而降低症状和长期并发症的风险。这篇综述着眼于POI、早期和诱导性更年期的诊断、原因、短期和长期并发症以及管理。
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引用次数: 0
Cardiovascular health and the menopause, metabolic health 心血管健康与更年期、新陈代谢健康
IF 7.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-01-01 DOI: 10.1016/j.beem.2023.101781
Panagiotis Anagnostis (Consultant Endocrinologist) , John C. Stevenson (Consultant Metabolic Physician)

Estrogen depletion following menopause predisposes to increased risk of cardiovascular disease (CVD), mainly due to ischemic heart disease. This is mostly evident in cases with premature menopause. The pathophysiological basis for this atherosclerotic process is the accumulation of several risk factors, such as abdominal obesity, atherogenic dyslipidemia, insulin resistance and arterial hypertension. The presence of vasomotor symptoms may further augment this risk, especially in women younger than 60 years. Menopausal hormone therapy (MHT) exerts many beneficial effects on lipid profile and glucose homeostasis as well as direct arterial effects, and may reduce CVD risk if initiated promptly (i.e.,<60 years or within ten years of the final menstrual period). Transdermal estradiol and micronized progesterone or dydrogesterone are the safest regimens in terms of venous thromboembolic events (VTE) and breast cancer risk. In any case, an individualized approach, taking into account the patient’s total CVD, VTE and breast cancer risk, is recommended.

绝经后雌激素耗竭易导致心血管疾病(CVD)风险增加,主要是缺血性心脏病。这主要表现在过早绝经的病例中。动脉粥样硬化过程的病理生理学基础是多种危险因素的累积,如腹部肥胖、致动脉粥样硬化性血脂异常、胰岛素抵抗和动脉高血压。血管运动症状的存在可能会进一步增加这种风险,尤其是对 60 岁以下的女性而言。更年期激素疗法(MHT)对血脂状况和葡萄糖稳态有许多有益的影响,对动脉也有直接影响,如果及时开始治疗(即 60 岁或末次月经后 10 年内),可降低心血管疾病风险。就静脉血栓栓塞事件(VTE)和乳腺癌风险而言,透皮雌二醇和微粒化黄体酮或地屈孕酮是最安全的方案。无论如何,建议根据患者的心血管疾病、静脉血栓栓塞和乳腺癌的总风险,采取个体化的治疗方法。
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引用次数: 0
Best practice & research clinical endocrinology & metabolism focusing on the menopause – Diagnostic and therapeutic strategies 最佳实践与研究 临床内分泌学与新陈代谢,聚焦更年期--诊断与治疗策略
IF 7.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-01-01 DOI: 10.1016/j.beem.2023.101856
Katie A. Barber (GP and Accredited Menopause Specialist, Clinical Lead, Clinical Director)
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引用次数: 0
Menopause: Physiology, definitions, and symptoms 更年期:生理、定义和症状
IF 7.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-01-01 DOI: 10.1016/j.beem.2023.101855
Charlotte Gatenby (Community Sexual and Reproductive HealthcareTrainee) , Paul Simpson (Consultant Gynaecologist)

The menopause transition is usually a gradual process occurring over many years, caused by the cessation of ovarian reproductive function, resulting in the end of menstrual bleeding. In the peri-menopause, ovarian function and therefore the production of the hormones oestrogen, progesterone and testosterone can fluctuate greatly, leading to a wide variety of symptoms, affecting multiple organ systems. Menopause and the management of its associated symptoms can be very challenging for patients and clinicians alike and can negatively impact quality of life. The management options include lifestyle adjustment, talking therapies, dietary supplements as well as prescribed medications, including hormone replacement therapy. The UK’s average life expectancy for women is approximately 81 years. Therefore, women will now live up to a third of their life being either peri- or postmenopausal. Thus, understanding and treating, where possible, the symptoms of menopause is essential to reduce the burden associated with this physiological state.

更年期的过渡通常是一个渐进的过程,历经多年,由卵巢生殖功能的停止引起,导致月经出血的结束。在围绝经期,卵巢功能以及雌激素、孕激素和睾酮等激素的分泌会发生很大波动,从而导致各种症状,影响多个器官系统。治疗方法包括调整生活方式、谈话疗法、膳食补充剂以及处方药,其中包括激素替代疗法。因此,妇女一生中有多达三分之一的时间是在绝经期前后或绝经后。因此,在可能的情况下,了解并治疗更年期症状对于减轻这种生理状态带来的负担至关重要。
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引用次数: 0
Non-oestrogen-based and complementary therapies for menopause 以非雌激素为基础的更年期辅助疗法
IF 7.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-01-01 DOI: 10.1016/j.beem.2023.101819
Bassel H. Al Wattar (Consultant Obstetrician and Gynaecologist) , Vikram Talaulikar (Associate Specialist in Reproductive Medicine & Hon Associate Professor in Women's Health)

Women are living a significant portion of their adult lives in the post-reproductive phase, and many seek help for debilitating menopausal symptoms. Every individual’s experience of menopausal transition is unique. Adopting a holistic approach to managing the menopause using a combination of lifestyle, hormonal, and non-hormonal interventions is key to maximise the quality of life of affected women. However, many opt to use non hormonal options or have contraindications to using hormonal therapy. Studies have shown that several pharmacological non-hormonal medications such as SSRIs, SSRI/SNRIs, Gabapentin, and Pregabalin are effective for managing vasomotor symptoms as well as other menopausal symptoms. Their main side effects are dry mouth, nausea, constipation, reduced libido, and loss of appetite. Clonidine is the only non-hormonal drug which is licenced for control of vasomotor symptoms in the UK, but has several side effects including dizziness and sleep disturbance. Cognitive Behavioural Therapy is recommended as a treatment for anxiety, sleep problems and vasomotor symptoms related to menopausal transition. Evidence for clinical efficacy and safety of herbal remedies and alternative therapies remains weak. Studies with neurokinin receptor 3 antagonists on women with hot flushes have shown improvement in vasomotor symptoms and results of large-scale studies are awaited.

女性成年后的大部分时间都生活在生育后阶段,许多人都会因衰弱的更年期症状而寻求帮助。每个人的更年期经历都是独一无二的。采用生活方式、激素和非激素干预相结合的综合方法来管理更年期,是最大限度地提高更年期妇女生活质量的关键。然而,许多人选择使用非激素疗法,或者有使用激素疗法的禁忌症。研究表明,一些药理非激素药物,如 SSRIs、SSRI/SNRIs、加巴喷丁和普瑞巴林,对控制血管运动症状和其他更年期症状非常有效。它们的主要副作用是口干、恶心、便秘、性欲减退和食欲不振。氯硝西泮是英国唯一获准用于控制血管运动症状的非激素类药物,但有多种副作用,包括头晕和睡眠障碍。建议采用认知行为疗法来治疗与绝经过渡期有关的焦虑、睡眠问题和血管运动症状。草药疗法和替代疗法的临床疗效和安全性证据仍然薄弱。对潮热妇女使用神经激肽受体 3 拮抗剂进行的研究显示,血管运动症状有所改善,但大规模研究的结果仍在等待中。
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引用次数: 0
New advances in menopause symptom management 更年期症状管理的新进展
IF 7.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-01-01 DOI: 10.1016/j.beem.2023.101774
Kanyada Koysombat MBBS BSc (Specialist Registrar in Endocrinology and Diabetes / NIHR Academic Clinical Fellow) , Patrick McGown MBBS BSc (Specialist Registrar in Endocrinology and Diabetes) , Sandhi Nyunt MBBS MSc (Specialist Registrar in Endocrinology and Diabetes) , Ali Abbara MBBS BSc PhD (Clinical Senior Lecturer / Honorary Consultant in Endocrinology / NIHR Clinician Scientist) , Waljit S. Dhillo MBBS BSc PhD (Professor in Endocrinology and Metabolism / Consultant Endocrinologist / NIHR Senior Investigator, Dean of the NIHR Academy, Head of Division of Diabetes, Endocrinology and Metabolism, ICHT Divisional Director of Research for the Division of Medicine & Integrated Care)

Vasomotor symptoms (VMS) are characteristic of menopause experienced by over 75% of postmenopausal women with significant health and socioeconomic implications. Although the average duration of symptoms is seven years, 10% of women experience symptoms for more than a decade. Although menopausal hormone therapy (MHT) remains an efficacious and cost-effective treatment, its use may not be suitable in all women, such as those at an increased risk of breast cancer or gynaecological malignancy. The neurokinin B (NKB) signaling pathway, together with its intricate connection to the median preoptic nucleus (MnPO), has been postulated to provide integrated reproductive and thermoregulatory responses, with a central role in mediating postmenopausal VMS. This review describes the physiological hypothalamo-pituitary-ovary (HPO) axis, and subsequently the neuroendocrine changes that occur with menopause using evidence derived from animal and human studies. Finally, data from the latest clinical trials using novel therapeutic agents that antagonise NKB signaling are reviewed.

血管运动症状(VMS)是 75% 以上绝经后妇女的更年期特征,对健康和社会经济有重大影响。虽然症状的平均持续时间为 7 年,但有 10% 的妇女症状持续时间超过 10 年。尽管绝经激素疗法(MHT)仍然是一种有效且经济的治疗方法,但并非所有妇女都适合使用这种疗法,例如那些罹患乳腺癌或妇科恶性肿瘤风险较高的妇女。据推测,神经激肽 B(NKB)信号通路及其与视前中核(MnPO)的复杂联系可提供综合的生殖和体温调节反应,并在介导绝经后 VMS 方面发挥核心作用。这篇综述介绍了下丘脑-垂体-卵巢(HPO)轴的生理结构,并随后利用动物和人体研究中获得的证据,介绍了随着绝经而发生的神经内分泌变化。最后,还回顾了使用拮抗 NKB 信号传导的新型治疗药物进行的最新临床试验数据。
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引用次数: 0
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