Anterior Pituitary Disease Adenohypophysis Disease

Presentation on theme: “Anterior Pituitary Disease Adenohypophysis Disease”— Presentation transcript:

1 Anterior Pituitary Disease Adenohypophysis Disease
余叶蓉 Department of Endocrinology and Metabolism West China Hospital Sichuan University

2 主要内容 下丘脑-垂体相关基础知识 腺垂体疾病的分类 腺垂体疾病的诊断思路 腺垂体疾病的治疗原则 病例讨论：垂体前叶功能减退症

3 The pituitary gland is located within the sella turcica ventral to the diaphragma sella

4 The hypothalamus – pituitary complex is the “master gland”，it orchestrates the regulatory functions of multiple other endocrine glands.

5 Vascular and Neural Connections Between the Hypothalamus and Pituitary
The hypothalamic nuclei produce hormones that traverse the portal system and impinge on anterior pituitary cells to regulate pituitary hormone secretion. Posterior pituitary hormones are derived from direct neural extensions

6 HYPOTHALAMUS–PITUITARY HORMONES Two major groups of hormones secreted: Inhibiting and Releasing
Hypothalamic Hormone Target Cell (Hormone) GHRH Somatotrope (+) GH Somatostatin Somatotrope (-) GH Thyrotrope (-) TSH Dapamine Lactotrope (-) PRL TRH Thyrotrope (+) TSH Lactotrope (+) PRL GnRH Gonadotrope (+) FSH Gonadotrope (+) LH CRH Corticotrope (+) ACTH

7 HYPOTHALAMUS–PITUITARY HORMONES Feedback Regulation

8 HORMONAL FEEDBACK REGULATION
Autonomous Secretion of Trophic H. or …… Primary Failure of target Endo. Organ High Normal Range Trophic Hormone Level Normal Autonomous Secretion of Target Endo. Organ Trophic H. Failure Low Low Normal High Target Gland Hormone Level

9 Case Study 38岁女性，因闭经半年就诊。  血E2水平降低 FSH/LH水平增高 闭经的原因？  血E2水平降低

10 DISORDERS OF ANTERIOR PITUITARY DISEASE

11 Anterior pituitary diseases can be divided into three major types of conditions
(1) Hormone overproduction(Excess): Hyperfunction disorder (2) Hormone underproduction(Deficiency): Hypofunction disorder (3) Altered tissue response to hormone: hormone resistance

12 1. ANTERIOR PITUITARY HYPERFUNCTION DISORDERS
What happens if: TOO MUCH Prolactin secretion? Prolactin-Secreting Adenomas GH-cell adenoma ACTH-Secreting Tumors TSH-Secreting Tumors

13 2. ANTERIOR PITUITARY HYPOFUNCTION DISORDERS
Most examples of hormone deficiency states can be attributed to anterior pituitary destruction caused by: Surgery Tumor infiltration Infarction Inflammation Infection Autoimmunity Hemorrhage Genetic abnormalities

14 3. HORMONE RESISTANCE SYNDROME
Glucocorticoid Resistance What happens if generalized GC resistance?

15 Approach to the Patients with Suspected Pituitary Disease

16 DIAGNOSIS of PITUITARY DISEASE
Suggestion of pituitary disease Symptoms, signs, others. H.measurement & endo. test Functional evaluating of pituitary.G. Hyper/hypo-function No Yes Localization of the lesion Etiology study ◆ Cytologic studies as semen analysis for hypogonadism/ or infertility ; fine needle biopsy for thyroid nodule . ◆ Genetic studies as karyotype exmination for Klinefilter Syndrome (47,XXY ) . genome mapping , microarray for G , mutation ◆ Immunologic studies Investigation of antithyroid globulin Ab ＆ antithyroid peroxidase Ab in Hashimoto’s thyroiditis . ◆ GAD-Ab for LADA . CT, MRI, and others Etiological diagnosis

17 DIAGNOSIS of PITUITARY DISEASE
HORMONE MEASUREMENTS Simultaneous measurement of H./effector pairs is necessary for assessment pituitary function. LH/FSH — E2 / T TSH — T4 ACTH — Cortisol The biorhythms of hormones, and factors that can affect their secretion such as sleep, meals, and medications, must be considered. ACTH / Cortiso , GH / IGF-1, PRL

18 Hypothalamus–Pituitary Hormones Biorhythms
Pituitary hormones are secreted in a pulsatile manner and entrained to sleep and the circadian cycle. Recognition of these rhythms is important for endocrine testing and treatment.

19 DIAGNOSIS of PITUITARY DISEASE
DYNAMIC ENDOCRINE TESTS Dynamic test involve the stimulation or suppression of H. production Dynamic test are useful for detecting subtle endocrine dysfunction and for localizing the site of the defect. Stimulation tests are used when hypofunction is suspected and are designed to assess the reserve capacity to form and secrete H. Suppression test are used when hyperfunction is suspected and are designed to determine whether negative feedback control is intact

20 Dexamethasone Suppression Tests
Case Study – 2 Anterior pituitary ACTH Adrenal gland Cortisol Targets tissue + 28岁女性患者，因近2年体 重逐渐增加，伴双下肢凹陷 性水肿及月经紊乱就诊。 查体：血压140/98mmHg， 满月面，上唇可见小须。向 心性肥胖。下腹部皮肤可见 粗大紫纹。 疑诊“库欣综合征”，查PTC （8Am） 520 nmol/L （Ref nmol/L） – –  Dexamethasone  Dexamethasone Suppression Tests

21 THERAPEUTIC STRATEGIES OF ANTERIOR PITUIATRY DISEASE

22 THERAPEUTIC STRATEGIES OF ANTERIOR PITUIATRY DISEASES
Treatment of hyperfunction Tumor: Remove a tumor by surgery Destroy a tumor by radiation (radiotherapy) Medication: Use chemical agents to block or inhibit the excessive biosynthesis or release of the hormone

23 THERAPEUTIC STRATEGIES OF ANTERIOR PITUIATRY DISEASES
Treatment of hypofunction ◇ The basic form of remedy is replacement therapy by using a hormone defected. ◇ Ablation of a tumor which destroys or compresses the endocrine tissue.

24 HYPOPITUITARISM Case Study

25 病历摘要 65岁女性，因闭经、乏力、脱发、怕冷30年，发热、咳嗽 伴头昏、口齿不清1周入院。
入院前30年，患者分娩时难产大出血，昏迷，经抢救后好 转。但产后无乳汁分泌，闭经，逐渐出现阴毛、腋毛脱落， 性欲减退，乏力、纳差、怕冷，易感冒，记忆力下降。 入院前10年渐出现全身浮肿，以胫前及颜面部明显。 入院前1周因受凉感冒后出现头昏、发热（T 38.5）、咽痛、 咳嗽，伴乏力、纳差及怕冷加重，在当地医院予抗感染治 疗后咽痛、咳嗽渐缓解，但乏力加重，伴恶心呕吐，不能 进食。 4小时前出现心悸、视物模糊、嗜睡，当地医院转诊至我院。 患病以来，患者体重增加10Kg。

26 病历摘要 查体：T 36.0， P 78次/分， R 16次/分， BP 100/60mmHg
慢性重病容，贫血貌，表情淡漠，神志恍惚，不语。 全身皮肤苍黄、干燥，四肢皮温低，颜面浮肿，阴毛、腋毛脱落。 甲状腺不大，双肺叩诊清音， 双下肺可闻及细湿罗音。叩诊 心界不大，心率78次/分，律齐， 各瓣膜区未闻及病理性杂音。 腹部查体无阳性发现。 双下肢非凹陷性水肿伴胫前色 素沉着。

27 Hypopituitarism Definition Major causes
Mass lesions – pituitary adenomas, other benign tumors, cysts Pituitary surgery Pituitary radiation Infiltrative lesions – lymphocytic hypophysitis, hemochromatosis Infarction – Sheehan syndrome Apoplexy Genetic diseases Definition Hypopituitarism refers to decreased secretion of pituitary hormones Hypopituitarism can result from diseases of the pituitary gland or from diseases of the hypothalamus. Major causes Pituitary diseases Hypothalamic diseases Mass lesions – benign and malignant tumors Radiation – for CNS and nasopharyngeal malignancies Infiltrative lesions – Langerhans cell histiocytosis Trauma – fracture of skull baseInfections – TB meningitis

28 Anterior Pituitary Infarction – Sheehan syndrome
The anterior pituitary lacks a major direct arterial blood supply; it is bathed in a dense capillary network : hypothalamic-hypophyseal portal venous system The pituitary gland is enlarged in pregnancy and prone to infarction from hypovolemic shock

29 CLINICAL MANIFESTATIONS OF HYPOPITUITARISM
The clinical manifestations of hypopituitarism depend on the following factors: The rapidity with which a disease affects anterior pituitary cells The severity of the hormonal deficiency. The number of different anterior pituitary cells that are affected, leading to impairment in the secretion of one, a few, or all the pituitary hormones.

30 CLINICAL MANIFESTATIONS OF HYPOPITUITARISM ACTH Deficiency
Symptoms/signs Frequency, percent Weakness, tiredness, fatigue 100 Anorexia Gastrointestinal symptoms 92 Nausea 86 Vomiting 75 Constipation 33 Abdominal pain 31 Diarrhea 16 Muscle or joint pains 6-13 Weight loss or Weight gain The presentation of ACTH deficiency is that of the resulting cortisol deficiency What differences between ACTH deficiency and primary adrenal insufficiency? Salt wasting, volume contraction, hyperkalemia Hyperpigmentation Hypoglycemia

31 Pituitary-Adrenal Crisis
The syndrome of adrenal crisis may occur in the following situations: In a previously undiagnosed patient with pituitary of adrenal insufficiency who has been subjected to serious infection or other acute, major stress. In a patient with known pituitary or adrenal insufficiency who does not take more glucocorticoid during an infection or other major illness. Clinical and laboratory findings suggesting adrenal crisis: Nausea and vomiting with a history of weakness, tiredness, fatigue and anorexia Abdominal pain, so-called “acute abdomen” Unexplained hypoglycemia Unexplained fever Hyponatremia

32 Clinical Manifestations of Hypopituitarism TSH Deficiency
Similar to but sometimes milder than those of primary hypothyroidism Common symptoms: fatigue, cold intolerance, muscle cramps, headache, weight gain Mechanism Symptoms Signs Slowing of metabolic processes Fatigue and weakness Cold intolerance, Dyspnea on exertion Weight gain Cognitive dysfunction Constipation Slow movement and slow speech Delayed relaxation of tendon reflexes Bradycardia Carotenemia Accumulation of matrix substances Dry skin Hoarseness Edema Coarse skin Puffy facies and loss of eyebrows Periorbital edema Enlargement of the tongue Other Decreased hearing Myalgia and paresthesia Depression Menorrhagia Arthralgia Pubertal delay Diastolic hypertension Pleural and pericardial effusions

33 Hypothyroidism Crisis— myxedema coma
Myxedema coma is defined as severe hypothyroidism leading to symptoms related to slowing of function in multiple organs. Clinical features of myxedema coma: Decreased mental status Hypothermia Bradycardia Hyponatremia Hypoglycemia Hypotension Precipitating illness Hallmarks of myxedema coma

34 Clinical Manifestations of Hypopituitarism Gonadotropin Deficiency
In women: ovarian hypofunction— decreased E2 secretion Irregular periods or amenorrhea, anovulatory infertility, vaginal atrophy After several years, breast tissue decreases, bone mineral density declines In men: testicular hypofunction—infertility , decreased T secretion decreased energy and libido decreased bone mineral density Prolactin Deficiency The only known presentation of prolactin deficiency is the inability to lactate after delivery.

35 Clinical Manifestations of Hypopituitarism GH deficiency
In children: growth retardation (short stature) In adults: Changes in body composition: increased fat mass with a decrease in lean body mass

36 Clinical features of Sheehan’s syndrome
A history of postpartum hemorrhage so severe as to cause hypotension and require transfusion of multiple units of blood. In severe cases, lethargy, anorexia, weight loss, and inability to lactate developed during the first days or weeks after delivery. In less severe cases, failure of postpartum lactation and failure to resume menses in the weeks and months after delivery, and loss of sexual hair, as well as milder degrees of fatigue, anorexia, and weight loss. In mild cases, possible delay in recognition for many years after the inciting event. Eventual development of a small pituitary within a sella of normal size, sometimes read as an “empty sella” on MRI.

37 DIAGNOSIS OF HYPOPITUIATROSM
Biochemical diagnosis is made by demonstrating low levels of trophic hormones in the setting of low target hormone levels Each pituitary hormone must be tested separately. ACTH: Basal ACTH-Cortisol secretion (8:00Am-9:00Am) ACTH reserve: Stimulating Test TSH-T4 LH/FSH – E2/T(8:00Am-10:00Am) Basal GH – IGF-1, Stimulating test

39 TREATMENT OF HYPOPITUITARISM
The treatments of ACTH, TSH, and LH /FSH deficiencies are the same as the treatments of primary deficiencies of the respective target glands Treatment regimens that mimic physiologic hormone production allow for maintenance of satisfactory clinical homeostasis. Hormone replacement therapy, including glucocorticoids, thyroid hormone, sex steroids, and growth hormone, is usually free of complications.

40 Hormone Replacement Therapy
Trophic Hormone Deficit Hormone Replacement ACTH Hydrocortisone (10–25 mg /d.) or Prednisone (2.5mg – 5 mg A.M.) TSH L-Thyroxine (75 g –150 g daily) LH / FSH Males: Testosterone Undecanoate Capsule ( mg/d) Females: Estradiol (1mg–2mg qd  21d ) Progesterone (5–10 mg qd) on days 14–21 For fertility: human chorionic gonadotropins GH Adults: Somatotropin (0.3–1.0 mg SC qd) Children: Somatotropin [0.02–0.05 (mg/kg/d)] All doses shown should be individualized for specific patients and should be reassessed during stress, surgery, or pregnancy

41 The management of this patient
1st and 2nd day: Fluid therapy Hydrocortisone 100mg iv. 3rd and 4th day: Hydrocortisone 50mg iv L-Thyroxine 25g/d, po 5 day later: Prednisone 5mg/d, po The patient discharged one week later and follow up regularly at outpatient department.

42 小结-1：腺垂体疾病 下丘脑-腺垂体是内分泌系统的中枢器官。 下丘脑-腺垂体激素的分泌具有节律性
下丘脑-垂体-靶腺激素通过正负反馈调节而维持体内激素水平 于生理范围。 腺垂体疾病可大致分为三大类：激素分泌增多、激素分泌减 少、激素抵抗。 腺垂体激素分泌增多的主要原因是相关内分泌细胞肿瘤 腺垂体激素分泌减少的主要原因包括鞍区肿瘤、手术、放射 性治疗、梗死、浸润性病变、感染、炎症、基因突变等。 腺垂体疾病诊断步骤为：详细收集病史、查体、检测相关激 素水平及功能试验（功能诊断）、定位诊断（病因诊断）。 腺垂体疾病的治疗原则：1）去除病因；2）“削峰填谷”

43 小结-2：垂体前叶功能低下 定义：垂体前叶一项或多项激素分泌不足
病因：垂体或下丘脑区域的肿瘤、手术、放射性治疗、梗 死、浸润性病变、感染、炎症、基因突变等。 因产后大出血诱发腺垂体组织梗死者特称为席汉综合征 临床表现：主要为各相关靶激素缺乏的症状与体征 临床诊断：靶激素水平降低而相关促激素水平正常或降低 治疗原则：去除病因，长期激素替代治疗，终身随访

44 Case Study 17岁女性，因身材矮小、原发性闭经就诊。 自幼生长缓慢，智力较差。 当地医院头颅CT发现垂体体积增大，疑“垂体 肿瘤”
查体：面容虚浮，皮肤干燥脱屑，乳腺发育差， 积压乳房可见少量乳汁溢出。外阴呈幼女型， 未见阴毛。 Division of Endocrinology and Metabolism West China Hospital, SCU

45 Case Study 该病例存在的问题： 哪些疾病可出现上述表现？ 进一步需作哪些检查？ 原发性闭经伴第二性征不发育
智力差，生长迟缓，皮肤干燥，面容虚浮 溢乳，垂体体积增大，疑占位性病变 哪些疾病可出现上述表现？ 进一步需作哪些检查？

46 Case Study 患者相关激素检测结果：
HPG axis: E2: 1.8 pg/ml; (Ref. 5-54) ; P: 0.08ng/ml (Ref ); FSH: 2.9 mU/L (Ref ); LH: 3.4 mU/L(Ref ) PRL: 42.8 ng/ml (Ref. 6-29) HPT axis：FT3: 2.1pmol/L (Ref ); FT4: 5.2pmol/L (Ref ); TSH: 100 mU/ L (Ref ). HPA axis：PTC（8Am）: 414 nmol/L (Ref ); ACTH: 35 pmol/L (Ref ). GH: 1.2ng/ml (Ref )