Transcript 腺垂体疾病的治疗原则：1）去除病因；2

Anterior Pituitary
Disease
Adenohypophysis
Disease
余叶蓉
Department of Endocrinology and Metabolism
West China Hospital
Sichuan University
1
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
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The pituitary gland is located within the sella turcica
ventral to the diaphragma sella
1-2
The hypothalamus - pituitary complex is the
“master gland”，it orchestrates the regulatory
functions of multiple other endocrine glands.
1-3
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
HYPOTHALAMUS–PITUITARY HORMONES
1-4
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
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HYPOTHALAMUS–PITUITARY HORMONES
Feedback Regulation
Low
Autonomous
Secretion of
Trophic H. or ……
Primary Failure of
target Endo.
Organ
Normal
High
HORMONAL FEEDBACK REGULATION
Trophic Hormone Level
1-6
Normal
Range
Autonomous
Secretion of
Target Endo.
Organ
Trophic H.
Failure
Low
Normal
High
Target Gland Hormone Level
1-7
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
FSH/LH水平正常
闭经的原因？
 血E2水平正常
FSH/LH水平正常
闭经的原因？
DISORDERS OF
ANTERIOR PITUITARY DISEASE
2
2-1
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
2-2
1. ANTERIOR PITUITARY
HYPERFUNCTION DISORDERS
 What happens if:
TOO MUCH Prolactin secretion?
Prolactin-Secreting
Adenomas
GH-cell adenoma
ACTH-Secreting Tumors
TSH-Secreting Tumors
2-5
2. ANTERIOR PITUITARY
HYPOFUNCTION DISORDERS
 Most examples of hormone deficiency states can be
attributed to anterior pituitary destruction caused by:
Surgery
Infarction
Infection
Hemorrhage
Tumor infiltration
Inflammation
Autoimmunity
Genetic abnormalities
2-6
3. HORMONE RESISTANCE SYNDROME
Glucocorticoid Resistance
What happens if generalized GC resistance?
Approach to the Patients with
Suspected Pituitary Disease
3-1
DIAGNOSIS of PITUITARY DISEASE
Symptoms, signs, others.
H.measurement & endo. test
No
Hyper/hypo
-function
Yes
CT, MRI, and others
Suggestion of
pituitary disease
Functional evaluating
of pituitary.G.
Localization of
the lesion
Etiological
diagnosis
3-2
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
3-3
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.
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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
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Case Study - 2
 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. 140-590nmol/L）
-
Anterior pituitary
+
-
 ACTH
+
Adrenal gland
+
Cortisol
Dexamethasone
+
Targets tissue
Dexamethasone Suppression Tests
THERAPEUTIC STRATEGIES OF
ANTERIOR PITUIATRY DISEASE
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4-1
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
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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.
HYPOPITUITARISM
Case Study
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5-1
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。
5-2
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。
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Hypopituitarism
Mass lesions - pituitary adenomas,
other benign tumors, cysts
Pituitary surgery
Definition
Pituitary radiation
Infiltrativesecretion
lesions - lymphocytic
Hypopituitarism refers to decreased
of
hypophysitis, hemochromatosis
pituitary hormones
Infarction - Sheehan syndrome
Apoplexy
Hypopituitarism can result from
diseases of the
Genetic
diseases
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
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Anterior Pituitary Infarction –
Sheehan syndrome
 The anterior pituitary lacks a major
direct arterial blood supply; it is
bathed in a dense capillary
network : hypothalamichypophyseal portal venous system
 The pituitary gland is enlarged in
pregnancy and prone to infarction
from hypovolemic shock
5-6
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.
5-7
CLINICAL MANIFESTATIONS OF
HYPOPITUITARISM
ACTH Deficiency
 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
Symptoms/signs
Frequency,
percent
Weakness, tiredness,
fatigue
100
Anorexia
100
Gastrointestinal
symptoms
92
Nausea
86
Vomiting
75
Constipation
33
Abdominal pain
31
Diarrhea
16
Muscle or joint pains
Weight loss or Weight gain
6-13
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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
5-8
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
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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
5-9
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.
5-10
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
5-11
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.
5-14
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
5-15
Case Study-Labs.
 ACTH(8:00Am) : 15.1 ng/L (Ref. 5.0-78ng/L),
 PTC: 84nmol/L (Ref.147-609nmol/L)
 TSH : 2.91mU/L (Ref. 0.2-4.5mU/L),
 FT4: 3.40pmol/L (Ref.12-24pmol/L)
 LH: <0.1mU/L (Ref. 7.7-58.8), FSH0.487mU/ml(Ref. 1.7-7.7)
 E2: < 5.0pg/ml(Ref. 5-54) ,
 GH: 0.92ng/ml (Ref. 0.126-9.88)
Final Diagnosis:
 Hypopituitarism or Sheehan's syndrome
5-16
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.
5-17
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 (40-120 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
5-18
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
L-Thyroxine 25g/d, po
 The patient discharged one week later and follow up
regularly at outpatient department.
6-1
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”
6-2
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
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
Case Study
该病例存在的问题：
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？
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.
0.1-0.8); FSH: 2.9 mU/L (Ref. 1.7-7.7); LH: 3.4
mU/L(Ref. 7.7-58.8)
 PRL: 42.8 ng/ml (Ref. 6-29)
 HPT axis：FT3: 2.1pmol/L (Ref. 3.6-7.5); FT4: 5.2pmol/L
(Ref. 13-23); TSH: 100 mU/ L (Ref. 0.3-5.0).
 HPA axis：PTC（8Am）: 414 nmol/L (Ref. 171-536);
ACTH: 35 pmol/L (Ref. 12-65).
 GH: 1.2ng/ml (Ref. 0.126 - 9.88)
1