class: center, middle, inverse, title-slide .title[ # Anterior Pituitary Gland ] .author[ ### 盧子文醫師 <br>.lk[(<a href="tel:46-05211">GSM: 46-05211</a>)] ] .institute[ ### 高醫附設中和紀念醫院<br>.lk[<a href="mailto:highker@gap.kmu.edu.tw" class="email">highker@gap.kmu.edu.tw</a>] ] .date[ ### 2024/05/14 (updated: 2024-06-01) ] --- ## 學習目標 .e3[ - Anatomy - Anterior pituitary hormones - Prolactin(PRL) - Growth Hormone(GH) - Adrenocorticotropic Hormone(ACTH) - Gonadotropins: FSH, LH - THYROID-STIMULATING HORMONE (TSH) - Hypopituitarism - Pituitary Tumor - Prolactinoma - Acromegaly - Cushing’s disease ] --- class: center, middle # Anatomy --- background-image: url(data:image/png;base64,#./pit01.png) background-position: 10% 70% background-size: 40% ### Anatomy .pull-right4[ .e4[ - The pituitary gland weighs ~600 mg and is located within the sella turcica ventral to the diaphragma sella; it consists of anatomically and functionally distinct anterior and posterior lobes. - Blood supply of the pituitary gland comes from the superior and inferior hypophyseal arteries. - The hypothalamic-pituitary portal plexus provides the major blood source for the anterior pituitary. ] ] --- background-image: url(data:image/png;base64,#./pit02.png) background-position: 50% 60% background-size: 95% ### Anterior Pituitary Hormone Expression and Regulation --- ### Anterior pituitary hormones - Growth Hormone(GH) - Adrenocorticotropic Hormone(ACTH) - Prolactin(PRL) - Gonadotropins: FSH, LH - THYROID-STIMULATING HORMONE (TSH) <table> <thead> <tr> <th style="text-align:left;"> Hormone </th> <th style="text-align:left;"> Stimulators </th> <th style="text-align:left;"> Inhibitors </th> <th style="text-align:left;"> Target </th> </tr> </thead> <tbody> <tr> <td style="text-align:left;"> GH </td> <td style="text-align:left;"> GHRH, ghrelin </td> <td style="text-align:left;"> Somatostatin, IGF-1 </td> <td style="text-align:left;"> Liver, bone, other tissues </td> </tr> <tr> <td style="text-align:left;"> ACTH </td> <td style="text-align:left;"> CRH, AVP, gp-130 cytokines </td> <td style="text-align:left;"> Glucocorticoids </td> <td style="text-align:left;"> Adrenal </td> </tr> <tr> <td style="text-align:left;"> PRL </td> <td style="text-align:left;"> Estrogen, TRH, VIP </td> <td style="text-align:left;"> Dopamine </td> <td style="text-align:left;"> Breast, other tissues </td> </tr> <tr> <td style="text-align:left;"> FSH, LH </td> <td style="text-align:left;"> GnRH, activins, estrogen </td> <td style="text-align:left;"> Sex steroids, inhibin </td> <td style="text-align:left;"> Ovary, testis </td> </tr> <tr> <td style="text-align:left;"> TSH </td> <td style="text-align:left;"> TRH </td> <td style="text-align:left;"> T3, T4, dopamine, somatostatin, glucocorticoids </td> <td style="text-align:left;"> Thyroid </td> </tr> </tbody> </table> --- background-image: url(data:image/png;base64,#pit03.png) background-repeat: false background-position: 92% 60% background-size: 55% <div id="htmlwidget-67d5e37440a2c872c338" style="width:40%;height:100%;" class="pixfigure html-widget"></div> <script type="application/json" data-for="htmlwidget-67d5e37440a2c872c338">{"x":{"path":["assets/6b4249fe81c535f891822b03f1eaf215.png"],"caption":[],"h":"auto","w":"100%","fit":"cover","position":"3% 60%"},"evals":[],"jsHooks":[]}</script> --- background-image: url(data:image/png;base64,#./pit05.png) background-repeat: false background-position: 90% 5% background-size: 33% ### Pituitary Hormone Axes <br> <br> <br> <div id="htmlwidget-45076409feed54ab07d7" style="width:95%;height:100%;" class="pixfigure html-widget"></div> <script type="application/json" data-for="htmlwidget-45076409feed54ab07d7">{"x":{"path":["assets/4a6eb61f7dc37d2e52d2849b127005bd.png"],"caption":[],"h":"50%","w":"100%","fit":"cover","position":"50% 100%;"},"evals":[],"jsHooks":[]}</script> --- ### Pituitary Disorders .e3[ - The most frequent cause of pituitary disorders is pituitary gland tumors. - Two types of tumors exist (secretory and non-secretory). - The problems fall into three categories: - Hypersecretion - It is usually caused by a secretory pituitary gland tumor. - Hyposecretion - It is usually caused by a non‐secretory tumor, interfering the ability of the normal pituitary gland to create hormones. - It can also be caused by a large secretory tumor. It can also happen after surgery or the radiation therapy. ] --- ### Pituitary Disorders .e3[ - Tumor mass effects - As a pituitary gland tumor grows and presses against other areas in the brain, it may cause headaches, vision problems, or other health effects related to hyposecretion. - It can be seen in any type of pituitary tumor that grows large enough. - Injuries,certainmedications,andotherconditionscan also affect the pituitary gland. Loss of normal pituitary function also has been reported after major head trauma. ] --- background-image: url(data:image/png;base64,#pit092.png) background-repeat: false background-position: 90% 50% background-size: 45% ### Hypopituitarism <div id="htmlwidget-af399979ec385548821e" style="width:50%;height:100%;" class="pixfigure html-widget"></div> <script type="application/json" data-for="htmlwidget-af399979ec385548821e">{"x":{"path":["assets/e508676160dd35d050537b4429b837df.png"],"caption":[],"h":"auto","w":"100%","fit":"cover","position":"center"},"evals":[],"jsHooks":[]}</script> --- ### Acquired Hypopituitarism .e2[ - Hypothalamic infiltration disorder - Inflammatory lesions - Cranial irradiation - doses as low as 18 Gy with higher doses (30–50 Gy) that can reach 50% to 100% within 3 to 5 years. - Lymphocytic hypophysitis - Pituitary apoplexy - Trauma, hemorrhage(Sheehan Syndrome) - Empty sella ] --- background-image: url(data:image/png;base64,#./pit10.png) background-position: 50% 40% background-size: 95% --- background-image: url(data:image/png;base64,#./pit11.png) background-position: 50% 40% background-size: 75% --- background-image: url(data:image/png;base64,#./pit121.png) background-position: 50% 65% background-size: 55% ### Treatment of hypopituitarism --- background-image: url(data:image/png;base64,#./pit13.png) background-position: 50% 70% background-size: 70% ### Pituitary tumors --- background-image: url(data:image/png;base64,#./pit14.png) background-position: 80% 70% background-size: 60% ### Pituitary 附近 --- background-image: url(data:image/png;base64,#./pit152.png) background-position: 92% 50% background-size: 45% ### Mass effect <div id="htmlwidget-f2777a8c185525473387" style="width:50%;height:100%;" class="pixfigure html-widget"></div> <script type="application/json" data-for="htmlwidget-f2777a8c185525473387">{"x":{"path":["assets/896795ac594ba0fd2501d645ab89d8a2.png"],"caption":[],"h":"auto","w":"100%","fit":"cover","position":"center"},"evals":[],"jsHooks":[]}</script> --- background-image: url(data:image/png;base64,#./pit07.png) background-position: 92% 50% background-size: 45% <div id="htmlwidget-927c36975c59b08bf052" style="width:50%;height:100%;" class="pixfigure html-widget"></div> <script type="application/json" data-for="htmlwidget-927c36975c59b08bf052">{"x":{"path":["assets/f771b210198e6da0cdcc70527d83311f.png"],"caption":[],"h":"auto","w":"100%","fit":"cover","position":"center"},"evals":[],"jsHooks":[]}</script> --- ### Other Sellar masses .e3[ - Craniopharyngiomas - Rathke’s cysts - Sella chordomas - Meningiomas - Histiocytosis - Pituitary metastases - Hypothalamic hamartomas and gangliocytomas - Hypothalamic gliomas and optic gliomas - Brain germ cell tumor ] --- background-image: url(data:image/png;base64,#./pit16.png) background-position: 50% 50% background-size: 90% --- background-image: url(data:image/png;base64,#./pit17.png) background-position: 50% 50% background-size: 90% --- class: center, middle # Prolactinoma --- ###Etiology and Prevalence .e4[ - Prolactin: Normal range: M<15, F<20 μg/L - Prolactinomas are the most frequently encountered secretory pituitary tumors - incidence of approximately 30 per 100,000 population - The female:male ratio for microprolactinomas is 20:1; macroprolactinomas is 1:1 - Macroprolactinomas have a greater propensity to grow and tumor size correlates with serum PRL levels - .y[PRL level higher than 200 ng/mL is strongly indicative of a PRL- secreting pituitary tumor] - < 100 μg/L → microadenomas - `>` 200 μg/L → macroadenomas - MRI should be performed in all patients with hyperprolactinemia ] --- background-image: url(data:image/png;base64,#./pit182.png) background-position: 90% 50% background-size: 45% <div id="htmlwidget-4f9747973618c8cf42c8" style="width:48%;height:100%;" class="pixfigure html-widget"></div> <script type="application/json" data-for="htmlwidget-4f9747973618c8cf42c8">{"x":{"path":["assets/d1e24879741a77bcb3d7c58bf7ae67e4.png"],"caption":[],"h":"auto","w":"100%","fit":"cover","position":"center"},"evals":[],"jsHooks":[]}</script> --- ### Presentation and Diagnosis .e4[ - Women: - amenorrhea, infertility, galactorrhea, visual field defects, mass effects - Galactorrhea is present in up to 80% of hyperprolactinemic women. - Decreased libido, weight gain, and mild hirsutism - If hyperprolactinemia is sustained, vertebral bone mineral density can be reduced. - Men: - impotence, loss of libido, infertility, headache, visual field defects, mass effects - Long-standing, secondary effects of hypogonadism including osteopenia, osteoporosis, reduced muscle mass, and decreased beard growth ] --- background-image: url(data:image/png;base64,#./pit183.png) background-position: 50% 50% background-size: 90% --- background-image: url(data:image/png;base64,#./pit19.png) background-position: 50% 80% background-size: 75% ### Management of prolactinoma --- ### Medical treatment .e4[ - Medical management of prolactinomas with dopamine agonist drugs has been widely recommended as the treatment of choice - Oral dopamine agonists (cabergoline and bromocriptine) are the mainstay of therapy for patients with micro- or macroprolactinomas. - About 20% of patients (especially males) are resistant to dopaminergic treatment - Side Effects of dopamine agonists: - Nausea , nasal stuffiness, depression, digital vasospasm Postural hypotension ,symptoms of psychosis CSF rhinorrhea, hepatic dysfunction and cardiac arrythmias (rare) ] --- .e4[ .pull-left[ Cabergoline 1. A long‐acting dopamine agonist (0.5 to 1.0 mg twice weekly). 2. Normalizes PRL and resumption of normal gonadal function in 80% of microadenomas; normalizes PRL and shrinks 70% of macroprolactinomas. 3. Mass effect symptoms usually improve within days after cabergoline initiation; improvement of sexual function requires several weeks of treatment . ] .pull-right[ Bromocriptine mesylate 1. A short‐acting dopamine agonist, preferred when pregnancy is desired. 2. Initiated by administering a low bromocriptine dose (0.625–1.25 mg) at bedtime with a snack, followed by gradually increasing the dose. Most patients are controlled with a daily dose of 7.5 mg (2.5 mg tid) ] ] --- ### Surgery .e3[ - Indications include .red[dopamine resistance or intolerance and the presence of an invasive macroadenoma with compromised vision that fails to improve after drug treatment.] - Initial PRL normalization is achieved in about 70% of microprolactinomas on, but only 30% of macroadenomas can be resected successfully. - Follow-up studies have shown that hyperprolactinemia recurs in up to 20% of patients within the first year after surgery; long-term recurrence rates exceed 50% for macroadenomas. ] --- ### Radiation Therapy .e3[ - Radiotherapy is reserved for aggressive tumors that do not respond to maximally tolerated dopamine agonists and/or surgery. - Linear accelerator radiotherapy is effective in controlling or reducing the tumor size. - It takes years to achieve maximal effect. - Higher doses are associated with complication ] ### Chemotherapy .e3[ - For aggressive PRL-secreting tumors unresponsive to other therapies, temozolomide, an alkylating compound that readily crosses the blood-brain barrier, may control tumor growth. ] --- background-image: url(data:image/png;base64,#./pit20.png) background-position: 50% 50% background-size: 60% --- background-image: url(data:image/png;base64,#./pit21.png) background-position: 50% 80% background-size: 70% ### Management of patients planning pregnancies --- class: center, middle # Acromegaly --- ### Incidence The prevalence of acromegaly is estimated to range from 28 to 137 cases per million. Recent surveys indicate an increase in the annual incidence to about 10 cases per million ### Pathogenesis GH and IGF1 act both independently and dependently to induce features of hypersomatotropism. Acromegaly is caused by pituitary tumors secreting GH or very rarely by extrapituitary disorders --- background-image: url(data:image/png;base64,#./acro01.png) background-position: 70% 50% background-size: 60% ### Etiology --- background-image: url(data:image/png;base64,#./acro02.png) background-position: 50% 50% background-size: 70% --- background-image: url(data:image/png;base64,#./acro03.png) background-position: 50% 50% background-size: 85% --- background-image: url(data:image/png;base64,#./acro041.png) background-position: 50% 50% background-size: 80% --- background-image: url(data:image/png;base64,#./acro042.png) background-position: 50% 50% background-size: 90% --- background-image: url(data:image/png;base64,#./acro05.png) background-position: 50% 50% background-size: 90% --- ### Acromegaly .e3[ - More than 95% acromegaly harbor a GH-secreting pituitary adenoma - Mixed GH-cell and PRL-cell adenomas are composed of distinct somatotrophs expressing GH and lactotrophs expressing PRL. - Screening colonoscopy for colon cancer should be performed at diagnosis - The most significant mortality determinants are GH levels and the presence of coexisting cardiac disease. - Control of GH levels to less than 2.5 μg/L significantly reduces morbidity and mortality ] --- ### Diagnosis .y[Measurement of Growth Hormone and IGF1 Levels] .e3[ - Age- and sex-matched serum IGF-I level provides a useful laboratory .red[screening measure]. - The diagnosis is confirmed by demonstrating the failure of GH suppression to < 1μg/L within 1 h of an oral glucose load (75 g). - Differential Diagnosis. * GHRH * Ectopic ] --- ### Oral Glucose Tolerance Test (OGTT) .ud[For the diagnosis of acromegaly] Blood sampling: GH at 0 min, 30 min, 60 min, 90 min, 120min .e3[ - Normal response: GH nadir < 1 ng/mL, usually at 60 min - Acromegaly: - GH nadir > 1 ng/mL (lower cut-off in newer more sensitive assays); 1/3 increase, 1/3 remain unchanged, 1/3 fall modestly (but not < 1 ng/mL) - False positive: starvation, protein-caloric malnutrition, anorexia nervosa ] --- background-image: url(data:image/png;base64,#./acro06.png) background-position: 50% 50% background-size: 55% --- ### Management goals .e2[ - Control tumor growth. - Relieve central compressive effects. - Preserveorrestorepituitarytrophichormone function. - Treat comorbidities (hypertension, cardiac failure, hyperglycemia, sleep apnea, arthritis). - Normalize mortality rates. - Prevent biochemical recurrence ] --- ### Surgery .e3[ - Transsphenoidal surgical resection by an experienced surgeon is the preferred primary treatment for both microadenomas (cure rate 70%) and macroadenomas (<50% cured). - Soft tissue swelling improves immediately after tumor resection. GH levels return to normal within an hour, and IGF-I levels are normalized within 3– 4 days. - In 10% of patients, acromegaly may recur several years after apparently successful surgery; hypopituitarism develops in up to 15% of patients after surgery. ] --- ### Radiation therapy .e3[ - External radiation therapy or high-energy stereotactic techniques are used as adjuvant therapy for acromegaly. - Patients may require interim medical therapy for several years before attaining maximal radiation benefits. - Most patients also experience hypothalamic-pituitary damage, leading to gonadotropin, ACTH, and/or TSH deficiency within 10 years of therapy. ] --- ### Medical treatment Somatostatin Analogues(somatostatin receptor ligands) - Somatostatin analogues exert their therapeutic effects through SSTR2 and SSTR5 receptors, both express in GH‐secreting tumors. - Octreotide is administered by subcutaneous injection,beginning with 50 g tid; the dose can be increased gradually up to 1500 g/d. - Sandostatin‐LAR is asustained‐release, long‐acting octreotide sustaining for several weeks. GH suppression occurs for as long as 6 weeks after a 30‐mg intramuscular injection; long‐term monthly treatment sustains GH and IGF‐I suppression and also reduces pituitary tumor size in 50% of patients - anreotide autogel,aslow‐releasesomatostatinanalogue,suppresses GH and IGF‐I hypersecretion after a 60‐mg subcutaneous injection. Long‐term monthly administration controls GH hypersecretion in two‐thirds of treated patients. Side Effects - drug‐induced suppression of gastrointestinal motility and secretion - suppresses postprandial gallbladder contractility and delays gallbladder emptying --- ### Medical treatment GH Receptor Antagonist - Blocking peripheral GH binding to its receptor. Consequently, serum IGF‐I levels are suppressed. - Pegvisomant(daily subcutaneous injection 10–20mg) normalizes IGF‐I in >90%. - GH levels remain elevated as the drug does not have antitumor actions. - Side effects include reversible liver enzyme elevation, and lipodystrophy. - Combined with somatostatin has been used effectively inresistant patients. Dopamine Agonists - Bromocriptine and cabergoline may modestly suppress GH secretion in some patients. - High doses of bromocriptine(20mg/d) or cabergoline(0.5mg/d) are usually required to achieve modest GH therapeutic efficacy. - Combined treatment with octreotide and cabergoline may induce additive biochemical control compared with either drug alone. --- background-image: url(data:image/png;base64,#./acro07.png) background-position: 50% 50% background-size: 90% --- background-image: url(data:image/png;base64,#./acro08.png) background-position: 50% 50% background-size: 90% --- background-image: url(data:image/png;base64,#./acro09.png) background-position: 50% 50% background-size: 90% --- background-image: url(data:image/png;base64,#./acro10.png) background-position: 50% 50% background-size: 90% --- ### Summary .e3[- Surgery is the preferred primary treatment for GH-secreting microadenomas. - The high frequency of residual GH hypersecretion after macroadenoma resection usually necessitates adjuvant or primary medical therapy for these larger tumors. - Patients unable to receive or respond to unimodal medical treatment may benefit from combined treatments, or they can be offered radiation. - Very rarely, repeat surgery may be required.] --- class: center, middle # ACTH-Secreting Tumors (Cushing Disease) --- ### Etiologies of hypercortisolism .e3[ - Most commonly iatrogenic caused by exogenous glucocorticoids (though underreported) - Cushing’s disease (60–70% of non-iatrogenic CS): ACTH- secreting pituitary adenoma (usually microadenoma) or hyperplasia - Adrenal tumor (10–15%): adenoma or (rarely) carcinoma - Ectopic ACTH (10–15%): small cell lung carcinoma, carcinoid, islet cell tumors, medullary thyroid cancer, pheochromocytoma - Cushing’s disease is 5–10 times more common in women than in men. ] --- background-image: url(data:image/png;base64,#./cu01.png) background-position: 50% 80% background-size: 53% ### Clinical presentation --- background-image: url(data:image/png;base64,#./cu02.png) background-position: 50% 50% background-size: 65% --- background-image: url(data:image/png;base64,#./cu03.png) background-position: 50% 50% background-size: 90% --- background-image: url(data:image/png;base64,#./cu04.png) background-position: 50% 50% background-size: 90% --- ###Laboratory Investigation .e4[ - Diagnosis—Does the Patient Have Cushing Syndrome? - 24 hours urine free cortisol - Low-dose dexamethasone suppression test - Late night salivary cortisol/circadian rhythm of plasma cortisol - Differential Diagnosis—What Is the Cause of the Cushing Syndrome? - Plasma ACTH - High dose dexamethasone suppression test - Corticotropin-releasing hormone - Inferior petrosal sinus sampling - CT, MRI scanning of pituitary, adrenals - Scintigraphy - Tumor markers ] --- background-image: url(data:image/png;base64,#./cu05.png) background-position: 50% 50% background-size: 40% --- background-image: url(data:image/png;base64,#./cu06.png) background-position: 50% 50% background-size: 70% --- ### Diagnostic Tests .e3[ - 24 hour Urine Free Cortisol - A. Purpose: Screening for Cushing's syndrome - B. Procedure: 24 hour urine free cortisol level. (Normal range: 4.3~176.0 μg/24hr) ] --- .e3[ - Overnight Dexamethasone Suppression Test - A. Purpose: Screening for Cushing's syndrome - B.Procedure - Give 1 mg dexamethasone orally at 11 pm - Check cortisol at 8 am of the following day prior to food intake - C. Interpretation - Normally serum cortisol are suppressed to < 1.8 (2.0) μg/dL - Depression, restless sleep, emotional or physical stress, recent heavy alcohol consumption, obesity, thyrotoxicosis, acromegaly, pregnancy, oral contraceptives, phenytoin, rifampin and barbiturates → false positive ] --- .e3[ - Low Dose Dexamethasone Suppression Test (LDDST) - A. Purpose: Confirmation of Cushing's syndrome - B. Procedure - Day 1: Obtain baseline serum cortisol, ACTH at 8 am - Day 1-2: Give dexamethasone 0.5 mg q6h po x 2 days - Day 3: Check serum cortisol level at 8 am - C. Interpretation: normal response → serum cortisol < 2 μg/dL at 8 am on D3 ] --- .e3[ - High Dose Dexamethasone Suppression Test (HDDST) - A. Purpose: D/D of Cushing's disease or ectopic ACTH secretion - B. Procedure - Day 1: Obtain baseline serum cortisol, ACTH at 8 am - Day 1-2: Give dexamethasone 2 mg q6h po x 2 days - Day 3: Check serum cortisol level at 8 am - C. Interpretation - Cushing's disease: D3 cortisol level is < 50% of D1 baseline cortisol level; - Ectopic ACTH: non-suppressible ] --- background-image: url(data:image/png;base64,#./cu07.png) background-position: 95% 60% background-size: 50% ### Management of Cushing's Disease .pull-left[ - Selective transsphenoidal resection is the treatment of choice for Cushing's disease - Remission rate is 80% for microadenomas , but <50% for macroadenomas. - After tumor resection, a postoperative period of symptomatic ACTH deficiency that may last up to 12 months. This usually requires low-dose cortisol replacement. - Biochemical recurrence occurs in approximately 5% initially successful surgery was ] --- background-image: url(data:image/png;base64,#./cu08.png) background-position: 50% 50% background-size: 90% --- ### Medical treatment for Cushing's disease - *Pasireotide* LAR 10–40 mg intramuscularly, an SRL with high affinity for SST5 > SST2 receptor subtypes, may control hypercor- tisolemia in a subset of patients with ACTH-secreting pituitary tumors. - *Osilodrostat* (2 mg twice daily titrated up to 30 mg twice daily), an oral 11β-hydroxylase inhibitor that blocks adrenal gland cortisol biosynthesis, normalized 24-h UFC in 86% of patients. - *Ketoconazole*(600–1200 mg/d), an imidazole derivative antimycotic agent, inhibits several P450 enzymes and effectively lowers cortisol. - *Mifepristone* (300–1200 mg/d), a glucocorticoid receptor antagonist, blocks peripheral cortisol action - *Metyrapone* (2–4 g/d) inhibits 11β-hydroxylase activity and nor- malizes plasma cortisol in up to 75% of patients. - *Mitotane* (3–6 g/d orally in four divided doses) suppresses cortisol hypersecretion by inhibiting 11β-hydroxylase and cholesterol side- chain cleavage enzymes and by destroying adrenocortical cells. - Other agents include *aminoglutethimide* (250 mg tid), *trilostane* (200–1000 mg/d), *cyproheptadine* (24 mg/d), and IV *etomidate* (0.3 mg/kg per h) --- ## Take Home Message .e3[ - Hormone - TSH/ACTH/GH/PRL/FSH,LH - Pituitary tumors - Prolactinoma () - Agromegaly (72 hours OGTT tests) - Cushing's disease (overnight/low dose/high dose Dexamethasone Suppression Test) ] --- # References .e2[ - Harrison's Principles of Internal Medicine, 21e - William's Endocrinology, 14e - Pocket Medicine, 8e - 臺大醫院代謝內分泌檢查工作手冊 ] --- class: center, middle # Thanks for your attention! 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