01 - SIsaacs - Thyroid Disease · PDF fileLearning Objectives ... Symptoms of Hypothyroidism...

Thyroid Disease

Scott D. Isaacs, MD, FACP, FACEHRT SymposiumSavannah GA

July 14‐16, 2016

Disclosure

Scott D. Isaacs, MD, FACP, FACE, is the Medical Director at Atlanta Center for Endocrinology, Diabetes, Metabolism and Weight Loss. Conflict of interest was resolved through peer review of slide content.

Professional Education Services Group staff have no financial interest or relationships to disclose.

Disclosure

This continuing education activity is managed and accredited by Professional Education Services Group. Neither PESG nor any accrediting organization supports or endorses any product or service mentioned in this activity.

Educational Grant Support

This continuing education activity is supported by an educational grant from PCCA.

Learning Objectives

• At the conclusion of this activity, the participant will be able to:– Discuss the endocrinology of thyroid hormones and the relationship to the hypothalamus, pituitary and peripheral organs.

– Discuss the laboratory evaluation of thyroid disorders.

– Explain the management of thyroid disease in a case‐based approach.

Hypothalamic‐Pituitary‐Thyroid Axis

Deiodinase

T4 and T3 Negative feedback inhibition

Peripheral actions

Is it a thyroid problem?

• A 72 year old woman has been experiencing fatigue, depression and difficulty losing weight for 2 years.

• Thyroid tests ordered online have been normal except a moderately low reverse T3.

• She has read that thyroid tests don’t accurately evaluate thyroid function and requests thorough thyroid testing and treatment.

Is it a thyroid problem?

• PMH: Negative Meds: Multiple supplements• PE: BP 122/84 P 80 Ht 5’6” Wt 172 lb.• Complete exam normal• Lab Report: TSH 3.2 mU/L (nl: 0.45‐4.5)• Free T4 1.3 ng/dl (nl: 0.8‐1.8)• Free T3 3.1 pg/ml (nl: 2.3‐4.2)• Reverse T3 9 ng/dl (nl: 10‐24)

Symptoms of Hypothyroidism• Weight gain• Fatigue• Aging• Menopausal symptoms• Neck or tongue swelling• Joint and muscle aches• Feeling cold• Constipation• Memory loss• Infertility

• Slow reflexes• Snoring or sleep Apnea• Hair loss/eyebrow Loss• Brittle nails• Fluid retention• Decreased sweating• Allergies or hives• Depression• Menstrual cycle problems• Galactorrhea

Physical Exam Findings in Hypothyroidism

• Diastolic Hypertension• Bradycardia• Dry Skin• Hair loss• Loss of lateral 1/3 eyebrows• Goiter• Delayed relaxation phase of reflexes• Edema

Possible Interpretations:

• Symptoms are not related to the thyroid• Hypothalamic‐Pituitary disease is the problem• TSH level is not in the optimal range• There is a coexisting autoimmune disease• Hashimoto’s Disease itself causes symptoms• Maybe we should consider other possibilities

Considerations:

• There are many potential problems that could occur along the entire hypothalamic pituitary thyroid axis.

• Current tests are not able to evaluate this axis completely.

Epidemiology of Primary Hypothyroidism

• Up to 5% of adult population has primary thyroid gland failure • Hypothyroidism with clinical features and abnormal labs in

0.8%‐1.1% (Wickham, England) • Elevated TSH (>6 mU/L) was found in an additional

asymptomatic 7.5% of females and 2.8% of males• Colorado Health Study found 9.5% prevalence of elevated TSH • 40% of individuals > 80 years old have TSH > 2.5 mU/L

1 VanderpumpMPJ et al. The Thyroid. 1996; 474‐4822 Tunbridge WMG et al. Clin Endocrinol. 1977;7(6); 481‐4933 Canaris GJ et al. Arch Intern Med. 2000; 160(4): 536‐5344 Surks MI et al. JCEM. 2007;92(12) 4575‐4582.

Risk factors for Primary Hypothyroidism

• Women• Over 60 years old• Other autoimmune disorders • Family members with hypothyroidism• Being pregnant or recently had a baby

Hashimoto’s Thyroiditis• Most common cause of hypothyroidism• Immune system mistakenly attacks key machinery in the thyroid gland (TPO & Tg)

• May have hyperthyroid phase followed by brief euthyroid phase

• Variable degrees of thyroid dysfunction• Family History—Hashimoto’s or Graves’• Other autoimmune problems• Eye symptoms (Dysthyroid ophthalmopathy)

Hypothyroidism and Thyrotoxicosis

Canaris, Arch Int Med. 2000;160:526‐534.

Colorado Health Study24,337 subjectsTSH normal range (0.3‐5.1)

Normal TSH Reference• Primary hypothyroidism is diagnosed with a TSH above

the upper limit of normal• Reference range for upper limit of normal is under

discussion 1

• 20 year follow up Wickham cohort 2

• TSH > 2.0 mU/L increases risk of progression to overt hypothyroidism

• Increased progression to hypothyroidism if thyroid antibodies positive

1 Baloch Z et al. Thyroid. 2003. 13(1): 33‐44.2 Vanderpump MPJ et al. The Thyroid. 1996; 474‐482

Thyroid laboratory

• TSH• Total T4• Free T4• Total T3• Free T3• T3RU• Corrected T4 and T3

Thyroid+ laboratory

• Thyroid antibodies (TPO, Tg)• Thyroglobulin• Reverse T3• T3/rT3 ratio• Alpha subunit• Thyroid binding globulin• Albumin

Thyroid+ laboratory• Selenium• Iodine• CK• LDL‐cholesterol• Iron, Ferritin• Cortisol• ACTH• Leptin• Celiac antibodies

– Anti‐tissue transglutaminase (tTG) antibodies – Endomysial antibodies (EMA) – Deamidated gliadin peptide (DGP) antibodies

Reverse T3

Thyroid hormone biochemistry

Causes of abnormal rT3

• Beta blockers• Chronic illness• Inflammation• Liver disease• Selenium deficiency• Obesity• Diabetes• Calorie restriction

Trends in Diagnosis

• More narrow TSH reference range for primary hypothyroidism

• 95% of screened healthy euthyroid subjects have serum TSH between 0.4 and 2.5 mU/L

• Treat all patients with TSH > 10 mU/L• Treat most patients with TSH between 4.5‐9.9 mU/L (especially those with low T4)

• Use “clinical judgment” to treat symptomatic individuals with TSH > 2 mU/L

Gharib, et al. Subclinical thyroid dysfunction. JCEM. 2005; 90 (1): 581‐585.

NHANES IIINormal TSH Range by Decade

• The lower TSH limit stays relatively constant with age.

• The MEAN TSH rises with age.

• The upper limit of normal rises with age.

• A “natural” rise of TSH with age? (survival benefit?)

• Is there a progression to hypothyroidism with age that is included in normal?

Cross‐sectional Population StudyAge‐related Changes in TSH

Hollowell JCME 2002; 87:489‐499; Surks JCEM 2007;92:4575‐4582;

Natural History Mild Hypothyroidism

• 107 patients followed for 72 months with subclinical hypothyroidism (elevated TSH, normal Free T4).– Mean age 62 years from outpatient Endo clinic– 26% required T4 RX

• Overt hypothyroidism associated if baseline:– + TPO Ab– Free T4 < 1– Extent of TSH elevation

• > 10 (~40%)• > 15 (~90%)

• Low risk of overt hypothyroidism if TSH 5‐10– Recommend biochemical monitoring

Diez & Iglesias JCEM 2004;89:4890‐7

Progression to Overt Hypothyroidism in CV Study

• Large population cohort followed for 4 years– 3992 >65 years– 12.8% subclinical hypothyroid– 0.61% overt hypothyroidism

• Overt hypothyroidism associated if baseline:– TSH >10– Not associated with age or TPO ab status

• Low risk of overt hypothyroidism if TSH 5‐10– Recommend biochemical monitoring

Somwaru JCEM 2012;97:1962

Subclinical Hypothyroidism and Cognitive Impairment

• Systematic review and meta‐analysis• 1,190 subjects >60 years in 15 studies• No association with:

– Mini mental state exam (MMSE)– Executive function– Memory (random effects model)

Akintola et al. Front. Aging Neurosci., 11 August 2015

Lower Mortality in Oldest Old with High TSH

• The oldest old, elderly individuals high TSH do not experience adverse effects and may have a prolonged life span.

• Risk of mortality of high TSH 0.76 (p 0.005) vs normal TSH.

Gussekloo et al. AMA. 2004;292(21):2591‐2599. doi:10.1001/jama.292.21.2591

Subclinical HypothyroidismProgression in the Elderly

Rosenthal, et al. JAMA. 1987; 258:209

Recommendation for Evaluation and Treatment ofElevated TSH in the Elderly

• TSH found on screening– Repeat with FT4 and TPO ab

• Progression to overt disease– Most likely if TSH >10– Free T4 < 1.0– Positive TPO antibody

• Subclinical disease is associated with subclinical hypothyroidism– LT4 therapy will reduce total and LDL cholesterol in subclinical hypothyroidism but rarely achieves goal levels

Hypothyroidism and Thyrotoxicosis

Canaris, Arch Int Med. 2000;160:526‐534.

Colorado Health Study24,337 subjectsTSH normal range (0.3‐5.1)

Risk of Subclinical Hyperthyroidism• Prevalence 1.5‐2% in > 65 years

– Etiology usually nodular goiter• Progression to overt disease

– 20‐70% normalize without treatment– 1‐3% progresses to hyperthyroidism

• More likely with very low TSH• More likely with nodular thyroid disease

• Risk of death – conflicting data but yes• Risk of atrial fibrillation –yes 2‐3 x risk• Risk of osteoporosis

– Hyperthyroidism associated with increased risk of hip and other fractures especially TSH <0.1

Evaluation and Treatment of Suppressed TSH in the Elderly

• If low TSH, repeat with FT4, total T3, TPOab (TSI) and thyroid US in 3 months

• If TSH 0.1‐0.4 mIU/L– Observation if TSH 0.1‐0.4, normal US, negative thyroid Ab,

normal HR, normal BMD, no CV or skeletal risk factors• Check TSH, FT4, total T3 every 6‐12 mo

• Graves disease: Treat with anti‐thyroidal drug (methimazole 5‐10 mg/d) if cardiovascular disease or risk factors

• Nodular goiter: Treat with radioactive iodine if cardiovascular disease or risk factors (consider normalize TSH first with anti‐thyroidal drug )– If cannot comply with radiation restrictions – long‐term anti‐

thyroidal drug

Evaluation and Treatment of Suppressed TSH in the Elderly

• If TSH < 0.1 mIU/L– Graves disease

• Treat with anti‐thyroidal drug , radioactive iodine or surgery

• Toxic nodular goiter– radioactive iodine or surgery– Surgery if large goiter or compressive symptoms

Back to our case:

• Symptoms are not related to the thyroid• Hypothalamic‐Pituitary disease is the problem• TSH level is not in the optimal range• There is a coexisting autoimmune disease• Hashimoto’s Disease itself causes symptoms• Maybe we should consider other possibilities

A 72 year old woman has been experiencing fatigue, depression and difficulty losing weight for 2 years.

TSH 3.2 mU/L (nl: 0.45‐4.5)Free T4 1.3 ng/dl (nl: 0.8‐1.8)Free T3 3.1 pg/ml (nl: 2.3‐4.2)Reverse T3 9 ng/dl (nl: 10‐24)

Euthyroid Hashimoto’sCoexisting Autoimmune Disease

• Rheumatoid arthritis• Lupus• Inflammatory bowel disease• Autoimmune hepatitis• Celiac disease• Vasculitis syndromes• Multiple sclerosis, pattern II

• Type 1 diabetes• Addison’s Disease• Lymphocytic hypophysitis• Alopecia• Vitiligo• Psoriasis

Autoimmune polyendocrine syndrome type 1Whitaker syndrome

• Hashimoto’s disease• Mucosal and cutaneous candidiasis• Hyposplenism• Hypoparathyroidism• Addison’s disease• Vitiligo • Alopecia • Malabsorption• Pernicious anemia• Autoimmune hepatitis

Autoimmune polyendocrine syndrome type 2Schmidt's syndrome

• Hashimoto's disease• Graves' disease• Addison's disease• Pernicious anemia• Type 1 diabetes• Celiac disease• Myasthenia gravis• Primary hypogonadism (less common)• Vitiligo (less common)

7.7% of euthyroid patients have symptoms of hypothyroidism.

Mrs. Johnson, we’ve done every possible test and your thyroid checks out completely normal, let’s look for other causes for your symptoms.

Follow up thyroid testing

• Free hormone levels• Equilibrium dialysis

method• Thyroid antibodies (TPO,

Tg, TSI, TBII)• Alpha subunit• TRH Stimulation Test• 24 Hr Urine Iodine

• Thyroid Ultrasound• Thyroid Scan and Uptake• Pituitary MRI Scan• Full Endocrine Evaluation• Reverse T3 • Basal Body Temperature

(not recommended)• Saliva Testing (not

recommended)

Hypothalamic‐pituitary‐thyroid axis physiology is highly complex

• Hypothyroidism most often develops as a result of thyroid disease (primary hypothyroidism).

• Can also occur from disorders of the pituitary gland or hypothalamus (central hypothyroidism).

Hypothalamic‐Pituitary Axis TRH

Paraventricular nucleus

Median eminence

TSH β subunit gene

α subunit TSH

Hypothalamus

Thyrotrophs

TSH β subunit

ThyroidTSH

TRH Receptor

Central Hypothyroidism

• 45.5 cases of CH occur annually per 100,000 of the general population.

• Pituitary adenomas are the most frequent cause.• Mechanical compression of portal vessels and the pituitary stalk.

• Ischemic necrosis of portions of the anterior pituitary.

• May have other pituitary hormone deficiencies.

Central Hypothyroidism

• Pituitary adenoma• Congenital• Craniopharyngioma• Rathke cleft cysts• Empty sella syndrome

• Sheehan syndrome • Lymphocytic hypophysitis• Head trauma• Subarachnoid hemorrhage • External beam radiotherapy

Bexarotene

• Synthetic retinoid analog (rexinoid).• Specific affinity for the retinoid X receptor.• Inhibits the expression of the TSHß gene through its binding to the retinoid X receptor.

• Approved for treatment of cutaneous T‐cell lymphoma.

• 40% incidence of CH• Marked reductions in serum TSH and T4 levels

Subclinical Central Hypothyroidism

• Mild symptoms• TSH < 2 mU/L (nl: 0.45‐4.5)• T4 and T3 low normal• Negative thyroid antibodies• Normal thyroid ultrasound

Adequate testing is lacking

• TRH gene mutations• TRH receptor mutations• TSH β subunit gene mutations• α subunit gene mutations• Problems with α subunit and β subunit conjugation

• Thyroid binding protein dysfunction• Deiodinase polymorphisms• TSH resistance• Thyroid hormone resistance• Thyroid hormone uptake across cellular and nuclear membranes into target cells

• Thyroid hormone regulation of transcription machinery to activate or suppress target genes

• Ubiquitination‐mediated regulation of thyroid hormone activation and deiodinase recycling

• Translation of mRNA into thyroid regulated proteins

• Actions of thyroid hormone regulated proteins

T4 is a Prohormone

CouplingOuter ring Iodine removed

PeripheralDeiodination

RT3: Inner ring Iodine removed

Iodination

Local T3 Production

• Every tissue in the body needs a specific amount of T3.

• Tissue specific deiodinases regulate the amount of T3 produced for each tissue.

• Peripheral deiodinase gene expression, translation and posttranslational modifications vary among organs.

• Liver and kidney express D1 deiodinase.• Bradioactive iodinen expresses D2 deiodinase.

Selenium Deficiency Causes Deiodinase Dysfunction

• Nutritional, from low fruit and vegetable consumption• Selenium content in soil varies by region (Russia and China have scant amounts of selenium in the soil)

• Malabsorption• Trigger for autoimmune diseases, cancer, heart disease

• RDA 70 mcg/d• Replacement 100‐200 mcg/d

Type 2 Deiodinase Gene Polymorphism

• Type 2 deiodinase (D2) converts T4 to T3 in the hypothalamus and pituitary.

• Pivotal role in the negative feedback regulation of TSH secretion.

• Common Thr92Ala variant causes decreased D2 enzymatic activity.

• Delayed T3 Secretion in Response to TSH• Changes in pituitary–thyroid axis homeostasis• Higher T4 intake needed to suppress TSH

Thyroid Hormone Resistance• 1 in 50,000 to 1 in 40,000 live births• Maybe 1‐3% have subtle resistance• Selective pituitary resistance variant• TRβMutations• Most common symptoms are goiter and tachycardia

• High T4, High TSH, normal alpha subunit• May be misdiagnosed as hyperthyroidism

Thyroid Hormone Resistance

• Possible links to ADHD, fibromyalgia• Patients can be difficult to treat: try dopamine agonists, T3, anti‐thyroidal drug s

• Symptomatic therapy with beta‐blockers • Antithyroid medications reduce symptoms of hyperthyroidism but increase goiter size.

Medications for Hypothyroidism

• Levothyroxine (LT4)• Branded levothyroxine• Desiccated Thyroid • Liothyronine (T3)• Compounded T3SR• Compounded T4 + T3

Achieving Natural T3 Levels

T3 (20%)

T4 (80%)

Cytokines Selenium Deficiency

T3 Supplementation

T4:T3 Combination Therapy• Physiologic is about 5:1• Natural desiccated thyroid is about 4:1• Liothyronine QD, BID, TID• T3SR (E4 Methylcellulose) QD, BID• T3SR with levothyroxine or compounded with T4• Patients less likely to be compliant with BID or TID• Dose of T3 varies with each patient

• 50 year old man with 12 year history of hypothyroidism managed by the Chief of Endocrinology at a major University Medical Center

• Always has taken branded levothyroxine 150 mcg with “perfect” TSH levels

• Reports weight gain, fatigue and dry skin• Requests “new” treatment for his thyroid

What would you do?

(a) Change to natural desiccated thyroid(b) Add liothyronine (c) Change to compounded T3SR/T4(d) Change brand, maintain same dose of

levothyroxine(e) No change. Evaluate for other problems

A patient….on levothyroxine 150mcg, normal TFTs but symptomatic.Treatment options:

1. natural desiccated thyroid 90 mg (1 ½ gradioactiveiodinens)

2. Levothyroxine 100-137 mcg + liothyronine 2.5-10 mcg BID or TID

3. T4:T3SR 50-70/5-10 BID4. Levothyroxine 100-137 mcg + T3SR 5-10 mcg BID5. Change brands or add ½-1 tablet weekly6. Evaluate for other problems

Compounded thyroid hormone

• Accurate dosing critical.• Narrow therapeutic window.• Test products.• T4 only• T3 only• T3SR (E4 Methylcellulose) • T4/T3SR• Tablets: gluten free, lactose free, dye free• Thyroid USP

T4:T3 Dose Considerations

• 5:1?• 4:1?• 3:1?• QD• BID• TID• Customize to the patient.• Give each change at least 6‐8 weeks before assessing.• Ratio needed to control symptoms may change with time.

T4:T3 Combination TherapyConsiderations

Monitor q 6-8 weeks and titrate accordingly Monitor q 3-4 months when stableTSH with symptoms is best monitor, T4 and T3 levels

are less helpfulTry several doses before changing to a new therapyExact ratios seldom workVariability from obesity, stress, illness, mineral

deficiencies, medications and type of thyroid disease all influence dose

Urge compliance!

Adverse Effects of Excessive Thyroid Hormone Replacement

• Overt, symptomatic thyrotoxicosis• Does not cause weight loss• Subclinical thyrotoxicosis• Excess bone loss• Cardiac dysfunction

– Increased pulse rate– Increased cardiac wall thickness– Increased cardiac contractility– Increased risk of atrial fibrillation– Worsening of ischemic heart disease

• Preterm delivery

Counseling Patients

• Counsel patients to know that medications and foods that may interfere with absorption.

• Do not eat within 1 hour of taking thyroid medications.• Do not take antacids, iron, calcium or fiber supplements within

4 hours of taking thyroid medications.• Tell your doctor about other medications you take which may

also interfere with the absorption (bile acid sequestrants, sertraline, sucralfate, phosphate binders).

• Soy products will interfere with absorption.• Tell your doctor if you become pregnant or are planning to

become pregnant.

• Take the medication every day at the same time if possible

• If you miss a dose, it is OK to take a double dose the following day if on T4 alone

• Talk to your doctor if you have symptoms of overreplacement or underreplacement.

• It takes 6‐8 weeks for blood levels to stabilize after a change in dosage or brand.

Counseling Patients

Recommendations:

• Good Sleep Habits• Regular Exercise• Good Nutrition• Stress Reduction• Depression Management• Treatment of Co‐existing Illnesses• Thyroid Support Supplements – No Proven Benefit

Iodine and the Thyroid

• 75% of the body’s iodine is used for thyroid hormone production

• Iodine is 65% of T4's weight, and 58% of T3's• RDA for iodine is 150 mcg daily• Normal iodine consumption in US is 300‐700 mcg• Iodine deficiency does exist in the US, more common abroad

• Iodine deficiency or iodine excess can cause thyroid dysfunction

Case 1: Unusual Thyroid Tests

• 47 year old male• Complains of fatigue, weight gain, insomnia and palpitations

• BP 124/76, HR 72, BMI=27• CMP, CBC, lipids all within normal limits• Normal TSH 0.91 uIU/mL (0.450‐4.500)• High free thyroxine (T4) 1.99 ng/dL (0.82‐1.77)

Case 1: Unusual Thyroid Tests (more information)

• Normal thyroid exam• No family history of thyroid disease• Negative TPO and thyroglobulin antibodies• Repeat TSH was normal (1.12 uIU/mL)

• Original free thyroxine was measured by radioimmunoassay.

• Total T3 and free T3 high normal• Repeat free thyroxine measured by equilibrium dialysis was normal.

Case 1: Unusual Thyroid Tests (more information)

Familial dysalbuminemic hyperthyroxinemia (FDH)

• Euthyroid hyperthyroxinemia (normal TSH, high free and total T4).

• Total T3 and free T3 may be high normal or slightly elevated.

• Inherited variant of serum albumin with preferential affinity for T4.

• Autosomal dominant transmission.• Prevalence is 0.17%.

Thyroxine carrier proteins

Total thyroxine is >99.9% bound to circulating T4 carrier proteins.Thyroid binding globulinAlbumin Prealbumin

Acquired or inherited alterations of T4 carrier proteins can cause changes in T4 and T3 concentrations.

Thyroid hormone testing in FDH

• Equilibrium dialysis: NORMAL Free T4 & Free T3• Radioimmunoassay: HIGH Free T4

Familial dysalbuminemic hyperthyroxinemia(clinical pearls)

• Clinically euthyroid (no clinical manifestations).• Can be confused with hyperthyroidism or thyroid hormone resistance syndromes.

• Patients with FDH may undergo unnecessary diagnostic testing or therapeutic procedures.

• FDH concurrent with primary hypothyroidism may complicate diagnosis or delay therapy.

• After a diagnosis of FDH is established, family screening is advisable.

• 53 year old female• Complains of fatigue, weight loss, insomnia and palpitations

• BP 148/86, HR 100, BMI=23• CMP, CBC, lipids all within normal limits• Thyroid gland is diffusely enlarged• High TSH 6.45 uIU/mL (0.450‐4.500)• High free thyroxine (T4) 2.05 ng/dL (0.82‐1.77)

TSH‐producing pituitary adenoma

• High TSH, high or normal T3 and T4• Clinically hyperthyroid• May be mistaken for primary hypothyroidism, hyperthyroidism or selective pituitary resistance to thyroid hormones

• Patients may be inappropriately treated with radioactive iodine or thyroid surgery

• Elevated molar ratio of α‐subunit to total TSH• May cosecrete growth hormone

• 28 year old female• Complains of fatigue, weight gain, heavy menses• BP 94/66, HR 80, BMI=27• CMP, CBC, lipids all within normal limits• Normal thyroid exam• Normal TSH 3.45 uIU/mL (0.450‐4.500)• High total thyroxine• Normal free thyroxine (T4) 1.02 ng/dL (0.82‐1.77)

TBG Excess

• Most common cause of hyperthyroxinemia• Clinically euthyroid• Normal TSH• High total T4 and normal free T4• High serum TBG• Low T3 resin uptake (normal calculated free thyroxine index)

• Congenital or acquired

Thank you!

Scott Isaacs, M.D., F.A.C.P., F.A.C.E.drisaacs@atlantaendocrine.com

“Hundreds of years of medical progress and all you can do is tell me to take levothyroxine?”

Obtaining CE

If you would like to receive continuing education credit for this activity, please visit:http://pcca.cds.pesgce.com

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