Pathophysiology of thyroid, Pathophysiology of thyroid, parathyroid and sexual parathyroid and sexual

glands.glands. By MD, PhD, Marta R. GerasymchukBy MD, PhD, Marta R. Gerasymchuk,

Pathophysiology departmentPathophysiology departmentIvano-Frankivsk National Medical Ivano-Frankivsk National Medical

UniversityUniversity

CONTENTCONTENT1.1. Pathology of thyroid gland. Hypothyroidism: etiology, Pathology of thyroid gland. Hypothyroidism: etiology,

pathogenesis, mechanisms of development of main pathogenesis, mechanisms of development of main manifestations.manifestations.

2.2. Radiation damage of thyroid gland, endemic goiter, Radiation damage of thyroid gland, endemic goiter, Hashimoto’s autoimmune thyroiditis. Hashimoto’s autoimmune thyroiditis.

3.3. Hyperthyroidism. Diffuse toxic goiter, role of immune Hyperthyroidism. Diffuse toxic goiter, role of immune mechanisms in its development. Pathogenesis of main mechanisms in its development. Pathogenesis of main manifestations of hyperthyroidism.manifestations of hyperthyroidism.

4.4. Pathology of parathyroid glands. Hypo- and Pathology of parathyroid glands. Hypo- and hyperparathyroidism.hyperparathyroidism.

5.5. Pathology of sexual glands. Male hypo- and Pathology of sexual glands. Male hypo- and hypergonadism, etiology and pathogenesis. hypergonadism, etiology and pathogenesis. Eunochoidism.Eunochoidism.

6.6. Female hypo- and hypergonadism. Disorder of sexual Female hypo- and hypergonadism. Disorder of sexual differentiation and development. differentiation and development. Disorders of cyclic functions of female organism; disorders Disorders of cyclic functions of female organism; disorders of pregnancy, delivery and lactation caused by hormones.of pregnancy, delivery and lactation caused by hormones.

7.7. Extragenital manifestations of sexual gland dysfunction. Extragenital manifestations of sexual gland dysfunction. Disorder of endocrine function of placenta.Disorder of endocrine function of placenta.

Actuality of the lectureActuality of the lecture The diseases in the basis of which is the disturbance of the endocrine glands The diseases in the basis of which is the disturbance of the endocrine glands functions are widely spread in all the world. On data the WHO, on a planet is not functions are widely spread in all the world. On data the WHO, on a planet is not less then 200 millions people suffer by diffuse toxic goiter. Except sporadic less then 200 millions people suffer by diffuse toxic goiter. Except sporadic cases ofcases of thyreotoxicosis thyreotoxicosis and and myxedemamyxedema, which meet everywhere, on territory , which meet everywhere, on territory of a number of the states there are regions, where the people are sick of of a number of the states there are regions, where the people are sick of endemic goiter, frequently with manifestations hypo- and hyperfunction of thyroid endemic goiter, frequently with manifestations hypo- and hyperfunction of thyroid gland. In our district such region is the Carpathians. Recently the gland. In our district such region is the Carpathians. Recently the diseases of diseases of thyroid glandthyroid gland show the tendency to increase. This is promoted by such factors: show the tendency to increase. This is promoted by such factors: inadequate receipt of iodium into the organism, radiation (scaning, radiotherapy, inadequate receipt of iodium into the organism, radiation (scaning, radiotherapy, external sources), medical drugs, biphenols, which are used in agricultures, external sources), medical drugs, biphenols, which are used in agricultures, features of nutrition, activity of the person in conditions of high and low features of nutrition, activity of the person in conditions of high and low temperature. The amount of persons with the disturbanced function of thyroid temperature. The amount of persons with the disturbanced function of thyroid gland hardly increased after Chornobel catastroph.gland hardly increased after Chornobel catastroph.The The diseases of parathyreoiddiseases of parathyreoid glands meet not so often. Because of large glands meet not so often. Because of large number and deleted accommodation of the glands of disease and the casual number and deleted accommodation of the glands of disease and the casual damages seldom lead them to destruction of such amount of parathyreoid damages seldom lead them to destruction of such amount of parathyreoid tissues to cause it insufficiency. More often hypofunction of this organ meets in tissues to cause it insufficiency. More often hypofunction of this organ meets in the patients, which the taken place as a result of operating interference on the the patients, which the taken place as a result of operating interference on the thyroid gland the destruction of glands. The second form of parathyreoid thyroid gland the destruction of glands. The second form of parathyreoid insufficiency is ideopatic. This state, it is a result of autoimune response, which insufficiency is ideopatic. This state, it is a result of autoimune response, which are arisen on base of an inflammation, infection, destructive processes in gland. are arisen on base of an inflammation, infection, destructive processes in gland. Hyperfunction of parathyroid glands is observed in many states, which are Hyperfunction of parathyroid glands is observed in many states, which are accompanied by calcium loss (osteomalation, rachitic, renal insufficiency, accompanied by calcium loss (osteomalation, rachitic, renal insufficiency, multiple myeloma,osteoporosis), and also as primary disease due to the multiple myeloma,osteoporosis), and also as primary disease due to the adenoma of one or several endocrine bodies.adenoma of one or several endocrine bodies.

Thyroid GlandThyroid Gland

The thyroid gland and the follicular structure

Chemistry of thyroid hormone Chemistry of thyroid hormone productionproduction

Hormones of the Thyroid GlandHormones of the Thyroid Gland

• Thyroxine (T4)• Principle hormone• Increases energy and protein metabolism

rate• Triiodothyronine (T3)

• Increases energy and protein metabolism rate

• Calcitonin• Regulates calcium metabolism• Works with parathyroid hormone and

vitamin D

Thyroid hormones are synthesised in adults as long as the dietary iodine (I2) supersedes 75 g daily. This is an adequate supply to prevent goiter formation. The daily ingestion of iodide is 400-500 g daily in many areas and the same amount is excreted in the urine in a steady state.

The synthesis in the thyroid gland takes place The synthesis in the thyroid gland takes place in the following way:in the following way:

AA. . Dietary iodine Dietary iodine (I(I22)) is reduced to is reduced to iodide iodide (I-)(I-) in the stomach and gut is in the stomach and gut is rapidly absorbed and circulates as iodide.rapidly absorbed and circulates as iodide.

BB. . Follicular cellsFollicular cells in the thyroid gland possess an active in the thyroid gland possess an active iodide trap iodide trap that that requires and concentrates iodide from the circulating blood. requires and concentrates iodide from the circulating blood. IodideIodide is is transported into the cell against an electrochemical gradient (more than transported into the cell against an electrochemical gradient (more than 50 mV) by a Na+50 mV) by a Na+--I-I---symport. The iodide pump is linked to a symport. The iodide pump is linked to a Na+Na+--K+K+--pump,pump, which requires energy in the form of oxidative phosphorylation which requires energy in the form of oxidative phosphorylation (ATP) and is inhibited by ouabain. The (ATP) and is inhibited by ouabain. The thyroid absorption of iodidethyroid absorption of iodide is is also inhibited by negative ions (such as also inhibited by negative ions (such as perchlorate, pertechnetate, perchlorate, pertechnetate, thiocyanate and nitratethiocyanate and nitrate), because they compete with the iodide at the ), because they compete with the iodide at the trap. trap. In the follicular cellIn the follicular cell, iodide passes down its electrochemical , iodide passes down its electrochemical gradient through the apical membrane and into the follicular colloid. gradient through the apical membrane and into the follicular colloid. Iodide is instantly oxidised – with hydrogen peroxide as oxidant - by a Iodide is instantly oxidised – with hydrogen peroxide as oxidant - by a thyroid peroxidase thyroid peroxidase to atomic or molecular iodine (Ito atomic or molecular iodine (I00 or I or I22) at the colloid ) at the colloid surface of the apical membrane. Thiouracil and sulfonamides block this surface of the apical membrane. Thiouracil and sulfonamides block this peroxidase.peroxidase.

CC. The . The rough endoplasmic reticulumrough endoplasmic reticulum synthesises a large storage synthesises a large storage molecule called molecule called thyroglobulinthyroglobulin. This compound is build up by a long . This compound is build up by a long peptide chain with tyrosine units and a carbohydrate unit completed by peptide chain with tyrosine units and a carbohydrate unit completed by the Golgi apparatus. Iodide-free thyroglobulin is transported in the Golgi apparatus. Iodide-free thyroglobulin is transported in vesiclesvesicles to the apical membrane, where they fuse with the membrane and finally to the apical membrane, where they fuse with the membrane and finally release thyroglobulin at the apical membrane.release thyroglobulin at the apical membrane.

The synthesis in the thyroid gland The synthesis in the thyroid gland takes place in the following way:takes place in the following way:

DD. . At the apical membraneAt the apical membrane the the oxidised iodideoxidised iodide is attached to the is attached to the tyrosine units (L-tyrosine) tyrosine units (L-tyrosine) in thyroglobulinin thyroglobulin at one or two positions, at one or two positions, forming the hormone precursors forming the hormone precursors mono-iodotyrosine mono-iodotyrosine (MIT)(MIT), and , and di-di-iodotyrosine iodotyrosine (DIT),(DIT), respectively. This and the following reactions respectively. This and the following reactions are dependent on are dependent on thyroid peroxidasethyroid peroxidase in the presence of hydrogen in the presence of hydrogen peroxide -both located at the apical membrane. As peroxide -both located at the apical membrane. As MIT couples to MIT couples to DIT it producesDIT it produces tri-iodothyronine tri-iodothyronine (3,5,3`-T3), whereas (3,5,3`-T3), whereas two DIT two DIT moleculesmolecules form form tetra-iodothyronine tetra-iodothyronine (T4),(T4), or or thyroxinethyroxine. These two . These two molecules are the two thyroid hormones. Small amounts of the molecules are the two thyroid hormones. Small amounts of the inactive inactive reverse reverse T3 (3,3`,5`- T3) is also synthesised.T3 (3,3`,5`- T3) is also synthesised.

EE. . Each thyroglobulin moleculeEach thyroglobulin molecule contains up to 4 residues of T4 contains up to 4 residues of T4 and and zero to one T3. zero to one T3. Thyroglobulin is retrieved backThyroglobulin is retrieved back into the follicular into the follicular cell as cell as colloid dropletscolloid droplets by by pinocytosispinocytosis. Pseudopods engulf a pocket . Pseudopods engulf a pocket of colloid. These colloid droplets pass towards the basal membrane of colloid. These colloid droplets pass towards the basal membrane and fuse with and fuse with lysosomeslysosomes forming forming phagolysosomes.phagolysosomes.

FF. . Lysosomal exopeptidasesLysosomal exopeptidases break the binding between break the binding between thyroglobulin and T4thyroglobulin and T4 (or T3). Large quantities of T4 are released to (or T3). Large quantities of T4 are released to the capillary blood. Only minor quantities of T3 are secreted from the capillary blood. Only minor quantities of T3 are secreted from the thyroid gland.the thyroid gland.

GG. The . The proteolysis of thyroglobulinproteolysis of thyroglobulin also releases MIT and DIT. These also releases MIT and DIT. These molecules are deiodinated by the enzyme deiodinase, whereby molecules are deiodinated by the enzyme deiodinase, whereby iodide can be reused into T4 or T3. iodide can be reused into T4 or T3. Normally, only few intact Normally, only few intact thyroglobulin molecules leave the follicular cellsthyroglobulin molecules leave the follicular cells..

HH. . TSHTSH stimulatesstimulates almost all processes involved in almost all processes involved in thyroid thyroid hormone synthesis and secretionhormone synthesis and secretion..

The hypothalamic-pituitary-thyroid feedback system, which regulates the body levels of thyroid hormone.

Control of thyroid gland activityControl of thyroid gland activity The The hypothalamic-pituitary-thyroid axishypothalamic-pituitary-thyroid axis controls the thyroid controls the thyroid

gland function and growth.gland function and growth. a.a. The production and release of thyroid hormone is controlled The production and release of thyroid hormone is controlled

by by thyroid-releasing hormone thyroid-releasing hormone (TRH)(TRH) from the hypothalamus. from the hypothalamus. TRHTRH reaches the reaches the anterior pituitaryanterior pituitary via the portal system, where via the portal system, where

the thyrotropic cells are stimulated to produce the thyrotropic cells are stimulated to produce thyroid-thyroid-stimulating hormone stimulating hormone (TSH) or (TSH) or thyrotropinthyrotropin..

TSHTSH is the is the only known regulatoronly known regulator of thyroid hormone secretion of thyroid hormone secretion in humans. in humans. TSH TSH is released to the systemic blood, by which it is released to the systemic blood, by which it travels to the thyroid gland. Here, travels to the thyroid gland. Here, TSHTSH stimulates the uptake stimulates the uptake of iodide, and all other processes that promote of iodide, and all other processes that promote formation and formation and release of T4 (and T3).release of T4 (and T3).

TSHTSH activates activates adenylcyclaseadenylcyclase bound to the cell membranes of bound to the cell membranes of the follicular cells and the follicular cells and increases their cAMPincreases their cAMP. .

T3 T3 has a strong has a strong inhibitory inhibitory effecteffect on on TRHTRH secretion, as well as secretion, as well as on the on the expression of the gene for the TRH precursor.expression of the gene for the TRH precursor.

Control of thyroid gland Control of thyroid gland activityactivity• bb.. Almost all Almost all circulating circulating T3T3 is derived from T4is derived from T4. . TSHTSH also also

stimulates the stimulates the conversion of T4conversion of T4 to the more to the more biologically biologically activeactive T3 T3. .

• Most of the Most of the circulating thyroid hormonescirculating thyroid hormones are are bound to bound to plasma proteinsplasma proteins, whereby the hormone is protected during , whereby the hormone is protected during transport. There is an equilibrium between the pool of transport. There is an equilibrium between the pool of protein-bound thyroid hormone and the free, biologically protein-bound thyroid hormone and the free, biologically active forms (T3 and T4) that can enter the body cells. active forms (T3 and T4) that can enter the body cells.

• Thyroid hormonesThyroid hormones are are lipid-solublelipid-soluble and they can and they can easily easily crosscross the cellular membrane by diffusion the cellular membrane by diffusion..

• cc.. Inside the cell, Inside the cell, T3T3 binds to binds to nuclear receptorsnuclear receptors and and stimulates cellular metabolism and stimulates cellular metabolism and increases increases metabolic metabolic raterate..

• dd.. The concentrations of The concentrations of T3T3 and and T4T4 in the blood are in the blood are recorded recorded by by pituitary and hypothalamic receptorspituitary and hypothalamic receptors. .

• This This negative feedback systemnegative feedback system keeps the blood keeps the blood concentrations within normal limits, and there is only a concentrations within normal limits, and there is only a minimal minimal nocturnal nocturnal increase in TSH secretion and T4 increase in TSH secretion and T4 releaserelease..

The hypothalamic-pituitary-thyroid axis controls the thyroid gland function and growth.

Actions of thyroid hormonesActions of thyroid hormones Thyroid hormones are lipid-soluble and pass through cell membranes easily. T3 binds to specific nuclear receptor

proteins with an affinity that is tenfold greater than the affinity for T4. The information alters DNA transcription into mRNA, and the information is eventually translated into many effector proteins. One type of thyroid receptor protein is bound to thyroid regulatory elements in target cell genes.

Important cellular constituents are stimulated by T3: The mitochondria, the Na+-K+-pump, myosin ATPase, adrenergic b-receptors, many enzyme systems and proteins for growth and maturation including CNS development.

Thyroid hormones stimulate oxygen consumption in almost all cells. Thyroid hormones stimulate the rate of: 1) hepatic glucose output and peripheral glucose utilisation; 2) hepatic metabolism of fatty acids, cholesterol and triglycerides; 3) the synthesis of important proteins (the Na+-K+-pump, respiratory

enzymes, erythropoietin, b-adrenergic receptors, sex hormones, growth factors etc);

4) the absorption of carbohydrates in the intestine and the gut excretion of cholesterol;

5) the modulation of reproductive function.

Actions of thyroid hormonesActions of thyroid hormones The many rate-stimulating effects are summarized in The many rate-stimulating effects are summarized in

an overall increase in an overall increase in oxygen consumptionoxygen consumption. This slow - . This slow - but long lasting - but long lasting - calorigeniccalorigenic and and thermogenic thermogenic effect effect is confined to the is confined to the mitochondriamitochondria..

The The thyroid hormones and the catecholaminesthyroid hormones and the catecholamines work work togethertogether in metabolic acceleration. in metabolic acceleration.

Thyroid hormones Thyroid hormones increase cardiac rate and output as increase cardiac rate and output as well as ventilationwell as ventilation..

The The high basal metabolic rate raiseshigh basal metabolic rate raises the the core and core and shell temperatureshell temperature, so that the , so that the peripheral vessels peripheral vessels dilatatedilatate. This . This vasodilatation forces the cardiac output vasodilatation forces the cardiac output to increaseto increase. A . A circulatory shock developscirculatory shock develops, , if the rise in if the rise in cardiac output is insufficient to match the cardiac output is insufficient to match the vasodilatationvasodilatation - socalled - socalled high output failurehigh output failure..

A human body overloaded with thyroid hormones for a A human body overloaded with thyroid hormones for a prolonged period (prolonged period (hyperthyroidismhyperthyroidism) will suffer from ) will suffer from muscle atrophia, bone destruction and hunger muscle atrophia, bone destruction and hunger damagedamage, due to , due to increased catabolism of cellular increased catabolism of cellular proteins and fatproteins and fat. Eventually . Eventually hypothyroidismhypothyroidism may may develop due to suppression.develop due to suppression.

Calcitonin Calcitonin is produced by the parafollicular C-cells of the thyroid.is produced by the parafollicular C-cells of the thyroid.

CalcitoninCalcitonin inhibits bone resorptioninhibits bone resorption by blocking the by blocking the parathyroid hormone (PTH)-receptorsparathyroid hormone (PTH)-receptors on the osteoclasts. on the osteoclasts. The result is an extremely effective lowering of plasma-The result is an extremely effective lowering of plasma-CaCa22++ and - and -phosphatephosphate. Calcitonin is important in bone . Calcitonin is important in bone remodelling and in treatment of remodelling and in treatment of osteoporosisosteoporosis..

CalcitoninCalcitonin is a single-chain peptide with a disulphide ring, is a single-chain peptide with a disulphide ring, containing containing 32 amino acids32 amino acids. Calcitonin . Calcitonin is secretedis secreted from the from the thyroid gland thyroid gland in response to hypercalcaemiain response to hypercalcaemia and it and it acts to acts to lower plasma [Calower plasma [Ca22+],+], as opposed to the effect of PTH. as opposed to the effect of PTH.

Administration of calcitonin Administration of calcitonin leads to a rapid fall in plasma leads to a rapid fall in plasma [Ca[Ca22+].+]. Calcitonin Calcitonin is the is the physiologic antagonist physiologic antagonist to PTHto PTH and and inhibits Cainhibits Ca22+ -liberation from bone+ -liberation from bone (ie, (ie, inhibits both inhibits both osteolysis by osteocytes and bone resorption by osteolysis by osteocytes and bone resorption by osteoclastsosteoclasts). But calcitonin ). But calcitonin reduces plasma phosphate just reduces plasma phosphate just as PTHas PTH..

Calcitonin Calcitonin probably probably inhibits reabsorption of phosphateinhibits reabsorption of phosphate in in the distal tubules of the kidney, but calcitonin also the distal tubules of the kidney, but calcitonin also inhibits inhibits the renal reabsorp tion of Cathe renal reabsorp tion of Ca22+, Na+ and Mg+, Na+ and Mg22+.+. Calcitonin Calcitonin may may inhibit gut absorption of Cainhibit gut absorption of Ca22++ and and promote phosphate promote phosphate entrance into boneentrance into bone and cause important bone remodelling. and cause important bone remodelling.

Calcitonin deficiencyCalcitonin deficiency does not leaddoes not lead to to hypercalcaemiahypercalcaemia, and , and excess excess calcitonin from tumours does not lead to hypocalcaemiacalcitonin from tumours does not lead to hypocalcaemia. . Therefore, most effects of calcitonin are evidently offset by Therefore, most effects of calcitonin are evidently offset by appropriate regulation through the actions of appropriate regulation through the actions of PTHPTH and and vitamin Dvitamin D..

CalcitoninCalcitonin in plasma declines with age and in plasma declines with age and is lower in women is lower in women than in menthan in men. Low levels of calcitonin are involved in accelerated . Low levels of calcitonin are involved in accelerated bone loss with age and after menopause (bone loss with age and after menopause (osteoporosisosteoporosis).).

CalcitoninCalcitonin protects the protects the female skeletonfemale skeleton from the from the drain of Cadrain of Ca22+ + during pregnancy and lactation.during pregnancy and lactation.

CalcitoninCalcitonin is a is a neurotransmitterneurotransmitter in in the hypothalamus the hypothalamus and in other CNS and in other CNS locations.locations.

Calcitonin Calcitonin is is administered to administered to postmenopausal postmenopausal femalesfemales in attempt to in attempt to prevent prevent osteoporosis.osteoporosis.

Disorders of the Thyroid GlandDisorders of the Thyroid Gland

• GoiterGoiter is enlargement of thyroid gland is enlargement of thyroid gland• Simple goiterSimple goiter• Adenomatous or nodular goiterAdenomatous or nodular goiter

• HypothyroidismHypothyroidism• Infantile hypothyroidism (cretinism)Infantile hypothyroidism (cretinism)

• MyxedemaMyxedema• HyperthyroidismHyperthyroidism

• Graves diseaseGraves disease• Thyroid stormThyroid storm

• ThyroiditisThyroiditis• Hashimoto diseaseHashimoto disease

Hypothyroidism (Hashimoto’s disease, Goiter) and Hyperthyroidism (Graves’ disease)

HyperthyroidismHyperthyroidism The The classical hyperthyroidismclassical hyperthyroidism or thyrotoxicosis (Graves or thyrotoxicosis (Graves

thyroiditis, Basedows disease) is a condition thyroiditis, Basedows disease) is a condition characterized by an abnormal rise in basal metabolic characterized by an abnormal rise in basal metabolic rate, struma and eye signs (thyroid eye disease). The rate, struma and eye signs (thyroid eye disease). The eyes of the patient typically bulge (ie, eyes of the patient typically bulge (ie, exophtalmusexophtalmus). ). Patients with Patients with thyrotoxicosisthyrotoxicosis have overwhelmingly high have overwhelmingly high metabolic rates.metabolic rates.

Neuromuscular systemNeuromuscular system Tremors, hyperactivity, emotional lability, anxiety, Tremors, hyperactivity, emotional lability, anxiety,

inability to concentrate, insomniainability to concentrate, insomnia Thyroid myopathy – proximal muscle weakness with Thyroid myopathy – proximal muscle weakness with

decrease muscle massdecrease muscle mass Ocular changesOcular changes

Wide, staring gaze and lid lagWide, staring gaze and lid lag Thyroid ophthalmopathyThyroid ophthalmopathy

Gastrointestinal systemGastrointestinal system Hypermotility, malabsorption, and diarrheaHypermotility, malabsorption, and diarrhea

Skeletal systemSkeletal system Stimulates bone resorption (inc. porosity of cortical Stimulates bone resorption (inc. porosity of cortical

bone and reduced volume of trabecular bone)bone and reduced volume of trabecular bone) Osteoporosis and increased risk of fracturesOsteoporosis and increased risk of fractures

Graves DiseaseGraves Disease

The disease is named for Robert Graves The disease is named for Robert Graves who in 1835 first identified the association who in 1835 first identified the association of goiter, palpitations, and exophthalmos. of goiter, palpitations, and exophthalmos.

Most common cause of endogenous Most common cause of endogenous hyperthyroidismhyperthyroidism

Triad:Triad:– HyperthyroidismHyperthyroidism– Infiltrative ophthalmopathy with resultant Infiltrative ophthalmopathy with resultant

exophthalmosexophthalmos– Localized, infiltrative dermopathy (pretibial Localized, infiltrative dermopathy (pretibial

myxedema)myxedema)

Hyperthyroidism Hyperthyroidism ((Graves DiseaseGraves Disease)) Thyroid eye diseaseThyroid eye disease (with exophtalmus) is not confined (with exophtalmus) is not confined

to Graves’s hyperthyroidism only. Some exophtalmus to Graves’s hyperthyroidism only. Some exophtalmus patients are euthyroid or hypothyroid. patients are euthyroid or hypothyroid.

Common to all types of thyroid eye diseases are Common to all types of thyroid eye diseases are specific antibodiesspecific antibodies that cause inflammation of the that cause inflammation of the retro-retro-orbital tissueorbital tissue with with swellingswelling of the of the extraocular eye extraocular eye musclesmuscles, so , so they cannot move the eyes normallythey cannot move the eyes normally. .

ProptosisProptosis and and lid lagslid lags are are typical signstypical signs, and , and conjunctivitis and scarsconjunctivitis and scars on the cornea follow due to lack on the cornea follow due to lack of protective cover. of protective cover.

The The oedematous retro-orbital tissueoedematous retro-orbital tissue may force the eye may force the eye balls forward and press on the optic nerveballs forward and press on the optic nerve to such an to such an extent that vision is impaired or blindnessextent that vision is impaired or blindness results. results.

The best treatment is to normalise the accompanying The best treatment is to normalise the accompanying thyrotoxicosis. Other therapeutic measures are thyrotoxicosis. Other therapeutic measures are palliative.palliative.

Lid lag in Graves disease

Hyperthyroidism Hyperthyroidism ((Graves DiseaseGraves Disease))TSH receptor antibodyTSH receptor antibody ( (IgG antibodiesIgG antibodies) release causes Graves’s disease ) release causes Graves’s disease from activated B-cellsfrom activated B-cells. A genetic deficiency is involved, which is shown by . A genetic deficiency is involved, which is shown by the 50% concordance in monozygotic twins. the 50% concordance in monozygotic twins. Trigger mechanismsTrigger mechanisms are are presumed to be bacterial or viral infections producing presumed to be bacterial or viral infections producing autoimmune autoimmune phenomenaphenomena in genetically deficient individuals. in genetically deficient individuals. The autoimmune system can produce the following autoantibodies:The autoimmune system can produce the following autoantibodies:

1.   1.   TSH-receptor antibodiesTSH-receptor antibodies to the to the TSH TSH receptors (antigens)receptors (antigens) on the on the surface of surface of the thyroid follicular cellsthe thyroid follicular cells, which they , which they stimulate just like TSH itself, stimulate just like TSH itself, causing causing thyroid hypersecretionthyroid hypersecretion. These . These IgG IgG antibodiesantibodies are also termed are also termed long-long-acting thyroid stimulatoracting thyroid stimulator..

2.   2.   Specific autoantibodiesSpecific autoantibodies causing causing retro-orbital inflammation and thyroid retro-orbital inflammation and thyroid eye diseaseeye disease..

3.   3.   ThyroglobinThyroglobin antibodiesantibodies against the against the storage molecule, thyroglobin.storage molecule, thyroglobin.

4.   4.   Microsomal antibodiesMicrosomal antibodies against against thyroid peroxidasethyroid peroxidase..These These autoantibodiesautoantibodies can be found in can be found in the plasma of most cases of Grave’s the plasma of most cases of Grave’s disease.disease.

The increased The increased metabolic ratemetabolic rate and and sympatho-adrenergic activitysympatho-adrenergic activity dominate the patient. dominate the patient.

The patient isThe patient is anxious with warm and sweaty skin, anxious with warm and sweaty skin, tachycardia, tachycardia, palpitations, palpitations, fine finger tremor, fine finger tremor, pretibial myxoedema (ie, accumulation of mucopolysaccharides). pretibial myxoedema (ie, accumulation of mucopolysaccharides). Typically is a Typically is a symmetrical, warm pulsating goitresymmetrical, warm pulsating goitre. Lean . Lean

hyperthyroid females - like female distance runners - have hyperthyroid females - like female distance runners - have small small fat storesfat stores and and greatly reduced menstrual bleedingsgreatly reduced menstrual bleedings ((oligomenorrhoeaoligomenorrhoea) or even ) or even amenorrhoeaamenorrhoea. .

The The high T3high T3 level level increases the density of increases the density of -adrenergic receptors-adrenergic receptors on the myocardial cellson the myocardial cells. The . The cardiac output is highcardiac output is high even at rest and even at rest and arrhythmias are frequentarrhythmias are frequent (eg, atrial fibrillation). (eg, atrial fibrillation).

Elderly patientsElderly patients may present with an may present with an apathetic hyperthyroidismapathetic hyperthyroidism, , where where they complain of tiredness and somnolencethey complain of tiredness and somnolence. Measurement . Measurement of serum TSH with T3/T4 reveals that the diagnosis of serum TSH with T3/T4 reveals that the diagnosis is not hypo- but is not hypo- but hyperthyroidismhyperthyroidism.. Erroneous treatment with thyroid hormone Erroneous treatment with thyroid hormone can can kill the patientkill the patient by causing vasodilatation and by causing vasodilatation and cardiac output cardiac output failurefailure..

A suppressed serum TSH confirms the diagnosis of A suppressed serum TSH confirms the diagnosis of hyperthyroidism, and the serum T3 or T4 is raised.hyperthyroidism, and the serum T3 or T4 is raised.

The pathogenesis of Graves disease, and the The pathogenesis of Graves disease, and the clinical manifestations of Graves’s disease.clinical manifestations of Graves’s disease.

The pathogenesis of Graves disease, and The pathogenesis of Graves disease, and the clinical manifestations of Graves’s the clinical manifestations of Graves’s

disease.disease.► Several drugs are used in the treatment of hyperthyroidism.Several drugs are used in the treatment of hyperthyroidism.► CarbimazoleCarbimazole and and methimazolemethimazole inhibit the production of thyroid inhibit the production of thyroid

hormonehormone and and have immuno-suppressive actionshave immuno-suppressive actions..► Monovalent anions and Monovalent anions and ouabainouabain inhibit inhibit the iodide trap.the iodide trap.► ThiocarbamideThiocarbamide inhibitsinhibits the iodination of tyrosyl residues. the iodination of tyrosyl residues.► SulphonamidesSulphonamides inhibitinhibit thyroid peroxidase, which oxidises iodide thyroid peroxidase, which oxidises iodide

to iodine.to iodine.► Large doses of iodideLarge doses of iodide inhibit inhibit the TSH-receptors on the thyroid the TSH-receptors on the thyroid

gland.gland.► The The high activity of the sympatho-adrenergichigh activity of the sympatho-adrenergic system is system is inhibited inhibited

by by -blockers-blockers, preferably , preferably with central sedative effectswith central sedative effects..► Subtotal thyroidectomySubtotal thyroidectomy is used to treat patients with a large is used to treat patients with a large

goiter, or patients with severe side effects to drug therapy.goiter, or patients with severe side effects to drug therapy.► Radioactive iodineRadioactive iodine is stored in the gland and destroys the follicle is stored in the gland and destroys the follicle

cells. This therapy is complicated, and some patients develop cells. This therapy is complicated, and some patients develop hypothyroidism. hypothyroidism.

Toxic goiterToxic goiter and and toxic solitary adenoma toxic solitary adenoma (Plummers disease) are cases of (Plummers disease) are cases of secondary secondary hyperthyroidism hyperthyroidism just as inflammation in just as inflammation in acute thyroiditis acute thyroiditis and and chronic thyroiditis. chronic thyroiditis. The cells secrete thyroid hormone without The cells secrete thyroid hormone without inhibition from the hypothalamo-pituitary inhibition from the hypothalamo-pituitary axis.axis.

Thyroid scintigraphies. Thyroid scintigraphies. A. Graves’ Disease. Diffuse thyroid uptake. A. Graves’ Disease. Diffuse thyroid uptake. B. Plummer’s Disease. Nodular uptake on left thyoid lobe B. Plummer’s Disease. Nodular uptake on left thyoid lobe with suppression of the gland.with suppression of the gland.

Hypothyroidism

Primary hypothyroidism is an abnormally low activity of the thyroid gland with low circulating thyroid hormone levels caused by thyroid disease.

Secondary hypothyroidism results from hypothalamic-pituitary disease.

Primary hypothyroidism is caused by microsomal autoantibodies precipitated in the glandular tissue. Lymphoid infiltration of the thyroid may eventually lead to atrophy with abnormally low production of T4. Another clinical form starts out as Hashimotos thyroiditis, often with hyperthyroidism and goiter.

Following atrophy caused by microsomal autoantibodies, the condition ends as hypothyroidism, or the patient is euthyroid.

• When hypothyroidismhypothyroidism is congenital both physical and mental development is impaired and cretinism is the result. Also iodide deficiency in childhood may also result in a cretincretin or a mentally retarded hypothyroid dwarf.

• Myxoedema in the adult is severe thyroid gland hypothyroidism with a puffy swollen face due to a hard, non-pitting oedema (called myxoedema or tortoise skin). The skin is dry and cold; there is bradycardia, often cardiomegaly (ie, myxoedema heart), hair loss, constipation, muscle weakness and anovulatory cycles in females.

• A high TSH level and a low total or free T4 in plasma confirms the diagnosis primary hypothyroidism. Thyroid autoantibodies are usually demonstrable in the plasma. Hypercholesterolaemia and increased concentrations of liver and muscle enzymes (aspartate transferase, creatine kinase) in the plasma is typical.

• As stated thyroid gland high TSH characterises hypothyroidism. A test dose of TSH to a patient with thyroid hypothyroidism will not stimulate the thyroid gland.

• A test dose of TRH (Thyroid releasing hormone) will result in an increased TSH response in thyroid gland hypothyroidism and decrease in hyperthyroidism. This is due to the negative feedback of thyroid hormones on the hypophysis.

• Hypothyroid females often have excessive and frequent menstrual bleedings (menorrhagia and polymenorrhoea). Hypothyroid patients exhibit slow cardiac activity.

Secondary hypothyroidismSecondary hypothyroidism is caused is caused by reduced TSH (by reduced TSH (Thyroid stimulating Thyroid stimulating hormonehormone) drive due to pituitary or ) drive due to pituitary or hypothalamic insufficiency. A test hypothalamic insufficiency. A test dose of TRH (dose of TRH (Thyroid releasing Thyroid releasing hormonehormone) to a myxoedema patient ) to a myxoedema patient with hypothalamic or pituitary with hypothalamic or pituitary insufficiency will result in a normal insufficiency will result in a normal TSH response.TSH response.

Replacement is given to the Replacement is given to the hypothyroid patient with hypothyroid patient with approximately 100 approximately 100 g T4 daily for the g T4 daily for the rest of the patients life.rest of the patients life.

HYPO-THYROIDISMHYPO-THYROIDISM CretinismCretinism

• Severe retardationSevere retardation• CNS/Musc-skelCNS/Musc-skel• Short statureShort stature• Protruding tongueProtruding tongue• Umbilical herniaUmbilical hernia• Maternal iodine defic.Maternal iodine defic.

Myxedema (coma)Myxedema (coma)• SluggishnessSluggishness• Cold skinCold skin

Structural or functional Structural or functional derangement that interfere with derangement that interfere with the production of adequate the production of adequate levels of thyroid hormonelevels of thyroid hormonePrimary, secondary, or tertiaryPrimary, secondary, or tertiary

CretinismCretinismHypothyroidism that occurs in infancy Hypothyroidism that occurs in infancy or early childhoodor early childhoodImpaired development of the skeletal Impaired development of the skeletal system and CNSsystem and CNSManifests as Manifests as severe mental severe mental retardationretardation, short stature, coarse facial , short stature, coarse facial features, protruding tongue and features, protruding tongue and umbilical herniaumbilical hernia

Cretinism, also known as Neonatal hypothyroidism

is decreased thyroid hormone production in a newborn.

CretinismCretinism This 1 year old baby This 1 year old baby was diagnosed with was diagnosed with Cretinism.The thyroid Cretinism.The thyroid profile showed a profile showed a hypothyroid picture. hypothyroid picture. Replacement therapy Replacement therapy has been started.has been started.

These four brothers work at a salt factory in Pakistan. Two of them suffer from cretinism, caused by iodine deficiency. All the brothers ensure they use iodized salt in their households to prevent cretinism in the next generation and give their children the iodine they need for intellectual development.

HH → Hypotonia → 1→ Hypotonia → 1 YY → Yellow (icterus >3) →1 → Yellow (icterus >3) →1 PP → Pallor, cold, hypothermia →1 → Pallor, cold, hypothermia →1 OO → Open post. fontanel →1 → Open post. fontanel →1 TT → Tongue enlarged →1 → Tongue enlarged →1 HH → Umbilical hernia →2 → Umbilical hernia →2 YY → absent Y (female) →1 → absent Y (female) →1 RR → Rough dry skin →1 → Rough dry skin →1 OO → Edematous typical face →2 → Edematous typical face →2 I.DI.D.→ Inactive defecation → 2 .→ Inactive defecation → 2 Birth weightBirth weight > 3.5 kg →1 > 3.5 kg →1 Post.maturePost.mature > 40w →1 > 40w →1 Total = 15.Total = 15. If score > 5If score > 5 suggest hypothyroidism, suggest hypothyroidism, must investigate.must investigate.

APGAR score of early suspicion of hypothyroidism

Simple Mnemonics for Clinical Simple Mnemonics for Clinical picture of cretinismpicture of cretinism at birth & early neonatal : 1- Feeding difficulty, choking & anorexia

2- Constipation, abdomenal distention, umbilical hernia, delayed passage of meconium 3- Heavy birth weight (Over weight). 4- Hypothermia, cold skin. 5- Open posterior fontanel. 6- Less activity, always sleep, little cry hoarse voice. 7- Prolonged physiological jaundice. 8- Bradycardia: ↓ HR (Slow Pulse) . 9- Apneic attacks: ↓ Respiratory rate. 10- X- Ray knee: absent ossific centers at birth of the lower end of the femur.

Typical Typical Symptoms & Symptoms &

Signs:Signs: • 3- Skin:

Pale yellow skin (carotenemia). & Dry, rough, cold.

• 4- Abdomen: Pott's belly abdomen. & Umbilical hernia.

• 5- C.V.S:  Bradycardia.

•  Haemic murmur. •  Cardiomegally → CHF. • 6- C.N.S:

Hypotonia • Hyporeflexia, • apathy.

• A- Delayed growth & development and metal retardation. Delayed motor mile stones.

• Delayed social development. • Growth retardation & short stature . • B- Characteristic features:

1- Head: Face → coarse puffy face.

• Skull → delayed closure of fontanels (anterior).

• Hair → coarse dry hair, low hair line. • Eyes → hypertdorism, puffy eye lids,

scanty hair of brows. •  Nose → depressed nasal bridge. •  Tongue → macroglossia, thick lips. •  Teeth → delayed eruption, tendency

to decay. • 2- Neck:

short & webbed. & thyroid may palpable.

MyxedemaMyxedema Hypothyroidism developing in the older child or adultHypothyroidism developing in the older child or adult Gull diseaseGull disease Characterized by slowing of physical and mental Characterized by slowing of physical and mental

activity activity Accumulation of matrix substances Accumulation of matrix substances

((glycosaminoglycans and hyaluronic acidglycosaminoglycans and hyaluronic acid) in the ) in the skin, skin, subcutaneous tissues, and visceral sitessubcutaneous tissues, and visceral sites edemaedema, , broadening and coarsening of facial features, broadening and coarsening of facial features, enlargement of the tongue, and deepening of the enlargement of the tongue, and deepening of the voicevoice

Measurement of serum Measurement of serum TSH levelTSH level is the most is the most sensitive sensitive screening testscreening test

Primary Primary hypotyrioidismhypotyrioidism

MyxedemaMyxedema

Myxedematous Coma.Myxedematous Coma.• Myxedematous comaMyxedematous coma is a lifethreatening, is a lifethreatening, end-stage end-stage

expression of hypothyroidismexpression of hypothyroidism. . • It is characterized by coma, It is characterized by coma, hypothermia, cardiovascular hypothermia, cardiovascular

collapse, hypoventilation, and severe metabolic disorders that collapse, hypoventilation, and severe metabolic disorders that include hyponatremia, hypoglycemia, and lactic acidosisinclude hyponatremia, hypoglycemia, and lactic acidosis. It . It occurs most often in elderly women who have chronic occurs most often in elderly women who have chronic hypothyroidism from a spectrum of causes. It occurs more hypothyroidism from a spectrum of causes. It occurs more frequently in the winter monthsfrequently in the winter months, which suggests that cold , which suggests that cold exposure may be a precipitating factor. The exposure may be a precipitating factor. The severely severely hypothyroid person is hypothyroid person is unable to metabolizeunable to metabolize sedatives, sedatives, analgesics, and anesthetic drugs, and buildup of these agents analgesics, and anesthetic drugs, and buildup of these agents may precipitate comamay precipitate coma..

• TreatmentTreatment includes aggressive management of precipitating includes aggressive management of precipitating factors; supportive therapy such as management of factors; supportive therapy such as management of cardiorespiratory status, hyponatremia, and hypoglycemia; and cardiorespiratory status, hyponatremia, and hypoglycemia; and thyroid replacement therapy. thyroid replacement therapy. PreventionPrevention is preferable to is preferable to treatment and entails treatment and entails special attention to high-risk populationsspecial attention to high-risk populations, , such as such as women with a history of Hashimoto’s thyroiditiswomen with a history of Hashimoto’s thyroiditis. These . These persons should be informed about the signs and symptoms of persons should be informed about the signs and symptoms of severe hypothyroidism and the need for early medical severe hypothyroidism and the need for early medical treatment.treatment.

Diffuse and Multinodular GoitersDiffuse and Multinodular Goiters

• Reflect impaired synthesis of thyroid hormonesReflect impaired synthesis of thyroid hormones• Diffuse nontoxic (simple) goiterDiffuse nontoxic (simple) goiter

– Diffusely involves the entire gland without producing Diffusely involves the entire gland without producing nodularitynodularity

– Enlarged follicles are filled with colloid = colloid goiterEnlarged follicles are filled with colloid = colloid goiter

• Multinodular goiterMultinodular goiter– Irregular enlargement of the glandIrregular enlargement of the gland– Produce the most extreme enlargement and are more Produce the most extreme enlargement and are more

mistaken for neoplastic involvement than any other mistaken for neoplastic involvement than any other form of thyroid diseaseform of thyroid disease

GOITERGOITER • ENLARGEMENT OF THE THYROID GLAND.ENLARGEMENT OF THE THYROID GLAND.TYPES:TYPES:

TOXIC NODULARTOXIC NODULAR • COMMON IN ELDERLYCOMMON IN ELDERLY• FROM LONG STANDING SIMPLE GOITERFROM LONG STANDING SIMPLE GOITER• NODULES NODULES

– FUNCTIONING TISSUE FUNCTIONING TISSUE – SECRETES THYROXINE AUTONOMOUSLY FROM SECRETES THYROXINE AUTONOMOUSLY FROM

TSHTSH

• NONTOXIC NONTOXIC SIMPLE/ COLLOID/ EUTHYROID)SIMPLE/ COLLOID/ EUTHYROID)

CAUSE :CAUSE :• IODINE DEFICIENCYIODINE DEFICIENCY• INTAKE OF GOITROGENIC SUBSTANCES/ INTAKE OF GOITROGENIC SUBSTANCES/

DRUGS:DRUGS:– CASSAVA,CASSAVA,– CABBAGE,CABBAGE,– CAULIFLOWER, CAULIFLOWER, – CARROTSCARROTS– RADDISHRADDISH– TURNIPSTURNIPS– RED SKIN OF PEANUTSRED SKIN OF PEANUTS– IODINEIODINE– COBALTCOBALT– LITHIUMLITHIUM

Many vegetables are goiterogens, fruits are NOT. Which one is NOT a goiterogen?Many vegetables are goiterogens, fruits are NOT. Which one is NOT a goiterogen?

NON-TOXIC GOITERNON-TOXIC GOITER

IMPAIRED THYROID HORMONE SYNTHESISIMPAIRED THYROID HORMONE SYNTHESIS

SERUM THYROXINESERUM THYROXINE

PITUITARY SECRETE TSHPITUITARY SECRETE TSH

THYROID GLAND ENLARGESTHYROID GLAND ENLARGES

TO COMPENSATE FOR THE REDUCED LEVEL OF THYROXINETO COMPENSATE FOR THE REDUCED LEVEL OF THYROXINE

IODINE DEFICIENCY OR IODINE DEFICIENCY OR INTAKE OF GOITROGENIC SUBSTANCESINTAKE OF GOITROGENIC SUBSTANCES

GOITER

Multinodular Multinodular goitergoiter

Hashimoto ThyroiditisHashimoto Thyroiditis Chronic lymphocytic thyroiditisChronic lymphocytic thyroiditis Struma lymphomatosaStruma lymphomatosa Most common cause of Most common cause of

hypothyroidism in areas of the hypothyroidism in areas of the world where iodine levels are world where iodine levels are sufficientsufficient

Pathogenesis:Pathogenesis: CD8+ cytotoxic T-cell mediated CD8+ cytotoxic T-cell mediated

cell deathcell death Cytokine mediated cell deathCytokine mediated cell death Binding of anti-thyroid Ab’s Binding of anti-thyroid Ab’s

ADCCADCC Anti-TSH receptor Ab’s, Anti-TSH receptor Ab’s,

antithyroglobulin, antithyroid antithyroglobulin, antithyroid peroxidase Ab’speroxidase Ab’s

A woman presenting with an enlarged thyroid who has Hashimoto's thyroiditis

Hashimoto’s thyroiditisHashimoto’s thyroiditis is is the most common form of the most common form of thyroiditis. It is a thyroiditis. It is a form of form of autoimmuneautoimmune thyroditis thyroditis; more ; more common in common in women and in late middle agewomen and in late middle age. Thyroid . Thyroid peroxidase (TPO) antibodies are usually present in this peroxidase (TPO) antibodies are usually present in this condition, often in very high levels. It may be associated condition, often in very high levels. It may be associated with other endocrine organ deficiencies such as with other endocrine organ deficiencies such as diabetes diabetes mellitus or Addison's disease.mellitus or Addison's disease.    Hashimoto’s thyroiditisHashimoto’s thyroiditis also occurs more commonly in also occurs more commonly in patients with Down’s and Turner’s syndromes.patients with Down’s and Turner’s syndromes.It produces atrophic changes with regeneration. This can It produces atrophic changes with regeneration. This can lead to a goitelead to a goiterr forming. Patients with forming. Patients with Hashimoto’s thyroiditisHashimoto’s thyroiditis are usually are usually hypothyroid or euthyroidhypothyroid or euthyroid. However, they may . However, they may have an initial thyrotoxic phase at presentation.have an initial thyrotoxic phase at presentation.Specific Specific helper-T lymphocyteshelper-T lymphocytes are activated in this condition are activated in this condition which results in an which results in an immune response directed against the immune response directed against the thyroid cellthyroid cell. This activation may be triggered by a viral . This activation may be triggered by a viral infection.infection.Although thyroid lymphoma is rare, the risk of thyroid Although thyroid lymphoma is rare, the risk of thyroid lymphoma is increased 60-fold in patients with Hashimoto’s lymphoma is increased 60-fold in patients with Hashimoto’s thyroiditis. Patients presenting with a new thyroid lump thyroiditis. Patients presenting with a new thyroid lump should undergo fine-needle aspiration biopsy.should undergo fine-needle aspiration biopsy.

Riedel ThyroiditisRiedel Thyroiditis Rare disorder of unknown etiologyRare disorder of unknown etiology Extensive fibrosis involving the Extensive fibrosis involving the thyroid and contiguous neck structuresthyroid and contiguous neck structures Hard and fixed thyroid massHard and fixed thyroid mass Riedel's thyroiditis is classified as rare. Most patients remain Riedel's thyroiditis is classified as rare. Most patients remain

euthyroideuthyroid, but approximately 30% of patients become , but approximately 30% of patients become hypothyroidhypothyroid and very few patients are and very few patients are hyperthyroidhyperthyroid. It is most . It is most seen in womenseen in women..

RRiedel’s thyroiditisiedel’s thyroiditis is a very rare chronic inflammatory disorder is a very rare chronic inflammatory disorder that leads to that leads to progressive fibrosisprogressive fibrosis of the thyroid gland of of the thyroid gland of unknown cause. It is often associated with other unknown cause. It is often associated with other fibroproliferative disorders (e.g. mediastinal and fibroproliferative disorders (e.g. mediastinal and retroperitoneal fibrosis, sclerosing cholangitis). Patients retroperitoneal fibrosis, sclerosing cholangitis). Patients present with a rock-hard, fixed and painless goitepresent with a rock-hard, fixed and painless goiter.r.

Manifestations of Hypothyroid and Manifestations of Hypothyroid and Hyperthyroid StatesHyperthyroid States

Level of Organization Hypothyroidism Hyperthyroidism

Basal metabolic rate Decreased Increased

Sensitivity to catecholamines

Decreased Increased

General featuresMyxedematous featuresDeep voiceImpaired growth (child)

ExophthalmosLid lagDecreased blinking

Blood cholesterol levels Increased Decreased

General behaviorMental retardation (infant)Mental and physical sluggishnessSomnolence

Restlessness, irritability, anxietyHyperkinesisWakefulness

Cardiovascular functionDecreased cardiac outputBradycardia

Increased cardiac outputTachycardia and palpitations

Gastrointestinal functionConstipationDecreased appetite

DiarrheaIncreased appetite

Respiratory function Hypoventilation Dyspnea

Muscle tone and reflexesDecreased Increased, with tremor and fibrillatory

twitching

Temperature tolerance Cold intolerance Heat intolerance

Skin and hairDecreased sweatingCoarse and dry skin and hair

Increased sweatingThin and silky skin and hair

Weight Gain Loss

The Parathyroid GlandsThe Parathyroid Glands Four glandsFour glands in posterior capsule of thyroid• Secrete parathyroid hormoneparathyroid hormone (PTH)

• Works with calcitonin to regulate calcium regulate calcium metabolismmetabolism

• If this gland is not working properly, your nerves and muscles will not function properly either due to calcium deficiency.

Parathyroid glandsParathyroid glands

Parathyroid HormoneParathyroid Hormone

1. Parathyroid hormone (PTH) increases blood calcium ion concentration and decreases phosphate ion concentration.

2. PTH stimulates bone resorption by osteoclasts, which releases calcium into the blood.

3. PTH also influences the kidneys to conserve calcium and causes increased absorption of calcium in the intestines.

4. A negative feedback mechanism involving blood calcium levels regulates release of PTH.CalcitoninCalcitonin and PTHPTH exert opposite effects in regulating calcium ion levels in the blood.

Calcium MetabolismCalcium MetabolismCalcium balance requiresCalcium balance requires• Calcitriol (dihydroxycholecalciferol)Calcitriol (dihydroxycholecalciferol)

• Produced by modifying vitamin D in liver then in Produced by modifying vitamin D in liver then in kidneykidney

• Parathyroid hormoneParathyroid hormone• CalcitoninCalcitonin

Disorders of the Parathyroid GlandsDisorders of the Parathyroid Glands• Tetany

• Inadequate production of parathyroid hormone (PTH)

• Fragile bones and kidney stones• Excess production of parathyroid hormone

(PTH)

HYPOPARATHYROIDISMHYPOPARATHYROIDISM Surgically inducedSurgically induced Congenital absenceCongenital absence Familial hypothyroidismFamilial hypothyroidism

Associated with chronic mucocutaneous Associated with chronic mucocutaneous candidiasis and primary adrenal insufficiencycandidiasis and primary adrenal insufficiency

Known as Known as autoimmune polyendocrine autoimmune polyendocrine syndrome type Isyndrome type I (APS I) (APS I)

Mutations in the Mutations in the autoimmune regulatorautoimmune regulator (AIRE) gene(AIRE) gene

Idiopathic hypothyroidismIdiopathic hypothyroidism

HYPOPARATHYROIDISMHYPOPARATHYROIDISM• Clinical presentationsClinical presentations

• Tetany – neuromuscular irritability• Mental status changes emotional instability,

anxiety, and depression, confusional states, hallucinations and psychosis

• Intracranial manifestations – calcification of the basal ganglia, parkinson-like movement disorders, increase ICP (intracranial pressure)

• Ocular disease – cataract formation• CV manifestations prolongation of QT interval• Dental abnormalities – dental hypoplasia,

failure of dental eruption, defective enamel and root formation, abraded carious teeth

HYPERPARATHYROIDISMHYPERPARATHYROIDISM INCREASED PTH PRODUCTIONINCREASED PTH PRODUCTION HYPERCALCEMIAHYPERCALCEMIA HYPOPHOSPHATEMIAHYPOPHOSPHATEMIA PRIMARY – PRIMARY – TUMOR OR TUMOR OR

HYPERPLASIA OF THE PARATHYROID HYPERPLASIA OF THE PARATHYROID GLANDGLAND

SECONDARY – SECONDARY – COMPENSATORY COMPENSATORY OVERSECRETION OF PTH IN RESPONSE OVERSECRETION OF PTH IN RESPONSE TO HYPOCALCEMIA FROM:TO HYPOCALCEMIA FROM: CHRONIC RENAL DSECHRONIC RENAL DSE RICKETSRICKETS MALABSORPTION SYNDROMEMALABSORPTION SYNDROME OSTEOMALACIA OSTEOMALACIA

HYPERPARATHYROIDISHYPERPARATHYROIDISMM

S/SX:S/SX:BONE PAIN : ESP. THE BONE PAIN : ESP. THE

BACK, PATHOLOGIC BACK, PATHOLOGIC FRUCTURESFRUCTURES

TUBULAR CALCIUM TUBULAR CALCIUM DEPOSITS - KIDNEY DEPOSITS - KIDNEY STONES, RENAL COLIC, STONES, RENAL COLIC, POLYURIA, POLYDIPSIAPOLYURIA, POLYDIPSIA

MUSCLE WEAKNESSMUSCLE WEAKNESS PERSONALITY CX, PERSONALITY CX,

DEPRESSIONDEPRESSION CARDIAC ARRHYTHMIAS, CARDIAC ARRHYTHMIAS,

HPNHPN

XRAY: XRAY: BONE BONE DEMINERALIZATIONDEMINERALIZATION

PseudohypoparathyroidismPseudohypoparathyroidism End-organ unresponsiveness to PTHEnd-organ unresponsiveness to PTH Serum PTH levels are normal or elevatedSerum PTH levels are normal or elevated Pseudohypoparathyroidism Type IAPseudohypoparathyroidism Type IA

Associated with multihormone resistance (PTH, TSH, & Associated with multihormone resistance (PTH, TSH, & FSH/LH) and Albright hereditary osteodystrophy (AHO)FSH/LH) and Albright hereditary osteodystrophy (AHO)

Short stature, obesity, short metacarpal and metatarsal Short stature, obesity, short metacarpal and metatarsal bones, and variable mental deficitsbones, and variable mental deficits

Hypocalcemia, hyperphosphatemia, and elevated Hypocalcemia, hyperphosphatemia, and elevated circulating PTHcirculating PTH

TSH resistance is mild; LH/FSH resistance manifests as TSH resistance is mild; LH/FSH resistance manifests as hypogonadotrophic hypogonadism in femaleshypogonadotrophic hypogonadism in females

Mutation is inherited on the maternal alleleMutation is inherited on the maternal allele PseudopseudohypoparathyroidismPseudopseudohypoparathyroidism

Mutation is inherited on the paternal alleleMutation is inherited on the paternal alleleCharacterized by AHO without Characterized by AHO without

accompanying multihormonal resistanceaccompanying multihormonal resistanceNormal serum calcium, phosphate, and PTH Normal serum calcium, phosphate, and PTH

PHYSIOLOGIC BASIS OF MALE PHYSIOLOGIC BASIS OF MALE REPRODUCTIVE FUNCTION AND THEIR REPRODUCTIVE FUNCTION AND THEIR

DISORDERSDISORDERS The male sex hormones are called The male sex hormones are called

androgensandrogens.. The testes secrete several The testes secrete several male sex hormones, including male sex hormones, including testosterone, testosterone, dihydrotestosteronedihydrotestosterone, and , and androstenedioneandrostenedione..

TestosteroneTestosterone, which is the most abundant , which is the most abundant of these hormones, is considered the main of these hormones, is considered the main testicular hormone. The testicular hormone. The adrenal cortex adrenal cortex also produces androgensalso produces androgens, although in , although in much smaller quantities (<5% of the total much smaller quantities (<5% of the total male androgens) than those produced in male androgens) than those produced in the testes. The the testes. The testes also secrete small testes also secrete small quantities of estradiol and estronequantities of estradiol and estrone. The . The male sex hormones are called male sex hormones are called androgensandrogens..

All or almost all of the actions of testosterone and other androgensAll or almost all of the actions of testosterone and other androgensresult from result from increased protein synthesis in target tissuesincreased protein synthesis in target tissues.. Androgens functionAndrogens function as as anabolic agentsanabolic agents in males and females in males and females to promote metabolism and to promote metabolism and musculoskeletal growthmusculoskeletal growth.. TestosteroneTestosterone and the and the androgensandrogens have a great effect have a great effect on the developmenton the development of increasing musculature during puberty, withof increasing musculature during puberty, with boys boys averaging approximately 50% more of an increase inaveraging approximately 50% more of an increase in muscle mass than do muscle mass than do girlsgirls..

Male InfertilityMale Infertility InfertilityInfertility is defined as the inability of a couple to achieve pregnancy despite is defined as the inability of a couple to achieve pregnancy despite

unprotected intercourse for a period of unprotected intercourse for a period of more than 12 monthsmore than 12 months. About . About 15%15% of all of all couples couples are infertileare infertile and it is estimated that a male factor plays a role in about and it is estimated that a male factor plays a role in about half of the cases. In spite of this, the evaluation of the male partner is often half of the cases. In spite of this, the evaluation of the male partner is often neglected, mainly because of the high pregnancy rates that can be achieved by neglected, mainly because of the high pregnancy rates that can be achieved by assisted reproductive techniques (ART). This practice is unfortunate since male assisted reproductive techniques (ART). This practice is unfortunate since male infertility can often be cured, sparing the female partner the extensive treatment infertility can often be cured, sparing the female partner the extensive treatment and cost of ART. Furthermore, evidence suggests that ART procedures can be and cost of ART. Furthermore, evidence suggests that ART procedures can be associated with increased risks for both mother and child. Finally, neglecting to associated with increased risks for both mother and child. Finally, neglecting to examine the infertile man properly risks overlooking serious conditions such as examine the infertile man properly risks overlooking serious conditions such as testicular cancer that may coexist with infertility.testicular cancer that may coexist with infertility.

For conception to occur, the following conditions must be met: For conception to occur, the following conditions must be met: (1) The testes must have normal spermatogenesis; (1) The testes must have normal spermatogenesis; (2) the spermatozoa must complete their maturation; (2) the spermatozoa must complete their maturation; (3) the ducts for sperm transport must be patent; (3) the ducts for sperm transport must be patent; (4) the prostate and seminal vesicles must supply adequate amounts of (4) the prostate and seminal vesicles must supply adequate amounts of

seminal fluid; seminal fluid; (5) the coital technique must enable the male partner to deposit his semen (5) the coital technique must enable the male partner to deposit his semen

near the female's cervix; near the female's cervix; (6) the spermatozoa must be able to penetrate the cervical mucus and (6) the spermatozoa must be able to penetrate the cervical mucus and

reach the uterine tubes; reach the uterine tubes; (7) the spermatozoa must undergo capacitation and the acrosome (7) the spermatozoa must undergo capacitation and the acrosome

reaction, fuse with the oolemma, and be incorporated into the ooplasm. reaction, fuse with the oolemma, and be incorporated into the ooplasm. Any defect in this pathway can result in infertility.Any defect in this pathway can result in infertility.

Causes of Testicular AtrophyCauses of Testicular Atrophy TraumaTrauma Testicular torsionTesticular torsion HypopituitarismHypopituitarism CryptorchidismCryptorchidism Klinefelter's syndrome (47,XXY)Klinefelter's syndrome (47,XXY) Alcoholism and cirrhosisInfection (eg, Alcoholism and cirrhosisInfection (eg,

mumps orchitis, gonococcal epididymitis)mumps orchitis, gonococcal epididymitis) Malnutrition and cachexiaMalnutrition and cachexia RadiationRadiation Obstruction to outflow of semenObstruction to outflow of semen AgingDrugs (eg, estrogen therapy for AgingDrugs (eg, estrogen therapy for

prostatic cancer)prostatic cancer)

Cigarette smokingCigarette smoking Cigarette smokingCigarette smoking has been associated with an overall reduction in has been associated with an overall reduction in

semen quality, and semen quality, and specifically a specifically a reduction in sperm countreduction in sperm count and and motilitymotility and an and an increase in abnormal formsincrease in abnormal forms. .

Cigarette smoking can also cause Cigarette smoking can also cause damage to sperm DNAdamage to sperm DNA. A meta-. A meta-analysis of 21 studies of the effect of cigarette smoking on semen analysis of 21 studies of the effect of cigarette smoking on semen quality revealed that quality revealed that smoking lowered sperm concentration by 13–smoking lowered sperm concentration by 13–17%17% in 7 studies and no effect in 14 studies. However, it remains in 7 studies and no effect in 14 studies. However, it remains controversial whether smoking controversial whether smoking actually decreases male fertility ratesactually decreases male fertility rates..

Also controversial is whether second-hand smoke from a male partner Also controversial is whether second-hand smoke from a male partner can affect female fertility. There is, however, some evidence that can affect female fertility. There is, however, some evidence that maternal smoking may be related to decreased sperm counts in the maternal smoking may be related to decreased sperm counts in the offspring. Finally, the risk of developing erectile dysfunction is almost offspring. Finally, the risk of developing erectile dysfunction is almost doubled for smokers compared to nonsmokers, and this can limit male doubled for smokers compared to nonsmokers, and this can limit male fertility.fertility.

Testicular temperaturesTesticular temperatures are approximately are approximately 2 °C below core body2 °C below core body temperature and spermatogenesis is dependent on this cooler temperature and spermatogenesis is dependent on this cooler temperaturetemperature.. Factors such as clothing, lifestyle, season, and fever can Factors such as clothing, lifestyle, season, and fever can cause increases in scrotal temperature. cause increases in scrotal temperature.

Increases in scrotal temperature reduce sperm quantity and qualityIncreases in scrotal temperature reduce sperm quantity and quality..

Semen Analysis: Normal Values and Semen Analysis: Normal Values and Definitions.Definitions.

Characteristic Reference Standard

Ejaculate volume > 2 mL

pH 7.2–7.8

Sperm concentration

20 million/mL

Sperm count 40 million/mL

Sperm motility 50% with normal motility

Sperm morphology

15%1–30% with normal forms

Term Definition 

Normospermia Normal ejaculate (as defined by reference standards above)

Oligozoospermia Sperm concentration < 20 million/mL

Asthenozoospermia

< 50% of spermatozoa with forward progression of

< 25% with rapid progression

Azoospermia No spermatozoa in ejaculate

Aspermia No ejaculate

STRUCTURE AND FUNCTION OF THE FEMALE STRUCTURE AND FUNCTION OF THE FEMALE

REPRODUCTIVE SYSTEMREPRODUCTIVE SYSTEM

► Ovarian hormonesOvarian hormones are are secreted in a cyclic pattern as secreted in a cyclic pattern as a result of the interaction a result of the interaction between the between the hypothalamic hypothalamic gonadotrophic releasing gonadotrophic releasing hormone (GnRH)hormone (GnRH) and the and the pituitary gonadotropic pituitary gonadotropic hormoneshormones, , follicle stimulating follicle stimulating hormonehormone (FSH), and (FSH), and luteinizing luteinizing hormonehormone (LH). The secretion of (LH). The secretion of LH and FSH is stimulated by LH and FSH is stimulated by GnRH from the hypothalamus. GnRH from the hypothalamus.

► The female genitourinary system consists of the external and The female genitourinary system consists of the external and internal genital organs. The external sex organs of the female internal genital organs. The external sex organs of the female are referred to as the genitalia or vulva. The internal genital are referred to as the genitalia or vulva. The internal genital organs include the vagina, uterus, uterine tubes, and ovaries. organs include the vagina, uterus, uterine tubes, and ovaries. These organs are largely located within the pelvic cavityThese organs are largely located within the pelvic cavity

Hypothalamic-pituitary feedback Hypothalamic-pituitary feedback control of estrogen and control of estrogen and

progesterone levels in the female. progesterone levels in the female. The dashed line represents The dashed line represents

negative feedback.negative feedback.

Actions of EstrogensActions of Estrogens General Function Specific Actions

Growth and Growth and developmentdevelopment

Reproductive organs Skeleton

Stimulate development of vagina, uterus, and fallopian tubes in utero and of secondary sex characteristics during puberty

Accelerate growth of long bones and closure of epiphyses at puberty

Reproductive processesReproductive processesOvulationFertilizationImplantation Vagina Cervix Breasts

Promote growth of ovarian folliclesAlter the cervical secretions to favor survival and transport of

spermPromote motility of sperm within the fallopian tubes by

decreasing mucus viscosityPromote development of endometrial lining in the event of

pregnancyProliferate and cornify vaginal mucosaIncrease mucus consistencyStimulate stromal development and ductal growth

General metabolic General metabolic effectseffects

Bone resorption Plasma proteins Lipoproteins

Decrease rate of bone resorptionIncrease production of thyroid and other binding globulinsIncrease high-density and slightly decrease low-density

lipoproteins

Dysfunctional Menstrual CyclesDysfunctional Menstrual Cycles

Normal menstrual function results from Normal menstrual function results from interactions among the central nervous system, interactions among the central nervous system, hypothalamus, anterior pituitary, ovaries, and hypothalamus, anterior pituitary, ovaries, and associated target tissues. associated target tissues.

Although each part of the system is essential to Although each part of the system is essential to normal function, the ovaries are primarily normal function, the ovaries are primarily responsible for controlling the cyclic changes responsible for controlling the cyclic changes and the length of the menstrual cycle. and the length of the menstrual cycle.

In most women in the middle reproductive In most women in the middle reproductive years, menstrual bleeding occurs every 25 to years, menstrual bleeding occurs every 25 to 35 days, with a median length of 28 days.35 days, with a median length of 28 days.

Symptoms of Premenstrual Symptoms of Premenstrual Syndrome (PMS) by SystemSyndrome (PMS) by System

Body System Symptoms

CerebralCerebral

Irritability, anxiety, nervousness, fatigue, and exhaustion; increased physical and mental activity; lability; crying spells; depressions; inability to concentrate

GastrointestinalGastrointestinalCraving for sweets or salts, lower abdominal pain,

bloating, nausea, vomiting, diarrhea, constipation

VascularVascular Headache, edema, weakness, or fainting

ReproductiveReproductiveSwelling and tenderness of the breasts, pelvic

congestion, ovarian pain, altered libido

NeuromuscularNeuromuscularTrembling of the extremities, changes in

coordination, clumsiness, backache, leg aches

GeneralGeneral Weight gain, insomnia, dizziness, acne

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