MEDICINE AND SURGERY "F"
Course of LABORATORY MEDICINE
Disturbances of the endocrine system

HORMONES

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      Hormones are produced by endocrine glands and serve to regulate the physiological functions of many organs and tissues. Their concentration in the blood is finely regulated. The blood concentration of some hormones may vary within a limited range, but that of other hormones may experience large changes, in response to external stimuli or because a circadian rhythm. As a consequence of their possible variability, the concentrations of hormones in blood should be interpreted with reference to other clinical and laboratory information. Dysregulation may occur both in the sense of excess secretion (possibly due due to benign, hormone-secreting tumours of the gland, or to overstimulation of the gland) or in the sense of insufficient secretion (possibly due to damage of the gland due to metabolic defects, malignancies, insufficient stimulation). Moreover, alterations of the circadian rhythms of secretion occur and in some instances cause symptoms and have diagnostic value.

Audio: Hormones


      When insufficient hormone production is suspected, stimulation tests may provide more relevant information than simple measurements of the serum hormone concentration. A stimulation test is carried out by administering to the patient a stimulus to secretion of a specific hormone and measuring its concentration increase (e.g. ACTH stimulation test for adrenal insufficiency), or a physiological response that parallels it (e.g. the glucose tolerance test). This type of test detects the level of the hormone regulation cascade that is affected. Consider, as an example, the case of the ACTH stimulation test: if administration of ACTH causes increased prodution of cortisol, the adrenal cortex is functioning correctly but is understimulated by the hypohysis; if administration of ACTH fails to increase the level of cortisol the adrenal cortex is affected and unresponsive.
      When excess hormone production is suspected, suppression tests may be used. Suppression tests are carried out by measuring the decrease of hormone concentration (or a physiological response parallel to it) induced by stimuli that provide a negative feedback to secretion (e.g. the dexamethasone suppression test for Cushing's disease, see below). Suppression tests may provide crucial information for the differential diagnosis of hypersecreting conditions. The clinical reasoning is analogous to that in suppression test, but the stimulus is of the opposite type.

Audio: Clinical laboratory tests for endocrine diseases


tests for endocrine diseases
testclinical indicationexamples
direct measurement of hormone concentration in the bloodwhen the hormone concentration is not subject to irregular variations during the dayT3 and T4 for thyroid
cortisol for the adrenal cortex
etc.
indirect estimate (measurement of the hormone effects)when the effect is clearly attributed to a single hormone basal metabolism for thyroid
glycemia for insulin
calcemia for parathyroid hormone
etc.
stimulation test, coupled to direct or indirect measurementin many cases of insufficient production of the hormone (endocrine insufficiency); establishes the step of the hormone regulation cascade that is affectedglucose tolerance test for insulin
TRH for thyroid hormones
etc.
suppression test, coupled to direct or indirect measurementin many cases of excess production of the hormone; establishes the step of the hormone regulation cascade that is affectedT3 suppression test for the thyroid - hypophysis - hypothalamus axis
cortisol suppression test for the adrenal cortex
etc.
imaging methods applied to the gland, possibly coupled to biopsywhen an anatomical lesion is suspected (e.g. thyroid adenomas)thyroid scintigraphy
NMR imaging of the relevant body segment
etc.

      An important comment to the above Table is that laboratory tests measure the organ's function, whereas imaging methods detect anatomical lesions. Although ultimately function damage must depend on a lesion, the two techniques complement each other and, depending on the specific disease, either may provide optimal sensitivity. E,g, a cleary detectable anatomical lesion may affect only a portion of the organ and may not cause a detectable impairment of the function. Conversely a microscopical or submicroscopical but diffuse lesion may be undetectable by imaging methods, yet it may cause significant functional impairment, reflected by obvious laboratory findings. Thus one should not consider laboratory and imaging evidences as alternative but as complementary.

      From a biochemical standpoint, hormones belong to several different families of compounds, and every endocrine gland may secrete one or more hormones, usually belonging to the same biochemical family. An exception is the thyroid which secretes two hormones belonging to different biochemical families: thyroxin is an aminoacid derivative, whereas thyrocalcitonin is a small protein. The adrenals do secrete hormones of two very different chemical types (catecholamines are aminocid derivatives, corticoids are cholesterol derivatives), but from an embriological viewpoint they are two different glands one of which surrounds the other. As a consequence of this variety several analytical methods are required, as summarized in the Table below:

HORMONES AND THE CLINICAL BIOCHEMISTRY LABORATORY
Endocrine glandHormoneChemical natureMeasurement methodSerum conc.
Epiphysis (pineal gland)MelatoninTyrosine derivativeExtraction in dichloromethane followed by HPL Chromatography 
 
Neurohypophysis (posterior pituitary) Vasopressin (Anti Diuretic Hormone, ADH) Polypeptide (extraction followed by immunoassay)<12 pg/mL
Oxytocin Polypeptide Immunoassay; mass spectrometry 
 
Adenohypophysis (anterior pituitary) Growth Hormone (GH, somatotropin) Protein Immunoassay (biological test)<7 ng/mL
Prolactin (PRL) Protein Immunoassay<20 ng/mL (women)
<15 ng/mL (men)
Gonadotropins (LH and FSH) Glycoproteins Immunoassay (biological test) 
Thryoid stimulating hormone (TSH) Glycoprotein Immunoassay 
Adrenal Cortex stimulating hormone (ACTH) Protein Immunoassay 
 
ThyroidThyroxine (tetraiodothyronine) and triiodothyronine (T4 and T3)Tyrosine derivativeRadioImmunoAssayT4=4-12 μg/dL;
T3=80-100 ng/dL
Thyrocalcitonin Protein Immunoassay 
 
PancreasInsulinProteinImmunoassay 
Glucagon Protein (Immunoassay) 
 
Adrenal cortexGlucocorticoid hormones (e.g. cortisol)Cholesterol derivativesRadioImmunoAssay, usually after extraction with organic solvents3-24 μg/dL
Mineralocorticoid hormones (e.g. aldosterone) Cholesterol derivatives RadioImmunoAssay, usually after extraction with organic solvents; chemiluminescence1-5 ng/dL
Sexual hormones (e.g. estrogens, progesterone, testosterone) Cholesterol derivatives RadioImmunoAssay, usually after extraction with organic solvents 
 
Adrenal medullacatecholamine hormones (e.g. adrenaline)Tyrosine derivatives HPL Chromatography 
 
Measurements methods in parentheses are possible, but not commonly used.

Disorders of the anterior pituitary
      The anterior pituitary gland produces protein hormones that control several body functions, and notably several other endocrine glands. Hormone secretion is stimulated by releasing factors produced by the hypothalamus and secreted in the special vascular structure of the hypothalamus-hypophysis portal system. The hypothalamus responds to peripheral hormones by reducing the production of the appropriate releasing factor, with a negative feedback mechanism. Each hormone is produced by a specific cell type and no cell produces two hormones. As a consequence of this anatom-functional organization, hyperfunctionality of the hypophysis is usually selective (e.g. because of a secreting adenoma of one cell type), whereas hypofunctionality is often generalized (panhypopituitarism due to ischemic or compresssive destruction of the gland with all its cell types), even though some cell types may be affected to a greater extent than others, due to their different location in the gland. An exception to this rule occurs in the rare case of genetically determined selective hypofunctionality (e.g. isolated GH decrease). An interesting and not uncommon condition is observed when the patient has a pituitary adenoma that produces one hormone and suppresses all other because of compressive lesion of the rest of the gland: in this case a selective hyperfunctionality is associated to a generalized hypofunctionality. In all cases of laboratory-demonstrated hyperpituitarism or hypopituitarism, an evaluation of the hypophysis by imaging methods is recommended, and the possibility of ectopic adenomas that produce pituitary hormones but do not reside in the hypophysis should be considered if the imaging analysis yields a negative result.

      Growth hormone (GH, somatotropin) is released in response to hypothalamus' GRH; its secretion is inhibited by somatostatin. At the periphearl level, GH acts by promoting the release of secondary hormones: insulin and somatomedins that stimulate the growth of tissues (notably of bone). Paradoxically, GH is an antagonist of insulin-induced glucose uptake. Release of GRH by the hypothalamus is stimulated by insulin, by hypoglycemia and by some aminoacids (e.g. arginine). Thus GH stimulation tests may be carried out using insulin and glucose, arginine or synthetic GRH. Basal measurements of GH are poorly informative because GH may be below detecable levels for much of the day. Selective hypersecretion of GH may be due to adenomas of the pituitary; more rarely to GRH-secreting adenomas that may develop in some endocrine glands (notably in the Langerhans islest of the pancreas). It causes gigantism in the infant and acromegaly in the adult, and is frequently associated to insulin resistance and subclinical type 2 diabetes mellitus, and to hypercalciuria. Diagnosis of acromegaly is confirmed by the suppression test with glucose: in normal subjects serum GH concentration, if detectable drops to < 5 ng/mL after oral administration of 100g glucose; in acromegalic patients no such drops is observed and GH is often > 10 ng/mL even after glucose administration. Insufficient production of GH or insufficient peripheral response to it causes armonic dwarfism (see Table).

Differential diagnosis of dwarfism
hypophysary dwarfism (insufficient production of GRH or GH) Normal proportions of the body parts; decreased serum concentration of GH; growth rate < 4 cm/year
Laron dwarfism (defective GH receptors; peripheral hypophysary dwarfism) like hypophysary dwarfism
Congenital hypothyroidism Non proportionate dwarfism, short extremities with almost normal body and head
Achondroplasia and similar osteochondrodysplasias (inherited, usually autosomal dominant) Non proportionate dwarfism, short extremities with almost normal body and head


      Thyroid Stimulating Hormone (Thyrotropin, TSH) is a heterodimeric glycoprotein released as a response to hypothalamus' tripeptide TRH, whose secretion is inhibited by thyroid hormones. Adenomas of the TSH-producing cells in the pituitary may cause secondary hyperthyroidism. The suppression test is carried out by measurement of TSH in the serum after oral administration of the thyroid hormone triiodothyronine (see below).

      Adrenocorticotrophic Hormone (ACTH) is a 39 polypeptide dervied from cleavage of a higher molecular weight protein precursor. It stimulates the secretion of steroid hormones by the adreanl cortex, most notably cortisol. Secretion of ACTH is stimulated by the hypothalamic protein CRH, whose secretion is inhibited by cortisol and synthetic steroid hormones. Hypersecretion of ACTH, usually due to benign adenomas, causes Cushing's syndrome (see below). Suppression test is carried out by administration of the synthetic steroid dexamethasone.

      Gonadotropins (LH and FSH) are protein hormones that control the production of gametes and most other sexual and reproductive functions. They act especially (but not only) on the gonads and regulate the production of (steroid) sex hormones. Excess production of gonadotropins (e.g. because of a pituitary adenoma) deranges the production of gametes, and may induce sterility. It is important to remember that gonadotropins are produced also by the placenta, and that may be ectopically produced by adenomas of other glands or tissues, in the presence of a perfectly normal (i.e. adenoma-free) pituitary.

      Prolactin is a protein hormone that stimulates the development of the breast in women and promotes lactation. Release of prolactin is inhibited by dopamine, which provides a convenient suppression test. Hyperprolactinemia may cause galactorrhea and infertility (both in men and women); it may be due to a prolactin producing adenoma, and may be associated to some breast tumors. Normal prolactin levels are < 20 ng/ml in non pregnant women and < 15 ng/mL in men. Serum levels > 300 ng/mL are usually due to adenomas; serum levels > 100 ng/mL in non-pregnant women (or in men) are suspect and warrant further investigation, unless they are explained by therapy with dopamine antagonists.

      Panhypopituitarism hypofunctionality of the adenohypohysis can be selective or generalized (panhypopituitarism). Generalized hypoituitarism is more frequent and is the result of compressive or ischemic destruction of the hypophysis, often due to tumours; a less common condition is the Sheehan syndrome (ischemic necrosis of the hypophysis due to post partum hemorrages and shock). Gonadotropins are lost first, followed by GH, and then by TSH and ACTH. Death may ensue, due to the lack of thyroid and adrenal stimulation. Diagnosis is by imaging methods (lesions of the sella turcica) and by laboratory determination of the hormones' concentration in the serum. Infertility and a syndrome indistinguishable from Addison's disease characterize the clinical picture. An important differential diagnosis is with anorexia nervosa. Diagnosis is confirmed by the measurement of the concentration of pituitary hormones, and of the hormones they stimulate (T3, T4, cortisol, etc.) that result low.
      Selective hypopituitarism, with isolated pituitary deficiencies, is suspected because of failure to grow (pituitary nanism due to deficiency of GH), or sterility and lack of menstruations (hypogonadotropic hypogonadism,may be due to genetic defects, e.g. Kallmann's disease). Isolated, pituitary induced hypothyrodism or adrenal insufficiency (pituitary Addison's disease) are uncommon, these conditions usually occurring (and some times dominating) a panhypopituitary condition.

      The pars intermedia of the hypophysis is active in the fetus but very small or absent in the human adult (it remains functional in lower vertebrates, and may be responsible for skin colour changes linked to camouflage). In the fetus it produces the Melanocyte Stimulating Hormone (melanotropin, MSH), derived fromthe cleavage of the precursor protein proopiomelanocortin. It is not responsible of diseases in humans.

Audio: Hormones of the anterior pituitary

Disorders of the posterior pituitary
      The posterior part of the hypophysis is of neurological origin and is directly connected to the hypothalamus; indeed the secreting cells are neurons whose body resides in the hypothalamus, and whose axon extends in the pposterior lobe of the hypophysis. These cells release two polypeptide hormones, the antidiuretic hormone (ADH) and oxitocin.
     Vasopressin (antidiuretic hormone, ADH) is a nonapeptide containing two Cys residues involved in a disulfide bond. It promotes water reabsoprtion in the distal tubuli of the nephrons and contributes to the control of the osmolarity of biological fluids (by which its secretion is regulated). Its serum concentration can be measured by radioimmunoassay.
      Diabetes insipidus is due to insufficient or absent production of ADH. Since this hormone causes the kidney to reabsorb water, its deficiency is associated with poliuria and diluted urine (to be distinguished from diabetic mellituria, in which the urine flow is increased because of the osmotic effect of glucose, and from nephrogenic diabetes insipidus, in which the kidney's function is reduced). The causes of diabetes insipidus are variable; often this condition is caused by neoplastic lesions or aneurisms compressing the hypothalamus. Diabetes insipidus is suspected in the presence of dilute urine and serum hyperosmolarity, and confirmed by the laboratory finding of severely reduced serum ADH. This condition is potentially lethal.

     Oxitocin is a nonapeptide hormone differing from ADH because of two aminacid residues. Its main function is to promote the contractility of the uterus during parturition and insufficient production of oxitocin may cause a dynamic dystocia (the expulsion of the fetus is slowed down or blocked because of insufficient contractions and independently of a mechanical incompatibility of the pelvis).

Audio: Vasopressin and oxitocin

Disorders of the thyroid
      The thyroid gland produces two Tyrosine derived hormones, called tetraiodothyronine (T4, Thyroxine) and triiodothyronine (T3). T4 and T3 regulate the metabolism of most tissues in our body. In addition, thyroid's parafollicular cells produce a completely different protein hormone called calcitonin or thyrocalcitonin that is important for the regulation of calcium metabolism and calcium concentration in the blood. These two types of hormones should be considered separately: they are produced by different cells in the gland, and under different stimuli. The action of thyrocalcitonin will be discussed further on, in conjunction with that of PTH, the hormone produced by the parathyroid glands.

      Biochemistry and physiology of T4 and T3
      The thyroxine-like hormones are iodinated derivatives of the aminoacid tyrosine. They are synthesized by chemical modification of Tyr residues in the sequence of the storage protein thyroglobulin (represented as P in the figure below); when necessary the protein is digested and the hormones are released in the bloodstream.


Audio: Thyroid hormones

      The hormones released in the blood are transported by a specific protein carrier called TBG (thyroxine-binding globulin), and by other proteins (e.g. albumin); only a tiny minority of the total T4 and T3 is freely dissolved in the plasma. Secretion of T4 and T3 is stimulated by the pituitary Thyroid-Stimulating Hormone (TSH), whose release is controlled by the hypothalamus' TRH. TRH secretion is suppressed by a negative feedback mechanism by T4 and T3. Some T4 may be deiodinated in the liver and converted to T3; this fraction of T3 is called the reverse T3 (rT3).
      The action of T4 and T3 is to stimulate the tissue metabolism and O2 consumption, and is mediated by protein synthesis.

      Hypothyroidism is the condition in which the production of thyroid hormones is reduced. It may be due to lack of iodine in the diet, to inflammatory diseases of the gland, or to inherited, congenital defects of the biosynthesis or secretion of T4 and T3. Congenital hypothyroidism may cause mental retardation (cretinism) and disarmonic dwarfism; these cases deserve special attention because the newborn is normal at birth (the hormones having been obtained from maternal blood during pregnancy), thus prompt treatment may prevent the development of symptoms. The thyroid is usually enlarged (goiter) beacuse of overstimulation by the pituitary, and the concentration of T4 and T3 in the blood is decreased. The clinical picture is ususally quite characteristic and diagnosis is confirmed by laboratory findings. If iodine administration does not cure the syndrome a substitutive therapy must be started.
      Hyperthyroidism (Basedow's disease; Graves' disease; thyrotoxicosis) may be due to diffuse enlargement of the gland (in some causes because of a benign adenoma of the pituitary, which secretes TSH) or to a secreting adenoma. 131I scintigraphy is diagnostic, and the laboratory analyses will confirm increased serum concentration of T4 and T3 (and possibly of TSH). Surgery is indicated.
      Euthyroid sick syndrome is a condition in which hypothyroidism-like symptoms are present in spite of normal thyroid tests. It is observed in several systemic diseases (e.g. liver cirrhosis, malnutrition, sepsis), and may be due to alterations in the peripheral metabolism of T4. TSH is normal.

      Clinical laboratory analyses of thyroid function T4 and T3 are the most important iodine-containing compounds in our body and thyroid the most important (and almost only) organ to utilize iodine; this allows the clinical laboratory several easy tests of thyroid function. The radioactive iodine uptake can be measured, and can be coupled to thyroid scintigraphy in order to reveal disomogenous captation by the gland.
      The concentration of T4 and T3 in the serum can be measured by radio-immuno assay; the normal ranges are:
T4 = 4-12 μg/dL;       T3 = 80-100 ng/dL;       rT3 = 10-40 ng/dL


Audio: Analytical methods for thyroid dysfunctions

      The concentration of TSH can also be measured by radio-immuno assay; its normal concentration in the serum is < 5 μ U/mL. Comparison of the concentrations of TSH and T4 / T3 is very important to establish whether a case of hyperthyroidism or hypothyroidism due to a disease of the hypophysis or the thyroid, as summarized in the table below:
  disease T4 / T3 TSHstimulation testsuppression test
  hyperthyroidism due to pituitary hyperstimulation increased increasednot indicatedwith T3: usually no effect
  hyperthyrodism due to thyroid disfunction increased strongly decreasednot indicatedwith T3: usually no effect
  hypothyroidism due to pituitary insufficiency decreased decreasedwith TSH:strong increase of T3 and T4
with TRH: usually no response
with T3: usually no effect
  hypothyrodism due to thyroid disfunction or iodine deficiency decreased strongly increasedwith TSH or TRH: usually no responsewith T3: strong decrease of TSH

      Stimulation and suppression tests to assess thyroid function and the hypothalamus-hypophysis-thyroid axis are available. The TRH stimulation test is useful for the differential diagnosis of hypothyroidism. It is carried out by the intravenous administration of TRH, and measurement of the TSH and T4/T3 responses. In healthy subjects TRH causes an increased release of TSH by the hypophysis (provided that the gland is functional) followed by an increased release of T4/T3 (provided that the thyroid is functional). Absence of a TSH and T4/T3 response is indicative of pituitary disfunction; presence of a TSH response but absence of a T4/T3 response suggests thyroid disfunction.
      The thyroid suppression test is useful in cases of hyperthyroidism. It is carried out by oral administration of L-triiodothyronine (100 μg a day for ten days). In healthy subjects this treatment causes a strong reduction of iodine uptake, and a strong decrease of the concentrations of T4 and TSH in the serum. A decrease in TSH, but not in iodine uptake and T4 suggest primary hyperthyroidism; no decrease of TSH, iodine uptake, and T4 suggests that hyperthyroidism is secondary to hyperfunctionality of the pituitary, e.g. because of an adenoma.

Audio: Thyroid suppression and stimulation tests

      An important additional test is the measurement of basal metabolism. This is carried out by measuring the oxygen consumption (indirect calorimetry). The reference values for this test are as follows:

inspired air: 5 L/min inspired O2: 5x0.2=1 L/min
espired air: 5 L/min espired O2: 5x0.15=0.75 L/min
O2 consumption: 1 - 0.75 = 0,25 L/min (= approx. 10 mMoles)
energy equivalent in animal metabolism: 117 kcal/mol O2
basal metabolism: 0.01 Moles/min x 60 x 24 x 117 = 1680 kcal /day

According to the above table, the normal reference values for adults are in the order of 1700 kcal/day (for more precise estimates corrected for age, sex and body weigth use appropriate tables) that can be measured from the O2 consumption, and the energy equivalent of O2 (117 kcal /mol). Hyperthyroidism causes a significant increase of basal metabolism / O2 consumption, hypothyrodism a significant decrease.


Disorders of the parathyroids (and of thyrocalcitonin)
      The parathyroid hormone, thyroid calcitonin, and vitamin D are involved in the homeostasis of calcium and control the levels of this ion in the human serum. This subject was hinted to in the lecture on electrolytes, but is dealth with here in greater detail. The parathyroid glands are four in number and adhere to the thyroid. They are quite small and may be accidentally removed in the course of thyroidectomies. Except for this event, diseases of the parathyroids are uncommon.
      The parathyroid hormone (PTH) is a small 84-residues protein. It has direct effects, and effects mediated by vitamin D, which it activates. It causes calcium to be mobilized from its reservoir in the bone matrix (as calcium phosphate), and to be released in the blood plasma, inducing hypercalcemia. The normal calcium concentration is 2-2.5 mM (4-5 mEq/L; 8-10 mg/dL). Since calcium is constantly lost in the urine, and constantly absorbed in the gut (in a process that requires vitamin D), PTH is required to maintain its concentration constant. Thyrocalcitonin plays the opposite role of promoting calcium deposition in the bone matrix and lowers its serum concentration. Secretion of both PTH and thyrocalcitonin responds to the serum calcium levels; however, the effectiveness of their action requires that dietary apport of the ion and of vitamin D is sufficient. The serum concentration of all the molecules and ions involved in this system can be measured in the clinical laboratory (calcium by potentiometry or by atomic spectroscopy; vitamin D, PTH and tyrocalcitonin by radioimmunoassay).
      Calcium is essential for muscular contraction, and spastic muscular palsies may occur if its concentration falls below the normal range. Paralysis of respiratry muscles may cause death. Hypoparathyroidism causes hypocalcemia, with possible tetany (sustained, painful, involuntary muscular contractions), and, possibly, neurological symptoms (pseudodementia). Pseudohypoparathyroidism (PHP) has similar symptoms but is due to unresponsiveness of the peripheral organs (kidney, bone) to PTH, whose concentration in the serum is normal or increased. Differential diagnosis is confirmed by analysis of the urine under stimulation of PTH (that in hypoparathyroidism causes phosphaturia and excretion of cAMP, whereas in PHP has no effect). We remark that the relationship between true hypoparathyroidis and PHP is reminiscent of that between type 1 and type 2 diabetes mellitus. Vitamin D deficiency is another possible cause of hypocalcemia. Since vitamin D is required for the intestinal absorption of calcium, this condition is associated to insufficient availability of the ion and insufficient deposition in the bone matrix, an effect which is absent in hypoparathyroidism and PHP. In childrem vitamin D deficiency causes rickets, in the adult osteomalacia.
      Hyperparathyroidism causes hypercalcemia, excess bone resorption (osteoporosis) and possibly nephrolythiasis. Osteoporosis is frequent in the elderly and may be counteracted by administration of calcitonin and vitamin D. There are several possible causes of hyperparathyroidism, including malignancies of the parathyroids; some malignancies (e.g. hematologic) may produce substances resembling PTH and causing bone resorption, in a paraneoplastic syndrome.

Endocrine disorders of the pancreas
      Insufficiency of the endocrine functions of the pancreas causes type 1 diabetes mellitus; hyperfunction, most often due to a benign insulin-secreting adenoma causes hypoglycemic crises. Both diseases are potentially lethal if undiagnosed and untreated. These diseases have been discussed in the lecture on glycemia, and will not be discussed again here; however it is important to underline that they conceptually belong to the class of endocrine disfunctions.

Disorders of the adrenal cortex
      The adrenal cortex produces steroid hormones, derived from cholesterol. They are classified, according to their main action as glycocorticoid hormones (e.g. cortisol), which regulate the cell metabolism; mineralcorticoid hormones (e.g. aldosterone), which regulate the kidney function; and sexual hormones (e.g. testosterone, estrogens, progesterone).

      Adrenal insufficiency (Addison's disease). The symptoms of Addison's disease are dominated by the reduced production of glucocorticoid hormones. The disease is fatal if untreated. The major causes of the destruction of adrenal cortex are: tuberculosis, cancer, amiloidosis and inflammatory necrosis. A clinically similar condition may be due to panhypopituitarism and by the (uncommon) selective reduction of hypophisary secretion of ACTH. Addison's disease due to the destruction of the adrenal cortex is characterized by increased serum ACTH; that due to panhypopitutarism by decreased or absent serum ACTH. Due to the numerous physiological effects of cortisol, several laboratory parameters are altered in Addison's diseas: hypoglycemia is common, as is a brownish discoloration of the skin. Serum sodium may be decreased and potassium increased.
      Glucocorticoid hypersecretion (Cushing's disease) may be due to a functioning adenoma of the hypophysis (that secretes ACTH) or of the adrenal cortex (that secretes cortisol). Less frequently, tumors of other tissues (e.g. the lung) can produce ACTH. In typical cases of Cushing's disease, secondary to an ACTH-secreting adenoma of the hypophysis, the secretion of both glucocorticoid and mineralocorticoid hormones is increased. Cortisol secretion follows a circadian rhythm being higher in the morning (serum concentration 9-24 μg/dL) and lower in the afternoon (3-12 μg/dL); thus the measured concentration should be referred to the time of sampling. Alternatively the concentration can be measured in the urines collected over the 24 hours (cortisol: 20-100 μg/24 hours; cortisol metabolytes - 17 hydroxycorticoid derivatives: 2-10 mg/24 hours). Hyperglycemia is common.
      An important diagnostic test is the dexamethasone suppression test. 0.5 mg of dexamethasone every 6 hours should strongly depress the production of ACTH and hence that of cortisol. Adenomas of the adrenal usually do not respond to dexamethasone suppression.

Audio: Dysfunctions of the adrenal cortex

      Hyperaldosteronism. The mineralcorticoid hormone aldosterone regulates the kidney function and promotes Na+ retention and K+ loss; it has an antidiuretic effect. It is regulated mainly by the renin-angiotensin system, and to a lesser extent by ACTH. Aldosterone can be measured in the plasma (normal value 1-5 ng/dL) or in the urine (2-10 μg/24 hours).
      Sex hormones are produced primarily by the gonads, but also by the adrenal cortex. As a general rule, their secretion is estimated from the metabolytes (17 ketosteroid derivatives) in the urine (normal values: male 7-25 mg/24 hours; female 4-15 mg/24 hours).
>
Laboratory findings in adrenal disorders
  electrolytes glycemia hormones
Adrenal hypofunction (Addison's disease) decreased Na+ increased K+ arterial hypotension decreased decreased cortisol; decreased aldosterone; ACTH stimulation test has no effect in primary Addison's disease, has effect in Addison's disease secondary to panhypopituitarism
Adrenal hyperfunction (Cushing's syndrome)   increased increased cortisol; dexamethasone suppression test has no effect in primary Cushing's disease, but may have an effect in Cushing's disease secondary to pituitary adenomas producing ACTH
Hyperaldosteronism (Conn's syndrome) increased Na+ decreased K+ arterial hypertension normal increased aldosterone

      The adrenal cortex and the thyroid are the most important glands whose function is governed by the anterior pituitary; their dysfunction may cause severe, potentially lethal disease, and may occur isolated or in combination. Thus it is useful to compare, in the Table below, the dysfunctions of these glands, which may occcur in various combinations.
Comparison of primary and secondary dysfunctions of the thyroid and the adrenals
DiseaseTSH ACTH T4 and T3cortisol stimulation test suppression test
Hypofunctionalities
Panhypopituitarism increase of T4/T3 or cortisol not indicated
Primary hypothytoidism   -   -no effect not indicated
Primary Addison's disease   -   - no effect not indicated
 
Hyperfunctionalities
TSH-producing hypophysary adenoma   -   - not indicated moderate effect
ACTH-producing hypophysary adenoma   -   - not indicated moderate effect
Primary hyperthyroidism   -   -not indicated no effect
Primary hyperfunction of the adrenal cortex   -   - not indicated no effect


Pheochromocytoma
      The pheochromocytoma is a benign tumour of the adrenal medulla that secretes catecholamines and causes severe arterial hypertension, either continuous or occurring in acute episodes. The laboratory diagnosis of this conditions rests on the demonstration of catecholamine metabolytes in the urine (metanephrines and vanillyl-mandelic acid). False negatives are not uncommon unless the urine sample is collected after an hypertensive crysis.


Endocrine disorders of the gonads
      The gonads produce the gametes and elaborate sexual steroid hormones. Their function is controlled by LH and FSH produced by the pituitary. The development of the testis and the ovary is dependent on the sex chromosomes, and is sensitive to sexual aneuploidies (e.g. Turner syndrome, 45 X0; Klinefelter syndrome, 47 XXY). Both sexes produce male and female steroids, but of course males produce more androgenic hormones and females more estrogens and progesterone.
      Male hypogonadism may be primary, due to Leydig cells dysfunction, or secondary to insufficient stimulation by the hypophysis (hypogonadotropic hypogonadism e.g in adiposo-genital and adreno-genital syndromes like Babinsski-Froelich's, or in Kallmann's syndrome). Testosterone production is decreased and sterility (aspermia, azoospermia) is present in both cases. The stimulation test is carried out by adminstration of he hypothalamic factor GnRH.
      Female hypogonadism with sterility and anovulation occurs in Turner syndrome, dysfunction of the hypophysis, anorexia nervosa, polycystic ovary, etc. The differential diagnosis is difficult because the causes can be numerous, and the endocrine dysfunction may be subtle (e.g. dysruption of the cyclic hormone changes).
      Hyperproduction of sex hormones may cause two very different disturbances, depending on the offending hormone being that of the patint's sex or of the opposite sex. Excess production of testosterone in males is scarcely symptmatic, unless it is due to diseases that cause non-sexual problems (e.g. neoplastic lesions of the testicle). Excess production of estrogens in males (e.g. because of an adenoma of the adrenals or the testicle) causes femininization. In women, excess production of estrogens may derange the gametogenesis resulting in reduced fertility; excess production of androgens causes hirsutism.

Further readings
Doubleday AR, and Sippel RS Hyperthyroidism
Cherella CE and Wassner AJ Congenital hypothyroidism: insights into pathogenesis and treatment.
Stieg MR, Renner U, Stalla GK, and Kopczak A Advances in understanding hypopituitarism.
Mihailidis J, Dermesropian R, Taxel P, Luthra P, Grant-Kels JM Endocrine evaluation of hirsutism

Questions and exercises:
1) Dwarfism can be:
armonic in congenital pituitary insufficiency, disarmonic in congenital thyroid insufficiency
disarmonic in congenital pituitary insufficiency, armonic in congenital thyroid insufficiency
disarmonic in both congenital pituitary insufficiency, and congenital thyroid insufficiency

2) A patient presents reduced basal metabolism, reduced T4 and T3, and reduced TSH. A likely diagnosis is:
Hypothyroidism due to a thyroid disease
Hypothyroidism secondary to a disease of the pituitary
Hyperthyroidism due to a thyroid disease

3) Insufficiency and hyperfunction of the endocrine functions of the pancreas cause, respectively
type 2 diabetes mellitus and type 1 diabetes
type 2 diabetes mellitus and hypoglycemic crises
type 1 diabetes mellitus and hypoglycemic crises

4) Diabetes insipidus is due to
reduced secretion of ADH by the neurohypophysis
reduced secretion of insulin by the pancreas
reduced sensitivity to insulin of the tissues

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Thank you Professor (lecture on bilirubin and jaundice).

The fourth recorded part, the one on hyper and hypoglycemias is not working.
Bellelli: I checked and in my computer it seems to work. Can you better specify
the problem you observe?

This Presentation (electrolytes and blood pH) feels longer than previous lectures
Bellelli: it is indeed. Some subjects require more information than others. I was
thinking of splitting it in two nest year.

Bellelli in response to a question raised by email: when we compare the blood pH
with the standard pH we do not mean to compare the "normal" blood pH (7.4)
with the standard pH. Rather we compare the actual blood pH of the patient, with
the pH of the same blood sample equilibrated under standard conditions.
Thus, if we say that standard pH is lower than pH we mean that equilibriation with
40 mmHg CO2 has caused absorption of CO2 and has lowered the pH with respect
to its value before equilibration.

(Lipoproteins) Is the production of leptin an indirect cause of type 2 diabetes since
it works as a stimulus to have more adipose tissue that produces hormones?
Bellelli: in a sense yes, sustained increase of leptin causes the hypothalamus to adapt
and to stop responding. Obesity ensues and this in turn may cause an increase in the
production of resistin and other insulin-suppressing protein hormones produced by the
adipose tissue. However, this is quite an indirect link, and most probably other factors
contribute as well.

(Urea cycle) what is the meaning of "dissimilatory pathway"?
Bellelli: a dissimilatory pathway is a catabolic pathway whose function is not to produce
energy, but to produce some terminal metabolyte that must be excreted. Dissimilatory
pathways are necessary for those metabolytes that cannot be excreted as such by the
kidney or the liver because they are toxic or poorly soluble. Examples of metabolytes
that require transformation before being eliminated are heme-bilirubin, ammonia,
sulfur and nitrogen oxides, etc.

Talking about IDDM linked neuropathy can be the C peptide absence considered a cause of it??
Bellelli: The C peptide released during the maturation of insulin, besides being an indicator
of the severity of diabetes, plays some incompletely understood physiological roles. For
example it has been hypothesized that it may play a role in the reparation of the
atherosclerotic damage of the small arteries. Thus said, I am not aware that it plays a direct
role in preventing diabetic polyneuropathy. Diabetic neuropathy has at least two causes: the
microvascular damage of the arteries of the nerve (the vasa nervorum), and a direct
effect of hyperglycemia and decreased and irregular insulin supply on the nerve metabolism.
Diabetic neuropathy is observed in both IDDM and NIDDM, and requires several years to
develop. Since the levels of the C peptide differ in IDDM and NIDDM, this would suggest
that the role of the C peptide in diabetic neuropathy is not a major one. If you do have
better information please share it on this site!

In acute intermitted porphyria and congenital erythropoietic porphyria why do the end product
of the affected enzymes accumulate instead of their substrate??
Bellelli: First of all, congratulations! This is an excellent question.
Remember that a condition is which the heme is not produced is lethal in the foetus; thus
the affected enzyme(s) must maintain some functionality for the patient
to be born and to come to medical attention. All known genetic defects of heme
biosynthesis derange but do not block this metabolic pathway.
Congenital Erythropoietc Porphyria (CEP) is a genetic defect of uroporphyrinogen
III cosynthase. This protein associates to uroporphyrinogen synthase (which is present
and functional in CEP) and guarantees that the appropriate uroporphyrinogen isomer is produced
(i.e. uroporphyrinogen III). In the absence of a functional uroporphyrinogen III
cosynthase other possible isomers of uroporphyrinogen are produced together with
uroporpyrinogen III, mostly uroporphyrinogen I. The isomers of uroporphyrinogen
that are produced differ because of the positions of propionate and acetate side chains,
and this in turn is due to the pseudo symmetric structure of porphobilinogen. Only
isomer III can be further used to produce protoporphyrin IX. Thus in the
case of CEP we observe accumulation of abnormal uroporphyrinogen derivatives, which, as
you correctly observed are the products of the enzymatic synthesis operated by
uroporphyrinogen synthase.
The case of Acute Intermittent Porphyria (AIP) is similar, although there may be variants
of this disease. What happens is that either the affected enzyme is a variant that does not
properly associate with uroporphyrinogen III cosynthase or presents active site mutations
that impair the proper alignement of the phoprphobilinogen substrates. In either case
abnormal isomers of uroporphyrinogen are produced, as in CEP.
Also remark that in both AIP and CEP we observe accumulation of the porphobilinogen
precursor: this is because the overall efficiency of the biosynthesis of uroporphyrinogens is
reduced. Thus: (i) less uroporphyrinogen is produced, and (ii) only a fraction of the
uroporphyrinogen that is produced is the correct isomer (uroporphyrinogen III).



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