Endocrine part one. Presented by Dr. Mohammad Saadeh The requirements for the Clinical Chemistry Philadelphia University Faculty of pharmacy

Transcription

1 Endocrine part one Presented by Dr. Mohammad Saadeh The requirements for the Clinical Chemistry Philadelphia University Faculty of pharmacy

2 HORMONES Hormones are chemicals released by a cell or a gland in one part of the body that send out messages to affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, they are chemical messenger that transport a signal from one cell to another. Hormones affect only specific target tissues with specific receptors. Receptors constantly synthesized and broken down Down-regulation Up-regulation Two (2) types of glands Exocrine ducted Endocrine ductless Secrete hormones into interstitial fluid, diffuse into blood Endocrine glands include pituitary, thyroid, parathyroid, adrenal and pineal glands Hypothalamus, thymus, pancreas, ovaries, testes, kidneys, stomach, liver, small intestine, skin, heart, adipose tissue, and placenta not exclusively endocrine glands

3 Nervous and Endocrine Systems Act together to coordinate functions of all body systems Nervous system Nerve impulses/ Neurotransmitters Faster responses, briefer effects, acts on specific target Endocrine system Hormone mediator molecule released in 1 part of the body but regulates activity of cells in other parts Slower responses, effects last longer, broader influence Copyright 2009, John Wiley & Sons, Inc.

4 Biochemical regulation and Hormone types 1. Endocrine regulation (circulating hormones) circulate in blood throughout body 2. Local hormones act locally, divided to Paracrine act on neighboring cells Autocrine act on the same cell that secreted them Copyright 2009, John Wiley & Sons, Inc.

5 Hormone structure The diverse biological effects of different hormones are reflected in different molecular structures. Three broad classes are recognized: Peptides or proteins. vary enormously in size. example, the hypothalamic factor thyrotrophin-releasing hormone has just three amino acids, whilst the pituitary gonadotrophins are large glycoproteins with subunits. Amino acid derivatives. Examples: include the thyroid hormones and adrenaline (epinephrine). Steroid hormones. This large class of hormones includes glucocorticoids and sex steroid hormones, all of which are derived structurally from cholesterol.

6 Assessment of endocrine control Low concentrations Variability Hormone binding Variability

7 Type of endocrine control Negative feedback (if product level increase, cause decrease in activity system). Positive feedback (if product level increase, cause increase in activity system).

8 Type of endocrine control Negative feedback (if product level increase, cause decrease in activity system). Hormone A in this axis is thyrotrophin-releasing hormone (TRH), hormone B is thyroidstimulating hormone (TSH) and hormone C is thyroid hormone (T4). Correspond to a certain intended concentration of T4. By means of negative feedback from T4. thyrotrophin-releasing hormone TRH Thyroid-Stimulating Hormone (TSH) Thyroid hormone (T4)

9 Type of endocrine control Hypothalamus of gonadotrophinreleasing hormone (GnRH) fluctuates. Positive feedback (if product level increase, cause increase in activity system). At a particular point in the cycle the feedback from oestrogen on LH production switches from being negative to being positive, and the resulting LH surge triggers ovulation. Follicle-stimulating hormone (FSH) Stimulate the development of Follicles to produce oestrogen Anterior pituitary-ovarian luteinizing hormone (LH) Triggers ovulation The reasons for this switch are not entirely clear (after all, the hypothalamic-pituitary-ovarian axis normally operates as a negative feedback loop), but positive feedback requires a threshold concentration of oestradiol (thought to be in the region of 700 pmol/l) to persist for at least 48. +

10 Pitfalls in interpretation 1. Immunoassay interference. Up to 40% of the population may have unsuspected antibodies that can interfere with immunoassays, by interacting either with the analyte being measured or with the antibody being used in the immunoassay mixture. These antibodies can produce falsely lowered or falsely raised results, with potentially serious consequences. This kind of problem is well recognized for some assays, e.g. thyroglobulin, prolactin. 2. Log-linear responses. In response to alterations in TRH, TSH may rise exponentially. This kind of relationship means that the biological significance of a rise in TSH from 1 to 5 mu/l is the same as a rise from 10 to 50 mu/l. Moreover, this kind of relationship applies to all trophins released by the anterior pituitary, including growth hormone, the trophic hormone for insulin-like growth factors. Interestingly, the (skewed) distribution of serum prolactin behaves in a similar way, as if it too was a trophins like TSH or ACTH, even though, as yet, no prolactin-controlled hormone has been identified.

11 Dynamic function tests Dynamic function tests (DFTs) involve either stimulating or suppressing a particular hormonal axis, and observing the appropriate hormonal response. Dynamic function tests: 1. Insulin stress test. 2. TRH test 3. GnRH test 4. Oral glucose tolerance test with GH measurement 5. Synacthen tests Short Synacthen test Long Synacthen test 6. Dexamethasone suppression test Low dose dexamethasone suppression test High dose dexamethasone suppression test

12 1. Insulin stress test (IST test) This test is carried out when hypopituitarism is suspected. It is also known as the insulin tolerance test. Hypoglycemia: potent stress stimulus for ACTH release. Methodology: Enough insulin is administered after an overnight fast to produce hypoglycaemic stress (blood glucose <2.2 mmol/l). Glucose level and Cortisol is measured instead of ACTH at 0, 30, 60, 90, 120 minutes; this assumes that the adrenals cortex can respond normally to ACTH. This tests the ability of the anterior pituitary to produce ACTH and GH in response. Note: o A peak of GH in excess of 20 mu/l is regarded as an adequate reserve. o In cortisol anything less than 500 nmol/l is inadequate. o IST use to diagnosis Cushing's disease Hypothalamus insulin Anterior pituitary Cortisol, GH & Aldosterone

13 Thyrotrophin releasing hormone test (TRH test) Central hypothyroidism is defined as hypothyroidism due to insufficient production of thyroid stimulating hormone (TSH), caused by hypothalamic or pituitary defect. Methodology: TRH is given as an intravenous bolus; blood sampling is at 0, 20, 60, 90 and 120 minutes. In normal subjects TRH stimulate of both TSH and prolactin. TRH test used to assess the adequacy of anterior pituitary or hypothalamic disease. In which the TSH response to TRH is characteristically delayed (TSH higher at 60 minutes than at 20 minutes). Result: Much less frequently it may be indicated in suspected hyper- or hypothyroidism or subclinical thyroid disease. Where there has been prolonged negative feedback due to hyperthyroidism, the pituitary response to reserve, or to evaluate suspected TRH is flat (TSH rises by <2 mu/l); conversely, an exaggerated TSH response (>25 mu/l) is seen in hypothyroidism.

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15 Gonadotrophin releasing hormone test (GnRH test) In normal adults, GnRH produces a marked rise in luteinizing hormone (LH) and a smaller rise in follicle stimulating hormone (FSH). Increments in adults are >15 U/L for LH and >2 U/L for FSH. In children the FSH response is greater than the LH response. Methodology: GnRH is administered. After that LH & FSH are assessed at 0, 30, 60, 90 and 120 minutes and also assess GH and gonadal (testosterone or oestradiol) function. This test is indicated evidence of hypogonadism, particularly in the absence of the expected compensatory rises in LH and FSH. It may be performed alone or as part of a combined anterior pituitary function test.

16 Gonadotrophin releasing hormone test (GnRH test) The latter simply consists of the three separate dynamic function tests (DFTs) described above: 1. Insulin stress test (IST), 2. Thyrotrophin releasing hormone test TRH test 3. Gonadotrophin releasing hormone test (GnRH test) performed simultaneously. Collectively they provide a comprehensive assessment of anterior pituitary reserve.

17 Oral glucose tolerance test (OGTT) with GH measurement Hypoglycaemia stimulates GH secretion, so hyperglycaemia suppresses it. Methodology: This forms the basis for performing an oral glucose tolerance test (OGTT) with GH measurement. Result: Normal adults suppress GH to <2 mu/l, but acromegalic patients do not; failure to suppress is therefore highly suggestive of acromegaly. Following treatment, patients who fail to suppress GH below 5mU/L have a higher prevalence of diabetes, heart disease and hypertension.

18 Synacthen tests Short Synacthen test (SST) Formal diagnosis or exclusion of adrenal insufficiency requires a short Synacthen test (SST). Methodology: Synacthen is a synthetic analogue of ACTH and is administered intravenously at a dose of 250 μg. Cortisol is measured at 0, 30 and sometimes 60 minutes. The criteria for a normal response are shown in Figure Adequate cortisol response to Synacthen; cut-offs for the final level vary between 500 and 580 nmol/l. elevated ACTH indicate primary adrenal failure Equivocal or inadequate responses may require a long synacthen test (LST). Hypothalamus Anterior pituitary cortisol

19 Synacthen tests Long Synacthen test Where the response to an Short Synacthen test (SST) is inadequate or equivocal, it may not be clear whether the adrenal insufficiency is (primary to adrenal cortex); or (secondary to pituitary or hypothalamic disease). Methodology: Synacthen (1 mg) is given intramuscularly daily for 3 days and the SST repeated on the fourth (cortisol is measured at 0, 10, 30 and 60 minutes; a normal response makes primary adrenal insufficiency unlikely (secondary adrenal insufficiency). Measurement of ACTH may obviate the need for a LST unequivocally elevated ACTH in the presence of an impaired response to Synacthen confirms the diagnosis of primary adrenal failure. Hypothalamus Anterior pituitary

20 Dexamethasone suppression tests Dexamethasone is an exogenous steroid that mimics the negative feedback of endogenous glucocorticoids. Dexamethasone suppression tests (DSTs) are important in the investigation of suspected over activity of the hypothalamic-pituitary-adrenal axis. Dexamethasone _ (1 mg) negative feedback suppression Hypothalamus Low dose dexamethasone suppression test Methodology: the patient taking 1 mg dexamethasone orally at 23:00 and attending for a cortisol blood test the following morning at 08:00 or 09:00. Result: If the cortisol has suppressed to <50 nmol/l, cortisol overproduction is unlikely and no further action is normally required. Anterior pituitary cortisol

21 cortisol Dexamethasone suppression tests High dose dexamethasone suppression test Failure to suppress in response to low dose dexamethasone may occur because of autonomous ACTH production by the pituitary (Cushing s disease), or ectopic ACTH production (usually malignant), or adrenal production of cortisol. Dexamethasone _ (8mg) negative feedback suppression Hypothalamus Methodology: The high dose DST (8 mg) is used to distinguish between ACTH production by the pituitary Cushing s disease and or ectopic ACTH production (usually malignant), or adrenal production of cortisol. Result: ACTH production in Cushing s disease does usually suppress in response to high dose dexamethasone. malignant production of ACTH usually does not. Anterior pituitary

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