Endocrinology Introduction Dynamic function tests Hypothalamus and pituitary function tests Adrenal function Thyroid function tests Other glands

Definitions Hormones: chemicals secreted by cells into extracellular fluid that regulate metabolic functions of other cells (tissues) in the body. Endocrine System: includes all endocrine cells and body tissues that produce hormones or paracrine factors. Endocrine cells: glandular secretory cells that release their secretions into extracellular fluids (blood, lymph, etc.).

Endocrine system

Endocrine system functions Provides long-term regulation and adjustments of homeostatic mechanisms: Fluid and electrolyte balance. Cell and tissue metabolism. Growth and development. Reproductive functions. Assists nervous system response to stressful stimuli through general adaptation syndrome.

Hormonal alterations Elevated hormones level. Depressed hormones level. Oversecretion: Cushing’s disease where pituitary adenoma secretes ACTH. Undersecretion: primary hypothyroidism where the thyroid gland is unable to make sufficient thyroid hormone despite continued stimulation by TSH. Failure of hormone responsiveness: Pseudohypoparathyroidism, no functioning receptors.

Hormonal alterations Causes of such alterations: Failure of feedback mechanisms. Dysfunction of endocrine gland: Secretory cells are unable to produce or do not obtain an adequate quantity of required hormone precursors. Secretory cells are unable to convert the precursors to the appropriate active form of hormone. Secretory cells may synthesize and release excessive amounts of hormone. Degradation or inactivation of hormones by antibodies before reaching the target cell. Ectopic sources of hormones. Failure of the target cells to respond to hormone: Receptor-associated disorders. Intracellular disorders.

Hormonal alterations Receptor associated disorders Decrease in the number of receptors   hormone-receptor binding. Impaired receptor function  sensitivity to the hormone. Antibodies against specific receptors. Unusual expression of receptor function. Intracellular disorders Inadequate synthesis of the second messengers. Number of intracellular receptors may be decreased or they may have altered affinity for hormones. Alterations in generation of new messenger RNA or absence of substrates for new protein synthesis.

Autoregulation Down-regulation: continued presence of a hormone triggers decrease in number of hormone receptors. High levels of a particular hormone cause cells to become less sensitive to it. Up-regulation: absence of a hormone triggers increase in number of hormone receptors, cells become more sensitive

Endocrine Reflexes Humoral stimuli: Changes in composition of extracellular fluid (e.g. increased Calcium levels cause PTH release). Hormonal stimuli: Arrival or removal of specific hormone (e.g. TSH hormone causes the release of thyroid hormone). Neural stimuli: Arrival of neurotransmitters at neuroglandular junctions (Sympathetic neurons cause adrenal medulla to release Epinephrine, Norepinephrine).

Humoral Hormonal Neural

Hormones Homeostasis, the tendency to maintain stability, is essential to survival. It is achieved by a system of control mechanisms (chemical agents): Endocrine control. Paracrine Autocrine All these regulators affect via receptor proteins, which may be on the cell surface or within the target cells. Endocrinology is the study of hormones Types of Hormone Hormones fall into one of three broad classes on the basis of their structure: Peptide or protein. Most hormones fall into this class. These may be small (the hypothalamic factor, thyrotrophin releasing hormone, has just three amino acids) or large (the pituitary gonadotrophins are glycoproteins with subunits). Amino acid derivatives. A few hormones fall into this class. e.g. adrenaline and the thyroid hormones. Steroid hormones. These are derivatives of cholesterol.

Assessment of endocrine function: Assessment of endocrine control presents particular difficulties: Low concentrations. Variability. Hormone binding. Assessment of endocrine control presents particular difficulties: Low concentrations: at or below the lower limit of detection method. Immunoassays improved the detection. Variability: not one measurement. GH released in a pulsatile manner, cortisol released in a circadian rhythm, Hormone binding: the unbound is the active part. The binding protein should also be measured.

Types of endocrine control Negative feedback: TRH, TSH, T4 Positive feedback: LH and estrogen.

Dynamic function tests Where the results of clinical assessment and baseline biochemical investigations fail to rule in or rule out a serious endocrine diagnosis dynamic function tests may be required. Example: acromegaly

Case 1 A 57 year old male had an Insulin Stress Test and the following results were obtained: Time (min) Glucose (gm/dL) Cortisol (nmol/L) GH mU/L 73 295 0.1 30 10 374 0.4 60 15 354 0.2 90 40 261 120 70 182 3.5

Case 1 When is such a test is carried on? What is this test? Did the test achieve adequate hypoglycemia? Is their adequate cortisol response? Is their adequate GH response? What other hormones are evaluated with this test? This test is carried out when hypopituitarism is suspected. Enough insulin is administered intravenously to produce hypoglycacmic stress (less than 40 gm/dL). This tests the ability of the anterior pituitary to produce ACTH and GH in response Cortisol is measured instead of ACTH; this assumes that the adrenals can respond normally to ACTH. A peak GH in excess of 20mU/L is regarded as evident of adequate reserve. For cortisol, anything less than 500 nmol/L is inadequate. Other hormones: TSH, FSH, LH (gonadal axis).

Dynamic function test Dynamic function tests (DFTs) involve either stimulating or suppressing a particular hormonal axis, and observing the appropriate hormonal response. If a deficiency is suspected, a stimulation test should be used; if excess is suspected, a suppression test is used. Often, the stimulus is an exogenous analogue of a trophic hormone; in other cases it is provided by biochemical or physiological stress, e.g. hypoglycemia or exercise. Commonly used DFTs: Insulin stress test (IST) This test is carried out when hypopituitarism is suspected. Enough insulin is administered intravenously to produce hypoglycacmic stress. This tests the ability of the anterior pituitary to produce ACTH and GH in response Cortisol is measured instead of ACTH; this assumes that the adrenals can respond normally to ACTH. A peak GH in excess of 20mU/L is regarded as evident of adequate reserve. For cortisol, anything less than 500 nmol/L is inadequate.

TRH test TRH is given as an intravenous bolus; blood sampling is at 0, 20 and 60 minutes. In normal subjects TRH elicits a brisk release of both TSH and prolactin. This test may be used to assess the adequacy of anterior pituitary reserve, or to evaluate suspected hypothalamic disease, in which TSH response to TRH is characteristically delayed (TSH higher at 60 minutes than at 20 minutes). Much less frequently it may be indicated in suspected hyper- or hypothyroidism. Where there has been prolonged negative feedback due to hyperthyroidism, the pituitary response to TSH is flat (TSH rises by <2mU/L); conversely, an exaggerated TSH response (>25mU/L) is seen in hypothyroidism.

GnRH In normal adults, GnRH (Gonadotrophin releasing hormone) produces a marked rise in LH (>15U/L) and a smaller rise in FSH (>2U/L). This test is indicated where there is clinical or biochemical evidence of hypogonadism, particularly in the absence of the expected rises in LH and FSH. It may be performed alone or as part of a combined anterior pituitary function test. It consists of the three separate DFTs described previously (IST, TRH and GnRH test) performed simultaneously. Collectively they provide a comprehensive assessment of anterior pituitary reserve.

Oral glucose tolerance test with GH measurement Just as hypoglycemia stimulates GH secretion, so hyperglycemia suppresses it. Normal adults suppress GH to <2mU/L, but acromegalic patients do not. Following treatment, patients who fail to suppress GH below 5mU/L have a higher prevalence of diabetes, heart disease and hypertension.

Synacthen tests Short Synacthen test (SST) This is one of the most commonly performed DFTs. Synacthen is synthetic 1-24 analogue of ACTH and is administered IV at a dose of 250µg. Cortisol is measured at 0, 30 and 60 minutes Of the three criteria that are used to define a normal response, the final cortisol is the most important and the increment the least important. Cut-offs for the final level vary between 500 and 580 nmol/L Long Synacthen test (LST) Where the response to an SST is inadequate, it may not be clear whether the adrenal insufficiency is primary, or secondary to pituitary or hypothalmic disease. If the SST is repeated after the administration of a much larger dose of Synacthen (1 mg IM for 3 days and the SST repeated on the fourth) a normal response makes primary adrenal insufficiency unlikely. Measurement of ACTH may prevent the need for a LST-unequivocally elevated ACTH in the presence of an impaired response to Synacthen confirms the diagnosis of primary adrenal failure.

Dexamethasone suppression tests (DSTs) Dexamethasone is an exogenous steroid that mimics the negative feedback of endogenous glucocorticoids. Dexamethasone suppression test are important in the investigation of suspected overactivity of the hypothalmic-pituitary-adrenal axis. Low dose DST In its simplest form, the low dose DST-usually performed on an outpatient basis- involves the patient taking 1 mg dexamethasone orally at 23:00 and attending the following morning at 8:00 or 9:00. if the cortisol has suppressed to <50 nmol/L, cortisol overproduction is unlikely and no further action is required. High dose DST 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. The high dose DST (8 mg) is used to distinguish the first two of these options. ACTH production in Cushing’s syndrome does usually suppress in response to high dose dexamethasone, whereas malignant production of ACTH usually does not.

DFT- protocol variations Many of these tests are complex and require careful attention to appropriate timing of samples for their results to be meaningful Protocols for individual DFTs vary from one center to another. For example, the LST may be performed as a day-long procedure, with 1 mg Synacthen administered in the morning and cortisol samples collected for up to 24 hours. The reasons for the different protocols are often practical rather than evidence-based

The End