Endocrine Disorders
College of MedicineIBN HIAN UNIVERSITY
Subject: Biochemistry / 2nd year Medicine/ 2016-2017
Dr. ABDUL HUSSEIN A. ALGENABIMBChB, MSc, PhD
Clinical Chemistry
Objectives
Definition of HormoneChemical classification of hormones (H. structure)
Mechanism of hormone action (water solubility)
Major endocrine glands
Control of Hormone secretion
Hormone is defined as a regulatory chemical substance secreted into the blood by an endocrine gland. Paracrine - regulatory molecules work without being transmitted by the blood not endocrine
Hormone concentration in blood can be present in three forms; protein bound form w is inactive, free (unbound) form w is the active form and total form that's of bound and free (usually measured in laboratory).
Chemical Classification of Hormones: i.e. hormone structure
a. Protein hormones effect is on receptors within the membrane, binds to the receptors on the outside of membrane; its effects are the most rapid of all the hormonesb. Amine hormones same relatively fast receptor response as protein hormones. Examples are catecholamines and thyroid hormones
i. Epinepherine
ii. Norepinepherine
iii. Thyroid hormones
iv. Melatonin
c. Steroid hormones binds to the intracellular receptors; slow actions
i. Gonadal hormones
1. Estrogen, progesterone, androgens
ii. Adrenal hormones
Glucocorticoids, mineralocorticoids
Mechanism of Hormone Action
All hormone action is receptor mediated
hormone binding to specific receptor results in conformational change in receptor that conveys a signal to target cell
Types of cell receptors: Another classification of hormones is according to their receptor location into two groups:
Group I: Intracellular Receptors
These diffuse through the membrane of cells forming HR-complex inside the cells which undergo structural changes that enhance the binding of complex to DNA of the cell results in gene transcription (mRNA production) which affects metabolic response. Ex; Steroid and thyroid hormones
Group II: Cell surface receptors
These are protein-derived hormones that are water-soluble compounds so they cannot diffuse inside the cell but they bind to surface receptors and the signals transmitted intracellularly through the second messenger, (hormone is the first messenger). Example; Peptide hormones
and catecholamines
This group can be classified according to their second messengers into 4 subgroups:
Subgroup (A) They act by increasing cAMP level inside the cells through activation of cell membrane enzyme (adenylate cyclase). Termination of hormonal response occurs by the action of phosphodiesterase which converts cAMP to 5ʹ-AMP which is inactive. Caffeine which is Xanthine derivative inhibits phosphodiesterase activity therefore causes prolonged hormonal action.
Subgroup (B) They act by increasing cGMP level inside the cells through activation of guanylate cyclase. It includes one hormone only called atrial natruretic factor (ANF) which is produced by atrial tissue of heart and causes natruresis, vasodilation and inhibition of aldosterone secretion, therefore; results in decreased sodium (Na⁺↓ and BP↓). cGMP breaks down by the action of cGMP phosphodiesterase. Therefore, drugs that activate guanylate cyclase increase cGMP level, such as Nitroprusside and Adalat (trademark for Nifedipine) are used in treatment of hypertension.
Subgroup (C) the second messenger is phosphoinositol e.g. ADH, when this hormone attaches to its receptor on the cell surface, it will activate an enzyme called phospholipase C, which acts to increased calcium ion levels intracellularly. This ion binds to specific protein called calmodulin, forming calcium- calmodulin complex, which are similar to cAMP.
Subgroup (D) the second messenger is unknown for hormones including insulin, GH, prolactin (PRL) and hCG. There is no a definitive messenger for them but they act almost all over the body.
Endocrine system control (axes and feedback loops):
Hypothalamic-Pituitary AxesThree main axes involving hypothalamus and pituitary control much of endocrine system
- operate by negative feedback (Short and long loops)
Hypothalamic-Pituitary-Thyroid axis (HPT)
Hypothalamic-Pituitary-Adrenal axis (HPA)
Hypothalamic-Pituitary-Gonadal axis (HPG)
Mechanisms in Endocrine Axis:-
The mechanism starts with neural signals which stimulate the production of releasing hormones (RH) from the hypothalamus. Each of these RH triggers its target cell in anterior pituitary gland to produce its corresponding tropic hormone. These tropic hormones circulate in blood and act on their target gland or tissue to produce their response.Note: prolactin is the exception because its secretion is normally inhibited (RHIH is high). But when there are tumour e.g. chromope adenoma, or when there is pregnancy and lactation, the RH of prolactin is dominant, which results in increased level of prolactin in blood ( hyperprolactinemia)
Q: Are all hormones under Axis Control? Give examples?
No, such as calcitonin of thyroid gland and parathyroid hormone that's produced by parathyroid glands. Both of these hormones are controlled by serum calcium level. Also Insulin and glucagon are secreted from the pancreas. They are under the control of blood glucose level.Q) How many endocrine glands are there in the body, what classes do they fall in?
They are two types:Master glands (hypothalamus and pituitary)
Target glands (all the other glands)
Major Endocrine Glands
HypothalamusAnterior pituitary
Posterior pituitary
Pineal
Thyroid
Parathyroids
Adrenal medulla
Adrenal cortex
Pancreas
Ovaries
Testes
Placenta
Control Mechanisms:-
These are mechanisms that maintain normal level of hormones both in serum and tissues, these are:
Negative feedback inhibition; it is the commonest type in which increase in product of axis more than normal level will inhibit the whole axis activity. For e.g. the hypothalamus-pituitary-adrenal axis (HPA axis). Any increase its end product level (cortisol) will inhibit the secretion of hypothalamic hormone which is CRH (for corticotropin-releasing hormone) and this in turn, will not stimulate pituitary hormone ACTH (adrenocorticotropin hormone) any longer. This is called long loop inhibition. While when pituitary hormones increase, they will inhibit hypothalamus secretion. This is called short loop inhibition. This mechanism is lost in patients of Cushing's syndrome in which case cortisol secretion is vast.
Neural stimulation: physical or emotional stress may result in neural signals from the brain to hypothalamus and therefore increase in pituitary hormone secretion as well as the target gland (axis stimulation). This is called (open loop control system) may result in clinical findings similar to endocrine diseases.
Inherited rhythm (circadian rhythm); intermittent release of hypothalamic or pituitary hormones results in regular daily secretion of target hormones. Example is cortisolit is higher at morning and lower at night. This rhythm is lost in patients of Cushing's syndrome.
Endocrine Disease:-
It is of two types:Primary endocrine disease:
Failures of target glands respond to hypothalamic or pituitary hormones, which are normal. This leading to loss of negative feedback inhibition, therefore there is excessive production of pituitary hormones
e.g. ovarian failure leading to very low oestrogen, which stimulates the hypothalamic (GnRH) or pituitary (LH and FSH) secretion.
Secondary endocrine disease:
Deficiency of hypothalamus or pituitary hormones that result in deficiency of target gland hormones as well.e.g. Damage to hypothalamus causes deficiency of GnRH which causes no stimulation for pituitary hormone production, i.e. low levels of LH and FSH which leads to no hormonal action on target tissues (ovaries) that means low levels of serum oestrogen and progesterone (in female). This example can applied to other systems.
Hypothalamic Hormones:-
The hypothalamus produces two groups of hormones that are associated with posterior and anterior pituitary.The first group includes 3 peptide hormones that travel down to the posterior pituitary through nerve fibres where they are stored there. These hormones are:
Arginine-vasopressin (or known as ADH): when there is hyperosmolality e.g. dehydration, this hormone acts on renal tubule through special receptors enhancing water reabsorption (without salts) from tubules to the blood. This means dilute the blood and corrects osmolality, but concentrated urine is produced.
The reverse is true, that is to say when the subject drinks a lot of water/fluid, this will decrease blood osmolality and inhibits ADH secretion, with more loss of water in urine (dilute urine is produced), so disease or trauma that causes damage of posterior pituitary causes deficiency of ADH resulting in a syndrome called diabetes insipidus. Also, congenital absence of tubular receptors of ADH (renal cause), results in a similar syndrome called nephrogenic diabetes insipidus. Dx by water restriction test or by measuring ADH
Oxytocin: a hormone similar in structure to ADH, controls ejection of milk from lactating breasts. It also initiates uterine contraction during labour. It can be used in obstetrics to induce labour, in the form of drugs called Pitocin.
Neurophysin: its function is not clear but it may transport and restore the above two hormones.
The second group includes tri or tetrapeptide molecules called regulatory hormones that are produced in the hypothalamus and are transported through blood network to anterior pituitary. These are of 2 types:
Releasing hormones (RH)
Releasing hormone-inhibitory hormones (RHIH)
The RH stimulates release of anterior pituitary hormones, whilst RHIH inhibits them. Normally, all pituitary hormones undergo stimulation, except prolactin (PRL), which undergoes inhibitory effect (its release is normally inhibited).
Classification of Anterior Pituitary Hormones:-
According to their chemical composition, these hormones are of 2 types:Simple polypeptides: such as GH and prolactin, both of them have no specific target endocrine tissues, but they act directly to do their effects, e.g. GH enhances bone and cartilage growth, while prolactin acts on mammary gland (lactation).
Glycoproteins: such as LH, FSH, TSH and ACTH. This group is more resistant to heat and other environmental factor outside the body. (Why?). Because of the presence of carbohydrate moiety (part) in their structures which make them more resistant to proteolysis and damage.
Hypopituitarism:-
Defect in secretion of pituitary hormones, which is of two types:Isolated hormonal deficiency: only one or two hormones are deficient while the other hormones are normal, usually due to congenital abnormalities in hypothalamic centers result in deficient releasing hormones. The usual hormones affected are gonadotropins and GH.
Panhypopituitarism: All hormones of anterior pituitary are deficient due to pituitary tumours or infarction (loss of blood supply) such as in post-partum haemorrhage (also called Sheehan's syndrome).
Clinical and biochemical consequences of hypopituitarism:
The features are usually due to target gland failure e.g.Deficiency of LH or FSH causes secondary hypogonadism, which results in amenorrhea (absence of menses), infertility, atrophy of secondary sex characters, loss of libido and impotence in male.
Deficiency of GH and TSH causes growth retardation (dwarfism).
Deficiency of ACTH causes secondary adrenocortical hypo-function. [This type should be differentiated from the primary type that's called Addison's disease [in which the adrenal gland itself is destroyed by bacterial infection or by auto-immune disease (auto-antibodies) which means loss of adrenocortical function (cortisol↓)].
In Addison's disease, there are low levels of cortisol with a very high level of ACTH. In the secondary type, both of these hormones (cortisol and ACTH) are on low levels. The second difference is that in primary, there is hyperpigmentation while in secondary there is no pigmentation (why?);
because the low level of cortisol in Addison's results in loss of negative feedback inhibition, which results in excessive secretion of CRH and so ACTH. But this latter is also stimulator of melanocytes (cells of melanin) which are important for melanin production that give us dark pigmentation of skin and mucous membranes.
Out comes: The student should be able to differentiate various functions of hypothalamic, posterior and anterior pituitary hormones and capable to use them in understanding and diagnosing different endocrine disorders.