Endocrinal Glands: The endocrinal glands are the small islands of tissues in various parts of the body, which secrete a substance directly into blood stream (ductless-glands) and circulate in the body, called hormones.
- These hormones act at sites located away from their place of origin, by interacting with specific receptors, thus producing their effects.
- Most of these hormones have been isolated and their structure determined, which has made it possible to prepare them synthetically and by recombinant DNA technology.
Hormones are classified into:
- Hypothalamic hormones: They are secreted by the median eminence of the hypothalamus and are regulating the secretion of hormones from anterior pituitary (AP) (Fig. 8.1.1).Releasing hormones: [from Basophilic cells]
- TRH (Thyrotropin releasing hormone)
- CRH (Corticotropin releasing hormone)
- FSH-RH (Follicle stimulating releasing hormone)
- LH-RH (Luteinizing hormone releasing hormone)
Inhibitory hormones + Releasing hormones (mix): [from Acidophilic cells]- PRH (Prolectin releasing hormone) or PRFPIH (Prolectin inhibiting hormone)
- SRH (Somatotropin releasing hormone) or GHRH (Growth hormones releasing hormones).GH-RIH (Somatostatin) Inhibitory
- MS-RH (Melanocyte stimulating releasing hormone)MS-IH (Melanocyte stimulating inhibitory hormone)
- Pituitary hormones (Fig. 8.1.1) – They are released by:
- Anterior pituitary (Adenohypophysis) - which exercise a controlling influence over rest of the endocrine glands:
- GH (Growth hormone) or Somatotropin
- Prl (Prolectin)
- ACTH (Adreno-cortico tropic hormone)
- TSH (Thyroid stimulating hormone)
- FSH (follicle stimulating hormone)
- LH (luteinizing hormone)
- MSH (Melanocyte stimulating hormone)
- Posterior pituitary (Neurohypophysis) – which affect the uterus and water conservation.
- ADH (Anti-diuretic hormone) or vasopressin
- Oxytocin
- Hormones affecting metabolismThyroid hormones:
- – Thyroxin (T4)
- – Tri-iodothyronin (T3)
- – Calcitonin (It reduces plasma calcium level)
Parathyroid hormones:- – Parathromones (It increases plasma calcium level)
Pancreatic hormones:- – Insulin
- – Glucagons
- – Somatostatin
- – Pancreatic polypeptide
Adrenal hormones:
- Cortex:
- Glucocorticoids: Hydrocortisone, Prednisolone, and Dexamethasone
- Mineralocorticoids: Aldosterone and Fludro-cortisone
- Sex Steroids: Dehydro-epiandrosterone
- Medulla
- Adrenaline and Nor-adrenaline
- Hormones affecting the reproductive system –Female and male sex hormones:
- Androgen (testosterone)
- Estrogen (estradiol)
- Progestin (progesterone).
- Placental Hormones
- Chorionic gonadotropins
- Estrogen
- Placental lactogen
- Prolactin
- Chorionic thyrotropins, etc.
- Local Hormones Autacoids: Discussed previously
Hormones may be steroids or peptides:
- Steroidal hormones: They need multiple enzymes in their biosynthesis. They have relatively longer half life, the binding proteins are present and their peripheral transformations are common.
- Peptide hormones: Their synthesis take place through single protein, prohormone. They are having short half life, binding proteins are very rare and peripheral transformations do not occur.
Sites and Mechanism of Action of Hormones:
- At cell membrane receptors:
- Through AC = Adenyl Cyclases/cAMP/pkA generation:
- Primary messenger: Hormone
- Secondary messenger: cAMP
- Tertiary messenger: Ca++
- Examples: Adrenalin, Glucagons, TSH, FSH, LH, PTH, ACTH, GH, Calcitonin.
- Through IP3/DAG/pkC generation:
- Examples: ADH, Vasopressin, Insulin.
- At cytoplasmic receptors:
- Examples : Steroid hormones : Glucocorticoids, Mineralocorticoids, Estrogen, Progestin.
Hormone bind with cytoplasmic receptors
↓
Expose its DNA binding domin
↓
Migrate to nucleus and bind with specific gene
↓
DNA mediated RNA synthesis
↓
- At nuclear receptors:
- Hormones directly penetrate the nucleus → Combined with receptor → Ulter DNA – RNA mediated protein synthesis.
- Examples: Thyroid hormones: Thyroxin, Triiodothyronin.
HYPOTHALAMIC HORMONES: The secretion from anterior pituitary (AP) is regulated by hormones released from the hypothalamus, which reach the pituitary through blood stream. These include:
Thyrotropin Releasing Hormone (TRH): It is secreted by the hypothalamus, stimulates the release of TSH from the anterior pituitary. Protirelin is a synthetic TSH.
Corticotropin Releasing Factor (CRF): It releases ACTH and β-endorphins from the anterior pituitary. It is used in diagnostic tests in Cushing's disease (adrenocortical insufficiency).
Gonadotrophin Releasing Hormone (GnRH): It causes release of follicle stimulating hormone (FSH) and Luteinizing hormone (LH) from AP. Synthetic GnRH is called Gonadorelin. Analogues of GnRH have been developed.
- Agonists – buserelin, leuprorelin, goserelin and nafarelin. Given SC in a pulsatile fashion, with an infusion pump, they stimulate gonadotropin release and are used to induce ovulation. When given continuosly, by SC injection or as nasal spray or as depot preparation, they inhibit gonadotropin release and are useful in endometriosis, precocious puberty, advanced prostatic cancer and polycystic ovary syndrome.
- Antagonists – danazol and gestrinone – inhibit gonadotropin release and are used in the treatment of endometriosis, menorrhagia and gynecomastia in males.
Prolacting releasing factor (hormone): Causes release of prolactin from AP. Prolactin release inhibiting factor (dopamine) – inhibits the release of prolactin from AP.
Growth hormone releasing hormone: It stimulates anterior pituitary to secrete growth hormone. It is used in diagnostic tests of growth hormone deficiency.
Somatostatin [SRIH]: It is growth hormone release –inhibiting hormone present in the hypothalamus, parts of the CNS, pancreas and in gastrointestinal tract. It inhibits secretion of GH, TSH, Prl, insulin, glucagons and all gastrointestinal (gastric and pancreatic) enzymes. It causes vasoconstriction in GIT. But it is very short-acting. It is utilized for controlling esophageal ulcer bleeding.
Octreotide [Octride]: It is the synthetic analog of somatostatin which is longer acting and is indicated in: Acromegaly, carcinoid tumors, bleeding esophageal varices, refractory diarrhea and acute pancreatitis.
ANTERIOR PITUITARY HORMONES: The pituitary gland, under the influence of the hypothalamus secretes many hormones which either control the secretion of other glands or directly act on the target tissues. These are peptides and act by binding to specific receptors present on the target cells.
Growth Hormone (GH)
- It is a peptide, stimulates the growth of all organs except brain and eyes.
- It increases the uptake of amino acids by the tissues, promotes protein synthesis and positive nitrogen balance.
- It (GH) promotes utilization of fat by causing lipolysis in adipose tissue and reduces glucose uptake by skeletal muscles. It induces glycogenolysis in liver leads to hyperglycemia. It brings about linear growth.
- These anabolic actions are mediated by somatomedins or insulin-like growth factors (IGF1) produced in the liver.
The secretion of growth hormone is regulated by GHRH and somatostatin (GHRIH). See Fig. 8.1.2.
GH deficiency in children results in dwarfism while excessive production results in gigantism in children and acromegaly in adults.
Indication of GH
- GH deficiency: Replacement therapy with GH deficient children brings about normal growth (treatment of pituitary dwarfism). It can also be used in GH deficient adults.
- Other conditions GH has been tried in:
- – Renal failure
- – Bone merrow hypoplasia (osteoporosis)
- – Juvenile spontaneous hypoglycemia
- – Burn and trauma.
Preparations
- From cadaver pituitary (high chances of fetal viral infection transmission)
- DNA recombinant technology: Somatrem and Somatropin
- Dose: 0.06 – 0.16 U/Kg.
Prolactin
- It causes secretion of crops glands of pigeon.
- This peptide hormone promotes the growth and development of breast during pregnancy. It stimulates milk production along with other hormones like estrogens and progestins.
Prolactin: It is responsible for:
- Proliferation and differentiation of mammary tissue during pregnancy.
- Control of milk production during lactation.
- Prolactin act upon the estrogen and progesterone primed mammary glands (lactogenic action). While ‘let down’ or flow of milk is being caused by Oxytocin.
Regulation of Secretion (Fig. 8.1.3)
- Suckling is the principal stimulus for prolactin secretion.
- Estrogens and dopamine antagonists like Chlorpromazines, matoclopramide and haloperidol, etc. also stimulate prolactin-release.
- Reserpine and methyl dopa, depletes DA, causes prolectin release causes hyper-prolectinemia, It may leads to development of Gynecomastia in males.
- Stress, exertion and hypoglycemia all stimulate prolactin secretion.
- Dopaminergic agonists like: DA, Bromcriptine, apomorphine, etc. reduces plasma prolactin level.
- Deficiency results in lactation failure while excess prolactin results in galactorrhea
Hyper-prolactinemia
- In females: Galactorrhea, amenorrhea and infertility syndrome.
- In males: Loss of libido, depressed fertility and gynecomastia.
Factors responsible for Hyper-prolactinemia
- Hypothalamic disorders.
- Increase in the concentration of anti-dopaminergic drugs.
- Prolactin secreting tumors.
- Hypothyroidism.
Important Note: Prolactin is not used clinically.
Bromocriptine (Potent dopaminergic agonist).
Bromocriptine is an ergot derivative with dopamine agonistic properties.
- It reduces Prl release from pituitary.
- Increases GH release.
- Levodopa like action in CNS that's why used in the treatment of parkinsonism.
- It can produces nausea and vomiting through (CTZ receptor).
- It may reduces blood pressure and produces hypotension.
- It also reduces GIT motility.
- It is mainly excreated in bile.
Clinical use of Bromocriptine
- – To prevent lactation without causing pain or engorgement of the breast, as well as to suppress established lactation; it is more effective than estrogens in this latter action.
- – To treat galactorrhea, i.e. non-puerperal lactation due to excessive prolactin secretion.
- – To treat prolactin-secreting pituitary tumors (prolactinomas).
- In the treatment of parkinsonism (levo dopa like action and of acromegaly).
- – Also found to be helpful hepatic coma.
Adverse effect: Postural hypotension and behavioral alteration.
Adrenocorticotropic Hormone(Corticotropin, ACTH) (Fig. 8.1.4)
ACTH: It stimulates adrenal cortex to increase synthesis (production) and release of glucocorticoids, mineralocorticoids, and androgens.
- Site of action of ACTH: Zona fasciculata and zona reticularis
- Regulation: negative feedback mechanisim.
- The production of Aldosterone from zona glomerulosa is independent of ACTH action.
- ACTH leads to reduced excretion of Na+ → leads to edema.
- It also increases excretion of : Uric acid, K+, Hydroxy-corticosteroid.
Therapeutic Uses:
- – Diagnostic use to determine the cause of adrenal insufficiency, i.e. Pituitary origin or due to adrenal failure.
- – Use intermittently to avoid adrenaline insufficiency and atrophy as a result of long-term steroidal use.
- – Therapeutically it is used for the treatment of : Status asthmatics, anaphylactic shock, rheumatic and collagen disease.
- – It is also found to be beneficial in: Multiple sclerosis, myasthenia gravis, ulcerative colitis, infantile convulsions, etc.
Contraindications
- – Allergic reactions
- – Tuberculosis.
- – Azotemic nephritis
- – Acute psychosis.
- – Peptic ulcers
- – Diabetes and heart failure.
Preparations: Short and long acting (20 – 40 U IM/SC)
Synthetic ACTH: Tetraco-sactrin.
Thyroid-stimulating Hormone (TSH, Thyrotropin)
- Thyrotropin stimulates the production and secretion of thyroid hormones and thus regulates thyroid function.
- Regulation: negative feedback mechanism.
- It causes hyperplasia, hypertrophy, and increases blood supply of thyroid glands.
- It increases iodine trapping by thyroid gland
- It increases organification and
- Also increases endocytotic uptake of thyroid colloid by follicular cells.
Pathological involvement
- High TSH: Hyperthyroidism (Grave's disease).
- Low TSH: Hypothyroidism (myxoedema).
Use: Only diagnostic as well as also used to increase the radioactive iodine uptake in thyroid carcinoma.
Gonadotropins [FSH] and [LH]
Follicle stimulating hormone (FSH) and luteinizing hormone (LH) – produced by the anterior pituitary; regulate gonadal function. See Fig. 8.1.5.
- FSH
- – In females FSH is responsible for the development of ovarian follicle, development of ovum and also stimulate ovarian steroidogenesis (estrogens and progesterone synthesis).
- – In men FSH promotes spermatogenesis and growth of seminiferous tubules.
- LH
- – In females LH is responsible for ovulation and later it maintains the corpus luteum. It is also responsible for secretion of progesterone
- – In males LH is responsible for testosterone secretion and maintenance of ICSH.
- Both FSH and LH act in harmony and follow cyclic pattern in female, characterized by human menstrual cycle (28 days).
- Follicular phase: High frequency and low amplitude
- Luteal phase: Low frequency and high amplitude, additionally
- Inhibin (from testis and ovaries): Inhibit FSH release.
- Dopamin: Inhibit LH release.
- Human Menopausal Gonadotropins (HMG): (menotropin)
- –Obtained from the urine of menopausal females and it mainly act as FSH.
- Human Chorionic Gonadotropins (HCG)
- – Obtained from the urine of pregnant female and it mainly act like LH.
Therapeutic Uses of Gonadotropins (Gns)
- Gonadotropin deficiency induced infertility in males.
- Un-descended testes.
- Secondary amenorrhea and infertility in females.
- In the treatment of habitual abortion.
- In vitro fertilization to precisely time the ovulation.
Posterior Pituitary Hormones: Posterior pituitary secretes oxytocin (see drugs acting on uterus) and Antidiuretic hormone (ADH, vasopressin). The main stimuli for the release of ADH are an increase in plasma osmolarity and a decrease in circulating blood volume (Fig. 8.1.6).
- There are two types of vasopressin receptors – V1 and V2, V2 receptors mediate reabsorption of water in the distal tubule and collecting ducts. V1a receptors mediate contraction of vascular smooth muscle and V1b receptors cause release of corticotropin from the anterior pituitary.
- Various preparations of vasopressin are available, which differ in route of administration, duration of action and relative selectivity for V1 and V2 receptors:
- V2 receptor (selective) – Vasopressin – short duration of action, given SC or IM. Desmopressin – longer acting, given as nasal spray. Lypressin- short acting, given as nasal spray.
- V1 receptor (selective) – terlipressin – longer acting, given IV Felypressin – short acting.
Disorder of ADH secretion results in diabetes insipidus, which can be neurogenic – due to reduced secretion of ADH or nephrogenic – due to impaired response of the nephron to ADH.213
- Some drugs (lithium, demeclocycline, colchicine, vinca alkaloids) cause diabetes insipidus.
Clinical use of vasopressin and analogues
- Treatment of neurohypophyseal diabetes insipidus: lypressin, desmopressin.
- The initial treatment of bleeding esophageal varices: vasopressin, terlipressin, lypressin. (Octreotide is also used but sclerothearpy is the main treatment).
- As prophylactic therapy (e.g. before tooth extraction) in hemophilia: vasopressin, desmporessin (by increasing the concentration of factor VIII; somatostain is also effective).
- Felypressin is used as a vasoconstrictor with local anesthetics
- Desmopressin is used in older children and adults with persistant enuresis.