Introduction
Recall that the hypothalamus is a gland found at the base of the midbrain and extends into the bony sella turcica via the hypophysial stalk to form the posterior pituitary gland (also known as the posterior hypophysis or neurohypophysis).  Closely associated with the posterior pituitary is a third gland, the anterior pituitary (anterior hypophysis, adenohypophysis).

Hypothalamus
The hypothalamus synthesises nine (9) hormones.  Two of these -- oxytocin and vasopressin (anti-diuretic hormone) -- are transported via the hypophysial stalk to the neurohypophysis where they are stored until a neural impulse causes their release.  The other seven hormones are synthesised in and released from the hypothalamus into the blood stream, where they travel the short distance to the adenohypophysis where they cause the release of the adenohypophysial hormones.  These hormones include the following:
Prolactin Releasing Hormone (PRH)
Prolactin Inhibitory Hormone (PIH, identified as dopamine)
Thyrotropin Releasing Hormone (TRH, protirelin)
Corticotropin Releasing Hormone (CRH)
Growth Hormone Releasing Hormone (GHRH, somatorelin)
Growth Hormone Inhibitory Hormone (GHIH, somatostatin)
Gonadotropin Releasing Hormone (GnRH, Gonadorelin, LHRH for luteinising hormone releasing hormone).
Posterior Pituitary
The posterior pituitary gland releases oxytocin and vasopressin in response to nerve impulses from various regions of the brain.  This will be discussed in more detail later.

Anterior Pituitary
The anterior pituitary synthesises and stores seven hormones.  These are

prolactin
thyrotropin (thyroid stimulating hormone, TSH)
adrenocorticotropic hormone (ACTH, adrenocorticotropin)
growth hormone (somatotropin)
follicle stimulating hormone (FSH)
luteinising hormone (LH)
beta-lipoprotein (a precursor to beta-endorphin).
These hormones are either released or inhibited in response to specific receptor mediated events by the hypothalamic hormones.

Each of the hypothalamic hormones interacts with a specific receptor on the anterior pituitary to cause or inhibit the release of one of the anterior pituitary hormones.   All receptors for the hypothalamic hormones are G protein coupled.  GnRH and TRH are linked to a G_q/11 protein that activates the phospholipase C second messenger system.  PIH and GHIH are both linked to G_i proteins that activate potassium channels.  All other hypothalamic hormone receptors are linked to G_s proteins that activate AC/cAMP second messenger systems.

The specific responses to each of the hypothalamic hormones is as follows:
PRH -- causes the release of prolactin from the anterior pituitary
PIH -- inhibits the release of prolactin from the anterior pituitary
TRH -- causes the release of thyrotropin (TSH) from the anterior pituitary
CRH -- causes the release of ACTH and beta-lipoprotein from the anterior pituitary
GHRH -- causes the release of GH from the anterior pituitary
GHIH -- inhibits the release of GH from the anterior pituitary
GnRH -- causes the release of FSH and LH from the anterior pituitary
Each of these anterior pituitary hormones then travels via the blood stream to specific sites within the body, where they produce specific effects, to be discussed later.

Growth Hormone Releasing Hormone (GHRH, Somatorelin)
Somatorelin may be administered intranasally (relative potency = 1), subcutaneously (relative potency = 10), or intravenously (relative potency = 300).  The pharmacodynamic response to somatorelin administration is the release from the anterior pituitary of growth hormone (GH, somatotropin).
Somatorelin and its analogues are used primarily as diagnostic tools to evaluate hypothalamic dysfunction.  (If the administration of GHRH causes the release of GH, then the problem lies within the hypothalamus, if no GH is observed following GHRH, then the GH deficiency is pituitary in origin.)  Following administration of GHRH, the patient may be observed for typical GH response (discussed below) or a more sensitive measurement is to measure blood levels of GH at time 0 (baseline prior to administration) and 15, 30, 45, and 60 min following GHRH administration.
GHRH analogues are also being investigated for the treatment of hypothalamic dysfunction that results in GH deficiency (the normal treatment even with hypothalamic dysfunction is GH replacement).  HEXERELIN is a GHRH analogue that is a growth hormone releasing peptide (GHRP).  It may be administered intravenously (100% bioavailability), subcutaneously (77%) or intranasally (4.8%).  Side effects most often presented include facial flushing and pain at the sight of injection.

Growth Hormone Inhibitory Hormone (GHIH, Somatostatin)
Somatostatin is found in the both the hypothalamus and the pancreas and other gastrointestinal sites.  In addition to its action of inhibiting GH release, it will suppress the release of glucagon, insulin, and gastrin.  The precursor to somatostatin (prosomatostatin) is actually a more potent inhibitor of the release of these hormones than somatostatin itself.  The half-life of somatostatin and its precursor is on the order of 1-3 min, which limits their usefulness therapeutically.  An analogue of somatostatin, OCTREOTIDE, is 45 times as potent as somatostatin in inhibiting the release of GH and only twice as potent in the inhibition of insulin and glucagon.  Its half-life is approximately 80 min.  Octreotide is used in the treatment of acromegaly (GH release after adulthood that results in thickening of soft tissues and bone (increases in bone diameter) which causes enlarged hands and feet, sloping of the forehead, flattening of the nose, and protrusion of the lower jaw).  It is less effective in the treatment of gigantism (abnormally high levels of GH during and after puberty).  Octreotide is also used to treat carcinoid tumours (which excrete gastrin) and to reduce bleeding from oesophageal varices.  The normal route and dose is 50-200 mcg every 8 hours during the GH surge, but may be given orally (usually doses of greater that 24 Gm are required) but the side effects (nausea, vomiting, flatulence, cramps, steatorrhoea) often limit its use by this route.  A depot injectable formulation that would provide active octreatide for 28 to 42 days is currently being developed.

Growth Hormone (GH, Somatotropin)
Somatotropin, upon its release from the anterior pituitary, exerts the majority of its actions on the liver, where it causes the synthesis and release of insulin-like growth factors (IGF) I and II (also called somatomedins (somatotropin mediators).  The majority of the effects of somatotropin are mediated through these IGFs, especially IGF-I or somatomedin C.  The pharmacodynamic response to somatotropin is two fold.  The initial response is insulin-like in nature and presents as increased tissue uptake of glucose and amino acids, and decreased lipolysis in adipose tissue.  The secondary response is somatomedin-mediated increased growth at open epiphyses of bones (through the increased synthesis of cartilaginous proteins), increased lipolysis in adipose tissue, and increased growth of skeletal muscle.  The half-life of circulating active somatotropin is 20-25 min.  Following intramuscular injection, active somatotropin may circulate for up to 36 hr.  The mechanism of action of somatotropin is increase synthesis and release of IGF-I and IGF-II in the growth plate of cartilage and in the liver.  (NOTE that a deficiency of IGF-I is the cause of Laron dwarfism while the lack of the normal pubertal surge of IGF-I presents as pygmyism.)  Somatotropin is used to treat GH deficiency in children (NOTE that there exists stringent guidelines that are used to establish GH deficiency, including growth of less than 4 cm/year and failure to respond to at least two challenges with GHRH) or neonates (GH deficiency in neonates often presents as hypoglycaemia and seizures).  It has also been used in the treatment of women with Turner's syndrome (absence of the second X chromosome).  Somatotropin is also used for muscle preservation in patients on chronic corticosteroid therapy, with severe burns, and acquired immunodeficiency syndrome (AIDS).  If administered to normal adults, somatotropin will increase lean body mass, decrease fat mass, increase exercise tolerance, and cause fluid retention and arthralgia (it is the former effects that make somatotropin attractive to certain athletes and leads to its abuse by that population).  Recombinant bovine growth hormone is used in the dairy industry to increase milk production (this has been correlated with an increase in mastitis, but a causative link has not been proven).  IFG-I is being investigated for possible efficacy in the treatment of osteoporosis.  Products currently used are all biosynthetic analogues of somatotropin (prior to 1985, all GH used clinically was derived from human pituitaries, however a positive correlation to this source and an increase in Creuzfeldt-Jakob syndrome incidence has ended the use of corpses as a source of GH -- GH analogues of bovine and ovine origin are still available).  Patients who are considered for GH administration should be screened for hypothyroidism, diabetes mellitus, and diabetes insipidus (all of which will decrease the efficacy of GH, as will glucocorticoid therapy).

Protirelin (TRH, thyrotropin releasing hormone) is released from the hypothalamus and, acting at a G_q/11 receptor, causes the anterior pituitary to release thyroid stimulating hormone.  NOTE that the thyroid hormones themselves will exert a negative feedback effect, inhibiting the release of TRH from the hypothalamus.  The pharmacodynamic response to TRH is a surge in TSH release from the anterior pituitary with a peak TSH level within 20-30 min following TRH release/administration.  NOTE that with hyperthyroidism, serum TSH would be suppressed in response to the negative feedback mechanism mentioned above.  Other pharmacodynamic responses to protirelin include an increase in the release of prolactin (in normal patients GH and ACTH will not be released in response to TRH, HOWEVER in patients with acromegaly or Cushing's disease, GH and ACTH respectively will be released in response to TRH.)  TRH receptors are also found on the exterior portion of the heart, in the CNS, the gut, and the pancreas.  Therefore, it presumably plays some role in regulating behaviour, thermoregulation, autonomic tone, and cardiovascular function.
Protirelin may be used to assess specific thyroid dysfunction (although it is rarely used since there are more sensitive measurements of thyroid function, which will be discussed later).  The response to protirelin is as follows A) Primary hypothyroidism (problem in the thyroid) -- increase TSH levels B) Secondary hypothyroidism (problem in the pituitary) -- blunted response, normal or subnormal TSH levels C) Tertiary hypothyroidism (problem in the hypothalamus) -- blunted response, normal or subnormal TSH levels.  As may be seen, the response is not well correlated with the specific source of thyroid dysfunction, hence the limited usefulness of protirelin in predicting the nature of dysfunction.    As stated, TRH is rarely used as a diagnostic tool.  When it is used, TSH levels should be measured at 0, 15, 30, 45, and 60 min following TRH administration.
TRH is being investigated for possible efficacy in partial spinal cord injuries.  The dose is 0.2 mg/Kg stat, then 0.2 mg/Kg/hr for six hours, to be administered within 7 days of the injury.  Side effects of TRH include an urge to void, metallic taste, nausea, flushing, and lightheadedness.

Thyrotropin (Thyroid Stimulating Hormone, TSH)
Upon its release from the anterior pituitary, TSH will cause the increased synthesis and release of thyroid hormones (T3 and T4) from the thyroid gland.  It mechanism of action is via G coupled proteins (both G_s and G_q/11 are present -- this will be discussed more in-depth in the thyroid section).  on the thyroid gland that cause an increase in iodine uptake into the gland, thus increasing the synthesis of the thyroid hormones (to be discussed more in depth later) and increasing the release of thyroid hormone.    The primary use of thyrotropin is to stimulate the uptake of ¹³¹I for either diagnostic or therapeutic (treatment of thyroid carcinoma) purposes.  The normal dose for bovine TSH is 5-10 units/day for 3 days (diagnostic) or 7 days (therapeutic).  Synthetic human TSH requires 2-3 injections/day.  Side effects of TSH include nausea and vomiting, thyroid tenderness, allergy, and "hyperthyroidism" (increased release of thyroid hormones).

Corticotropin Releasing Hormone
CRH causes the release of ACTH (adrenocorticotropin) and beta-endorphin from the anterior pituitary, by acting at a G_s receptor..  The pharmacodynamic response to CRH is virtually identical to that of ACTH itself, represented by the effects of cortisol, aldosterone, and androgen, since the action of ACTH is to release these hormones from the adrenal cortex.
CRH is used diagnostically to distinguish between ectopic and adrenal Cushing's disease (adrenal Cushing's usually responds with an increase in cortisol release while ectopic tumours do not respond to CRH), although this test is not 100% reliable.  There are more sensitive measurements to assay the source of Cushing's syndrome.  Sources of CRH to be used diagnostically include human and sheep.  Side effects include facial flushing and dyspnea.
Adrenocorticotropic Hormone (Adrenocorticotropin, ACTH)
Adrenocorticotropin may be derived from human, ovine, porcine, or bovine sources.  There is also a synthetic analogue, COSYNTROPIN, that is most often used.  ACTH is formed from pro-opiomelanocortin (POMC) which gives rise not only to ACTH, but also to gamma-melanocyte stimulating hormone (MSH), gamma-lipoprotein (LPH), and beta-endorphin.
ACTH analogues are used primarily for diagnostic purposes.  It is administered intramuscularly.  Its biological half-life is approximately 20 min, although depot forms exist that permit biological activity of up to 18 hr.  The pharmacodynamic response to ACTH is a stimulation of adrenal cortex production of glucocorticoids (cortisol), mineralocorticoids (aldosterone), and androgen.  The mechanism of ACTH action is an increase in the activity of cholesterol esterase, the rate limiting enzyme that converts cholesterol to pregnenolone (in the synthesis of steroidal hormones).  ACTH may also produce adrenal hypertrophy and hyperplasia and hyperpigmentation (ACTH possesses some intrinsic MSH-like activity).
ACTH is used primarily as a diagnostic test for adrenal insufficiency.  Plasma cortisol is measured 30 and/or 60 min post ACTH administration.  A normal response would be plasma cortisol of greater than 18 mcg/dL, indicating functional adrenal glands.  Subnormal responses indicate either primary or secondary adrenal insufficiency (NOTE that primary is distinguished from secondary adrenal insufficiency by plasma levels of endogenous ACTH).  ACTH may also be used to distinguish three different forms of late onset adrenal hyperplasia from ovarian hyperandrogenism (all four conditions result in hirsutism of the female patient).
Ovarian hyperandrogenism will produce the normal response to ACTH, described above.
If the patient has the
21-hydroxylase-deficiency form of adrenal hyperplasia, ACTH will cause a rise of 17-hydroxyprogesterone;

11-hydroxylase-deficiency, a rise in 11-deoxycortisol will occur

deficiency of 3-beta-hydroxy-delta-5 steroid dehydrogenase, a rise in 17-hydroxypregnenolone will occur.

ACTH is also used to treat neuropathy that is caused by the anti-neoplastics cisplatin and vincristine.
Side effects of ACTH -- Diagnostic use of ACTH is virtually side effect free.  Therapeutic use may cause side effects similar to those seen with glucocorticoids.  Allergic reaction or the development of antibodies (which would reduce the efficacy of the treatment) may also be seen with sustained use of ACTH.  Additionally, the depot forms may cause pain at the injection site (more often seen with zinc depot forms, less so with the gelatin depot forms).

Gonadorelin and analogues of it may by used for both diagnostic and therapeutic purposes.  Typically the analogues are more potent with a longer (3 hr vs. 4 min) duration of action than gonadorelin.
The normal physiologic response to gonadorelin is a function of its pulsatile release.  Under these conditions, gonadorelin, acting at G_q/11 receptors,  will cause the synthesis and release of the gonadotropins follicle stimulating hormone (FSH) and leutinising hormone (LH).  However, if GnRH is continuously released (which does not normally occur physiologically) or administered in a like manner, it will decrease the synthesis/release of FSH and LH.

RECALL that the hypothalamic-pituitary-gonadal axis is subject to negative feedback as well as other endogenous controls of release.  By the feedback mechanism, increases in testosterone or œstrogen will decrease the release of GnRH from the hypothalamus and FSH/LH from the pituitary.  Conversely, decreases in these gonadal hormones will increase the release of GnRH and FSH/LH.  Additionally, the hormone inhibin, synthesised in the testes and ovary, will inhibit the release of FSH and LH.  In opposition to the normal feedback mechanism, œstrogen will cause in increase in the release of FSH and LH during the late follicular phase (pre-ovulatory surge) of the menstrual cycle.

Uses of GnRH

Diagnostics -- GnRH may be used to determine if delayed puberty is hypothalamic or pituitary in origin (versus a problem within the sex organs).  A dose of 100 mcg of GnRH is administered.  Plasma LH is measured at 0, 15, 30, 45, 60, and 120 min post-injection.  If the peak LH is >15.6 IU/mL, then the response is normal and puberty is either imminent or due to unresponsiveness within the testes/ovaries.  If the peak is below that level, then the problem exists within the hypothalamus or pituitary.

Therapeutics --

GnRH or its analogues may be used to stimulate FSH/LH in the treatment of infertility.  This therapeutic approach requires the pulsatile flow (cyclic administration to coincide with the normal endogenous release of GnRH) described above to be effective as a fertility drug.
For female infertility, 5 mcg is administered q 90 min until ovarian follicles have attained a diametre of 14 mm (as measured by Doppler techniques).  Following this, human chorionic gonadotropin (hCG, discussed below) is administered to induce ovulation.  hCG must continue to be administered q 3 d for 12 days to maintain the luteal phase.  During this time conception is possible.
For male infertility, the patient must be treated with hCG for 1 year to correct the prepubertal hypogonadotropic hypogonadism (the lack of FSH/LH release causing the infertility) and prepare the testes for spermatogenesis and maturation.  Following the year's treatment, GnRH is administered for 3-6 months to stimulate spermatogenesis.  After this phase of treatment, the sperm count should be high enough to ensure potential fertilisation.
Fortunately, for both patients, there now exists a pump that permits outpatient administration of GnRH in a pulsatile fashion (before the release of this dosage form, the patient had to be present in the clinic for administration of GnRH).
GnRH may also be administered in a continuous fashion to suppress FSH/LH release in the treatment of prostate cancer, uterine fibroids, endometriosis, polycystic ovary disease, and precocious puberty (inappropriate early onset of puberty).  Each of these disease states is either testosterone or œstrogen dependent.  Therefore, continuous administration will decrease the release of the gonadal hormones.  Continuous administration of GnRH may also be used to suppress FSH/LH in infertility to synchronise patients before treatment for the infertility begins.
Specific Drug Preparations that are available include
GnRH for both direct injection and as a pulsatile administration pack (Lutrepulse®)
Histrelin and Buserelin -- for repeated injections
Leuprolide -- depot injection (monthly) for prostate cancer, endometriosis, precocious puberty
Goserelin -- 28 day implant for treatment of prostate cancer, endometriosis, precocious puberty
Nafarelin -- available as a nasal spray for b.i.d. administration for prostate cancer, endometriosis
Adverse effects of GnRH
Diagnostics -- Rare, but may include headache, flushing, abdominal pain
Therapeutics -- Severe bone pain in prostate cancer, hot flushes in both genders, osteoporosis. (the latter effects due to decreased œstrogen/testosterone).
 
Follicle Stimulating Hormone (FSH)
Mechanism of Action and Pharmacodynamics -- FSH acts via an AC/cAMP second messenger system in the testes/ovaries.  It causes the maturation of oocytes in the female and initiates spermatogenesis in the male.  Additionally in the male it acts in the Sertoli cells to increase the synthesis and release of androgen binding protein (a carrier protein that acts as a storage site for androgenic hormones).

Analogues of FSH that are used therapeutically include

Menotropin (human Menopausal Gonadotropin, hMG) -- a complex of peptides with relatively weak FSH and LH like activity.  It is used primarily for the FSH-like effects.  It is derived from the urine of post-menopausal women.

Urofollitropin -- Derived from the same source, this analogue possesses only FSH-like activity.

Therapeutic Use -- FSH, Menotropin, and Urofollitropin are used in the treatment of infertility in both males and females.  (NOTE -- It must be used with hCG to provide LH activity, as described below).  The infertility must be due to hypothalamic/pituitary hypogonadism for the treatment with these agents to be effective (however it is useful in women who are amenorhœaic due to lack of FSH).  Illegal use of hMG may be seen with anabolic steroid abusers to stimulate spermatogenesis (the negative feedback seen with supraphysiologic doses to the steroid will reduce FSH/LH release, thus causing testicular atrophy and decreased spermatogenesis).  N.B.  Treatment must be monitored and balanced to prevent overproduction of androgens, which could decrease the efficacy of hMG and similar compounds in the treatment of fertility.

Side Effects include ovarian enlargement (which will resolve), ascites, hydrothorax, hypovolæmia, multiple births (20%), spontaneous abortion (25%, due to continued treatment once pregnancy has occurred), and gynecomastia.
 

Leutinising Hormone (LH)
Pharmacodynamic Response -- LH will increase hormone production.  It acts in the Leydig cells of the male to increase testosterone production and the ovary of the female to cause oocyte maturation (along with FSH), induce ovulation, and in the corpus luteum to increase the synthesis of progesterone and androgens.

There are no products on the market that are analogues of LH.  However, human chorionic gonadotropin is virtually identical to LH in its actions and is used as a substitute for LH.
 

Human Chorionic Gonadotropin (hCG)
The normal role of hCG in physiology is to increase progesterone synthesis by the corpus luteum and maintain the placenta during pregnancy.  It is produced by the placenta and excreted in the urine of pregnant women, from which it is recovered and purified.  Chemically, it is almost identical to LH with the addition of a carboxyl group at one terminus.  This gives it a biological half-life of 8 hr (vs 30 min for LH, which is why it is used as the LH analogue).

The pharmacodynamic response is identical to that described for LH above.

Uses

Diagnostics -- hCG is used to distinguish between cryptorchidism and pseudocryptorchidism.  This is a failure of the testes to descend at puberty.  (Failure to descend will cause infertility and an increased risk of testicular cancer.)  Administration of hCG that results in descent indicates that puberty is simply delayed in that individual.  If descent does not occur, continued administration may cause testicular descent (if that is not effective orchiplexy, or surgical intervention is required to manually descend the testes).

Therapeutics -- hCG is used to treat pseudocryptorchidism as described above.  It is also used in the treatment of hypogonadotropic hypogonadism as the LH analogue along with FSH analogues as described above.  hCG has also proven beneficial in the treatment of Kaposi's Sarcoma in AIDS patients.  It causes regression of the cancerous lesion (the mechanism of this effect is not known).

Side Effects -- headache, depression, dyspnœa, œdema, precocious puberty, and gynecomastia.

A state of hypoprolactinæmia will result in decreased lactation.  There is no replacement therapy for this condition.
 
Hyperprolactinæmia will cause unwanted lactation.  Additionally in women and men, excess prolactin will exert a negative feedback response to decrease FSH and LH release causing amenorrhœa in women and infertility in both genders.  Prolactin secretion increases post-partum, with prolactin-secreted tumours, and some cases of acromegaly.  Treatment of hyperprolactinæmia employs dopamine agonists (RECALL that PIH or prolactin inhibitory hormone is dopamine).
Bromocriptine, Pergolide (also cabergoline, quinagolide) -- are dopamine agonists.
Therapeutic Uses -- these agents are used in the treatment of prolactin-secreting adenomas, prolactin-induced amenorrhœa/galactorrhœa, acromegaly with prolactin secretion, and in Parkinson's disease (the dopaminergic activity in this disease state is central and unrelated to the effects on prolactin secretion).  Bromocriptine was formerly used to prevent post-partum breast engorgement (in women who choose not to breast feed), however the FDA has removed this as an approved indication, due to potentially serious cardiac side effects.
 
Side Effects -- nausea, lightheadedness, orthostatic hypotension and fatigue.  Higher doses may cause a cold-induced peripheral digital vasoconstriction (Raynaud's phenomenon).

Pharmacodynamic Responses
Oxytocin will cause milk ejection.  The suckling action of infants will increase the release of oxytocin.

Oxytocin causes uterine contraction.  At term, the movement of the fœtus (lengthening of the birth canal) also increases oxytocin release.  At physiologic levels, the uterine contractile response is relatively mild and the role of oxytocin in delivery is not fully elucidated.

Oxytocin also possesses mild anti-diuretic and vasoconstrictive activity.
 

Mechanism of Action
Oxytocin acts via a G_q/11 coupled receptor, altering transmembrane currents (possibly by opening ion channels).  This action causes contraction of smooth muscle in the mammary gland and uterus.  Its action may be inhibited by beta-adrenergic agonists, MgSO₄, and inhalational anæsthetics.

Uses of Oxytocin

Diagnostic -- Oxytocin may be used to test fœtal blood supply and placental/uterine integrity.
Therapeutic
Oxytocin may be used to induce and/or sustain labour (intravenous administration) in cases of prolonged deliver and in cases of maternal health (erythroblastosis fœtalis, eclampsia, diabetes mellitus).  It should not be used with delivery complications (breach presentation, pelvic insufficiency).

Oxytocin may also be used to reduce post-partum hæmorrhage. NOTE that if oxytocin-sustained uterine contraction occurs, the muscle may fatigue and loose its tone, thus worsening post-partum hæmorrhage.  Ergot alkaloids are preferred for the treatment of post-partum hæmorrhage.

Oxytocin is also used to induce milk ejection in nursing insufficiency.  It is administered nasally 1-3 min prior to feeding.

Side Effects -- rare, but may see hypertension, water intoxication, uterine rupture.

Mechanism of Action and Pharmacodynamic Response
Vasopressin has three distinct effects, mediated by different receptor subtypes.
V₁ receptors -- coupled to G_q/11 proteins on vascular smooth muscle.  Activation of this receptor will cause smooth muscle contraction and vasoconstriction.

V₂ receptors -- coupled to G_s proteins.  These receptors are present renally and extra-renally.

Renal Response -- the DCT and CT/CD of the nephron.  Activation of this receptor causes the formation vesicles that act as water channels or pores to increase water reabsorption (as discussed previously-- RECALL that a deficiency of this hormone results in central diabetes insipidus).

Extra-Renal Response -- Activation of V₂ receptors extra-renally will cause the release of clotting factor VIII and von Willebrand's factor.
 

Analogues of ADH include lypressin and DDAVP (deamino-D-arginine vasopressin).  DDAVP is relatively selective in its agonist action for the V₂ receptor.  Therefore it produces minimal vasoconstriction.

Uses -- Vasopressin or its analogues may be used in the treatment of

Diabetes Insipidus -- Vasopressin may be used for acute DI.  Analogues (lypressin, DDAVP) are preferred treatments for chronic DI.  DDAVP (nasal administration) may also be used h.s. in the treatment of enuresis (bed-wetting).

Œsophageal Varices and Colonic Diverticula with bleeding -- Vasopressin has been shown to be effective in reducing bleeding associated with these two conditions.

Hæmophilia A and von Willebrand's Disease -- DDAVP is used intranasally to stimulate the release of clotting factors in these two bleeding disorders.
 

Side Effects -- headache, nausea, abdominal cramps, agitation, and allergic reaction.  The efficacy of nasal DDAVP is reduced if the patient is also experiencing nasal congestion.

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