Pharm Ch. 26: Pharm of the Hypothalamus and Pituitary Gland
Hypothalamic and Pituitary Physiology
Relationship Between the Hypothalamus and Pituitary Gland
 Anterior pituitary – ectodermal tissue
 Posterior pituitary (aka neurohypophysis) – ventral surface of
diencephalon
 Hypothalamus controls activity of both lobes
o Acts as neuroendocrine transducer, integrates neural signals
from brain and converts them into chemical messages
(peptides) that regulate pituitary hormone secretion
 Control of anterior pituitary: hypothalamic-pituitary portal vascular
system (indirect vascular connection)
o Superior hypophyseal artery fans around axon terminals of
hypothalamic neurons – forms initial capillary bed
o Fenestrations allows hypothalamic factors to be released into
blood stream (hypothalamic pituitary portal system)
o Second capillary bed bathes neuroendocrine cells at the AP with
hormones secreted by hypothalamus
 Control of posterior pituitary (direct vascular connection)
o Neurons synthesized hormones in cell bodies of the
hypothalamic supraoptic and paraventricular nuclei
o Hormones transported down axons to the posterior pituitary
gland, stored until released; PP – acts as an extension of
hypothalamus
o Fenestrated endothelial cells also facilitate release
 Anterior pituitary transcription factors key in development: Pit-1, T-Pit, Prop-1
 AP cell types: thyrotrophs, corticotrophs, lactotrophs, somatotrophs, gonadotrophs
 Relationship btwn hypothalamic releasing factors and pituitary hormones is not always 1:1, and the
interaction isn’t always stimulatory
o Somatostatin: inhibits release of GH, TSH, prolactin
o TH: stimulates TSH release, can also cause prolactin release
 All known hypothalamic releasing factors are peptides, except dopamine
o AP: proteins and glycoproteins
 3 groups:
 Somatotropic hormones: GH, prolactin
 Glycoprotein hormones: LH, FSH, TSH
 ACTH
 Intact peptides and proteins are not absorbed across intestinal lumen, local proteases digest them into their
constituent amino acids; this is why therapeutic administration of a peptide hormone or hormone
antagonist must be accomplished by a non-oral route (Intro case – octreotide and pegvismant had to be
injected)
 AP gland cell response initiated when hypothalamic factor binds to specific G protein-coupled receptors
located in plasma membrane of appropriate anterior pituitary cell
o Most receptors alter intracellular cAMP, IP3, and Ca2+
o Ex: GH binds to receptors on somatotrophs, which increases intracellular cAMP and Ca2+ levels;
Somatostatin binding to its receptors on somatotrophs decreases intracellular cAMP and Ca 2+
 Timing and pattern of hypothalamic release factors important for determining AP cell response
o Most hypothalamic RFs are secreted in a cyclical or pulsatile manner (rather than a continuous)
 Ex: hypothalamus releases pulses of GnRH every few hours, frequency and magnitude of
GnRH release determines the extent of pituitary gonadotropin release AND the ratio of
LH:FSH secretion
 Continuous administration of GnRH suppresses rather than stimulates pituitary
gonadotroph activity
Feedback Inhibition
 Endocrine axis: each pathway, including a hypothalamic factor, its pituitary gland target cell type, and the
ultimate target gland
 Simplified model, 5 endocrine axes:
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Generally: systemic hormones produced by target organs negatively regulate the pituitary and hypothalamus
to maintain an equilibrium level of hormone release
Endocrine diseases are described based on etiology
o Primary endocrine disorder – target organ pathology
o Secondary endocrine disorder – pituitary disease
o Tertiary endocrine disorder – hypothalamic pathology
Physio, Pathophysio, Pharm of Individual Axes
Anterior Pituitary Gland
Hypothalamic-Pituitary GH Axis
 Regulates general processes that promote growth
 Somatotrophs of the anterior pituitary gland produce and secrete GH; first expressed at high concentrations
at puberty; pulsatile manner, largest pulses at night during sleep
 Anabolic effects of GH mediated by insulin-like GFs, esp. IGF-1, a hormone release into circulation by
hepatocytes in response to stimulation by GH; lots of cell types capable of producing IGF-1, liver contributes
majority of detectable IGF-1
 IGF-1 is protein bound and stable in the circulation for longer periods of time at steady concentrations, unlike
GH; IGF-1 measurements represent an integrated surrogate for GH activity that is stable throughout the day;
IGF-1 also better for screening acromegaly
 Environmental (hypoglycemia, sleep, exercise, adequate nutrition all increase GH secretion) and biological
(hypothalamic GHRH, sex steroids [puberty], dopamine, and ghrelin) stimuli regulate GH secretion
o Ghrelin acts synergistically with GHRH to promote GH release, acting in a receptor different than the
GHRH receptor
o Majority of ghrelin secreted by gastric fundal cells during fasting state, linking growth with
nutritional status and energy balance
 Environmental factors that inhibit GH release: hyperglycemia, sleep deprivation, and poor nutritional status
 Biological factors that inhibit GH secretion are somatostatin, IGF-1, and GH
Pathophysio and Pharmacology of Growth Hormone Deficiency
 Failure to secrete GH or enhance IGF-1 during puberty  growth retardation (26-3A-D)
 GH deficiency usually from defective hypothalamic release of GHRH (tertiary deficiency 26-3D) or from
pituitary insufficiency (secondary deficiency 26-3C)
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However, failure of IGF-1 secretion in response to GH (Laron dwarfism or primary deficiency 26-3B) not
amenable to treatment with GH
Semorelin: administered to help determine disease etiology; no longer available in U.S. as of 2009
o Alternative exogenous agents to stimulate GH release: glucagon, arginine, clonidine, insulininduced hypoglycemia
Tesamorelin: GHRH analogue, augments base and pulsatile GH secretion
If a pt. has defective hypothalamic release of GHRH but a normally functioning AP gland somatotrophs,
administration of exogenous of exogenous GHRH  increases GH release
Most cases of GH-dependent growth retardation treated with recombinant human growth hormone (aka
somatotropin, generic name); daily subQ/IM injections, $$$, specific use only
o Adults: either confirmed GH deficiency or panhypopituitarism (at least 3 hormonal axes affected)
 Unapproved use in competitive sports
o Pediatric: idiopathic short stature, chronic kidney disease, Tuner’s, Prader-Willi
 Recombinant IGF-1 (mecasermin) effective for pts with GH insensitivity (Laron dwarfism)
o Also for pts with w/GH deficiency and antibodies against GH
o Adverse effects: hypoglycemia, intracranial HTN
Pathophysio and Pharm of GH Excess
 somatotroph adenoma; rarer: ectopic production of GH or GHRH
 2 different disease presentations, depending on whether GH excess occurs before or after closure of bone
epiphyses
o Gigantism: abnormally high GH secretion before closure of epiphyses be increased IGF-1 levels
promote excessive longitudinal bone growth
o acromegaly: abnormally high levels of GH after epiphyses close; IGF-1 can still promote growth of
deep organs and cartilaginous tissue
 Somatrotroph adenoma: surgical resection, medical therapy, radiation therapy
o Trans-sphenoidal surgical approach is the current SOC; variable success, esp, when adenoma > 1cm,
adjuvant medical therapy is frequently required
 Somatostatin receptor ligands (SRLs) mainstay; somatostatin physiologically inhibits GH
secretion, somatostatin itself is not used, half life too short
 Octreotide and lanreotide – synthetic, longer-acting peptide analogues of somatostatin
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Somatostatin receptors distributed widely – octreotide can be used for esophageal
varices and some hormone-secreting tumors
 Systemic administration of SRLs  adverse effects: Nausea, diarrhea, gallstones,
lightheadedness
 Efficacy of SRLs: they can normalize GH and IGF-1 levels in 60-80% acromegliac patients,
and can decrease pituitary adenoma size in 40-40% pts
 Dopamine – acts mainly on lactrophs to physiologically inhibit prolactin release; also stimulates
somatotrophs to release GH under physiologic conditions, pts with acromegaly can have paradoxical
decrease in GH secretion in response to dopamine
o Maybe bc lactotrophs and somatotrophs have shared embryonic lineage; 20-30% somatotroph
adenomas also secrete excess prolactin
 Bc of this, dopamine analogues bromocriptine and cabergoline sometimes used as
adjunctive treatment in acromegaly (dopamine receptor agonists generally much less
effective than SRLs, 2nd line agents)
 GH molecule has 2 binding sites – each of which can bind one GH receptor monomer
o GH action requires dimerization of the receptor by GH in order to initiate receptor activation and
intracellular signaling
o Pegvisomant – GH analogue, binds to GH receptor with higher affinity than native molecule, but the
other binding site is inactive; prevents receptor dimerization and intracellular signaling; acts as a
competitive antagonist of GH activity; multiple PEG residues which prolong half life and allow once
daily dosing; most potent IGF-1 reducing potential, also decreases GH levels by decreasing IGF-1
mediated feedback inhibition of GH secretion
Hypothalamic-Pituitary-Prolactin Axis
 Lactotrophs (AP) produce and secrete prolactin
o Inhibited dopamine secretion
 TRH can enhance prolactin release, also stimulates other thyrotrophs
 Estrogen and breast feeding also enhance prolactin release
 Lactotrophs – tonic inhibition by the hypothalamus; disease condition
that interrupts the hypothalamic-pituitary portal system  decreased
secretion of most AP hormones, BUT increased prolactin release
o Elevations of prolactin seen in pts taking dopamine receptor
antagonists
 Prolactin secretion not regulated by any (-) feedback
 Physio actions of prolactin:
o Mammary gland development and milk protein biosynthesis and
secretion
o Normally low in men and non-pregnant women
o During pregnancy, increased estrogen stimulates lactotrophs to secrete increasing quantities of
prolactin
 Estrogen antagonizes prolactin action in the breast; prevents lactation until after
parturition
 Suckling – powerful neural stimulus for prolactin release; prolactin levels increase 100x
w/in 30 min of breastfeeding; (+) feedback ensures continued replenishment of milk
reserves; if mom not breast feeding, prolactin levels decrease over several weeks
o Increased prolactin levels suppress estrogen synthesis; antagonize hypothalamic release of GnRH
AND decreasing gonadotroph sensitivity to GnRH
 Decrease in LH and FSH release decreases end-organ stimulation of the hypothalamicpituitary gonadal axis
 Suppression of estrogen synthesis by prolactin – mechanism to suppress ovulation while a
woman is still breast feeding
 Chronically high secretions of prolactin (prolactinoma) also suppress hypothalamicpituitary-gonadal axis; bc of this, prolactinomas frequently cause infertility, esp. in women
who present with oligomenorrhea or amenorrhea
o
Bromocriptine – synthetic dopamine receptor agonist that inhibits lactotroph cell growth, used for
prolactinomas; orally bioavailable
 Adverse effects: N/V – area postrema in medulla, which stimulates nausea, has dopamine
receptors
o Cabergoline (U.S.) and quinagolide (Europe) – dopamine receptor agonists, also used to treat
prolactinomas; both Category B – bromocriptine still prescribed more frequently
 Cabergoline: weekly/biweekly dosing, less frequent GI adverse effects; link with valvular
heart disease (higher dose therapy used in Parkinson’s, smaller dose for prolactinomas no
significant tie to heart disease
Hypothalamic-Pituitary-Thyroid Axis
 Hypothalamus secretes TRH, which stimulates thyrotrophs in the AP to produce and secrete TSH; TSH
promotes biosynthesis and secretion of TH by thyroid
 TH regulates overall body energy and homeostasis; negatively controls hypothalamic and pituitary release of
TRH and TSH
 Thyroid hormone replacement effective treatment for hypothyroidism, TRH and TSH are mainly used to Dx
disease etiology
o Hypothyroidism bc of unresponsive gland (primary deficiency)  serum TSH will be high
 Serum TSH is the main test used in screening for primary thyroid disease
o Hypothyroidism bc of defect in pituitary production (secondary deficiency)  TSH will not be high
despite low TH levels; if TRH given in this scenario, TSH wouldn’t increase, or it would be significantly
reduced
 Recombinant TSH (thyrotropin) commonly used during radioactive iodine treatment of thyroid cancer; given
before radioactive iodine therapy to maximize uptake of radiolabeled 131I isotope into cancerous thyroid
Hypothalamic-Pituitary-Adrenal Axis
 Neurons from paraventricular nucleus of hypothalamus synthesize and secrete CRH, binds to cell-surface
receptors on corticotrophs of the AP, stimulates corticotrophs to synthesize and secrete ACTH
o ACTH synthesized as part of POMC; along with ACTH, cleavage of
POMC  MSH, lipotropin, and β-endorphin
 MSH – skin pigmentation, structurally similar to ACTH,
high [ACTH] can bind and activate MSH receptors,
important in primary hypoadrenalism – increased ACTH 
skin pigmentation
 ACTH stimulates synthesis and secretion of adrenocortical
steroid hormones (glucocorticoids, androgens,
mineralocorticoids) 26-5A
 ACTH required for secretion of glucocorticoids and adrenal
androgens
 Mineralocorticoid production also regulated by K+ balance
and volume status - ACTH has minor role
 ACTH trophic affect in zona fasciculata and zona reticularis
of the adrenal cortex
 Excessive ACTH secretion  adrenal hyperplasia
 Deficiency of ACTH  adrenal atrophy
 Cortisol is the most crucial product of steroid biosynthesis
 Main feedback inhibitor of pituitary ACTH release , “stress hormone”, vascular
tone, electrolyte balance, glucose homeostasis
 Deficiency  crucial illness/death; excess  Cushing’s
 Synthetic cortisol, cosyntropin, used to Dx adrenal insufficiency, specifically to
determine whether primary of secondary
o If primary: administration of cosyntropin will fail to increase plasma
[cortisol] bc of inherent dysfunction of adrenal biosynthesis
o If new-onset secondary adrenal insufficiency : administration of
cosyntropin  robust increase in plasma cortisol
o Long standing secondary: blunted cortisol response to cosyntropin, mainly
due to adrenal cortical atrophy in the absence of trophic effects from
ACTH
 Conditions requiring physiological replacement of glucocorticoids usually treated
with synthetic analogues of cortisol, instead of ACTH, bc of more precise control
o CRH used as Dx tool in petrosal sinus sampling for ACTH
 Used to distinguish whether excessive cortisol secretion results from an ACTH-secreting
pituitary adenoma or from an ectopic ACTH-secreting tumor
 Pituitary corticotroph adenoma (Cushing’s Disease) administration of CRH usually
increase blood ACTH levels; this response is NOT seen in pts with ACTH-secreting
ectopic tumor, which secretes ACTH at an autonomous rate
 Cushing’s syndrome (primary adrenal tumor) treated with surgical resection
 Medical therapies: metyrapone, ketoconazole, mitotane – potent inhibitory
effects on steroidogenesis, can be used to reduce cortisol production
 Mifepristone antagonizes peripheral cortisol receptor
Hypothalamic-Pituitary-Gonadal Axis
 Gonadotrophs – secrete LH and FSH (glycoprotein hormones);
referred to as gonadotropins
 Gonadotrophs regulate secretion of LH and FSH independently
 Gonadotropins control hormone production by gonads; synthesis
of androgens and estrogens
o Males: gonadotropins inhibited via (-) FB by testosterone
o Females: depending on rate of change, absolute
[estrogen], stage of menstrual cycle; estrogen can exert
both inhibitory and excitatory effects on gonadotropins
 Inhibin – hormone produced in gonads that has inhibitory effect
on FSH secretion, some on LH secretion
 Activin – paracrine factor produced and acts locally both in the
pituitary and in the gonads, function: stimulate FSH production
(pituitary gland)
 Native GnRH (short half life) can be administered in a pulsatile fashion to stimulate patterned gonadotropin
release, GnRH analogues with longer half lives are used to suppress production of sex hormones by
desensitizing pituitary gland to the stimulating activity of the releasing factor
o Leuprolide – most commonly used GnRH agonist, can be administered daily as a subQ injection or as
a monthly depot injection, osmotic pump implants available that deliver leuprolide acetate at a
controlled rate for up to 12 months
o Long acting agonists used to suppress gonadotropins in: endometriosis, uterine fibroids, precocious
puberty, androgen dependent prostate cancer
o Main drawback: gonadotroph suppression does not occur immediately, transient (several days)
increased in sex hormone levels, followed by lasting suppression of hormone synthesis and secretion
 FSH – clinically used to stimulate ovulation for in vitro
o Urofollitropin: purified FSH isolated from urine of postmenopausal women
o Follitropin: recombinant from of FSH
o Both agents effectively stimulate ovulation by may cause ovarian hyperstimulation syndrome
 Familial gestational ovarian hyperstimulation syndrome – caused by inherited mutation in
the FSH receptor, allows hCG to activate FSH receptor  follicular enlargement
 GnRH antagonists cetrorelix and ganirelix also sometimes used in assisted reproduction
o They suppress premature surges in LH in the early to mid-follicular phase of menstrual cycle ->
improved rates of implantation and pregnancy
o Also have palliative applications for metastatic prostate cancer – avoids initial surge in testosterone
caused by treatment with GnRH agonists
Posterior Pituitary Gland – secretes ONLY ADH and oxytocin
ADH
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Peptide hormone, produced by magnocellular cells of hypothalamus
o Cells in this region have osmoreceptors – sense changes in osmolality
 Increased osmolality  ADH secretion
 ADH binds to V1 and V2 located in systemic arterioles, mediates vasoconstriction
(why its also called vasopressin)
 V2 receptors located in nephrons stimulate cell surface expression of water
channels in order to increase water reabsorption in the collecting duct
 2 actions of ADH combine to maintain vascular tone by:
 1. Increasing BP
 2. Increasing water reabsorption
o Disruption of ADH homeostasis:
 Excessive ADH  SIADH
 ADH secretion occurs irrespective of plasma volume status or osmolality
 Most common cause: ectopic secretion of ADH by small cell lung carcinoma
 Persistent stimulation of V1 and V2 receptors  HTN and excessive water retention
 Conivaptan and tolvaptan are vasopressin receptor antagonists approved for
SIADH hyponatremia (due to excess water retention) – both available as oral
agents
o Tolvaptan: specific V2 receptor antagonist approved for heart failure
o Conivaptan: mixed V1a and V2 receptor antagonist approved for use in
euvolemic and hypervolemic hyponatremia
 Demeclocycline and lithium also used to treat SIADH
 Deficient ADH/decreased response to ADH  diabetes insipidus
 Disorder of vasopressin deficiency or resistance
 Polyuria and polydipsia, secondary to inability to concentrate urine and retain free
water at the level of the renal collecting duct
o Neurogenic diabetes insipidus: inability of hypothalamic neurons to
synthesize or secrete ADH
 Desmopressin (ADH analogue)  stimulated V2 receptors,
allows urine to be concentrated and thirst to decrease
o Nephrogenic diabetes insipidus: inability of renal collecting duct cells to
respond to ADH (aka ADH resistance); Caused by mutation in the V2
receptor or medication-induced (ex: lithium)
 Treat with diuretics: amiloride or hydrochlorothiazide  induce
a volume-contracted state, which promotes enhanced
absorption of water in proximal tubule and thereby decreased
delivery of water to the side of ADH resistance (i.e. collecting
ducts)
Oxytocin
 Peptide hormone, produced by
paraventricular cells of the hypothalamus
 Muscular contraction: mile release and
uterine contraction
 Used pharmacologically to induce labor
artificially