Overview/Background

Master Gland--produces six major hormones, Stores two hormones:  Anatomy

• Midsagittal section through human pituitary

Midsagittal section of a human pituitary gland; courtesy of Robert H. Parsons, used with permission

• Sagittal section of a human pituitary, showing the relationship of its blood supply to the hypothalamic neurosecretory cells in the adenohypophysis

• Sagittal section of a human pituitary, showing the relationship of its blood supply to the hypothalamic neurosecretory cells in the adenohypophysis. Neurosecretory neurons are shown secreting releasing factors into the capillary networks giving rise the long and short hypophyseal portal vessels, respectively. The releasing hormones reach the hormone-secreting cells of the anterior lobe via the portal vessels.

• courtesy of Robert H. Parsons, Ph.D., Rensselaer Polytechnic Institute, used with permission

• Sagittal section of a human pituitary, showing the relationship of its blood supply to the neurosecretory cells of the supraoptic and paraventricular nuclei of the hypothalamus

• "Sagittal section of a human pituitary, showing the relationship of its blood supply to the neurosecretory cells of the supraoptic and paraventricular nuclei of the hypothalamus. The neuron labeled N represent a neurosecretory cell releasing ADH (antidiuretic hormone) or oxytocin at its axon terminals into the capillaries giving rise to the venous drainage of the posterior lobe. "

• courtesy of Robert H. Parsons, used with permission

• Growth hormone (GHRH)-- anterior pituitary synthesis

  • growth regulation

  • intermediary metabolism effects

• Prolactin (PRL)-- anterior pituitary synthesis

  • required for lactation

• Luteinizing hormone (LH) & Follicle-stimulating hormone (FSH)--anterior pituitary synthesis

  • male and female gonadal control

• Thyroid-stimulating hormone (TSH, thyrotropin)--anterior pituitary synthesis

  • thyroid function regulation

• Adrenocorticotropin (ACTH)--anterior pituitary synthesis

  • regulation: adrenocortical glucocorticoid functions

• Vasopressin (AVP; antidiuretic hormone, ADH) --synthesis site: hypothalamic neurons; storage site: posterior pituitary.

  • AVP: regulation of renal water conservation

• Oxytocin: --synthesis site: hypothalamic neurons; storage site: posterior pituitary.

  •  Oxytocin: required for milk let-down; may assist in parturition

• Feedback Relationships:

  • Feedback between anterior pituitary and its three target glands:

    • gonads

      • if gonads fail or removed then LH & FSH increased ­ (primary hypogonadism)

    • adrenal cortex

      • with adrenal cortex destruction/removal, primary adrenal-insufficiency occurs (Addison's disease) with increased­ serum ACTH concentration

    • thyroid

      • thyroid failure  leads to  primary hypothyroidism resulting in increased ­ TSH

  • With removal/destruction of the pituitary gland, trophic hormone is lost:

    • Secondary hypogonadism

    • Adrenal-insufficiency

    • Hypothyroidism

  • With removal/destruction of the pituitary gland: no effect on vasopressin (AVP) and oxytocin provided intact hypothalamus

   

• Pituitary Control:Hypothalamus- chemical mediation (hormones)

  • Hypothalamic hormonal synthesis through portal vascular system to the pituitary stalk to the pituitary anterior lobe

  • Pituitary stalk interruption causes:

    • decreased release from the anterior pituitary of: GH, LH, FSH, TSH, & ACTH

    • increased prolactin (hypothalamic influence is normally inhibitory for prolactin secretion)

  • Hypothalamic ablation:

    • decreased levels of GH, LH, FSH, TSH, ACTH, AVP & oxytocin

    • increased prolactin

• Secretion Control: hypothalamic factors (peptides)

  • growth hormone-releasing hormone (GHRH) dominant GH release influence (+)

  • Somatostatin: inhibitory hormone for GH release (-)

  • Luteinizing hormone-releasing hormone (LHRH) -- also called gonadotropin-releasing hormone (GnRH): controls LH & FSH

  • Thyrotropin-releasing hormone (TRH) controls TSH release; influences prolactin release

  • Corticotropin-releasing hormone (CRH) & other factors control ACTH release

  • Dopamine: major prolactin inhibitory influence (PIF)

• "Action of corticotrophin-releasing hormone (CRH) on cells of the adrenal cortex. CRH binds to membrane receptors (R), which are coupled to adenylate cyclase (AC) by stimulatory G proteins (Gs). Adenylate cyclase is stimulated and cAMP rises in the cell. cAMP activates protein kinase A (PKA), which then phosphorylates proteins (P-Proteins) involved in stimulating ACTH secretion and the expression of the POMC (proopiomelanocortin) gene. The proteolytic processing of POMC occurs in the secretory granulas where it is split into several hormones, ACTH (adrenocorticotrophic hormone) and Beta-LPH (Beta-lipotropin). "

• courtesy of Robert H. Parsons, Ph.D., Rensselaer Polytechnic Institute, used with permission

{adapted from Table 328-1: Biller, Beverly, M. K. and Daniels, Gilbert, H. Neuroendocrine Regulation and Diseases of the Anterior Pituitary and Hypothalamus, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 197

• Physiological Consequences of Pituitary Tumors:

  • hormonal over production/under production

  • Pituitary tumors: most common syndromes due to:

    • growth hormone excess

      • gigantism, acromegaly

    • prolactin excess

      • galactorrhea and/or hypogonadism

  • ACTH-secreting tumors: Cushing's disease

  • TSH-secreting tumors: hyperthyroidism (rare)

  • Gonadotropin-secreting tumors: hypogonadism (paradoxical)

  • Large pituitary tumors:

    • hypopituitarism (due to gland compression; or pituitary stalk compression) ® visual field disturbances {optic chiasm compression}

• Hypothalamic disease:

  • Hypopituitarism

  • Prolactin secretion increased

  • Significant Diagnostic Indication:

    • Diabetes insipidus (due to vasopressin {AVP} deficiency)

Anatomy : Pituitary

• Pituitary gland (hypophysis) resides within sella turcica of the sphenoid bone at the skull base (weight = between 0.4 and 0.8 grams)

• Midsagittal section through human pituitary (above)

• Sagittal section of a human pituitary, showing the relationship of its blood supply to the hypothalamic neurosecretory cells in the adenohypophysis (above)

• Sagittal section of a human pituitary, showing the relationship of its blood supply to the neurosecretory cells of the supraoptic and paraventricular nuclei of the hypothalamus (above)

• Pituitary gland components:

  • anterior lobe (adenohypophysis)

  • posterior lobe (neurohypophysis)

• Separated from brain by diaphragma sella (dura mater extension) and by thin bone layers from the sphenoid sinus anteriorly and inferiorly

• Sella lateral walls abut on the cavernous sinuses (containing internal carotid arteries & cranial nerves III, IV, V, and VI. Recurrent

•  Optic chiasm located slightly anterior to pituitary stalk -- just above diaphragma sella.

  • Reason why pituitary tumors result in visual field effects, cranial nerves palsies, sphenoid sinus invasion

Anatomy: Hypothalamus

image source attribution:  University of Manitoba Anatomy

• Hypothalamus:

  • anterior extension to optic chiasm margin

  • posterior extension including mammillary bodies

  • Separated from pituitary by:

    • hypothalamic sulcus of the third ventricle

  • Rounded inferior hypothalamic base: tuber cinereum

    • Base central portion (median eminence or infundibulum) formed by third ventricle floor, continuing inferiorly to form the pituitary stalk

      • Hypothalamic releasing factors synthesized in neurons located along third ventricular margins

        • Fibers from these neurons terminate in the median eminence adjacent to portal capillaries

  • Neuronal cell bodies of supraoptic and periventricular hypothalamic nuclei produce vasopressin and oxytocin which are transported  along nerve axons (supraopticohypophyseal and paraventriculohypophyseal tracts) to the posterior lobe

  • Hypothalamic-anterior pituitary communication: chemical

    •  Hypothalamic neuronal releasing factors flow through the portal system to stimulate or inhibit anterior pituitary hormone production

    •  Anterior pituitary blood supply: (highest blood flow of any tissue --{0.8mL/g/min})

      • Blood supplied by way of the hypothalamus

        • Two derivatives of the internal carotid arteries (superior hypophyseal arteries {SHA} terminate in median eminence {which resides outside the blood-brain barrier} capillary network.

        •  These capillaries exhibit a fenestrated endothelium which results in easy access to hypothalamic releasing hormones (regulation: vasoactive intestinal peptide)

        • Capillaries form 6-10 straight veins: the hypothalamic pituitary portal circulation -- main blood supply to anterior lobe (supply nutrients and hypothalamic factors)

Mechanisms of Hormone Action

• Overview:hormone action mechanisms

  • Hypothalamic/Pituitary hormones: all peptides;bind to target cell surface receptors

• GHRH, Somatostatin, PRH, TSH, CRH, ACTH, GnRH, FSH, LH, and Dopamine receptors:

  • Seven-transmembrane-domain serpentine peptides

  • Ligand binding:  conformational change (activating)

    • G protein coupling

      •  G₁₄ protein :GnRH & TRH

      •  G_i protein: dopamine receptor

      •  G_s protein: other receptors noted above

• GHRH, CRH, GnRH, TSH, ACTH, FSH, LH, and Dopamine receptors associated G protein-GTP complex:   adenylyl cyclase activation :  ­cAMP production:  protein kinase activation:  ­intracellular protein phosphorylation:  ­hormonal effects

• Dopamine receptor -- G_i protein coupling (lactotroph receptor system):   decreased adenylyl cyclase activity:   decreased prolactin secretion

• Growth hormone: a-GTP complex related to somatostatin receptors:  potassium channels:  inhibit growth hormone (GH) secretion

• Thyrotropin-releasing hormone: G protein complexes related to thyrotrophs' TRH receptors:  phosphoinositide-specific phospholipase C:  cytoplasmic free calcium  :  stimulating TSH secretion

• Growth hormone & Prolactin receptors:

  • single peptides

  • extracellular amino-terminal hormone-binding domains

  • intracellular carboxyl terminal sequence activates JAK2 (tyrosine kinase) leading to intracellular protein tyrosine phosphorylation and gene regulation

  • GH receptor fragments (GH binding protein, GHBP): bind 50% of circulating growth hormone

Growth hormone-releasing hormone (GHRH, Sermorelin) & Growth hormone-releasing peptides (GHRPs)

• Overview: GHRH; GHRPs

  • Hypothalamic growth hormone-releasing hormone (GHRH):  pituitary growth hormone (GH) secretion

  • GHRH belongs to a family of molecules including:

    • secretin, VIP, gastric inhibitory peptide (GIP), glucagon

  • Major site of GHRH production: arcuate nucleus hypothalamus;

  • GHRH receptor:

    • G protein-coupled transmembrane receptor

    • Activation :  ­GH gene transcription, ­synthesis & ­GH release (cAMP mediated)

• Chemistry, Pharmacokinetics, & Pharmacodynamics:GHRH & GHRP

  • Chemistry: GHRH & GHRP

    • Growth hormone-releasing hormone:

      • 40-amino acid peptide; 44-amino acid peptide ® GH release stimulation

      • Activity: first 29-amino acids

    • Growth hormone-releasing peptides

      • groups of small, synthetic peptides

      • stimulate GH secretion (similar to GHRH)

  • Pharmacokinetics: GHRH & GHRP

    • GHRH: Routes of administration:

      • IV

      • subcutaneous

      • intranasal

  • Pharmacodynamics:GHRH & GHRP

    • Stimulation: growth hormone secretion only (anterior pituitary)

• Clinical use:GHRH & GHRP

  • GHRH: evaluation of short children with subnormal GH response to:

    • insulin-induced hypoglycemia, oral L-DOPA, IV arginine

    •  Normal response in this group:  GH deficiency secondary to hypothalamic dysfunction

    •  Subnormal response in this group:   pituitary or hypothalamic dysfunction

    •  Growth hormone level increase following GHRH:   favorable clinical response to GHRH treatment

•  Toxicity: GHRH & GHRP:

  • facial flushing; injection site discomfort (nasal GHRP- 2-- well tolerated)

Somatostatin (Growth hormone-inhibiting hormone, Somatotropin release-inhibiting hormone)

• Overview:somatostatin

  • 14- and 28-amino acid peptide forms, most widely distributed of the hypothalamic releasing hormones

    • 14-amino acid peptide form: more abundant, less bioactive in GH inhibition (compared to 28-of the glass of form)

  • Localization: hypothalamus & other CNS locations

    •  periventricular & medial pre-optic areas of anterior hypothalamus

    •  neurosecretory granules at nerve terminals in the median eminence

    • serves as neurotransmitter in the spinal cord, cerebral cortex, brain stem -- in addition to hormonal action

    • also gastrointestinal & pancreatic location

      •  Pancreatic D cells (somatostatin-secreting) -- insulin & glucagon regulation {paracrine action}

  • Inhibits growth hormone release

    • also decreases GH responds to secretagogues without altering GH mRNA levels

    • somatostatin lowers serum TSH in response to TRH

  • Precursor: Prosomatostatin

  • Pharmacokinetics: somatostatin

    • half-life-- 1-3 minutes

    • significant renal metabolism

    • renal excretion

    • limited clinical usefulness due to short duration of action and multiple effects on many secretory processes

• Overview: octreotide:

  • Somatostatin analog -- longer plasma elimination half-life (80 minutes)

  • > 40X more potent than somatostatin in inhibiting growth hormone release

  • only 2X more potent in decreasing insulin secretion

• Clinical Use: octreotide

  • Relatively small effect on insulin secretion (compared to somatostatin) allows clinical use without concern for inducing hyperglycemic states

  • Octreotide used to manage:

    • acromegaly, thyrotropin-secreting pituitary adenomas & carcinoid tumors

    • acute bleeding control: esophageal varices

•  Adverse Effects: octreotide

  • Gastrointestinal disturbances

  • Biliary sludge; gallstones (frequency: 20-30% {> 6 months treatment}; symptomatic gallstones: yearly frequency -- 1%)

Growth Hormone (Somatotropin, GH)

• Overview: GH

  • Peptide hormone: synthesized in anterior pituitary

  • Growth promotion:

    • at open epiphyses: mechanism --

      • stimulation of insulin-like growth factor I (IGF-I, somatomedins C)

  • Promotes lipolysis: adipose tissue

  •  Promotes skeletal muscle growth

• Chemistry:growth hormone

  • 191-amino acid peptide

  • structurally similar to prolactin and chorionic somatomammotropin

  • recombinant DNA growth hormone

    • somatotropin (191-amino acid form)

    • somatrem (192 amino acid form (additional methionine)

• Pharmacokinetics:growth hormone

  • Plasma have life: 20-25 minutes

  • Clearance: hepatic

  • Administration: intramuscular (peak plasma concentration: 2-4 hours)

• Pharmacological Effects:growth hormone

  • Initial insulin-like effects

    • increase glucose uptake

    • increased amino acid uptake

    • decreased lipolysis

  • Delayed anti-insulin effect -- impaired glucose uptake; increase lipolysis

  • Promotes longitudinal growth indirectly through:

    •  Somatomedins, insulin-like growth factors (IGFs)

    • ­  GH stimulates growth plate cartilage & liver synthesis of:

      •  IGF-I I & IGF-I II

    • Somatomedins: mediator of processes promoting bone growth --e.g., increased of DNA thymidine incorporation & increased RNA uridine incorporation --

      • ­cellular proliferation

      • ­ increased proline to hydroxyproline conversion (cartilage synthesis)

  • GH deficiency:  reduced somatomedin :  short stature

    • Short stature:

      • IGF-I deficiency (in the presence of high GH):  Laron dwarfism

      •  Absence of IGF-I pubertal surge (pygmies)

    • Criteria for growth hormone deficiency:

      •  growth rate index -- < 4 cm/year

      •  lack of increase serum GH following growth hormone secretagogue challenge

    • Causes of congenital growth hormone deficiencies:

      •  Most frequent cause: lack of hypothalamic growth hormone-releasing factors, usually due to pit-I gene abnormality

      • hypophyseal-pituitary disease, e.g. craniopharyngiomas

    • Growth hormone deficiency manifestation of the newborn:

      •  seizures

      •  hypoglycemia

    • GH deficiency often associated with multiple pituitary hormonal deficiencies

  • Growth Hormone-Responsive Clinical Conditions

    • GH deficiencies

    • some non-GH deficiencies -- delayed bone age/slow growth rate + GH:  increased growth (short-term GH treatment)

    • Girls with Turner's syndrome: high-dose treatment effective

•  Adverse Effects:growth hormone

  • Following rapid growth:

    • slipped capital femoral epiphyse:  limp; lower extremity pain (rare)

  • leukemia incidence (slight increase -- may not be causal)

  • Screening suggested for hypothyroidism & diabetes during GH treatment

• Impairment of GH response:

  • untreated hypothyroidism

  • diabetes mellitus/diabetes insipidus

Thyrotropin-Releasing Hormone (Protirelin, TRH)

• Overview: thyrotropin-releasing hormone,TRH

  • Tripeptide

  • Location: hypothalamus (and other brain regions)

  • TRH:   portal venous system:   pituitary stimulation :  thyroid-stimulating hormone (TSH, thyrotropic) production :  thyroid-stimulation and release :   thyroxine (T4) & triiodothyronine

  • TRH stimulation of thyrotropin:

    • blocked by thyroxine

    • enhanced by thyroxine deficiency

• Chemistry/pharmacokinetics: TRH

  • Glu-His-Pro-NH₂

  • IV administration

  • plasma half-life: 4-5 minutes

• Pharmacodynamics:TRH

  • Hyperthyroidism: serum thyrotropin level reduced

  • Primary hypothyroidism:

    • thyrotropin levels: high

    • enhanced thyrotropin response to TRH

  • Secondary (pituitary) hypothyroidism:

    • thyrotropin serum levels: low (by sensitive TSH assay) or "inappropriately normal"

    • TSH often does not increase after TRH

  • Tertiary (hypothalamic) hypothyroidism:

    • serum thyrotropin levels: normal or low

    • thyrotropin response to TRH: normal or attenuated

  • TRH infusion:

    • ­ increased prolactin released by the pituitary

    • no effect on growth hormone or ACTH

    •  Pituitary tumors:

      • some pituitary tumors:

        1.  release growth hormone in response to TRH (acromegaly)

        2.  release ACTH in response to TRH (Cushing's disease)

        3.  failure to release prolactin (prolactinoma).

Thyroid-Stimulating Hormone (Thyrotropin, TSH)

• Overview:thyrotropin, TSH

  • Anterior pituitary hormone

  • Thyroid function regulation -- stimulation of thyroxine & triiodothyronine production and release

• Chemistry:thyrotropin, TSH

  • consists of two peptides (a and b) with associated carbohydrate side chains

  • Therapeutic thyrotropin:

    • source -- bovine anterior pituitaries

    • homology between bovine & human peptides: 70% (a) & 90% (b).

    • TSH-b subunit provides thyroid specificity since TSH-a subunit is nearly identical to a subunit of FSH, LH, hCG.

• Pharmacokinetics:thyrotropin, TSH

  • Route of Administration:

    • intramuscular

    • subcutaneous

  • half-life: one-hour

  • renal degradation

• Pharmacodynamics:thyrotropin, TSH

  • Thyrotropin :   thyroid cell adenylyl cyclase activation :   increased cyclic AMP production:  ­ increased iodine uptake:  ­increased thyroid hormone production

• Clinical Use:thyrotropin, TSH

  • Diagnostic/therapeutic:

    • possible diagnostic use in a metastatic thyroid carcinoma

    • bovine TSH: top toxic for therapeutic stimulation of radioactive iodine for treatment of metastatic thyroid carcinoma

 Corticotropin-Releasing Hormone (CRH)

• Overview:corticotropin-releasing hormone,CRH

  • hypothalamic hormone;

  • stimulates ACTH & b-endorphins pituitary release.

• Chemistry:corticotropin-releasing hormone, CRH

  • Human CRH: 41-amino acid peptide

• Pharmacokinetics:corticotropin-releasing hormone, CRH

  • Route of Administration: IV

  • serum half-life (first phase): approximately nine minutes

  • widely metabolized; < 1% excreted unchanged in the urine

• Pharmacodynamics:corticotropin-releasing hormone, CRH

  • Diagnostic use only:

    • Cushing's syndrome -- distinguishing between Cushing's disease and ectopic ACTH secretion-- limited usefulness;

Adrenocorticotropin (corticotropin, ACTH, ACTH_1-24 )

• Overview:ACTH

  • peptide hormone;

  • synthesis site: anterior pituitary

  • Major endocrine function: stimulation of cortisol synthesis & release from adrenal cortices

  • Synthetic corticotropin-derivative use clinically to assess adrenocortical status

    •  reduced adrenocortical response to corticotropin administration:  adrenocortical insufficiency

• Chemistry:ACTH

  • single 39-amino acid peptide

    • amino acids 1-24: required for full biological activity

    • amino acids 25-39: species specificity

  • Synthetic, human ACTH_1-24: cosyntropin

  • Amino terminal sequence (1-13): identical to melanocyte-stimulating hormone (a-MSH)

    •  with excess ACTH pituitary secretion hyperpigmentation due to a-MSH activity due to ACTH

• Pharmacokinetics:ACTH

  • Porcine & synthetic corticotropin: well absorbed following intramuscular administration

  • Corticotropin: no oral administration due to GI proteolysis

  • half-life: < 20 minutes

  • Tissue concentration: in liver & kidney

• Pharmacodynamics: ACTH

  • ACTH stimulates adrenal cortex to produce glucocorticoid, mineralocorticoid, & androgen.

  • ACTH increases cholesteryl esters activity ( cholesterol:  pregnenolone step: rate-limiting in steroid hormone production)

  • ACTH promotes adrenal hypertrophy & hyperplasia

  • corticotropin may cause increased in skin pigmentation

• Clinical Use:ACTH

  • ACTH adrenal stimulation: inadequate response in adrenal-insufficiency

  • Cosyntropin may be used rule out adrenal-insufficiency

    • following cosyntropin, plasma cortisol should exceed 18 ug/dL

      •  subnormal response:   primary or secondary adrenocortical insufficiency

      •  Primary adrenocortical insufficiency: increased endogenous plasma ACTH levels

      •  Secondary adrenocortical insufficiency: decreased endogenous plasma ACTH levels

  • Differentiation of "late-onset" (non-classic) congenital adrenal hyperplasia from states of ovarian hyperandrogenism

    •  21-hydroxylase deficiency: ACTH stimulation:   incremental increase in plasma 17-hydroxyprogesterone (substrate for the deficient enzyme)

    •  11-hydroxylase deficiency: ACTH stimulation:  increase 11-deoxycortisol

    •  3-b-hydroxy-D 5 steroid dehydrogenase deficiency: ACTH stimulation:  increase in 17-hydroxypregnenolone

  • Therapeutics: corticotropin -- no advantage over direct glucocorticoid administration

Gonadotropin-Releasing Hormone (GnRH., luteinizing hormone-releasing hormone {LHRH};Gonadorelin)

• Overview: Gonadotropin-releasing hormone (GnRH)

  • Synthesis site: arcuate nucleus of the hypothalamus

  • Controls gonadotropins FSH & LH release

• Chemistry:GnRH

  • decapeptide

  • For pharmacological use -- synthetic forms (analogs)

    •  Leuprolide, nafarelin, buserelin, goserelin, histrelin

    •  Synthetic forms -- more potent & longer lasting then GnRH

• Pharmacokinetics:GnRH

  • GnRH Route of Administration: IV or subcutaneous

  • GnRH analogues Route of Administration: subcutaneous, nasal spray, intramuscular

  • GnRH half-life: 4 minutes

  • GnRH analog half-life: three hours

  • Sites of degradation: hypothalamus & pituitary

• Pharmacodynamics:GnRH

  • Binding site: receptors on pituitary gonadotropes

  • pulsatile IV administration (frequency every 1-4 hours):   FSH & LH secretion stimulation

  • continuous GnRH administration (or GnRH analog depot formulation):  inhibition of gonadotropin release

• Clinical Uses:GnRH

  • Diagnostic Applications:GnRH

    •  Assessment of delayed puberty-- (a) constitutional delay or (b) hypogonadotropic hypogonadism

      • LH response to GnRH distinguishes between causes.

      • Following subcutaneous GnRH bolus:

        • peak LH response > 15.6 mIU/mL:   normal {indicating puberty will occur soon}

        • peak LH response impaired suggests hypogonadotropic hypogonadism (probably indicative of pituitary/hypothalamic dysfunction {could be still seen in constitutional adolescence delay})

  •  Therapeutic Applications: GnRH

    • Stimulation: Infertility due to hypothalamic hypogonadotropic hypogonadism (both sexes)

      • GnRH:  stimulation of pituitary function

      • programmable pump technology allows pulsatile GnRH treatment (frequency: every 90 minutes)

    • Inhibition: management of prostate cancer, uterine fibroids, endometriosis, polycystic ovary syndrome, precocious puberty

      • by continuous administration of GnRH analog agonists {leuprolide, nafarelin, goserelin and, histrelin}

    • Other uses:

      •  in vitro fertilization approaches: GnRH analog

        1. suppression of endogenous gonadotropin release

        2. then exogenous gonadotropins added to promote synchronous follicular development.

  •  Toxicity: GnRH

    • For diagnosis, occasional headache, abdominal discomfort, flushing

    • GnRH analogs: initial bone pain exacerbation in prostate cancer & hot flushes {both sexes}

    • Increased risk of osteoporosis in women if treatment > 6 months duration

Follicle-Stimulating Hormone (FSH)

• Overview:FSH

  • Glycoprotein hormone

  • Synthesis site: anterior pituitary

• Function:FSH

  • FSH + LH (luteinizing hormone): gonadal function regulation-- mediated by increasing cAMP levels in gonadal tissue

  • FSH -- principal function:

    •  gametogenesis and follicular development stimulation in women

    •  spermatogenesis in men

  • FSH site of action: immature ovarian follicular cells:  promoting development of the mature follicle and oocyte

    • FSH + LH required for correct ovarian steroidogenesis

      • {LH stimulates and production; FSH stimulates androgen conversion into estrogens (granulosa cells)}

  • Testes-- Site of action for FSH: Sertoli cells, enhance androgen-binding protein production

• Modified FSH molecules

  • Obtained from postmenopausal women's urine

  • one agent --FSH-like characteristics; 4% potency

  • another agent --LH-like characteristics

  • FSH-LH combination: menotropins

  • Another preparation: also from postmenopausal women's urine but with no LH is urofollitropin

 Leutinizing Hormone (LH)

• Glycoprotein hormone (two chains)

• Site of synthesis: anterior pituitary

• Major physiological role:

  • regulation of gonadal steroid hormone production

  • Site of action-- male:

    • testicular Leydig cells:   stimulation of testosterone production

  • Site of action -- female:

    • mature follicle:  induce ovulation;

    • stimulation of corpus luteum (in menstrual cycle luteal phase):  to produce progesterone & androgens

  • Note: no LH preparation available for clinical use. Human chorionic gonadotropin (very similar structure) may be used as a leutinizing hormone substitute

Gonadotropins (hMG, Menotropins & FSH, Urofollitropin)

• Overview:gonadotropins

  • Human menopausal gonadotropins (hMG): Composition

    •  mixture, partially catabolized human FSH & LH {extraction -- postmenopausal women's urine}

    • standardized for FSH & LH content

    • used for treating infertility --

      •  in women: stimulation of ovarian follicle development

      •  in man: spermatogenesis

      •  both sexes: hMG must be used with luteinizing hormone (human chorionic gonadotropin, hCG) to ensure:

        • ovulation implantation women

        • testosterone production & full masculinization in men

• Pharmacokinetics:gonadotropins

  • 7-12 day course daily hMG or urofollitropin (simulating ovarian cycle follicular phase in women with hypothalamic amenorrhea): 

    •  FSH levels increase to 2X baseline;

    •  LH levels increase to 1.5X baseline (hMG only; not with urofollitropin)

• Pharmacodynamics:gonadotropins

  • Women: hMG or FSH treatment of gonadotropin-deficient women:   ovarian follicular growth/maturation

    • Ovulation: chorionic gonadotropin requirement following follicular maturation

  • Men with gonadotropin deficiency: chorionic gonadotropin pre-treatment:  external sexual maturation

    • Subsequent hMG treatment:  permatogenesis, fertility

• Clinical Use:gonadotropins

  • Indication: pituitary or hypothalamic hypergonadism with infertility

  • Population of anovulatory women would these conditions may benefit from human menopausal gonadotropin:

• hMG & FSH: used in in vitro fertilization programs for ovarian hyperstimulation

• Men with hypogonadotropic hypogonadism become fertile following hMG administration: success frequency = 50%.

•  Toxicity: gonadotropins

  • Ovarian overstimulation with hMG: ovarian enlargement (uncomplicated) -- frequency 20% of patients

  • "Hyperstimulation syndrome": more serious: frequency = 0.5-4%

    • hMG-induced ovarian enlargement

    • ascites

    • hydrothorax

    • hypovolemia (shock may occur)

    • hemoperitoneum (secondary to ruptured ovarian cyst)

    • fever

    • arterial thromboembolism

  • Possible abnormal development/premature corpus luteum degeneration in some patients

  • in men: gynecomastia -- occasionally

• Other Effects:gonadotropins

  • frequency multiple births following hMG treatment: 25%

•  Contraindications:gonadotropins

  • Human menopausal gonadotropin and urofollitropin should not be used in the presence of uterine, tubal, or ovarian diseases or pregnancy

Hypothalamic/ Pituitary Agents

Human Chorionic Gonadotropin (hCG)

• Overview:hCG

  • hCG -- produced by the placenta; excreted into the urine

  • glycoprotein; 92-amino acid a-chain + 145-amino acid b-chain.

    • a-chain-- closely resembles FSH, LH, TSH a-chain

    • b-chain-- closely resembles LH b-chain

    • Similar to LH structurally;

    • Used to treat women & men with LH deficiency

  • Function:hcG

    • Ovarian corpus luteum stimulation to produce progesterone

    • placental maintenance

• Pharmacokinetics:hCG

  • intramuscular administration; well-absorbed

  • half-life: 8 hours (compared to LH half-life -- 30 minutes)

• Pharmacodynamics:hCG

  • human chorionic gonadotropin (hCG) stimulates gonadal steroid hormone production

    • Cells affected:

      • female: interstitial & corpus luteum cells produce progesterone

      • male: Leydig cells produce testosterone

    • hCG administration: simulates midcycle LH surge:   promote ovulation in hypogonadotropic states

• Clinical Uses:hCG

  • Diagnostic:hCG

    • pre-pubertal boys with undescended gonads: hCG can distinguish between retained testes (cryptorchid) and retracted testes (pseudocryptorchid)

      •  if transient testicular descent occurs with hCG administration:  permanent pubertal descent

      •  if transient testicular descent does not occur with hCG administration, orchiopexy will be required to insurer spermatogenesis

    • Constitutional puberty delay vs. hypogonadotropic hypogonadism: distinguished using repetitive hCG administration

      •  with hCG administration: serum testosterone & estradiol levels increase in constitutional puberty delay -- not in hypogonadotropic hypogonadism states

  • Therapeutic:hCG

    •  hCG + human menotropin:  ovulation in women with hypogonadotropic hypogonadism or as part of in vitro fertilization approach

    •  hCG: testicular testosterone stimulation in men with hypogonadotropic hypogonadism (increased intratesticular testosterone:   promotes spermatogenesis; menotropins often also required for fertility)

• Toxicity:hCG

  • headache, edema, gynecomastia, pretentious puberty, depression, hCG antibody production (rare)

•  Contraindications:hCG

  • presence of androgen-dependent neoplasia

  • presence of precocious puberty

Prolactin

• Structure:prolactin

  • 198-amino acid peptide

  • Site of production: anterior pituitary

  • resembles growth hormone

• Function:prolactin-- hormone primarily responsible for lactation

  • lactation requires appropriate circulating concentrations of progestins, estrogen, corticosteroids & insulin.

• Abnormal prolactin levels:

  • Deficiency:prolactin-- may be associated with pituitary deficiency states

    • Manifestations:

      •  lactation failure

      •  luteal phase defect

  • Excess:prolactin --may be associated with hypothalamic destruction due to reduced dopamine delivery to the pituitary {dopamine = prolactin-inhibiting hormone}

    • Hyperprolactinemia may cause:

      1.  galactorrhea

      2.  hypogonadism

    • Hyperprolactinemia symptomatic management:

      • administration of bromocriptine & other dopamine agonists inhibit prolactin secretion

Bromocriptine and Other Dopamine Agonists

• Overview:bromocriptine & other dopamine agonists

  • Bromocriptine:

    • Background:bromocriptine

      • most widely used drug for treating hyperprolactinemia

      • ergot derivatives: dopamine agonist properties

      • decreases serum prolactin

      • shrinks pituitary (prolactin-secreting) tumors

  • Mechanism of Action:bromocriptine

    • dopamine-like action

    • Site of action:

      1. reduces dopamine turnover in the tuberoinfundibular neurons of the arcuate nucleus (increasing hypothalamic dopamine)

      2. pituitary: activates dopamine receptors causing prolactin release inhibition

  • Effects on other hormones:

    • normal subjects: increases pituitary growth hormone release

    • patients with acromegaly: suppresses growth hormone release (paradoxical response)

  • Pergolide -- also used for hyperprolactinemia management

• Clinical Uses:bromocriptine

  • Prolactin-secreting adenomas

    • bromocriptine-- initial treatment

    • 85% response rate at six months-- judged by tumor size reduction and decreasing serum prolactin levels

  • Amenorrhea-Galactorrhea:

    • bromocriptine -- management of clinical sequelae of hyperprolactinemia, including:

      • amenorrhea, galactorrhea, infertility, hypogonadism

      • amenorrhea/galactorrhea recurrence if treatment is discontinued

  • Physiologic lactation:

    • bromocri

    • ptine-prolactin secretion suppression following parturition/abortion ® prevents breast engorgement when breastfeeding not desired/required

    • possible increase in stroke risk in women receiving bromocriptine postpartum

Posterior Pituitary Hormones

• Overview:posterior pituitary hormones

  • Oxytocin

  • Vasopressin

  • Synthesis Site:

    • hypothalamus:  posterior pituitary:  stored :  released

• Oxytocin:Overview

  • Levels:

    • physiologic levels:cause milk ejection in lactating women

    • pharmacological doses:

      • induce uterine contraction/maintain labor

  • Chemistry:oxytocin

    • 9-amino acid peptide

  • Pharmacokinetics: oxytocin

    • IV administration for labor stimulation

    • nasal spray: postpartum lactation induction

    • catabolism: renal & hepatic

    • half-life: (circulating) 5 min.

  • Pharmacodynamics: oxytocin

    • influences ionic currents in myometrial smooth muscle :  uterine contraction

    • uterine sensitivity to oxytocin: ­ increases in pregnancy

    • inhibition of oxytocin-induced myometrial uterine contraction:

      •  magnesium sulfate

      •  b-adrenergic receptor agonists

      •  inhalation anesthetics

    • promotes myoepithelial cell contraction (surrounding mammary alveolar) :   milk ejection

    • normal lactation requires oxytocin

• Clinical Uses:oxytocin

  • Diagnostic Applications:oxytocin

    • Checking placental circulatory reserve:

      • IV oxytocin near-term:  uterine contractions:  decrease fetal blood supply:   fetal heart rate response monitored (abnormal response may suggest intrauterine growth retardation; may suggest advisability of cesarean section

  • Therapeutic Uses:oxytocin

    • labor induction

    • promoting dysfunctional labor

      1. when early vaginal delivery is required

         • Rh factor concerns, maternal diabetes, preeclampsia

      2. uterine inertia

      3. incomplete abortion

    • control of postpartum uterine bleeding

    • enhance impaired milk ejection (nasal Route of Administration)

•  Toxicity:oxytocin

  • serious toxicity: rare

  • reported adverse reactions include: hypertensive reactions, uterine rupture, water intoxication, fetal death, afibrinogenemia

•  Contraindications:oxytocin

  • fetal distress, abnormal fetal presentations, factors predisposing to uterine rupture

• Vasopressin:Overview:

  • peptide hormone

  • released by posterior pituitary in reaction to:

    • rising plasma tonicity

    • decreasing blood pressure

  • antidiuretic properties

  • vasopressor properties

  • vasopressin deficiency: :   diabetes insipidus

• Structure:vasopressin

  • nonapeptide

• Pharmacokinetics:vasopressin

  • Routes of administration:

    • IV, intramuscular, intranasal

  • half-life: 20 minutes

  • Renal & hepatic catabolism

  • minimal vasopressin excreted unchanged in the urine

• Pharmacodynamics:vasopressin

  • Receptor types:

    • V₁-- vascular smooth muscle (vasoconstriction)

    • V₂ -- renal tubule cells: antidiuresis

      • Mechanism: (1) increased water permeability and (2) increased collecting tubule water resorption

    • extrarenal V₂ receptors--promote coagulation factor VIII_c and von Willebrand factor release.

  • Desmopressin acetate (DDAVP, 1-desamino-8-D-arginine vasopressin)

    • synthetic vasopressin derivative

    • long-acting

    • limited V₁ receptor activity

    • significant antidiuretic/vasopressor ratio compared to vasopressin (4000: 1)

• Clinical Use:vasopressin

  • Vasopressin & desmopressin: alternative treatment for pituitary diabetes insipidus

  • Nocturnal enuresis (desmopressin at bedtime) -- mechanism: reduced night urine production

  • IV vasopressin: may be effective in managing esophageal variceal bleeding and colonic diverticular leading

• Toxicity:

  • Vasopressin (not desmopressin): vasoconstriction -- cause issues in patients with coronary vascular disease

  • Unusual side effects include: agitation, allergic reactions, abdominal cramping, headache, nausea