37 HYPOTHALAMIC AND PITUITARY HORMONES

FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

Hypothalamus and pituitary gland

Controls metabolism, growth, and reproduction that is mediated by a combination of neural and endocrine
systems
Hypothalamic and Pituitary Hormones
All the hormones produced by the anterior pituitary except prolactin (PRL)
Key participants in hormonal systems in which they regulate the production of hormones and autocrineparacrine factors by endocrine glands and other peripheral tissues
Hypothalamic and Pituitary Hormones
ANTERIOR PITUITARY & HYPOTHALAMIC HORMONE RECEPTORS
Anterior pituitary hormones
Growth hormone (GH) and prolactin
Single chain protein hormone with significant homology
Activate receptors of the JAK/STAT superfamily
Adrenocorticotropic hormone (ACTH)
Single peptide
G protein-coupled
Thyroid stimulating hormone (TSH, thyrotropin), follicle-stimulating hormone (FSH) and luteinizing hormone
(LH)
Dimeric and activate G protein-coupled receptors
TSH, FSH, LH
Share a common alpha chain
Beta chains differ enough to confer receptor selectivity
TSH, FSH, and ACTH
Share similarities in the regulation of their release from the pituitary
Under the control of a distinctive hypothalamic peptide
Subject to feedback inhibitory regulation by the hormones whose production they control
TRH-TSH-T3 and T4
GnRH-LH and FSH-estrogen and progesterone
CRH-ACTH-cortisol
GH
Hypothalamus regulates by secretion of 2 hormones
GHRH-stimulates GH production
Somatostatin (SST)-inhibits GH production
GH and insulin-like growth factor [(IGF-1), primary peripheral mediator] provide feedback to inhibit
GH release
Prolactin
Inhibited by dopamine thru the D2 receptors
Hypothalamus does not produce a hormone that stimulates its production
All are available for use in humans
Only a few are of major clinical importance
TRH, TSH, CRH, ACTH, GHRH
Either not used clinically
Used rarely for specialized diagnostic testing
GH, SST, LH, FSH, GnRH and dopamine and analogs
Commonly used
GH (somatotropin-rhGH)
Required during childhood and adolescence for attainment of normal adult size
Important effects on lipid and carbohydrate metabolism, and on lean body mass
Effects are primarily mediated by IGF-1 (somatomedin C) and to a lesser extent IGF-2

 Half-life of 20-25 minutes

Closely resembles prolactin
Somatropin (rhGH)
Recombinant form, identical with the predominant human GH
Given subcutaneously and persist for 36 h
Complex effects on growth, body composition, and carbohydrate, protein and lipid metabolism
Anabolic effects on muscles and catabolic effects on lipid cells
GH and IGF have opposite effects on insulin
GH reduces insulin sensitivity-increase in insulin
IGF-1 thru insulin receptors lowers glucose and reduces insulin
Clinical Pharmacology
GH deficiency
GH treatment of pediatric patients with short stature
Other uses
Anabolic effect
Component of anti-aging programs
Not a direct target for development of new drugs to treat obesity
Toxicity and CI
Well tolerated by children
Pseudotumor cerebri-intracranial hypertension is rare-vision changes, headache, n/v
Adults tend to have more s/e
Peripheral edema, myalgias, arthralgias
CI in patients with known malignancies
Mecasermin rifanbate
Complex of recombinant human IGF-1 (rhIGF-1) and recombinant IGF-binding protein-3 (rhIGFBP-3)
Treatment of severe IGF-1 deficiency that is not responsive to GH
Rifanbate-binding protein needed to maintain the half-life of rhIGF-1
Hypoglycemia is the most important s/e
Meal 20 minutes before or after administration
GH Antagonists
Secreting tumors like pituitary adenomas
Acromegaly in adults
Gigantism in children
Pegvisomant
GH receptor antagonist
Treatment of acromegaly
PEG derivative of mutant GH B2036
Less potent than B2036 but pegylation reduces its clearance and improves clinical effectiveness
Somatostatin Analogs
Found in the hypothalamus, other parts of the CNS, pancreas, GIT
Inhibits the release of GH, glucagon, insulin and gastrin
Half-life of 1-3 minutes
Kidney is responsible for metabolism and excretion
Limited usefulness due to its short duration and multiple effects
Octreotide
Longer acting analog
Most widely used
45 times more potent in inhibiting GH release
2 times as potent in reducing insulin release
Given subcutaneously every 8 h

Long-acting suspension
A brief course of regular octreotide should be demonstrated to be effective and tolerated
Slow release IM formulation is administered
Every 4 weeks for long term therapy
Adverse effects
A. N/V, abdominal cramps, flatulence, steatorrhea
Lanreotide
o Long-acting
o Comparable effects

The Gonadotropins (FSH, LH)

Complementary functions in the reproductive process
Women
FSH-direct ovarian follicle development
FSH and LH-ovarian steroidogenesis
Men
FSH-primary regulator of spermatogenesis
LH-production of testosterone
The Gonadotropins (FSH, LH) and hCG
Share identical alpha chain with distinct beta chain
Beta chains of hCG and LH are nearly identical and are used interchangeably
Administered subcutaneously or IM on a daily basis
A.

Menotropins
Human menopausal gonadotropins (hMG)
Extracted from urine of postmenopausal women
FSH-like properties and LH-like substance

B. Follicle-Stimulating Hormone
3 purified forms
Urofollitropin (uFSH)
Two recombinant forms
Follitropin alfa and beta
Differ from each other in the carbohydrate side chain
Shorter half-life, more efficient, more expensive
C. Luteinizing Hormone
Lutropin alfa
Recombinant form
Approved only for use in combination with follitropin alfa for stimulation of follicular development in infertile women with
profound LH deficiency
D.

Human Chorionic Gonadotropin

Produced by the human placenta and excreted in the urine
Choriogonadotropin alfa (rhCG)
Recombinant form with greater consistency in biologic activity
Only gonadotropin packaged and dosed on basis of weight rather than units of activity
Given subcutaneously

Clinical Pharmacology
A. Ovulation induction
Controlled ovarian hyperstimulation (COH)-assisted reproductive technology procedures

Day 3, daily injections for 7-12 days

Serum estradiol
Ultrasound of ovarian follicle development
Endometrial thickness
Prevent premature endogenous LH surge
GnRH agonist or GnRH receptor antagonist
When appropriate follicle maturation occurs
Inject thru IM 5,000-10,000 units of hCG
To induce ovulation
Provide exogenous progesterone for luteal support
Preferred than hCG because of higher risk of ovarian hyperstimulation
Male infertility
4-6 months of treatment
Toxicity and CI
Ovarian hyperstimulation syndrome (OHSS)
Ovarian enlargement
Ascites, hydrothorax, hypovolemia and sometimes shock
Multiple pregnancies
15-20%
Gonadotropin-Releasing Hormones & its Analogs
Pulsatile GnRH secretion is required to stimulate production and release of LH and FSH
Sustained nonpulsatile administration of GnRH analogs inhibits the release of FSH and LH by the pituitary
resulting to hypogonadism
Gonadorelin
Acetate salt of synthetic human GnRH
Goserelin, histrelin, leuprolide, nafarelin, triptorelin
Synthetic analogs
More potent and longer-lasting
Given IV or subcutaneously, IM or via nasal spray (nafarelin)
Preparations with a range of duration of action from several hours (ovulation induction-daily administration) to
1-12 months (prostate cancer-depot forms)
Continuous administration produces a biphasic response
Initial phase due to agonist effect-flare
Followed by inhibitory action that manifest as drop in concentration of gonadotropins and gonadal steroids
Clinical Pharmacology
A. Stimulation
Female infertility
Use is uncommon due to inconvenience and cost of IV pump
Male infertility
Diagnosis of LH responsiveness
B. Suppression of Gonadotropin Production
COH
Endometriosis
Myoma
Prostate cancer
Central precocious puberty
Other-Ovarian and breast cancer
Toxicity
Headache, nausea and flushing
Continuous treatment

Typical symptoms of menopause

Hot flushes, sweats, headaches
Depression, decreased libido, generalized pain, dryness, breast atrophy
Osteoporosis, gynecomastia in males
GnRH Receptor Antagonists
Ganirelix, cetrorelix, abarelix, degarelix
Inhibit the secretion of FSH and LH in a dose-dependent manner
Ganirelix, cetrorelix
Approved for COH
Subcutaneous injection
Abarelix, degarelix
For advanced prostate cancer
Intramuscular
Clinical Pharmacology
A. Suppression of Gonadotropin Production
Advantages over GnRH agonist
Immediate antagonist effect
Duration of administration is shorter
Less negative impact on ovarian response to stimulation
Lower risk of OHSS
Antagonistic effect reverses more quickly after discontinuation
B. Advanced prostate cancer
Toxicity
When used for COH, well tolerated
Nausea and headache
For prostate cancer
Allergic responses-hypotension and syncope
Continuous use
S/s of androgen deprivation
Prolactin
Principle hormone for lactation
Hyperprolactinemia
Due to impaired transport of dopamine to the pituitary
More commonly due to prolactin-secreting tumor
Syndrome of amenorrhea and galactorrhea in women
Loss of libido and infertility in men
No preparation is available for use
Dopamine agonist
Used to inhibit prolactin secretion
Bromocriptine and cabergoline
Ergot derivatives
High affinity to D2 receptors
Quinagolide
Nonergot alkaloid
Similarly high D2 receptor affinity
Dopamine agonist
Oral prep
Cabergoline with the longest duration of action
Bromocriptine has a half-life of 7 h
Peaks more slowly after vaginal insertion
Clinical Pharmacology

Hyperprolactinemia

Standard treatment

Prevent breast engorgement when breast feeding is not desired

Physiologic lactation
Acromegaly
Can reduce GH secretion but not as effective in hyperprolactinemia
Toxicity and CI
Nausea, headache, light-headedness, hypotension and fatigue
Psychiatric manifestations are rare
Cabergoline causes nausea less often than bromocriptine
Not associated with spontaneous abortion during early weeks of pregnancy
Posterior Pituitary Hormones
Oxytocin and vasopressin
Produced in the nerve cell bodies in the hypothalamus
Transported via the axons to the posterior pituitary where they are stored
Released into the general circulation
Oxytocin
Effective stimulant of uterine contraction
Stimulates release of prostaglandins and leukotrienes that augment uterine contraction
Elicits milk ejection in lactating women
Causes contraction of myoepithelial cells in the mammary gland causing milk ejection
IV for initiation and augmentation of labor
IM to control postpartum bleeding
Weak antidiuretic at high concentration and pressor activity due to activation of vasopressin receptors
Toxicity and CI
Serious toxicity is rare
Excessive stimulation of uterine contractions
Fetal distress, placental abruption, uterine rupture
Excessive fluid retention-hyponatremia, hypotension (bolus), seizure, death
Atosiban
Oxytocin receptor antagonist
Used for preterm labor
Given IV
As effective as beta adrenoceptor agonist with fewer s/e
Vasopressin (Antidiuretic Hormone [ADH])
Acts on V receptors (renal tubular cells)
Increases the synthesis or insertion of water channels by a cAMP dependent mechanism
Increase in water permeability in the collecting tubules of the kidney
Permits water absorption
Acts on V1 receptors (vascular beds)
Causes smooth muscle contraction
Released in response to rising plasma tonicity and falling BP
Given IV or IM
Desmopressin
Selective agonist of V receptors
Clinical Pharmacology
Treatment of choice for diabetes insipidus
Nocturnal enuresis

Toxicity and CI
Headache, nausea, allergic reactions are rare
Hyponatremia and seizures
Not used in patients with coronary artery disease due to vasoconstrictive effects (vasopressin)
Vasopressin Antagonists
Conivaptan
High affinity for both V1 and V2 receptors
Approved for IV administration in hyponatremia
Tolvaptan
Higher affinity for V2 receptors