Block 3 review Flashcards
Anterior Pituitary Hormones share a common alpha subunit structure:
TSH, LH, FSH, and HCG
Hypothalamic/Pituitary Hormones
Peptides Hormones
Not stored in granules
Released into Hypothalamic portal system
ACTH is derived from:
POMC
Growth Hormone (GH) is structurally similar to
Prolactin and chorionic somatomammotropin (HPL)
Hormones of the hypothalamus
CRH GHRH GnRH (LHRH) PIH TRH PRH
Hormones of the anterior pituitary
GH ACTH LH FSH TSH Prolactin
Functions of homones released by Anterior Pituitary
GH–––liver–––insulin-like growth factor
ACTH–––adrenal cortex–––glucocorticoids, mineralocorticoids, + androgens
LH (female)–––ovary–––estrogen + progesterone
LH (male)–-–testes–––testosterone
FSH–––ovary–––estrogen
TSH–––thyroid–––thyroxine
Prolactin–––breast
GnRH (LHRH) ANALOGUES
Are Used to treat sex hormone responsive cancers by decreasing gonadal stimulation and preventing release of steroid sex hormones
Stimulate the LHRH receptor in a non-pulsatile fashion causing downregulation of receptors
Inhibit release of FSH and LH
Examples of GnRH (LHRH) ANALOGUES
Gonadorelin – GnRH (LHRH) Goserelin - Synthetic GnRH superagonist Histrelin - Synthetic LHRH agonist Leuprolide – Synthetic LHRH analogue Nafarelin – Synthetic LHRH analogue
Side Effects of GnRH ANALOGUES
Hot flashes, sweating, diminished libido, ovarian cysts (women), gynecomastia (men), initially causes a rise in testosterone.
OCTREOTIDE
Somatostatin analogue Longer half-life Used to treat acromegaly Somatostatin inhibits release of GH, TSH, IGF-1, Insulin, Glucagon and Gastrin Lanreotide is a long acting analogue
Side Effects of Octreotide
diarrhea, abdominal pain, flatulence, nausea, steatorrhea (delays bile secretion)
CRH
Stimulates the synthesis of POMC
Used diagnostically to differentiate between Cushing’s disease and Cushing’s syndrome
Also Dexamethasone is used for this purpose
ANTERIOR PITUITARY
Urofollitropin – Purified FSH derived from urine Follitropin alpha - FSH alpha subunit Follitropin beta – FSH beta subunit Menotropin – LH and FSH derived from menopausal women Somatropin - GH Pegvisomant – GH receptor antagonist Corticotropin - ACTH Cosyntropin – synthetic ACTH analogue
ACTH
Peptide hormone derived from POMC
Stimulates the adrenal cortex
Necessary for synthesis of adrenocortical hormones including cortisol, aldosterone, and sex hormones produced in the adrenal cortex
Stimulates Desmolase
Stress stimulates secretion, cortisol is a negative feedback regulator of ACTH
Cosyntropin is an analogue of the 24 a.a. amino terminus. Used to diagnose adrenal insufficiency
Adverse Effects of ACTH
Since ACTH stimulates cortisol, the adverse effects of high concentrations would be similar to Cushing’s syndrome side effects: osteoporosis, gastric ulcers, hypertension, peripheral edema, hypokalemia, immunosuppression, glaucoma, cataracts, etc.
Cushing Syndrome
is seen with any elevation in cortisol levels (endogenous or exogenous)
Cushing’s Disease
Cushing’s Disease is a specific type of Cushing’s Syndrome specifically caused by high levels of ACTH produced by the pituitary gland
Elevated ACTH caused by ectopic tumors is not considered Cushing’s Disease
Since only the Anterior Pituitary contains receptors for CRH, this will respond to CRH stimulation
SOMATOTROPIN
Growth Hormone is a protein produced by somatotroph in the anterior pituitary
Highest secretion occurs during sleep
Inhibited by Somatostatin
Induced by GHRH
Effects of GH are mediated through Somatomedins (IGF-1, IGF-2)
Protein synthesis, Cell proliferation, Bone growth, cartilage synthesis, myocyte proliferation, GFR, adipocyte proliferation, lipolysis, etc.
Side Effect of SOMATOTROPIN
hyperglycemia, joint swelling
Growth Hormone (GH)
is used to treat GH deficiency (hypopituitarism) or growth failure in children from other causes
Used in Prader-Willi syndrome
Pegvisomant
is a GH receptor blocker used to treat acromegaly. Its use is limited to inefficacy of somatostatin analogues. Protein that is administered parenterally (SQ)
FSH
Used to stimulate the follicles used to treat infertility
Glycoproteins that share the same alpha subunit
Effects: ovarian maturation, spermatogenesis
Ovulation when HCG
FSH ANALOGUES
Urofollitropin – purified FSH
Follitropin alpha - Recombinant
Follitropin beta – Recombinant
Menotropin – LH and FSH
PROLACTIN
Peptide produced by anterior pituitary lactotrophs
Stimulates and maintains lactation
Also decreases libido and inhibits ovulation
Prolactin secretion is inhibited by Dopamine acting at D2 receptors
Hyperprolactinemia can be treated by Bromocriptine, Pergolide and Cabergoline
Hormones of the POSTERIOR PITUITARY
Vasopressin
Desmopressin (DDAVP)
Oxytocin
Desmopressin
is a synthetic analogue (of ADH) used for Diabetes Insipidus and nocturnal enuresis
Desmopressin only has activity at V2 receptors
Longer half-life
Administered intranasally
ADH
Vasopressin is a nonapeptide that affects expression of aquaporins in the renal collecting ducts (V2 mediated)
Also has vasopressor effects (V1 mediated)
Released in response to plasma osmolarity changes (and hypovolemia)
Side effects of ADH
water intoxication and hyponatremia
OXYTOCIN
Peptide hormone that acts on the pregnant uterus to stimulate contraction
Used to induce labor
Also plays a role in milk let-down
Causes contraction of myoepithelial cells around mammary alveoli
THYROID FUNCTION Meds
Levothyroxine
Liothyronine
Liotrix
Methimazole
Propylthiouracil
Iodine
Functions of thyroid gland
- Uptake of iodide ion
- Synthesis of thyroglobulin
- Iodination
- Condensation
- Proteolytic release of hormones
THYROID GLAND
Under control of Pituitary gland Stimulated by TSH Iodine Uptake Synthesis of thyroglobulin Iodination of tyrosine residues Condensation Release of T3 and T4 T3 is more potent than T4, but more T4 is synthesized and released. Conversion occurs in the periphery.
Thyroid gland also secretes Calcitonin (parafollicular cells)
HORMONE REGULATION
TRH is released by hypothalamus and stimulates TSH production in the anterior pituitary
TSH stimulates thyroid hormone production and secretion
Thyroid Hormone feedback regulates TRH and TSH secretion
Dopamine, somatostatin and glucocorticioids also can inhibit TSH secretion
PROTEIN BINDING
Thyroid hormone is hydrophobic so it is transported in the bloodstream attached to various plasma transport proteins:
Albumin – lowest affinity but highest capacity
Transthyretin – intermediate affinity and capacity
Thyroglobulin – highest affinity but low capacity
In equilibrium with free fraction which is pharmacologically active
Increased protein-binding extends half-life but decreases free fraction
Decreased protein-binding increases free fraction
Treatment of Hyperthyroidism
Treatment of Hyperthyroidism is accomplished by using drugs that inhibit synthesis and release of thyroid hormones:
Propylthiouracil
Methimazole
Iodine preparations
Inhibit iodination and condensation reactions
PTU also inhibits conversion of T4 to T3
PTU is more toxic: Hepatotoxicity
Other side effects: Agranulocytosis, rash, edema
STEROID SEX HORMONES
Produced in the gonads
Necessary for development of primary and secondary sexual characteristics, conception, fertility, and embryonic maturation
Replacement therapy is used when there is a blockage in hormone production, antagonists are used in treatment of sex hormone responsive neoplasias
SEX HORMONE ANALOGUES
SEX HORMONE ANALOGUES ESTROGENS Estradiol Estrone Ethinyl Estradiol Mestranol PROGESTINS Desogestrol Drosperinone Levonorgestrol Medroxyprogesterone Norethindrone Norgestrel Progesterone ANTIPROGESTINS Mifepristone
ANDROGENS Danazol Fluoxymesterone Oxandrolone Testosterone ANTIANDROGENS Bicalutamide Dutasteride Finasteride Flutamide Nilutamide SERMs Clomiphene Tamoxifen Raloxifene
ESTROGEN EFFECTS
Estrogen binds to an intracellular receptor
Estrogen affects may organs and molecular processes:
- Increased bone mass
- Positive effects on Lipid Profile
- Increased biliary cholesterol secretion
- Increase plasma levels of CBG, TBG, SHBG
- Increase coagulation factors but decrease proteins S, C and Antithrombin III
- Increase induction of NO Synthase
- Induction of Progestin Receptors in endometrium
- Increases thrombosis
- Stimulates the development of sexual organs, breast development, shaping the skeleton, epiphyseal closure
- Affects secondary sex characteristics in puberty
- Vasodilation and positive effects on blood pressure and cardiovascular system
- Feedback inhibition of LHRH, LH and FSH
- Stimulate of cell proliferation of many tissues (breasts)
MENSTUAL CYCLE
At the start of the menstrual cycle, FSH levels increase due to LHRH, stimulating Estrogen production
Estrogen produced by the growing follicle feedback inhibits FSH secretion and sensitizes the endometrium for proliferation and progesterone receptor expression
At midcycle, an LH/FSH surge stimulates ovulation
The corpus luteum secretes both estrogen and progesterone, maintaining the endometrium.
ESTROGEN
Prescribed as oral contraceptive, hypogonadism, hormonal replacement therapy
Oral Contraceptive - Estrogens inhibit pituitary hormone secretion and prevent ovulation. However unopposed estrogen has been linked to the development of uterine cancer
Hypogonadism – Estrogens are prescribed for the development of secondary sexual characteristics in Turner’s Syndrome and enzyme deficiencies
Hormonal Repalcement Therapy - used in post-menopausal women to treat vasomotor symptoms, osteoporosis, cardiovascular disease including lipid profile, vaginal and urogenital atrophy. Unopposed estrogen replacement in postmenopausal women leads to uterine cancer. Hysterectomy can be performed or progestins must be added.
SERMs
Selective Estrogen Receptor Modulators are drugs that exert tissue specific action on estrogen receptors
Different types of Estrogen receptors:
GPCR
Intracellular receptors
ERα
ERβ
The receptors form homo- and heterodimers once bound to ligands: (αα) (ββ) (αβ) The effects seen on transcription depend on which dimers are formed.
