Three Flashcards
(21 cards)
What are the hormone secreting cells of the anterior pituitary gland? What hormone do they produce? What percent of cells in the anterior pituitary does each cell type represent?
Table 1. Hormone Secreting Cells of the Anterior Pituitary Gland
Cell type Hormone Content % of total cell number
Somatotroph Growth Hormone (GH) 50%
Lactotroph Prolactin (PRL) 10-25%
Corticotroph Pro-opiomelanocortins 15-20%
(ACTH, lipotropins, endorphins)
Thyrotroph Thyroid-stimulating Hormone (TSH) <10%
Gonadotrophs Luteinizing Hormone (LH) 10-15%
Follicle Stimulating Hormone (FSH)
What kind of hormone is growth hormone? What is its timing of release? Describe (an overview) the different regulatory mechanisms and feedback systems of growth hormone?
GH is a protein hormone (191 amino acids) that circulates mainly free in plasma, [t1/2 = 20 min, 2-4 ng/ml in adults (double that in adolescents).
Daily surges=Late postprandial and at onset of sleep
The hypothalamus produces GHRH which causes GH to be released. It also produces SRIF (somatostatin) which inhibitis GH release. They travel in the portal vessels. The Ant. pituitary releases GH into the general circulation. It acts at various target tissues but especially at the liver, where it causes IGF to be released. IGF acts at various sites. It binds to IGF-BPs and then inhibits release of GH and GHRH.
What are 7 actions of GH?
- decrease blood amino acid levels
- decrease blood urea nitrogen (positive nitrogen balance)
- increase DNA, RNA, and protein synthesis
- decrease respiratory quotient due to increased fat oxidation
- somatic growth
- growth and calcification of cartilage
- insulin resistance at high concentrations
What are 8 stimulatory factors for GH? What are two hypersecretory conditions?
Stimulatory factors:
- exercise
- arginine
- insulin-induced hypoglycemia
- stress
- stages III and IV of sleep
- Ghrelin
- dopamine
- alpha adrenergics
Hypersecretion states
- gigantism (before puberty)
- acromegaly (after puberty)
What are 4 inhibitory factors of GH? What are two hyposecretion states?
Inhibitory factors:
- REM sleep
- GH and IGFs
- beta adrenergics
- hyperglycemia
Hyposecretion states:
- aging (physiologic)
- dwarfism (symmetric)
Describe the mechanism of GH.
Mechanism of GH action:
- Receptors present on liver, muscle, fibroblasts, adipocytes and lymphocytes.
- Direct stimulation of amino acid uptake.
- Increases blood glucose levels (via decrease on glucose utilization and decreased sensitivity to insulin’s action to lower blood glucose)
- Stimulate IGF production and release (hepatocytes).
What are the two types of IGF? Where are they synthesized? Aside from IGF, what else does GH binding induce? What are the actions of IGF? What do deficiencies of the two types of IGF lead to?
The Somatomedin Hypothesis (Somatomedin = IGF = sulfation factor)
- IGF-1 and IGF-2 production induced by GH (primarily in liver but also in bone, brain, prostate, mammary tissues)
- IGF-binding proteins and acid labile substance production also induced by GH
- IGF actions
a. Increased DNA synthesis and cell division (fibroblasts, liver, muscle)
b. Increased sulfate incorporation into proteoglycans (chondrocytes)
c. Mimic insulin actions (increased glucose oxidation, increased lipid and glycogen synthesis), IGF resembles insulin and can bind the insulin receptor
d. IGF-2 deficiency = intrauterine growth retardation
e. IGF-1 deficiency = intrauterine growth deficiency, postnatal growth retardation
How is GHRH used clinically?
GHRH (Sermorelin, or truncated GH releasing peptides such as Hexarelin)
- Administration: i.v., s.c., intranasal (relative potency 300, 10, 1 respectively); GHRH given iv in single bolus of 1 microgram/kg and plasma GH measured at 0-15-30-45-60 min; Hexarelin given at same dose)
- Used to stimulate GH release (diagnostic testing)
How is somatostatin used clinically? What are some adverse effects?
Somatostatin (SRIF-14 amino acids, or the prohormone which is 28 amino acids)
- SRIF-14 or SRIF-28 rapidly cleared from body (kidney) so of little therapeutic or diagnostic value
- Octreotide (somatostatin analog) is 45 X more potent that SRIF to inhibit GH secretion due to longer half-life in plasma (80 vs 2.5 min)
- Adverse effects: nausea with cramping, occasional vomiting, flatulence and steatorrhea.
What is GH therapy? What are the effects? When is it useed? What limits its use?
GH therapy:
- Recombinant protein (Somatotropin, Somatrem) has longer half life than endogenous GH, peak levels occurring 2-4 hrs after administration (endogenous GH has a half life of only 20 min)
- Effects
a. Impaired glucose uptake and increased lipolysis
b. Increased linear growth before epiphyseal plate closure
c. Positive metabolic effects - Use:
a. GH deficiency (short stature: growth rate of less than 4 cm per year and an absence of GH response to two stimulatory regimens)
b. Not effective in Laron dwarfs (who lack IGF-1)
c. In short stature children, hrGH given three times per week, i.m., doses up to 0.1 mg/kg. Looking for an increase in growth velocity of at least 2 cm per year. Cost ranges from $10,000-$30,000 per year.
d. Risks: too rapid growth can lead to slipped capital femoral epiphyseal plate, with limping and leg pain; slight increased incidence in leukemia, hypothyroidism and diabetes.
What kind of hormone is Prolactin? What is its timing of release? Describe (an overview) the different regulatory mechanisms and feedback systems of growth hormone?
PRL is a protein hormone (198 a.a.) that circulates mainly free in plasma, t1/2 = 20-30 min, 10 ng/ml in nonpregnant/nonlactating females (slightly lower in males and adolescents)]. It is cleared in liver and kidney. The high catabolic clearance rate indicates very high synthetic capability of the lactotroph (about 0.2 mg/day). Pulsatile secretion occurs, with a minor peak (circadian = daily) in early morning.
Dopamine from the hypothalamus inhibits it. That is the main regulation though TRH/VIP/OT from hypothalamus will stimulate it. These are released into portal system. Ant. Pituitary release prolactin into the general circulation. There are many receptors that it hits. Estrogens stimulate the release of prolactin from pituit. and inhibit release of dopam. from hypoth. Neural afferents will also inhibit release of DA from Hypothal.
What are five actions of prolactin? What is its mechanism of action?
Actions of PRL:
- Mammary gland development (ductal and lobuloalveolar growth)
- Milk production in properly primed breast
- Immune modulation
- Ovarian and adrenal effects (stimulates 20-22 desmolase, a.k.a. cholesterol side chain cleavage
enzyme) - Stimulation of maternal behaviors
Mechanisms of action:
- Cell surface, tyrosine-kinase linked receptors and intranuclear receptors (like those for the steroid hormones)
- Promitogenic actions related to both signaling pathways
What are 5 stimulatory factors for prolactin? Inhibitory factors?
Stimulatory factors:
- Stress
- Estrogen
- Hypothermia
- Vaginal or nipple stimulation
- Numerous neuropeptides (TRH, OT, VIP)
Inhibitory factor: Dopamine (*This is the major controller of PRL secretion.)
What are 7 things that lead to hypersecretion states of Prolactin? What are 4 potential consequences of hypersecretion?
Hypersecretion states:
- PRL-secreting tumors
- Pituitary stalk section
- Hypothyroidism
- Renal failure
- Oral contraceptive use
- Estrogen therapy
- Psychotropic drugs (phenothiazines, reserpine)
Potential consequences of hypersecretion:
- Infertility/menstrual irregularity
- Impotence
- Galactorrhea
- Visual field disturbances
What are 3 treatments of hyperprolactinemia?
Treatment of hyperprolactinemia:
- Transphenoidal surgery
- Bromocriptene therapy (and ergot derivative that activates the Dopamine D-2 receptor on the
lactotroph, inhibiting PRL production and release). Also used to suppress GH secretion in
acromegalics (paradoxic effect).
- Cabergoline (an ergot derivative) taken 2X/week (0.5-1.0 mg, oral or vaginal).
What are the three locations which make proopiomelanocortin? What hormones are made in each location? What is the target tissue for the hormones made?
The anterior lobe: ACTH and betalipotropin (Adrenal)
Intermediate lobe: Alpha MSH (Melanocytes?)
Brain (hypothalamus): ACTH and Alpha MSH, beta endorphin (brain)
What kind of hormone is ACTH? What is its timing of release? Describe (an overview) the different regulatory mechanisms and feedback systems of growth hormone?
ACTH circulates free in plasma with a half-life of 20 min. Levels under unstressed conditions are low
(about 10 pg/ml) and secretion is pulsatile (20 min intervals). Peak levels are present between 2:00 and
8:00 a.m. ACTH is cleared in kidney and liver.
Hypothalamus releases CRH which stimulates ACTH release from the ant. pituitary (actually stimulates POMC). ACTH reaches the adrenal glands causing it to release Cortisol.
What are the actions of ACTH? What are its mechanisms of action?
Actions of ACTH:
- Stimulates 20,22 desmolase and cholesterol esterase activities in adrenal, resulting in increased levels of glucocorticoids, mineralocorticoids, and adrenal androgens.
- At high levels causes increased skin pigmentation
Mechanism of ACTH action:
- Membrane bound ACTH receptor linked to adenylyl cyclase, increasing cAMP formation
- Initial increase in cortisol secretion due to increased adrenal blood flow and stimulation of conversion of cholesterol to pregnenolone
- Prolonged effects (via increased synthesis of rate limiting enzymes in adrenal steroidogenesis)
What are the stimulatory factors for ACTH? Inhibitory factors? Describe the regulation of CRH?
Stimulatory factors:
- Stress
- Hypothermia
- Pyrogens
- Hypoglycemia
- Epinephrine, CRH, AVP
Inhibitory factors: Cortisol!!!!!
Neuroendocrine regulation:
- Primarily stimulatory due to CRH (corticotropin releasing hormone, 41 amino acids)
- CRH released into vicinity of portal vessels by ACH, 5-HT, interleukins and other cytokines
- GABA and cortisol inhibit CRH release
- AVP can also act on the corticotroph to stimulate ACTH release
What is the hypersecretion of ACTH? Hyposecretion?
Hypersecretion state: Cushing’s Syndrome (see lecture on adrenal gland)
Hyposecretion state: Addison’s Disease (see lecture on adrenal gland)
How can ACTH be used clinically? Side effects?
- Diagnosis of adrenal insufficiency. Cosyntropin or generic ACTH given i.v. or i.m. Cosyntropin (0.25 mg i.v. or i.m.) administration should be followed 30-60 minutes later by a rise of plasma cortisol in excess of 18 microgram/deciliter.
- Therapeutic use: No advantage over glucocorticoids.
- Side effects: same as those with glucocorticoids when used in therapeutic doses.
