Block 9 - L1 Flashcards
(119 cards)
1
Q
List the major homeostatic functions regulated by the HPA axis.
A
- Metabolic changes
- Growth
- Reproduction and fertility
- Lactation
- Response to stress
- Water homeostasis
2
Q
The anterior pituitary is derived from ___ tissue.
A
Ectodermal
3
Q
Which nuclei in the hypothalamus release hormones that bind to the anterior pituitary? To the posterior pituitary?
A
AP - paraventricular and acurate nuclei
PP - paraventricular and supraoptic nuclei
4
Q
Discuss the steps of the HPA axis for the anterior pituitary.
A
- Neuroendocrine cells in the paraventricular and acurate nuclei synthesize and secrete releasing-hormones (often pulsatile).
- Releasing-hormones are released into the hypothalamic-pituitary portal system and transported to the AP
- Release-hormones act on specific cells of the AP, triggering release of trophic hormones
- Trophic hormones are released into the blood, where they act on peripheral endocrine organs (stimulate end-stage hormone) and target tissues.
5
Q
Discuss the steps of the HPA axis for the posterior pituitary.
A
- Neurosecretory cells in the supraoptic and paraventricular nuclei synthesize ADH and oxytocin.
- ADH and oxytocin are transported down neuronal axons and stored in vesicles in nerve terminals of the PP.
- In response to appropriate neuronal inputs, these hormones are secreted into the bloodstream, to act on their target.
6
Q
What are the 5 cell types in the AP?
A
- Somatotroph
- Lactotroph
- Thyrotroph
- Gonadotroph
- Corticotroph
7
Q
What are the stimulatory hypothalamic factors acting on each AP cell type?
A
- Somatotroph - GHRH and Grehlin
- Lactotroph - TRH
- Thyrotroph - TRH
- Gonadotroph - GnRH (pulsatile)
- Corticotroph - CRH
8
Q
What are the anterior pituitary hormones produced from the 5 cell types in the AP?
A
- Somatotroph - GH
- Lactotroph - PRL
- Thyrotroph - TSH
- Gonadotroph - FSH and LH
- Corticotroph - ACTH
9
Q
What are the inhibitory hypothalamic factors regulating AP hormone secretion?
A
- Somatostatin (inhibits GH and TSH release)
2. Dopamine (tonically inhibits PRL release)
10
Q
What is the target organ and effect of GH?
A
Liver, muscle, bone, and adipose tissue
Production of IGF-1, leading to increased muscle mass and bone growth
11
Q
What is the target organ and effect of PRL?
A
Mammary gland
Lactation
12
Q
What is the target organ and effect of TSH?
A
Thyroid gland
Production of TH
13
Q
What is the target organ and effect of LH and FSH?
A
Gonads (testes and ovaries)
Production of Testosterone, Estrogen, Progesterone
Sperm maturation or follicle development
14
Q
What is the target organ and effect of ACTH?
A
Adrenal cortex
Production of cortisol and aldosterone
15
Q
What are the stimulating factors acting on the hypothalamus in the HPG axis?
A
- Hypoglycemia
- Fasting/starvation
- Puberty
- Exercise
- Stress
- Sleep
- Alpha-adrenergic agonists
16
Q
What are the inhibitory factors acting on the hypothalamus in the HPG axis?
A
- Hyperglycemia
- Obesity
- Old age
- Sleep deprivation
- Poor nutritional status
- Beta-adrenergic agonists
- GH/IGF-1
17
Q
What are the stimulating and inhibitory factors regulating GH directly?
A
Stimulatory - ghrelin (hunger hormone from the stomach)
Inhibitory - somatostatin
18
Q
GH has both direct and indirect effects. What mediates the indirect effects and what is the outcome?
A
IGF-1 (from the liver); leads to linear growth
19
Q
List the organs/systems upon which GH has a direct effect.
A
- Bone
- Muscle
- Liver
- Adipose tissue
- Carbohydrate metabolism
- Heart
- Brain
20
Q
What are the physiological effects of GH on bone?
A
Increased cartilage, bone density, bone growth, and strength
21
Q
What are the physiological effects of GH on muscle?
A
Decreased glucose uptake, increased protein synthesis, increased lean musclemass
22
Q
What are the physiological effects of GH on the liver?
A
Increased gluconeogenesis, glycogenolysis, and blood glucose
23
Q
What are the physiological effects of GH on adipose tissue?
A
Increased lipolysis, decreased lipogenesis, glucose uptake, and adiposity
24
Q
What are the physiological effects of GH on carbohydrate metabolism?
A
Decreased peripheral glucose uptake, increased insulin resistance and blood glucose
25
What are the physiological effects of GH on the heart?
Increased myocardial function
26
What are the physiological effects of GH on the brain?
Neural growth and development, protects the CNS from injury, increased sense of well-being and cognitive function
27
Upon which organs does IGF-1 act?
Bone and muscle (anabolic effects)
+/- brain and heart (?)
28
What causes GH deficiency in children?
Mutations in genes involved in GHRH response, pituitary development, or GH expression
29
What causes GH deficiency in adults?
Pituitary adenoma or effects related to surgery or radiotherapy of a pituitary tumor
30
What are the symptoms of GH deficiency in children?
1. Abnormal postnatal growth
2. Short stature, delayed bone age, low age-adjusted growth velocity
3. Mild adiposity and hypoglycemia
4. Micropenis and delayed puberty (sometimes)
31
What are the symptoms of GH deficiency in adults?
1. Decreased lean muscle mass and increased adiposity
2. Decreased exercise capacity
3. Decreased bone density/increased frequency of bone fractures
4. Fatigue, weakness, poor memory, depression, overall malaise
5. Cardiovascular changes - decreased cardiovascular function and atherogenic lipid profiile
32
How is GH deficiency diagnosed?
Determination of IGF-1 levels (GH has a short half-life and is difficult to measure)
GH stimulation test (use clonidine or glucagon to stimulate GHRH/GH production)
33
What is the treatment for GH deficiency?
Somatropin (recombinant human GH, aka rhuGH)
Administered subQ once a day
34
What is the MOA of somatropin?
Directly activates the GH receptor expressed on target tissue
35
What are the indications of somatropin?
1. Children with GH deficiency
2. Other conditions affecting children associated with short stature (Prader-Willi, Turner, Noonan, chronic renal insufficiency, small-for-gestational age with failure to catch up by age 2, idiopathic short stature)3
3. Adults with GH deficiency in childhood that persists into adulthood
4. Adult onset GH deficiency (controversial - high cost, daily injects, modest benefit)
5. AIDS-associated wasting syndrome
6. Short bowel syndrome w/malabsoprtion
36
Why is somatropin indicated for AIDS-associated wasting syndrome?
GH promotes maintenance of lean muscle mass
37
Why is somatropin indicated for short bowel syndrome?
GH promotes intestinal growth and adaptation
38
How is the clinical efficacy of somatropin monitored in children?
Increased growth
IGF-1 levels within the normal range
Discontinue treatment when linear growth is <2-25.cm/year
39
How is the clinical efficacy of somatropin monitored in adults?
Improved body composition, muscle mass, lipid profile, cardiac function, sense of well-being
40
What are the AE of somatropin in children?
Idiopathic intracranial HTN, increased intraocular pressure, development of insulin resistance (only a slightly increased risk)
41
What are the AE of somatropin in adults?
```
Peripheral edema
Arthralgias
Carpal tunnel syndrome
parathesis
Worsening glucose intolerance
Acute pancreatitis
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42
What are the contraindications of somatropin?
```
Active malignancy
Uncontrolled diabetes
Proliferative retinopathy
Pediatric patients with closed epiphyses
Prader-Willi with severe obesity and/or respiratory obstruction (can lead to death)
```
43
True or false - there is no evidence that GH increases muscle strength or aerobic exercise capacity in normal healthy individuals.
True
44
What is Mecasermin?
Recombinant human IGF-1; used to stimulate IGF-1 dependent responses by direct activation of IGF-1R
45
When is Mecasermin indicated?
In children with impaired growth that are non-responsive to GH (mutations in GHR, in GHR signaling pathway - both seen in Laron dwarfism, development of Ab to GH, IGF-1 gene defects)
46
What are the AE of Mecasermin?
Hypoglycemia due to direct effect on insulin receptors (can address with CHO meal/snack)
Intracranial HTN (possibly due to increased CSF production)
Increased liver enzymes
47
What are the contraindications of Mecasermin?
```
Active neoplasia (growth factor effects of IGF-1)
Children with closed bone epiphyses (will not have an effect)
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48
What is gigantism?
Excessive linear growth, tall stature, and mild to moderate obesity in children; caused by GH excess prior to closure of bone epiphyses
49
What is growth hormone excess in adults?
Acromegaly
50
What are the symptoms of acromegaly?
Insidious onset and slow progression of soft tissue overgrowth, skin thickening, enlargement of the jaw, hands, and feet, coarse facial features (enlargement of nose and tongue), enlargement of visceral orgoans (heart, thyroid, liver, lungs, kidneys), enlarged cartilage (hypertrophic arthropathy of the joints), increased CVD, metabolic symptoms (hyperinsulinemia, insulin resistance, diabetes)
51
What are the increased risks associated with acromegaly?
Colon polyps and colon cancer, and increased mortality
52
What are the effects of somatostatin?
Inhibition of GH (and TSH)
Decreased gastric acid, gastric enzymes, TSH, GI motility, and splanchnic blood flow
Decreased blood flow to the liver, bile duct secretion, and gallbladder contraction
53
What are the somatostatin analogues used to treat GH excess?
Octreotide and Lanreotide
54
What is the MOA of Octreotide/Lanreotide?
Long-lived analogues of somatostatin that bind the receptor and inhibit GH production
55
What are the AE of Octreotide/Lanreotide?
GI effects (N/V, diarrhea, constipation)
Gallstones
Suppresses TSH (have to monitor for hypothyroidism)
Bradycardia
56
What are other indications of Octreotide and Lanreotide?
1. Bleeding esophageal varices (decreases blood flow)
2. Carcinoid syndrome (decreases serotonin release)
3. Gastrinoma and glucagonoma (decreases hormone release)
4. Gi fistulae (decreased GI secretions and motility)
57
What is Pegvisomant?
GH receptor antagonist (attenuates the effects of excess GH in gigantism/acromegaly)
58
What is the MOA of Pegvisomant?
Normally, GH binds to 2 GHR subunits and promotes dimerization. In PegV, one GHR binding site is deleted and the other has an increased affinity for GHR. It binds to a single GHR subunit, blocking GH binding and preventing dimerization.
59
What is the most common cause of hyperprolactinemia?
Prolactin-secreting adenoma
60
What are the effects of increased prolactin?
Excessive milk production and lactation
Antagonizes GnRH release and decreases GnRH sensitivity (leads to reduced FSH and LH - infertility, and reduced E/T synthesis)
61
What are the symptoms of hyperprolactinemia in women?
Hypogonadism
Infertility
Oligomenorrhea/amenorrhea
Galactorrhea
62
What are the symptoms of hyperprolactinemia in men?
```
Hypogonadism
Loss of libido
Erectile dysfunction
Infertility
Gynecomastia
```
63
What is used to treat hyperprolactinemia and what is the outcome?
Dopamine agonists - high affinity for D2 receptor (Bromocriptine and Cabergoline)
Restoration of fertility
Reversal of galactorrhea
64
What are the AE of Bromocriptine/Cabergoline?
```
Nausea, headache
Orthostatic hypotension
Psychiatric symptoms (DA excess)
```
65
Why can Bromocriptine/Cabergoline be used to treat GH excess at high doses?
Due to shared embryology, ~20-30% of somatotrophs express D2 receptors and respond to this treatment
66
Describe the normal HPG (gonadal) axis.
GnRH release (pulsatile) -> FSH and LH release -> Testosterone/Estrogen production (both have negative feedback + E has positive feedback at ovulation)
67
What happens when GnRH is continuously released?
FSH and LH production is inhibited
68
What is the physiological role of the HPG (gonadal) axis?
1. Initiate puberty (GnRH release is low in childhood, increases/becomes pulsatile in adolescence, receptor sensitivity increases) -> elevated FSH/LH, gonadal hormone production, induction of puberty and secondary sexual characteristic development
2. Regulation of adult sexual function (promotes spermatogenesis / oogenesis, follicular development, ovulation and testosterone / estrogen and progesterone synthesis)
69
What are the physiological effects of FSH and LH in males?
1. LH binds to Leydig cells and testosterone is produced
2. Testosterone diffuses to Sertoli cells. FSH binds to Sertoli cells and increases androgen-binding protein
3. ABP and Testosterone and other FSH-induced proteins promote spermatogenesis
70
What are the physiological effects of FSH and LH in females?
1. LH binds to thecal cells, increases androgen synthesis and progesterone
1a. Progesterone causes the endometrium to switch from proliferative to secretory
2. Androgens also diffuse to Granulosa cells. FSH binds, increases aromatase, which catalyzes conversion of androgens to estrogen.
3. Estrogen causes endometrial proliferation/maturation, granulosa cell proliferation, positive and negative regulation of the axis, and ovulation (also increases FSHR and LHR receptors on the granulosa cell)
71
Discuss the role of the HPG (gonadal) axis int the control of ovulation.
1. Pulsatile GnRH induces FSH/LH during the follicular phase - FSH and LH promote growth and maturation of the ovarian follicle.
2. Developing follicles secrete increasing levels of estrogen - estrogen increases LH/FSH receptors (# and responsiveness)
3. Initial low levels of estrogen negatively regulate GnRH/FSH/LH secretion - most follicles degenerate, primary follicle that produces the most estrogen/most responsive to FSH and LH survives
4. Primary follicle rapidly grows and secretes high levels of estrogen - induce GnRH, leading to LH surge
5. Mid-cycle LH surge causes follicle rupture and ovulation
6. Progesterone prepares the endometrium for implanation
72
How does estrogen negatively regulate GnRH/FSH/LH stimulation? Positive regulation?
Negative - Inhibition of Kiss1+ ARC neurons
Positive - activation of Kiss1+ AVPV neurons
73
What are the 4 classes of drugs targeting the HP-gonadal axis?
1. Natural GnRH (no longer available in US)
2. GnRH agonists
3. GnRH antagonists
4. Gonadotropin agonists
74
List the 5 GnRH agonists.
1. Leuprolide
2. Goserlin
3. Buserelin
4. Triptorelin
5. Naferelin
75
What is the MOA of GnRH agonists?
Potently activate the GnRH receptor, which leads to down regulation of GnRH receptor and downstream signaling pathways. There is an initial transient flare-up of FSH/LH and gonadal hormones (first 7-10 days).
76
What are the indications for GnRH agonists?
1. Controlled ovarian stimulation during assisted reproduction procedures
2. Palliative therapy of sex hormone-dependent tumors
3. Suppress inappropriate growth of hormone-dependent tissues (endometriosis, uterine fibroids)
4. Treatment of central precocious puberty caused by early onset of HP-gonadal axis (7-8 y/o)
5. Suppression of endogenous puberty in adolescents with gender dysphoria
77
What is the function of GnRH agonists in ovarian stimulation during assisted reproduction procedures?
Suppress endogenous LH surge and prevent premature luteinization of the ovarian follicle
78
What are the AE of GnRH agonists?
Generally well-tolerated
Initial flare-up - initial worsening of symptoms
Long term - hot flashes, decreased bone density, vaginal dryness/atrophy, ED
79
What are the contraindications of GnRH agonists?
Pregnancy
80
List the GnRH antagonists.
Ganirelix, Cetrorelix, Degarelix
81
What is the MOA of GnRH antagonists?
Competitive inhibition of the binding of endogenous GnRH to its receptor leading to suppression of production of endogenous gonadotropins
82
Compare GnRH agonists and antagonists.
Antagonists have an immediate effect and NO transient flare-up of gonadotropins; there is more complete inhibition and it is more readily reversible
83
What are the indications of GnRH antagonists?
1. Controlled ovarian stimulation during assisted reproduction producedures (Ganirelix/Cetrorelix)
2. Treatment of advanced prostate cancer (Degarelix - decrease in androgen production decreases growth of prostate cancer)
84
What are the AE of GnRH antagonists?
Side effects associated with gonadal hormone deprivation
85
What are the contraindications of GnRH antagonists?
Pregnancy
86
What is human chorionic gonadotropin?
Hormone produced by the trophoblast/placenta following fertilization; signals to the corpus luteum that pregnancy has occurred, promotes E and P synthesis to maintain the endometrium for implantation, structurally similar to LH, binds and activates LH receptor
87
Discuss the composition of FSH, LH, and HCG.
All are composed of alpha-beta heterodimers (share identical alpha chains); beta chain determines binding - LH and HCG share homologous beta chains and bind to the same receptor
88
What are the available gonadotropin formulations?
1. Menotropins (hMG) - combined human FSH and LH
2. FSH (uFSH - urofollitropin, rFSH - recombinant, shorter half life, lower potency than uFSH)
3. LH (no longer commercially available in the US)
4. HCG (rHCG or HCG)
89
What are the clinical uses of gonadotropins?
1. Treatment of female infertility in anovulatory women
2. Ovarian hyperstimulation in assisted reproduction procedures
3. Treatment of male infertility in men with hypogonadotropic hypogonadism
90
When can gonadotropins be used to treat female infertility in anovulatory women?
1. Hypogonadotropic hypogonadism secondary to hypothalamic/pituitary dysfunction
2. Hypothalamic amenorrhea due to excessive exercise or low body weight
3. Women with PCOS who have failed to ovulate with other treatments
91
What is the goal of gonadotropin use in infertile anovulatory women?
To induce the formation and ovulation of a single dominant follicle to allow for pregnancy
92
Describe the treatment regimen with gonadotropins in female infertility/anovulatory women.
1. Gonadotropins (FSH or hMG) during pre-peak to promote follicle development (increasing dose)
2. Detect <2 follicles >17 mm with ultrasound
3. Administer HCG to trigger LH receptors/promote ovulation
4. Intercourse or artificial insemination within 36 hours
93
Describe the treatment regimen with gonadotropins in assisted reproduction procedures.
1. High doses of gonadotropins (rFSH or hMG) administered to stimulate maturation of multiple ovarian follicles
2. GnRH agonists or antagonists are administered in parallel to suppress endogenous LH surge and prevent ovulation/premature luteinization of the ovarian follicles
3. Monitor production of healthy follicles by ultrasound
4. Trigger ovulation by HCG, harvest eggs 36 hours later
5. Oocytes are fertilized in vitro and transferred to a prepared uterus for implantation
94
Compare ovarian hyperstimulation protocols using agonists vs. antagonists.
Agonist long protocol: give GnRH agonist during luteal phase to suppress LH surge/ovulation through to ovulation vs. Antagonist short protocol: give GnRH antagonist midway through pre-peak
95
What are the symptoms of hypogonadotropic hypogonadism in males?
Delayed or absent puberty
Under-developed testes
Infertility
96
How are gonadotropins used to treat male infertility in men with hypogonadotropic hypogonadism?
1. Androgen therapy provided initially to stimulate secondary sexual characteristic development.
2. HCG injections 3x/week for 8-12 weeks to stimulate LH responses and induce T synthesis (monitor levels)
3. Lower HCG dose and provide FSH treatment 3x/week (hMG or rFSH)
4. Monitor sperm count
97
What are AE of gonadotropins in women?
1. Multiple pregnancies
2. Ovarian hyperstimulation syndrome (OHSS) - potentially life-threatening, results from ovarian secretion of factors that promote vascular permeability
98
What is seen in OHSS?
Rapid accumulation of fluid in the peritoneal cavity, thorax, and pericardium, hypovolemia and electrolyte abnormalities, ARDS, ovarian enlargement, ascites, hepatic dysfunction, and thromboembolic events
99
What are AE of gonadotropins in men?
Gynecomastia due to elevated estrogen synthesis
100
What is oxytocin?
Nonapeptide that stimulates the frequency and force of uterine contractions and plays a role in milk ejection from the breast
101
What is the MOA of oxytocin?
Acts through G-protein coupled receptors on uterine SMC and breast myoepithelium
102
What are the indications of oxytocin?
1. Induce labor (IV infusion) under conditions requiring expedited vaginal delivery (uncontrolled maternal diabetes, worsening pre-eclampsia, intrauterine infection, ruptured membrane, protracted labor)
2. Treat uterine atony (failure to contract after delivery) - compressed blood vessels to prevent hemorrhage
103
What are the AE of oxytocin?
Rare with correct use
Excessive stimulation of the uterus prior to delivery can cause fetal distress, placental abruption, or uterine rupture
High concentrations can activate vasopressin receptors leading to excessive fluid retention, hyponatremia, heart failure, seizures, and death
104
Describe the role of ADH on the cardiovascular system.
Stimulates V1 vasopressin receptors on peripheral arterioles, promotes vasoconstriction, increases arterial BP
105
Describe the role of ADH on the kidney.
Stimulates V2 vasopressin receptors in the DCT and CD, induces expression of water channels, and increases water reabsorption from the nephron
106
How is ADH release triggered?
Reduced plasma volume activates low pressure baroreceptors in veins OR increased plasma osmolality activates osmoreceptors
107
What is the main ADH agonist?
Desmopressin
108
What is the MOA of Desmopressin?
Selective agonist of the V2 receptor, promotes water reabsorption in the kidney; also activates V2 on endothelial cells, promote release of VW factor and blood coagulation
109
What are the indications of Desmopressin?
1. Neurogenic diabetes insipidus (ADH secretion deficiency)
2. Nocturnal enuresis
3. Minor bleeding in patients with mild hemophilia and VW disease
110
What are the AE of Desmopressin?
Headache, hyponatremia, acute thrombotic events (rare)
111
What is the MOA of vasopressin?
Synthetic full agonist of V1 and V2 receptors, promotes vasoconstriction and BP
112
What is the indication of Vasopressin?
Second line agent in treatment of refractory vasodilatory shock (unresponsive to EPI)
113
What are the AE of Vasopressin?
CV (Afib, low CO, arrhythmia) and hyponatremia
114
What are the two vasopressin receptor antagonists?
Conivaptan and Tolvaptan
115
What is the MOA of Conivaptan?
Antagonist of both V1 and V2, blocks ADH, promotes increased water excretion and raises serum Na+
116
What are the indications of Conivaptan?
Treatment of hypervolemic hyponatremia associated with SIADH
117
What is hte MOA of Tolvaptan?
Selective antagonist of ADH at V2, promotes increased water excretion and raises serum Na+
118
What are the indications of Tolvaptan?
Treatment of hypervolemic hyponatremia associated with SIADH
119
What are the AE of Conivaptan and Tolvaptan?
Conivaptan - none
Tolvaptan - hepatotoxicity (contra in liver disease), osmotic demylination syndrome (overly rapid correction of hyponatremia)
