Lecture 4: Receptors, Signaling, Hypothalamic, and Pituitary Hormones Flashcards
1
Q
Which 2 hormones bind to cytokine receptor-linked kinases and what are the effectors and pathway used for signaling?
A
- GH and prolactin
- JAK and tyrosine kinases
- Pathways = STAT, MAPK, PI 3-kinase, IRS-1, IRS-2
2
Q
What type of receptor does TGF-β bind to and what is the signaling pathway?
A
Serine kinase —> Smads
3
Q
List the 9 hormones that binds Gαs and result in stimulation of cAMP signaling pathway.
A
- FSH, LH, ACTH, TSH
- CRH, GHRH and glucagon
- PTH and PTHrP
4
Q
Which hormone acts through the Gαi receptor and results in inhibition of cAMP production and activation of K+/Ca2+ channels?
A
Somatostatin
5
Q
Which 2 hormones act through the Gαq receptor and stimulate the PLC, DAG, IP3, PKC, voltage-gated Ca2+ channel pathway of signaling?
A
TRH and GnRH
6
Q
Which receptor does insulin bind, what are the effectors of the pathway and results in activation of waht signaling pathway?
A
- Receptor tyrosine kinase
- Effectors = tyrosine kinases, IRS-1 to IRS-4
- Signaling via RAS/MAPK and PI 3-kinase
7
Q
Which kinase-linked receptor lacks intrinsic enzyme activity and when occupied associates w/ and activates cytosolic kinases?
A
Cytokine receptors i.e., receptors for GH and PRL
8
Q
How do serine/threonine kinase receptors differ from RTKs?
A
Similar in structure to RTKs but phosphorylate serine and/or threonine residues (instead of tyrosine)
9
Q
Briefly describe the steps of the kinase signaling cascade upon ligand binding.
A
- Ligand binds kinase-linked receptor —> receptor dimerization
- Close assoc. of 2 intracellular kinase domains allows autophosphorylation of intracellular tyrosine residues
- End result of cascase is to activate or inhibit, via phosphorylation, a variety of TF’s that induce/suppress genes
10
Q
What is the role of the β and γ subunits of GPCRs?
A
- Form a dimer and remain together as βγ complex
- βγ confers both membrane locazlization of the G-protein and directs signaling such as activation of ion channels and binding sites for G-protein receptor kinases
11
Q
What is the role of adenylyl cyclase?
A
Enzyme responsible for converting ATP —> cAMP
12
Q
What is the role of Phospholipase C?
A
Enzymes responsible for PIP2 —-> DAG and IP3 formation
13
Q
What is the role of the Rho A/Rho kinase system as a target of GPCRs?
A
Controls activity of many signaling pathways influencing cell growth and proliferation, smooth m. contraction, etc.
14
Q
List 5 steroids which bind classic steroid nuclear recptors.
A
- Glucocorticoids (GR)
- Mineralocorticoids (MR)
- Estrogen (ER)
- Progesterone (PR)
- Androgens (AR)
15
Q
List 7 ligands for the nuclear receptors which are not classified as classic steroid nuclear receptors.
A
- Retinoids
- Thyroid hormone
- Vitamin D
- Xenobiotics
- Androstane
- Lipids and Fatty Acids
16
Q
What is the function of the DNA binding domain (DBD) of a nuclear receptor?
A
- Highly conserved and functions to recognize and bind specific sequences of DNA called HREs upstream of target gene
- Also plays a role in receptor dimerization
17
Q
What is the function of the C-terminal ligand-binding domain (LBD) of a nuclear receptor?
A
- Selectively binds to agonists or antagonists and confers ligand-dependent activation
- Ligand binds –> LBD undergoes conformational change = recruitment of coactivators or corepressors for activation or repression of gene transcription
18
Q
What is responsible for the inhibition of FSH, LH, and GnRH is both women and men?
A
- Women = estrogen and progesterone
- Men = androgens
19
Q
What hormone provides negative feedback for both ACTH and CRH?
A
Cortisol
20
Q
Which hormones provide negative feedback to inhibit GH production and release?
A
- Somatotrpin release-inhibiting factor (SRIF) = Somatostatin inhibits production
- GH and IGF-1 provide neg. feedback
21
Q
Which kind of dopamine receptor is responsible for the inhibition of prolactin and what specific type of GPCR is it?
A
- D2 dopamine receptor
- Dopamine receptor coupled to Gi
22
Q
What is the effect of disruption of the pituitary stalk and the hypothalamohypophysial portal vessesl on anterior pituitary hormones?
A
- FSH, LH, ACTH, TSH, and GH will ↓↓↓
- Prolactin will ↑↑↑
23
Q
How do the effects of endogenous release of GnRH differ from that of a continous infusion?
A
- Endogenous = pulsatile manner —> stimulates LH and FSH
- Continous GnRH and its analogs –> inhibit LH and FSH
24
Q
What is the recombinant human form of GH (rhGH) used clinically and is identical to the predominant native form of human GH?
A
Somatropin
25
How does the half-life of endogenous GH differ from that of active blood levels of rhGH (somatropin)?
- **Endogenous GH** = **20-25 minute** half-life
- **Somatropin** (**rhGH**) = active blood levels for **36 hours**
26
What is the effect of GH (somatotropins) on CYPs?
**Induction** of P450s
27
What is the effect of GH on muscle and in lipid cells (anabolic/catabolic)?
- **Anabolic** effect on **muscle cells**
- **Catabolic** effect on **lipid cells**
28
What is the effect of GH vs. IGF-1 on insulin sensitivity?
- **GH** ↓ **insulin sensitivity** (causes mild **hyperinsulinemia**) and **hyper**glycemia
- **IGF-1** acts thru IGF-1 and insulin receptors to **lower** serum glucose and **reduce** insulin
\***GH** and **IGF-1** have **opposite effects** on **insulin sensitivity**\*
29
Other than using GH as an agent for tx of deficiency in adults or short stature in children, what are a couple other clinical uses?
- **Wasting** in pt's with **AIDS**
- Pt's w/ **short bowel syndrome** who are **dependent** on **total parenteral nutrition**
30
How well tolerated is GH treatment in children and what are 6 of the associated AE's?
- **Well tolerated** in **children**; rare AE's include:
- **Intracranial HTN** (vision changes, HA, N/V)
- **Scoliosis**
- **Otitis media** in pt's with **Turner Syndrome**
- **Hypothyroidism**
- **Pancreatitis**
- **Gynecosmastia**
31
What are 4 AE's which may be seen in adults treated with GH (somatropin)?
- **Peripheral edema**
- **Myalgias**
- **Arthralgias**
- **Carpal tunnel syndrome**
32
Treatment with GH is contraindicated in which patients?
Pt's w/ **known malignancy**
33
What is the IGF-1 agonist (rhIGF-1) called?
**Mecasermin** = (rh)IGF-1
34
What is the IGF-1 agonist (rhIGF-1), Mecasermin, used for clinically?
- Tx of **growth failure** and **short stature** in **children** w/ severe **primary IGF-1 deficiency**, which is not responsive to exogenous GH
- Children with **GH gene deletions** who have developed **neutralizing antibodies** to **recombinant GH therapy**
- **Laron syndrome** (GH insensitivity)
35
What is special about mecasermin rinfabate?
- **Combo** of **rhIGF-1** and **insulin-like GF binding protein-3 (****IGFBP-3)**
- **IGFBP-3** serves to **prolong** the action of **IGF-1** in the body
36
How is the IGF-1 agonist (rhIGF-1), Mecasermin, administered and what is the most common AE and how can this be avoided?
- **Subcutaneous** administration
- **Hypoglycemia** is most common, so **eating 20 mins** before administration is recommended
37
What are 2 somatostatin (SST) analogs?
- Octre**otide**
- Lanre**otide**
38
How likely are somatostatin analogs used in tx of acromegaly to assure biochemical control of disease (improving clinical sx's and tumor shrinkage)?
**Only** in a **subset of patients**
39
How much more potent is octreotide than SST in inhibiting GH release and reducing insulin secretion?
- **45x** more potent in inhibiting **GH release**
- **2x** as potent as SST in reducing insulin secretion (hyperglycemia is **rare**)
40
How is octreotide administered; what is the half-life?
- **Subcutaneous** administration
- Half-life = **80 minutes**
41
Which sx's associated with hormone secreting tumors do the SST analogs, octreotide and lanreotide, reduce?
- **Acromegaly\*\*\*\***
- **Carcinoid syndrome**
- **Gastrinoma + glucagonoma** + **VIPoma (WDHA syndrome)**
- **Nesidioblastosis** (aka hyperinsulinemic hypoglycemia )
- **Diabetic diarrhea**
42
What are some of the GI and cardiac AE's associated with SST analogs, Octreotide and Lanreotide?
- **Diarrhea**, nausea, and abdominal pain (**50% of pt's**)
- **GB sludge** and **gallstones\*\***, due to ↓ GB contraction and bile secretion
- **Cardiac** = **brady**cardia + **conduction disturbances**
43
Pt's taking the SST analogs, Octreotide and Lanreotide, are at risk for what vitamin deficiency?
Vitamin **B12**
44
What is the GH receptor antagonist and its MOA?
- **Pegvisomant**
- A **PEG** derivative of mutant GH that binds to GH recetor and allows receptor to **dimerize**, but does **NOT** activate JAK-STAT pathway or stimulate IGF-1
45
How do octreotdie and lanreotide differ from pegvisomant?
- **Octreotide** and **lanreotide** are somatostatin analogs which **inhibit** GH release; also inhibit release of GHRH and TRH
- **Pegvisomant** works by **blocking** the GH **receptor**
46
What are the 3 drugs used in tx of acromegaly?
- **SST analogs**: octreotide + lanreotide
- **GH receptor antagonist**: pegvisomant
47
What is the purified human FSH extracted from urine of postmenopausal women called?
**Urofollitropin** (**uFSH**)
48
What are the 2 recombinant forms of FSH?
**Follitropin alfa** and **beta** (**rFSH**)
49
How does the half-life and estrogen stimulation ability of rFSH compare to uFSH?
**rFSH** preparations have a **shorter half-life**, but stimulate estrogen secretion **equal** to or **greater** than uFSH (rFSH = very expensive)
50
Which type of FSH preparation is used for ovulation induction in patients who previously received pituitary suppression?
**Urofollitropin** (**uFSH**)
51
Which type of FSH preparation is used for ovulation induction in patients in whom the cause of infertility is functional ad not caused by primary ovarian failure?
**Follitropin alfa** and **beta** (**rFSH alfa** and **beta**)
52
Which FSH preparation is use for spermatogenesis induction?
**rFSH alfa = follitropin alfa**
53
uFSH + rFSH alfa and beta can be used with assisted reproductive technologies (ART) for what?
Development of multiple follicles
54
What is the recombinant form of human LH called and what is it used for clinically?
- **Lutropin alfa**
- **Only** in combo w/ **follitropin alfa** for stimulation of **follicular development** in **infertile women** w/ **profound LH deficiency**
55
What is the recombinant form of hCG called?
**Choriogonadotropin alfa (rhCG)**
56
What are the 3 clinical uses for hCG?
- **Induce ovulation** and **pregnancy** in anovulatory, infertile females
- Tx of **hypogonadotropic hypogonadism**
- **Spermatogenesis** induction with **follitropin alfa**
57
What are the 2 clinical uses for rhCG?
- **Induces ovulation** in infertile females who have been **pretreated** w/ follicle stimulating hormones
- **Induces ovulation** and **pregnancy** in infertile females when the cause of infertility is **functional**
58
How are gonadotropin preparations (FSH, LH, and hCG) administered?
**SQ** or **IM** injection
59
What are the AE's associated with gonadotropin treatments?
- **Overstimulation of the ovaries** during **ovulation induction** leading to uncomplicated enlargement that usually resolves
- **Ovarian hyperstimulation syndrome**: ovarian enlargement + ascites + hydrothorax + hypovolemia; sometimes shock
- **Risk of multiple pregnancies**: ↑ risk for gestational diabetes, preeclampsia and preterm labor
60
What is the prototypical GnRH analog called and how is it administered?
- **Leuprolide**
- **Pulsatile IV** administration every **1-4 hours** stimulates FSH and LH secretion
61
Explain the biphasic response which occurs with continous administration of the GnRH analogs?
- **First 7-10 days** = **agonist effect** results in ↑ concentrations of gonadal hormones (referred to as **flare**)
- **\>10 days** = **inhibitory action** causing drop in concentration of gonadotropins and gonadal steroids (due to receptor down-regulation and changes in the signaling pathways)
62
Other than the prototypical GnRH analog, Leuprolide, what is the suffix of the other drugs in this class?
- **-relin**
- Gose**relin** + hist**relin** + nafa**relin** + tripto**relin** and gonado**relin**
63
What are 3 clinical situations in which GnRH analogs (i.e., Leuprolide) are useful for **stimulation** of gonadotropin production?
- **Female infertility**
- **Male inferitility**
- **Diagnosis** of **LH responsiveness**
64
What are 5 clinical situations in which GnRH analogs (i.e., Leuprolide) are useful for **suppression** of gonadotropin production?
- **Controlled ovarian hyperstimulation** (i.e., to prevent premature ovulation by endogenous LH in IVF patients)
- **Endometriosis**
- **Uterine leiomyomata** (uterine fibroids)
- **Prostate cancer**
- **Central precocious puberty**
65
Continous treatment of women with a GnRH analog causes what common sx's?
Typical **menopause sx's**, including **hot flushes, sweats**, and **HA**
66
In addition to sx's of menopause, what are 6 other AE's associated with GnRH analogs in women; which is specific to long-term use?
- **Depression**
- **Diminshed libido**
- **Generalized pain**
- **Vaginal dryness**
- **Breast atrophy**
- ↓ **bone density** and **osteoporosis** w/ long-term use
67
What are 2 contraindications for the use of GnRH analogs?
- **Pregnancy**
- **Breast feeding**
68
What are 7 AE's associated with continous GnRH analog secretion in males?
- **Hot flushes** + **sweats**
- **Edema**
- **Gynecomastia**
- ↓ **libido**
- ↓ **hematocrit**
- ↓ **bone density**
69
What are the 2 GnRH receptor antagonists indicated for controlled ovarian hyperstimualtion procedures (i.e., to prevent premature ovulation)?
- Gani**relix**
- Cetro**relix**
70
Which 2 GnRH receptor antagonists are used to treat advanced prostate cancer?
- Aba**relix**
- Dega**relix**
71
Why are GnRH antagoists (abarelix and degarelix) preferred over GnRH agonists (leuprolide) in the treatment of advanced prostate cancer?
- GnRH antagonists reduce gonadotropin and androgen concentrations significantly **more rapidly** (**immediately**)
- **Avoids** the **testosterone surge**
72
What are the dopamine D2 receptor agonists used to treat hyperprolactinemia?
**Bromocriptine** and **cabergoline**
73
Other than hyperprolactinemia, what else is the D2 receptor agonist, bromocriptine, used for for?
Tx **Acromegaly** and **Parkinsons disease**
74
How are the D2 receptor agonists, bromocriptine and cabergoline, formulated for administration?
**Oral** or **vaginal suppository**
75
Which D2 receptor agonist, bromocriptine or cabergoline, has the longest half-life?
**Cabergoline** has **65 hour** half-life vs. **15 hours** for **bromocriptine**
76
Why are dopamine agonists not recommended to suppress postpartum lactation?
Due to **increased incidence** of **stroke** or **coronary thrombosis**
77
What are the most common, rare, and long-term tx AE's associated with D2 receptor agonists, bromocriptine and cabergoline?
- **_Most common_** = **Nausea**, **HA**, **light-headedness**, **fatigue,** and **orthostatic hypotension**
- **Psychiatric manifestations** occur occasionally and can take months to resolve
- **Pulmonary infiltrates** may occur w/ **chronic high-dose** therapy
78
What is the recommendation for pregnant pt's w/ macroadenomas vs. microadenomas in regards to continuing therapy with D2 receptor agonists, bromocriptine and cabergoline?
- **Pregnant** w/ **MACRO****adenoma**can**continue** therapy
- **Pregnant** w/ **mico**adenoma should **discontinue** therapy because microadenoma growth during pregnancy is rare
79
Why is a women given IV oxytocin before labor and IM injection after?
- **IV** for **initiation** and **augmentation** of **labor**
- **IM** for control of **postpartum bleeding**
80
How does desmopressin differ from vasopressin in terms of receptor activity and half-life?
- **Desmopressin** is **longer-acting** (half life = **1.5-2 hours**) and is **more selective** for **V2 receptor** (minimal V1 receptor activity)
- **Vasopressin** has a **half-life** of **15 minutes** and **activates** both **V1** receptors (**vasoconstriction**) and **V2** receptors of renal tubule cells
81
Extrarenal vasopressin (V2) receptors regulate the release of which coagulation factors; why is this significant?
- **Factor VIII** and **von Willebrand factor**
- **Desmopressin** is used for tx of **coagulopathy** in **hemophilia A** and **von Willebrand disease**
82
What are the tx's of choice for central DI; which is the preferred agent?
- **Desmopressin** and **vasopressin**
- **Desmopressin** is **preferred** due to **selectivity** of **V2 receptor**
83
What are the AE's associated with desmopressin and vasopressin?
- **HA**
- **Nausea**
- **Abdominal cramps**
- **Agitation**
- **Allergic rxn** are rare
84
What occurs in OD with desmopressin and vasopressin?
**HYPOnatremia** and **seizure**
85
Vasopressin should be used with caution in which patients?
Pt's with **coronary artery disease** due to **vasoconstriction**
86
What are the 2 vasopressin (ADH) antagonists and how do they differ in their MOA?
- **Tolvaptan** is **selective** for **V2 receptors**
- **Conivaptan** is **nonselective** and **blocks V1** and **V2** **receptors**
87
Vasopressin antagonists, Conivaptan and Tolvaptan, are utilized in the tx of what?
**Euvolemic** and **hypervolemic HYPOnatremia** (i.e., CHF and SIADH)
88
Conivaptan and tolvaptan (ADH-receptor antagonists) are metabolized by which CYP?
**CYP3A4**
89
Which ADH-receptor antagonist was found to reduce EF, ↓ body weight and improve dyspnea in pt's with CHF?
Tolvaptan
90
Bromocriptine works by inhibiting what?
**Prolactin** and **GH**
91
List 5 dopamine D2 receptor antagonists which can be used to increase prolactin levels?
- Domperidone
- Metoclopramide
- Haloperidol
- Risperidone
- Sulpiride
