Final exam 1

Mechanism of Bromocriptine

Dopamine agonist —> stops cAMP and decreases transcription of prolactin

Use of bromocriptine

• Used for hyperprolactinemia

• Acromegaly

• Small GH producing tumors

How does prolactin modulate GnRH and Estrogen

Prolactin can negatively affect GnRH, which will in turn decrease FSH and LH production, which can decrease estrogen production

Does vasopressin induce water retention or water elimination?

Goal of vasopressin is to increase BV:

Therefore, we would increase water retention via

• Controls aquaporin tubes via GPCR cAMP

• ADH binds to its receptor in the collecting ducts. When the blood delivers vasopressin -> triggers cAMP - moves tubes to the membrane and water is reabsorbed into the body 

A 7-year-old boy underwent successful chemotherapy and cranial radiation for Treatment of acute lymphocytic leukemia. One month after the completion of therapy, the patient presented with excessive thirst and urination plus hypernatremia. Laboratory testing revealed pituitary diabetes insipidus. To correct these problems, this patient is likely to be treated with which of the following?

A. Corticotropin

B. Desmopresin

C. hCG

D. Menotropins

E. Thyrotropin

HYPERnatremia = high salt

We want to reabsorb water yes? How do we do that? Vasopressin analogue IE increase water reabsorption via desmopressin

Vasopressin antagonists

Conviaptan and Tovaptan

What 2 hormones are released by the posterior pituitary

Oxytocin and Vasopressin

Oxytocin receptors activate:

GPCR, triggers IP3 and phospholipase C —> increase influx of calcium —> stimulates muscle contraction

Oxytocin leads to

Milk stimulation, uterine contraction

Prostaglandin and leukotriene release

Induce labor

Oxytocin antagonist

Atisoban

Nifendipine is a CCB used for this purpose but is controversial

Vasopressin MOA?

• ADH binds to the receptor and activates adenylyl cyclase → cyclic AMP → protein kinase a → movement of aquaporins to the apical membrane (the side with the pee). This allows for more water to move out of the collecting duct back into the blood for reabsorption. (Diuretics block this and make us pee to lower BP)

Role of prolactin?

• Principle hormone for lactation, stimulated by circulating estrogen, progestin, corticosteroids, and insulin

Mediators of prolactin

• Prolactin does not have a direct hypothalamic releasing hormone, but it can be regulated by other hormones 

• TRH can increase prolactin

• Estrogen can increase prolactin

• Dopamine can block prolactin

Excess prolactin leads to:

• Fertility problems (alters feedback mechanism of estrogen and can alter ovulation, as estrogen excess can lead to GnRH inhibition) 

• Loss of libido

Causes of prolactin secretion:

• PRL stimulation in primary hypothyroidism or adrenal insufficiency 

• Increase PRL production can occur via pituitary tumors or PCOS 

• Pregnancy

• Hepatic insufficiency or renal failure (reduced clearing of prolactin)

Effect of opiates and neuroleptics on dopamine:

These typically inhibit dopamine release. If dopamine typically negatively affects prolactin release, then removing the inhibitor allows for less downregulation of dopamine and thus increase dopamine levels.  (hyperprolactinemia is a side effect of antipsychotics)

Effect of bromocriptine on prolactin?

Bromocriptine is a dopamine agonist

Dopamine activates gai to block cAMP production. This decreases the transcription of prolactin and suppresses prolactin release 

This reduces prolactin expression 

Therapeutic use of bromocriptine 

• Dopamine receptor agonists reduce PRL

• Can shrink pituitary prolactin secreting tumors

Examples of dopamine agonists:

Bromocriptine, cabergoline (ergot derivative) 

Quinagolide, pramipexole, ropinirole (nonergot) ← antiparkinson treatment, give them dopamine and anticholinergics

What neurohormone is released in the anterior pituitary but acts directly on its target organs?

Prolactin

How is oxytocin activated?

Activates GPCR, which activates Phospholipase C →  IP3 pathway → , which results in release of calcium, which leads to muscle contraction. This releases milk and stimulates uterine contraction and stimulates prostaglandin and leukotriene release

Therapeutic use of oxytocin

Release milk, induce labor 

Can be used to control uterine hemorrhage

What is a physiological trigger that will release vasopressin

Release is triggered by rising tonicity (high salt in the blood will trigger the reabsorption of water) or falling BP 

Released by the kidney to increase water retention

ADH activates a GPCR adh receptor. This enhances cAMP to activate PKA, which triggers the movement of aquaporins (water channels) to move to the apical membrane. This induces water reabsorption to increase BP

Modified vasopressin analogue:

• Desmopressin, long lasting analog and more selective to V2 

Desmopressin therapeutic use:

• Can be used to treat mild hemophilia A

• Diabetes Insipidus (inability to control water levels in the blood due to pituitary insufficiency)

Use for vasopressin antagonists

• Used in hyponatremia, antagonize the binding of add to the receptor and block the reabsorption of water. This increases excretion and increases the tonicity of the blood by removing the water volume to concentrate the blood with more salt 

What hormones are released by the anterior pituitary?

GH, TSH, ACTH, LH, FSH, Prolactin

What hormones are released by the hypothalamus?

GnRH, TRH, GHRH, CRH, Dopamine, Somatostatin

What 2 hormones are produced in the posterior pituitary?

ADH and Oxytocin

What 2 hormones activate the JAK/STAT pathway?

Prolactin, GH

Key functions of growth hormone

1. Carbohydrate and lipid metabolism 

2. Lean body mass and bone density

3. Growth during adolescence

Axis of GH?

Hypothalamus releases GHRH

Stimulates anterior pituitary to release GH

Stimulates Liver, Bones, or Muscles to release IGF-1

Growth hormone agonist

Somatostatin - Growth Hormone Agonist

Mecasermin - Recombinant IGF-1

Clinical use of growth hormone antagonist?

Acromegaly, when too much growth hormone is produced

Examples of growth hormone antagonists?

Pegvisomant - Growth Hormone receptor antagonist

Somatostatin analogues - Octreotide, Lanreotide

D2 Receptor agonists (due to negative feedback of dopamine on GH) - Bromocriptine

Somatostatin analogues

Octretide, Leuprolide

Examples of gonadotropins

FSH, LH, hCG

All gonadotropins exert their effects on what kind of receptors?

GPCR

What is the role of FSH in women?

Follicle support and development

What hormones play a role in steroidogenesis for women?

FSH and LH

What is the role of FSH in men

Regulation of spermatogenesis

What is the role of LH for men?

Regulation of androgen production

Name 3 therapeutic forms of FSH

Follitropin Alpha

Follitropin Beta

Urofollitropin

Complete the following chart:

FSH and LH are dimeric gonadotrophic hormones. FSH binds a _______ and induces transcriptional changes in the cell by activating ______.

A. Dimer of receptors, Calcium channels

B. G protein–coupled receptor, Calcium channel

C. G protein–coupled receptor, cyclic AMP

D. Dimer of receptors, JAK/STAT signaling

E. G protein–coupled receptor, JAK/STAT signaling

C. G protein-coupled receptor, cyclic AAMP

The only ones that are JAK/STAT are Prolactin and GH

Why does a continuous dose of GnRH agonist block steroid hormone expression in controlled ovarian hyperstimulation?

A. High blood GnRH agonist concentration blocks LH activity in the ovaries.

B. Continuous GnRH activation triggers GnRH receptors degradation

C. GnRH agonists inhibit gonadotropin activity.

D. Continuous GnRH agonist administration shrinks the ovaries.

Why does a continuous dose of GnRH agonist block steroid hormone expression in controlled ovarian hyperstimulation?

A. High blood GnRH agonist concentration blocks LH activity in the ovaries.

B. Continuous GnRH activation triggers GnRH receptors degradation

C. GnRH agonists inhibit gonadotropin activity.

D. Continuous GnRH agonist administration shrinks the ovaries.

Pulsatile GnRH increases fertility, as it can lead to hormone surges and increase in steroidogenesis. By providing a continuous dose of hormones, you downregulate the amount of receptors that are available to respond to FSH and LH

Which of the following drugs are alternative GnRH analogues?

1. Aberelix

2. Nafareline

3. Goserelin

4. Leuprolide

5. Degarelix

A. 1 & 5

B. 2 &4

C. 2 & 3

D. 2, 3, & 4

E. All of the above

* These are activators that drive down regulation 

Which of the following drugs are alternative GnRH analogues?

1. Aberelix

2. Nafareline

3. Goserelin

4. Leuprolide

5. Degarelix

A. 1 & 5

B. 2 &4

C. 2 & 3

D. 2, 3, & 4

E. All of the above

Relix = GnRH antagonists

* These are activators that drive down regulation 

Which graph would be seen in LH serum levels for a constitutional delay in LH?

1) Administration of GnRH would lead to an increase in LH levels if the parts are working

Which graph would be seen in LH serum levels for hypogonadotropic hypogonadism?

2) Administration of GnRH would have minimal effect of LH levels because the parts are not responding properly

Growth hormone antagonists can be used to treat acromegaly, by blocking the GH pathway. Which of the following is NOT a Growth hormone antagonists??

A. Bromocriptine

B. Lanreotide

C. Octreotide

D. Pegvisomant

E. Somatropin 

Growth hormone antagonists can be used to treat acromegaly, by blocking the GH pathway. Which of the following is NOT a Growth hormone antagonists??

A. Bromocriptine - D2 agonist

B. Lanreotide - Somatostatin agonist

C. Octreotide - Somatostatin agonist

D. Pegvisomant - Growth hormone antagonist

E. Somatropin - growth hormone analogue

Bromocriptine and Pegvisomant are all antagonists for which endocrine pathway?

A. They suppress ACTH release

B. They suppress growth hormone release

C. They suppress Follicle Stimulating hormone release

D. They suppress thyroid stimulating hormone release

Bromocriptine and Pegvisomant are all antagonists for which endocrine pathway?

A. They suppress ACTH release

B. They suppress growth hormone release

C. They suppress Follicle Stimulating hormone release

D. They suppress thyroid stimulating hormone release

Bromocriptine is a D2 agonist - dopamine can have inhibitory effects on GH

Pegvisomant is a GH receptor antagonist

Clinical uses for somatotropin

Somatotropin is a GH agonist

It can be used for disease related to GH deficiency

Genetic Disease associated with short stature

HIV Wasting

Use of mecasermin

treatment for children irresponsible to GH

Clinical use of growth hormone antagonists?

Acromegaly or GH secreting tumors; used for defective IGF-1 negative feedback loop

Therapeutic use of gonadotropins

Fertility, controlled ovarian hyperstimulation

Explain the gonadal axis

Hypothalamus releases GnRH

GnRH stimulates the release of LH and FSH

FSH is used for follicle development → produces estrogen to select the best follicle

LH surge is used for ovulation

Follicle expels the oocyte for implantation and awaits fertilization

Leftover sac is corpeus luteum, which releases progesterone and more estrogens to develop the lining

If no pregnant (hCG), drop in hormones initiates the restarting of the cycle

Examples of LH analogs

Lutropin alfa

Therapeutic use of LH

In combination with follitropin alfa for follicular development

Diagnostic use for distinguishing between retained testis (undescended) from retracted in prepubertal boys

use of hCG

Excreted in the urine and produced by the human placenta 

Choriogonadotropin alfa can be used in the final follicular development stage or development 

Pulsatile GnRH ____ and Sustained GnRH ____

Pulsatile GnRH stimulates gonadotropin release, and sustained GnRH inhibits FSH and LH release

GnRH analogues:

Gonadorelin, Leuprolide, Goserelin, histerelin, narfarelin, triptorelin

GnRH antagonists:

Ganirelix, Cetrorelix, and Degarelix inhibit FSH and LH secretion by binding to GnRH receptors 

Clinical use of GnRH and analogous:

Controlled ovarian hyperstimulation suppresses the LH surge and increases mature oocyte number

Ovarian suppression in endometriosis; helps reduce fibroid size to reduce progesterone and estrogen production

Prostate cancer in men

Central precocious puberty - GnRH agonists to suppress FSH to delay development of secondary sexual characteristics

How does fertility treatment work?

Via long GnRH agonist protocol, which seeks to use GnRH to suppress the LH surge alongside the use of FSH to help enhance follicle development to create a large amount of oocytes 

GnRH antagonist will help block the LH surge to help alongside FSH to enhance oocyte development

Fill in the respective drugs to the chart

Role of FSH and LH in the testes:

• LH stimulates androgen production

• FSH stimulates spermatogenesis

Name a Growth hormone (GH)

Somatropin

Somatropin

Recombinant form of GH

Acts through GN receptors to increase IGF-1 production

Somatropin uses

- Replacement in GH deficiency

- increased final adult height in children with certain conditions associated with short stature

- wasting in HIV infection

- short bowel syndrome

Name a IGF-1 agonist

Mecasermin

Mecasermin

Recombinant form of IGF-I that stimulates IGF-I receptors

Mecasermin uses

Replacement in IGF-1 deficiency that is not responsive to exogenous GH

Somatostatin analogs

- Octreotide

- Lanreotide

Octreotide

Agonist at somatostatin receptors

Octreotide uses

- Acromegaly and several other hormone-secreting tumors

- acute control of bleeding from esophageal varices

Lanreotide

Somatostatin analog similar to octreotide; available as a long-acting formulation for acromegaly

Growth hormone receptor antagonist

Pegvisomant

Pegvisomant

Blocks GH receptors

Pegvisomant uses

Acromegaly

Gonadotropins: Follicle-stimulating hormone (FSH) analogs

- Follitropin alpha

- Follitropin beta

- Urofollitropin

- Menotropins (hMG)

Follitropin alpha

Activates FSH receptors

Follitropin alpha uses

- Controlled ovulation hyperstimulation in women

- infertility due to hypogonadotropic hypogonadism in men

Follitropin beta

Follicle-stimulating hormone (FSH) analog recombinant product with the same peptide sequence as follitropin alpha but differs in its carbohydrate side chains

Urofollitropin

FSH analog, human FSH purified from the urine of postmenopausal women

Menotropins (hMG)

FSH analog, extract of the urine of postmenopausal women; contains both FSH and LH activity

Gonadotropins: Luteinizing hormone (LH) analogs

- Human chorionic gonadotropin (hCG)

- Choriogonadotropin alfa

- Lutropin

- Menotropins (hMG)

Human chorionic gonadotropin (hCG)

Agonist at LH receptors

Human chorionic gonadotropin (hCG) uses

- Initiation of final oocyte maturation and ovulation during controlled ovarian stimulation

- male hypogonadotropic hypogonadism

Choriogonadotropin alfa

LH analog recombinant form of hCG

Lutropin

LH analog recombinant form of human LH

Menotropins (hMG)

LH analog extract of the urine of postmenopausal women; contains both FSH and LH activity

Gonadotropin-releasing hormone (GnRH) analogs

-Leuprolide

- Gonadorelin

- goserelin

- buserelin

- histrelin

- nafarelin

- triptorelin

goserelin

Gonadotropin-releasing hormone (GnRH) analogs

buserelin

Gonadotropin-releasing hormone (GnRH) analogs

histrelin

Gonadotropin-releasing hormone (GnRH) analogs

nafarelin

Gonadotropin-releasing hormone (GnRH) analogs

triptorelin

Gonadotropin-releasing hormone (GnRH) analogs

Leuprolide

Agonist at GnRH receptors

Leuprolide uses

- Ovarian suppression

- controlled ovarian stimulation

- central precocious puberty

- block of endogenous puberty in some transgender early pubertal adolescents

- advanced prostate cancer

Gonadorelin

synthetic human GnRH