Sermorelin

Advantages 

• GHRH analogue 
• Advantages:  Preservation of feedback on the pituitaryw/possible restoration of normal pituitary regulation even after treatment. Lower cost than synthesizing GHRH.   

• Inhibits growth hormone release 
• Decreases insulin + glucagon + gastrin release 
• Interferes with release of T4/T3 after induction by TRH 

*Cannot be used as a treatment because the 1/2 life is too short*

Octreotide 

MOA

Use

Somatostatin analogue

• 45X more effective in inhibiting GH release but only 2X in reducing insulin secretion 
• So it is particulary useful in the treatment of acromegaly because of the effectiveness at inhibiting GH release without provoking hypoglycemia because of reduced insulin concentrations
• However, it is also used in a variety of hormone-secreting tumors such as:  acromegaly, carcinoid syndrome, gastrinoma, glucagonoma, nesidiobastosis, watery diarrhea, hypokalemia, AIDS related diarrhea 

GH-analogue

• Normal GH has a half-life of 20-25 minutes and cleared by the liver.  Somatropin has a half life of 2-4 hours. 
• Can be given in an injectable suspension that is long-acting in a microsphere that allows the release of it over a month

MOA of GH

Consequences of pharmocological GH (somatropin or somatrem)

Anabolic consequence of pharm dose of GH (somatropin or somatrem)

• GH binds to cell membrane receptor → activates tyrosine kinase JAK2 → causes intracellular protein phosphorylation → causes gene regulation 
• Causes insulin like effects initially → increased tissue uptake of glucose + protein + decreased lipolysis 
• Causes insulin-antagonistic effects after a few hours → decreased glucose uptake and increased lipolysis 
• Major anabolic consequence is longitudinal growth...this is mediated though the somatomedins/IGFs 

• It has been shown that a decrease in GH leads to a decrease in somatomedin production → dwarfism 
• There are states of dwarfism where there are elevated levels of GH but they fail to cause an increase in somatomedins → leads to dwarfism 

• This is a GH receptor antagonist 
• May be useful in the treatment of acromegaly 

• This is an analogue of TRH

Thyrotropin

Use

Thyrotropin = TSH

• TSH binds to thyroid follicular cells → causes G-protein coupled activation → causes increased cAMP → cuses increased iodine uptake → causes increaed thyroxin 
• Diagnostic use:  Following a thyroidectomy, follow-up tests are performed for recurrence of thyroid cancer.  TSH stimulated whole-body 131-scans are part of the surveillance 
• Therapeutic use:  Treatment of metastatic thryoid cancer requires large doses of 131-I in the presence of high serum levels of TSH.  Purified TSH is used for this

• CRH can be administered intravenously
• Diagnostic use:  Has been use to distinguish Cushing's disease from ectopic ACTH secretion.  ACTH producing tumors cells of the pituitary have some feedback response to both stimulation and inhibition, but not ones of ectopic locations.  However, this test is unreliable so it is often not conducted.  A better and more reliable test is to look for CRH-stimulated ACTH concentration in the inferior petrosal sinus (high in Cushing's) compared to peripheral venous sample (lower in Cushing's). Test results will be the opposite for an ectopic ACTH production source

• Released by the anterior pituitary. Stimulates release of adrenocortical hormones. Causes increased cortisol, adrenal androgens, and mineralcorticoids.  

• Synthetic human ACTH

• Porcine ACTH (ACTH 1-39)
• Cosyntropin (ACTH 1-24) 

ACTH 1-39 and 1-24

Half-lives 

Uptake

Excretion

• Half-lives:  Under 20 minutes
• Uptake:  Occurs in the liver and kidneys 
• Excretion:  Not excreted in the urine in sig. amounts. 

• Persist up to 18 hours in a gelatin complex 
• Up to several days with zinc hydroxide complex

• ACTH increases activity of cholesterol esterase → cholesterol esterase is the rate-limiting step for steroid hormone producton → cholesterol + cholesterol esterase → pregnenolone 
• ACTH stimulates adrenal hypertrophy + hyperplasia 
• May cause adipose tissue lipolysis and increased skin pigmentation if given in pharmacological doses 

Diagnostic:  

• ACTH stimulation will fail to cause response in the adrenals in adrenal insufficiency. A rapid test for ruling out adrenal insufficiency uses cosyntropin.  
• Cortisol is measured 30-60 minutes before cosyntropin.  Cosyntropin is given (.25 mg) → if cortisol increases to at least 20 ug/dL → this is a normal response.  If there is a subnormal response that means it is either a primary or secondary adrenocortical insufficiency.  Can tell it is primary or secondary.  Primary = increased ACTH, secondary = decreased ACTH.  An incremental rise in plasma alodsterone occurs in secondary but not primary adrenal insufficiency after cosyntropin stimulation. 

• Sustained, non-pulsatile administration of GnRH or GnRH analogs inhibits the release of FSH and LH by the pituitary 

• GnRH synthetic analogue

GnRH:

• Given IV (4-minute half-life) or SC
• Pulsatile IV adminstration every 1-4 hours → stimulates FSH and LH secretion

GnRH analogues:

• SC (3-hour half-life) or IM or nasal spray (3 hour half-life)
• Have increased affinity for GnRH receptors 
• Reduced suseptibility to degradation
• GnRH administration continuously → inhibits FSH/LH secretion 

• Delayed puberty may occur in hypogonadotropic adolescents
• GnRH may be used to diagnose between constitutional delay or hypogonadotropic hypogonadism delay in puberty. The LH response (not the FSH response) to GnRH distinguishes these two.  
• Serum LH is measured before → then GnRH is given every 15, 30, 45, 60, and 120 minutes → a peak LH response > 15.6 is normal and suggests constitutional delay in puberty.  Impaired LH response suggests hypogonadotropic hypogonadism bc of the pitutiary or hypothalmus. 

• Stimulation:  Treatment of hypogonadotrpioc hypogonadism, delayed puberty, and crptochidism.  This is done by a pump that delivers IV-GnRH every 90 minutes
• Suppression:  Use to treat prostate cancer, uterine fibroids, endometriosis, and polycystic ovary syndrome, and pre-coccious puberty.  Also used to suppress GnRH endogenous gonadoptropin release followed by exogenous gonadotropin to achieve synchrnous follicular development. This is done by giving leuprolide continuously.  GnRH analgoue therapy for causing pituitary suppression causes transient rise in sex hormone concentrations in the first 2 weeks.  This might be deleterious in prostate cancer, precocious pubery, and infertility.  

• Synthetic reversible antagonist of GnRH receptors
• Produces less hyperstimulation than GnRH analogs
• Used in vitro fertilization treatment to suppress endogenous FSH and LH while FSH is given exogenously to allow for ovulation-induction.  
• Also used to treat endometriosis + uterine fibroids 

• Stimulates follicle production in the ovary
• Stimulates spermatogenesis in men 
• LH stimulates androgen production by the ovarian follicular cells → FSH stimulates androgen conversion into estrogen 
• FSH acts on the sertoli cells and stimulates production of androgen-binding protein 

• Modified form FSH for therapeutic use
• Post-menopausal women have an FSH-like substance and LH-like substance in the blood
• The FSH-LH combination = menotropins or human menopausal gonadotropin (hMG)

• A form of FSH from the urine of postmenopasual women that has virtually no LH 

• Synthetically modified form of FSH 

• Used with hCG to stimulate ovarian follicle developement 
• Used with hCG to stimulate spermatogenesis in men 

• Regulation of gonadal steroid hormone production 
• LH acts on testicular leydig cells → stimulate testosterone production 
• LH acts with FSH → stimulates follicular development → LH acts on mature follicles → induce ovulation + stimulates formation of the corpus luteum → the luteal phase produces progesterone + androgens 

• There is no LH preparation presently available for clinical use. 

• ALMOST identical in structure to LH and is available and can be used as an LH substitute in many situations
• hCG is produced by the placenta and can be extracted and purified.  
• hCG stimulates the coprus luteum to produce progesterone and maintain the placenta. It is very similar to LH and can be used to treat both men and women with LH deficiency.  

hCG 

Half-life

Use

• Half-life:  8 hours via IM (vs 30 minutes for LH)

Use:

• Stimulates prodution of gonadal steroid hormones 
• Causes prouction of progesterone by corpus leuteal cells and causes production of testosterone in men 
• HCG mimicsa midcycle LH surge and triggers ovulation in hypogonadotropic women 

Diagnostic: 

• In pre-pubertal boys w/undescended gonads → can be used to distinguish true (crytochid) testis from retracted (pseduo-crypotochid) testis.  HCG given → if testis decend it was pseudo because LH rose and caused increased in testosterone → if the testis stay up, it was crytochid → will need orchiopexy at puberty to maintain spermatogenesis 
• Can be used to distinguish late onset puberty vs hypogonadotrpic hypogonadism.  Use repeated hCG stimulation.  Repeated stimuation will increase testerone/estradiol in late onset but not in hypogonadatropic hypogonadism 

• Bromocriptine 
• Cabergoline 

1. Decrease dopamine turnover in the neurons of the arcuate nucleus which increases dopamine 
2. Act directly on pituitary dopamine receptors to inhibit prolactin release 

Use of bromocriptine (dopamine agonists)

Toxicity

1. Prolactin-secreting adenoma 
2. Amenorrhea-galactorrhea:  Occurs in hyperprolactinemia
3. Physiologic lactation
4. Acromegaly:  Not used unless GH tumor is also secreting prolactin

• Toxicity:  Nausea, headache, light headedness, orthostatic hypotension, fatigue