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hypothalamic-pituitary-gonadal axis

-hypothalamus releases Gonadotrophin releasing hormone (GnRH)


-GnRH acts on the anterior pituitary to release Luteinizing hormone (LH) and Follicle stimulating hormone (FSH)


-LH and FSH act on Gonads to secrete the sex steroids (androgens, estrogens, progesterone)


-sex steroids negatively feed back on hypothalamus and anterior pituitary




*note the pre-ovulatory surge of estrogen actually has a stimulatory effect on GnRH and Gn production

gonadotropins

follicle-stimulating hormone (FSH)


luteinizing hormone (LH)


Chorionic gonadotropin (CG)

what is chorionic gonadotropin

a gonadotropin


-produced by fertilized ovum, then by placenta in pregnancy


-sequence similar to LH, interacts with LH receptors in both men and women

FSH action in females

-stimulates the growth of the developing ovarian follicles during the first half of the menstrual cycle


-promotes the synthesis of estrogen (LH is also required)

LH action in females

-induces ovulation


-stimulates progesterone and estrogen synthesis by the corpus luteum (formed from the remaining cells of the ruptured follicle) during the second half of the menstrual cycle

CG action in females

acts to maintain the corpus luteum when ovum is fertilized

LH action in males

stimulates the synthesis of testosterone by the Leydig cells of the testes

FSH action in males

promotes spermatogenesis (testosterone is also required)

CG action in males

not produced


-exogenous CG acts like LH

diagnostic uses of gonadotropins

1. pregnancy testing


-CG levels in maternal blood and urine




2. prediction of ovulation


-ovulation occurs ~36h after onset of LH surge and 10-12h after peak




3. to assist in determining cause of impaired sex hormone production


-primary gonadal failure: ovaries or testes fail to respond to stimulation by gonadotropins


-secondary gonadal failure: failure of hypothalamus to secrete GnRH or pituitary to secrete gonadotropins (this is also known as hypogonadotrophic hypogonadism)

therapeutic uses of gonadotropins

treatment of infertility in both men and women


-usually hypogonadotrophic hypogonadism

side effects in women who use gonadotropins to treat infertility

-multiple births


-ovarian hyperstimulation syndrome (massive ovarian enlargement, fluid accumulation leading to abdominal pain, renal failure)

gonadotropin preparations

originally obtained from human urine


-menotropins: roughly equal amounts of FSH and LH


-urofollitropin: FSH only


-chorionic gonadotropin




recombinant versions of FSH, LH and CG now available

endometriosis

-presence of fxnal endometrial tissue outside the uterine cavity


-development and growth are estrogen-dependent; implants produce prostaglandins (contribute to pain and inflammation)


-may result in chronic pain, as well as infertility

pharmacological approaches to treat endometriosis

-involve disrupting the normal hormonal environment, including producing a hypoestrogenic state by interfering with gonadotropin produciton

GnRH

-decapeptide


-very short half-life (2-4 min) -necessary for pulsitile action





GnRH agonist/antagonist

-both GnRH agonists and GnRH antagonists now available


-both groups of drugs are analogues of GnRH with changes to aa sequence that alters their activity


-both used in situations where we want to decrease release of Gn and sex steroids

how do GnRH agonists work?

-have increased affinity for GnRH receptor on pituitary gland - more potent


-less susceptible to proteolysis - longer duration


-results in down-regulation of GnRH receptors on pituitary gland




(agonist phase at beginning of tx)

uses of GnRH agonists

in conditions in which we want to suppress Gn and sex steroid secretion:


-endometriosis


-advanced prostate cancer


-precocious puberty


-uterine fibroids


-hyperandrogenism in women

GnRH antagonists

-analogues of GnRH that are competitive reversible antagonists of GnRH at its receptor on pituitary cells


-induce a rapid, reversible inhibition of LH and FSH secretion, with no agonist phase at beginning of tx




-ADRs appear to be similar to GnRH agonists (result of decreased steroid production)

GnRH analogue uses

used to investigate delayed puberty and tx of infertility in both men and women

example of GnRH analogue

Gonadorelin acetate

examples of GnRH agonists

Buserelin


Leuprolide


Nafarelin

examples of GnRH antagonist

Ganirelix

uses of GnRH antagonists

approved to prevent premature LH surge and ovulation in in vitro fertilization cycles




for use in advanced prostate cancer