Anterior pituitary hormones

Pulsatile release of GnRH

increases LH and FSH secretion

continuous release of GnRH

decreases LH and FSH secretion

due to receptor down regulation, desensitization in receptor signaling pathways

Gonadotropins

LH and FSH
stimulate gonads to produce sex steroids - sex steroids provide negative feedback to maintain homeostasis and proper hormone levels (excepting the preovulatory estrogen surge that stimulates FSH and LH secretion)

GnRH (gonadotropin releasing hormone)

concentration is low in childhood

at puberty the receptors are activated by kisspeptin (mutation of this receptor results in failure of puberty)

released in pulses every 60-90 minutes, increases FSH and LH

specific receptor for the molecule on gonadotroph in anterior pituitary

FSH/LH secretion depends on pulse amplitude and frequency

Why does FSH increase in women with old age?

menopause leads to a lack of estrogen → less feedback inhibition of the pituitary →Higher levels

Gonadorelin

recombinant GnRH

diagnostic: evaluate capacity of the pituitary to secrete LH (eg. delayed puberty due to hypothalamic defects - induced hypogonadism)

Lutrepulse

GnRH receptor stimulation

used to stimulate follicle development and ovulation in female infertility

discontinued in US since 2003

Synthetic GnRH antagonists

T ½ > 10

- ganirelix, cetrorelix, degarelix

non-peptide, oral tablets

- elagolix, relugolix (approved 2020)

Synthetic GnRH agonists

T ½ = 3h (due to addition of unnatural amino acids to increase stability and half-life)

leuprolide, goserelin, histrelin, nafarelin, triptorelin

continuous administration of GnRH agonists

decreases FSH and LH
Tx breast cancer, endometriosis, prostate cancer, BPH, precocious puberty, controlled ovarian hyperstimulation

long-acting GnRH agonists: Therapeutic effects

initial flare: stimulation of LH/FSH secretion

prolonged activation leads to reduced LH and FSH secretion

long-acting GnRH agonists: indications

prostate and breast cancer (often combined with androgen or estrogen receptor blockers)

endometriosis (leuprolide, goserelin, nafarelin)

central precocious puberty (puberty starts too early, leuprolide depot/histrelin implant)

long-acting GnRH agonists: Administration

IV, SC, IM, or intranasal (nafarelin)

depot formulations available

long-acting GnRH agonists: Adverse effects

headache, light-headedness, nausea, symptoms of hypogonadism with continuous treatment

menopause-like symptoms in women (headache, hot flashes, sweats, mood changes, osteoporosis, deep vein thrombosis)

GnRH agonists: osteoporosis prevention

add-back therapy

low-dose estrogen-progestin combo and 1000 mg calcium daily (similar to postmenopausal dose)

agonists not recommended for more than 6 months due to risk of bone loss

GnRH receptor antagonists: administration

SC injection

except elagolix and relugolix, which are oral tablets

GnRH receptor antagonists: therapeutic indications

Degarelix, Relugolix: advanced prostate cancer

Elagolix: endometriosis

Ganirelix, Cetrorelix: controlled overian hyperstimulation (prevention of premature LH surge which triggers ovulation - infertility management)

GnRH receptor antagonists: advantages over agonists

ganirelix, cetrorelix: because of immediate effect, they can be used in IVF for a shorter period of time

GnRH receptor antagonists: adverse effects

toxicity: nausea, headache, injection site reactions

Follicle-stimulating hormone (FSH)

gonadotropin

stimulates pre-ovulatory follicle development in women

stimulates spermatogenesis in men

Luteinizing hormone (LH)

gonadotropin

stimulates ovulation in women

stimulates testosterone production in men (Leydig cell stimulation)

Human chorionic gonadotropin (hCG)

gonadotropin

secreted by placenta. presence in urine during early pregnancy is basis for pregnancy tests

longer half-life than LH - used to induce final oocyte maturation

gonadotropin analogs

follitropin (recombinant FSH), Urofollitropin (purified from urine: FSH)
hCG, Lutropin (recombinant LH)

gonadotropins: clinical uses

infertility management

- controlled ovulation hyperstimulation in women

- infertility due to hypogonadotropic hypogonadism in men

SC or IM injections

FSH analogs

follitropin (recombinant FSH)

Urofollitropin (purified from urine)

LH analogs

hCG Lutropin (recombinant LH)

mimics endogenous FSH and LH

Gonadotropins: Adverse effects

ovarian hyperstimulation syndrome, multiple pregnancies in women, Gynecomastia in men

in both sexes: headache, depression, edema

Gonadotropins: contraindications

endocrine disorders that can be worsened by excess sex hormones

Controlled ovarian hyperstimulation: time/steps

1. Daily gonadotropin injections to stimulate follicle development

2. to prevent premature ovulation, a long-acting GnRH agonist or antagonist is given daily to inhibit LH surge

3. When oocyte is ready, an injection of hCG induces ovulation. hCG can activate LH receptors, long t ½

4. progesterone is given daily to maintain pregnancy

PollEv: In the controlled hyperstimulation graph, why a GnRH antagonist can be used for a shorter period than a GnRH agonist?

Because GnRH agonists cause receptor downregulation after several days

PollEv: Ganirelix is used in assisted reproduction such as IVF for which of the following reasons?

To inhibit the natural LH surge that causes ovulation

PollEv: Which of the following is a correct statement regarding GnRH?

It controls the secretion of both FSH and LH

PollEv: A long-acting GnRH agonist is useful in treating endometriosis because it

Decreases cyclic progesterone production