Download Infertility: Hormone Relationships: Preoptic Area and Hypothalamus

Infertility:
Hormone Relationships:
Preoptic Area and Hypothalamus  GnRH (pulsatile) [note: continuous administration of GnRH has an inhibitory effect] 
Pituitary  LH and FSH 
Ovaries and Testes  estrogen, testosterone, inhibin (negative feedback on pituitary +/- hypothalamus except estrogen which can have + effect)
Women:
LH (E2)  ovulation and steroidogenesis (estrogen) via mediation of cholesterol  pregnenolone
FSH  oocyte and follicle recruitment for next ovulatory cycle
Men:
LH  steroidogenesis (testosterone) via mediation of cholesterol  pregnenolone
FSH  germ cell maturation (spermatogenesis)
Hypogonadism:
Tertiary: Hypothalamic problem: low LH and FSH
Secondary: Pituitary problem: low LH and FSH
Primary: Gonad problem: low estrogen/testosterone with high LH and FSH
Consider a pulsatile GnRH stimulation test to evaluate secondary/tertiary vs. primary hypogonadism
Menopause:
Drop in estradiol  loss of negative feedback on pituitary  increase in LH and FSH (seen in urine)
Infertility Problems:
R/O other causes of infertility (i.e. thyroid dysfunction, hyperprolactinemia, polycystic ovarian syndrome)
Ovulation Induction (OI): for pts NOT ovulating (PCOS, hypogonadotropic hypogonadism, hyperprolactinemia) - cases where gonads are FINE
Goal: create a dominant follicle
Controlled Ovarian Stimulation (COS): for pts already ovulating, but structural abnormalities, etc, make pregnancy less likely
Goal: create MULTIPLE follicles
Hyperprolactinemia: inhibition of GnRH release caused by prolactin
TRH  anterior pituitary  prolactin (inhibited by dopamine/PIF)
S/S: primary amenorrhea, galactorrhea, female infertility
Etiology: pituitary cancer, medications
Drug Name
MOA
GnRH Agonist
Continuous
administration
Continuous application of
exogenous GnRH inhibits
gonadotropin (LH) release
GnRH Agonist
Continuous Administration
Drug
Class
Indications
AE/DI/CI
"Long" IVF protocol
7-10 days to
suppress
gonadotropin
release
Precocious puberty
CI:
Pregnancy
(Category X)
Lactation
Other
Anemia
Endometriosis
SQ or
intranasally
throughout
follicular
phase
GnRH Antagonist
Cetrorelix
(Cetrotide)
Ganirelix
(Antagon)
GnRH Antagonist
Pharmacokinetics/
dynamics
Long latency
Inhibits endogenous
GnRH release, preventing
premature LH surge
during ovarian
hyperstimulation
Short latency
Rapid onset
SQ during
mid-late
follicular
phase
Prostate Cancer
Breast Cancer
"Short" IVF protocol
AE:
Anaphylaxis
(Cetrorelix) - rare
CI:
Pregnancy
(Category X)
Up to 16%
lower
pregnancy
rate
compared
to GnRH
AGONISTS
Drug
Class
Drug Name
MOA
Pharmacokinet/ dynam
Indications
AE/DI/CI
Other
Follitropin (FSH)
Stimulates follicular
growth, maturation, and
gonadal steroid production
r-FSH has a
shorter
half-life than
u-FSH
Oocyte recruitment
AE:
Ovarian
Hyperstimulation
Syndrome (OHSS)
(less than with
hMG)
OHSS:
Bloating
Fullness
Nausea
Diarrhea
Wt Gain
Vomiting
Darker/No
Urine
SOB
Pleural
Effusion
Calf Pain
Chest Pain
Urofollitropin
(u-FSH)
u-FSH: purified from
Bravella
postmenopausal urinary
Fertinex (purified)
FSH
_________________
Gonadotropins
Recombinant
Follitropin (r-FSH)
$$$
Cannot be used alone in
women with
hypogonadotropic
hypogonadism b/c of the
low LH levels
CI:
Pregnancy
(Category X)
r-FSH: synthetically
created
Follitropin alfa
(Gonal-F RFF)
Follitropin beta
(Follistim AQ)
Human
Menopausal
Gonadotropins
(hMG)
Gonadotropins
IM
SQ
In vitro fertilization
Combination
FSH and LH
(menotropins)
Menopur (SQ)
Repronex
(SQ or IM)
Pergonal
Stimulates follicular
growth, maturation, and
gonadal steroid production
Ovulation induction
IM once after follicle
maturation
Derived from urine of
postmenopausal women
Infertility hypogonadotropic
hypogonadism
Men and women
IM 3x / wk
In vitro fertilization
AE:
Ovarian
Hyperstimulation
Syndrome (OHSS)
Multiple Pregnancy
CI:
Pregnancy
(Category X)
Drug
Class
Drug Name
MOA
Human Chorionic
Gonadotropin
(hCG)
Released from the
syncytiotrophoblasts of
the placenta to maintain
the corpus luteum's
production of
progesterone which
prevents contractility of
the uterus
u-hCG
Pregnyl
Profasi
Chorex
Novarel
Gonadotropins
Recombinant
human chorionic
gonadotropin
(r-hCG)
Choriogonadotropin
alfa (Ovidrel)
hCG mimics the
physiologic LH surge
LH receptor agonist
u-hCG: purified from
urine of pregnant women
Pharmacokinet/ dynam
Indications
Hypogonadotropic
hypogonadism
in men
(supports testosterone
production, which
impacts Sertoli cells, but
does NOT directly
impact initiation of
spermatogenesis)
Ovulation induction
following ovarian
follicle maturation
AE/DI/CI
Other
Mimicking
of LH
causes
testosterone
production
in male
fetuses
when hCG
levels
increase
Drug Name
MOA
Pharmacokinet/ dynam
Indications
AE/DI/CI
Other
SERMs
Selective Estrogen
Receptor
Modulator
Induces ovulation:
T1/2 = 5-7 days
Increases GnRH, FSH, LH PO x 5 days
secretion
Ovulation Induction in
pts with
Adequate HPO function
and PCOS
Lower cost
than
gonadotropins
Clomiphene
Partial agonist nature of
SERM prevents estrogen's
negative feedback on
hypothalamus
Infertility:
Ovulatory disorder
PCOS
Idiopathic
AE:
Hot flushes
(10-20%)
Ophthalmic:
Blurring
Spots
Flashes
(most reversible)
Ovarian
Enlargement
Multiple Pregnancy
Ovulation Induction Agents
Ovulation Induction Agents
Drug
Class
CI:
Pregnancy
Category X
SERMs
Selective Estrogen
Receptor
Modulator
Mixed estrogen receptor
agonist/ antagonist
Uterine and bone agonist
Ovulation Induction in
pts with
Adequate HPO function
and PCOS
Tamoxifen
Breast and hypothal
antagonist
FDA approved for
various breast CAs
Similar effectiveness to
clomiphene
Precaution with
existing ovarian
hypertrophy
AE:
Flushing (40-80%)
Pregnancy
Category D
Ovulation Induction Agents
Drug
Class
Drug Name
MOA
Pharmacokinet/ dynam
Indications
AE/DI/CI
Aromatase
Inhibitors
Decreases estrogen
production 
PO x 5 days
AE:
Hot flushes
Nausea
Anastrozole
(Arimidex)
Decreases negative
feedback 
Ovulation Induction in
pts with
Adequate HPO function
and PCOS
Ietrozole
(Femara)
Increases GnRH, FSH,
and LH
May also modestly
increase androgen levels
 increased follicular
sensitivity to FSH
Ovulation
Induction
Agents
Ovulation Induction Agents
Metformin
Decreases hepatic glucose
production
FDA approved for
Breast CA
Alternate to clomiphene
Used after clomiphene
failure/intolerance
Similar effectiveness to
clomiphene
Ovulation Induction in
pts with
Adequate HPO function
and PCOS
FDA approved for
Type 2 DM
Gonadotropins
SEE ABOVE
Other
Increases menstrual
cyclicity
Improves spontaneous
ovulation
Ovulation Induction in
pts with
Adequate HPO function
and PCOS
Does NOT
improve
birth rates
Ovulation
Induction
Agents
Drug
Class
Drug Name
MOA
Pharmacokinet/ dynam
Non-selective dopamine
receptor agonist
T1/2 = 6-20 hr
Ovulation Induction in
pts with
PO
Bromocriptine
(Parlodel)
Hyperprolactinemia
Induced Infertility
Ovulation Induction Agents
Ovulation Induction Agents
AE/DI/CI
Ovulation Induction in
pts with
Secondary
hypogonadism
Gonadotropins
+
hCG
Dopamine Agonists
Indications
In vitro fertilization
protocol
AE:
Lightheadedness
HA
Dizziness
Nervousness
Fatigue
Nausea
Abd Pain
Diarrhea
No longer used for postpartum breast
engorgement in nonbreastfeeding mothers
Dopamine Agonists
Cabergoline
(Dostinex)
Long-acting selective D2
receptor agonist
T1/2 = 65 hrs
Dosed 2x / wk
Inhibits release of
prolactin
PO
Ovulation Induction in
pts with
Hyperprolactinemia
No longer used for postpartum breast
engorgement in nonbreastfeeding mothers
AE:
Lightheadedness
HA
Dizziness
Nervousness
Fatigue
Nausea
Abd Pain
Diarrhea
Other
Controlled Ovarian Stimulation
Agents
Controlled Ovarian
Stimulation Agents
Drug
Class
Drug Name
Pharmacokinet/ dynam
Indications
Non-ART
(assisted reproduct.
technology)
Regimens:
Oral OI (see above)
+
Gonadotropins
+/hCG
ART:
In vitro fertilization
Stage 1:
COS with:
GnRH analog,
FSH (gonadotropins), +/OC
Stage 2:
OI with hCG
ART:
Controlled Ovarian
Stimulation Agents
MOA
Controlled Ovarian
Hyperstimulation
Stage 3:
Luteal phase support
with progesterone
Follicle development:
gonadotropin injections
Oocyte maturation:
hCG injection
Luteal phase and
prevention of premature
LH surge:
progesterone +
GnRH agonist/ antagonist
Preparation for ART
(in vitro fertilization)
AE/DI/CI
Other
Vitamin
Supplementation
Gonadotropins
Gonadotropins
Drug
Class
Drug Name
MOA
Pharmacokinet/ dynam
Indications
Conventional
Protocol:
SEE ABOVE
hCG
8-12 weeks
Male Infertility
hMG
remaining
time of 4-6
mo regimen
hCG
followed by
hMG
Alternative
Protocols:
Clomiphene may increase
sperm concentrations
Male Infertility
Urofollitropin
r-FSH
Clomiphene
Antioxidant Vitamin
Supplementation:
Zinc
Magnesium
Vitamin E
L-carnitine
Male Infertility
AE/DI/CI
Other