LECTURE 21

Nov 29th
REPRODUCTIVE PHARMACOLOGY

SEX STEROIDS
- Subclass of steroid hormones:
estrogens (E) progesterones (P) and
androgens (A)
- Sex differences exist in prevalence
not the type of steroids

MENSTRUAL CYCLE
- Follicle-stimulatin hormone (FSH) and
lutenizing hormone (LH) stimulate
follicle growth
o as follicle grows, it releases estrogen
that first inhibits (-ive feedback), then
stimulates (at higher levels, +ive
feedback) LH/FSH production LH
surge stimulates ovulation at
approximately Day 14 of menstrual
cycle

follicle, post-ovulation turns into

corpus luteum source of P/E
secretion that promotes endometrial
growth, and suppresses LH/FHS levels
thru ive feedback
- degeneration of corpus luteum results
menstruation in absence of hormonal
support
CONTRACEPTION
FEMALE CONCENTRATION
- Hormonal
o Synthetic estrogen + synthetic
progesterone (aka progestins) oral
only
o Synthetic progesterone alone: oral,
injectable, implantable
o Non-hormonal: copper intrauterine
device (IUD) (inhibit sperm movement
and fertilization)
COMBINED ORAL CONTRACEPTIVES
- Combination of synthetic estrogen
(usually ethinyl estradiol) and
progestin (usually one of
levonorgestrel or norethindrone)
- MOA: inhibition of FSH and LH release
(estrogen and progestin)
o Inhibition of ovulation (follicle cant
develop)
o Inhibition of endogenous hormone
release
- Thickening of uterine mucus lining
(progestin)
o Inhibition of sperm mobility
- Standard prescription
o 21 combination hormone tablets and
7 placebo tablets (withdrawal
bleeding period)
- extended-cycle formulations possible
o Seasonale: 84 combination hormone
tablets; 7 placebo tablets
o Lybrel/Amethyst: only combination
hormone tablets (no placebo)
useful for women with significant
perimenstrual side effects and/or
anemia
- monophasic formulation: identical
E/progestin doses throughout
- biphasic/triphasic formulation:
two/three different combination
doses; designed to more closely
-

approximate natural hormone

variations
- there isnt much buildup of the
endometrial wall when youre on
contraceptives so even during the
placebo week the bleeding will not be
very strong
- between monophasic, biphasic and
triphasic the choice is to use the one
with the lowest side effects (e.g.
people cant handle high [progestin])
- placebo does not have to be taken
but its easier to incorporate taking a
pill everyday than needing to
remember what day to take what
PROGESTIN-ONLY CONTRACEPTIVES
- aka the minipill typically a lower
dose than in combined oral
contraceptive (reduced possibility of
negative feedback on pituitary gland
on endogenous hormone levels not
inhibiting menstrual cycle as much,
not inhibiting ovulation)
- MOA: decreased sperm motility thru
thickening of uterine mucus lining;
may suppress ovulation in some
cases
- Useful where estrogen is inadvisable
(eg breastfeeding, estrogenresponsive cancers)
- Sources of potential anxiety that limit
patient acceptance
o Daily administration; no placebo
period withdrawal bleeding may or
may not occur
o Requirement of more consistent
dosing (take at same time every day)
EFFECTIVENESS OF HORMONAL
CONTRACEPTION
- Similar rates of effectiveness
(combination and progestin-only)
o Approximately 3 unplanned
pregnancies per 1000 (99.7%) when
used perfectly
o Typical use 80-90 unplanned
pregnancies per 1000 woman years
(91-92%)
- Why discrepancy b/t perfect and
typical use?
o Missed doses/improper dose timing
(off by a few hours)

o Drug interactions
CYP450 induction (by phenytoin, St.
Johns Wort)
Altered GI flora (some antibiotics
rifampin (the only antibiotic shown
to have clinical significance in terms
of this) leads to reduced
enterohepatic circulation lower
plasma level of hormones that
previously were reactivated by
normal flora)
LONG TERM CONTRACEPTIVES
- Injectable treatments Depo-provera
intramuscularly every 3 months
- Implantable devices
o IUD
IUD (progestin-releasing IUD 3-5
years of contraceptives)
Copper IUDs ~10 years of
contraception
o Subcutaneous implantations
o Important to screen carefully; hard to
change mind
NON-CONTRACEPTIVE USES:
- Hormone replacement therapy in
response to various disorders
- Estrogens: primary hypogonadism;
postmenopausal hormonal therapy
- Progestins: ovarian suppression
(dysmenorrhea, endometriosis)
ADVERSE EFFECTS MILD/MODERATE
- Breast pain (mastalgia)
- Breakthrough (mid-cycle) bleeding
- Lack of withdrawal bleeding
- Weight gain
- Acne/Hirsutism some progestins are
more androgenic (ie have
testosterone-like properties) than
others
- Many effects will respond to a change
in pill formulation different synthetic
hormone and/or change in dose
ADVERSE EFFECTS SEVERE
- Depression
- Thromboembolic disease (blood-clot
formation) (3-fold increase 1 to 3
events per 1000 women years after
35)
- Cardiovascular event/stroke
(increased risk over age 35)

HORMONAL CONTRACEPTION AND

CANCER
- Growth-stimulating effects of estrogen
- Breast and cervical cancer increase
initially but then go down to 0
increased risk
- Ovarian and womb cancer risk goes
down a lot and the risk increases but
still less risk than no contraceptives
- Greater concern for combined oral
contraceptives compared to
progestin-only contraceptive
- Temporary increases in relative risk;
long-term decreases in relative risk
EMERGENCY CONTRACEPTION
- High-dose progestins
o >> prophylactic contraception doses
o aim to inhibit ovulation
- antiprogestins
o Ulipristal, RU-486 (mifepristone - only
recently approved in Canada, not
readily available yet) prevent
fertilization by delaying ovulation as
primary mechanism
- Copper IUD: toxicity to sperm and
ova, local inflammatory response
most effective method, with pro/con
of ongoing contraception
MALE PHARMACOLOGICAL
CONTRACEPTION
- Testosterone preparations (w/ or w/o
progestins) have been shown to be
effective in most, but not all males
o 2-3 months to achieve severe
oligozoospermia (<1 million/mL
ejaculate) ~1% pregnancy risk
- most recent clinical study:
o 320 males i.m.
progestin/testosterone injections
every 8 weeks
o 95% reduction rate within 6 months
o 4 pregnancies over 56 weeks (98.4%
effective)
o after independent review of high
number of adverse events,
terminated early
acne (>45%), increased libido (38%),
mood disorders (>20%)

high satisfaction rate among

participants - >80% males said they
would use, 76% of female partners

REPRODUCTIVE ASISTANCE
Clomiphene (male and females)
- partial agonist at estrogen receptors
- competes w/ estrogen for binding, but
does not produce the same degree of
gonadotropin reduction
o i.e. reduced negative feedback
increased FSH/LH/estrogen secretion
- can help induce ovulation in some
women who are anovulatory, and/or
have related dysfunctions
- 10% multiple pregnancy rate
GONADOTROPHIN-MEDIATED OVULATION
- where anovulation is secondary to
hypogonadic secretions
- expensive, complex try clomiphene
first
- can also use to harvest oocytes for in
vitro fertilization
- protocol:

give gonadotropins and reducing

endogenous hormone fluctuations
then inseminate or retrieve oocytes
ERECTILE DYSFUNCTION
Pathophysiology
- inability to produce or maintain an
erection sufficient for intercourse
- organic
-

o altered function of the major systems

involved in penile erection: vascular,
neurologic, endocrine
o may arise from any/all of: certain
chronic diseases, medication use,
lifestyle factors, aging
- psychogenic
o lack of response to psychological
arousal often derives as result of
attempt to cope w/ organic ED
o Harder to treat pharmacologically
PHYSIOLOGY OF AN ERECTION
- Basal sympathetic tone is reduced
and increased parasympathetic
activity dilates cavernosal artery
smooth muscle
o Nitric oxide and prostaglandinmediated
o Complex testosterone role
- Resulting vasodilation leads to
increased blood flow increases
volume of corporal spaces
- Compression of venules helps retain
blood locally
PHARMACOLOGICAL TREATMENT
- Phosphodiesterase Type 5 (PDE-5)
inhibitors
o The -afil drugs (sildenafil (Viagra),
tadalafil (Cialis), and vardenfil
(Levitra)
- Alprostadil (Prostaglandin EI analogue)
- Testosterone only effective if basal
endogenous hormone levels are low,
but in such cases should be first line
treatment
MOA
- Cyclic GMP and cAMP can both lead to
decreased smooth muscle calcium
concentration and consequently,
smooth muscle relaxation

PDE-5 metabolizes cGMP: its inhibition

by sildenafil et al. will preserve cGMPmediated vasodilation but there has
to be an initial stimulus that produces
the messenger molecules (erection
facilitators, not initiators)
- PGEI-mediated stimulation of adenylyl
cyclase is sufficient to initiate an
erection without prior stimulus
PHOSPHODIESTERASE -5 INHIBITORS
- First-line therapies: convenient oral
dosing, limited (severe) adverse
effects
- Sildenafil and vardenafil 3-4 hour
half-lives
o Tadalafil 18 hour half-life
- Side effects:
o primarily related to non-specific
vasodilation (headache, facial
flushing, nasal congestion, myalgia)
o altered color perception (interaction
with PDE6 in retina)
- contraindicated with nitrate therapy
(cautioned with patients using alphaadrenoceptor antagonists b/c of
vasodilation function)
-

ALPROSTADIL
- second-line therapy
o reqs direct injection to corpus
cavernosum or via transurethral
suppository (training reqd; bad for
people with fear of needles)
o lack of spontaneity (inject 5-20 mins
before intercourse; short half-life,
erection lasts < 1hour)
o adverse effects: pain, bleeding and/or
bruising at injection site; priapism
(painful, persistent erection)