Drug Pharmacokinetics Physiological Effects Other

Estrogens

E1 estrone E2 ~ 90% bound to hormone binding proteins like SHBG Female maturation
In females, produced by ovaries, adrenals, & adipose tissue

(naturally occurring and albumin development of sex organs, In males, produced by testes (Sertoli cells), adrenals, & adipose tissue
estrogen) prevalent
Absorbed rapidly, but huge first-pass effect secondary sex characteristic (converted from testosterone by aromatase)
estrogen
Closure of epiphyseal plates * Aromatase inhibitors = Testolactone, Anastrozole
postmenopause Reduce first-pass effect by on long bones

E2 17-estradiol
Chemical modifications (i.e., ethinyl estradiol
has longer half-life than 17b-estradiol)
Endometrial effects (proliferative)

(naturally occurring
estrogen) prevalent
estrogen during repro
years
E3 estriol (naturally
occurring estrogen)
prevalent estrogen
during pregnancy
(produced by
placenta)
Ethinyl estradiol
Diethylstilbestrol
(DES)
Non-oral preparations of estrogen (vaginal, Metabolic and cardiovascular effects ethinyl group reduces first pass effect
transdermal, injection) no first pass hepatic
Reduce bone resorption
exposure
Liver effect: increase SHBG
E2 can be converted in liver to E1 and E3 (less potent at less free T in circulation
non-steroidal estrogen
may interfere with the timing of uterine maturation (used for post-
the ER) HDL and triglycerides, coital prevention of pregnancy)
E2 can also be converted to catechol estrogens that may LDL (modest)
have neurotransmitter efficacy Enhance coagulative ability of blood
Estrogen and its metabolites are excreted in the bile, and
Induce progesterone receptors
t : 10 24 hrs
Time to peak concentration: 4 10hrs
can be reabsorbed from the intestine (enterohepatic
cycling) Behavioral effects (mood, specific
Protein binding
Mainly to albumin (in contrast, non-conjugated estrogens
Can serve as the basis of drug interactions cognitive domains, libido) bind to both albumin & SHBG)
Ex. broad spectrum antibiotics alter intestinal Elimination:
flora such that reduced hormone may be Renal (major route) acidic ionized conjugates
reabsorbed lowered efficacy of oral Fecal (minor route)
contraceptives

Conjugated equine
estrogens (CEE)
Mechanism of Action of Estrogens, Progestins, Androgens:
Genomic effects are mediated by the intracellular (nuclear receptor) transcriptional modulation
Metabolites (such as DHEA, for androgens; Allopregnanolone for progesterone) can elicit effects via other receptor systems as well (Allopregnanolone GABAA receptor)
Another major metabolite of testosterone is estradiol (about 80% of the developmental effects of testosterone in the brain are mediated by prior conversion to estrogen)
Membrane hormone receptors
Receptor mediated and genomic activation of trxn
Receptor mediated and non-genomic activation of signaling pathway
Receptor mediated, at the plasma membrane
Non-receptor mediated (membrane fluidity effects, antioxidant effects of estradiol can be nerve protective)
Drug Pharmacokinetics Physiological Effects Other
Progestins
Development of secretory apparatus of breast Produced by corpus luteum, placenta
Progesterone Progesterone half life ~ 5 min Causes maturation of endometrium
(naturally occurring Like estrogen, huge first pass effect body temperature CNS (hypothalamic) Follicular levels: ~ that in males (0.03g/dL)
progestin) Metabolized in liver to pregnanediol and effect Luteal levels: 0.5 2 g/dL
conjugated to glucuronide excreted in Depressant effects, sedative or hypnotic effects
urine (probably mediated by metabolites of
Norethindrone progesterone like Allopregnanolon)
19-nortestosterone derivatives can be highly
Medroxyprogesterone acetate (MPA): androgenic
Medroxyprogesterone t of 38-46hrs
acetate (oral or IM) Elimination: causes LH release from pituitary; prevents ovulation;
Renal (minor) gives endometrium good dose of progesterone Prodrug (converted to 3-keto desogestrel in vivo)
Fecal (major) 100X more potent than norethindrone
Norgestrel Oral contraceptives - implantable contraceptive preps

Desogestrel Suppress pituitary LH release reduce

ovarian androgen production
Low androgenic activity
Androgens
Produced by testes (Leydig cells) & adrenals; does NOT bind -
Testosterone
Most of Testosterone is protein bound ~ 65% to SHBG; ~
30% to Albumin T or DHT is responsible for development of
fetoprotein like estrogens and progestins
(naturally occurring Orally administered T is rapidly absorbed, BUT many 2o sexual characteristics in
androgen) only 1/6 of dose is available in active form due to
conversion to inactive metabolites
Changes in skin, including growth of pubic hair, Levels in women: ~0.03ug/dL
Levels in men (post-pubertal): 0.6ug/dL
Dihydrotestosterone Propionate, cypionate esters of testosterone can axillary hair, beard Converted to DHT by 5-reductase type II (but also by
(DHT) be administered parenterally greater activity,
but prolonged absorption times
Growth of larynx and thickening of vocal type I)
chords, deepening of the voice Finasteride inhibits type II but not type I
Testosterone Alkylation at the 17-position results in more
cypionate orally active androgens (ex. Methyltestosterone,
Oxymetholone)
Sebum secretion (fatty secretion of sebaceous has been used to Tx acquired aplastic anemia, myelofibrosis,
glands of skin) acne hypoplastic anemia
Methyltesterone
Oxymetholone Can stimulate erythropoietin secretion

Anabolic effects

Liver effect: decrease SHBG (estrogen

increases SHBG)
Estrogen Antagonists
Clomiphene Tamoxifen Raloxifene (SERM)
Partial estrogen agonist
Partial
agonist/ partial
No stimulatory effect on endometrium, but has positive effects
on bone and lipids
Competes w/ E to negative feedback gonadotropins & estrogens
antagonist
Tx of breast
cancer
Progestin Antagonists
RU486 (mifepristone) also an anti-glucocorticoid Danazol
t : ~ 20 hrs
Inhibits midcycle surge of LH and FSH (E and P antagonist)
Can bind to AR, GR and PR, but not ER
luteolytic effect, usually combined with a prostaglandin (PGE1) to prevent post-coital pregnancy
By binding to SHBG, may increase clearance of hormones

needs to be used typically within 72 hrs of intercourse

 Oral Contraceptives
Side Effects assoc. w/ Estrogen Side Effects assoc. w/ Progestins Contraindications for OCPs
Thromboembolism due to effect of estrogens on clotting factors ( factors II, VII, IX, X; Cardiovascular disease Pregnancy
antithrombin III)
Stroke Women with history of estrogen-
risk of stroke in current, but not past, OC users (Absolute risk: 0.037%)
appetite may be result of glucose
dependent neoplasms or breast
Cardiovascular risk Risk of MI particularly enhanced in smokers intolerance and consequential insulin
cancer

May be related to effect of estrogens on clotting & effects of progestagens (particularly influences satiety centers in the brain Women with thromboembolic
disorder or liver disease
Norethindrone) on HDL
Weight gain may be more prevalent with the
HTN incidence is ~ 5% in long term OC users (> 5 yrs) androgenic progestins Heavy smokers (cardiovascular
risk is higher if >35yrs of age)
Related to levels of renin substrate and sodium retention
Fatigue
Nausea related to amount of estrogen
Depression may be related to the ratio of
Headache or worsening of migraine Estrogen increases the enzyme that converts tryptophan to Progesterone to Estrogen
nicotinic acid; tryptophan can be used to treat migraine (serotonin mechanism)
Breast regression
Edema (Bloating) assoc. w/ estrogens ability to promote sodium retention
HTN in certain individuals
Breast tenderness or fullness
Androgenic progestins may reduce HDL levels
Over-ride normal ovarian steroid regulation Effects on ovaries: Some preps contain Mestranol (Orthonovum ); Mestranol is Monophasic combination tablets (ex. Ovral-28)
of reproductive function Steroidogenesis converted to Ethinyl Estradiol
Exert negative feedback on
(particularly
progesterone) is Levonorgestrel: ~ 5x more potent than norethindrone, but also ~
Biphasic combination tablets (Nelova) 2 doses of progestin

hypothalamus and pituitary suppressed 8x more androgenic Triphasic combination tablets (Triphasil, Ortho Tricyclen)
GnRH secretion
Effects on uterus: Norgestimate: about same potency as norethindrone, but ~2x more
Constant estrogen, 3 different doses of progestin

FSH secretion incomplete Progestagenic

component of OCs
androgenic Daily progestin tablets (Ovrette - Norgestrel)
follicular development interferes w/ Implantable Progestin (Norplant system Norgestrel)
Drospirenone (in Yasmin ): ~1.5x more potent than
LH secretion without pre-ovulatory endometrial structure
& consistency of
norethindrone, virtually no androgenicity
Injectable Progestin Medroxyprogesterone acetate (Depot
LH surge, no ovulation cervical mucous Desogestrel: more assoc. w/ thromboembolism Provera)
P4 is particularly suppressed because no Alteration in
Seasonale (ethinyl E2 + levonorgestrel) = extended OC (84 + 7 Progestin Only Pills
ovulation no corpora lutea cervical mucous
diminished P4 sperm
day regimen; menstrual period once in 3 months) Less consistent at inhibiting ovulation

Phenytoin, Rifampin (drugs that alter liver

motility Rank order of progestagenic potency: Other effects on uterus and cervix underlie its efficacy
metabolism) and antibiotics/ antimicrobials Alteration in Desogestrel > norgestrel > norgestimate norethindrone
(drugs that decrease enterohepatic circulation) endometrial May be considered for women at risk for certain
will result in lower efficacy of the oral Rank order of androgenicity: estrogen-dependent cancers, or women who dont
structure
contraceptives Norgestrel >> norgestimate > norethindrone > desogestrel tolerate estrogenic component of OCs
uterus
unreceptive for
implantation
May be better choice for women who are breast-
feeding (only ~0.1% of administered Progestin ends up
Remember: ethinyl in breast milk)
group makes estrogen
more bioavailable,
but makes progestins
more androgenic

Hormone Therapy (E alone or E + P)

Now called HT for E+P, ET for E only treatment Menopause Benefits of HT:
Post-menopausal hormone therapy (for more long Vasomotor changes, osteoporosis, incidence of heart attacks and strokes in women by 50% and 40% respectively
term consequences of E & P loss) urogenital atrophy, psychological
hot flashes
For menopausal symptoms (i.e., hot flashes)
(mood) disorders.
Tx: Low dose E + progestin (esp. loss of bone (inhibit osteoclasts)
For reducing risk of Osteoporosis in women w/ intact uterus)
Primary hypogonadism (ovarian failure, w/ progestin, incidence of Adverse Effects of HT:

hypopituitarism along with other hormones) endometrial carcinoma Post-menopausal uterine bleeding
reduced below normal
Routes of Administration incidence Nausea

Oral route Estrogens: Breast tenderness

Many consequences of first pass effect Premarin (estradiol,
estrone sulfate, equilin
Hyperpigmentation
Beneficial to serum lipid profiles sulfate) Pregnant Mare frequency of migraines
Transdermal Urine conjugated

Less first pass effect

equine E Cancer [may be associated with prolonged (> 5 yrs) or very high dose therapy (adenocarcinoma of
PremPro [estradiol, vagina)]
Reduced conversion of E2 to E1 estrone sulfate, equilin
No effect on SHBG sulfate, equilin and Some cancers can be reduced w/ combo progestin therapy

Little to no thromboembolic risks

Provera (Medroxy-
progesterone Acetate)] or Androgenic progestins may HDL levels and cause unwanted side effects assoc. w/ androgen
excess
Local
PremPhase - phasic

replacement of progestin
Compliance is poor because of cyclical bleeding assoc. w/ sequential therapy and fear of cancer
Fewer side effects due to local delivery, Estradiol patch
reduced first pass effect (ex. Progesterone) (Estraderm) Contraindications for HT:
IM estrogen conjugates
(estradiol cypionate, once
Pregnancy
a month) Women w/ Hx of estrogen-dependent neoplasms or breast cancer
Progestins:
Women with thromboembolic disorder or liver disease
Given for last 10-14 days
of each month to prevent Heavy smokers (CV risk is higher if > 35 yrs of age) may be related to effects of nicotine on
possibility of estrogen- clotting factors
induced endometrial and
uterine cancer
 Hormone Therapy (androgens)
Androgen Therapy Adverse Effects: Contraindications:
Androgen replacement therapy in hypogonadal men (male menopause = andropause) Masculinizing effects (gynecomastia in males) Men with

Certain gynecological disorders in women Hirsutism

history of
prostate or
Anabolic agent to reverse atrophy following trauma, surgery or debilitating diseases Acne
breast
cancer
Anemia [17-alkyl derivatives of Testosterone, but not as favorable as using EPO (Procrit)] Hepatic dysfunction Pregnant women

Osteoporosis (us. in combo w/ estrogens) Azoospermia (may be less evident with androgenic progestins)
Bisphosphanates more common Tx now Abuse of androgens:
Athletes
Erectile Dysfunction
Phosphodiesterase Type 5 Inhibitors Contraindications: Systemic side effects:
Increase arteriolar flow Tx with nitrites/nitrates Headache (15%)
Excess blood engorges the BP < 90/55 Flushing
tissue and compresses veins G.I. upset
Flaccidity is brought about by Warning: ED drugs of Visual disturbance (hue; clarity)
normal sympathetic tone sildenafil type should not be Nasal congestion (4%)
Note: many types of PDE used within 4 hrs of alpha
Type 5 is predominant in blockers (does not apply to
arterioles of cavernosa tamsulosin)
Some Type 5 also found in
arteries and veins

Sildenafil (Viagra) 4 hr duration

Vardenafil (Levitra) 4 hr duration

Tadalafil (Cialis) 24-36 hr duration

Much longer lasting, with a significantly
greater likelihood of priapism
Much less visual disturbance
BPH Tx w/ 5a-reductase inhibitors

5-reductase inhibitors Dutasteride Saw Palmetto

Inhibits both isozymes of the 5-reductase Berries of Serona repens
Androgen stimulation is known to be one of the key players in BPH Slow onset typically 3 months OTC
Promotes tissue hyperplasia Side-effect profile looks same as Mechanism similar to
finasteride finasteride (inhibition of
Finasteride Approved for BPH 5-reductase), but also
Selective for Type 2 of the 5-reductase Glaxo is working with the see some small blockade
Does not result in negative feedback for T synthesis FDA for approval in of androgen receptors
Us. see ~ 25% reduction in size of prostate alopecia Must be taken for at least
Safe and Efficacious 6 weeks to see onset of
See improvement in urine flow and retention problems positive effects
Slow onset often need 6 months to see a full effect Significant improvement
Tx for BPH with finasteride often results in positive effects on men who have alopecia in urinary symptom scores
Side-effects: and nocturia, resembling
5% ejaculation problems effects of finasteride
10% erection problems ED is most frequent side-
5% libido problems effect (rates similar to
PSA about 50% finasteride)
PSA test is still valid, but data have to be interpreted differently. Get a PSA
before starting.
Benign Prostatic Hyperplasia Tx w/ alpha blockers
Phentolamine (nonselective) blockers block the 1 stimulation: Drugs that aggravate BPH:
Also an agonist at M and H receptors
effects of any compound
acting at receptors Arterioles, Veins Adrenergic agonists
(whether that compound Constricts Psuedoephedrine (any direct
Prazosin (1 selective) acts directly or or indirect agonist)
indirectly) Eye (Radial Muscle of the Iris)
Typically not much used in BPH Antimuscarinics
b.i.d. dosing and orthostatic hypoTN limit use Endogenous Contracts (leads to pupil dilation)
Atropine/scopolamine
agonists (Epi, Intestine
Doxazosin (1 selective) NE).
Constricts sphincters
Antihistaminics
Sympathetic tone
Very popular Tx for BPH explains why motility (hyperpolarization leads to H1 antagonists, particularly
antagonists first-generation drugs
Once daily dosing produce effects.
relaxation)

Prostate (note: this is an 1A receptor; vascular Side Effects of 1 selective blockers:

Orthostatic problems (relatively minor if pt is properly managed) Exogenously
Give in evening and start w/ small doses to minimize applied drugs
receptors are likely 1B) Reflex tachycardia may occur;
(e.g. NE, Contraction significantly less than with non-
Stuffy nose common phenylephrine, Promotes tissue growth, although DHT selective blockers.
Essentially no tachycardia
tyramine) is much more important in this regard Syncope, particularly when first

Low incidence of sexual dysfunction

Alpha blockers are
much faster onset and
Terazosin (1 selective) have slightly greater
2 stimulation:
Similar to doxazosin, but side-effect profile more severe
efficacy than
finasteride/dutasteride.
Tamsulosin (1A selective)
Competitive blocker; binds 1A (and 1D) with little 1B
Alpha blockers reduce
smooth muscle tone in
binding both the prostate and in
Highly efficacious in BPH
the bladder sphincter
Very limited (if any) vascular effects
Well tolerated
Urinary bladder sphincter administered (first dose
phenomenon)
Constricts
Mechanism (and subsequent
tolerance to this
phenomenon) not entirely
NE Nerve Terminals clear
NE outflow (autoreceptor) Some component of
orthostatic hypotension, but
CNS CNS-mediated reduction of
sympathetic tone also seems
sympathetic outflow
to be involved
Caution patients to avoid
sudden postural changes
Asthenia loss of strength
 Effective for years (little tolerance)

Conclusions:
Vascular effects of blockers likely mediated by 1B
receptor
Prostate/bladder receptors are 1A subtype

Ejaculatory problems in 4-18% of subjects short term. Rate rises

close to 30% with long-term Tx

If due to hyperprolactinemia
Dopamine receptor agonists
(Bromocriptine, Cabergoline)
Can be taken orally or
administered intra-vaginally
to reduce nausea
Activate D2 receptors assoc.
w/ tubero-infundibular DA
system system
suppresses prolactin release
from ant. pit.
Nausea associated with
bromocriptine is due to
effect of Dopamine on CTZ
(chemoreceptor trigger
zone, group of cells close to
postrema on floor of 4th
ventricle) via D2 receptors
Oral contraceptives (containing
Norgestimate, Desogestrel) shut down
pituitary LH release
Progestagenic component
should have low androgenic
activity (ex. Desogestrel)
free androgens by plasma
SHBG (effect of estrogen)
Sequential (E, then P) or E alone
oral contraceptives will inhibit
the H-P-G axis, thus reducing
ovarian androgen production
Tx of Amenorrhea
If due to medication
Bromocriptine = ergot alkaloid Tricyclic anti-depressants, some anti-hypertensives, DA antagonists, Premarin, MPA may
Tx of prolactin secreting adenomas cause hyperprolactinemia
Galactorrhea suppresses physiologic Treatment discontinue offending medication
lactation Tricyclics interfere with D2 receptor function
Tx of Hirsuitism
AR antagonists DHT synthesis inhibitors Inhibitors of ovarian function GnRH
Spironolactone: androgen receptor Prevent conversion to active androgens
analogs administered continuously
suppression of FSH and LH release
antagonist; also K+ sparing diuretic
(aldo receptor blocker); may reduce Finasteride inhibits 5-reductase type II to block conversion of
1)
2)
Leuprolide acetate
Buserelin
androgen synthesis by adrenals testosterone to DHT
(decreases activity of 17-
hydroxylase)
Dutasteride inhibitis 5-reductase type I and type II
GnRH analogs also used for Tx of
Use in combo w/ OCPs These drugs also used for BPH endometriosis, leiomyomata, precocious
puberty, androgen excess
Flutamide inhibits androgen Ketoconazole side effects incl. headache, nausea, hepatitis, and
action at the receptor loss of scalp hair
Cyproterone acetate