Transcript GONADAL DRUGS

GONADAL DRUGS
Ma. Janetth B. Serrano, M.D., DPBA
Gonads: Ovary

Quiescent during rapid growth & maturation

At puberty:
- Gonadarche → beginning of ovarian function
- Menstrual cycle
→ a 30- to 40- year period of cyclic function
→ manifested as regular episodes of bleeding
- Menopause
→ if ovaries fail to respond to gonadotropins
secreted by the ant. pituitary.
Gonads: Ovary
Hypothalamus
↓
GnRH
↓
Anterior Pituitary
(-)
↓
(-)
FSH / LH
↓
Ovary / Testes
Estrogen/
Progestins
Testosterone/
Androgens
NEUROENDOCRINE CONTROL OF THE MENSTRUAL
CYCLE
Gonads: Ovary

DISTURBANCES IN OVARIAN FUNCTION:
 environmental or emotional stress
 anovulatory cycles:
eating disorders (bulimia,anorexia)
 severe exercise

organic causes:
 pituitary prolactinomas
 ovary gives rise to:
 androgen producing neoplasms (arrhenoblastoma, Leydig
cell tumors, estrogen producing granulosa cell tumors)
 minor causes: inflammatory or neoplastic processes that
inluence function of the ovaries, uterus or pituitary

Estrogens
Naturally occuring:
 17β – estradiol (most potent)
 Estrone
 Estriol
Synthetic Steroidal:
Synthetic Nonsteroidal:
 Ethinyl estradiol
 Diethylstilbesterol
 Mestranol
 Quinestrol
 Equilin







Chlorotrianesene
Methallenestril
Methestrol
Dienestrol
Benzestrel
Hexistrol
Genistein
Estrogens



Immediate precursors:
Androstenedione / Testosterone
Ovaries – principal source of circulating estrogen
Other sources:
 liver (estrone, estriol fr. estrsdiol)
 Peripheral tissues (fr. androstenedione & other
androgens)
 Pregnancy: fetoplacental unit ( fetal adrenal zone,
secreting androgen precursor, placenta)
 Stallion – equilenin and equilin
 Soybeans - flavinoids
PHARMACOKINETICS
 binds
strongly to SHBG and less to albumin
 estrdiol



Estrogens
converted by the liver to:
estrone & estriol
2-hydroxylated derivatives
conjugated metabolites catechol estrogens
 may
serve as neurotransmitters in the CNS
 converted
by COM-T to 2- and 4- methoxy
compounds
 excreted
in the bile; small amounts in breastmilk
Biosynthetic Pathway for Estrogens:
Dehydroepiandrosterone
16 α-OHase
Androstenedione
TESTOSTERONE
16α-Hydroxydehydroepiandros
terone
16α-Hydroxydehy hydroepiandrosterone
Estrone
Estriol
aromatase
aromatase
ESTRADIOL
MECHANISM OF ACTION
 primarily
Estrogens
by regulating gene expression
estrogens  dissociate &
enter cell  bind to their receptor
 SHBG-bound
complex  bind to
Estrogen Response Elements or ERE’s
(specific sequence of nucleotides)
 Receptor-hormone
PHYSIOLOGIC EFFECTS
Estrogens
1. Female maturation

required for 2
O
sexual characteristics:

stimulate development of vagina, uterus & tubes

breast development  stromal development,
ductal growth and accretion of fat

accelerated growth phase and closure of epiphysis

axillary and pubic hair

regional pigmentation of axilla, areola & genital
area
PHYSIOLOGIC EFFECTS
Estrogens
2. Endometrial effects
 hyperplasia of the endometrium  continuous exposure
3. Metabolic and Cardiovascular effects:
 Lipoprotein:  HDL , slight  LDL
  plasma cholesterol
  plasma triglycerides
4. Blood Coagulation
 enhance coagulability
  Factors II, Vii, IX, X
  antithrombin III
  plasminogen level   platelet adhesiveness
CLINICAL USES
1.
Estrogens
Primary hypogonadism
 associated with hypopituitarism
 Turner’s syndrome – ovarian dysgenesis with dwarfism
 treatment begins at puberty – 11 to 13 years:
 to stimulate development of 2O sexual characteristics
and menses
 to prevent osteoporosis
 to avoid physiologic consequenses of delayed puberty
and estrogen deficiency

Dosage:
Conjugated estrogen 0.3 mg or Ethinyl estradiol 5-10ug


on days 1 to 21 of each month
when growth is completed  Chronic Tp with
estrogen and progestins
CLINICAL USES
Estrogens
2. Postmenopausal Hormone Replacement
Therapy

major indication

prevent bone loss (osteoporosis)

decrease vasomotor symptoms

prevention of cardiovascular disease

prevent vaginitis

Dosage:
Conjugated Estrogen – 0.3 to 1.25 ug/day
Ethinyl Estradiol – 0.01 to 0.02 mg/day
CLINICAL USES

Estrogens
Replacement Regimen:
A: Sequential hormone administration
1. Estrogen for first 25 days
2. MPA (Medroxyprogesterone acetate) 10 mg/day for
the last 10 to 14 days of estrogen therapy
3. No hormone treatment for 5 to 6 days  (+) withdrawal
bleeding
B: “Continuous” hormone administration
1. estrogen 0.625 mg given continuously on a daily basis
2. progestin MPA 2.5 to 5 mg jointly given during the first
days of each month
3. no cyclic bleeding

10 to 13
PROGESTINS – included to decrease endometrial
hyperplasia and incidence of endometrial
carcinoma
CLINICAL USES
Estrogens
3. Contraception
 major indication
4. OTHER USES:
 DUB & intractable dysmenorrhea
(Es + Progestins)
 Hirsutism & amenorrhea
 DES  prostate carcinoma
 Severe cystic acne
ADVERSE EFFECTS







Estrogens
postmenopausal bleeding
carcinogenic action – breast, endometrial
thromboembolic disease, HPN
GB disease, cholestasis
Nausea & breast tenderness
Migraines
Changes in mood
CONTRAINDICATIONS

Estrogens
CONTRAINDICATIONS:
 estrogen-
dependent neoplasms
 undiagnosed
genital bleeding
 history
of liver disease
 history
of thromboembolic disorder
 heavy
smokers
Gonadal Inhibitors
Anti - Estrogens
ANTI-ESTROGENS:
A. Tamoxifen







a competetive partial agonist inhibitor of estradiol at
estrogen receptors
nonsteroidal agent given orally
initial half-life: 7 to 14 hours
excretion: liver
Cl. Indication: palliative/adjuvant tp of breast CA
Dosage: 10-20 mg BID orally
Adverse effects: nausea & vomiting





hot flashes
vaginal bleeding, menstrual irregularities, skin rash
 risk of endometrial cancer
 loss of lumbar spine bone density
plasma lipid changes   risk of atherosclerosis
Gonadal Inhibitors
Anti - Estrogens
B. TOREMIFENE
C. RALOXIFENE




“selective estrogen receptor modulator”
high first pass effect, large Vd
long half-life: >24 hours
Cl. Indication: prevention of postmenopausal osteoporosis
D. CLOMIPHENE
competetive inhibitor of endogenous estrogen
 partial agonist at pituitary
 ovulation-inducing agent

Gonadal Inhibitors
Anti - Estrogens
ESTROGEN SYNTHESIS INHIBITORS
1. GnRH

continuous administration prevents ovarian synthesis of
estrogen
2. AMINOGLUTETHIMIDE

inhibits aromatase activity
3. AROMATASE INHIBITORS
a. Testolactone – weak inhibitor
b. Anastrozole
 selective nonsteroidal inhibitor of aromatase
 effective in tamoxifen-resistant breast tumors
c. Letrozole – similar to anastrozole
d. Exemestane
 steroid molecule that irreversibly inhibits aromatase
 advanced breast CA
e. Fadrozole – newer oral nonsteroidal
Ovulation Inducing Agents
CLOMIPHENE

Partial agonist at estrogen receptors

MOA:  secretion of gonadotropins & estrogens by
inhibiting estradiol’s negative feedback effect

Effects:
1. stimulate ovulation in females with amenorrhea & other
ovulatory disorders
2. blocks inhibitory influence of estrogen on the hypothalamus

Clinical Use:
1. Treatment of disorders of ovulation in patients wishing to
be pregnant
 no use in ovarian & pituitary failure
 single ovulation induced by a single course of therapy
Ovulation Inducing Agents
CLOMIPHENE

Dosage: 50 mg/ d X 5 days



Adverse Effects:







(+) ovulation  same course repeated until pregnancy
occurs
(-) ovulation  100 mg/d X 5 days  if (+) menses &
ovulation, start next course on 5th day of cycle
hot flushes – most common
eye symptoms – due to intensification & prolongation of
after images
ovarian enlargement
multiple pregnancy – 10%
rare: headache, constipation, allergic reactions, reversible
hair loss
C/I: patients with enlarged ovaries
> 1 year tx: assted with low-grade ovarian CA
Progestins
 Natural:
 most
PROGESTERONE
important progestin in humans
 precursor
to estrogens, androgens,
adrenocortical steroids
 synthesized
in the ovary (corpus luteum),
testis, adrenals, placenta
Progestins

Synthetic:
A. 21-Carbon compounds (Progestrone &
derivatives)
 Hydroxyprogesterone
- longest DOA (8-14 days)
 Medroxyprogesterone
 Megestrol
B. 17-Ethinyl testosterone derivatives
 Dimethisterone
Progestins
C. 19-Nortestosterone derivatives
(3rd generation)
1. Desogestrel
6. Norethindrone acetate
2. Norethynodrel
7. Ethynodiol acetate
3. Lynestrenol
8. L-Norgestrel
4. Norethindrone
9. Gestodene
5. Norgestimate

MECHANISM:
 binds to progesterone receptors
PHYSIOLOGIC EFFECTS

Progestins
Carbohydrate metabolism
  insulin levels
  insulin response to glucose
 promote glycogen storage in the liver
favor fat deposition
 promote ketogenesis
 compete with aldosterone

( Na+ reabsorption)

PHYSIOLOGIC EFFECTS
Progestins
 body temperature
  ventilatory response to CO2
 depressant & hypnotic effects

o
Sexual characteristics:
 breast: alveolobular devt. of the secretory
apparatus
 endometrium: maturation & secretory changes
o
Important in the maintenance of pregnancy
 plasma amino acid levels   urinary nitrogen
excretion
o
Progestins
Synthetic progestins:

no androgenic activity:
desogestrel,
 norgestimate,
 gestodene
PHARMACOKINETICS
 rapidly
Progestins
absorbed
 approx. half life: 5 min
 stored in body fats
 metabolite: Pregnanediol
 Elimination: urine as
Pregnanediol glucoronate
CLINICAL USES
Progestins
 Hormone
replacement therapy
 Hormonal contraception
 Ovarian suppression:
> dysmenorrhea
 endometriosis
 Premenstrual
> hirsutism
> uterine bleeding
syndrome
progesterone & MPAProgestins
CLINICAL USES

Progestins
Diagnostic test  Estrogen secretion
 Progesterone 150 mg/d or MPA 10 mg/d
for 5-7 days  withdrawal bleeding in
amenorrheic patients
o Single drug:
 MPA 150 mg IM every 90 days 
prolonged anovulation and amenorrhea
 MPA 10-20 mg p.o. twice weekly or 100
mg/m2 I.M. every 1-2 weeks  prevent
menstruation
ADVERSE EFFECTS
Progestins

 BP

 HDL  androgenic progestins
Other Ovarian Hormones
1. ANDROGENS



testosterone, androstenedione,
dehydroepiandrosterone
responsible for hair growth, stimulation of libido,
metabolic effects
asstd. with hirsutism & amenorrhea
2. INHIBIN and ACTIVIN


 dimer (inhibin)  inhibits FSH secretion
 dimer (activin)   FSH secretion
Other Ovarian Hormones
3. RELAXIN



found in the ovary, placenta, uterus
 glycogen storage and water uptake
facilitates dilatation & shortens labor
4. Non steroidal substances


corticotropin-releasing hormone, follistatin,
PG
with paracrine effects within the ovary
Gonadal Inhibitors
Anti - Progestins
1. MIFEPRISTONE (RU486)
a derivative of ‘19-nor progestin norethindrone’
 a potent competetive antagonist of progesterone
and glucocorticoid at their receptors
 acts as partial agonist if progestin is absent
 (+) luteolytic in women at midluteal period
 Pharmacokinetics:

 oral
route with good bioavailability
 plasma half-life: 20 to 40 hours
 hepatic metabolism
 elimination: feces
Gonadal Inhibitors
Anti - Progestins
MIFEPRISTONE

Therapeutic indications:
1. Medical abortion during the first trimester

dosage:
400-600mg/day X 4 days or 800 mg/day X 2 days +
Prostaglandin 48 hrs after antiprogestin to  myometrial
contraction & ensure expulsion of detached blastocyst
 major adverse effect: prolonged bleeding

combination:
600 mg o.d. SD + PG E1 vaginal pessary or 1 gm. Misoprostol
(95% effective during 1st 7 weeks post conception)
 adverse effects: vomiting, diarrhea, abdominal pain, pelvic
pain
Gonadal Inhibitors
Anti - Progestins
MIFEPRISTONE
Therapeutic indications:
2. Postcoital contraceptive


prevents implantation
dosage: 600 mg SD
3. Induction of labor after fetal death & at
the end of 3rd trimester
4. Tx of endometriosis, leiomyoma, breast
cancer, meningiomas
Gonadal Inhibitors
Anti - Progestins
DANAZOL

an isoxazole derivative of ethisterone

weak agonist at progestational, androgenic and
glucocorticoid receptors

inhibitor of gonadal function

MOA: binds to receptors  initiate androgenspecific RNA synthesis

Major metabnolite: ETHISTERONE –with
progestational & androgenic effects

t ½ = >15 hrs

Elimination: urine & feces
Gonadal Inhibitors
Anti - Progestins
DANAZOL
Clinical Uses:

treatment of endometriosis

600 mg/d reduced to 400 mg/d after 1 mo. then
200 mg/d after 2 mos (85% with improvement in
3-12 mos)

fibrocystic disease of the breast

hematologic or allergic disorders:

hemophilia, Christmas disease, ITP, angioneurotic
edema
Gonadal Inhibitors
Anti - Progestins
DANAZOL
Major adverse effects:

weight gain, edema,  breast size, acne & oily
skin,  hair growth, headache, deepening of voice,
hot flushes, muscle cramps

Caution: hepatocellular damage

C/I: pregnancy & lactation  urogenital
abnormalities
Gonads: Testis
both gametogenic & endocrine functions
Anterior Pituitary
(+)
FSH
Activin
Inhibin
(-)
(-)
LH
TESTOSTERONE
Sertoli
cells
Mullerian
Inhibitory
factor
ESTRADIOL
SEMINIFEROUS TUBULES
LEYDIG CELLS
Testosterone
TESTOSTERONE
 most important androgen secreted by the
testes
 8 mg/day produced daily
 95% by Leydig cells; 5% by androgens
 Plasma levels:
 0.6
ug/dL after puberty
 (declines after 50 years of age)
 0.03 ug/dL = females
Gonads: Testis
HYPOTHALAMUS
GnRH
Anterior Pituitary
LH
Testes
Ketoconazole
TESTOSTERONE
5α - Reductase
Spirinolactone
FINASTERIDE
Dihydrotestosterone
Androgen Receptor Complex
Androgen
Response
Element
Flutamide
Cyproterone
Expression of Appropriate genes in
androgen-responsive cells
Spirinolactone
Gonads: Testis
Other androgens/hormones produced:





dihydrotestosterone
androstenedione
dehydroepiandrosterone
pregnenolone
progesterone & 17-hydroxylated
derivatives
Testosterone

BINDING:
65% - SHBG
2% - free
33% - albumin

METABOLISM:
Testosterone converted to
dihydrotestosterone (major active
androgen) by 5--reductase
Testosterone
PHYSIOLOGIC EFFECTS:
A. Changes during puberty (Adrenarche)




testosterone & 5 dihydrotestosterone
 penile & scrotal growth
skin
 pubic, axillary & beard hair
(Androstenedione, DHEA)
 more active sebaceous glands  thicker
& oilier skin
larynx  vocal cords thicker  low pitch voice
skeletal growth
Testosterone
PHYSIOLOGIC EFFECTS:
B. increase lean body mass
C. male development (2O sexual characteristics)
stimulate development & maturation of sperm
 stimulate development of the epididymis, vas
deferens, seminal vesicles, scrotum, penis,
prostate

D. anabolic effect on muscle & bone mass


increase protein synthesis, decrease protein
breakdown
measured by  urine nitrogen secretion
Testosterone
PHYSIOLOGIC CHANGES
E. musculinization in females
F. metabolic effects:
  hormone binding
  liver synthesis of clotting factors,
triglyceride, lipase,  anti-trypsin
  HDL
 stimulate renal erythropoietin secretion
Testosterone
PREPARATIONS:
Natural androgen: testosterone
Synthetic:
Parenteral:
Oral:
~ testosterone proprionate
~ testosterone enanthate
~ testosterone cypionate
~ Danazol
~ Fluoxymesterone
~ Methyltestosterone
Anabolic steroids:
~ Oxandrolone
~ Stanozolol
CLINICAL USES:
Testosterone
1. Androgen replacement therapy in men
 hypogonadism
 pituitary deficiency
 given at puberty  growth spurt & 2O sexual
characteristics
 Dosage: Testosterone enanthrate
50 mg IM q 4 wks; then q 3 wks; then q 2 wks (@
change at 3 mos interval)
o double dosage at 100 mg q 2 wks until maturation is
complete  then adult dose of 200 mg q 2 wks
o
Testosterone

Other drugs:
 Testosterone
proprionate
– short DOA
 Testosterone
undecanoate
– asstd. with liver tumors
- 40mg/d p.o.

Caution: reduce dose if (+) polycythemia
& HTN
CLINICAL USES:
Testosterone
2. Gynecologic disorders




reduce breast engorgement postpartum
DANAZOL = weak androgen for endometriosis
Postmenopausal women: eliminate menstrual
bleeding & enhance libido
Premenopausal: chemotp of breast tumors
3. As Protein Anabolic agents

reverse protein loss after trauma, surgery,
prolonged immobilization, debilitating diseases
CLINICAL USES:
Testosterone
CLINICAL USES:
4. Anemia


stimulates erythropoiesis
Aplastic anemia, Fanconi’s anemia, Sickle cell
anemia, Myelofibrosis, Hemolytic anemia
5. Osteoporosis
6. Used as Growth Stimulator


stimulate boys with delayed puberty to achieve
expected adult height
too rapid or vigorous tp  accelerated
epiphyseal closure
CLINICAL USES:
Testosterone
7. Anabolic steroid & androgen abuse in
sports

 strength & aggressiveness  improved
competetive performance
8. Aging

androgen replacement:  lean body mass
 hematocrit
 bone turnover
9. Carcinoma of the breast


palliative effect
act as antiestrogen
ADVERSE EFFECTS:
Testosterone
1. masculinizing effects in women:
 hirsutism, clitorial enlargement, acne,
deepening of voice
 endometrial bleeding upon
discontinuation
2. alteration in serum lipid profile:
 lower HDL2 and higher LDL
3. sodium & water retention
ADVERSE EFFECTS:
Testosterone
4. hepatic dysfunction:
  AST levels,  alkaline phosphatase, 
bilirubin levels
 hepatic adenomas; hepatocellular
carcinomas
5. Prostatic hyperplasia
6. Behavioral changes
 physiologic dependence,
 aggressiveness, psychotic symptoms
CONTRAINDICATIONS:
Testosterone
1. pregnant women
2. male patients with cancer of the breast &
prostate
3. infants & young children  CNS effects
4. renal & cardiac disease  predisposd to
edema
5. patients with aplastic anemia treated with
androgen anabolic tp  hepatocellular
carcinomas
Gonadal Inhibitors
Androgen Suppression
Inhibition of Androgen Synthesis:
1. GnRH analogs

produce gonadal suppression when blood levels are
continuous & not pulsatile

C.I.: prostatic carcinoma

Cause a significant surge of androgen secretion at the
beginning of therapy assted with a flare of tumor activity &
increase in symptoms

Drugs:
1. LEUPROLIDE ACETATE - 1 mg SQ o.d.
2. GOSERELIN
- once every 4 wks as SQ slow-release inj.
3. BUSERELIN
4. NAFARELIN
5. GONADORELIN
Gonadal Inhibitors
Anti-Androgen
A. Steroid Synthesis Inhibitors
KETOCONAZOLE





antifungal agent of imidazole class
MOA: block cytochrome P450 enzymes involved in gonadal
& adrenal steroid hormone biosynthesis
Displaces estradiol & dihydrotestosterone from SHBG
Tx of prostatic CA
Revesible gynecomastia in males
SPIRINOLACTONE





A competetive inhibitor of aldosterone
MOA: weak inhibitor of the binding of androgen to androgen
receptors
inhibits androgen biosynthesis
Cl. Use: women with hirsutism
S/E: metorrhagia – give with oral contraceptives
Gonadal Inhibitors
Anti - Androgen
B. 5 Reductase Inhibitors:
FINASTERIDE






a steroid-like inhibitor of 5 reductase  
conversion of testosterone to
dihydrotestosterone
 dihydrotestosterone in plasma & prostate
within 8O up to 24O
CL. Uses:
benign prostatic hyperplasia: 5 mg/day
hirsutism in females
male pattern baldness: 1 mg/day
Gonadal Inhibitors
Anti - Androgen
Androgen Recptors Antagonists:
1. CYPROTERONE ACETATE

inhibits action of androgen at target organ
competes with dihydrotestosterone for binding
to androgen receptor

acetate form  with marked progestational
effect  suppress feedback enhancement of LH
& FSH

Clinical Uses:





Hirsutism in females – 2 mg/d with estrogen
Excessive sexual drive in men – 100 mg/d
Acne, male pattern baldness, virilizing syndromes
Precocious puberty
Prostatic hyperplasia & CA
Gonadal Inhibitors
Anti-Androgen
Androgen Recptors Antagonists:
2. FLUTAMIDE

a nonsteroidal antiandrogen that acts like a
competetive antagonist at androgen receptors

Cl.Uses:

Hirsutism in females

causes mild gynecomastia

mild reversible hepatic toxicity
Prostatic Ca
Gonadal Inhibitors
Anti-Androgen
Androgen Recptors Antagonists:
3.BICALUTAMIDE and NILUTAMIDE



Bicalutamide



potent orally active antiandrogens
Cl.Use: metastatic prostatic carcinoma
combined with GnRH analog to reduce tumor
flare
dosage: single drug- 150-200 mg/d to reduce
prostate-specific antigen
with GnRH analog– 50 mg/d
Nilutamide


post-surgical castration
300 mg/d for 30 days; ffd. by 150 mg/d
Gonadal Inhibitors
Anti -Androgen
Androgen Receptors Antagonists:
4. SPIRINOLACTONE

An aldosterone antagonist

Competes also with dihydrotestosterone for
androgen receptors in target tissues

Reduces 17-hydroxylase activity   plasma
levels of testosterone & androstenedione

Cl.Use: hirsutism in women – 50-200 mg/d
Gonadal Inhibitors
Chemical Contraception in Men
GOSSYPOL



cottonseed derivative
destroys elements of seminiferous tubules but
donot alter endocrine function of the testis
Dosage:
20 mg/d X 2 mos, ffd. by maintenace dose of 60 mg/wk



(99% dev. Sperm count <4 million/ml)
Recovery ffg d/c: better if sperm ct donot fall to
extremely low levels or not more than 2 yrs. tp.
Major Adverse Effect: HYPOKALEMIA  transient
paralysis
Preparation: Oral tabs
Intravaginal spermicide contraceptive
Gonadal Inhibitors
Chemical Contraception in Men
OTHER CHEMICAL CONTRACEPTIVES:
1. Testosterone & Testosterone enanthrate
 400 mg/month (azoospermia in <50% of men)
 minor adv. Rxn: gynecmastia, acne
2. Testosterone + Danazol  not very effective
3. Testosterone 100mg IM weekly + Levonorgestrel
500 mg p.o. (azoospermia in 94%)
4. Cyproterone acetate  oligospermia
5. Testosterone + GnRH  reversible azoospermia
Hormonal Contraception

Mechanism of Action:
 selective
inhibition of pituitary function
inhibition of ovulation
 produce
changes in the cervical mucus,
uterine endometrium, motility &
secretion in the fallopian tubes
Hormonal Contraception
Pharmacologic Effects:
 Ovary



Uterus



chronic use depresses ovarian function
on discontinuation: 75% ovulate in the 1st post tx cycle
2% amenorrheic for several years
cervix – hypertrophy & polyp formation; thicker & less
copious cervical mucus
“19-nor” progestins  glandular atrophy & less bleeding
Breast


Estrogen containing agents  breast enlargement
Es + Progestins  suppress lactation
Hormonal Contraception
Pharmacologic Effects:
 CNS
Es   excitability
 Prog   excitability; (+) thermogenic action
 Profound changes in mood, affect & behavior  used
in tp of PMS, postpartum depression, climacteric
depression


Endocrine





alter adrenal structure & function
attenuation of ACTH reponse to metyrapone
alterations in angiotensin-aldosterone system
( plasma renin activity;  aldosterone secretion)
 TBG   total plasma thyroxine (T4)
 plasma SHBG
Hormonal Contraception
Pharmacologic Effects:
 Blood
serious thromboembolic phenomena
  in serum iron & total iron binding capacity


Liver


reduce flow of bile  cholelithiasis
Lipids

Es   serum triglycerides & cholesterol   phospholipids
 HDL &  LDL
 Es + Prog  slight  in triglycerides & HDL

Hormonal Contraception
Pharmacologic Effects:

Carbohydrate metabolism
 rate of absorption from the GIT
 Prog -  basal insulin level; produce progressive  on
glucose tolerance which is reversible on
discontinuation


CVS


small  in CO, higher SBP, DBP and HR
Skin
 pigmentation (chloasma)
  sebum production  acne

Hormonal Contraception
CLINICAL USES:

Oral contraception
– pregnancy rate = 0.5 to 1/100 woman
years at risk

Endometriosis
Hormonal Contraception
PREPARATION:
I. Combination Oral Contraceptives
1. Monophasic – constant amount of estrogen
and progesterone throughout 21 day cycle
2. Biphasic – constant amount of estrogen with
varying amounts of progestins
3. Triphasic – varying amounts of estrogen &
progestins
Hormonal Contraception
Adverse Effects:

Mild:
Nausea, myalgia, breakthrough bleeding, edema
Changes in serum proteins & other endocrine fxns
Headache
No withdrawal bleeding

Moderate:
requires discontinuation
Breakthrough bleeding – bi- & tri-phasic causes 
bleeding
Weight gain
 skin pigmentation
Acne, hirsutism
Ureteral dilation, vaginal infections
Amenorrhea
Hormonal Contraception
ADVERSE EFFECTS:

Severe:
Vascular disorders – Venous thromboembolic
disease
- M.I., Cerebrovascular disease
GIT disorders cholestatic jaundice
symptomatic GB disease
hepatic adenomas
ischemic bowel disease

Depression

Cancer

Others: alopecia, erythema multiforme, erythema nodosum
Hormonal Contraception
DRUG INTERACTIONS:

Phenytoin -  catabolism of contraceptives

Antibiotics – those that interfere with
normal GI flora who  enterohepatic
cycling & bioavailability of estrogen

Potent hepatic inducers (Rifampin) - 
liver catabolism of Es & Prog
Hormonal Contraception
CONTRAINDICATIONS & CAUTIONS:
Thrombophlebitis / thromboembolic phenomenon
 CV disorders
 Vaginal bleeding if cause is unknown
 Known or suspected tumor of the breast or other
estrogen-dependent neoplasm
 CHF or other edema
 Fibroid tumors – use progestational agents alone
 Adolescents whose epipjhyseal closure is not yet
completed

Hormonal Contraception
PREPARATION:
Progesterone Oral Contraceptives:
I. Oral formulation (Norethindrone, Norgestrel)

“mini-pill”

less effective

II. Subdermal (Norgestrel)

delivered via 6 silastic tubes implanted in the
upper arm

lasts 5-6 years

disadv:
need for surgical incision

irregular bleeding

IC HTN – rare
Hormonal Contraception
CLINICAL USES:


pts. with hepatic diseases, HTN, prior TE,
psychosis, mental retardation
SIDE EFFECTS:
Headache, dizziness, bloating & weight gain
 reversible reduction of glucose tolerance

Post Coital Contraception
 Estrogen alone

Combination Estrogen + Progestins → “MORNING
AFTER”
 Schedules:





Conjugated Estrogen:
10 mg TID X 5 days
Ethinyl Estradiol:
2.5 mg BID X 5 days
Diethylstilbesterol:
50 mg OD X 5 days
L-Norgestrel:
0.75 mg BID X 1 day
Norgestrel 0.5 mg with ethinyl estradiol 0.05 mg.
4 mg immediately then 2 tabs at 12 hours


S/E: N & V, HA, dizziness, breast tenderness,
abdominal & leg cramps
MIFEPRISTONE
• Antagonistic at progesterone & glucocorticoid receptors
• (+) luteolytic effect
• Combined with prostaglandins
“Men do not usually give themselves
any reasons for marrying…
… except that they
want to marry that
particular woman”