Estrogens, progestins and antiestrogens.
Androgens and antiandrogens.
Estrogens and progestins:
•two major classes of female sex hormones
•functions in the development of female secondary
sex characteristics
•control of pregnancy
•control of ovulatory-menstrual cycle
•modulation of many metabolic processes
ESTROGENS
•17β-estradiol, estriol, estrone
•responsible for the development of secondary sex
characteristics
•initiate breast development by increasing ductal and
stromal growth
•contribute to accelerated growth at puberty
•stimulate closure of the epiphyses in the shafts of
the long bones
•stimulate the synthesis and secretion of prolactin
from pituitary lactotrophs
•accelerate cellular proliferation of uterine
endometrium and stroma in the absence of
progesterone, as occurs in the follicular phase of the
menstrual cycle
•induce RNA and protein synthesis in cells
•generate thickening of the vaginal mucosa and
thinning of cervical mucus
•aid in maintaining bone mass, as evidenced by
substantial but preventable with estrogen
replacement therapy) bone loss in postmenopausal
women
•stimulate hepatic production of sex hormonebinding globulin, thyroid-binding globulin, bloodclotting factors (VII, VIII, IX, X), plasminogen,
HDL
•inhibit antithrombin III, LDL formation
•increase retention of sodium and water (edema)
•decrease bowel motility
•role in the progression of some endometrial tumors
•risk factor for breast cancer
•endometrial hyperplasia, increased risk of
endometrial cancer
Clinical uses
 Hypogonadism
 Relief of menopausal symptoms – in
postmenopausal hormonal therapy
 Hot flushes
 Relief of atrophic vaginitis
 Preventing bone loss and osteoporosis
 In combination with progestins for
contraception
Contraindications
 endometrial cancer,
 breast cancer,
 undiagnosed genital bleeding,
 liver disease,
 history of thromboembolic disorder,
 histories of coronary or cerebrovascular
disease,
 heavy smokers
Adverse effects
 Cancer: breast cancer, endometrial cancer,
adenocarcinoma of the vagina
 Thromboembolic
disease,
myocardial
infarction, strokes,
 Uterine bleeding, Excessive bleeding,
Amenorrhea,
 Breast tenderness,
 Migraine, headaches,
 Depression
 Acne,
 Hirsutism
 Elevated triglycerides, serum glucose
PROGESTINS
Progesterone – the major progestin in humans
Synthetic progestins - eg Medroxyprogesterone,
Desogestrel, Gestodene, Norgestimate
•partially responsible for mediating mammary
glandular development, role in ductal growth
•high concentrations in the luteal phase of the
menstrual cycle – modulation of estrogen’s action on
the uterus
•without
estrogen,
progesterone
receptor
concentrations are low and estrogen priming is
necessary for progesterone receptor induction in
almost all progesterone-responsive tissues
•increased basal body temperature (luteal phase)
•aid in the maintenance of pregnancy
•inhibits uterine contraction
•increase sodium and water elimination by competing
with aldosterone for binding to mineralocorticosteroid
receptor
Therapeutic applications:
 Hormone replacement therapy (HRT)
o Micronized form used orally
o Progesterone-containg vaginal creams
 Hormonal contraception (alone or in
combination with an estrogen),
 In combination with an estrogen in HRT to
prevent estrogen-induced endometrial cancer
Diagnostic uses:
 As a test of estrogen secretion – the
administration of progesterone is followed
by withdrawal bleeding in amenorrheic
patients only when the endometrium has
been stimulated by estrogens
 A combination of estrogen and progestin can
be given to test the responsiveness of the
endometrium in patients with amenorrhea
Contraindications:
Thromboembolic disorder,
Liver disease,
Undiagnosed genital bleeding,
Adverse effects
The toxicity of progestins is low
•decrease HDL and increase LDL concentration
Oral contraceptives
Two types of oral contraceptives are
available:
• Combinations of estrogen and
progestins
• Progestins only
Action:
-Inhibition of ovulation by altering the
hypothalamic-gonadotropin axis
-Alteration in cervical mucus to prevent sperm
entry and uterine endometrium to prevent
implantation
-Suppression of ovarian function
-Breast stimulation
Progestogen-only pill:
Makes endometrium unsuitable for implantation
and cervical mucus hostile to sperm
May inhibit ovulation in 40% of women
Contraindications:
• Not to be used in clients with history of
thromboembolic or cerebrovascular
disease
• Avoid in clients with estrogen-dependent
neoplasms (breast cancer, endometrial
cancer)
• Women with bleeding for which a cause
is not known
Used with caution in clients with:
• hepatic disease,
• migraines,
• diabetes,
• hypertension,
• seizure disorders
because exacerbation of the above may
occur
Used with caution in women with fibroids (may
worsen)
Used with caution in coronary artery disease
Pregnancy
Smoking will increase the likelihood of
pulmonary embolic disease
Oral contraceptives-Estrogenic effect
• Nausea
• Increased breast size
• Cyclic weight gain due to fluid retention
• Leukorrhea (discharge of white mucous
material from the vagina)
• Cervical eversion or ectopy
• Hypertension
• Rise in cholesterol concentration in
gallbladder bile
• Growth of leiomyoma
• Telangiectasia
• Hepatocellular adenomas or hepatocellular
cancer (rare)
• Cerebrovascular accidents (rare)
• Thromboembolic complications including
pulmonary emboli (rare)
• Stimulation of breast neoplasia
(exceedingly rare)
Progestogenic and estrogenic effect:
• Headaches
• Hypertension
• Breast tenderness
• Myocardial infarction (rare)
Androgenic effect/antiandrogenic effect:
• All low-dose combined pills suppress a
woman’s production of testosterone,
which has beneficial effect on acne, oily
skin, and hirsutism (excessive hairiness in
females).
Androgenic effect :
•
•
•
•
•
•
•
Increased appetite and weight gain
Depression, fatigue, tiredness
Acne, oily skin
Increased breast size or breast tenderness
Decreased HDL
Increased LDL concentration
Increased insulin resistance
Oral contraceptives-Postcoital contraceptives
• Administration progestins alone or in
combination with estrogens
• „morning after” pill
• EMERGENCY CONTRACEPTION
• May reduce the risk of pregnancy by:
-Preventing ovulation
-Preventing fertilization
-Preventing imlantation
ANTIESTROGENS
SERMs - selective estrogen receptor modulators
– agonists/antagonists
 Tamoxifen
•Partial agonist inhibitor of estradiol at the estrogen
receptor
•Used in the palliative treatment of advanced breast
cancer in postmenopausal women
•Nonsteroidal agent, given orally
•Adverse effects - hot flushes, nausea, vomiting
Agonistic effects on
• bone,
• serum lipid profiles
• endometrial tissues
(cancer!)
Antagonistic effects on
• breast tissue
 Raloxifene
•Another partial estrogen agonist-antagonist at some
but not all target tissues,
•Similar effects on lipids and bone
•Not stimulates the endometrium or breast
•Prevention of postmenopausal osteoporosis
Agonistic effects on
• bone,
• serum lipid profiles
Antagonistic effects on
• endometrial,
• breast tissues
Danazol - Inhibits FSH and LH release from the
pituitary gland
Indications
• Endometriosis
• Fibrocystic breast disease
• Hereditary angioedema
• Hemophilia
Adverse effects
• Hot flushes
• Weight gain
• Acne and oily skin
• Hirsutism
• Changes in libido
• Impaired renal, liver function
• Vaginal bleeding
Anastrozole & Letrozole:
Selective nonsteroidal inhibitors of aromatase,
Are effective if breast tumors have become
resistant to tamoxifen
ANDROGENS
•Known as anabolic steroids because they are steroid
compounds that have the ability to exhibit te tissue
building and masculinization characteristics of the
male hormone testosterone
•Testosterone – the most important androgen
produced by the Leydig cells and adrenal gland
responsible for the development of secondary sex
characteristics in the male
Synthetic steroid drugs related to testosterone are
known as anabolic steroids, and these drugs tend to
have similar actions as testosterone
Indications:
 Androgen replacement in hypogonadism,
 Protein anabolic agent (severe injury or
debilitating illness),
 Refractory anemia,
Adverse effects:
 Females - virilization and mentrual
irregularityty
 in pregnancy with a female fetus – virilization
of the fetus’s external genitalia
 paradoxically, excessive doses in men –
feminization
 both sexes – cholestatic jaundice, elevation of
liver enzyme levels, hepatocellular carcinoma
(possibly)


Common androgen inhibitors
Finasteride: Blocks conversion of testosterone to its
most active intracellular form (dihydrotestosterone),
shrinks prostate size
Indications
• Prostatic hypertrophy
Adverse effects
• Decreased libido
• Impotence
Receptor inhibitors: Cyproterone, Cyproterone
acetate, Flutamide
Cyproterone & Cyproterone acetate
• Effective antiandrogens that inhibit the action
of androgens at the target organ
• Acetate form – progestational effect that
suppresses the feedback enhancement of LH
and FSH – more effective antiandrogen effect
• Women – treatment of hirsutism
• Men – to decrease excessive sexual drive
Flutamide
• Treatment of prostatic carcinoma
• Causes gynecomastia
•
(probably by increasing testicular
estrogen production)
• Reversible hepatic toxicity