Basic and Clinical Pharmacology

C40 THE GONADAL HORMONES & INHIBITORS

ANITA Q. SANGALANG, MD, MHPEd, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

Gonadal hormones
 Steroids
 From the ovary
 Estrogen and progestins
 From the testis
 Chiefly testosterone
 Importance as contraceptives
 Many synthetic estrogens and progestins
 Partial agonists
 Receptor antagonists
 Some drugs with mixed effects
 Agonist effects in some tissues
 Antagonist effects in other tissues
 Mixed agonists with estrogenic
effects (SERMs)
 Selective estrogen receptor
modulators
 Synthetic androgens
 With anabolic activity
 Diverse group of drugs with
antiandrogenic effects
 Treatment
 Prostate cancer
 Benign prostatic hyperplasia
in men
 Mechanism of action of both estrogen and
 Hirsutism in women progesterone
 Entry into cells by binding to cytosolic
Ovarian Hormones
receptors
 Ovary  Translocation of receptor-hormone
 Primary source of sex hormones in women complex into the nucleus
during the childbearing years
 Binds to estrogen receptor elements
 Regulated by FSH and LH from the pituitary (EREs)
 Menstrual cycle consists of the following  Modulates gene expression
events
 A follicle in the ovary matures  Estrogens
 Secretes increasing amounts of estrogen  Estrone (E1), estriol (E3)
 Releases an ovum  Estradiol (E2)
 Transformed into a progesterone secreting  Major ovarian estrogen in women
corpus luteum
 Low oral bioavailability
 If the ovum is not fertilized and implanted
 Available in a micronized form for oral
 Corpus luteum degenerates use
 Uterine endometrium which has proliferated
under the stimulation of estrogen and
 Administered via
 progesterone is shed
 Transdermal patch
 Part of the menstrual flow
 Vaginal cream
 Cycle repeats
 Intramuscular injection
 Estradiol cypionate
 Long-acting esters of estradiol
 Converted in the body to estradiol
 Administered by IM injection
 Premarin
 Mixtures of conjugated estrogen from
biologic sources
 Oral for hormonal replacement therapy
(HRT)
 Ethinyl estradiol, mestranol
 Synthetic estrogens with high
bioavailability
 Used in hormonal contraceptives
 Effects
 Female maturation
 Essential for normal female sexual
development
 Growth of the genital structures
 Vagina, uterus, and uterine tubes during
childhood
 For the appearance of secondary sexual
characteristics
 Growth spurt associated with puberty
 Endometrial effects
 Development of the endometrial
lining
 When properly coordinated with the
production of progesterone
 Regular periodic bleeding and
shedding of the endometrial lining
 Metabolic and cardiovascular effects
 Modifies serum protein levels
 Reduces bone resorption
 Enhances coagulability of blood
 Increases plasma triglyceride
 Reduces low density lipoprotein
(LDL)
 Increases HDL
 Metabolic effects
 Continuous administration of
estrogen, especially in
combination with a progestin
 Inhibits the secretion of
gonadotropins from the anterior
pituitary
 Metabolic alterations in the liver
 Higher circulation of proteins
(CBG,TBG, SHBG,
transferrin, renin substrate
and fibrinogen)
 Increase levels of thyroxine,
estrogen, testosterone, iron,
copper and other
substances
 Clinical use
 Hypogonadism in young females
 Prevents bone loss and osteoporosis
 Components of hormonal
contraceptives
 HRT in women with estrogen deficiency
 Premature ovarian failure
 Menopause
 Surgical removal of the ovaries
 Ameliorates hot flushes and
atrophic changes in the urogenital
tract
 Toxicity
 In hypogonadal girls
 Dose of estrogen must be adjusted
carefully
 To prevent premature closure of
the epiphyses of the long bones
and short stature
 When used as HRT
 Increases the risk of endometrial
cancer
 Prevented by combining estrogen
with progestin
 Small increase in the risk of breast
cancer and stroke
 Not ameliorated by
concurrent progestin therapy
 Dose dependent toxicity
 Nausea Breast tenderness
 Hypertriglyceridemia
 Hypertension
 Gallbladder disease
 Increased risk of migraine
headache
 Thromboembolic events (deep vein
thrombosis)
 Progestins
 Progesterone
 Major progestin in humans
 Micronized form is used orally for HRT
 Vaginal creams are also available
 Medroxyprogesterone
 Synthetic progestin
 Improved oral bioavailability
 19-nortestosterone compounds
 Differ primarily in the degree of
androgenic effects
 L-norgestrel and norethindrone
 Older drugs
 More androgenic than newer
progestins
 Norgestimate, desogestrel,
gestodene
 3 gen synthetic progestins
rd
 “Impeded progestins”,
minimal estrogenic and
androgenic activity
  Hormonal Contraceptives
 3 different types of oral contraceptives
are available
 Effects
 Postcoital contraceptives
 Induces secretory changes in the
endometrium
 Required for the maintenance of
pregnancy
 Other progestins stabilize the
endometrium but do not support
 Mechanism of action
pregnancy
 Do not significantly affect plasma
proteins
 Affect carbohydrate metabolism
 Stimulate the deposition of fats
 High doses
 Suppress gonadotropin secretion
 Cause anovulation
 Clinical use
 Used as contraceptives
 Either alone or in combination with an
estrogen
 Combined with an estrogen in HRT
 To prevent estrogen induced
endometrial cancer
 Used in assisted reproductive
technology
 To promote and maintain pregnancy
 Toxicity
 Low
 May increase BP
 Decrease HDL
 Long term use of high doses in
premenopausal women
 Reversible decrease in bone density
 Delayed resumption of ovulation after
termination of therapy
 Combination of an estrogen and a
progestin or a progestin alone
 Available in variety of preparations
 Oral contraceptive pills (OCPs)
 Long-acting injections
 Transdermal patches
 Vaginal rings
 Intrauterine devices (IUDs)
 Monophasic preparation
 Combination of estrogen-
progestin tablets
 Taken in constant dosage
throughout the menstrual cycle
 Biphasic and triphasic preparations
 Progestin or estrogen dosage,
or both, changes during the
month
 To more closely mimic
hormonal changes in a
menstrual cycle
 Progestin only preparations
 “Emergency contraception”
 Prevent pregnancy if administered
within 72h after unprotected
intercourse
 Oral preparations are effective
 Inhibition of ovulation
 Primary action
 Effects in the cervical mucus
glands, uterine tubes, and
endometrium
 Decrease the likelihood of
fertilization and implantation
 Progestin only agents
 Do not always inhibit
ovulation
 Act through other
mechanisms
 Postcoital contraceptives
 Mechanism of action is not
well understood
 When administered before
the LH surge
 Inhibit ovulation
 Affect cervical mucus, tubal
function and the endometrial
lining
 Other clinical uses and
beneficial effect
 In young woman with primary
hypogonadism after their growth
has been achieved to prevent
estrogen deficiency
 Acne, hirsutism, dysmenorrhea
and endometriosis
 Users of combination hormonal
contraceptives reduces risk of
 Ovarian cyst, ovarian and
endometrial cancer
 Benign breast disease
 Pelvic inflammatory disease
 Ectopic pregnancy
 Iron deficiency anemia
  Rheumatoid arthritis
 Toxicity
 Introduction of the low dose
combined oral contraceptives
 Decrease the incidence of dose
dependent toxicity
 Thromboembolism
 Major toxic effects
 Action of the estrogenic
component on blood
coagulation
 Well documented increase
in the risk of
thromboembolic events
 Myocardial infarction,
stroke, deep
vein thrombosis, pulmonary
embolism
 Older women, smokers,
women with a personal or
family history of such
problems
 Genetic defects that affect
the production or function of
clotting factors
 Risk usually less than that
imposed by pregnancy
 Breast cancer
 Lifetime risk of breast
cancer in women who are
current or past users of
hormonal contraceptive is
not changed
 There may be an earlier
onset of breast cancer
 Other Toxicities
 Low-dose combined oral
and progestin only
contraceptives
 Significant breakthrough
bleeding
 First few months of therapy
 Nausea, breast tenderness,
headache, skin
pigmentation, depression
 Older, more androgenic progestins
 Weight gain, acne, hirsutism
 High dose of estrogen in the
estrogen-containing postcoital
contraceptives
 Significant nausea
 Selective Estrogen Receptor Modulators
(SERMs)
 Mixed estrogen agonists
 Estrogen agonist effects in some
tissues
 Partial agonists or antagonists of
estrogen in other tissues
 Tamoxifen
 Treatment of hormone-responsive
breast cancer
 Antagonist to prevent receptor
activation by endogenous estrogen
 Prophylactic use
 Reduces the incidence of breast
cancer in women who are at very
high risk
 Causes hyperplasia and increases
the risk of endometrial cancer
 Agonist at endometrial
receptors
 Causes hot flushes
 Antagonist effect
 Increases the risk of venous
thrombosis
 Agonist effect
 Prevents osteoporosis in women
who are taking the drug for breast
cancer
 More agonist than
antagonist action on bone
 Toremifene
 Structurally related
 Similar properties, indications, and
toxicity
 Raloxifene
 Prevention of osteoporosis in
postmenopausal women
 Partial agonist effect on bone
 Reduces the incidence of breast
cancer in women who are at very
high risk
 Antagonist effects in breast
tissue
 No estrogenic effects on endometrial
tissues
 Adverse effects
 Hot flushes
 Antagonist effect
 Increased risk of venous thrombosis
 Agonist effect
 Estrogen and Progesterone Agonists, Antagonists,
and Synthesis Inhibitors
 Clomiphene
 Used to induce ovulation in anovulatory
women who wish to become pregnant
 Nonsteroidal compound
 Selectively blocks estrogen receptors in
the pituitary
 Reduces negative feedback and
increases FSH and LH output
 Increase in gonadotropin stimulates
ovulation
 Diethylstilbestrol (DES)
 Nonsteroidal compound
 Estrogen agonist activity
 No longer used commonly
 Associated with infertility, ectopic
pregnancy, and vaginal adenocarcinoma
in the daughters of women who were
treated with large doses of DES during
pregnancy
 Mifepristone (RU 486)
 Orally active steroid antagonist of
progesterone and glucocorticoids
 Major use is as abortifacient in early
pregnancy
 Up to 49 days after the last menstrual
period
 Given as a single oral dose
 Followed by administration of
prostaglandin E (PGE) or PGF analog
 High percentage of complete abortion
 Low incidence of serious toxicity
 Effective postcoital contraceptive
 Danazol
 Weak partial agonists that binds to
progestin, androgen, and glucocorticoid
receptors
 Inhibits several P450 enzymes involved
in gonadal steroid synthesis
 Treatment of endometriosis and
fibrocystic disease of the breast
 Aromatase inhibitors
 Anastrozole and related compounds
(letrozole)
 Nonsteroidal inhibitors of aromatase
 Enzyme required for estrogen synthesis
 Treatment of breast cancer
 Androgens
 Testosterone and related androgens
 Produced in
 Testis
 Adrenals
 To a small extent, the ovary
 Testosterone
 Synthesized from progesterone and
dehydroepiandrosterone (DHEA)
 Partly bound to sex hormone-binding
globulin (SHBG)
 Transport protein
 Converted in several organs (prostate) to
dihydrotestosterone (DHT) which is the
active hormone
 Little effect when given oral due to rapid
hepatic metabolism
 Given by injection or transdermal patch
 Long-acting esters
 Orally active variants are also available
 Mechanism of Action
 Enter cells and bind to cytosolic receptors
 Hormone-receptor complex enters the
nucleus and modulates the expression of
target genes
 Effects
 Necessary for normal development of the
male fetus and infant
 Responsible for the major changes in the
male at puberty
 Growth of penis, larynx, and skeleton
 Development of facial, pubic, and axillary
hair
 Darkening of skin
 Enlargement of the muscle mass
 After puberty
 Maintain secondary sex characteristics,
fertility and libido
 Acts on hair cells to cause male-pattern
baldness
 Anabolic action is another major effect
 Increased muscle size and strength
 Increased red blood cell production
 Excretion of urea nitrogen is reduced
 Nitrogen balance becomes more positive
 Helps maintain normal bone density
 Clinical Use
 Replacement therapy in hypogonadism
 Primary clinical use
 Stimulate red blood cell production in certain
anemias
 Promote weight gain in patient with wasting
syndromes (e.g., AIDS patients)
 Treatment of osteoporosis, either alone or in
conjunction with estrogens
  Growth stimulators in boys with delayed
puberty
 Anabolic effects
 Exploited illicitly by athletes
 Increase muscle bulk and strength
 Enhance athletic performance
 Toxicity
 Use in females
 Virilization
 Hirsutism, acne, enlarged clitoris,
deepened voice, menstrual irregularity
 In women who are pregnant with a
female fetus
 Exogenous androgen can cause
virilization of the fetus’ external
genitalia
 Excessive dosage in men
 Feminization
 Gynecomastia, testicular shrinkage,
infertility
 Paradoxical effect
 Feedback inhibition of the pituitary and
conversion of the exogenous androgens
to estrogens
 High doses
 Behavioral effects
 Hostility and aggression
 In both sexes, high doses
 Cholestatic jaundice
 Elevation of liver enzyme levels
 Possible hepatocellular carcinoma
 Antiandrogens
 Reduction of androgen effects
 Mode of therapy for both benign and malignant
prostate disease
 Precocious puberty
 Hair loss
 Hirsutism
 Receptor Inhibitors
 Flutamide and related drugs
 Nonsteroidal compounds
 Competitive antagonists at androgen
receptors
 Decrease the action of endogenous
androgens in patients with prostate
carcinoma
 Causes mild gynecomastia and
reversible hepatic toxicity
 Bicalutamide
 Orally active , single daily dose and well
tolerated
 Lesser GI side effects
 Combined with GnRH analog for
metastatic carcinoma of the prostate
 Nilutamide
 Spironolactone
 Used principally as a potassium-sparing
diuretic
 Competitive inhibitor of aldosterone
 Competes with dihydrotestosterone for
the androgen receptors
 Reduces 17 alpha hydroxylase activity-
lowering testosterone and
androstenedione
 Treatment of hirsutism
 Cyproterone and cyproterone acetate
 Acetate form has marked progestational
effect that suppresses the feedback of
LH and FSH leading to a more effective
antiandrogen effect
 Treatment of hirsutism in women and
decrease sexual drive in men
 Combined with estrogen for hirsutism
and OCP use
 Gonadotropin-Releasing Hormone
Analogs (GnRH Agonists)
 Leuprolide or similar GnRH agonists
 Long-acting depot preparations
 Reduction of gonadotropins, especially
LH,
 Reduces the production of testosterone
 Used in prostatic carcinoma
 First week of therapy
 Flutamide (androgen receptor
antagonist)
 Added to prevent the tumor flare
that can result from the surge in
testosterone synthesis caused by
the initial agonistic action on the
GnRH agonist
 Testosterone production falls to
normal and then below normal
within several weeks
 5α-Reductase Inhibitors
 Testosterone is converted to DHT by 5α-
reductase
 Prostate cells and hair follicles
 Depend on DHT for androgenic
stimulation
 Finasteride
 Dutasteride
 Oral, slower onset of action, longer
half-life
 Finasteride
 Treatment of benign prostatic
hyperplasia
 At lower doses
 Prevents hair loss in men
 Does not interfere with the action of
testosterone
 Less likely to cause impotence,
infertility and loss of libido
 Combined Hormonal Contraceptives
 Exert antiandrogenic effects
 When used in women with hirsutism
 Due to excess production of androgenic
steroids
 Estrogen in the contraceptive
 Acts in the liver to increase the production of
SHBG
 Acts to reduce the concentration of free
androgen

 Inhibitors of Steroid Synthesis

 Ketoconazole
 Antifungal agent
 Inhibits gonadal and adrenal synthesis
 Used to suppress adrenal steroid
synthesis in patients with steroid
responsive metastatic tumors
 Gossypol
 Cottonseed derivative
 Destroys elements of the seminiferous
epithelium
 Does not significantly alter endocrine
function of the testis
 44% developed sperm counts below 4M/ml
 Hypokalemia is the major adverse effect