GONADAL HORMONES AND

INHIBITORS
Ma. Victoria Matias-Villarica, RN, MD, DPPS, FPSECP
Dept. of Pharmacology
Our Lady of Fatima University
College of Medicine
 Estrogen
• Natural Estrogen Non-steroidal Synthetic Estrogen
a. 17-β-estradiol
a. Methestrol
b. Estrone b. Dienestrol
c. Estriol c. Benzestrol
d. Hexistrol
• Synthetic Estrogen e. Diethylstilbestrol
a. Ethinyl estradiol f. Chlorotrianisene
g. Methallenestril
b. Quinestrol
c. Mestranol Anti-Estrogen
a. Tamoxifen
b. Clomiphene
 Progesterone
• Natural Progestin
- Progesterone
• Synthetic Progestin
a. Norgestrol
b. Medroxyprogesterone
c. Norethindrone
• Anti-progestin
a. Danazol
b. Mifepristone
Androgens
• Natural Androgen
- Testosterone
• Synthetic Androgen
a. Methyltestosterone
b. Fluoxymesterone
• Anabolic Steroid
a. Oxandrolone
b. Stanozolol
Androgens (cont.)
•Androgen Antagonist
a. Finasteride
b. Flutamide
c. Cyproterone
d. Ketoconazole
e. Spirinolactone
Ovary
- Quiescent (childhood-related inhibitory effect) –
GnRH

- Gonadarche (puberty) – breast enlargement,

alterations in fat distribution and growth spurt that leads to
epiphyseal closure in the long bones

- Menarche – a year after gonadarche, sufficient estrogen

induce endometrial changes and periodic bleeding

- Menopause – cessation of uterine bleeding (mean age:

52 yrs.)
- Disturbances of ovarian function: amenorrhea or anovulatory cycles
a. emotional or physical stress
b. eating disorders (bulimia, anorexia nervosa) and severe
exercise (distance running and swimming)
c. organic causes – pituitary prolactinomas, arrhenoblastoma,
Leydig cell tumors
Estrogen
•Major estrogens produced by women
Natural Estrogen
a. 17-β-estradiol (E2) – major secretory product of the ovary
b. Estrone (E1)
c. Estriol (E3)
Most estrone and estriol are formed
in the liver and peripheral tissues
Estrogen:

• Secreted by the theca cells, corpus luteum, placenta (during

pregnancy, assay of maternal urinary estriol excretion can be used to assess
fetal well-being) and adrenals and testes
• 50 pg/mL to 350-850pg/mL
• Bounded by SHBG
• Estrogen receptor – α and β isoforms
• Metabolites: cathecol estrogen → neurotransmitters →
converted to 2- and 4-methoxycompounds by COMT
• Enterohepatic circulation
 Estrogen
• Natural Estrogen Non-steroidal Synthetic Estrogen
a. 17-β-estradiol a. Methestrol
b. Estrone b. Dienestrol
c. Benzestrol
c. Estriol d. Hexistrol
• Synthetic Estrogen e. Diethylstilbestrol
f. Chlorotrianisene
a. Ethinyl estradiol g. Methallenestril
b. Quinestrol
Anti-Estrogen
c. Mestranol
a. Tamoxifen
b. Clomiphene
 Estrogen: Physiologic effects

• Female maturation
- stimulate the development of vagina, uterus, uterine tubes
- breast: stromal development, ductal development
- growth: accelerated; closure of epiphysis of long bones
- growth of axillary/pubic hair
- typical female body contour (alter distribution of body fat)
- skin pigmentation (nipples, areolae and genital region)
Estrogen: Physiologic effects (cont.)
• on sexual organs (primary and secondary sexual
characteristics)
• ovaries : stimulate follicular growth; small doses cause an increase in
weight of ovary; large doses cause atrophy
• uterus: endometrial growth
• vagina: cornification of epithelial cells with thickening and stratification of
epithelium
• cervix: increase of cervical mucous with a lowered viscosity (favoring
sperm access)
Estrogen: physiologic effects (continued)
• Endometrial effects – development of endometrial lining (continuous exposure to estrogen for
prolonged periods leads to hyperplasia with abnormal bleeding patterns)
• Metabolic and Cardiovascular effects:
- partially responsible for maintenance of the normal structure of the skin and blood vessels in
women
- ↓ rate of bone resorption (promotes apoptosis of osteoclasts and antagonizes the
osteoclastogenic and pro-osteoclastic effects of PTH and IL-6)
- stimulate adipose tissue production of leptin (hormone of energy expenditure)
- higher circulating levels of proteins (CBG, TBG, SHBG, transferrin, renin substrate and
fibrinogen) results to increased levels of thyroxine, estrogen, progesterone, iron, copper, and
other substances
- ↑HDL, slight ↓LDL, ↑TG, reduction in total plasma cholesterol levels ;
• Effects of blood coagulation:
- enhances blood coagulability : ↑ Fx II, VII, IX, X
- ↓ antithrombin III
- ↑plasminogen levels, ↓platelet adhesiveness
Estrogen: physiologic effects (cont)

• Other effects:
- induce synthesis of progesterone receptors
- influence behavior and libido in humans; estrous behavior in animals
- promotes a sense of well-being (stimulates central components of stress
system– CRH and sympathetic nervous system) when given to women that
are estrogen deficient
- loss of fluid from intravascular into the extravascular space (edema) due to
compensatory retention of Na and water by the kidney
- modulate Sympathetic nervous system control of smooth muscle function
- electrolytes: retention of Na+, Cl- and water by the kidney

-
 Estrogen: Clinical uses
A. Primary Hypogonadism - initiated at 11-13 y/o (0.3mg conjugated
estrogen or 5- 10mcg ethinyl estradiol on D1 to D21 each month and slowly
increased to adult doses until the age of menopause

B. Postmenopausal Hormonal Therapy

Menopausal Changes:
• Loss of menstrual period
• Vasomotor symptoms
• Sleep disturbances
• Acceleration of bone loss (vertebral, hip and wrist fractures) – Daily Ca intake: 1500mg
• Acceleration of atherosclerotic cardiovascular disease
• Accelerated rise in plasma cholesterol and LDL concentrations while LDL receptors
decline; HDL, VLDL and triglycerides levels are relatively unaffected
Estrogen: Clinical uses
• Post-menopausal hormonal therapy
reduction of MI (50%), fatal strokes (40%) – controversial
prevent fractures
colon Ca (small protective effect)
Alzheimer’s disease

• 0.3mg – 1.25mg/d of conjugated estrogen or 0.01-0.02 mg/d ethinyl estradiol

D1-D25 monthly + 10mg/d of medroxyprogesterone acetate on last 10-14 days
– to ê risk of endometrial carcinoma

• S/P hysterectomy – 5 days/week continuously

• atrophic vaginitis - topical (50 – 100 mcg estradiol transdermally

• Continuous therapy: 0.625mg conjugated equine estrogen and 2.5 – 5mg of

medroxyprogesterone will eliminate cyclic bleeding, control vasomotor symptoms,
prevent genital atrophy, maintain bone density and show a favorable lipid profile
(disadvantage: need for uterine biopsy if bleeding occurs after the 1st few months)
• C. Other Uses :
• suppress ovulation in patients with intractable dysmenorrhea
• suppression of ovarian function in the treatment of hirsutism and amenorrhea
due to excessive secretion of androgens by the ovary (oral contraceptives
50mcg of estrogen or low-estrogen pill with GnRH suppression
• oral contraception
Adverse effects of Estrogen:
A. Uterine bleeding – use smallest amount of estrogen, given cyclically so
bleeding occurs more likely during withdrawal period and use a
progestational agent with estrogen to prevent endometrial hyperplasia
B. Cancer – breast cancer; endometrial cancer; adenocarcinoma of the
vagina in young women whose mothers were treated with large doses of
DES early in pregnancy
C. Other Effects – nausea, breast tenderness, hyperpigmentation; migraine
headaches, cholestasis, gallbladder disease and hypertension
 Estrogen: Contraindications
• Estrogen dependent neoplasm (high risk Ca of the
breast, endometrial Ca)
• Undiagnosed genital bleeding
• Liver disease
• History of thromboembolic disorders
• Avoided by heavy smokers
Progesterone:
• Synthesized in the ovary, testes, adrenals from circulating
cholesterol; placenta
• Produced primarily by corpus luteum
• Males: 1-5mg daily or 0.03ug/dl plasma level; Luteal phase:
0.5mcg/dL – 2 mcg/dL
• Kinetics: rapidly absorbed; t1/2 – 5mins; completely
metabolized in the liver (pregnanediol and conjugated with
glucuronic acid); excreted in the urine (preganediol
glucuronide - index)
PROGESTERONE
CH3

C O Natural hormone secreted

by the corpus luteum and the
H
placenta ( a C-21 steroid)

H H it is also an important
O
intermediate in steroid
biogenesis in all tissues that
PROGESTERONE
produce steroids (testes,
adrenal cortex)

Intestinal absorption is quite erratic; must be micronized for

most effective absoption (Prometrium)
 Progesterone: Physiologic effects:
• Stimulates lipoprotein lipase activity and seems to favor fat deposition
• Affects carbohydrate metabolism
• Increase basal insulin secretion and insulin response to glucose
• Liver: promotes glycogen storage by facilitating the effect of insulin; promotes ketogenesis
• Compete with aldosterone for the mineralocorticoid receptor of the renal tubule, causing a
decrease in Na reabsorption è é secretion of aldosterone by the adrenal cortex
• ↑ body temperature (unknown)
• Respiratory function:é ventilatory response to CO2 (but progestins + ethinyl group do not
have respiratory effects) that leads to reduction in arterial and alveolar PCO2
• Breast: alveolobular development of the secretory apparatus of the breast
• Endometrium: maturation and secretory changes (participates in the preovulatory LH surge)
• ↓plasma levels of amino acids èé urinary nitrogen excretion
Synthetic Progestins
• 21-carbon analogs - antagonize aldosterone-induced sodium retention

• 19-nortestosterone 3rd generation:

- produce a decidual change in the endometrial stroma
- do not support pregnancy in test animals
- are more effective gonadotropin inhibitors and may have minimal estrogenic
and androgenic or anabolic activity (impeded androgens)
 Progesterone: Clinical uses
• Hormonal replacement therapy
• Contraception – long term ovarian suppression
• Prolonged anovulation and amenorrhea (medroxyprogesterone acetate 150mg IM
every 90 days) – for dysmenorrhea, endometriosis, bleeding disorders when
estrogens are contraindicated and contraception
• Diagnosis of estrogen secretion
• - 150mg/d or medroxyprogesterone 10mg/day X 5-7 days ; then, if followed by
withdrawal bleeding → (+) estrogen secretion
• Precocious puberty: Medroxyprogesterone acetate: 10 – 20mg orally twice weekly
or IM 100mg/m2 every 1-2 weeks (will prevent menstruation but it will not arrest
accelerated bone maturation in these children)
• NO PLACE in habitual abortion
• Premenstrual syndrome
 Progesterone: CI/AE/CAUTIONS
• May increase BP
• Decrease plasma HDL (more androgenic progestins)
• é breast Ca risk (combined progestin plus estrogen
replacement therapy in postmenopausal women)
Other androgens secreted by the ovary:
• Androgens: - normal hair growth, stimulates female libido, metabolic effects; associated with
hirsutism and amenorrhea(abnormal state)
• 1. Testosterone – 200 mcg/24 hrs.; significant amount of biologic activity (1/3 from the ovary)
• 2. Androstenedione
• 3. DHEA (dehydroepiandosterone)
• Inhibin- inhibits FSH secretion
• Activin – increases FSH secretion; modulates the response to LH (suppress LH-induced
progesterone response by 50% but markedly enhance basal and LH-stimulated aromatase
activity) and FSH (enhance progesterone synthesis and aromatase activity)
• Relaxin – growth promoting peptide;
synthesized by leutinized granulosa cells of the corpus luteum:églycogen synthesis and water
uptake by the myometrium and decreased uterine contractility; if applied to cervix at term,
facilitates dilation and shortens labor
Testes:
• Functions: sperm production (FSH) – Sertoli cells
testosterone synthesis (LH) – Leydig cells
• 8mg testosterone daily
• Weak androgen: androstenedione, dehydroepiandrosterone
• Pregnenolone and progesterone
• Active androgen: dihydrotestosterone
(5-α-reductase)
• Testosterone is converted to estradiol by p450 aromatase
• é SHBG – estrogen, TH, cirrhosis of the liver
• êSHBG – androgen, GH, obese individual
 Testosterone: Physiologic effect
• Changes in the skin (pubic, axillary, beard)
• Larynx grows; vocal cords – thicker, low-pitched
• Skeletal growth; epiphyseal closure
• ↑ lean body mass
• Male development
• Metabolic effect: é liver synthesis of clotting factors, TG, lipase, α1-
antitrypsin, haptoglobin and sialic acid; êhormone binding and carrier
proteins
• Anabolic effect on muscle and bone mass: ↑ CHON synthesis, ↓ CHON
breakdown
• Other effects: erythrocyte production, musculinization in females
 Testosterone: Clinical Uses
• Androgen replacement therapy (pituitary deficiency): testosterone
enanthate or cypionate 50mg IM q 4wk, then q 3wk, then q 2wk then
100mg q with each taking place at 3-mo interval until maturation is
complete; then 200mg at 2-week interval (adult replacement dose)
• Gynecologic disorders: reduce breast engorgement
• Protein anabolic agent (trauma, surgery or prolonged immobilization and
debilitating disorders)
• Refractory anemia (replaced by erythropoietin)
• Osteoporosis (replaced by biphosphanates)
• Growth stimulators
• Abused in sports – strength and aggressiveness
• “Slows” aging
Testosterone: Contraindication
• Pregnant women
• Ca of the prostate, breast

Adverse effect:
• Musculinizing effect in women
• Alteration of serum lipid profile
• Hepatocellular Ca
Anabolic, androgenic, and growth hormones
• Anabolic refers to muscle building (Testosterone, Dianobol, and
Deca Durabolin)
• Androgenic refers to increased masculine characterictics
(Equipoise, Masteron, and Trenbolone)
• Growth hormones are different in nature from anabolic-
androgenic steroids.
 Anti-Estrogen
• Clomiphene
- partial agonist at estrogen receptors
- act as competitive inhibitors
- stimulates ovulation by preventing feedback inhibition
- AE: hot flushes, eye symptoms, ovarian cyst, skin rxn,
multiple births
- 50mg OD x 5days;
100mg OD x 5days;
100mg OD x 5days
 Anti-Estrogen:
• Tamoxifen – 1st SERM
- Act as competitive partial agonist/ inhibitor of estradiol at estrogen receptor; nonsteroidal;
given orally
- For palliative treatment of breast cancer in postmenopausal women and is approved for
chemoprevention of breast Ca in high risk women
- May increase risk if endometrial cancer
- AE: hot flushes, N and V, vulvar pruritus, menstrual irregularities
- 10-20mg BID (35% ↓ but not >5yrs: no improvement in outcome)

□ Toremifene – prevent bone loss, ↓atherosclerosis; (+) uterus

□ Raloxifene - prevent bone loss, ↓atherosclerosis; (-) uterus; (-) breast; taken once a
day due to long t ½ ; approved for the prevention of postmenopausal osteoporosis and
prophylaxis of breast cancer in women with risk factors

Bazedoxifene – new SERM; approved for the treatment of menopausal symptoms and
prophylaxis of postmenopausal osteoporosis
AROMATASE INHIBITORS
• aromatase is a cytochrome P450 enzyme that catalyzes the
conversion of adrenal androgen androstenedione to estrone in
both pre- and post menopausal women
• reaction occurs in the liver, muscle, adipose and breast tissue
• in post-menopausal women, aromatization is responsible for
the majority of circulating estrogen
• aminoglutethimide was used but has now been replaced by
more selective drugs
• drugs may be steroidal (testolactone, exemestane) or
non-steroidal (anastrozole, letrozole)
• estrogen deprivation through aromatase inhibition is an
effective and selective treatment for some post-menopausal
patients with hormone-dependent breast cancer
Exemestane (Aromasin)
• 6-methylenandrosta-1,4-diene-3,17-dione
• structurally related to androstenedione
• acts as an irreversible (suicide) inhibitor of aromatase
• has no effect on other enzymes involved in
steroidogenesis
• indicated for the treatment of advanced breast cancer
in postmenopausal women whose disease has
progressed following tamoxifen therapy
 Anti-Progestin
• Mifepristone – RU 486
- inhibits activity of progesterone
- post-coital contraceptive (600mg SD), abortifacient
(400-600mg x 4days/ 800mg/day x 2days (85%) or
600mg SD + misoprostol 1mg (95% 7wks); Cushing’s
syndrome
- AE: heavy bleeding, N and V, anorexia, abd. pain
Anti-Progestin
•Danazol
- suppress ovarian function; inhibits mid-cycle surge of
LH, FSH
- endometriosis (600mg/d)
- fibrocystic dis. of the breast
- AE: weight gain, edema, acne, cramps
- CI: pregnancy, breastfeeding
 Anti-Androgen
Inhibitor of conversion of steroid precursor to androgen:
• Finasteride – inhibits 5-α – reductase (5mg/d)
- BPH(5mg/D), early male pattern-baldness (1mg/D)
• Dutasteride - BPH; 0.5mg daily
• Abiraterone – metastatic prostate Ca

Steroid synthesis inhibitor:

• Spirinolactone - ↓synthesis of testosterone on the testes
• Ketoconazole - ↓synthesis of testosterone on the testes
•
Receptor Inhibitors:
• Spirinolactone – hirsutism in women (50-200mg/d)
- inhibits binding to androgen receptor
• Cyproterone and cyproterone acetate – inhibits binding to
androgen receptor
- hirsutism in women (2mg + estrogen)
• Flutamide – inhibits binding to androgen receptor
- prostatic Ca; excessive androgen in women
1. Bicalutamide (150-200mg/d)
2. Nilutamide (300mg/d x 30 days then 150mg/d)
3. Enzalutamide – 160mg/d
Hormonal Contraception
• Oral contraceptives:
1. combination of estrogen and progestins
2. continuous progestin therapy without administration of
estrogen
• Implantable:
1. Etonogestrel
• Vaginal rings or intrauterine devices
• Intramuscular injection
Hormonal Contraceptives
• Combination oral contraceptive
I. Monophasic – provide constant amount of estrogen
and progesterone (21day)
II. Biphasic – provide constant amount of estrogen but
varying amount of progestin
III. Triphasic - provide varying amounts of estrogen and
progestin
• Transdermal combination contraceptive
Pharmacologic Effects:
• Mechanism of action:
- selective inhibition of pituitary function results in inhibition of ovulation; change in the
cervical mucus, in the uterine tubes
• Ovary: depress ovarian function, minimal follicular development and absent corpora
lutea, larger follicles, stromal edema; low maturation index on vaginal smears
• Uterus: hypertrophy and polyp formation; thicker and less copious cervical mucus;
progestins (in combined contraceptives) stimulates glandular secretion throughout the
luteal phase; “19-nor” progestins – more glandular atrophy and less bleeding
• Breast: some enlargement; suppress lactation but when given in small doses, no
suppression and can cross breast milk
Pharmacologic Effects:
• Other effects:
• CNS: estrogen – excitability; progesterone – decrease excitability
• Endocrine system: alter adrenal structure and function; éα2globulin that binds cortisol;
éplasma renin activity; éaldosterone secretion; éthyroxine binding globulin; étotal
plasma thyroxine (T4); éSHBG; ê plasma free androgens by increasing their binding
• Blood - éFVII, VIII, IX, X; êantithrombin III (increase amount of anticoagulants when
taking oral contraceptives); éserum iron and TIBC in patient é
• Liver – delay the clearance of sulfobromophthalein and reduce blood flow of the bile;
é cholic acid and ê chenodeoxycholic acid; é cholelithiasis
• Lipid metabolism - éserum triglycerides, free and esterified cholesterol; éHDL,
êLDL ; (100mcg mestranol or ethinyl estradiol); doses of 50 mcg or less have have
minimal effects – slightly êtriglycerides and HDL
• Carbohydrate metabolism – reduce rate of absorption of carbohydrates;ébasal insulin
level; norgestrel - êcarbohydrate tolerance
• Cardiovascular system – small increase in CO
• Skin – increase pigmentation of the skin (chloasma)
Examples of Oral Contraceptives
• 4 types:
• monophasic: Loestrin, Levlen, Levora, Levlite,
Desogen, Lo/Ovral, Ortho-Cept, Nordette, Demulen,
Ovcon, Modicon, Zovia, Loestrin, Apri, Microgestin,
Yasmin, Ortho-Cept, Levora, Alesse
• biphasic: Ortho-Novum 10/11, Nelova 10/11, Necon
10/11, Jenest-28, Mircette
• triphasic: Ortho-Novum 7/7/7, Tri-Norinyl, Tri-Levlen,
Triphasil, Trivora-28, Estrostep
• progestin-only: Micronor, Nor-QD, Ovrette
Adverse effect of combination oral contraceptive:

• Mild: nausea, mastalgia, breakthrough bleeding, changes in

serum protein, transient headache, withdrawal bleeding
• Moderate: breakthrough bleeding, weight gain, skin
pigmentation, acne, hirsutism, vaginal infections, amenorrhea
• Severe: vascular disorders (MI, CVA), cholestatic jaundice,
depression, Ca
OTHER CONTRACEPTIVE PRODUCTS
Progesterone only contraceptive
• Levonorgestrel implants (Norplant system)
• intrauterine progesterone contraceptive system (Progestasert)
• medroxyprogesterone contraceptive injection (Depo-Provera)
• nonoxynol contraceptive creams and gels
Emergency contraceptives
• drugs used for the prevention of pregnancy following
unprotected intercourse or a known or suspected
contraceptive failure
• to be effective these must be taken within 72 hours of
intercourse
Postcoital contraceptives
• Conjugated estrogens: 10mg 3x/day X 5days
• Ethinyl estradiol: 2.5mg 2x/d X 5days
• Diethylstilbestrol: 50mg daily X 5days
• Mifepristone: 600mg once (D1) with Misoprostol 400mg
once (D3)
• L-Norgestrel: 1.5mg once (plan B 0ne step)
• L-Norgestrel: 0.75mg 2x/d X 1 day (plan B)
• Norgestrel: 0.5mg with etinyl estradiol 0.05mg (2 tabs
then another 2 tabs in 12hrs.)
 Male Contraceptive
• Gossypol – phenolic compound that reduces sperm density by
99% in men and impairs sperm motility
- 20mg/D x 2 mos. or 60mg/wk
- not continued >2yrs.; hypokalemia – major adverse effect
Thank you