GONADAL PHARMACOLOGY

KARL J. ANG
A-MED 2026

ESTROGENS
Types of estrogen
natural Synthetic
*Presence of alterations in their structure to increase oral
effectiveness
• Estrone (E1) • Steroidal
• Estradiol (E2) o Ethinyl estradiol
• Estriol (E3) o Mestranol
o Quinestrol
o Estradiol cypionate
o Estradiol valerate
• Non-steroidal
o Diethylstilbesterol
o Chlorotriansene
o Methallenestril
o Hexestrol
o Benzestrol
o Dienestrol

• NATURAL ESTROGEN
o ESTRONE (E1)
▪ Found in post-menopausal
▪ Obese: peripheral conversion of fats to estrone
o Estradiol (E2): Major
▪ Reproductive age grp
o ESTRIOL (E3)
▪ Pregnant women
• SYNTHETIC STEROIDAL ESTROGEN
o Esterified Estrogens
▪ DRUGS:
• Estradiol cypionate
• Estradiol valerate
▪ Short chain fatty acids at C17
• MAKES THE DRUG LESS POLAR
• NOT ORALLY ACTIVE > Better abs when in oil and IM injection
• Provide slow but sustained effects
o Alkylated Estrogens
▪ DRUGS:
• Ethinyl estradiol
• Mestranol- with an added group at C3 of steroid ring A
▪ Ethinyl substitution (Alkylation) at C17
• Alkylation improves oral bioavailability
• Inhibits first pass hepatic metabolism = longer drug effects
• Increases affinity to estrogen receptors that contributes to higher
Potency

• SYNTHETIC NONSTEROIDAL ESTROGENS

o Diethylstilbesterol
▪ A/E:
• increased lifetime risk of clear cell adenocarcinoma of the vagina

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 • congenital uterine abnormalities in the female offspring
▪ Indications:
• PREVIOUSLY USED FOR THREATHENED ABORTION
• Hormonal therapy of prostate cancer
• Palliation of metastatic breast cancer
• Pharmacokinetics
o Estradiol binds strongly to an α2 globulin (sex hormone binding globulin [SHBG])
o lower affinity to albumin
o Estrone and estriol – low affinity for the estrogen receptor
• (ESTROGEN RECEPTORS)
o ERα has growth-promoting properties
o ERβ has anti-growth effects
• (PROPERTIES OF ESTROGEN)
o Free estrogen binds to an intracellular receptor
o Receptor-hormone complex forms dimers that bind to
estrogen
o response elements (EREs) and regulate their transcription
• (CLINICAL USES OF ESTROGEN)
o FOR REPLACEMENT THERAPY IN ESTROGEN DEFICIENCIES
▪ PRIMARY HYPOGONADISM
• To stimulate development of secondary
sex characteristics and menses
• Progestin is added after the first uterine
bleeding
▪ POSTMENOPAUSAL HORMONAL THERAPY
• Prevent vasomotor symptoms
• Sleep disturbances
• Atrophic vaginitis
o in patients at low risk of
developing osteoporosis
• Prevention of fractures brought about by
osteoporosis
• Prevent acceleration of atherosclerotic
cardiovascular disease
o OTHER USES OF ESTROGEN
▪ Suppress ovulation in patients with intractable
dysmenorrhea
▪ Combined with Progestin
• Treatment of hirsutism and acne
• Treatment of amenorrhea
• Helps in correcting irregular menstrual
pattern and decrease dysmenorrhea
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(EFFECTS OF ESTROGEN)
• NORMAL SEXUAL MATURATION AND GROWTH
OF THE FEMALE
• METABOLIC AND CARDIOVASCULAR EFFECTS
o Maintain normal structure and function
of skin and blood vessels
o Decrease bone resorption
• METABOLIC ALTERATIONS IN THE LIVER
o Higher level CBG, TBG, SHBG,
transferrin, renin substrate, and
fibrinogen
o Increases level of thyroxine, estrogen,
testosterone, iron, and copper
o Cardioprotective
▪ Inc. HDL, TG
▪ Dec. LDL, total plasma
cholesterol
• OTHER EFFECTS OF ESTROGEN
o Induces synthesis of progesterone
receptors for 2nd half of cycle
o Influence behavior and libido
o Facilitates intravascular fluid loss to
extracellular space producing edema
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(CONTRAINDICATIONS)
• Estrogen-dependent neoplasms
o Carcinoma of the endometrium
o Carcinoma of the breast
• Undiagnosed genital bleeding
• Liver disease
• History of thromboembolic disorder due to
enhanced coagulability of blood
• Heavy smokers
(Adverse effects)
• Increased risk for endometrial cancer when
taking estrogen alone
• Increased risk of breast cancer
• Most common cause of postmenopausal
bleeding (due to thickened endometrium)
 SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERM) AND
ANTI-ESTROGENS
SERMS ANTI-ESTROGEN ESTROGEN SYNTHESIS INHIBITORS
• Tissue selective activity • partial agonist • Aromatase inhibitor
o Agonist o Clomiphene o Exemestane
o Antagonist • Full agonist o Anastrozole
▪ Tamoxifen o Fulvestrant o Letrozole
▪ Raloxifene
▪ toremifene

SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)

o MOA:
o Bind to both ER alpha and ER beta
o Competitively block estradiol binding

[TAMOXIFEN]
o Competitive partial agonist of estradiol at the estrogen receptor
o Acts as an inhibitor
o Endoxifen
o Metabolites via CYP2D6
o More potent SERM
o PHARMACOLOGIC EFFECTS
o Inhibits proliferation of breast cancer cells (antagonistic effect)
o Stimulates proliferation of endometrial cells and causes endometrial thickening that may lead to hyperplasia and possible
malignancy (Agonistic Effect)
o Antiresorptive effect on bone preventing osteoporosis
o Reduction in the risk for atherosclerosis
o Increases the risk for endometrial cancer
o Increase in the risk of DVT and pulmonary embolism
o CLINICAL INDICATIONS
o Palliative treatment of breast cancer in postmenopausal women
o Chemoprevention of breast cancer in high-risk women
o ADVERSE EFFECTS
o Nausea, vomiting, hot flushes, vaginal bleeding,
o dermatitis, anorexia, depression,
o mild leucopenia, ocular changes

[TOREMIFENE]
o Structurally similar to Tamoxifen
o Similar properties, indications and toxicities
o For treatment of metastatic breast cancer

[RALOXIFENE]
o Partial estrogen agonist-antagonist at some but not all target tissues
o Estrogenic effects on lipids and bone (agonist)
o DOES NOT STIMULATE ENDOMETRIUM OR BREAST (does not increase risk for breast or endometrial cancer)
o PHARMACOLOGIC EFFECT
o prevention and treatment of postmenopausal osteoporosis
o Prophylaxis of breast cancer in women with risk factors
o ADVERSE EFFECTS
o Deep vein thrombosis, pulmonary embolism, hot flushes, leg cramps,
o vaginal bleeding, teratogenic (multiple birth defects)

[BAZEDOXIFENE]
o Blocks estrogen proliferation of the endometrium

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 o Used in combination with conjugated estrogens
o Treatment of menopausal symptoms
o Prophylaxis of postmenopausal osteoporosis

ANTI-ESTROGENS
[CLOMIPHENE]
o Partial estrogen agonist
o Distributed to adipose tissues
o PHARMACOLOGIC EFFECT
o Inhibits action of estrogen (competes with estrogen)
o Inhibits estradiol negative feedback effect on the release of gonadotropins
▪ Increases secretions of gonadotropin (FSH, LH)
o Stimulates ovulation (given to PCOS patients)
▪ Blocks the negative feedback of estrogen > surge of gonadotropins that causes the increase of the size of the follicle >
ovulation
o CLINICAL INDICATIONS
o Disorders of ovulation in patients who wish to become pregnant
o Used as an ovulation inducing agent
o ADVERSE EFFECTS
o Hot flushes
o Ovarian enlargement
o Eye symptoms (temporary intensification and prolongation of after images)
o CONTRAINDICATIONS
o Enlarged ovaries
o Visual disturbances
o Patient who complains of abdominal enlargement

[FLUVESTRANT]
o Pure estrogen receptor antagonist
o Tamoxifen-resistant breast cancer

ESTROGEN SYNTHESIS INHIBITORS

Aromatase inhibitors
STEROIDAL (TYPE 1) AGENTS NON-STEROIDAL (TYPE 2) AGENTS
o Substrate analogues that acts as suicide inhibitors o Interact reversibly with the heme groups of CYPs
o Irreversibly inactivate
o EXEMESTANE o ANASTROZOLE
o FORMESTAE o LETROZOLE
o VOROZOLE

[ANASTROZOLE]

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 o Breast tumors resistant to tamoxifen

[LETROZOLE/FADROZOLE]
o Breast cancer
o Adjuncts in precocious puberty
o Primary treatment for excessive aromatase syndrome

[EXEMESTANE]
o Irreversible aromatase inhibitor
o Advanced breast cancer

Other Inhibitors
GnRH Analogs ICI 164, 384

o Both stimulating and inhibiting ovarian function o Inhibits dimerization of the occupied estrogen receptor
o Continual administration of GnRH agonists prevents ovarian o Interferes with binding to DNA
synthesis from adrenal androgens

PROGESTINS
• Natural Progestin: PROGESTERONE
o Precursor to estrogen, androgen, and adrenocortical steroids
o Synthesized in the ovary, testis, and adrenal cortex from circulating cholesterol
• Synthetic Progestins
21-CARBON COMPOUNDS 19-NORTESTOSTERONE THIRD
GENERATION
o Hydroxyprogesterone o “Third Generation Impeded androgens” -
o Medroxyprogesterone without androgenic activity
▪ Most common preparation o Desogestrel
o Megestrol o Gestodene
o Dimesthisterone o Norgestimate
o Closely related to progesterone o 19-nor, 13-ethyl steroid compounds
o o Combined with estrogen for OCP
o Combined to prevent endometrial lining
thickening
o Produce a decidual change in the endometrial
stroma
o More effective gonadotropin inhibitors
o Minimal estrogenic activity

o MOA:
o Enters the cell and bind to progesterone receptors in the nucleus and the cytoplasm
o forms heterodimers and homodimers between two isoforms, PRA and PRB
o Binds to a progesterone response element (PRE) to activate gene transcription
o PHYSIOLOGIC EFFECTS OF PROGESTIN
o Stimulated lipoprotein lipase activity and favors fat deposition
o Promotes glycogen storage by facilitating the effect of insulin
o Competes with aldosterone and causes decrease in Na+ reabsorption
o Increases body temperature in humans
o Thermogenic and is responsible for the change in basal body temperature during ovulation

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 o Depressant and hypnotic effects on the brain
o Development of the secretory apparatus in the breast
o Participates in the preovulatory LH surge
o Maturation and secretory changes in the endometrium after ovulation
o CLINICAL USES
o Hormone replacement therapy and hormonal contraception
o Long-term ovarian suppression
o Used as test of estrogen secretion
▪ Given to test responsiveness of the endometrium in patients with amenorrhea and thickened endometrium are given
progestins to check for withdrawal bleed which happens when there is unopposed estrogen secretion
o Treatment of dysmenorrhea, endometriosis, and bleeding disorders when estrogens are contraindicated
o Relieves hot flashes
o ADVERSE EFFECTS
o Not to be used for patients planning a pregnancy
▪ Prolonged time for ovulatory function to return after cessation of therapy
o Increases blood pressure
o More androgenic progestins reduce plasma HDL levels
o 👉Combined progestin plus estrogen replacement therapy in postmenopausal women may increase breast cancer risk significantly
compared with the risk in women taking estrogen alone

SELECTIVE PROGESTERONE RECEPTOR MODULATORS

o MIFEPRISTONE
o ZK 98734 (LILOPRISTONE)
o ZK 98299 (ONAPRISTONE)
o ULIPRISTAL

o MIFEPRISTONE
o Moa:
▪ Binds to progesterone and glucocorticoid receptors → inhibits activity of both progesterone and glucocorticoid →
Decidual breakdown of the endometrial lining → Abortion
▪ Increases prostaglandin levels that causes myometrial contraction
▪ Cervical softening
▪ Can delay or prevent ovulation (Action on hypothalamus and pituitary gland)
▪ Impairs the development of a secretory endometrium and produces menses
o USES
▪ Used as an emergency postcoital contraceptive, though it may result in delay ovulation in the following cycle
o ADVERSE EFFECTS
▪ Vaginal bleeding
▪ Patients on chronic glucocorticoid therapy are not given because of its anti-glucocorticoid activity

o ZK 98734 (LILOPRISTONE)
o Potent experimental progesterone inhibitor
o Anti-glucocorticoid activity

o ZK 98299 (ONAPRISTONE)
o Pure progesterone antagonist
o Similar in structure to Mifepristone

o ULIPRISTAL
o Moa:
▪ Selective progesterone receptor modulator (SPeRM)
▪ Partial agonist at PRs → inhibiting progesterone
▪ Weak glucocorticoid antagonist
▪ Inhibits ovulation
• Inhibits LH release through hypothalamus and pituitary gland

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 • Inhibits LH-induced follicular rupture within the ovary
o Uses:
▪ Treatment of uterine fibroids/myoma
▪ Reduces excessive uterine bleeding
▪ Reduces fibroid size
▪ Correcting anemia
▪ Suppressing fibroids-related pain
o Adverse effects:
▪ self -limited headache and some abdominal pain
▪ may cause liver injury due to its effect on the glucocorticoid receptor

ESTROGEN-PROGESTIN COMBINATION
TWO TYPES OF PREPARATIONS PHYSIOLOGIC EFFECTS
o Monophasic - everyday there is constant dosage of both o Selective inhibition of pituitary function → inhibition of ovulation
components during the cycle o Changes seen in the:
o Uterine endometrium
o Biphasic or triphasic - dosage of one or both components are o Cervical mucus
changed once or twice during the cycle o Motility and secretion in the uterine tubes
o Tries to mimic the normal hormone levels in the body o Suppresses lactation
o Estrogen tends to increase excitability in the brain
------------------------------------------------------------------------------------------------- o Therapy of postpartum depression, climacteric
CLINICAL USES depression, and premenstrual tension syndrome
o Progesterone tends to decrease excitability in the brain
o POSTMENOPAUSAL HORMONAL THERAPY (HRT) o Thermogenic action - increase in basal body
o Addition of progestin decreases risk of endometrial temperature after ovulation
hyperplasia and carcinoma o Increases: (estrogen)
o Relief of vasomotor symptoms o Factors 2, 7, 9, 10
o Beneficial effects: o Serum and total iron-binding capacity
▪ Increased bone density to prevent o Decrease in antithrombin 3
osteoporosis o promote hypercoagulable state → DVT
▪ Reduced risk of colorectal cancer o Serum haptoglobins in the liver are depressed
o increased risk: o Estrogen reduces the flow of bile and affects levels of bile acids
▪ Breast cancer with long term use (>5 years of → formation of gallstones
therapy) o Estrogen
▪ Stroke o Increases triglycerides, free and esterified cholesterol,
▪ Heart attack phospholipids, and HDL
▪ Hypercoagulable state: DVT and pulmonary o Decreases LDL levels
embolism o Progestins (“19-nortestosterone”) antagonizes these
o ENDOMETRIOSIS effects
o Decreasing menstrual flow and regressing endometrial o Progesterone increases the basal insulin level and the rise in
implants insulin induced by carbohydrate ingestion
▪ FSH and LH inhibition o Small increases in cardiac output (SBP, DBP, and HR)
▪ Induction of an anovulatory and/or o Increase pigmentation of the skin (chloasma)
hypoestrogenic state o Androgen-like progestins → production of sebum → acne
o ABNORMAL UTERINE BLEEDING
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ADVERSE EFFECTS
o Mild
o Nausea, mastalgia, breakthrough bleeding, and edema
o changes in serum proteins and other effects on
endocrine function
o Moderate
o Breakthrough bleeding
o Weight gain

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 ▪ more common with the combination agents
containing androgen-like progestins
o Hirsutism
▪ may also be aggravated by the “19-
nortestosterone” derivatives
o Vaginal infections
o Amenorrhea
o Severe
o Thromboembolism , MI, Stroke
o GI disorders: Cholestatic jaundice, hepatic edema
o Depression
o Cancer
o Alopecia, erythema nodosum

OVULATION INDUCING AGENTS

● Clomiphene
● Aromatase inhibitors
● Gonadotropins
○ Motropins
○ FSH
○ hCG
● GnRH analogs
○ GnRH agonists
○ GnRH antagonists
● Bromocriptine

Usually given to patients who are trying to conceive, who have fertility problems

o ANTI-ESTROGEN
o CLOMIPHENE
▪ MOA:
• Blocks the negative feedback to hypothalamus and pituitary, thus increasing FSH and LH which would
eventually cause ovarian follicle stimulation
▪USES:
• Disorders of ovulation in patients who wish to become pregnant
• used in patients with PCOS
o AROMATASE INHIBITORS
o LETROZOLE
▪ MOA:
• Induces follicle development by inhibiting estrogen synthesis by decreasing estrogen negative feedback
resulting to increase FSH levels
▪ USES:
•
treatment of breast cancer
o GONADOTROPINS
o MENOTROPINS
▪ gonadotropin product containing FSH and LH
▪ Used for the stimulation of follicle development
▪ Absolute requirement is ovarian competence for patients with defective gonadotropin secretion
▪ Can also stimulate spermatogenesis in males with isolated gonadotropin deficiency
o FSH ANALOGS
▪ Recombinant forms of FSH (rFSH)
• Follitropin alfa
• Follitropin beta

o HUMAN CHORIONIC GONADOTROPIN

▪ actions are nearly identical to those of LH

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 ▪ Administered following menotropins treatment, done to mimic the naturally occurring surge of LH that triggers ovulation
▪ Choriogonadotropin alfa (rhCG)
• Recombinant form of Hcg
▪ Supports the normal development of an ovum
▪ Can bind to LH receptors in ovaries and testes
• Mimics LH surge → Induces ovulation
▪ Stimulates spermatogenesis in males with gonadotropin deficiency
▪ USES:
• Treatment of prepubertal cryptorchidism (not recommended anymore)
• Used as a diagnostic test in boys with cryptorchidism
• Induce follicle development and ovulation secondary to hypogonadotropic hypogonadism and polycystic ovary
syndrome
• Anovulatory women who fail to respond to clomiphene
• Controlled ovarian stimulation (COS) in assisted reproductive technology procedures
▪ ADVERSE EFFECTS:
• Ovarian hyperstimulation syndrome (OHSS)
• multiple pregnancies
o BROMOCRIPTINE
o MOA:
▪ Dopamine receptor agonist
▪ Inhibits prolactin secretion → Shrinking the tumor → Ovulation
o USES:
▪ Restores fertility in patients with amenorrhea and galactorrhea with hyperprolactinemia
▪ Increases ovarian responsiveness to clomiphene therapy
▪ Polycystic syndrome
o Adverse effects
▪ Long term therapy
• Can lead to severe vascular diseases and connective tissue lesions

GNRH ANALOGS

GNRH AGONISTS GNRH ANTAGONISTS

• Gonadorelin, • Ganirelix,
• Goserelin, • Cetrorelix,
• Buserelin, • Abarelix,
• Histrelin, • Degarelix
• Leuprolide (prototype drug),
• Nafarelin,
• Triptorelin
• Pulsatile administration • Ganirelix and cetrorelix
o Causes/stimulates the release of FSH and LH o Approved for use in COS
• Degarelix and abarelix

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 o 1 - 10 ug every 60 - 120 mins for patients with o Approved for men with advanced prostate cancer
hypothalamic amenorrhea • Suppression of Gonadotropin Production
• Advantages: o Prevent the LH surge during COS
o No hyperstimulation syndrome because of receptor • Advantages over GnRH agonist:
down-regulation o Immediate antagonist effect
o Approved only for diagnostic use in hypogonadism o Duration of administration is shorter
o 100 ug bolus → LH surge o Less suppressive effect on the ovarian response to
• Sustained nonpulsatile gonadotropin stimulation
o Inhibit the release of FSH and LH by the pituitary in o Reverse more quickly after their discontinuation
both women and men o More complete suppression of LH secretion than
o Results in hypogonadotropic hypogonadism agonists
• Continuous treatment of women causes the symptoms of
menopause
• Ovarian cysts may develop
• Contraindications:
o Pregnancy
o breastfeeding

ANDROGENS AND ANABOLIC STEROIDS

• Natural Androgen • Synthetic Anabolic Steroids
o Testosterone o Propionate, enanthate, undecanoate, or cypionate
o Dihydrotestosterone (DHT) ester
o Androstenedione o Methyltestosterone
o Dehydroepiandrosterone (DHEA) o Fluoxymesterone
o Danazol
• TESTOSTERONE
o Rapidly absorbed by mouth
o Can also be administered parenterally (synthetic)
▪ Prolonged absorption time vs oral administration
▪ Greater activity
• Propionate, enanthate, undecanoate, or cypionate ester
o Alkylated at the 17 position
▪ Methyltestosterone and fluoxymesterone: Active by mouth
o Testosterone and its derivatives are used for their anabolic effects and in treatment of testosterone deficiency
o MOA:
▪ Skin, prostate, seminal vesicles, epididymis
• Converted to 5α–DHT by 5α–reductase
• Dominant and more potent androgen
▪ Androgen binds to its receptor → Forms androgen-AR complex → Dimerization before entry into nucleus → Affect
transcription of genes
o EFFECTS:
▪ In men, development of secondary sex characteristics
• Increased androgen concentration exerts negative feedback → Suppresses gonadotropin secretion
▪ In women, produces changes similar in the male
▪ Natural androgens stimulate erythrocyte production
▪ Increases protein synthesis
o CLINICAL USES:
▪ Androgen Replacement Therapy in Men
• Hypogonadism
• Hypogonadotropism ( Testosterone Enanthate or Cypionate)
• Hypopituitarism
• Side effects: Polycythemia, hypertension
▪ Gynecologic Disorders
• In combination with estrogen
o To reduce breast engorgement during postpartum period

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 o Hormonal replacement therapy in the postmenopausal period: Decreases risk for endometrial
hyperplasia
• Chemotherapy of breast tumors in premenopausal women
▪ Protein Anabolic Agents
• Increase lean body mass
• Used in patients who are in catabolic state (with dietary measures and exercises) to reverse protein losses
▪ Anemia
• used to treat refractory anemias due to its effect on EPO secretion
▪ Growth Stimulators
• Boys with delayed puberty
▪ Anabolic steroid & androgen abuse in sports (athletes)
▪ Aging
▪ In combination with estrogens, androgens can be used for osteoporosis
o ADVERSE EFFECTS:
▪ Excessive masculinizing actions
▪ Endometrial bleeding upon discontinuation
▪ Alters serum lipids → Atherosclerotic disease in women
▪ Prostatic hyperplasia – DHT
o CONTRAINDICATIONS:
▪ Pregnancy
▪ CA of prostate and breast
▪ Young children
▪ Renal and liver disease

o DANAZOL
o MOA:
▪ Binds to androgen, progesterone, glucocorticoid receptors
▪ Suppression of ovarian function
▪ Inhibits enzymes in estrogen biosynthesis pathway
▪ Does not inhibit aromatase
▪ Does not bind to intracellular estrogen receptors
• Binds to SHBG and CBG
• Increase in free levels of testosterone
▪ Increases mean clearance of progesterone
▪ Ethisterone
• Major metabolite of danazol
• Progesterone and mild androgenic effects
o CLINICAL USES:
▪ DOC for endometriosis before
• Replaced now by GnRH agonists
▪ Fibrocystic disease of the breast
• Due to its antiprogesterone effect
o ADVERSE EFFECTS
▪ Adrenal suppression
▪ Mild to moderate hepatocellular damage
▪ Contraindicated during pregnancy and breastfeeding
• Congenital urogenital abnormalities

ANDROGEN SUPPRESSION AND ANTIANDROGENS

Steroid Synthesis Inhibitors Enzyme Inhibitors Receptor Inhibitors
o Ketoconazole o Abiraterone o Flutamide
o 5-alpha reductase inhibitors o Bicalutamide
o Finasteride o Nilutamide
o Dutasteride o Cyproterone
o Spironolactone

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o STEROID SYNTHESIS INHIBITORS
o KETOCONAZOLE
▪ MOA:
• Inhibiting testosterone production (major androgen produced by the testis)
• Inhibitor of adrenal and gonadal steroid synthesis
• Displaces estradiol and DHT from binding to SHBG
• Increases the estradiol:testosterone ratio in plasma
• Does NOT affect ovarian aromatase; reduces human placental aromatase activity
▪ USES:
• Treatment of fungal disease
• Not clinically useful in women with increased androgen
o ENZYME INHIBITORS
o ABIRATERONE
▪ Inhibits the 17-hydroxylation of progesterone or pregnenolone
▪ Preventing the action of the side chain-splitting enzyme (P450 SCC) → Blocking conversion to androgens
▪ Clinical use: Metastatic prostate cancer

o 5-ALPHA REDUCTASE INHIBITORS (-teride)

▪ FINASTERIDE
• Steroid-like inhibitor of 5α-reductase
• Clinical uses:
o Reduces prostate size in men with BPH
o Hirsutism in women
o Early male pattern baldness in men
▪ DUTASTERIDE
• Alpha-reductase inhibitor
• Clinical use: BPH
o RECEPTOR INHIBITORS (-lutamide)
o MOA: competitive antagonist at the androgen receptor
o FLUTAMIDE
▪ Clinical use:
• Main indication: Treat prostatic carcinoma
• Management of excess androgenic effect in women
▪ Adverse effect:
• Mild gynecomastia (probably by increasing testicular estrogen production)
• Mild reversible hepatotoxicity
o BICALUTAMIDE, NILUTAMIDE
▪ Clinical use:
• Patients with metastatic carcinoma of the prostate
▪ Bicalutamide
• In combination with a GnRH analog
• Fewer GI side effects than flutamide
• To reduce tumor flare
• Less hepatotoxic
o CYPROTERONE (ACETATE)
▪ MOA: competes with GnRH and with DHT for receptor binding
▪ Combined w/ Estradiol
• More effective anti-androgen effect
• Progesterone effect - Suppresses LH and FSH release (negative feedback)
▪ Clinical uses:
• In combination with estrogen for regulation of menses
o GIven in women who are diagnosed with PCOS
• In women, to treat hirsutism
• In men, to decrease excessive sexual drive
o SPIRONOLACTONE
▪ Competes with DHT for androgen receptors in target tissues
▪ Reduces 17α-hydroxylase activity

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 • Same MOA as abiraterone
• Lowers plasma levels of testosterone and androstenedione
▪ Clinical use: Treatment of hirsutism in women
• As effective as finasteride, flutamide, or cyproterone
▪ Dual mechanism of action
• Competitive androgen receptor antagonist
• Enzyme inhibitor by blocking 17α-hydroxylase - preventing synthesis of steroid hormones

DRUGS AFFECTING UTERINE MOTILITY

o OXYTOCICS: UTEROTONIC AGENTS

o Clinical uses of uterine stimulants
▪ To induce or augment labor in selected patients
▪ To control postpartum uterine atony and hemorrhage
▪ To cause uterine contraction or during other uterine surgery
o OXYTOCIN
o MOA:
▪ Acts on the smooth muscles located in the myometrium
▪ Mobilizes intracellular Ca in the SER to bind to calcium calmodulin, activating the myosin light chain kinase → uterus
contracts
o Physiologic effects:
▪ Contraction of myoepithelial cells surrounding mammary alveoli
• Milk letdown
▪ High concentrations: weak antidiuretic and pressor activity
o Clinical Uses:
▪ Induction and augmentation of labor
▪ Control of postpartum hemorrhage, uterine atony
▪ Milk ejection
▪ Oxytocin challenge test (Contraction Stress Test - CST)
o Contraindications:
▪ Fetal distress, fetal malpresentation, placental abruption, previous extensive uterine surgery
o CARBETOCIN
o Only indicated for the prevention of uterine atony and postpartum hemorrhage
o Adverse effects:
▪ Nausea, vomiting and flushing
▪ Hypotension
o PROSTAGLANDINS
o MOA: Releases Ca2+ making the uterus contract, while changes in cAMP and cGMP causes relaxation
o Contraindications
▪ Hypersensitivity to the compound
▪ Acute pelvic inflammatory disease

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 ▪ Asthma
▪ Fetal malpresentation
▪ Placenta previa
o DINOPROSTONE
▪ Synthetic preparation of PGE2
▪ Clinical Use
• Missed abortion
• Benign hydatidiform mole
• Ripening of the cervix for induction of patients at or near term
o CARBOPROST TROMETHAMINE
▪ 15-methyl-PGF2α
▪ Clinical Use
• Missed abortions
• Control postpartum hemorrhage that does not respond to conventional
• methods of management
▪ Contraindications
• Asthma
▪ Adverse Effects
• Vomiting and diarrhea occur commonly
• Transient bronchoconstriction can occur
• Transient elevations in temperature is rare
o ALPROSTADIL
▪ PGE1
▪ Second-line treatment for erectile dysfunction
o MISOPROSTOL
▪ Synthetic derivative of PGE1
▪ Originally used for treatment of ulcers
▪ Off-label use either orally or vaginally to induce cervical ripening
▪ Adverse Effects
• ○ Uterine hyperstimulation
• ○ Uterine rupture
o ERGOT ALKALOIDS
o Clinical Use
▪ Promote uterine involution in the postpartum period to prevent uterine atony and hemorrhage
• Given after delivery of placenta
• NEVER used during labor because of the potential for sustained uterine contractions and fetal compromised,
which are NOT pharmacologically reversible
o Adverse Effects
▪ Vomiting
▪ Vasoconstriction
o ERGONOVINE MALEATE
▪ Combined α agonist, serotonin agonist
▪ Evokes rhythmic contraction and relaxation of the uterus
▪ Higher concentrations: induce powerful and prolonged contractions
▪ Agent of choice in obstetric applications of the ergot drugs

UTERINE RELAXANTS (TOCOLYTICS)

Prevent contraction Oxytocin receptor antagonist COX-inhibitor Beta-2 agonist
o CCB (Nifedipine) o Atosiban Reduce production of PGF2 → Increase cAMP → relaxation of
o Prevent o Directly binds prevent contraction of uterus myometrium
opening of L- to oxytocin
type calcium
channel
o Magnesium sulfate

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 o Prevent
opening of
both voltage-
dependent
and voltage-
independent
calcium
channels
o Clinical Use:
o To delay or prevent parturition in selected PATIENTS
▪ Preterm labor
o To slow or arrest delivery for brief periods (at least 24 hrs) in order to undertake other therapeutic measures
▪ To administer steroids → hasten maturity of fetal lung

BETA-2 AGONISTS
o MOA:
o increases cAMP → sequestration of calcium intracellularly → prevents muscle contraction
o Adverse Effects
o Dose related bradycardia
o Hypotension
o Hyperglycemia
o Hypokalemia
o Pulmonary edema
o Tachyphylaxis
o Nausea, vomiting
o Headache, nervousness, anxiety
o Contraindications
o Cardiac disease
o Type 1 DM
o Untreated hyperthyroidism poorly controlled hypertension
o RITODRINE
o Selective β2 agonist
o Uterine relaxant
o TERBUTALINE
o FDA-approved for asthma
o Used off-label as a tocolytic
o May delay births during the first 48 hours of treatment
o Adverse maternal effects
▪ Tachycardia, hypotension, pulmonary edema
o ISOXSUPRINE
o Direct relaxation of uterine and vascular smooth muscle
o Clinical Use
▪ Peripheral vasodilator
▪ Uterine hypermotility disorders
• Threatened abortion
• Dysmenorrhea
o Adverse Effects
▪ Hypertension
▪ Tachycardia
o Contraindications
▪ Arterial bleeding
o MAGNESIUM SULFATE
o Moa:
▪ Competes with calcium at both voltage-dependent and voltage-independent sites
▪ High Mg concentrations may also increase the activity of the Mg-Ca-ATPase in the cell membrane
• Increasing the calcium extrusion from the smooth muscle cell
▪ Stimulates the Ca dependent ATPase

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 • Promotes Ca uptake by the SER
• Decreasing Ca available for light chain phosphorylation of myosin
o Adverse Effects
▪ Nausea, vomiting
▪ Muscle weakness
▪ Dry mouth
▪ Blurred vision
▪ Transient hypotension
o Contraindications
▪ Renal failure
▪ Myasthenia gravis
▪ Heart block
▪ Myocardial infarction

CALCIUM CHANNEL BLOCKERS

o MOA:
o Blocking of voltage dependent channels
o Inhibit the influx of Ca through depolarization-activated,
o voltage-sensitive Ca channels in the plasma membrane
▪ Preventing activation of MLCK and the stimulation of uterine contraction
o First line
o NIFEDIPINE
o Ca channel blocker used most commonly for this purpose
o Less likely to cause maternal side effects than beta agonists
o USES:
▪ Used in preterm labor
o Adverse Effects
▪ Transient facial flushing
▪ Nausea and headache
▪ Decreased BP
▪ Increased heart rate
o Contraindications
▪ Hypersensitivity
o NICARDIPINE

COX INHIBITORS
o MOA:
o Affects PGF2α
o Used to inhibit preterm labor
o Can inhibit platelet function and induce closure in utero of the
ductus arteriosus
o Contraindications
o Pregnancies >32 wks AOG
▪ Risk of severe complications of prematurity is relatively lower
▪ Ductus arteriosus is more sensitive to prostaglandin inhibition near term
o INDOMETHACIN
o Adverse Effects
▪ Nausea, vomiting
▪ Rash
▪ Constriction of fetal ductus arteriosus - reversible
▪ Decreases neonatal GFR and urine output

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 o Contraindications
▪ Maternal history of gastric ulcer or hemorrhage
▪ Renal disease
▪ Bleeding disorders
▪ Allergy to prostaglandin synthetase inhibitors

OXYTOCIN ANTAGONIST (ATOSIBAN)

o Modified form of oxytocin

o Competitive oxytocin receptor antagonist (VOTra)
o As effective as β agonist tocolytics and produces fewer adverse effects
o Uses:
o Indicated to delay imminent preterm birth in pregnant adult women
o Adverse effects
o Vasodilation
o Nausea, vomiting
o Hyperglycemia
o Rash

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