PHARMA-R4.3-Gonadal Hormones - Inhibitors

PHARMACOLOGY
GONADAL HORMONES & INHIBITORS SHIFT 4

REVIEWER | MAY 2020 REVIEWER #3
OUTLINE
I. Neuroendocrine Control of the Female Reproductive System III. Estrogen and Progestin Inhibitors
A. Hormonal Interplay During Menstrual Cycle A. Anti-Estrogen
B. HPG Axis B. Anti-Progestins
C. Neuroendocrine Control of Gonadotropin Secretion IV. Testosterone and Anti-Testosterone
D. The ovary A. Testosterone
E. The Synthesis of Steroid Hormone B. Anti-Androgens
II. Estrogens, Progesterone and Hormonal Contraception V. Ovulation- Inducing agents
A. Estrogen VI. Drugs affecting Uterine motility
B. Progestins (Progesterone) A. Oxytocics:Uterine Stimulating Agents (Contract)
C. Relationship Between Estrogen and Progesterone B. Tocolytics: Uterine Relaxing Agents(Relax)
D. Hormonal Contraception (Oral, Parenteral, Implanted) VII. Chemical Contraception in Men
NEUROENDOCRINE CONTROL OF THE FEMALE REPRODUCTIVE SYSTEM
Follicular Phase Luteal Phase
GnRH secreted in pulses Ruptured follicle → corpus luteum → produce large amounts of progesterone
FSH and LH also secreted in pulses from pituitary → rise in estrogen level which is ‒ Progesterone is also responsible in converting the endometrium to a secretory
also responsible for the thickening of the endometrial lining → Estrogen has a state for possible pregnancy
negative feedback on gonadotropins during the early follicular phase →Then a ‒ If no pregnancy occurs, corpus luteum ceases to function, undergoes lysis →
positive feedback that triggers a surge of LH release only at mid cycle resulting to corpus albicans, no progesterone produced, menstruation occurs (14 days after
OVULATION the LH surge), then, cycle will go back to the follicular phase
A. Hormonal Interplay During Menstrual Cycle
As each cycle starts, vesicular Follicles (containing an ovum) become larger in response to FSH → After 5-6 days, a dominant follicle (lined by granulosa and theca cells)
develops more rapidly → Theca and granulosa cells multiply to release estrogens in response to LH; Estrogen inhibits FSH release →regression of the remaining follicles
→ Estrogen secretion peaks just before mid-cycle followed by a brief surge in LH and FSH leading to ovulation → Follicle ruptures → ovum is released into the abdominal
cavity near the opening of the uterine tube → after ovulation, the follicular cavity fills with blood (corpus hemorrhagicum) → luteinized theca and granulosa cells proliferate
to form the corpus luteum which then produces estrogen and progesterone for the rest of the cycle
*Normal ovulatory menstrual cycles are maintained by the pulsatile release of hormones
*Note: Constant infusions of GnRH will stop LH and FSH release and, consequently, decrease estrogen and progesterone causing amenorrhea
B. HPG-Hypothalamic Pituitary Gonadal Axis
• Onset of ovarian function at the time of puberty is neural in origin
• Pulsatile pituitary gonadotropin secretion under the guidance of GnRH is
responsible for pubertal onset
→ Secretion of GnRH in the hypothalamus is regulated by kisspeptin and its
receptor, and by permissive or opposing signals mediated by neurokinin B
and dynorphin acting on their respective receptors.
• Gonadarche - change of ovarian function at puberty
→ Initially, FSH and LH are released in small amounts at night → limited ovarian
estrogen secretion in response → Subsequently, FSH and LH are secreted
throughout day and night → increased estrogen → further breast
enlargement, alterations in fat distribution, growth spurt culminating in • Hypothalamus: secretes GnRH
epiphyseal closure in the long bones • Anterior pituitary: stimulated by GnrH to secrete FSH & LH
→ A year or so after gonadarche, there is sufficient estrogen production to induce • Ovaries: stimulated by FSH to produce estrogen
endometrial changes and periodic bleeding (menarche) • Follicles: stimulated by LH to produce Progesterone
▪ First few cycles irregular and anovulatory • Testes: stimulated by FSH and LH to produce Testosterone
C. Neuroendocrine Control of Gonadotropin Secretion
• The hypothalamic pulse generator functions as a neuronal “clock” that fires at

regular hourly intervals located in the arcuate nucleus of the hypothalamus
• This results in the periodic release of GnRH from GnRH-containing neurons into
the hypothalamic-pituitary portal vasculature
• GnRH neurons receive inhibitory input from opioid, dopamine, and GABA neurons
and stimulatory input from noradrenergic neurons.
• The pulses of GnRH trigger the intermittent release of LH and FSH from pituitary
gonadotropes
• FSH and LH regulate ovarian production of estrogen and progesterone, which
exert feedback control
D. The Ovary
• Target organ for the gonadotropins FSH and LH Disturbances in Ovarian Function
• Childhood • Common even in the peak years of reproduction
→ Quiescent • A minority result from inflammatory or neoplastic processes
→ Period of rapid growth and maturation
Reviewer # PREPARED BY: SALAS, CHRISTIAN RENZO C. 1 of 17
PHARMA REVIEWER 4.3: Gonadal Hormones & Inhibitors 2 of 17
• Puberty • Most are self-limited and are often associated with emotional or physical stress
→ Begins a 30 to 40 year period of cyclic function (temporary alterations in the stress centers in the brain that control GnRH
→ Menstrual cycle secretion)
• Menopause • Anovulatory cycles are associated with
→ Fails to respond to gonadotropins secreted by the anterior pituitary gland → eating disorders (e.g. bulimia, anorexia nervosa),
→ Cessation of cyclic bleeding → severe exercise,
→ Estrogen persists due to conversion of adrenal and ovarian steroids to estrone → organic causes (pituitary prolactinomas and syndromes; tumors producing
and estradiol in adipose and other non endocrine tissues excessive ovarian or adrenal androgens)
• Ovaries give rise to androgen-producing neoplasms (e.g. arrhenoblastomas) and
estrogen-producing granuloma cell tumors
E. Steroid Hormone Synthesis
II. ESTROGEN, PROGESTINS, AND HORMONAL CONTRACEPTION

A. ESTROGEN
Natural Estrogens Synthetic Estrogens (increased oral effectiveness)
1. Estrone (E1): Maintains healthy thin uterine lining Steroidal synthetic estrogens Non-steroidal synthetic estrogens
during menopause • Esterified estrogens • Polycyclic compounds with a phenolic ring
‒ Major secretory product of the ovary → Estradiol esters resembling the steroid A ring
2. Estradiol (estradiol-17β, E2): Maintains healthy → Estradiol cypionate and estradiol valerate • Diethylbestrol (DES)
uterine lining for possible → Short chain fatty acids at C17 → It was previously used for the treatment of
pregnancy during reproductive years → less polar therefore not orally absorbed threatened abortion
3. Estriol (E3): Maintains healthy thick uterine lining → Prepared in oil and are administered → Was used widely for gynecologic conditions
providing blood to the placenta during pregnancy intramuscularly → Associated with an increased incidence of
• Most estrone and estriol are formed in the liver → Primary microcrystalline depot at injection site congenital uterine abnormalities in female
from estradiol or in peripheral tissues from offspring
→ They are released slowly and hydrolyzed in the
androstenedione and other androgens → Increased lifetime risk of clear cell
liver
• After ovulation, the estrogens and progesterone adenocarcinoma of the vagina and vaginal
→ have sustained effects
are synthesized by corpus luteum adenosis of the cervix
• Alkylated estrogens
• During pregnancy, a large amount of estrogen is → Used in the hormonal therapy of male
→ These estrogens are alkylated at carbon 17 that
synthesized by the fetoplacental unit (fetal adrenal prostate cancer and in application of
improves oral bioavailability
zone, which secretes androgen precursor + metastatic breast cancer
placenta, which aromatizes it into estrogen) → This inhibits first pass hepatic metabolism and
increases affinity to estrogen receptors that • Chlorotrianisene
• The estriol produced is released into the maternal
contributes to higher potency
circulation and excreted in urine (used as
assessment for fetal well-being) → For mestranol, there is an additional group at
C3 of steroid ring A
• Stallion - a potent animal source of estrogenic
substances
• Esterified estrogen - Red -
estradiol valerate
• Alkylated estrogen - Pink and
violet - ethinyl estradiol and
mestranol
• Ethinyl at C17 – Pink
• Nonsteroidal estrogen -
Green- diethylstilbestrol
MECHANISM OF ACTION PHYSIOLOGIC & METABOLIC EFFECTS PHARMACOKINETICS

• bound to sex hormonebinding • Development of the vagina, uterus, • Absorption • Metabolism:
globulin (SHBG), from which they and uterine tubes → Ethinyl derivative inhibit hepatic → Drugs such as phenytoin,
dissociate to cross the cell • Stromal development and ductal 1st pass effect and result to better phenobarbital, and rifampin
membrane and enter the nucleus growth in the breast oral absorption may enhance Metabolism
• Free estrogen binds to its • Growth of axillary and pubic hair and • Distribution: → Hepatic effects cause some
intracellular receptor alteration in the distribution of body → Estrogen are highly protein undesirable actions such as
• Estrogen Receptors (ER) fat bound, size lipophilic in nature increased clotting factors and
→ Steroid receptor superfamily • Pigmentation in the skin → nipples hence, distributed rapidly plasma renin substrate
→ ER genes on 2 separate and areolas and genital region → More than 99% of estrogen is → Minimized by routes that avoid
chromosomes • prevents osteoporosis (inhibiting bound to circulating albumin first-pass liver exposure
▪ ESR1 encodes ER alpha osteoclasts →apoptosis) and sex hormone binding (vaginal, transdermal,
(growth-promoting properties) • cardioprotective effect globulin (SHBG), an α2-globulin injection)
▪ ESR2 encodes ER beta (anti • Synthesis of progesterone receptors ▪ Estradiol: Mainly to SHBG • Excretion:
growth effects; dominant • Influences behavior and libido in ▪ Ethinyl Estradiol: Mainly to → Through the bile (2-hydroxylated
negative inhibitor of ERα) humans Albumin derivatives and conjugated
• Facilitates loss of intravascular fluid → Free estrogen concentrations are metabolites which are insoluble in
into the extracellular space, about 1 to 10 pmol/L. lipid)
producing edema → The bound estrogen is → through kidneys as conjugates of
→ Proper coordination of estrogen unavailable for diffusion into cells glucuronide and sulfates
and progesterone production while the free fraction which is → Estrogens are also excreted in
during the menstrual cycle → physiologically active breastmilk in small amounts
periodic bleeding and → Estrogen is converted by the liver → Ethinyl Estradiol and
shedding of the endometrium and other tissues to estrone and Mestranol: Cleared much slower
→ Continuous exposure to estrogen estriol (have low affinity for the due to decrease hepatic
for prolonged periods → estrogen receptor) metabolism
hyperplasia of the endometrium
associated with abnormal
bleeding patterns
PHARMACOKINETICS BY PREPARATION CLINICAL USES
Replacement therapy in estrogen-deficiencies
• Primary Hypogonadism
• Natural Estrogens: 17β -estradiol, estrone, and estriol have poor oral → Use conjugated estrogens
bioavailability → It is not to be given at higher doses to prevent premature closure of the epiphysis
• Microcrystalline formulation of estradiol confers greater oral • Postmenopausal hormonal therapy
bioavailability by reducing the capacity of the liver for first-pass → Relieve vasomotor symptoms (hot flushes), sleep disturbances
metabolism. → Atrophic vaginitis and UTI in patients at low risk of developing osteoporosis
• Ethinyl Substitution at c17: Inhibits first-pass hepatic metabolism, → prevention of osteoporosis
increases affinity for ER contribute to higher potency → Lipid changes: Prevent acceleration of atherosclerotic cardiovascular disease
• Conjugated estrogen: endogenous sulfatase activity increases the → Combined oral preparations of 0.625 mg conjugated estrogens + 2.5 mg
serum concentrations of estradiol and estrone in postmenopausal women medroxyprogesterone acetate
as hormone replacement • Combined with Progestin to suppress ovarian function for treatment of:
• IM injections: Aqueous or oil-based esters of estradiol → Dysmenorrhea
• Oral administration: Estradiol, conjugated estrogens or esters of estrone → Acne and hirsutism
• Topical Administration to the Vagina - Vaginal Ring; bypasses hepatic → Amenorrhea caused by excessive ovarian secretion of androgens
first-pass metabolism • Dysfunctional uterine bleeding
• Estradiol via transdermal patch: Provides slow sustained release and ADVERSE EFFECTS
more constant blood levels, transdermal delivery also bypasses hepatic
• Nausea, vomiting, diarrhea • Cholestasis, gallbladder disease
first-pass metabolism
• Uterine bleeding - major cause of • Thromboembolism (Deep vein
• Estradiol as topical emulsion: Does not lead to high levels of the drug in
Postmenopausal Uterine Bleeding thrombosis)
the portal circulation - minimize hepatic effect of estrogen
• Breast Tenderness • Teratogenicity - DES (clear cell adeno
• NOTE: 5 mcg of ethinyl estradiol = 50 mcg of transdermal estradiol =
• Hyperpigmentation CA)
625 mcg of conjugated estrogens
• Migraine • Hypertension
CONTRAINDICATIONS
• Estrogen - dependent CA of breast and • Thromboembolic disorders
endometrium • Avoided in heavy smokers (prone to
• Undiagnosed genital bleeding have MI)
• Liver disease
B. Progestins (Progesterone)
Precursor to estrogen, androgen, and adrenocortical steroids
Preparations Pharmacokinetics
Natural •
Rapidly absorbed from any route of administration
• Progesterone: Locally irritating when administered parenterally; in oil, aqueous •
Plasma half-life: about 5 min
suspension •
Small amounts stored in body fat
Synthetic •
Rapid first pass metabolism: completely metabolized after one passage
• C-21 progestins (pregnanes) through the liver where it forms pregnanediol, is conjugated with glucuronic acid,
→ medroxyprogesterone acetate (IM or Oral) - contains a methyl group at and then excreted in urine as pregnanediol glucuronide
carbon 6 that improves bioavailability by reducing first-pass hepatic → Oral preparations are ineffective
metabolism; given IM for every 3 months → Oral micronized: better absorption
• Testosterone derivatives • Highly bound to albumin and CBG, not to SHBG
→ 19 Nortestosterone (C19 of testosterone was removed) - 3rd Gen → less • Urinary pregnanediol is used as an index of progesterone secretion
adrenergic and anabolic activity • Synthetic progestins - longer half-life of 7-24 hrs
→ “Impeded” androgens - minimal estrogenic, androgenic, anabolic activity Clinical Uses
→ More effective gonadotropin inhibitors • Hormone replacement therapy
▪ Estranes - ethyl group added to C17 producing better oral absorption
• Contraception; Inhibits ovulation
− 17 ethinyl testosterone or Norethindrone
• Long term ovarian suppression
▪ Gonanes
→ large doses of IM Medroxyprogesterone results in anovulation and
− Higher affinity for the progesterone receptor; used at lower doses and
amenorrhea; used for:
produce relatively less androgenic effects
▪ treating dysmenorrhea, endometriosis, and bleeding disorders when
− Norgestrel, Norgestimate (less androgenic)
estrogen is contraindicated
− Desogestrel, Gestodene (least androgenic) ▪ contraception
Mechanism of Action ▪ Hirsutism
Progesterone Receptor ▪ Dysfunctional uterine bleeding
• Steroid receptor ▪ Precocious puberty
• distributed between nucleus and cytoplasm • Carcinoma - advanced endometrial CA, breast CA - Megestrol
• Forms a dimer before binding to DNA • Diagnostic use - test of estrogen secretion
• Forms heterodimers and homodimers between two isoforms, A and B → 50 mg/d progesterone or 10 mg/d medroxyprogesterone for 5-7 days is
→ PR alpha: effects on the uterine endothelium followed by withdrawal bleeding in amenorrheic patients when endometrium
→ PR beta: stimulatory activities especially in the breast tissue is successfully stimulated by estrogens
Physiologic and Metabolic effects: • Luteal phase support for infertility
• Neuroendocrine Effects: decrease frequency of GnRH pulses but greater • relieves hot flushes
amplitude; Decreases FSH stimulation → Decreases production of Estrogen; • Premenstrual syndrome (at doses sufficient to suppress ovulation)
participates in the preovulatory LH surge • Medroxyprogesterone acetate, 10-20 mg orally twice weekly or 100 mg/m2 IM
• Reproductive tract: cervical mucus secretion become scanty and viscid, every 1-2 weeks - prevents menstruation but does not stop accelerated bone
suppress uterine contractility, maturation and secretory changes in the maturation in precocious puberty
endometrium after ovulation Adverse Effects
• Mammary gland: together with estrogen cause proliferation of acini • Prolonged time for ovulatory function to return after cessation of therapy (not to
• CNS: increase basal body temperature, increase ventilatory response to pCO2 be used for patients planning a pregnancy)
leading to decrease arterial and alveolar PCO2, depressant and hypnotic • May increase blood pressure
effects on the brain • Reduces plasma HDL (more androgenic progestins), increases plasma LDL
• Plasma lipoproteins: stimulates lipoprotein lipase, increase LDL, decrease • Irregular unpredictable bleeding/spotting
HDL; favors fat deposition • Acne due to Norethindrone containing preparation
• Renal tubules: competes with aldosterone at mineralocorticoid receptors → • Headache
decrease in Na+ reabsorption, increased aldosterone secretion • Mood changes, weight gain
• Carbohydrate metabolism: increase basal insulin and postprandial insulin but • Mild nausea, flushing, dizziness depression or irritability
no effect on glucose tolerance
• Amenorrhea of variable duration on cessation of taking the pill
• Decreases plasma levels of many amino acids → increased urinary nitrogen
• Combined progestin plus estrogen replacement therapy in postmenopausal
excretion
women may increase breast cancer risk significantly compared with the risk in
women taking estrogen alone
C. Relationship Between Estrogen and Progesterone
• Estrogen exerts a positive feedback on its own activity • Progesterone has anti-estrogenic activity - which helps to terminate estrogenic
→ Estrogen stimulates the expression of estrogen receptors activity
• Estrogen must precede Progesterone to elicit full progesterone sensitivity → Progesterone suppresses expression of estrogen receptors
→ Estrogen stimulates the expression of progesterone receptors → Progesterone facilitates the metabolism of estradiol to weaker metabolites
D. Hormonal Contraception (Oral, Parenteral, Implanted)

1. Hormone and hormonal analogues
Estrogen-Progestin Combination Progestin Only
Mechanism of Action:
→ adequately absorbed when given oral • In situations where estrogen may be contraindicated
→ Neither drug is significantly altered by the other when combined • Alter frequency of GnRH pulsing and decrease anterior pituitary gland to GnRH
→ GnRH, LH, & FSH secretion are suppressed and follicular development → • Alterations in cervical mucus, endometrial receptivity, and tubal peristalsis
inhibiting ovulation • Progestin Only OCPs
→ Alterations in tubal peristalsis, endometrial receptivity, and cervical mucus → Norethindrone
secretion → decrease likelihood of conception and implantation → Desogestrel
• Formulations: Monophasic, Biphasic, or Triphasic → ALL provide 21 days packs • Injectable and Implants
with the last 7 days → Inert ingredients → Medroxyprogesterone Acetate → given every 3 months
→ Monophasic: fixed amount of Estrogen and Progesterone → Etonogestrel → silastic implant injected subcutaneously effective for 3 years
→ Biphasic and Triphasic: contain varying amounts of active ingredients to be *NOTE: continuous use of progestins alone does not always inhibit ovulation.
taken at different times
• Approximates Estrogen-Progesterone cycle
EFFECTS ON ORGANS
• Ovary: Inhibits ovulation - negative feedback on gonadotropin release • Cardiovascular System
→ Chronic use → depress ovarian function → Increase sBP, dBP
→ Corpora lutea, larger follicles, stromal edema, and other morphological → Increase heart rate
features seen in ovulating women are absent → Increase cardiac output → Increase BP and HR
→ smaller in size • Skin
• Uterus → Increase pigmentation (chloasma); enhanced in woman with dark
→ Cervix: Hypertrophy and polyp formation complexions and by exposure to UV light
→ Endometrium: “Stromal-glandular dissociation”, decidual stroma and → Acne; androgen-like progestins might increase sebum-production
glandular atrophy • Hematologic
→ Cervical mucus → thicker and less copious → Increase factors VII, VIII, IX, X; decrease antithrombin III
→ 19-Nor Progestins→ produce more glandular atrophy; less bleeding ▪ increased amounts of coumarin anticoagulant may be required to prolong
• Fallopian Tubes: Decrease motility and Altered secretions PT of patients
• Vagina: Intermediate cells predominate and Increased vulvovaginitis → Some develop folic acid deficiency anemia
• Breasts: Stimulation → enlargement; Suppress lactation → Increased serum iron and total iron binding capacity
• Metabolic → These effects can promote a hypercoagulable state and may lead to DVT
→ Lipid - increases triglycerides, free and esterified cholesterol, HDL and • Liver
phospholipids; LDL usually decreased → Estrogen: decreases production of serum haptoglobins, delays clearance of
▪ Progestins (“19-nortestosterone”) antagonize these effects sulfobromophthalein and reduces bile flow
▪ Preparations with small amounts of estrogen and a progestin may slightly → Proportion of cholic acid in bile acids is increased
decrease triglycerides and HDL → Proportion of chenodeoxycholic acid is decreased
→ increase occurrence of cholelithiasis
SIDE EFFECTS
Mild Moderate Severe
• Nausea, mastalgia, breakthrough bleeding and • Breakthrough bleeding • Vascular disorders
edema - related to the amount of estrogen → Most common problem in using progestational • Thromboembolism
• Shift to a preparation containing smaller amounts of agents alone (low dose preparation) • Venous thromboembolic disease - if used for more
estrogen or to agents containing progestins with → The biphasic and triphasic oral contraceptives than 5 years (100% risk)
more androgenic effects. decrease breakthrough bleeding without • Myocardial infarction
• Changes in serum proteins and other endocrine increasing the total hormone content. • Cerebrovascular disease
effects • Weight gain- more common with combination • GIT disorders
• Headache → migraine agents with androgen-like progestins → Ischemic bowel disease
• Withdrawal bleeding - most often with combination • Increased skin pigmentation - often reversible upon → Cholestatic jaundice
preparations discontinuance of medication but may disappear → Gallbladder disease
very slowly → Hepatic adenomas
• Acne - may be exacerbated by agents containing • Depression
androgen-like progestins • Breast CA
• Hirsutism- may also be aggravated by the “19-
nortestosterone” derivatives
• Ureteral dilatation
• Vaginal infections- more common and more
difficult to treat in patients who are using OCP
• Amenorrhea
→ After discontinuance of oral contraceptives, 95%
of patients with normal menstrual histories
resume normal periods.
→ Some patients remain amenorrheic for several
years and may be associated with galactorrhea.
prolactin should be determined
Contraindications & Cautions Beneficial Effects

• Thrombophlebitis, thromboembolic phenomena, cardiovascular and • increase bone density - lowers risk of fracture by 31%
cerebrovascular disorders • reduces risk of ovarian cysts, ovarian and endometrial CA, and benign
• Vaginal bleeding with unknown cause breast disease, and colorectal CA
• Patients with known or suspected tumors of the breast and other estrogen • lower incidence of ectopic pregnancy
dependent neoplasms
• avoided or used with caution: liver disease, asthma, eczema, migraine, diabetes, Drug Interactions
hypertension, optic neuritis, retrobulbar neuritis, or convulsive disorders • Decrease effect of anticoagulants
• may produce edema- used with great caution in patients with heart failure • Increased metabolism in the presence of hepatic enzyme inducers such as:
• avoided in adolescents in whom epiphyseal closure has not yet been completed Rifampicin, Alcohol, Antiepileptics (e.g. Phenytoin, Ethosuximide,
• antimicrobial drugs that interfere with normal GI flora may reduce efficacy of oral Primidone, Carbamazepine, Barbiturates)
contraceptives
2. Postmenopausal Hormonal Replacement Therapy
• At the time of menopause, the ovary is depleted of selectable follicles → Gonadotropin concentrations rise without stimulating further ovariansteroidogenesis
• Relative estrogen deficiency is accompanied by increased bone resorption and increased risk for coronary artery disease
General Rule! Clinical Use of HRT Side Effects:
• If still with uterus: use ESTROGEN and Start treatment immediately upon onset of • Increased risk for breast cancer with long term use
PROGESTERONE menopause. Use the lowest dose and shortest (>5 years)
• If without uterus (surgical menopause): use duration possible (less than • Increased risk of endometrial cancer by 5-15x in
ESTROGEN alone 5 years) those using estrogen alone; Unopposed Estrogen
• Progestin decreases risk of endometrial 1. Improve vasomotor symptoms: (hot flushes) therapy is associated with increased risk of
hyperplasia and carcinoma: progestin is not 2. To prevent osteoporosis endometrial carcinoma
required in women who have had a hysterectomy 3. To prevent vaginal dryness or atrophy: use vaginal • 3. Increased risk of Heart attacks by 29% , strokes
• Unopposed estrogen therapy is associated with cream by 41%, deep vein thrombosis and pulmonary
increased risk of endometrial carcinoma Beneficial Effects embolism (if >5 years use: 100%)
• Most commonly used preparation: Conjugated • Increase Bone Density, lowers risk fracture by 34%;
estrogen and Medroxyprogesterone acetate • Reduced Risk of Colorectal Cancer
3. Endometriosis 4. Abnormal Uterine Bleeding
• Estrogen dependent disease • Estrogen-Progestin Oral Contraceptives (OCS) are First-line Management
• Presence of endometrial glands and stromal tissue outside the uterine cavity → Advantages:
• Retrograde Menstrual Flow ▪ Bleeding more regular, lighter; Reduces dysmenorrhea; Inhibits ovulation
• Principles of Treatment: → Adverse Effects of OCPs:
→ Decreasing menstrual flow and regressing endometrial implants ▪ MILD
→ FSH and LH Inhibition − Nausea, mastalgia, breakthrough bleeding, and edema are related to
→ Induction of an anovulatory and/or Hypoestrogenic state. the amount of estrogen
→ Continuous therapy is used to suppress menstruation and induce a ▪ Moderate
“Pseudopregnancy” like state or pseudomenses − Breakthrough bleeding (More frequent in low-dose preparations)
• Treatment Options: − weight gain, increased skin pigmentation, acne
→ Combined estrogen and progesterone therapy (continuous or cyclical): − Hirsutism (aggravated by the “19-nortestosterone” derivatives)
inhibitory to negative feedback − Vaginal infections more common and more difficult to treat in patients
→ Oral Progesterone Therapy: Inhibitory to estrogen, physiologic antagonist − Amenorrhea occurs in some patients
→ Depot Progesterone Therapy (IM Injection): Inhibitory to estrogen, physiologic ▪ Severe
antagonist − Vascular Disorders: Thromboembolic Disease, Myocardial Infarction,
→ Danazol: desensitizes GnRH receptors, Cerebrovascular Disease
→ GNRH Agonists − Gastrointestinal Disorders: Gallstones, cholestatic jaundice, hepatic
adenoma
− Depression, Alopecia, erythema multiforme, erythema nodosum, and
other skin disorders
III. ESTROGEN & PROGESTIN INHIBITORS

A. ANTI-ESTROGEN
Receptor Antagonist: Synthesis Inhibitors Antagonistic Physiologic Action
• Selective Estrogen Receptor Modulators (SERMs) - • GnRH agonists - Leuprorelin (Leuprolide), • Progestins
Tamoxifen, Raloxifene, Toremifene Goserelin, Narafelin, etc. • Androgens
• Pure estrogen antagonist - Enclomiphene, • Aromatase inhibitors
Fulvestrant
• Partial estrogen antagonist - Clomiphene
i. Receptor Antagonists
a. Selective Estrogen Receptor Modulators (SERMS)
• Pharmacological goal: agonist activity in tissues like bone and brain where estrogen effects are wanted, but antagonistic effect in breast and endometrium where estrogen
effects are unwanted
• Compounds with tissue-selective estrogenic activities
Mechanism of Action:
→ ‒ Bind to ligand-binding pocket of both ER ALPHA and ER BETA and competitively block estradiol binding
→ ‒ Compete with estrone which are primarily found on post-menopausal women
→ ‒ Tissue-specific actions of SERMs
• ■ Distinct conformation of the ER when occupied by different ligands
• Different coactivator and corepressor levels in different cell types
Tamoxifen Raloxifene
• Prototype for SERMS • Partial estrogen agonist-antagonist at some but not all target tissues
• It is a nonsteroidal oral drug given orally • Pharmacokinetics:
• Mechanism of action not completely understood → Rapidly absorbed after oral administration
Pharmacokinetics: → Bioavailability: 2% (extensive first pass glucuronidation)
→ Half-life: 7-14 hours → Half-life: 28 hrs (Administered once a day)
→ Excreted by liver → Elimination: Feces
• Inhibition of estrogen dependent breast cancer → High first-pass effect
→ Antagonist to breast cell proliferation • Estrogen receptor agonist to bone, decrease vertebral fractures by 50%,
• Increase risk of endometrial CA (because of its partial agonism) decrease total cholesterol and LDL
→ Agonistic effect on endometrium causing thickening of the lining that may • Antagonist to endometrium and breast
lead to hyperplasia and possible malignancy • Does not increase the risk of endometrial cancer
• Agonist in bone and endometrium, decreases total cholesterol and LDL • Does not alleviate vasomotor symptoms of menopause
→ Agonistic effect to bone preventing osteoporosis • Tamoxifen has better outcome in terms of preventing non-invasive carcinoma but
→ Reduction in the risk for atherosclerosis raloxifene has lesser incidence of endometrial carcinoma
• Increase in the risk of DVT and pulmonary embolism Uses:
Uses: → Prevents/delays progression and treatment of osteoporosis
→ Palliative treatment of advanced breast CA in postmenopausal women, male → Reduce the risk of invasive breast cancer in postmenopausal women
infertility
Adverse Effects: Adverse Effects:
→ Nausea, vomiting, hot flushes, vaginal bleeding, dermatitis, anorexia, → Deep vein thrombosis, pulmonary embolism, hot flushes, leg cramps, vaginal
depression, mild leucopenia, ocular changes bleeding, teratogenic (multiple birth defects
• Endoxifen
→ Metabolites via CYP2D6 (strong inhibitors of 2D6 avoided in patients receiving
Tamoxifen)
→ More potent SERM
OTHER SERMS:
Toremifene
• Structurally similar compound with similar properties,
indications, and toxicities
• Receptor antagonist to breast tissue
• Use: Treatment of metastatic breast cancer
Bazedoxifene
• Blocks estrogen proliferation of the endometrium
• Combined with conjugated estrogen
• Treatment of menopausal symptoms (e.g. hot flushes)
• Use: Prevention of osteoporosis
Ospemifene
• Estrogen receptor agonist to vaginal tissue
• Uses: Improves vulvovaginitis and atrophy
b. Pure Estrogen Antagonist:
c. Partial Estrogen Agonist: Clomiphene
Fulvestrant
• 17-alkylamide derivative of estradiol Pharmacokinetics: Adverse Effect:
• Stimulates proteolytic degradation of → Well absorbed orally → hot flushes (most common side effect, due to its
ER alpha ▪ Half-life: 5-7 days (long half-lives of metabolites, plasma hypoestrogenic effect)
• Increases intracellular degradation of protein binding, enterohepatic circulation, accumulation → enlarged ovaries d/t the increased gonadotropin
ER alpha while protecting ER beta in fatty tissues) → Eye symptoms (afterimages)
• Binds to ERα and ERβ with high ▪ Elimination: urine → Headache, constipation, allergic skin reactions,
affinity comparable to estradiol • Closely related to estrogen chlorotrianisene and reversible hair loss
• Administration - IM depot • Inhibits estradiol negative feedback effect on the release of → Hormonal changes associated with an ovulatory
Pharmacokinetics gonadotropins thereby increasing secretion of gonadotropin menstrual cycle
→ ‒ Cmax: 7 days • Estrogen receptor antagonist in the hypothalamus and anterior ▪ Nausea and vomiting, increased nervous
→ ‒ Duration of action: 1 month pituitary gland tension, depression, fatigue, breast soreness,
→ ‒ Elimination: feces • Partial agonist at the ovary weight gain, urinary frequency, and heavy
Use: Use: menses
→ Tamoxifen-resistant breast CA → Polycystic ovary syndrome ▪ Multiple gestation (see Clomiphene under
▪ patients whose ovaries contain more than 12 antral Ovulation-Inducing agents)
follicles Contraindications and cautions:
▪ Gonadotropin-dependent ovarian hyperandrogenism → Special precautions
with anovulation and infertility ▪ Enlarged ovaries (More sensitive)
▪ Blocks the negative feedback effect of estrogen → ▪ Visual disturbances
surge of gonadotropins → ovulation → Patients who complain of abdominal symptoms
→ indicated in patients with disorders of ovulation who wants ▪ Maximum ovarian enlargement after the 5-day
to become pregnant course
→ Patients can be treated repeatedly until pregnancy is ▪ Palpable by the seventh to tenth day
achieved (Normal cyclic ovulatory function does not
usually resume)
ii. SYNTHESIS INHIBITORS

a. GnRH Agonists:Leuprolide, Nafarelin, Goserelin, Histrelin(Continuous) b. Aromatase Inhibitors
• Both stimulating and inhibiting ovarian function • Both stimulating and inhibiting ovarian function
• Continual administration of GnRH agonists prevents ovarian synthesis of • Mechanism of Action:
estrogens but not their peripheral synthesis from adrenal androgens → Inhibits the growth of estrogen-dependent tumors
• GnRH (Pulsatile) → Stimulatory → Bind Covalently to aromatase
• GnRH (Continuous) → Inhibitory ▪ Type I: Steroidal (suicide inhibitors, irreversible): Formestane,
Therapeutic Use: Exemestane
→ Treatment of estrogen-dependent diseases → Competitive inhibitors of aromatase
→ Treatment of androgen-dependent diseases (prostate cancer) ▪ Type II: Nonsteroidal (reversible interaction with the heme group of
→ Suppress premature hypothalamic activity in precocious puberty CYPs): Anastrozole, Letrozole, Vorozole, Fadrozole
→ Prostate CA, breast CA, endometriosis, uterine fibroids, early puberty Uses:
Adverse Reactions: → Anastrazole → Breast tumors resistant to tamoxifen
→ Headache, lightheadedness, nausea, and flushing → Letrozole and Fadrozole
→ Hypersensitivity reaction ▪ Breast cancer
→ Pituitary apoplexy and blindness ▪ Adjuncts in precocious puberty
→ Symptoms of menopause (because of decreased production of estrogen/ ▪ Primary treatment for excessive aromatase syndrome
hypoestrogenic state) → Exemestance → Advanced breast cancer
Adverse Effects
→ Mainly due to increase in testosterone levels or decrease in estrogen levels:
hirsutism, hot flushes, atrophic vaginitis, acne, constricted pupils, water
retention, osteoporosis
B. ANTI-PROGESTINS
Mifepristone (RU 486) Ulipristal Danazol
• 19-norsteroid • Derivative of 19-norprogesterone • A derivative of testosterone
• Partial agonist, binds strongly to progesterone • Selective progesterone receptor modulator • Binds to androgen, progesterone, and
receptor and inhibits the activity of progesterone; (SPeRM) glucocorticoid receptors (weak activity)
• binds to glucocorticoid receptor as antagonist → Partial agonist at PRs thereby inhibiting Mechanism of Action: used to suppress ovarian
→ treatment of Cushing’s syndrome progesterone function
→ Also used in treatment of endometriosis, breast → Weak glucocorticoid antagonist → Inhibits the midcycle surge of LH and FSH
CA and other neoplasms such as meningiomas • It does not have any androgenic, estrogenic or → Inhibit enzyme involved in steroid synthesis
that contain glucocorticoid or progesterone mineralocorticoid effects → Translocates the androgen receptor into the
receptors → Low affinity for androgen and no affinity for nucleus to initiate androgen-specific RNA
• Luteolytic properties estradiol or mineralocorticoid receptor synthesis
• Sensitizes the uterus to the action of prostaglandins • Inhibits ovulation → Does not bind to intracellular estrogen receptors
• Inhibits ovulation of given in the late follicular phase → Inhibits LH release through the hypothalamus ▪ Binds to SHBG and CBG
Use: and pituitary → Increases the mean clearance of progesterone
→ Termination of pregnancy for blighted ovum → Inhibits LH-induced follicular rupture within the • does not inhibit aromatase (needed for estrogen
→ used as an emergency postcoital ovary synthesis)
contraceptive → delayed ovulation in the Mechanism of Action • Ethisterone
following cycle → It acts on regulation of gene transcription and → major metabolite of Danazol
• In the early stages of pregnancy, mifepristone binds progesterone receptors with high → has both progestational and mild androgenic
causes decidual breakdown by blockade of selectivity and affinity effects
uterine PRs leading to decreased hCG production → Once bound, PR dimers act as either agonists, Pharmacokinetics
and decrease in progesterone secretion antagonists or mixed agonist-antagonists. → Half-life: >15 hours
• It increases uterine PG levels and sensitizes the → Agonist function is mediated by coactivators, ▪ stable circulating levels when the drug is
myometrium to their contractile actions antagonist function mediated by corepressors administered twice daily
• It also causes cervical softening → Thus producing a direct effect on uterine → Highly concentrated in the liver, adrenals, and
• And can also delay or prevent ovulation due largely fibroids, endometrium and the pituitary gland kidney
to actions on the hypothalamus and pituitary Uses → Excreted in the feces and urine
• It impairs the development of a secretory → Treatment of uterine fibroids/ uterine myomas Uses
endometrium and produces menses ▪ Reduces excessive uterine bleeding → Suppress ovarian function, endometriosis
Pharmacokinetics: − Antiproliferative effects on endometrial (Previously, it was the drug of choice for
→ Good oral bioavailability tissue endometriosis but has now been replaced by
▪ Reduces fibroid size GnRH agonists)
→ Half-life: 20-40 hours
▪ large doses may prolong the follicular phase − Antiproliferative and apoptotic effects → fibrocystic disease of the breast (due to its
of the subsequent cycle → Correcting anemia anti-progesterone effect)
→ Metabolized by CYP3A4 enzyme → Suppressing fibroids-related pain → gynecomastia
→ first pass metabolism and enterohepatic Adverse effects → hematologic disorders (hemophilia, Christmas
circulation → Treatment duration is limited to 3 months only to disease, ITP)
→ Elimination: feces prevent development of adverse effects → Infertility, precocious puberty in boys
Adverse Effects (prolonged, can last for 8-17 days) → Self-limited headache and some abdominal → hereditary angioneurotic edema
→ vaginal bleeding, vomiting, diarrhea, abdominal pain (most severe side effect) Adverse Effects
and pelvic pain, uterine cramps, nausea. → Ongoing studies have shown that ulipristal may → The major adverse effects of danazol are in
→ Not given to patients on chronic glucocorticoid cause liver injury due to its effects on the relation to its androgenic and hypoestrogenic
therapy because of its anti-glucocorticoid activity glucocorticoid receptor effects
since high doses can result in adrenal → It can also cause adrenal suppression due to
insufficiency its effect on glucocorticoid receptors
→ mild to moderate hepatocellular damage
• Additional: → Edema, weight gain

→ Lilopristone (ZK 98734) → Masculinization: decreased breast size, acne
▪ Experimental Abortifacient and oily skin, increased hair growth, deepening
▪ Anti-glucocorticoid activity of the voice
→ Onapristone (ZK 98299) → Headache, hot flushes, changes in libido,
▪ Similar in structure to mifepristone muscle cramps
▪ Methyl substituent in the 13α rather than 13β Contraindications
orientation → Hepatic dysfunction
▪ Pure progesterone antagonist → Pregnancy and lactation (can cause urogenital
abnormalities)
IV. TESTOSTERONE & ANTI-ANDROGENS

A. TESTOSTERONE
• Testosterone is synthesized by testicular Leydig cells in response to LH − Converted by peripheral tissues to estrone in very small amounts (1–
stimulation 5%)
→ can also be derived from peripheral conversion of other hormones, as was Mechanism of action:
seen in the pathway → similar to estrogen and progesterone wherein androgen binds to its receptor
• Plasma concentrations are relatively stable because of plasma proteinbinding and forms the androgen-AR complex
→ Approximately 50% (book: 65%) of circulating testosterone is bound with → This complex then undergoes dimerization before entry into the nucleus
high affinity by SHBG, which limits the bioavailability of testosterone. SHBG where it will affect transcription of genes
concentrations rise with age → decline in androgen action (more bound). Clinical Uses
→ Most of the remainder is weakly bound by albumin or unbound (2%)and → Increased androgen concentration exerts a negative feedback effect which
constitutes the pool of readily available testosterone suppresses gonadotropin secretion
• Present in the plasma of women → Androgens also increase protein synthesis
→ Equal parts from the ovaries and adrenals → Androgen Replacement Therapy in Men
→ From peripheral conversion of other hormones ‒ much smaller amounts ▪ Hypogonadism at 15-17 years old male
than in males ▪ Hypogonadotropism
• Aside from testosterone, the body also produces other androgens in smaller ▪ Hypopituitarism
amounts such as DHT (Dihydrotestosterone) which is more − androgens are not added to the treatment regimen until puberty,
potent than testosterone and weaker androgens like androstenedione and which is then instituted in gradually increasing doses
DHEA from the adrenal − Testosterone Enanthate or Cypionate (IM; long acting agents)
• Converted to DHT by 5α-reductase ▪ Testosterone propionate (IM and SL)
→ DHT is the major active androgen (DHT is 5x more potent than testosterone) − Short duration of action
• Converted to estradiol by P450 aromatase − not for long-term use
→ Adipose tissue, Liver, Hypothalamus (regulating gonadal function) ▪ Testosterone undecanoate (oral)
• Physiologic Effects (Testosterone or its active metabolite 5α-DHT) − administered in large amounts twice daily (40mg/d)
→ Changes that occur in puberty − Oral administration has been associated with liver tumors
▪ Penile and scrotal growth ▪ Side Effects:
▪ Pubic, axillary, and beard hair − Polycythemia and Hypertension
▪ Sebaceous glands become more active → Protein anabolism
▪ Skin thicker and oilier ▪ With dietary measures and exercises to reverse protein loss
▪ Lower-pitched voice ▪ After trauma, surgery, or prolonged immobilization, debilitating
▪ Skeletal growth is stimulated ▪ disease
▪ Epiphyseal closure accelerated → Treatment of Refractory Anemia
→ Metabolic effects ▪ big doses and prolonged treatment
▪ Reduction of hormone binding and other carrier proteins ▪ Aplastic anemia, Fanconi’s anemia, sickle cell anemia, myelofibrosis, and
▪ Increased synthesis of clotting factors, triglyceride lipase,α1- antitrypsin, hemolytic anemia
haptoglobin, and sialic acid − replaced by recombinant erythropoietin
▪ Stimulate erythropoietin secretion → Osteoporosis (anabolic effect)
▪ Decrease HDL levels → Hereditary angioneurotic edema (17-alpha alkylated) → swelling of
→ Other effects mouth or tongue secondary to c1 esterase deficiency
▪ Growth of the prostate and seminal vesicles ▪ Drug of Choice: Icatibant
▪ Darkening of the skin, and increased skin circulation Adverse Effects
▪ Stimulate and maintain sexual function → Masculinization (most noticeable in women and prepubertal children)
▪ Increase lean body mass ▪ Acne, facial hair growth, etc.
Preparations ▪ Prostatic hypertrophy
→ Natural Testosterone: ▪ Prostatic hyperplasia → urinary retention
▪ ‒ Oral of IM in oil, rapidly absorbed and metabolized ▪ Increased libido, priapism
▪ ‒ Protein Binding - 98% ▪ Women and prepubertal children
▪ ‒ One sixth of the dose is available in active form ▪ Hirsutism, acne, amenorrhea, clitoral enlargement, deepeningof the voice
→ Parenteral → Progesterone activity
▪ More prolonged absorption time → Greater activity ▪ Endometrial bleeding upon discontinuation
− Propionate, enanthate, undecanoate, or cypionate ester → Toxic
→ Derivatives: (with structural modifications) ▪ Edema and sodium retention (not uncommon)
▪ Esterification: preferred agents in all situations, androgenic ▪ Hepatic dysfunction - jaundice (increased bilirubin levels), increased
▪ Alkylation: 17 position, orally effective, anabolic SGOT, ALP (17 alkyl derivative)
Pharmacokinetics ▪ Cholestatic jaundice is reversible upon cessation of therapy
→ 40% bound to SHBG, 58% bound to albumin 2% as free testosterone ▪ degree is proportionate to dose
→ Dihydrotestosterone (DHT)
▪ the major active androgen ▪ Hepatic CA - in patients with aplastic anemia treated with androgen
▪ exerts most of its activity on the skin, prostate, seminal vesicles and anabolic therapy (methyltestosterone, etc.)
epididymis → Alters serum lipids → atherosclerotic disease in women
→ Major pathway for degradation: liver → excreted in the urine ▪ Lowers plasma HDL and may increase LDL → hypertension
▪ Inactive substances androsterone and etiocholanolone → Not to be used in infants
→ Half-life of free testosterone is short: 10-20 minutes ▪ affects maturation of CNS centers governing sexual development,
→ Inactivated in the liver by conversion to androstenedione particularly in the female
▪ Androstenedione, DHEA and DHEAS → psychological dependence, increased aggressiveness and psychotic
− Adrenal androgens symptoms
− Development of pubic and axillary hair and bone maturation → Polycythemia
− Improve the sense of wellbeing Contraindications
− Inhibit atherosclerosis → Pregnancy (masculinization or undermasculinization of the external genitalia
− Metabolized like testosterone in the female or male fetus, respectively)
▪ DHEAS but particularly androstenedione → CA of prostate and breast (male)
→ Young children
→ Renal and liver disease
→ Caution - heart disease, epilepsy, migraine
B. ANTI-ANDROGENS
Receptor Antagonists Inhibitors of Synthesis Inhibitors of Conversion to DHT
→ Cyproterone acetate → GnRH Agonist - Leuprorelin (Leuprolide), → Finasteride
→ Flutamide, Nafarelin, Buserelin, → Dutasteride
→ Bicalutamide, Nilutamide, Enzalutamide → Gonadorelin
→ Spironolactone → Ketoconazole
i. RECEPTOR ANTAGONISTS
Cyproterone and Cyproterone Bicalutamide, Nilutamide, and
Flutamide Spironolactone
Acetate Enzalutamide
• Partial agonist at androgen receptor • substituted anilide; pure potent • orally active • competitive inhibitor of aldosterone
→ inhibits the action of androgens at competitive anti-androgen • administered as a single dose • Weak inhibitor of androgen receptor
the target organ • Non-steroidal compound • Limited efficacy when used alone • Weak inhibitor of testosterone
• suppresses the feedback • rapidly metabolized • Used with GnRH agonists for synthesis
enhancement of LH and FSH, Mechanism of Action: treatment of metastatic prostate CA Mechanism of Action
leading to a more effective → Competitive antagonist at the (well tolerated) → Competes with DHT in target
antiandrogen effect androgen receptor • Bicalutamide tissues
Mechanism of Action: Uses → less hepatotoxic → Decreases 17alpha-hydroxylase
→ Competes with GnRH → Metastatic prostatic CA, in → used in combination with GnRH activity → decreases
→ Competes with DHT for receptor conjunction with GnRH analog to reduce tumor flare testosterone and
binding analogues (seldom used alone), → fewer GI side effects than androstenedione
Therapeutic Uses: benign prostatic hyperplasia, Flutamide Use
→ Severe hirsutism, acne, hirsutism, management of → Dosage: 150-200 mg/d when → Hirsutism (dosage: 50-200
masculinization excess androgen effect in used alone; 50 mg/d when with mg/d)
→ Prostatic cancer women GnRH analog → As effective as finasteride,
→ used in combination with Adverse Reactions: • Nilutamide flutamide, or cyproterone
estrogen for regulation of menses → Mild gynecomastia → Dosage: 300 mg/d for 30 days
→ decreases excessive sexual → Mild reversible hepatotoxicity followed by 150 mg/d
drive in men • Enzalutamide
• Cyproterone Acetate → Dosage: 160 mg/d orally
→ has progestin activity
→ dosage: 2 mg/d; administered
concurrently with an estrogen
(treatment of hirsutism in
women)
ii. INHIBITORS OF SYNTHESIS iii. INHIBITORS OF CONVERSION TO DHT
GnRH Analogues (Agonists) - Leuprolide, Goserelin, Nafarelin,Buserelin, Abiraterone
Triptorelin (Continuous) • a newer 17α-hydroxylase inhibitor
• Receptor downregulation in anterior pituitary if given continuously • Preventing the action of the side chain-splitting enzyme
• Can be combined with receptor antagonist • Use: metastatic prostate CA
• Paradoxical effect of therapeutic agonists to suppress HPG axis Finasteride
Uses
• 5alpha-reductase inhibitor especially type II → decreasing DHT
→ Prostatic CA
→ begins within 8 hours after administration and lasts for about 24 hours
→ Precocious Puberty
Adverse Effects • orally active
• Half-life: 4-8 hours (longer in older individuals)
→ Bone loss
→ Menopausal symptoms • Dosage: 5 mg/d
• 40-50% of dose is metabolized
Ketoconazole • More than half is excreted in the feces
Uses:
• primarily for fungal diseases
→ Benign prostatic hypertrophy
• Inhibitor of adrenal and gonadal steroid synthesis particularly testosterone, not
→ Male pattern baldness (dose: 1 mg/d)
estrogen (CYP450 enzymes)
→ Hirsutism in women
• Does not affect ovarian aromatase; reduces human placental aromatase activity
Mechanism of Action: Adverse Effects

→ Displaces estradiol and DHT from SHBG in vitro → Decreased libido and volume of ejaculate, impotence, rashes, swelling of lips
→ Increases the estradiol:testosterone ratio in plasma in vivo by a different Dutasteride
mechanism
• Inhibitor of both 5 alpha reductase types I and II
Side Effect
• Similar orally active steroid derivative
→ Reversible gynecomastia in men
• slow onset of action and longer half-life than finasteride
• Use: Treatment of benign prostatic hypertrophy (0.5 mg daily)
• Contraindicated in women and children
V. OVULATION-INDUCING AGENTS
i. Anti-estrogen: Clomiphene v. Gonadotropins
ii. Aromatase inhibitors: Letrozole → Human Menopausal Gonadotropins/ HMG (Menotropins); FSH; LH; Human
iii. Dopamine Receptor Agonist: Bromocriptine Chorionic Gonadotropins
iv. GnRH analogues
Clomiphene Letrozole Dopamine Receptor Agonist: Bromocriptine
• Weak estrogen agonist/antagonist at hypothalamic • Aromatase inhibitors • ergoline derivative
receptors thus increase LH, FSH, and estrogen • Induces follicle development by inhibiting estrogen • Oral preparation
• Partial estrogen agonist → blocks estrogen synthesis Uses:
receptors at the pituitary → Decreases estrogen negative feedback → Inhibits prolactin secretion
Mechanism of Action: → increases FSH levels → used in the treatment of pituitary tumors and
→ Blocks the negative feedback to hypothalamus • Fewer estrogen deprivation side effects (hot Parkinson's disease
and pituitary, thus, increasing FSH and LH which flushes, mood change) → Restore fertility in patients with amenorrhea and
would eventually cause ovarian follicle • Fewer multifetal gestations than clomiphene galactorrhea with hyperprolactinemia
stimulation → Increase ovarian responsiveness to clomiphene
Uses: therapy
→ Male and female infertility, in vitro fertilization → Polycystic syndrome
▪ Given on Day 3 to 5 of menstruation → Lactotroph adenoma which causes
→ Single ovulation is induced by a single course of prolactinoma causing a decrease in surge of
therapy FSH and LH
→ Treated repeatedly until pregnancy is achieved → It may also increase ovarian responsiveness
▪ Normal cyclic ovulatory function does not to clomiphene
usually resume Mechanism of Action:
Pharmacokinetics: → Inhibits prolactin secretion → shrinking the
→ Well absorbed orally tumor → ovulation
→ Half-life: 5-7 days because of: Adverse Effects:
→ High affinity to plasma binding proteins → GIT: nausea, diarrhea
→ Enterohepatic circulation → CNS: headache, dizziness, psychiatric
→ Accumulation in fatty tissues manifestations
Adverse Effects: → Long term therapy can lead to severe vascular
→ Ovarian hyperstimulation syndrome (rapid diseases (stroke) and connective tissue lesions
enlargement of ovaries, multiple cysts, renal → can also cause heart attack and seizures
complications) → Lightheadedness, orthostatic hypotension
→ Multiple pregnancy (10%) → Erythromelalgia → because of massive
→ Hot flushes vasoconstriction, it
→ Skin rash → causes intermittent swelling
→ Blurring of vision
→ GIT upset (constipation, nausea, and vomiting)
GnRH ANALOGUES
GnRH AGONISTS (Leuprolide, -relin) GnRH ANTAGONISTS (-relix)
• used to stimulate ovulation in females and spermatogenesis in male infertility • Inhibit the secretion of FSH and LH in a dose-dependent manner
and diagnosis of LH responsiveness → Ganirelix, Cetrorelix, Abarelix, Degarelix
• Suppression of GnRH is used to treat controlled ovarian stimulation, ▪ Ganirelix and cetrorelix are approved for use in COS (Controlled
endometriosis, fibroids, prostate cancer and central precocious puberty Ovarian Stimulation)
• Continuous treatment of women causes the symptoms of menopause ▪ Degarelix and abarelix are approved for men with advanced prostate
→ Depression, diminished libido, generalized pain, vaginal dryness, and breast cancer
atrophy • Suppression of Gonadotropin Production
→ Reduced bone mineral density and osteoporosis → Prevent the LH surge during COS
• Ovarian cysts may develop due to its flare effect on gonadotropin secretion and • Advantages over GnRH agonist
generally resolve after → Immediate antagonist effect
• Contraindications: → Duration of administration is shorter
→ Pregnancy and breastfeeding → Less suppressive effect on the ovarian response to gonadotropin stimulation
• Drugs under this category (Most of the drugs end in “relin” except for its → Reverse more quickly after their discontinuation
prototype): → More complete suppression of LH secretion than agonists
→ Gonadorelin, Goserelin, Buserelin, Histrelin, Leuprolide (prototype drug), • Advanced Prostate Cancer
Nafarelin, Triptorelin → Degarelix and abarelix
• Pulsatile administration ▪ Reduce concentrations of gonadotropins and androgens more rapidly
→ (1-10 ug every 60-120 minutes) for patients with hypothalamic amenorrhea ▪ Avoid the testosterone surge seen with GnRH agonist therapy
stimulates endogenous FSH and LH surge → ovulation
→ Maintains normal feedback mechanisms → single dominant follicle ▪ This leads to signs and symptoms of androgen deprivation, including hot
→ GnRH is continued for entire cycle; discontinued after ovulation flushes and weight gain but the most common side effects are nausea and
→ Advantages: headache
▪ No hyperstimulation syndrome because of receptor downregulation
▪ Approved only for diagnostic use in hypogonadism
▪ 100 ug bolus → LH surge → functional pituitary gonadotrophs
▪ Rates of multiple gestation are extremely low
→ Disadvantages:
▪ Need to monitor the IV site for swelling, pain, or erythema
▪ Risk of ovarian hyperstimulation syndrome (OHSS)
• Sustained nonpulsatile
→ Inhibit the release of FSH and LH by the pituitary in both women and men
→ Result in hypogonadotropic hypogonadism
GONADOTROPINS (HMG, FSH, LH, hCG)
HUMAN MENOPAUSAL GONADOTROPINS/HMG (MENOTROPINS) HUMAN CHORIOGONADOTROPIN
• First commercial gonadotropin product containing both FSH and LH • administered following menotropins treatment to mimic the naturally occurring
• 1:1 ratio of LH to FSH bioactivity surge of LH that triggers ovulation
• 75 IU FSH + 75 IU LH from urine of postmenopausal women given IM; • produced by the human placenta and excreted into the urine
• Daily injection for 9 to 12 days (orally ineffective) • α subunit is virtually identical to that of FSH, LH, and TSH and the β subunit
• Followed by a single shot of hCG to induce ovulation resembles that of LH
Indications: • Choriogonadotropin alfa (rhCG)
→ Used for the stimulation of follicle development → recombinant form of hCG
→ Women with polycystic ovarian syndrome (PCOS) who have not ovulated → Packaged and dosed on the basis of weight rather than units of activity
or conceived with weight loss, clomiphene, or letrozole therapy • isolated from urine of pregnant women
→ Hypogonadotropic anovulatory women with hypopituitarism or women with Uses
hypothalamic amenorrhea (HA) who do not have access to pulsatile → used to treat infertility in women, and to increase sperm count in men
gonadotropin-releasing hormone (GnRH) therapy ▪ Stimulate spermatogenesis in males with gonadotropin deficiency
→ Absolute requirement is ovarian competence for patients with defective → HCG was previously used for the treatment of prepubertal cryptorchidism
gonadotropin secretion ▪ Long-term efficacy of hormonal treatment is lower than that of surgical
▪ Patients with amenorrhea or anovulatory cycles treatment
▪ Patients with ovulatory disturbances with galactorrhea or hirsutism ▪ Early childhood treatment has a negative impact on germ cell
→ To prepare infertile patients for in-vitro fertilization ▪ Increasing the risk of precocious puberty
→ Stimulation of spermatogenesis in males with isolated gonadotropin deficiency → Induce follicle development and ovulation secondary to hypogonadotropic
FSH hypogonadism and polycystic ovary syndrome
• uFSH (Urofollitropin) → Anovulatory women who fail to respond to Clomiphene
• Purified human FSH from urine of postmenopausal women (Follitropin α and β) → Controlled ovarian stimulation (COS) in assisted reproductive technology
→ Has some LH activity but RHFHS does not procedures
• Recombinant (Recombinant Human FSH 9RHFSH) → Used as a diagnostic test in boys with cryptorchidism
→ SQ Adverse effects:
→ Shorter half-life → Ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies
→ Lesser proteins (most serious complications)
→ More expensive ▪ Ovarian hyperstimulation syndrome presents with ovarian enlargement
▪ intravascular depletion, ascites, liver dysfunction, pulmonary edema,
→ Much less batch-to-batch variability
electrolyte imbalance, and thromboembolic events
→ May cause less local tissue reaction
→ Multiple pregnancies
→ need exogenous HCG to maintain adequate estradiol biosynthesis and follicle
▪ Increased when ovulation induction and assisted reproductive
development
technologies (ART) are used
• Stimulate spermatogenesis in males with isolated gonadotropin deficiency ▪ Risk is 5–10%
LH ▪ Increased risk of complications (Gestational diabetes, Preeclampsia,
• Recombinant; SQ Preterm labor)
• Half-life: 10 hours → Although it is often self-limited, severe disease may require hospitalization
• Approved only in combination with follitropin alpha → Due to the short half-life of the GnRH agonist, it reduces the risk for ovarian
hyperstimulation
VI. DRUGS AFFECTING UTERINE MOTILITY

A. Oxytocics: Uterine Stimulating Agents (Contract)
Prostaglandins: Misoprostol (synthetic PGE1), Ergot Alkaloids: Ergotamine; Ergonovine maleate
Oxytocin
Dinoprostone (PGE2), Carboprost (PGF2a-alpha) (more selective for uterus); Methylergonovine maleate
• Peptide hormone secreted by the posterior pituitary • Prostaglandins causes contraction of smooth • Produced by Claviceps purpurea, a fungus that
• Stimulates muscular contractions in the uterus muscle which is mediated by the release of calcium infects grasses and grains
and myoepithelial contractions in the breast and relaxing effects mediated by the generation of Mechanism of Action:
• Cyclic 9-amino acid peptide with an intrapeptide cAMP → Direct smooth muscle receptor stimulation
disulfide that is synthesized in the paraventricular Misoprostol: → Serotonergic receptor agonist in smooth
nucleus of the hypothalamus and transported within • Synthetic derivative of PGE1 muscles
hypothalamic neurons • Initially used for GI ulcers but was found out to have → Weak agonist of dopaminergic receptors
• Promotes milk ejection by contraction of an effect on the uterus → Partial agonist of alpha adrenergic receptors
myoepithelium in mammary glands Pharmacokinetics: →constricts blood vessels
• Low doses produce slow, generalized uterine → Route: → Induce sustained uterine contraction
contractions with full relaxation in between ▪ Parenteral
• Second half of pregnancy ▪ Local - intraamniotic, vaginal suppository Pharmacokinetics:

→ Increases expression of oxytocin receptors in (usually used), etc. → Oral absorption is rapid and almost complete
the uterine muscles ▪ Oral → Half-life: 0.5-2 hours
→ Sensitive to the stimulant action of endogenous → Metabolism: Tissues utilizing them → Duration of action: 3-6 hrs
oxytocin → Half-life: <1 min; <8 mins (metabolites) → Onset of uterotonic
Pharmacokinetics: → Excretion: Urine (90%) ▪ Oral: 10 mins
→ Absorption: Obstetrical Therapeutic Uses: ▪ IM: 7 mins
▪ ‒ Oral - inactivated in GIT • Medical management of miscarriage ▪ IV: 40 secs
▪ ‒ IV infusion is preferred • Termination of pregnancy in cases of missed → Metabolism: Liver
→ Not bound to plasma protein abortion, IUFD, H-mole → Excretion: Urine
→ Metabolism: • “Cervical ripening” before surgical procedures - Clinical Uses:
▪ Liver, tissues softening and dilation to normal or induced labor • • To promote uterine involution in the post-abortion
▪ Half-life: 12-17 mins; 5 mins • Management of postpartum hemorrhage or postpartum
→ Rapidly eliminated by liver and kidney Contraindications: • periods to prevent postpartum uterine atony and
Mechanism of Action: → Hypersensitivity, acute PID, asthma, hemorrhage
→ Contraction through G-protein coupled unfavorable fetal disposition (placenta previa), • Given after delivery of the placenta
receptors and IP3-Ca second messenger pregnancy • Routine expulsion of the placenta after delivery
system Adverse Reactions: → Ergot products should NEVER be used during
→ Stimulates the release of prostaglandins and → Uterine pain, pelvic pain, nausea, vomiting, labor because of the potential for SUSTAINED
leukotrienes to augment uterine contraction diarrhea, phlebitis, fever, chills, rashes, uterine UTERINE CONTRACTIONS and FETAL
→ In small doses → increases both the frequency hyperstimulation, uterine rupture COMPROMISE, which are not
and force of uterine contractions Toxic Effects: (all are possible for Misoprostol) pharmacologically reversible.
→ At higher doses → produces sustained → Vomiting, diarrhea in 50% of patients Adverse Effects:
contraction → Hyperpyrexia - PGE2 and 15-methyl PGF2-α • Vomiting, vasoconstriction, increase in BP, blurred
→ At high concentrations, weak antidiuretic and → Hypertension - PGF2 and 15-methyl PGF2- α vision, headache, angina
pressor activity due to activation of vasopressin → Vasodilation - PGE2
receptors → Cardiovascular collapse Ergonovine
Therapeutic Uses:
Alprostadil • Ergometrine
→ IV: Induction and augmentation of labor • Combined α agonist, serotonin agonist
• PGE1
▪ Oxytocin is generally considered to be the • Evokes rhythmic contraction and relaxation of
• Second-line treatment for erectile dysfunction
DRUG OF CHOICE for inducing labor at the uterus
term Dinoprostone → At higher concentrations these drugs induce
→ IM: Control of postpartum hemorrhage • Synthetic preparation of PGE2 powerful and prolonged contractions
→ Milk ejection • Administered vaginally • Agent of choice in obstetric applications of the
▪ Oxytocin Challenge Test - antepartum test • Superior to oxytocin for inducing labor in women ergot drugs
of uteroplacental insufficiency in high-risk with preeclampsia, eclampsia, or cardiac and renal
pregnancies → monitoring the heart rate of diseases
the baby • No anti-diuretic effects
Adverse Effects: (Rare) Pharmacokinetics:
→ Hyperstimulation → uterine rupture, fetal → Half-life is 2.5–5 minutes
distress, placental abruption → Metabolized in local tissues and on the first pass
→ PVC’s (arrhythmia/premature ventricular through the lungs (about 95%)
contractions) with IV bolus → Excreted in the urine
→ Hypotension with general anesthesia in high Uses:
doses → For missed abortion
→ Activation of vasopressin receptors → benign hydatidiform mole
▪ Fluid retention → water intoxication → ripening of the cervix for induction of labor in
▪ hyponatremia, heart failure, seizures, and patients at or near term
death → Directly affects the collagenase of the cervix,
→ Fetal hypoxia and hyperbilirubinemia resulting in softening
Contraindications
Carboprost tromethamine
→ Fetal distress, fetal malpresentation, placental
• 15-methyl-PGF2α
abruption, previous, extensive uterine surgery
• Prolonged duration of action
Carbetocin • Dosing: 250-mcg IM, repeated if necessary
→ Long acting synthetic oxytocin analog Uses:
→ Single IV administration → second trimester missed abortions
→ Only indicated for the prevention of uterine atony → control postpartum hemorrhage that does not
and postpartum respond to conventional methods of
→ hemorrhage following elective CS under management
epidural or spinal anesthesia Adverse effects
→ also binds to oxytocin receptors → Vomiting and diarrhea occur commonly
→ Lower potency, longer duration of action, and → Transient bronchoconstriction can occur
rapid onset of action vs oxytocin → Transient elevations in temperature is rare
→ Adverse effects Contraindications of PG Analogs:
▪ Nausea, vomiting and flushing → Hypersensitivity to the compound
▪ Hypotension → Acute pelvic inflammatory disease
→ Asthma
→ Fetal malpresentation
→ Placenta previa
B. Tocolytics: Uterine Relaxing Agents (Relax)

• Prostaglandin Synthetase Inhibitors Mechanism of Action
(Indomethacin) → The elevation of cellular Ca2+ promotes contraction via the Ca2+/calmodulin dependent activation of
• Ca Channel Blockers (Nifedipine) MLCK
• Magnesium Sulfate → Relaxation is promoted by the elevation of cyclic nucleotides (cAMP and cGMP) and their activation of
• Beta-adrenergic Agonists protein kinases, which cause phosphorylation/inactivation of MLCK
→ Terbutaline, Isoxsuprine, Salbutamol, Pharmacological manipulations to reduce myometrial contraction include the following:
Ritodrine → Inhibiting Ca2+ entry (Ca2+ channel blockers, MgSO4)
• Nitric Oxide Donors (Glyceryl trinitrate) → Reducing mobilization of intracellular Ca
• Oxytocin Receptor Antagonist (Atosiban) → Antagonizing IP3-DAG signal transduction pathway (with antagonists of the PGF2 and OXT receptors)
→ Reducing production of PGF2α (with COX inhibitors)
→ Elevating cellular cAMP (with β2 adrenergic agonists that activate Gs-AC) and cellular cGMP
Prostaglandin Synthetase Inhibitor: Indomethacin Calcium Channel Blockers: Nifedipine, Nicardipine Magnesium Sulfate
Mechanism of Action: Mechanism of Action: Mechanism of Action:
→ Inhibits myometrial contractility by inhibiting • Directly blocks voltage-dependent channels, → Competes with Ca at plasma membrane
gap junction and preventing prostaglandin- thereby inhibiting influx of Ca into the cell membrane voltage gated channels; hyperpolarizes the
mediated increases in intracellular calcium and also inhibits release of intracellular Ca from the membrane causing relaxation
→ Inhibits both COX-1 (synthesized in gestational sarcoplasmic reticulum → Competes with Ca at both the voltage-
tissues) and COX-2 (inducible) enzymes Maternal Side Effects: dependent and voltage-independent sites
▪ COX enzymes increase decidual • Mainly due to its vasodilatory effects: transient → High Mg concentrations may also increase the
myometrium during preterm and term facial flushing, nausea, headache, dizziness, activity of the Mg-Ca- ATPase in the cell
▪ COX-2 inhibition → decreases Ca decreased BP, increased cardiac rate, palpitations membrane thus increasing the calcium extrusion
(decrease contraction) in the myometrium Contraindication: from the smooth muscle cell
− not yet good tocolytics compared to • Hypersensitivity, hypotension, preload-dependent → Stimulates the Ca dependent ATPase that
Indomethacin • cardiac lesions (i.e. aortic insufficiency) promotes Ca uptake by the sarcoplasmic
• Dose: 50-100 mg (loading dose) then 25 mg q4-6 Nifedipine reticulum thus decreasing Ca available for light
hrs for 24-48 hrs • Ca channel blocker used most commonly chain phosphorylation of myosin
Pharmacokinetics • Dose:
• Used in preterm labor
→ Rapid absorption after oral or rectal → IV load over 20 mins → continuous infusion
• Administered parenterally or orally
administration → Dose adjustment if with renal insufficiency
• More likely to improve fetal outcomes
→ Peak plasma concentration: 1-2 hrs Pharmacokinetics:
• Less likely to cause maternal side effects than
→ Half-life: 5-8 hrs (2.6-11.2 hrs) • Plasma level: 4-8 mg/dL
beta agonist
→ Effective plasma concentration: 0.8 mg/mL
• Dose: 30 mg PO then 20 mg TID x 3 days or 10 mg • Excretion:
→ Metabolism: Liver cap SL then 20 mg q4-6 hrs • ‒ Urine
→ Excretion: Kidneys Pharmacokinetics: • ‒ Competes with Ca for a common reabsorptive site
Uses → Absorption: almost complete after oral, SL, or in the loop of Henle thus decreasing Ca by 25%;
→ Used to inhibit preterm labor rectal adm. increase PTH by 25%
→ Can inhibit platelet function and induce → Bioavailability: 65% after oral ingestion Side Effects
closure in utero of the ductus arteriosus → Peak Drug Concentration: 30 mins • Nausea and vomiting, muscle weakness, dry
Side Effects mouth, blurred vision, feeling of warmth, transient
→ Half-life: 2-4 hrs
→ Maternal: Nausea, vomiting, emesis, rash, hypotension
→ Metabolism: Liver
platelet dysfunction Contraindications
→ Excretion: Kidneys 70-80%; Feces
→ Fetal: Constriction of fetal ductus arteriosus • Renal failure, myasthenia gravis, heart block,
Side Effects
(reversible), decreased neonatal GFR and urine • myocardial damage
→ Transient facial flushing
output, oligohydramnios Magnesium Sulfate Association of Side Effects with
Contraindications: → Nausea and headache Plasma Concentration
→ Platelet dysfunction or bleeding diathesis → Decreased BP • 8-12 mg/dL - DTRs disappear
→ hepatic dysfunction → Increased cardiac rate • 12-15 mg/dL - muscle weakness, respiratory
Contraindications: paralysis, hypotension and ECG changes
→ maternal history of gastric ulcer or hemorrhage
→ Hypersensitivity • 30 mg/dL asystole
→ renal disease
→ asthma, allergy to prostaglandin synthetase
Nicardipine
inhibitors
Pharmacokinetics:
Cautions
→ Bioavailability: 20 mins after oral dose
→ Treatment is generally limited to 48 hrs
→ Peak Drug Concentration: 30 min - 2 hrs
(because prostaglandins cause narrowing of the
ductus arteriosus) unless surveillance of the → Half-life: 2-4 hrs
fetal ductus arteriosus and amniotic fluid volume → Metabolism: Liver
is possible
→ Inadvisable to use after 34 weeks AOG
because the ductus arteriosus is more
responsive to prostaglandin inhibition near term
Beta-adrenergic Agonists: Terbutaline, Isoxsuprine,Salbutamol, Ritodrine Nitric Oxide Donors: Glyceryl Oxytocin Antagonist: Atosiban
trinitrate
Mechanism of Action Mechanism of Action • Modified form of oxytocin
→ use GPCRs by binding to a transmembrane receptor that activates adenylyl → Increases cGMP inactivating • Competitive oxytocin receptor
cyclase which facilitates conversion of ATP to cAMP causing sequestration myosin light chain kinases thus antagonist (VOTra)
of calcium intracellularly thereby inhibiting smooth muscle contraction causing smooth muscle • Indicated to delay imminent
Side Effects of Beta--2 Agonists relaxation preterm birth in pregnant adult
→ Dose related tachycardia, Hypotension, Hyperglycemia, Hypokalemia • Transdermal Patches: women
→ Pulmonary edema → Applied to the skin of the • As effective as β agonist tocolytics
→ Tachyphylaxis abdomen and produces fewer adverse effects
→ Nausea, vomiting, Headache, nervousness and anxiety → If with no improvement → • Selective serotonin-vasopressin
Contraindications additional patch receptor antagonist
→ Cardiac disease, Type 1 DM (insulin dependent), Untreated hyperthyroidism, → Patch left for 25 hrs (max) Mechanism of Action:
poorly controlled hypertension • IV Infusion: → Atosiban inhibits the oxytocin-
Terbutaline (mostly used) → An IV infusion rate of 20 mcg/min mediated release of IP3 from
• FDA-approved for asthma; Used off label as tocolytic until contractions stop the myometrial cell membrane
• May delay births during the first 48 h of treatment Maternal Side Effects → Reduced release of intracellular,
Pharmacokinetics: → Headache, hypotension stored calcium from the
Contraindications sarcoplasmic reticulum of
→ Absorption:
→ Hypotensive women, preload myometrial cells
▪ Oral: Rapid but incomplete (30%)
▪ 32% albumin bound cardiac lesions → Reduced influx of Ca from the
extracellular space through
→ Metabolism: Liver
voltage gated channels
→ Excretion: Urine
→ Suppresses oxytocin-
▪ Conjugated sulfate and glucuronide forms
mediated release of PGE and
• Doses:
PGF from the decidua
→ 2.5 mg q4-6 hrs
• Administration: IV bolus infusion for
▪ Oral admin: Peak: 1.5-2 hrs
not more than 24 hrs
▪ Half-life: 1.5 hrs
Use: Preterm labor
▪ Labor-inhibiting conc.: 5-15 ng/mL
Side Effects:
→ SQ: Every 20-30 mins until tocolysis is achieved
• Hypersensitivity and injection site
Ritodrine reactions
• Selective β2 agonist • Uncommon: Nausea and
• Uterine relaxant and remains the only tocolytic drug to have gained FDA vomiting, vasodilation,
approval hyperglycemia, rash
Isoxsuprine
• Chemical structure similar to sympathomimetic amines
• Direct relaxation of uterine and vascular smooth muscle
• Lacks uterine specificity
• Dose: 10-20 mg TID-QID (trade name Duvadilan) VII. CHEMICAL CONTRACEPTION IN MEN
Uses Gossypol
→ Peripheral vasodilator with direct smooth muscle relaxing effect • cottonseed derivative
→ Control of uterine hypomotility disorders (main use) → stops the • destroys elements of the seminiferous epithelium but does not alter the
contraction endocrine function of the testis
→ Threatened abortion Adverse Effect
→ Dysmenorrhea → hyperkalemia: which may lead to paralysis
Side Effects: Hypotension, tachycardia **Due to its low efficacy and significant toxicity, this drug has been
Contraindication: Arterial bleeding abandoned as a candidate male contraceptive
Salbutamol
• Dose: (2mg/tab) 2 tabs TID or QID
→ Oral admin: Peak: 1-3 hrs
→ Half-life: 6 hrs
REFERENCES
A2022 Pharma-Therapeutic Trans
Katzung’s Basic and Clinical Pharmacology (14th ed)
Powerpoint by Dr. Sangalang (2022)
END OF REVIEWER
Prepared by: SALAS, CHRISTIAN RENZO C.

UNIVERSITY OF SANTO TOMAS

FACULTY OF MEDICINE AND SURGERY
D2022 Reviewer
Sample EXAMINATION
May 2020
Instructions:
1. There are 20 items in this questionnaire
2. CHOOSE THE BEST ANSWER.
3. Try to answer on your own (without the use of reviewers/trances)
4. Answers are given in a separate document.
5. God bless!
------------------------------------------------------------------------------------------------------------------------------------------------------------------
CHOOSE THE BEST ANSWER
MULTIPLE CHOICE.
1. A 30 year old known asthmatic with elevated BP is about to give birth. In order to augment labor this should be given?
A. Oxytocin B. Misoprostol C. Terbutaline D. Dinoprostone
2. This hormone can be given in order to test for hypogonadism

A. Medroxyprogesterone derivative B. HCG alpha recombinant C. GnRH analogues D. hCG
3. This drug can be given to a patient with prostate cancer with elevated liver enzymes, mild gynecomastia, and increased libido. The most appropriate anti-androgen
is:
A. Ketoconazole B. Cyproterone acetate C. Flutamide D. Spironolactone
4. Principal effect of DHT include:

A. Erythropoiesis B. LH inhibition C. Prostate hypertrophy in elderly D. spermatogenesis
5. This is a pharmacologic effect of tamoxifen on the following tissue:

A. Agonist in the bone B. Antagonist to prostate gland C. Agonist to breast cell proliferation D. Antagonist to the endometrium
6. Which of the following is your favorite subject? This is the most appropriate hormone replacement therapy for a 25 year old who underwent hysterectomy and
bilateral salphingoophorectomy in order to prevent osteoporosis and improve vasomotor symptoms.
A. Mestranol and norgestrel B. Norethisterone and ethynodiol C. Levonorgestrel D. Ethinyl estradiol
7. The mechanism of action of Bromocriptine as an ovulation-inducing agent:

A. Estrogen agonist B. Dopamine receptor agonist C. B-adrenergic agonist D. Serotonin receptor antagonist
8. This cyclic 9 amino acid peptide synthesized in the paraventricular nucleus of the hypothalamus, when synthesized in low doses, produces slow generalized
uterine contractions with full relaxation in between:
A. PGE1 B. Ergonovine C. Oxytocin D. Bromocriptine
9. The mechanism by which Atosiban exerts its tocolytic effect is:

A. Competes with calcium at voltage dependent sites C. Oxytocin receptor antagonist
B. Prevents prostaglandin-mediated increases intracellular calcium D. B2 receptor smooth muscle membrane agonist
10. A 37 year old on her 30th week AOG is having preterm labor. She suddenly feels warm with nausea, vomiting, and dryness of mouth. The most probable tocolytic
given to this patient is
A. Nifedipine B. Indomethacin C. Salbutamol D. Magnesium sulfate
11. Substitution at C17 of estrogen molecule with ethinyl derivative produces this effect om estrogen pharmacologic property:
A. decreased excretion B. decreased protein binding C. higher bioavailability D. fewer adverse effects
12. Which of the following effects of estrogen may lead to thromboembolism

A. increased coagulation factors 2,7,9,10
B. decreased circulatory binding globulins
C. increased Protein C and S
D. decreased quantity and quality of platelets
13. By causing long term ovarian suppression, progestins are beneficial in patients with:
A. infertility B. endometriosis C. osteoporosis D. ovarian cancer
14. Testosterone is used as an anabolic agent in this condition:

A. osteoporosis B. anaplastic anemia C. precocious puberty D. menopause
15. The advantage of GnRH analogue as ovulation-inducing agents is that it:

A. is devoid of drug-drug interactions C. can be given orally as well as parenterally
B. has very long duration of action D. dopes not cause hyperstimulation syndrome
16. Which of the following can be given to a 30 year old G2P1 who just had an abortion in order to promote involution of the uterus?
A. Ergonovine B. Misoprostol C. Magnesium sulfate D. carboprost
17. A 30 year old female was diagnosed to have endometriosis. She has no history of ddep veon thrombosis and plasma lipoproteins are normal. The most appropriate
anti-estrogen to be given to her is:
A. tamoxifen B. Fulvestrant C. Leuprolide D. Progestins
18. A 55 year old breast cancer patient is already on tamoxifen, however there was progression of the disease and it is suspected to be resistant to the drug. Patient
history of leg cramps. The most appropriate anti-estrogen for her:
A. Raloxifene B. Flutamide C. Fulvestrant D. Clomiphene
19. This is the mechanism of action of danazol:

A. sensitizes the uterus to the action of prostaglandins
B. inhibits the midcycle surge of LH & FSH
C. enhances enzyme involved in steroid synthesis
D. Decreases the mean clearance rate of progesterone
20. A couple in their 30s wanted to have a baby. The male, known to have gonadotropin deficiency was noted to have low sperm count. This can be given to him to
stimulate spermatogenesis:
A. menotropin B. GnRH analogue C. finasteride D. urofollitropin
CRCS2020
- END OF QUIZ-
GOD BLESS!

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PHARMACOLOGY

GONADAL HORMONES & INHIBITORS SHIFT 4

• The hypothalamic pulse generator functions as a neuronal “clock” that fires at

II. ESTROGEN, PROGESTINS, AND HORMONAL CONTRACEPTION

MECHANISM OF ACTION PHYSIOLOGIC & METABOLIC EFFECTS PHARMACOKINETICS

D. Hormonal Contraception (Oral, Parenteral, Implanted)

Contraindications & Cautions Beneficial Effects

III. ESTROGEN & PROGESTIN INHIBITORS

ii. SYNTHESIS INHIBITORS

• Additional: → Edema, weight gain

IV. TESTOSTERONE & ANTI-ANDROGENS

Mechanism of Action: Adverse Effects

VI. DRUGS AFFECTING UTERINE MOTILITY

• Second half of pregnancy ▪ Local - intraamniotic, vaginal suppository Pharmacokinetics:

B. Tocolytics: Uterine Relaxing Agents (Relax)

Prepared by: SALAS, CHRISTIAN RENZO C.

UNIVERSITY OF SANTO TOMAS

2. This hormone can be given in order to test for hypogonadism

4. Principal effect of DHT include:

5. This is a pharmacologic effect of tamoxifen on the following tissue:

7. The mechanism of action of Bromocriptine as an ovulation-inducing agent:

9. The mechanism by which Atosiban exerts its tocolytic effect is:

12. Which of the following effects of estrogen may lead to thromboembolism

14. Testosterone is used as an anabolic agent in this condition:

15. The advantage of GnRH analogue as ovulation-inducing agents is that it:

19. This is the mechanism of action of danazol:

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