Drugs Used in Reproductive Health: Estrogen and Progestin

For BNS Ist YearDr. Pravin Prasad

Ist Year Resident, MD Clinical PharmacologyMaharajgunj Medical Campus

2nd October, 2015(Asoj 15, 2072); Friday

Drugs Used in Reproductive Health

• Estrogens, Progestins• Oral Contraceptives• Uterine Stimulants– Oxytocin– Methylergotmetrine

• Uterine Relaxants

ESTROGENS

Estrogens: Introduction

• Female sex hormone• Natural Estrogens:– Estradiol (secreted by graafian follicles, corpus luteum and placenta

in females and by aromatization of testerone in testes and extraglandular tissues in males; most active/potent),

– Esterone (oxidised form of estradiol E2, in liver)– Estriol (formed by hydroxylation of esterone)

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Types of Synthetic Estrogens

Estrogens: Introduction

Steroidal Non-steroidal

Ethinylestradiol Diethylstilbestrol (stilbestrol)

Mestranol Hexestrol

Tibolone Dienestrol

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Estrogen Synthesis

Ref: http://www.apsubiology.org/anatomy/2010/2010_Exam_Reviews/Exam_5_Final_Review/steroid_hormone_synthesis.png

Regulation of Estrogen secretion

Actions of Estrogens

• Sex organs:– Responsible for pubertal changes– Growth of uterus, fallopian tubes and vagina– Mensturation in anovulatory cycles– Enhances sperm penetration– Deficiency leads to atrophic changes in female reproductive tract

• Secondary Sex Characters:– Breasts: proliferation of ducts and stroma, accumulation of fat– Pubic and axillary hair appears– Feminine body contours and behaviours

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• Anabolic, weaker than testosterone– Responsible for pubertal growth spurt in both boys and girls

• Bone Mass: Retards bone resorption; Promotes fusion of epiphyses• Water and salt retention: edema treatable by diuretics; Blood

pressure may rise on prolonged use• Glucose tolerance(high doses as in combined OCPs): impaired,

normal blood sugar not affected, diabetes precipitated, control lost• Lipid Profile: decreased plasma LDL cholestrol, increase HDL and TG

levels; raised HDL:LDL ratio

Actions of Estrogens: Metabolic Effects

• Blood Coagulability: increased due to induction of synthesis of clotting factors (factors II, VII, IX and X); Fibrinolytic activity increases (lowering of plasminogen-activator inhibitor-I, PAI-I)

• Vascular Endothelium: Nitric oxide synthase and Prostaglandin I2 (PGI2) production promotes vasodilatation,

• Gallbladder: increases lithogenicity (increased cholesterol secretion and decresed bile salt secretion)

• Hormone Binding Globulins: increases plasma Sex Hormone Binding Globulin (SHBG), Thyroxine Binding Globulin (TBG), Cortisol Binding Globulin (CBG)

Actions of Estrogens: Metabolic Effects

Estrogen ReceptorsEstrogen Receptor Alpha (ERα) Estrogen Receptor Beta (ERβ)

Both Subtypes Expressed by most tissues

Predominates in: uterus, vagina, breast, bone, hypothalamus, blood vessels

Predominates in: Prostate gland of males, ovaries in females

• E2 bind to both receptors with equal affinity;• Certain ligands (types of estrogens) have differing affinity• These receptors have different pattern of interaction(different activity) with

coactivators and corepressors

Estrogen: Mechanism of Action

• Genomic Actions:– Binds to specific nuclear receptors (Estrogen receptors, ER)

conformational changes (receptor dimerization leading to interaction with Estrogen Response Elements, ERE, of target genes) regulates protein synthesis

• Nongenomic Actions:– ERs located on the cell membrane

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Estrogen: Mechanism of Action

Ref: Laurentino S, Pinto P, Correia S, Cavaco JE, Canário AVM, Socorro S. Structural variants of sex steroid hormone receptors in the testis: from molecular biology to physiological roles. OA Biotechnology 2012 Dec 17;1(2):4.

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Estrogen: PharmacokineticsPharmacokinetic Parameters ProfileAbsorption • Well absorbed orally as well as transdermally

• Natural estrogen inactivated due to rapid metabolism in liver when given orally

Distribution • Natural estrogens are largely plasma protein bound (SHBG and albumin)

Metabolism • Converted to Esterone and vice versa in liver• Esterone converted to estriol• Phase I reaction: Conjugation with glucuronic acid• Phase II reaction: sulfation

Excretion • Due to deconjugation in intestines: considerable enterohepatic circulation

• Mainly excreted in urine, may be excreted in bile

Estrogen: Doses

• Equivalent parenteral doses are:– Estradiol1 0.1 mg = Ethinylestradiol3 0.1 mg = Mestranol3 0.15 mg =

Coniugated estrogen2 10 mg = Estriol succinate2 16 mg = Diethylstilbestrol3 10 mg

– 1: inactive orally, 2: partially metabolised, 3: similar activity of both dosage forms

• Preferred Route Oral; Intramuscular used when high dose is required (Ca. prostate)

Estrogen: Preparations• Estradiol: 2.5-10mg intramuscular injection• Conjugated Estrogens: 0.625-1.25 mg/day, oral (Dysfunctional Uterine

Bleeding)• Ethinylestradiol: 0.02-0.2 mg/day, oral (postmenopausal syndrome)• Mestranol: 0.1-0.2 mg/day, oral• Estriol: 4-8 mg/day initially then 1-2 mg/day, oral• Fosfestrol: intravenous preparation• Dienestrol: 0.01%, topical preparation• Estradiol-TTS: Transdermal patch of 5, 10, 20 cm2 delivering 0.025, 0.05, 0.1

mg respectively for 3-4 days (postmenopausal syndrome)

Estrogen: Transdermal patch Pros and Cons

• Effects on menopausal symptoms, bone density, vaginal epithelium, plasma Gonadotrophin level are comparable to those of oral therapy

• Milder systemic side effects in comparison to oral preparations• Avoids hepatic delivery:– Levels of Thyroid binding globulin (TBG), Cortisol binding globulin

(CBG), angiotensin and clotting factors are not raised risk of thromboembolic phenomenon avoided

• Effect of serum lipid profile: less marked

Estrogens: Indications

• Hormonal Replacement Therapy (HRT)• Senile Vaginitis• Delayed puberty in girls• Dysmenorrhoea• Acne• Dysfunctional Uterine Bleeding• Carcinoma prostate

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Estrogen: Side EffectsPopulation Groups Side Effects

Males Suppression of libido, gynaecomastia and feminization

Children Fusion of epiphyses and reduction of adult stature

Postmenopausal women/ on HRT

Risk of irregular bleeding and endometrial carcinoma

Existing Breast cancer Growth of existing breast cancer

Women under long term estrogen therapy

Increased incidence of gallstones, benign hepatoma

Co-morbidity Worsening of Migraine, epilepsy, endometriosis

Pregnant Women(esp. first trimester)

Vaginal and cervical carcinoma in female offspring in childhood or early adulthood

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ANTIESTROGENS AND SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)

Antiestrogens

• Clomiphene– Useful for infertility due to failure of ovulation, aid in vitro

fertilization, oligozoospermia in males• Fulvestrant– Selective Estrogen Receptor Down-Regulator– Used for metastatic ER positive breast cancer in postmenopausal

women which has stopped responding to Tamoxifen

Selective Estrogen Receptor Modulators (SERMs)

• Exerts both estrogenic and anti-estrogenic actions in a tissue selective manner• Tamoxifen– Antagonist action in Breast carcinoma cells, blood vessels and some peripheral sites

(ERα receptors)– Partial agonistic activity on uterus, bone, liver and pituitary.– Used in treatment for breast cancer in both pre- and post-menopausal patients• Early cases: Used post mastectomy for adjuvant therapy• Advanced cases: part of palliative therapy• Only drug approved for breast carcinoma in premenopausal women (early and advanced)

– Other use: primary prophylaxis of breast cancer in high-risk women, as an alternative to clomiphene in male infertility

Selective Estrogen Receptor Modulators (SERMs)

• Raloxifene:– Estrogen partial agonist in bone and cardiovascular system– Antagonistic action on endometrial and breast tissue– Distinct DNA target “raloxifene response element”– Used as second line drug for prevention and treatment of

osteoporosis in postmenopausal women

Aromatase inhibitors (AI)

• Third generation AI: Letrozole, Anastrozole, Exemestane• Letrozole and Anastrozole– Orally active, nonsteroidal (Type 2) compound– Reversibly inhibits aromatization of testosterone and androstenedione all

over body total estrogen deprivation– Used in Early breast cancer (first line adjuvant therapy post mastectomy in

ER+ve postmenopausal women), Advanced breast cancer (first line as well as tamoxifen failure cases)

• Exemestane– Orally active, steroidal and irreversible (Type 1) inhibitors

PROGESTINS

Progestins

• Converts the estrogen primed proliferative endometrium to secretory and maintain pregnancy in animals spayed after conception

• Natural Progestin:– Progesterone– Secreted form corpus luteum post-ovulation and immediately after

fertilization (corpus luteum sustained by chorionic gonadotrophins released by blastocyst); from placenta during 2nd and 3rd trimester; from adrenals and testes in men (? role)

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Synthetic Progestins• Progesterone Derivatives:– Medroxyprogesterone acetate, Megesterol acetate, Dydrogesterone,

Hydroxyprogesterone caproate; Nomegestrol acetate• 19-nortesterone Derivatives: – Older Compounds: Norethindrone, Lynestrenol (Ethinylestrenol), Allylestrenol,

Levenorgestrel (gonanes)• Weak estrogenic, androgenic, anabolic and potent antiovulatory action

– Newer Compounds (Gonanes): Desogestrel, Norgestimate, Gestodene• Very potent progestins, antiovulatory action, little or no androgenic property• Preferable in women with hyperandrogenemia

• 19-norprogesterone Derivative:– Nomesgestrol• Weak antiandrogenic property, less antiovulatory, strong antiestrogenic effect on endometrium

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Actions of Progestins (Progesterone as Prototype)

• Uterus:– Secretory changes in the estrogen primed endometrium: hyperemia,

tortuosity of glands, increased secretion.– Continued action (as during pregnancy): decidual changes and sensitivity of

myometrium to oxytocin decreased• Cervix:– Secretion made viscid, scanty and cellular secretion: hostile to sperm

penetration• Vagina:– Pregnancy like changes

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• Breast:– Leutal phase exposure: cyclic epithelial proliferation and turnover of

acini in mammary glands– Continuous exposure: halts mitotic activity and stabilizes mammary

cells; prepares breast for lactation• CNS:– High concentration has sedative effect

• Body Temperature:– Slight rise in body temperature (0.5oC)

Actions of Progestins (Progesterone as Prototype)

• Respiration:– Stimulates respiration at higher doses

• Metabolism:– Prolong use of Oral contraceptives impairs glucose tolerance– Raises LDL and lower HDL, cholesterol levels (androgenic activity; not seen

with natural progesterone)• Pituitary:– Weak inhibitor of Gonadotrophin secretion– Supresses preovulatory LH surge and prevents ovulation if given during

follicular phase

Actions of Progestin (Progesterone as Prototype)

Progesterone

• Progesterone Receptors:– Limited distribution: female genital tract, breast, CNS, pituitary– Nucleus of target cells– Short (PR-A) and Long (PR-B) isoforms

• Mechanism of Action:– Binds to Progesterone Receptor (PR) present in nucleus Undergoes

conformational changes (dimerization) attaches to Progesterone Response elements (PRE) regulates transcription through coactivators

– Cell membrane receptors: rapid effects (Ca++ release from spermatozoa, Oocyte maturation)

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Progesterone: PharmacokineticsPharmacokinetic Parameters Profile

Absorption • Inactive orally, high first pass metabolism in liver• Injected intramuscularly as oily preparation• Micronized formulation for oral administration; absorption

through lymphaticsDistribution • Short half life (5-7 mins)

Metabolism • Converted to Pregnanediol in liver• Phase I reaction: Conjugation with glucuronic acid• Phase II reaction: sulfation

Excretion • Excreted in urine

• Effects lasts longer than the hormone itself• Synthetic Progestins: orally active, metabolized slowly; longer half life

Progesterone: Indications

• As Contraceptive• Hormone Replacement Therapy (HRT)

– Nonhysterectomized postmenopausal women to counteract risk of endometrial carcinoma• Dysfunctional uterine bleeding• Endometriosis• Premenstrual syndrome/tension

– Severe cases and in severe dysmenorrhoea• Threatened/habitual abortion

– In cases with established deficiency of progesterone• Endometrial carcinoma

– Palliative treatment

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Progestins: Side Effects

• General:– Breast engorgement, headache, rise in body temperature, edema, esophageal reflux,

acne mood swings with higher doses– Irregular bleeding or amenorrhoea on continuous administration– Painful injection

• 19-nortesterone derivatives:– Lowers plasma HDL levels promotes atherogenesis– Impaired glucose tolerance, precipitate diabetes

• Long term administration(HRT): Increase risk of breast cancer• Early pregnancy: Masculinization of female foetus and other congenital

abnormality

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ANTIPROGESTIN

Antiprogestin: Mifepristone• 19-norsteroid with potent antiprogestational and significant antiglucocorticoid,

antiandrogenic activity• Mechanism of Action:– Follicular phase: attenuates mid-cycle Gonadotrophin (FSH/LH) surge from pituitary

(antiprogestin activity) slowing of follicle development and delay/failure of ovulation– Secretory/Luteal Phase: prevents secretory changes by blocking progesterone action on

endometrium– Later stages of cycle: blocks progesterone support to endometrium and increases

Prostaglandin (PG) release stimulates uterine contraction– Sensitizes myometrium to PG and induces mensturation– Post implantation: blocks decidualization conceptus gets dislodged human chorionic

gonadotrophin (hCG) falls, luteolysis occurs decreased endogenous progesterone and cervix softens abortion

Mifepristone: Antiprogesterone or Progesterone Receptor Modulator?

• Partial agonist and competitive antagonist at both PR-A and PR-B isoforms.– Weak agonistic activity seen in the absence of

progesterone(anovulatory cycles or after menopause) predecidual changes

Mifepristone: Pharmacokinetics

• Absorption:– Active orally– Bioavailability only 25%

• Distribution– Half life 20-36 hrs

• Metabolism– Liver by CYP3A4 (interaction with inhibitors and inducers seen)

• Excretion– Mainly in bile– Enterohepatic circulation seen

Mifepristone: Uses

• Termination of Pregnancy– Up to 7 weeks, 600mg single oral dose (+/- 400mg misoprostol after 48 hrs)

• Cervical ripening– Prior to attempting surgical abortion of induction of labour (600mg oral)

• Post-coital contraception (emergency contraception)– Within 72 hrs of intercourse (600mg oral)

• Once a month contraceptive (?)• Induction of Labour– In cases of Intra uterine foetal death or abnormal foetus

• Cushing Syndrome (?)

Mifepristone: Side Effects

• General:– Anorexia, nausea/vomiting, tiredness, abdominal discomfort, uterine

cramps, loose motions• When used for termination of pregnancy:– Prolonged bleeding, failed abortion

• When used as postcoital contraceptive:– Subsequent menstrual cycle is disturbed

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