Lecture Classes for BNS 1st Year Maharajgunj Nursing Campus

1. Drugs Used in Reproductive Health: Estrogen
and Progestin
For BNS Ist Year
Dr. Pravin Prasad
Ist Year Resident, MD Clinical Pharmacology
Maharajgunj Medical Campus
2nd October, 2015(Asoj 15, 2072); Friday

2. Drugs Used in Reproductive Health
• Estrogens, Progestins
• Oral Contraceptives
• Uterine Stimulants
– Oxytocin
– Methylergotmetrine
• Uterine Relaxants

3. ESTROGENS

4. 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)

5. Types of Synthetic Estrogens
Estrogens: Introduction
Steroidal Non-steroidal
Ethinylestradiol Diethylstilbestrol (stilbestrol)
Mestranol Hexestrol
Tibolone Dienestrol

6. Estrogen Synthesis
Ref:
http://www.apsubiology.org/anatomy/2010/2010_Ex
am_Reviews/Exam_5_Final_Review/steroid_hormone
_synthesis.png

7. Regulation of Estrogen secretion

8. 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

9. • 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

10. • 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

11. Estrogen Receptors
Estrogen 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

12. 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

13. 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.

14. Estrogen: Pharmacokinetics
Pharmacokinetic Parameters Profile
Absorption • 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

15. 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)

16. 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)

17. 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

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

19. Estrogen: Side Effects
Population 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

20. ANTIESTROGENS AND SELECTIVE ESTROGEN
RECEPTOR MODULATORS (SERMs)

21. 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

22. 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

23. 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

24. 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

25. PROGESTINS

26. 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)

27. 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

28. 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

29. • 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)

30. • 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)

31. 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)

32. Progesterone: Pharmacokinetics
Pharmacokinetic Parameters Profile
Absorption • Inactive orally, high first pass metabolism in liver
• Injected intramuscularly as oily preparation
• Micronized formulation for oral administration; absorption
through lymphatics
Distribution • 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

33. 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

34. 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

35. ANTIPROGESTIN

36. 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

37. 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

38. 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

39. 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 (?)

40. 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

41. THANK YOU
Lets have a Break……