Pharmacology of female sex hormones

1. PHARMACOLOGY OF
FEMALE SEX
HORMONES
Dr Shinde Viraj Ashok
Junior Resident -3
Dept of Pharmacology

2. OVERVIEW
Introduction
The estrogens
Selective estrogen receptor modulators & antioestrogens
The progestins
Antiprogestins
Hormonal contraceptives
Summary
Pharmacology of female sex hormones 2

3. INTRODUCTION
Female sex
hormones
include
Oestrogens
Progesterone
Other
ovarian
hormones
• Inhibin
• Activin
• Relaxin
• Androgens
Pharmacology of female sex hormones 3

4. Pharmacology of female sex hormones 4

5. THE ESTROGENS
Estrogens – substances which can induce estrus in
spayed (ovariectomised) animals
Natural estrogens
• Major estrogens are
• Estradiol (estradiol-17ß, E2)
• Estrone (E1)
• Estriol (E)
Pharmacology of female sex hormones 5

6. • Estradiol major secretory product of ovary
• Most estrone & estriol are formed in
• Liver from estradiol or
• Peripheral tissues from androstenedione &
other androgens
Pharmacology of female sex hormones 6

7. PHARMACOKINETICS
• Estradiol binds
• Strongly to sex hormone-binding globulin
[SHBG] &
• Lower affinity to albumin
• Estrone & estriol have low affinity for estrogen
receptor
Pharmacology of female sex hormones 7

8. PHARMACOKINETICS
• Because significant amounts of estrogens & their
active metabolites are excreted in bile &
reabsorbed from intestine,
Pharmacology of female sex hormones 8
Resulting enterohepatic circulation ensures that orally
administered estrogens will have a high ratio of hepatic
to peripheral effects
Hepatic effects are responsible for some undesirable
actions
synthesis of ↑↑ clotting factors & plasma renin
substrate

9. Pharmacology of female sex hormones 9
• Hepatic effects of estrogen -
minimized by routes that avoid
first-pass liver exposure, ie,
vaginal, transdermal, or by
injection

10. MECHANISM OF ACTION
Mechanism
• Two genes code for two estrogen receptor
isoforms
• a & ß members of superfamily of steroid, sterol,
retinoic acid, & thyroid receptors
• Estrogen receptors are found predominantly in
nucleus bound to heat shock proteins that stabilize
themPharmacology of female sex hormones 10

11. MECHANISM OF ACTION CONT’D
• Receptor-hormone complex forms dimers (usually
ER a-ER a, ER ß- ER ß, or ER a-ER ß) - bind to a
specific sequence of nucleotides {estrogen
response elements (EREs)} in regulatory regions of
various genes → regulate their transcription
Pharmacology of female sex hormones 11

12. MECHANISM OF ACTION CONT’D
• Complex interactions with various coregulators
appear to be responsible for some of tissue-
specific effects that govern actions of selective
estrogen receptor modulators (SERMs)
• ERa → Many growth-promoting properties
• ERß → Antigrowth effects
Pharmacology of female sex hormones 12

13. MECHANISM OF ACTION CONT’D
Female Maturation
Estrogens are
1. Required for normal sexual maturation & growth
of female
2. Stimulate development of vagina, uterus & uterine
tubes as well as secondary sex characteristics
3. Stimulate stromal development & ductal growth in
breast
Pharmacology of female sex hormones 13

14. MECHANISM OF ACTION CONT’D
4. Responsible for accelerated growth phase
5. Closing of epiphyses of long bones that occur at
puberty
6. Alter distribution of body fat to produce typical
female body contours
Pharmacology of female sex hormones 14

15. MECHANISM OF ACTION CONT’D
Metabolic & Cardiovascular Effects
• Estrogens also ↓ rate of resorption of bone by
promoting apoptosis of osteoclasts & by
antagonizing osteoclastogenic & proosteoclastic
effects of parathyroid hormone & interleukin-6
• Estrogens stimulate adipose tissue production of
leptin
Pharmacology of female sex hormones 15

16. MECHANISM OF ACTION CONT’D
• Metabolic alterations in liver -higher circulating level of
proteins such as
• Transcortin (cortico-steroid binding globulin [CBG])
• Thyroxine-binding globulin (TBG)
• SHBG , Transferrin
• Renin substrate and Fibrinogen
• Leads to ↑ circulating levels of thyroxine, estrogen,
testosterone, iron, copper & other substances
Pharmacology of female sex hormones 16

17. MECHANISM OF ACTION CONT’D
• Estrogens are responsible for
• ↑ in high density lipoproteins (HDL)
• Slight ↓ in low-density lipoproteins (LDL)
• ↓ in total plasma cholesterol levels
• Plasma triglyceride levels are ↑
• So good for heart
Pharmacology of female sex hormones 17

18. MECHANISM OF ACTION CONT’D
Effects on Blood Coagulation
• Estrogens enhance coagulability of blood
• Changes in factors influencing coagulation -
• ↑ Circulating levels of factors II, VII, IX & X
• ↓ Antithrombin III
• ↑ Plasminogen levels
• ↓ Platelet adhesiveness
Pharmacology of female sex hormones 18

19. CLINICAL USES
• Primary Hypogonadism
• Treatment begun at 11–13 years of age in order
• To stimulate development of secondary sex
characteristics & menses
• To stimulate optimal growth
• To prevent osteoporosis and
• To avoid psychological consequences of delayed
puberty & estrogen deficiency
Pharmacology of female sex hormones 19

20. CLINICAL USES
Postmenopausal Hormonal Therapy
• Daily therapy with 0.625 mg of conjugated equine
estrogens & 2.5–5 mg of medroxyprogesterone will
eliminate
• Cyclic bleeding , control vasomotor symptoms,
• Prevent genital atrophy,
• Maintain bone density
• Favourable lipid profile - small ↓ in LDL & ↑ in HDL
concentrations
Pharmacology of female sex hormones 20

21. CLINICAL USES
Postmenopausal hormone therapy cont’d-
Results of a large study from Women’s Health Initiative
(WHI) project -women who received replacement
therapy
• Showed no cardiovascular benefit from estrogen plus
progestin replacement therapy in perimenopausal or
older postmenopausal patients
• Small ↑ in cardiovascular problems & breast cancer
Pharmacology of female sex hormones 21

22. CLINICAL USES
Other Uses
Estrogens combination with progestins
• To suppress ovulation in patients with intractable
dysmenorrhea
• Suppression of ovarian function (Hormonal
Contraceptive Pills)
• Treatment of hirsutism
• Amenorrhea due to excessive secretion of
androgens by ovary
Pharmacology of female sex hormones 22

23. ADVERSE EFFECTS
• Uterine Bleeding
• Estrogen therapy - Major cause of postmenopausal uterine
bleeding
• Cancer
• Although no adverse effect of short-term estrogen
therapy on incidence of breast cancer has been
demonstrated, a small ↑ in incidence of this tumor may
occur with prolonged therapy
Pharmacology of female sex hormones 23

24. ADVERSE EFFECTS
• Many studies show an ↑ risk of endometrial
carcinoma in patients taking estrogens alone
• Concomitant use of a progestin prevents this ↑ risk
& may in fact ↓ incidence of endometrial cancer to
less than that in general population
Pharmacology of female sex hormones 24

25. CONTRAINDICATIONS
• Patients with estrogen - dependent neoplasms such
as carcinoma of endometrium or in those with or at
high risk for carcinoma of breast
• Avoided in patients with
• Undiagnosed genital bleeding,
• Liver disease, or a
• History of thromboembolic disorder
Pharmacology of female sex hormones 25

26. PREPARATIONS & DOSAGES
• Synthetic oestrogens
• A variety of chemical alterations have been applied
to natural estrogens
Pharmacology of female sex hormones 26

27. SELECTIVE ESTROGEN RECEPTOR
MODULATORS AND ANTI-ESTROGENS
• By altering conformation of two different ERs & there by
changing interactions with co-activators & co-repressors in
a cell-specific & promoter-specific contexts
• Ligands - broad spectrum of activities from
• Purely anti-estrogenic in all tissues
• Partially estrogenic in some tissues
• Anti-estrogenic or no activities in others
• Purely estrogenic activities in all tissues
Pharmacology of female sex hormones 27

28. AROMATASE INHIBITORS (AI)
• Aromatization of ‘A’ ring of testosterone & androstenedione
is final & key step in production of estrogens
(estradiol/estrone) in body
• Three recent ‘third generation’ AIs
• Letrozole & Anastrozole – nonsteroidal & reversible (type
2) AI
• Exemestane - steroidal & irreversible (type 1) AI
• Have demonstrated clinical superiority & are widely used
now in treatment of breast cancer
Pharmacology of female sex hormones 28

29. COMPARATIVE PROPERTIES OF
TAMOXIFEN (SERM) AND
LETROZOLE/ANASTROZOLE (AIS)
Tamoxifen Letrozole/Anastrozole
Estrogen antagonist in
breast & blood vessels but
agonist in uterus, bone, liver
and pituitary
Inhibits production of estrogens
in all tissues. (total estrogen
deprivation.)
Can be used for breast Ca. in
premenopausal women as
well.
Not to be used in premenopausal
women
Less effective in delaying
recurrence when used as
adjuvant therapy after
surgery.
More effective in delaying
recurrence of early stage
breast Ca. (adjuvant therapy)
Pharmacology of female sex hormones 29

30. Tamoxifen Anastrozole / letrozole
Prophylactic use for breast
Ca. recurrence limited to 5
years.
Continues to exert
prophylactic effect beyond 5
years
Less delay in disease
progression and lower survival
advantage
advanced/metastatic breast
carcinoma. than AIs.
Greater delay in disease
progression and greater
survival advantage in palliative
treatment of advanced/
metastatic breast Ca.
Not effective in failure cases. Effective in tamoxifen failure
cases of advanced breast Ca.
Causes endometrial
hyperplasia, predisposes to
endometrial carcinoma
No endometrial
hyperplasia/cancer
predisposition.
Pharmacology of female sex hormones 30

31. Tamoxifen Anastrozole / letrozole
No bone loss, no increase in
fractures or arthritic
symptoms
Accelerates bone loss,
predisposes to fractures
arthritic symptoms.
Increases risk of venous
thromboembolism
No increase in thromboembolic
risk
Improves lipid profile; small
lowering of LDL Ch.
No effect on lipid profile
Pharmacology of female sex hormones 31

32. • Toremifene is a structurally similar compound to
tamoxifen with very similar properties, indications &
toxicities
Raloxifene –
• Estrogenic effects on lipids & bone
Pharmacology of female sex hormones 32

33. Raloxifene cont’d
• Appears not to stimulate endometrium or breast
• Has a very large volume of distribution & long half-
life (> 24 hours) (can be taken once a day)
• Use – second line drug for prevention and
treatment of osteoporosis in postmenopausal
women ; Ca++ and vitamin D enhance benefit
Pharmacology of female sex hormones 33

34. Fluvestrant
• Selective oestrogen receptor downregulator
• Or pure oestrogen antagonist
• Treatment of metatstatic ER positive breast
cancer in postmenopausal women who have stopped
responding to tamoxifen
Pharmacology of female sex hormones 34

35. ANTIOESTROGENS
Clomiphene
• Binds to both ERa & ERß & acts as a pure estrogen
antagonist in all human tissues, but racemate
displays weak agonistic action in rats
• Induces Gn secretion in women by blocking
estrogenic feedback inhibition of pituitary
• In response, ovaries enlarge & ovulation occurs if
ovaries are responsive to GnPharmacology of female sex hormones 35

36. ANTIOESTROGENS
Clomiphene cont’d
• Chief use of clomiphene is for infertility due to
failure of ovulation: 50 mg once daily for 5 days
starting from 5th day of cycle
• Treatment is given monthly
• Conception occurs in many women who previously
were amenorrhoeic or had anovular cycles
Pharmacology of female sex hormones 36

37. THE PROGESTINS
• Progesterone – Substances that convert estrogen
primed proliferative endometrium to secretory and
maintain pregnancy in animals spayed after
conception
Pharmacology of female sex hormones 37

38. THE PROGESTINS
• Natural Progestins : Progesterone
• Important hormonal effects
• Precursor to estrogens, androgens & adrenocortical
steroids
• Synthesized in ovary, testis & adrenal cortex from
circulating cholesterol
Pharmacology of female sex hormones 38

39. Synthetic Progestins
• In general, 21-carbon compounds (hydroxyprogesterone,
medroxyprogesterone, megestrol, & dimethisterone) -
most closely related, pharmacologically as well as
chemically, to progesterone
• Third-generation synthetic progestins - Components of
oral contraceptives
• “19-nor, 13-ethyl” steroid compounds - Desogestrel,
Gestodene & Norgestimate
• Have lower androgenic activity than older synthetic
progestins
Pharmacology of female sex hormones 39

40. PHARMACOKINETICS
• Rapidly absorbed following administration by any
route
• Half-life in plasma 5 minutes
• Completely metabolized in one passage through
liver & ineffective when administered orally
• High-dose oral micronized progesterone
preparations have been developed that provide
adequate progestational effect
Pharmacology of female sex hormones 40

41. • Micronised progesterone – Microfine particles of
drug are suspended in oil & dispensed in gelatin
capsules
Pharmacology of female sex hormones 41

42. MECHANISM OF ACTION
• Mechanism of action of progesterone — enter cell &
bind to progesterone receptors (distributed between
nucleus & cytoplasm)
• Progesterone-receptor complex forms a dimer before
binding to DNA
• Can form heterodimers as well as homodimers between
two isoforms, A & B
Pharmacology of female sex hormones 42

43. MECHANISM OF ACTION CONT’D
Effects of Progesterone
• Little effect on protein metabolism
• Stimulates lipoprotein lipase activity & favours fat
deposition
• ↑ basal insulin levels & insulin response to glucose
Pharmacology of female sex hormones 43

44. MECHANISM OF ACTION CONT’D
• Effects of Progesterone
• In liver, progesterone promotes glycogen storage &
also promotes ketogenesis
• Responsible for alveolobular development of secretory
apparatus in breast
• Participates in preovulatory LH surge & causes
maturation & secretory changes in endometrium that
are seen following ovulation
Pharmacology of female sex hormones 44

45. CLINICAL USES
Therapeutic uses - Major uses of progestational
hormones are for
1. Hormone replacement therapy & hormonal
contraception
Pharmacology of female sex hormones 45

46. CLINICAL USES CONT’D
2. Useful in producing long-term ovarian suppression
Used alone in large doses parenterally (eg,
medroxyprogesterone acetate, 150 mg
intramuscularly every 90 days) - Prolonged
anovulation & amenorrhea result
Employed in treatment of dysmenorrhea,
endometriosis & bleeding disorders when estrogens
are contraindicated & for contraception
Pharmacology of female sex hormones 46

47. CLINICAL USES CONT’D
Diagnostic Uses
• To test estrogen secretion
• Administration of progesterone, 150 mg/d, or
medroxyprogesterone, 10 mg/d, for 5–7 days → followed by
withdrawal bleeding in amenorrheic patients only when
endometrium has been stimulated by estrogens
• Combination of estrogen & progestin → to test
responsiveness of endometrium in patients with amenorrhea
Pharmacology of female sex hormones 47

48. CONTRAINDICATIONS,
CAUTIONS, & ADVERSE EFFECTS
• Progestin may ↑ blood pressure
• More androgenic progestins ↓ plasma HDL levels in
women
• Two recent studies suggest that combined progestin
plus estrogen replacement therapy in postmenopausal
women may ↑ breast cancer risk significantly
compared with risk in women taking estrogen alone
Pharmacology of female sex hormones 48

49. ANTIPROGETINS
MIFEPRISTONE
• “19-norsteroid” - binds strongly to progesterone
receptor & inhibits activity of progesterone
• Drug has luteolytic properties in 80% of women when
given in midluteal period
• Single dose of 600 mg → Effective emergency
postcoital contraceptive - though it may result in
delayed ovulation in following cycle
Pharmacology of female sex hormones

50. MIFEPRISTONE
• Major use terminate early pregnancies
• Doses of 400–600 mg/d for 4 days or 800 mg/d for 2
days successfully terminated pregnancy in over 85% of
women studied
• Binds to & acts as an antagonist at glucocorticoid
receptor
• Mifepristone or other analogues → useful in treatment
of endometriosis, Cushing’s syndrome, breast cancer &
possibly other neoplasms such as meningiomas that
contain glucocorticoid or progesterone receptors
Pharmacology of female sex hormones 50

51. ULIPRISTAL
• Recently approved ‘selective progesterone receptor
modulator’ (SPRM) for use as emergency contraceptive
• Inhibits ovulation by
• Suppressing LH surge
• Direct effect on follicular rupture
• Action on endometrium can interfere with implantation
• In clinical trials efficacy of ulipristal (30 mg) as
emergency contraceptive has been rated equal to that
of levonorgestrel (1.5 mg)
Pharmacology of female sex hormones 51

52. OTHER ANTIPROGESTINS
• Onapristone - Pure progesterone antagonist
• Gestinone - More efficacious in endometriosis
Pharmacology of female sex hormones 52

53. OTHER OVARIAN HORMONES
• Androgens including testosterone, androstenedione,
& dehydroepiandrosterone – produced in small
amounts
• Physiologic significance of androgens is not
established
but they may be partly responsible for
normal hair growth at puberty, for stimulation of female
libido & possibly, for metabolic effects
Pharmacology of female sex hormones 53

54. OTHER OVARIAN HORMONES
• Inhibin & activin – Physiological role not fully
understood
• Relaxin –
↑ glycogen synthesis & water uptake by
myometrium & to ↓ uterine contractility
It changes mechanical properties of cervix &
pubic ligaments, facilitating delivery
Pharmacology of female sex hormones 54

55. HORMONAL
CONTRACEPTIVES
• Hormonal preparations used for reversible
suppression of fertility
Pharmacology of female sex hormones 55

56. TYPES
Oral
1. Combined pill –
• Contains estrogen & progestin in fixed dose for all days
of a treatment cycle (monophasic)
• ‘Second generation’ OC pills –
• Reduced amount of estrogen & progestin without
compromising efficacy
• Reducing side effects & complications
Pharmacology of female sex hormones 56

57. Combined pills cont’d
Third generation’pills (Introduced in 1990s)
• Containing newer progestins like desogestrel with
improved profile of action
• Ethinylestradiol 30 µg daily is considered threshold
but can be reduced to 20 µg/day if a progestin with
potent antiovulatory action is included
Pharmacology of female sex hormones 57

58. TYPES CONT’D
2. Phased pill –
• Triphasic regimens
• Introduced to permit reduction in total steroid dose
without compromising efficacy
• By mimicking normal hormonal pattern in a menstrual
cycle
• Estrogen dose - kept constant (or varied slightly between
30–40 µg), while amount of progestin is low in first phase
& progressively higher in second & third phases
Pharmacology of female sex hormones 58

59. TYPES CONT’D
• Phasic pills cont’d
• Recommended for women ≥ 35 years of age
• For those with no withdrawal bleeding or
breakthrough bleeding while on monophasic pill
Pharmacology of female sex hormones 59

60. TYPES
CONT’D
3. Progestin-only pill (Minipill)
• Devised to eliminate estrogen, because many of long-term
risks have been ascribed to this component
• Low-dose progestin-only pill - alternative for women
estrogen is contraindicated
• Taken daily continuously without any gap
• Efficacy is lower (96– 98%) compared to 98–99.9% with
combined pill
Pharmacology of female sex hormones 60

61. 4. Emergency (postcoital) pill –
• Use in a woman not taking any contraceptive who had a
sexual intercourse risking unwanted pregnancy
• Most commonly used & standard regimen is -
Levonorgestrel 0.75 mg two doses 12 hours apart, or
1.5 mg single dose taken as soon as possible, but
before 72 hours of unprotected intercourse
Pharmacology of female sex hormones 61
TYPES
CONT’D

62. TYPE CONT’D
Injectable
• Developed to obviate need for daily ingestion of
pills
• Given i.m. as oily solution - highly effective
Pharmacology of female sex hormones 62

63. TYPES CONT’D
Major limitations of injectables are:
(a) Animal data - indicated carcinogenic potential
No proof from human studies despite >30 years of
experience
(b) Menstrual irregularities, excessive bleeding or
amenorrhoea are very common
Return of fertility may take 6–30 months after
discontinuation
Permanent sterilityPharmacology of female sex hormones 63

64. TYPES CONT’D
Two compounds have been marketed:
(a) Depot medroxyprogesterone acetate (DMPA) 150 mg
at 3-month intervals
(b) Norethindrone (Norethisterone) enanthate (NEE) 200
mg at 2-month intervals
• Most important drawback is complete disruption of
menstrual bleeding pattern or total amenorrhoea (more
common with DMPA)
Pharmacology of female sex hormones 64

65. TYPES CONT’D
• Implants These are drug delivery systems implanted
under skin, from which steroid is released slowly over a
period of 1–5 years. They consist of either—
(a) Biodegradable polymeric matrices—do not need to be
removed on expiry
(b) Non-biodegradable rubber membranes—have to be
removed on expiry
Pharmacology of female sex hormones 65

66. CONTRAINDICATIONS
Combined oral contraceptive pill is absolutely
contraindicated in:
1. Thromboembolic, coronary & cerebrovascular disease or
a history of it
2. Moderate-to-severe hypertension; hyperlipidaemia
3. Active liver disease, hepatoma or h/o jaundice during
past pregnancy
Pharmacology of female sex hormones 66

67. CONTRAINDICATIONS
4. Suspected/overt malignancy of genitals/ breast
5. Prophyria
6. Impending major surgery—to avoid excess risk of
postoperative thromboembolism
Pharmacology of female sex hormones 67

68. CONTRAINDICATIONS
Relative contraindications (requiring avoidance/
cautious use under supervision)
1. Diabetes: control may be vitiated.
2. Obesity
3. Smoking
4. Undiagnosed vaginal bleeding
Pharmacology of female sex hormones 68

69. RELATIVE CONTRAINDICATIONS
CONT’D
5. Uterine leiomyoma: may enlarge with estro-genic
preparations; progestin only pills can be used.
6. Mentally ill
7. Age above 35 years
8. Mild hypertension
9. Migraine
10. Gallbladder diseasePharmacology of female sex hormones 69

70. NON-CONTRACEPTIVE BENEFITS
OF OCPS
• ↓↓ in endometrial cancer
• ↓↓ in benign breast disease
• ↓↓ in blood loss, anemia, & dysmenorrhea
• Protection against pelvic inflammatory disease
• Possible reduction in risk of colon cancer
• Possible protection against rheumatoid arthritis
Pharmacology of female sex hormones 70

71. SUMMARY
• Oestrogens and progestins – hormonal contraception
• Selective oestrogen receptor modulators – breast cancer
• Aromatase inhibitors – advanced/ metatstatic breast
cancer
• Antiprogestin (Mifepristone) – termination of pregnancy
• Selective progesterone receptor modulators (Ulipristal)-
emergency contraceptive
Pharmacology of female sex hormones 71

72. REFERENCES
• Goodman & Gilman’s The Pharmacological Basis of
Therapeutics 12th edition
• Katzung Basic and Clinical Pharmacology 12th edition
• “Principles of pharmacology” S. K. Sharma, (2nd
edition)
Pharmacology of female sex hormones 72

73. Pharmacology of female sex hormones 73

74. Pharmacology of female sex hormones 74

75. Endometrial Effects of estrogen
• Growth effects on uterine muscle
• Plays an important role in development of
endometrial lining
• Continuous exposure for prolonged periods leads to
hyperplasia of endometrium → associated with
abnormal bleeding patterns
Pharmacology of female sex hormones 75

76. • Transdermal preparations were developed to avoid this
effect
• When administered transdermally, 50–100 mcg of estradiol
has effects similar to those of 0.625–1.25 mg of
conjugated oral estrogens on gonadotropin concentrations,
endometrium & vaginal epithelium.
• Transdermal estrogen preparations do not
• Significantly ↑ concentrations of renin substrate, CBG
& TBG &
• Produce characteristic changes in serum lipids
Pharmacology of female sex hormones 76

77. • Tamoxifen - Competitive partial agonist inhibitor of estradiol
at estrogen receptor
• Extensively used in palliative treatment of breast cancer in
postmenopausal women & is approved for chemoprevention of
breast cancer in high-risk women
• Studies of patients treated with tamoxifen as adjuvant
therapy for early breast cancer have shown a 35% ↓ in
contralateral breast cancer
Pharmacology of female sex hormones 77

78. LETROZOLE , ANASTROZOLE
• Inhibits production of oestrogens in all tissues . (total
oestrogen deprivation )
• Not to be used in premenopausal women
• More effective in delaying recurrence of early stage breast
carcinoma (adjuvant therapy) compared to tamoxifen
• Continues to exert effect beyond 5 years
• Greater delay in
Pharmacology of female sex hormones 78

79. • Letrozole
• Orally active non-steroidal (type 2) compound that
reversibly inhibits aromatization all over body,
including that within breast cancer cells, resulting in
nearly total estrogen deprivation
• Proliferation of estrogen dependent breast carcinoma
cells is suppressed to a greater extent than with
tamoxifen
• Letrozole is rapidly absorbed with 100% oral
bioavailability
• Large volume of distribution, slow metabolism
• t½ of ~40 hours
Pharmacology of female sex hormones 79

80. • Letrozole
(a) Early breast cancer: Letrozole is a first line drug for
adjuvant therapy after mastectomy in ER+ive
postmenopausal women. Extended adjuvant therapy with
letrozole beyond standard 5 year tamoxifen treatment
continues to afford protection, whereas continuation of
tamoxifen is not useful.
(b) Advanced breast cancer: Current guidelines recommend
letrozole as first line therapy because of longer time to
disease progression & higher response rate obtained with it
compared to tamoxifen. It is also effective as second line
treatment when tamoxifen has failed.
Pharmacology of female sex hormones 80

81. Anastrozole - Another nonsteroidal & reversible (Type 2)
AI
• More potent than letrozole & suitable for single daily dosing
• Useful as adjuvant therapy in early ER+ive breast cancer as
well as for palliation of advanced cases in postmenopausal
women
• Many tamoxifen resistant cases responded with ↑ survival
• First line drug for early as well as advanced breast carcinoma
in postmenopausal women
• Side effects are hot flushes, vaginal dryness, vaginal
bleeding, nausea, diarrhoea, thinning of hair
Pharmacology of female sex hormones 81

82. • Clomiphene cont’d
• If 1–2 months treatment does not result in conception—daily
dose may be doubled for 2–3 cycles
• Clomiphene is well absorbed orally, gets deposited in adipose
tissue & has long t½ of ~6 days
• Adverse effects - Polycystic ovaries, multiple pregnancy, hot
flushes, gastric upset, vertigo, allergic dermatitis
• Risk of ovarian tumour may be ↑
Pharmacology of female sex hormones 82

83. Pharmacology of female sex hormones 83

84. Synthetic Progestins
• 21- Carbon progesterone analogues antagonize aldosterone-
induced sodium retention
• Remaining compounds (“19-nortestosterone” third-
generation agents) produce a decidual change in endometrial
stroma, do not support pregnancy in test animals, are more
effective gonadotropin inhibitors, & may have minimal
estrogenic & androgenic or anabolic activity Sometimes
referred to as “impeded androgens.”
• Progestins without androgenic activity - desogestrel,
norgestimate, & gestodene
Pharmacology of female sex hormones 84

85. CONTRAINDICATIONS (ACCORDING TO
WHO)
Pharmacology of female sex hormones 85

86. AROMATASE INHIBITORS
Exemestane :
• Steroidal & Irreversible (Type 1) inhibitor of
aromatase acts like a suicide substrate by covalent
binding to enzyme
• Administered orally & is well tolerated
• Found beneficial in early breast cancer by ↓ risk of
disease progression when it was substituted for
tamoxifen as adjuvant therapyPharmacology of female sex hormones 86

87. NON-CONTRACEPTIVE BENEFITS
OF OCPS
• Possible decrease in uterine leiomyoma
• Reduction in acne
• Protection against osteoporosis
Pharmacology of female sex hormones 87