PH1.37 Describe the mechanism of action, types, doses, side effects, indications and contraindications of the drugs used as sex hormones, their analogues

1. PH1.37 Describe the mechanism of action, types,
doses, side effects, indications and
contraindications of the drugs used as sex
hormones, their analogues
Dr Pankaj Kumar Gupta,
Assistant Professor,
Department of Pharmacology,
ESIC Medical College & hospital, Faridabad

2. Androgens
Natural
Androgens
Synthetic
Androgens
•Testosterone
•Dihydrotestosterone (DHT)
•Dehydroepiandrosterone
•Androstenedione
•Androsterone
•Methyltestosterone
•Fluoxymesterone
•Testosterone Undecanoate
•Mesterolone
•Testosterone Enanthate
•Testosterone Undecanoate
•Testosterone Propionate
•Testosterone Isocaproate
Oral Parenteral
ANDROGENS (Male Sex Hormones)

3. ANDROGENS (Male Sex Hormones)
• These are substances which cause development of
secondary sex characters in the castrated male.
– Natural Androgens:
• Testes produce 5-12 mg of testosterone daily
• A part of it is converted in extraglandular tissues to the
more active dihydrotestosterone, by the enzyme
steroid 5α- reductase.
– Synthetic Androgens:

4. REGULATION OF SECRETION

5. Secondary
Sex
Characters
Sperm
Production

7. ACTIONS
1) Sex organs and secondary sex characters (Androgenic):
 Testosterone: Puberty
– Growth of genitals – penis, scrotum, seminal vesicles , prostate
– Growth of hair – pubic, axillary, beard, moustache, body hair and male pattern
of its distribution.
 Behavioural Effects: increased physical vigour, aggressiveness.
2) Testes: Testosterone is needed for normal spermatogenesis and
maturation of spermatozoa
3) Skeleton and skeletal muscles (Anabolic):
– Testosterone is responsible for the pubertal spurt of growth in boys and to a
smaller extent in girls.
– There is rapid bone growth, both in thickness as well as in length.
– Testosterone also promotes muscle building , especially if aided by exercise.
4) Erythropoiesis:
– Testosterone accelerates erythropoiesis by increasing erythropoietin
production and probably direct action on haem synthesis .

8. Mechanism of Action
• Androgen receptors belong to nuclear receptor family.
• Testosterone can largely be regarded as the circulating
prohormone.
• In most target cells, dihydrotestosterone binds more
avidly with the cytoplasmic receptor, and this complex
is more active than testosterone-receptor complex in
combining with DNA.
• After combining with androgen response elements of
the target genes, DNA transcription is enhanced and
effects are expressed through modification of protein
synthesis.

9. Mechanism of Action

10. USES
1. Testicular failure:
• Primary-in children
• Resulting in delayed puberty.
• Treatment with parental testosterone esters or transdermal
testosterone/dihydrotestosterone in courses of 4-6 months.
• Secondary testicular failure
• Occurring later in life
• manifests as loss of libido and impotence
• Corrected by androgen treatment
2. Hypopituitarism:
• Hypogonadism is one of the features of hypopituitarism.
• Androgens are added at the time of puberty to other hormonal
replacements.
3. AIDS related muscle wasting
4. Hereditary angioneurotic edema
5. Ageing
6. Osteoporosis in elderly
7. Refractory Anaemia
8. Idiopathic male infertility

11. SIDE EFFECTS :
1. Virilization, excess body hair and menstrual irregularities in women
2. Acne: in males and females
3. Oligozoospermia with moderate doses given for a few weeks
4. Edema
5. Cholestatic jaundice
6. Hepatic carcinoma
7. Gynaecomastia (Testosterone→Estrogen)
CONTRADICATIONS :
• BPH
• Carcinoma of prostate
• Hepatic, Renal diseases, CAD, CHF
• Elderly
• During pregnancy-musculinization of female foetus
• Epilepsy, migraine may aggravated

12. ANABOLIC STEROIDS
• Testosteone has both androgenic (Secondary sex characters) &
anabolic (↑skeletal muscle mass & strength).
• The anabolic:androgen ratio of testosterone is considered as 1.
• Synthetic steroids have been developed to minimize androgenic
action & to maximize anabolic action.
• Ex- Nandrolone, Oxandrolone, Oxymetholone, Stanozolol and
Metanedienone.
• Stanozolol: anabolic to androgenic ratio is 3:1.
• Uses
• Protein Loss
• Reduced muscle mass due to trauma
• After major surgical procedures
• Prolonged hospitalization or immobilization
• Chronic debilitating diseases, cachexia
• Misuse by athletes- to improve performance

13. Adverse effects:
• Ruptured tendon, liver damage, psychotic symptoms, acne, reduced
size of testes, impotence
• Premature closure of epiphysis in adolescents
• Hirsutism, musculinization, menstrual irregularities, deep voice in
female
• “Dope Test”

14. Anti-androgens/Impeded Androgens

15. Anti-androgens/Impeded Androgens
1 Feedback inhibition in
hypothalamus
Estrogen, Progesterone,
Testosterone
2 Inhibition of GnRH
Receptors in pituitary
GnRH Antagonists
3 Decrease synthesis of
testosterone in testis
Ketoconazole, Anastrazole,
Spironolactone
4 Decrease synthesis of DHT
by inhibition of 5α-
reductase
Finasteride
5 Competition for binding to
cytosol androgen receptors
Flutamide, Spironolactone,
Cyproterone

17. Cyproterone
• Androgen receptor antagonist
• Inhibiting hypothalamus-pituitary axis: LH↓, FSH↓, testosterone↓
• Uses: treatment of
• Prostatic cancer
• Severe acne
• Hirsutism
• Contraception
• Adverse effects
• Antiandrogenic action- gynecomastia (breast growth), galactorrhea (milk
outflow), erectile dysfunction.
• Liver toxicity high dose (200–300 mg/day).
• Increased risk of DVT (in combination with ethinylestradiol)
• Other reactions- Depressive mood changes, Suppression of adrenal function
and reduced response to ACTH, osteoporosis, suppresses production of
estrogen due to its anti-gonadotrophic effect.

18. Danazol
• An orally active ethisterone derivative having weak androgenic,
anabolic and progestational activities.
• Prominent effects:
• Suppression of Gn (FSH & LH) secretion from
pituitary-inhibition of testicular/ovarian functions
• Inhibition of steroidogenic enzymes directly
• Uses:
1. Endometriosis
2. Menorrhagia
3. Fibrocystic Breast Disease
4. Hereditary Angioneurotic Edema
5. Infertility
• Side effects: Amenorrhea, Androgenic effects in women (↓breast size,
hirsutism, weight gain etc), hot flashes, night sweats, cramps, loss of
libido.
•Endometrial atrophy
•Amenorrhea

19. Flutamide
• Non-steroidal and no hormonal activity but specific anti-androgenic
action
• Active metabolite “2-hydroxyflutamide” causes competitive block
Androgen action – Accessory sex organs and Pituitary
• Increased LH secretion by blocking feedback inhibition
• Plasma testosterone level may increase – to overcome direct
antiandrogenic effect
• Uses:
• Cancer of prostate along with GnRH agonist
• Female hirusitism
• ADRs: Gynaecomastia, breast tenderness, liver damage
• Dose: 250 mg tds.
Bicalutamide: This is more potent and longer acting congener of flutamide and is
suitable for once daily administration in metastatic carcinoma of prostate .

20. 5α- reductase inhibitors
Finasteride:
• This is a competitive inhibitor of the enzyme 5α-reductase which
converts testosterone into more active dihydrotestosterone
responsible for androgen action in many tissues including prostate
gland and hair follicles.
• Uses:
• BPH- dose-5 mg OD
• Decreased prostate size
• Increased peak urinary flow rate in ~50% patients with symptomatic BHP
• Can retard disease progression
• Male pattern baldness- 1 mg OD
• PK:
• Effective orally well tolerated by most patients, metabolized in liver, t1/2- 4 6 hrs.
• ADRs:
• Decreased libido
• Impotence
• Skin rashes
• Swelling of lips

21. Estrogens & related drugs

22. Estrogens & related
Drugs
Estrogens
Natural
•Estradiol
•Esterone
•Estriol
Steroidal
•Ethinylestradiol
•Mestranol
•Tibolone
Synthetic
Non-steroidal
•Diethylstilbestrol
•Hexestrol
•Dienestrol
Antiestrogen- Clomiphene Citrate
Selective Estrogen Receptor
Downregulator- Fulvestrant
Selective Estrogen Receptor
Modulators- Tamoxifen Citrate,
Toremifene, Raloxifene
Aromatase Inhibitors-Letrozole,
Anastrozole, Exemestone

23. ESTROGENS (Female Sex Hormones)
• These are substances which can induce estrus in spayed
animals:
• Natural estrogens:
• Estradiol
• Major estrogen secreted by the ovary.
• Synthesized in the graffian follicle, corpus luteum and placenta
from cholesterol.
• Synthetic Estrogen:
• Steroidal: Ethinylestradiol, Mestranol, Tibolone
• Non-steroidal: Diethylstilbestrol (stilbestrol), Hexesrol,
Dienestrol

24. Regulation of secretion
• The daily secretion of estrogens in menstruating women varies from 10-
100 μg depending on the phase of the cycle .
• Secretion starts from the graffian follicle under the influence of FSH and
the blood level rises gradually during the follicular phase .
• Due to the modest pre-ovulatory FSH surge, estrogens further rise
transiently.
• After ovulation, corpus luteum continues to secrete estrogens till about
two days before menstruation.
• Estrogens exercise feedback inhibition of FSH (also LH at higher
concentrations) by direct action on pituitary as well as through
hypothalamus.
• During pregnancy, placenta secretes large quantities of estrogens,
reaching a peak of upto 30 mg/day at term.
• Their level declines sharply after delivery.
• In the postmenopausal women, daily production of estrogen has been
estimated as 2-10 μg.

25. ACTIONS
Sex organs
• The estrogens bring about pubertal changes in the female including growth of
uterus , fallopian tubes and vagina.
Secondary Sex Characters
• Estrogens produce at puberty cause growth of breasts – proliferation of ducts
and stroma, accumulation of fat.
• The pubic and axillary hair appear, feminine body contours and behaviour are
influenced.
Metabolic Effects
• Bone:
• Maintains bone mass
• Inhibits Osteoclast formation
• Promotes positive calcium balance
• Fluid Balance:
• Mild salt and water retention
• Edema and mild rise in BP after prolonged use
• Lipid Profile:
• ↑HDL , ↓ Triglycerides, ↓LDL

26. Mechanism of Action
• Estrogens bind to specific nuclear receptors in target cells and
produce effects by regulating protein synthesis.
• Estrogen receptors (ERs) have been demonstrated in female sex
organs, breast, pituitary, liver, bone, blood vessels, heart, CNS and in
certain hormone responsive breast carcinoma cells.
• The ER is analogous to other steroids receptors: agonist binding to
the ligand binding to the ligand binding domain brings about receptor
receptor dimerization and interaction with ‘estrogen response-
elements’ (EREs) of target genes. Gene transcription is promoted
through certain coactivator proteins.
• On binding an estrogen antagonist the receptor assumes a different
conformation and interacts with other corepressor proteins inhibiting
gene transcription.
• Two ERs designated ERα and ERβ have been identified, cloned and
structurally characterized .
• Estradiol binds to both ERα and ERβ may have a different pattern of
interaction with co activators and co repressors.

27. USES
Currently the two most common uses of estrogens are
• As contraceptives
• for hormone replacement therapy in postmenopausal women
Hormone Replacement Therapy (HRT)
• Physical, psychological and emotional consequences
• Estrogen ±progestin HRT or ‘menopausal hormone therapy ‘ (MHT) is
highly efficacious in suppressing the perimenopausal syndrome of
vasomotor instability.
• The dose of estrogen used in HRT is substantially lower than that for
contraception.
• Conjugated estrogens are used 0.625 mg/day (equivalent to
ethinylestradiol 10 μg) either cyclically (3 weeks treatment 1 week
gap)

28. ADVERSE EFFECTS
• Suppression of libido, gynaecomastia and feminization when given to
males.
• Stilbestrol given to pregnant women, especially during first trimester-
increased the incidence of vaginal and cervical carcinoma in the
female offspring in childhood or early adulthood. Estrogens are
contraindicated during pregnancy.
• In postmenopausal women, estrogens can increase the risk of
irregular bleeding endometrial carcinoma (5-15 fold). A progestin
given concurrently blocks the risk.
• Estrogens can accelerate the growth of existing breast cancer.
• Migraine, epilepsy and endometriosis may be worsened by
estrogens.

29. Distribution of ERα & ERβ
•ERα and ERβ have different distributions and functions in the body.
•Selective targeting of ERβ may be preferable to estrogen as hormone therapy in
menopausal women.

30. Estrogens & related
Drugs
Estrogens
Natural
•Estradiol
•Esterone
•Estriol
Steroidal
•Ethinylestradiol
•Mestranol
•Tibolone
Synthetic
Non-steroidal
•Diethylstilbestrol
•Hexestrol
•Dienestrol
Antiestrogen- Clomiphene Citrate
Selective Estrogen Receptor
Downregulator- Fulvestrant
Selective Estrogen Receptor
Modulators- Tamoxifen Citrate,
Toremifene, Raloxifene
Aromatase Inhibitors-Letrozole,
Anastrozole, Exemestone

31. Antiestrogens
Clomiphene citrate
• It binds to both ERα and ERβ and acts as a pure estrogen antagonist in all human
tissues.
• Induces Gn secretion in women by blocking feedback mechanism- ↑LH, ↑FSH-
ovulation
• Uses
• Sterility due to failure of ovulation:
• 50 mg once daily for 5 days starting from 5th day of cycle. Monthly treatment
and no more than 6 treatment cycles.
• For male infertility (Oligozoospermia):
• 25 mg daily given for 24 days in a month with 6 days rest for upto 6 months
• Promotes spermatogenesis and testosterone secretion.
• Adverse Effects
• Polycystic ovaries, multiple pregnancy, hot flushes, gastric upset,
vertigo, allergic dermatitis
• Risk of ovarian tumour may be decreased.
• The antiestrogenic effect of clomiphene on developing follicle,
endometrium or cervical mucus can be counterproductive.

32. Fulvestrant
• Pure estrogen receptor antagonist
• Reduces no. of estrogen receptors (downregulation) therefore
effective in metastatic breast cancer resistant to Tamoxifene
• ADR- nausea, headache, pain, hot flashes

33. What is SERM ?
• SERM is a group of drugs which are –
• Synthetic
• Non Steroidal
• Tissue selective Estrogenic and Anti Estrogenic actions
• So, SERM may have one or combination of-
• Full agonist such as the natural endogenous estrogen
• Mixed agonist /antagonist such as Tamoxifen
• Full antagonist such as Fulvestrant

34. Ideal SERM
• Prevents bone loss
• No risk of uterine or breast cancer
• + ve effect on lipids & cardiovascular system
• Relieves PMS (Post-menopausal symptoms)
• Maintains cognitive function of the brain

35. Comparative Analysis
Organ Ideal Estrogen Tamoxifen Raloxifen
Liver ↑HDL , ↓
TG, ↓LDL
↑HDL , ↓ TG,
↓LDL
±HDL , ± TG, ↓ LDL ±HDL , ± TG, ↓ LDL
Bone Formation Formation Formation (Agonist) Formation (Agonist)
Breast Antagonist Agonist Antagonist (↓ Ca
breast)
Antagonist
Uterus Antagonist Agonist Agonist (↑Endometrial
cancer)
Antagonist
Pituitary Agonist Agonist Agonist Agonist
Blood vessels Agonist Agonist Inhibit hot flashes
(Agonist)
± (No relieve in hot
flashes)
Peripheral
tissue
Agonist Agonist Antagonist ± (No improvement
in cognition)
VTE Antagonist ↑risk of VE ↑risk of VE ↑risk of VE

36. Tamoxifen
• MOA: Competitive inhibitor of estradiol binding to the ER
• Binding of estradiol & SERM to the estrogen binding sites of
the ER’s initiate a change in conformation of the ER,
dissociates the ER form heat-shock proteins and inhibition of
ER dimerisation.
• PK:
• Readily absorbed on oral administration
• Peak concentration – 3-7 hours
• Steady state – 4-6 weeks
• Oral dose 20mg/day
• At high doses 200mg/day can cause retinal degeneration
• Metabolism- CYP3A4/5 , metabolite-N desmethyl tamoxifen
• T ½ Parent drug – 7days Metabolites – 14 days
• Enterohepatic circulation
• Excreted in stool

37. Uses
• Pre and Postmenopausal breast cancer
• Primary prophylaxis of Breast cancer in High risk women
• Post menopausal Osteoporosis
• Male infertility – alternative to Clomiphene
• Dose : - 20mg/day in 1 or 2 doses - maximum 40mg/day.
Side Effects: vomiting, vaginal bleeding, vaginal discharge, menstrual
irregularities, increased risk of venous thrombo-embolism.

38. Aromatase Inhibitors
• Aromatase inhibitors (AIs) lower estrogen levels by stopping an
enzyme in fat tissue (called aromatase) from changing other
hormones into estrogen.
• Estrogen can fuel the growth of breast cancer cells.
• These drugs don’t stop the ovaries from making estrogen. They only
lower estrogen levels in women whose ovaries aren’t making
estrogen (Post-menopause).
• Third generation:
• Letrozole,
• Anastrazole
• Exemestane
• Demonstrated clinical superiority in the treatment of breast cancer.

39. Aromatase Inhibitors
•Uses:
• To treat hormone receptor-positive breast cancer
a. Early Breast Cancer: as adjuvant therapy after mastectomy in ER+ cases
b. Advanced Breast Cancer
•ADRs:
• Hot flashes, night sweats, and vaginal dryness,
osteoporosis, dyslipidemia.

40. Progestins
• These are substances which convert the estrogen primed
endometrium to secretory and maintain pregnancy.
• Natural Progestin:
• Progesterone, a 21-carbon steroid, is the natural progestin and is derived
from cholesterol.
• Secreted by the corpus luteum (10-20 mg/day) in the later half of the
menstrual cycle under the influence of LH.
• Its production declines a few days before the next menstrual flow.
• Synthetic Progestin:
• A number of synthetic progestins with high oral activity have been produced.
• These are either progesterone derivatives (21-C) or 19-nortestosterone
derivatives (18-C).

41. PROGESTERONE DERIVATIVES (21-C) :
• Medroxyprogesterone acetate
• Megestrol acetate
• Dydrogesterone
• Hydroxyprogesterone caproate
19-NORTESTOSTERONE DERIVATIVES (18-C)
Older compounds
• Norethindrone (Norethisterone)
• Lynestrenol (Ethinylestrenol)
• Allylestrenol
• Levonorgestrel (Gonane)
Newer Compounds
• Desogestrel
• Norgestimate
• Gestodene

42. ACTIONS
• The main function of progesterone is preparation of the uterus for
nidation and maintenance of pregnancy.
1. Uterus: Secretory changes in the estrogen primed endometrium.
2. Cervix: Progesterone converts the watery cervical secretion
induced by estrogens to viscid, scanty and cellular secretion which
is hostile to sperm penetration.
3. Vagina: Progesterone induces pregnancy like changes in the
vaginal mucosa.
4. Breast: Progesterone causes proliferation of acini in the mammary
glands. Prepares the breast for lactation. Withdrawal of these
hormones after delivery causes release of prolactin from pituitary
and milk secretion starts.
5. Pituitary: Progesterone is a weak inhibitor of Gn secretion from
pituitary. Adminstration of progestin during follicular phase
suppresses the preovulatory LH surge and prevents ovulation.

43. USES
1. As Contraceptive
2. Hormone Replacement Therapy (HRT)
3. Dysfunctional Uterine Bleeding
4. Endometriosis
5. Premenstrual Syndrome / tension
6. Threatened / Habitual abortion
7. Endometrial Carcinoma

44. ADVERSE EFFECTS
• Breast engorgement, headache, rise in body temperature, edema.
• Irregular bleeding or amenorrhoea can occur if a progestin is given
continuously.
• Long-term use of progestin in HRT may increase the risk of breast
cancer.
• Blood sugar may rise and diabetes may be precipitated by long-term
use of potent agents like levonorgestrel.
• I.M. adminstration of progesterone is painful.
• Given in early pregnancy, progestins can cause masculinization of
female foetus and other congenital abnormalities.

45. ANTIPROGESTIN
Mifepristone
• It is a 19-norsteroid with potent competitive anti-progestational and
significant anti-glucorticoid as well as anti-androgenic activity.
• If implantation has occurred, it blocks decidualization, conceptus is
dislodged, HCG production falls, secondary luteolysis occurs–
progesterone secretion decreases and cervix is softened.
• Mifepristone is a partial agonist and compeititive antagonist at both
A and B forms of PR .
• Uses:
• Termination of Pregnancy of up to 7 weeks
• 600 mg as single oral dose causes complete abortion in 60-85% cases. To improve
the success rate, current recommendation is to follow it up 48 hours later by a
single 400 mg oral dose of misoprostol.
• Cervical Ripening
• Postcoital Contraception
• Induction of Labour
• Cushing’s Syndrome

46. Thank You