1. Gonadal Hormones & Inhibitors
Dr. Kaukab Azim. MBBS, PhD

2. Hypogonadism in males and females
Precocious puberty, leiomyoma, endometriosis, dysmenorhea
Hormonal contraceptives
Menopausal replacement therapy
Infertility
SERMs
Medical abortion
Gonadal hormones agonist and antagonists
Hormonal drugs for some cancers

3. ant. pituitary hormones
Gonadal Hormones and Inhibitors
Hypothalamic and
ant. pituitary hormones
Estrogens
&
Inhibitors
Progestins
Androgens
GnRH analogs
Natural & Synthetic
Natural and synthetic
GnRH antagonists
SERMs
Anabolic steroids
Gonadotropins:
FSH LH
Partial agonists &
antagonists
Antagonist
Antiandrogens
-Gn release inhibitors
-Receptors inhibitors
-5-a reductase inhibitor
-Synthesis inhibitor
Aromatase inhibitors

4. Key concepts of Pharmacology of Gonadal Hormones:
Hypothalamus-Pituitary-Gonadal Axis
Key concepts of Pharmacology of Gonadal Hormones:
Effects of GnRH release frequency on gonadotropin release.
Interaction between estrogen and the pituitary gland.
Tissue selectivity of estrogen agonists and antagonists.
Various strategies to antagonize the effect of endogenous sex hormones.
(Ovulation inducer)

5. Gonadotropin releasing hormone (GnRH)
released in “pulsalite manner” from the hypothalamus and acts on Pituitary to stimulate the secretion of gonadotropins-
FSH & LH

6. GnRH analogs Short-acting analogs Gonadorelin (t1/2 = 4 min.)
It can be used in “Pulsatile” manner to stimulate pituitary to secrete FSH and LH.
Uses:
Diagnostic purpose
In infertility: Hypothalamic amenorrhea
Long-acting analogs
Goserelin
Nafarelin- nasal spray
Leuprolide
After initial stimulation, they will cause suppression of gonadotropin (FSH, LH) secretion.
(down-regulation)

7. Long-acting GnRH analogs
Goserelin
Nafarelin
Leuprolide
After initial stimulation, they will cause suppression of gonadotropin (FSH, LH) secretion.
Therapeutic Uses:
For Medical castration:
In precocious puberty
Breast Ca
Prostate Ca
Leiomyoma
Endometriosis

8. GnRH analogs: Adverse effects
Adverse effects of long-acting analogs:
Gonadal steroidal inhibition in females can cause:
Hot flashes
Vaginal atrophy
Decreased bone density

9. GnRH antagonist
Ganirelix
Cetrorelix
These are pure GnRH antagonists and do not cause initial increase in gonadotropin secretion.

10. Gonadotropins: FSH & LH
Gonadotropin preparations:
Menotropins (LH + FSH)
Recombinant FSH and LH
hCG (Human chorionic gonadotropin)

11. Estrogens Physiological Role: Secondary sexual characteristics
Menstrual cycle
During follicular phase it cause endometrium to grow
For normal mineralization and osteoid formation
Deficiency of estrogens cause osteoporosis

12. Estrogens Natural estrogens Estradiol Estriol Estrone
Synthetic estrogens
Ethinyl estradiol
Mestranol

13. Estrogens
Oral:
Estradiol: micronized form
Conjugated estrogens: conjugated equine estrogens
Ethinyl estradiol & Mestranol (synthetic estrogens)
IM: aqueous or oil based esters of estradiol and estrione
Transdermal preparations: estradiol

14. Uses of Estrogens Hormone Replacement therapy: Oral contraception
Primary hypogonadism
Premature ovarian failure; surgical removal of ovaries
Menopause
Oral contraception
Osteoporosis
Atrophic vaginitis

15. Estrogens: Adverse effects
Nausea, vomiting
Thromboembolic problems
Myocardial infarction
Breast Ca
Endometrial Ca
Postmenopausal uterine bleeding
Diethylstilbestrol: Clear cell Ca (cervical & vagina)

16. Progestins Physiological role:
helps maintaining pregnancy
They are often combined with estrogen in various formulations to counteract the harmful effects of estrogens
Estrogen can cause endometrial carcinoma

17. Progestins Natural progestins: Synthetic progestins:
Progesterone, 17-alpha hydroxyprogesterone
Synthetic progestins:
Hydroxyprogesterone (IM, every 1-2 weeks)
Medroxyprogesterone (Oral-daily, IM every 1-3 months)
Norethindrone: belongs to 19-nortestoserone analogs
Norgestrel, Levonorgestrel
Norgestimate (less androgenic)
Desogestrel (less androgenic)

18. Progestins: Uses As contraceptive and menopausal hormone therapy
Combined with estrogen (in COCPs & menopausal hormonal therapy)
Progestin only contraceptive preparations
As postcoital contraception
Dysmenorrhea
Dysfunctional uterine bleeding
Endometriosis

19. Progestines: Adverse effects
Edema
Depression
ADRs of progestins having Androgen-like activity:
Increase the ratio of LDL to HDL cholesterol
Thrombophlebitis
Pulmonary embolism
Acne
Hirsutism
Weight gain

20. Hormonal Contraceptives
Combined Oral Contraceptive Pills (COCPs)
contain both estrogen and progesterone
Monophasic, Biphasic, Triphasic forms
Progestin only preparations
Progestin-only pills (“mini-pill”)
Progestin implants/depot (Levonorgestrel, medroxyprogesterone)
Progestin containing Intrauterine device
Postcoital contraception (emergency contraception)

21. COCPs: Mechanism of action
Feedback inhibition
Estrogen and progesterone causes feedback inhibition of FSH and LH secretion from the pituitary gland to inhibit ovulation.
(main mechanism)
Progestins thicken the cervical mucous and prevent the entry of sperm.
3. Effects on uterine tubes and endometrium decrease the likelihood of fertilization and implantation
↓ LH surge
No Ovulation

22. COCPs: Adverse effects
Nausea, vomiting, mastalgia
Headache
Breakthrough bleeding
Wt. gain
Acne and Hirsutism (19-nortestosterone derivatives)
Chloasma (skin pigmentation)

23. COCPs: Serious complications
Leg vein and pulmonary thrombosis
Coronary and cerebral thrombosis
Rise in BP

24. COCPs: Contraindications
COCPs are absolutely contraindicated in
Thromboembolic, coronary, cerebrovascular disease. Greater risk for :
Women > 35 years of age
Heavy smokers
Obese
Active liver disease
Suspected or overt malignancy of genitals/breast
Undiagnosed vaginal bleeding

25. COCPs: Relative contraindications
Hypertension
Migraine
Diabetes mellitus
Uterine leiomyoma
Mental illness
Gall bladder disease

26. COCPs: Drug Interactions
Enzyme inducers (Phenytoin, barbiturates, carbamazapine, Rifampin) cause contraceptive failure
Antibiotics (Tetracyclines, ampicillin, etc.) cause contraceptive failure by suppressing intestinal microflora:
Decreased deconjugation of estrogens excreted in bile
Decreased enterohepatic circulation of estrogens
Blood levels of estrogens fall contraceptive failure

27. Progestin-only preparations
Progestin-only pill (“Mini-pill”)
norethindrone or levonorgestrel
Progestin implants/depot
Levonorgestrel: subcutaneous implant, 5 years
Medroxyprogesterone acetate (DMPA): IM, every 3 months.
Progestin containing Intrauterine devices
Progestasert contains progesterone & mirena contains levonorgestrel

28. Progestin-only preparations
Progestin-only preparations are suitable for women when estrogens are contraindicated :
Smokers
Age > 35 years
h/o cardiovascular disease
Migraine
Liver impairment

29. Progestin-only preparations
Disadvantages of progestins:
Frequent spotting
Irregular and unpredictable menstrual cycles
Failure rate is higher as compared to combined COCPs
Unfavorable effect on lipid profile

30. Emergency contraception
Postcoital or “morning after” contraception
Combined oral contraceptive pills: 2 pills within 72 hours of unprotected sexual intercourse and 2 exactly 12 hours later.
Progestin-only pills (Levonorgestrel): one tablet within 72 hours of unprotected sexual intercourse followed by second dose exactly 12 hrs later.
Ulipristal: a selective progesterone receptor modulator; taken within 120 hrs of unprotected sexual intercourse

31. Menopausal hormone therapy (HRT)
Estrogen deficiency symptoms:
Hot flashes, chills, night sweats, mood swings, insomnia, headache, palpitation
Vaginal and urethral atrophy
Osteoporosis (others drugs are preferred)
Lowest effective dose of estrogen for the shortest duration to relieve estrogen deficiency symptoms in postmenopausal period.

32. Selective estrogen receptor modulators (SERMs)
Tamoxifen, Raloxifene
These are drugs that interact with estrogen receptors but have different effects on different tissues. They can show agonism or antagonism depending upon the tissue type.

33. Tamoxifen Antiestrogenic effect: on Breast
Effective in the treatment of breast Ca in patients with tumor cells that are estrogen receptor- positive.
can be given after surgery to eradicate micrometastases
Estrogenic effect: on Endometrium
Can cause endometrial Ca
Not prescribed to treat breast Ca for longer than 3-5 years in non-hysterectomized women

34. Tamoxifen: Adverse effects
Nausea/Vomiting
Hot flashes
Vaginal bleeding
Risk of Endometrial Ca
Thromboembolic disorders

35. Raloxifene Antiestrogenic effect: Breast, Endometrium
Estrogenic effect: Bones, lipid metabolism
Unlike Tamoxifen, it does not increase the risk of endometrial Ca.
Approved to be used for the prevention of osteoporosis in postmenopausal women

36. Estrogen antagonists Clomiphene (Ovulation inducer): Fulvestrant
blocks estrogen receptors in the hypothalamus and anterior pituitary
reduces negative feedback
↑ FSH and LH secretion
ovarian follicle development and ovulation
Fulvestrant

37. Progesterone antagonist
Mifepristone (RU 486)
Progesterone receptor antagonist
Glucocorticoid receptor antagonist
Therapeutic uses:
Medical termination of pregnancy
(Mifepristone followed 48 hrs later by Misoprostol)

38. Aromatase inhibitors
Anastrozole, Letrozole : non-steroidal agents; competitive inhibitors
Exemestane : steroidal agent; irreversible inhibitor
Estriol
Estrone
Estradiol

39. Aromatase inhibitors Endometriosis
Aromatase inhibitors block the synthesis of estrogens from androgen precursors by inhibiting aromatase enzyme.
This approach can be used to inhibit the growth of estrogen-dependent tumors e.g., breast cancer.
Used in postmenopausal women with advanced breast cancer
Unlike tamoxifen, they do not increase the risk of endometrial carcinoma or venous thromboembolism.
Endometriosis

40. Androgens Testosterone esters: Testosterone propionate
Testosterone enanthate
Testosterone cypionate
17-alpha alkylated androgens:
Methyltestosterone
Fluoxymesterone
Oxandrolone (anabolic steroid)
Danazol (Danocrine)

41. Androgens: Therapeutic Uses
Hypogonadism: as hormonal replacement therapy.
For Anabolic effects:
Osteoporosis
severe burns
to increase lean body mass, muscle strength
Endometriosis
Hereditary angioedema

42. Danazol synthetic derivative of 17-ethinyltestosterone
It has weak androgenic, progestational and glucocorticoid activity
Inhibits CYP450 enzymes involved in gonadal hormone synthesis
Uses:
Endometriosis
Fibrocystic breast disease
Hereditary angioedema (It occurs due to deficiency of C1- esterase inhibitor)

43. Danazol: Adverse effects
Acne
Hirsutism
Menstrual irregularities
Hepatotoxicity
Thromboembolism
Teratogenic

44. Anabolic steroids Adverse drug reactions:
Greater anabolic:androgenic activity
Oxandrolone (anabolic: androgenic=3:1-13-1)
Adverse drug reactions:
Infertility: due to suppressed FSH and LH
Decreased testicular size and function
Feminization in men, gynecomastia
Masculinization in women: Hirsutism, deepening of voice, menstrual irregularities
Hepatic dysfunction, Cholestatic jaundice
Psychotic symptoms

45. Antiandrogens Gonadotropin release inhibitors
Androgen Receptor blockers
5a-reductase inhibitor
Androgen synthesis inhibitors

46. Gonadotropin release inhibitors
Long acting GnRH analogs
Leuprolide
Goserelin
Nafarelin

47. Androgen Receptor blockers
Nonsteroidal antiandrogens
Flutamide
Bicalutamide
They block the action of dihydrotestosterone on testosterone receptors and inhibit the synthesis of new proteins in prostate and prostate cancer cells.
Combined with GnRH analogs to treat inoperable prostate Ca.

48. Androgen receptor blockers: Adverse effects
Gynecomastia or nipple tenderness
Diarrhea
Hepatotoxicity
Impotence

49. 5a-reductase inhibitor
In the prostate, testosterone is converted into dihydrotestosterone (DHT) by the action of 5a-reductase
DHT acts on prostate cells to stimulate new growth
Finastride: synthetic testosterone derivative
It inhibits the synthesis of Dihydrotestosterone (DHT) by inhibiting 5a-reductase

50. 5a-reductase inhibitor
Therapeutic uses:
Benign prostatic hyperplasia
Male pattern baldness

51. Androgen synthesis inhibitors
Ketoconazole:
It is an antifungal agent.
It inhibits gonadal & adrenal steroid synthesis by inhibiting cholesterol side chain cleavage (inhibits P450SCC).
Adverse effects:
Gynecomastia
hepatotoxicity

52. Hormones in cancer chemotherapy
Used as adjunctive therapy
Breast Ca
Prostate Ca
Anastrozole, Exemestane
Flutamide, Bicalutamide
Tamoxifen
Leuprolide, Goserelin
Glucocorticoids