1. The Gonadal hormones & Inhibitors

2. Estrogens

3. Estrogens Synthetic estrogens: Natural Estrogens
Estradiol (17 β estradiol, E2), estrone (E1), & estriol (E3)
Estradiol is the major and most potent estrogen
Synthetic estrogens:
Steroidal: e.g. ethinyl estradiol & mestranol
More effective when administered orally at lower doses: undergo less first-pass metabolism
Nonsteroidal compounds: e.g dienestrol, benzestrol, diethylstilbestrol, etc

4. Cholesterol
Progesterone
DHEA
Aromatase
Androstenedione
Estrone
Estriol
Aromatase
Testosterone
Estradiol

5. Estrogen pharmacokinetics
Estradiol is extensively bound to SHBG
Estradiol is converted primarily by the liver to estrone and estriol, the major urinary metabolite
Estradiol undergo enterohepatic recirculation

6. Estrogen preparations
Available as an estrogen alone or in combination with a progestin
Estrogens are available for oral, parenteral, transdermal, or topical administration
Oral route of administration is most common. It allows greater concentrations of hormone to reach the liver, thus increasing the estrogen effects on hepatic

7. Estrogen preparations
Other preparations:
Transdermal preparations: provides slow, sustained release of the hormone, systemic distribution, and more constant blood levels than oral dosing of estrogens. It does not lead to the high level of the drug that enters the liver via the portal circulation after oral administration
Estradiol and conjugated estrogen creams also are available for topical administration to the vagina

8. Physiological effects
Growth and Development
Endometrial Effects
Estrogen plays an important role in the development of the endometrial liningand
Continuous exposure to estrogens for prolonged periods leads to hyperplasia of the endometrium

9. Physiological effects
Metabolic Effects:
Decrease bone resorption rate
Increase HDL levels and a slight decrease in LDL , a reduction in total plasma cholesterol, and a slight increase in TG levels
Increase plasma levels of CBG, TBG, & SHBG
Enhance the coagulability of blood: increase circulating levels of factors II, VII, IX, and X and decrease antithrombin III

10. Therapeutic uses of estrogens
Primary Hypogonadism
Due to primary failure of development of the ovaries or premature menopause
Rationale:
Stimulation of 2ndary sex characteristics & menses
Stimulation of optimal growth
Prevent osteoporosis
Avoid psychological effects of the delayed puberty
Usually begun at 11–13 years of age and continue until the age of menopause (51 years)

11. Therapeutic uses of estrogens
Menopausal Hormone therapy (MHT)
Benefits: amelioration of vasomotor symptoms and the prevention of bone fractures and urogenital atrophy
MHT with estrogens should use the lowest dose and shortest duration necessary to achieve an appropriate therapeutic goal
ERT in postmenopausal women is associated with an increased incidence of endometrial carcinoma; this led to the use of HRT to reduces the risk of this cancer
Various "continuous" or "cyclic" HRT regimens have been used

12. Adverse Effects
Nausea and vomiting: disappear with time and may be minimized by taking estrogens with food or just prior to sleeping
Breast tenderness: minimized by using the smallest effective dose
Postmenopausal uterine bleeding
Increased frequency of migrane headache
Cholestasis and gallbladder disease

13. Adverse Effects Cancer Increase risk of endometrial cancer
Progestins effects on estrogen-related endometrial hyperplasia involve a decrease in estrogen-receptor content, increased local conversion of estradiol to the less potent estrone, and/or the conversion of the endometrium from a proliferative to a secretory state

14. Selective Estrogen Receptor Modulators (SERMs)
Class of estrogen-related compounds with tissue-selective actions
Their pharmacological goal is to produce beneficial estrogenic actions in certain tissues (e.g., bone) but antagonist activity in others (e.g., breast and endometrium)

15. Tamoxifen
It is a partial estrogen agonist in breast and is used as a palliative treatment and chemopreventative for breast cancer in high-risk women
It is a full agonist in bone and endometrium, and prolonged use of tamoxifen leads to a fourfold to fivefold increase in the incidence of endometrial cancer
ADEs: nausea, vomiting, hot flushes, & increases the risk of venous thrombosis

16. Raloxifene
It is an estrogen agonist in bone and is approved for the prevention of osteoporosis in postmenopausal women
Like tamoxifen, it has antagonist effects in breast tissue and reduces the incidence of breast cancer in women who are at very high risk
Unlike tamoxifen, the drug has no estrogenic effects on endometrial tissue
ADEs: hot flushes, leg cramps, & increased risk of DVT

17. Clomiphene Partial estrogen agonist
Interfere with the negative feedback of estrogen on the hypothalamus: GnRH secretion becomes more pulsatile, which results in increased pituitary gonadotropin (FSH, LH) release
Uses: Infertility associated with anovulatory cycles
Adverse effects: headache, nausea, hot flushes, visual disturbances, & ovarian enlargement
Clomiphene binds to estrogen receptors and stays bound for long periods of time. This prevents normal receptor recycling and causes an effective reduction in hypothalamic estrogen receptor number. Since estrogen can no longer effectively feedback on the hypothalamus, GnRH secretion becomes more pulsatile, which results in increased pituitary gonadotropin (FSH, LH) release

18. Estrogen-Synthesis Inhibitors: Aromatase inhibitors
Aromatase is the enzyme required for estrogen synthesis
Agents:
Irreversible steroidal inhibitors: Exemestane
Reversible Non-steroidal inhibitors: anastrozole & letrozole
These agents may be used as first-line treatment of breast cancer or as second-line drugs after tamoxifen

19. Cholesterol Progesterone Aromatase Inhibitors Aromatase
DHEA
Aromatase
Androstenedione
Estrone
Aromatase
Testosterone
Estradiol

20. Estrogen-Synthesis Inhibitors: Aromatase inhibitors
Unlike tamoxifen, they do not increase the risk of uterine cancer or VTE
ADEs: related to reduce circulating and local levels of estrogens (e.g. hot flushes and significant bone loss)

21. Progestins

22. Progestins Natural progestins: Progesterone
It is secreted by the corpus luteum in the second part of the menstrual cycle, and by the placenta during pregnancy
Small amounts are also secreted by testis and adrenal cortex

23. Progestins pharmacokinetics
Progesterone is rapidly absorbed following administration by any route
It undergoes rapid first-pass metabolism, with a t1/2 of 5 minutes
Progesterone is metabolized primarily in the liver to pregnanediol and its sulfate and glucuronide conjugates are eliminated in the urine

24. Preparations 2) 19-nortestosterones derivatives
Naturally occurring hormone and its derivatives
Undergo rapid first-pass metabolism, and is orally inactive
Available for oral administration (micronized), intramuscular injection, or administration via the vagina or rectum
Have limited binding to glucocorticoid, androgen, and mineralocorticoid receptors
2) 19-nortestosterones derivatives
Can be given orally
Have progestational activity and retain some androgenic activity
Newer progestogens without androgenic activity include desogestrel, norgestimate, and gestodene

25. Properties of Some Progestational Agents.
Route
Duration of Action
Activities1
Estrogenic
Androgenic
Antiestrog,
Antiandrog.
Anabolic
Progesterone and derivatives
Progesterone IM
1 day – +
Hydroxyprogesterone caproate
8–14 days sl
Medroxyprogesterone acetate
IM, PO
Tabs: 1–3 days; injection: 4–12 wks
Megestrol acetate PO
1–3 days
17-Ethinyl testosterone derivatives
Dimethisterone
19-Nortestosterone derivatives
Desogestrel
Norethynodrel2
Lynestrenol3
Norethindrone2
Norethindrone acetate2
Ethynodiol diacetate2
L-Norgestrel2
1Interpretation: + = active; – = inactive; sl = slightly active. Activities have been reported in various species using various end points and may not apply to humans.
2See Table 40–3.
3Not available in USA.

26. Effects of Progesterone
Reproductive tract: Decrease estrogen-driven endometrial proliferation and induces a secretory endometrium
CNS: Increases basal body temperature
Progesterone stimulates lipoprotein lipase activity and favor fat disposition
Increases basal insulin levels and the insulin response to glucose
In the liver, it promotes glycogen storage by facilitating the effect of insulin
Decreases the plasma levels of many a.as and leads to increased urinary nitrogen excretion
Decreases Na+ reabsorption in the kidney

27. Therapeutic uses of Progestins
Hormone replacement treatment: in combination with estrogen
Contraception: either alone or with an estrogen
Test for estrogen secretion and for responsiveness of the endometrium
Decrease the occurrence of endometrial hyperplasia and carcinoma caused by unopposed estrogens
Treatment of dysmenorrhea , endometriosis, and bleeding disorders when estrogens are contraindicated

28. Adverse Effects
Major effects: headache, fluid retention, depression, weight gain, & changes in libido
Progestins with androgenic activity (19-nortestosterone derivatives):
Plasma lipids: increase LDL and cause either no effect or modest reduction in serum HDL levels
Acne
Hirsutism

29. Antiprogestin: Mifepristone
It effectively competes with progesterone for binding to PR: increases uterine prostaglandin levels and sensitizes the myometrium to their contractile actions
Clinical uses: Early termination of pregnancy (abortificant) in combination with misoprostol or other prostaglandins
ADEs: Prolonged vaginal bleeding (major), abdominal pain, uterine cramps, & NVD
Mifepristone effectively competes with both progesterone and glucocorticoids for binding to their respective receptors

30. Hormonal contraception

31. Types of hormonal contraceptives
Combined oral contraceptive
Progestin-only contraceptives
Postcoital or emergency contraceptives

32. Combined oral contraceptive
The most frequently used agents containing both an estrogen and a progestin
Their theoretical efficacy is considered to be 99.9%
Combination oral contraceptives are generally provided in 21-day packs with an additional 7 pills containing no active hormone
The U.S. Food and Drug Administration today approved Beyaz tablets, an estrogen/progestin combined oral contraceptive that also contains a folate (levomefolate calcium mg)

33. Combined oral contraceptive
Further divided into:
Monophasic: constant dosage of both components during the cycle
Multiphasic: dosage of one or both components is changed during the cycle

34. Multiphasic vs Monophasic Preparations*18 10 5
1.0
0.75
0.5
0.4 20
Norethindrone
(mg)
Endogenous progesterone (ng/mL)
SLIDE 7
menses
Day of pill cycle
Monophasic (Ovcon 35)
Multiphasic (Ortho Novum 7/7/7)
Endogenous progesterone level
*Ethinyl estradiol content is constant (35 µg) for both preparations.
Adapted from Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 3rd ed. 1996:1416.

35. Combined oral contraceptive
The estrogen in most combined preparation is ethinyl estradiol
Progestins are 19-nor compounds that have varying degrees of androgenic, estrogenic, and antiestrogenic activities that may be responsible for some side effects

36. Oral contraceptive progestins
Progesterone
Classification
Family
Ethynodiol diacetate
Norethindrone
Norethindrone acetate
1st Generation
Estrane (short ½ life)
Levonorgestrel (LNg)
Norgestrel
2nd Generation
Gonane (longer ½ life)
Desogestrel
Norgestimate
3rd Generation
Gonane
Deospirnone (Yasmin®)
4th Generation --

37. Combined oral contraceptive
Additional options for combined hormonal contraceptives include:
Transdermal patch containing ethinyl estradiol and norelgestromin: applied weekly for 3 weeks. Week 4 is patch-free, and withdrawal bleeding occurs
Vaginal ring containing ethinyl estradiol and etonogestrel: is used for 3 weeks. Week 4 is ring-free, and withdrawal bleeding occurs
Efficacy, contraindications, and ADEs similar to those of oral contraceptives

38. Mechanism of action
Estrogen: inhibits secretion of FSH via negative feedback on the anterior pituitary, and thus suppresses development of the ovarian follicle
Progestin:
Inhibits secretion of LH and thus prevents ovulation
Induces viscous mucus that reduces sperm penetration and induces an endometrium that is not receptive to implantation

39. Clinical uses Contraception
Endometerosis when dysmenorrhoea is the major symptoms: long term treatment with estrogen and progestins

40. Adverse effects
Cardiovascular Effect: relatively low but in women ≥35 years who are heavy smokers (with predisposing risk factors)
VTE (e.g. PE) : Risk is related to the estrogen but not the progestin content of oral contraceptives and is higher in women using transdermal contraceptives
MI: higher in women who are obese, have a history of preeclampsia or hypertension, or have hyperlipoproteinemia or diabetes & depends on the the specific composition of the pill
The association with myocardial infarction is thought to involve acceleration of atherogenesis because of decreased glucose tolerance, decreased levels of HDL, increased levels of LDL, and increased platelet aggregation

41. Adverse effects Their ability to induce neoplasms is controversial
Cancer
Combined oral contraceptives reduce the risk of endometrial and ovarian cancer
This is due to the inclusion of progestins which opposes estrogen-induced proliferation, throughout the entire 21 days
Their ability to induce neoplasms is controversial

42. Adverse effects Weight gain: mandrogen-like progestins Serum lipids
Breakthrough bleeding: prevented by switching to a pill with a higher ratio of oestrogen or using biphasic and triphasic oral contraceptives
Mild headache and migraine headaches
Increased skin pigmentation, acne, and hirsutism
Cholestatic jaundice & increase the incidence of symptomatic gallbladder disease
Amenorrhea in some patients following cessation of administration of oral contraceptives
Vaginal infections and bacteriuria

43. Contraindications
The presence or history of thromboembolic disease, cerebrovascular disease, MI, CAD, or congenital hyperlipidemia
Known or suspected carcinoma of the breast
Carcinoma of the female reproductive tract
Estrogen-dependent/responsive neoplasias
Abnormal undiagnosed vaginal bleeding
Pregnancy
Past or present liver tumors or impaired liver function
Women over 35 years of age who smoke heavily (e.g., >15 cigarettes/day)

44. Drug interactions
CYP450 enzyme inducers (e.g. rifampin, barbiturates, and phenytoin): may result in contraceptive failure
Antibiotics (e.g. amoxicillin): reduce estrogen enterohepatic recycling and may decrease the effectiveness of oral contraceptives

45. Progestin only contraceptives
Minipills: Continuous progestin therapy without concomitant administration of estrogens
Particularly suited for use in patients for whom estrogen administration is undesirable
ADEs: irregular bleeding episodes, headache, weight gain, and mood changes
Progestin Implant: offers long-term contraception (~ 2-4 yrs) and associated with Low failure rate
Progestin intrauterin devices: provide contraception for up to 5-years

46. Progestin only contraceptives
Medroxyprogesterone acetate (MPA)
Administered IM every 3 months
Major disadvantage is the prolonged time required in some patients for ovulatory function to return after cessation of therapy
It should not be used for patients planning a pregnancy in the near future
MPA for contraceptive injection increase the risk of osteoporosis