1. Pharmacology of Estrogens and Progestins
December 15, 2015
Carol L. Beck, Pharm.D., PhD
The lecturer has no conflicts of interest related to this topic.

2. Educational Goals
To understand how the structure and function of the estrogen and progesterone receptors affects drug actions and tissue specificity.
To know the mechanism of action of: mifepristone, misoprostol, tamoxifen, raloxifene, fulvestrant, ulipristal. Know contraindications for their use.
To know how estrogens and progesterones are used in contraception, menstrual cycle control, and hormone replacement therapy.

3. I. Estrogen and Progesterone
Remember:
Estrogens and ANDROGENS (testosterone) are the Sex Steroids
Bound by Sex Steroid Binding Globulin (SSBG)
Progesterone and Cortisol
Bound by Transcortin aka Corticosteroid Binding Globulin
Only free drug/ hormone available to bind to receptors and produce response….

4. I. Estrogen and Progesterone
Steroid structure
Steroids are lipids with three 6-C rings and one 5-C ring
Five classes of steroid hormones
Estrogens
Prostagens
Androgens
Mineralocorticoids
Glucocorticoids

5. Structure STEROIDAL* ESTROGEN PROGESTERONE Progestin + Progesterone
Combined Name
Progestin +
Luteo-sterone
Progesterone
*Yes, there are non-steroidal estrogens

7. Metabolism/ Inactivation
Inactivated by conjugation to sulfate esters or glucuronic acids
Metabolism of estrogen occurs in peripheral tissue
Metabolism is by oxidation– primarily in liver
Excreted in urine

8. C. Biosynthesis 1. Progesterone
Ovary (primarily corpus luteum) makes cholesterol  progesterone
-During pregnancy, placenta also produces progesterone
Other sources:
Testis makes cholesterol  progesterone
Adrenal makes cholesterol  progesterone

9. Progesterone Progesterone (natural progestin): Additional info:
Produced by corpus luteum of the ovaries and the placenta during 2nd half of menstrual cycle
(males– testes)
Also synthesized by adrenal cortex (male, female)
Promotes development of a secretory endometrium for implantation of newly forming embryo
If no pregnancy, release from corpus luteum ends abruptly, and this decrease stimulates onset of menses
If conception, progesterone levels continue to support the endometrium and also inhibit future ovulation by suppressing LH.

10. 2. Biosynthesis of Estrogen
Producted by the Ovaries* (primarily follicular phase—1st half-- but also by the corpus luteum)
-makes estradiol which is converted to estriol and estrone
Liver makes estradiol which is converted to estriol and estrone
Peripheral tissue (adipose tissue) makes androstendione which is converted to estradiol  estriol and estrone
* Primary source of sex hormones for women between puberty and menopause.

11. Biosynthesis of Estrogen
Suppresses FSH– so no dominant follicle, (no ovulation)

12. 3. Metabolism
Can occur in peripheral tissue, in which androsteindione is converted to estrone

13. 4. Estrogen: Protein Binding
95% of estrogens circulate attached to proteins, primarily sex hormone binding globulin (SHBG) and albumin.
~5% is free/unbound
SHBG has low capacity for binding but high affinity, albumin has high capacity but low affinity.
Decreased SHBG leads to increased unbound circulating estrogens and androgens.

14. 5. Neuroendocrine Regulation of Steroid Production
Hypothalamic secretion of GnRH acts on pituitary to release gonadotropins (FSH and LH)
Anterior Pituitary produces FSH (follicle stimulating hormone) and LH (luteinizing hormone) which act on the ovary and testis to stimulate steroid synthesis and gamete development.
FSH and LH on Ovary: Estrogen, Progesterone
LH on Testis: Testosterone (androgen)

15. Hypothalamus
Anterior
(Progesterone)

16. D. Pharmacodynamics 1. Molecular Mechanism of Steroid Action
Steroid hormones dissociate from binding protein and enter most cells by diffusion
In target cells (i.e., cells sensitive to hormone), the steroid binds to receptors located in the cytoplasm and/or the nucleus (AKA “nuclear receptors”)
Steroid receptor is activated by hormone (ligand); dimerizes; binds DNA; induces transcription.
More later about Estrogen and Progesterone receptors!

17. E. Female reproductive system
The menstrual cycle depends on a complex interaction between hypothalamus, pituitary, ovaries, and endometrium.

18. F. Systemic Effects of Estrogen Female
1. Anabolic: Female Maturation
Development of vagina, uterus and tubes
Development of secondary sex characteristics
Pubertal growth spurt

19. F. Systemic Effects of Estrogen
2. Blood Chemistry
Reduces plasma cholesterol
Increases HDL and decreases LDL
3. Suppresses cellular immune responses
4. Increases coagulation factors (increased coagulability) by:
 antithrombin III
 plasminogen, II, VII, IX, X

20. F. Systemic Effects of Estrogen
5. Bone
Decrease rate of bone resorption by decreasing osteoclast activity
6. Reproductive system
Regulation of menstrual cycle
Proliferation of uterine and vaginal epithelium
Stimulates production of cervical mucus, making it less viscous
7. Endrocrine: Increase thyroxine

21. Physiologic Effects of Estrogen – Menstrual Cycle

22. F. Systemic Effects of Estrogen Male
Stimulates growth of stromal cells in prostate
Essential for spermatogenesis

23. G. Systemic Effects of Progesterone
1. Blood chemistry
 HDL
 LDL
2. Reproductive system, female
Regulation of menstrual cycle
Modulates secretory differentiation and increases vascularity in uterus
Maintains pregnancy
Represses uterine contractions (smooth muscle relaxant)

24. G. Systemic Effects of Progesterone
SUMMARY: Menstrual cycle regulation:
Induces secretory change in the endometrium
At high doses suppresses gonadotropin release and suppresses ovulation
This is not because of declining estrogen levels, but rather because successful fertilization becomes less likely. The number and quality of ovarian follicles declines with age, possibly related to impaired meiotic spindle formation or function.
For women over age 40, the risk of abortion (recognized and unrecognized) is 75 %. Most of these will have chromosomal abnormalities.

25. Physiologic Effects of Progesterone – Menstrual Cycle
This is not because of declining estrogen levels, but rather because successful fertilization becomes less likely. The number and quality of ovarian follicles declines with age, possibly related to impaired meiotic spindle formation or function.
For women over age 40, the risk of abortion (recognized and unrecognized) is 75 %. Most of these will have chromosomal abnormalities.

26. Other Systemic Effects of Progesterone
Endocrine:
Increase basal insulin levels
Increase insulin response to glucose
Increase ketogenesis
Other:
Increase body temperature
Increase breathing response to CO2
Depressant/hypnotic effect on the brain
This is not because of declining estrogen levels, but rather because successful fertilization becomes less likely. The number and quality of ovarian follicles declines with age, possibly related to impaired meiotic spindle formation or function.
For women over age 40, the risk of abortion (recognized and unrecognized) is 75 %. Most of these will have chromosomal abnormalities.

27. II. Clinical Uses of Steroid Hormones and their Antagonists

28. Estrogens as Therapeutic Agents
1. Can be naturally derived or synthetic
2. Most often PO, but also by vaginal, intranasal, IM, IV, and transdermal routes
3. Menstrual cycle control, ovulation induction, hormone replacement therapy

29. Progestagens as Therapeutic Agents
1. Prophylaxis against endometrial hyperplasia or carcinoma in estrogen-treated women
2. In some cases, appropriate for solo use:
Induction of withdrawal bleeding in amenorrhea
Contraception
Inhibition of gonadotropin secretion– precocious puberty or treatment of endometriosis

30. Clinical Uses of Exogenous Hormones*
Contraception
Infertility treatment
Menopausal Management
Labor and Delivery
*To be discussed primarily in other lectures

31. A. Oral Contraception
Most oral contraceptives (OC) consist of a synthetic estrogen and a synthetic progestin.
Synthetic hormones because natural are rapidly inactivated when given PO
OC differ in estrogen dose and dose/nature of progestin
Combination OC prevent ovulation by inhibiting gonadotropin release via feedback to the hypothalamus and pituitary

32. A. Oral Contraception
Clinical pharmacology of contraception lecture will discuss the side effects, toxicities, and selection of most appropriate OC for specific patients

33. Mechanism of Action: Combination Hormonal Contraception
Comgination OC prevent ovulation by inhibiting gonadotropin secretion through effects on the hypothalamus and pituitary.
Progestin– suppresses LH secretion;
Estrogen– suppresses FSH secretion

34. Adverse Effects: Combination Hormonal Contraception
A detailed discussion of adverse effects and indications and contraindications will be part of Dr. Lackritz’s lecture.
Drug Interactions: Combination Hormonal Contraception
MANY!! Remember, hepatic metabolism….
(consequences of decreased metabolism? Increased metabolism?)

35. Structure
Estrogens used in oral contraceptive agents are ethinyl estradiol and mestranol.
Synthetic progestins in oral contraceptives in the United States include:
norethindrone, norethindrone acetate, ethynodiol diacetate, norgestrel levonorgestrel, desogestrel, drospirenone, and norgestimate.

36. Mechanism of Action: Combination Hormonal Contraception
Act in central nervous system and reproductive organs.
CNS: acts on the hypothalamus and pituitary to prevent mid-cycle surge of luteinizing hormone (LH) and prevents ovulation.
Reproductive:
causes glandular atrophy in endometrium
inhibits implantation of the blastocyst
causes the formation of a thick cervical mucus that inhibits sperm motility and migration.

37. Pharmacokinetics
Mestranol and ethinyl estradiol are absorbed efficiently in GI tract; up to 60% excreted in urine after 24 h.
Can be absorbed transdermally and transvaginally.
Mestranol is an inactive prodrug– must be converted in liver to estrone/estriol
Progesterone metabolism– liver, more than 30 metabolites identified.

38. B. Other routes of contraceptive administration
Vaginal rings
NuvaRing
Transdermal contraceptive patches
OrthoEvra
Progestin-only
Long-activing injectable (Depo-Provera)
Sub-dermal implants (Implanon)

39. C. Emergency Contraception
Efficacy - 75 % reduction in pregnancy rate; potential prevention of 1.7 million unplanned pregnancies per year in U.S.
Mechanism - Delay or inhibition of ovulation; possible inhibition of implantation

40. C. Emergency Contraception (covered in more detail by Dr. Lackritz)
Plan B (Levonorgestrol 0.75 mg)
(Progesterone) or
2. Ella (Ulipristal acetate 30 mg)
3. Other regimens:
Preven (levonorgestrel 0.25mg and ethinyl estradiol 0.05 mg)
Any OC at adequate doses
Insertion of an IUD within 72 hours

41. 2. Ulipristal
Partial agonist/ partial antagonist at progesterone receptor
MOA: Binds to Progesterone receptor; prevents ovulation and prevents fertilized egg from attaching to the uterus

42. D. Medical Abortion
An abortion option for the first 49–63 days of pregnancy
Most common regimen consists of:
An oral dose of mifepristone which blocks the receptors of progesterone
Followed by a dose of misoprostol (prostaglandin analogue) which causes the uterus to contract and empty
Alternate regimen:
Methotrexate followed by misoprostol
Several case reports have associated misoprostol use with limb defects and Mobius syndrome. However, an absolute causal relationship between misoprostol use and fetal deformities has yet to be demonstrated through prospective trials. Women electing to use misoprostol-only regimen should be informed of the possible teratogenic effects of the drug.
Source:
Sources:
Medical Management of Abortion. ACOG Practice Bulletin Number 67. American College of Obstetricians and Gynecologists. Obstetrics and Gynecology 2005;106:
Schaff, Eric, et al.Low-Dose Mifepristone Followed by Vaginal Misoprostol at 48 Hours for Abortion up to 63 Days Contraception, 2000;61(1), 41-6.
Trupin SR, Moreno C (2001). Medical abortion: Overview and management. Medscape Women's Health eJournal, 7(1). [Online]. Available:
Paul M, et al. (1999). A Clinician's Guide to Medical and Surgical Abortion. New York: Churchill Livingstone.
PRCH © 2005

43. E. Menstrual Cycle Control
For severe menorrhagia/ dysmenorrhea and cannot tolerate OC
Progesterone (Medroxyprogesterone)
GnRH analogs such as Leuprolide– feed back to pituitary and cause initial increase in LH/FSH secretion followed by decrease to menopausal levels. (Patients will develop symptoms of menopause.)
Several case reports have associated misoprostol use with limb defects and Mobius syndrome. However, an absolute causal relationship between misoprostol use and fetal deformities has yet to be demonstrated through prospective trials. Women electing to use misoprostol-only regimen should be informed of the possible teratogenic effects of the drug.
Source:
Sources:
Medical Management of Abortion. ACOG Practice Bulletin Number 67. American College of Obstetricians and Gynecologists. Obstetrics and Gynecology 2005;106:
Schaff, Eric, et al.Low-Dose Mifepristone Followed by Vaginal Misoprostol at 48 Hours for Abortion up to 63 Days Contraception, 2000;61(1), 41-6.
Trupin SR, Moreno C (2001). Medical abortion: Overview and management. Medscape Women's Health eJournal, 7(1). [Online]. Available:
Paul M, et al. (1999). A Clinician's Guide to Medical and Surgical Abortion. New York: Churchill Livingstone.
PRCH © 2005

44. F. Hormone Replacement Therapy for postmenopausal women
The controversy: increased risks of MI, stroke, breast cancer, pulmonary emboli, deep venous thrombosis in post-menopausal women treated with estrogens and progesterone during a 5 year study.
(should there have been additional subsets of the data? Helpful in some; harmful in others?)
Because of these risks, HRT should be prescribed at the lowest effective doses and for the shortest duration consistent with the treatment goals and risks for the individual woman.

45. Hormone Replacement Therapy
FDA –approved indications
a. treatment of moderate to severe vasomotor symptoms
b. treatment of moderate to severe atrophic vaginitis
c. prevention of postmenopausal osteoporosis, NOT treatment

46. Hormone Replacement Therapy-- Estrogens
Natural estrogens include estrone, estradiol, and conjugated equine estrogens.
Synthetic estrogens
Estrogens are most often administered by mouth, but they can also be administered effectively by vaginal, intranasal, intramuscular, intravenous, and transdermal routes.

47. Rational for Progestion Use in HRT
Prophylaxis against endometrial hyperplasia or carcinoma in estrogen treated women
Adding progestin attenuates endometrial cancer risk
Continuous combined, continuous sequential– both are used.

48. Hormone Replacement Therapy
Guiding Principles for ET/EPT therapy
a. Lowest effective dose
b. Shortest duration required
c. Type/route/regimen of E and P
d Individualized risks and benefits
e Patient satisfaction with therapy

49. Hormone Replacement Therapy
Contraindications to ET/EPT
a. Hormone-sensitive cancer
b. Unexplained uterine bleeding
c. Active liver disease (esp. with oral ET)
d. History of DVT/PE
e. Confirmed CVD

50. Hormone Replacement Therapy
Common side effects of ET/EPT
a. Uterine bleeding
b. Breast tenderness
c. Nausea/Abdominal bloating

51. III. Drugs acting on Estrogen and Progesterone Receptors

52. A. Review of Estrogen and Progesterone Receptor Physiology
1. Estrogen receptors: alpha and beta
Different genes on different chromosomes
Different tissue/cell distribution
Different affinity for ligands
Different genes activated

53. A. Review of Estrogen and Progesterone Receptor Physiology
2. Ligands for Estrogen receptors
Estrogens: estradiol
SERMS: tamoxifen, faloxifene, toremifene
Novel ER-alpha and ER-beta selective ligands

54. A. Review of Estrogen and Progesterone Receptor Physiology
3. Receptor activity
ER in many body tissues
ER-Alpha and ER-beta levels depend on tissue
ER-Alpha: reproductive system
ER-beta: bone, brain, urinary tract
Estradiol binds to both alpha and beta
SERMS designed to be selective

55. Progesterone Receptors
1. Progesterone receptors: alpha and beta
Different transcriptional activities
Cell type and promoter specific effects– often PR-beta > PR alpha
PR alpha can repress PR beta and ER signaling

56. B. ER/PR Pharmacology/ Pharmacodynamics
In uterus PR opposes ER stimulation
In breast PR increases ER stimulation

57. ER/PR Pharmacology/ Pharmacodynamics
Ligands can be
Agonists
SERMs/SPRMs
Antagonists

58. ER/PR Pharmacology/ Pharmacodynamics
Different ligands induce different receptor confirmations that determine response
Partner proteins/ co-regulators
Many interrelationships between ER and PR pathways
Progestins modulate estrogen action BUT also act independently
Progestin effects on estrogen action vary in different tissues.

59. C. SERMs & Antagonists SERDs
Selective Estrogen Receptor Modulator
Mixed estrogen receptor agonist and antagonist, effect depends on tissue type
DRUGS THAT BLOCK ER ACTIVATION AND FUNCTION ARE ANTIESTROGENS
SERMS: Tamoxifen, Raloxifene
SERD: Fulvestrant

60. SERMs & Antagonists SERDs
Current hypothesis to explain the antiestrogen effects in different tissues:
a. protein conformation
b. co-activators for ER
c. alternate response elements

61. 2. Tamoxifen (a SERM) Tamoxifen (Nolvadex)
Estrogen antagonist effect centrally and on breast tissue
Estrogen agonist on uterus and coagulation profile
Therapeutic Uses: metastatic breast cancer, prophylaxis
Adverse Effects: hot flashes, vaginal bleeding, endometrial hyperplasia
Contraindications: Hx DVT, PE, coagulopathy
Pharmacogenetics…..

62. 3. Raloxifene (a SERM) Raloxifene (Evista)
Estrogen antagonist centrally and on uterus and breast tissue
Estrogen agonist on bone, lipids and coagulation profile
Indications: postmenopausal osteoporosis, breast cancer prophylaxis
Contraindications: Hx DVT, PE, coagulopathy
Increase hot flashes
Warnings: NOT for pre-menopausal women; incr. incidence DVT/PE

63. 4. Fulvestrant (a SERD) Fulvestrant (Faslodex)
Estrogen antagonist on breast; competes with estradiol
Down regulates estrogen receptor protein in breast cancer
Indications: metastatic breast cancer

64. D. Selective PR modulators (SPRMs) and Antagonists
Ulipristal (Ella)
SPRM
Emergency contraception
Take within 120 hours of unprotected intercourse or contraceptive failure (vs. 72 hours for other EC)

65. D. Selective PR modulators (SPRMs) and Antagonists
2. Mifepristone (Mifeprex, RU-486)
PR antagonist
Antagonist at glucocorticoid receptors
Restricted access

66. Pharm to Watch for….. More…. SERMS
Selective PR modulators (SPRMs) and Antagonists

67. Handsome Blake, demonstrating the Greyhound TechniqueTM of resting.
That’s all!
Handsome Blake, demonstrating the Greyhound TechniqueTM of resting.
Get some rest over the break!