Estrogens - mechanism of action, metabolism, adverse effects, pharmacokinetics and metabolism Estradiol Estriol Estrone Ethynyl Estradiol Selective Estrogen - Receptor Modulators ( SERMs )

1. Estrogens
Tural Abdullayev
Group 30

2. Estrogens
1. Estradiol – known also as 17β – estradiol
– Most patent estrogen produced and secreted by the ovary
– Principle estrogen in premenopausal women
2. Estrone – metabolite of estradiol that has approximately
1/3 the estrogenic potency of Estradiol
– Primary circulating estrogen after menopause
– Generated mainly from conversion of Androsteredione in peripheral
tissues
3. Estriol – metabolite of estradiol, is significantly less potent
than estradiol
– Present in significant amounts during pregnancy, because its principal
estrogen produced by placenta

3. Estrogens
4. Ethynyl Estradiol ( Synthetic Steroid )
– Undergo less 1st – pass metabolism than naturally occurring steroids
– Effective when administered orally at lower doses
– Readily absorbed when taken orally
– Absorbed in the small intestine
– Excreted with the bile
5. Conjugated Estrogens
– reduce symptoms of menopause ( hot flushes and vaginal dryness )

4. Mechanism of Action
• After dissociation from their binding sites on sex hormone –
binding globulin or albumin in the plasma, steroid hormones
diffuse across the cell membrane and bind with high affinity
to specific – receptor proteins

5. Mechanism of Action
• 2 estrogen – receptor subtypes mediate the effects of the
hormone :
1. α receptor – considered as the classic Estrogen Receptor
2. β receptor – highly homologous to the α receptor
– α receptor
o N - terminal portion of receptor contains a region that Promotes
transcription activation
– β receptor
o contains a Repressor Domain

6. Mechanism of Action
• Affinity for the receptor type varies with the particular
estrogen
• The α and β estrogen receptor isoforms vary in:
– Structure
– Chromosomal location
– Tissue distribution

7. Mechanism of Action
• Activated Steroid – Receptor Complex interacts with nuclear
chromatin to initiate Hormone – Specific RNA synthesis :
– Attachment of 2 estrogen – linked receptors ( estrogen receptor
dimer ) to the genome is required for a response
• This results in synthesis of specific proteins that mediate a
number of physiologic functions
• Steroid hormones are tissue and receptor specific :
– They may elicit the synthesis of different RNA species in diverse
target tissues

8. Mechanism of Action
• Activation of an estrogen receptor in the membranes of
hypothalamic cells has been shown to couple to a G – protein,
thereby initiating a 2nd – messenger cascade

9. Therapeutic uses
1. Contraception
2. Post – menopausal hormone therapy, called Estrogen –
Progesterone therapy ( EPT )
– It’s prescribed at the lowest effective dose for the shortest possible
time to relieve vasomotor symptoms and vaginal therapy
3. Osteoporosis
– Alendronate should be considered 1st – line therapy
4. Replacement therapy
– In Premenopausal patients in deficient in estrogen
– This deficient may be due to premature menopause because of lack
of development of ovaries

10. Therapeutic uses
5. Post – menopausal hormone therapy
– Primary indication for estrogen therapy is Menopausal Symptoms
1. Vasomotor instability – Hot flushes
2. Vaginal atrophy
6. For women who have not undergone a hysterectomy
– Combination of Estrogen with Progestin in Estrogen Therapy
decrease the risk of Endometrial Carcinoma associated with
unopposed estrogen
7. For women whose uterus has surgically removed
– Unopposed estrogen therapy is recommended
8. Primary Hypogonadism
– In combination with Progestins is stimulating development of
secondary sex characteristics in young women (11 – 13 years of age )

11. Pharmacokinetics
• Naturally occurring estrogens
1. Readily absorbed though:
• GI tract
• Mucous membranes
• Skin
2. Taken orally
3. Estradiol
• Rapidly metabolized and partially inactivated by liver
4. Micronized Estradiol
• Has better bioavailability
• Although there’s 1st – pass metabolism, it’s not sufficient to
lessen the effectiveness when taken Orally

12. Pharmacokinetics
• Synthetic Estrogen Analogs
• Compounds such as Estradiol and Mestranol
1. Well absorbed through mucous membranes and skin
2. Oral Administration
• Mestranol quickly demethylated to Ethinyl Estradiol, which is
metabolized more slowly than naturally occurring estrogens
by Liver and Peripheral Tissues
– Being fat soluble, they are stored in adipose tissue from which they
are slowly released
– Synthetic Estrogen Analogs have prolonged action and higher
potency compared to natural ones

13. Metabolism
• Estrogens are transported in the blood while bound to serum
albumin or sex hormone – binding globulin
• Bioavailability of estrogen taken orally is low due to 1st – pass
metabolism in liver
• To decreased the 1st – pass metabolism, the drugs may be
administered by :
1. Transdermal patch
2. Intravaginally
3. Inection
4. Topical gel or emulsion
• They are hydroxylated in the liver to derivatives that are
subsequently Glucuronidated or Sulfated.
• Parent drugs and their metabolites undergo excretion into the bile
and then reabsorbed through the enterohepatic circulation
• Inactive products are excreted via urine

14. Adverse Effects
• Most common of estrogen therapy
1. Nausea
2. Breast tenderness
• Post menopausal uterine bleeding may occur
• There is increased risk of :
1. TE events
2. Myocardial infarction
3. Breast cancer
4. Endometrial cancer
• Other effects
1. Headache
2. Peripheral edema
3. Hypertension

15. Selective Estrogen – Receptor
Modulators
SERMs
• Interact at estrogen receptors
• They display Selective Agonism or Antagonism according to
issue type
– For example :
• Tamoxifen is an estrogen antagonist in breast cancer tissue,
but can cause endometrial hyperplasia by acting as partial
agonist in the uterus

16. Selective Estrogen – Receptor
Modulators
SERMs
1. Tamoxifen ( 1st generation SERMs )
– Competes with estrogen for binding to the estrogen receptor in
breast tissue
– Currently used in the palliative treatment of metastatic breast
cancer in postmenopausal women
– May also be used as adjuvant therapy following mastectomy or
radiation and to decrease risk of breast cancer in high risk
patients
• Adverse effects
1. Hot flashes
2. Nausea
3. Vaginal bleeding
4. Menstrual irregularities
5. Hyperplasia in endometrium
6. Malignancies in endometrium

17. Selective Estrogen – Receptor
Modulators
SERMs
2. Raloxifene ( 2nd generation SERMs )
– Use is based on its ability to decrease bone resorption and
overall bone tumor
1. Bone density is increased
2. Vertebral fractures are decreased
– Has little to no effect on the endometrium
– Lowers total cholesterol and LDL in the serum
– No effect on HDL or TAG levels
– Currently used for treatment of osteoporosis in
postmenopausal women
– Reduce the incidence of invasive breast cancer in
postmenopausal women

18. Selective Estrogen – Receptor
Modulators
SERMs• Raloxifene
– Pharmacokinetics
1. Readily abrorbed orally
2. Rapidly converted to Glucuronide Conjugates through 1st – pass
metabolism
3. More than 95% is bound to plasma proteins
4. Undergo enterohepatic cycling
5. Excreted through the bile into the feces
– Adverse effects
1. Hot flashes
2. Leg cramps
3. Increased risk of DVT
4. Increased risk of PE
5. Increased risk of retinal – vein thrombosis
6. Should be avoided in women who are or may become pregnant
7. Women with past history or active history of TE should avoid use of the drug
8. Coadministration with cholestyramine can decrease the absorbtion by 60%

19. 3. Toremifene
– Properties and side effects similar to those of Tamoxifen
– Risk of endometrial hyperplasia and cancer are lacking
– Restricted to postmenopausal women with metastatic breast
cancer
Selective Estrogen – Receptor
Modulators
SERMs

20. 3. Clomiphere
– Acting as Partial Estrogen Agonist
– Interfering with negative feedback of estrogens on hypothalamus
– It’s increasing the secretion of GnRH and gonadotropins, leading to
stimulation of ovulation
– Used to treat infertility associated with anovulatory cycles
– No effect on women with ovulatory dysfunction due to Pituitary or
Ovarian failure
• Adverse effects
1. Headache
2. Nausea
3. Vasomotor flushes
4. Visual disturbances
5. Ovarian enlargement
Selective Estrogen – Receptor
Modulators
SERMs