Rpdwk3- 3-28 Segears Hrt/serms

Front 1

What are the key time intervals of menopause?

Back 1

1. Reproductive stage
2. Menopausal transition- aka peri-menopause, shows increases in FSH, and variable cycles... classically seen with 2 skipped cycles
3. post- menopause

Front 2

What are the examples of symptoms

Back 2

– Hot flashes
– Night sweats
– Vaginal dryness/Painful intercourse/Sexual dysfunction
– Sleep disturbances
– Mood/Cognitive problems
– Somatic symptoms
– Urinary incontinence
– Reduced Quality of Life

Front 3

What is primary therapy for menopause?

Back 3

estrogen replacement (HRT/ERT/MHT/MHRT)
AND women with intact uterus must also be on a progestin

Front 4

What are the 6 estrogenic components in estrogen replacement therapy?

Back 4

1. estradiol
2. conjugated equine estrogens (CEE, premarin)- derived from urine of pregnant mares
3. synthetic conjugated estrogens- A- blend of 9 synth estrogens
4. synthetic conjugated estrogens- B- blend of 10 synth estrogens
5. Esterified estrogens
6. estropipate- stabilized with PIPerazine

Front 5

Most common world wide estrogen replacement therapy and MC USA one?

Back 5

World-wide: estradiol most common
• USA: CEE most common- MHRT/ERT overall use, and duration, lower/shorter today
due to WHI Study

Front 6

What are the two available progestinic components used solely for menopausal hormone replacement therapy (MHRT)

Back 6

– Medroxyprogesterone (MPA; alone or with CEE)
– Methyltestosterone (with Est. Estrogens)

Front 7

Dosage form of ERT?

Back 7

1. oral- estrogen only or both
2. topic cream- estrogen only
3. injectable- estrogen only
4. transdermal patch
5. vaginal (ring, cream, tablet, estrogen only)

Front 8

MOA of estrogen replacement therapy

Back 8

Bind to endogenous estrogen receptors in various tissues in the body
- this generates increase DNA and resulting protein regulation with increased or decreased production, depending on site of receptor...
(natural estrogen's effects)---> causes endometrial proliferation

Front 9

What are biochemically decreased with ERT?

Back 9

– Cholesterol (TC/LDL-C)
– Anti-thrombin III
– LH/FSH
– Osteoclastic activity (bone turnover)

Front 10

Biochemical effects of ERT that both decrease and increase chance of clots?

Back 10

Decreased- ATII
INcreased- platelet aggregation and clotting factors

Front 11

Biochemical effects of eRT that are increased?

Back 11

– Triglycerides & HDL-C
– Clotting factors
– Thyroid Binding Globulin (TBG)
– Platelet aggregation
– Sodium/Fluid retention

Front 12

What is the WHI?
Study groups of HT trial?

Back 12

NIH/NHLBI set forth to formally, officially evaluate claims with ERT
1. estrogen (.625 mg) + Progestin (2.5 mg) vs. placebo in women w/uterus
2. estrogen only vs placebo in women w/hysterectomy

Front 13

What happened with the WHI study?

Back 13

NHLBI Safety Data Monitoring Board halted
both arms early:
– Estrogen + Progestin stopped in 2002
– Estrogen only stopped in 2004
• Extension (F/U) Study began in 2005

Front 14

WHI had made the following changes to doctors practices?

Back 14

Only reason for HPT- symptoms are too great and quality of life is too poor w/o therapy
- not to be used to prevent: CVD, dementia, bone and colon cancer

Front 15

According to the WHI what has been increased or rx with estrogen/progestin therapy?

Back 15

Increased rx:
1. CHD (24% MI~ 81% in first year),
2. TE stroke (31%),
3. PE,
4. DVT (2x),
5. ovarian cancer (58%),
6. invasive breast cancer (24%),
7. dementia (over 65; 2x)

Front 16

According to the WHI what has decreased rx with estrogen/progestin therapy?

Back 16

1. colorectal cancer (44%)
2. endometrial cancer (19%)
3. fractures (24%)
4. hip fractures (33%)

Front 17

According to the WHI what has increased rx with just estrogen therapy? (women w/o uterus)

Back 17

1. stroke
2. VTE

Front 18

Is invasive breast breast cancer increased or decreased rx with estrogen alone therapy?

CHD (AMI/CHD related deaths?

Cognitive decline/ dementia, colorectal, breast, or total cancers, PE, mortality

Back 18

no significant increased rx

Front 19

According to the WHI what has decreased rx with just estrogen therapy? (women w/o uterus)

Back 19

hip fractures

Front 20

Describe the rx analysis "excess" cases for the following...
a. CHD
b. Strokes/PE/invasive breast cancer
c. VTE
d. dementia

Back 20

each in 10000 women- yrs
a. 7
b. 8
c. 18
d. 23

Front 21

If therapy needed for moderate-severe symptoms what should the dosage/treatment be for MHRT?

Back 21

5 years or less with the lowest dose possible

Front 22

What is a SERM and what is the goal?

Back 22

Selective estrogen receptor modulators
Goal- Beneficial estrogenic actions in select tissues with antiestrogenic action in other tissues
– Bone, Brain, and Liver
– Breast, Endometrium

Front 23

Name the SERMs

Back 23

• Tamoxifen (Nolvadex)
• Toremifene (Fareston)
• Raloxifene (Evista)

Front 24

What are the indications for Tamoxifen/Toremifene

Back 24

Tata's--> used for breast cancer
- prevention and treatment of ER + breast cancer

Front 25

What are the indications for raloxifene

Back 25

1st used for prevention and treatment of osteoporosis
- also breast cancer prophylaxis in high risk patients (NOT treatment!)

Front 26

How do you define someone who is at "high rx" for breast cancer?

Back 26

» at least one breast biopsy showing lobular carcinoma in situ (LCIS) or atypical hyperplasia
» one or more first-degree relatives with breast cancer
» a 5-year predicted risk of breast cancer of > 1.66% (based on the modified Gail model)

Front 27

Which form tamoxifene and toremifene is used for the breast cancer tx?

Back 27

trans-

Front 28

What is the slight difference in MOA of tamoxifene and toremifene?

Back 28

Both are Competitive inhibition of estrogen binding to ER
Toremifene (added benefit) also shown to promote production of transforming growth factor-beta (TGF beta) – inhibitory GF

Front 29

What do you have to watch for increased rx for with tamoxifen/tormifene?

Back 29

can stiumlate endometrial proliferation and thickening

Front 30

Describe tamoxifen's effect on the following...
a. bone
b. TC, TDL, and Lp(a)
c. Apo-A1

Back 30

a. anti-resorptive effects
b. decreases
c. raises Apo-A1

Front 31

Main benefit of raloxifene compared to the other SERMs?

Back 31

Does not induce proliferation or thickening of endometrial tissue – no apparent risk of endometrial cancer at this time

Front 32

What pregnancy class is Raloxifene

What are big side effects?

What effects does it have on lipids?

Back 32

pregnancy class X

- hot flashes, leg cramps, increased DVT/PE rx but less than tamoxifen

- positive effects on lipids and shown to reduce coronary events (nonfatal MI, death hospitalization) in at risk-patients

Front 33

What are the anti-estrogens? What are their indications?

Back 33

• Clomiphene (Clomid/Serophene)- infertility in anovulatory women
• Fulvestrant (Faslodex)- Metastatic ER+ breast cancer in
women with disease progression after tamoxifen therapy (tamoxifen failure)

Front 34

What is the MOA of clomiphene

Back 34

Clomiphene acts as falsse signal and tells brain
- blocks inhibitory actions of estrogen on hypothalamus GnRH and pituitary gonadotropin release which increased gonatropin secretion thereby stimulating ovaries to develop oocyte follicles

Front 35

S/E clomiphene?

Back 35

1. multiple births (3-5% increase, but 99% are twins)
2. ovarian cysts- ovarian cancer with prolonged use
3. hot flashes
4. blurred vision
5. luteal- phase dysfunction- inadequate progesterone production

Front 36

Describe why fulvestrant has an advantage in treatment of hormone receptor breast cancer when tamoxifen fails

Back 36

Because of bulky side chain, fulvestrant hinders ER dimerization and increases degradation thereby abolishing ER-mediated gene transcription (not just a receptor blocker)
- Administrated- monthly IM depo injections