27 – Estrogens and Hormone Replacement Therapy

Estrogen Basics

1. What are the three different physiologic estrogens and where are they produced?
• (E1) – produced by peripheral conversion
• (E2) – produced by
• (E3) – produced by placenta

2. What enzyme is essential for the generation of estrogen?

3. Pause the video and complete the following chart.

4. Complete the following hypothalamic-pituitary-gonadal (ovary) axis diagram.

5. How do the hypothalamus and the anterior pituitary regulate estrogen production?

6. What is the action of estrogens at the nuclear receptor?

• Alter RNA and protein synthesis
• Direct intracellular

7. What are the effects of estrogen?

• Female sexual maturation – breast and • Maintains healthy skin and teeth
female fat distribution • Maintains bone strength
• Genital development • Maintains blood vessels
• growth • Improves cholesterol – lower LDL and higher
development HDL
• Feedback inhibition of LH and FSH

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8. Outline the general hormone sequence of the female reproductive cycle.
FSH  Follicle maturation  Production of estradiol  Production of LH surge
Ovulation  Corpus Luteum  Progesterone (with Estradiol)  Maintenance of endometrial lining &
inhibition of FSH and LH production Decline of corpus luteum  Shedding of endometrial lining (No
production of estradiol and progesterone)
Loss of FSH inhibition  Increase in FSH  (repeat step 1)

9. What are some of the common uses of estrogen?

• Hypogonadism
•
• Contraception
• Hormone replacement therapy

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Estrogen Supplementation

10. What were the first natural estrogens?

11. What are examples of two synthetic estrogens?

12. How are synthetic estrogens an improvement upon equine estrogen?

They are synthetically altered to decrease first-pass metabolism resulting in a longer
and increase (lower dose is required)

13. What are methods of exogenous estrogen delivery?

• Pills •
• • Foams
• Creams • Transdermal patches
• Gels

14. What disadvantage does oral estrogen administration have over other routes of administration?
Detrimental effects of stimulating the

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Quick Review 1

1. Which hormones are made by the aromatase enzyme?

2. How do the effects of estrogen relate to its therapeutic uses?

Effects of Estrogen Common Uses for Estrogen

Female sexual maturation and genital development

Endometrial lining growth and follicle development

Feedback inhibition of LH and FSH

Maintains healthy skin and teeth

Maintains bone strength

Maintains blood vessels

Improves cholesterol – Higher HDL and lower LDL

3. What are some of the more testable causes of hypogonadism?

• Hypergonadotropic (high LH and high FSH) = ovarian dysfunction

• Hypogonadotropic (low LH, low FSH) = hypothalamic or pituitary dysfunction

4. What stimulates the ovarian follicle to produce estradiol?

5. What effect do high levels of estrogen and progesterone have on LH and FSH?

6. Which is a more potent manner to dose estrogen: oral pill or transdermal patch?

7. What is the relationship between estrogen, progesterone, OCPs, and HRT?

• OCPs: estrogen and progesterone
• HRT: estrogen

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Menopause and HRT

1. What is the average age of menopause?

2. What are the classic signs and symptoms of menopause?

• • loss
• Sleep disturbance • Osteoporosis
• Urogenital • Lipid changes
 Dyspareunia  ↑ total cholesterol
 UTIs  ↑
 Urinary  ↓
• Skin and teeth changes • Loss of

3. What are the benefits of hormone replacement therapy in postmenopausal women?

• Helps
• Helps sleep
• Helps
• Helps urinary incontinence
• Helps symptoms

4. What is the most influential study to date that has elucidated the effects of postmenopausal hormone
replacement therapy?

5. What did the WHI teach us about the dosage, timing, and indication of hormone replacement therapy?
• Dosage – prescribe the dose needed to treat symptoms
• Timing – start right away and stop
• Indication – best for and

6. What are some of the non-estrogen treatments for menopausal vasomotor symptoms (hot flashes)?
•
- Venlafaxine
- Desvenlafaxine
• Clonidine
• Gabapentin

7. What are the common methods of administering estrogen hormone replacement?

8. In a woman with urogenital atrophy, what is the preferred method of dosing hormone replacement?

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9. What problems can arise when giving postmenopausal estrogen replacement without coadministration of
progesterone (AKA unopposed estrogen)?
Unopposed estrogen

10. What are some of the adverse effects of estrogen replacement?

•
• Strokes and heart disease
• Endometrial cancer
•
• Breast cancer

11. Which populations are at higher risk of venous thromboembolism including deep venous thrombosis (DVT)
and pulmonary embolism when prescribed estrogen?
• Those with hereditary
• Smokers
• Increase in risk after age

12. What are the absolute contraindications to estrogen?

• Severe cardiac disease • Liver cancer
• Stroke • Known
• • >5 years after menopause
• History of blood clots • Migraines with
• endometrial • Undiagnosed uterine bleeding
or breast cancer

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Quick Review 2

1. What is the precursor pathology to uterine cancer?

2. What is the biggest risk factor for uterine cancer?

• Polycystic Ovarian Syndrome (PCOS)

• Obesity
• Sertoli-Leydig cell tumor of the ovary
• HRT

3. What are the most common hereditary thrombophilias that can increase one’s risk for DVT and PE when
estrogen is given?
• mutation
• Prothrombin gene mutation
• Protein C Deficiency / Protein S Deficiency
• Antithrombin deficiency

4. Is hormone replacement therapy contraindicated in smokers over age 35?

5. A 55 year-old female comes to her physician to discuss menopause because all of her friends are complaining
about it. She is not having menopausal symptoms and is still having monthly cycles. She continues to take
the combination oral contraception pill that she has taken since age 35. What would the physician do for this
patient?
• She should be switched
• More conservative option: and determine if she has any
uncomfortable menopausal symptoms that would necessitate HRT

6. How should the clinical use of OCPs and HRT be adjusted with respect to breast cancer risk?
• Do not use OCPs in patients with
• HRT may the risk of invasive breast cancer but does not increase the risk of
noninvasive breast cancer
• Do not use HRT in a patient with

7. A 50 year-old female comes to the clinic for treatment of menopausal symptoms. During the history she
states she has been having some vaginal spotting about every 2 weeks for the last few months. What work-
up needs to be done prior to being prescribed HRT?

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Selective Estrogen-Receptor Modulators (SERM)

1. Complete and study the following table of selective estrogen-receptor modulators. (LP p302-303)

SERM MECHANISM OF ACTION THERAPEUTIC USE ADVERSE EFFECT

Tamoxifen Partial antagonist in Estrogen-receptor positive _____________________

___________________ breast cancer Nausea
Agonist in uterine tissue Abnormal bleeding
_____________________
Toremifene Partial antagonist in breast Estrogen-receptor positive Same as tamoxifen
tissue breast cancer
Cannot use for tamoxifen-
resistant breast cancer
Raloxifene _________________ in bone Restricted to osteoporosis Hot flashes
Antagonist in breast tissue Joint pain
Nausea
Clomiphene Partial agonist in Ovulation induction Nausea
______________________ Headache
Hot flashes

Other Anti-Estrogen Drugs

2. What medication is a pure estrogen-receptor antagonist that is used in the treatment of breast cancer that
has developed resistance to tamoxifen?

3. What medications inhibit the aromatase enzyme, and what are the uses of these medications?
• Reversible – , letrozole
• Irreversible –

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GnRH Agonists

4. How does hypothalamic GnRH secretion cause different effects than continuous administration of a GnRH
agonist?
• Hypothalamus secretes GnRH in a manner and the pituitary secretes FSH
and LH
• Continuous administration leads to a drop in estrogen to levels

5. What are the different GnRH agonists?

6. In a premenopausal woman taking leuprolide, if the side effects of the medication become problematic, what
can be given to provide relief?

7. What are the therapeutic uses for GnRH agonists such as leuprolide?
• Fibroids
• Endometriosis
• cancer
• Prostate cancer
•

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Quick Review 3

1. A 40-year-old black female with menorrhagia due to uterine fibroids is placed on leuprolide. She comes to the
clinic complaining of severe hot flashes. What is the treatment for this patient?

2. A 72-year-old thin, white female is being treated with a bisphosphonate and raloxifene. What is she at
increased risk for because of the raloxifene?

3. In treating a female for osteoporosis with an estrogenic agent, what are the advantages of using raloxifene
rather than conjugated estrogen?
• Reduces the risk of cancer
• Raloxifene will not increase the risk of cancer

4. What is the drug of choice for infertility treatment due to anovulatory cycles?

5. How exactly does clomiphene work?

• Partial estrogen agonist at the
• Results in negative feedback inhibition of endogenous estrogen

6. A 40-year-old female undergoes surgery for the resection of breast cancer. Pathologic analysis of the tumor
reveals that is an estrogen-receptor positive tumor. What medication will this patient probably have to take?

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End of Session Quiz

1. Why is a patient’s past surgical history an important consideration when determining post-menopausal
hormone replacement therapy needs? (LP p301)

2. For what duration is tamoxifen dosing limited due to increased risk of uterine cancer? (LP p302)

3. What SERM used to prevent breast cancer may not increase the risk of endometrial cancer? (LP p302)

4. What enzyme is essential for the generation of estrogen?

5. What is the therapeutic use of each of the following agents?

Drug Therapeutic use

Leuprolide
Clomiphene

Tamoxifen
Ethinyl estradiol

6. What are the signs and symptoms that HRT aims to alleviate? (LP p300-301)

7. What are the adverse effects associated with estrogen therapy? (LP p301-302)

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8. Which drugs are classified as selective estrogen-receptor modulators? How do they work? (LP p302-303)

SERM Mechanism of Action

Tamoxifen
Raloxifene

Toremifene

Clomiphene

9. What changes are seen in serum estrogen, LH, and FSH after the onset of menopause?

10. How does the body synthesize estradiol from cholesterol?

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