Up to Midterm #2 Flashcards
1
Q
Estrogen Synthesis
A
- Most prevalent forms are estradiol and estrone
- Produced primarily by developing ovarian follicles, the corpus luteum, and the placenta
- Estrone also produced in smaller amounts by the liver, adrenal glands, and the breasts
- These secondary sources of estrogens are important in postmenopausal women
- In females, synthesis of estrogens starts in theca interna cells in the ovary by the synthesis of androstenedione from cholesterol
- Androstenedione crosses the basal membrane into the surrounding granulosa cells, where it is converted to estrone or estradiol, either immediately or through testosterone
2
Q
Estrogen Synthesis in the Ovary
A
- Cholesterol→Pregnenolone (LH, P450scc)
- Pregnenolone→Progesterone
- Progesterone→Androstenedione
- Androstenedione→Testosterone
- Androstenedione→Estrone (FSH, aromatase)
- Estrone→Estriol
- Testosterone→17-beta-estradiol (FSH, aromatase)
- 17-beta-estradiol→Estriol
3
Q
Progestagen Synthesis
A
- Named for maintaining pregnancy (progestational), although they are also present at other phases of the estrous and menstrual cycles
- Precursors to all other steroids
- All steroid-producing tissues produce progestagens
- Progesterone is the major progestagen
- Progesterone levels are highest in the proestrus-estrus phase (development and maintenance of the endometrium)
- During pregnancy, the placenta takes over the majority of progestagen production
4
Q
Feedback Control in the HPO axis
A
- Higher brain centers→hypothalamus
- (-) NPY, opioid, GABA, dopamine
- Hypothalamus→Anterior pituitary
- (+) GnRH
- Anterior pituitary→Ovary
- (+) LH, FSH
- Follicle & Ovum development
- Ovary→breast, bone, brain, liver
- Inhibin, estradiol, progesterone
- Feedback
- (-) Inhibin to anterior pituitary
- (+/-) Estradiol/progesterone to anterior pituitary
- (-) Estradiol/progesterone to hypothalamus
5
Q
Therapeutic purposes for manipulating the estrogen and progesterone pathways
A
- Hormone replacement therapy (HRT)
- Dyspareunia (painful intercourse)
- Infertility
- Cancer chemotherapy
- Birth control
- Pregnancy termination
- Endometriosis
6
Q
Menopause
A
- With age, estrogen and progesterone levels decline to a point where pregnancy is no longer possible
- Usually occurs in late 40s, early 50s
- Since estrogen plays other roles within the body, many systems are affected
- Symptoms
- Hot flashes
- Changing sleep patterns
- Emotional changes (mood swings)
- Headaches
- Heart palpitations
- Generalized itching
7
Q
Potential for selective ER modulators for menopause?
A
- Raloxifene
- Reduced risk of vertebral fracture by 40% but other fractures were not affected
- Did not show a significant increase in bone density
- Studies indicated a 2-fold decrease in breast cancer
- Side Effects:
- Heart risk under study
- Blood clots occurred in 1/155 women over 3 years
- Generally in calf
- Leg cramps were seen in about 7% of women
- 2x more than usual
- Caused hot flashes
- ~10% of older women and about 25% in women closer to menopause
- Not as severe as early menopause, went away with time
8
Q
Estrogen effects associated with HRT during menopause
A
- Beneficial
- Strengthens bones
- Lowers LDL cholesterol
- Raises HDL cholesterol
- Reduces menopausal symptoms
- May reduce risk of Alzheimer’s
- Detrimental
- Increases breast cancer risk
- Increase uterine cancer risk
- Can be reduced or eliminated by addition of progesterone
- Increases blood clot risk
- Increases risk of heart attack and stroke
9
Q
Dyspareunia
A
- Pain during intercourse
- Pain occurs primarily on the external surface of genitalia
- Can be deep in the pelvis with pressure against the cervix
- Need to understand the duration, location, and nature of the pain for treatment
- Causes
- Hormone imbalance (menopause)
- Infection
- Injury
- Anatomic variations
- Cysts, tumors, or fibroids
- Bladder irritation
- Psychologic
- Treatment
- Rebuild vaginal wall thickness
- Prempro: vaginal cream
- Ospemifene (Osphena): oral, SERM
10
Q
Infertility Treatment
A
- Clomiphene is a partial agonist/antagonist of estrogen
- Acts at both pituitary and hypothalamus
- Blocks estrogen feedback and increases GnRH, LH, FSH
- Can produce up to 80% ovulation rates
- Complications: multiple births in 5-12% cases
- Pulsatile GnRH pump for 2 wks followed by human chorionic gonadotropin (similar to LH)
11
Q
Tamoxifen: Selective ER modulator
A
- Tamoxifen is most effective in treatment of tumors that are ER and/or PR-positive
- 70-80% response rates
- Response of ER negative tumors is <10%
- Adjuvant therapy with chemotherapy or radiation in treatment of node-negative breast cancer after total or partial mastectomy
- Treatment for advanced metastatic breast cancer
- Preventative agent for women at high risk for breast cancer
- 50% decrease of both invasive and noninvasive breast cancers
- Resistance is usually developed in 5 years
- Due to alterations in the ER receptors in the tumors
12
Q
Tamoxifen can increase uterine cancer risk
A
- Breast
- Breast cell receptors not activated
- No breast cell proliferation
- Decreased cancer risk
- Uterus
- Uterine cell receptors activated
- Endometrial cell proliferation
- Increased cancer risk
13
Q
Aromatase Inhibitors
A
- Lower estrogen in circulation and in tumor cells in post-menopausal women
- Second-line treatment for breast cancer in patients when tamoxifen therapy is unsuccessful
14
Q
Contraceptive Mechanisms
A
- Feedback inhibition
- Prevents LH surge
- No ovulation or follicular growth
- Alter endometrial lining of uterus
- Prevents implantation
- Alter cervical mucosa
- Secrete mucous that is “hostile” to sperm
15
Q
Beneficial effects of birth contraceptives
A
- Nearly 100% effective in preventing pregnancy
- Protects against ectopic pregnancy
- Protects against anemia
- 50% decrease in benign breast tumors
- 50% decrease in endometrial cancer
- 50% decrease in ovarian cancer
- 50% decrease in PID
