Gonadal Hormones: Progesterone and Estrogen

Question 1

Explain the hormonal regulation of hypothalamic pituitary axis

Answer 1

Increased TRH — increased TSH (pituitary hormone) — increased T3 and T4 (pituitary hormonal effect)
Increased GnRH — Increased FSH and LH —– Increased Estrogens, Progesterone and Testosterone
Increased CRH —- Increased ACTH, MSH, and Beta-Endorphins —- Increased Mineralocorticoids, Increased Glucocorticoids and Sex Hormones (DHEA)
Increased GHRH — Increased GH — Increased IGF-1

Question 2

Explain the various stimulation (prolactin, exercise, glucose and dopamine) on hormone secretion

Answer 2

Increased Prolactin —– Decreased GnRH — Decreased Spermatogenesis and Ovulation
Increased Exercise and Sleep — Increased GHRH — Increased IGF-1
Decreased Glucose and Somatostatin — Increased GHRH —Increased IGF-1
Increased Dopamine (dopamingeric drugs) — Decreased prolactin — Increased GnRH

Question 3

What are the major categories of natural sex steroids?

Answer 3

1. Estradiol (Estrogens)
2. Progesterone
3. Androgens

Question 4

What is the general mechanism of action of steroid hormones (estrogen, progesterone and testosterone)?

Answer 4

1. Binds to the cytosolic receptor
2. Hormone receptor complex (HRC) travels into nucleus
3. Activation of HRC leads to changes in the rates of transcription of steroid hormone regulated genes this modulates gene expression

Question 5

Know the picture on slide 13 of 62

Answer 5

Glomerulosa: Mineralocorticoids (Aldosterone)
Fasciculata: Glucocorticoids (Cortisol)
Reticularis: Androgens (DHT and testosterone)

Question 6

If a patient has 17 alpha hydroxylase deficiency this leads to what?

Answer 6

Decreased sex hormones and cortisol
Increased mineralocorticoids (aldosterone)
–pathway is on slide 14

Question 7

How will a patient present with 17 alpha hydroxylase deficiency?

Answer 7

Increased BP and decreased Potassium
If XY: decreased DHT show cryptochidism and indistinct genitalia (tx with androgens, glucocorticoids, and HTN meds)
If XX: outwardly phenotypic female with normal internal sex organs but lack of secondary characteristics (tx with estrogens and HTN meds)

Question 8

If a patient has 21 hydroxylase deficiency this leads to what?

Answer 8

Increased sex hormones

Decreased cortisol and mineralcorticoids (aldosterone)

Question 9

How will a patient present with 21 hydroxylase deficiency?

Answer 9

Decreased BP but Increased Potassium and Increased Renin activity and volume depletion
If XY: over masculinization
If XX: pseudohermaphroditism
Rx: fluids + salt repletion and administer cortisol to decrease ACTH

Question 10

If a patient has 11 beta hydroxylase deficiency this leads to what?

Answer 10

Increase in sex hormones
Decrease in cortisol and in mineralocorticoid (Aldosterone)
Increase in 11- deoxycorticosterone

Question 11

How will a patient present with 11 beta hydroxylase deficiency?

Answer 11

Increased BP due to increased mineralocorticoid 11- deoxycorticosterone
Over masculinization
Rx: estrogens and Anti-HTN

Question 12

What are some features of estrogen?

Answer 12

Sources: Ovary, adrenal gland, placenta and in adipose tissue via aromatization
Main estrogens: Estradiol (more potent), Estrone, Estriol
Estriol is for pregnancy

Question 13

In regards to drugs, what are the various antiestrogens?

Answer 13

Receptor antagonist: selective estrogen receptor modulators and Full antagonist (Fulvestrant) 
Aromatase inhibitors 
GnRH Agonist (continuous administration)

Question 14

What are the physiological effects of estrogen?

Answer 14

Sexual development: growth and development of vagina, uterus, fallopian tube, breast enlargement
Non-reproductive functions: reduce bone resorption and prevent bone loss and epiphyseal closure in long bones
Pro-coagulation state: increase factor II, VII, IX, X, XII in higher doses and decrease in antithrombin III, protein C and S
Favorable lipid profile: increase HDL and decrease LDL
Effect on Hormone levels: increase the transport protein level of various hormones and free hormone level is unaffected
Increased cholesterol in bile: formation of gall stones

Question 15

What are the estrogen drugs?

Answer 15

Ethinyl Estradiol
Conjugated Estrogen 
Mestranol 
Diethylstilbestrol 
Estradiol
Estrone 
Estriol

Question 16

What is Mestranol?

Answer 16

Prodrug converted into Ethinyl Estradiol, present in some contraceptives
–increased bio-availability, increased half life and decreased FSH and LH via feedback

Question 17

Metabolism of estrogens relies on cytochrome P-450 system; they have enterohepatic circulation. There combination with P-450 inducers leads to what?

Answer 17

Failure of contraceptive effectiveness

Question 18

What are the clinical uses of Estrogens?

Answer 18

IM: long acting estrogen preparations are used in females with hypogonadism
Oral contraceptives in combo with progestins: suppress FSH and LH secretion and inhibit ovulation
Postmenopausal hormone replacement therapy (HRT): help and reduce hot flashes, prevent bone loss and fractures, decrease incidence of colon cancer, decrease urogenital atrophy and increase feeling of well being
Used in dysmenorrhea, uterine bleeding, prostate cancer, and acne

Question 19

What are benefits associated with estrogen replacement therapy?

Answer 19

Osteoporosis: estrogen decreases the resorption of bone but has no effect on bone formation. decreases the frequency of hip fractures. tx with estrogen must begin right after menopause
Vasomotor: estrogen treatment reestablishes feedback on hypothalamic control of NE secretion, leading to decreased frequency of hot flashes
Urogenital Tract: Estrogen treatment reveres postmenopausal atrophy of the vulva, vagina, urethra, and trigone of the bladder

Question 20

What are the adverse effects of estrogens?

Answer 20

1. increased incidence of thromboembolism
2. Increased incidence of breast cancer
3. Endometrial hyperplasia and cancers
4. Migraine, cholestasis, and mood changes
5. Nausea, breast tenderness and bloating
6. Diethylstilbestrol (DES): a non-steroidal estrogen agonist use in pregnancy results in female child to infertility and vaginal cancer

Question 21

What are contraindications for estrogen use?

Answer 21

1. History of thromboembolism
2. Breast and Endometrial Cancer
3. Pregnancy
4. Liver Disease

Question 22

Selective Estrogen Receptors Modulators (SERMs): exhibit agonistic action in some tissues and antagonists in other tissues. Explain this using Tamoxifen

Answer 22

Tamoxifen: E-receptor antagonist effect on breast tissue but agonist effect on liver, bone and partial agonist endometrium

• -used in tx of breast cancer and prophylaxis for high risk patients
• -AE: hot flushes (antagonist) and thrombosis (agonistic) and risk of endometrial cancers

Question 23

The next two SERMs are Toremifene and Raloxifene what are some features?

Answer 23

Toremifene: tx of breast cancer and prevention of breast cancer in high risk women
Raloxifene: E- receptor antagonist at breast but agonist at bone (increase in bone density). No estrogenic effect on endometrium – so no increased risk of endometrial cancer. Use: prophylaxis against breast cancers and prevention of postmenopausal osteoporosis

Question 24

What is the estrogen receptor antagonist in all tissues?

Answer 24

Fulvestrant IM: used in tx of breast cancer in tamoxifen resistant patients
AE: hot flushes, injection site reactions and headache

Question 25

Moving on to Aromatase inhibitors, these drugs inhibit the conversion of androgens to estrogen. What are the three drugs?

Answer 25

Letrozole Anastrozole Exemestane: an irreversible aromatase inhibitor All used in tx of breast cancer (Estrogen dependent) as 2nd line drugs following tamoxifen resistant Oral AE: hot flushes, decreased bone mineral density

Question 26

Clomiphene is a fertility drug that acts as estrogen antagonist in hypothalamus and anterior pituitary. Explain this MOA

Answer 26

1. Estrogen Antagonist 2. Prevents feedback inhibition of GnRH release by hypothalamus 3. Continued release of GnRH from hypothalamus 4. Increased LH and FSH from the pituitary 5. Increased ovulation

Question 27

What are some features of Clomiphene (fertility drug)?

Answer 27

Orally Half-life 5-7 days Protein binding and Enterohepatic circulation Tx of anovulatory infertility Side Effects: ovarian hyperstimulation leading to enlargement of the ovary, multiple pregnancies, and hot flushes

Question 28

Moving on to Progesterone and Its derivatives (progestins), what are these drugs?

Answer 28

``` Progesterone Medroxyprogesterone Norgestrel Norethindrone Norgestimate Desogestrel --these 5 drugs (Excluding progesterone) are newer preps lacking androgenic and anti-estrogenic effects Drospirenone: a spironlactone derivative used as OC antagonize aldosterone effects useful in acne in females Antiprogestin: Mifepristone ```

Question 29

What are the sources and functions of progesterone?

Answer 29

Sources: Corpus Luteum, Placenta, Testes and Adrenal Cortex Functions: --elevation of progesterone signifies ovulation --stimulates endometrial glandular secretion --maintains pregnancy--pro-gestation --decrease myometrial contraction and effects uterine smooth muscle relaxation --associated with increased body temp ---produce thick cervical mucus that inhibits sperm access into uterus --prevents endometrial hyperplasia and decrease estrogen receptor expression

Question 30

What are the uses of Progestins?

Answer 30

1. Used alone or in combo with estradiol for contraception 2. In combo with estrogen they are used in HRT 3. Decreased incidence of endometrial hyperplasia and carcinoma caused by unopposed action of estrogens --in this setting patients may have irregular bleeding 4. Used in ovarian suppression in the tx of dysmenorrhea and endometriosis 5. They are used to dx estrogen secretion and for responsiveness of endometrium. Menstruation occurs after progesterone administration in patient with amenorrhea this occurs after 5-7 days

Question 31

What are the AE of long term use of Progestins?

Answer 31

``` Weight Gain Glucose Intolerance Androgenic: hirsutism and acne Anti-estogenic (Blocks lipid changes) Depression Edema Acne Increased HDL and decreased LDL HTN ```

Question 32

Finally the Antiprogestin is RU486 or Mifepristone which is given orally. What are some features of this drug?

Answer 32

Competitive inhibitor of progesterone and Glucocorticoid receptors Controversial morning after drug used as an abortifacient It is given concomitantly with PG-E or PG-F to increase myometrial contraction AE: excessive bleeding, GI effects as nausea, vomiting, anorexia and abdominal pain