Flashcards in Gonadal hormone Pharmacology Deck (38)
Name two GnRH analogs.
- Gonadorelin hydrochloride(Factrel®)
- Gonadorelin diacetate tetrahydrate(Cystorelin®)
* Both are injectable
Describe the pharmacokinetics/dynamics of GnRH analogs.
1) Highly bioavailable and more stable than native GnRH peptide:
2) Can be administered as a nasal spray, SC injection, IM injection, or in a SC time-release device.
3) Renal clearance.
What are the indications for GnRH analogs?
- Suppression of estrogen production in hormone-dependent breast cancer
- Suppression of androgen production in hormone-dependent prostate cancer
- Delay the onset of precocious puberty. (Also used to delay puberty in transgendered youth who are too young for hormone-replacement therapy.)
- Hypergonadism: Disrupts the GnRH pulse generator
What contraindications are associated with GnRH analogs?
What precautions should be taken in male patients on GnRH analogs?
- Increased risk of diabetes, MI, sudden cardiac death, stroke; monitor blood glucose and for signs/symptoms of CVD during therapy.
- Co-symptomatic with androgen suppression/Low Testosterone.
- Risk of ureteral obstruction or spinal cord compression
What precautions should be taken in female patients on GnRH analogs?
- Not recommended for nursing mothers and abnormal vaginal bleeding
- Risk factors for decreased bone mineral density (e.g. chronic alcohol, tobacco, anticonvulsants, corticosteroids).
- Premenopausal women: use nonhormonal contraception during and for 12 weeks after therapy or until menses resume.
What states do steroid receptor exist in the absence of an agonist?
1) In the cytoplasm of androgen target cells associated with a multi-protein complex known as the heat-shock complex.
2) Bound to target genes and associated with a co-repressor complex with innate histone-deactylase activity.
Describe the state of a steroid receptor in the presence of an antagonist.
In the presence of an antagonist a steroid receptor is bound to target genes and associated with a co-repressor complex with innate histone deactylase activity.
Where is estrogen produced in the female body?
Most estrogen in the female is produced in the ovaries by the theca interna and the granulosa cells of the follicles
What are the clinical uses of estrogen?
- Hormone Replacement Therapy
- Oncology (anti-estrogens>>estrogens)
- Male to female transgender promotion
What are the systemic effects of estrogen?
- Ovaries : stimulate follicular growth; small doses cause an increase in weight of ovary; large doses cause atrophy
- Uterus: endometrial growth
- Vagina: cornification of epithelial cells with thickening and stratification of epithelium
- Cervix: increase of cervical mucous with a lowered viscosity (favoring sperm access)
- Development and maintenance of internal (fallopian tubes, uterus, vagina), and external genitalia.
- Mammary gland: Promotes ductal outgrowth and branching during puberty and in each mammary regenerative cycle.
- Skin: increase in vascularization, development of soft, textured and smooth skin
- Bone: increase osteoblastic activity
- Electrolytes: retention of Na+, Cl- and water by the kidney
- Cholesterol: hypocholesterolemic effect
What is the mechanism of estrogen as a contraceptive?
- Ectopic estrogen treatment mimics the negative feedback on the HPG axis resulting in reduced LH and FSH production.
- Many formulations include progesterone which help to offset unwanted side-effects of estrogens.
How is estrogen administered when used as a contraceptive?
Can be delivered orally or via injection, transdermally or placement of a time-release implant.
What types of breast cancer are tamoxifen and Arimidex
- Useful for hormone dependent breast cancer
What is the mechanism of action of Tamoxifen?
- Selective inhibitor of the hormone-binding domain of the estrogen receptor.
- Selective Estrogen Receptor Modulator (SERM) that has anti-estrogenic activity in certain tissues (e.g. mammary gland) and estrogenic activity in others (e.g. uterus).
- Has been shown to reduce the risk of breast cancer recurrence.
What is the mechanism of action of Arimidex?
- Blocks the enzymatic conversion of testosterone to estradiol.
- Results in sharp reduction in estrogen and a concurrent increase in testosterone.
What are the contraindications for estrogen use?
- Breast cancer
- Personal breast cancer history
- Familial breast cancer history
- In post-menopausal women HRT can increase the risk of ovarian cancer, breast cancer, stroke, dementia, blood clots.
What are the contraindications for anti-estrogen use?
- Uterine Cancer
- Personal uterine cancer history
What are the clinical uses of progesterone?
- Support pregnancy where there is a high risk of miscarriage.
- Counteract the thickening of the uterine lining caused by post-menopausal estrogen.
What are the clinical uses of Mifepristone?
1) Post-coital contraceptive => Interferes with progesterone signalingendometrial thickening and implantation
2) Abortifacient => Sufficient to cause miscarriage of implanted embryo in 1st trimester.
What are the contraindications for progesterone use?
What are the contraindications for Mifepristone?
Prolonged anti-coagulant use
Prolonged corticosteroid use.
What are the effects of testosterone and DHT?
-General growth promotion
-Thickening of skin and increases in sebaceous gland activity
-Thickening of vocal cords
-Skeletal growth and epiphysial closure of long bones (analbolic effect)
-Maturation of prostate and seminal vesicles
-Stimulation and maintenance of sexual function
-Increase in lean body mass (anabolic effect)
What are the effects of Androstenedione, DHEA and DHEAS?
- Support development of secondary sex characteristics
- Pubic hair
- Axillary hair
- Bone maturation
Why does circulating free testosterone decline with age?
- Decreased androgen biosynthesis
- Increased levels of Steroid Hormone Binding Globulin.
What are the symptoms of androgen deficiency?
-Low libido (with or without erectile dysfunction)
-Decreased strength, energy or stamina
-Increased irritability and/decreased enjoyment
-Alterations in cognitive function
-Androgens are metabolized to estrogens in bone, suggesting that bone loss associated with ADAM may be due to local decreases in estrogenic tone.
-Loss of muscle mass
-Increased visceral adipose
-Cardiovascular disease (onset and progression)
What are the testosterone esters?
- More gradual absorption and greater activity than testosterone. Given parenterally
What are the alkylated testosterones?
- Orally active (are associated with increased liver toxicity)
What are the clinical uses of androgen enhancement?
1) Androgen Replacement Therapy
- hypopituitarism and hypogonadism
- ADAM (aka andropause)
-Female to male transgender promotion
2) Gynecologic Disorders
- Post-partum breast engorgement
- Chemotherapy in ER-positive Breast tumors in pre-menopausal women (very rarely used)
3) As a protein anabolic agent following trauma or surgery
4) Anemia: Rarely used
5) Osteoporosis: Alone or with estrogens
6) Growth Stimulation: Delayed puberty in males
7) Anabolic Abuse in sports
8) Treatment of mammary hyperplasia and breast cancer