OPT 212 Drugs Affecting the Endocrine system (ESTROGENS AND ANDORGENS)

What produces the sex hormones?

gonads

What are the sex hormones necessary for?

conception, embryonic maturation and development at puberty

What is the therapeutic use of sex hormones?

-hormone replacement
-infertility
-contraception
-management of menopausal symptoms
-cancer therapy
-abortifacients

GnRH is released from the hypothalamus. What does it stimulate the anterior pituitary to release?

-LH
-FSH

What does FSH do in females?

control follicular development and maturation

What does LH do in females?

controls the production of estradiol which produces ovulation and maintains the corpus luteum

What does FSH do in males?

controls spermatogenesis

What does LH do in males?

controls testosterone production

What controls GnRH release from the hypothalamus?

feedback loop; increase in testosterone and estrogen cause a reduction in the release of GnRH

What are analogs of GnRH?

-leuprolide
-gonadorelin
-nafarelin

What does pulse cause an increase in?

production of FSH and LH

What is the result of GnRH in males?

stimulate spermatogenesis and testosterone production

What is the result of GnRH in females?

induce ovulation or treat primary hypothalamic amenorrhea

What does chronic administration of GnRH analogs lead to?

decrease in production of FSH and LH (due to ecrease in receptor density)

What are GnRH analogs used for in males?

treatment of advanced prostate cancer and prostatic hyperplasia

What are GnRH analogs used for in females?

treatment of endometriosis, polycystic ovary disease, and other uterine disorders

What is the most potent estrogen?

estradiol; it is the principal estrogen in the premenopausal women

What is the primary circulating estrogen after menopause?

estrone

What is the form of estrogen that is produced by the placenta?

estriol (present in significant amounts during pregnancy)

What are therapeutic uses of estrogens?

-contraception
-infertility
-hormone therapy
-stimulate development in young women with hypogonadism (combined with progesterone)
-treatment of premature menopause or premature ovarian failure
-treatment of osteoporosis
-treatment of cancer

Why is estrogen used for hormone therapy?

-relieves menopausal symptoms
-combines with progesterone for women with intact uterus
-dose is less than that for contraception

Why is estrogen not always effective orally?

most undergo extensive first pass metabolism; this is why synthetic compounds are more effective

What are selective estrogen receptor modulators?

non steroidal compounds that bind to estrogen receptors

What is the mechanism of action of estrogen hormones?

diffuse across cell membrane and bind to specific nuclear receptor proteins (estrogen receptors)

What are adverse effects of estrogen?

-uterine bleeding
-endometrial cancer risk (given with progesterone to decrease risk)
-thromboembolism
-myocardial infarction
-hypertension
-headache
-peripheral edema
-nausea

What do selective estrogen receptor modulators do?

interact at estrogen receptors (have different effects depending on the tissues)

What are examples of SERMs?

-tamoxifen
-raloxifene
-clomiphene

What is the mechanism of action of tamoxifen and raloxifene?

compete with estrogen for binding in breast tissue (antagonist)
-causes regression in some breast tumors
-tamoxifen is an agonist in the uterus and has been shown to increase risk of uterine cancer

What is the mechanism of action of raloxifine?

decreases bone reabsorption and overall bone turnover (acts as an agonist in bone)
-little effect on endometrium, lower risk of uterine cancer

What is the mechanism of action of clomiphene?

acts as a partial estrogen agonist at all receptor types; major action is to block estrogen mediated negative feedback in the pituitary (increases amplitude of LH and FSH pulses and induced ovulation/spermatogenesis)

What are therapeutic uses of SERMs?

-palliative treatment of metastatic breast cancer
-post mastectomy or radiation
-prevention and treatment of osteoporosis
-infertility associated with anovulatory cycles

What are adverse effects of SERMs?

-hot flashes and nausea
-many drug interactions
-increased risk of thrombosis and embolism with raloxifene
-ocular side effects with tamoxifen

What are examples of ocular side effects associated with tamoxifen?

-crystalline retinopathy
-macular edema
-corneal opacities
-cataract
-optic neuritis

What is progesterone produced in response to?

LH in both males and females (also in the adrenal cortex)

What does progesterone do in females?

promotes development of secretory endometrium
-accommodate implantation of embryo
-continued to be secreted if conception takes place (inhibits production of gonadotropin; prevent further ovulation)

What is the normal menstrual cycle?

-pulse release of GnRH
-production of FSH and LH
-production of estrogens
-LH surge results in ovulation and production of progesterone

What does the feedback loop do initially when estrogen is produced?

decrease release of GnRH, then causes surge in LH release

What does the feedback loop do when LH surges?

feedback loop to decrease release of GnRH

What are therapeutic uses of progestogens?

-treatment of hormonal deficiency
-contraception
-used to control dysfunctional uterine bleeding

Why are progestogens used with estrogens in contraception?

rapidly metabolized if used by itself

What is useful about synthetic progestogens?

more stable to first mass metabolism

What are adverse effects of progestogens?

-headache
-depression
-weight gain
-some can cause acne
-changes in libido

What are some mechanisms for contraceptives?

-prevent ovulation (most common)
-impair gametogenesis or gamete maturation
-interfere with gestation

What is the most common combination of oral contraceptives?

-estrogen
-progestin

*last seven days are placebo

What is meant by monophasic?

constant dose of estrogen and progestin given over 21 days

What is meant by triphasic?

attempt to mimic natural cycle; constant dose of estrogen with increasing progestin over three successive weeks

What is a transdermal patch?

patch containing ethinyl estradiol and norelgestromin; one patch applied each week for 3 weeks

slightly increased risk of adverse effects

When is a transdermal patch less effective?

if weight over 90 kg (198 lbs)

What is the progestin only pill?

norethindrone; taken daily, less effective than combination; used for women who are breast feeding, intolerant to estrogen, or smokers

What is injectable progestin?

medroxyprogesterone acetate administered every 3 months

What is common with injectable progestin?

weight gain

What is possible if injectable progestin is continued for more than 2 years?

-return to fertility may be delayed
-may contribute to bone loss and predispose patients to osteoporosis and/or fractures

What are progestin implants?

subdermal implant of etonogestrel (lasts for 3 years); nearly as reliable as sterilization but it is reversible

What is emergency contraception?

-high dose of progestin (0.75 mg levonorgesterol)
-high dose estrogen plus progestin (100 ug ethinyl estradiol with 0.5 mg levonorgestrel)

must be administered within 72 hours

What is the mechanism of action of contraceptives?

-suppresses ovulation by feedback inhibition of the hypothalamus and pituitary
-estrogen suppresses FSH
-progestin suppresses LH
-also directly cause cerival thickening

What are adverse effects of contraceptives?

-fluid retention
-headache
-nausea
-vomiting
-thromboembolism
-thrombophlebitis
-hypertension
-increased Incidence of MI
-cerebral and coronary thrombosis

*most due to estrogen component

What are other adverse effects of contraceptives?

-may increase risk of cervical cancer (but decrease risk of endometrial and ovarian cancer)
-abnormal glucose tolerance
-weight gain
-estrogen causes increase in HDL and decrease in LDL

What are andorgens?

steroid hormones that have anabolic and/or androgenic effects in both males and females

Where are androgens produced?

testes, ovaries, and adrenal glands

What is the most important androgen in humans?

testosterone

Why are androgens considered anabolic?

-promote bone growth and prevent reabsorption
-development of internal genitalia
-increases muscle mass

Why are androgenic considered anabolic?

development of male secondary sexual characteristics

What is the mechanism of action of androgens (testosterone)?

bind to specific nuclear receptor; testosterone itself is active ligand in muscle and liver

hormone receptor complex binds to DNA and stimulates the synthesis of specific RNAs and proteins

Why is testosterone used for males therapeutically?

used for males with inadequate androgen secretion

Why are testosterone used therapeutically for the anabolic effects?

treat osteoporosis and chronic wasting associated with HIV or cancer; sometimes used in adjunct therapy in severe burn and to speed recovery from surgery or chronic debilitating diseases

What is the main use of testosterone?

treatment of male hypogonadism

What is an unapproved use of testosterone?

used to increase lean body mass, muscle strength, and endurance (anti aging or performance enhancer)

there is no evidence that it improved athletic performance at normal therapeutic doses

What are the pharmacokinetics of testosterone?

-ineffective orally (inactivated by first pass metabolism)
-metabolized quickly and eliminated though urine

derivatives have different structure and allow for oral administration (fluoxymesterone and oxandrolone)

What are adverse effects of testosterone?

-masculinization
-acne
-growth of facial hair
-deepening of the voice
-male pattern baldness
-excessive muscle development

in both genders

What are adverse effects of testosterone in males?

-priapism
-impotence
-decreased spermatogenesis
-gynecomastia
-stimulate growth of prostate

What are adverse effects of testosterone in children?

abnormal sexual maturation and growth disturbances

What are adverse effects of testosterone in general?

-increase LDL and lower HDL (increase risk for coronary heart disease)
-fluid retention
-increased aggression
-mood disorders

What are antiandrogens?

androgen receptor antagonists

What are bicalutamide and nilutamide used for?

treatment for BPH and/or prostate cancer

usually combined with GnRH analog to decrease LH and testosterone production

What is flutamide used for?

blocks action of testosterone in target organs (treatment of prostatic carcinoma)