androgens, estrogens, progestins

hypothalamus releases GnRH, goes to anterior pituitary that releases LH and FSH, which then go to the gonads for the sex hormone release, then to target cells

HPG axis

hormone transport, Circulate Freely or Bound——-(SHBG)- regulates availability and activity in body

sex hormone binding globulin

regulates sex hormones availability and activity in body

feedback mechanism

Metabolic Transformation - liver(main site), periphery, Metabolic Clearance - undergo urinary secretion, liver, saliva, sweat, brain

removal of hormone from circulation

gonads release —— = target tissue product, which then go to other tissues and accessory sex organs

inhibin, sex steroids

luteinizing hormone (LH) for females does:

ovulation, corpus luteum

follicular stimulating hormone (FSH) for females does:

follicle development, estradiol, progesterone

luteinizing hormone (LH) gives way to leydig cells in males that then produces 

testosterone 

follicular stimulating hormone (FSH) gives way to Sertoli cells that then gives way to

spermatogenesis

Preovulatory surge of estrogen: —-feedback.

positive

Androgens and estrogens: —-feedback

negative

negative feedback on FSH secretion by the pituitary

inhibin 

bind to G coupled protein receptors - cell membrane receptor, Signal transduction, Can activate or repress gene transcription, Binding of hormone to its receptor leads to synthesis and secretion of hormones

GnRH, LH, FSH

is normally secreted in pulsatile manner (released in bursts as opposed to steadily)

GnRH

stimulates FSH and LH release in a non pulsatile manner causes continuous stimulation of the gonadtrophs receptors and causes down regulation of GnRH receptors on gonadotrophs (clinical use)

GnRH agonists 

Palliative therapy and treatment of advanced prostate cancer and premenopausal hormone receptor-positive (HR+) advanced breast Avoid premature LH surge (ovulation) in in-vitro fertilization (IVF protocols), Suppress/delay puberty in gender-questioning and transgender youth (off-label), Suppress steroid-responsive condition: endometriosis, uterine fibroids, acute, intermittent porphyria, priapism, Pharmacological castration (e.g., precocious puberty), Test hypothalamic vs. pituitary defects in diagnoses of hypogonadotropic hypogonadism (HH)

GnRH agonists 

GnRH agonist, ultimately causes a down-regulation of production of LH and FSH and a resultant decrease in testosterone and estrogen levels (desensitization of GnRH receptor), releases sex hormones in a non pulsatile manner, (Zoladex)

goserelin

Adverse Effects: bone pain, hot flashes, sweating, decreased bone density, decreased libido, dizziness, vertigo, insomnia, headaches, Females: Typical symptoms of menopause: depression, generalized pain, vaginal dryness might occur, Males: erectile dysfunction

GnRH agonists

GnRH agonists therapy in non-life-threatening diseases (e.g. endometriosis, uterine fibroids) typically limited to—

6 mo

GnRH agonists can decrease efficacy of —

androgen therapy

Contraindications: pregnancy, breast-feeding, osteoporosis, undiagnosed abnormal vaginal bleeding

GnRH agonists

GnRH antagonist, Inhibit premature (LH) surges in women undergoing ovarian hyperstimulation with FSH and human chorionic gonadotropin (hCG), followed by subsequent Assisted Reproductive Technology (ART) procedures, administer mid to late follicular phase of menstrual cycle. Inhibits the secretion of LH>>FSH in a dose dependent manner, (Antagon, Cetrorelix, Cetrotide)

ganirelix

adverse effects of ganrelix:

nausea, headaches, anaphylaxis

Contraindications: primary ovarian failure, pregnancy, breast feeding

GnRH antagonists

target this molecularly to lower estrogen

androstenedione

converts testosterone to dihydrotestosterone (DHT) - more potent than testosterone 

5a reductase 

Function as molecular switches in response to hormone binding, Hormone (androgen, estrogen) diffuses through the cell membrane binds to receptor in the cytoplasm, The hormone bound receptor can now travel to the nucleus through a nuclear pore, The hormone bound receptor binds to its hormone receptor element (HRE) located on DNA, Binding of the hormone bound receptor to HRE leads to modulation of gene transcription

nuclear receptor

androgen cell for males, cells of the testes, Adrenal gland

leydig

androgen cell for women, cells of the ovarian follicle, Adrenal gland

theca

symptoms of adult male hypogonadism:

infertility, small prostate and testes, gynecomastia

Symptoms: Delayed onset of puberty, Lack of facial or body hair development, Shortness of stature, Underdeveloped testicles and penis

adolescent male hypogonadism

(Covaryx) - testosterone analog, tx for adult male hypogonadism

methyltestosterone 

routes include: transdermally, injections, gel, buccal, implantable pellets, orally

methyltestosterone

oral methyltestosterone has the possibility for —- in long term use

liver problems

androgen receptor antagonist, in conjunction with GnRH analogs to treat metastatic prostate cancer, Treatment for Hirsutism in women (due to hepatoxicity should not be used for cosmetic purposes), (EVLEXIN)

flutamide

5a-DHT synthesis inhibitor (5a reductase inhibitor), (Proscar, Propecia), Used to treat benign prostatic hypertrophy and male patterned baldness, Use in women: Treatment for polycystic ovary syndrome (PCOS), Contraindicated for women of childbearing age: Can cause birth defects in male children

finasteride 

5a-DHT synthesis inhibitor (5a reductase inhibitor), (Avodart), Used to treat benign prostatic hypertrophy and male patterned baldness

dutasteride

Potential Side Effects of Excessive ——: Reduced spermatogenesis and fertility due to feedback inhibition of LH and FSH secretion from anterior pituitary, Acne, particularly in women due to androgen stimulation of sebaceous glands beneath skin, Virilization (including facial hair and hirsutism) in women and children, In older men, increased risk of benign prostate hyperplasia and prostate cancer, Hepatotoxicity ( for testosterone derivatives )

androgen treatment

disrupts the normal production of hormones in the body, causing both reversible and irreversible changes

anabolic steroid and androgen abuse

website for anabolic steroid and androgen abuse: ———NIDA.NIH.GOV

national institute on drug abuse

17 β-estradiol (estradiol), Produced by the Leydig cells and in adipose tissues, Growth spurt, skeletal maturation, epiphyseal plate closure, maturation of sperm

estrogen in men

(estradiol) principal estrogen premenopausal

17 b-estradiol

primary circulating estrogen post menopause

estrone

Principal estrogen produced by the placenta

estriol

Development of female sex organs and secondary sex characteristics, regulate menstrual cycle, skeletal maturation, mood, neuroprotection

estrogen 

agonist at the estrogen receptor, used for hormone replacement therapy in women, Usually occurs in late 40s, early 50s, Estrogen and progesterone levels decline, Since estrogen plays other roles within the body, other systems are affected

ethinyl estradiol

progestin hormone replacement therapy drug:

medroxyprogesterone

s/s of menopause:

hot flashes, changed sleep, mood swings, headaches, heart palpitations, itching

Side effects: Nausea, fluid retention, breakthrough bleeding, change in menstrual flow, breast tenderness, Adverse Effects: Thrombolytic complications; endometrial carcinoma; breast carcinoma; and hypertension, In men feminization of genitalia & impotence.

therapeutic estrogen

Contraindications: Pregnancy, incomplete bone growth, undiagnosed genital bleeding; stroke, thrombophlebitis, or thromboembolic disease, heart disease, Women with family history of breast or uterine cancer (BRCA gene)

therapeutic estrogen

Drug Interactions: decrease efficacy of hypoglycemic agents, increase adverse effects of tricyclic antidepressants

therapeutic estrogen

may cause loss of contraceptive or hormonal-replacement efficacy of estrogens

st john wort

display selective agonism or antagonism according to different tissues, used for cancer chemotherapy, prevent and treat osteoporosis, and fertility

SERMs

SERM stands for

selective estrogen receptor modulators

how SERMs is possible: Estrogen receptors (ER), ER-α and ER-β show —-

differential tissue expression

how SERMs is possible: —— ranging between pro-estrogenic, partially estrogenic and anti-estrogenic effects

tissue dependent responses

SERM drug used for cancer chemotherapy

tamoxifen 

good effects: reduces breast cancer risk, lowers LDL, strengthens bone, bad effects: increases uterine cancer risk, increased blood clot risk (2-3x increased risk for DVT and PE)

tamoxifen

SERM drug, Fertility induction of ovulation in women with an intact hypothalamic-pituitary-ovarian axis, Oppose the negative feedback effects of endogenous estrogen. Increases GnRH and therefore increases the amplitude of the LH and FSH pulses, Adverse effects: multiple births, ovarian cysts

clomiphene

SERM drug, Used off-label by men to treat both male infertility and secondary hypogonadism because it increases serum testosterone levels, Abused by health athletes for performance enhancement

clomiphene

third generation SERM, (Duavee): combination therapy, First modern HRT therapy without a progestin for postmenopausal women with an intact uterus – reduced risk of breast tenderness compared to traditional HRT

bazedoxifene

anti estrogen, ICI 182,870 (FASLODEX), pure estrogen antagonist, effective in treating tamoxifen-resistant tumors, no gene activation

fulvestrant

estrogen synthesis inhibitor, (Femara)- aromatase inhibitor, Specifically block the local production of estrogens in hormonally-responsive tissues, Second-line treatment for breast cancer in patients whom tamoxifen therapy is unsuccessful, but new studies rapidly proving its efficacy and promoting earlier use

letrozole

Aromatase inhibitors (——-)do not have the bone protecting activity of tamoxifen, and adjuvant therapies to prevent bone loss are in trials

letrozole

Produced in response to LH, Secreted by the testes and adrenal gland

progesterone

Produced in response to LH, Secreted by the corpus luteum, placenta and adrenal gland

progesterone

used for birth control, menstrual cycles, Other Conditions: Help maintain pregnancies (during low progesterone production), Counteracts estrogen effect on thickening of the uterine lining during HRT, Treat pain related to endometriosis, Stimulate appetite in AIDS or cancer patients

progestins

19-nor testosterone derivatives display primarily progestational rather than androgenic activity - form of therapeutic progesterone

synthetic progestins 

first generation progestin:

norethindrone

second and third generation progesterone, replacement of the 13-methyl group of norethindrone with a 13-ethyl substituent are more potent progestins and less androgenic:

levonorgestrel, drospirenone

Early HRT used estrogen alone: increased risk of uterine (endometrial) cancer. As a result, addition of progestin is now used to limit endometrial hyperplasia,—— (MPA) is most used. - HRT formulation

medroxyprogesterone acetate

Combos of estrogens with —-: FEM HRT (estradiol plus norethindrone acetate), ORTH PREFEST (estradiol plus norgestimate)

progestins 

(PREMARIN) or a ring device (ESTRING) can be used instead of oral doses . Reduces vaginal dryness, yeast infections and urinary tract infections - HRT formulation

vaginal creams

oral formulations of progesterone only contraceptives:

norethindrone, levonorgestrel

progestin only contraceptive, of etonogestrel (Nexplanon) for slow-release and long-term contraceptive actions (up to four years)

subdermal implant

progestin only contraceptive, IM injection that lasts up to 3 months 

medroxyprogesterone 

progestin only contraceptive, that releases low amounts of progesterone locally (Mirena lasts up to 8 years), intrauterine device

IUD

other beneficial effects of ——: Decreases Dysmenorrhea, Decreases benign breast and ovarian cysts, Regulates cycle in anovulatory women, Decreased blood loss during menstruation, Reduction in ovarian and endometrial cancer

oral contraceptives

estrogen contraception, Absorbed efficiently in GI tract. Mestranol is biologically inactive and must be metabolized, Peak plasma levels within 1 hr after oral administration

ethinyl estradiol 

progestin contraception, Removal of 19-carbon changed major hormonal effect from an androgen to progestin while maintaining oral activity, includes: estranes, gonanes

19-NOR steroids

progestin contraception: 19-NOR steroid, have some androgenic activity as well as estrogenic/anti-estrogenic actions, Rapidly absorbed (norethindrone)

estrane

progestin contraception: 19-NOR steroid, More potent than estranes and less androgenic activity and are now used in the 3rd generation combination oral contraceptives, (norgestrel, norgestimate, levonorgestrel, drospirenone- helps with water retention)

gonanes

combined oral contraceptive, Fixed concentrations of estrogen and progestin, which is taken for 21 days followed by 7 days of “hormone-free” pills

monophasic

combined oral contraceptive, Fixed concentration of estrogen with 2 different concentration of progestin. Lower concentration in the first 1-14 days and then higher concentration for the next 15 – 21 days. followed by 7 days of “hormone-free” pills.

biphasic

combined oral contraceptive, Fixed concentration of estrogen with 3 different concentrations of progestin. Lower concentration in the first 1-6 days and then higher concentration for the next 7-11 days. Then highest dose 12-21 days followed by 7 days of “hormone-free” pills.

triphasic 

extended cycle birth control pill, Advantages, Period once every 3 months, Period last about 3 days with decreased bleeding, Side Effects: Breakthrough bleeding and spotting, 84/7 formulation

levonorgestrel, ethinyl estradiol

prevents pregnancy by delaying or inhibiting ovulation, or release of an egg, regimens are highly effective and decrease the risk of pregnancy by 75%, must be taken within 3 days

emergency contraception

Two products are available: Plan B: 0.75 mg levonorgestrel, Preven: 0.25 mg levonorgestrel and 0.05 mg ethinyl estradiol (this product includes a pregnancy test kit)

emergency contraception

Drugs that disrupt liver metabolism and increase estrogen metabolism in—-, Anti-seizure medications, St. John’s wort, Anti-tuberculosis drugs such as rifampin, HIV protease inhibitors

oral contraceptives 

effect the activity of other drugs, anticoagulants – increases effectiveness, benzodiazepines - inhibit metabolism in some benzodiazepines, beta-blockers - inhibit metabolism in some benzodiazepines, corticosteroids, tricyclic antidepressants – increase levels in the blood; therefore, higher risk of toxicity and side effects

oral contraceptives

absolute contraindication for contraceptives with estrogen in it, these people can only use progestin only contraceptives

smokers over 35