Unit 1 - Pharmacology of Reproduction Flashcards
early follicular phase happenings
days 1-7
- menstruation occurs at the beginning of the follicular phase
- FSH and LH levels are increased relative to baseline
- estrogen and progesterone levels are low
late follicular phase happenings
days 7-14
- growth, maturation of ovarian follicles, and one follicle becomes dominant in growth and hormone escretion
- FSH levels decrease due to negative feedback
- estrogen levels increase due to positive feedback
- progesterone levels remain low
- endometrial lining continues to grow and thicken
pre-ovulation and ovulation happenings
days 13-14
-LH surge stimulates follicular rupture and ovulation occurs within 48 hours
luteal phase happenings
ruptured follicle develops into corpus luteum that makes large amounts of progesterone and estrogen
- progesterone facilitates thickening of endometrial lining and development of blood vessels
- absence of fertilization, the corpus luteum begins to degenerate and ceases hormone production
- thus levels of estrogen and progesterone drop, and menstruation occurs
what are the different levels of estrogens?
- natural estrogens (E1/2/3)
- synthetic estrogens
- steroidal synthetic estrogens
- nonsteroidal synthetic estrogens
all differ by their R2/3 side chains (C3/17)
what is the primary source of estradiol in premenopausal women?
ovary
- granulosa cells of ovarian follicles make estrogens
- estradiol can be converted to estrone and estriol in liver
- estrogens converted from androstenedione and testosterone in ovaries or in other tissues
what are examples of synthetic steroidal estrogens in use?
- estradiol esters - estradiol valerate, estradiol cypionate
- conjugated estrogens - estrone sulfate, equilin sulfate
- aklyl estrogens - ethinyl estradiol, mestranol
what is the major circulating estrogen in premenopausal women, men, and postmenopausal women?
pre: estradiol
men/post: estrone
where is aromatase expressed?
estrogen-producing cells of ovaries, placenta, adrenal gland, adipose tissue, testicles, and brain
what are examples of nonsteroidal synthetic estrogens?
- diethylstilbestrol (DES) was reported to increase risk of clear cell adenocarcinoma in vagina and cervix
- chlorotrianisene
- methallenestril
pharmocokinetics of estrogens
absorbed through skin, mucous membranes, and GIT
-in circulation, bind to SHBG (sex-hormone binding globulin), and albumin with lower affinity
pharmacokinetics of E2
mainly metabolized in liver to E1
- significant amounts of estrogens and active metabolites are excreted in bile and reabsorbed from intestine
- estradiol is not used orally frequently due to extensive first pass effect
- -micronization increases t 1/2 of E2 and reduces GIT destruction
- excretion of inactive metabolites occurs via urine
effects of estrogen on female maturation and reproductive system
develpoment of secondary sexual characteristics and sexual organs
- stimulates proliferation of endometrium and follicular growth
- stimulates breast cell growth
- induces synthesis of progesterone receptors
negative feedback of estrogen
high estrogen causes negative feedback loop on anterior pituitary and hypothalamus to slow release of FSH and estrogen
positive feedback of estrogen
high concentrations at end of follicular phase to positively regulate pituiary to trigger FSH and LH release that causes ovary to produce more estrogen
-high estrogen and LH cause ovulation
cardiovascular effects of estrogen
“estrogen-alone” hormone therapy has no effect on CHD, but increases the risk of stroke and deep vein thrombosis in postmenopausal women
effects of estrogen on lipoprotein
increase HDL and decrease LDL levels
how is estrogen used as contraception
synthetic estrogen like ethinyl estrodiol (steroidal alkyl estrogen) is used with progestin to prevent pregnancy
postmenopausal hormone therapy?
give estrogen to reduce postmenopause symptoms like hot flashes, atrophic vaginitis, and osteoporosis
what are common adverse effects of estrogen therapy?
nausea, breast tension/pain, vaginal bleeding, headache, weight gain, HTN
relationship between estrogen therapy and breast/cervical/endometrial cancers
breast: controversial; previous showed increased risk with >5 year use, but recently no increase with estrogen alone
cervical: may increase
endometrial: may increase
relationship between estrogen therapy and HA, stroke, GB disease
increases risk of all
contraindications of estrogen therapy
strongly contraindicated if breast/endometrial cancer, endometriosis, and undiagnosed vaginal bleeding
-generally contraindicated if pregnant, thromboembolic disease, HTN, hepatic disease, or family history of breast/uterine cancer
what are antiestrogen therapeutics and example?
compounds that are estrogen receptor competitive antagonists (or partial agonists in some setting)
-include tamoxifen citrate and clomiphene citrate
affinity of tamoxifen for ER?
estrogen has much higher binding affinity for its receptor than Tamoxifen
- must be used in concentration much higher than estrogen to maintain inhibition of breast cancer cells
- given orally, 10-20 mg 2x daily, with 7-14 hour halflife
clomiphene citrate isomers
cis: zuclomiphene (weak estrogen agonist)
trans: enclomiphene (potent antagonist)
where is progesterone made?
secreted in females by CL of ovary
-in pregnancy, high levels are made and secreted by placenta
males make it in the testes
-adrenal cortex makes it in both sexes
-production is stimulated by LH and gonadotropin
physiological functions of progesterone
stimulates endometrium to develop secretory glands and support fertilized egg implantation
- low levels in first several weeks lead to miscarriage
- can suppress endometrial cancers b/c long-term use atrophies emdometrium
- high levels trigger negative FB on hypothalamus to stop releasing gonadotropin and suppress ovulation
what are the 2 general uses of progestins?
- contraception - used in combo with estrogens or in progestin-only methods
- hormone replacement therapy - postmenopausal women
- counters endometrial stimulatory effects of estrogen and reduces risk of endometrial cancer
what are the two types of progestins?
- natural (micronized and transvaginal)
2. synthetic
