Pharm MHT/SERM - Segars Flashcards
what do you see an increase in prevalence of during menopause?
- bone effects: osteopenia/osteoporosis/fractures
2. CV effects: ACS/MI/CVD
what is the primary therapy for menopausal symptoms?
estrogen
women with an intact uterus must also be on what??
PROGESTIN
- due to increased risk of endometrial hyperplasia/carcinoma from unopposed tissue proliferation with prolonged duration
what are the two most popular estrogenic forms of menopausal hormone therapy (MHT)?
- estradiol (tablet/vaginal ring)
2. conjugated estrogens (CE) - blend of 6 estrogen derivatives
what does progestin do?
it opposes estrogen’s effects
what are the 3 available progestinic MHT compounds?
- medroxyprogesterone (MPA)
- methyl testosterone (alone) or Covaryx (with EE)
- progesterone
what are the effects of estrogen?
endometrial proliferation
what does estrogen decrease the production of?
- cholesterol (TC.LDL-C)
- anti-thrombin III
- osteoclastic activity (bone turnover)
what does estrogen increase the production of?
- tryglycerides and HDL-C
- clotting factors
- platelet aggregation
- sodium/fluid retention
- thyroid binding globulin (TBG)
what were the objectives of hormone trial of Women’s Health Initiative (WHI) study?
examine MHT’s purported beneficial or preventative effects on heart disease, osteoporosis-related fractures, and risk of various cancers (breast, endometrial, and colon cancers)
what did the WHI study identify as harms of combined estrogen and progestin treatment? INCREASED risk of: (7)
- breast cancer
- CAD
- dementia
- gallbladder disease
- stroke
- venous thromboembolism
- urinary incontinence
what did the WHI study identify as benefits of combined estrogen and progestin treatment? DECREASED incidence of:
- colorectal cancer
- diabetes
- all fractures (decrease in osteoclastic activity)
what did the WHI study identify as harms of estrogen only treatment? INCREASED risk of: (5)
- dementia
- gallbladder disease
- stroke
- venous thromboembolism
- urinary incontinence
what did the WHI study identify as benefits of estrogen only treatment? DECREASED incidence of: (3)
- breast cancer
- diabetes
- all fractures
what is the summary message from the WHI findings?
MHT very effectively minimizes/treats vasomotor symptoms and vaginal changes (and their associated complications)
MHT is an acceptable option for treating moderate to severe menopausal symptoms for who?
relatively young (up to age 59 or within 10 years of menopause) and healthy women
when is low dose vaginal estrogen (topical) the preferred treatment?
for women with vaginal symptoms only
women who still have a uterus need to take what?
progestin along with estrogen to prevent uterine cancer
women who have had their uterus surgically removed are able to take what?
estrogen alone
both estrogen alone and combination therapy increase the risk of what?
blood clots
an increased risk of what, is seen within 3-5 years of continuous estrogen with progestin therapy?
breast cancer
if therapy is needed for moderate-severe vasomotor symptoms, what is the dose and duration?
- lowest dose possible to control sx
- treat for the shortest duration possible, and re-evaluate at least yearly
these drugs have beneficial pro-estrogenic (agonist) actions in select tissues with beneficial (or non-harmful) anti-estrogenic (antagonist) actions in other tissues
selective estrogen receptor modulators (SERM)
these drugs combine the unique elements of a SERM with an estrogen compound
tissue selective estrogen complex (TSEC)
ospemifene, clomiphene
SERMs
Bazedoxifene
TSEC
- currently only used as combo with CE
this drug is used to treat moderate-severe dyspareunia
- a sx of vulvar and vaginal atrophy (VVA) of menopause
osemifene
- topical estrogen cream
- or oral product tailored to more beneficial estrogen-like effects
this drug functions as estrogen agonist by binding to ER’s in vagina, but also anti-estrogenic on breast
- increases superficial cell growth (on vaginal smear), increases vaginal secretions, decreases vaginal pH, reduces pain/discomfort during intercourse
ospemifene
what are the side effects of ospemifene? (3)
- worsening hot flashes/sweating
- estrogenic-similar effects of coagulation (stroke/VTE demonstrated)
- endometrial thickening (proliferation)
what are the contraindications for ospemifene?
- unusual/abnormal vaginal bleeding
- thromboembolic disease (CVA, MI, VTE, PE, DVT)
- estrogen-related neoplasia (uterine, ovarian, breast)
this drug is used to treat:
- moderate-severe vasomotor symptoms associated with menopause in women with a uterus
- prevention of post-menopausal osteoporosis (along with Ca and vitD) in women with a uterus
Bazedoxifene (with CE)
antagonistic activity in endometrium (replaces progestin-concept in women with an intact uterus) and in breast tissue; but also estrogenic (agonist)
Bazedoxifene MOA
how is Bazedoxifene different than 1st generation SERMs?
- does not stimulate endometrial proliferation
- has been shown to destroy HER2 malignant cells (SERDs), including cells resistant to Tamoxifen, similar to anti-estrogen drug Fulvestrant
what is the main Bazedoxifene-specific side effect (other than estrogen-related effects)?
it has the potential of worsening hot flashes/sweating (similar to Tamoxifen, Raloxifene and Ospemifene)
what situation is Bazedoxifene contraindicated?
in all situations that estrogens are contraindicated (due to CE component)
- NOTE: Bazedoxifene is ONLY available as a complex in the US
Clomiphene
anti-estrogen
what is the indication for clomiphene?
infertility in anovulatory women
- used to stimulate ovulation
- dose orally between cycle-days 5-9
what is the MOA of clomiphene?
most significant effect on induction of ovulation in women with amenorrhea, PCOS, and dysfunctional bleeding with anovulatory cycles
what does Segars especially want us to know about the MOA of clomiphene?
it primarily blocks inhibitory actions of estrogen on hypothalamus GnRH and pituitary gonadotropin release
- increases gonadotropin secretion thereby stimulating the ovaries to develop oocyte follicles
what are the side effects of clomiphene?
- multiple births
- ovarian cytst (ovarian cancer with prolonged use)
- hot flashes
- luteal-phase dysfunction
