Hormone Replacement Therapy
skeletal
1-5% of ________ mass can be lost per year 1st 1-3 years after menopause
peak
A bone density test can be done that quantifies the bone mass of the individual, as compared to a young woman or man, depending on the sex of the patient who's having a test done at ______ bone mass.
20
A low estradiol level also helps diagnosis menopause, in an estradiol level of less than _____ is usually indicative of menopause. And that's an abnormally low estrogen level for a young woman who is not going through menopause. And so sometimes if you get an estrogen level that's also helpful.
Bisphosphonates
AE of which meds: Osteonecrosis of the jaw, "Frozen bone", atypical fracture, impaired healing after fracture, IV forms: Flu like symptoms, hypocalcemia
Should not
According to WHI and HERS, women who are relatively older and many years postmenopausal should/should not take oral HT for cardioprotection
Heart attacks, stroke, breast cancer and blood clots
According to the WHI what are the main things that estrogen + progestin increased?
10
According to the latest evidence, hormone therapy initiated fewer than _____ years after menopause lowered CHD in post-menopausal women
3
According to the national osteoporosis foundation, treatment is cost-effective for osteoporosis when the 10 year probability of hip fracture reaches ______% or the 10-year probability of osteoporotic fractures combined is greater than/equal to 20%
vertebral fracture (65%) and non-vertebral fracture risk (35%)
After 21 months, what does PTH reduce?
5
After _____ years with a stable BMD and no fracture with bisphosphonates: stop due to continued benefit of drug (drug holiday)
Bisphosphonates
Alendronate (Fosamax), Risendronate (Actonel), Ibandronate (Boniva) are oral forms available under which category of meds
progesterone
And _____________'s job is actually to help induce endometrial shedding at the end of the menstrual cycle. Estrogen builds, and progestin tends to oppose the action of estrogen and keep the endometrial lining thin and cause shedding of the endometrial lining.
standard deviations
And so a T-score of less than 2.5, that means 2 and 1/2 ______ ______ below that peak bone mass of young age, of young adulthood.
increased
Breast cancer: May depend on estrogen formulation, longer duration of use and increased/decreased risk
Yes- Fragility fracture at spine, hip, wrist, humerus, rub or pelvis (low impact fractures!)
Can a fragility fracture be a diagnosis for osteoporosis?
Alpha 2 adrenergic agonist, decreased hot flashes through CNS medication but not in all patients.
Clonidine can be used as an alternative to what? How does it work?
50
Effects of estrogen depletion: Bone- at age ______, bone remodeling increases with bone loss exceeding bone reformation
Esterfied estrogens + methyltestosterone is used to treat decreased libido/loss of libido or severe vasomotor disturbances.
Estratest HS is what and is used for what?
lowest (oral 17-beta estradiol 0.5 mg daily; 0.025 mg of transdermal estrogen)
Estrogen dosing is highest/lowest dose possible for symptom relief
1
For administrating estrogen cyclically: estrogen with __ week(s) daily with one week off & progestin 5-10 mg for 10-12 days of month
Goal 1200 mg/day; supplemental 500-1000 divided doses at meals
For osteoporosis, what is the adequate calcium/vitamin D intake?
Denosumab (Prolia)
For renal insufficiency, it is recommended up to stage 5 kidney disease but not first line tx.; use in bony mets
10
High risk (osteoporotic fx., T-score -3.5) continued tx. for _______ years
Urine, feces, and unchanged
How are bisphosphonates excreted?
By salivary hormone testing
How are compounded hormones often dosed?
Inhibits reabsorption of bone by osteoclasts, increases bone mass and reduces incidence of vertebral and non-vertebral fractures
How do bisphosphonates work?
7% vs. 3.6% in placebo
How do hot flashes compare to placebo with Ospemifene (Osphena)?
SQ every 6 months
How is Denosumab (Prolia) given?
Approved for only 2 years of treatment
How long is Teriparatide approved for?
400-800 IU per day
How much vitamin D to recommend to menopausal women?
At least 20 minutes
How much weight bearing exercise should post menopausal do per day?
Alendronate: For osteoporosis weekly or monthly. Preventative is weekly. Risendronate: Both osteo/preventative can be weekly or monthly Ibandronate: Osteo/preventative monthly
How often do dose alendronate, risendronate and ibandronate
If they're on a patch, you can decrease the dose of the patch to taper off, or you can keep the patch on for a longer interval. If they're taking oral preparations, you can decrease them to every other day then every third day and then stop. They will more than likely have an increase in symptoms. And so talking about the increase in symptoms that's tolerable or what to expect is important with a woman.
How to taper off HRT
Zoledronic Acid (Reclast): given once yearly; Denosumab (Prolia) every 6 months SQ, Teriparatide (Forteo)
If a patient has a CI to oral bisphosphonates, what are alternatives?
Topical therapy
If a woman is experiencing vaginal dryness, what should be used as treatment?
estrogen
If you give what I call unopposed ______ to a woman as HRT-- you give her ________ alone, and she has a uterus-- you are building, building, building the endometrial lining. And that continued building of the endometrial lining with estrogen alone can lead to abnormal cell growth and result in endometrial cancer. So never ever, ever, ever, ever give unopposed or __________ alone to a woman who has a uterus.
progesterone
In the menstrual cycle, _______ levels typically don't start to rise until the second half of the menstrual cycle.
NO: depending on what the ovaries are doing, sometimes you can have ovulation or not have the ovulation during the perimenopause. A low FSH is not inconclusive that the woman is not going through menopause. So that's when you go more to the history, the menstrual history and the symptoms that the woman is having to help confirm it.
Is a low FSH conclusive that a woman is not in menopause? Why?
No- no additional benefits noted and it may induce "Frozen bone"
Is combination therapy recommended for bisphosphonates?
No
Is estrogen recommended as first line prevention/treatment of osteoporosis?
estradiol (estrogen produced by the ovaries)
Menopause is characterized by rapid and progressive reduction in endogenous __________
the most appropriate window is really in that peri-menopausal women window in the ages of around the early 50s to the mid to late 50s
Most appropriate ages to prescribe HRT
Elestrin is a gel, and it's given and dosed in pumps. The Vivelle-Dot is a patch and so is Climara. And there are a gazillion generic formulations of the patches. The estrogen gel is brand name only.
Names of various estrogen formulations
SERMs
Net effect of ________: Improves bone density by 2-3% after 24 months of treatment, decreased vertebral fracture risk by 30-50% after 36 months treatment, also associated with decreased risk for BC
40
Premature ovarian failure (spontaneous ovarian insufficiency) is defined by loss of ovarian function prior to age ____
Hypocalcemia, serious skin infections, cautious use in poor kidney function (CrCl <30 mL/min)
SE of Denosumab (Prolia) include what?
7.4 years up to 10.4 years in AA women
Study of women's health across the nation duration of symptoms usually lasts how long?
True
T/F A lot of the evidence points to giving estrogen transdermally or as a gel or a lotion because you avoid the first pass effect of the liver. And it may be associated with a decrease in clot risk.
True
T/F Bone density is used as a marker for risk for fracture.
True
T/F Hormone therapy more than 10 years after menopause or >60 years: no risk reduction with HT, increase risk of stroke and VTE
True
T/F Oral HT should not be used to treat cardiovascular disease
True
T/F The probability of hip fracture for any given T-score is higher with increasing age
True
T/F The scientific efficacy and safety data is scant
True
T/F With progestin treatment, there is a decreased risk of estrogen-induced irregular bleeding, endometrial hyperplasia and carcinoma
Estrogen
The following are ABSOLUTE CIs for what: Known/suspected breast cancer, known/suspected endometrial cancer, undiagnosed genital bleeding, acute liver disease, active thromboembolic disease and known or suspected pregnancy
Hypocalcemia (drives calcium into bone), disorders of esophageal motility and inability to remain upright after dosing
The following are CI for what?
Estrogen
The following are relative CIs for what: Chronic liver dysfunction, uncontrolled/poorly controlled hypertension and acute intermittent porphyria
Osteoporosis
The following are risk factors for what: Age, previous fragility fracture/1st relative with fragility fracture, steroid use, weight <127 lbs., smoking, >2 alcoholic drinks daily, PMH: Inflammatory dx., malabsorption, ESRD, and dementia
17-beta estradiol associated with lower risk of stroke, VTE, and increased triglycerides
The transdermal estrogen is beneficial/detrimental how?
Bisphosphonates
These work by inhibiting the resorption of the bone by osteoclasts. By doing this, they will increase bone mass.
What is Raloxifene (Evista)- a SERM
This binds to estrogen receptors throughout the body, mimics estrogen action in bone, but blocks estrogen action in breast and uterus, associated with 2-3 fold increase in thromboembolic events as seen with estrogen
Ospemifene (Osphena)
This has estrogen agonistic effects on the endometrium and is used for treatment for moderate to severe dyspareunia of menopauses
Calcitonin
This inhibits the action of osteoclasts, increases bone mass and reduces fraction risk in spine, has an important analgesic action for pain associated with vertebral fractures****
osteoporosis
This is a decrease in bone mass and micro-architecture
1500
To maintain positive calcium balance in postmenopausal women requires ______ mg per day
>25-30 (may fluctuate in peri-menopausal patient) **remember, high FSH is helpful in diagnosing menopause
What FSH would you want when prescribing HRT?
HA, depression, gall bladder disease, N/V abdominal cramps, HTN, thromboembolic disease, breakthrough bleeding, edema, breast tenderness, risk of breast cancer/heart disease, increased serum triglycerides
What are AEs of estrogen?
bloating, abdominal cramps, edema, irritability, weight gain, HA, breakthrough bleeding, breast tenderness and acne
What are AEs of progestin?
Skeletal malignancy, hypercalcemia and previous bone radiation
What are CIs for PTH/Teriparatide (Forteo)?
Hot flashes, GI distress and leg cramps
What are SE of SERMS?
Dry mouth, dizziness, constipation and sedation ... can be troublesome
What are SEs of clonidine?
vaginal rings/tablets/creams; gels/lotion; transdermal
What are forms of estrogen HRT?
Micronized progesterone and Medryoxyprogesterone (Progestin)
What are forms of progesterone used?
Barbiturates, phenytoin (dilantin), carbamazepine (tegretol), and rifampin
What are medications that decrease levels of estrogen?
Hot flashes, night sweats, sleep disruption, increase in vaginal infections, UTI, vaginal dryness, cessation of menses, net loss of bone density, changes in cholesterol profile, stress incontinence and cognitive function changes
What are some symptoms seen as the net effect of menopause process?
Venlafaxine (Effexor) decreased hot flashes 21-64%; Paroxatine (Paxil) decreased hot flashes 62-64%; citalopram/sertraline, other SSRIs also appear helpful.
What are specific SSRIs/SNRIs that can improve hot flashes?
Relieve hot flashes, improve mood liability, improve sleep disturbances, treat vaginal atrophy, and help with joint aches/stiffness. Target hormone delivery to site and symptoms as much as possible.
What are the goals of hormonal replacement?
GU symptoms, hypogonadism (primary ovarian failure, early surgical menopause), prevention of bone loss, and vasomotor symptoms, transgender hormone therapy
What are the main FDA approved indications for HRT?
Improved symptoms in 25-38% vs. 28-19% in placebo arm (improved dyspareunia)
What did RCTs reveal about Ospemifene (Osphena)?
Hot flashes
What do SSRIs/SNRIs improve?
Correct calcium and vitamin D first
What do you need to correct first before treating with bisphosphonates?
Annual mammogram, breast exam, baseline LFTs, pap smear, lipid panel, risk review, discuss tapering
What do you need to monitor for HRT?
Calcium, phosphorus, BUN/Creatinine
What do you need to monitor if a patient has impaired renal function (CrCl <30) when taking bisphosphonates
Thyroid dysfunction and pregnancy as cause of amenorrhea; temperature fluctuations
What do you need to rule out when prescribing HRT?
900 mg/day effective dose; Randomized trial vs. placebo- reduced hot flashes 46-15%, pregabalin also helpful more expensive
What does the research reveal for Gabapentin (Neurontin)?
Typically, estrogen has a positive effect on the lipid panel, as far as HDL and LDL. Estrogen will tend to lower LDL and keep HDL high. And that's thought to be the previous benefit of estrogen in especially younger women against heart disease. Hence, during menopause, the depletion may cause opposite effect. However, depletion of estrogen DOES decrease triglycerides which is a benefit.
What effect does estrogen have on lipid panel?
Increased LDL cholesterol, decreased HDL and decreased triglycerides
What happens with liver and lipids in menopause?
Teriparatide (Forteo)
What is PTH medication name?
A selective estrogen receptor modulator (SERM)
What is Raloxifene (Evista) ?
part of HRT in women with an intact uterus
What is a necessary consideration in a patient taking medroxyprogesterone (Provera)?
They MUST have combined estrogen/prostin treatment !
What is a necessary stipulation with women with an intact uterus?
Ospemifene (Osphena)
What is an estrogen agonist/antagonist with tissue selective effects?
insufficiency: 10-30 ng/mL Deficiency: <10 ng/mL
What is an insufficiency vs. deficiency with Vitamin D?
52
What is average age of menopause?
Bisphosphonates
What is first line choice to treat/prevent osteoporosis?
0.625 mg conjugated estrogen will increase systemic levels and may induce endometrial proliferation * (need to give progestin with this)
What is high dose topical local estrogen? What may it cause?
HT is effective for treating vasomotor symptoms and vaginal dryness and for preventing osteoporosis
What is hormonal therapy effective for treating according to FDA guidelines?
0.3 mg conjugated estrogen will improve symptoms but not raise serum estradiol levels
What is low dose topical local estrogen? Will it raise estradiol levels?
Endometrial protection
What is progestin used for?
Breast exam and mammography, complete physical exam and history
What is required before prescribing HRT?
400-800 IU daily or ergocalciferol 50,000 IU weekly for 6-8 weeks
What is standard Vitamin D replacement?
Esophageal irritation; take with a full glass of water on an empty stomach. No other food or beverages /meds for 30 mins (risondronate and alendronate) or 60 mins (ibandronate). Remain upright/do not lie down after taking meds for 30 mins (risondronate and alendronate) or 60 mins (ibandronate), antacids interfere with absorption
What is the biggest SE of bisphosphonates? What is the patient teaching with this?
In women have had breast cancer and who are also taking tamoxifen: There are some women who have polymorphism. When they take the SSRIs, it can basically reduce the efficacy of the tamoxifen. So in women who are getting breast cancer treated with tamoxifen, these drugs may not be indicated. So you've got to look at the interaction between these two and women with breast cancer.
What is the caveat for women who have BC and tamoxifen?
200 Units nasally; daily cost for one month is $60
What is the dosage of calcitonin?
0.625 mg/1.25 mg
What is the dosage that you add Estratest HS to HRT?
10 years
What is the half life of bisphosphonates?
Lowest dose and shortest duration possible (5 years is considered the limit)
What is the limit for HT use?
Very low: 0.6%, impaired by another 60% if given with food.
What is the oral bioavailability for bisphosphonates?
TD route: Preferred due to less effect on vasculature: No difference in onset of symptom relief
What is the preferred administration of HRT?
Patients with breast cancer
What is topical local estrogen contraindicated in?
ETOH
What meds/drugs increases levels of estrogen?
estrogen
When ____ binds to osteoclasts, it decreases the activity of osteoclasts (net effect is decreased bone resorption)
PTH (parathyroid hormone)
When _______ is injected, bone formation predominates and bone mass improves significantly
In a history of thromboembolic event: DVT, pulmonary embolism. **DC for patient with prolonged immobilization
When are SERMS CI?
Nighttime average one every hour, daytime average 1-2 per day
When are hot flashes more frequent?
Reserved for those at "very high risk" of fracture who have failed other treatments for osteoporosis
When is Teriparatide used?
In patients with peanut allergies
When is oral micronized progesterone (prometrium) contraindicated?
Change will be slow- usually monitor one-two years after starting therapy
When to monitor bone density?
Titrate dose after one month treatment
When to titrate estrogen treatment?
Alendronate (Fosamax) and Risendronate (Actonel)
Which bisphosphonates have the strongest data on vertebral and hip fracture
FSH. As the ovaries fail and estrogen levels decline, the negative feedback loop of the endocrine system occurs. And so as estrogen levels fall, the FSH is going to become higher. The pituitary gland is going to raise FSH levels and tell the ovaries to get back to work. However, the ovaries are not listening because they're progressively declining basically due to normal aging in the most part. So when the FSH is high, usually over like about 35, that's very helpful in diagnosing menopause.
Which hormone do we use to monitor for FSH?
women who have had breast cancer, who have a risk for blood clots, who may have other contraindications for HRT such as smoking or clotting disorders
Which women would you want to consider alternatives for HRT?
Estrogen and progesterone
____ and _____ receptors in vasculature, restores normal vasodilatation responses: menopause dampens this response; decreased endothelial nitric oxide production post menopause
PTH (parathyroid hormone)
____ stimulates bone formation as well as resorption
Denosumab (Prolia)
_____ blocks osteoclast activation, thereby resulting in decreased bone resorption (less bone breakdown).
CAD
according to the Nurses Health Study, hysterectomy and BSO associated with increased incidence of ______
peri-menopause
characterized by normal ovulatory cycle interspersed with anovulatory cycles of varying length
estrogen continuous or take a week off the estrogen and then give progesterone for 10 to 12 days of the month to stabilize the endometrial lining when you take it like that, you'll tend to see some bleeding after the progestin.
for cycline estrogen/progestin what is the routine?
by subdermal implants, pellets or troches.
how can compounded hormones be administered?
Injectable
how is teriparatide administered?
every year
how often to evaluate if woman still needs HRT?
estrogen's
it's ____'s job to build up the lining of the endometrium to prepare it for a possible implantation.
Hot flashes
sudden sensation of heat in upper chest/face. Profuse perspiration/chills/papitations.
2-8
the __ to ___ years preceding menopause and the one year following the last menstrual period defines peri-menopause
FRAX risk assessment tool (used in addition to the T score)
this also factors in other risk factors such as age, smoking status, and previous use of steroids. And looking at their fracture risk for 10 years. So the National Osteoporosis Foundation says that treatment is cost-effective.
every day, the woman takes a combination of estrogen and progesterone. That's typically the easiest regimen because you don't have to worry about what day of the month that you're on, and it will tend to keep the endometrial lining thin. It will also avoid the cyclic bleeding that you'll get with cyclic progesterone.
what are benefits of continous combined HRT?
Breast, uro-genital tract, brain, liver, blood vessels, bone, connective tissue
what are the tissues that have estrogen receptors?
brain causes hot flashes
what does this process cause: centrally mediated and related to surges of LH and abnormal hypothalamic response to increased NE activity
>30 ng/mL
what is a normal vitamin D level?
FRAX risk assessment tool and threshold for treatment
what is a tool you can use to assess fracture risk?
It helps maintain and stabilize bone density
what is estrogen's role in bone density?
Secondary causes (Vitamin D, hypocalcemia, or PTH problems & steroid use)
what is it really important to rule out before treating for osteoporosis?
less than -2.5. Osteopenia: -1/5 to -2.5.
what is the T-score that defines osteoporosis? Osteopenia?
There is a tendency for the blood pressure to be higher and less elasticity within the blood vessels.
what is the effect on vasculature from estrogen depletion?
vasomotor symptoms
what is the first line therapy with the most efficacy?
bone health- risk of osteoporosis
what is the one big concern with low estrogen?
GnRH released by the hypothalamus
what stimulates the release of LH and FSH?
sleep disruption
what symptom may occur before hot flashes become apparent?
After age 65 for men and women
when do you start recommending 800-1000 IU of vitamin D?