Sex Steroids and HRT Flashcards by Halei Moody

All sex hormones in humans share a common ________

synthetic pathway
(they are structurally related to adrenal steroids)

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Estrogens (E) are …

female sex hormone, mainly E2

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Progestins (P) are …

hormones that promote gestation, mainly progesterone

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Androgens are ..

male sex hormones, mainly testosterone (T)

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Native hormones have good/poor oral bioavailability?

POOR
(rapidly metabolized in liver)

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Synthetic derivatives of hormones have good/poor bioavailability?

GOOD
(orally effective with longer DOA)

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Active metabolites of E and T are …

used as drugs

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What kind of receptors do sex hormones have?

nuclear transcription factor receptors
(effects by protein synthesis)
Distinct E, P and T R (response elements provide specificity)
Drugs may be agonists or antagonists of these R

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Estrogens stimulate growth of

endometrium

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Progestins inhibit

endometrial growth

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Progestins maintain

vascular supply and secretory capacity and pregnancy

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progesterone withdrawal leads to

menstruation (or absorption)

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E and P decline markedly at menopause but are still produced at low levels by

non-ovarian tissues

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Estrogen physiological effects

sexual maturation, 2nd sex characteristics
stimulation of long bone growth, closure of epiphyses
decrease bone resorption throughout adulthood
improves lipid profiles
increase risk of blood clotting and thromboembolic diseases (stimulates liver enzymes involved in clotting)

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Uses of Estrogen as replacement therapy

hypogonadism/
hypopituitarism (low dose for growth promotion, THEN higher doses for epiphyseal closure and sex dev at puberty) ** setting where estrogen alone is safe **
postmenopausal or after oophorectomy (in combo w/ progestins)

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Uses of estrogen as suppressive therapy

birth control (in combo with progestins)
menstrual disorders

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estrogens can be used for _____ therapy and ______ therapy

replacement; suppressive

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What are 3 available preparations of estrogen?

estradiol
conjugated estrogens
Ethinyl estradiol (EE2)

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Estradiol has three forms and include:

oral, IM, topical

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What two things is estradiol mainly used for?

HRT, hypogonadism

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Oral estradiol is orally bioavailable, rapidly absorbed and evades …

the extensive hepatic first pass metabolism of conventional estradiol

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Explain estradiol IM form

it is a slow-release “depot” forms (FA esters) – slow release of estrogen over time

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What are some examples of topical form of estradiol?

vaginal cream, transdermal patches

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What is the main use for conjugated estrogens?

HRT

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Admin of conjugated estrogens include?

oral, IV, IM, vaginal

Is conjugated estrogen a natural prep?

YES, it is the most common of several natural preps (it contains conjugates of E3 active metabolites -- estrone and estriol)

Ethinyl estradiol (EE2) is synthetic estrogen used in

nearly ALL oral contraceptives and HRT

What is the benefit of the ethinyl group in ethinyl estradiol?

increases oral bioavailability, slows clearance, increases potency (relative to estradiol)

conjugated estrogens are natural/synthetic?

natural

ethinyl estradiol is natural/synthetic?

synthetic

MC side effects of estrogen?

Nausea, Edema = MC also, breast tenderness, hyperpigmentation

Other side effects of estrogen include:

1. migraine headaches 2. liver disease, insulin resistance 3. increased risk of blood clotting/TE disease (mainly from higher doses)

What is a side effect of estrogen if used in males?

gynecomastia, feminization

A side effect of estrogen includes cancer risk, explain.

Elevated risk of endometrial hyperplasia/cancer (ONLY if estrogen is used alone). This is REDUCED by progestins -- so E should NOT be used alone

Estrogen use is contraindicated in:

breast cancer, or any other estrogen-responsive tumor

Progestin uses include _____ therapy and _____ therapy

replacement; suppressive

how is progestin used in replacement therapy?

post menopausal use with estrogens as protective factor

how is progestin used in suppressive therapy? 3 main uses ...

1. birth control (either alone or in combo with E) 2. uterine bleeding from endometrial hyperplasia 3. endometriosis and accompanying dysmenorrhea

What are the available preps for progestin?

1. Progesterone 2. Medroxyprogesterone acetate 3. norethindrone

Progesterone comes in various forms including:

IM, creams, suppositories, slow release from IUD, orally bioavailable micronized powder

Medroxyprogesterone acetate is a ____ progesterone

synthetic

Medroxyprogesterone acetate is structurally related to progesterone as it:

retains the 19-methyl group and C20-21 structure

what kind of effects do Medroxyprogesterone acetate produce?

progesterone-like effects, with little/no androgen or estrogen activity

what are the forms of Medroxyprogesterone acetate?

oral, IM

Norethindrone is a prototype synthetic progestin that is structurally related to

testosterone (C18) (LACKS the C20-21 structure)

how does Norethindrone differ from testosterone?

it lacks the 19-methyl group (NOR refers to)

Norethindrone is orally effective, more progesterone-like with decreased androgen activity ...

compared to others in this class that have more androgen-like effects

adverse effects of all progestins include:

menstrual changes nausea bloating potenital teratogen

what are the side effects of nor-progestins, androgenic?

acne weight gain masculinization altered libido worsened lipid profile

Postmenopausal HRT may be used for ...

1. short-term use 2. longer-term use

Use of short-term postmenopausal HRT ...

alleviated symptoms at onset of menopause

What symptoms (that occur with menopause onset) can be alleviated with short-term use of postmenopausal HRT?

1. vasomotor - hot flashes, sweating, palpitations 2. urogenital atrophy -incontinence, painful intercourse, UTIs 3. psychological -mood changes, depression, loss of libido

Use of longer-term postmenopausal HRT

to prevent/treat osteoporosis-related increased risk of fractures (suppression of RANK-L)

Estrogen/progestin combos may be continuous or cyclic for postmenopausal HRT and include:

1. conjugated estrogens + medroxyprogesterone = MC 2. ethinyl estradiol + norethindrone = synthetic agents

when can estrogen be used alone for postmenopausal HRT?

if uterus has been removed

Side effects of HRT include:

1. return of menstrual bleeding, breast swelling and tenderness 2. increased cancer and CV disease risk

how are the side effects of HRT mitigated?

via local admin (vaginal)

benefits of long-term HRT include:

1. reduce risk of osteoporosis/hip fx 2. reduction of colorectal cancer risk 3. protect from Alzheimer's disease risk

risk of long-term HRT

1. E+P increased risk of heart disease, strokes, PE -reverse when HRT is d/c 2. E increases risk of endometrial cancer (adding progestin reduces this risk) 3. E+ P increased breast cancer risk

recommendations for HRT

1. short-term use <5 years of E+P for menopause onset symptoms is probably safe but consider pt history 2. NOT recommended for long-term use, especially in older women

SERMs =

selective estrogen response modifiers

are SERMS orally effective?

yes

are SERMs non-steroidal analogs?

yes

SERMs have mixed ..

agonist-antagonist properties on estrogen receptors

each SERM drug stabilizes

a different receptor conformation (which can yield estrogen AGONIST effects in some tissues and estrogen ANTAGONIST effects in others)

SERM prototypes include:

raloxifene, tamoxifen

the main uses of protoype SERMs include

osteoporosis breast cancer tx and prevention

newer SERMS are used for

treating postmenopausal dyspareunia and hot flashes

Raloxifene uses:

1. tx of postmenopausal osteoporosis, improves lipid profiles 2. for prevention of breast cancer

Raloxifene LACKS the following cancer risks

lacks uterine cancer risk (as seen w/ estrogen and tamoxifen) lacks breast cancer risk (as seen w/ estrogen)

Does Raloxifene cause or relieve hot flashes? why?

CAUSES -- due to its antagonist effects

does Raloxifene increase or decrease clotting/thrombosis? why?

increases and causes leg cramps -- due to its agonist effect

Tamoxifen is used as an

anti-estrogen

Tamoxifen, an anti-estrogen, treats

ER+ advanced/metastatic breast cancer ALSO used for breast cancer PREVENTION

agonist effects of tamoxifen decrease osteoporosis and heart disease risk but ...

are not approved for these uses

does tamoxifen increase endometrial cancer risk?

yes, via agonist action in the uterus

does tamoxifen increase risk of thrombotic disease?

yes

does tamoxifen cause menopausal symptoms?

yes