PDA 2 estrogen

How is estrogen and progesterone production regulated?

Hypothalamus releases pulsatile GnRH → anterior pituitary releases FSH + LH → ovaries produce estrogen + progesterone. Estrogen and progesterone usually provide negative feedback.

What causes ovulation?

High estrogen at mid-cycle switches to positive feedback → LH surge → ovulation.

What do LH and FSH do in estrogen biosynthesis?

LH acts on thecal cells to make androgens. FSH acts on granulosa cells, where aromatase converts androgens to estrogen.

What happens after ovulation?

The follicle becomes the corpus luteum, which produces mainly progesterone plus some estrogen. Progesterone prepares the endometrium for implantation.

What are the 3 major natural estrogens?

Estradiol (E2), estrone (E1), and estriol (E3). E2 is the principal estrogen in females.

What is estrogen's mechanism of action?

Estrogen binds ER-α or ER-β → receptor dimerizes and enters the nucleus → binds estrogen response elements (EREs) → alters gene transcription.

What are the major effects of estrogen?

Endometrial proliferation, bone maintenance, ↑ HDL, and ↓ LDL/total cholesterol. It also increases clotting factors, fluid retention, and gallstone risk.

What are the major adverse effects of estrogen?

Nausea, migraines, gallstones, hypertension/fluid retention, DVT/VTE, stroke, endometrial cancer with unopposed estrogen, and increased breast cancer risk.

What is important about estradiol pharmacokinetics?

Estradiol is rapidly metabolized in the liver to estrone and undergoes enterohepatic cycling, which prolongs its half-life.

What happens to estradiol during elimination?

About 50% is excreted in urine as glucuronide/sulfate conjugates and about 50% undergoes enterohepatic cycling.

What are the major clinical uses of estrogen?

Hormone replacement/MHT for estrogen deficiency and contraception.

What are the specific clinical uses of estrogen replacement?

Primary hypogonadism, premature menopause, and peri-/postmenopausal estrogen replacement.

What 2 synthetic estrogens are used in oral contraceptives?

Ethinyl estradiol (EE) and mestranol. Mestranol is a prodrug converted to EE.

Can estrogen be used alone as an oral contraceptive?

No. Estrogen must be combined with a progestin.

Why is ethinyl estradiol more orally active than estradiol?

Its C17 ethinyl group protects it from oxidation, making it more orally active and potent.

What is the potency order of the estrogens?

Ethinyl estradiol > estradiol (E2) > estrone (E1) > estriol (E3).

What are the 3 main systemic/oral MHT estrogen preparations?

Conjugated equine estrogens (CEE), synthetic conjugated estrogens, and micronized 17β-estradiol.

Why is 17β-estradiol micronized?

To improve oral absorption.

Why are conjugated estrogens orally available?

Conjugation increases water solubility, allowing oral administration.

How do the main MHT estrogen preparations compare with estradiol?

Conjugated estrogens are modified to increase water solubility and oral availability; micronized 17β-estradiol has improved oral absorption; transdermal 17β-estradiol avoids first-pass metabolism.

What is the main advantage of transdermal estrogen over oral estrogen?

Transdermal estrogen avoids first-pass liver metabolism, has higher bioavailability, and has a lower risk of thrombosis and stroke.

When is local vaginal estrogen used?

For genitourinary syndrome of menopause (GSM), including vaginal dryness/atrophy, dyspareunia, and recurrent UTIs.

What is the main advantage of local vaginal estrogen?

Limited systemic absorption, so it causes fewer systemic adverse effects.

How does vaginal estrogen help reduce recurrent UTIs?

It increases vaginal Lactobacillus and improves the vaginal environment. Systemic HRT does not reliably reduce recurrent UTI risk.

What happens to estrogen, FSH, and LH during menopause?

Estrogen decreases, while FSH and LH increase.

Who can receive estrogen alone for MHT?

Women who have had a hysterectomy.

Why must systemic estrogen be combined with progestin in women with an intact uterus?

Unopposed estrogen causes endometrial proliferation, increasing the risk of endometrial hyperplasia and cancer. Progestin protects the endometrium.

What is continuous cyclic MHT?

Estrogen daily + progestin for the last 12–14 days of a 28-day cycle. Main adverse effect: withdrawal bleeding.

What is continuous combined MHT?

Estrogen + progestin every day. It can cause breakthrough bleeding and endometrial atrophy but provides the best protection against endometrial hyperplasia/cancer.

What is intermittent combined MHT?

A newer MHT regimen. Its long-term effect on endometrial protection is undetermined.

What were the major findings of the Women's Health Initiative (WHI)?

MHT decreased fractures and colorectal cancer but increased CAD, DVT, stroke, and breast cancer. It did not improve cognition or dementia in women over 65.

What are the 3 major WHI recommendations?

1) Do not use HRT to prevent CVD, cognitive impairment, or dementia. 2) Use the smallest effective dose for the shortest duration to treat GSM. 3) Add progestin if the uterus is intact.

What is a SERM?

A selective estrogen receptor modulator that acts as an estrogen agonist in some tissues and an antagonist in others.

What is important to know about SERMs as a drug class?

SERMs are nonsteroidal drugs chemically different from estradiol. They have tissue-selective agonist and antagonist effects, and no ideal SERM exists.

Why can SERMs have different effects in different tissues?

Their effects depend on ligand-receptor conformation and the coactivators/corepressors present in each tissue.

What are the general pharmacologic effects and adverse effects of SERMs?

They can benefit bone and lipids but may cause hot flashes, leg cramps, VTE, and stroke.

Why can SERMs worsen hot flashes?

They act as estrogen antagonists in the brain.

Why can SERMs increase VTE risk?

Their estrogen agonist effect in the liver increases clotting-factor synthesis.

What are the tissue actions, use, and key adverse effect of tamoxifen?

Breast antagonist → used for breast cancer. Bone and uterine agonist → increased risk of endometrial cancer.

What are the tissue actions and uses of raloxifene?

Breast and uterine antagonist; bone agonist. Used for breast cancer and postmenopausal osteoporosis.

What are the tissue actions and use of bazedoxifene?

Uterine antagonist and bone agonist. Used with conjugated estrogens for hot flashes and prevention of postmenopausal osteoporosis.

Why is bazedoxifene useful with conjugated estrogen?

It blocks estrogen effects in the uterus, helping protect against endometrial hyperplasia/cancer.

What is the main action and use of ospemifene?

Estrogenic effect (agonist) on vaginal tissue. No effect on breast and uterus. Used for dyspareunia and vaginal dryness from GSM.

What important warning is associated with ospemifene?

Boxed warning for increased risk of endometrial hyperplasia/cancer.

What are the mechanism, use, and adverse effects of clomiphene?

Blocks estrogen negative feedback at the pituitary → ↑ FSH and LH → ovulation. Used for ovulatory infertility. Adverse effects include ovarian enlargement and hot flashes.