Lecture 3: Estrogens

Name the three natural human estrogens.

Estradiol (E2), Estrone (E1), and Estriol (E3).

Which natural estrogen is the major one secreted by the ovaries?

Estradiol (E2).

How are Estrone (E1) and Estriol (E3) primarily formed?

Most are formed by liver conversion, or from adrenal androgens in peripheral tissues.

What ovarian structures produce estrogen before ovulation?

Ovarian follicles, specifically theca and granulosa cells.

What structures produce estrogen post-ovulation?

The theca and granulosa cells of the corpus luteum.

What additional hormone does the corpus luteum produce?

Progesterone.

Where is estrogen produced during pregnancy?

The placenta and fetus.

When are estrogen levels lowest during the ovarian cycle?

In the early follicular phase.

When are estrogen levels highest during the ovarian cycle?

Right before ovulation.

Rank the natural estrogens by their affinity for the estrogen receptor (highest to lowest).

E2 > E1 > E3.

What is the main source of estrogen in premenopausal women?

Ovaries, with estradiol being the major product.

What is the main source of estrogen in postmenopausal women?

Adrenal glands.

What is the major estrogen product in postmenopausal women?

Estrone (E1).

From what precursor is estrone produced in postmenopausal women?

Adrenal DHEA.

Name two locations that produce smaller amounts of estrogen besides the primary sources.

Liver, breast tissue, and adrenal glands.

What two plasma proteins does estrogen bind to?

SHBG (high affinity) and albumin (lower affinity).

Where is estradiol converted to estrone and estriol?

In the liver and other tissues.

Estrone and estriol have lower affinity for the ER than estradiol; what other characteristic of their metabolism is noted?

They form derivatives that are excreted into bile.

How can estrogen conjugates excreted into bile be reabsorbed in the body?

They can be hydrolyzed into active reabsorbable products in the intestines via enterohepatic circulation.

Oral estrogens will have a high ratio of effects in which organ compared to peripheral tissues?

Liver.

Name two effects associated with the high liver-to-peripheral ratio caused by oral estrogens.

Increased clotting factors and increased renin in plasma.

Name two dosage forms used to minimize first-pass metabolism of estrogens.

Transdermal forms, creams, or depot forms.

What common substance does the source note as containing phenols used in plastic manufacturing?

Estrogens in ocean sediments.

What is the purpose of chemically altering natural estrogens to create synthetic forms?

To improve oral efficacy.

What steroidal synthetic estrogen is Quinestrol (Estrovis) a prodrug of?

Ethinyl estradiol.

What non-steroidal synthetic estrogen is only used today for prostate cancer?

Diethylstilbestrol (Stilbestrol).

What protein is the estrogen receptor (ER) bound to in the nucleus before ligand binding?

HSP 90.

What happens immediately after estrogen binds to the ER in the nucleus?

Estrogen binding causes dissociation from HSPs (Heat Shock Proteins).

After binding and dissociation, how does the receptor-ligand complex interact with DNA?

The complex dimerizes and binds to EREs (Estrogen Response Elements) on DNA.

The binding of the dimerized complex leads to the formation of what complex by recruiting co-regulators and TFs?

A transactivation complex.

Name the two estrogen receptor subtypes.

ER alpha and ER beta.

Which receptor subtype primarily mediates effects on the uterus, breast tissue, bone maintenance, and metabolism?

ER alpha.

Which receptor subtype appears to have effects on immune function and the nervous system?

ER beta.

What effect does ER beta have on the growth-stimulating effects of ER alpha on breast and uterine tissue?

ER beta reduces the effects of ER alpha (growth-inhibiting effects).

What are the rapid effects of estrogen attributed to?

Non-genomic effects.

Name two specific tissues whose development is stimulated by estrogen, aiding sexual maturation.

Vagina, uterus, uterine tubes, and breast tissue.

What physical growth event is stimulated by estrogen, leading to the cessation of growth?

Accelerated growth phase and epiphyseal plate closure.

Estrogen stimulates the development of the endometrial lining in conjunction with which other hormone?

Progesterone.

What two specific structures related to integumentary and circulatory systems are maintained by estrogen?

Normal skin and blood vessel structures in women.

What is the dual mechanism by which estrogen maintains bone health?

It causes osteoclast apoptosis and inhibits PTH osteoclast stimulation.

What hormone does estrogen stimulate adipose production of?

Leptin.

What are conjugated equine estrogens (e.g., Premarin) combined with for HRT?

Progesterone (Prempro).

Name two phytoestrogens mentioned in the sources.

Soy and saw palmetto.

Phenols used in plastic manufacturing are associated with increased breast cancer risk in which population?

In both sexes.

Is estrogen excreted into breast milk?

Yes.

At what age is estrogen treatment usually initiated for primary hypogonadism to mimic puberty?

11-13 years old.

For primary hypogonadism treatment, until what age are estrogen doses maintained?

Until menopausal age (50s).

What hormone must be added to the regimen when treating primary hypogonadism?

Progestin.

Name three symptoms of menopause that HRT addresses.

Osteoporosis, hot flashes, thinning skin, sleep disturbances, or memory disturbances.

Regarding cardiovascular effects after menopause, how do LDL and HDL levels compare to pre-menopausal levels?

LDL increases, but HDL still remains higher than in males.

When is HRT recommended specifically based on the timing of menopause?

For women with premature menopause.

HRT breast cancer risk is minimal if initiated immediately after menopause and maintained for how long?

For the first 7 years of therapy.

How is the risk of endometrial cancer minimized when giving estrogen for HRT?

A progesterone is also given.

Why does the addition of progesterone reduce endometrial cancer risk during HRT?

It reduces endometrial hyperplasia.

For women with an intact uterus, how is progesterone typically scheduled in relation to estrogen during HRT?

Progesterone is added the last 10-14 days of the estrogen dosing cycle (first 25 days of each month).

What is the HRT regimen for women who have had a hysterectomy?

Estrogen alone.

If estrogen is used primarily to reduce symptoms like hot flashes, what dosing strategy is recommended?

The lowest dose that provides relief for the briefest amount of time.

If estrogen is used for osteoporosis prevention, what dosing strategy should be used?

The smallest therapeutic dose should be used.

What type of cancer risk increases greatly with dose and duration if estrogen is given alone?

Endometrial cancer.

Estrogen is used to suppress increased ovarian androgen production to reduce what condition?

Hirsutism.

What common adverse effect of estrogen, especially at menopausal age, must be taken seriously as it can indicate endometrial cancer?

Uterine bleeding.

How does the risk of breast cancer change with prolonged courses of estrogen therapy?

It increases.

Does adding progesterone help reduce the risk of estrogen-induced breast cancer?

No.

Name three non-cancerous adverse effects of estrogen use.

Nausea, breast tenderness, migraines, gallstones, or hypertension.

Name two cancer-related contraindications for estrogen use.

Estrogen-dependent cancers or high risk for breast cancer.

Name two contraindications for estrogen use related to vascular health or smoking status.

Risk for thromboembolic disorders or heavy smokers.

What is the mechanism of action of Tamoxifen (Nolvadex)?

It is a partial agonist inhibitor at the estrogen receptor (a SERM).

Describe Tamoxifen's dual effects on breast and endometrial tissue.

Antiestrogenic in breast tissue, estrogenic in endometrial tissue.

Tamoxifen is metabolized by which specific enzyme into a more active metabolite?

CYP2D6.

What percentage reduction in contralateral breast cancer is seen when Tamoxifen is used as adjuvant therapy?

35% reduction.

Name two adverse effects of Tamoxifen.

Nausea/vomiting and hot flashes.

What are the two primary uses for Raloxifene (Evista)?

Prevention of postmenopausal osteoporosis and prophylaxis of breast cancer in high-risk patients.

Raloxifene exhibits estrogenic effects on which two tissues but not on the endometrium or breast?

Liver and bone.

What is the mechanism of action of Fulvestrant (Faslodex), which has no oral dosage form?

It is an ER antagonist that downregulates and degrades the ER.

What is the primary use of the aromatase inhibitor Anastrozole (Arimidex)?

Approved for use in advanced breast cancer.