Estrogens/Progestins

Estrogen Synthesis and Secretion

1. the hypothalamus releases ______, which stimulates the anterior pituitary to release ______ and _______

2. ________ GnRH release maintains normal pituitary stimulation, while ________ GnRH leads to receptor desensitization and suppression of FSH/LH

3. LH increases ______ ______ —> increase in ______ precursors

4. FSH stimulates ______ activity which converts androgens into ______

• three estrogens produced by aromatase activity —>

• the ______ ______ is responsible for high affinity binding to estrogen receptors

• ______ inhibits FSH and LH

• GnRH, LH, FSH

• pulsatile, continuous

• cholesterol transport, androgen

• aromatase, estradiol

• estradiol, estrone, estriol

• phenolic ring

• progesterone

Sources of Estrogen in Different Physiological Stages

• In premenopausal women, the main source of estrogen is the ________.

• In postmenopausal women and men, the primary site of estrogen synthesis is ________ tissue.

  • In postmenopausal women, ________ produced by the ________ ________ is converted to estrogens in adipose tissue.

  • In men, ________ precursors and ________ are converted to estrogens in adipose tissue.

• During gestation, large quantities of estrogen are produced by the ________ unit.

  • In this process, the ________ ________ produces androgen precursors that are transported to the ________, where they are aromatized to ________.

• ovary

• adipose

• DHEA, adrenal cortex

• androgen, testosterone

• fecoplacental

• fetal adrenal, placenta, estriol

Estrogen Receptor MOA

• ERs exist as ______ stabilized by HSPs in the ______

• ERs then ______

• ERs interact with coactivators —>

• two receptor types —>

• monomers

• dimerize

• agonist OR antagonist

• ERa, ERB

ERa is expressed abundantly in —> (4)

• female reproductive tract —> uterus, vagina, ovaries, and mammary glands

• hypothalamus

• endothelial cells

• vascular smooth muscle

ERB is expressed in:

high expression —> ______ and ______

lower expression —> (4)

• prostate, ovaries

• lung, brain, bone, and vasculature

Estrogen Physiological Effects —> (4)

• female development

• bone

• cardiovascular

• CNS

Estrogen Physiological Effects —> Female Development

• changes in females at ______

• ______/______ of vagina, uterus and fallopian tubes

• ______ & ______ of breast tissue

• ______

• most of the changes in organs during the ______ ______

• puberty

• growth, development

• enlargement, differentiation

• libido

• menstrual cycle

Estrogen Physiological Effects —> Bone

• ______ bone mineral density & ______ of epiphyses

• increase ______ production

• decrease ______ number and activity

• increase, closing

• osteoblast

• osteoclast

Estrogen Physiological Effects —> Cardiovascular

• beneficial effect on blood lipids by decreasing ______ and increasing ______

• promotes vasodilation by stimulating endothelial production of ______ ______

• estrogen enhances blood coagulation by:

  • increasing production of coagulation factors in the ______

  • decreasing levels of anticoagulation factors such as ______, ______, and ______

  • increase ______

• mild ______ and ______ retention

• LDL, HDL

• nitric oxide

• lipid

• Protein C, S anti-thrombin

• fibrinolysis

• sodium, water

Estrogen Physiological Effects —> CNS

• stimulates ______ —> hormone involved in stress regulation

• enhances ______ activity, promoting a sense of ______ in women

• CRH

• SNS, well-being

Therapeutic Uses —> (4)

• primary female hypogonadism —> due to estrogen deficiency

• contraception

• endometriosis, dysmenorrhea

• menopause and hormone replacement

Menopause and Hormone Replacement

• ______ of menstrual cycle and ______ in estradiol levels

• ______ years of age

• common signs and symptoms of menopause include:

  • ______ (vasomotor symptoms)

  • ______

  • ______ and ______ disturbances

  • ______ of estrogen-dependent tissues

  • increase risk of ______ and ______

  • increase ______ risk

  • ______/cognitive difficulties

• cessation, decline

• 45-60

• hot flashes

• sweating

• irritability, sleep

• atrophy

• osteoporosis, bone fractures

• cardiovascular

• memory loss

Postmenopause Hormone Replacement Goals

• reduce ______ symptoms —> hot flashes

• HRT helps ameliorate atrophy of ______-dependent tissue

• prevent bone loss associated with ______

  • 1st line-therapy —> ______

  • adequate intake of ______ and _______

• vasomotor

• estrogen

• osteoporosis

• biphosphonates

• calcium, vitamin D

Estrogen Preparations

• Pharmacokinetics:

  • readily absorbed from ______ sites

  • ______ application is sufficient to produce systemic effects

  • after absorption, ______ metabolism can be significant

• all

• topical

• hepatic 1st pass

Estrogen Adverse Effects

• large doses of estrogen can cause ______ and other ______ side effects

• large doses may also cause ______ retention

• increases the risk for ______ and ______

• can cause ______ bleeding

• Carcinogenic Concerns:

  • used by ______ women —> increases ______ cancer (5-15x)

  • in women with an intact uterus, estrogen replacement therapy should be combined with ______ to decrease cancer risk

  • do not use in ______-dependent cancers

  • contraindicated in ______

    • increases the risk of cancer in ______ offspring

    • ______ ______ in male offspring

    • has no proven efficacy in pregnancy disorders

• nausea, GI

• fluid

• DVT, PE

• uterine

• postmenopausal, endometrial

• progestin

• estrogen

• pregnancy

• female

• genital teratogenesis

Anti-Estrogens Therapeutic Uses —> (3)

• breast cancer

• osteoporosis

• infertility

Selective Estrogen Receptor Modulators (SERMs)

• SERMs have selective beneficial estrogenic actions in the ________, ________, and ________.

• SERMs have anti-estrogenic actions in the ________ and maybe the ________.

• Examples of SERMs include:
  → ________, ________, and ________.

• bone, brain, liver

• breast, endometrium

• Tamoxifen, Toremifene, Raloxifene

SERMs —> Tamoxifen

• ______ has similar actions

• educes ______ tumor size and number

• stimulates ______ cell proliferation —> increases the risk of ______ ______ by 2-fold

• blocks bone ______

• decreases total ______ and ______, but causes no increase in HDL or triglycerides

• increases the risk of ______ and ______ by 2-3 fold

• ______ bioavailable and has a ______ half-life

• requires ______ weeks to reach steady-state levels

• metabolized by _______, producing a potent active metabolite

  • drug ______ and enzyme ______ can alter effectiveness

• primarily used to treat ______ ______

• toremifene

• breast

• endometrial, endometrial carcinoma

• resorption

• cholesterol, LDL

• DVT, PE

• orally, longer

• 3-4

• CYP2D6

• interaction, deficiency

• breast cancer

SERMs —> Raloxifene

• activates ______ in bone —> blocks ______ resorption

• decreases total ______ and ______ but does not increase ______

• reduces proliferation in ______ breast cancer

• does not stimulate ______ cell proliferation

• increases the risk of ______ and ______ by 3-fold

• increases ______ flashes and ______ cramps

• ______ absorption after oral administration

• metabolized in the ______ and eliminated in the ______

• primarily used to treat ______ ______

• ER, bone

• cholesterol, LDL, HDL

• ER+

• endometrial

• DVT, PE

• hot, leg

• rapid

• liver, feces

• post-menopausal osteoporosis

Estrogen Receptor Antagonist —> Fulvestrant

• binds ER with ______ affinity than estradiol

• represses ______ _______

• increases ______ ______

• primarily used to treat ______ breast cancer

• monthly ______ injections

• side effects: ______ symptoms

• greater

• gene transcription

• ERa degradation

• tamoxifen-resistant

• IM

• menopausal

Estrogen Receptor Antagonist —> Clomiphene

• blocks ______ in the ______, preventing the normal ______ ______ inhibition by estrogen

• increases ______ and ______

• increases ______

• primarily used to treat _______

• well absorbed and bioavailable with ______ administration

• ER, pituitary, negative feedback

• LH, FSH

• ovulation

• infertility

• oral

Estrogen Synthesis Inhibitors

• the three main aromatase inhibitors are ________, ________, and ________

• primarily used to treat ______ cancer

• often used as ______ or ______ line therapy after ______

• compared to tamoxifen:

  • no increase in ______/______ cancer

  • no increase in ______ and ______ risk

  • increased ______ ______

  • no beneficial effect on ______ ______

• exemestane, anastrozole, letrozole

• breast

• first, second, tamoxifen

• endometrial/uterine

• DVT, PR

• hot flashes

• bone density

Progesterone MOA and Physiological Effects

• MOA similar to ______ complex

• mediated by two receptor subtypes:

  • ______ —> mediates the stimulatory activities of progesterone

  • ______ —> strongly inhibits PR-B actions and inhibits ______ of other steroid receptors

• estrogen-ER

• PR-B

• PR-A, transcription

Progesterone Physiological Effects —> Female Reproductive Effects

• ______ development

• maturation and ______ changes in ______ following ovulation

• helps maintain ______ by suppressing ______ and ______ contractility

• breast

• secretory, endometrium

• pregnancy, menstruation, uterine 

Progesterone Physiological Effects —> Carbohydrate Metabolism

• increases ______ insulin and the ______ response to glucose

• promotes ______ storage

• basal, insulin

• glycogen

Progesterone Physiological Effects —> Cardiovascular/Renal

• competes with ______ for the ______ receptor

  • decrease in ______ reabsorption and a compensatory increase in ______ release

• increases ______ levels and causes a modest reduction in ______

• aldosterone, mineralcorticoid

• sodium, aldosterone

• LDL, HDL

Progesterone Physiological Effects —> CNS

• ______ —> temperature regulating center

  • increase in ______ temperature during ______

• alters regulatory centers by increasing ______ ______ ventilation

• has ______ and ______ effects on the CNS

• hypothalamus

• body, ovulation

• carbon dioxide

• depressant, hypnotic

Progestins Therapeutic Uses —> (2)

• hormone replacement therapy

• contraception

Progestin Agents

• ______ —> agents similar to progesterone

  • examples —> (4)

• ______ —> agents similar to 19-nortestosterone

  • examples —> (3)

• ______ —> agents similar to 19-norgestrel

  • examples —> (3)

• pregnanes

• progesterone, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate

• estranes

• norethynordel, norethindrone, norethindrone acetate

• gonanes

• desogestrel, L-norgestrel, norgestimate

Progestins — PK

• well absorbed by any ______

• T1/2 in plasma —> ~______ minutes

• metabolized in ______

• route

• 5

• liver

Progestins — Adverse Effects —> (7)

• depressant and hypnotic actions

• irregular menstrual bleeding

• weight gain

• mood changes

• decreased bone mineral density

• decreased HDL and increased LDL

• androgenic effects —> acne and hirsutism