Lecture 14: Progestins Flashcards by Brooke Thornburg

Progesterone

-most important progestin
-functions as hormone and precursor to estrogens, androgens, corticosteroids
-bind progesterone receptor
-alter rate of transcription

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Progesterone synthesis

-ovary, testis, adrenal glands
-corpus luteum in luteal phase
-placenta during pregnancy

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Progesterone metabolism

-rapidly absorbed
-5 min half life
-almost completely first-passed metabolized
-converted to pregnanediol
-conjugated with glucaronic acid

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Progesterone excretion

-urine

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Physiological effects of progesterone

-menstruation cycle
-metabolic effects
-interference with aldosterone
-deppressant/hypnotic

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progesterone effect on menstrual cycle

-cause maturation and secretory changes in endometrium after ovulation

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progesterone effect on metabolism

-inc insulin and insulin response to glucose
-promote glycogen storage in liver

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progesterone interference with aldosterone

-compete for mineralcorticoid receptor
-dec Na+ reabsorption
=inc aldosterone secretion by adrenal cortex in pregnancy

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Clinical uses of progesteron

-contraception
-hormonal replacement therapy
-endometriosis
-dysmenorrhea
-bleeding disorders

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Progesterone effect in hormone replacement therapy

-reduce adverse effects of estrogen
-uterine bleeding and carcinoma

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Progestin effect on endometriosis

-suppress growth of endometrial cells

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endometriosis

-growth of endometrial cells outside uterine cavity
-cells respond to hormonal changes
=cause pain from inflammation during period

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Progestin structure requirements

-ketone at C-3
-C-18 Me group
-C-19 Me, H, or double bond
-C-17a and B

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19-nor, 17-ethynyl steroids

-1st gen progestins
-oral contraceptives
-norethindrone
-ethynodiol diacetate

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17-ethynyl group

-triple bond
-inc oral availability

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19-methyl group

-not necessary for activity
-replace with H enhances activity

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17-acetyl

-replace with OH to inc oral bioavailability

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Levonorgestrel

-2nd gen progestin
-levo isomer
-active form
-high oral bioavailability
-iud and mirena

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Norgestimate

-prodrug
-converted to levonorgestrel oxime then to levonorgestrel

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2nd gen progestins

-levonorgesterel (active)
-norgestimate (prodrug)

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3rd gen progestins

-desogestrel (prodrug)
-etonogestrel (active)

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Desogestrel

-3rd gen
-prodrug
-metabolized to etonogestrel
-high oral bioavailability

Etonogestrel

-active
-analog to levonorgestrel
-used in nexplanon implant or nuvaring

Drospirenone

-4th gen
-weak activity (10% of levo)
-antimineralocorticoid activity
-negate side effects of estradiol in combination therapy

Medroxyprogesterone acetate

-1st gen -used for depot injection

Optimal hormonal activities of progestins

-minimize androgenic and antiestrogenic effects

Types of hormonal contraceptive

-combinations of estrogens and progestins (phasic) -progestin w/o estrogen

Hormonal contraceptive routes of admin

-mostly oral -implantable, injection

adherence to bc schedule more critical for

progestin-only therapies

Effects of oral bc on ovulation

-selectively inhibited by combo estrogen and progestins (inhibit pituitary) -not always inhibited by progestin-only

effects of oral bc on ovary

-suppress function -return to normal cycle in 1-2 months after discontinued use

effect of oral bc on uterus

-change in mucus and endometrium -dec chance of conception and implantation

Effect of oral bc on breasts (combo only)

-stimulation of breasts -enlargement -suppress lactation

estrogen and progestin combo therapy

-ethinyl estradiol + norethindrone (usually)

mild adverse effects of oral bc

-nausea, HTN, edema, breast fullness due to estrogens -appetite, datigue, breast regression due to progestins

Moderate adverse effects of oral bc

-irregularities in menstruation (~progestin-only) -weight gain, acne, hirsutism (~combos w/ androgen-like progestins) -ammenorrhea

severe adverse effects of oral bc

-venous thromboembolic disease (estrogens) -MI (androgenic progestins) -not for women over 35 who smoke

Interactions with other steroids

-may inc blood levels of other steroids by interfering with their metabolism

interactions with anticonvulsants

-phenytoin -induces drug-metabolizing enzymes in liver

Interactions with rifampin (antibiotic)

-induce drug metabolizing enzymes in liver -inc rate of metabolism of many drugs

interactions with tetracyclines (antibiotic)

-suppress gut flora that participate in enterohepatic recycling

emergency contraceptives

-99% effective within 72 hours -higher doses than bc

types of emergency contraceptives

-combo (ethinyl estradiol + norgestrel) -progestin only (planB (levonorgestrel)

side effects of emergncy contraceptive

-nausea and vomiting (~combo)

Ulipristal acetate

-SPRM -emergency contraceptive -upto 5 days after sex

Ulipristal acete side effects

-nausea -abdominal pain

SPRM

selective progesterone receptor modulator

Mifepristone

-RU-486 -progesterone ANTAgonist -abortifacient up to 70 days (combo with misopristol)

Mifepristone side effects

-nausea, vomitting -bleeding (5%) -requires intervention/admin by physician

Danazol

-weak adrogen, weak progestin, antiestrogen -effective for endometriosis -inhibit LH and FSH surge -suppress ovarian function -atrophy of endometrium

Adverse effects of Danazol

-mostly from weak androgenic activity -weight gain -little bitties -acne, oily skin, hirsutism

Danazol contraindications

-hepatic dysfunction -pregnancy and breast feeding