Progesterone

Progesterone

Natural progestational hormone

What secretes progesterone

• Corpus luteum in luteal phase and first 10 weeks of pregnancy

• Placentation rest of pregnancy

• Small amounts: testis and adrenal cortex

Progesterone in menstrual and uterine cycle

Facilitates implantation and maintenance of pregnancy, promotes uterine growth, suppresses myometrial contractility

Progesterone in immunity

Immunosuppressive effect during pregnancy and in non-pregnant healthy women with regular menstrual cycle

P in mammary gland

Involved in development during puberty, adulthood, and pregnancy

P in CNS

• Neuroprotective

• Increases BDNF which increases nerve and brain repair

• increases myelination

• Limits cellular death

Classic genomic mechanism of P

PR-A and PR-B

B is stronger, A may act as repressor

Transcription factor

In balance can cause gynaecological pathologies: endometriosis and endometrial hyperplasia

non genomic effects of P

Activation of many signal transduction pathways

• Ion channels, putative cell surface receptors, cytoplasmic second messengers

P response in endometrial cancer (abnormal)

protective role, inhibits growth of endometrium and endometrial epithelial cells reduces cancer cell viability and invasion

P in endometriosis (abnormal)

Stops development

Endometriotic lesions display: decreases P-regulated genes and PR-B expression

P response in breast cancer (abnormal)

Complex and variable

-Drives proliferation, survival, invasion, and angiogenesis of breast cancer cell

-Has been shown to induce anti proliferative effects

P response in fibroids (abnormal)

Stimulates growth and development of uterine fibroids

• Stimulation of cell proliferation

• Facilitates extracellular matrix accumulation

• Can cause problems or not depending on age

P in postpartum depression (abnormal)

Freely passes the BBB, and is converted to allopregnanolone which stimulates the GABA inhibitor system (GABA is involved in calmness, good mood, sleep)

P response in lactation (abnormal)

P inhibits lactogenesis during gestation, elevated postpartum P may delay lactogenesis and fail lactation

Key PK of P

• high-does preparation of micronized-oral use

• Rapidly absorbed by other routes

• Binds to albumin not sex hormone binding globulin

• half life of 5 mins

• Rapid and completely metabolized in liver (not great for oral)

• Excreted in urine

Synthetic progestins (progestogens)

From pregnanes, estranes, gonanes

Can have antiandrigenic effects

Selective progesterone receptor modulators (SPRMs)

Synthetic steroid ligands designed to compete at the PR target site (tissue specific manner)

Agonist, antagonist, or mixed effects

Lots identified, only two licensed for gynecologic use

Mifepristone

SPRM

Binds to PR with higher affinity than P

At low doses- selective antagonist of P

Single dose in late follicular phase inhibits LH surge and ovulation (emergency contraceptive, not in Canada)

Blocks effects of progesterone, thins uterine lining, making embryo unstable

Misopristol

used with mifepristone in medical abortion the first trimester

triggers muscle contractions in uterus, softens and dilates the cervix- expels embryo

Ulipristal acetate

SPRM

Uses: signs and symptoms of uterine fibroids (possible liver damage), emergency contraception (not in Canada)

Pharmacological use of SPRM

• Female reproduction and hynescological therapies (uterine fibroids, treatment of some tumours)

• Medical abortion

• Emergency contraception

hormonal contraception

• Contain a progestin with or without an estrogen

• Now use synthetic progestins

• Now use lower doses of estrogens and progestins

• new delivery systems

• oral is most used

P only contraception

• Pill, injectable, intrauterine

• Effectiveness varies on : progestin, dose, potency, half life, use dependent factors

• IUD: thins endometrium, thickens cervical mucus, local foreign body triggers inflammation )toxic for sperm, prevents implantation)

Combined hormonal therapy

• Pill, ring, transdermal

• Same mechanism as P only

• Biggest advantage- produce consistent, regular bleeding pattern

P contraceptive effect

• Decrease GnRh which lowers LH-no ovulation

• Direct negative effects on cervical mucus permeability

• Reducing sperm survival

How do estrogens enhance contraceptive effectiveness

• Reduce GnRH

• Prevent development of dominant follicle

Emergency contraceptive pill- plan B

Progestin: Levonorgestrel

Prevents or delays ovulation, impairs luteal function

Yuzpe method

Combined estrogen and progestins

Ordinary birth control pills in specific combinations

Inhibit implantation of a fertilized egg

Other possible: delaying or suppressing ovulation, interfearing with corpus luteum function, changing the endometrium to prevent implantation

Can ulipristal be used as an emergency contraceptive?

Not in Canada

But ut does inhibit or delay ovulation

Non contraceptive health effects of hormonal contraception

• Methods that suppress ovulation: reduced benign ovarian tumours, functional ovarian cysts

• Combined hormonal diminish premenstrual disorder: headaches, bloating, fatigue

• Estrogen imporoves androgen-sensitive conditions (acne, hirsutisme) increases hepatic SHBG which reduces testeosterone

• progetsin- reduce menstrual blood loss and menstrual pain (endometrial atrophy)

Symptoms of menopause

Irregular or absent period, hot flashes, night sweats, sleep and mood disturbances

Menopausal hormonal therapy

Severe symptoms can be treated, combined estrogen and progesterone in people with a uterus, estrogen alone if the uterus has been surgically removed

What risks increase after menopause

heart disease, stroke, diabetes, cancer, bone fractures

Don’t know if menopause can cause these or not, dont know if treatment helps or not