PMCOL 343 Progesterone

What is progesterone secreted by

- Corpus luteum in the luteal phase of the menstrual cycle and the first ten weeks of pregnancy

- The placenta the rest of pregnancy

- Testis and adrenal cortex in small amounts

Physiological effects of progesterone: Menstrual and Uterine cycle

- Facilitates implantation and maintenance of pregnancy. Promotes uterine growth and suppresses myometrial contractility

Physiological effects of progesterone: Mammary gland

Develops mammary gland during puberty, adulthood, and pregnancy

Physiological effects of progesterone: Immunity

Progesterone exerts an immunosuppressive effect during pregnancy and in non-pregnant healthy women with regular menstrual cycle

Physiological effects of progesterone: CNS function

- Progesterone is neuroprotective

- Increases BDNF which increases nerve and brain repair

- Increases myelination

- Limits cellular death

Slow Classic genomic mechanism of Progesterone

- Nuclear receptors that are transcription

- Two major receptors are PR-A and PR-B (B is stronger and A may act as a repressor)

- Progesterone is hydrophobic, so it crosses the cell membrane, binds to PR, which then translocates to nucleus to elicit cellular response through gene transcription

Rapid non-genomic effects of progesterone

- Activation of many signal transduction pathways

- Involves secondary messengers

- Ion channels, putative cell surface receptors has actions within seconds

- Cytoplasmic second messengers have action that takes minutes

What can imbalance of PR-A and PR-B lead to

Gynaecological pathologies such as endometriosis and endometrial hyperplasia

Abnormal progesterone Responses: Endometrial cancer

- Thought to play a protective role in the developmental of some endometrial cancers

- Inhibits the growth of endometrial epithelial cells

- Reduces cancer viability and invasion

Abnormal progesterone Responses: Breast cancer

- Effect on breasts is complex and variable

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

- has also been shown to induce anti proliferative effects

Abnormal progesterone Responses: Endometriosis

- Thought to negatively impact the development of endometriosis

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

Abnormal progesterone Responses: Fibroids

- Stimulates the growth and development of uterine fibroids

- Stimulation of cell proliferation and facilitates extracellular matrix accumulation

Postpartum depression

Progesterone freely passes the BB and is converted to allopregnanolone which stimulates the GABA inhibitory system (This promotes calmness, good mood, sleep)

Lactation and progesterone

- Progesterone inhibits lactogenesis during gestation

- Elevated postpartum progesterone may delay lactogenesis and fail lactation

Distribution of progesterone

- Bound to serum in albumin

- Does not bind to SHBG

- Half-life in plasma is around 5 mins

Progesterone route of elimination

urine

Selective Progesterone Receptor Modulators (SPRMs)

- Synthetic steroid ligands designed to compete at the PR-target site in a tissue specific matter

- SPRMs can exert agonist, antagonist, or mixed effects on target tissue

Mifepristone

- A SPRM

- Binds to PR with higher affinity than progesterone

- A low doses, it is a selective antagonist for progesterone

- A single dose in late follicular phase inhibits LH surge and ovulation, emergency contraception.

- Blocking progesterone makes lining of the uterus thin, making embryo unable to stay implanted in uterine wall

Misoprostol

- Prostaglandin analogue

- Used for medical abortion in first trimester

- Triggers muscle contractions in the uterus while also softening and dilating the cervix. The contractions expel the embryo and the uterine tissues through the vagina

Ulipristal acetate (UPA)

- A SPRM

- Treatment of signs and symptoms of uterine fibroids

- Emergency contraception (not in Canada)

Progesterone general medical uses

- Hormonal contraception

- Menopausal therapy

- Dysmenorrhea and endometriosis when estrogens are contraindicated

SPRMs general medical uses

- Female reproduction and gynaecological therapies (uterine fibroids and some tumours)

- Medical abortions

- Emergency contraception

Hormonal contraception

- Contains a progestin with or without an estrogen

Progestin-Only contraception

- Delivered orally, injected, or intrauterine device

- Effectiveness varies based on: progestin, dose, potency, half-life.

- In IUDs, it things endometrium and thickens cervical mucus

- Also local foreign body triggers inflammation which prevents implantation and is toxic for sperm

Combined Hormonal Contraception

- Contains estrogen and progestin

- Includes daily oral pills, monthly vaginal ring, and transdermal patch

- Can produce consistent, regular bleeding patterns unlike progestin only methods.

How do progestins provide contraceptive effect

- Decreasing GnRH which lowers LH which in turns prevents ovulation

- Having direct negative effects on cervical mucus permeability

- Reducing sperm survival

How do estrogens enhance contraceptive effectiveness

- Reduces GnRH which lowers LH and in turn prevents ovulation

- Preventing the development of the dominant follicle

Emergency contraception pill (ECPs)- Plan B

- Emergency Hormonal Contraceptive

- Progestin (Levonorgestrel)

- Prevents or delays ovulation

- Impairs luteal funciton

Yuzpe method

- Emergency Hormonal Contraceptive

- Combined estrogen and progestin

- uses ordinary birth control pills in specified combinations

- inhabits implantation of a fertilized egg

- delays/suppress ovulation, interferes with corpus luteum functioning, changing the endometrium prevents implantation

Ulipristal

- Emergency hormonal contraceptive

- SPRM

- inhabits or delays ovulation

Non-contraceptive health effects of hormonal contraception

- reducing ovulation reduces chances of ovarian tumours and ovarian cysts

- Diminishes premenstrual disorder symptoms such as headaches, bloating, and fatigue

- Estrogen improves androgen-sensitive conditions (acne and hirsutism)

- Progestin-containing contraceptives reduce menstrual blood loss and menstrual pain

Menopause

- Levels of estrogen naturally decreasing

- Typical symptoms are irregular or absent period, hot flashes, night sweats, sleep and mood disturbances

Menopausal hormonal therapy

- Severe menopausal symptoms effectively treated with hormone therapy.

- Combined estrogen and progesterone in people with uterus. Estrogen alone for those with uterus surgically removed

Chronic conditions that have higher rate after menopause

- heart disease

- Stroke

- diabetes

- dementia

- cancer

- bone fractures