Progesterone

Four Key Topics for Non-Packaged Molecules

1. Reasons for not being packaged → lipophilicity (would diffuse out of vesicles)

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2. Requirements for the signalling → synthesis machinery must be present; cannot rely on stored pools; synthesis rate + blood flow control magnitude

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3. Properties of the molecules → lipophilic, low MW, not stored, persist in tissue fluids

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4. Properties of the receptors → mostly intracellular because molecule can cross membranes freely; very high affinity and specificity

What are non-packaged molecules?

molecules that are not put into vesicles

synthesized and released immediately

controlled by synthesis rate at a moment, not by how much is st

What are the main characteristics of steroid hormones?

• lipophillic: can diffuse into membranes easily as they are fat-liked

• not packaged

• RECEPTOR AND SYNTHESIS SITES ARE DIFFERENT- making them endocrine

• low molecular weight

What are the functions of steroids?

behaviour

growth

secondary sex characteristics

immune functions

Water and electrolyte balance

What are the two main categories of steroids? locations of synthesis?

corticosteroids: mostly made in adrenal cortex

sex steroids:mostly made in gonads

Are steroids always hormones and vice versa?

NOOOONONO

The secretion rate of steroids is a function of both…(1)(2)

(1) the rate of synthesis

and…

(2)the flow of blood past the synthesis site

What do steroids need for protection in the blood? What are some examples(for cortico vs sex)?

• carrier proteins - globulin

• make them also not bioavailable

• sex steroids: ALBUMIN and SHBG(sex hormone binding globulin)

• corticosteroids: corticosteroid-binding globulin, transcortin, serpine A6

what animal are steroids sometimes actually stored?

INSECTS CRICKET CRICKET YUCK

Why are steroid receptors usually in the cell?

no benifit in being outside since they can SO easily diffuse, theyre so coolio

4 types of steroid receptors?- actually mainly 2 but others too

Class I Nuclear:

• receptor is in cytoplasm→ binds→ heat shock proteins release→ crosses nuclear membrane→ binds to PRE(progesterone response element) on DNA→ transcription

Class II Nuclear(simpler):

• crosses nucleur membrane directly→ binds to receptor on DNA→ transcription

Cell surface:

• GCPR, ion channel,

Cytoplasmic: no genomic effects

why do steroids not need to be constantly present on the receptor for it to carry out its functions?

works transcriptionally → long lasting response

Examples of Class I Nuclear Receptors?

estrogen receptor, glucocorticoid receptor, progesterone receptor, etc…

5 ways that steroids can be terminated?

1. double bonds broken= inactivated

2. combining with other molecules= inactivated

3. catabolised by enzymes in the liver and kidney

4. cytochrome P450 terminates them

5. made more water soluble so you can pee them out

What is the abbreviation of progesterone?

P4,

what is a synthetic derivative of progesterone?

progestogin—levonorgestrel

What class of steroids is progesterone?

C21

what is the nickname of pregnonolone? why?

grandmother steroid, can give rise to all other steroids.

What did the germans vs americans call progesterone?

Germans: luteosterone

Americans: progestin

What does progestational refer to?

1. The LUTEAL phase of menstruation; when progesterone is released

2. Any of the actions of progesterone/it’s derivatives: progestin

3. Anything related to blastocyst implantation

Why is progesterone a misnomer/ inaccurately named+defined?

defined: only in female, reproductive system

WRONGG❌❌

not just reproductive system; its a neurosteroid(made in brain); found in males too

what is the importance of the two ketone groups on progesterone?

allows the steroid to interact with receptors

3 key structural features of progesterone?

2 KETONE GROUPS:

1. C3- allows it to interact with glucocorticoid and mineralocorticoid receptors

2. C20-allows it to interact with neural receptors

Delta-4 unsaturated bond at C4–C5

• gives stability and flexibility

• structure does not change even during chemical reactions- structural skeleton is so strong

What is the primary source/location of progesterone synthesis?

corpus luteum

What is the corpus luteum?

impermenant endocrine gland; forms on the ovary during menstrual cycle then goes away

what is corpus luteum in Latin?

yellow body 👩👩👩

What is the follicular phase?

start of the mentrual cycle

How is the corpus luteum formed?

FOLLICULAR PHASE

1. many follicles compete—only one is selected

• follicles have space in body called antrum

• antrum has granulosa cells(inner)+ theca cells(outer)

2. after ovulation… theca+granulosa cells remain in ovary

3. the cells differentiate into corpus luteum cells

4. The cells undergo HYPERTROPHY= EXPAND

• happens due to LH/HCG

• needs space for lipid droplets and machinery

5. After ovulation… cells don’t separate due to focal adhesion

• merge with neighbouring cells

Why is the corpus luteum yellow?🥕

1. Contains fat deposits(cholesterol)- appear yellow with tissue\

2. LUTEIN- carotenoid from green leafy vegetables, CARROTS YUM YUM

How is the corpus luteum terminated? What is this called?

LUTEOLYSIS:

immune cells; e.g. macrophages; take over→ release cytokines(IFN-gamma, TNF-alpha) → TNF-alpha KILLS cells→ estrogen takes over→ menstruation

What circumstance causes the corpus luteum to shed?

NO PREGNANT🫄🫄🫄🫄🫄🫄🫄🫄🫄

what is a blastocyst?

fertilized egg

what is the outer layer of the blastocyst called?

trophectoderm

What happens to corpus luteum when pregnant?

continues producing progesterone till week 7-9→ placenta takes over progesterone production

What is the HPG axis?

three-way system that controls reproduction an puberty and stuff

What are the components of HPG axis?

Hypothalmus: produce GnRH(gonadotropin-releasing hormone)

anterior Pituitary: releases LH and FSH

Gonads: produce sex steroids

What is the role of FSH? diff in receptor location in males and females?

• triggers FOLLICULAR PHASE— recruits follicle ton proliferate

  • females: receptor on GRANULOSA CELLS

  • males: receptor on SERTOLI CELLS

What 3 things are the LH in charge of?diff in receptor location in males and females?

• progesterone production

• triggers ovulation

• causes the granulosa/theca cells to differentiate

females: receptors on THECA and GRANULOSA

males: receptors on LEYDIG CELLS

stages of the cycle?

1. menstruation

2. follicular phase-find a follicle

3. ovulation- LH lots— oocyte released(immature egg)

4. luteal phase— progesterone release

What are the 2 opposite feedback mechanisms in the cycle?

progesterone: NEGATIVE: stops hypothalamus and pituitary from making LH

estrogen: POSITIVE: stimulated LH

what puts the brakes on the HPG axis- think negative feedback

PROGESTERONE

How do progesterone and estrogen work together to do the cell lining?

• estrogen proliferates the cell lining- builds it up

• progesterone matures the cell lining

what is a reason people have heavy periods?

too much estrogen→ too much proliferation→not enough progesterone to balance and mature

How do you know if you have a LUTEAL PHASE DEFECT?

if it only lasts less than 10 days for 3+months

What are the consequences of LUTEAL PHASE DEFECT? Risk Factors?

• heavy periods, infertility, miscarriages

risk factors: heavy exercise, smoking, poor nutrition

How does high energy/exercise/stress/anorexia impact periods?

1. low energy levels detected→↑ inflammatory cytokines

• disrupts…

• leptin: signals fat stores

• ghrelin: signals hunger

2. leptin, ghrelin signal to hypothalamus(arcuate nucleus)→ kisspeptin reduces

3. kisspeptin reduces→ GnRH reduces

4. less LH and FSH

5. no support for menstrual cycle

insulin also feeds back on HPG

what is kisspeptin in charge of ?

reproductive cycle💋

Why is cholesterol needed for progesterone?(3)

1. it is the precursor to all steroids

2. blood vessels are needed to carry cholesterol

   1. VEGF- vascular endothelial growth factor; helps by angiogenesis(creating new blood vessels)

What are the 3 sources of cholesterol for luteal cells?

1- LIPID DROPLETS- large space in luteal cells with cholesterol

2-LDL(carry cholesterol) cell uptake via endosomes

3-De Novo Biosynthesis- made on the spot, but rare

What does HDL vs LDL do to cholesterol in bloodstream?

LDL carries, HDL removes😛

How is cholesterol freed from LIPID DROPLETS? what is being blocked during this?

LH binds to it’s receptor→ activates PKA via cAMP→ PKA phosphorylated HSL(hormone sensitive lipase)→ frees cholesterol

• **AMPK is being BLOCKED: promotes fatty acid breakdown

• blocking it prevents the cholesterol from being terminated

what is AMPK?

• AMP-activated protein kinase

• promotes fatty acid breakdown

Transport- how can cholesterol enter the mitochondria/whats helping it? This is the _ _ step

StAR- Steroidogenic Acute Regulatory protein

shuttles cholesterol into mitochondria

RATE LIMITING

StAR must be___ to function?

phosphorylated

What is HCG?

human chorionic gonadotropin

produces by placenta

carries on progesterone production

What G-protein does HCG vs LH couple to to signal progesterone production?

HCG-Gs

LH-Gq

What enzymes are involved from cholesterol entering mitochondria, cholesterol→progesterone, termination?

1. cholesterol enters mitochondria—StAR

2. cholesterol→pregnenolone—-CYP11A1

3. pregnenolone→progesteron—-3β-HSD

4. pregnenolone termination—-20α-HSD

what happens if you take away 20a-HSD from mice?

this is used as a model for ___ ___ in humans

labour can’t happen→ prolonged pregnancy

overdue pregnancies

What controls these enzymes prescence/production or termination?

LH- in charge of quite literally everything for some reason

What is steroidogenesis?

the process of converting cholesterol into steroid hormones

What is detected by pregancy tests?

HCG

What are the two main structural parts of the blastocyst?

Inner cell mass: becomes every part of the human body

Trophectoderm: becomes the placenta-produces HCG

What is a marker of a healthy blastocyst and why ?

‘zinc spark’

oocytes contain lots of zinc→ fertilization= release of it all

pluripotent meaning

an immature cell that can give rise to other cells— like the inner cell mass of a blastocyst

What eliminates free radicals?

SOD- superoxide dismutase

What are reasons zinc is so important?

1. needed for transcription- zinc finger transcription factors

2. FEMALE: needed for luteal phase- without it defects happen

3. MALE: needed for sperm and testosterone production

4. antioxidant- SOD(superoxide dismutase)

5. cofactor for steroidogenic enzymes

where do we have to rely on getting zinc from

• our diet since our body cannot store it

Good sources of zinc?

• beef and seafood- SURF AND TURF

• plants-nuts, legumes seeds

What are some causes of zinc deficiency?

1. poor absorption: phytates in leafy greens interfere with this

2. pregnancy: high need for zinc in fetus ad steroidogenics

3. alcoholism: bad absorption

4. diuretics: zinc goes out peepee

5. Crohn’s disease/leaky gut: bad absorption

What are the three nuclear receptor subtypes?

1. PRA- activates transcription-

2. PRB- represses transcription- MORE NEAR LABOUR

3. PRC- inhibits PRB

what does progesterone do for labour? what does oxytocin do?

suppresses it

contractions→ labour

How does progesterone stop labour from happening?

During pregnancy: lots of PRB suppressing nuclear receptors

→PRB+progesterone actives expression of ZEB1/2 transcription factors

ZEB1/2 → represses oxytocin receptor

no oxytocin receptor→ no binding→ no contractions

what is oxytocin

love steroid hormone, neurotransmitter- binding people together

What happens near term(mature time) in pregnancy?

PRA more dominant than PRB→ ZEB1/2 drops→ oxytocin binds to receptor→ contractions

what conditions cause a c-section to be necessary

too much progesterone still→oxytocin can’t act if not dominant→ no labour→ c-section needed

Progesterone acts as a ____ to mineralo/glucocorticoid receptors

competitive antagonist

what is the result of progesterone blocking gluco and mineralo receptors?

mineralo— competed with aldosterone: doesn’t allow aldosterone to retain sodium—sodium excretion

gluco— immune suppression and anti-inflammatory effects

what pathways can progesterone take to worth not involving gene transcription?

1. Src Kinase Pathway

2. PGRM- mitochondrial progesterone receptor

3. mPRs- membrane progesterone receptors

4. eNOS and iNOS

5. PGRMCs

6. Sigma-1 receptor

7. GABA receptor-Allopregnenolone

8. Nicitinic and Muscarinic ACh receptors

9. Catsper

10. Cytochrome P450

How does the Src Kinase Pathway work?

• involves PRB receptor

• progesterone+PRB→interact with Src kinase→phosphorylates proteins→ acts quickly

What effects does PGRM have? How does it work?

• helps with METABOLISM and CELL ENERGY PRODUCTION

• in the mitochondria

How do mPRs work?— 2 possible ways

• membrane bound GCPRs

• VASODILATION

• 1. mPRs→ block Ca+ channels in vasculature→ relaxation

• 2. Activates eNOS→ makes NO→relaxation

what non genomic pathway occurs when progesterone is HIGH?

eNOS in uterus→NO→relaxation→ vasodilation, better blood flow, uterine relaxation

what non genomic pathway occurs when progesterone is LOW?

IL-1β and TNF-alpha→activate iNOS in cervix→ more NO→ cervix opening/dilation

How do PGRMCs work?

• Membrane-bound adapter/chaperone proteins

• Involved in: tumour progression, nerve viability, metabolism

• PGRMC1: acts in GnRH NEURONS → regulates GnRH secretion → direct HPG axis connection

How do Sigma-1 Receptor work?

located at MAM (Mitochondria-Associated Membrane)

When progesterone binds → allows progesterone to interfere with VOLTAGE-GATED CALCIUM ION CHANNELS at the membrane

Produces rapid effects

what is allopregnonolone?

a METABOLITE of progesterone produced by NERVE CELLS — not progesterone itself

Where do pregnant women get their maternal glow from?

allopregnonolone binds to GABA receptor—-inhibitory signalling—- anti-anxiety, calming

you get your pregnant glow

CANNOT COME FROM SYNTHETIC PROSTEGIN

How do Nicotinic & Muscarinic Acetylcholine Receptors relate to progesterone?

• Progesterone acts as a NEGATIVE ALLOSTERIC MODULATOR-reduces activity-of these receptors

• Muscarinic receptor M3: linked to symptoms of menopause such as hot flashes and excessive sweating

What is CatSper? Location? How work?

CatSper = calcium channel on SPERM

• Responsive to PROGESTERONE from the corpus luteum in the female oviduct

• cross-system process- from female progesterone to male sperm

What does CatSper do for sperm?

• gives hypermotility—move fast with tail

• otherwise can’t reach the egg

What does cytochrome p450 do for progesterone?

• This is the SAME enzyme involved in the grapefruit juice–drug interaction

• Progesterone may therefore modulate drug metabolism

WHERE IS PREOGESTERONE FOUND+ FUNCTION?-6

1. Uterus

• pregnancy maintenance:

• maintains lining

• relaxes smooth muscle

• suppresses oxytocin

• prevents maternal immune response

2. Brain

• neurosteroid effects

• allopregnonelone stuff happens here

3. Cardiovascular system

• mPRs help with blood supply

4. Immune system

• Anti-inflammatory during pregnancy

5. Breast

• prepares them for lactation

6. Kidneys

• Competes with aldosterone at mineralocorticoid receptor → promotes sodium excretion

what plant is bioidentical progesterone derived from? What country?

• Mexicooco

• giant tropical TUBER (rhizome/yam)

what compound does TUBER have? How does it convert to progesterone?

• DIOSGENIN

• Diosgenin is chemically converted to progesterone via the MARKER DEGRADATION process

Who made the marker degredation?

Russel Marker

what did the aztecs use plant tuber as?

contraceptive

What ‘medicine‘ did Lydia Pinkham create?

beth root— advertised as a fix to womens issues

same flower as Ontario Drivers Liscence

What has to be done if a mother develops preeclampsia? what is it?

C-section immediately, blood pressure disorder