Progesterones Progesterones and Breast Cancerand Breast Cancer

Endogenous and Exogenous Endogenous and Exogenous

Synthetic or Natural Bio-identicalSynthetic or Natural Bio-identical

Progestins, Progestogens orProgestins, Progestogens or ProgestagensProgestagens

““Act like progesterone”Act like progesterone”

Dr Ellen C G GrantDr Ellen C G Grant MBChB, DObst RCOG

ellengrant@talktalk.net

Contraceptive and MenopausalContraceptive and MenopausalPProgestogensrogestogens and and OestrogensOestrogens

• W H OW H O International Agency for Research International Agency for Research in Cancerin Cancer ((IARCIARC monograph, 2005) monograph, 2005)

• ““Group 1 Carcinogen”Group 1 Carcinogen”

• Highest level (dioxin, mycotoxins)

• Direct GenotoxinsDirect Genotoxins

Collaborative (51)Collaborative (51), MWS, , MWS, WHIWHI

• xs Breast Caxs Breast Ca 5 yr 10 yr5 yr 10 yr StudyStudy

• Oestrogen HRTOestrogen HRT 2 6 CollabCollab

1.5 5 MWSMWS

• P plus O HRTP plus O HRT 6 19 MWSMWS

• 6 18 WHIWHI• BeralBeral Lancet 2003Lancet 2003

• HRT Studies (1.09 – 19) 2 – 8

Contraceptive Breast Cancer RisksContraceptive Breast Cancer Risks

• OESTROGENOESTROGEN + + PROGESTOGENPROGESTOGEN• Combined OCs (1.6 - 7.8) 2 - 5

• By age 50 By age 50 - Ever use ≥ 4yrs before FFTPbefore FFTP 1.521.52• Kahlenborn,2006Kahlenborn,2006

• Combined OCs + Ethinyl oestradiolEthinyl oestradiol 35 mcg 2• >35 mcg 4

• PROGESTOGENPROGESTOGEN only 1.6 - 6 • (UK study, P mostly lactation 1 – 12 months)

Breast cancer Breast cancer ↑↑ with ↑↑ with PP use use

Progesterone carcinogenesisProgesterone carcinogenesis

• Why does Progesterone Progesterone cause – 3-4 x more 3-4 x more breast cancersbreast cancers than Oestrogen?Oestrogen?

• 4 x 4 x moremore genesgenes up up or or downdown regulatedregulated

• All tissuesAll tissues CarcinCarcinogenic Metabolitesogenic Metabolites• + or -+ or - Progesterone Receptors Progesterone Receptors

• AngiogenesisAngiogenesis ↑ ↑ ↑ ↑ Immune diseases Immune diseases ↑ ↑ (x9)↑ ↑ (x9)

Actions of ProgesteroneActions of Progesterone

• ↑↑ oestrogen primingoestrogen priming

• Subnuclear vacuolesSubnuclear vacuoles • ESPESP Alkaline phosphatase Alkaline phosphatase ↓↓↓↓• Acid phosphatase, SODase, COMTAcid phosphatase, SODase, COMT ↑↑↑↑• LSPLSP Monoamine oxidaseMonoamine oxidase ↑↑↑↑

• Immediate AImmediate Angiogenesisngiogenesis ↑↑↑↑

Normal endometrial cycleNormal endometrial cycle

• 2 days subnuclear vacuoles mid cycle2 days subnuclear vacuoles mid cycle

P treated endometriumP treated endometrium

Normal Late SecretoryNormal Late Secretory

Progestogenic ++Progestogenic ++ arterioles ++arterioles ++

Dilated sinusoidDilated sinusoid - - thrombosisthrombosis

ThrombosedThrombosed cerebral vesselscerebral vessels – 5 yrs OC – 5 yrs OC

Norgestrel Dose EffectsNorgestrel Dose Effects

↑↑ ↑↑ AAggressionggression ↑Vascular↑Vascular

Types of ProgestogensTypes of Progestogens

• AndrogenicAndrogenic PregnanesPregnanes

• EstranesEstranes GonanesGonanes

• OCs 10 13 MPA - depotMPA - depot

• HRT 13 5 MPA inMPA in USA

• MPAMPA and MAMA (banned UK 1970s)

• Breast cancerBreast cancer small or largesmall or large dosesdoses

Progestogen PotencyProgestogen Potency•

ANDROGENICANDROGENIC PROGESTOGENICPROGESTOGENIC• Estrane Estrane GonaneGonane PregnanePregnane•

• NorethisteroneNorethisterone 1 dl-Norgestrel 2.6 MPAMPA 0.3 • N AcetateN Acetate 1.2 MA 0.4

• Micronised x 2 potency - OralOral ProgesteroneProgesterone•

• Levonorgestrel Levonorgestrel 5.3 • NorgestimateNorgestimate 1.3 • Desogestrel Desogestrel 9 • GestodeneGestodene 12.6

•

Actions of ProgesteroneActions of Progesterone

• Blocks FSH and LH - prevents Blocks FSH and LH - prevents ovulationovulation

• Switches immune balance T1 Switches immune balance T1 →→ T2 T2

• Antibody production Antibody production ↓↓↓↓• Symptoms – increased - Symptoms – increased - decreaseddecreased

• Immune diseases - Immune diseases - PMS, SLEPMS, SLE

Genetics and EpigeneticsGenetics and Epigenetics

• Epigenetics – changes in gene functionEpigenetics – changes in gene function

• Koa 2002 12,686 genes 12,686 genes implantation windowimplantation window

• I in 25 genes activatedI in 25 genes activated

• ProgesteroneProgesterone 4 x 4 x genes genes cf Oestrogencf Oestrogen

Progesterone –activated genesProgesterone –activated genes

• 377 up 377 up regulatedregulated

• 156 down regulated156 down regulated• Striking Regulation of Striking Regulation of Secretory Proteins Secretory Proteins • Water and Ion Channels Water and Ion Channels • Signalling MoleculesSignalling Molecules • Immune ModulatorsImmune Modulators

• Endometrial Development Endometrial Development • Embryonic Interactions.Embryonic Interactions.

P upregulated genesP upregulated genes

• cholesterolcholesterol trafficking and transport trafficking and transport • apolipoprotein E 100-foldapolipoprotein E 100-fold• prostaglandin (PG)prostaglandin (PG) biosynthesis (PLA2) and biosynthesis (PLA2) and

action (PGE2 receptor)action (PGE2 receptor)• proteoglycan synthesis (glucuronyltransferase), proteoglycan synthesis (glucuronyltransferase),

secretory proteinssecretory proteins (glycodelin, mammaglobin, (glycodelin, mammaglobin, Dickkopf-1 - a Wnt inhibitor), Dickkopf-1 - a Wnt inhibitor), IGF binding proteinIGF binding protein and TGF-beta superfamiliesand TGF-beta superfamilies, signal , signal transduction, extracellular matrix components transduction, extracellular matrix components (osteopontin, laminin)(osteopontin, laminin)

• neurotransmitter synthesis -MAO, receptorsneurotransmitter synthesis -MAO, receptors

PP down regulated genes down regulated genes

• Intestinal Trefoil Factor (ITF) - 50-foldIntestinal Trefoil Factor (ITF) - 50-fold• matrilysin, members of the G protein-coupled

receptor signaling pathway, frizzled-related protein (FrpHE, a Wnt antagonist)

• Transcription Factors, TGF-beta signaling Transcription Factors, TGF-beta signaling pathway memberspathway members

• Immune ModulatorsImmune Modulators (major histocompatibility (major histocompatibility complex class II subunits) and other cellular complex class II subunits) and other cellular functions functions

PP up regulated genesup regulated genes

• Numerous Numerous Immune ModulatorsImmune Modulators

• Detoxification genesDetoxification genes MetallothioneinsMetallothioneins

• Genes involved in water and ion Genes involved in water and ion transport - transport - K(+) ion channelK(+) ion channel

• Genes corresponding to IGFBP-1, glycodelin, Genes corresponding to IGFBP-1, glycodelin, CPE1-R, Dkk-1, mammaglobin, and ApoDCPE1-R, Dkk-1, mammaglobin, and ApoD.

↑↑↑↑ Cu/Zn ratios in sweatCu/Zn ratios in sweat (serum and hair) (serum and hair) in in treatedtreated women - parts per billion at Biolab women - parts per billion at Biolab

RCGP OCRCGP OC Study Study VascularVascular

• 1974 DVTHROMBOSIS /PE 5.66DVTHROMBOSIS /PE 5.66• Heart disease 5.2• Cerebrovascular 4.1 DeathsDeaths• 1981 VascularVascular 4.24.2• non smoker 1.6 - 4.6• smoker 3.4 - 7.4 • 1983 AMI +Toxaemia history 41.0• 1999 Cerebrovascular Cerebrovascular +10 years+10 years 2.72.7

RCGP OC Study - RCGP OC Study - CancersCancers

• Breast cancer age 25-29 2.53

• Breast cancer age 30-34 3.33• Breast + 10 yrs 10.17• Breast 8-9 yrs later 15.8• Breast cancerBreast cancer deaths deaths 154 5- 9 yrs later 1.51.5• Lung cancerLung cancer 75 1.3 + 10 yrs 1.61.6 • Liver cancer 5 5.0Liver cancer 5 5.0

RCGP OC StudyRCGP OC Study

• Cervical cancerCervical cancer 2 - 3 Deaths Deaths > 10yrs> 10yrs 5.3 5.3• Pruritis, vaginitis, 2• Trichomonas, leukorrhoea, cervicitis 1.6Trichomonas, leukorrhoea, cervicitis 1.6• Ex OC Irregular bleeding 1.55Ex OC Irregular bleeding 1.55• Fibroids 2.5Fibroids 2.5• Post Pill amenorrhoea - infertility 3.2Post Pill amenorrhoea - infertility 3.2

• Abortions 13.3% Abortions 13.3% →→ 30.61% 30.61%

RCGP OC STUDYRCGP OC STUDY

NOT “ALL CLEAR”NOT “ALL CLEAR”

Over 60 conditions increasedOver 60 conditions increased immune diseases, infections and allergiesimmune diseases, infections and allergies

SERIOUS IMMUNE SERIOUS IMMUNE DYSFUNCTIONDYSFUNCTION

Walnut Creek OC StudyWalnut Creek OC Study

• Cervical cancer x12Cervical cancer x12

• Ovarian retention cystsOvarian retention cysts• Severe acute iron deficiency Severe acute iron deficiency anaemiaanaemia

• FibroidsFibroids (vascular)(vascular)

• Adenomyosis (Adenomyosis (endometriosisendometriosis))

• Hysterectomies Hysterectomies < age 40< age 40 6.3% x2.5 6.3% x2.5• All Significantly Increased All Significantly Increased → HRT “use” ++→ HRT “use” ++

Endocrine-disrupting chemicalsEndocrine-disrupting chemicals

• Over Over 7070 years of animal research years of animal research

• Hormones organise the brainHormones organise the brain • Peri-natally - critical timingPeri-natally - critical timing

• Modify sexuality, perception and learning

• Endogenous - twins - risk taking – Endogenous - twins - risk taking – aggressionaggression

• Aromatase inhibitors , pesticides, fungicidesAromatase inhibitors , pesticides, fungicides

• Crews and McLachlan 2006Crews and McLachlan 2006

Fertility and pregnancy hormonal Fertility and pregnancy hormonal “treatments”“treatments”

• Genital organ malformations infertility treatmentGenital organ malformations infertility treatment

• HR HR 2.32 2.32 Zhu JL, Danish national birth cohort. BMJ, 2006

• Progesterone /progestogensProgesterone /progestogens• 4 weeks 4 weeks beforebefore toto14 weeks 14 weeks afterafter conceptionconception

• HYPOSPADIASHYPOSPADIAS OROR 3.73.7 Carmichael 2005

Effects of P on developmentEffects of P on development• Most pregnancy Most pregnancy ProgesteroneProgesterone use use nownow• ↑↑ Cancers in children,Cancers in children, DES breast, vaginal DES breast, vaginal

• Testicular Leukaemia Neuroblastomas Testicular Leukaemia Neuroblastomas

• Brain DevelopmentBrain Development ↓↓SStress copingtress coping

↑↑MMental illnessental illness ↑↑Autism x4Autism x4

• Sexual Orientation - Organ AbnormalitiesSexual Orientation - Organ Abnormalities

• Immune DysfunctionImmune Dysfunction ↑ ↑ AllergiesAllergies

Progesterone carcinogenesisProgesterone carcinogenesis

• A Preventable Epidemic ?A Preventable Epidemic ?

• WHI, MWS and WISDOM HRT trials WHI, MWS and WISDOM HRT trials terminated earlyterminated early

• butbut very young OC use very young OC use

• off prescription very high doses ECsvery high doses ECs

• depot MPA depot MPA still vigorously promotedstill vigorously promoted

Ellen Grant on lineEllen Grant on line

• www.tandf.co.uk/journals

• J Nutr Environ Med June 1998J Nutr Environ Med June 1998

• www.bmj.com Search - Grant, EGrant, E Articles and Rapid Responses

• NCBI www.pubmed.gov - grant ecgrant ec