pcos workshop

AE PCOS 2024

Posted by Ruby on May 10, 2024

Testosterone and immune

Masculinizing hormone therapy

n=23 XX — 0-12 month

Profile immune system by

  • Mass cytometry
    • pDC⬇️ CD141+DC⬆️ MDSC⬇️ Monocytes⬇️
  • bulk RNA-seq and scRNA-seq
    • IFNa
  • Olink
    • inflammatory: CXCL9, OSM, TNF, RANKL, S100A12, TRAIL p11

in-vitro functional test (cellular)

4h TLR7/8 —> scRNA profile

pDC: IFNa ⬇️ , Type-I and Hallmark IFNa

Monocyte: Hallmark IFNa⬇️

p12

PCOS

  • low grade inflammation
  • asthma
  • SARS-COV2, COVID19

n=58 control, n=108 PCOS,

p13

→ Olink

→ metbaolic markers: HOMA_IR, BMI (~CSF1, PDL1), SHBG

→ reproductive markers: testosterone, FGscore, LH

correlation between metabolic and reproductive markers lost in PCOS

testosterone, positive with immune marker in control, negative in PCOS

??cells: CSF1, CCL2,

myeloid cells: IL-6, S100A12, OSM

?? cells: S10A12, OSM

—> IL-18, IL18R1 —> TYPE 1 IMMUNE RESPONSE

—> turning down immune ??

MYELOID CELL ACTIVATION, INFLAMMASOME SIGANLING AND IMMUNE EXHASUTION

QA

Q1: from genetics, testestrone not the driver? Q2: transman vs man Not completely switched

PCOS endometrium

proinflammatory Macrophage <- ?? cell type antiflammatory Macrophage <- ?? cell type

hyperandrogenism –> immune functions –> insulin + xx (androgen?)

mice model: normal weight PCOS

in uterus eosinophil⬇️ （Eotaxin⬇️, IL5 not changed） NK matruation (with markers) ⬆️

Adipose tissue

  • eosinophole ⬇️ in visceral adipose tissue
  • CD69+ NK ⬇️
  • mature NK ⬇️

Testosterone on TLR in transmen

Background

TLR higher in female, TLR7/8 on chrX, GAHT on immune (Gap and Aim)

Methods and results

Prospective observatory study, 21 transmen,

karyotype + RT-PCR for TLRs（8, 10 ⬇️）, CD144, MD2 ⬆️

Prepubertal Primate model and Immune function

primate models and metabolism

2.5 yo –> 5.5 yo

  • chow
  • T+chow
  • WSD
  • T+WSD

-> fetility trials (util 7yo) -> reversal with chow to 7.5 yo

—- functional dissection – 3 yo treatment (not sig. until 2 yo)

  • T+WSD: fasting insulin HOMA-IR BW (BV,VF), FFA update, lipolysis ⬆️
  • NOT with individual treatments
  • innate immunity and TLRs

– 7 yo treatment and 0.5 yo reverse

another cohort to focus on immune

1 yo treatment (from 6 yo to 7 yo)

  • chow

  • T+WSD –> metabolism & immune

  • adipocyty% changed
  • C-peptide and CCL5 not changed

–> immune cells in peripheral tissues and blood by FC with

  • lymphoid surface
  • macrophage surface
  • TLR stimulation cytokine response NOT significant

–> macrophage response to TLR1/2

control response in IL6⬆️, and %CD11b+HLA-DR+cells

–> T cells not significant changes

–> memory T cells Tn, Tcm, Tem (CD28, CD95) in omental fat, CD8+ effector memory cells ⬇️ by hyperandrogenemia, coor with HOMA-IR in OM-FAT WSD alone does not alter

summary-p4

11-oxygenated androgens in PCOS

chronic kidney disease (Hsd) -> 11-oxygenated androgens⬇️

methods

  • oral DHEA (n=10)
  • oral 11KA4 (97% purity) (n=10) -> androgen metabolism -> insulin resistance [2-step (low -> high dose insulin) hyperinsulinaemic-euglycaemic clamp]

results

D7:

  • DHEA: [classic] A4, T, DHT; DHEA ⬆️, 11KA4: not change
  • [11O androgen pathway] 11OHA4, 11KA4, 11OHT, (urinay) 11OHAn, 11OHRt, … ⬆️ in 11KA4, not in DHEA
  • insulin resistance, neither changed

QA-p5

  • dosage effects
  • adipose tissue (no), muscle biopses (on going): data awaited
  • clinical concern: androgen to high-androgen pcos women; side effects after D7? three month DHEA before IVF, so probably no side effects with 7 days oral treatment

Kispeptin as a test of hupothalamic function in women with oligo-amenorrhea

Presenter: Bijal Patel

menstrual disturbance (1/5) <- PCOS/HA(hypothalamic amenorrhoea)M- low bw, excessive exercise, ??, ?? difficulty in differentiation

both have divergent hypothalanic function:

GnRh frequency： PCOS: ⬆️, HA: ⬇️

congenital structural aberrance (CHH)

Results from kisspeptin given

kisspeptin-54 9.6nmol/kg: ⬆️LH and FSH in PCOS, the LH response similar to control; FSH reduced compared to control

Influencers by correlation: Inhibin B; AMH obesity increase LH and FSH response

Clinical lean PCOS; different after kispeotin vs HA

My question: discriminate three group AUCROC? PCOS vs CHH?

My guess: too obvious so no need clinically?

prenatal testosterone and offspring body composition (7yo)

Odense child cohort odense flowchart testosterone –> fetus (free testestrone ⬆️ from 3rd trimester)

monkeys: ⬆️abdominal fat mass in females

  • mother: total by LC-MS/MS; free by -SHBG; diagnosis
  • children: Fat%
  • DAG: factor analysis

results in boys

free testosterone ~ BMI, Fat mass index ⬆️； lean ⬇️

results in girls

NOT as significant in the sig. changes in boys

maternal PCOS ~ gynoid fat%⬇️ only

QA-p7

  • why corrected for birth weight, but not taking as interaction
  • Androgen/Estrogen ratio

Kidneys in PCOS

renal injury, AR ⬆️-> IL-6⬆️ ->(STAT)-> mitochondra

Other reference: placental stat3

so maybe we could look into IL-6/mitochondra (not feasible in the current project but future) in our PCOS project?

mice experiment

  • veh
  • pcos (DHT): IL-6, JAK1/2, STAT ⬆️, STAT inhibitors⬇️
  • STAT3 inhibitor
    • normal levels in the aforementioned expression
    • complex I, II, III, IV-; mtROS -> mitochondra dysfunction restore
    • renal injury restore

cellular experiments

DHT on renal cells

immune-metabolism and pregnancy loss

Tregs - uNK

Tregs deficiency in early pregnancy failure (EPF)

  • %Trreg/CD$+T
  • CTLA+ (suppressive marker)
  • /Th1 and /Th17

EPF upregulated in Treg pro-inflammatory 1/4 are FOXP3 targets

Q: if cellular abundance lower but transcription abundance increase; so much more increased from the cells?

Insulin/glycemic <–> inflammmation/immune tolerance

fasting and OGTT at 6w mid-phase post-miscarriage (at least 2 times, n=64) & T cell

  • HOMA-IR ⬆️ (insulin resistance)
    • not alter CD4+ & CD8+ T cell abundance, not Treg neither
    • reduce HLADR+CTLA4+HELLOs+ (suppressive markers)
    • reduce proliferating Treg (Ki67)
    • increase naive CCR7+CD45RA+ Treg
    • reduce central memory and effector memory Treg with genetically normal fetuses

targeted therapies

cluster of patients with immune and metabolic dysregulation

cytokines in PCOS pregnancy

presenter: Eszter Vanky

immune develppment in PCOS vs. normal

  • Normal (n=258):inflammation –> anti –> inflammation
  • PCOS (n=358) eszter inflammatory and growth cytokines eszter-2 In PCOS-placebo Score PC1, contributors: Eolaxin, IL-4, IL-17, PDGF-BB, FGF-b (decrease through pregnancy); IL-13, IL-IRa, … (increase through pregnancy) eszter-3 Also with mobility analysis
  • overweight/obesity
    • IL-IRa
    • CRP
  • hyperandrogenism
    • FGF-b
    • IL-2
    • IL-16
    • IL-8
  • fetal sex
    • meta-analysis with >12m individuals: male more PE and preterm
  • metformin
    • increase immune, eolaxin, FGF-b, IL-17, IL-4, …
    • less viral infection and allover infection
  • children at 7 yo
    • higher allergy and eczema from metformin

Now I have controlled fetal sex, or maternal BMI, two batches of analysis; but not both of them. Maybe I should just try one batch with both controlled.

In combination with our data, probably the effects to the offspring could be directly to the fetus, not really from placenta.

QA-Estzer

  1. 80% compliance for dosage (2.5g)
  2. insulin resistence ~ allergy: randomized controlled study, so the mechanism causes are random, no cause-effect from other factors
  3. concentration in the umbinical cord is the same in the the maternal serum
  4. placenta is highly vascularized so small molecules can accumulate
  5. leaky placentas

we have the results for the prior usage of metformin, it’s better to put them in hidden slides and answer the questions

CATALOG
    FEATURED TAGS
    诗歌 随笔 政治哲学 life server bioinformatics database thesis popular science workshop single cell technology
    FRIENDS