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Integrating the dimension of sex and gender into basic life sciences research: problems and solutions. Dr Anita Holdcroft MB ChB MD FRCA Reader in Anaesthesia and Honorary Consultant Anaesthetist. Sex……. the “ classification of living things, generally as male or female

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Integrating the dimension of sex and gender into basic life sciences research:problems and solutions

Dr Anita Holdcroft MB ChB MD FRCA

Reader in Anaesthesia and Honorary Consultant Anaesthetist

Gender Basic January 2007


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Sex……

the “classification of living

things, generally as male or female

according to their reproductive organs

and functions assigned by

chromosome complement”

‘Exploring the biological contributions to human health.

Does sex matter?’

Wizemann and Pardue IO M, National Academy Press 2001 p17.

Gender Basic January 2007


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Gender………..

“a person’s self-representation as

male or female, or how that person

is responded to by social

institutions on the basis of the

individual’s gender presentation”

‘Exploring the biological contributions to human health.

Does sex matter?’

Wizemann and Pardue IO M, National Academy Press 2001 p17.

Gender Basic January 2007


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Gender ………

  • Use of language

  • Masculinity

  • Femininity

  • Or a continuum

    MaleFemale

Gender Basic January 2007


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Sex

Genetic

Molecular

Cellular

Physiological

Gender

Psychological

Environmental

Social

Cultural

Sex and Gender

Gender Basic January 2007


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Sex

Genetic

Molecular

Cellular

Physiological

Gender

Psychological

Environmental

Social

Cultural

Sex and Gender

interactions

Gender Basic January 2007


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Example of sex/gender interaction

Irritable bowel syndrome: symptoms

  • Females > Males

    (Corney & Stanton 1990, Talley 1991, Taub et al 1995, Heitkemper et al 2003)

    • Longer episodes of pain

    • Constipation

    • Bloating

  • Why?

    • Physiology (Heitkemper et al 2003)

    • Factors exacerbating symptoms

      • Greater female:male use of OTC medications

        (Isacson & Bingefors 2002)

Gender Basic January 2007


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Developing guidelines in Sex and Gender research

  • Endocrinology Becker et al 2005;146:1650

    “Strategies and methods for research on sex differences in brain and behavior”

    Supported by the Society for Women’s Health Research (USA)

  • IASP SIG Sex, gender and pain

    (International Association for the Study of Pain, Special Interest Group)

    3 groups: basic science, translational (human experimental), clinical (human disease)

    in progress from September 2006

Gender Basic January 2007


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Experimental questions:

No

Is there a sex difference?

‘Yes’-Test for sex hormones at time of testing

‘No’ -Test for developmental effects of sex hormones

‘No’- Test for sex chromosome effects

Was the sex difference lost on the way?

Strategies and methods for research on sex differences in brain and behavior’ Becker 2005

Gender Basic January 2007


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Experimental questions:

Consider forces that cancel each other out

No

Is there a sex difference?

‘Yes’-Test for sex hormones at time of testing

‘No’ -Test for developmental effects of sex hormones

‘No’- Test for sex chromosome effects

Is this a gender effect?

Was the sex difference lost on the way?

Does this change with pathophysiology?

Gender Basic January 2007


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Is there a sex or gender difference?

Examples of factors influencing results:

  • Age

  • Physical composition/size

  • Environment/time of day/experimenter

  • Methodology (site, stimulus, analysis)

  • Reproductive history (cycle, parity)

Gender Basic January 2007


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Age

‘Qualitative sex differences in kappa-opioid analgesia in mice are dependent on age.’

Sternberg WF, Ritchie J, Mogil JS. (Neurosci Lett. 2004)

Response to -opioid analgesia and

NMDA antagonist blocked in

  • male rodents

  • elderly females (partial)

    not blocked in

  • hormonally intact females

Gender Basic January 2007


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Confounding factors for age:

  • Definition of aging:variable e.g. 9 – 30m

  • Time of gonadectomy

    • Perinatal: organisation of neural pathways

    • Adult: activation

  • Analysis: young versus old; continuous

  • Changes in opioid mechanisms with age

    • Opioid receptor binding, affinity and concentrations decreased in regional and whole brain assays

    • Levels of beta-endorphin, leu-enkephalin, met-enkephalin decreased

      (Organismic variables and pain inhibition: roles of gender and aging.

      Bodnar RJ, Romero M-T, Kramer E. Brain Res Bull, 1988)

Gender Basic January 2007


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Is there a sex or gender difference?

Examples of factors influencing results:

  • Age

  • Physical composition/size

  • Environment/time of day/experimenter

  • Methodology (site, stimulus, analysis)

  • Reproductive history (cycle, parity)

Gender Basic January 2007


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Body composition

water

fat

solids - proteins

men women

Gender Basic January 2007


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Physical factors – application

  • 1 acid glycoprotein

  • reduced by oestrogen

  • albumin

  • reduced in pregnancy

men women

Gender Basic January 2007


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Is there a sex or gender difference?

Examples of factors influencing results:

  • Age

  • Physicalcomposition/size

  • Environment/time of day/experimenter

  • Methodology (site, stimulus, analysis)

  • Reproductive history (cycle, parity)

Gender Basic January 2007


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Visceral stimulation and vasopressin (AVP) release

(Holdcroft et al Br J Anaesth 2000)

EMG

Inhalation anaesthetic

Inflate

colorectal balloon

  • Males (n = 5) and females (n = 22)

  • AVP measured pre and post stimulation

  • Balloon pressure measured at the time when the visceromotor response was obtained (EMG)

Gender Basic January 2007


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Visceromotor response

(Holdcroft et al Br J Anaesth 2000)

Gender Basic January 2007


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inhalation

Visceral stimulation and AVP release

balloon

  • Sex differences

  • Post stimulation in AVP (P=0.002)

  • Balloon pressure (P=0.002)

  • Hypothalamopituitary axis is more reactive-females>males

(Holdcroft et al Br J Anaesth 2000)

Gender Basic January 2007


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Is there a sex or gender difference?

Examples of factors influencing results:

  • Age

  • Physical composition/size

  • Environment/time of day

  • Methodology (site, stimulus, analysis)

  • Reproductive history (cycle, parity)

Gender Basic January 2007


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Parity and breast pain

Pain scores

parity

Holdcroft, A., Snidvongs, S., Cason, A., Dore, C., Berkley, K.J. “Pain and uterine contractions during breast-feeding in the immediate post-partum period increased with parity.”

Pain 104, (2003), 589-596.

Gender Basic January 2007


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NGF increases in painful breast tissues

No pain

Breast pain

Gopinath, Wan, Holdcroft et al 2005

Gender Basic January 2007


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Is there a sex difference?

Examples of how sex differences are lost -

  • Select random females

  • Small groups

  • Housing: females living together synchronise cycles

  • Variability among animals/humans

Gender Basic January 2007


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ACTH

Angiotensin II

αMSH

AVP

Bradykinin

CCK

CorticotropinRH

Galanin

GABA

Glucagon

GH

GHRH

Insulin

LH

Motilin

NGF

Prolactin

Somatostatin

Thyrotropin

Thyrotropin RH

VIP

VR1

AVP

Bradykinin

Bombesin

Cannabinoids

CCK

Choline acetyltransferase

Dopamine

Enkephalins

Galanin

GABA

Glutamate

Insulin-like growth factor

NMDA

Neurokinin A

NGF

NO

Oxytocin

Preproenkephalin

Serotinin (5-HT)

Substance P

VR1/TRPV1/Vanilloid receptor

Nociceptor neurochemicals/receptors influenced by hormone manipulations(Holdcroft & Berkley 2005)

Animals

Humans

(from Medline search using agent and ‘hormone’ ‘reproductive cycle’ etc)

Gender Basic January 2007


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Morphine analgesia and sex differences depend on strain of mice M = ; F =

F>M

M>F

M>F

M>F

Kest, Wilson and Mogil 1999

Gender Basic January 2007


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Small gender differences become BIG

Coronary artery disease (Visceral pain)

  • Symptoms and co-morbidity differ

  • Females: nausea, SOB, throat, neck, jaw and back pain more common (Philoptt et al 2001, Kyker & Limacher 2002)

  • Females: more diabetes and older (Weintraub et al 1993)

  • Diagnosis and treatment ‘a woman has to masquerade as a man in order to receive the same treatment’ = Yentl syndrome (Swahn 1998)

  • Females had twice the morbidity of males for CABG surgery (Woods etl al 2003)

Gender Basic January 2007


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Study design

  • Animal models relate to human conditions

    • Comorbidity (in human disease)

    • Gender effects

  • Reduce variation

    • Physical factors

    • Biological rhythms

    • Other factors

  • Study size and analysis

    • Meta-analysis (comparison, evidence basis)

    • Selection of measurement time/state

  • Interactions at molecular level

  • Peer review

Gender Basic January 2007


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Heat stimuli and cerebral activation

PET = positron emission tomography

H215O

regional

blood

flow

Heat

stimulus

Gender Basic January 2007


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Gender differences to somatic pain

Paulson et al Pain 1998

40oC

Innocuous

More

response

in

females

P = 0.05

50oC

Noxious

Gender Basic January 2007


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Sex differences in the perception of noxious stimuli: threshold(Riley 1998)

* mean males – mean females/pooled SD

Gender Basic January 2007


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Thermal stimuli and sites

Heat

stimulus

‘Forced choice method’

Gender Basic January 2007


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Thermal stimuli:males and females

Arm

Abdomen

Back

Forced choice method

Patel A, Keogh E, Stephens D, Holdcroft A. Sex differences in pain: a new methodological approach. Br J Anaesth 2005;94:402P.

Gender Basic January 2007


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Thermal stimuli - hormones

Significant difference between F&M vs OCP

(P=0.001, Wald test)

Gender Basic January 2007


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Study design

  • Animal models relate to human conditions

    • Comorbidity (in human disease)

    • Gender effects

  • Reduce variation

    • Physical factors

    • Biological rhythms

    • Other factors

  • Study size and analysis

    • Meta-analysis (comparison, evidence basis)

    • Selection of measurement time/state

  • Interactions at molecular level

  • Peer review

Gender Basic January 2007


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Thanks to….

Mary Forsling

Preethi Gopinath

Elaine Wan

Praveen Anand

Sue Sapsed-Byrne

Daqin Ma

MK Chakrabarti

Karen Berkley

Saz Snidvongs

Caroline Doré

Angie Cason

Nadeem Sayeed

Paul Facer

Ed Keogh

Akta Patel

Katherine Mc Ginn

David Stephens

Gender Basic January 2007


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