Gender Basic January 2007 Integrating the dimension of sex and gender into basic life sciences...

Gender Basic January 2007

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 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………..

“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 ………

• Use of language• Masculinity• Femininity• Or a continuum

Male Female


Sex and Gender

Sex• Genetic• Molecular• Cellular• Physiologica

l

Gender• Psychological• Environmenta

l• Social• Cultural


Sex and Gender

Sex• Genetic• Molecular• Cellular• Physiologica

l

Gender• Psychological• Environmenta

l• Social• Cultural

inte

ract

ions


Example of sex/gender interactionIrritable 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)


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


Experimental questions:

Is there a sex difference? No

‘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


Experimental questions:

Is there a sex difference? No

Consider forces that cancel each

other out

‘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?

Is this a

gender effect?

Does this change with pathophysiology?


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)


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


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)


Body composition

0%

50%

100%

1 2men women

water

fat

solids - proteins


Physical factors – application

0%

50%

100%

1 2

1 acid glycoprotein• reduced by oestrogen

• albumin• reduced in pregnancy

men women


Visceral stimulation and vasopressin (AVP) release(Holdcroft et al Br J Anaesth 2000)

•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)

Inflate colorectal balloon

Inhalation anaestheticEMG


Visceromotor response

(Holdcroft et al Br J Anaesth 2000)


Visceral stimulation and AVP release

Mean (SEM) male female

AVP pmol/lPre-stimulation

1.34(0.38)

1.54(0.24)

AVP pmol/lPost-stimulation

2.24(0.74)

2.88(0.58)

BalloonPressure mmHg

64(4)

41(1)

(Holdcroft et al Br J Anaesth 2000)

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

male F proestrous F oestrous F metestrous F diestrus

AV

P d

iffe

ren

ce p

mo

l/l

0

10

20

30

40

50

60

70

male F proestrous F oestrous F metestrous F diestrus

ball

oo

n p

ressu

re m

mH

g

Sex differences•Post stimulation in AVP (P=0.002)•Balloon pressure (P=0.002)Hypothalamopituitary axis is more reactive-females>males

balloon

inhalation




• Age• Physical composition/size• Environment/time of day• Methodology (site, stimulus,



Parity and breast pain

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.

Pain scores parity


NGF increases in painful breast tissues

Gopinath, Wan, Holdcroft et al 2005

No pain

Breast pain


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


Nociceptor neurochemicals/receptors influenced by hormone manipulations (Holdcroft &

Berkley 2005)

• 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

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

Hu

mans

An

imals


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


Small gender differences become BIGCoronary 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)


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


Heat stimuli and cerebral activation

H215O

Heat stimulus

PET = positron emission tomography

regionalblood flow


Paulson et al Pain 1998

Gender differences to somatic pain

40oCInnocuous

50oCNoxious

Moreresponsein femalesP = 0.05


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

1998)

Stimulus M/F Effect size*

Number of studies

pressure 490/459 0.59 5

thermal heat

168/153 0.46 8

electrical 74/56 0.59 3

ischaemia

34/44 0.18 1

* mean males – mean females/pooled SD


Thermal stimuli and sites

Heat stimulus

‘Forced choice method’


Thermal stimuli: males and females

Arm

Back

Abdomen

Temperature

Pro

ba

bili

ty

40 42 44 46 48

0.0

0.2

0.4

0.6

0.8

1.0

FEMALEMALE

Probability of reporting alldata (with 95% CI) over temperature range 40-49 Celsius

ARM

Temperature

Pro

ba

bili

ty

40 42 44 46 48

0.0

0.2

0.4

0.6

0.8

1.0

FEMALEMALE


ABDOMEN

Temperature

Pro

ba

bili

ty

40 42 44 46 48

0.0

0.2

0.4

0.6

0.8

1.0

FEMALEMALE


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.


Thermal stimuli - hormones

Significant difference between F&M vs OCP

(P=0.001, Wald test)


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


Thanks to….Karen BerkleySaz SnidvongsCaroline DoréAngie CasonNadeem SayeedPaul Facer

Ed Keogh Akta Patel Katherine Mc Ginn David Stephens

Mary ForslingPreethi GopinathElaine WanPraveen AnandSue Sapsed-ByrneDaqin MaMK Chakrabarti

Gender Basic January 2007 Integrating the dimension of sex and gender into basic life sciences...

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