Gender Aspects in Cognitive Neuroscience Do Ovarian Hormones Affect Somatosensation, Pain, and Mood? Laboratory of Cognitive Neuroscience and Women s Health Department of Pyschology and School of Public Health University of Toronto Visiting Professor of Neuroscience and Gender Medicine, Linköping University
Plan: i. Brief overview of estrogenic (an ovarian hormone) effects on neurons ii. Highlight what is known about ovarian hormones and Pain Somatosensation Mood
Do Hormones (esp. Estrogens) Act On Neurons?
Estrogenic Actions in CNS transcription neurite outgrowth (Toran-Allerand, 1976) spine density & connectivity (Woolley & McEwen, 1992)
Do Ovarian Hormones Affect Somatosensation? Penfield & Cantlie s Homunculus
Ovarian Hormones & Somatosensation Variation in the size and sensitivity of a genital sensory field in relation to the estrous cycle in rats Adler et al., 1977. Hormones & Behavior 9, 334-344. Estrogens increase spine density in rat somatosensory cortex Khan et al., 2013. Steroids 76, 614-623. Nursing alters the representation of the ventrum and receptive field sizes of neurons in rat somatosensory cortex Xerri et al., 1994. J. Neurosci. 14, 1710-1721.
What Do We Know About Humans? Significant differences in regional activation during different phases of the menstrual cycle. During midfollicular phase, increased RGM in prefrontal cortex Reiman et al., 1996. Hum Reprod 11, 2799-2806. What Do We Know About the SS Map?
What Do We Know About the SS Map?
Wilder Penfield s Work Penfield recorded from 1065 patients, 107 of which were women, 121 for whom sex was not reported Penfield and Rasmussen, 1950: 400 operations, 9 were women
What Have Those Since Penfield Shown?
What needs doing re Somatosensation? Fill in the female somatosensory map to include the rest of the body. What happens during pregnancy, menopause, normal aging, and neurodegenerative disease? What happens to the map after surgeries such as oophorectomy, prostatectomy, heart and kidney transplants Given the often experienced outcome of chronic pain, of particular interest to understand changes in cortical maps After cosmetic surgery e.g., breast implants, labia reduction, and traditional practices such as female genital mutilation/circumcision/cutting (Einstein 2008)
Ovarian Hormones & Pain ER in PA grey, thalamus, amygdala, central grey Places on the pain pathway that estrogens might act density of ER changes with estrogen levels over the MC Modulate Signal transmission
Pain: Clinical Studies Women are more sensitive to experimentally induced pain & tend to have lower pain thresholds than men (Paller, Campbell et al., 2009; Riley et al. 1998; Wiesenfeld-Hallin, 2005) Many chronic non-cancer pain (CNCP) conditions occur more frequently in women (Berkley, 1997; LeResche, et al., 2003; Unruh, 1996) CNCP displays a significant increases in prevalence between puberty and menopause, i.e., in the reproductive years (Martin, 2009) Does the literature support ovarian hormones as responsible for this sex difference?
Ovarian Hormones & Pain
Pain Open-ended Search of literature 1983-2012 50 relevant clinical studies! musculoskeletal pain (MSP) = 8 migraine headache = 9 temporomandibular disorder = 5 chronic pelvic pain = 28 Endometriosis (22 RCTs trying hormone therapy)
Pain conditions more common in reproductive years musculoskeletal pain (MSP) fibromyalgia, rheumatoid arthritis migraine headache temporomandibular disorder chronic pelvic pain irritable bowel syndrome ulcerative colitis Crohn s disease Endometriosis interstitial cystitis
Pain All pain conditions overwhelming reported changing pain with changing cycle phase or exogenous hormones
Pain Some good evidence! Defined a menstrual migraine, treatable with Oral Contraceptives Endometriosis is as successfully treated with exogenous hormones as with surgery
Pain Some methodological problems Used MC as a proxy for ovarian hormones Interpreted cycle phases as indication of hormone levels Only 3 studies/50 actually measured hormones Didn t take into account any treatments participants might be taking Didn t take into account overlapping pain conditions
Summary re Pain Some good evidence that ovarian hormones affect CNCP, driving this sex difference This could have important clinical implications for treatment; and already does for some conditions But methodological gaps mandate better studies before findings will have clinical impact
Do Ovarian Hormones Affect Women s Mood?
PMDD: depressive condition in sync with menstrual cycle PMDD3-9% adult females Disinterest in daily activities and relationships Fatigue or low energy Feeling of sadness or hopelessness, possible suicidal thoughts Feelings of tension or anxiety Feeling out of control Food cravings or binge eating Mood swings marked by periods of teariness Panic attack Persistent irritability or anger that affects other people Physical symptoms, such as bloating, breast tenderness, headaches, and joint or muscle pain Problems sleeping Trouble concentrating (Rubinow & Schmidt, 2006) 22/61
What about the Lesser Form, PMS? PMS 80%? adult females PMDD symptoms to a lesser extent EIGHT in ten women experience it and finally there s a medical explanation for premenstrual syndrome evolution! http://www.news.com. au/lifestyle/health/pms -or-premenstrualtension-is-naturesway-for-women-toget-rid-of-theirunproductive-malepartners/storyfneuzlbd- 1227022139214
Premenstrual Syndrome (PMS) What is the evidence that women suffer negative moods at the premenstrum?
PMS Literature Review 1806 to 2012 T = 646 published papers 47 = daily prospective data for at least 1 full cycle 43 = adequate power 38% = no association of mood with any MC phase 38% = neg mood in premenstrum + 14% = neg mood in post-menstrum 8.5% = neg mood in another ms phase When MC focus of the study was obscured, association of the premenstrual phases of the MC with negative mood was unusual.
Mood & Daily Life Study 76 non-help seeking community dwelling women (GTA) Over 3 months; backward counting method
Does menstrual cycle influence daily mood?
Does menstrual cycle influence daily mood? A time series periodogram was created for each DLQ item for each participant (17! 78 = 1,326 individual time series). If menstrual mood cyclicity does exist, the periodograms would reveal a predominance of significant spectral peaks in the 24- to 32-day period region They did not
Mood & Daily Life Study measure hormones directly
Mood & Daily Life Study measure hormones directly is mood actually linked to hormones? subgroup of the larger study (19 participants) who agreed to collect 1st urine of the day are mood items, positive or negative, correlated with levels of E1G or PdG?
Mood & E1G & PdG Schwartz et al., 2012
Summary PMS In healthy, non-help seeking women: mood does not correlate with one stage of the menstrual cycle (such as premenstrual or late luteal) mood is not correlated with E1G or PdG mood is highly correlated with psychosocial factors: stress & social support no good evidence that estrogens and progestagens contribute to mood PMS may be gender
Take Home Messages re Estrogens in the CNS & CNS Conditions NEURONS: Estrogens affect neurons; their connectivity; & their excitability SOMATOSENTATION: We need more studies of somatosensation in women but good evidence that estrogens affect the size of representations in rodents CNCP: Hormones are implicated in some CNCP conditions: pelvic pain (endometriosis) & menstrual migraine. MOOD: No good evidence for hormones affecting mood in healthy non-help seeking women
Conclusion Telling participants that you are studying the menstrual cycle leads to studies of what they (and the rest of society) thinks about the menstrual cycle. Something can have an effect on neurons but not, necessarily on behaviour (like estrogens) (it takes many neurons across many systems to generate a behaviour) So many variations in menstrual cycle both within and between women that it cannot be taken for granted studies that use the menstrual cycle as a proxy for hormone levels will have muddied and possibly no significant results
Current Study to Understand Effects of Ovarian Hormones on Cognition Cognition in women with oophorectomy prior to natural menopause April Au, PhD candidate
Ovarian Hormones & Pain Mood in Daily Life Samah Hassan Sarah Romans, MD Abi Meure Mary Jane De Souza Soumia Meiyappan Deborah Schwartz, MA Somatosensory Cortex Paula Di Noto, PhD candidate Leorra Newman, PhD candidate Shelley Wall, PhD
Thank You!
Schwartz et al., unpublished data
Mood & Menstrual Cycle Phase
Mood & Menstrual Cycle Phase 60 50 DLQ Rating (/100) 40 30 20 Early Follicular Late Follicular Early Luteal Late Luteal 10 0 Positive Mood Negative