Hersenen en geslachtshormonen: over neurosteroïden, seksueel gedrag en de hersencyclus. Petra De Sutter UZ Gent Since Prof. Van Herendael asked me to talk about three topics, I thought he would give me three quarters of an hour to talk. I will do my very best to clear the job in 15 minutes. NEXT

Inleiding hersenen voortplanting seksualiteit Considering a presentation on alternative techniques for evaluation of abnormal uterine bleeding, the first question that came to my mind was : why? Why should we still use other investigational methods when we have such a powerful tool as hysteroscopy? So why not use it as a primary investigational tool? We already focused yesterday on the costs of hysteroscopy, which are considerably higher than for example ultrasound. Secondly, since in more than half of the cases of abnormal bleeding it is dysfunctional in cause, the « return » on surgical intervention will be much lower than 50%, so that preliminary screening is very appealing. Furthermore it remains an invasive procedure, which can cause some discomfort for the patients and can induce some complications. Of course we all know that these are rare in experienced hands, and I think that this is the main disadvantage of hysterocopy : it takes quite some experience. First, I would like to adress the case of transvaginal sonography. NEXT SLIDE voortplanting seksualiteit

hersenen voortplanting seksualiteit neurosteroïden ? steroïden Considering a presentation on alternative techniques for evaluation of abnormal uterine bleeding, the first question that came to my mind was : why? Why should we still use other investigational methods when we have such a powerful tool as hysteroscopy? So why not use it as a primary investigational tool? We already focused yesterday on the costs of hysteroscopy, which are considerably higher than for example ultrasound. Secondly, since in more than half of the cases of abnormal bleeding it is dysfunctional in cause, the « return » on surgical intervention will be much lower than 50%, so that preliminary screening is very appealing. Furthermore it remains an invasive procedure, which can cause some discomfort for the patients and can induce some complications. Of course we all know that these are rare in experienced hands, and I think that this is the main disadvantage of hysterocopy : it takes quite some experience. First, I would like to adress the case of transvaginal sonography. NEXT SLIDE voortplanting seksualiteit

Seksuele differentiatie en dimorfisme van de hersenen Seksualiteit en hersenen Oestrogenen, humeur en cognitie Considering a presentation on alternative techniques for evaluation of abnormal uterine bleeding, the first question that came to my mind was : why? Why should we still use other investigational methods when we have such a powerful tool as hysteroscopy? So why not use it as a primary investigational tool? We already focused yesterday on the costs of hysteroscopy, which are considerably higher than for example ultrasound. Secondly, since in more than half of the cases of abnormal bleeding it is dysfunctional in cause, the « return » on surgical intervention will be much lower than 50%, so that preliminary screening is very appealing. Furthermore it remains an invasive procedure, which can cause some discomfort for the patients and can induce some complications. Of course we all know that these are rare in experienced hands, and I think that this is the main disadvantage of hysterocopy : it takes quite some experience. First, I would like to adress the case of transvaginal sonography. NEXT SLIDE

Werking van steroïden Oestradiol: Bindt op ER-α en op ER-β (verschillende weefseldistributie, ook in de hersenen) Traag en langdurend genomisch effect Klassiek effect Snel en kortdurend non-genomisch effect Seksuele differentiatie hersenen? Plasticiteit hersenen ? T -> aromatase -> E2 (differentiatie in mannelijke richting ~ hogere dosis E2, o.a. de novo) Considering a presentation on alternative techniques for evaluation of abnormal uterine bleeding, the first question that came to my mind was : why? Why should we still use other investigational methods when we have such a powerful tool as hysteroscopy? So why not use it as a primary investigational tool? We already focused yesterday on the costs of hysteroscopy, which are considerably higher than for example ultrasound. Secondly, since in more than half of the cases of abnormal bleeding it is dysfunctional in cause, the « return » on surgical intervention will be much lower than 50%, so that preliminary screening is very appealing. Furthermore it remains an invasive procedure, which can cause some discomfort for the patients and can induce some complications. Of course we all know that these are rare in experienced hands, and I think that this is the main disadvantage of hysterocopy : it takes quite some experience. First, I would like to adress the case of transvaginal sonography. NEXT SLIDE

Werking van steroïden Oestradiol: Progesteron is ’ neurotroof ’: induceert synapsformatie, gaat de synapsdestructie oiv progesteron tegen remt apoptose en is anti-oxydans Induceert progesteron receptoren (progesteron doet E2 receptoren dalen!) Progesteron Allopregnanolon (metaboliet en neurosteroïd): bindt centraal op GABA-A receptor (centrale inhibitie -> sedatief-hypnotisch cfr barbituraten) >< pregnenolon: GABA antagonist ! Considering a presentation on alternative techniques for evaluation of abnormal uterine bleeding, the first question that came to my mind was : why? Why should we still use other investigational methods when we have such a powerful tool as hysteroscopy? So why not use it as a primary investigational tool? We already focused yesterday on the costs of hysteroscopy, which are considerably higher than for example ultrasound. Secondly, since in more than half of the cases of abnormal bleeding it is dysfunctional in cause, the « return » on surgical intervention will be much lower than 50%, so that preliminary screening is very appealing. Furthermore it remains an invasive procedure, which can cause some discomfort for the patients and can induce some complications. Of course we all know that these are rare in experienced hands, and I think that this is the main disadvantage of hysterocopy : it takes quite some experience. First, I would like to adress the case of transvaginal sonography. NEXT SLIDE

Prenatale steroïden en de hersenen Steroïdreceptoren: limbisch systeem (hypothalamus en amygdala) Regelt « overlevings » gedrag zoals honger, dorst, agressie, reproductie Sexueel dimorfe hersenkernen (knaagdieren) -> hypothalamus Mannetjes: A -> E2 -> mannelijk fenotype Geen LH surge op E2 stijging, agressief seksueel gedrag Vrouwtjes: E2 vnl gebonden en niet voorbij bloed-hersenbarrière -> vrouwelijk fenotype Wel LH surge op E2 stijging, receptief seksueel gedrag Omkeerbaar door castratie (M->V) of androgeentherapie (V->M) Considering a presentation on alternative techniques for evaluation of abnormal uterine bleeding, the first question that came to my mind was : why? Why should we still use other investigational methods when we have such a powerful tool as hysteroscopy? So why not use it as a primary investigational tool? We already focused yesterday on the costs of hysteroscopy, which are considerably higher than for example ultrasound. Secondly, since in more than half of the cases of abnormal bleeding it is dysfunctional in cause, the « return » on surgical intervention will be much lower than 50%, so that preliminary screening is very appealing. Furthermore it remains an invasive procedure, which can cause some discomfort for the patients and can induce some complications. Of course we all know that these are rare in experienced hands, and I think that this is the main disadvantage of hysterocopy : it takes quite some experience. First, I would like to adress the case of transvaginal sonography. NEXT SLIDE

Seksueel dimorfisme van de hersenen Mens: dimorfisme aangetoond, bepaalde kernen groter bij mannen dan bij vrouwen, behalve bij homoseksuelen (INAH3 – 3rd interstitial nc of the anterior hypothalamus) en transseksuelen (BSTc -bed-nucleus of the stria terminalis) Mol Brain res (2003): differentiële genexpressie (50tal genen) in de hersenen bij muizen, vóór steroïd differentiatie ! Considering a presentation on alternative techniques for evaluation of abnormal uterine bleeding, the first question that came to my mind was : why? Why should we still use other investigational methods when we have such a powerful tool as hysteroscopy? So why not use it as a primary investigational tool? We already focused yesterday on the costs of hysteroscopy, which are considerably higher than for example ultrasound. Secondly, since in more than half of the cases of abnormal bleeding it is dysfunctional in cause, the « return » on surgical intervention will be much lower than 50%, so that preliminary screening is very appealing. Furthermore it remains an invasive procedure, which can cause some discomfort for the patients and can induce some complications. Of course we all know that these are rare in experienced hands, and I think that this is the main disadvantage of hysterocopy : it takes quite some experience. First, I would like to adress the case of transvaginal sonography. NEXT SLIDE

Seksueel dimorfisme thv de hersenen Gender Mannelijk Vrouwelijk Gedrag Dominant, competitief Sociaal, intuïtief agressief emotioneel Inzicht Ruimtelijk, abstract Verbaal, artistiek Lateralisatie +++ - C. Callosum minder meer connecties INAH3 groot klein

hormonen hersenen “nature” “nurture” Primaire & secundaire - Permanente structurele invloeden - Reversibele effecten “nature” hersenen Primaire & secundaire seksuele kenmerken hormonen “nurture” T E2

steroïden en seksueel gedrag Knaagdieren: perivulatoir: seksueel receptief (lordose) postovulatoir: vijandig tov mannetjes Considering a presentation on alternative techniques for evaluation of abnormal uterine bleeding, the first question that came to my mind was : why? Why should we still use other investigational methods when we have such a powerful tool as hysteroscopy? So why not use it as a primary investigational tool? We already focused yesterday on the costs of hysteroscopy, which are considerably higher than for example ultrasound. Secondly, since in more than half of the cases of abnormal bleeding it is dysfunctional in cause, the « return » on surgical intervention will be much lower than 50%, so that preliminary screening is very appealing. Furthermore it remains an invasive procedure, which can cause some discomfort for the patients and can induce some complications. Of course we all know that these are rare in experienced hands, and I think that this is the main disadvantage of hysterocopy : it takes quite some experience. First, I would like to adress the case of transvaginal sonography. NEXT SLIDE

Hersenen en seksualiteit bij de vrouw Androgenen: verhogen libido, seksuele fantasieën en motivatie bij de vrouw (Money 1961) Female Sexual Dysfunction: stoornissen van seksuele begeerte, opwinding, orgasme stoornissen en seksuele pijnsyndromen 43% van alle vrouwen Masters/Johnson en Kaplan model = typisch mannelijk (begeerte -> opwinding -> orgasme -> resolutie) Considering a presentation on alternative techniques for evaluation of abnormal uterine bleeding, the first question that came to my mind was : why? Why should we still use other investigational methods when we have such a powerful tool as hysteroscopy? So why not use it as a primary investigational tool? We already focused yesterday on the costs of hysteroscopy, which are considerably higher than for example ultrasound. Secondly, since in more than half of the cases of abnormal bleeding it is dysfunctional in cause, the « return » on surgical intervention will be much lower than 50%, so that preliminary screening is very appealing. Furthermore it remains an invasive procedure, which can cause some discomfort for the patients and can induce some complications. Of course we all know that these are rare in experienced hands, and I think that this is the main disadvantage of hysterocopy : it takes quite some experience. First, I would like to adress the case of transvaginal sonography. NEXT SLIDE zelfbeeld Houding tov sex Sex drive hormonen partnerrelatie

Hersenen en seksualiteit bij de vrouw Female Sexual Dysfunction: stoornissen van seksuele begeerte, opwinding, orgasme stoornissen en seksuele pijnsyndromen (International Consensus Classification System(1999)) I. Sexual desire disorders A. Hypoactive sexual desire disorder (33%) B. Sexual aversion disorder (phobic) II. Sexual arousal disorder (lubrication) (20%) III.Orgasmic disorder (25%) IV. Sexual pain disorder A. Dyspareunia B. Vaginismus C. Other sexual pain disorders (non-coital) (V. Sexual satisfaction disorder ? -20%) Considering a presentation on alternative techniques for evaluation of abnormal uterine bleeding, the first question that came to my mind was : why? Why should we still use other investigational methods when we have such a powerful tool as hysteroscopy? So why not use it as a primary investigational tool? We already focused yesterday on the costs of hysteroscopy, which are considerably higher than for example ultrasound. Secondly, since in more than half of the cases of abnormal bleeding it is dysfunctional in cause, the « return » on surgical intervention will be much lower than 50%, so that preliminary screening is very appealing. Furthermore it remains an invasive procedure, which can cause some discomfort for the patients and can induce some complications. Of course we all know that these are rare in experienced hands, and I think that this is the main disadvantage of hysterocopy : it takes quite some experience. First, I would like to adress the case of transvaginal sonography. NEXT SLIDE

Hypothese - Invloed van testosteron op libido 1. Directe invloed op libido zelf (AR receptoren in limbisch systeem) 2. Via een centraal effect op stemming, ‘energie’, assertiviteit, ‘well-being’ en motivatie 3. Als precursor van E2 in hypothalamus belangrijk voor vrouwelijke seksuele functie en zelfbeeld 4. Direct vasomotorisch effect op vaginale doorbloeding en lubrificatie

Fysiologie van androgenen bij de vrouw Testosteron HERSENEN bot, vetweefsel, huid, vasculaire endothel en glade spier, ovarium, placenta 5 reductase types 1 & 2 in androgeen responsieve weefsels Aromatase 17-Oestradiol 5-DHT

Androgene productie bij de premenopauzale vrouw Bijnier 40-50% Androstenedion 40-50% 10-20% DHEA 50-60% 0% DHEAS 90% Perifere conversie 50% Testosteron 25%-35% 25%

Androgene productie bij de postmenopauzale vrouw Bijnier 20% Androstendion 70% 10-20% DHEA 50-60% 0% DHEAS 90% Perifere conversie 40% Testosteron  40-50% 10%

Androgene productie bij de vrouw na OE Bijnier 20% Androstendion 70% 10-20% DHEA 50-60% 0% DHEAS 90% Perifere conversie 40% Testosteron 40-50% 10%

Het CZS en coïtus Perifeer visuele, tactiele, auditieve of reukprikkels Lokaal aanraking/stimulatie genitalia sensoriële banen sacrale spinale tractus autonome reflexen (secretie, spiercontracties) Centraal sensoriële cortex: bewuste perceptie limbisch systeem: plezier hypothalamus stimulatie hypofyse: FSH, LH en oxytocine Considering a presentation on alternative techniques for evaluation of abnormal uterine bleeding, the first question that came to my mind was : why? Why should we still use other investigational methods when we have such a powerful tool as hysteroscopy? So why not use it as a primary investigational tool? We already focused yesterday on the costs of hysteroscopy, which are considerably higher than for example ultrasound. Secondly, since in more than half of the cases of abnormal bleeding it is dysfunctional in cause, the « return » on surgical intervention will be much lower than 50%, so that preliminary screening is very appealing. Furthermore it remains an invasive procedure, which can cause some discomfort for the patients and can induce some complications. Of course we all know that these are rare in experienced hands, and I think that this is the main disadvantage of hysterocopy : it takes quite some experience. First, I would like to adress the case of transvaginal sonography. NEXT SLIDE

Oxytocine, het « love hormone » - gesecreteerd door hypothalamus -> hypofyse onder invloed van diverse prikkels (cervicovaginaal, tepels) - piekt tijdens masturbatie/coïtus met orgasme - doet uterus samentrekken (semen transport) - belang tijdens de arbeid, piekt onmiddellijk postpartum (inductie van materneel gedrag) - stijgt bij prikkels vanwege de baby (geluid, zicht, gedachten) -> piekt tijdens het zuigen - parallel met oxytocine pieken ook de endorfines (pijn en plezier, bonding) - wordt uitgelokt door aanraking, knuffelen, intimiteit, bonding (ook gestimuleerd door E2: belang voor de vrouw groter dan de man?) Considering a presentation on alternative techniques for evaluation of abnormal uterine bleeding, the first question that came to my mind was : why? Why should we still use other investigational methods when we have such a powerful tool as hysteroscopy? So why not use it as a primary investigational tool? We already focused yesterday on the costs of hysteroscopy, which are considerably higher than for example ultrasound. Secondly, since in more than half of the cases of abnormal bleeding it is dysfunctional in cause, the « return » on surgical intervention will be much lower than 50%, so that preliminary screening is very appealing. Furthermore it remains an invasive procedure, which can cause some discomfort for the patients and can induce some complications. Of course we all know that these are rare in experienced hands, and I think that this is the main disadvantage of hysterocopy : it takes quite some experience. First, I would like to adress the case of transvaginal sonography. NEXT SLIDE

3 emotie-motivatie systemen die instaan voor het paren, reproductie en ouderschap Dopamine Noradrenaline Serotonine Oestrogenen Androgenen Lust Attraction Attachment Oxytocine Vasopressine

Het hypo-oestrogeen continuum van de vrouwelijke hersenen PMS/PMDD, postnatale depressie en perimenopause: Depressie, slaapstoornissen, irritabiliteit, angst en paniekaanvallen, geheugen- en cognitieve dysfunctie, gedaald ‘well-being’ gevoel Gemeenschappelijk: oestrogeen deprivatie ! E2: veroorzaakt stijging van dopamine, norepinefrine, serotonine en beta-endorfines, vermindert MAO activiteit E2 stimuleert het NN-methyl-D-aspartaat (NMDA) netwerk: excitatie (>< GABAa balanceert het NMDA netwerk): bvb meer epilepsie preovulatoir, ‘restless legs’ syndroom Progesteron: veroorzaakt daling van amines, stijging van MAO activiteit < daling E2 receptoren? -> ‘mood changes’ Neurosteroïden: de novo gesynthetiseerd uit cholesterol in de hersenen ~ geen verband met serumspiegels Considering a presentation on alternative techniques for evaluation of abnormal uterine bleeding, the first question that came to my mind was : why? Why should we still use other investigational methods when we have such a powerful tool as hysteroscopy? So why not use it as a primary investigational tool? We already focused yesterday on the costs of hysteroscopy, which are considerably higher than for example ultrasound. Secondly, since in more than half of the cases of abnormal bleeding it is dysfunctional in cause, the « return » on surgical intervention will be much lower than 50%, so that preliminary screening is very appealing. Furthermore it remains an invasive procedure, which can cause some discomfort for the patients and can induce some complications. Of course we all know that these are rare in experienced hands, and I think that this is the main disadvantage of hysterocopy : it takes quite some experience. First, I would like to adress the case of transvaginal sonography. NEXT SLIDE

PMS/PMDD E2 P ovulatie serotonine

Geheugen, cognitie en oestrogenen Hippocampus: centrum van korte termijn geheugen en cognitie < wordt door E2 gemodelleerd E2 doet acetylcholine en lokale doorbloeding stijgen waardoor imprinting van nieuwe gegevens beter gebeurt E2 substitutie verbetert korte termijn geheugen en cognitie, beschermt tegen Alzheimer (primaire, zeker geen secundaire preventie) ??? WHI-Memory Study (JAMA mei 2003): Cognitieve functie slechter bij 6.7% E+P behandelde vrouwen Vs 4.8% placebo -> in vitro is progesteron neuroprotectief (potentialiseert E2), doch MPA NIET (eerder antagonist)! Belang van SERMs? Considering a presentation on alternative techniques for evaluation of abnormal uterine bleeding, the first question that came to my mind was : why? Why should we still use other investigational methods when we have such a powerful tool as hysteroscopy? So why not use it as a primary investigational tool? We already focused yesterday on the costs of hysteroscopy, which are considerably higher than for example ultrasound. Secondly, since in more than half of the cases of abnormal bleeding it is dysfunctional in cause, the « return » on surgical intervention will be much lower than 50%, so that preliminary screening is very appealing. Furthermore it remains an invasive procedure, which can cause some discomfort for the patients and can induce some complications. Of course we all know that these are rare in experienced hands, and I think that this is the main disadvantage of hysterocopy : it takes quite some experience. First, I would like to adress the case of transvaginal sonography. NEXT SLIDE

Dank U voor Uw aandacht ! Considering a presentation on alternative techniques for evaluation of abnormal uterine bleeding, the first question that came to my mind was : why? Why should we still use other investigational methods when we have such a powerful tool as hysteroscopy? So why not use it as a primary investigational tool? We already focused yesterday on the costs of hysteroscopy, which are considerably higher than for example ultrasound. Secondly, since in more than half of the cases of abnormal bleeding it is dysfunctional in cause, the « return » on surgical intervention will be much lower than 50%, so that preliminary screening is very appealing. Furthermore it remains an invasive procedure, which can cause some discomfort for the patients and can induce some complications. Of course we all know that these are rare in experienced hands, and I think that this is the main disadvantage of hysterocopy : it takes quite some experience. First, I would like to adress the case of transvaginal sonography. NEXT SLIDE