Könshormoner, PCOS och neuropsykiatri en gynekologs synpunkter. Inger Sundström Poromaa Dept Women s and Children s Health Uppsala University

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1 Könshormoner, PCOS och neuropsykiatri en gynekologs synpunkter Inger Sundström Poromaa Dept Women s and Children s Health Uppsala University

2 Endokrinologen i mig hade tänkt tala om: Polycystiskt ovariesyndrom Premenstruellt dysforiskt syndrom

3 Premenstruellt dysforiskt syndrom En rapport om ökad förekomst av premenstruella besvär hos kvinnor med autismspektrumtillstånd 92% vs 11% Ingenting om ADHD Förvånande, tycker mig ha många såna patienter. Obaydi H, Puri BK. Prevalence of premenstrual syndrome in autism: a prospective observer rated study. The Journal of international medical research. 2008;36(2):

4 Den lätta delen

5 PCOS 2 av 3 kriterier 1. Oligomenorre (glesa menstruationer) eller amenorre (ingen mens) 2. Klinisk eller biokemisk hyperandrogenism Hirsutism Förhöjt fritt androgenindex Testosteron/SHBG > Typisk ultraljudsbild Många antralfolliklar i äggstocken

6 Klinisk bild varierande Prevalenssiffror mycket varierande 1,5 % i Svenska register 6,5% i Svensk prevalensstudie Omkring hälften av kvinnorna är överviktiga i Sverige Skandinaviska kvinnor har mindre besvär med hirsutism än andra nationaliteter Stark heritabilitet men den manliga fenotypen kan ej urskiljas

7 En ond androgen cirkel

8 Gynekologens synpunkter Väl känt att depression och ångest är vanligare i patientgruppen Många remisser från psykiatrin Mensstörning, obesitas

9 PCOS, ADHD och annan samsjuklighet Kvinnor med PCOS har högre scores på ADHD skalor Wender Utah Rating Scale, Adult ADHD Self Report Scale Ökad impulsivitet snarare än uppmärksamhetsstörning Liten studie Psykiatrisk samsjuklighet hos kvinnor med PCOS Matchad case control studie Depression 23,1% vs 19,3% Ångest 11,5% vs 9,3% Bipolär sjd 3,2% vs 1,5% Herguner S, Harmanci H, Toy H. Attention deficit hyperactivity disorder symptoms in women with polycystic ovary syndrome. International journal of psychiatry in medicine. 2015;50(3):317 25; Berni TR, Morgan CL, Berni ER, Rees DA. Polycystic Ovary Syndrome Is Associated With Adverse Mental Health and Neurodevelopmental Outcomes. The Journal of clinical endocrinology and metabolism. 2018;103(6):

10 PCOS och autismspektrumtillstånd

11 PCOS och ASD

12 Schizofreni Bipolär sjukdom Depression Ångestsyndrom Bulimi Personlighetsstörning, alla typer Autismspektrumtillstånd Aspergers syndrom Tics PCOS och ASD Cesta CE, Mansson M, Palm C, Lichtenstein P, Iliadou AN, Landen M. Polycystic ovary syndrome and psychiatric disorders: Co morbidity and heritability in a nationwide Swedish cohort. Psychoneuroendocrinology. 2016;73:

13 Gynekologens fundering.. Är detta ett orsakssamband? Testosteronexponering i fosterlivet? Eller beror det på att dessa kvinnor i högre grad remitteras till gyn? Eller beror det på att de läkemedel ni använder leder till obesitas och metabola förändringar?

14 PCOS och deras syskon Bröder ASD, särskilt Aspergers syndrom Systrar Depression, ångestsyndrom, schizofreni och ASD Cesta CE, Mansson M, Palm C, Lichtenstein P, Iliadou AN, Landen M. Polycystic ovary syndrome and psychiatric disorders: Co morbidity and heritability in a nationwide Swedish cohort. Psychoneuroendocrinology. 2016;73:

15 PCOS mamma och risk för ADHD hos barn Kosidou K, Dalman C, Widman L, Arver S, Lee BK, Magnusson C, Gardner RM. Maternal Polycystic Ovary Syndrome and Risk for Attention Deficit/Hyperactivity Disorder in the Offspring. Biological psychiatry. 2017;82(9):651 9; Berni TR, Morgan CL, Berni ER, Rees DA. Polycystic Ovary Syndrome Is Associated With Adverse Mental Health and Neurodevelopmental Outcomes. The Journal of clinical endocrinology and metabolism. 2018;103(6):

16 PCOS mamma och risk för ADHD hos barn Kosidou K, Dalman C, Widman L, Arver S, Lee BK, Magnusson C, Gardner RM. Maternal Polycystic Ovary Syndrome and Risk for Attention Deficit/Hyperactivity Disorder in the Offspring. Biological psychiatry. 2017;82(9):651 9; Berni TR, Morgan CL, Berni ER, Rees DA. Polycystic Ovary Syndrome Is Associated With Adverse Mental Health and Neurodevelopmental Outcomes. The Journal of clinical endocrinology and metabolism. 2018;103(6):

17 Gynekologens funderingar. De flesta kvinnor med PCOS i denna studie (givet tidsperioden då barnen är födda) bör ha identifierats i slutenvårdsregistret De flesta kvinnor med PCOS behandlas i öppenvård Selektion av svårare sjuka kvinnor med PCOS?

18 Obstetrikerns fundering. Graviditeter hos kvinnor med ADHD mer kaotiska

19 Gravida kvinnor med ADHD Kontroller Kvinnor med ADHD OR 95% CI Antal kvinnor n(%) n(%) Total Kohort Ålder (år) < (2,9) 1141 (15,1) 8,50 7,93 9, (20,0) 2889 (38,2) 3,07 2,91 3, (64,8) 3046 (40,3) Referens (12,3) 477 (6,3) 0,82 0,75 0,91 BMI < 18, (2,8) 237 (3,1) Referens 18,5 24, (58,7) 3824 (50,6) 0,77 0,67 0, , (21,7) 1764 (23,4) 0,96 0,84 1, , (6,6) 682 (9,0) 1,22 1,05 1, , (2,0) 258 (3,4) 1,51 1,26 1,81 > (0,7) 93 (1,2) 1,57 1,23 2,01 Missing (7,5) 695 (9,2) Rökning Röker ej (90,2) 5225 (69,2) Referens Röker (5,7) 1956 (25,9) 5,96 5,65 6,29 Missing (4,2) 372 (4,9) Födelseland Nordiska länder (79,6) 7036 (93,2) Referens EU (3,5) 101 (1,3) 0,33 0,27 0,40 Övriga världen (16,9) 416 (5,5) 0,28 0,25 0,31 Diabetes pregravid Nej (99,4) 7466 (98,8) Referens Ja (0,6) 87 (1,2) 1,82 1,47 2,26 Malin Helin, pågående studentarbete

20 Sammanfattning lätta delen Psykiatrisk samsjuklighet vanligt hos kvinnor med PCOS Samband mellan PCOS och autismspektrumtillstånd Inga studier på PCOS och ADHD Kvinnor med PCOS får i högre utsträckning barn med ADHD och autismspektrumtillstånd Oklart kunskapsläge Hur kan vi minska risken för tonårsgraviditeter bland kvinnor med ADHD?

21 Svåra delen

22 The extreme male brain theory

23 Fetal programmering

24 Hur blir hjärnan manlig eller kvinnlig? Hjärnan har full potential att utvecklas till både manlig och kvinnlig fenotyp. Default mode är en kvinnlig hjärna Maskulinisering av hjärnan sker under kritisk period i fosterlivet Testosteron hos människa Östrogen hos gnagare

25 Maskulinisering Det manliga fostret producerar lika mycket testosteron som en 25 årig man

26 Testosteronsyntes Flickfostrets ovarier tysta Hormonproduktion från binjurar Kortisol och testosteron närliggande DHT utveckling av manliga genitalier, finns i princip inte hos kvinnor Aromatas omvandlar testosteron till östrogen

27 Hormoneffekter under hjärnans utveckling

28 Organiserande och aktiverande effekter Hormonell exponering under fosterlivet leder till permanenta förändringar i hjärnan Organiserande effekt Hur hjärnan svarar på hormoner i vuxenlivet beror på den ursprungliga exponeringen Aktiverande effekt

29 Feminisering av hjärnan

30 Vad vet vi om androgenexponering hos människa?

31 Biologiska experiment Behandling med dietylstilbestrol under graviditet Hög dos av östrogen Tidig utveckling av livmodercancer hos döttrarna Disorders of sexual development Kongenital binjurebarkhyperplasi (CAH)

32 Andra sätt att mäta androgenexponering 2D:4D ratio Pekfingret kortare än ringfingret tyder på hög androgenexponering Viss skepsis till metoden sannolikt sund CAH ASD PCOS Cattrall FR, Vollenhoven BJ, Weston GC. Anatomical evidence for in utero androgen exposure in women with polycystic ovary syndrome. Fertil Steril 2005; 84:

33 Hur mycket mer testosteronexponering? When analyzed on the log scale, we found that the mean finger length ratio in the right hand of the women with PCOS was 98.3% that of the controls (95% CI, 99.3% 97.3%). 2 negativa studier Cattrall FR, Vollenhoven BJ, Weston GC. Anatomical evidence for in utero androgen exposure in women with polycystic ovary syndrome. Fertil Steril 2005; 84: ; Lujan ME, Bloski TG, Chizen DR, Lehotay DC, Pierson RA. Digit ratios do not serve as anatomical evidence of prenatal androgen exposure in clinical phenotypes of polycystic ovary syndrome. Human reproduction (Oxford, England). 2010;25(1):204 11; Lujan ME, Podolski AJ, Chizen DR, Lehotay DC, Pierson RA. Digit ratios by computer assisted analysis confirm lack of anatomical evidence of prenatal androgen exposure in clinical phenotypes of polycystic ovary syndrome. Reproductive biology and endocrinology : RB&E. 2010;8:156.

34 Ytterligare sätt att mäta androgenexponering Testosteron i fostervattenprov Enstaka värde Prov taget i samband med amniocentes för fosterdiagnostik Dålig forskning Testosteron i navelsträngsblod Enstaka värde Peak vid förlossning, sannolikt stressbetingad Dålig forskning Testosteron hos den gravida kvinnan Riktigt dålig forskning Könsdiskordanta tvillingar

35 Aromatas i placenta Omvandlar testosteron till östrogen Nästan 100% effektivt i att omvandla testosteron till östrogen Skyddar mamman från testosteron producerat av fostret Skyddar fostret från mammas testosteron

36 Mer och mindre effektivt aromatas Kallak TK, Hellgren C, Skalkidou A, Sandelin Francke L, Ubhayasekhera K, Bergquist J, et al. Maternal and female fetal testosterone levels are associated with maternal age and gestational weight gain. European journal of endocrinology. 2017;177(4):

37 Organiserande effekter av testosteron Lekbeteende rough and tumble play Autism Polycystiskt ovariesyndrom (PCOS)

38 Testosteron i fostervattenprov lekbeteende Auyenung B et al, Psychological Science 2009; 20(2),

39 Testosteron och lekbeteende Melissa Hines et al., Child Development 73, , 2002.

40 Autism 2 3 gånger vanligare hos män än hos kvinnor Låg grad av ärftlighet (0,5 0,9%) Extreme male brain theory Female protective effect Större inslag av genetisk koppling när kvinnor drabbas av autism Vanligare med släktingar med autism när kvinnor drabbas PCOS och förtidig pubertet vanligare hos flickor med autism Högre nivå av androstendion, progesteron, testosteron och kortisol i fostervatten hos barn som sedan utvecklar autism

41 PCOS Gener Miljö Fetal exponering för androgener? Möss, råttor, lamm och apa PCOS liknande drag; högt testosteron, multifollikulära ovarier, förändrad LH pulsatilitet Dihydrotestosteron har använts som exponering påverkas ej av det placentära aromataset

42 Gynekologens fundering Om man tänker att PCOS = ökad androgenexponering Hur kommer då androgenerna över till fostret?

43 Female fetal amniotic fluid testosterone Kan det trots allt vara stress? Kallak TK, Hellgren C, Skalkidou A, Sandelin Francke L, Ubhayasekhera K, Bergquist J, et al. Maternal and female fetal testosterone levels are associated with maternal age and gestational weight gain. European journal of endocrinology. 2017;177(4):

44 Sammanfattning Insult under fosterlivet Stress leder till höga testosteronnivåer Svårt forskningsområde Genetik och miljö Sannolikt kan prenatal androgenexposition förklara en liten del av dessa tillstånd

45 AMH exposure during pregnancy AMH treatment of pregnant dams lead to: PCOS like reproductive and neuroendocrine phenotype in the offspring Increased testosterone levels in mothers and offspring Decreased placental aromatase function Hyperactivated GnRH neurons in the offspring Tata B, El Houda Mimouni N, Barbotin A L, Malone SA, Loyens A, Pigny P, Dewailly D, Catteau Jonard S, Sundström Poromaa I, Piltonen TT, Prevot V, Clasadonte J, Giacobini P. Prenatal Anti Müllerian Hormone Programming of Polycystic Ovary Syndrome. Nature Medicine 2018.

46 Increased AMH in pregnant PCOS women AMH in pregnancy highest in Lean women with PCOS Hyperandrogenic phenotype Tata B, El Houda Mimouni N, Barbotin A L, Malone SA, Loyens A, Pigny P, Dewailly D, Catteau Jonard S, Sundström Poromaa I, Piltonen TT, Prevot V, Clasadonte J, Giacobini P. Prenatal Anti Müllerian Hormone Programming of Polycystic Ovary Syndrome. Nature Medicine, in press.

47 The menstrual cycle

48 The ovary Oogenesis Primordial and primary follicles 7 millon in the female fetus 2 million at birth at puberty Antral follicles mature at puberty 400 ovulations

49 No ovarian stem cells (so far) Nature 2012 Nature Medicine 2015

50 Hypothalamus pituitary gonadal axis +

51 GnRH neurons Surprisingly few Longest migration of all neurons during neurodevelopment Odd morphology with synapses all along the dendrite (dendrone) No estrogen or progesterone receptors

52 GnRH pulsatility Slow pulsatility favors FSH relase Fast pulsatility favors LH release The mechanism behind the GnRH pulsatility is virtually unknown Except the LH surge

53 Positive feedback mediated by kisspeptin

54

55 The menstrual cycle is controlled by the ovary FSH stimulation Follicular recruitment Estradiol production and expression of FSH receptors Increased estradiol levels turns off the FSH stimulation

56 Selection of the leading follicle Estradiol levels > 730 pmol/l for more than 50 hours triggers the positive feedback mechanism on LH release.

57 The corpus luteum The leading follicle matures into a corpus luteum after ovulation Capable of estradiol and progesterone synthesis Preparations for implantation and pregnancy

58 The endometrium Follicular phase; proliferation Luteal phase: maturation, spiral arteries and glands

59 The implantation window

60 Implantation Glucose, lactate and pyruvate are required for human blastocyst development Blastocysts communicate with the endometrium Human chorionic gonadotropin (hcg) is secreted by hatched human blastocysts in close apposition to the endometrium The endometrium produces leukaemia inhibitory factor (LIF), VEGF, IL 11 and other chemokines and cytokines mirnas in uterine fluid are taken up by pre implantation mouse embryos and alter embryonic mrna expression in vitro

61 A few words on puberty

62 Pubertal development

63 Kisspeptin central for puberty

64 Puberty

65 Early puberty More frequently in girls but appear to occur also in boys impact somatic and psychological maturation adult height psychosocial problems Earlier puberty is associated with an increased risk of cardio metabolic disease, including hypertension and Type 2 diabetes, in both men and women Causation? Kisspeptin not acting on its own; leptin, NPY and many more SNPs at or around genes known to influence body weight (e.g. FTO) or energy homeostasis (e.g. the receptor of the orexigenic factor MCH, or the transcription factors BSX and CRTC1) have been shown to associate with modest variations in the age of puberty

66 Reproductive research, why?

67

68 The pill

69 In vitro fertilization

70 IVF success rates IVF success rates have remained static at around 25 30% Elevated oxygen concentrations may have a negative impact through oxidative stress Oxygen levels that are too low may impair embryogenesis po 2 within the female reproductive tract shows cyclical variation and minute tominute oscillations, influenced by uterine contractility, hormones, the autonomic system, cardiac pulsatility, and myometrial and smooth muscle integrity. ph is important for sperm binding and motility, oocyte maturation and embryo development The ph in the female reproductive tract is graduated, with lowest ph in the vagina (ph 4.42) increasing toward the Fallopian tubes (FTs) (ph 7.94). In humans, temperature is biphasic, increasing in the luteal phase; with the caudal region of the oviduct 1 2 degrees cooler than the cranial portion.

71 Obesity a new challenge in research BMI has been associated with delayed conception in women in a dose dependent fashion Obesity lead to anovulation and menstrual irregularity impairment of oocyte development and quality has direct effects on the endometrium With ovulation induction (OI) treatment, higher doses of medications longer period of stimulation With IVF the chances of achieving a pregnancy decrease with each unit increase in BMI implantation rates are lower in obese increased risk of miscarriage following IVF.

72 Sperms Decline in sperm counts between 1973 and 2011, driven by a 50 60% decline among men unselected by fertility from Western countries

73 Obesity and fertility in men Increased testicular temperature Increased oestrogen production in fat with disruption of the hypothalamo pituitary gonadal axis Reduced sperm concentration and motility Lower clinical pregnancy rates with IVF

74 Delayed childbearing At least, social freezing works Vitrification was associated with increased ongoing CPR per cycle in comparison with slow freezing embryos (RR = 2.81, 95% CI: ; P = 0.039) In vitrification and fresh cycles, respectively, no evidence for a difference in clinical pregnancy rate per randomized woman (RR = 1.03, 95% CI: ; P = 0.744)

75 Ovarian aging Great inter individual variability of ovarian ageing Quantitative and qualitative decline Almost 20% of patients consulting for infertility show signs of premature ovarian ageing. Between groups p < 0,001 Difference over time, p < 0,001 Group x time, ns PCOS Controls

76 Mitochondria and ovarian aging The oocyte is the richest cell of the body in mitochondria and depends largely on these organelles to acquire competence for fertilization and early embryonic development. Age related mitochondrial DNA instability, accumulation of mtdna mutations in the oocyte

77 Pregnancy endocrinology Inger Sundström Poromaa Dept Women s and Children s Health Uppsala University

78 Pregnancy endocrinology key players

79 Fetoplacental unit

80 Fetal adrenals Produces pregnanolone sulphate and DHEAS DHEAS precursor for placental estrogen At term, 90% of placental estrogen production has fetal origin

81 Other placental hormones and peptides Human placental lactogen Greatest production of any known hormone at term Lactation Growth hormone like effects Lipolysis and increased free fatty acids Anti insulin actions Placental ACTH Placental CRH Placental GnRH Placental PTH, placental GH and many more

82

83 CRH regulation during pregnancy

84 Onset of labor Many hypotheses Functional progesterone withdrawal Shift in PR receptor expression in the myometrium (PRB PRA) Increases myometrial sensitvity to estradiol and oxytocin The CRH clock hypothesis Increased CRH and decreased CRHBG leads to increased free CRH at term Fetal ACTH and cortisol the final trigger?

85 CRH a predictor for preterm birth?

86 Gestational diabetes the new challenge

87 Maternal glucose and birth weight

88 The immune system

89 The immune system and depression When hit by influenza we feel sick Innate immune cells produce pro inflammatory cytokines that act on the brain Sickness includes; fatigue, fragmented sleep, depression and irritability Interleukin (IL) 1, IL 6, TNF Interferon as treatment of hepatitis C 25% of patients develop depression 40 Depression symptoms 8,00 Pro inflammatory cytokine 30 7, , Baseline Interferon alpha 6,50 6,00 Baseline Interferon alpha Posttreatment Posttreatment

90 The immune system in pregnancy In pregnancy Upregulated innate immunity Downregulated adaptive immunity Shift from Th1 to Th2 responses

91 The immune system in pregnancy Placenta decidua Uterine NK cells Decidual macrophages

92 Inflammatory Pre presentation phases during pregnancy IL 1 IL 6 TNF CCL2 ROS NO M1 IL 10 IL 4 TGF M2 M1? Implantation Placentation Fetal growth Delivery