Verborgen oestrus Ivo Brosens VVOG Gent 24 october

Verborgen oestrus Ivo Brosens VVOG Gent 24 october 2009

Verborgen oestrus • Hoe onvruchtbaar is de mens? • Kan vruchtbaarheidsbewustzijn helpen? • Een verborgen mechanisme voor succesvolle zwangerschap?

Human Ovulation Brosens & Gordts 1998 6 pm

Ovum pick-up, on the road to the nest

Cues of Human Oestrus • Body odours loss during OC • Facial appearance • Language • Clothing • Voice • Eye pupil’s size loss during OC • Gesture loss during OC

Is oestrus really “lost” in humans? Miller et al. Evol & Hum Behav 2007 Gesture • Tip earnings by 18 professional lap dancers working in a gentleman’s club • Earnings significantly higher during estrus. Not in OC users • First direct economic evidence for existence of oestrus effect

Fertility awareness methods (FAM) • Cycle variability • Biomarkers - BBT - cervical mucus • Hormonal tests

Variability of ‘fertile window” Cole et al. (Fert & Steril 2009) Menstrual cycle length 27. 7 +/- 2. 4 d Fertile window (LH peak) d 14. 7 +/-6. 6

Classification of mucus symptoms (Scarpa EJOGRB 2006) APPEARANCE SENSATION SCORE nothing dry 1 nothing slightly moist 2 thick, creamy, whitish, sticky. . damp 3 clear, stretchy, watery … wet slippery 4

Probability of pregnancy relative to peak mucus day in fertile couples Stanford et al. Obst Gyn 2003

Cervical mucus: an accurate marker of highly fertile days (Scarpa EJOGRB 2006) Mucus type Probability of conception Mean SD 1 (dry) 0, 003 0, 002 2 0, 01 0, 006 3 0, 03 0, 008 4 ( wet) 0, 29 0, 04

Endocervical canal at TVU by courtesy of Patrick Puttemans

Cervix : preovulatory pupil sign

Femiscope

Duration of fertility window (days) Fertile window: pupil sign vs peak mucus Pupil sign Peak mucus

Time to Clinical Pregnancy Gnoth et al. 2003 _____________________ • Prospective (grade A) • Users of vulvar mucus changes (NFP) • 346 German women

Time to Clinical Pregnancy Gnoth et al. 2003 _____________________ • Pregnancy rate at: - 3 months 68% - 6 months 81% - 12 months 92% • It is assumed that after 6 cycles 50% of the remaining couples are subfertile

Use of natural methods for predicting ovulation - Calendar method: unreliable BBT: not predictive Mucus method: tends to overestimate Cervical pupil sign: predictive in 70%

NICE Fertility Guidelines 2004 • People who are concerned about their fertility should be told that sexual intercourse every 2 to 3 days optimizes the chances of pregnancy. • Timing intercourse to coincide with ovulation causes stress and is not recommended. • Grading of evidence: C

Can FAM be recommended for subfertile couples?

Probability of pregnancy relative to peak mucus day for normal and subfertile couples Stanford et al. Obstet Gynecol 2003

Fertile window in subfertility Keulers F & S 2007 • 410 subfertile couples • Detection of first normal sperm-mucus interaction day • Ovulation day determined by serial ultrasound

Fertile window in subfertility Keulers et al. F & S 2007 • Length varied between <1 to 5 days • The longer, the higher the probability of spontaneously conceiving and ongoing pregnancy

Length of the fertile window (5 d, 4 d, 3 d, 2 d, 1 d) is associated with the chance of spontaneously conceiving an ongoing pregnancy in subfertile couples M. J. Keulers et al 2007

Clearblue Easy Fertility Test Robinson et al. F&S 2007 • Women trying to conceive for up to 2 y • Pregnancy increased during the first 2 cycles • No point in trying longer than 6 mo

Verborgen oestrus Een mechanisme van uteriene ‘precondionering’ voor succesvolle zwangerschap i. e. diepe placentatie?

Junctional zone myometrium Hricak 1983

Human Reproduction “Concealed” oestrus Spontaneous decidualisation Menstruations Time to pregnancy Uterine ‘preconditioning’ Deep placentation

Menstruations to prepare the nest Preconditioning The term “preconditoning” refers to the paradoxal phenomenon that a brief exposure to a harmful stimulus at a dose below the threshold for tissue injury provides robust protection against, or tolerance to, the injurious effects of a subsequent more severe insult.

Menstruation to prepare the nest? Preconditioning • Both menstruation and pregnancy cause a degree of physiological ischemiareperfusion tissue injury, albeit much more so in pregnancy. • Cyclic menstruations have a critical role to protect tissues from hyperinflammation and oxidative stress associated with deep placentation.

Menstrual preconditioning and pregnancy outcome Brosens et al AJOG 2008

RR of LBW and PD among Infants Born to Younger and Older Teenage Mothers Fraser et al. NEJM 1995 Mother’s Age Low birth weight Premature delivery 13 -17 1. 7 (1. 5 -2. 0) 1. 9 (1. 7 -2. 1) 18 -19 1. 4 (1. 3 -1. 5) 1. 5 (1. 4 -1. 6) 20 -24 1 1

Boomsma, C. M. et al. Hum Reprod Update 2006 12: 673 -683; doi: 10. 1093/humupd/dml 036 Copyright restrictions may apply.

Preconditioning Protection, but also Risks 1. Preconditioning endows endometrial cells with mechanisms to survive in unfavourable ectopic locations. Preconditioning favours in the absence of pregnancy the development of endometriosis

Endometriosis and age (Redwine 1987) Number of peritoneal areas involved (%) ---------------------------------- 16 -20 yrs 21 -25 yrs 26 -30 yrs 2. 60 4. 20 3. 27 ------------------------------------

Preconditioning Protection, but also Risks 2. Endometriosis is associated with JZ thickening/adenomyosis.

JZ thickness in endometriosis (Kunz et al 2005) Without E With E N mm/SD Total patients 67 8. 5/2. 6 160 11. 5/5. 3* Stage I & II 81 10. 5/4; 0 Stage III&IV 79 12. 5/6. 4

Endometriosis associated with adenomyosis (Kunz 2000)

Adenomyosis >34 y

Preconditioning Protection, but also Risks 3. Endometriosis/adenomyosis impairs deep placentation and pregnancy outcome.

Risk of Obstetrical Syndromes Endometriosis Adenomyosis - Preterm birth and SGA - Preterm birth and babies doubled PPROM (Juang 2007) (Fernando 2009) - Preterm birth (Stephansson 2009)

Where have all the eggs gone? Summary • ‘Concealed’ oestrus is a major cause of loss of eggs and results in cyclic menstruations before pregnancy occurs. • Menstruations may have a critical role in ‘preconditioning’ the uterus for successful deep placentation.

Where have all the eggs gone? Summary • Delaying pregnancy favours in predisposed women endometriosis/adenomyosis which is a risk factor for obstetrical syndromes. • In conclusion, major obstetrical syndromes may have roots in a distrubed periconceptual utero-tubal environment.

Action Plan for Reducing TTP • She and he learn ‘subtle oestrus cues’. • A love dinner - lap dance on the peak day at 6 pm relieves stress more than compulsory intercourse every 2 -3 days. • After 6 failed love dinner-dances: see your fertility doctor!

Acknowledgment Giuseppe Benagiano, University of Roma Jan J. Brosens, Imperial College, London Robert Pijnenborg, University of Leuven Patrick Puttemans, L. I. F. E. , Leuven

Hidden ovulation Where have all the eggs gone?