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Female infertility Clinical investigations and

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Female infertility Clinical investigations and Powered By Docstoc
					                                                                                                                                23-11-2011




                                                                       Female infertility
Female infertility. Clinical 
investigations and therapeutic                                         Fertility:
                                                                                ability to conceive and have children
approach                                                               ’
                                                                       Infertility 
                                                                               failure to conceive after a year of regular intercourse
                                                                               failure to conceive after a year of regular intercourse 
                                                                               without contraception
                                                                       Fecundity
                                                                               the potential for reproduction, influenced by gamete 
                                                                               production, fertilisation and carrying a pregnancy to 
                                                                               term. A 
                         Leif Bungum                                   Sterility
                         Reproductive Medicine Centre,                         lack of fecundity
                         Malmö University Hospital




Infertility/sterility in humans


     Human beings are not fertile mammals.
      ◦ baboons 80%
      ◦ rabbits 90% in bred 
      ◦ MFR(monthly fecundity rate) for humans is only 20% (average)
     Western societies; one in six couples need 
      specialist help at some point in their lives 
                                                                                                                     Evers Lancet 2002
      because of inability to conceive
                                                                       Not so simple…mixed factors…




                                                                             The human fertilization process




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Essensial assumptions for conception 
                                                           Gametes – the oocyte
                                                           Gametes –
 Gametes             Presence of oocytes and sperm
  presence number
 Quality             Sufficient quality of the gametes
  ◦ Of gametes                                                 • Presence of  : ovulation
 Interaction 
  between  gamets     Fertilization
 Transport                                                    •Number of ‐ reflects the ovarian reserve
  ◦ of gametes and    Transport of sperm to the oocyte, 
   embryos
                      transport of the embryo to the 
                      uterine cavity
 Implantation
  ◦ of embryo




        The oocyte
                                                                   Ovulation




                                                                     Clinical investigations
                                                                     Ovulation

                                                           70,00
                                                                                                                       •   Detect an growing 
                                                           60,00
                                                                                                                           follicle in the follicular 
                                                           50,00
                                                           50 00
                                                                                                                           phase
                                                           40,00                                                       •   Detect the LH surge in 
                                                           30,00                                                           urine or blood
                                                           20,00                                                       •   Detect the progesterone 
                                                           10,00
                                                                                                                           rise in the luteal phase
                                                            0,00
                                                                   Day   2   3   5   8   11   14   17   20   23   26




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                                                  •Number of Gametes
Ovulation defect
Thearapeutic approach
                                                             Actual number of primordial follicles 
    •   hormonal ovulation induction                         at time of wanted conception 
        • anti estrogens
           anti‐estrogens                                    influenced by
                                                             influenced by
        • Follicle stimulating hormone                             Age
                                                                   Medical condition
                                                                   Genetic?
          •   key goal: mono‐ovulatory cycles                      Idiopatic pathologic




Ovarian reserve/ number of primordial follicles   Gametes – the oocyte
                                                  Gametes –
                                                  Clinical investiagtion
                                                   •Number of ‐ reflects the ovarian reserve

                                                            l f lli l
                                                      •Antral follicle count 
                                                      •FSH
                                                      •Anti‐Müllerian Hormone




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                                                                               23-11-2011




                           Number and quality of primordial follicles related to 
                           woman’s age




                                                              Klinkert 2005 PhD Tesis Utrecht




Quality of gametes


       •Toxic influence
         Cancer theraphy
         Cancer theraphy
         Smoking/drugs
         Environmental?
       •Age




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                                                                                             Down Syndroem Risk
                                                                                        Mother´s Age           Incidence of Down Syndroem

                                                                                        Under 30               Less than 1 in 1000
                                                                                        30                     1 in 900
                                                                                        35                     1 in 400
                                                                                        36                     1 in 300
              is the leading cause of reproductive 
Aneuploidy is the leading cause of reproductive                                         37                     1 in 230
failure and congenital birth defects in humans. The                                     38                     1 in 180

strong association between maternal age and                                             39                     1 in 135
                                                                                        40                     1 in 105
trisomy, coupled with changing reproductive 
                                                                                        42                     1 in 60
trends that have steadily increased the maternal                                        44                     1 in 35
age at first birth, suggests that the aneuploidy                                        46                     1 in 20
problem is not going to diminish.                                                       48                     1 in 16
                                                                                        49                     1 in 12




                Ålder på förstföderskor                                                 Mödrarnas medelålder




 The decrease in monthly fecundity rate (rate of healthy childbirth) relative to the   ART pregnancy and live birth rates, own oocytes vs. 
 fecundity rate of women in the 20–30-year age group
                                                                                       donoroocytes related to age




Noord Zaadstra 1991                                                                                CDC Report December 2003




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                                                                               Interaction between gamets: fertilization
Gametes –
Gametes – the oocyte
Therapeutic approach                                                            Depends on

 •None?                                                                            the state of the spermatozoe

 •Use your oocytes at an appropriate age                                           the state of the oocyte

                                                                                         stage of development (GV, MI, MII)
                                                                                         zona pellucida
                                                                                         toxic influence
                                                                                                 environmental?
                                                                                                 smoking?
                                                                                                 drugs?




 Fertilization
                                                                          Transport of gametes and embryos
                                            Två mekanismen säkrar
                                                monospermi
                                                1) Kortikale granula         In fertilization in vivo  the Fallopian tube plays an 
                                                (block för penetration)
                                                2) Zonal inhibiting           essential role in 
                                                     proteiner (ZIPs)
                                                (nedbryter sperma
                                                     reseptorer)                    ◦ gamete transport, fertilization 
                                                                                    ◦ early development of the embryo
                                                                                      early development of the embryo.
                                                                             “It is becoming increasingly evident that the mechanism of tubal 
                                                                              transport is much more complex than first thought and can be 
                                                                              affected by a wide range of factors and conditions that may impair 
                                                                              fertility”




          Synchronisation
                                                                              Structure of the human Fallopian tube epithelium
                                                                           tubal mucosa is arranged into longitudinal folds
                                                                           increasingly convoluted towards the distal end of the
                                                                            tube
                                                                           two major cell types are the ciliated and secretory cells




                               mM                          mM
                                0.32     Pyruvate         0.10
                                 10.5     Lactate         5.87
                                 0.5      Glucose         3.15




           Gardner et al., 1996; Fertil. Steril., 65, 349-53.




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Tuboperitoneal disorders
          ◦ Cilia dysfunction
             Smoking
             endometriois

          ◦ Postinfectious tubal damage
                           tubal damage
             Neisseria gonorrhoeae
             Chlamydia

          ◦ Hydrosalpinx
          ◦ Pelvic adhesions
             Laparatomy
             Pertneal infections                                              Normal tube/ cilia
             endometriosis




                                                           Tuboperitoneal disorders
                                                           Clinical investigation
                                                               Hysterosalpingo-Contrast-Sonography (HyCoSy)




              Post PID (pelvic inflammatory disease)




                                                                        Implantation
Tubal patency vs. tubal function
   Hysterosalpingo-Contrast-Sonography                       Zona hatching
    (HyCoSy)                                                   ◦ blastocyst first quits the zona pellucida “hatching".
    ◦ Open (tubal patency) vs. Closed tubes                   Apposition
                                                               ◦ Inner cell mass aligned closest to the decidua.
   “It is becoming increasingly evident that the 
    mechanism of tubal transport is much more                 Adhesion
                                                               ◦ penetrating the endometrium
    complex than first thought and can be affected by a 
                                                              Invasion
    wide range of factors and conditions that may              ◦ penetrating into the endometrium
    impair fertility”
                                                            Requires a synchronized crosstalk between a receptive endometrium and 
                Lyons et al. Hum Reprod Update 2006         a competent blastocyst 




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                                                                      23-11-2011




Unexplained infertility
 Ovulation  ok

 Tubal patency   ok

 Sperm count/motility/ morphology  ok

 Diagnosis:  unexplained infertility




                                               Infertility dignosis




Therapeutic approach
    Anovulation
     ◦ hormonal stimulation
    Unexplained infertility
     ◦ AIH (artificiel insemination husband)
           (                               )
     ◦ Unsucessfull: ivf
    All other diagnosis
     ◦ ivf/icsi




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