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INFERTILITY

Rukmono Siswishanto

Obstetric  and  Gynecology  Department  Gadjah  Mada  University/Sardjito  Hospital  Jogjakarta  

 

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Infertility

   No  pregnancies  occurred  in  couples  who  have  intercourse  without  protecBon  in  a  

period  of  1  year  

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Primary  inferBlity  Previously  had  never  been  pregnant  

Secondary  inferBlity  Previously  been  pregnant  

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INTRODUCTION

q   The  dilemma  of  inferBlity  vs  populaBon  overgrowth  

q   AffecBng  around  8%  couples  •  ReproducBve  problem    50-­‐80  million  couples  •  Two  million  new  inferBle  couples  per  year    

q   Frequency:  12%  (Indonesia),  10-­‐15%  (USA)  

q   PrevenBon  potenBal  

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Fecundability

The  probability  of  being  pregnant  in  a  single  menstrual  cycle

Factors  affecBng  fecundability  Age,  Oocyte  depleBon,  Spontaneous  aborBon,  Male  factor  

Fecundity  The  probability  of  achieving  a  live  birth  within  a  single  cycle  

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CHAPTER 2 • Dynamics for Human Growth: Morphologic, Dynamic, and Functional Aspects 27

INITIATION OF THE FOLLICULARGROWTH

Oogenesis and Composition of the Ovarian Reserve

In humans, at the beginning of the fourth week of embry-onic development the primordial germ cells (PGC)migrate to the coelomic epithelium of the gonadal ridges.When sexual differentiation occurs, the PGC continue toproliferate in the embryonic ovary and become oogonia.By the twentieth week of pregnancy, about 7 millionoogonia are present [2]; thereafter oogonia enter meioticprophase, which marks the end of germ cell production.Around the twenty-fourth week of gestation, almost allthese germ cells, now called oocytes, have passed throughthe first four stages of meiosis I and are arrested at thediplotene stage. The oocytes are surrounded by a layer ofepithelial pregranulosa cells to form primordial follicles.Although some of these follicles start to grow almostimmediately, most remain in a resting stage until theyeither degenerate or enter the growth phase. After birththe pool of follicles at the resting stage constitutes theovarian reserve, including primordial follicles in which theoocyte is surrounded by flattened granulosa cells (GC)(Figure 2.3, A), transitory follicles in which the oocyte issurrounded by a mixture of flattened and cuboidal GC(Figure 2.3, B), and small primary follicles in which theoocyte is surrounded by a single layer of cuboidal GC(Figure 2.3, C).

Aging Changes

In humans, as in other mammals, the size of the ovarianreserve decreases drastically with age (Table 2.1). Attritionof the ovarian reserve has started during fetal life, as soonas the twenty-fourth week of pregnancy when the numberof oocytes began to reduce dramatically. At birth the sizeof the ovarian reserve varies among individuals. Althoughfollicular counts have been performed in a small numberof newborn ovaries, it can be proposed from direct counts

[2, 3] and mathematical extrapolation [4] that each ovarycontains between 250,000 and 500,000 resting follicles. Inhumans the rate of follicular depletion might vary amongsubjects and accelerates from approximately 38 years ofage onward, leading to a stock at menopause estimatedbetween less than 100 [4] and 1000 [5] resting follicles per ovary.

Given the age range, comprised between 40 and 60years, for menopause occurence it takes 50% more timefor some women to exhaust their follicle pool than it does for others. This may be related to variable depletionrates, differences in the initial number of resting follicles,or both. The menopausal age of a given woman is corre-lated with the timing of menopause in her mother andsisters, which strongly suggests a genetic component infactors that regulate depletion of the follicle pool. Parityand environmental factors such as nutrition, race, andsocioeconomic status also influence the age at whichmenopause occurs [6]. Among these factors, lifestyle exposures—especially smoking—can hasten menopauseoccurence [7].

In all mammalian species, follicles leave the stock ofresting follicles in a continuous stream, either by apopto-sis or by entry into the growth phase. By taking intoaccount the number of growing follicles within the ovariesthroughout life [4], it can be estimated that more than 90%of the ovarian reserve escapes by apoptosis mainly duringinfancy and early adulthood.

Depletion of the Pool by Atresia

It is now widely accepted that apoptosis, an active energy-consuming process controlled by a number of intracel-lular proteins, is mainly responsible for attrition of theovarian reserve (see Part V for a detailed discussion of follicular apoptosis). Two comments can be made con-cerning apoptosis of nongrowing follicles in humans.Firstly, atresia of these follicles is difficult to appreciate.Careful examinations of the ovarian reserve show that the oocyte is the first cell to disappear, which leads to follicles exhibiting an irregular ring of transformed GC

TABLE 2.1 Total number (¥10–3) of different types of small follicles from humanovaries in various age groups. Values are mean ± SEM; number ofovaries is indicated in parentheses.

Age groups (years)

19–30 31–35 36–40 41–45 !46Follicular types (5) (9) (13) (28) (26)

Primordial 51.9 ± 9.0 19.5 ± 2.8 9.7 ± 1.1 4.9 ± 1.5 1.3 ± 0.2Transitory 21.8 ± 2.7 10.6 ± 1.7 6.0 ± 1.3 3.1 ± 0.7 0.9 ± 0.1Primary 4.9 ± 0.6 2.3 ± 0.3 1.5 ± 0.4 0.7 ± 0.1 0.3 ± 0.1Total 79.6 ± 12.4 33.3 ± 4.0 20.6 ± 3.7 8.9 ± 2.1 2.7 ± 0.4

SEM, standard error to the mean.

Total number (¥10–3) of different types of small follicles from human ovaries in various age groups. Values are mean ± SEM; number of ovaries is indicated in parentheses

Burden of the Disorder

32.7  

57  

72.1  

85.4  

93.4  

0  

10  

20  

30  

40  

50  

60  

70  

80  

90  

100  

M  1   M  3   M  6   M  12   M  24  

Pregnancy  %age      

 90%  of  couples  will  conceive  a]er  12  months  

As  many  as  10-­‐15%  of  couples  experiencing  inferBlity  

30%  inferBlity  among  women  35-­‐44  year  old       6

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q Study  in  Dakota  &  Montana  (USA):    -­‐    Peak  of  ferBlity  in  women:  25  years  old    -­‐    1/3  women:  inferBle  starBng  from  40  

q Intrauterine  InseminaBon  Programme  (France),  pregnancy  rate  a]er  1  year  inseminaBon:    -­‐    74  %  in    ≤ 30  years  old      -­‐    62  %  in  30-­‐35  years  old  

q The  Importance:    -­‐    Screening  &  adequate  treatment    -­‐    Limits  of  therapy  &  others  alternaBve  

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The Importance of Age

Why Infertile

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Causes of Infertility

①  Sperm abnormality(male factors)

②  Ovulation disorders (ovulation factors)

③  Tubal injury/ occlusion, paratubal adhesion, or endometriosis (tubal & peritoneal factors)

④  Interaction abnormalities between cervical mucus & sperm(cervical factors)

⑤  Rare condition: uterine abnormalities, immunological problems, & infection

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The Cause of Infertility

Male Factors 25 - 40%

Female Factors 40 – 55%

Mix Factors 10%

Unexplained 10%

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40  

10  10  

Male  

Female  

Mix  

Unexplained  

Prevalence of Female Infertility

Disfunction of Ovulation 30 – 40%

Tubal/ Peritoneal Factors 30 – 40%

Unexplained 10 – 15%

Others 10 – 15%

80  %  

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Ovaries Factors

q Anomaly:  -­‐  UnovulaBon                                              -­‐  Luteal  phase  defect                                              -­‐  Amenorea  due  to  low  level  of  estrogen    q Test:  -­‐  cervical  mucus                                  -­‐  basal  body  temperature                                -­‐  hormonal  vaginal  cytology                                -­‐  hormonal  test                              -­‐  endometrial  biopsy    

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Anomaly:    obstruc4on  due  to  infec4on,  tumor,  endometriosis,  hydrosalphynx,  congenital  segmental    obstruc4on.  

Test:      Rubin  test,    HSG,    Laparoscopy  &  Falloscopy  

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Tubal Factors

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Anomaly  •  Pelvic  endometriosis  •  InflammaBon  adhesion  •  Surgical  adhesion  Test  •  Laparoscopy  •  Surgery    

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Peritoneal Factors

Prevalence of Male Infertility

Unknown 48,5%

Idiopathic semen abnormalities 26,4%

Varicocele 12,3%

Infection 6,6%

Immunologic 3,1%

Other acquired 2,6%

Congenital 2,1%

Sexual factors 1,7%

Endocrine disorders 0,6%

>80%

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Normal Semen Analysis

① Volume ≥ 2,0 ml ② Sperm Concentration ≥ 20 juta/ml ③ Motility ≥ 50% ④ Morfology ≥ 30% normal

Normospermia – Oligospermia – Asthenospermia - Teratospermia

2   3   4  

Preparing Semen Analysis

1.  Abstinence 2-5 days

2.  Directly put into clean container (never use condom)

3.  Protect from cold

4.  Received at the laboratory within 1 hour

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Management of Infertility

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Management Option

The majority of infertility therapy aimed to condense the time of the pregnancy

without intervention.

For example, attempts to get pregnant before or during the natural decline in

female fecundity

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Management Option: Male

1.  Medical therapy(GnRH, CC, phenylepephrine, glucocorticoid)

2.  Surgical therapy

3.  Arificial insemination

Management Option: Anovulation

1.  Medical Therapy

2.  Surgical Therapy

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Treatment •  OvulaBon  factors:    

–  InducBon  of    ovulaBon  –  OperaBve:  policysBc  ovary      

•  InducBon  of    ovulaBon:    –   clomiphene  citrate  –  Gonadotropin  –  GnRH  –  BromocripBn  –  Dexamethazone    

•  Surgical  treatment:  –  Laparotomy  à  Wedge  resecBon  –  Laparoscopy  à  Wedge  resecBon  –  Electrocauter  –  Diathermi  –  VaporizaBon  

 

                                                             

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•  Clomiphene  Citrate  (CC)  50-­‐150  mg  given  at  5,  6,  7,  8,  9  day  of  menstrual  period  

•  hMG  2-­‐3  ample  daily  given  at  7,8,9,10,11,12,13,14,15  day  of  menstrual  period  

•  Pure  FSH  (Metrodin)  75  IU  given  at  7,8,9,10,11,12,13,14,15  day  of  menstrual  period  (=  hMG)  

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Induction of Ovulation

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Management Option: Tubal & Peritoneal

1.  Medical Therapy

2.  Surgical Therapy

3.  IVF (in vitro fertilization)

Assisted  ReproducBve  Technology  (ART)  

•  Include:  IVF  (In  Vitro  FerBlizaBon)                      GIFT  (Gamete  Intra  Fallopian  Transfer)                      ZIFT  (Zygote  Intra  Fallopian  Transfer)                      oocyte  donor                      Cryopreserved  embryo  transfer  •  IndicaBons:  severe  damage  of  the  tubes                                                post  sterilizaBon  the  tube                                                InducBon  of  ovulaBon  &                                                                inseminaBon:  failed                                                  ovary  failed                                                InferBle  due  to  oocyte  factors  

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IN VITRO FERTILIZATION

① SBmulaBon  of  the  ovaries  with/without  central  supression  

② Oocyte  retreieval    

③ PreparaBon  for  the  spermatozoa  

④ FerBlizaBon  and  growing  embryo  

⑤ Embryo  transfer  &  treatment  of  luteal  phase  

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Timing  for  InseminaBon  &  Embryo  Transfer  

•  PreparaBon  for  spermatozoa  (swimming  up/percol)    2  hours  before  ovum  pick  up.  

•  Oocyte  incubaBon  about  6  hours,  depend  on  the  quality  •  1  day  a]eràobserv  is  there  any  ferBlizaBon    •  Embryo  transfer  was  done  a]er  concepBon  at  stage  2-­‐4  

cells  •  The  next  stageà  pregnancy  rate  per  transfer  increased,  

the  difficulty  is  need  specific  media  for  the  embryo  life.  

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Medical  treatment:  the  result  is  poor  

•  GnRH:    hypogonadotropic  hypogonadism  •  Retrograd  ejaculaBon:  α adrenergic  agonist  

•  Clomiphene  citrate:  idiopaBc  inferBlity  •  GlucocorBcoid:  anBsperm  anBbody    

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Surgical  treatment  

•  CorrecBon  to  varicocel  and  vasectomy  ,  arBficial  inseminaBon,  ART  (IVF,  GIFT,  MicromanipulaBon)  

•  ArBficial  inseminaBon:  intra  uterine  inseminaBon,  intra  cervical,  intra  peritoneal  dan  intra  fallopian  tube.  

•  ArBficial  inseminaBon:  preparaBon  for  sample,  quanBty  of  sperm  &  Bming  

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Female  Problems  

a.  Cervical  factors  b.  Uterine  factors  c.  Tubal  factors  d.  Peritoneal  factors  e.  Ovarian  factors  

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a. Cervical factors

l  Poor mucus l  Inflammation l  Stenosis l  Antisperm-Antibody l  Estrogen

l  Huhner l  Culture l  Dilatation l  Immune test l  Antibiotic

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Uterine  factors  

•  Septum  •  Fibroid  •  Adhesion  •  Polyp  •  Endometriosis  

•  HSG  •  Hysteroscopy  •  Biopsy  •  OperaBve  hysteroscopy    

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b.  Uterine  factors  

l   about  5%  l   distorBon  uterine  cavity  due  to  synechiae,      myoma,  uterine    polyps,  endometriBs          à  defect:  implantaBon,  growth  of  concepBon,  nutriBon  &  oxygenaBon  of  the  fetus  l   Test:  HCG  l   Therapy:  operaBve  

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Tubal  factors  

•  Tubo  Ovarial  adhesion  •  Tubal  obstrucBon  •  Endosalphyng  damage  •  HSG  

•  Laparoscopy  •  Salphyngoscopy  •  Micro  laparoscopy  •  Micro-­‐surgery  

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OvulaBon  factors  

•  UnovulaBon  •  Follicle  rupture  •  Lutein  •  DisfuncBon  •  Ovary  •  UnovulaBon  

•  Endometrial  biopsy  •  Basal  body  temperature  •  LH  test  •  Progesteron  level  •  InducBon  of  ovulaBon  •  Ultrasound  

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FEMALE  FACTORS  a.  Vulva  and  vagina  •  <  5%  as  causal  factor  •  Anomaly:          -­‐  congenital;  vaginal  septate,  hymen  imperforate          -­‐  infecBon          -­‐  Phsycogen  (vaginismus,  disparenia)          -­‐  C.  Albicans  and  Trichomonas:    inferBle  due  to  coital  defect  

•  Treatment  depend  on  the  cause:  operaBve  &  medical  treatment  

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b.  Cervical  factors  •  About  5%:  cause  of    inferBly  •  Some  anomalies  can  be  find:          canal  obstrucBon,  cervical  mucus  anomaly,  

malposiBon,  atresia,  polyps,  synechiae  &  inflammaBon  

•  Test:  -­‐  cervical  mucus  test                            -­‐  postcoital  test                            -­‐  in  vitro  test  •  Treatment:  -­‐  operaBve                                              -­‐  ArBficial  inseminaBon                                              -­‐  InducBon  of  ovulaBonà  then:                                                      

IVF,  GIFT  atau  ZIFT                                              -­‐  InfecBon  à  culture    

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UNEXPLAINED  INFERTILITY  •  Result  of  all  the  standard  test  are  normal  •  About  10-­‐15%  inferBle  couples  •  Fecundity  about  1.5%  •  60%  couples  become  pregnant  in    3  years  with  

expectaBve  therapy  •  With  ART  à  become  pregnant  is  higher    •  Pregnancy  rate  about  40%  a]er    6  periodes  of    

superovulaBon  or  3  periodes  in  vitro  ferBlizaBon  •  Monthly  pregnancy  rate:  10-­‐15%  

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Luteal  phase  defect  

•  Progesteron  at  luteal  phase,  clomiphene  citrate  at  follicular  phase  

•  Progesteron  à  IM/Vag.  Supp  50-­‐100  mg  daily  IM  

•  Clomiphene  =  inducBon  of  ovulaBon  50  mg  daily  

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f.  InfecBon  factors  

•  Chlamidia  trakhomaBs  &  mycoplasma  sp.  •  20%  acute  salphyngiBs  due  to  clamidia  (USA)  •  InferBle  couples:  become  pregnant  à  47%  mycoplasma  +  (cervical  isolaBon)  

•  InferBle  couples:  failed  to  become  pregnant  à  53%  mycoplasma  +  

•  Treatment  depend  on  the  cause  

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Tubal  Factors  l  Therapy:  opera4ve  laparotomy/laparoscopy;      •       salphygoovorolysis  (59%    pregnant,  Gomel,  1975)  •       -­‐  Fimbrioplasty  (48%  pregnant,  Gomel,  1975)  •                                                         (31%  pregnant,  MeTler,  et  al)  •       -­‐  Salphyngostomy  (18%  pregnant,  Daniell  &  Herbert)  •                                                           (29,4%  pregnant,  Dubuisson)  l   Therapy  for  peritoneal  factors    =    tubal  factors  

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