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14.Infertility And Art2009.3.24

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  • 1. Infertility and Assisted Reproductive Technologies Tianjin Medical University General Hospital Obstetrics and Gynecology Department
  • 2. content
    • Definition
    • Causes
    • Ovulatory factor
    • Cervical factor
    • Uterine- tubal factor
    • Peritoneal factor
    • Male factor
    • Unexplained infertility
    • Assisted reproductive technology
  • 3.
    • Infertility affects approximately 10-15% of couples in the reproductive age group which makes it an important component of the practices of many physicians.
  • 4. Definition
    • A couple is considered infertile after unsuccessfully attempting to achieve pregnancy for a certain period of time
    • (2 years, WHO 1 year ) of sexual intercourse without using any type of contraception
    • Infertility is termed primary when it occurs without any prior pregnancy and secondary when it follows a previous conception.
  • 5.
    • 25% conceive within the first month, 60% within 6 months ,75% by 9 months ,and 90% by 12months.
    • The average time fertile couples take to conceive is 6 months.
  • 6.
    • Female fertility is highest in the age range 20-24 years, and declines gradually after the age of 35 years.
    • In men, ageing has only a minor effect on fertility.
  • 7. Human gamete oocyte sperm
  • 8. oocyte Normal ovulation Hypothalamus Pulsatile secretion of GnRH pituitary FSH LH positive feedback ovary Development productione of follicles ostrogen LH surge Maturation ovulation Corpus luteum progesterone
  • 9. sperm Normal sperm production
    • Spermatozoa are produced in the seminiferous tubules and undergo further maturation in the epididymis
    • Production of mature spermatozoa takes around 70 -80 days
    • Requires an enviroment of 1℃ below normal body temperature
    • After swimming through the favourable cervical mucus, spermatozoa are transported to the ampullary portion of the fallopian tube
    • Penetration and fertilisation of the oocyte takes place in the tubal ampulla.
  • 10.  
  • 11.
    • Conception requires
    • Juxtaposition of the male and female gametes at the optimal stage of maturation
    • Transportation of the conceptus to the uterine cavity at a time when the endometrium is supportive of its continued development and implantation.
  • 12.  
  • 13.
    • For these events to occur, the male and female reproductive systems must be both anatomically and physiologically intact, and coitus must with sufficient frequency.
    • Even when fertilization occurs ,more than 70% embryos are abnormal and fail to develop.
  • 14.
    • The rate of conception declines gradually after the age of 35 years.
    • Reduced embryo quality
    • 卵子老化,纺锤体有丝分裂异常
  • 15. Causes 原因
    • Causes Percentage
    • Female factors 60 %
    • Male factors 30 %
    • Both male and
    • female factors 10 %
  • 16. Female Factors 女方因素
    • Ovulatory dysfunction
    • ( 排卵障碍 )
    • Pelvic factors
    • ( 盆腔因素 )
  • 17.
    • 1. Hypothalamic dysfunction;
    • GnRH 分泌失去节律
    • 2. Pituitary Insufficiency;
    • 垂体器质性或功能性异常
    • 3. Ovarian factor
    • Premature ovarian failure
    • PCOS
    • luteinized unruptured follicle syndrome
    • 4. Others: thyroid or adrenal dysfunction;
    Ovulatory dysfunction 排卵障碍 hypothalamus pituitary ovary
  • 18. Pelvic factors 盆腔因素
    • 1. Tubal factors:
    • blockage, adhesion
    • — inflamation ( gonococcus , tuberculosis , chlamydia trachomatis )
    • — endometriosis — operation – 宫外孕
    • 2. Uterine factors:
    • congenital anatomic abnormalities;
    • endometrium disorder;
    • 3. Cervical factors:
    • Infection, cervix mucus abnormalities;
    • 4. Extra-genital tract factors;
    • Infection, congenital abnormalities;
  • 19. Male Factors 男方因素
    • 1. Abnormal spermatogenesis
    • oligospermia 、 azoospermia 、 asthenospermia
    • congenital – chromosome abnormality ( Klinefelter syndrome : 47-XXY )
    • infectious factors
    • varicocele
    • 2. Obstructive
    • sperm transport abnormalities
    • 3. Immunologic factors - antisperm antibody
    • 4. Sexual dysfunction;
  • 20. Both Male and Female Factors
    • 1. Psychological factors;
    • mental stress , anxiety
    • 2. Immunologic factors
    • Isoimmunity- antisperm antibody
    • autoimmunity-AZP(antizona pellucida antibody)
  • 21. Basic evaluations
    • Younger couples-1 year
    • Older couples-6 months
    • Some deceases corelation to infertility
    • endometriosis pelvic inflammation
    • menstruation disorder
  • 22. The goals of infertility evaluation
    • Determine the probable cause of infertility
    • Provide accurate information regarding prognosis
    • Provide counseling support
    • Provide guidance regarding options for treatment
  • 23. Male factor
  • 24. History
    • There are advantages to having the male present during the initial interview. He may contribute valuable historical information. It also gives the physician the opportunity to emphasize that both partners are involved in the infertility investigation.
    • The male partner should to complete a semen analysis prior to the initial consultation.
  • 25. Male infertility questionnaire
    • age
    • length of infertility
    • reproductive history
    • sexual history
    • Occupational and recreational activities
    • illnesses: parotitis,varicocele,
    • hypospadia
    • family history - hereditary diseases
  • 26.
    • Infection: Prostatitis, orchiditis,
    • Surgery or trauma
    • Exposure to lead, radiation, chemotherapeutic agents
    • Excessive alcohol or cigarettes
  • 27.
    • Lack of either sexual hair or mascular build may indicated insufficient testosterone production.
    • The normal location of the urethral meatus should be ensured.
    • Testicular size
    • varicocele ,orchiditis, epididymitis
    • Rectal examination - prostatitis
    Physical examination
  • 28. Investigation
  • 29. Semen analysis
  • 30. Normal Values for Semen ( following 2 to 7day period of abstinence)
    • volume ≥ 2.0 mL
    • sperm concentration ≥ 20 x 10 6 /mL
    • motility ≥ 50 %
    • normal morphology ≥ 15 %
    • WBC < 10 6 /mL
    • Data from WHO, 1999
    • Please keep in mind:
    • 1. Cycle of Spermiogenesis takes about 74 days;
    • 2. Semen parameters in males may vary;
    • 3. Abnormal semen analysis should repeat at least once;
  • 31. Endocrine evaluation
    • Low levels of gonadotropins and testosterone indicated hypothalamic-pituitary failure.
    • An elevated FSH suggests substantial parenchymal damage to the testes.
    • An elevated prolactin suggests hyperprolactinemia or pituitary tumor.
    • Hypothyroidism can cause infertility. 性欲低下,精子生成异常
    hypothalamus pituitary testis
  • 32. treatment
  • 33.
    • General :
    • to have intercourse approximately every 1 to 2days during the periovulatory period.
    • Lubricants , postcoital douching , should be avoided. Smoking should be reduced or stopped, as should alcohol intake.
  • 34.
    • Low sperm density(oligospermia) or low motility(asthenospermia) caused by hypothalamic-pituitary failure- HMG
    • Hypothalamic suppressed by hyperprolactinemia -bromocriptine
    • Low semen quality coexists with a varicocele-ligation of this venous plexus
  • 35.
    • Low semen volume, count,density
    • Intrauterine insemination(IUI)
    • In vitro fertilization(IVF)
    • Intracytoplasmic sperm injection(ICSI)
    • Donor sperm: azoospermia or severe oligospermia
  • 36. Female infertility questionnaire
    • age
    • length of infertility
    • menstrual history - interval, amount and duration
    • reproductive history - abortion, ectopic pregnance
    • contraceptive history - IUD
    • sexual history
    • family history - twinning, hereditary diseases
    • social history - occupation, tobacco, alcohol,drugs
  • 37. Female infertility questionnaire
    • medical history – 异位症 , 炎症 tuberculosis, present medications
    • surgical history - appendicitis
  • 38. Physical examination
    • Bimanual and rectovaginal examination
    • secondary sexual character
    • internal and external genitalia developmental condition
    • abnormalities 、 pelvic inflammatory disease 、 myoma 、 endometriosis
  • 39. Ovulatory factor
  • 40. ovarian functions detection
    • Ovulation luteal function
    • sexual hormone
    • BBT
    • midluteal level of serum progesterone
    • Endometrial biopsy
    • Urinary LH testing
    • Transvaginal ultrasonography
  • 41.
    • Irregular menstral cycle or age≥35
    • FSH < 10 IU/L
    • LH < 10 IU/L
    • E 2 30-50 pg/ml
    • PRL <29ng/ml
    • (PRL↑ , galactorrhea)
    • p > 5ng /ml - ovulation
    • T <75ng/dl
    • (T↑ , signs of androgen(virilism, with deepening of the voice, hirsutes, acne,amenorrhoea)
    sexual hormone assay
  • 42. Basal body temperature(BBT)
    • BBT is the temperature on awakening before any activity.
    • BBT is the simplest screening to confirm reasonably normal ovulation and can assesses the duration of luteal function.
    • The low point occurs at or about the day of ovulation
    • The temperatures rises in the second half of the cycle to a plateau higher than that in the first half
    • It rises about 0.4 ºC after ovulation owing to the thermogenic effect of progesterone and should remain elevated for at least 11 day.
  • 43. Basal body temperature(BBT)
  • 44. Midluteal level of serum progesterone
    • The midluteal level of serum progesterone can assesses the level of luteal function.
    • A progesterone level greater than 5ng /ml indicates ovulatory activity, but usually exceed 10 ng /ml in cycles in which conception can take place.
  • 45. Endometrial biopsy
    • Time: in the premenstrual phase
    • Histodiagnosis: ovulation
    • luteal function
    • Well developed secretory changes in the premenstrual phase usually indicate satisfactory progestational activity
  • 46. Proliferative phase Luteal phase
  • 47. Urinary LH testing
    • Accurate ovulation timing may be accomplished by measurement of daily luteinizing hormone(LH) concentration.
    • Ovulation may occurs 36 to 44 hours following the LH surge.
    • The interval from the urinary LH surge to the onset of menses should be at least 12 days.
  • 48. Transvaginal ultrasonography
    • Follicular development and ovulation
    • Follicle 1.8-2.0 cm, round
    • Follicle disappear or shrinking small
    • Some fluid in the pelvic
  • 49.  
  • 50. Treatment
    • Induction of ovulation by medical means is the most effective way of treating ovarian disorders which cause infertility.
    • The diagnosis of anovulation or defective luteal phase should have been made before starting treatment.
    • It should be certain that the patient has no other medical disorder which should be treated first.
    • Fallopian tubes should have been shown to be patent
  • 51. Clomiphene citrate
    • Clomiphene can induce ovulation in about 70 % anovulatory women .
    • The usually dosage is 50mg daily for 5 days beginning on day 5 of the menstrual cycle.
    • If response to this dosage is poor , it may be increased by 100mg daily for 5 days in the next cycle.
    • The maximum safe dose is 150mg daily.
    • The risk of both multiple pregnancy and ovarian hyperstimlation are less with clomiphene, and clomiphene should be the initial treatment for inducing ovulation.
  • 52.
    • HMG : extract from the urine of postmenopausal women.
    • HMG is a mixture of FSH and LH,chiefly with FSH action.
    • HMG alone
    • CC+HMG
  • 53.
    • Pituitary insufficiency requires the injection of HMG.
  • 54.
    • ovarian hyperstimulation syndrome (OHSS)
    • ovary enlargement –abdominal distention and pain
    • exudation of fluid and protein into peritoneal and pleural cavity-blood volume decrease ,renal failure
    • Careful monitoring is important to allow adjustment of dosage and to avoid ovarian hyperstimulation.
    • multiple pregnancy
    • occurs in 6-8% of CC conceptions
    • occurs in 20-30% of HMG conceptions
    Main Complication Of Induce ovulation
  • 55.
    • The appropriate method for ovulation induction is determined by the patient’s specific diagnosis
    • Oligomenorrhea-it is helpful to induce more frequenct ovulation, thus increasing the opportunity for pregnancy.
    • Ovarian failure –no responds to induce ovulation
  • 56.
    • Hypothalamic amenorrhea: caused by infrequent or absent pulsatile release of GnRH.
    • GnRH can be administered in small pulses every 90-120 min by a pump.
    • If this treatment is not available,HMG is quite effective.
  • 57.
    • Hyperprolactinemia: treated by use of the dopamine agonists-bromocriptine , 1.25-2.5mg/d
  • 58.
    • Follicles develop to maturation but not rupture – result from the normal LH surge fail to occur.
    • HCG
    • FSH or HMG – induce ovulation
  • 59. Correction of a luteal phase defect
    • use progesterone
    • The second or third day after ovulation. vaginal or intramuscular.
    • use clomiphene or HMG
  • 60. Cervical factor
  • 61.
    • During the few days before ovulation, the cervix produces a profuse watery mucus that exudes out of the cervix to contact the seminal ejaculate.
  • 62.
    • postcoital test
    • Assess the number and motility of sperm that entered the cervical canal.
    • The patient must be seen during the immediate preovulatory
    • Performed 2 to 8 hours after intercourse
    • The mucus should extend in a thread to at least 6 cm,
    • The number of sperm is greater than 20 / HP indicates normal semen characteristics.
    Investigation(2)
  • 63.  
  • 64.  
  • 65.  
  • 66.
    • Cervical infection : antibiotic drug
    • chronic cervicitis : cryotherapy , microwaves
    • pH is low:
    • sodium bicarbonate, gentle douche 30 minutes before coitus.
    • Poor mucus quality :
    • small dose of estrogen from D7 until ovulation
    • IUI
    Treatment
  • 67. Uterine - tubal factor
  • 68. Uterine
    • The commonest congenital abnomalies of the uterus are associated more with recurrent abortions than with primary infertility.
    • Large submucosal myomas or endometrial polyps may rare be associated with infertility but more often are associated with abortion.
    • Subserous fibroids do not affect fecundity.
    • Tuberculous endometritis is always secondary to tuberculous salpingitis and the prognosis for fertility is very poor.
  • 69. Tube
    • Tubal occlusion may occur at three locations: the fimbrial end, the midsegment, or the isthmus-cornu.
    • Prior salpingitis , pelvic endometriosis and the use of an intrauterine device are common causes.
  • 70. Test for tubal patency
    • Hysterosalpingography
    • Laparoscopy
    • hysteroscopy
  • 71. Hysterosalpingography
    • The injection of lipiodol or meglumine diatrizoate through the cervix under radiographic control.
    • The passage of the dye into the uterus and out along the tubes is observed. As well as determining the exact site of any tubal blockage.
    • The test should be performed during the first 10 days of the cycle, after menstrual bleeding has ceased .
  • 72. HSG Free spill of dye from the distal ends of the tubes The dye in the peritoneal cavity after 24 h
  • 73. Bilateral tubal occlusion Proximal part distal ends of the tubes
  • 74. Laparoscopy
    • Premenstrual laparoscopic examination of the tubes combined with injection of a dilute solution of methylene blue through a tightly fitting cannula placed in the cervical canal.
    • If the tubes are patent they fill with dye which finally spills from the distal ends.
    • The patient should be warned to avoid the risk of becoming pregnant during the cycle in which investigation is performed.
  • 75.  
  • 76.  
  • 77. Treatment
  • 78.
    • Injection liquid medicine into the tubes
    • dexamethasone 5mg + gentamicin 40000 U+ physiological saline 20ml
    • Microsurgical tuboplasty - Salpingostomy
    • Proximal occlusions: selective catheterization.
    • In general the results of tubal surgery are dissappointing because , even when tubal patency can be restored , the ciliary action of the tubes has usually been irretrievably damaged.
    • IVF
    Treatment
  • 79. Peritoneal factor
  • 80.
    • Laparoscopy identifies previously unsuspected pathologic conditions in 30% to 50% of women with unexplained infertility.
    • Endometriosis is the most commom finding.
  • 81. Endometriosis of the Ovary Copyright Trehan UTERUS RIGHT OVARY SKIN OF THE PELVIS UTERUS ENDOMETRIOTIC CYST ON OVARY BOWEL LARGE OVARIAN CYST (CHOCOLATE CYST) UTERUS LEFT OVARY RIGHT OVARY ADHESIONS Copyright Trehan Copyright Trehan
  • 82. Endometriosis interferes with fertility in a number of ways(1):
    • Interfere with tubal motility
    • Cause tubal obstruction
    • Cause adhesion disturb the pick-up of the oocyte
    • The inflammation caused by retrograde menstruation and the ectopic endometrium induces an increased number of peritoneal macrophages, reducing the number of sperm available to penetrate the oocyte-cumulus complex.
  • 83.
    • Associated with an increased incidence of luteinized unrupture follicle syndrome.
    • Luteal phase defects may more common in women with endometrosis.
    Endometriosis interferes with fertility in a number of ways(2 ):
  • 84. Unexplained infertility
  • 85.
    • No cause is found for infertility in 5% to 10% of patients who have documented ovulation, normal semen analyses, and a normal HSG.
    • The problem appears to be
    • sperm transport
    • defect in the ability of the sperm to fertilized the oocyte
    • The presence of the antisperm antibodies
  • 86. Treatment
    • IUI
    • IVF
  • 87. Assisted Reproductive Technologies (ART) 辅助生育技术
    • Intrauterine insemination ( IUI);
    • 宫腔内人工授精 ;
    • In vitro fertilization and embryo transfer
    • (IVF-ET); 体外受精与胚胎移植 ;
    • Intracytoplasmic sperm injection (ICSI);
    • 单精子卵泡浆注射;
    • Gamete intrafallopian transfer (GIFT);
    • 配子输卵管移植 ;
  • 88. Intrauterine insemination ( IUI) 人工授精
    • Indications:
    • 1. as treatment of male factor infertility;
    • 2. psychological factors;
    • 3. unexplained infertility;
    • 4. genetic defects;
    • Types:
    • 1. artificial insemination with husband’s sperm (AIH) ;
    • 2. artificial insemination by donor (AID) ;
    • Method:
    • placement of about 0.3 ml of washed, processed
    • and concentrated sperm into the intrauterine cavity
    • by trans-cervical catheterizaion.
  • 89.
    • The inseminations done approximately 36 to 39 hours after LH surge or the HCG injection.
    • The sperm must be washed to remove prostaglandin and bacteria.
  • 90. cervixs uterus sperm oocyte Intrauterine Insemination IUI Sperm preparation
  • 91. In vitro fertilization –embryo transfer IVF-ET
  • 92.
    • Most ART procedure invovle a common set of steps that are based on In vitro fertilization –IVF.
    • In IVF the doctor uses the hormonal medications to stimulate the ovaries, gathers the eggs, fertilizes the eggs in vitro, then transfers the resulting embryos through the cervix into the uterus.
    • The first livebirth resulting from this technique occurred in June1978.
    • Male factor infertility may benefit from microfertilization process, such as ICSI,which uses one sperm to fertilize an egg.
  • 93. Indications
    • Tubal factor
    • IVF-ET bypasses the mechanical transport functions of the female reproductive tract.
    • Bilateral salpingectomy
    • Tubes are so badly damaged that they cannot function.
    • Antisperm antibodies,
    • Endometriosis,
    • Oligospermia
    • Unexplained infertility.
  • 94. IVF procedure(1)
    • Ovarian stimulation
    • All IVF-ET programs use superovulation to stimulate production of several eggs and to improve timing of egg aspiration.
    • Ultrasound scanning monitors the number and growth of ovarian follicles.
    • At least 2 or 3 follicles should be developing before proceeding with egg aspiration. Otherwise, the cycle is abandoned and an alternative stimulation regimen is selected for a subsequent cycle.
  • 95. Ovarian stimulation
    • GnRH-a : reduced the likelihood of a premature LH surge.
    • FSH or HMG, or both on the D2 or D3 of the next cycle.
    • Follicle size is assessed by transvaginal ultrasonography.
    • An injection of hCG is given to induce the resumption of meiosis and to complete oocyte maturation.
  • 96.  
  • 97.
    • Oocytes retrieval
    • 35 hours after the hCG injection, oocytes are aspirated under transvaginal ultrasonography guidance.
    IVF procedure(2)
  • 98.  
  • 99. Oocytes retreival
  • 100. Oocytes collection
  • 101.
    • The method of the fertilization is different between IVF and ICSI
    • IVF: the eggs are incubated with sperm
    • ICSI: a sperm is injected into the cytoplasm of the egg
    IVF procedure(3)
  • 102.  
  • 103. Culture of Fertilized Eggs in the Laboratory
    • Eggs are incubated in an atmosphere of 5% carbon dioxide. Various culture median are used and are often supplemented with either the patient ' s serum or bovine serum albumin.
    • Pronuclei are examined in order to confirm fertilization, as well as blastomeres, which confirm cleavage.
  • 104.  
  • 105.
    • Embryo transfer
    • D2 or D3 or D5
    • to the uterine cavity
    IVF procedure(4)
  • 106. Outcome of IVF
    • The mean live delivery rates per retrieval with IVF and GIFT in 1994 were 21% and 28%, respectively.
    • Ectopic pregnancy occurs in about 3%.
    • The rate of fetal abnormalities is not increased.
  • 107. Complications
    • ( 1 ) Multiple gestations--transferring more embryos in order to a greater IVF success rates.
    • (2) Ectopic and heterotopic pregnancies
    • (3) Preterm birth and abortion
    • (4) Ovarian hyperstimulation syndrome.
  • 108. Other techniques in IVF
    • GIFT is similar to IVF-ET.
    • GIFT is useful only in patients who have normal tube function.
    • Superovulation is induced as in IVF-ET; an hCG injection is given and the follicles are aspirated via laparoscopy. Sperm are then mixed with the eggs and drawn up into a catheter.The eggs and sperm are then transferred to the uterine tubes, permitting natural fertilization and cleavage.
  • 109. Other techniques in IVF
    • Embryo frozen
    • Sperm frozen
    • PGD (preimplantation genetic diagnosis)
  • 110. Phychological aspect
  • 111.
    • The infertility specialist must be aware of and sensitive to the phychological stresses associated with infertility.
    • A supportive relationship with the physician, a frank discussion of the lengthy of various treatment, realistic expectations to the couple’s prognosis.
  • 112. Thanks thanks