Infertility

Chapter 27. Infertility


18, September, 1997, 1st year resident J. S. Lee. M .D.



Ⅰ. Introduction


  • Infertility - 1 year of unprotected intercourse without pregnancy
  • Primary infertility - no previous pregnancies
  • Secondary infertility - prior pregnancy
  • Fecundability - probability of achieving pregnancy within a single menstrual
    cycle (normal couple : 20 ~ 25%)
  • Fecundity - probability of achieving live birth within a single cycle
  • Approximately 90% of couples should conceive after 12Mo
  • Infertility - 10 ~ 15% of reproductive-age couples


Ⅱ. Infertility and age


  • Age↑ → reduced fecundability
  • Begins in early 30s and accelerates in late 30s & early 40s
  • 30% of couples in which the female partner is age 35 - 44yrs - infertile
  • Peak - 25yrs of age
  • Pregnancy rate after 1yr of insemination : 74% in < 30yrs, 62% in 30 ~ 35yers,
    54% in > 35yrs

A. Oocyte depletion


  • Age-related decline in fertility - attributable to oocyte depletion

    .Late 30s - small increase in FSH → correlates with subtle changes in oocyte number
    and perhaps oocyte competence → reduced fertility

    .As FSH levels rise and a woman approaches menopause, the chances of successful
    pregnancy decline further oocyte donation


  • Embryo produced from oocyte retrieved from younger women are transferred into
    older women

    → Pregnancy rate - older women (up to50yrs) approximate those of the younger women

    ⇒ age of the oocyte, rather than the age of endometrium that accounts for the age-related decline in
    female fertility

B. Spontaneous abortion


  • In older reproductive-age women : increased risk of spontaneous abortion
  • Rate of clinically recognizable spontaneous abortion

    : more than doubles between 20 & 40yrs of age

    .↑loss rate with ↓conception rate - significantly reduces the chance of a live birth over 40 yrs.


Ⅲ. The infertile couple



A. Initial visit



  • Complete medical, surgical & gynecologic history


    . Specifically, information regarding menstrual cyclicity, pelvic pain, obstetrical history

    . Risk factor for infertility - PID, IUD use, pelvic surgery, intrauterine exposure to DES, ??
    pituitary,

    ?? adrenal & thyroid function

    . Male partner - genital surgery, infection, trauma, history of mumps

    . Coital frequency, dyspareunia, sexual dysfunction


  • Physical exam - particular attention to height, weight. body habitus, hair distribution, thyroid gland,
    galactorrhea & pelvic exam.

B. Causes of infertility


  1. Abnormalities in the semen (male factor infertility)
  2. Ovulatory disorder (ovulatory factor)
  3. Tubal injury, blockage, paratubal adhesion or endometriosis (tubal/peritoneal factor)
  4. Abnormalities in cervical mucus -sperm interaction (cervical factor)
  5. Rarer condition, such as uterine abnormalities, immunologic aberration & infection


  • Table 27.1




1. Male factor



  • Most common cause of infertility
  • Semen analysis - basic study assessing such abnormalities
  • Physiology



    • Male reproductive tracts - testis, epididymis, vas deferens, prostate, seminal vesicle,
      ejaculatory duct, bulbourethral gland. & urethra


    • Testes : Sertoli cell - lines seminiferous tubules -site of spermatogenesis

      ??????????????
      Leydig cell - the site of androgen synthesis


    • Pituitary gland - LH & FSH secretion



      • LH - stimulate the synthesis & secretion of testosterone
      • FSH - stimulate the sertoli cells to secrete inhibin


    • FSH & testosterone - act on seminiferous tubule to stimulate spermatogenesis


    • Process of transforming spermatogonia into mature sperm cell lasts 74 days



      • immature spermatogonia -> mitotic division -> spermatocyte → meiosis → spermatozoa →
        → enter epididymis which they traverse in 12-21 days as they mature & become progressively
        more motile


      • released spermatozoa - capacitation - biochemical & electrical events within the sperm's
        outer surface membrane before fertilization


      • acrosomal reaction → release of enzymes of the inner acrosomal membrane → result in the
        breakdown of the outer plasma membrane & its fusion with the acrosome membrane

        → sperm's penetration of the egg's zona pellucida


      • as the sperm penetrates the egg, it initiates a hardening of the zona pellucida (cortical reaction)

        - which prevents penetration by additional sperm



    • Semen analysis


      • Measures semen volume, sperm concentration, motility & morphology, pH,. fructose, WBC


      • Normal value : Table 27.2


      • Specimen collection



        • 2-3days of abstinence


        • By masturbation, collected in a clean container, taken to the laboratory within 1-2hrs of collection


        • Sperm volume : normal (2-6ml)

          low in cases of retrograde ejaculation

          high in long period of abstinence, inflammation of the accessory gland.

          absence of fructose or high pH - ejaculatory tract obstruction or seminal vesicle dysfunction



      • Sperm concentration : number of sperm per milliliter in total ejaculate



        • WHO - 20 million sperm per milliliter - lower limit of normal
        • Some - have advocated concentrations of 5 million


      • Sperm motility : Percentage of progressive motile sperm in the ejaculate



        • WHO - cutoff of 50% motility
        • SART - 40%


      • Sperm morphology



        • 15% normal sperm - normal rate of fertilization
        • 4 ~ 14% - intermediate
        • <4% - greatly reduced rate of fertilization


      • White cells



        • number of round cells : may be lymphocyte (can signify the prostatitis) or immature germ cells

          → distinguished by an immunoperoxidase staining


        • WHO : > 5 million round cells per milliliter

          ???????????
          > 1 million leukocyte per milliliter → abnormal


        • Presence of immature sperm cells → defect in spermatogenesis : relatively poor prognosis
          for fertilization


      • Sperm penetration assay



        • Measure the ability of sperm to undergo capacitation to fuse with & penetrate the
          oocyte membrane & to undergo nuclear decondensation


        • Golden hamster's egg - treated with enzyme to remove the cumulus & zona pellucida


        • Sperm are placed in protein-rich environment which promote capacitation

          → Zona-free eggs are exposed to sperm

          → presence of one or more swollen sperm heads within the oocyte demonstrate penetration


        • Prognostic value of SPA - controversial, does not discriminate between fertile & infertile


      • Human zona-binding assay (Hemizona test)

      • Hypoosmotic swelling test

      • ATP content in semen



    • Table 27.3 : Male factor causes of infertility.


    2. Ovulatory factor




    • Account for 30 ~ 40% of all cases of female infertility

    • Most easily diagnosed & most treatable causes

    • Monthly menses with monillial symptom - almost invariably have ovulatory cycles

    • Ovulation - obvious prerequisite to conception - must be documentedas part of the basic
      assessment of the infertile couple

    • Initial diagnose may be anovulation (complete absence of ovulation) or oligo-ovulation (infrequent ovulation)

    • DDx- hypothalamic & pituitary abnormality, thyroid disease, adrenal disorder &
      hyperandrogenic oligoovulation

      (Methods to document ovulation)


    • Basal body temperature




      • Easiest & least expensive method of detecting ovulation

      • Significant progesterone secretion by the ovary generally occurs only after ovulation

      • Progesterone - thermogenic hormone - 0.5'F over the base line temperature in the follicular phase
        → biphasic patter → indicative of ovulation

      • Confirm rather than predict ovulation

      • Small percentage of pt. BBT chart are monophasic despite the documentation of ovulation by other method


    • Midluteal serum progesterone



      • Indirect evidence of ovulation, >3 ng/ml confirms ovulation

      • Peak - typically on day 21-23 of an ideal 28 day cycle



    • LH monitoring




      • Documentation of the LH surge - predicting ovulation

      • Ovulation - occurs 34 ~ 36 hrs after the onset of LH surge & approximately 10-12 hrs after LH peak

      • LH - pulsatile hormone - 2 to 3 fold elevation of the serum LH levels over baseline sufficient to
        document an LH surge


    • Endometrial biopsy



      • Findings of secretory endometrium confirms ovulation

      • More invasive & uncomfortable

      • Role in infertility - not in documentation of ovulation but rather in diagnosis of LPD

      • 2-3 days before the expected onset of menses

      • Interpreted by dating of endometrium according to the criteria of Noyes, Hertig & Rock may be significant variability


    • Ultrasound monitoring



      • Monitoring the development of the dominant follicle by USG until ovulation takes place

      • ↓ in follicular size & the appearance of fluid in the cul-de-sac

      • Inconvenient & expenses - recommended to the monitoring of ovulation induction in ART pts


    • Luteal phase defect



      • 2 endometrial biopsies show a delay of more than 2 days beyond the actual cycle day in the histologic development of the endometrium


      • Presumed cause - reduction in progesterone production by corpus luteum

        ?? →lead to poor secretory endometrial development

        ?? →could cause a failure of implantation or a very early abortion


      • Underlying causes of LPD - inadequate follicular development, inadequate FSH secretion


      • Abnormal LH secretion or an abnormal effect of progesterone on endometrium


      • Davis - 31.4% - out of phase biopsies, 6.6% sequential out of phase biopsies in normally fertile
        women


      • Luteal phase serum progesterone level - correlates sufficiently with biopsy results to serve as a substitute


    3. Tubal/Peritoneal factors




    • Account for 30-40% of cases of female infertility

    • Tubal factor - damage or obstruction of the fallopan tubes, usually associated with previous. PID, pelvic or tubal surgery

    • Peritoneal factor - peritubal & periovarian adhesion - from PID, surgery or endometriosis

    • Tubal infertility - 12%, 23%, 54% after one, two & three episodes of PID

    • 50% of pt with documented tubal damage - no identifiable risk factors for tubal disease, presumed to have subclinical chlamydial infection


    • Hysterosalpingography



      • Initial test of tubal patency

      • Performed between cycle days 6 & 11, after cessation of mens flow & before ovulation

      • 1-3% - infection : exclusively with current or prior pelvic infection

      • Chronic PID is suspected - ESR before HSG

      • Bimanual exam before test - identify adnexal masses or tenderness which could signal current
        infection

      • Antibiotic prophylaxis - controversial

      • Mainly in women with hydrosalpinx- routine prophylaxis - doxycycline for 3 to 5 days

      • Water soluble contrast material - rapid absorption, cramping

      • Oil based dye - lipid embolism, lipid granuloma formation, better resolution of tubal architecture, higher postprocedure pregnancy rate


    • Laparoscopy




      • Gold standard for diagnosing tubal & peritoneal disease

      • Opportunity to treat abnormalities at the time at diagnosis


    • Falloposcopy



      • Direct observation of the lumen of the fallopian tube via laparoscopy or hysteroscopy can define normal tubal appearance & has identify abnormal mucosal tubal patterns : tubal ostial spasm, presence of intraluminal debris as a cause of tubal obstruction


    4. Cervical factor


    - Cause of infertility in no more than 5% of cases


    • Postcoital test (PCT)




      • Assess the quality of cervical mucus, presence & number of motile sperm in the female
        reproductive tract after coitus, interaction between cervical mucus & sperm

      • Performed just before ovulation - proper interpretation requires sufficient estrogen exposure

      • Less than 2 hrs from intercourse to PCT (can be within 24 hrs)

      • Withdraw cervical mucus from endocervical canal

      • Evaluation : spinnbarkeit (8~10cm), ferning & clarity (clear & watery) presence, number
        &

        ?????????????
        ?? ???
        motility of sperm per several HPF

      • Abnormal PCT



        • poor timing within menstrual cycle - repeat

          hormonal abnormality (oligoovulation)

          production of poor guilty cervical mucus

          anatomic factor (prior cervical conization or cryotherapy)

          infection

          medication (clomiphene citrate)


        • Observation of shaking sperm or uniformly dead sperm : suggest the presence of
          antisperm antibodies


      • Prognostic value - controversial, lack of standard methodology, uniform definition of normal,
        unknown degree of reproducibility


      • Value - screening mechanism for ASA or poor cervical mucus due to hormonal, anatomic or
        infectious factor



    5. Uterine factor



    • Generally associated with recurrent pregnancy loss rather than with infertility (ex. fibroid,
      congenital uterine malformation)

    • Association of in utero DES exposure with infertility - controversial, classical T-shaped endometrial cavity, cervical & tubal abnormalities

    • Intrauterine adhesion - Ashermann's SD : may be infertile, associated with amenorrhea, menstrual irregularity & spontaneous abortion, interfere with embryo implantation

    • HSG, hysteroscopy



    6. Immunologic factors



    • Sperm - antigenic, autoantigenic

    • Antibody response to sperm - could reduce fertility

    • Antisperm Ab - detected in human male & female : in serum, cervical mucus & semen



      • IgG and IgM (exclusively in serum) class

      • Agglutinating antibodies of IgA class : typically found in cervical mucus & seminal
        plasma

      • Etiology : not well defined, may be multifactorial, breaks in the vaginal epithelium, breaks the blood-testis barrier (trauma, torsion, vasectomy reversal & infection)

      • Significance


        • Ab. binding to sperm head - interfere with sperm binding to zona pellucida
        • Tail-binding antibodies - reduce sperm motility
        • Interfere with fertilization by disrupting sperm transport., by obstructing gamete interaction or by promoting sperm phagocytosis


      • Available test


        • Immuno-bead
        • Mixed agglutination test

          ? sperm agglutination test (Kibrick's or Franklin-Dukes)

          ? sperm complement-dependent immobilization test (Isojima's)

        • Antisperm antibodies as a cause of infertility - not clear
        • Older studies demonstrate an association between reduced fertility & antisperm Ab in the male & female
        • Prospective double-blind cohort analysis comparing conception in Ab(+) & Ab(-) couples failed to identify a less favorable prognosis for conception to Ab (+) couples


    7. Infection



    • Chlamydia trachomatis



      • PID, acute salpingitis - may be subclinical

      • Higher in infertile pt. than among controls

      • Treatment of asymptomatic chlamydia-positive pts : improves fecundity - remain unresolved


    • Mycoplasma specie




      • Mycoplasma hominis, Ureaplasma urealyticum

      • Have been recovered from cervical mucus & semen of infertile couples

      • Higher rate among infertile couple than among fertile controls



    C. Unexplained infertility



    • Contemporary treatment of unexplained infertility

    • Empiric therapy with ovulation induction & IUI or the use of ART


    Ⅳ. Treatment options


    • Very few couples who are unable to conceive are diagnosed absolute infertility



    • Treatment - independent pregnancies

      : occurring in untreated patients or occurring more than 3months after last medical treatment or more
      than 12months after adnexal surgery

      : impressive rate of 'spontaneous cure' illustrates why it is best to view the treatment of infertility as an attempt to improve fertility efficacy



    • Most infertility therapy is directed toward decreasing the time it would take to conceive without intervention


    A. Male factor infertility



    1. Medical therapy



    • GnRH - hypothalamic dysfunction, Kallmann's syndrome, hypogonadotropic hypogonadism
    • Phenylephrine - retrograde ejaculatory dysfunction
    • Clomiphene citrate - idiopathic infertility
    • Condoms and glucocorticoids - infertility associated with antisperm antibodies


    2. Surgical therapy


    • Varicocele - corrective procedures
    • Surgical reversal of vasectomy
    • Artificial insemination
    • ART(assisted reproductive technologies) - IVF, GIFT, micromanipulation

    3. Artificial insemination




    • Encompasses a variety involving placement of whole semen or processed sperm into the
      female reproductive tract : permits sperm-oocyte interaction in the absence of intercourse



    • Type of insemination : intracervical, intrauterine, intraperitoneal, intrafollicular insemination, fallopian tube sperm perfusion

    • Processing semen



      • Washing

      • Separation procedure : centrifugation through density gradients , sperm migration protocols, differential adherence procedure

      • Phosphodiesterase inhibitors (pentoxiphylline) : enhance sperm motility, fertilization capacity, acrosome reactivity for IVF procedures

      • Sperm retain their fertilizing capacity for 24-48hr after ejaculation if they are able to escape the intravaginal environment, oocytes can be fertilized for approximately 12-24hr after ovulation


    • Donor insemination


      1. Use of frozen samples



        • Semen donors are screened for HIV inf. hepatitis B. hepatitis C. syphilis. gonorrhea. Chlamydial CMV infection.

        • All cryopreserved samples are quarantined for 6months and the donor is retested for HIV prior to clinical use of the specimen

        • Questioned concerning a family history of genetically transmitted diseases both Mendelian and
          polygenic / multifactorial


      2. Success rate




        • Under 30 years of age no other infertility factors : conception rate approach 62% after 12cycles of treatment with frozen sperm



      3. Length of recommended treatment



        • When frozen semen is used, more than 80% of consequent pregnancies will occur during the first 12months of treatment

        • Pt should be encouraged to terminate treatment or more to alternative form of therapy after 1 year of unsuccessful efforts at donor insemination




    B. Ovulatory factor




    • Pt with ovulatory factor infertility have the greatest success rates with infertility therapy


    1. Clomiphene citrate



    • Weak synthetic estrogen, acts clinically as an estrogen antagonist for ovulation induction at typical pharmacologic doses


    1. Action



      • Hypothalamus - binds to and block receptor for prolonged periods, functionally decreasing the normal ovarian-hypothalamus feed back loop

      • Direct action on pituitary or ovary

      • Antiestrogenic effect at the level of the endometrium or the cervix



    2. Success rate




      • Ovulation rate : 80-85%

      • Conception rate : 40%

      • Most pregnancy occur during the first 6months of therapy


    3. Side effect




      • Infrequent ovarian hyperstimulation syndrome, vasomotor flushed, nausea, pelvic discomfort, breast pain, visual abnormalities, multiple gestations : 5-8%

      • Spontaneous abortion and teratogenicity : not increased with the use of clomiphene citrate



    4. Typically used for ovulation induction



      1. Starting dosage 50mg/day

        begin on the 5th day after onset of a spontaneous or progesterone induced menses

        continued through day 9 of the menstrual cycle


      2. Ovulation



        • BBT change

        • Luteal-phase progesterone measurement

        • Timed endometrial biopsy

        • Ovulation doses not occur at the initial dosage→ dosage increased in each subsequent cycle by 50ng/day, safe up to a dosage of 250ng/day


      3. Ovulation is expected to occur 5-10 days after the last day of therapy


      4. Clomiphene citrate therapy fails may respond to ultrasound monitoring of follicular develop and hCG for the induction of ovulation or to an appropriate individualized combination of clomiphene citrate with glucocorticoids or bromocriptine




    2. Gonadotropins


    • Treatment of choice for women in whom clomiphene citrate therapy has failed for women with ovulatory dysfunction secondary to hypogonadotropic hypogonadism.



    • Action : FSH and LH act in concert to stimulate folliculogenesis hCG typically used in hMG-stimulated cycles to promote oocyte maturation, induce ovulation, and allow appropriate corpus luteum formation and function


    • Success rate



      1. Ovarian hyperstimulation syndrome.



        • Onset : 7 ~ 12days after the administration of hCG

        • Severe form : significant ovarian enlargement, ascites, pleural effusion, hemoconcentration,
          hypercoagulability , ovarian torsion or rupture, severe electrolyte disturbance, seizure, respiratory compromise, renal failure, even death


      2. Multiple gestation 11 ~ 44%


      3. Linked to an increase rate of ectopic pregnancy


    • Typical treatment regimen



      1. begin therapy 2,3 or 4 days after onset of a spontaneous or induced menses


      2. pt with evidence of endogenous estrogenic activity begin therapy by taking 1 or 2 ampules of hMG per day


      3. daily dosage is maintained until cycle day 6 or 7 when the serum estradiol level is measured to document ovarian response


      4. hMG dosage is increased by 1 or 2 ampules per day every 3 or 4 days until a response is evidenced by rising estradiol level or until a protocol-determined maximal dosage is reached


      5. once an ovarian response is obtained, treatment is typically continued without further increase in dose


      6. vaginal ultrasonography and serum estradiol measurements are performed every 2 ~ 3 days to evaluate follicular size, number and quality



        • adequate : maximal follicular diameter exceeds 16 ~ 18mm with a corresponding serum estradiol level of 150 - 250 pg/ml per mature follicle


        • serum estradiol level should be >600pg/ml and should not exceed 1500 - 2000 pg/ml



      7. when appropriate follicular size and estradiol level have been attained, 5000 - 1000 IU of hCG is administered intramuscularly, ovulation is expected 36hr later


    • Combination therapy



      • Clomiphene citrate and hMG - minimal stimulation

      • Addition of growth hormone to the hMG regimen



    • PCO syndrome




      • GnRH agonist : because the down regulation of the hypothalamic - pituitary - ovarian axis blocks the hormonal feedback loops involved in the disorder



      • purified FSH




    3. Pulsatile GnRH therapy

    • Administered in a pulsatile fashion
    • Normal pituitary negative and positive feedback mechanisms remain intact
    • Cumulative pregnancy rate : hypothalamic hypogonadism approach 80% after six treatment cycles and 43% after 12 cycles


    • Typical regimen



      • IV route is sup to the subcutaneous route
      • Best dosing interval is 60 - 90mutes
      • Optimal dosage is 75mg/kg/pulse → ovulation occurs on day 14 and can be documented by standard LH testings, luteal phase support
      • Continuation of the GnRH pump



        • Administration of hCG
        • Progesterone supplementation




    4. Bromocriptine and Dexamethasone supplementation

    • Bromocriptine - hyperprolactinemia , unexplained infertility and galactorrhea
    • Dexamethasone - hyperandrogenism and ovulatory factor infertility

    5. Surgical treatment

    • Ovarian wedge resection
    • Laparoscopic technique

    6. Luteal phase defect

    • Luteal phase progesterone supplementation
    • Follicular phase clomiphene citrate use begin on the third day after the midcycle temperature rise or on the second or third day after the onset of the LH surge



      • dosage 25 ~ 50ng twice a day for vag suppository, 50 - 100ng each day for IM inj given orally at a dosage at 50mg/day on days 5 ~ 9 of the menstrual cycle


      • endometrial biopsy is performed in the late luteal phase of the treatment cycle to assay efficacy


      • dosage is increased by 50ng/day per cycle


      • maximal dosage is typically 150 - 250mg/day




    C. Tubal and peritoneal factor



    • As success rates continues to improve for ART, indication for surgical therapy for tubal factor may become increasingly limited


    • Adhesion prevention is integral to the treatment of adhesive periadnexal disease


    • Hemostatic surgical techniques and judicious use of the laparoscopic approach are generally recommended for the treatments of tubal factor infertility


    • Proximal tubal occlusion



      • Tubocornual anastomosis

      • Minimally invasive transcervical techniques may involve the use of u.s. fluoroscopy, hysteroscopy or recanalization falloposcopy



    • Distal tubal occlusion


      • Fimbrioplasty, neosalphingostomy


      • Poor prognostic factor

        ??? hydrosalpinx >30cm in dia

        ??? absence of visible fimbriae

        ??? dense pelvic or adnexal disease


      • Sterilization reversal




        • Success of tubal reanastomosis is dependent on the method of sterilization the site of anastomosis the presence of other infertility factor

        • Prognosis is best when anastomotic sites had no significant discrepancy in diameter

        • Final anastomosed tubal lengths of less than 4cm are associated with low pregnancy rates



      • Peritoneal factor



        • Peritoneal adhesive disease

        • Endometriosis


    D. Cervical factor infertility



    • Two cervical characteristics necessary for normal reproduction

      ? : anatomic patency, production of adequate amounts of hospitable mucus


    • Potential for cervical stenosis or poor mucus quality

      ? : exposure to DES, prev cone biopsy or cauterization, congenital anomalies, cervicitis, anovulation, use of clomiphene citrate for ovulation induction, antisperm antibodies


    • Treatment


      • Surgery

      • IUI alone or ovulation induction combined with IVF,GIFT or ZIFT

      • Cervical culture for bacteria ( C. tracomatous, N.gonorrhea) & for yeast infection, bacterial vaginosis, tricomoniasis

      • Ovulation induction : hMG. pure FSH




    E. Uterine factor




    • Treatment of uterine factor infertility is predominantly surgical

    • Postoperative hormonal supplementation may be employed for adhesion prevention in cases of extensive intrauterine resection

    • Tuberculous endometritis, fibrotic endometritis (Asherman's syndrome) - intrauterine synechiae can be treated with lysis of adhesions via either dilation and curettage or hysteroscopic resection

    • Postsurgical estrogen therapy

      ?? : conjugated estrogen at dosage of 2.5mg/day for 1-2months

    • Intrauterine device or intrauterine pediatric Foley catheter for be retained for 1wk postoperative.

    F. Unexplained infertility




    • Up to 65% of 'normal' infertile patients will become pregnant during 3 years of expectant manage ovulation induction with or without IUI, IUI alone, and ART

    • Assisted Reproductive technologies : IVF, GIFT, ZIFT, use donor oocytes, Cryopreserved embryo transfer



    • Gonadotropins



      • Gonadotropins (hMG or purified FSH) - standard agents used for the induction of ovulation for ART 1000 USP units of hCG are administered when at least two follicles have reached an average diameter of 18 mm and estradiol level are >600pg/ml



    • GnRH Agonists



      • Advantage - downregulation of the physiologic hypothalamic pituitary ovarian feedback mechanisms and subsequent effective suppression of spontaneous ovulation

      • Luteal phase support



        • Intramuscular administration of hCG (2500IU) every 3days for three doses beginning 5days after the ovulatory doses of hCG


        • IM administration of progesterone (100mg/day) for 14days, beginning the evening after embryo transfer


      • Micromanipulation



        • Male - factor infertility or semen parameters too poor to permit IVF (<1 million total motile sperm)

        • Micromanipulation is a broad term encompassing a number of prefertilization gamete-processing technique

        • Most of which are intended to enhance fertilization capability

        • Assisted hatching partial zona dissection, zona drilling, subzonal sperm injection intracytoplasmic sperm injection

        • In unassisted conception





      • Fertilized oocyte transport through the tube require approximately 2-3days

      • In a 28-day cycle, period of maximal endometrial receptivity is form cycle day 16 to cycle day 17
      • Implantation begins 5 ~ 7 days after retrieval with assisted reproduction

      • Fertilized embryos typically remain in culture for a total 48hr after oocyte retrieval

      • In an attempt to more closely simulate physiologic conditions, a prolonged pretrensfer culture period and alternative culture condition have been investigated


        • Period of in vitro embryo culture - important window for embryonic evaluation by micromanipulation


      • Preimplantation genetic diagnosis




      • In Vitro fertilization



        • Indication

        • No fallopian tubes, with previous tubal damage, poor prognosis for effective repair

        • Prior tubal sterilization

        • Who fail to conceive with 18months after tubal repair

        • Three to six cycle of ovulation induction in combination with insemination have failed



    • IVF Protocol



      1. GnRH agonist downregulation is performed prior to ovulation induction with gonadotropins

      2. Follicular maturation and ovulation are effected with combined hMG/hCG administration

      3. Oocyte retrieval is performed transvaginally under ultrasonographic guidance

      4. Analgesia for oocyte retrieval is provided on an individualized basis but most commonly involves intravenous sedation or spinal nerve block

      5. Embryo transfer is undertaken 48hr after oocyte retrieval - transcervical cannulation and injection of embryos into the intrauterine cavity

      6. Luteal phase support is provided until menses or pregnancy is documented



        • Initial evaluation for pregnancy - quantitative βhCG measurement 16days after embryo transfer


    • Embryo transfer



      • Morphologic criteria - cell number, symmetry, fragmentation, granularity

      • Cryopreserved of excess embryo transfer to the same patient in future nonstimulated cycle



    • Success rate




      • Vary form program to program

      • 1992. American fertility society

      • 16.8% delivered pregnancy per oocyte retrieval for standard IVF

      • 15.4% Cancellation rate

      • 20% Pregnancy loss

      • Ectopic pregnancy 1.2%





    • GIFT/ZIFT/TET



      1. GIFT procedure




        • Oocyte retrieval is performed either transvaginally or laparoscopically and is followed immediatelyby laparoscopic placement of the recovered oocytes and processed sperm into the fallopian tubes



      2. ZIFT procedure by




        • Retrieved oocytes are fertilized and cultured overnight.

        • Zygote-stage embryos are then transferred to the fallopian tubes laparoscopically 24hours after oocyte retrieval



      3. TFT (tubal embryo transfer)



        • Culture of embryos longer than 24hours before laparoscopic tubal transfer or thelaparoscopic transfer of cryopreserved embryos to the fallopian tubes




      • Donor Oocytes


        • Women with ovarian failure

        • Screening oocyte donors



          • Transmissible infectious or genetic diseases

          • Oocytes cannot presently be cryopreserved and quarantined

          • Oocyte donation involves the use of intensive monitoring and of medications with significant potential side effect



        • Method of oocyte donation




          • mock cycle - all hormonal agents are administered, and endometrial adequacy is documented by timed endometrial biopsy