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Infertility 

Infertility is defined as failure of a couple of reproductive age to conceive after 12 months or more of regular coitus without using contraception. Infertility is considered primary when it occurs in a woman who has never established a pregnancy and secondary when it occurs in a woman who has a history of one or more previous pregnancies. Fecundability is defined as the probability of achieving a pregnancy within one menstrual cycle. It is estimated that 10% to 20% of couples are infertile. 

    
  1. Diagnostic evaluation

    1.  History
      1.  The history should include the couple's ages, the duration of infertility, previous infertility in other relationships, frequency of coitus, and use of lubricants (which can be spermicidal). Mumps orchitis, renal disease, radiation therapy, sexually transmitted diseases, chronic disease such as tuberculosis, major stress and fatigue, or a recent history of acute viral or febrile illness should be sought. Exposure to radiation, chemicals, excessive heat from saunas or hot tubs should be investigated.
      2.  Pelvic inflammatory disease, previous pregnancies, douching practices, work exposures, alcohol and drug use, exercise, and history of any eating disorders should be evaluated.
      3.  Menstrual cycle length and regularity and indirect indicators of ovulation, such as Mittelschmerz, mid-cycle cervical mucus change and premenstrual molimina, should be assessed.

    2.   Physical examination for the woman
      1.  Vital signs, height, and weight should be noted. Hypertension hair distribution, acne, hirsutism, thyromegaly, enlarged lymph nodes, abdominal masses or scars, galactorrhea, or acanthosis nigricans (suggestive of diabetes) should be sought.
      2.  Pelvic examination should include a Papanicolaou smear and bimanual examination to assess uterine size and any ovarian masses.
      3.  Testing for Chlamydia trachomatis, Mycoplasma hominis, and Ureaplasma urealyticum are recommended.

    3.   Physical examination for the man
      1.  Height, weight, and hair distribution, gynecomastia, palpable lymph nodes or thyromegaly should be sought.
      2.  The consistency, size, and position of both testicles and the presence of varicocele or abnormal location of the urethral meatus on the penis should be noted. Testing for Chlamydia, Ureaplasma, and Mycoplasma should be completed.

    4.  The cornerstone of any infertility evaluation relies on the assessment of six basic elements: (1) semen analysis, (2) sperm-cervical mucus interaction, (3) ovulation, (4) tubal patency, and (5) uterine and (6) peritoneal abnormalities. Couples of reproductive age who have intercourse regularly without contraception have approximately a 25-30% chance of conceiving in a given menstrual cycle and an 85% chance of conceiving within 1 year.

    5.  Semen analysis. The specimen is routinely obtained by masturbation and collected in a clean glass or plastic container. It is customary to have the man abstain from ejaculation for at least 2 days before producing the specimen. Criteria for a normal semen analysis include a sperm count greater than 20 million sperm/mL with at least 50% motility and 30% normal morphology.
    Semen Parameter Normal Values Poor Prognosis
    Sperm concentration >20 x 106/mL <5 million/ mL
    Sperm motility >50% progressive motility <10% motility
    Sperm morphology >50% normal <4% normal
    Ejaculate volume >2 cc <2 cc
    1. The postcoital test (PCT) is used to assess sperm-cervical mucus interaction after intercourse. The PCT provides information regarding cervical mucus quality and survivability of sperm after intercourse. The PCT should be performed 8 hours after intercourse and 1 to 2 days before the predicted time of ovulation, when there is maximum estrogen secretion unopposed by progesterone.
    2.   Ovulation assessment
      1.  Commonly used methods used to assess ovulation include measuring a rise in basal body temperature (BBT), identifying an elevation in the midluteal phase serum progesterone concentration, luteal phase endometrial biopsy, and detection of luteinizing hormone (LH) in the urine. The BBT chart is used to acquire information regarding ovulation and the duration of the luteal phase. Female patients are instructed to take their temperature upon awaking each morning before any physical activity. A temperature rise of 0.4EF (0.22EC) for 2 consecutive days is indicative of ovulation. The initial rise in serum progesterone level occurs between 48 hours before ovulation and 24 hours after ovulation. For this reason, a rise in temperature is useful in establishing that ovulation has occurred, but it should not be used to predict the onset of ovulation in a given cycle.
      2.  Another test used to assess ovulation is a midluteal phase serum progesterone concentration. A blood sample is usually obtained for progesterone 7 days after the estimated day of ovulation. A concentration greater than 3.0 ng/mL is consistent with ovulation, while a concentration greater than 10 ng/mL signifies adequate luteal phase support.
      3.  Alternatively, urine LH kits can be used to assess ovulation. Unlike the rise in BBT and serum progesterone concentrations, which are useful for retrospectively documenting ovulation, urinary LH kits can be used to predict ovulation. Ovulation usually occurs 24 to 36 hours after detecting the LH surge.
    3.   Tubal patency can be evaluated by hysterosalpingography (HSG) and/or by chromopertubation during laparoscopy.
Test Day
Hysterosalpingogram day 7-10
Postcoital Test day 12-14
Serum Progesterone day 21-23
Endometrial Biopsy day 25-28
 
    
  1. Differential diagnosis and treatment

    1.  The differential diagnosis of infertility includes ovarian (20%), pelvic (25%), cervical (10%), and male (35%) factors. In approximately 10% of cases no explanation is found. Optimal frequency of coitus is every other day around the time of ovulation; however, comparable pregnancy rates are achieved by 3-4 times weekly intercourse throughout the cycle.

    2.  Ovarian factor infertility
      1.  An ovarian factor is suggested by irregular cycles, abnormal BBT charts, midluteal phase serum progesterone levels less than 3 ng/mL, or luteal phase defect documented by endometrial biopsy. Ovulatory dysfunction may be intrinsic to the ovaries or caused by thyroid, adrenal, prolactin, or central nervous system disorders. Emotional stress, changes in weight, or excessive exercise should be sought because these disorders can result in ovulatory dysfunction. Luteal phase deficiency is most often the result of inadequate ovarian progesterone secretion.
      2.  Clomiphene citrate (Clomid, CC) is the most cost-effective treatment tor the treatment of infertility related to anovulation or oligo ovulation, . The usual starting dose of CC is 50 mg/day for 5 days, beginning on the second to sixth day after induced or spontaneous bleeding. Ovulation is expected between 7 and 10 days after the last dose of CC.
      3.  Ovulation on a specified dosage of CC should be confirmed with a midluteal phase serum progesterone assay, BBT rise, pelvic ultrasonography, or urinary ovulation-predictor kits. In the event ovulation does not occur with a specified dose of CC, the dose can be increased by 50 mg/day in a subsequent cycle. The maximum dose of CC should not exceed 250 mg/day. The addition of dexamethasone is advocated for women with elevated dehydroepiandrosterone sulfate levels who remain anovulatory despite high doses of CC. The incidence of multiple gestations with CC is 5% to 10%. Approximately 33% of patients will become pregnant within five cycles of treatment. Treatment with CC for more than six ovulatory cycles is not recommended because of low success rates.
      4.  Human menopausal gonadotropins (hMG, Pergonal, Metrodin) ovulation induction with is another option for the treatment of ovulatory dysfunction. Because of its expense and associated risk of multiple gestations, gonadotropin therapy should be reserved for patients who remain refractory to CC therapy. The pregnancy rate with gonadotropin therapy is 25% per cycle. This is most likely the result of recruitment of more follicles with gonadotropin therapy. The incidence of multiple gestations with gonadotropin therapy is 25% to 30%.
      5.  Luteal phase deficiency is treated with progesterone, usually prescribed as an intravaginal suppository at a dose of 25 mg twice a day until 8 to 10 weeks of gestation.
      6.  Women with ovulatory dysfunction secondary to ovarian failure or poor ovarian reserve should consider obtaining oocytes from a donor source.

    3.  Pelvic factor infertility
      1.  Pelvic factor infertility is caused by conditions that affect the fallopian tubes, peritoneum, or uterus. Tubal factor infertility is a common sequela of salpingitis. Appendicitis, ectopic pregnancy, endometriosis, and previous pelvic or abdominal surgery can also damage the fallopian tubes and cause adhesion formation.
      2.  Endometriosis is another condition involving the peritoneal cavity that is commonly associated with infertility. Uterine abnormalities are responsible for infertility in about 2% of cases. Examples of uterine abnormalities associated with infertility are congenital deformities of the uterus, leiomyomas, and intrauterine scarification or adhesions (Asherman's syndrome).
      3.  The mainstay of treatment of pelvic factor infertility relies on laparoscopy and hysteroscopy. In many instances, tubal reconstructive surgery, lysis of adhesions, and ablation and resection of endometriosis can be accomplished laparoscopically.

    4.  Cervical factor infertility
          
      1. Cervical factor infertility is suggested when well-timed PCTs are consistently abnormal in the presence of a normal semen analysis. Cervical factor infertility results from inadequate mucus production by the cervical epithelium, poor mucus quality, or the presence of antisperm antibodies.
      2.  Patients with an abnormal PCT should be screened for an infectious etiology. The presence of immotile sperm or sperm shaking in place and not demonstrating forward motion is suggestive of immunologically related infertility. Sperm-cervical mucus and antisperm antibody testing are indicated when PCTs are repeatedly abnormal, despite normal-appearing cervical mucus and normal semen analysis.

    1.  Male factor infertility includes conditions that affect sperm production, sperm maturation, and sperm delivery. Intrauterine insemination is frequently used to treat men with impaired semen parameters.
    2.  Unexplained Infertility
      1.  The term unexplained infertility should be used only after a thorough infertility investigation has failed to reveal an identifiable source and the duration of infertility is 24 months or more. History, physical examination, documentation of ovulation, endometrial biopsy, semen analyses, PCT, hysterosalpingogram, and laparoscopy should have been completed.
      2.  Because couples with unexplained infertility lack an identifiable causative factor of their infertility, empirical treatment with clomiphene therapy increases the spontaneous pregnancy rate to 6.8% per cycle compared with 2.8% in placebo-control cycles. For optimal results, gonadotropins should be used for ovulation induction. Intrauterine insemination, in vitro fertilization and gamete intrafallopian transfer (GIFT) are additional options.
  
Copyright © MD Milos Kupresak, 2007