INFERTILITY by: William Mann UND Dept of Family Medicine Definition Infertility exists when unprotected coitus for one year does not result in pregnancy. Two thirds of couples have achieved pregnancy within three months of regular unprotected intercourse, and 75-80% couples have become pregnant after six months, 80-90% by the end of the first year. By definition, by the end of the first year. By definition, one marriage in seven, or 15% of the population, are infertile. Since 5% of normal couples will conceive only in the second year, the application of this definition should be modified by individual circumstances. Mechanisms and Natural History In about 40% of cases, the male factor is predominantly responsible. An equal percentage is attributable to a female component, while the remainder have no obvious etiology. Frequently, several factors co-exist. Clinical Management Assessment A clear idea of the basic steps necessary to determine the cause of infertility is essential. Frequently, confusion exists between the work-up of amenorrhea, dysfunctional uterine bleeding, and infertility. Common errors in management include failure to secure basic steps, and generation of complex hormonal studies without a clear application for these results. Hormone studies have limited application. The occasional patient genuinely in need of hormone studies is probably best served by appropriate referral. It should be remembered that follicular stimulating and luteinizing hormone are released from the pituitary cyclicly, every 30 minutes. Accuracy demands a collection of specimens 20 minutes apart with pooling of these specimens at the least, or separate analysis with retention of the higher value as an ideal. The expense is considerable, and the benefit is difficult to establish. The basic assessment should seek to answer the following questions: 1. Is regular intercourse taking place in a satisfactory manner? 2. Are viable sperm, in sufficient quantities, with obvious motility, being produced? 3. Are factors, due to lack of education, being introduced inadvertently which will reduce the chance of successful conception? Amongst common deleterious practices are: a. The wearing of tight jockey shorts; b. Repeated hot bathing, particularly before intercourse; c. Douching before or after intercourse; d. Restricting intercourse to the immediate premenstrual period on the mistaken assumption that this represents peak fertility. 4. Is ovulation taking place? If not, does it prove possible to induce ovulation? 5. Are there local cervical factors which are hostile to the sperm? 6. Is there an obstruction to the uterine cavity or tubes which prevents fertilization? 7. In spite of optimistic responses to these questions, are there are other subclinical factors which may be influencing the problem? Because of the frequent occurence of multiple co-existing factors, a simple but complete work-up should be carried out systematically in all couples. It is a common error to repeatedly induce ovulation in a woman in the presence of inadequate sperm production by the husband. Plan Testing should be carried out over a six to eight week period. Nothing is gained by further delay. A small group of individuals, 5-10%, will remain in whom no detectable cause of infertility can be determined after complete evaluation. When this happens, these couples should not be told that they are normal, but rather that they have an infertility factor that is not detectable by the present stc group is poor. Male Factor Subjective Male factor may be suspected if there is a history of infertility in one or more marriages with women of proven fertility. A history of vasectomy, or trauma to the testes or epididymis, is important. Although mumps is traditionally listed as a cause of infertility, there is almost no practical or theoretical basis for this belief. Attention should also be paid to inappropriately tight underwear and frequent hot bathing before intercourse. Objective The body habitus should demonstrate normal male characteristics, with male escutcheon and two normally sized testes in the scrotum. Local examination should evaluate the penile anatomy, the testes for size, the epididymis for tender areas suggestive of scarring, and the pampiniform plexus for evidence of a varicocoele. A venous impulse should be specifically examined for, by having the patient perform a valsalva maneuver, while the pampiniform plexus is palpated in the standing position. Assessment Semen analysis is the only direct method for detecting male infertility. A specimen should be collected by masturbation after a two to three day abstinence. A longer period will result in an artificially high count. Coitus interruptus is not an acceptable method of collection, as spermatozoa are not evenly distributed throughout the sample, and erroneous results will be obtained by inevitable loss of early parts of the specimen. Also, the use of a condom is inadvisable because of the presence of spermicides. A glass container should be used. The specimen should be collected as near to the laboratory as possible, and then transported as soon after collection as feasible since motility decreases after two to four hours. It should be kept warm by being placed in a trouser pocket or under the armpit. Occasionally, social or religious taboos will prevent the collection of a specimen by masturbation. Then, the post-coital test will be the only means of evaluating sperm. Analysis Normal seminal fluid is a thick viscous mass which liquifies within 15-20 minutes. It is usually translucent and whitish-grey, and a white or yellow color may indicate an increased number of white blood cells or prolonged sexual abstinence. It has a strong pungent odor. Volumes of 2-4 ml. are accepted as normal. When a sample is less than 1 ml., it is necessary to discover whether or not the entire ejaculate was collected. Otherwise, low volume may indicate congenital absence of seminal vesicles, retrograde ejaculation, obstruction of the ejaculatory duct, or pituitary or Leydig cell deficiency. Large volumes may result from over activity of the accessory sex glands or sexual abstinence, but high volumes are frequently associated with sub-normal sperm concentrations. Sperm Concentration Sperm are counted on a white cell counting chamber using a diluent containing eosin B. This dye will enter the heads of dead spermatozoa, staining them red. Hence, motile, non-motile, dead and grossly abnormal forms can be differentiated and counted. Sperm counts of greater than 60 million per ml. are considered normal, although pregnancy has occurred with counts below 20 million. It takes approximately 10 weeks for sperm to travel from the testes to the ejaculate, and sperm counts may vary as a function or stress or febrile illness. For this reason, a minimum of two to three specimens should be examined allowing at least two or three weeks between collections, before a male factor is presumptively identified as a result of a low count. If a low count is obtained, it is useful to examine a specimen of urine immediately. This will tell whether or not large quantities of sperm are being refluxed by retrograde ejaculation into the bladder. Progressive Sperm Motility Ideally, 70% of sperm should be actively motile. A sample with less than 50% progressive movement is considered abnormal. Morphology A minimum of 200 cells should be counted. There is wide variability in normal spermatozoa and a determination of abnormal forms is dependent on observer experience. However, if the percentage of abnormal forms is above 50% infertility often occurs. Predominance of one abnormal type may be indicative of the cause of the abnormality e.g., tapered headed sperm may indicate a varicocoele. Endocrine Evaluation In the absence of clinically apparent endocrine abnormalities, neither evaluations of FSH, LH and prolactin, nor treatments with Bromocriptine and Testosterone have survived critical evaluation. Plan In azoospermia due to vasectomy, microsurgical reversal can be achieved in 80% of the cases with subsequent fertility varying from 20-70%. A defect in the vas of 2 cms. or more denotes a poor outlook. Microsurgical repair in traumatic azoospermia remains experimental. With oligospermia and/or decreased motility due to varicocele, ligation of the vein has resulted in pregnancy rates of up to 55%. Female Factor Female factor is best described under the headings of: 1) Cervical factor, 2) Uterine factor, 3) Tubal factor, and 4) Ovulatory factor. Scrupulous attention should be paid to the assessment of these factors, with particular regard to the detection of anatomical abnormalities. In the long run, this is much more rewarding than hormonal manipulations, which, with the exception of induction of ovulation, are rarely indicated and best dealt with by referral to an experienced sub-specialist. Cervical Factor Natural History Of the factors attributed to the female, 5% are due to gross pelvic conditions, 20% are due to failure of cervical insemination, 30-40% are due to partial or total tubal occlusion, and 15-25% are due to female endocrine abnormality. Incidence of infertility due to cervical factor has a reported occurrence of 15-50%. Until mid-cycle, cervical mucus is watery and can be penetrated by the sperm. Though estrogen secretion continues in the luteal phase, progesterone influence produces a denser cervical mucus structure which forms an effective barrier to sperm transport. This is a mechanism which prevents superfertilization of eggs which may be released after fertilization. Cervical mucus is an energy source and a reservoir for spermatozoa. Sperm are probably gradually released into the upper genital tract from the mucus, compensating for the short life span of the ovum. The mucus may also act as a screen, and imped the progress of abnormal spermatozoa. In mid-cycle, from about day 10-15, classical luteal characteristics such as spinnbarkeit and ferning appear. The evaluation should be timed by the basal body temperature chart, the day of temperature elevation being considered as the day following ovulation. Cervical mucus evaluation should be done one or two days prior to the temperature rise. In the absence of a clear basal body temperature change, an initial assumption that ovulation is occurring 12-14 days before the next menstrual period should be made. In patients with irregular cycles, evaluation should be carried out every second or third day beginning on day 10, to detect the changes of spinnbarkeit and ferning. If these changes do not occur, or do not correlate with menstruation two weeks later, then anovulation should be suspected. The cervical canal appears black because it is filled with clear mucus which has no particles to reflect light. Uterine Anomalies Reported rates vary from 1 in 32 to 1 in 2,000. Anomalies may be symmetric (by bicornuate uterus, uterus didelphis), or asymmetric uterine _____, mi uterus hermassociation with concomitant urological anomalies should be remembered, particularly in asymmetric cases, and an intravenous pyelogram may be indicated. A strong association between uterine anomalies and primary infertility is not widely accepted and many such patients have normal reproductive histories. On the other hand, symptoms may include dysmenorrhea, habitual abortion, premature delivery, and abnormal fetal presentations. The diagnosis is made by hysterosalpingogram. Surgical treatment of a symptom are unification of uterine horns is recommended only in cases of repeated reproductive failure. Intrauterine Adhesions - Fibrotic Endometritis - Asheiman's Sydrome Hypomenorrhea, amenorrhea, infertility, habitual abortion, and placenta accreta are the hallmarks of this syndrome. It is classically associated with post-partum or post-abortal curettage, but has been noted after diagnostic D & C, myomectomy, and tubereulous endometritis. The diagnosis is frequently suspected by the failure of a patient to experience withdrawal bleeding after treatment with estrogen-progestrone preparations, during the investigation of amenorrhea. The salpingogram is characteristic, showing single or multiple filling defects in the uterine cavity in all films. Demonstration of this major form of abnormality requires referral. Hysteroscopy is useful for both diagnosis and therapy. Treatment includes lysis of adhesions and the placement of an intrauterine device or Foley catheter to prevent recurrence of synechia. A relatively high dose of estrogren for one to three months is ??? the endometrium. It should be noted that this may be a worthwhile prophylaxis when difficulty has been encountered with a post-partum or post-abortal curettage. The chances of restoring normal menses are excellent, but fertility results are poor. Endometrial polyps, hyperplasia, neoplasia The common symptom is abnormal uterine bleeding. These abnormalities are rare in young women, but more common in anovulatory patients undergoing evaluation. The presence of these lesions may be noted on hysterosalpingogram, but diagnosis usually requires endometrial biopsy or D & C. Leiomyoma An enlarged and irregular uterus, menorrhagia, and irregularities of the cavity upon curettage or hysterosalpingogram are the hallmarks of this condition. The fibroid may include the endocervical canal or the cornual region, preventing movement of sperm. Submucus or intramural fibroids may affect blood supply to the endometrium, preventing nidation. Finally, fetal wastage may be incurred by faulty implantation, irritable uterus, or degeneration of the fibroid. The significance of small leiomyomas in infertile patients is difficult to assess, and they are not necessarily an indication for myomectomy. With large fibroids, a history of infertility of unknown cause, or in cases of habitual abortion, myomectomy may be indicated. Once more, this is an area requiring experience, judgement, and surgical technique, and appropriate referral should be carried out. There are no large prespective studies which accurately indicate the success of myomectomy. Summary 1. evaluation of the male a. complete physical examination b. semen analysis 2. evaluation of the female a. temperature charts b. evaluation of cervical mucus c. evaluation of uterus and tubes d. evaluation of ovulatory function e. laparoscopy This can be expeditiously carried out as follows: 1. First visit by both partners: day 21 a. history and physical examination b. serum progesterone c. semen analysis d. patient instruction 2. Second visit: day 8-10 of the cycle - hysterosalpingogram 3. Third visit: day 12-14 of the cycle a. Huhner test b. evaluation of cervical mucus 4. Fourth visit a. evaluation of results of studies and temperature charts b. further evaluation or planning of therapy Costs Nineteen eighty-four serum prolactin-$39.40 Follicular stimulating hormone-$37.30 Lutinizing hormone-$35.40 Progesterone-$43.70 Semen Analysis-$34.00 Hysterosalpingogram- Laparoscopy Assessment Cervix should be observed with a speculum. Abundant mucus pouring out a black appearing cervical os indicates mid-cycle. Cultures are inappropriate because of difficulty within the interpretation due to contamination with cervical mucus. Recent reports have suggested a causal relationship between T-micoplasma infections and fetal wastage and infertility. Positive cervical cultures are seen in both infertile and fertile women, but endrometrial cultures were positive more frequently in the infertile and habitual aborters. Diagnosis is made by culture. Therapy requires 200 milligrams of doxycycline for both partners on day one of the menstrual cycle and then 100 milligrams per day for ll days. There are no results of therapy in primary infertile couples. The inhabitual aborters, in one series, can term pregnancies when noted in a group of 11 subsequent pregnancies, inhabitual aborters treated with this regimen. terine Adhesions - Fibrotic Endometritis - Asheiman's Sydrome Hypomenorrhea, amenorrhea, infertility, habitual abortion, and