Скачати 41.96 Kb.
ЗмістDiagnosis and treatment
Female Gamete Factor
Female Genital Tract Factors
Upper Genital Tract
on the conference of the Department
of Obstetrics and Gynecology with the Course
of Infant and Adolescent Gynecology
“____” _____________200 p.
T.a.The Head of the department, Professor
on the themes singled out for independent study
For 5 year students of medical faculty
2 academic hours
Developed by assistant, PhD
I. Scientific and methodical grounds of the theme
Marriage is considered to be sterile, if during 1 year of regular sexual life without using of contraceptives, pregnancy does not occur. Infertility happens in 10-12% of all marriages. It is subdivided into male, female and mixed. About 45% of sterile marriages are connected with male infertility, 55% of them with female infertility.
A student must know:
1. Etiology and pathogenesis of infertility.
2. Immunological factors of infertility.
3. Treatment of infertility.
A student should be able to:
1. Carry out an objective gynecologic examination of a patient.
2. Make up a plan of a patient’s examination.
III. Recommendations to the student
A traditional approach to the diagnostic assessment of human infertility is to simply follow the path of sperm up the genital tract to the point of fertilization and subsequent implantation. This conceptual approach suits our biological understanding but is not representative of an efficient and practical diagnostic approach. As an alternative, infertility categories can be defined by diagnostic test groups. In this concept there are three groups of factors: (1) male gamete factor, (2) female gamete factor, and (3) female genital tract factors. This simplified concept is compatible with the nature of the available diagnostic tests and is quite easy to explain to patients as their evaluation is undertaken.
Male Gamete Factor
If the male partner produces no sperm, then azoospermia is the diagnosis and the couple has sterility on the basis of male factor. Compromises of spermatogenesis that result in decreased numbers, motility, or fertilizing capability of spermatoza are much harder to define. Many criteria have been applied to semen analysis results in an attempt to distinguish fertile from infertile males, but this effort has been frustrated by both the surprising fertility of some men with poor counts and the great variability in counts that is known to occur even in normal fertile males. Diagnoses that result from such a systematic evaluation range from normal results on further seminal testing through a wide range of endocrine disorders, anatomical obstructions of the male system, and failure of the spermatogenic production constituents per se. The incidence of ejacula-tory dysfunction or sexual dysfunction in infertility populations is not well documented, but occasional infertility couples will benefit from psychiatric counseling services with focus on sexual dysfunction problems.
The periodic shedding of an ovum is necessary for conception, and women who are physiologically anovulatory, such as prepubertal children, castrate women, and late postmenopausal women, are sterile. Infertility owing to an ovulatory problem in reproductive-age women is more difficult to define because all available measures in the clinical setting are indirect. In other words, the only absolute proof that ovulation has occurred is detection of a conception or observation of an egg outside the ovary. All other measures, such as menstrual rhythm, basal body temperature chart, changes in cervical mucus, systemic symptomatology, urinary pregnanediol excretion, endometrial biopsy, serum progesterone levels, ultrasound monitoring of follicle growth and collapse, and oral/vaginal electrical resistance, are all indirect. Therefore, all such tests of ovulation have some false-positive and some false-negative results. Consequently the clinical significance of normal but rarely occurring ovulation (oligoovulation) and abnormal ovarian cycles (ovulatory dysfunction) remains a point of diagnostic contention among some infertility experts. Relatively subtle abnormalities of ovarian cycles can be practically grouped together, but there are definable subsets. Although it is not totally clear that detailed characterization of dysfunctional cycles is essential before initiating rational therapy, advances in management of ovulatory dysfunction have probably been limited by inadequate scrutiny and subgrouping of study subjects. Numerous names given to abnormal ovarian cycles include anovulatory cycles, luteal phase deficiency, luteal phase defect, short luteal phase, poor progesterone surge, luteinized unruptured follicle syndrome, and poor preovulatory follicular maturation. Although no broad-based prospective study of human populations will probably ever permit absolute characterization of the incidence and consequences of these entities, studies in animals such as rhesus monkeys and sheep strongly suggest that cycle fecundity is profoundly decreased in such abnormal cycles
Several diagnostic tests are available for assessing ovulatory function The patient's history of menstrual interval is the defining parameter for distinguishing anovulation from normal or abnormal but cyclic ovarian function Even if the patient is having relatively regular menses at a normal interval of 28 ± 2 days, additional tests are indicated to distinguish normal ovulatory function from abnormal cycles. The traditional basal body temperature (BBT) chart can be reassuring if measurements are normal, but it is difficult to interpret if it does not show a clear-cut stepwise shift of temperature at midcycle with an appropriate 12+-day luteal interval. In general, if a BBT chart looks normal, then the clinician can be somewhat reassured, but confirmation of ovulatory status with additional testing (e g, serum progesterone, endometrial biopsy) is usually appropriate If, however, the chart looks extremely abnormal or has a subtler change, such as a slow midcycle temperature nse or an apparently short luteal interval, then ad ditional testing of ovulation is absolutely required to distinguish normal ovulatory function from ovulatory dysfunction.
Historically, urinary pregnanediol excretion was used as a direct measure of progesterone production during the luteal phase This highly reliable measure of ovulatory function is somewhat cumbersome, and other modalities have subsequently been adopted.
Quite commonly endometrial biopsy is used to evaluate ovulatory dysfunction, and at the time of its initial validation this technique was estimated to be approximately 80% accurate relative to menstrual interval, BBT charts, and pregnanediol excretion. Direct measurement of serum progesterone levels also provides useful assessment of normality of ovarian cycles. A single midluteal progesterone level that is greater than 15 ng/ml is better than 80% accurate in distinguishing normal from abnormal cycles. Values between 10 ng/ml and 15 ng/ml are found often in both normal and abnormal cycles, whereas values less than 10 ng are rare in normal cycles, especially if samples are drawn during the morning hours. A powerful and persuasive assessment of ovarian function is the "cycle profile'. In this approach, detailed analysis of a cycle is generated by daily samples for a panel of reproductive hormones and by performance of serial ultrasound scans to monitor follicle growth and subsequent collapse. Obviously, such a detailed approach to cycle analysis is not a practical screening test, but it does provide the "gold standard" with which other diagnostic tests can be compared. One such modern test is daily measurement of salivary and vaginal electrical resistance. Patients can easily take these readings and document characteristic resistance changes, which have greater than 80% correlation with more intensive cycle monitoring schemes. Because these resistance changes precede ovulation in the cycle, such a self-administered test should be useful in timing such activities as coitus and insemination. Other relatively new self-administered ovulation predictor tests depend on monoclonal antibodies to human luteinizing hormone (LH) and immunosorbent colorimetric "dipstick" testing of urine samples. Semiquantitative color changes indicate recent occurrence of the LH surge, and therefore would be expected to slightly anticipate the ovulatory event. Although these urine LH tests appear to be somewhat helpful in characterizing cycle events, correlation of results obtained with kits from different manufacturers can be quite variable and accuracy estimates can vary widely.
Once anovulation or ovulatory dysfunction is diagnosed, some additional evaluation is necessary to distinguish certain endocrinopathies that commonly disrupt ovulatory function from primary ovulatory disorders. Many obvious systemic illnesses or metabolic/endocrine diseases can interfere with normal cyclicity, but only subtler hyperprolactinemia and hypothyroidism are commonly diagnosed by the consultant gynecologist during infertility evaluation. Although a complete discussion of evaluation and management of hyperprolactinemia and thyroid disorders is beyond the scope of this chapter, specific treatment of these entities often restores normal ovarian function.
Whether caused by pituitary adenoma or idiopathic excess, hyperprolactinemia commonly responds well to the drug bromocriptine (Parlodel). This potent dopaminergic-receptor agonist directly inhibits prolactin secretion from the anterior pituitary and is nearly universally effective in reducing prolactin secretion, whether or not an adenoma is present. Many patients with hyperprolactinemia have true amenorrhea, whereas others may simply have subnormal luteal phase production of progesterone. When hyperprolactinemia is the cause of anovulation or ovulatory dysfunction, normalization of prolactin secretion with bromocriptine therapy can be expected to result in normal ovulatory function in most patients.
A related abnormality of hyperprolactinemia is primary hypothyroidism. When hypothyroidism is clinically apparent there is no diagnostic difficulty. However, occasional patients present with a normal thyroid panel but an elevated thyroid-stimulating hormone (TSH) level, implying primary compensated (subclinical) hypothyroidism. The proper treatment of these patients who have mild elevations of TSH (and prolactin) is thyroid hormone replacement. The typical response is normalization of both TSH and prolactin levels, and restoration of normal ovarian cyclicity is, again, common.
There are three diagnostic categories of ovulatory dysfunction that are independent of a prolactin/ thyroid-mediated mechanism. First, ovarian failure can occur at any age. Elevated gonadotropins are the usual diagnostic test. Treatment of infertility owing to this cause requires modern reproductive technologies with donor eggs. Second, patients who have normal prolactin levels and no gonadotropin elevation but are relatively hypoestrogenic are usually described as having "hypothalamic amenorrhea'. Failure to bleed with a progestin challenge is the usual diagnostic hallmark of this group of hypogo-nadotropic hypogonadal patients. Truely specific therapy for this entity is available in the form pulsatile administration of gonadotropin releasing hormone (GnRH). This highly specific therapy for augmenting pituitary output of gonadotropins can be somewhat cumbersome but does seem to provide a more regulated ovarian response than is obtained with other ovulation induction regimens in this group of patients. With no change in dosage administration, the patient conceived a singleton gestation in the next cycle after this study. Many patients with hypothalamic amenorrhea fail to respond to clomiphene but do respond to human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG) readily, and have a significant risk of multiple gestation in such treatment cycles. Third, a wide range of ovulatory disturbances that occur in relatively well estrogenized patients are initially distinguished by withdrawal bleeding after progestin challenge. In general, the designation for all of these estrogenized patients is polycystic ovarian disease, although there is a wide range of presentations from mild luteal dysfunction up to and including complete acyclicity and marked androgen excess. Many of these patients, especially those with milder disturbances, respond to clomiphene citrate for ovulation induction. The patient conceived a singleton gestation, and hCG was first detectable in her serum on the day after the study sampling.
For patients who do not conceive after either specific directed endocrine therapies or a trial of clomiphene, induction of ovulation with hMG and hCG is usually appropriate. Administration of hMG typically begins between cycle days 2 and 5. Therapy is monitored with daily estradiol and ovarian ultrasonic scans from approximately day 6 onward. Once one or more follicles exceed a diameter threshold (usually 18 mm), hCG may be given for ovulatory release. Estradiol levels provide a measure of the functional state of all follicles within the ovary; thus a very low estradiol level with large follicles suggest relatively poor health, whereas a very high estradiol level would imply a significant risk of hyperstimulation, owing to excessive recruitment of large numbers of small follicles. Experience with hMG/hCG ovulation induction has shown that a significant number of failed cycles are due to premature luteinization. That is, the LH surge, or at least a progressive rise in LH levels, may occur before follicle maturation is completed. Blockade of LH release with long-acting GnRH agonists that downregulate the pituitary has been effective in preventing this premature luteinization phenomenon. The hope that such agents would greatly reduce the risk of ovarian hyperstimulation has been only partially fulfilled.
Treatment of milder forms of ovulatory dysfunction, such as luteal phase deficiency (luteal phase defect), has often been undertaken by providing luteal phase progesterone supplementation. This can be done with vaginal suppositories of 25 mg twice a day, and treatment of such luteal phase abnormalities has typically been monitored by correction of endometrial biopsies from "out of phase" to "in phase." This treatment seems to have reasonable efficacy that has generally been attributed to an endometnal action of the progesterone supplement. Recent studies have shown that m cycles m which the luteal progesterone production is subnormal, the LH secretory pattern is increased. Furthermore, administration of progesterone in the follicular phase reduces the LH secretory pulse pattern to that found in normal luteal phases. These observations certainly suggest that luteal phase progesterone supplements may actually be normalizing function of the hypothalamic pituitary axis as follicle recruitment is being initiated for the next cycle, rather than ''fixing" an endometrial problem m the current treatment cycle.
Lower Genital Tract
Although it is obvious that complete or partial vaginal agenesis precludes conception, these types of defects are seldom found at the time of infertility evaluation. Virtually all of these abnormalities will have been previously detected during the assess ment of penpubertal symptoms such as amenorrhea and hematocolpos. Practically speaking, if coital frequency is at least two to three times per week and true intromission is occurring, then vaginal infertility factors do not exist.
Cervical factor infertility is often suggested by poor sperm motility or poor sperm survival in cervical mucus after intercourse one to ten hours earlie.r Cervical factor infertility as a single diagnosis seems to be relatively rare in practice, and it is easy to understand that cervical mucus may lack appropriate biophysical properties in women with hypoestrogenic state.s There is little doubt that the most common cause of the abnormal postcoital test is poor timing of the test within the cycle, with "good" cervical mucus occurring during the immediate preovulatory interval (one to three days before ovulation). The second most common cause of a bad postcoital test is a male factor such as oligospermia. On the other hand, if the male partner has relative oligospermia but good postcoital test results can be obtained with the couple, then it is difficult to attnb ute the couple's infertility solely to lack of sperm m the female upper genital tract.
Other than the biophysical properties of cervical mucus that permit sperm penetration and survival, factors that might be injurious to sperm have also been identified or proposed. Clearly, antisperm antibodies can be detected in cervical mucus, and if one or more subsets of antibodies are directed toward critical surface components of spermatozoa, then an immume basis for infertility can be supposed. The difficulty is a technical limitation in distinguishing irrelevant antisperm antibodies from those that actually impede sperm migration or fertilization ability. Independent of immune-mediated mechanisms, an inflammatory process in the cervix, such as cervicitis, could be nonspecifically toxic to sperm or could alter the physicochemical properties of cervical mucus Such a toxic mechanism for infertility can be readily imagined, but there seems to be little data to support this as a important infertility diagnosis
A common iatrogenic cause of hostile-appearing cervical mucus is use of clomiphene for ovulation induction. Since clomiphene is an antiestrogen, estrogenic stimulation of cervical mucus production should be decreased. This virtually universal effect argues for use of clomiphene relatively early in the cycle (days 3-7), rather than the more traditional later follicular phase use (days 5-9). There is certainly no pharmacologic justification for giving supplemental estrogens during clomiphene cycles, since (a) this amounts to giving exogenous agonist to compete with the administered antagonist and (b) if the early follicular phase administration of clomiphene has not engendered an adequate late follicular phase estradiol rise, then the dose was probably inadequate. Because there is a significant conception rate with clomiphene and because virtually all treated patients have some disturbance of cervical mucus production, it is difficult to conclude that the cervical mucus perturbation is of profound significance in clomiphene cycles.
No specific directed therapy for cervical factor infertility exists short of the newer reproductive technologies that mechanically bypass the cervix. Therefore, a reasonable treatment strategy for a couple with cervical factor infertility would be an interval of prospective observation of 6 to 12 cycles with subsequent options, including washed intrauterine insemination, gamete intrafallopian transfer (GIFT) procedure, or in vitro fertilization with embryo transfer. Because this same sequence of treatment options applies for idiopathic infertility, there is a general trend away from postcoital testing. If a specific, less invasive treatment is devised for the management of cervical factor infertility, then distinguishing between cervical factor infertility and idiopathic infertility will become clinically important rather than simply academically interesting
The assessment of the upper female genital tract, including the uterus, fallopian tubes, and peritoneal cavity, is most efficiently accomplished by performance of a single combined procedure of laparoscopy, hysteroscopy, and hydrotubation. This outpatient surgical procedure permits direct visualization of the endometrial cavity with concurrent inspection of the serosal surface of the myometrium, thereby enhancing the quality of information that is obtained. Similarly, dye injection at the time of lapa-roscopy may detect tubal patency and permit direct inspection of the mobility and morphology of the fallopian tubes. The detection of endometriosis and pelvic adhesions requires an inspection of the peritoneal cavity, these diagnoses cannot be reliably made without such a direct inspection.
Hysterosalpmgography provides a useful adjunct in the assessment of the uterine cavity and fallopian tubes either in the setting in which hysteroscopy is not available or as a confirmatory study of tubal patency, especially if bilateral proximal tubal occlusion was believed to be present at laparoscopy and hydrotubation.
A variety of intrauterine abnormalities can be found at hysteroscopy or hysterosalpmgography, including retained intrauterine device, endometrial polyp, leiomyomata, intrauterine adhesions, and various developmental abnormalities. On hysterosalpmgography it may be difficult or impossible to distinguish a uterine septum (septate or subseptate) from a bicornuate or didelphic uterus. At combined hysteroscopy with laparoscopy specific diagnosis can be immediately made, and if a septum is present, hysteroscopic resection can be performed at that time.
Occlusion of one or both fallopian tubes is most commonly detected at the time of dye injection, whether at laparoscopy or at hysterosalpmgography. Occlusion may be bilaterally proximal or dis tal, or exist at a combination of those sites. If there is proximal tubal occlusion for which resection and end-to-end reanastamosis can be performed, then fertility rates can approach those of sterilization reversal operations. If implantation is required, then the fertility prospects are poor, with no more than 10% of patients conceiving in the first two years after surgery. Distal tuboplasty of hydrosalpmges is commonly performed, and subsequent pregnancy rates vary widely. The biggest problem in estimating subsequent outcome is the inability to assess the functional integrity of the tubal mucosa It is proba bly fair to advise patients that fimbnoplasties will yield a 25% pregnancy rate in the first two years after surgery, but clearly this is very variable from individual to individual, depending on the degree of immeasurable intraluminal injury.
Although laparoscopy may reveal pertinent observations such as polycystic changes of the ovaries, the most significant diagnoses to be made are presence and extent of pelvic adhesions and endometriosis. If pelvic adhesions are minimal but constrain tubal motility, then laparoscopic lysis of adhesions is a reasonable undertaking. Extensive adhesions would generally require laparotomy for lysis (with or without tuboplasties), and the results of such surgery are quite variable. If adhesions are extensive, or if the patient has undergone prior procedures for lysis but has suffered re-formation, then advancement to in vitro fertilization would probably be the best strategy.
Endometriosis is commonly found at laparoscopy in infertile couples either as the single detectable diagnosis or with other factors. In severe endometriosis significant destruction of ovaries and fallopian tubes and formation of extensive pelvic adhesions are associated with an exceedingly low cycle fecundity, which is only slightly above zero. All milder forms of endometriosis (minimal, mild, and moderate) seem to have a cycle fecundity that is one-half to one-fifth that of normal couples, and is not graded m association with disease severity.This implies that the mechanism of infertility in milder forms of endometriosis may not be the same as that in severe disease .The current best evidence is that endometriosis is associated with an intraperitoneal inflammatory process with elevated concentrations of chemical mediators of inflammation and an increased number of activated phagocytic cells. Either one or both of these aspects of an established in flammatory process could explain infertility in terms of decreased sperm survival and possibly injury of eggs or embryos.
There is no reason to suppose that infertility factors may not coexist in any couple, and the clinician and the couple must allow that the "obvious" factor is not the only problem. Therefore, it is good practice to undertake the assessment of each couple in a systematic way and then proceed with less invasive or demanding therapies initially as therapeutic trials. Specifically, male gamete factor can be evaluated by semen analysis and female gamete factor can be initially evaluated by a luteal phase progesterone or endometrial biopsy, and a large fraction of diagnoses will be made. It is then quite reasonable to proceed with a more detailed analysis of the male or complete the endocrine evaluation of the female with ovulatory dysfunction and to initiate a trial of therapy before proceeding with invasive assessment such as laparoscopy and hysterosalpingography. For example, if there appears to be ovulatory dysfunction and a trial of clomiphene is undertaken, four to eight cycles should be sufficient to determine whether this sole intervention has been effective. At this point completion of the infertility survey is appropriate; this primarily means performance of laparoscopy, hysteroscopy, and hydrotubation.
If the patient's history or examination initially suggests a particular diagnosis, such as female genital tract problems or male gamete factor, then those specific areas should be pursued early in the assessment. For example, if the patient describes cyclic progressive dysmenorrhea, then it is appropriate to proceed with laparoscopy for evaluation of both her infertility and pelvic pain syndrome as a very early step.
The incidence of idiopathic (unexplained) infertility is relatively low. Estimates range from 5% to 20%, but the incidence seems to be inversely correlated with the severity of criteria used. For example, if regular cyclic menses and a luteal progesterone level of more than 4 ng/ml are taken as sufficient evidence of normal ovulation, then the rate of diagnosis of ovulatory dysfunction will be very low, compared with the criteria of a normal "cycle profile" with demonstrated follicular collapse on serial ultrasounds, LH surge detection, and normal luteal phase progesterone secretion by daily blood samples for an entire cycle. If a couple has undergone a complete survey, which would include as a minimal assessment semen analysis, measurement of serum progesterone levels, laparoscopy, hysteroscopy, and hydrotubation with or without a postcoital test, then idiopathic infertility can be tentatively diagnosed.
Treatment of multifactorial or idiopathic infertility usually comes down to empirical therapies that are either conservative or aggressive. The most conservative empirical therapy is prospective observation. This strategy of allowing conceptive attempts with no medical intervention for six to twelve months frequently makes practical sense and permits treatment-independent conceptions to occur. The next level of empirical therapies might include more precise timing of coital activity (e.g., by BBT charts, LH surge indicators, and salivary/vaginal electrical resistance indicators), use of a condom for a few cycles followed by discontinuation of condom use for a few cycles, administration of clomiphene for six to eight cycles or empirical antibiotic such as tetracycline to the woman or the couple, which might treat undetected genital tract pathogens.
Additional aggressive empirical therapies include several recently developed technological options. In vitro fertilization with embryo transfer is certainly effective when fallopian tubes are absent or occluded, and has also been used for a variety of other diagnoses with apparent success. When the fallopian tubes are present and relatively normal, GIFT or superovulation with intrauterine insemination can be used. These alternatives appear to be more effective treatment modalities for many couples in some of the several diagnostic subgroups. All of these reproductive options currently require the use of ovulation induction drugs to increase the number of oocytes available It remains to be seen whether these techniques will actually increase the overall ultimate conception rate, or whether they simply compact several cycles of conceptive possibilities down into a single event.
IV. Control questions and tasks
1. Classification of infertility.
2. Pathogenesis of infertility.
3. What methods of functional diagnostic are used for diagnostic of infertility?
4. What are tubal and peritoneal infertility?
V. List of recommended literature
1. Danforth’s Obstetric and gynaecology.-Seventh edition.-1994.-P.807-820
2. Gynecology.-Stephan Khmil, Zina Kuchma, Lesya Romanchuk.-2003.-P.195-213
3. Gynaecology illustrated. David McKay Hart, Jane Norman.-Fifth Edition.-2000.-P.389-409
Approved on Session of Department of Obstetrics and Gynecology with course of Infant and Adolescent Gynecology_________________ protocol No__________
T.a.The Head of Department:_______________ O.A.Andriiets’
|On the conference of the Department||On the conference of the Department|
|On the conference of the Department||On the conference of the Department|
|On the conference of the Department||On the conference of the Department|
|On the conference of the Department||Application form ХV international scientific conference «Ideas of Academician Vernadskyi and Problems of Regional Sustainable Development»|
«Kremenchuk Plavni». The conference fee does not cover meals and accommodation. For foreign participants the conference fee may be...
|Application form ХІV international scientific conference «Ideas of Academician Vernadskyi, Problems of Research and Evaluation of Regional Sustainable Development»|
«Kremenchutski Plavni». The conference fee does not cover meals and accommodation. The conference fee for foreign participants may...
|M. Gorky Donetsk National Medical University Department No. 2 of Pediatrics Head of the Department Dr. Churilina A. V., Ph. D. Rickets|