An infertile couple is diagnosed with unexplained infertility when all the indicators examined are normal and the cause of infertility is unexplained. In these seemingly normal couples, the causes of infertility may be multiple. Some of these couples are indeed normal and the infertility is a random delay, mostly related to age factors, while others appear to be “normal” but have a true subclinical infertility factor, which may be an underlying cause that cannot be detected and verified by current conventional means. Couples with unexplained infertility should be treated clinically according to certain steps and procedures or with the help of advanced assisted reproductive technologies. However, the possibility of spontaneous pregnancy unrelated to treatment still exists in these patients during the consultation and treatment process.
According to the understanding of the meaning of normal human fertility (Fecundity), under normal circumstances, successful human pregnancy also occurs only in 1/5 to 1/6 of the intercourse cycles. about 14% of couples with normal sexual intercourse do not become pregnant in 1 year, but about 9% of couples become pregnant again spontaneously in the second year.
1. Definition and diagnostic steps
1.1 Definition There is some disagreement about the definition of unexplained infertility. The main point of contention is what diagnostic criteria are set to conclude “unexplained”. The diagnosis of infertility is based on a comprehensive set of tests.
The basic criteria include ovulation tests, tubal function tests and semen tests, which are called the three major tests for infertility. In fact, strictly speaking, these three basic tests are not necessarily able to prove whether pregnancy is possible or not. The reason is that we do not yet have a sufficient test to determine normal ovulation; we lack a practical method to reflect the mid-luteal progesterone level; hysterosalpingography
The hysterosalpingogram can only reflect the patency of the fallopian tubes, but cannot predict the occurrence of ectopic pregnancy; laparoscopy can detect endometriosis and pelvic adhesions, but cannot confirm the function of the fallopian tubes; semen analysis can determine the sperm production, but not the ectopic pregnancy.
Even the results of in vitro fertilization are not guaranteed to be consistent from cycle to cycle.
1.2 There is considerable controversy as to whether anti-sperm antibody and chlamydia testing can also be used as diagnostic criteria for unexplained infertility. Some clinicians try to prove that they are the cause of infertility based on the results of some assays they perform
while others insist that the results of these tests must be reliably demonstrated to be related to impairment of fertility. In conclusion, the diagnosis of infertility is based on the three major tests of ovulation monitoring, tubalography, and semen analysis.
The diagnosis of infertility is based on three major tests: ovulation monitoring, tubal imaging, and semen analysis. Once the exact cause of the patient’s infertility is discovered, the diagnosis of unexplained infertility is not valid.
2. Diagnostic protocol
The diagnostic tests for infertility are usually grouped into 3 main categories.
2.1 Tests directly related to pregnancy outcome include semen analysis, hysterosalpingography or laparoscopy to diagnose patency of the fallopian tubes, and measurement of mid-luteal progesterone. Absolute diagnoses include azoospermia, bilateral tubal obstruction and anovulation, which are definitive diagnoses of the etiology of infertility and the inability to conceive without treatment.
2.2 Tests not directly related to pregnancy outcome include hamster egg penetration test, post-coital test, cervical mucus penetration test, hysteroscopy and anti-sperm antibody assay. Those with abnormal results on these tests are often able to conceive on their own without treatment.
2.3 Tests that do not appear to be associated with pregnancy outcomes endometrial chronotype, varicocele, chlamydia, and tuboscopy. These test results have either been shown to be unrelated to pregnancy outcome or lack follow-up information.
We emphasize the inclusion of laparoscopic diagnosis in the final criteria for infertility testing, but the diagnostic significance of laparoscopy has been somewhat neglected in recent years. Currently, physicians often treat patients with unexplained infertility, mild sperm abnormalities and cervical sexual problems with normal hysterosalpingograms directly with intrauterine insemination (IUI) or in vitro fertilization (IVF). In contrast, diagnostic laparoscopic surgery in these patients resulted in a change in the planned IUI or IVF regimen in 25% of patients.
3. Prevalence of unexplained infertility
It is difficult to count the true prevalence of unexplained infertility in a population. However, it is possible to calculate the proportion of unexplained infertility occurring in infertile couples. According to the statistical results of 14141 infertile couples in 21 clinical research groups abroad from 1950 to 1991, 2425 (17.5%) couples were diagnosed with unexplained infertility, and the proportion of unexplained infertility in each clinical research group ranged from 0% to 26%, which was due to the composition of patients in each clinical group and the different diagnostic criteria used by individual physicians and hospitals. This is due to the different composition of patients in each clinical group and the diagnostic criteria used by individual physicians and hospitals.
The age of the female partner was the only significant predictor when compared with other causes of infertility. Years of infertility, male partner’s age, maternal history, frequency of sexual intercourse, and socioeconomic status were not correlated.
The prevalence of unexplained infertility was slightly increased, which may be related to the female age factor.
4. Possible causes of unexplained infertility
It is not yet possible to prove whether the decrease in fertility with increasing female age is due to impaired oocyte development, fertilization, or the process of implantation. It is speculated that age factors may be involved in many aspects of conception. In addition
In addition, defects in the reproductive system may also be the cause of unexplained infertility. Examples include defects in gamete development, fertilization, and implantation. These defects can be serious, but the current level of medical diagnosis does not allow them to be used as routine clinical tests.
Although the field of reproductive medicine has evolved very rapidly in recent years, our means of detection of infertility remains so insensitive. In male infertility, the comprehensive tests we have available still do not provide an indication of the fertility of sperm. Semen analysis describes the number and proportion of normal morphology and motile sperm, but a normal semen analysis result does not necessarily reflect the fertilization capacity of sperm. A cervical mucus penetration test for spermatozoa has been devised, but the relationship between the results of this test and the ability to conceive is still unproven. There is also no test that reflects the ability of sperm to pass through the interstitial part of the uterine tube. There are also a number of tests to assess the acrosome reaction of sperm and the ability of sperm to bind to and penetrate the zona pellucida, but none of them have reliable and practical results. Even IVF is not a perfect test. Thus, many potential defects in various parts of the conception process in both men and women are far from being sufficiently sensitive for even the most comprehensive tests available.
It has been suggested that varicocele is a cause of subclinical male infertility, but an analysis of the extensive literature statistics suggests that the relationship between varicocele and male infertility is uncertain and that surgery has no significant significance in the treatment of infertility. The literature also suggests that oxidation of reactive oxygen system (ROS) in semen can affect semen liquefaction and sperm nuclear DNA integration, accelerate the apoptotic process of spermatozoa and cause male infertility, but it is not available as a routine clinical test.
Other presumed etiologies of unexplained infertility may include the following: (1) the effect of poor cervical secretions; (2) poor endometrial receptivity to early embryos; (3) poor peristaltic function of the fallopian tubes; (4) defective ovarian
(3) poor peristaltic function of the fallopian tube; (4) defective egg collection function of the umbilical end of the fallopian tube; (5) luteinization non-rupture syndrome; (6) mild poor hormonal secretion, such as luteal insufficiency; (7) impaired fertilization of sperm and eggs; (8) mild endometriosis; (9) immune factors, such as anti-sperm antibodies, anti-hyaline antibodies or anti-ovarian antibodies; (10) abnormal function of peritoneal macrophages; (11) impaired antioxidant function in the peritoneal fluid.
5. Natural regression of unexplained infertility
There is no research data on the long-term prognosis of the natural course of unexplained infertility. Most of the available studies are short-term observations. The results of long-term observations may prove that the prognosis is very good. For infertile couples, the final
outcome should be a live birth and not just a pregnancy. Because statistics have found a relatively high rate of miscarriage after pregnancy in this group, establishing a score to predict long-term outcomes should use live birth as an indicator. If a couple is infertile
of <3 years, secondary infertility, and the female partner is <30 years of age, a live birth rate of 60-70% can be expected.
6. Treatment of unexplained infertility
Couples with younger age and shorter infertility should be given sufficient time to wait, usually at least 2 years. During this period, attention should be given to other health problems related to pregnancy, such as quitting smoking, losing excess weight, and improving existing bad habits. Three years of infertility is a reasonable period to start treatment. When starting a treatment plan it is important to consider the individual patient, what are the chances of a natural pregnancy during the treatment; the price and effectiveness ratio of the treatment plan; and the side effects of the treatment. Therefore, we should develop a treatment plan that is as simple, straightforward, and effective as possible, with a reasonable time frame. The steps of treatment for unexplained infertility are summarized in a “three-step process”: ovulation induction, intrauterine insemination, in vitro fertilization and embryo transfer.
6.1 Ovulation induction
Athaullah et al. summarized the comparative effects of ovulation induction with clomiphene and gonadotropin preparations in 231 unexplained couples and found that although the pregnancy rate was lower in the oral group than in the injectable gonadotropin group, the differences were not significant in terms of multiple birth rate, live birth rate, miscarriage rate, and ovarian hyperstimulation. Therefore, it is suggested that oral ovulation-promoting drugs, such as clomiphene, should be preferred for the patient’s medication. Clomiphene may increase follicular recruitment and promote egg maturation to correct patients with unexplained infertility with underlying ovulatory disturbances. Many studies have shown that 4-6 cycles of clomiphene can increase pregnancy rates by a factor of 2. Clomiphene is simple, easy to use, and has few side effects, and can be used as a first-line treatment for unexplained infertility. 3-4 cycles of treatment is a course of treatment, but it is important to inform the patient about multiple pregnancies, the possible long duration of treatment, and the potential risk of ovarian cancer before treatment.
6.2 Induction of ovulation plus intrauterine insemination (COS+IUI)
Ovulation induction plus intrauterine insemination becomes the treatment of choice for unexplained infertility after treatment with clomiphene has failed. Ovulation induction drugs can be used with gonadotropins. The pregnancy rate per cycle of expectant therapy in couples with unexplained infertility is 2-4% and 3.8% for IUI without ovulation induction therapy. When comparing the conception rate in the group treated with IUI in the first cycle with that in the group with single time-controlled intercourse, there was a non-significant difference of -6 pregnancies in 145 cycles compared to 3 pregnancies in 123 cycles with time-controlled intercourse. Therefore, IUI alone does not improve pregnancy rates and should be used in conjunction with an ovulation induction protocol. Multiple data show that COS plus IUI can improve pregnancy rates 5-fold to about 18% over IUI alone, and cumulative pregnancy rates over 3 cycles can reach about 35%. This is a higher pregnancy rate than either IUI alone or ovulation alone. The main complications of this treatment are ovarian hyperstimulation and multiple pregnancies.
The number of dominant follicles required for ovulation in IUI is inconclusive and 1-2 follicles is generally considered to be the optimal number.
6.3 In vitro fertilization and embryo transfer (IVF-ET)
If COS+IUI treatment is unsuccessful after more than 3 cycles, the outcome of the treatment is no longer promising. Aboulghar et al. suggested that the cumulative pregnancy rate for COS+IUI after more than 3 cycles would decrease to less than 10%, and Stone et al. reported a pregnancy rate of less than 4% for more than 5 cycles. Therefore, after a patient has been treated with 3 cycles and at most 4 cycles of COS plus IUI, a treatment plan with in vitro fertilization should be used.
. Aboulghar reported that patients with unexplained infertility who had failed COS plus IUI treatment and switched to, IVF treatment had a pregnancy rate of about 40-50% per cycle . In addition, IVF also provides a diagnosis of the etiology of unexplained infertility to see if the problem of infertility occurs during the fertilization session, and it was found that about 15-30% of patients with unexplained infertility may have no or low fertilization during the IVF cycle, and there can be an 11-22% risk of fertilization failure in couples with primary unexplained infertility using IVF for fertilization. In such patients, switching to single sperm intracytoplasmic injection (ICSI) in subsequent cycles can result in higher pregnancy rates. Although we cannot use this as an indication for ICSI, it can be an important part of informed patient counseling.
7. Effectiveness of treatment
There should be a full discussion with the patient couple on whether to treat unexplained infertility. There is no very definite rationale for any treatment in the case of unknown etiology of unexplained infertility. Because of the lack of true randomized controlled studies in clinical practice, there is no way to assess the effectiveness of treatment. Spontaneous pregnancy can also occur at any time during the course of investigations and treatment. Although there have been many reports on the treatment of unexplained infertility, they are mostly
are treatment subgroup or retrospective studies, the treatment is also selective rather than randomized and subject to some subjective factors, so the conclusions lack overall and rigorous statistical significance.