Report of a normal semen analysis according to the WHO criteria.
Plasma levels of FSH, LH, testosterone, and prolactin should be measured in cases of total absence of live spermatozoa (azoospermia) or severe oligospermia. Normal volume ejaculate (>1 mL) from a man with high FSH, high or normal LH, and normal or low testosterone suggests testicular failure. Such cases should be further investigated with a chromosome analysis in order to exclude Klinefelter’s syndrome or other chromosomal abnormalities. Low levels of FSH, LH, and testosterone indicate hypogonadotropic hypogonadism; Kallman’s syndrome, hyperprolactinemia, or other acquired causes would then be assessed. Causes of nonobstructive azoospermia or severe oligospermia include Y-chromosome deletions of the azoospermia factor region (AZF), translocations, and chromosomal abnormalities (such as Klinefelter’s syndrome). Diagnosis of obstructive azoospermia is increased in the presence of normal hormonal levels and normal testicular size. A common genetic cause of obstructive azoospermia is inheritance of cystic fibrosis genes, which results in vasal aplasia. Fertilization is possible for men with azoospermia or severe oligospermia by means of testicular biopsy and intracytoplasmic sperm injection (ICSI).
Low volume ejaculate (<1 mL) from a man with azoospermia or oligoasthenospermia, normal FSH level and normal testicular size suggests ejaculatory duct obstruction. A referral to a specialist urologist is indicated in such cases.
Increased levels of antisperm antibodies (ASAs) IgA and IgG have been associated with male factor subfertility. Antisperm antibodies reduce the sperm progression through the cervical mucus and the zona pellucida. However, the exact role of ASAs, the level that is clinically significant and the management of the affected couples are still unclear.[14]
The fertility ultrasound scan
An accurate, noninvasive assessment of the female pelvic organs has become feasible due to recent advances in u/s technology. The scan performed for the evaluation of subfertility is called a fertility scan. As opposed to other types of scans (such as the gynecological or the early pregnancy scans), a fertility scan is focused on specific aspects related to the female fertility potential.
An advanced fertility scan requires high-resolution equipment with sensitive color and spectral Doppler modalities. Although a 3D facility is not absolutely necessary, it is desirable as it can eliminate the need for additional tests such as hydrosonography or hysteroscopy. Precise imaging of the female pelvic organs requires the scan to be performed transvaginally.
A fertility scan can provide different but useful information when performed in different times of the menstrual cycle. Traditionally it was recommended that fertility scans should be arranged in the beginning of the cycle, most studies suggesting day 2 or 3 for a more accurate assessment of ovarian reserve. A mid-cycle scan, however, could provide information on the dominant follicle and the quality of the endometrium. A scan in the luteal phase of the cycle can reveal the presence of a corpus luteum as a proof of ovulation. It is clear that some compromise has to be made for the timing of the scan. However, we believe that it is quite important to determine whether a “good quality” dominant follicle is present and also to assess the endometrial response to follicular development. For women with a regular 28- to 30-day cycle, these assessments would prerequisite a scan ideally on day 10, 11, or 12. A comprehensive fertility scan should include all the data shown in Table 26-2.
| Uterus | Position Mobility Dimensions Identification of fibroids or adenomyosis Uterine arteries Doppler assessment (peak systolic velocity, pulsatility index) Congenital malformations (mainly with a 3D scan) |
| Endometrium | Thickness Morphology Identification of polyps Doppler assessment Assessment of cavity with hydrosonography |
| Ovaries | Position Mobility Morphology Accessibility for oocyte retrieval Dimensions, volume Identification of cysts (simple, endometriotic, dermoid, complex, etc.) Antral follicle count Stromal blood flow Doppler assessment Identification of a dominant follicle, its dimensions, and the perifollicular blood flow |
| Fallopian tubes | Identification of hydrosalpinx Assessment of patency with HyCoSy |
| Pouch of Douglas | Presence of free fluid Identification of masses |
Uterus
The scan should ideally show an anteverted uterus, measuring about 75 mm in length (from fundus to cervix) with a normal myometrium. Good diastolic velocities with a mean pulsatility index (PI) <3 in the blood flow of uterine arteries are favorable signs. Abnormal findings consist of large intramural fibroids (especially in close proximity to the endometrium), submucous fibroids, excessive adenomyosis (especially close to the endometrium), and high-resistance uterine artery blood flow.
Transverse imaging of the uterus could raise the suspicion of an arcuate, subseptate, bicornuate, or didelphys uterus. If 3D facilities are available, such an investigation would help with high accuracy to confirm or exclude those anomalies and also to differentiate between each other (Figure 26-2). Otherwise, an outpatient hysteroscopy will need to be added in the evaluation of the woman in order to understand the degree to which such abnormalities will affect her fertility potential and if there is need for further management. It’s our policy to perform as a routine a 3D scan to obtain a coronal plane of the uterus, not only to identify such congenital malformations but also to demonstrate the precise position of any submucous fibroids (Figure 26-3) and to assess the appearance of the junctional zone between the endometrium and the myometrium in cases of suspected adenomyosis (Figure 26-4).
3D transverse coronal u/s view of the cavity of: (a) a normal; (b) an arcuate; (c) a subseptate; (d) a unicornuate; (e) a didelphys uterus.
3D transverse coronal u/s view of the cavity of a uterus with a submucous fibroid.
3D transverse coronal u/s view of a uterus with severe adenomyosis.
Endometrium, receptivity
A day 10–12 scan should normally demonstrate a triple layer endometrium with a thickness greater than 7 mm. A clear layer of mucus might also appear in the cervical canal. Vessels (spiral arteries) extending into the triple layer should appear after applying color Doppler (Figure 26-5). A thin or echogenic endometrium and the presence of an endometrial polyp greater than 5 mm in diameter are not favorable signs.
(A) u/s view of a mid-cycle receptive endometrium; (B) color Doppler depicts spiral arteries extending into the triple layer.(A)(B)
Although the endometrial scan can usually raise the suspicion of a polyp, sometimes it is difficult to differentiate whether that is actually a polyp (especially if it’s less than 10 mm in size) or an endometrial fold or even a small submucous fibroid. A 3D scan can contribute toward such a clarification; however, in order to achieve a more accurate diagnosis in cases of suspected intrauterine adhesions, sonohysteroscopy is usually recommended. Sonohysteroscopy is a simple technique, performed with the infusion of a negative contrast (saline) into the uterine cavity through a catheter during vaginal ultrasound; it can easily be performed at the same time as the tubal patency test (HyCoSy) or independently in cases where it is decided that a HyCoSy is not necessary. Alternatively, outpatient hysteroscopy would easily establish the diagnosis of an endometrial polyp, submucous fibroid, or Asherman’s syndrome. It is recommended that big endometrial polyps (greater than 5 mm), submucous fibroids and endometrial adhesions may require hysteroscopic removal before any type of fertility treatment begins.
Assessing endometrial receptivity is an important aspect of fertility investigation. Ultrasound scanning assessment is based on endometrial thickness and morphology in conjunction with an estimation of the blood flow velocities in the uterine arteries using Doppler. An endometrial thickness of 7 mm or more, a triple layer appearance and a uterine artery pulsatility index (PI) <3 are considered reliable markers of adequate receptivity. More recently, the visualization of the spiral arteries extending into the layer of the endometrium has been correlated with good receptivity. Older methods of endometrial assessment including endometrial biopsy for analysis and correlation with various molecular and biochemical markers can be abandoned due to low specificity and the invasive nature of technique.
Ovarian reserve assessment
The volume of each ovary is calculated by measuring the organ in three dimensions. There should be five or more antral follicles (mean diameter 2 mm–9 mm) scattered in the stroma of each one of the ovaries. Ideally, the stromal blood flow velocity should be 6 cm–12 cm/sec. On the day 10–12 scan, a dominant follicle should normally be present in one of the ovaries, with a mean diameter of 16 mm–18 mm and with a ring of blood vessels around the follicle demonstrated with color Doppler (Figure 26-6). The peri-follicular peak systolic velocity (PSV) at this stage is expected to be 5 cm–10 cm/sec. The mobility of each ovary in relation to the uterus can be assessed in response to abdominal palpation.
Ring of blood vessels around a dominant follicle as demonstrated with (A) color Doppler and (B) 3D scan.(A)(B)
Abnormal findings consist of the presence of ovarian cysts (simple, endometriotic, dermoid, complex), a polycystic appearance of the ovaries, absence of a dominant follicle, low ovarian volume (less than 3 mL for the non-dominant ovary), less than four or five antral follicles and low velocity in stromal blood flow (PSV less than 6 cm/sec). Ovarian cysts may have to be removed before starting fertility treatment, especially if they are large and complex cysts. Small simple cysts usually do not require surgery. The evidence on whether the endometriotic cysts should be removed is controversial. For endometriomas measuring less than 5 cm, especially with previous surgery to the ovaries or in a woman with low ovarian reserve or over the age of 40 it would be wiser to proceed with no delay to fertility treatment.
The prevalence of polycystic ovaries in the population of women with subfertility is around 33% (though many women remain asymptomatic) and is the most common cause of anovulatory subfertility. Polycystic ovaries can be easily differentiated from normal ovaries with the day 8–10 scan. By definition, they are larger and each has more than 12 small follicles.[15]
The fertility scan should be able to determine if the PCO is ovulatory or anovulatory. Moreover, women with PCOS are known to exhibit an excessive response to ovarian stimulation with gonadotrophins; they are at an increased risk of ovarian hyperstimulation syndrome (OHSS).[16] Lower doses of gonadotrophins may be considered. PCO patients with higher ovarian stromal blood flow velocities may be experiencing over response to low dose gonadotrophins thus increasing their risk of OHSS.[17, 18]
An increasing number of women delay conception until their late thirties or even early forties. This has resulted in a significant increase in subfertility, which is due to aging of oocytes and lower ovarian reserve. Thus, assessing a woman’s ovarian reserve is an important aspect of the evaluation in fertility investigation. The role of u/s scan in such an assessment is widely recognized.[19] Ovarian volume, antral follicle count (AFC), and ovarian stromal flow are the main parameters that reflect ovarian reserve and response. Ovarian volume less than 3 mL or less than 5 antral follicles in total suggests diminished ovarian reserve. The standard 2D measurement of the AFC is considered accurate. Doppler measurement of PSV in one or two stromal vessels is a simple technique that can provide complementary information when assessing ovarian response.[20] Difficulty in visualizing stromal vessels or PSV less than 6 cm/sec suggests low ovarian reserve.[21]
Ovarian reserve has been traditionally assessed with an FSH blood test at the beginning of the menstrual cycle, but this is an indicator with low sensitivity. More recently, the blood test for AMH has been introduced in the evaluation of the subfertile woman. The AMH blood test can be performed on any day of the cycle and is considered as an accurate indicator of ovarian reserve. It is not clear so far if a hormonal assessment is absolutely necessary in the evaluation of ovarian reserve, especially if advanced u/s facilities are available to an experienced clinician.[22, 23] In our practice, we have found u/s parameters accurate and predictive of ovarian response for women undergoing treatment. However, for women over 35 years old with a suspected low ovarian reserve we recommend an AMH blood test in order to confirm (or refute) the findings from ultrasound.
The lack of a dominant follicle on the day 10–12 scan usually suggests ovarian dysfunction. But even if a dominant follicle with appropriate size is present, it doesn’t necessarily mean that it contains a “good quality” oocyte. Perifollicular vascularity is an important indicator of the oocyte quality. Optimal peri-follicular flow as demonstrated with color or power Doppler (more than 50% of the follicular perimeter) and an adequate PSV in the peri-follicular vessels (more than 10 cm/sec) have been associated with the production of “good quality” oocytes and embryos.[24, 25]
Tubal patency assessment
Assessment of the fallopian tube patency in the outpatient evaluation of the infertile couple is quite important, as tubal problems are present in about 30% of the subfertile patients.[26] Fallopian tubes are not normally visible with u/s imaging. Hydrosalpinges on the other hand are generally easily visible even by operators with moderate experience.
A tubal patency test can be avoided in cases of obvious bilateral hydrosalpinges, low ovarian reserve, and severe male factor problem. IVF tends to be the only treatment option in such cases, and the result of a tubal patency test would not change the management of the situation.
The most widely used technique to assess tubal patency is x-ray hysterosalpingography (HSG), which also offers the added advantage of evaluating the uterine cavity for defects like fibroids and polyps. Alternatively, laparoscopy with chromopertubation can be used for tubal patency assessment. Laparoscopy can additionally provide information about other pelvic pathology, such as endometriosis and peritubular adhesions, but there is growing evidence against performing laparoscopy as a routine for tubal patency due to its high cost and morbidity. Some abnormalities detected at the time of laparoscopy, however, can also be treated during the procedure.
Although HSG has been the gold standard for confirmation of tubal patency, its use for the outpatient evaluation of the couple is restricted by the demand of x-ray facilities. The development of HyCoSy has offered an alternative to HSG, as it seems to provide similar information regarding tubal patency and the uterine cavity.[27] HyCoSY can be combined with the fertility scan and performed following the sonohysteroscopy. From the patient’s perspective, HyCoSy seems to be a more acceptable technique compared to HSG, with significantly less total pain scores.[28]
The original HyCoSy technique consists of injecting 10 mL of a positive contrast (Echovist, Schering AG, Berlin, Germany) into each fallopian tube through a balloon catheter, in order to demonstrate fill of the tubes and spill of medium into the peritoneal cavity. Its main risks involve infection and allergic reaction to the contrast medium. For this reason it is carried out under antibiotic prophylaxis and is not offered to patients with a known allergy to the medium. The authors have adapted the original technique by injecting less Echovist (only 2–5 mL) slowly into each tube and by using a fine intrauterine insemination catheter instead of the balloon catheter. Those modifications have helped to eliminate side effects and reduce patient discomfort without compromising effectiveness.
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