Female partner’s age

There is a well-documented decrease in female fertility that is age dependent and occurs many years prior to menopause. Eventually, this decline manifests as diminished ovarian reserve. This is reflected in both reduced oocyte quantity as well as oocyte quality. Decreased oocyte quantity results in a diminished response to ovarian stimulation, whereas decreased oocyte quality is reflected by a decrease in embryo implantation. This process occurs even in the absence of a rise in serum FSH levels.

A decline in fertility begins in many women in their early 30s, and becomes more pronounced as they grow older. A recent study examined a cohort of 1654 women undergoing donor insemination for male or situational infertility. The cumulative delivery after 12 cycles of natural, clomiphene or gonadotropin ovarian stimulation varied by age group. Specifically, it was 87% for the group aged 20–29, 77% for ages 30–34, 76% for ages 35–37, 66% for ages 38–39 and 52% for ages 40–45. This difference in age was the only variable that significantly affected the cumulative delivery rate. Prior observational trials in several countries corroborate the finding that fertility decreases with advancing age.

An associated finding is that success with assisted reproductive technologies (ART) decreases with increasing age. Also, the incidence of spontaneous miscarriage increases as the woman becomes older. This is thought to be due to oocyte abnormalities, such as anomalous meiotic spindles, and microtubule matrix changes, which lead to an increase in aneuploidy. These defects contribute to the increased miscarriage rate in older women of over 50% by the the age of 43.

Male partner

Semen analysis parameters have been determined by the World Health Organization (WHO) to evaluate sperm concentration, motility, and normal morphology. However, the normal values are based on limited data. Furthermore, there is sizeable overlap between normal and abnormal ranges in men both fertile and infertile. It is also recognized that the same man may produce semen that varies markedly in these parameters, depending on the sample. Therefore, subtle abnormalities in sperm may result in an intermittent ability to fertilize oocytes and the couple may present with infertility that will appear to be unexplained.

Many tests have been developed over the years to better assess sperm function. The sperm penetration assay, also known as the zona-free hamster oocyte penetration test, is one such evaluation. Normally, the zona pellucida protects the oocyte against multiple sperm entry or sperm from different species. In the hamster oocytes to be tested, the zona pellucida is removed by enzymes, and sperm from the infertile male are introduced. Simultaneously, sperm from a proven fertile male are incubated with another zona-free hamster oocyte. Comparative results are then generated. While this test initially appeared very promising for being able to quantify sperm function, it eventually proved not to be clinically useful, primarily because of variability between samples and overlap between normal and abnormal males. The hemi-zona binding assay evaluated the ability of sperm to bind to the human zona pellucida. Unfortunately, this test was also shown to have limited predictive value.

At the present time, sperm are evaluated with a standard semen analysis including semen volume, sperm concentration, evaluation of the percentage of motile sperm, and a morphologic assessment according to “strict” criteria. This has proven to be as good a predictor of fertilization in vitro as any other test. If the percentage of normal forms is less than 5%, intracytoplasmic injection (ICSI) in conjunction with IVF is recommended.

Cervical factor

The cervix is the entry point of sperm into the uterine cavity. Anatomic abnormalities in the cervical area (such as cervical stenosis) may interfere with sperm transport and result in infertility. It has also been hypothesized that abnormal cervical mucus production can impede sperm transport.

It was for this reason that the postcoital test was developed. The test analyzed the volume, consistency, ferning, spinnbarkeit, cellularity, and pH of the cervical mucus. It also assessed the sperm count and motility. Normally, the test was performed a few days before expected ovulation. After intercourse, the woman was examined and a sample of cervical mucus was obtained.

However, the clinical utility of this test was found to be limited. There was no standardized range of normal values, and results from clinical trials demonstrated conflicting results on the utility of the test. Most importantly, a randomized trial showed no difference in pregnancy rates whether the postcoital test was included in the infertility work-up or not. Eventually, the test was abandoned. This does not mean that the cervix may not play a role in unexplained infertility. The utility of intrauterine insemination (IUI) may be inferred as indirect evidence that the cervix may indeed play a role in some cases of unexplained infertility.

Subtle ovulatory dysfunction

Subtle ovulatory dysfunction has also been postulated as an etiology of unexplained infertility. A history of regular menstrual cycles provides an indication that ovulation is most likely taking place. Nevertheless, current diagnostic tests for ovulation (for example, basal body temperature shift and mid-luteal phase serum progesterone) provide only indirect evidence of ovulation and cannot confirm the actual release of the oocyte.

In the absence of an ideal method, the measurement of mid-luteal progesterone levels in plasma is probably the most cost-effective compromise to indicate that ovulation has occurred using hormonal methods. Because progesterone is released in a pulsatile manner, more than one assay may be needed to determine serum levels accurately. The value of 3 ng/mL correlates with a finding of secretory endometrium and has been used for presumptive indication of ovulation. Hull et al. found that a value of 10 ng/mL more closely correlates with subsequent conception, suggesting that lower levels, while indicative of ovulation, may be associated with subtle ovulatory inadequacy. The utility of superovulation may thus be inferred as indirect evidence that subtle ovulatory dysfunction may be a part of the etiology of unexplained infertility.

Luteal-phase defect

Luteal-phase defect (LPD) is defined as an abnormality in the endometrium during the postovulatory (luteal) phase of the menstrual cycle. This has been hypothesized to lead to diminished endometrial receptivity and consequent lack of embryo implantation. The diagnosis of LPD has traditionally been confirmed by obtaining a biopsy of the endometrium in the late luteal phase. The biopsy was histologically evaluated to ascertain the day of the cycle to which it corresponded. The date of the biopsy was then established by counting the number of days from the biopsy to the first day of the next menstrual cycle and subtracting this number from 28. The two dates were then compared. If a discrepancy of more than 2 days was found in two separate cycles, a diagnosis of LPD was made.