The Basic Infertility Evaluation by Dr. Janet Kennedy, MD
There are three basic areas of concern when a couple has not conceived within 6-12 months of discontinuing contraception. These include: Ovarian factors, sperm factors and pelvic anatomy factors. Each of these can be broken down into 2 subsets of each concern:
- Ovarian
- Ovulation
- Ovarian reverse
- Sperm
- Count
- Functionality
- Pelvic anatomy
- Tubal condition
- Uterine condition
Ovarian Factors:
Our investigation of ovarian factors requires an understanding of ovarian physiology. At birth, the ovary is populated with approximately a million eggs each of which is protected by an encircling layer of cells called a 'primordial follicle'. At any given point in time, a portion of those follicles begin to grow and develop into small cystic structures called 'antral follicles' which are visible to us by ultrasound measuring between 2 and 10 mm. Only these antral follicles have the ability to mature under the influence of the pituitary hormone, follicle stimulating hormone, or FSH.
The normal ovulatory cycle is broken down into the follicular and the luteal, or post-ovulatory, phase. During the follicular phase, those antral follicles that happen to be present in the ovaries are subjected to relatively higher levels of FSH causing them to begin the maturation process. Usually, several follicles start to grow and release estrogen but, as they grow, FSH declines. Consequently, only one follicle continues to grow. When that follicle and its corresponding egg reach maturity, luteinizing hormone, or LH is suddenly released from the pituitary as a 'surge' of activity. This LH surge is responsible for egg release from the follicle as well as the initiation of progesterone production by the follicle. Thus, the luteal phase is characterized by high progesterone levels relative to the follicular phase. The luteal phase lasts just 14 d.
Thus, to determine if ovulation is occuring, a blood progesterone level drawn is drawn 7 days after the presumed day of ovulation. In a typical 28 d. cycle, this is on cycle day 21 but, not all normal cycles are actually 28 d. in length. So, when we draw a progesterone level will be determined by your particular cycle length.
Progesterone is secreted in pulses so an ovulatory progesterone level can range from 5 to 15 ng/ml. A single progesterone level, while it can determine if you have ovulated, cannot tell you if your luteal phase is normal. To do this, some employ a technique called a 'pooled progesterone level' that combines blood drawn on 3 consecutive days in the luteal phase. A pooled progesterone level of more than 10 ng/ml suggests a normal luteal phase.
The term 'ovarian reserve' refers to the age related aspect of ovarian function. Because no new eggs are generated after embryonic ovarian development, as a woman ages, her eggs age as well. As eggs age, the 'machinery' within them that is required for normal division of chromosomes begins to break down. This accounts for the increase in infertility, miscarriage and chromosomally abnormal offspring as women age. There are several tests that we employ to assess ovarian reserve and each tells us about a slightly different aspect of ovarian aging. These tests include:
- Cycle day 3 FSH and estradiol level
- Antimullerian Hormone level (AMH)
- Antral follicle count (AFC)
On cycle day 3 (CD3), the third day of full menstrual flow, the ovaries are normally at rest and estradiol is quite low, <50 pg/ml, while FSH is relatively high as it initiates maturation of the existing antral follicles. As antral follicles age, they become more resistant to stimulation so CD3 FSH levels rise accordingly. A high CD 3 FSH level is an indicator of decreasing ovarian reserve. The table below illustrates the significance of various FSH levels. If estradiol is elevated above normal on CD 3, the FSH level will not be reliable. An inappropriately elevated CD 3 estradiol level also indicates declining ovarian reserve.
Day 3 FSH Level in relation to Ovarian Reserve*
*assumes simultaneous D-3 estradiol is <50pg/ml| Ovarian Reserve | FSH Levels |
|---|---|
| Good | < 10 |
| Mild Decrease | 10-12 |
| Moderate Decrease | 12-15 |
| Severe Decrease | > 15 |
AMH, antimullerian hormone, is produced by the primordial follicles. So, this level declines with age as the primordial follicles are 'used up'. In the reproductive years, AMH is expected to be between 1 and 5 ng/ml. A level lower than 1 indicates that the ovary is becoming depleted of primordial follicles.
The number of antral follicles, those follicles that are receptive to FSH stimulation, in an ovary is proportional to the number of follicles in the whole ovary so an Antral Follicle Count, AFC, can provide important information on ovarian reserve. We expect to see somewhere between 5 and 10 antral follicles in each ovary at any given time. If there are fewer than 5 antral follicles in an ovary, it tells us 2 things: First, the ovary is becoming depleted of follicles and secondly, our ability to obtain multiple eggs by stimulating the ovaries is limited thus limiting our treatment options.
Sperm factors:
Semen analysis is the mainstay of our assessment of sperm function. First, it tells us if sperm are present and, if so, in what concentration. Can they swim adequately, are they normally formed and is there any sign of infection? An abnormality in any of these parameters may indicate poor sperm function. Even when the semen analysis is entirely normal, we may not know with certainty that the sperm are capable of fertilizing eggs but, in general, if the semen analysis is entirely normal, we assume that the sperm function normally. The currently accepted normal values for each of these parameters is summarized in the table below:
Normal values for Semen Analysis
| Parameter | Normal value |
|---|---|
| Volume | 2.0 - 5.0 ml |
| Concentration | ≥ 15 million/ml |
| Motility | ≥ 50% |
| Morphology (strict) | ≥ 4% |
The semen analysis is critical to the evaluation of infertility even if a man has fathered children previously. Many things can influence day to day sperm production and sperm counts can vary accordingly. Changing life circumstances will alter male fertility just as changing circumstances alter female fertility. Age, however, plays less of a role in sperm function because new sperm are constantly being generated. Because sperm are 'new' cells, they are not so subject to the functional deterioration that impacts their egg counterparts.
Pelvic Anatomy Factors:
The condition of the fallopian tubes is most often assessed using an X-ray test called the "Hysterosalpingogram" or HSG. This test consists of injecting X-ray contrast, or dye, into the uterus through the cervix while imaging the pelvis with X-ray fluoroscopy. In a normal HSG, first the uterus then the tubes fill with X-ray contrast. Finally, the contrast will 'spill' from the far end of each tube into the pelvic cavity indicating that the tube is open or 'patent'. A tube can be blocked at its junction with the uterus, called 'proximal occlusion' or at its far end, called 'distal occlusion'. If the tube is blocked at its far end, often it will fill with fluid resulting in a balloon shaped structure called a 'hydrosalpinx'. If both tubes are blocked, there is no pathway by which sperm and egg can meet resulting in infertility. If one tube is normal, fertility may be preserved though often with a lower than normal per cycle probability of conceiving. At times, the HSG may indicate open, or patent, tubes even when substantial scarring within the pelvis causes an impediment to sperm-egg interaction. This type of pelvic factor can sometimes be suspected by the appearance of the dye on HSG after spillage from the tube but only surgical inspection, usually via laparoscopy, can make a definitive diagnosis.
The uterine cavity, lined by a delicate tissue called 'endometrium', is the site where the early embryo sets its roots, or implants. In order to implant properly, the uterine cavity should be free of abnormalities. While not all abnormalities prevent implantation altogether, many will impair the ability of the embryo to grow and develop normally. We gain important information about the uterine cavity from the HSG but often the X-ray contrast actually can obscur a small abnormality. Alternative methods for evaluating the uterine cavity include a simple office procedure by which we look inside the uterus with a tiny 'scope', called 'office hysteroscopy', and an ultrasound test called a sonohysterogram or 'saline infusion sonohysterogram' (SIS). Each method has its advantages and disadvantages so which one we choose will depend on the patient's characteristics and the physician's preference.
The basic tests most often employed to assess the causes of infertility are the day 3 FSH and estradiol, AMH level, luteal progesterone assessment, semen analysis and the hysterosalpinogram. In the majority of cases this information is enough to guide us to an appropriate treatment plan. We no longer routinely perform post coital tests or laparoscopy because, as our treatment of infertility has become more sophisticated, these tests are no longer likely to change the ultimate treatment decision.
When to Test for Infertility
Evaluation of infertility is warranted for a couple when the female partner is older than 35 and has been trying to conceive for 6 months without success. It is also indicated if the female partner is 35 years of age or less, after the couple has been trying to conceive for one year. Immediate evaluation and treatment of infertility is warranted in cases of known anovulation, bilateral tubal occlusion, or severe male factor infertility. We also recommend a more aggressive time table to evaluate and treat women 40 years and greater. This is because of the increased potential for significant loss of ovarian reserve in this age group. Ovarian reserve is the 'rate limiting step' in treatment since any treatment we have depends on the quality and number of eggs available.
With a streamlined work up, a couple can be efficiently evaluated, specific major causes of infertility identified, and treatment options considered. As with all medical assessments, infertility evaluation and treatment must be tailored to each couple's individual situation.
