Common Diagnosis

The prevalence of infertility over the last 30 years has been stable, but the treatment and demand for infertility services has increased substantially during that time. This increase is due to several factors: changes in population demographics (older couples trying to conceive), increased patient awareness and access to services, and advances and improvements in fertility treatments.

Male factor

Confirm any abnormal study result with a repeat semen analysis (SA) at least 4 weeks apart. The average time of sperm turnover is approximately 60-70 days. Since semen parameters can be affected by acute illness and environmental factors, a repeat SA will give a more accurate reflection of overall semen quality. If results remain abnormal, the patient is referred to a urologist to evaluate for any genetic, anatomic, hormonal, or infectious causes. If the sperm concentration is less than 20 million/mL, yet the swim-up extraction yields at least 1 million total motile sperm, intrauterine inseminations (IUI) is the treatment of choice. If sperm counts are extremely low or if motility is poor, in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI) may be required.

Ovulatory Dysfunction

If a patient has a normal ovarian reserve, determining the potential cause of the ovulatory defect is prudent. The practitioner should consider the following scenarios prior to initiating treatment. In the presence of obesity and chronic anovulation, polycystic ovarian syndrome (PCOS) may be evident and in the case of hirsutism, the patient may have elevated androgen levels or hyperinsulinemia, requiring further testing. In a patient with low body mass index and low gonadotropin levels, weight gain and decreased exercise may improve fertility. If oligomenorrhea remains, ovulation induction can be achieved with exogenous gonadotropins. If the physical examination findings are unremarkable, ovulation induction is the next treatment approach to consider.

The following clomiphene citrate (CC) treatment regimens are often used for ovulation induction in patients with idiopathic ovulatory dysfunction or PCOS:

• Clomiphene citrate (50-150 mg on days 3-7 or days 5-9)
• Clomiphene citrate (100 mg on days 3-7) plus follicle stimulating hormone (FSH) (1-2 amps starting on day 6-8)
• Clomiphene citrate plus human chorionic gonadotropin (hCG) for ovulation induction
• Hyperinsulinemia with elevated androgens - Metformin (500 mg tid) plus clomiphene citrate. Many women spontaneously ovulate on metformin alone; thus, many clinicians allow a trial of 1-3 mo prior to adding clomiphene citrate. However, recent data suggest that the combination of metformin with clomiphene citrate may be more successful.
• Aromatase inhibitors (Letrozole) (2.5 mg PO on cycle days 3-7) has been shown in early studies to work as well as clomiphene citrate to induce mono-ovulation and to have little or no adverse affect on endometrial thickness. Questions regarding their safety limit their use at present.

The goal of therapy is to achieve 3 ovulatory cycles; 40-50% of women should become pregnant in this timeframe in the absence of any other abnormalities. If conception has not occurred after 3 clomiphene citrate cycles, the practitioner should investigate other causes of infertility. No more than 6 consecutive cycles are recommended because of the theoretical risk of borderline ovarian tumors and extremely low pregnancy success rates after this point.

Evidence suggests that starting clomiphene citrate earlier (day 2 or 3 rather than day 5) is more beneficial because this conforms to a more typical cycle length of 28 days. Beginning on cycle day 2 or 3 promotes ovulation around days 12-16, which is more physiologic and may avoid delayed ovulation and excessive maturity of the oocyte. Studies from the 1970s in women with documented delayed ovulation (after cycle day 16) revealed a higher relative miscarriage rate. This was believed to be caused by meiotic dysfunction within the oocyte.

Evidence demonstrates that a day 2 or 3 clomiphene citrate start allows the endometrium to thicken to a more normal, physiologic range. Endometrial thinning is a well-known adverse effect of clomiphene citrate. An endometrium that is thinner than 7-8 mm may be associated with a lower pregnancy rate in IVF cycles.

Ovulation induction can also be initiated with exogenous FSH. During such cycles, FSH is generally started on cycle day 3 and the patient is monitored for development of a few dominant follicles. When these dominant follicles have grown to the appropriate size, ovulation is hormonally induced and IUI is performed. Unlike in vitro fertilization, there is no control over the number of embryos that implant. Unfortunately, as many eggs that develop and fertilize can implant.

Tubal disease

IVF offers the best chance for conception in patients with significant tubal disease. Often, if only 1 tube is affected, ovarian stimulation with gonadotropins produces mature oocytes in the ovary near the patent tube. In patients with minimal or moderate tubal disease, laparoscopic lysis of adhesions and procedures should be performed to normalize tubal function, with an emphasis on prevention of adhesion recurrence. In patients with an irreparable hydrosalpinx, removing the tube or disconnecting it from the uterus may reduce the risk of a tubal pregnancy and enhance embryo implantation by eliminating the reflux of inflammatory fluid from the hydrosalpinx into the uterine cavity.

Pregnancy rate following treatment can be dependent upon location of tubal disease (see Table 3 below).

Laparoscopic lysis of adhesions offers an opportunity to conceive either naturally or with minimal types of therapy. If only proximal tubal occlusion is present, these obstructions can be fixed with a balloon tuboplasty under fluoroscopic guidance similar to the common angioplastic procedure in cardiology.

Table 3. Treatment of Tubal Pathology 

Cervical Factor

Intrauterine inseminations may offer a reasonable option for treatment. The presence of antisperm antibodies in the female or male warrants IUI. If this is unsuccessful IVF is the next step and is often successful.

Uterine Factor

An operative hysteroscopy is usually required to lyse adhesions or remove endometrial polyps or submucosal fibroids. Intramural fibroids and subserosal fibroids may be removed by laparotomy, traditional laparoscopy or robotically assisted laparoscopy. 

Endocrine Abnormalities

Ensure that any endocrine abnormality is normalized prior to attempts at conception. Keep in mind that women with luteal phase defects also have ovulatory dysfunction. Clomiphene citrate, as previously mentioned, and luteal phase progesterone supplementation may be potentially effective treatments. The recommended progesterone is either micronized progesterone in vaginal suppositories (50-100 mg bid) or progesterone vaginal cream (Crinone 8%; 90 mg/d).

Uexplained Infertility

The choice of treatment protocol depends on how aggressive the couple wants to be with their efforts to conceive. Most physicians start with either clomiphene citrate or gonadotropins in conjunction with IUIs. Patients should completely understand the success rates (see Table 4) and the risks of multiple pregnancy with any treatment protocol.

Table 4. Unexplained Infertility and Pregnancy Rates per Cycle According to Treatment