Infertility: etiologies, evaluation and treatments.

Approximately 12-15% of couples are considered infertile and seek medical care. This review will delineate the current etiologies of infertility and outline a detailed evaluation. Treatment of the infertile couple should be targeted towards specific causes with empiric therapies reserved for those with unexplained infertility. Currently, great advances in the area of assisted reproductive technology allow physicians to treat couples with severe male factor infertility and tubal disease who previously had little hope of conceiving. The most common etiologies of infertility include tubal and peritoneal disorders, ovulatory dysfunction and male factor. Other conditions causing infertility are mentioned in this review for completeness sake. Surgery often corrects infertility due to tubal and peritoneal disease while a variety of medications exist to successfully manage ovulatory dysfunction. Couples who fail to conceive with those conservative measures are candidates for assisted reproductive technology such as in vitro fertilization (IVF). Recent advances in IVF lab techniques allow for correction of severe male factor infertility through use of intracytoplasmic sperm injection.

Infertility. A clinical guide for the internist.

Infertility is a common condition that internists practicing primary care may increasingly encounter. Abnormal male semen parameters, ovulation disorders, and tubal dysfunction account for most cases of infertility. By performing a complete initial evaluation and through appropriate and timely referral, internists can contribute to the care and improve outcomes for couples with this condition (Table 9).

Contraception. A clinical review for the internist.

Effective use of contraception allows couples to control their fertility and, in certain instances, is associated with important noncontraceptive benefits. Surgical sterilization offers safe, effective, and permanent contraception for women and men. Low-dose OCPs offer safe, effective contraception for most women able and willing to take pills consistently. In addition, their use confers a variety of important noncontraceptive benefits. The availability of long-acting progestin injectable and implantable methods has made highly effective and convenient birth control available for women who are not good pill takers as well as for those for whom contraceptive doses of estrogen are contraindicated. Barrier methods are readily available and provide protection against STDs; unfortunately, erratic use is all too often associated with inadequate contraceptive efficacy. IUDs offer convenient, highly effective contraception for appropriate candidates.

Evaluation of the impact of concurrent gonadotropin-releasing hormone (GnRH) antagonist administration on GnRH agonist-induced gonadotrope desensitization.

OBJECTIVE: To evaluate the impact of chronic GnRH antagonist therapy on the extent of GnRH agonist-induced gonadotrope desensitization. DESIGN: Prospective and controlled. SETTING: Primate Research Center. PARTICIPANTS: Six reproductive age cycling female baboons (Papio cyanocephalus anubis). INTERVENTIONS: The animals were divided into two groups. Group A received a total of 19 pulses of 0.83 microgram/kg leuprolide acetate (LA) on a 12-hour dosing schedule. Group B received Nal-Lys (3 mg/kg then 1 mg/kg every other day) for 1 week and then added an identical 19 pulses of LA while continuing Nal-Lys therapy. MAIN OUTCOME MEASURES: Characterization of the gonadotropin response was done by collecting serum samples at -15, 0, 15, 30, 60, 90, 120, 240, and 480 minutes relative to the injection of the LA. RESULTS: After equivalent baseline responses, the baboons pretreated with Na-Lys had an increased LH and FSH response to the administration of the LA. After a total of 19 pulses of the LA, the Nal-Lys-treated animals had an increased FSH response in comparison to the untreated controls. This indicates that the extent of gonadotrope desensitization was reduced in the presence of the GnRH antagonist. CONCLUSIONS: The presence of GnRH antagonist reduces the extent of gonadotrope desensitization in response to the administration of repetitive pulses of GnRH agonist.

Life table analysis of pregnancy rates in a general infertility population relative to ovarian reserve and patient age.

This study evaluated the impact of age and ovarian reserve status on cumulative pregnancy rates. Approximately 1200 women from a general infertile population underwent ovarian reserve screening with the clomiphene citrate challenge test in the first few months of their initial evaluation. All patients then underwent a thorough infertility evaluation with therapy appropriate for their specific diagnoses. Patients with evidence of tubal disease, peritoneal adhesive disease, or male factor were eliminated. The 588 remaining patients were evaluated based on their age and ovarian reserve status, and their long-term pregnancy rates were compared using life table analyses. There was a dramatic decrease in pregnancy rates associated with an abnormal clomiphene citrate challenge test which was uniformly poor independent of age. Patients with normal ovarian reserve had much higher pregnancy rates, but a significant age-related decline in pregnancy rates was clearly identified. We conclude that women with evidence of diminished ovarian reserve have uniformly poor pregnancy rates independent of their age, but that age remains an important prognostic factor among those with a normal ovarian reserve. The combined use of maternal age and ovarian reserve screening should be used when counselling individual patients regarding their long-term prognoses for conception.

Evaluation of the Tru-Trax cervical mucus penetration test in predicting fertilization and pregnancy rates in in-vitro fertilization.

To evaluate the role of the Tru-Trax cervical mucus penetration testing of prognosis of patient performance in in-vitro fertilization (IVF) and to examine its use as a possible screening test prior to IVF, 133 couples presenting with infertility prospectively underwent in-vitro cervical mucus penetration testing. Of these, 66 couples subsequently underwent IVF. The penetration distance of the vanguard spermatozoa in both human and bovine mucus was compared to the fertilization and pregnancy rates during IVF. The fertilization rates in couples with normal human mucus penetration (n = 42, 80.6%) were higher than those with abnormal scores (n = 24, 49.6%; P < 0.001). Similarly, the fertilization rates in those couples with normal bovine mucus penetration (n = 50, 77.5%) were higher than those with abnormal results (n = 16, 40.0%; P < 0.001). Fertilization rates and penetration scores were highly correlated for both human (r = 0.66; P < 0.0001) and bovine (r = 0.66; P < 0.0001) mucus. However, the predictive value of an abnormal result for failed fertilization was poor for both human and bovine penetration, since 83.33 and 81.25% fertilized respectively. Pregnancy rates did not differ among couples with normal and abnormal penetrations. In conclusion, in-vitro cervical mucus penetration testing was highly correlated with fertilization rates in IVF. However, the poor predictive value of an abnormal result may limit the value of this test for generalized pretreatment screening.

Use of the GnRH agonist stimulation test in the diagnosis of ovarian remnant syndrome. A report of three cases.

Ovarian remnant syndrome is an uncommon problem that may follow bilateral oophorectomy. These patients may present with chronic pelvic pain or pelvic masses and may require surgery to confirm or exclude the diagnosis. In this report we describe the successful use of the gonadotropin releasing hormone agonist (GnRH-a) stimulation test to identify the presence of functioning ovarian tissue in three women with ovarian remnant syndrome who presented for evaluation of persistent chronic pelvic pain. In these cases the endogenous gonadotropin flare was able to stimulate the production of significant quantities of estradiol to confirm the diagnosis. The GnRH-a stimulation test may be a useful adjunct in the evaluation of women at risk for ovarian remnant syndrome prior to proceeding with surgery.

Gonadotropin-releasing hormone antagonist administration enhances gonadotrope responsiveness at doses inadequate to suppress immunoassayable gonadotropin levels.

Chronic GnRH antagonist therapy produces enhanced gonadotrope responsiveness to supraphysiologic stimuli despite the lack of any measurable suppression of gonadotropin levels. This indicates that GnRH antagonists fundamentally alter gonadotrope response mechanisms without inhibiting gonadotropin release. Beyond the physiologic implications, these data may eventually impact the development of clinical protocols. Benefits could include enhancements in the endogenous gonadotropin flare during controlled ovarian hyperstimulation cycles. Additionally, proposed contraceptive protocols where GnRH antagonists are used to produce the initial inhibition in gonadotropin release and are then followed by a GnRH-a (to avoid the gonadotropin flare) may in fact produce paradoxical results.

Comparison of leuprolide acetate and human chorionic gonadotropin for the induction of ovulation in clomiphene citrate-stimulated cycles.

OBJECTIVE: To examine the relative efficacies of leuprolide acetate (LA) and hCG in inducing ovulation and a normal luteal phase during clomiphene citrate (CC)-stimulated superovulation cycles. DESIGN: Prospective, randomized, blinded, and cross-controlled in consecutive cycles. SETTING: Large military tertiary care center. PATIENTS: Twenty-one ovulatory patients undergoing superovulation with CC and IUIs for the treatment of unexplained or male factor infertility. INTERVENTIONS: Clomiphene citrate (100 mg/d) on cycle days 5 through 9 in both of the study cycles. Administration of 2 mg SC LA in one cycle and 10,000 IU IM hCG in another cycle for induction of the midcycle surge. MAIN OUTCOME MEASURES: Serum LH, FSH, E2, and P levels every 12 hours for 36 hours after administration of either LA or hCG to characterize the midcycle hormonal dynamics. Luteal phase duration and serum P levels during the midluteal phase were used to estimate the adequacy of the luteal phase. Serial ultrasounds also were done to determine the incidence of luteinized unruptured follicle syndrome. RESULTS: Serum FSH levels in the periovulatory interval were significantly higher after the administration of LA. There were no differences in the periovulatory E2 or P levels or the incidence of sonographic evidence of ovulation after administration of either LA or hCG. Although midluteal serum P levels were higher in the cycles in which hCG was administered, all 42 treatment cycles had adequate luteal phases as assessed by luteal phase duration and three midluteal P levels. Ongoing pregnancies occurred after both LA- and hCG-stimulated cycles. CONCLUSION: Leuprolide acetate and hCG were equivalent in their abilities to induce ovulation. Further evaluation of the adequacy of the luteal phase and the ensuing pregnancy rates after LA induction of an endogenous gonadotropin surge are indicated.

A prospective evaluation of clomiphene citrate challenge test screening of the general infertility population.

OBJECTIVE: To assess the results of screening an unselected general infertility population for diminished ovarian reserve with the clomiphene citrate challenge test. METHODS: Two hundred thirty-six couples were followed prospectively and studied for the relationship between clomiphene citrate challenge test screening and final diagnoses and long-term fertility rates. RESULTS: Abnormal clomiphene citrate challenge tests were found in two of 61 (3%) of the patients younger than 30 years, in five of 72 (7%) aged 30-34, in seven of 68 (10%) aged 35-39, and in nine of 35 (26%) aged 40 or older. An abnormal test predicted lower pregnancy rates; conception occurred in 92 of 213 (43%) of patients with normal results, but only two of 23 (9%) of patients with abnormal results (P < .004). Unexplained infertility (not considering the clomiphene citrate challenge test) was a common finding in patients with abnormal clomiphene citrate challenge test results (12 of 23). This incidence was significantly higher than that in patients with normal clomiphene citrate challenge test results (20 of 213) (P < .001). CONCLUSIONS: Approximately 10% of the patients in the general infertility population had abnormal clomiphene citrate challenge tests. The incidence of abnormal results increases with age beginning in the early 30s, occurs with a higher frequency in patients who would otherwise be diagnosed with unexplained infertility, and prognosticates decreased long-term pregnancy rates.

Evaluation of the significance of the estradiol response during the clomiphene citrate challenge test.

OBJECTIVE: To evaluate the relationship between the E2 response during the clomiphene citrate (CC) challenge test and ovarian responsiveness to exogenous gonadotropins. DESIGN: Performance of a CC challenge test followed by ovulation induction with exogenous gonadotropins as part of participation in an assisted reproduction program. SETTING: Assisted reproduction program in a large military tertiary care center. PATIENTS: Two hundred forty-seven women between the ages of 24 and 39 years with normal CC challenge tests within 1 year of their assisted reproduction cycle. INTERVENTIONS: Performance of CC challenge tests and ovulation induction with exogenous gonadotropins as a component of an assisted reproduction cycle. MAIN OUTCOME MEASURES: Correlation of the E2 response during the CC challenge test and peak E2, the duration of stimulation, number of ampules of exogenous gonadotropins, number of mature follicles, number of mature oocytes recovered, and fertilization and pregnancy rates in an assisted reproduction program. RESULTS: No correlation exists between the E2 response during the CC challenge test and any of the parameters evaluated. CONCLUSION: Monitoring of the E2 response during the CC challenge test did not predict ovarian responsiveness or pregnancy rates in patients participating in an assisted reproduction program and one may choose not to include it in routine testing.

The duration of leuprolide acetate administration prior to ovulation induction does not impact ovarian responsiveness to exogenous gonadotropins.

OBJECTIVE: To evaluate the possible impact that the duration of GnRH agonist (GnRH-a) suppression has on subsequent ovarian responsiveness to exogenous gonadotropins. DESIGN: Prospective evaluation of the relationship between the duration of GnRH-a and multiple parameters of ovarian responsiveness. SETTING: Assisted reproduction program in a large military tertiary care center. PATIENTS: One hundred sixty-five women being pretreated with leuprolide acetate (LA) before ovulation induction with exogenous gonadotropins. INTERVENTIONS: Variable duration of LA administration before stimulation. MAIN OUTCOME MEASURES: Outcome measures include duration of stimulation, days until doubling of basal E2, number of ampules of exogenous gonadotropins, peak E2, number of mature follicles, and number of mature oocytes. RESULTS: The duration of LA pretreatment had no effect on any of the parameters of ovarian responsiveness analyzed. CONCLUSION: Once complete suppression of gonadal function is attained, the duration of GnRH-a suppression has no impact on subsequent ovarian responsiveness to exogenous gonadotropins.

Establishment of an assisted reproduction program in the Armed Forces.

Approximately one in seven couples are infertile. Half of these couples fail to conceive following conventional therapies. Recently, technologies have evolved which provide hope to these couples and lead to cumulative pregnancy rates of 65%. An assisted reproduction (AR) program has recently been established at Wilford Hall Medical Center. The reproductive endocrinologists, on-service residents, and clinic support staff are responsible for all aspects of care including stimulation, retrieval, andrology, embryology, and transfer. To date, there have been 104 transfers with 28 pregnancies. In summary, AR is available in the Armed Forces and allows infertile couples to receive state-of-the-art health care.