Occult Male or Oocyte Factors Occult male factor despite normal semen analysis and oocyte factors, such as premature zona hardening, mitochondrial dysfunction, and/or aberrant spindle formation, has been suggested as a mechanism for unexplained infertility (293).
Treatment of Unexplained It is reasonable to discuss no intervention or expectant management with younger patients Infertility presenting with unexplained infertility. Some patients will want to proceed with diagnostic (and potentially therapeutic) laparoscopy. Typical interventions proceed stepwise with superovulation (first with clomiphene or letrozole for three to four cycles, then gonadotropins for three to four cycles) combined with intrauterine insemination, followed by ART (294). ART options for unexplained infertility include conventional IVF, split IVF/ICSI, and full ICSI, even though no male factor has been identified. Risks with clomiphene, letrozole, and non-ART gonadotropins, as well as gonadotropin preparations, have been discussed above.
Baseline Ovarian Cysts Prior to beginning therapy, a baseline ultrasound may be performed on cycle day 2 or 3 during menses (or following GnRH agonist suppression) to confirm an optimally thin (<4 mm) endometrium and quiescent ovaries. With clomiphene citrate cycles, the presence of ovarian cysts on a baseline scan was associated with decreased rates of ovulation but not of pregnancy, although cyst size was not predictive of response (295). Ovarian cysts on baseline evaluation have been associated with decreased pregnancy rates in ovulation induction cycles employing gonadotropins (296). In IVF patients, functional (estrogen-producing) cysts are seen in 9.3% of women following GnRH agonist suppression (297). Although nonfunctional ovarian cysts up to 5.3 cm did not affect IVF outcomes, functional ovarian cysts (mean diameter 2 cm and baseline estradiol 180 pg/mL) have been associated with increased gonadotropin requirements (dosing and duration), higher cancellation rates, fewer retrieved oocytes, poorer embryo quality, and lower pregnancy rates per cycle (9.6% vs. 29.7% in cyst-free cycles) (297,298). Ovarian cysts greater than 10 mm that are seen on the baseline scan tend to resolve spontaneously within 1 to 2 months, and oral contraceptive administration does not appear to hasten their resolution (299). However, oral contraceptive pretreatment prior to GnRH agonist cycles is associated with decreased risk of cyst formation (300). Functional cyst aspiration prior to gonadotropin stimulation, which is commonly performed to expedite initiation of treatment, did not improve IVF outcomes in one large study (297).