Infertility is defined as the inability to achieve pregnancy after one year of regular, unprotected intercourse. Evaluation may be initiated sooner in patients who have risk factors for infertility or if the female partner is older than 35 years. Causes of infertility include male factors, ovulatory dysfunction, uterine abnormalities, tubal obstruction, peritoneal factors, or cervical factors. A history and physical examination can help direct the evaluation. Men should undergo evaluation with a semen analysis. Abnormalities of sperm may be treated with gonadotropin therapy, intrauterine insemination, or in vitro fertilization. Ovulation should be documented by serum progesterone level measurement at cycle day 21. Evaluation of the uterus and fallopian tubes can be performed by hysterosalpingography in women with no risk of obstruction. For patients with a history of endometriosis, pelvic infections, or ectopic pregnancy, evaluation with hysteroscopy or laparoscopy is recommended. Women with anovulation may be treated in the primary care setting with clomiphene to induce ovulation. Treatment of tubal obstruction generally requires referral for subspecialty care. Unexplained infertility in women or men may be managed with another year of unprotected intercourse, or may proceed to assisted reproductive technologies, such as intrauterine insemination or in vitro fertilization.
Evaluation of Women
The etiology of female infertility can be broken down into
Cervical factors are also thought to play a minor role, although they are rarely the sole cause. Evaluation of cervical mucus is unreliable; therefore, investigation is not helpful with the management of infertility.
The initial history should cover menstrual history, timing and frequency of intercourse, previous use of contraception, previous pregnancies and outcomes, pelvic infections, medication use, occupational exposures, substance abuse, alcohol intake, tobacco use, and previous surgery on reproductive organs. A review of systems and physical examination of the endocrine and gynecologic systems should be performed. Other considerations include preconception screening and vaccination for preventable diseases such as rubella and varicella, sexually transmitted infections, and cervical cancer, based on appropriate guidelines and risk.
Women with regular menstrual cycles are likely to be ovulating and should be offered serum progesterone testing at day 21 to confirm ovulation. If a woman has irregular cycles, the testing should be conducted later in the cycle, starting seven days before presumed onset of menses, and repeated weekly until menses. A progesterone level of 5 ng per mL (15.9 nmol per L) or greater implies ovulation.6,23 Anovulatory women should have further investigation to determine treatable causes such as thyroid disorders or hyperprolactinemia based on symptoms.8 A high serum FSH level (greater than 30 to 40 mIU per mL [30 to 40 IU per L]) with a low estradiol level can distinguish ovarian failure from hypothalamic pituitary failure, which typically reveals a low or normal FSH level (less than 10 mIU per mL [10 IU per L]) and a low estradiol level. Basal body temperatures are no longer considered a reliable indicator of ovulation, and are not recommended for evaluating ovulation.
A high FSH level (10 to 20 mIU per mL [10 to 20 IU per L]) drawn on day 3 of the menstrual cycle is associated with infertility. A high serum estradiol level (greater than 60 to 80 pg per mL [220 to 294 pmol per L]) in conjunction with a normal FSH level has also been associated with lower pregnancy rates. This combination of laboratory test results may indicate ovarian insufficiency or diminished ovarian reserve.24 Other tests of ovarian reserve, such as the clomiphene (Clomid) challenge test, antral follicle count, and antimüllerian hormone level, are also generally performed to predict response to ovarian stimulation with exogenous gonadotropins and assisted reproductive technology. However, these tests have only poor to moderate predictive value despite widespread use.
Women with no clear risk of tubal obstruction should be offered hysterosalpingography to screen for tubal occlusion and structural uterine abnormalities.8,26,27 As opposed to laparoscopy or hysteroscopy, hysterosalpingography is a minimally invasive procedure with potentially therapeutic effects and should be considered before more invasive methods of assessing tubal patency.6 Women with risk factors for tubal obstruction, such as endometriosis, previous pelvic infections, or ectopic pregnancy, should instead be offered hysteroscopy or laparoscopy with dye to assess for other pelvic pathology.8 These studies are more sensitive and may delineate an abnormally formed uterus or structural problems, such as fibroids. This allows for the diagnosis and treatment of conditions such as endometriosis with one procedure. Treatment of tubal obstruction generally requires referral for subspecialty care.
Endometrial biopsy should be performed only in women with suspected pathology (chronic endometritis or neoplasia). Histologic endometrial dating is not considered reliable nor is it predictive of fertility.6,28 Additionally, postcoital testing of cervical mucus is no longer recommended because it does not affect clinical management or predict the inability to conceive.
Treatment of Unexplained Infertility
Couples who have no identified cause of infertility should be counseled on timing of intercourse for the most fertile period (i.e., the six days preceding ovulation).Therefore, a simple recommendation is for vaginal intercourse every two to three days to optimize the chance of pregnancy.
Patients should be counseled that 50% of couples who have not conceived in the first year of trying will conceive in the second year.8 Couples with unexplained infertility may want to consider another year of intercourse before moving to more costly and invasive therapies, such as assisted reproductive technology.8 Intrauterine insemination and ovulation induction do not result in increased pregnancy rates in women with unexplained infertility.