Here are the steps to take before recommending IVF to your patients having trouble conceiving.
Dr. Jensen is Assistant Professor, Reproductive Endocrinology and Infertility, Mayo Clinic, Rochester, Minnesota.
She has no conflicts of interest to report with respect to the content of this article.
During 1 year of unprotected intercourse, approximately 85% of reproductive-aged couples will conceive. Thus 15%-nearly one out of 6 couples-experience infertility.1 Data from the 2006–2010 National Survey of Family Growth revealed that among women aged 25–44, 17% (6.9 million) had used infertility services, and the estimated US market for fertility services was $3.5 billion in 2012.2,3 Infertility was historically defined as 1 year of attempting to conceive without success. In 2008, however, the American Society for Reproductive Medicine (ASRM) issued a statement that earlier evaluation and treatment may be justified based on medical history and physical findings for select patients and is warranted after 6 months for women older than age 35.4
Normal human fecundability-the probability that a single cycle will result in pregnancy-is approximately 20%–25%, partly due to the relative inefficiency of human reproduction. Still, during the course of 1 year, most couples will achieve a pregnancy. A prospective study following 200 couples trying to conceive showed that 82% were successful over 12 months.5 Cycle fecundability remained relatively high for the first 4 to 5 cycles and decreased thereafter. Most successful conceptions occurred within the first 6 months. By the twelfth cycle, fecundability dropped to about 3%.
The etiologies of infertility are complex but are roughly divided as follows:6
· Male problems: 35%
· Tubal and pelvic pathology: 35%
· Ovulatory dysfunction: 15%
· Unexplained: 10%
· Unusual problems (eg, sexual dysfunction): 5%
This composition may vary by clinical demographics. For example, populations with low rates of sexually transmitted infections may have fewer cases of tubal infertility, whereas areas with a high prevalence of obesity may observe an increased percentage of ovulatory dysfunction. In addition, with many women choosing to delay childbearing for career or other reasons, the age-related decline in fertility due to ovarian aging also contributes to the list of reasons for seeking fertility services.
Evaluation of the infertile couple should begin with both partners at the same time. Consultation should include a complete medical and reproductive history for the female partner, relevant male partner history, a targeted physical examination for the woman and general preconception counseling, such as recommending adequate folic acid intake, documenting immunity to rubella, performing targeted genetic screening based on ethnicity and family history, and screening for infectious diseases (Tables 1 and 2).
The initial visit is also a good time to instruct couples on optimization of coital timing to achieve pregnancy.7 Although the window of fertilization for an oocyte is less than 24 hours, sperm can survive in the female reproductive tract for several days. Thus a fertile window exists from a few days prior to ovulation to the day of ovulation. The highest probability of pregnancy appears to be when intercourse occurs 1 to 2 days before ovulation.8 Delaying intercourse until the day of ovulation decreases fecundability to less than 10% and waiting until 1 day after ovulation reduces it to approximately 3%.9 There is no difference in fecundability between daily and every-other-day intercourse during the days leading up to ovulation.10 One simple recommendation is to advise couples to have intercourse every other day from cycle days 10 to 20. For women with normal menstrual cycles, this should ensure adequate overlap of viable sperm and egg.
Once infertility is diagnosed or suspected, there are 3 critical areas of evaluation to determine the etiology:
Step 1: Assess ovulatory status and ovarian function
Ovulatory status can be assessed in several ways. Menstrual history alone may suffice. Women who have reliable menstrual periods more than 21 days and less than 35 days apart are likely ovulating on a regular basis. Other tests to determine ovulation include measuring mid-luteal phase progesterone, because a value greater than 3 ng/mL is consistent with ovulation. Ovulation predictor kits detect the urinary spike of luteinizing hormone (LH), which appears approximately 36 hours before ovulation. These kits are also helpful for couples to time intercourse relative to ovulation.
A reliable but costly way to track ovulation is to perform serial ultrasounds, monitoring the development and ultimate rupture of a dominant ovarian follicle. Several methods to monitor temperature and/or cervical mucus changes have been described. Basal body temperature increases by approximately half a degree F after ovulation; thus temperature charting provides retrospective evidence of ovulation. Endometrial biopsies were previously used to date the endometrium but provide little clinical utility because fertile and infertile women have similar rates of dating inconsistency on biopsy.11,12
The World Health Organization (WHO) classifies women with ovulatory disorders into 3 groups (Table 3). Further evaluation can determine into which category an oligo- or anovulatory woman may fit. Suggested tests include:
Ovarian reserve testing will be the next step for many women. Because every woman is born with a finite oocyte supply, one critical early step is to determine whether the quantity and quality of her oocytes are normal relative to other women her age. Various methods are used to test ovarian reserve, and most fertility specialists assess multiple parameters. FSH and estradiol are often measured during their nadir in the early follicular phase, usually cycle days 2 or 3. Although variation exists among laboratories, in general a cycle day 3 FSH of 10 IU/L or less is considered optimal, with a concordant estradiol of 50 pg/mL or less.
Two variants of FSH/estradiol patterns deserve special attention. The first is the patient with significantly elevated FSH and low estradiol in the early follicular phase. In this scenario, the pituitary is excessively attempting to signal the ovaries to develop oocytes, but the ovaries are unable to respond, resulting in low circulating estradiol and inability to negatively feed back to the hypothalamus and pituitary. This pattern indicates hypergonadotropic hypogonadism and diminished ovarian reserve. The second variant is the patient with low or normal FSH but high estradiol (> 75 pg/mL) early in the menstrual cycle. This suggests that the available pool of oocytes is small and one follicle is able to gain dominance early in the menstrual cycle. This pattern also suggests diminished ovarian reserve.
The clomiphene citrate challenge test (CCCT) is a dynamic assessment of ovarian function. The steps to complete the test are:
The CCCT is abnormal if either cycle day 3/10 FSH or cycle day 3 estradiol is elevated (FSH > 10 IU/L on either occasion or estradiol > 75 pg/mL).
Another useful screen is serum testing of AMH,which is produced by granulosa cells within the follicles. High AMH levels (≥ 1 ng/mL) are correlated with good ovarian reserve. Reference tables defining normal AMH levels in healthy women are available.13 One potential advantage to AMH is that it may be less susceptible than FSH to fluctuation across the menstrual cycle, allowing a determination to be made regardless of cycle day.
A final marker of ovarian reserve is the antral follicle count (AFC), which represents the number of oocytes able to develop in a given cycle. Both ovaries are examined via ultrasound in the early follicular phase and the number of small follicles (2–9 mm) is counted. A normal AFC is 10 or higher (both ovaries combined). Some women, particularly those with PCOS, may have an AFC that is 50 or higher, whereas women with severely diminished ovarian reserve may have no observable antral follicles.
Determining which patients should undergo ovarian reserve testing can be difficult. ASRM recommends ordering ovarian reserve tests for all women aged 35 and older and in selected younger women with a history suggestive of hypergonadotropic hypogonadism.
Step 2: Evaluate tubal patency
Evaluation of tubal patency is often done with a hysterosalpingogram (HSG). This test is usually performed after the end of menses but prior to ovulation (typically cycle days 7 to 12). There may be a slight increase in fecundability during the cycle in which the HSG is performed. Patients may safely attempt to conceive that month. For women with a high a priori risk of tubal disease (eg, those with prior pelvic inflammatory disease or suspected hydrosalpinx), a short course of oral antibiotics (doxycycline 100 mg BID beginning 1 day prior to the HSG and continuing for a total of 3 days) may be given.
Step 3: Analyze semen
Semen analysis is an important early component of the fertility evaluation. Patients should abstain from intercourse 2 to 7 days before sample collection. The sample should be collected via masturbation and examined within 1 hour. Normal semen parameters are listed in Table 4.14
An abnormal semen analysis should be repeated to determine if the findings are spurious. Men with significant abnormalities in the semen analysis should be referred to a urologist and may ultimately require in vitro fertilization (IVF). Subtle abnormalities in sperm quality or quantity can potentially be overcome by concentrating the sperm and performing intrauterine insemination (IUI).
Once evaluation is complete, a plan for treatment of infertility can be made. Specific disorders such as hyperprolactinemia should be appropriately addressed. One principle to keep in mind is that most couples who conceive with fertility treatment do so within the first 3 treatment cycles.15 Patients who are unsuccessful after that length of intervention should consider more aggressive therapies and be referred to a reproductive endocrinologist.
Basic infertility treatment involves one or more of the following:
For anovulatory women, it is reasonable to give a trial of ovulation induction for 3 to 6 cycles. Clomiphene citrate, a nonsteroidal compound with mixed estrogen agonist and antagonist properties, is the most common first-line agent.16 Clomiphene was synthesized in the mid-1950s and approved for clinical use in the United States in 1967. In early clinical trials, approximately 80% of anovulatory women treated with clomiphene achieved ovulation. Half of the women who ovulated also conceived.17 Intact communication within the hypothalamic-pituitary-ovarian axis is required for successful response to clomiphene; thus women with hypogonadotropic hypogonadism will not likely respond.
Clomiphene is given orally for 5 days, beginning on the third to fifth day of the menstrual cycle. The initial dose is 50 mg daily but can be titrated to 150–200 mg if ovulation does not occur.18 Three-quarters of women respond to clomiphene at either 50 mg (52%) or 100 mg (22%) daily.15 Monitoring for ovulation can be done with any of the methods previously described. One approach is to recommend using ovulation predictor kits starting on cycle day 10 and instructing couples to have intercourse when the kit becomes positive. For women who fail to detect an LH surge, a mid-luteal-phase progesterone can be measured. A level higher than 3 ng/mL confirms ovulation. If the progesterone is less than 3 ng/mL, clomiphene can be increased by 50 mg daily in the subsequent cycle. Anovulatory women may need a short course of oral progesterone (medroxyprogesterone acetate 10 mg daily for 5 to 10 days) to induce a withdrawal bleed although that is not required and has been associated with a lower conception rate.19
Side effects of clomiphene include hot flashes (10%), mood changes, breast tenderness, mild pelvic pressure or pain, and nausea.20 Rarely patients may experience reversible visual side effects while taking clomiphene, and this should be considered a contraindication to further clomiphene use. The risk of multiple gestation is approximately 5%.21 Pregnancy rates per cycle are 5%–8% when timed intercourse is used.22 Ovulation induction with clomiphene or any other agent, however, is more effective when combined with IUI, as this places a concentrated volume of sperm closer to the oocytes.23 Combined treatment with clomiphene and IUI achieves a cycle fecundability rate of 10%–12%.22
Recent evidence suggests that for women with PCOS, letrozole, an aromatase inhibitor, may be preferable to clomiphene as a first-line agent.24 In this study 750 women with PCOS were randomized to receive either letrozole or clomiphene for up to 5 cycles. Women who received letrozole were more likely to ovulate (61.7% vs 48.3%, P <.0001) and also had higher live birth rates (27.5% vs 19.5%, P =.007). There were no differences in the rates of multiple gestations, pregnancy loss, or congenital anomalies in offspring. Like clomiphene, letrozole is given orally for 5 days beginning on cycle day 3. Doses can be titrated from 2.5 mg to 7.5 mg daily. Monitoring for ovulation proceeds per clomiphene treatment. Ovulation induction is an off-label use of letrozole.
Women with hypogonadotropic hypogonadism require injectable gonadotropins for follicular development. Gonadotropin preparations can be purified from urinary extracts from postmenopausal women or may be recombinant formulations. Urinary extracts contain bioequivalent amounts of FSH and LH per ampule. Doses for ovulation induction range from 75 to 225 IU daily beginning on cycle day 3. In addition to hypogonadotropic hypogonadism, other indications for gonadotropin treatment include clomiphene- or letrozole-resistant anovulation, unexplained infertility in which clomiphene or letrozole have failed to result in pregnancy, and moderately diminished ovarian reserve.
Gonadotropin therapy must be carefully monitored to avoid ovarian hyperstimulation and minimize the risk of multiple gestation. Serum estradiol measurements and ultrasounds are used to assess follicular development. When follicles measuring 18 mm or greater are visualized on ultrasound, it is likely that the eggs contained within are mature. Human chorionic gonadotropin (hCG) is given to initiate release of the developing oocytes, and timed intercourse or IUI is performed approximately 36 hours later.
Approximately 15% of pregnancies following gonadotropin treatment are multiple gestations.25 Prudent use of the lowest possible dose to achieve follicular development and avoidance of hCG trigger when a large cohort of follicles (5 or more) has developed can minimize risk. Given their more direct effect on the ovaries, gonadotropins result in a higher pregnancy rate than does clomiphene. Cycle fecundity rates with gonadotropins and IUI are 15%–20%.22
As noted above, all treatments that incorporate IUI are more successful than ovulation induction with timed intercourse.26 Although couples with normal sperm parameters may opt for timed intercourse (often for financial reasons), IUI should be considered a first-line treatment for any couple with an abnormal semen analysis. Evidence also suggests that couples with unexplained infertility may benefit from ovulation induction with IUI.22,26
Currently, IVF is the most aggressive and successful method to treat infertility. IVF is a complex process that involves controlled ovarian hyperstimulation with gonadotropins, retrieval of oocytes under anesthesia, fertilization of the oocytes in a laboratory, and subsequent placement of embryos into the uterus. For women younger than 35, pregnancy rates are nearly 50% per fresh embryo transfer.27 While IVF is not typically the first-line treatment for infertility, it may be considered earlier in certain circumstances, such as for couples with a predetermined amount of insurance coverage for fertility services who do not wish to exhaust funds on less aggressive-and consequently less successful-strategies.
Infertility is a common disorder affecting approximately 1/6 of all couples. Evaluating both partners should begin immediately and the initial evaluation should assess ovulatory status and ovarian reserve, fallopian tube patency, and semen analysis. Complex problems such as severe abnormalities in the semen analysis or bilaterally blocked fallopian tubes likely require immediate referral to a reproductive endocrinologist, but outside of this, it is reasonable to begin less-aggressive treatments for a limited number of cycles for most patients. Seeing couples for a fertility evaluation is also an excellent opportunity to provide preconception counseling and optimize health prior to pregnancy (Table 5).
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Davis OK, Berkeley AS, Naus GJ, Cholst IN, Freedman KS. The incidence of luteal phase defect in normal, fertile women, determined by serial endometrial biopsies. Fertil Steril. 1989;51(4):582–586.
Coutifaris C, Myers ER, Guzick DS, et al. Histological dating of timed endometrial biopsy tissue is not related to fertility status. Fertil Steril. 2004;82(5):1264–1272.
Shebl O, Ebner T, Sir A, et al. Age-related distribution of basal serum AMH level in women of reproductive age and a presumably healthy cohort. Fertil Steril. 2011;95(2):832–834.
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Diamond MP, Kruger M, Santoro N, et al. Endometrial shedding effect on conception and live birth in women with polycystic ovary syndrome. Obstet Gynecol. 2012;119(5):902–908.
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Deaton JL, Gibson M, Blackmer KM, Nakajima ST, Badger GJ, Brumsted JR. A randomized, controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis. Fertil Steril. 1990;54(6):1083–1088.
NIH/NICHD Reproductive Medicine Network. Effect of letrozole versus clomiphene on live birth in women with anovulatory infertility due to polycystic ovary syndrome (PCOS): a randomized double-blind multi-center trial. Fertil Steril. 2013;100(3):S51.
Kaplan PF, Patel M, Austin DJ, Freund R. Assessing the risk of multiple gestation in gonadotropin intrauterine insemination cycles. Am J Obstet Gynecol. 2002;186(6):1244–1247.
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