Amanda Kallen, MD

This is the second part of a 2-part Infertility series. Read Part 1: 

Infertility treatment begins with shared decision-making with the couple. Besides the usual risks, benefits, and alternatives, the couple’s desire for a biologic child, their resources, and their insurance coverage will govern subsequent therapy. 

Accurate diagnosis from a basic infertility evaluation often results in an easy therapeutic recommendation. 

Based on their diagnosis, a couple may be offered a variety of treatments: often simple, sometimes very complex. Genetic testing of couples or their embryos will also provide additional opportunities in family building. Donor gametes, donor embryos, and adoption are often the most cost-effective route to having a child.

 is a synthetic estrogen receptor modulator. By blocking the estrogen receptor at the level of the hypothalamus and pituitary, the negative feedback of estrogen is eschewed and gonadotropin-releasing hormone (GNRH) pulses increase follicle-stimulating hormone (FSH) and luteinizing hormone (LH) production.

These elevated gonadotropins stimulate early follicle development, increase estradiol production, and mature the oocyte. Clomiphene is most often administered as a daily oral dose for 5 days in the early follicular phase (eg, beginning between day 3 and day 5 of the menstrual cycle), beginning at 50 mg/day. 

Clomiphene citrate causes FSH and LH to rise; after discontinuation, gonadotropins fall and allow the normal estrogen feedback of a developing follicle to return. Thus, when the oocyte is mature, an LH surge is triggered by the ovary, or an exogenous human chorionic gonadotropin hormone (HcG) trigger can be administered, and ovulation ensues. 

Adverse effects (AEs) of clomiphene citrate include hot flashes, thickened cervical mucus, vaginal dryness, scotomata, pelvic “heaviness,” and headaches.

Hyperstimulation of the ovaries is rare. Because clomiphene citrate may cause thickened cervical mucus, it is often used in combination with intrauterine insemination, especially in treatment of unexplained infertility.

 act in a similar fashion to clomiphene citrate, although by a different mechanism. 

These medications block aromatase, the enzyme which converts androgens to estrogens; estrogen is decreased to menopausal levels. The low concentration of estrogen results in increased GNRH pulses and stimulates gonadotropin release from the pituitary. 

Aromatase inhibitors are given orally, starting at 2.5 mg per day from day 3 to 8 of the cycle. AEs include hot flashes, vaginal dryness, nausea, muscle aches, and headaches. Data from meta-analyses, registry studies, and retrospective cohort studies do not appear to suggest increased risk of birth defects with either clomiphene citrate or letrozole.

Patients treated with clomiphene citrate or aromatase inhibitors may use an ovulation predictor kit to measure the LH surge and time their intercourse accordingly. Ovulation occurs an average of 7 days after discontinuation of clomiphene citrate and approximately 34 to 40 hours after detection of the LH surge. 

Thus, patients may start testing their urine with an ovulation predictor kit on day 11 of their cycle and have intercourse on the day of the surge and the day after. Both clomiphene citrate and aromatase inhibitors have a multiple pregnancy rate of less than 10%, the majority of which are twin pregnancies,11 compared with 3% of the general population.

 (LH and FSH) directly stimulate the ovarian follicles and have been used in the treatment of anovulation related to eugonadotropic hypogonadism (eg, polycystic ovary syndrome), when clomiphene citrate or aromatase inhibitors fail, as well as for women with hypogonadotropic hypogonadism who will typically not respond to clomiphene or letrozole. 

Estrogen concentrations are stimulated to much higher than physiologic concentrations and thus inhibit the natural ovulatory LH surge; thus, the LH surge must be exogenously administered and is done so by treating with HcG, which has LH activity. 

Gonadotropin administration should be performed only under the supervision of a reproductive endocrinologist. Administration must be monitored by frequent estradiol measurement and ultrasonography of the ovaries.

 Multiple pregnancy rates can be in excess of 25% per cycle with 3% to 5% higher-order multiple pregnancy rates. 

Another serious consequence of gonadotropin treatment is ovarian hyperstimulation syndrome (OHSS), resulting in ascites, pleural effusion, hyponatremia, pulmonary edema,13,14 and vascular depletion, with the resultant hemoconcentration leading to decreased renal perfusion and pulmonary embolism. 

In light of the high multiple pregnancy rate as well as the need for stringent monitoring and cycle cancellation,

 gonadotropin therapy for anovulation related to eugonadotropic hypogonadism is generally discouraged.

It is important to note that once a patient is ovulating, she has the same chance of conceiving that fertile patients of similar age have, 

Therefore, after 4 to 6 ovulatory cycles without pregnancy in an anovulatory patient, the patient should be evaluated for other causes of infertility, if a workup has not already been completed.

Intrauterine insemination (IUI) is used in the treatment of mild male factor infertility, cervical factor infertility, and, along with ovarian stimulation, in the treatment of unexplained infertility. This requires serial dilution of the ejaculate,

 centrifugation, and reconstitution with media. 

The washed, concentrated sperm is placed into the uterus with a catheter 24 to 36 hours after an endogenous LH surge or the exogenous ovulation trigger. The sperm will be waiting in the Fallopian tube to fertilize the oocyte after ovulation. 

For unexplained infertility in the absence of male factor, IUI alone does not increase pregnancy rates over expectant management; therefore, IUI should be utilized in combination with OS in these instances.

If severe male factor infertility exists (eg, less than 4 million total sperm, or the strict morphology reveals less than 4% normal forms), the pregnancy rate with in vitro fertilization (IVF) is higher than with IUI.

 may be used to treat unexplained infertility, male factor infertility, or hypogonadotropic hypogonadism

and may be performed with clomiphene citrate, aromatase inhibitors, or gonadotropins. The premise of OS is to allow for 2 or 3 oocytes to be ovulated and increase the statistical change of conception that might occur in any 1 cycle. 

Pregnancy rates with OS depend on the diagnosis, choice of therapy, sperm viability, and ovarian response. OS in combination with IUI is largely used in the treatment of unexplained infertility or male factor infertility; particularly for unexplained infertility, neither clomiphene nor letrozole is more effective than expectant management when combined with timed intercourse alone.

Pregnancy rates with OS-IUI depend on the diagnosis, sperm viability, and ovarian response. 

With respect to OS with gonadotropins, the Fast Track and Standard Treatment Trial randomized women aged less than 40 years with unexplained infertility to treatment with clomiphene-IUI followed, if unsuccessful, by (1) gonadotropins-IUI or (2) IVF; results showed that the time to pregnancy was significantly shorter in the clomiphene to IVF group.

Therefore, in most cases, it is generally recommended that unsuccessful trials of OS with oral medications be followed by IVF rather than gonadotropins. Additionally, multiple pregnancies, as well as OHSS, represent serious consequences of OS with gonadotropins, and their use to treat unexplained infertility is not recommended.

Infertile women may be at an increased risk of invasive ovarian, endometrial, and breast cancer, but fertility drugs do not appear to increase this risk significantly.

Small cohort studies suggest that infertility medications may increase the risk of borderline ovarian cancer slightly in infertile women treated with infertility drugs, but the absolute risk is small. However, it appears that this risk does not occur unless clomiphene is given for an extended time, and it has not been shown with aromatase inhibitors.

In vitro fertilization (IVF) initially used for the treatment of tubal factor infertility in 1978, has been extended to treat a variety of causes of infertility; IVF is also used by noninfertile individuals pursuing fertility preservation. 

Indeed, IVF allows women without oocytes or a uterus and men without sperm in the ejaculate to have a biological child. IVF is indicated in cases of severe oligospermia or azoospermia, untreated tubal factor, or infertility in women 40 years and older, and it may also be utilized in women with endometriosis, anovulation, or unexplained infertility when ovulation induction and IUI have been unsuccessful. IVF is also utilized when genetic screening of embryos is planned.

IVF protocols vary depending on the indication, patient age, treatment history, and other considerations. 

A typical IVF cycle involves, first, ovulation induction to stimulate multiple ovarian follicles, followed by oocyte aspiration using a transvaginal ultrasound-guided needle. Collected oocytes are fertilized in vitroby mixing them with spermatozoa (IVF) or by injecting selected spermatozoa directly into the oocyte cytoplasm (intracytoplasmic sperm injection). 

Embryos are cultured under carefully controlled conditions, optimizing oxygen concentration, embryo culture media, and other modifications to promote the development of high-quality embryos. 

The embryos are then transferred into the uterus through a catheter under ultrasound guidance. In the case of severe male factor infertility, sperm retrieval from the epididymis or testis may also be performed. Embryos not transferred may be cryopreserved to transfer in a later cycle (frozen embryo transfer).

Preimplantation genetic testing (PGT) is a procedure in which cultured embryos can be biopsied and tested in order to select the most appropriate embryos for transfer. 

Prior to transfer, PGT can be used to screen for euploid embryos for transfer (PGT-aneuploid [PGT-A]); however, specific groups of infertility patients most likely to benefit from PGT-A have not been clearly defined. PGT may also be utilized to identify embryos with a single gene disorder (PGT-monogenic or preimplantation genetic diagnosis); this would be used, for example, if both partners are carriers for the same autosomal recessive condition, such as cystic fibrosis.

Donor gametes may be considered when either partner has severe defects in gamete quality or quantity. For males, such situations may include severe oligospermia, azoospermia, failure of fertilization in prior IVF cycles, ejaculatory dysfunction, or other severe male factor infertility (ie, after gonadotoxic chemotherapy). 

Donor oocytes or embryos may be used when a woman’s oocyte reserve is low (ie, advanced reproductive age or diminished ovarian reserve) or oocyte quality is poor, when multiple attempts at IVF with her own oocytes have failed, or when a condition such as premature ovarian insufficiency makes the likelihood of conceiving with her own gametes extremely low. 

Donor gametes may also be utilized when either partner has a significant genetic defect, or if there is a family history of a genetic condition for which carrier status cannot be determined. 

Females without male partners, same-sex couples, or males without female partners may also utilize donor gametes, either anonymously from donor gamete banks or known donors.

(GC) is defined as a woman who carries a pregnancy and is not sexually intimate with the genetic parents or gamete donors.

A GC may be used when a medical condition prevents a woman from carrying a pregnancy or when she has a congenital or surgical absence of a uterus. A GC may also be indicated if a pregnancy would pose significant risk to a woman’s health or life, or if there is a biological inability to carry a pregnancy, as with single males or gay male couples. 

is an emerging option for individuals without a uterus; it is currently available only in the setting of clinical research trials.

Although legal adoption has allowed couples to build a family for more than a century, modern technology now allows for effective therapy for infertility in many cases, guided by accurate diagnosis and shared decision-making. 

The basic evaluation of an infertile couple has been supplemented with an evaluation of related health issues, as our knowledge has advanced to include surveillance beyond the reproductive system (Table). 

The primary care practitioner is vital in not only initiating the evaluation, surveying for related health problems, and referring to specialty care, but also longitudinally, following patients for possible disease processes harbingered by infertility. 

an assistant professor of Obstetrics, Gynecology, and Reproductive Sciences in the Division of Reproductive Endocrinology and Infertility within the Department of Obstetrics, Gynecology, and Reproductive Sciences at Yale School of Medicine, Yale University.

is a professor of Obstetrics, Gynecology, and Reproductive Sciences in the Division Chief, Division of Reproductive Endocrinology and Infertility within the Department of Obstetrics, Gynecology, and Reproductive Sciences at Yale School of Medicine, Yale University.

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Articles

Effective treatment will depend on the diagnosis, but can range from simple to very complex.

Treatment of the infertile couple

Many couples choose to be childless; no one chooses to be infertile. In a classic 1956 study by Alan Guttmacher examining conception rates among 5,574 women attempting pregnancy, 85% conceived within 12 months.

However, it has also become increasingly clear that time to conception is strongly influenced by age-related factors, including declining oocyte quantity and quality over time. Indeed, Guttmacher also reported a doubling of median conception time from age 24 to 44.

Thus, while infertility is more the lack of a “normal” physiological outcome than a disease per se, a thorough workup for infertility is essential to identify underlying disease. In addition, lifestyle issues and environmental factors can adversely affect infertility. 

Importantly, infertility may be a marker of non-reproductive disease and often portends serious health issues. 

how each of these factors affect normal physiology, their diagnosis, and the treatment designed to achieve the delivery of a healthy term baby.

The breathtaking physiology of reproduction may go astray in any facet and result in infertility. Evaluation for that aberration, followed by diagnosis-specific treatment, is perhaps the most cost-effective way to help a couple conceive. This is an opportune time to add antenatal screening to the basic diagnostic evaluation of the infertile couple (

Tubal disease is a common cause of infertility, with reported rates between 25-35% of infertility diagnoses

 depending on the population being tested. Tubal obstruction is suspected in women with a history of sexually transmitted infection, cervical dysplasia, abdominal surgery or previous intra-abdominal infection (e.g., ruptured appendix). 

While laparoscopy with chromotubation is often considered the “gold standard” for evaluation of tubal disease, hysterosalpingography (HSG), with a sensitivity and specificity of 65% and 83%, respectively

 is considered the first-line diagnostic tool. 

Radiopaque dye is injected into the uterus and followed through the Fallopian tubes under fluoroscopy. A similar procedure utilizing ultrasound instead of fluoroscopy, sonohysterography (SHG), is less reliable in determining tubal patency although more accurate for uterine evaluation6 with a sensitivity and specificity of 76% and 67%.

Treatment options for tubal infertility include tubal cannulation (for proximal tubal obstruction)

, surgery for tubal reanastomosis, or in vitro fertilization (IVF), which bypasses tubal blockage, with IVF being frequently employed due to success rates and comparable costs with surgery.

Endometriosis is a complex condition characterized by the presence of endometrial tissue in sites outside the uterine cavity. Endometriosis frequently presents with pain and affects 25-40% of women with infertility.

 Posited mechanisms for the relationship between endometriosis and infertility include distortion of pelvic anatomy, tubal obstruction, impaired oocyte quality, release and pickup, and altered endometrial receptivity, although a definite cause-effect relationship between any of these pathologies and endometriosis-related infertility is controversial. 

While excisional surgery has been shown to improve spontaneous pregnancy rates in women with endometriosis

, surgery is not recommended for the routine evaluation of infertility in women without other symptoms of endometriosis.

Endometrial polyps, intracavity leiomyomas, intrauterine synechiae and Mullerian anomalies with associated distortion of the endometrial cavity may be associated with infertility. 

Superior to the HSG in detecting uterine anomalies, sonohysterography detects intrauterine polyps or leiomyomas with a sensitivity and specificity of 91% and 84%, respectively.

 Direct visualization via hysteroscopy may be used to confirm the diagnosis (Figure 1). Treatment to remove the distorting mass is surgical.

The cervix is the entry to the upper reproductive tract. Its alkaline mucus protects sperm from the acidity of the vagina and guides sperm into the upper reproductive tract. 

Structural alterations of the cervix, either congenital or post-surgical (for example, after loop electrosurgical excision procedure (LEEP) or large cervical cone biopsy) can cause cervical stenosis and prevent sperm entry.

Post-operative stenosis is diagnosed by the failure to pass a 1 mm probe into the uterine cavity. The post-coital test, performed after intercourse to assess the viability of sperm in mucus, has been used to evaluate cervical function; however, the limited predictive value of this test has relegated it to history (Table 2). 

In the absence of mucus and in the presence of cervical stenosis, intrauterine insemination is a successful therapy, assuming all other factors are normal.

Failure to ovulate results from a variety of non-reproductive influences including thyroid disease, pituitary disease, elevated androgens from adrenal hyperplasia, obesity, and stress. Anovulation is diagnosed by a mid-luteal serum progesterone concentration <3 ng/ml, although mid-luteal serum progesterone levels are usually higher than 7 ng/mL,

 and should be suspected when cycles are irregular and occur more often than every 21 days and less often than every 36 days. 

The most common cause of anovulation is a metabolic disease, polycystic ovarian syndrome (PCOS) in which multiple follicles exist in various stages of development and are simultaneously a result of and caused by an altered hormonal milieu including insulin resistance, elevated LH, and elevated androgens.

Women who do not ovulate do not produce progesterone and thus are at risk for the consequences of unopposed estrogen:endometrial hyperplasia and cancer. 

Similarly, women with PCOS may experience non-reproductive disorders, particularly, acne, hirsutism and hyperinsulinemia. The metabolic consequences of PCOS increase a woman’s risk of diabetes mellitus, hyperlipidemia, gestational hypertension and gestational diabetes. 

Correcting thyroid deficiency, lowering elevated prolactin, blocking elevated adrenal androgen production often stimulates ovulation. Weight loss of 15% of body weight often prompts ovulation to resume.

Infertility associated with anovulation is best treated with ovulation induction unless other factors such as diminished ovarian reserve and male factors are present.

OVARIAN AGING (DIMINISHED OVARIAN RESERVE)

Female fecundity (the ability to conceive and carry a pregnancy to term) declines with increasing age, decreasing more rapidly after age 35,

 reflecting, in part, the progressive loss of oocytes (the “ovarian reserve”) that occurs with age. Aging oocytes also accumulate meiotic defects and DNA damage, causing deterioration of gamete quality and increasing the risk of aneuploid embryos and miscarriage.

Therefore, women over 35 who have failed to conceive for six months should be offered expedited evaluation and treatment; for women over 40, immediate evaluation is warranted.

Ovarian reserve refers to the number of oocytes available for stimulation and ovulation. It can be evaluated using serum FSH and estradiol concentrations on days 3-5 of a menstrual cycle, serum anti-Müllerian hormone (AMH), and/or ultrasound imaging of the ovaries for antral follicle count and ovarian volume determination (Table 3).

Notably, these tests may be predictive of response to exogenous ovarian stimulation and are not predictive of live birth or even natural fertility. Accelerated oocyte loss can result in loss of fertility and early menopause (prior to age 40). 

While the majority of these cases are idiopathic,

 ovarian reserve should be monitored in women with a history of prior ovarian surgery, chemotherapy, radiation therapy, or with a family history of premature menopause. These women may be at risk for carrying the fragile X (FMR1) pre-mutation and also the consequences of estrogen deprivation.

Disorders of male physiology occur in 35% of infertile couples and are the sole factor in 17% of couples.

Similar to the female, in the male, FSH and LH stimulate the testes to produce testosterone and develop the immature gametes. Unlike the oocytes, sperm mature for three months in the male reproductive tract before being ejaculated.

 of the male may arise from all areas of male reproductive physiology. When testosterone is low but not absent, erectile dysfunction and decreased libido commonly accompany alter semen parameters

 also results in azoospermia. In addition, the concomitant lack of testosterone results in decreased libido and erectile dysfunction. As testosterone concentrations drop in the male, risk for heart disease, hyperlipidemia, osteopenia, and muscular mass loss increases. 

Testosterone failure is diagnosed by a low serum testosterone and elevated LH and FSH. Of course, correcting any hormonal abnormality and screening for related disorders should precede treatment.

Diagnosis of male factor infertility begins with a well collected, comprehensive semen analysis performed in a certified andrology laboratory (Table 4). The semen sample is best collected at the laboratory, but when it must be collected at home, it should be delivered to the laboratory at body temperature within 30 to 60 minutes after ejaculation.

A diagnosis of an “abnormal” semen analysis should only be made after a confirmatory semen analysis has been performed, and must be interpreted in the context of the couple’s overall fertility evaluation. Other tests of sperm function are available, but their practical diagnostic value is subject to interpretation and are clinically not as useful.

 is the absence of sperm in the ejaculate, not necessarily indicating an absence of sperm in the upper reproductive tract or the testes. 

When the vas is patent, retrograde ejaculation may be diagnosed by retrieving sperm from the urine after orgasm and may be washed and used for intrauterine insemination. If the vas is blocked, sperm may be aspirated from the epididymis (MESA) or surgically extracted from the testes (TESA) and used for intracytoplasmic sperm injection (ICSI) at IVF. 

In cases of azoospermia in which the sperm must be retrieved from the testes, testing for a mutation in the DAZ (Deleted in Azoospermia) gene can be a useful predictor of testicular sperm presence, as presence of the DAZ-c mutation predicts an almost 0% likelihood of finding sperm in the testes.

These genes may also be passed on to offspring; affected male patients may opt to use a donor sperm to prevent this outcome. 

Similarly, men with an absent vas deferens may have a mutated allele for cystic fibrosis or a 5-T variant and if sperm is aspirated from the epididymis or testes for use in IVF, the resultant child may inherit cystic fibrosis.

 Thus, screening for the mutations is recommended when an absent vas deferens is detected.

, or less than 15 million sperm/ml, and may signal partial retrograde ejaculation, hormonal disturbance or genetic conditions. If the testosterone levels are normal or low and the LH and FSH are normal, an empirical treatment with clomiphene citrate for 6 to 12 months may increase the sperm count.

Monitoring testosterone and the semen analysis after three months is recommended. 

 is diagnosed when motility is < 40%, while 

Male factor infertility may be treated by intrauterine insemination, possibly combined with ovulation induction of the female (COH-IUI) as discussed below. However, success rates with ICSI at IVF far exceed those with COH-IUI, especially when the normal morphology is <4% or the count is < 2million sperm/cc.

is an assistant professor of Obstetrics, Gynecology, and Reproductive Sciences in the Division of Reproductive Endocrinology and Infertility within the Department of Obstetrics, Gynecology, and Reproductive Sciences at Yale School of Medicine, Yale University.

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This peer-reviewed article discusses the main causes of infertility, including tubal disease, uterine factor, cervical factor, and ovulatory dysfunction and anovulation. 

Amanda Kallen, MD

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