Definition

Infertility is the inability to achieve a pregnancy with regular intercourse and no contraception. In normally fertile couples, the chance for pregnancy is between 15 and 20% per menstrual cycle. 70% of all couples will attain a pregnancy within 6 months, and about 85% within a year. Couples that are attempting but failing to become pregnant are deemed ‘infertile’ after one year if the woman is under 35, or after six months if the woman is 35 or older.

Infertility may be further described “primary” or “secondary”

• Primary Infertility means the patient has never been pregnant.
• Secondary infertility means the patient has previously been pregnant, but has been unable to conceive again.

Subfertility means that the woman has not conceived as quickly as expected, but has not yet met the duration criteria for infertility. It is a softer term, more often used in communicating with patients.

Causes of Male and Female Infertility

Human reproduction requires coordination of several critical factors, including male factors, ovulation, and an unobstructed passage for the sperm to meet the egg.

Large numbers of sperm must be available at the cervix. They must be able to ascend through the cervix, uterus, and fallopian tubes, and subsequently have the capacity to fertilize the egg.

Reduced numbers of functionally normal sperm is considered a “male factor,” and contributes to infertility in 30-40% of couples.

Male-factor infertility has a variety of causes.

Hypothalamic-Pituitary Disorders

Normal spermatogenesis requires normal FSH (follicle-stimulating hormone) and LH (luteinising hormone) release.

Any disorder that disrupts these signals may lead to low sperm counts. Fewer than 15 million sperm per cc seminal fluid is considered low.

Disorders that may cause low sperm counts include idiopathic gonadotropin deficiency, Kallmann Syndrome (congenital GnRH deficiency), hypothalamic or pituitary tumors, chronic systemic illnesses, hyperprolactinemia, certain pharmacologic agents (androgens, estrogens, glucocorticoids), and obesity. 

 The absence or destruction of functional testicular tissue may also cause male-factor infertility.

Examples include Klinefelter Syndrome (46XXY), Y chromosome microdeletions, cryptorchidism, Pharmacologic pharmacologic agents (specifically chemotherapeutic agents), environmental toxins (such as smoking), infections (e.g. viral orchitis), and chronic systemic illnesses.

Finally, an unobstructed pathway from the epididymis to the urethral meatus is required for sperm to be emitted during intercourse.

Obstructions may be caused by epididymal cysts, congenital bilateral absence of the vas deferens, and infections such as gonorrhea and Chlamydia, which can cause scarring of the vas deference.

Erectile or ejaculatory problems such as spinal cord disease, retrograde ejaculation, or erectile dysfunction may cause male-factor infertility, as can Kartagener syndrome (primary ciliary dyskinesia).

For pregnancy to occur, sexual intercourse must take place shortly before or with ovulation. This timing is important because while normal sperm can remain functional inside the woman’s body for up to several days, the egg is only viable for fertilization for 12-24 hours after ovulation.

Ovulation Disorders

Ovulation problems are found in 20-40% of all infertile couples. Problems may occur anywhere along the hypothalamic-pituitary-ovarian axis.

Hypothalamic Pituitary Disorders

Any condition that interferes with FSH or LH signaling from the pituitary (required for follicular recruitment and maturation) can lead to ovulation failure.

Examples include idiopathic gonadotropin deficiency, Kallmann Syndrome (congenital GnRH deficiency), hypothalamic or pituitary tumors, chronic systemic illnesses, hyperprolactinemia, thyroid dysfunction and certain pharmacologic agents (androgens, estrogens, glucocorticoids), and obesity.

Primary Ovarian disorders

Abnormally functioning ovarian tissue may cause anovulation.

One example is premature ovarian insufficiency. This insufficiency may be linked to ovarian dysgenesis, prior use of chemotherapy, pelvic radiation therapy, or a genetic predisposition. Maternal age may also contribute to this problem as infertility among women age 40 and above approaches 70%.

Another leading cause of anovulatory infertility is polycystic ovary syndrome (PCOS). Although often considered a disorder of the ovary, this disease is the result of a complex pathophysiology involving the hypothalamus, pituitary, and ovary.

Passageway

Sperm need an unobstructed passage to meet the mature egg, as well as an optimal environment for the pregnancy to implant and grow.

This requires a patent cervix, open and functional fallopian tubes, and a normal uterine cavity with a receptive endometrium. Cervical and uterine factors are infrequent causes of infertility. In contrast, tubal and peritoneal pathology comprise 30-40% of all causes of infertility.

Cervical Factors

Cervical mucous functions as a healthy reservoir for sperm.

If the cervical glands are reduced in number due to previous cervical excision procedures (such as cone biopsy, or Loop Electrosurgical Excision Procedure (LEEP)) this may lead to reduced cervical mucous. Cervical procedures may also cause scarring and cervical stenosis.

Uterine Factors

Fibroids may contribute to a uterine-factor infertility if they have a submucosal component or if they distort the uterine cavity. Large endometrial polyps can also result in distortion of the uterus.

Uterine scarring (Asherman’s syndrome) or the absence of a uterus altogether (also known as Mayer-Rokitansky-Juster-Hauser syndrome) may cause uterine-factor infertility.

Tubal and Peritoneal Pathology

Tubal and peritoneal pathologies together comprise a large proportion of the most common etiologies of infertility.

Pelvic inflammatory disease, tubo-ovarian abcess, and gonorrhea or chlamydia infections may cause long-term structural changes that ultimately compromise tubal integrity and function.

These abnormalities not only may lead to infertility, but also increase the risk for ectopic pregnancy. Conversely, a history of ectopic pregnancy should be a red flag to the practitioner for underlying tubal disease, especially if tubal surgery (like a salpingostomy) is performed.

Endometriosis – a condition in which ectopic endometrial tissue is found on the peritoneum, ovary, tube, and sometimes in extrapelvic organs – has a strong association with infertility.

With severe endometriosis, inflammation and scar tissue are considered major contributors to infertility. But with lesser degrees of endometriosis, it may be unclear whether the endometriosis is the cause for infertility, or rather represents an effect of some other factor that causes both the endometriosis and the infertility. Endometriosis is present in between 9 and 50% of infertile women.

Unexplained Infertility

In approximately 10-15% of all infertile couples [[all couples – or all infertile couples? All infertile couples. Problem fixed.]], there is no identifiable reason for infertility; these couples are considered to have unexplained infertility. This doesn’t mean there is no cause. Rather, it means that whatever is causing the infertility is not yet detectable with our proven methods.

Some unexplained infertility relates to natural reproductive ageing, and the likely underlying etiologies relate to anomalies in gametes or implantation, for which there are no recognized validated tests. Other theories include abnormal uterine contractile patterns, and immunologic causes.

Evaluation

The evaluation of an infertile couple should begin with a history and physical examination.

This includes the duration of infertility, the results of any prior testing or treatment, and the couple’s sexual history, particularly coital frequency.

For the female, inquiry is made about her obstetric history (if any), gynecologic history, and menstrual history. Significant issues would include galactorrhea, hirsutism, dyspareunia, and (pelvic pain

Noted are prior contraceptive use, any history of surgical procedures in the genital area or abdomen, and any history of STDs (sexually transmitted diseases).

In addition to inquiring about any chronic medical illnesses or surgical history, family history is important. Evidence may be found for premature ovarian insufficiency, recurrent pregnancy loss, infertility, or other inheritable disorders.

It is important to also ask about the couples’ ethnic background in order to offer the most targeted preconception genetic screening tests.

A social history is obtained, to include an assessment of occupational exposures, use of alcohol, tobacco, or recreational drugs.

Current medications and allergies are noted.

The female’s physical exam will include height, weight, signs of androgen excess, examination of the thyroid, breasts, and a pelvic exam.

The male partner is generally referred to a urologist, or family physician with special skills in evaluating and treating male infertility.

Testing

The laboratory evaluation of the infertile couple involves an assessment of (1) ovarian reserve (2) tubal patency (3) assessment of ovulatory and endocrine function and (4) male factor (through a semen analysis).

Ovarian Reserve Testing

The most dynamic component of infertility testing is the assessment of ovarian reserve. Ovarian reserve testing aims to determine the functional capacity of a woman’s remaining eggs. It is important to remember that these tests do not tell whether a woman can or cannot get pregnant, they simply offer a guide for the practitioner in determining the likelihood of success with fertility treatment.

In general there are 3 validated blood tests for ovarian reserve: FSH, estradiol, and AMH. In addition, a follicle count can be obtained using ultrasound.

The first day of a menstrual flow is day 1. On Day 3, blood tests including FSH and estradiol are obtained, and an ultrasound scan for antral follicle count is performed.

An FSH level >10-20 IU/mL is considered abnormally high, suggesting the ovary is not responding normally. This is related to a poor chance for success with fertility treatment.

An elevated estradiol level (>60-80pg/mL) in the presence of a normal FSH level is also associated with a poor prognosis for fertility treatments. Women with poor ovarian reserve tend to demonstrate premature follicle recruitment, which results in an abnormally high estradiol.

The number of ovarian follicles is evaluated using transvaginal ultrasound. Low numbers of follicles correlates with poor ovarian reserve.

The cycle-independent test for ovarian reserve is antimullerian hormone level (AMH). AMH level reflects the availability of primordial follicles, declines with advancing maternal age, and drops to nil at menopause. Age-adjusted normal values are used to evaluate the ovarian function potential for infertile women.

The number of ovarian follicles is evaluated using transvaginal ultrasound. Low numbers of follicles correlates with poor ovarian reserve.

Assessing Tubal Patency

There are several ways to assess tubal patency.

Hysterosalpingogram (HSG) utilizes real time fluoroscopy to image the uterus and fallopian tubes, by injecting a radio-opaque dye into the uterus and fallopian tubes.

Abnormal tubal morphology and the absence of free spill into the peritoneal cavity can be helpful surrogate markers for the presence of extra-tubal pelvic adhesive disease.

Sono-hysterosalpingography with saline instillation has become a popular replacement for HSG. This technique utilizes Doppler flow to visualize the tubes as they fill with saline; the presence of fluid in the cul de sac confirms patency of at least one fallopian tube. If either of these tests are abnormal or indeterminate, the gold standard assessment of tubal patency is chromotubation at the time of laparoscopy.

Assessment of ovulatory function and Endocrine evaluation

The single best predictor that a woman is ovulating regularly is the presence of regular menstrual cycles every 21 to 35 days. Lab and imaging studies are usually done to confirm this.

In a woman with typical 28-30 day cycles, serum progesterone values on cycle days 21-24 should be elevated, reflecting ovulation.

Progressive follicular growth and then collapse with ovulation can be visualized with serial transvaginal ultrasounds, confirming development and release of an egg.

Women with a history suggesting ovulatory dysfunction should undergo a thorough endocrine evaluation. This includes serum TSH (thyroid-stimulating hormone), FT4 (free thyroxine), and fasting prolactin levels, and –in women with complaints or signs of androgen excess – targeted evaluation of male hormone levels.

Male Factor (Semen analysis)

The final component of the infertility evaluation is the semen analysis.

The male partner should provide a specimen after 2-5 days of abstinence. The specimen is evaluated on several criteria, including volume, concentration, motility, and morphology. Abnormalities in any one of these parameters may warrant additional evaluation by a urologist.

For instance if no sperm is found (azoospermia), this may suggest gonadal failure (if normal volume ejaculate is present) or obstruction (if low volume ejaculate is present). In the former, a serum FSH, E2 (estradiol), testosterone, and prolactin level should be obtained.If obstruction is suspected, a thorough physical exam should be performed by a urologist.

Preconception Counseling

Another important component of the initial evaluation is preconception counseling.

Here, we have a unique opportunity to reduce antenatal risks by ensuring adequate testing and preconception treatment. All pre-existing medical conditions should be assessed and optimized prior to pregnancy. Titers for rubella and varicella should be obtained to determine ongoing immunity.

Finally, preconception genetic screening should be offered. This screening can include an assessment of carrier status for cystic fibrosis, spinal muscular atrophy, thalassemia, and sickle cell disease, amongst others.

Management

In some cases, infertility is a result of a single major problem that is preventing pregnancy. In other cases, there are a number of minor factors, none of which will completely prevent pregnancy, but which collectively make it unlikely.

The choice of fertility treatment is dependent on each couple’s initial evaluation. Targeted treatment is best for isolated abnormalities, such as anovulation or azoospermia. However, when more than one abnormality exists, or the evaluation is normal, a more empiric approach should be considered. Consultation with a reproductive endocrinologist and infertility specialist is critical for determining the best treatment approach for couples with infertility.

Psychosocial issues associated with infertility

Numerous studies have shown increased symptoms of stress and anxiety in infertile women compared to the general population; not only is the diagnosis stressful, but chronic stress itself may reduce the success of fertility treatment (although the mechanism for this is poorly understood).

There are reasons for increased stress. The diagnosis of infertility can impact the couple’s relationship, their relationship with family and friends, their financial well-being, and potentially their outlook on life. Ultimately, both diagnosis and treatment requires not only a physical commitment from the couple, but an emotional and financial commitment as well.

As the infertile couple is vulnerable to psychosocial issues, it is important for the practitioner to recognize signs of stress, depression, and anxiety. Professional counseling –– through a psychiatrist, psychologist, social worker, marriage or family therapist –– can be very helpful, and sometimes relationship or life-saving. Consider referral for counseling if a patient or her partner experience any of the following:

• Persistent feelings of sadness, guilt, or worthlessness
• Social isolation
• Loss of interest in usual activities and relationships
• Depression
• Agitation and or anxiety
• Mood swings
• Constant preoccupation with infertility
• Marital problems
• Difficulty with “scheduled” intercourse
• Difficulty concentrating or remembering
• Increased use of alcohol or drugs
• Changes in appetite, weight, or sleep patterns
• Thoughts about suicide or death

The American Society for Reproductive Medicine (ASRM) patient website (ReproductiveFacts.org) provides several resources addressing the concerns of couples who have been given a diagnosis of infertility or who choose to pursue treatment. Links to support groups and other national organizations, including Resolve (www.resolve.org), American Fertility Association (TheAFA.org), and the InterNational Council on Infertility Information Dissemination, Inc. (www.inciid.org), are also provided.

Ethical Issues in Reproductive Medicine

As the field of reproductive medicine evolves, so do the ethics of practice.

As humans, we value the right to reproduce, to build a family, and to take care of that family. As practitioners, we have an obligation to understand the risks, benefits, and indications of treatment, and also the impact of treatment (or of no treatment) on the individual, the couple, and the society— we must use the available technologies in the most conscientious way.

The American Society for Reproductive Medicine provides guidance for tackling some of the most common ethical issues in practice. Those issues include:

• Child rearing ability and the provision of fertility services
• Embryo donation
• Disparities in access to care
• Disposition of abandoned embryos
• Fertility treatment when the prognosis is poor or futile
• Oocyte or embryo donation in women of advanced age
• Financial compensation for oocyte donation
• Pre-implantation genetic diagnosis
• Family members as gamete donors and surrogates.

To help address these issues, infertility centers may collaborate with legal counsel in drafting office policies and procedures. Some practitioners work hard to maintain open dialogues with their patients from the beginning of treatment to foster accurate expectations. Some centers have developed ethics committees.

Impact of genetic screening and testing associated with infertility treatments: PGS and PGD

Among the most significant breakthroughs in reproductive medicine have been pre-implantation genetic screening (PGS) and pre-implantation genetic diagnosis (PGD).

Pre-implantation genetic screening tests for aneuploidy, chromosome translocations, copy-number variations, or other gross abnormalities of the autologous and sex chromosomes.

Preimplantation genetic diagnosis tests for specific diseases, including single-gene disorders for which the parents are known or likely carriers. Examples include Cystic Fibrosis, Spinal Muscular Atrophy, Thalassemia, Fragile X Syndrome, Sickle Cell anemia, Hereditary Breast/Ovarian cancer (BRCA1 and BRCA2), Tay Sachs, and Myotonic Dystrophy.

The process of preimplantation genetic screening first requires the couple to undergo in vitro fertilization (IVF). The female partner takes injections to stimulate follicle development, and subsequently undergoes ultrasound-guided oocyte retrieval.

After retrieval, the cohort of mature eggs are selected and injected with the male partner’s sperm through a process called intracytoplasmic sperm injection (ICSI).

While a number of embryo biopsy strategies have been used with varying degrees of success, most centers have moved towards earlier genetic analysis, at the blastocyst stage.

Although effective and reasonably safe, there are drawbacks to blastocyst biopsy. One is the possibility that in the presence of placental mosaicism, the sample may fail to include all of the genotypes present.

To counteract this risk, patients are still advised to undergo routine noninvasive prenatal screening during pregnancy (in cases of PGS) and consider invasive prenatal screening (in cases of PGD).

Another drawback to blastocyst biopsy is the possibility of having no blastocysts survive to the embryo stage in vitro, which means there would be no embryos to biopsy.

To counteract this risk, couples often “batch” their IVF cycles, meaning they undergo several cycles of IVF back-to-back to increase the pool of embryos available for analysis, especially if the female partner has decreased ovarian reserve.

The current literature suggests that the chance of live birth after the transfer of a euploid embryo, regardless of the age of the recipient, is ultimately approximately 65%.

The indications for PGD are clear: individuals that are carriers of diseases that cause significant morbidity or mortality can elect to reduce their risk of having children with those diseases.

The indications for PGS however are still evolving.

Patient populations that might benefit from this technology include couples in whom the female partner is of advanced age, couples with a history of recurrent pregnancy loss or recurrent implantation failure following previous IVF cycles, infertile women with uterine anomalies, or women with prior poor antenatal outcomes who require the lowest risk for multiple gestation.

Resources

Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertility and Sterility 2013; 99:63

Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile male: a committee opinion. Fertility and Sterility 2015; 103:e18-25

Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion. Fertility and Sterility 2015; 103:e44-50

Practice Committee of the American Society for Reproductive Medicine. Female Age Related fertility decline. Fertility and Sterility 2014; 101:633-4

American Society for Reproductive Medicine. Infertility Counseling and Support: When and Where to Find it. Fact Sheet. www.reproductivefacts.org

Ethics Committee of the American Society for Reproductive Medicine. American Society for Reproductive Medicine. (2011-2016) www.asrm.org/Ethics/Reports

Bayer, S. R., Alper, M.M., & Penzias, A.S. (2002). The Boston IVF handbook of infertility: A practical guide for practitioners who care for infertile couples. Boca Raton, FL: Parthenon.