Infertility treatment depends on multiple factors such as age, duration of infertility, cause of infertility, and financial burden. Some patients may need only one or two treatment options, while others may need a combination of different treatment options.

Lifestyle therapies

• Weight optimization: Women who are either overweight or underweight have greater risk for ovulatory dysfunction and reduced fertility. Weight loss and exercise is recommended as the first-line management for obese women, especially women with polycystic ovarian syndrome (PCOS). Even a 5% to 10% reduction in body weight has been shown to restore ovulation in women with PCOS. On the opposite spectrum, women with low body weight and ovulatory dysfunction are advised to gain weight, modify their diet, and reduce exercise.

• Stress management: Stress has been associated with pregnancy failure. Patients with higher stress levels have lower pregnancy rates when undergoing IVF treatments. Some commonly used stress management strategies include meditation, breathing exercises, therapy, and joining support groups.

Medications

Women with ovarian problems are commonly prescribed ovulation induction agents that help stimulate the ovaries. Below are some commonly prescribed medications.

• Clomiphene citrate. This oral drug is often the initial treatment for many infertile women who have irregular menstrual cycles. Clomiphene works by indirectly increasing the reproductive hormones (LH and FSH) levels, which in turn, stimulate more eggs to develop.

• Letrozole. This oral drugs works by decreasing estrogen levels and was originally developed for breast cancer treatment. Letrozole is commonly used in women with PCOS. Recent studies show letrozole may work better than clomiphene in women with PCOS to induce ovulation and become pregnant.

• Metformin. This oral drug is a common diabetic drug used to control high blood sugar levels. Metformin is commonly prescribed to women with PCOS. Women with PCOS have higher insulin resistance and this negatively affects ovulation. Metformin can help reduce the insulin resistance and thereby increase the likelihood of ovulation.

• Gonadotropins. Although clomiphene citrate is easy to use and its use leads to ovulation in most patients, the pregnancy success rates are low. Patients who cannot get pregnant using clomiphene citrate are often classified as “clomiphene citrate resistant.” The next step in these patients can be the administration of gonadotropins (reproductive hormones) injections. These medications stimulate the ovaries directly to produce more eggs. Gonadotropin medications include FSH and human chorionic gonadotropin (hCG), which contains both LH and FSH. Gonadotropin injections carry the risks of excessive ovarian response, need close medical monitoring, and are typically expensive to purchase.

Surgery

Corrective surgery can be an option for some anatomic abnormalities of the female reproductive tract that is causing infertility.

• Fallopian tubes abnormalities. If the fallopian tubes are blocked or if there are adhesions, laparoscopic surgery may be performed to re-open the tube or create a new tubal opening to allow the sperm and the fertilized egg to travel through the fallopian tube unobstructed.

• Uterine abnormalities. Doctors may suggest laparoscopic or hysteroscopic surgery to correct uterine abnormalities. Some examples are removing fibroids in patients with leiomyomas, restoring the normal uterine cavity size in patients with intrauterine adhesions, and restoring the pelvic anatomy in patients with pelvic adhesions.

Assisted reproductive technology (ART)

Assisted reproductive technology is used to achieve pregnancy in infertile couples for whom the underlying cause of infertility cannot be effectively treated or is unknown.

• Intrauterine insemination (IUI). IUI is typically the first step in the treatment of young couples with no evidence of tubal damage or severe male factor infertility. This procedure involves injecting previously collected sperm into the uterus by a catheter placed inside the uterine cavity through the vagina.

• Intracytoplasmic Sperm Injection (ICSI): ICSI is used to assist the fertilization process when a male’s sperm is abnormal. This technique involves using specialized equipment to select and pick up one sperm that is then directly injected into the inner part of the egg held with a specialized pipette. 

• In vitro fertilization (IVF): IVF is a medical and surgical procedure that involves fertilizing the egg outside the woman’s body and transferring the resulting embryo back into the woman’s body. The procedure is a multistep process over 4 to 6 weeks that requires medications to stimulate egg production in the ovaries, minor surgical procedures to retrieve the eggs and implant the embryo, and clinical monitoring by the doctor throughout the process.

Reference

Crosignani PG, Colombo M, Vegetti W, et al. Overweight and obese anovulatory patients with polycystic ovaries: parallel improvements in anthropometric indices, ovarian physiology and Fertility rate induced by diet. Hum Reprod. 2003;18(9):1928-32.

Thiering P, Beaurepaire J, Jones M, et al. Mood state as a predictor of treatment outcome after in vitro fertilization/embryo transfer technology (IVF/ET). J Psychosom Res. 1993;37(481):481-91.

Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014;371:119.

How common is it?

Infertility in women is ranked the 5th highest serious global disability. About 6% of married women aged 15 to 44 years in the United States are unable to get pregnant after one year of trying. Infertility is defined as not being able to get pregnant after one year or longer of unprotected sex. It can be further divided into:

• Primary infertility: Infertility without any previous pregnancy.
• Secondary infertility: Fertility occurring after having a child in the past.

Time required for conception, approximately 50% of women will be pregnant at 3 months, 75% at 6 months, and more than 85% by 1 year. (Adapted from Barbara LH. ed., (2016). Evaluation of the Infertile Couple. In: Williams gynecology, 3rd ed , pp. 427- 446.)

How is it diagnosed?

Fertility is not just a woman’s problem; both men and women contribute to infertility. In about 35% of couples with infertility, both male and female fertility problems were identified. In about 8% of cases, only the male problem was identified as contributing to the infertility. An infertility evaluation is recommended after 1 year of unprotected sex for women under 35 years or after 6 months for women 35 years and older.

Female Infertility Evaluation:

The evaluations for female infertility fall into two basic categories: ovulatory function and health of the reproductive organs

Ovulatory function:

• Ovulation function is typically evaluated with blood tests to determine if ovulation occurs. A progesterone level >3ng/mL a week prior to expected menses would indicate recent ovulation.  Patients can also use over-the-counter ovulation predictor kits to measure urinary luteinizing hormone (LH) concentrations to determine ovulation. As these kits are not 100% accurate, a blood test may be needed to confirm the results. If ovulation is not detected, a further evaluation would be conducted to determine the cause for the lack of ovulation.

• Some women have regular menses but have a reduced response to ovarian stimulation. These patients will need to have their ovarian reserve evaluated. Various ovarian reserve tests are available to provide an indirect assessment of the woman’s ovarian reserve. Day 3 FSH levels and estradiol (E2) levels are commonly used to determine the ovarian reserve. Other tests include clomiphene citrate challenge test (CCCT), anti-mullerian hormone (AMH) level, and antral follicle count (AFC) using transvaginal ultrasound.

Evaluation of the reproductive organs:

The causes of female infertility from anatomic abnormalities are usually in the following areas: ovaries, fallopian tubes, and uterus. Any problems in these organs can cause infertility or difficulty in achieving pregnancy. Examples include obstruction in the fallopian tubes, polyps in the uterus, intrauterine adhesions, endometriosis, and ovarian cysts.

There are several procedures that are used to evaluate the reproductive organs: hysterosalpingogram (HSG), transvaginal sonography (sonohysterography), hysterosalpingo-contrast sonography (HyCoSy), hysteroscopy, and laparoscopy.

Initial evaluations generally involve procedures that are less invasive like HSG, sonohysterography, and HyCoSy. If abnormalities were found during the initial evaluation, more invasive procedures like hysteroscopy, laparoscopy, and MRI would be required for further evaluation.

• Hysterosalpingogram (HSG) is a radiographic tool that evaluates the uterine cavity and the fallopian tubes. This procedure is commonly used to look for abnormalities of the uterus and to look for obstructions or blockages in the fallopian tube. If abnormalities are found during the HSG, further evaluations with more invasive procedures will be required. HSG involves a contrast media that is infused through a catheter from the vagina into the uterus and a fluoroscopy camera. This procedure is minimally invasive and is associated with minimal complications. However, there may be slight discomfort when the catheter is injected and vaginal spotting may occur for a few days after the procedure.

Examples of hysterosalpingogram findings. A. Normal hysterosalpingogram. B. Bilateral hydrosalpinges, distally blocked fallopian tubes filled with serous or clear fluid. (Adapted from Barbara LH. ed., (2016). Evaluation of the Infertile Couple. In: Williams gynecology, 3rd ed , pp. 427- 446.)

• Transvaginal sonography (VS) or sonohysterography uses ultrasound to provide images and assess the reproductive organs. This procedure uses a transducer that is placed in the vagina and a monitor to view the images. The images produced are typically 2D but 3D/4D ultrasound images are also available. Saline can be infused into the uterus to increase the sensitivity and specificity for detecting defects in the lining of the uterus like intrauterine adhesions and polyps and is the preferred procedure for assessing the uterine cavity. When saline is used with sonography, the procedure is called saline infusion sonohysterography. These procedures are simple and well tolerated, although some patients may have some cramping during the procedure.

• Hysterosalpingo-contrast sonography (HyCoSy) is a type of sonohysterography that uses ultrasound and contrast media injected into the uterus through the vagina to provide images of the uterine cavity, fallopian tubes, and the ovaries. This procedure is simple and well tolerated with minimal side effects. Like the saline infused sonohysterography, some patients may have some cramping during the procedure. HyCoSy is commonly used to quickly look for tubal obstructions and assess the uterine cavity.

• Hysteroscopy is an endoscopic evaluation used to examine the uterine environment and is the definitive method for evaluating the uterine cavity. This procedure involves a thin, lighted telescope-like device called a hysteroscope that is inserted and gently moved through the cervix and into the uterus. Hysteroscopy is typically not done during in an initial evaluation and has limitation in evaluating the fallopian tubes and the adjoining structures to the uterus. This is an invasive procedure and may involve anesthesia. Hysteroscopy is a relatively safe procedure but complications such as bleeding, infection, and injury to the reproductive structure can occur.

• Laparoscopy is a direct inspection of the pelvic anatomy using a special instrument called the laparoscope. The laparoscope is a long, slender device with a camera that is inserted into the abdomen through a small incision and the abdominal and pelvic organs are then viewed on an electronic screen. Laparoscopy can be used in patients suspected to have endometriosis or pelvic adhesions. This procedure is not performed during an initial fertility evaluation, as it is invasive and expensive. Some complications that can occur with laparoscopy include bleeding, infection, and damage to the pelvic organs.

Male Evaluation:

The evaluation for potential male infertility concerns mainly with the sperm. As such, the initial evaluation typically consists of collection of semen and basic health assessment. The results of the semen analysis will further guide the evaluation process.

Initial diagnostic tests:

• Semen analysis is the first test done to evaluate male infertility. For this test, the male is asked to refrain from ejaculation for 2 to 3 days before submitting the sample. A semen analysis evaluates the number of sperm, the sperm’s movement, and the shape of the sperm. If the initial semen analysis finds abnormal results, an additional semen sample is requested and analyzed to confirm the initial results. An abnormal result could indicate many different causes including infertility, infection, hormonal imbalance, and genetic defects.

• Hormonal testing is often done in males to detect any hormone abnormalities that may affect sperm production. This is a blood test that typically measures FSH, LH, testosterone, prolactin, and TSH levels.

• The results from the physical examination, semen analysis, hormonal testing, and patient’s medical history will typically be enough to determine the cause of male infertile in most cases. If the cause is still not defined, further evaluation will be done.

Second-level diagnostic tests:

• Genetic assessment. Males with severely decreased sperm counts have a high risk of having genetic abnormalities. Although the low sperm count cannot be corrected, the genetic test will provide information about the status of male health and possible genetic abnormalities their offspring may inherit.

• Bacteriological examination and transrectal/scrotal ultrasound. These tests can identify anatomical abnormalities resulting from chronic inflammation, which usually cause obstruction of the ductal outflow tract. Testicular ultrasonography can be used as a diagnostic tool and is especially useful in patients with an increased risk of cancer.

Third-level diagnostic tests:

• Testicular biopsy. This invasive procedure is done to differentiate testicular failure, whether it is primarily from obstruction or from other causes. Today, testicular biopsy can be considered as both a diagnostic and treatment procedure. Sperm can be obtained from testicular biopsies of males whose semen contains no sperm. The collected sperm would then be used to fertilize an egg in the lab to create an embryo to be implanted into the uterus.

Reference

Infertility definitions and terminology. http://www.who.int/reproductivehealth/topics/infertility/definitions/en/ (Assessed 2017–05–12)

Infertility FAQs. https://www.cdc.gov/reproductivehealth/infertility/ (Assessed 2017–05–12)

Grimbizis GF, Solakidis D, Mikos T, et al. A prospective comparison of transvaginal ultrasound, saline infusion sonohysterography, and diagnostic hysteroscopy in the evaluation of endometrial pathology. Fertil Steril. 2010;94(7):2720.

De Hondt A, Peeraer K, Meuleman C, et al. Endometriosis and subfertility treatment: a review. Minerva Ginecol. 2005;57:257.

The ovaries of a newborn girl contain approximately 2 million eggs. By the time the girl reaches puberty, this number is reduced to 400,000 eggs. After puberty, the quantity of eggs progressively decline until the woman reaches menopause.

Many studies have shown that human fertility naturally declines with age. A woman’s ovarian reserve is used to describe the quantity and quality of the eggs available for fertilization. Poor ovarian reserve (POR) indicates a reduction in the quantity and quality of the eggs in women of reproductive age, and is an important cause of infertility for many couples.

How is it diagnosed?

For many years, there has been no universal definition for POR. In 2011, the European Society of Human Reproduction and Embryology (ESHRE) has worked on the definition of POR and introduced the Bologna Criteria to standardize the diagnosis of POR.

The Bologna criteria recommends the presence of at least two of the following three features for diagnosis of POR:

• Advanced maternal age (≥40 years) or any other risk factors for POR
• A previous POR (≤3 oocytes with a conventional stimulation protocol)
• An abnormal ovarian reserve test.

There are multiple ovarian reserve tests (ORTs) that provide an indirect assessment of the ovarian reserve. These tests will provide an estimate to the women’s sensitivity to ovarian stimulation and the relative chance for IVF success. The tests cannot predict a woman’s fertility in the future.

Typically, a day 3 FSH level and estradiol (E2) level are done to evaluate the ovarian reserve. Other tests include the clomiphene citrate challenge test (CCCP), antral follicle count (AFC), and anti-mullerian hormone (AMH) levels. Among the ovarian reserve tests, antral follicle count (AFC) and the anti-Mullerian hormone (AMH) level are the most sensitive and reliable markers of ovarian reserve. These markers permit the prediction of the whole spectrum of ovarian response with reliable accuracy.

What are the risk factors?

Age is the most important factor in predicting the ovarian reserve. The optimal age for women to conceive a child is before the age of 30. After that age, fertility starts to decline faster. The decline accelerates rapidly after the age of 37 years when the ovaries have less than 25,000 eggs.

In addition to age, other factors that affect ovarian reserve during reproductive age include endometrioma, certain pelvic infections, ovarian surgery, bacterial infections, chemotherapy, and radiotherapy. Obesity and chronic smoking is also believed to be associated with POR.

What are the success rates of IVF?

Women with POR are associated with low pregnancy success rates and high pregnancy loss. Currently, there are no available treatment interventions that can reverse the low quantity and quality of the eggs in women with POR. IVF is the only treatment option available with a reasonable chance of achieving pregnancy in women diagnosed with POR but the rates are much lower compared to women without POR. In a study of 1,152 fertile women undergoing IVF in China, the chance of conceiving a child were significantly lower in women with POR than those with normal ovarian response; 35.8% in women with POR vs. 62.8% in women with normal ovarian response.

Reference

Baker TG. A quantitative and cytological study of germ cells in human ovaries. Proc R Soc Lond B Biol Sci. 1963;158:417-33.

Ferraretti AP, La Marca A, Fauser BC, et al. ESHRE Working Group on Poor Ovarian Response Definition. ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: The Bologna criteria. Hum Reprod. 2011;26:1616–24.

P.B. Maseelall, P.G. McGovern. Ovarian reserve screening: what the gynecologist should know. Womens Health. 2008;4(3):291-300.

Jirge, Padma Rekha. Poor Ovarian Reserve. J of Hum Reprod Sci. 2016;9(2):63–69.

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Chai J, Lee VC-Y, Yeung TW-Y, et al. Live Birth and Cumulative Live Birth Rates in Expected Poor Ovarian Responders Defined by the Bologna Criteria Following IVF/ICSI Treatment. PLoS ONE. 2015;10(3):e0119149.