By: Satya Harika Manda MBBS, Mubashira Khijar Sarnaik MBBS, Sidra Qamar MBBS
Mentor: Lubna Mirza, MD (Norman Endocrinology Associates)

INFERTILITY AND ITS CAUSES

Infertility is the inability to conceive after 12 months of regular unprotected sexual intercourse. Infertility rates are steadily increasing, and it is estimated that around 48 million couples and 186 million individuals of reproductive age live with infertility globally. In the United States, it affects 8.8% of women aged 15 to 49 years.

Among 85% of the infertile couples, you can find a definitive cause. But in the rest of the 15%, infertility is unexplained. Ovulatory dysfunction, male factor infertility, and tubal disease are the most common causes of infertility.

MAJOR CATEGORIES OF INFERTILITY:

OVULATORY DYSFUNCTION:
Accounts for 25% of infertility diagnoses.

Ovulation, which means the release of a mature egg from the ovary, usually occurs 14 days before the onset of menstruation. Intercourse 5 days before ovulation or on the day of ovulation itself is believed to result in a successful pregnancy. However, in some women, the release of the egg does not happen. This is called anovulation, and it can lead to infertility. Anovulation must be suspected in women with irregular menstrual cycles, cycles shorter than 21 or longer than 35days, abnormal uterine bleeding, or amenorrhea. Polycystic ovary syndrome (PCOS) is the most common cause of anovulation, followed by Obesity (with a BMI>27), thyroid disease, pituitary disease (e.g., prolactinoma), elevated androgens from adrenal hyperplasia or adrenal tumor, idiopathic chronic anovulation (unknown cause, and functional hypothalamic amenorrhea (e.g., due to underweight, eating disorders, and excessive exercise).

TUBAL INFERTILITY:

Accounts for between 11% and 67% of infertility diagnoses.
Tubal infertility occurs either due to blockage of fallopian tubes or their inability to grab an oocyte released from the ovary (due to fibrous scar-like tissues in the pelvic region). History of sexually transmitted infection in the past increases the risk of tubal disease. Cervical dysplasia (precancerous changes of cells on the surface of the cervix), abdominal surgery, or previous intraabdominal infection (e.g., ruptured appendix) are the other risk factors for tubal infertility.

ENDOMETRIOSIS:

Accounts for 25% to 40% of infertility diagnoses.
The endometrium is a tissue that lines the inside of the uterus. Endometriosis is a disorder in which this tissue grows outside the uterine cavity and is found on other pelvic organs like ovaries, fallopian tubes, or intestines. This extrauterine tissue thickens, breaks down, and bleeds with each menstrual cycle, just like the normal endometrium. However, the blood gets trapped in the pelvic cavity leading to inflammation, scarring, and adhesions formation (fibrous bands formation between two tissues/organs binding them together) in the surrounding normal tissue. Within the ovaries, they may form cysts called endometriomas. The presence of adhesions in the fallopian tubes or ovarian masses between the tubes and site of ovulation impairs tubal patency, oocyte retrieval by tubal fimbria (finger-like structures at the end of fallopian tubes), and fertility.

DIMINISHED OVARIAN RESERVE:

As age increases (>30), the fertility rate decreases because of the progressive loss of follicles and oocytes (the “ovarian reserve”) within the ovaries. History of ovarian surgery, chemotherapy, radiation exposure to the ovaries, family history of premature menopause, or a fragile X (FMR1) premutation are the other risk factors that could lead to a diminished ovarian reserve.

UTERINE AND CERVICAL FACTORS:

Congenital uterine malformations (septate uterus) or other conditions like endometrial polyps, fibroids (leiomyomas), and intrauterine adhesions can distort the uterine cavity causing adverse pregnancy outcomes such as miscarriage and preterm birth.
Abnormalities in the cervical anatomy (congenital), postsurgical scarring/stenosis, or decreased cervical mucus production (interferes with the entry of sperm into the uterus) are the factors associated with cervical infertility.

MALE FACTOR INFERTILITY:

Accounts for 35% of infertility diagnoses.
Low testosterone levels, low sperm count, or absence of sperm in the ejaculate (azoospermia) either due to congenital bilateral absence of vas deferens (obstructive type) or primary testicular failure (nonobstructive type) are commonly associated with male factor infertility.

WHAT CAN A PATIENT DO TO MAXIMIZE THE LIKELIHOOD OF PREGNANCY?

Individuals can increase their fertility rates by adopting lifestyle changes like increasing the intake of fruits and vegetables with low pesticide residue, maintaining a healthy weight, regular exercise, abstaining from cigarettes and alcohol. Increasing supplemental folic acid intake and including whole grains, seafood, dairy, and soy in the regular diet is highly recommended. Couples should monitor cervical mucus or use ovulation predictor kits (available without a prescription) to determine the ovulation timing. Having sexual intercourse during highly fertile days of the menstrual cycle (the 3-day interval ending on the day of ovulation) can increase the chances of pregnancy.

DOES FEMALE AGE AFFECT FERTILITY?

Yes, as age increases fertility rate decreases among women because of the progressive loss of follicles and oocytes (the “ovarian reserve”) within the ovaries. With increasing age, errors during meiotic divisions increase, leading to the deterioration of gamete quality and increased risk of congenital malformations/miscarriage. Also, women are more likely to acquire uterine fibroids or endometriosis with advancing age, impairing fertility. The decrease in female fertility rates occurs more rapidly after age 37 years.

WHAT ARE THE SIGNS OF INFERTILITY?

Normally, it can take up to a year to conceive. After a year of trying to get pregnant, women under the age of 35 should consider getting evaluated. Doctors recommend women over the age of 35 should be assessed after six months, while women under the age of 40 should be evaluated immediately for infertility. Women with painful periods, endometriosis, irregular menstrual cycles, a history of pelvic inflammatory disease, or a partner with a low sperm count, for example, should seek treatment sooner. Women with repeated miscarriages should also consult a doctor for further evaluation.

WHERE SHOULD A COUPLE GO TO SEEK HELP FOR INFERTILITY?

A couple should visit their primary care physician or a gynecologist for infertility testing and discussion of the next steps to take. The physician will take a detailed history and complete a physical examination first to decide which tests to order. The couple can be referred to a fertility clinic for further evaluation and fertility treatments.
Some of the investigations done for infertility include:

1.  Blood tests:
*   Complete blood count
*   Thyroid profile
*   Prolactin
*   FSH, LH
*   Estradiol, progesterone, testosterone
*   Sexually transmitted disease testing

2.  Imaging tests: to look for any blockages or anatomical problems in the reproductive organs
*   Ultrasound of the pelvis
*   Hysterosalpingogram: A test in which a colored dye is inserted in the uterus to look for any blockage in the uterus or fallopian tubes
*   Laparoscopy: done for more difficult to diagnose cases

3.  Semen analysis: assesses the quality and amount of sperm of the male partner. If the sperm count is very low, hormone levels will need to be tested. Sometimes, a karyotype analysis or a Y-chromosome study may be required to check for any genetic disorders.

4.  Home ovulation kits: these kits give easy-to-follow instructions on how to track ovulation at home. Patients will be instructed to check cervical mucus and take their temperature to determine when ovulation occurs. Keeping track of menstrual cycles can give doctors information on what could be causing infertility.

TREATMENT OPTIONS FOR INFERTILITY

Infertility treatment options include ovarian induction, ovarian stimulation, timed intercourse, or intrauterine insemination (IUI). In Vitro Fertilization commonly known as IVF is a step ahead treatment option and had shown much promise.

OVARIAN INDUCTION:

In this method medicines are given which stimulate organs in brain (hypothalamus and pituitary) to release hormones for increasing egg production. Clomiphene citrate (selective estrogen receptor modifier) causes a substance called GnRH to release from hypothalamus which in turn increases hormone release and mature egg production. Letrozole (aromatase inhibitor) stimulates pituitary to release hormones (FSH and LH) for ovarian egg release. According to one trial, Letrozole is the First line therapy for PCOS patients receiving infertility treatment. In women with hypogonadotropic hypogonadism, a condition where there is lesser to no pituitary hormone response, pulsatile GnRH is used. This fixes the levels of FSH and LH inside the body, hence leading to follicular maturation and ovulation. Research shows that treatment with pulsatile GnRH results in pregnancy rates of 93% to 100% after up to 6 months.

OVARIAN STIMULATION:

Ovarian stimulation, which aims to induce multiple mature egg production, works by using Clomiphene citrate, Letrozole, Gonadotropins (exogenous FSH, LH), or the combination of these medications. In 2019 a review showed that Gonadotropins have higher chance of live births compared to clomiphene citrate. However, reproductive endocrinologist supervision is much recommended with gonadotropins administration because of serious risk of complication i.e., Ovarian hyperstimulation syndrome (includes ascites, electrolyte imbalance and ascites).

INTRAUTERINE INSEMINATION:

The placement of sperm directly in the uterus is called intrauterine insemination (IUI). IUI along with ovarian stimulation is used for treating unexplained infertility.

IN VITRO FERTILIZATION:

A rather new option for treatment which became a household word not so long ago is In vitro fertilization (IVF). It is done in steps which includes super stimulation of ovary, ultrasound guided removal of eggs from women’s body and finally fertilization of eggs by mixing with sperm outside the body in controlled chamber. In cases where chance of fertilization is low, the sperm is directly injected into the egg. This is called intracytoplasmic sperm injection (ICSI). The cultured embryos are then planted into the uterus by the help of ultrasound again.

NEWER ADVANCEMENTS:

Further advancement in medical knowledge and technology have opened new prospects of treating infertility by third party reproduction and uterine transplants. There are cases where egg or sperm from either partner are not viable (genetic conditions) at all. In this situation idea of donor egg or sperm is utilized. This is called Third party reproduction. Uterine transplant is a promising experimental procedure. The first clinical trial of a living donor uterine transplant resulted in a 32-week delivery in 2014 in Sweden, followed by the first live birth from a deceased donor at 36 weeks in 2017 in Brazil. Two live births have also been reported in US after deceased donor transplant.

Age should also be considered in making a treatment plan. Modifications in lifestyle will have good implications as well. Maintaining a healthy weight, appropriate intake of fruits and vegetable with abstinence of smoking can be a good measure in enhancing natural fertility.

The cost of treatment varies with places. Most of the insurances cover infertility treatment and at least one cycle of IVF. Therefore, to better understand the coverage, one should ask the healthcare provider or the insurance company directly.

 

Dr Lubna Mirza
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