Role of Genetics in Female Infertility

Infertility is an issue for millions of couples around the world. Around 50% of all infertility cases are attributed to women. The causes may include age, lifestyle factors, reproductive disorders, and hormonal imbalances, but the role of genetics in female infertility is an exciting and important field of study. With the development of genetic testing and reproductive medicine, it is now understood that the majority of infertility cases are due to the inherited and/or de novo genetic alterations that negatively impact women’s ovarian functions, the quality of oocytes and embryos, and the viability of pregnancies.

By identifying the genetic components of infertility, women will be empowered by the ability to receive precise diagnoses, targeted infertility treatments, and the opportunity to make more educated reproductive choices. Women will also benefit from the identification of the genetic component of infertility, whether it is due to chromosomal instability, gene mutations, or inherited diseases, as it will help to improve the treatment strategies and reproductive prognosis.

In this guide, we will examine the role of genetics in female infertility, elucidate the genetic causes, review the genetic tests relevant to infertility, and discuss the treatment options and the ways to minimize the risk of infertility.

What Is Female Infertility?

Infertility in women is the inability to achieve pregnancy after:

– 12 months of regular and unprotected sexual intercourse (for women under 35)

– 6 months of regular and unprotected sexual intercourse (for women 35 years and older)

Infertility can be due to a:

– Ovulatory disorder

– Abnormalities of the Fallopian tubes

– Uterine disorders

– Cervical disorders

– Disorders of endocrine regulation

– Disorders of oocyte quality

– Genetic abnormalities

Genetics can be an important contributor to infertility, but it is often overlooked.

Genetics and Female Infertility

Genetics and female infertility are intertwined when a chromosome or gene is altered and affects their reproductive health. These changes may impact:

– The ovarian reserve

– The maturation of eggs

– The secretion of hormones

– The implantation of embryos

– The ability to sustain a pregnancy

– The development of reproductive organs

– Genetic alterations may be inherited or the result of a spontaneous occurrence during cell division.

Modern fertility experts are advocating for the assessment of the genetics of women with unexplained infertility, unsuccessful IVF, frequent miscarriages, or early menopause.

Common Genetic Causes of Female Infertility

1. Chromosomal Changes

Chromosomes, which contain genetic information, are important to the function of reproduction. Typically, women have 46 chromosomes (46,XX) and any changes in the structural integrity or the number of chromosomes may result in infertility.

Some examples are:

Turner syndrome (45,X)

The women who are affected by Turner syndrome are those that have a complete X chromosome and a partial X chromosome. Turner syndrome may result in:

– Poor development of the ovaries

– Ovarian failure (early)

– Delayed development of secondary sexual characteristics

– Low levels of estrogen

– Infertility

Women with mosaic Turner syndrome may have a natural conception, but women are usually required to obtain assisted reproductive technology.

Balanced Chromosomal Translocations

Balanced translocations occur when a segment of a chromosome is translocated to another segment of a different chromosome. This change is seen in women who appear normal, but may be affected by:

– Frequent miscarriages

– IVF failures

– Embryos with chromosomal alterations

– Conception difficulties

Karyotyping is a test that is used to identify chromosomal abnormalities.

2. Premature Ovarian Insufficiency (POI)

Premature ovarian insufficiency is characterized by the loss of ovarian function and the presence of infertility prior to the age of 40. POI is estimated to have a 10-20% of occurrence that is associated with a genetic deviation.

Genes that have associations with Premature Ovarian Insufficiency (POI) include:

– FMR1

– BMP15

– NOBOX

– FOXL2

Symptoms are:

– Irregular Menstruation

– Early Menopause

– Ovarian Reserve Reduction

– Increased FSH

– Infertility

Diagnosis at an early stage can give women the chance to preserve their fertility.

3. Fragile X Premutation

The FMR1 gene is the cause of Fragile X Syndrome.

Women with the Fragile X Premutation are at risk of:

– Premature Ovarian Insufficiency

– Infertility

– Early Menopause

It is recommended that women who have a diminished ovarian reserve with no explanation, and have a family history of intellectual disability, undergo genetic testing.

4. Single Gene Mutations

There are mutations in many genes that affect the formation of gametes and ovarian function.

Some genes that are included are:

– FOXL2

– FIGLA

– GDF9

– NOBOX

– BMP15

These mutations can affect:

– Development of Oocytes

– Formation of Follicles

– Ovulation

– Maintenance of Ovaries

There are numerous studies that are continuing to look at the genes that are associated with infertility.

5. Congenital Reproductive Tract Disorders

Some women are born with congenital disorders due to mutations in the genes, that affect their reproductive organs.

One of the examples is:

Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome

Women with MRKH Syndrome have the following:

– No Uterus

– Underdeveloped Vagina

– Ovaries are Normal

– 46,XX Normal Female Karyotype

Natural Pregnancy is not possible with the absence of a Uterus. However, in the places where it is allowed by law, it can be achieved by assisted reproductive technology and gestational surrogacy.

Genetic Disorders Associated with Female Infertility

There are numerous genetic conditions that can increase the likelihood of infertility.

Polycystic Ovary Syndrome (PCOS)

PCOS is caused by multiple factors, however, it has a significant genetic component.

Women with female relatives suffering from PCOS are likely more prone to developing any of the following:

– Irregular ovulation
– Hormonal imbalance
– Insulin resistance
– Infertility

Researchers are looking into various susceptibility genes associated with PCOS.

Endometriosis also has a genetic aspect.

Women with endometriosis-related first-degree relatives are likely more prone to the condition.

Endometriosis renders infertility by way of pelvic inflammatory response, adhesions, damage to fallopian tubes with a subsequent degradation of egg quality and impairment of successful implantation.

Congenital Adrenal Hyperplasia (CAH)

CAH is a genetic, endocrine disorder.

Women with CAH are likely to suffer from irregular ovulation, high levels of androgen, disturbances in menstruation and infertility.

The prognosis of fertility of patients with CAH is improved with the correct management of hormones.

How Genetics Affect Egg Quality

The impact of genetics on female infertility can be manifested in the quality of oocytes (egg).

Cell division can be represented at the level of the arrangement of chromosomes where the separation is correct.

However, genetic alterations can lead to loss of chromosomal integrity resulting in the development of poor quality embryos, failed embryo implantations, and ultimately, recurrent pregnancy losses.

The natural decline of fertility in women after the age of 35 can be explained by the increase of the risk of chromosomal alterations.

Genetics and Recurrent Pregnancy Loss

Recurrent pregnancy loss is often associated with a genetic cause.

It is estimated that in the first trimester of pregnancy, 35% of embryonic deaths are due to chromosomal alterations of the embryo.

Alterations can also arise from the parents due to balanced translocations, inversions, and chromosomal mosaicism.

In preparation of a subsequent pregnancy, genetic factors should be evaluated in order to determine the appropriateness of PGT – Preimplantation Genetic Testing – during IVF.

Genetic Testing for Female Infertility

With the rapid development of reproductive genetics, infertility assessments have advanced significantly.

Common tests include:

1. Karyotyping

Karyotyping assesses the number and structure of chromosomes. This test is particularly beneficial for women who have:

– Recurrent miscarriages

– Primary infertility

– Premature ovarian insufficiency

– Repeated IVF failures

2. Carrier Screening

Carrier screening assesses whether a couple would be at risk of having a child with a genetic disorder, and may test for:

– Cystic fibrosis

– Spinal muscular atrophy

– Thalassemia

– Tay-Sachs disease

Carrier screening is especially beneficial in assessing the risk of genetic disorders prior to the couple attempting to conceive.

3. FMR1 Gene Testing

FMR1 Gene Testing is available for women with:

– Premature ovarian insufficiency

– Diminished ovarian reserve

– Fragile X syndrome in the family

4. Whole Exome Sequencing

For cases of infertility with no diagnosis, a genetic search of reproductive disorders may assess if a rare disorder may be the cause of infertility. For this reason, Whole Exome Sequencing is increasingly useful for challenging infertility cases.

IVF with Preimplantation Genetic Testing (PGT)

The use of Preimplantation Genetic Testing (PGT) is the assessment of embryos created via IVF, prior to embryo transfer.

The potential benefits to this technology include:

– Identification of normal embryos

– Lowers the risk of a miscarriage

– Improves the likelihood of embryo transfer success

– Increases the likelihood of a baby being born

– Lowers the risk of a genetically inherited disorder for the child

Different techniques are available when using PGT, which may assess:

PGT-A for evaluating normal embryos

PGT-M for single gene disorders

PGT-SR for evaluating structurally rearranged chromosomes

This technology greatly impacts women who are of advanced maternal age, who suffer from recurrent pregnancy loss, or who have a known hereditary condition.

Can Genetic Infertility Treatment Be Successful?

Although not all genetic conditions can be treated, it is still possible for many women to have successful pregnancies.

The cause of the infertility should dictate the treatment.

Some examples of possible treatment options may include:

– IVF

– Hormonal therapy

– Egg Donation

– Embryo Donation

– Fertility Preservation

– Preimplantation Genetic Testing

– Genetic Counseling

– Ovulation Induction Medications

Women who receive a diagnosis of the cause of infertility have a greater number of options to make reproductive choices.

When Is Genetic Testing Merited?

Women should consider consulting with a fertility specialist to discuss genetic testing if they have experienced the following:

– Unexplained Infertility

– Multiple Recurrent Pregnancy Losses

– Failed IVF Cycles

– Premature/Ovarian Insufficiency

– Very Low Ovarian Reserve

– Early-Onset Menopause (before age 40)

– Congenital Reproductive Anomalies

– Family History of Genetic Disorders

Women and couples who have known genetic disorders who are planning a pregnancy should consider preconception genetic counseling.

Can Healthy Lifestyles Affect Genetic Risks?

Although it is not possible to change inherited conditions, healthy lifestyles may improve fertility and support reproductive health.

Positive changes to a person’s lifestyle can include:

– Monitoring body weight

– Smoke-free and Less Alcohol Lifestyle

– Stress Relief Techniques

– More Sleep

– Following Health Care Provider Recommendations

-Diet Improvements

-Increased Physical Activity

While a healthy lifestyle cannot treat genetic infertility, it can improve the treatment of infertility.

The Future of Genetics in Female Infertility

The rapid change of research in genetics and the fertility field will continue to improve the options available for fertility care.

These technologies are the first of their kind:

– Genomic sequencing

– Polygenic structure risk appraisal

– AI for embryo selection

– Discovery of genes for the infertility of unknown origin

– Tailored reproductive medicine

This technology provides the ability to diagnose and treat more efficiently and improve clinical pregnancy outcomes in the target population of women with infertility.

Conclusion

Genetics is significantly shaping the understanding of female infertility. Genetic factors can affect most stages of conception and pregnancy, due to chromosomal abnormalities, mutations of genes, premature ovarian insufficiency, and the Fragile X premutation among others. However, the landscape of genetic testing, counseling, and assisted reproductive technologies is more optimistic than in years past, as many of these factors can be recognized and treated accordingly.

If infertility, pregnancy loss, or the repeated failure or pregnancy attempts through assisted reproductive technologies is unexplained, comprehensive genetic testing is helpful to customize treatment and improve the chances of pregnancy. The combination of the early diagnosis, advanced reproductive technologies, and an improved lifestyle empowers women to have more successful births.

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