Did you know? Approximately 35% of all infertility cases are due to female factors alone? Infertility in women can impact egg development, egg maturation, and the ability to conceive. Furthermore, these factors can also affect post-fertilization processes such as the potential of fertilised egg for preimplantation development, implantation, and foetal growth.

Female infertility can arise from a variety of causes, including structural issues in the reproductive system, infections, autoimmune disorders, and more. However, many people may not be aware of the genetic causes of female infertility. These factors are equally important to consider when looking at the cases of infertility in women, since nearly 50% of infertility cases occur due to genetic factors.

In this blog, we’ll be going over the factors that can influence some of the most important aspects of female fertility such as egg development, maintenance of ovarian reserve, hormonal signalling, development of female reproductive organs, and implantation potential of fertilised eggs.

But before getting to the genetic causes of female infertility, let’s first understand female infertility in general.

What Is Female Infertility?

Female infertility refers to a woman’s inability to conceive after one year of unprotected intercourse. It may be caused by ovulatory disorders, tubal occlusion, endometriosis, hormonal imbalances, and genetic causes.

What Are Risk Factors For Infertility?

Several factors can contribute to female infertility, including:

• Hormonal Imbalances: Conditions like polycystic ovary syndrome (PCOS) and thyroid disorders can disrupt ovulation.
• Structural Abnormalities: Uterine fibroids, endometriosis, or blocked fallopian tubes can prevent conception.
• Lifestyle Choices: Smoking, excessive alcohol consumption, high stress levels, and poor diet may contribute to infertility.
• Genetic Factors: Mutations or chromosomal abnormalities can affect ovarian function, hormone production, and embryo implantation.

How Does Age Impact Female Infertility?

A woman’s fertility declines with age due to diminishing ovarian reserve. The number and quality of eggs decrease over time, leading to lower chances of conception and higher risks of chromosomal abnormalities. Women over 35 experience a more significant decline in fertility, often requiring medical assistance for conception.

Diagnosis & Tests For Female Infertility

If a woman struggles to conceive, a fertility specialist may recommend various tests, such as:

• Hormone level assessments (FSH, LH, AMH, and estrogen) to evaluate ovarian function.
• Ultrasounds and imaging to check for structural abnormalities in the uterus or ovaries.
• Genetic testing to identify potential chromosomal abnormalities or gene mutations that may be contributing to infertility.

How Is Female Infertility Treated?

Treatment depends on the underlying cause. Some common options include:

• Lifestyle modifications like maintaining a healthy diet, reducing stress, and avoiding smoking.
• Medications such as fertility drugs to stimulate ovulation.
• Surgical interventions to remove fibroids, treat endometriosis, or repair blocked fallopian tubes.
• Assisted reproductive technologies (ART) like in-vitro fertilization (IVF) for cases where natural conception isn’t possible.

Can Female Infertility Be Prevented?

While some causes of infertility, such as genetic mutations, cannot be prevented, certain steps may help preserve fertility:

• Early family planning to avoid age-related decline in ovarian reserve.
• Maintaining reproductive health by managing conditions like PCOS and endometriosis.
• Considering egg freezing for those who want to delay pregnancy but preserve their eggs for the future.

What Can I Expect if I Have Infertility?

Infertility can be emotionally and physically challenging, but many women conceive with the right treatment. Identifying the cause — whether hormonal, structural, or genetic — is key to making informed decisions. A reproductive specialist can help determine the underlying factors and recommend suitable options.

Advanced solutions like genetic testing, such as LifeCell’s InferGenes-Female, offer valuable insights into genetic influences on fertility, empowering you to take informed steps.

Next, let’s explore the genetic causes of female infertility by understanding the basics of genes.

What Are Genes?

Genes are made up of DNA, which are passed on from parents to their children. They carry vital information that enable cells to function and produce specific proteins. Genes are responsible for various physical characteristics, such as the colour of your eyes or hair. Normally, genes function without any issues, effectively expressing specific information or instructions. However, if genes undergo mutations or changes owing to various risk factors, they may cause genetic conditions or disorders that further trigger various health complications including infertility.

Now, let’s take a look at how genes affect various reproductive-related factors in women.

Genetic Causes Of Female Infertility

As we’ve already discussed above, there are a variety of factors that can cause infertility in women. However, here we will focus only on the genetic causes of female infertility. Given below are some of the most prevalent fertility aspects that can be influenced by genetic factors:

i. Egg Development/ Oocyte Development

Egg development refers to the process through which an oocyte matures before it is released during ovulation, and is ready to be fertilised by sperm. An oocyte is an egg that is still in the developmental stage. Just like any other biological procedures taking place within your body, oocyte development involves the interaction of multiple genes.

Mutations that occur in genes that participate in oocyte development have been identified as responsible for a wide range of reproductive system abnormalities. These abnormalities lead to reproductive disorders associated with female infertility.

The genetic mutations associated with above-mentioned genes can give rise to conditions such as:

• Premature ovarian insufficiency (POI)- A disorder in which the ovaries stop functioning completely.
• Disorders of sex development (DSD)- A condition wherein, an individual has chromosomes, different from their gender. For instance, if someone has XY- sex chromosome, it means they should have male sex organs. But in cases where a person is diagnosed with DSD, their sex organs can be of a female or look different from typical male reproductive organs.
• Gonadal dysgenesis- It is the abnormal development of ovaries.

ii. Maintenance Of Ovarian Reserve

The quantity of remaining eggs in a woman’s ovaries (that can be fertilised to conceive a baby) is known as ovarian reserve. It tends to diminish or decrease in number as a woman ages. However, there are cases when the decline of ovarian reserve could also occur due to a variety of factors, including a woman’s genes.

Let’s examine some genetic causes of female infertility that may also impact the maintenance of ovarian reserve in women:

Fragile X Mental Retardation (FMR) Genes

FMR genes are the group of regulatory genes that are present on the X chromosome. Any mutation to these genes are known to give rise to neuropsychiatric disorders (a generalised term for all the disorders inclusive of both neurology and psychiatry-related conditions). Moreover, mutations of these genes can also cause low ovarian volume and primary ovarian insufficiency (POI).

Single Nucleotide Polymorphism (SNP)

It’s a genetic mutation that occurs in the genes which helps with the production of AMH (Anti-Müllerian hormone), FSH (follicle stimulating hormone), LH (luteinizing hormone) and oestrogen. Development of SNPs are known to cause poor ovarian response (when the ovaries do not respond well to fertility medications, resulting in few or no eggs being produced14), and diminished ovarian reserve in females. This phenomenon not only impacts natural pregnancies but also hinders the IVF results.

Mutations Of Genes Involved In Germ Cell Formation, Meiosis & DNA Repair

BRCA genes are responsible for DNA repair in cells in females.15 Studies show the mutation in BRCA genes causes ovarian reserve decline and premature ovarian ageing. Additionally, it’s also known to develop a number of mutations in the DNA of female germ cells (cells from which oocytes/ eggs develop) and follicular function of ovaries.

iii. Hormonal Signalling

In humans, the activity and release of sex hormones related to reproduction (pregnancy) are regulated by the hypothalamic-pituitary-gonad axis (HPG axis). The HPG axis comprises different parts of the brain that work together harmoniously to perform various functions. This mechanism signals the secretion of GnRH (gonadotropin-releasing hormone) whenever reproductive activities are required. GnRH, in turn, stimulates the release of other hormones essential for reproductive functions, such as LH (luteinizing hormone) and FSH (follicle-stimulating hormone).

In women, FSH and LH help the body prepare for pregnancy. Moreover, FSH also helps in the maturation of eggs in ovaries, while LH triggers ovulation, which allows the egg to be released from the ovary for fertilization.

Until now, you may have understood how vital GnRH is for reproductive functions. However, certain genetic factors can affect its production. In the following section, we will explore some of these genetic causes that influence GnRH and eventually also impact female fertility:

Idiopathic hypogonadotropic hypogonadism (IHH)

It’s an umbrella term for genetic disorders, which impact the production and/ or function of GnRH, consequently lowering levels of sex hormones.

Mutations Of Gonadotropins

Gonadotropins, namely LH (luteinizing hormone) and FSH (follicle-stimulating hormone), are secreted by the pituitary gland. Mutations in the receptors of these gonadotropin (molecules that bind to LH and FSH), can have various effects. These mutations can lead to abnormal activation, complete inactivation, or excessive activation of LH and FSH hormones. In certain cases, when such mutations cause continuous activation of the FSHR (follicle-stimulating hormone receptor), it results in ovarian tumours and premature menopause in women.

iv. Development Of Female Reproductive Organs

Development of female reproductive organs could be influenced by a number of genetic factors, some of which we’ve discussed briefly below.

Sex Chromosome Abnormality

Sex chromosomal abnormalities are disorders or diseases that arise due to mutations in either the number or composition of sex chromosomes. Did you know? Approximately 1 in every 650 female live births involves some form of sex chromosome abnormality? However, not every case is reported as the mutations may not be severe enough to manifest noticeable symptoms.

Turner’s Syndrome is an example of a sex chromosome abnormality. Females with this condition are born with partial or complete absence of X chromosome (females typically have two X chromosomes). A common symptom of Turner syndrome includes abnormally developed ovaries.

Genetic Mutations

Mutations that occur in specific genes which are involved in the development of female reproductive organs can result in anatomical (structural) abnormalities. For instance, mutations in the HNF1B, LHX1, WNT4, WNT7A, and WNT9B genes have been associated with abnormalities in the development of the ovaries, uterus, and vagina.

Homeobox Genes

Homeobox genes, a family of genes responsible for regulating the growth of various body parts, also play a crucial role in the development of reproductive organs. Mutation taking place in homeobox genes- HOXA10 and HOX11, can lead to abnormal development of the uterus.

v. Implantation Potential Of Fertilised Egg

After fertilisation (when egg and sperm fuse), the fertilised egg travels down the fallopian tube to the uterus. There, it divides into many cells and becomes a blastocyst (mass of multiple, dividing cells). The blastocyst implants in the lining of the uterus, which marks the first step in pregnancy. Given below are a couple genetic factors that can influence implantation.

Mitochondrial DNA Gene Mutation

The POLG gene is responsible for initiating the synthesis of mitochondrial DNA (circular chromosome/ genetic material found inside mitochondria24). If the POLG gene undergoes mutations or develops defects, it can lead to primary ovarian insufficiency (POI) in women. Furthermore, if the mitochondrial DNA functions abnormally, it can also cause poor pre-implantation development and implantation failure.

Maternal Genes

A mother’s genes play a crucial role in various functions and activities that occur during post-fertilization processes (events taking place when egg and sperm have fused). This includes pre-implantation development, which takes place when the fused egg develops into an embryo before attaching itself into uterine wall/womb. It must be noted that mutations in genes from both the mother’s and father’s side (such as PADI6, PATL2, TLE6, NLRP2, NLRP5, and WEE2) can contribute to implantation failure (when the embryo is not able to attach itself to uterine wall25).

After learning how different genetic factors can impede one’s reproductive journey towards parenthood, you may have realised the importance of determining whether genetic mutations affect your fertility. To find the answer to this question, exploring InferGenes-Female can be helpful!

Parting Thoughts!

In conclusion, this blog has shed light on the genetic causes of female infertility, highlighting the significant role genetics play in female reproductive health. We exclusively explored how gene mutations can impact female fertility by influencing factors related to the development of eggs, reproductive organs, and hormones. Through the aforementioned discussed topics, we hope to have raised awareness of how genetics may impact your reproductive treatment and choices. This makes opting for tests like InferGenes even more imperative, especially for women planning to start their motherhood journey.

Moreover, taking this test can provide you with invaluable insights in many cases, some of which are listed below:

• If you have been trying to conceive but have been unsuccessful.
• If you have a family history of genetic diseases and want to know the probability of passing them down to your baby.
• If you have recently received abnormal hormone test results.
• If you are planning to start a family soon.

So, ladies and gents, regardless of your current or future parenthood plans, it is important to understand that undergoing genetic testing can help you gain valuable information and make informed decisions regarding your reproductive health and family planning!

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