The Role of Homocysteine and How to Optimize It for Healthier Fertility

What is Homocysteine?

Homocysteine is a blood test marker that we look at with everyone who works with us.  We use it along with other blood markers to assess how well the body is using B vitamins (especially B6, B9, and B12), and how much inflammation may be present in the body.  If homocysteine levels are elevated beyond the optimal range, it may be an indicator of poor egg or sperm quality and less than optimal fertility.

So where does it come from?  Homocysteine is an amino acid produced in the body as a byproduct of methionine metabolism. In other words, we don’t eat it, like we do other amino acids in protein-rich foods, and it should be an intermediate product that gets converted either to methionine or cysteine.  Methionine is important for many functions in the body, according to Martinez et al, (PMID:28929442) methionine can regulate metabolic processes, the innate immune system, and digestive functioning in mammals. It also is important in the biosynthesis of glutathione, our “master antioxidant.”  Cysteine also contributes to glutathione formation in the body, among other roles.  

What factors contribute to an increase in homocysteine levels?

Several factors can contribute to elevated homocysteine levels. Here are some common causes:

1. Nutritional deficiencies: Deficiencies in vitamins B6, B12, and folic acid (B9) can impair the body's ability to metabolize and convert homocysteine into other substances. Inadequate intake or absorption of these vitamins can lead to increased homocysteine levels.
2. Genetic factors: Certain genetic mutations can affect the enzymes involved in homocysteine metabolism, leading to elevated levels. For example, mutations in the MTHFR gene can impair the conversion of homocysteine to methionine, resulting in increased homocysteine levels.
3. Lifestyle choices: Unhealthy lifestyle habits such as smoking, excessive alcohol consumption, and sedentary behavior have been associated with higher homocysteine levels. These factors can disrupt normal homocysteine metabolism and contribute to elevated levels.
4. Medical conditions: Certain medical conditions can impact homocysteine levels. For example, kidney disease, hypothyroidism, and certain gastrointestinal disorders can interfere with homocysteine metabolism and lead to increased levels.
5. Medications: Some medications, such as certain anticonvulsants and methotrexate (used for certain medical conditions), can affect homocysteine metabolism and result in elevated levels.
6. Age and gender: Homocysteine levels tend to increase with age, particularly in postmenopausal women. The reasons for this are not fully understood, but hormonal changes and decreased nutrient absorption with age may contribute.

It's important to note that while these factors can contribute to elevated homocysteine levels, individual reasons for elevated homocysteine are varied.  Often there is more than one root cause, but what we see is giving the body a boost of nutrients like B vitamins usually lower homocysteine.  

Why is Homocysteine important to male fertility?

Homocysteine has been implicated in male fertility due to its potential impact on sperm quality and function. Elevated levels of homocysteine have been associated with reduced sperm parameters and fertility issues in men. Here are some ways in which homocysteine may affect male fertility:

1. Sperm production: Homocysteine has been found to disrupt the process of spermatogenesis, which is the production of mature sperm cells. High levels of homocysteine can interfere with the normal development and maturation of sperm, leading to reduced sperm count and impaired sperm quality.
2. DNA damage: Increased homocysteine levels have been linked to DNA damage in sperm. DNA integrity is crucial for normal fertilization and embryo development. When sperm DNA is damaged, it can lead to reduced fertility and an increased risk of miscarriages.
3. Oxidative stress: Homocysteine can induce oxidative stress, which occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defense mechanisms. Excessive oxidative stress can negatively affect sperm function and viability.
4. Blood flow: Elevated homocysteine levels have been associated with impaired blood vessel function and reduced blood flow. In the context of male fertility, this can lead to inadequate blood supply to the testes, affecting sperm production and overall reproductive function.

What does the research look like for male fertility? 

The studies below look at homocysteine and DNA integrity in males.  Higher DNA fragmentation, or damage, has been shown to be a factor in recurrent pregnancy loss.  We look at homocysteine levels in men and address them for both their own health as a father and for preventing pregnancy loss.

1. “The Influence of Sperm DNA Damage and Semen Homocysteine on Male Infertility”  The spermatozoa and Homocysteine levels in the study group with severe sperm abnormalities were significantly higher than those of the normal sperm group. The sperm DNA Fragmentation Index was higher in the group with high serum Homocysteine level, and high Serum Homocysteine level was correlated with decreased sperm concentration and sperm vitality.

2. "The Influence of Sperm DNA Damage and Semen Homocysteine on Male Infertility” - This case-control study looked at males with very low or no sperm counts and found that serum homocysteine level was negatively correlated with sperm concentration and sperm vitality. 

3. “Hyperhomocysteinemia in men with a reproductive history of fetal neural tube defects: Three case reports and literature review”  Findings from this case reports and published literature imply that hereditary hyperhomocysteinemia in men affects sperm quality and sperm DNA methylation and causes epigenetic modifications that can result in fetal NTDs. We recommend monitoring homocysteine and folate levels in men before conception and supplementing with folate as needed, especially in men with a reproductive history of fetuses with a neural tube or other birth defects.

4. "The male contribution to recurrent pregnancy loss” - This paper evaluated the current evidence on the male role in pregnancy loss.  Is it likely due to the fact that abnormal DNA fragmentation is the end result of multiple different mechanisms including environmental exposures, varicoceles, gene alteration, and epigenetic changes resulting in an inherent susceptibility to DNA damage? They conclude that more studies are needed, especially focusing on epigenetic modifications and gene alterations.

Why is Homocysteine important to female fertility?

Homocysteine can play a role in female fertility due to its impact on various aspects of reproductive health. Here are some reasons why homocysteine is considered important in female fertility:

1. Ovulation: Elevated levels of homocysteine have been associated with disturbances in the normal ovulation process. Disruptions in ovulation can affect fertility by reducing the release of mature eggs necessary for conception.
2. Implantation and Pregnancy: Healthy homocysteine metabolism is important for the successful implantation of a fertilized egg in the uterine lining. High levels of homocysteine have been linked to impaired embryo implantation and an increased risk of early pregnancy loss.
3. Hormone Regulation: Homocysteine can influence hormone balance, including estrogen and progesterone levels. Hormonal imbalances can disrupt the menstrual cycle and affect fertility by interfering with the development and release of eggs.
4. Vascular Health: Elevated homocysteine levels can impair blood vessel function and lead to reduced blood flow to reproductive organs. Sufficient blood flow is crucial for optimal ovarian function, development of the uterine lining, and overall reproductive health.
5. Egg Quality: Homocysteine has been implicated in oxidative stress, which can negatively impact egg quality. High levels of homocysteine may increase oxidative damage and affect the genetic integrity of eggs, potentially reducing fertility.
6. Pregnancy Complications: Elevated homocysteine levels have been associated with an increased risk of pregnancy complications such as preeclampsia, gestational hypertension, and fetal growth restriction. These conditions can affect the health of both the mother and the developing baby.

Evidence correlating elevated Homocysteine to female fertility

1. “Comparison of the Levels of Blood Homocysteine between Women with Unexplained Infertility and Normal Fertility” This was a cross-sectional study of 30 women with normal fertility as controls and 30 with unexplained infertility as cases.  Based on the institutional cut-off value for normal serum fasting homocysteine level of 15 micromoles/L, the frequency of hyper-homocysteinemia was significantly higher in the unexplained infertility group compared to the control group. Fasting serum homocysteine levels were significantly higher in the unexplained infertility group compared to the normal fertility group. Serum fasting homocysteine levels and frequency of hyper-homocysteinemia were increased in women with unexplained infertility compared to age and BMI-matched women with normal fertility.

2. “Folate, homocysteine and the ovarian cycle among healthy regularly menstruating women”  This study asked the question how are concentrations of plasma homocysteine and serum folate associated with reproductive hormones and anovulation in regularly menstruating women?  What they determined was higher homocysteine was associated with sporadic anovulation and hormonal changes that may be indicative of impaired ovulatory function, but higher serum folate was associated only with higher luteal phase progesterone.

3. “Effects of hyperhomocysteinemia and metabolic syndrome on reproduction in women with polycystic ovary syndrome: a secondary analysis,” This study asked: What is the association between hyperhomocysteinemia (HHCY), metabolic syndrome, and reproductive outcomes among women with polycystic ovary syndrome (PCOS).   They found in women with PCOS, HHCY contributes to increased pregnancy loss and reduced ovulation, and metabolic syndrome was related to defects in ovulation, conception, pregnancy, pregnancy loss, and live birth, indicating that the two conditions lead to defects at various reproductive stages.

How to improve Homocysteine levels for healthier fertility?

To improve homocysteine levels for healthier fertility, you can focus on lifestyle and dietary modifications that promote balanced methylation processes in the body. Here are some tips that may help:

1. Increase intake of B vitamins: Consume foods rich in vitamins B6, B12, and folic acid (B9). These vitamins play a crucial role in homocysteine metabolism. Include sources such as leafy green vegetables, legumes, nuts, seeds, fish, poultry, and eggs in your diet. You may also consider taking supplements under the guidance of a healthcare professional.
2. Consume foods high in folate: Folate is particularly important for healthy homocysteine metabolism. Incorporate folate-rich foods such as spinach, asparagus, broccoli, chickpeas, and lentils into your meals.
3. Limit alcohol consumption: Excessive alcohol intake can deplete B vitamins, including folate, necessary for homocysteine regulation. Moderation is key, so limit alcohol consumption or avoid it altogether if possible.
4. Quit smoking: Smoking is associated with increased homocysteine levels. If you smoke, consider seeking support to quit smoking to improve your overall health and fertility potential.
5. Manage stress: Chronic stress can affect methylation processes (and thus homocysteine levels)  in the body. Engage in stress-reducing activities such as exercise, meditation, yoga, or other relaxation techniques to help manage stress levels.
6. Maintain a healthy weight: Obesity has been linked to higher homocysteine levels. Focus on maintaining a healthy weight through regular exercise and a balanced diet.
7. Get regular exercise: Engaging in regular physical activity promotes overall health, including healthy metabolism. Aim for a combination of cardiovascular exercises, strength training, and flexibility exercises to support optimal health.
8. Consult with a healthcare professional: If you have concerns about homocysteine levels and fertility, it is advisable to consult with a healthcare professional. They can assess your situation, conduct relevant tests, and provide personalized recommendations tailored to your needs.

It's important to recognize that optimizing fertility involves multiple factors beyond homocysteine alone. Maintaining overall health, following a balanced diet, managing stress, and adopting a healthy lifestyle is crucial for promoting reproductive well-being. By taking a comprehensive approach to fertility, addressing various aspects of health, and seeking professional advice, you can optimize your chances of achieving the family of your dreams. Remember, each person's journey is unique, and healthcare professionals like HFI can provide tailored recommendations based on individual needs and circumstances.  Reach out to us and schedule your Fertility Insight Session today!