Authors:
Rebecca Cohen1, Avril DJ Cooper2, Teonna Sharpe3, Yusuf Mehkri4, Moshe Shalom5
Institution
1-Long Island University, Brooklyn, NY, USA
2-New York University, New York, NY, USA
3-University of Virginia, Charlottesville, VA, USA
4- University of Florida College of Medicine, Gainesville, FL, USA
5- Tel Aviv University Sackler Faculty of Medicine, Tel Aviv, Israel
Abstract
The use of isotretinoin (ITT) for the treatment of acne vulgaris and other cutaneous diseases has been associated with potential side effects, including depression, myopic changes in vision, and inflammatory bowel disease. ITT induces apoptosis of sebocytes and keratinocytes, resulting in reduced hyperkeratinization and sebogenesis. ITT’s lipophilic nature allows it to cross the blood brain barrier, altering cellular processes via all-trans-retinoic acid and retinoic acid receptor-mediated gene transcription, resulting in decreased metabolic activity and increased mood dysregulation. Physicians should take into account the increased risk of developing psychiatric disorders when prescribing ITT to patients. The use of ITT hasbeen demonstrated to cause a significant decrease in thyroid hormones T4 and T3, while increasing thyroid-stimulating hormone (TSH) levels, which is positively associated with the incidence of depression. It is important for clinicians to set realistic treatment expectations, especially with adolescents who are experiencing biological thyroid hormonal changes.The severity of acne can be linked to increased depressive symptoms, and ITT’s direct target of the CNS has shown to directly affect mood regulation and behavior. Establishing realistic treatment expectations prior to ITT initiation can prevent negative psychological effects. Low-dose ITT combined with oral prednisolone or azithromycin results in subtherapeutic levels, which only correlate to moderate treatment outcomes and lower patient satisfaction. It is crucial for clinicians to illustrate realistic outcomes to prevent further mental health decline, especially in vulnerable cohorts.
Introduction
In Vitro Fertilization (IVF) is widely used for couples who are unable to conceive naturally due to a variety of reasons (Kieffer, 1980). The main aim of IVF is the result of the birth of at least one baby per intention to treat (ITT) (Rienzi, 2021). In the United States, according to the Centers for Disease Control and Prevention (CDC) 2019 Fertility Clinic Success Rates Report, there were about 330,773 assisted reproductive technology (ART) cycles performed at 448 reporting clinics (excluding 8 cycles in which new treatment procedures were evaluated) (2019). Of the ART cycles reported by the CDC, there were a resulting 77,998 live births and 83,946 live born infants (2019). IVF is regarded as the main type of ART. As reported in the 2019 CDC data, approximately 2.0% of all infants born were conceived using the ART method (2019).
While male fertility, stress, and other outside factors all play a role in IVF outcome on a patient's IVF experience (Barnea & Tal, 1991), one of the most influential factors on IVF outcome is diet (Hornstein, 2016). While “diet,” in the medical sense simply refers to the food one eats, society has come to use the word “diet” to refer to sets of eating habits that are aimed at modifying weight. This is possibly a result of the obesity epidemic that the United States and the world are currently facing, and the increased awareness of diet and weight’s effects on overall health (Benton and Young, 2017). The prevalence of obesity has increased to about 27.5% for adults and 47.1% for children worldwide over the past 30 years (Apovian, 2016). In response, the promotion of unhealthy dietary habits, such as the promotion of eating disorder behaviors, has become common practice, and there has been a growing awareness and concern with this thin-seeking behavior, especially in online communities. (Cavazos-Rehg et al., 2019). Messages and images on the internet promote the “thin ideal,” which has led to the popularization of harmful weight management practices rather than healthier lifestyle management tools (Cavazos-Rehg et al., 2019). Some diets pose potential health hazards, and many of them lead to nutritional imbalances that may lead to a plethora of health issues (Joshi and Mohan, 2018).
As one’s diet supplies every cell in the body with vital energy and nutrients, it comes as no surprise that one’s diet can affect many physiological processes, including fertility (Sun et al., 2019). The goal of this review is to highlight the relationship between diet and IVF success that can enable clinicicians to better understand the conditions in which certain dietary choices can affect IVF and fertility.
Procedures prior to IVF implantation
The process of IVF begins with a future mother donating some of her eggs to be fertilized by sperm, either from the father or another source (Kieffer, 1980). Generally, the female partner is given the hormone Human Chorionic Gonadotropin (HCG) to stimulate the ovaries for release and harvest of eggs (Kieffer, 1980). HCG normally maintains pregnancy in women, but in IVF HCG is used to stimulate the Luteinizing Hormone (LH) surge that is necessary for ovulation (LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, 2012).
This process, from HCG administration to ovulation, takes approximately 36 hours, and it is during this time that egg retrieval occurs (Kol & Humaidan, 2021). At this stage, eggs can be harvested laparoscopically, in which the physician is able to view the state of the ovaries directly (Kieffer, 1980). This is usually done through laparoscopic ovum pick-up using an endoscope and a Verres needle to directly harvest the eggs (Gibbons et al., 2007). When IVF is performed, multiple eggs are implanted at once, with hopes of one successful pregnancy. In 4% of cases, pregnancies result in twins or higher ordinance pregnancies (Cohen, 1991).
Prior to egg harvesting, the male partner, or another male source, provides a sperm sample, which is then washed and diluted sterilely to prevent microbial contamination (Kieffer, 1980). Microbiological contamination of the sperm, although extremely rare due to safety and sterile procedures, contamination may occur from the receiving egg or from the surrounding air in the lab (Borges et al., 2020). Most commonly, contamination comes from staphylococcus species and viridans streptococci, gram-positive bacteria that may persist after washing (Borges et al., 2020). Following washing, the sperm is placed in a saltwater solution to simulate the natural conditions found in the fallopian tubes, including maintaining a pH of around 7.94 (Ng K et al., 2018). Previously, it was common for sperm morphology to be analyzed under a microscope for subnormal or abnormal morphology (Gatimel et al., 2017). Currently, however, microscopic analysis is not widely practiced, and sperm values and motility are commonly used instead, with normal values being defined as more than one million motile spermatozoa (Lundin, 2007). As for sperm morphology, recent literature has found that, unless severely deformed, morphology will not make much of a difference and therefore be non-scientific as it is not a significant predictor of IVF success. (Danis & Samplaski, 2019).
Additionally, the embryologic microbiome is very delicate, and even the smallest contaminant can decrease chances for pregnancy (Borges et al., 2020). The most subtle change in the uterine microbiota, the most common being asymptomatic genital tract infection, resulted in a negative IVF outcome in 46.3% of couples (Borges et al., 2020). The most common species present in these infections are Enterococcus faecalis (24.1%) and Streptococcus agalactiae (15.9%), and, along with other species, these infections can reduce the chances of successful pregnancy significantly. (Borges et al., 2020)
After a few hours of the sperm cells situated in a saltwater solution to simulate the female reproductive track, capacitation occurs, which enables the sperm to enter the female oocyte (Kieffer, 1980). Capacitation is when the head of the sperm undergoes a chemical reaction that allows it to penetrate the outer membrane of the oocyte (Takano & Abe, 2000). Capacitation usually occurs within 24 hours in humans, but it is important to note that there is no standard time, so long as the sperm is ready once the oocyte becomes present (LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, 2012). Under IVF conditions, this process is referred to as capacitation “in glass,” and includes holding the sperm in a state of decapacitation until they are ready to fertilize an oocyte. (Takano & Abe, 2000) This is done by exposing the sperm to extracellular Ca2+ and HCO3- among other factors (LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, 2012). Capacitation medium consists of electrolytes and energy substrates, and cholesterol acceptors (Puga Molina et al., 2018) to remove cholesterol in the head of the sperm to decrease the cholesterol and phospholipid ratio in terms of increasing membrane fluidity (LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, 2012). Unfortunately, acrosome loss is common within 24 hours of the sperm being placed in the capacitation medium (Mallett et al., 1985).
To ensure sperm penetration into the oocyte, one oocyte is confined to a volume of sperm solution, practically ensuring successful fertilization (Kieffer, 1980). If the oocyte and a sperm complete successful fertilization, the fertilized egg is then transported to a solution that supports zygote development (Kieffer, 1980). After four days, once the zygote reaches the blastocyst stage, it is implanted into the woman's uterus (Kieffer, 1980).
During the pre-implantation stages of IVF, the female patient is adequately prepared with hormones for retrieval of the blastocyst (Kieffer, 1980). One of these hormones is LH and is necessary during IVF preparation as it stimulates the maturation of the ovarian follicle (LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, 2012). LH is usually administered via subcutaneous injection during the first three days of the woman’s menstrual cycle (LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, 2012). Follicle Stimulating Hormone (FSH) is also commonly used, and it stimulates ovulation in women. It is generally administered via subcutaneous injection from Day 3 of the menstrual cycle and is administered until the body is ready for egg retrieval (LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, 2012).
Other Factors Affecting IVF Success
As with most biological processes, reproduction, including IVF, is susceptible to the effects of hormone levels of various hormones in the body. IVF requires a specific balance of hormones inside the mother’s body, such as hormones that fluctuate with normal emotional and stress levels (Barnea & Tal, 1991). This includes a careful balance between adrenocorticotropic hormone and corticotropin hormone, as well as LH, GH, GnRH, and FSH. (Barnea & Tal, 1991). Therefore, preventing exposure to stressful environments is important to maintaining the appropriate environment for a young oocyte (Barnea & Tal, 1991).
There is also a correlation between women’s preconception of diet and a successful pregnancy using IVF (Hornstein, 2016). One study established a preconception dietary risk score to estimate the nutritional habits prior to pregnancy and found that subpar nutrition was correlated with higher rates of infertility. This suggests a possible link between diet and fertility (Twigt et al., 2012). Women who conventionally use IVF as a method of reproduction generally have higher BMI scores (Lin et al., 2021), and IVF has become a conventional choice for women and men with high preconception dietary risk scores since it is more difficult for them to conceive naturally (Twigt et al., 2012).
Cigarettes, alcohol, and caffeine consumption have also been shown to lead to an increased number of miscarriages following IVF (Hornstein, 2016). Smoking in both parents, specifically, is a common risk factor for failure of implantation and miscarriage (Bashiri et al., 2018). It has also been found that alcohol consumption decreases the number of oocytes that are ready for harvesting, as well as increasing the number of miscarriages (Hornstein, 2016). With regards to caffeine's effect on IVF, the number of eggs available for retrieval and the rate of live births following IVF decrease significantly with caffeine use, in addition to the increased chance of miscarriage (Hornstein, 2016). One hypothesis for these correlations suggests that the endogenous opioids and dopamine produced following the consumption of alcohol, caffeine, or smoking inhibit GnRH secretion (Barnea & Tal, 1991). GnRH inhibition is directly correlated with LH secretion, and fluctuation of LH levels is related to decreased implantation success, as described previously. (Barnea & Tal, 1991)
For men, reducing the risk of testicular hypothermia and exposure to environmental toxins may optimize the chances of having a successful pregnancy and maintaining spermatic DNA integrity (Zini et al., 2008). It has been indicated that damaged spermatic DNA leads to an increased risk of pregnancy loss in IVF (Zini et al., 2008), and as such it has been suggested that spermatic DNA be tested by semen analysis prior to implantation (Panner Selvam et al., 2021).
Age also plays a role in IVF success, and chances of pregnancy are reduced every year after the maternal age of 40 (Ray et al., 2012). For this group, IVF is only recommended for women who have been unsuccessful with Gonadotropins and Intrauterine Insemination (IUI) (Ray et al., 2012). IVF is not meant for everyone, and unexplained infertility affects approximately 16% of couples (Ray et al., 2012). IVF is an expensive procedure and is not a consistently successful method for pregnancy, and, as the percentage of successful pregnancies decreases with increased age, most physicians prefer to attempt IUI before trying IVF (Ray et al., 2012). In addition, increased age is also a risk factor for a premature delivery, potentially putting the baby at risk (Cohen, 1991).
Alternatives to IVF
IUI, as stated previously, is the front-line treatment for female infertility (Tjon-Kon-Fat et al., 2016). IUI aims at increasing the proximity between spermatozoa and the oocyte. It is generally done alongside gonadotropin ovarian stimulation to increase the rate of success (Prentice et al., 2020). Six cycles of IUI are comparable in success rates to one cycle of IVF, although the chance of pregnancy with IUI decreases with each cycle (Prentice et al., 2020).
Recently, there have been advancements in the IVF procedure, and some clinicians have begun preferring natural cycle IVF as a means of assisted reproduction (von Wolff, 2019). This process requires no hormone injections and consists of timing the patient’s natural hormone cycles for the best implantation period (von Wolff, 2019). Natural cycle IVF is a cheaper alternative to traditional IVF, but the price paid for cost effectiveness is an increase in the amount of cycles needed to have a successful outcome (von Wolff, 2019). Although this method is becoming more popular, it still faces many problems such as unexpected LH surges and preterm ovulation (Roesner et al., 2014). Without hormone injections, there is no regulation of the maternal hormonal cycles, and it becomes increasingly more difficult to predict follicle maturity and optimal harvest periods.
Supplementation and and IVF Success
Vitamins and IVF
A variety of supplementation options have played an important role in the success of IVF. Vitamins with antioxidant properties, such as vitamins A, E, and C, play an important role in embryo development (Truong and Gardner, 2017), and an imbalance between reactive oxygen species (ROS) and antioxidants has been shown to promote oxidative stress (Rodríguez-Varela and Labarta, 2020). Overproduction of ROS can lead to precipitous pathologies affecting female reproduction and poor ovarian response (Rodríguez-Varela and Labarta, 2020), both of which can impair embryologic development and IVF success. It has been shown that ROS in seminal plasma is significantly and negatively correlated with IVF success (Majzoub and Agarwal, 2018). Antioxidants such as vitamins can neutralize free radical activity (Rodríguez-Varela and Labarta, 2020), and as such may promote IVF success.
Vitamin E is an antioxidant found mainly in high-fat vegetable products (Olson and Seidel, 2000). Interestingly, it has been shown that vitamin E has a beneficial effect on in vitro sperm function and fertilization rate in IVF (Majzoub and Agarwal, 2018). Similarly, vitamin E supplementation given to males was found to reduce malondialdehyde levels, a measure of lipid peroxidation, and contributed to improved fertilizations in patients with prior history of IVF failure (Majzoub and Agarwal, 2018). This evidence was similarly reproduced in a study by E. Kessonpoulo et al., in which men were given 600 mg of vitamin E and presented with improved spermatozoa function in vitro (Kessopoulou et al., 1995). While these results seem promising, there is no significant relationship between vitamin E serum levels, oocyte maturation, and quality in IVF (Bahadori et al., 2017), and further research is needed to understand vitamin E’s role in the female IVF patient.
Vitamin C supplementation has been found to increase serum and follicular fluid levels (Rodríguez-Varela and Labarta, 2020). The follicular microenvironment is important for the development of oocytes, and follicular fluid levels may play a role in determining the oocyte quality (Dehghani Firouzabadi et al., 2012). It is still unknown, however, if vitamin C supplementation would be beneficial for IVF patients, and more studies are needed to understand the relationship between vitamin C and fertility.
Vitamin A and its metabolites play an important role in follicular growth, steroidogenesis, oocyte maturation and embryo development (Rodríguez-Varela and Labarta, 2020). In vitro supplementation with 5nM of 9-cisRA, a vitamin A derivative, was shown to lead to a higher oocyte maturation rate. This occurred by enhancing the mitochondrial membrane potential activity, lowering ROS levels, and decreasing apoptosis in animal models (Abdelnour et al., 2019). Higher oocyte competence was a result of all-trans retinoic acid (ATRA) synthesis in the cumulus-oocyte complex and was positively correlated with higher fertilization rates (Damdimopoulou et al., 2019; Xu et al., 2018). Despite this, there have no human studies have been conducted thus far to assess the effect of Vitamin A supplementation on oocyte quality (Rodríguez-Varela and Labarta, 2020).
Coenzyme-Q10 and IVF
Co-enzyme Q10 (CoQ10) is a lipid-soluble coenzyme that is an essential component of the inner mitochondrial membrane and inhibits lipid peroxidation and DNA oxidation (Xu et al., 2018). CoQ10 supplementation has been shown to improve mitochondrial function in aged mice (Ben-Meir et al., 2015), as well as prevent mitochondrial ovarian aging in a mouse model (Özcan et al., 2016). CoQ10 supplementation in vivo was also able to restore the aging deterioration of oocyte quality in mice and porcelain cells (Ma et al., 2020). CoQ10 also improved glucose uptake in cumulus cells and increased the number of cumulus cells per oocyte, leading to improved reproductive capabilities (Rodríguez-Varela and Labarta, 2020). In the clinical setting, CoQ10 supplementation has been shown to decrease the odds of fetal aneuploidy in females between the ages of 35-43 years (Bentov et al., 2014), but these results were not reproducible in younger women (Ma et al., 2020). In younger patients, CoQ10 supplementation was shown to increase ovarian response, especially in younger women with poor ovarian reserves, however there was no observed difference in clinical pregnancy or live birth rates (Rodríguez-Varela and Labarta, 2020). More research is needed to fully assess the effects of CoQ10 on human fertility (Rodríguez-Varela and Labarta, 2020).
Melatonin and IVF
Melatonin is a hormone that is synthesized in the pineal gland from the amino acid tryptophan and plays an important role in circadian rhythm. It also plays an important role in reducing oxidative stress due to its anti-apoptotic, anti-inflammatory, and anti-androgenic properties (Rodríguez-Varela and Labarta, 2020), and, as such, follicular fluid melatonin has been shown to be a good biomarker in predicting the success of IVF and ovarian response (Zheng et al., 2018). Due to its antioxidants effects in oocytes and granulosa cells, it has been proposed that melatonin supplementation may improve oocyte quality by protecting oocytes from oxidative stress and enhance the oocytes maturation process (Rodríguez-Varela and Labarta, 2020). In one study in which patients were given melatonin supplementation, it was found that oocyte quality improved in women with a history of IVF failure due to poor oocyte quality, but this did not result in a significant difference in the number of oocytes obtained (Takasaki et al., 2003). In patients with unexplained infertility, melatonin was shown to rebalance the intrafollicular oxidative status and improved oocyte quality with a small correlated enhanced IVF success rate (Espino et al., 2019). This study suggests that melatonin holds promise for enhancing IVF success, but more research should be done to analyze the direct effects of melatonin on IVF.
Popular Diets and Health Benefits
Caloric Deficit and Macro Nutrition
The most fundamental weight loss diet is the caloric deficit, or calorie restriction, diet, which involves the intentional reduction of energy intake to below the number of calories one would have consumed otherwise (Bales and Kraus, 2013). Caloric restriction has been found to be the only non-genetic intervention that extends the mean and maximal lifespan across species (Anton and Leeuwenburgh, 2013). Studies have shown that maintaining a caloric deficit may delay cardiac aging and prevent atherosclerotic cardiovascular disease in some individuals (Bales and Kraus, 2013). Similarly, increasing evidence has shown that caloric restriction and fasting may have anticancer properties by reducing tumor progression and elevating the tolerability of chemo and radiotherapies (Alidadi et al., 2020).
While the overall effects of a low-calorie diet in overweight individuals are positive, there has been conflicting evidence with regards to its effects on fertility and IVF outcomes. Diets based on a caloric deficit have shown to reduce insulin levels, which in turn results in an improved hormonal balance in the body and a subsequent improvement in fertility for some women, such as those with polycystic ovary syndrome (McGrice and Porter, 2017). Another study has shown that the utilization of a very low-calorie diet (VLCD) in the short term may be helpful for IVF patients, but may not be feasible for all patients. For example, in the study during a period of 4-6 weeks results showed that the patients had a significant weight loss that ranged from 2.2% - 8.8% of their initial weight (Tsagareli, Noakes and Norman, 2006).
IVF treatments outcomes in this study were not evaluated definitively due to small sample sizes and individuals who had dropped out of the study. In the first group, three of the patients who were on the VLCD diet for more than 4 weeks had their oocytes collected, fertlized and transferred (independent of weight loss) (Tsagareli, Noakes and Norman, 2006). Three patients in another group had completed the dietary intervention in 4 weeks but had no fertilization. With these inconsistent trends, the benefits of caloric deficit are not readily as apparent and suggests that although this diet may work for some the duration of the diet should be chosen with caution before treatments in overweight and obese women (Tsagareli, Noakes and Norman, 2006). Additonally, in the study it was noted that the long -term approaches with caloric energy restrictions prior to IVF might be a better option for thise who are overweight and obese because it allows moderate metabolic and endrone adaption (Tsagareli, Noakes and Norman, 2006).
Caloric deficit diets reduce overall caloric intake, which subsequently reduces both carbohydrate and fat consumption. It is possible that the reduction of carbohydrate and fat intake is responsible for some of the diet’s success with regards to IVF, but more research is needed to elucidate these effects, and whether a low calorie diet should be advised for women wishing to undergo IVF.
Mediterranean Diet
The Mediterranean Diet has gained popularity recently and is based on the traditional foods from countries that border the Mediterranean Sea (Widmer et al., 2015). The diet emphasizes the consumption of fish, monounsaturated fats such as olive oil, vegetables, fruits, alcohol in moderation, whole grains, and legumes/nuts (Widmer et al., 2015). More specifically, the Mediterranean Diet does not limit calorie intake, but rather is designed to emphasize an abundance of plant-based foods and olive oil as primary sources of fat (Widmer et al., 2015). The diet also includes limited dairy and moderate amounts of fish, wine, and red meat (Widmer et al., 2015).
One benefit of this diet is that it has been suggested to help individuals preserve their health status and reduce occurrence of chronic disease (Sofi et al., 2008). For example, previous studies have reported a correlation between the Mediterranean Diet and lower risks of mortality from coronary heart and cardiovascular disease (Sofi et al., 2008). Another study, published in 2006 by Scarmeas and colleagues, reported that adhering to a Mediterranean-like diet was associated with reduced prevalence of Alzheimer’s Disease (Scarmeas et al., 2006). Despite this, more replicative studies with the Mediterranean Diet and reduced cognitive impairments must be conducted before generalizing these findings (Féart, Samieri and Barberger-Gateau, 2010).
Studies have shown that infertile women with greater adherence to the Mediterranean Diet are likely to obtain more embryos during an IVF cycle and have a rate of IVF success up to 40% greater than women who do not adhere to the diet (Sun et al., 2019, Vujkovic et al., 2010). The Mediterranean Diet has also been shown to increase the levels of folate and Vitamin B6, both of which are crucial for fetal development and whose deficiencies have been linked to congenital defects and fetal loss (Vujkovic et al., 2010). Additionally, the Mediterranean Diet’s promotion of vegetable oil consumption increases levels of n-6 fatty acids such as linoleic acid, precursors of prostaglandins that are important for optimal ovulation and endometrial receptivity.
Ketogenic Diet
The Ketogenic Diet, also known as “Keto,” was developed in the 1920s to help treat children suffering from epilepsy (Kulak and Polotsky, 2013). The Keto Diet limits an individual's consumption of carbohydrates, which in turn results in the substitution of ketone bodies as an energy source (Kulak and Polotsky, 2013). The Keto Diet has been used to treat epilepsy since the 1920s, and one study even suggested that the diet and its variants are good non-surgical alternatives for pharmaco-resistant patients with epilepsy of all ages (D’Andrea Meira et al., 2019). The Keto Diet can induce rapid weight loss with changes in biomarkers, including a reduction in serum hemoglobin A1c in patients with diabetes mellitus type 2 (O’Neill and Raggi, 2020). However, many physicians remain hesitant towards recommending this diet due to the observed rise in low density lipoprotein (LDL) cholesterol that has been seen in individuals following it (O’Neill and Raggi, 2020). Additionally, the Ketogenic Diet has been associated with the reversal of Diabetic Neuropathy. Researchers cited that diabetic neuropathy and the expression of stress-induced genes were reversed completely by maintaining the ketogenic diet for at least a 2-month time span (Poplawski et al., 2011). Despite these reports, other controlled studies examining diabetes and whether the ketogenic diet can benefit glycemic control have reported mixed outcomes, and more research must be conducted to determine the benefit of the Keto Diet on Diabetes mellitus (Evans, 2018).
Beyond epilepsy and diabetes mellitus, the ketogenic diet has the potential to help manage other conditions. For example, an increased genetic diversity of the microbiome has been observed in individuals following the Keto Diet (Dowis and Banga, 2021). The ketogenic diet has also been suggested to have a positive impact as an adjuvant treatment for cancer by starving cancer cells, making them more vulnerable to chemotherapies (Dowis and Banga, 2021). The potential impacts and benefits of the ketogenic diet in some of these areas need further analysis, and more studies to further explore the therapeutic potential of the diet should be conducted.
The effects that the ketogenic diet may have on all systems of the body, including fertility, has been a topic of intense research of late. The consensus has been thus far that it is still unproven if the ketogenic diet improves fertility (Kulak and Polotsky, 2013). One study analyzed the diets of women that were IVF eligible and found no significant association between carbohydrates and fertility (Noli et al.). Research is still needed to elucidate whether there is a significant association between the ketogenic diet and fertility, and whether any effect is due to the weight loss caused by the diet or other metabolic effects (Kulak and Polotsky, 2013).
Conclusion
Albeit the increased interest in diet, amongst researchers and in every day life, little is known about the effects of diet on IVF and fertility. More research is needed to further elucidate the role of diet in IVF, and diet should be a part of discussions between clinicians and patients wishing to conceive using IVF technology.
References
Abdelnour, S.A., Abd El-Hack, M.E., Swelum, A.A.-A., Saadeldin, I.M., Noreldin, A.E., Khafaga, A.F., Al-Mutary, M.G., Arif, M., Hussein, E.-S.O.S., 2019. The Usefulness of Retinoic Acid Supplementation during In Vitro Oocyte Maturation for the In Vitro Embryo Production of Livestock: A Review. Animals (Basel) 9. https://doi.org/10.3390/ani9080561
Alidadi, M., Banach, M., Guest, P.C., Bo, S., Jamialahmadi, T. and Sahebkar, A. (2020). The effect of caloric restriction and fasting on cancer. Seminars in Cancer Biology, 73, 30–44. https://doi.org/10.1016/j.semcancer.2020.09.010
Anton, S. and Leeuwenburgh, C. (2013). Fasting or caloric restriction for Healthy Aging. Experimental Gerontology, 48(10), 1003–1005. https://doi.org/10.1016/j.exger.2013.04.011
Apovian, C.M., 2016. Obesity: definition, comorbidities, causes, and burden. Am J Manag Care, 22(7 Suppl), 176-85.
Bahadori, M.H., Sharami, S.H., Fakor, F., Milani, F., Pourmarzi, D., Dalil-Heirati, S.F., 2017. Level of Vitamin E in Follicular Fluid and Serum and Oocyte Morphology and Embryo Quality in Patients Undergoing IVF Treatment. J Family Reprod Health 11, 74–81.
Bales, C.W. and Kraus, W.E. (2013). Caloric Restriction. Journal of Cardiopulmonary Rehabilitation and Prevention, 33(4), .201–208.https://doi.org/10.1097/HCR.0b013e318295019e
Barnea, E. R., & Tal, J. (1991). Stress-related reproductive failure. Journal of In Vitro Fertilization and Embryo Transfer, 8(1), 15–23. https://doi.org/10.1007/BF01131586
Bashiri, A., Halper, K. I., & Orvieto, R. (2018). Recurrent Implantation Failure-update overview on etiology, diagnosis, treatment and future directions. Reproductive Biology and Endocrinology, 16(1), 121. https://doi.org/10.1186/s12958-018-0414-2
Ben-Meir, A., Burstein, E., Borrego-Alvarez, A., Chong, J., Wong, E., Yavorska, T., Naranian, T., Chi, M., Wang, Y., Bentov, Y., Alexis, J., Meriano, J., Sung, H.-K., Gasser, D.L., Moley, K.H., Hekimi, S., Casper, R.F., Jurisicova, A., 2015. Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging. Aging Cell 14, 887–95. https://doi.org/10.1111/acel.12368
Benton, D. and Young, H.A. (2017). Reducing Calorie Intake May Not Help You Lose Body Weight. Perspectives on psychological science : a journal of the Association for Psychological Science, 12(5), 703–714.https://doi.org/10.1177/1745691617690878
Bentov, Y., Hannam, T., Jurisicova, A., Esfandiari, N., Casper, R.F., 2014. Coenzyme Q10 Supplementation and Oocyte Aneuploidy in Women Undergoing IVF-ICSI Treatment. Clin Med Insights Reprod Health 8, 31–6. https://doi.org/10.4137/CMRH.S14681
Borges, E. D., Berteli, T. S., Reis, T. F., Silva, A. S., & Vireque, A. A. (2020). Microbial contamination in assisted reproductive technology: source, prevalence, and cost. Journal of Assisted Reproduction and Genetics, 37(1), 53–61. https://doi.org/10.1007/s10815-019-01640-5
Cavazos-Rehg, P.A., Krauss, M.J., Costello, S.J., Kaiser, N., Cahn, E.S., Fitzsimmons-Craft, E.E. and Wilfley, D.E. (2019). ‘I just want to be skinny.’: A content analysis of tweets expressing eating disorder symptoms. PLOS ONE, 14(1), e0207506.https://doi.org/10.1371/journal.pone.0207506
Cohen, J. (1991). The efficiency and efficacy of IVF and GIFT. Human Reproduction, 6(5), 613–618. https://doi.org/10.1093/oxfordjournals.humrep.a137393
D’Andrea Meira, I., Romão, T.T., Pires do Prado, H.J., Krüger, L.T., Pires, M.E.P. and da Conceição, P.O. (2019). Ketogenic Diet and Epilepsy: What We Know So Far. Frontiers in Neuroscience, 13(5).https://doi.org/10.3389/fnins.2019.00005
Damdimopoulou, P., Chiang, C., Flaws, J.A., 2019. Retinoic acid signaling in ovarian folliculogenesis and steroidogenesis. Reprod Toxicol 87, 32–41. https://doi.org/10.1016/j.reprotox.2019.04.007
Danis, R. B., & Samplaski, M. K. (2019). Sperm Morphology: History, Challenges, and Impact on Natural and Assisted Fertility. Current Urology Reports, 20(8), 43. https://doi.org/10.1007/s11934-019-0911-7
Dehghani Firouzabadi, R., Mohammadian, F., Mashayekhy, M., Davar, R., Eftekhar, M., 2012. The correlation between follicular fluid pregnancy-associated plasma protein A levels, fertilization, and embryo quality in GnRH agonist and GnRH antagonist protocols in ART cycles. Iran J Reprod Med 10, 477–82.
Department of Health, U., Services, H., for Disease Control, C., Center for Chronic Disease Prevention, N., & Promotion, H. (n.d.). 2019 Assisted Reproductive Technology Fertility Clinic and National Summary Report. www.cdc.gov/art/reports
Dowis, K. and Banga, S. (2021). The Potential Health Benefits of the Ketogenic Diet: A Narrative Review. Nutrients, 13(5), 1654.https://doi.org/10.3390/nu13051654
Espino, J., Macedo, M., Lozano, G., Ortiz, Á., Rodríguez, C., Rodríguez, A.B., Bejarano, I., 2019. Impact of Melatonin Supplementation in Women with Unexplained Infertility Undergoing Fertility Treatment. Antioxidants (Basel) 8. https://doi.org/10.3390/antiox8090338
Evans, M. (2018). Keto diets: good, bad or ugly? The Journal of Physiology, 596(19), 4561–4561.https://doi.org/10.1113/JP276703
Féart, C., Samieri, C. and Barberger-Gateau, P. (2010). Mediterranean diet and cognitive function in older adults. Current Opinion in Clinical Nutrition and Metabolic Care, 13(1), 14–18.https://doi.org/10.1097/MCO.0b013e3283331fe4
Gatimel, N., Moreau, J., Parinaud, J., & Léandri, R. D. (2017). Sperm morphology: assessment, pathophysiology, clinical relevance, and state of the art in 2017. Andrology, 5(5), 845–862. https://doi.org/10.1111/andr.12389
Gibbons, A., Bonnet, F., Cueto, M., Catala, M., Salamone, D., & Gonzalez-Bulnes, A. (2007). Procedure for Maximizing Oocyte Harvest for In Vitro Embryo Production in Small Ruminants. Reproduction in Domestic Animals, 42(4), 423–426. https://doi.org/10.1111/j.1439-0531.2006.00802.x
Hornstein, M. D. (2016). Lifestyle and IVF Outcomes. Reproductive Sciences, 23(12), 1626–1629. https://doi.org/10.1177/1933719116667226
Hornstein, M.D. (2016). Lifestyle and IVF Outcomes. Reproductive Sciences, 23(12), 1626–1629.https://doi.org/10.1177/1933719116667226
Joshi, S. and Mohan, V., 2018. Pros & cons of some popular extreme weight-loss diets. The Indian journal of medical research, 148(5), 642.https://doi.org/10.4103/ijmr.IJMR_1793_18
Kessopoulou, E., Powers, H.J., Sharma, K.K., Pearson, M.J., Russell, J.M., Cooke, I.D., Barratt, C.L., 1995. A double-blind randomized placebo cross-over controlled trial using the antioxidant vitamin E to treat reactive oxygen species associated male infertility. Fertil Steril 64, 825–31. https://doi.org/10.1016/s0015-0282(16)57861-3
Kieffer, G. H. (1980). IVF: In Vitro Fertilization. The American Biology Teacher, 42(4), 211–231. https://doi.org/10.2307/4446902
Kol, S., & Humaidan, P. (2021). IVF and the exogenous progesterone-free luteal phase. Current Opinion in Obstetrics & Gynecology, 33(3), 188–195. https://doi.org/10.1097/GCO.0000000000000682
Kulak, D. and Polotsky, A.J. (2013). Should the ketogenic diet be considered for enhancing fertility? Maturitas, 74(1), 10–13.https://doi.org/10.1016/j.maturitas.2012.10.003
Lin, D., Li, P., Fan, D., Chen, G., Wu, S., Ye, S., Ma, H., Rao, J., Zhou, Z., Zeng, M., Huang, Z., Guo, X., & Liu, Z. (2021). Association between IVF/ICSI treatment and preterm birth and major perinatal outcomes among dichorionic‐diamnionic twin pregnancies: A seven‐year retrospective cohort study. Acta Obstetricia et Gynecologica Scandinavica, 100(1), 162–169. https://doi.org/10.1111/aogs.13981
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. (2012).
Lundin, K. (2007). L’impact de l’analyse de la morphologie du sperme sur le résultat de la FIV. Journal de Gynécologie Obstétrique et Biologie de La Reproduction, 36, 69–73. https://doi.org/10.1016/S0368-2315(07)78733-1
Ma, L., Cai, L., Hu, M., Wang, J., Xie, J., Xing, Y., Shen, J., Cui, Y., Liu, X.J., Liu, J., 2020. Coenzyme Q10 supplementation of human oocyte in vitro maturation reduces postmeiotic aneuploidies. Fertil Steril 114, 331–337. https://doi.org/10.1016/j.fertnstert.2020.04.002
Majzoub, A., Agarwal, A., 2018. Systematic review of antioxidant types and doses in male infertility: Benefits on semen parameters, advanced sperm function, assisted reproduction and live-birth rate. Arab J Urol 16, 113–124. https://doi.org/10.1016/j.aju.2017.11.013
Mallett, P. J., Stock, C. E., & Fraser, L. R. (1985). Acrosome loss in human sperm incubated in vitro under capacitating conditions. International Journal of Andrology, 8(5), 357–364. https://doi.org/10.1111/j.1365-2605.1985.tb00848.x
McGrice, M. and Porter, J. (2017). The Effect of Low Carbohydrate Diets on Fertility Hormones and Outcomes in Overweight and Obese Women: A Systematic Review. Nutrients, 9(3), 204.https://doi.org/10.3390/nu9030204
Ng, K. Y. B., Mingels, R., Morgan, H., Macklon, N., & Cheong, Y. (2018). In vivo oxygen, temperature and pH dynamics in the female reproductive tract and their importance in human conception: a systematic review. Human Reproduction Update, 24(1), 15–34. https://doi.org/10.1093/humupd/dmx028
O’Neill, B. and Raggi, P. (2020). The ketogenic diet: Pros and cons. Atherosclerosis, 292, 119–126.https://doi.org/10.1016/j.atherosclerosis.2019.11.021
Olson, S.E., Seidel, G.E., 2000. Culture of in vitro-produced bovine embryos with vitamin E improves development in vitro and after transfer to recipients. Biol Reprod 62, 248–52. https://doi.org/10.1095/biolreprod62.2.248
Özcan, P., Fıçıcıoğlu, C., Kizilkale, O., Yesiladali, M., Tok, O.E., Ozkan, F., Esrefoglu, M., 2016. Can Coenzyme Q10 supplementation protect the ovarian reserve against oxidative damage? J Assist Reprod Genet 33, 1223–30. https://doi.org/10.1007/s10815-016-0751-z
Panner Selvam, M. K., Ambar, R. F., Agarwal, A., & Henkel, R. (2021). Etiologies of sperm DNA damage and its impact on male infertility. Andrologia, 53(1). https://doi.org/10.1111/and.13706
Poplawski, M.M., Mastaitis, J.W., Isoda, F., Grosjean, F., Zheng, F. and Mobbs, C.V. (2011). Reversal of Diabetic Nephropathy by a Ketogenic Diet. PLoS ONE, 6(4), e18604.https://doi.org/10.1371/journal.pone.0018604
Prentice, L., Sadler, L., Lensen, S., Vercoe, M., Wilkinson, J., Edlin, R., Chambers, G. M., & Farquhar, C. M. (2020). IVF and IUI in couples with unexplained infertility (FIIX study): study protocol of a non-inferiority randomized controlled trial. Human Reproduction Open, 2020(3). https://doi.org/10.1093/hropen/hoaa037
Puga Molina, L. C., Luque, G. M., Balestrini, P. A., Marín-Briggiler, C. I., Romarowski, A., & Buffone, M. G. (2018). Molecular Basis of Human Sperm Capacitation. Frontiers in Cell and Developmental Biology, 6. https://doi.org/10.3389/fcell.2018.00072
Ray, A., Shah, A., Gudi, A., & Homburg, R. (2012). Unexplained infertility: an update and review of practice. Reproductive BioMedicine Online, 24(6), 591–602. https://doi.org/10.1016/j.rbmo.2012.02.021
Rienzi, L., Cimadomo, D., Vaiarelli, A., Gennarelli, G., Holte, J., Livi, C., Aura Masip, M., Uher, P., Fabozzi, G., & Ubaldi, F. M. (2021). Measuring success in IVF is a complex multidisciplinary task: time for a consensus? In Reproductive BioMedicine Online (Vol. 43, Issue 5, pp. 775–778). Elsevier Ltd. https://doi.org/10.1016/j.rbmo.2021.08.012
Rodríguez-Varela, C., Labarta, E., 2020. Clinical Application of Antioxidants to Improve Human Oocyte Mitochondrial Function: A Review. Antioxidants (Basel) 9. https://doi.org/10.3390/antiox9121197
Roesner, S., Pflaumer, U., Germeyer, A., Montag, M., Strowitzki, T., & Toth, B. (2014). Natural cycle IVF: evaluation of 463 cycles and summary of the current literature. Archives of Gynecology and Obstetrics, 289(6), 1347–1354. https://doi.org/10.1007/s00404-013-3123-2
Scarmeas, N., Stern, Y., Tang, M.-X., Mayeux, R. and Luchsinger, J.A. (2006). Mediterranean diet and risk for Alzheimer’s disease. Annals of Neurology, 59(6), 912–921.https://doi.org/10.1002/ana.20854
Sofi, F., Cesari, F., Abbate, R., Gensini, G.F. and Casini, A. (2008). Adherence to Mediterranean diet and health status: meta-analysis. BMJ, 337(sep11 2), a1344–a1344https://doi.org/10.1136/bmj.a1344
Sun, H., Lin, Y., Lin, D., Zou, C., Zou, X., Fu, L., Meng, F. and Qian, W. (2019). Mediterranean diet improves embryo yield in IVF: a prospective cohort study. Reproductive Biology and Endocrinology, 17(1).https://doi.org/10.1186/s12958-019-0520-9
Takano, H., & Abe, K. (2000). Changes in the surface structure of the hamster sperm head associated with maturation, in vitro capacitation and acrosome reaction: an atomic force microscopic study. Journal of Electron Microscopy, 49(3), 437–443. https://doi.org/10.1093/oxfordjournals.jmicro.a023826
Takasaki, A., Nakamura, Y., Tamura, H., Shimamura, K., Morioka, H., 2003. Melatonin as a new drug for improving oocyte quality. Reprod Med Biol 2, 139–144. https://doi.org/10.1111/j.1447-0578.2003.00035.x
Tjon-Kon-Fat, R. I., Bensdorp, A. J., Scholten, I., Repping, S., van Wely, M., Mol, B. W. J., & van der Veen, F. (2016). IUI and IVF for unexplained subfertility: where did we go wrong? Human Reproduction, 31(12), 2665–2667. https://doi.org/10.1093/humrep/dew241
Truong, T., Gardner, D.K., 2017. Antioxidants improve IVF outcome and subsequent embryo development in the mouse. Hum Reprod 32, 2404–2413. https://doi.org/10.1093/humrep/dex330
Tsagareli, V., Noakes, M. and Norman, R.J. (2006). Effect of a very-low-calorie diet on in vitro fertilization outcomes. Fertility and Sterility, 86(1), 227–229.https://doi.org/10.1016/j.fertnstert.2005.12.041
Twigt, J. M., Bolhuis, M. E. C., Steegers, E. A. P., Hammiche, F., van Inzen, W. G., Laven, J. S. E., & Steegers-Theunissen, R. P. M. (2012). The preconception diet is associated with the chance of ongoing pregnancy in women undergoing IVF/ICSI treatment. Human Reproduction, 27(8), 2526–2531. https://doi.org/10.1093/humrep/des157
Von Wolff, M. (2019). The role of Natural Cycle IVF in assisted reproduction. Best Practice & Research Clinical Endocrinology & Metabolism, 33(1), 35–45. https://doi.org/10.1016/j.beem.2018.10.005
Vujkovic, M., de Vries, J. H., Lindemans, J., MacKlon, N. S., van der Spek, P. J., Steegers, E. A. P., & Steegers-Theunissen, R. P. M. (2010). The preconception Mediterranean dietary pattern in couples undergoing in vitro fertilization/intracytoplasmic sperm injection treatment increases the chance of pregnancy. Fertility and Sterility, 94(6), 2096–2101. https://doi.org/10.1016/j.fertnstert.2009.12.079
Widmer, R.J., Flammer, A.J., Lerman, L.O. and Lerman, A. (2015). The Mediterranean Diet, its Components, and Cardiovascular Disease. The American Journal of Medicine, 128(3), 229–238.https://doi.org/10.1016/j.amjmed.2014.10.014
Xu, Y., Nisenblat, V., Lu, C., Li, R., Qiao, J., Zhen, X., Wang, S., 2018. Pretreatment with coenzyme Q10 improves ovarian response and embryo quality in low-prognosis young women with decreased ovarian reserve: a randomized controlled trial. Reprod Biol Endocrinol 16, 29. https://doi.org/10.1186/s12958-018-0343-0
Zheng, M., Tong, J., Li, W.-P., Chen, Z.-J., Zhang, C., 2018. Melatonin concentration in follicular fluid is correlated with antral follicle count (AFC) and in vitro fertilization (IVF) outcomes in women undergoing assisted reproductive technology (ART) procedures. Gynecol Endocrinol 34, 446–450. https://doi.org/10.1080/09513590.2017.1409713
Zini, A., Boman, J. M., Belzile, E., & Ciampi, A. (2008). Sperm DNA damage is associated with an increased risk of pregnancy loss after IVF and ICSI: systematic review and meta-analysis. Human Reproduction, 23(12), 2663–2668. https://doi.org/10.1093/humrep/den321
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