Sperm DNA fragmentation (SDF) can be caused by a variety of factors such as infection, chemotherapy, radiotherapy, smoking, drug use, or advanced age. SDF is linked to impaired fertilization, poor embryo quality, increased spontaneous abortion rates and reduced pregnancy rates after assisted reproduction.

Currently, there seems to be insufficient evidence to support the routine use of SDF in male factor evaluation nevertheless the importance of DNA fragmentation in spermatozoa has been acknowledged in the latest American Urological Association (AUA) and European Association of Urology (EAU) guidelines on male infertility.

Several strategies have been proposed to minimize the influence of abnormal chromatin integrity on ART outcomes. Obesity, smoking, toxins, pollutants, and Bisphenol A (BPA). They include intake of oral antioxidants, varicocele ligation, frequent ejaculation, and sperm sorting. 

Sperm DNA Fragmentation is caused by oxidative stress, a topic we explore at length in our vitamins and fertility post! Navigating the world of supplements is tough work. That doesn’t mean that all supplements are “good” or all of them are “bad”. Finding out what works and what doesn’t is important and it’s always important to confide in your physician. 

The following dietary supplements seem to have the most evidence for male fertility in general. 

L-Carnitine

Analysis showed that carnitines significantly improve total sperm motility, progressive sperm motility and sperm morphology, but don’t sperm concentration. Meat, poultry, fish, and dairy products are the richest sources of L-carnitine. Tempeh, wheat, and avocados contain some L-carnitine, while fruits, vegetables, and grains contain little. It is primarily made in the liver and kidneys and plays an important role in energy production by mitochondria.

Vitamin E

Studies have shows that vitamin E improves sperm motility (movement). Vitamin C functions to regenerate vitamin E; thus, these vitamins may work together to improve sperm function. Vitamin C has been shown to increase sperm count, motility, and morphology. Antioxidants, such as Vitamin E, which are present in some foods, can prevent damage to cells from “free radicals”, which are naturally present by-products of metabolism. Numerous studies have reported beneficial effects of antioxidant drugs on semen quality, but there is no well-defined therapeutical protocol in male infertility.

Vitamin C 

Vitamin C may aid male fertility. A 2016 study found that men with obesity who consumed vitamin C had improved sperm concentration and mobility.

Vitamin D

Vitamin D status has been linked with sexual function, testosterone levels and fertility. In addition, studies have found vitamin D deficiency is more prevalent among men with low semen production, quality and motility, along with lower inhibin B levels. Most of these studies we found highlighted a potential beneficial role of vitamin D on male reproductive health, particularly through a better sperm motility.

CoQ10

Coenzyme Q10 (CoQ10) helps generate energy in human cells. Recent studies on this enzyme’s ability to treat infertility have been very positive.

Zinc

Getting enough zinc is one of the cornerstones of male fertility. Observational studies show that low zinc status or deficiency is associated with low testosterone levels, poor sperm quality, and an increased risk of male infertility.

Folic Acid

Folic Acid is a B-vitamin that is necessary for DNA synthesis. Low levels of folic acid have been associated with a decreased sperm count and decreased sperm motility. In a recent study, the combination of zinc and folic acid results in a 75% increase in total normal sperm count in sub-fertile men.

Image by Sarah Pflug

Antidepressant use during conception and pregnancy, Anxiety, depression, and insomnia are not unusual among women TTC. However, a study in the journal Human Reproduction demonstrates that common drugs taken for combating anxiety and insomnia may increase the risk of women having an ectopic pregnancy.⁠

But what exactly is an ectopic pregnancy?⁠

It’s when a fertilized egg becomes stuck and is unable to enter the womb. This is dangerous because if the egg remains in the Fallopian tube it can burst and damage the insides of the tube resulting in internal bleeding. They are responsible for 13% of pregnancy-related deaths. Benzodiazepine contributes largely to causing such pregnancies. ⁠

These theories arose after the previously mentioned study was conducted by Stanford University School of Medicine. 1.7 million women were included in the study of which one percent were taking at least two prescriptions of ten days of pills of benzodiazepines within 90 days of conceiving between 2008 and 2015. Those taking the benzodiazepines were at a higher risk of having ectopic pregnancies. ⁠

Antidepressant use during conception and pregnancy. This study does not say that anxiety and insomnia medications do not benefit pregnant women. But it also does not say that they induce no harm. 

SSRIs are generally considered an option during pregnancy, including citalopram (Celexa), fluoxetine (Prozac) and sertraline (Zoloft). Potential complications include an increased risk of heavy bleeding after giving birth (postpartum hemorrhage), premature birth and low birth weight. There are reports of more than 10,000 pregnancies exposed to sertraline during the first trimester. A small number of studies have found associations between sertraline use during pregnancy and particular birth defects, such as heart defects.

If you feel medication is the best option, reach out to your physician first and get their opinion. 

References:⁠Elizabeth Wall-Wieler, Thalia K Robakis, Deirdre J Lyell, Reem Masarwa, Robert W Platt, Suzan L Carmichael, Benzodiazepine use before conception and risk of ectopic pregnancy, Human Reproduction, , deaa082, https://doi.org/10.1093/humrep/deaa082⁠

For more information check out The Daily Mail’s article on this study:

https://www.dailymail.co.uk/news/article-8382083/Common-anxiety-insomnia-drugs-raise-womens-risk-ectopic-pregnancy-study-shows.html

Infertility Research
Image by Sarah Pflug

Infertility research priorities have been proposed for 2021. Healthcare professionals, people with fertility problems and infertility researchers (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process resulting in an article that was published in Human Reproduction in November 2020 outlining the top future infertility-related research priorities. The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions.

The top 10 infertility research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care for people with fertility problems were identified. These top ten research priorities in each topic area outline the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems and others, to assist research funding organizations and researchers to develop their future research agenda.

Blog Series: Top Ten IVF Research Priorities

The first of the top ten infertility research priorities for medically assisted reproduction is “What are the causes of implantation failure?” In this post we will dissect the various hypotheses, tests, treatments and potential avenues of research. 

The placental paradox

The riskiest moment in any human pregnancy is when the fertilized egg attaches to the uterine wall and tries to establish a link between embryo and mother. About half of IVF pregnancies fail during this implantation stage, and we all know how many natural pregnancies end at that time as well.

At some stage in the evolution of animals, we went from mammals that lay eggs, like the monotreme family (the platypus and echidna are the living members of), to marsupials or pouch gestating mammals like kangaroos, koalas and possums, to placental mammals like us. But even among placental mammals NOT all placentas are the same.

For example, in cows there are specific spots of attachment between the fetus and the mother called cotyledons, and this is so different than in humans where we have a total attachment between the placenta and the uterus. That is why you do NOT see cows bleeding out form a uterine rupture or suffering from, for example gestational diabetes or high blood pressure. Their blood supply is just not that connected to the developing fetus. We really see that our complex placenta developed evolutionarily to protect the embryo from our own immune system.

There is a kind of paradox that perplexes researchers of infertility, a mother’s inflammatory reaction to the embryo is the biggest threat to pregnancy, it also seems necessary for the pregnancy to be successful.

Implantation Failure 

Implantation failure or RIF is an imprecisely defined clinical disorder characterized by failure to achieve pregnancy after repeated embryo transfers with genetically normal embryos. multicomponent, bidirectional signaling between the embryo and endometrium. A healthy uterus, free from endometriosis, polyps, fibroids, and with a thick lining is one piece of the puzzle, a euploid, or chromosomally normal embryo is another piece, less than 60% of euploid embryos result in pregnancy.

There are 4 main culprits or areas of active infertility research investigations. The 4 are; progesterone resistance, shifted window of receptivity, decreased integrin expression, and immune system disturbances.

Infertility researchers are identifying all of the biological components involved, developing tests to definitively say if that process is in a disease or abnormal state, and then drug treatments that work!

Progesterone resistance and infertility research

Estrogen stimulates endometrial proliferation, estrogen also causes an increase in progesterone receptor expression, enabling the establishment of the “window of receptivity”. Progestogen is directly responsible for the timing – the opening and closing of the window of receptivity. Endometriosis can actually cause progesterone resistance, disrupting the establishment, and opening or closing of the window.

There is a gene called BCL6 and its expression in the endometrium has been correlated in patients with unexplained or endometriosis-associated infertility. There is a test to see what the activity of this gene is called the Receptiva DX test.

Shifted window of receptivity 

The window of receptivity itself has a molecular signature – meaning certain genes are expressing certain proteins- and this can be determined with a test called the ERA test. Implantation itself is actually a tightly controlled inflammatory response that coordinates the embryo “invasion”.

The embryo is essentially a foreign invader. It is half NOT your own DNA but the partner or sperm source. So the uterine lining and muscular wall must allow invasion by this foreign entity, without alerting your immune system to attack, and establish a vascular blood supply that can support pregnancy.

Decreased integrin expression and infertility research

Integrins are cell to cell adhesion molecules. They are the principal receptors on animal cells for binding most extracellular matrix proteins. They are basically a little ladder that crosses the membranes of both cells, in this case the embryo’s and the uterine endometrium.

Endometrial integrins are key molecules that promote embryo attachment. Right now, we have one good drug candidate to increase integrin expression, called letrozole. Letrozole is known as an “aromatase” inhibitor there is another very common mild aromatase inhibitor – Aspirin! Aromatase, is also called estrogen synthetase or estrogen synthase, because it is an enzyme responsible for a key step in the biosynthesis of estrogens.

There are so many features of embryo implantation that are consistent with the hallmarks of cancer and tumor invasion. In fact, it is often noted that “all the tricks cancer knows, were learned from the embryo”. The tricks here being invading tissue, establishing a blood supply for uncontrolled cell growth, and evading detection by the immune system. There are dozens of drug molecules from the cancer treatment world that can inhibit aromatase.  

The immune system and infertility research

Two immune system components cytokines (which are generally associated with inflammation) and uterine natural killer cells have important roles in successful implantation.

Excessive and altered inflammatory signaling has long been suspected in implantation failure and recurrent pregnancy loss. Natural killer (NK) cells are members of a rapidly expanding family of innate lymphoid cells (ILCs). During pregnancy, NK cells are the most abundant lymphocytes in the uterus at the maternal-fetal interface and are involved in placental vascular remodeling. So discovering the complete set of cells and all their functions is still necessary.

We had one good drug molecule called glucocorticoids to investigate – they are a type of corticosteroid hormone that is very effective at reducing inflammation and suppressing the immune system. Glucocorticoids were selected to study, based on the biologic plausibility of restoring a normal immunologic response in the endometrium to promote healthy embryo implantation- however many gold standard clinical trials and meta-analysis of the data have failed to show improvement. For this reason, ASRM guidelines currently recommend against the routine use of glucocorticoids to improve implantation rates. 

But there are dozens of other suspected immune pathways and drug molecules to explore.