Lithium and male fertility

A few months ago, we covered the topic of lithium carbonate and its effects on pregnancy outcomes. The research we uncovered is detailed here—an essential read for bipolar patients who are planning a pregnancy.

However, as we’ve been learning through our blogs dedicated to pregnancy and preconception, male health is a vital factor to consider for preconception health and fertility.

Here, we will review critical studies on the role of lithium and male fertility. Because this is a niche topic, there is a lack of research, particularly human research, regarding the effects of lithium on the male reproductive system.

One of the main issues with the studies is that they are almost all conducted on rats, and the human sperm studies I found were in vitro, not in vivo.

However, the available yet scant literature on lithium and male fertility is essential to consider for couples focused on preconception health or struggling with infertility.

In this blog, we’ll examine what animal studies show us and then move on to results from human studies exploring the effect that lithium has on sperm. Finally, we’ll consider the protective effects lithium may have concerning sperm damage by other toxic substances.

Lithium and male fertility from the lens of animal studies

Most research on lithium and male reproductive health is available from studies conducted on rats. As with any other model looking at cause and effect, the trouble with animal studies is that while providing insight into disease mechanisms, extrapolation to humans can be unreliable.

The other issue is that many of the rat studies were done with very high doses of lithium (often in dosages over 100 mg/kg), whereas clinical dosing is around 5-10 mg/kg. Thus, it was essential to find studies and review papers that covered these physiological doses, as erroneous conclusions can easily be drawn from studies using exponentially higher doses than those used pharmacologically.

A 2021 article in the journal Toxicology reviewed unpublished lithium toxicity animal studies. It concluded that when lithium carbonate is administered under 45 mg/kg of body weight per day (8.6mgLi+/kg), there is no reproductive toxicity or organ changes in rats (1).

In a two-generation rat study, lithium did not seem to affect sperm health, with no observed changes in total motility, progressive motility, and morphology of testicular and cauda epididymal sperm. Interestingly, the NOAEL value (No Observed Adverse Effects Level) for systemic toxicity was lower than that for reproductive toxicity (1).

Based on the generational rat studies, it seems likely that lithium is safe and poses no risk to male reproductive health.

By the way, the results are quite different for women, as lithium use during pregnancy may contribute to heart defects in offspring. You can read more about lithium use during pregnancy here.

Lithium’s effect on spermatogenesis in humans

As previously mentioned, there are limited clinical studies on lithium and male fertility. We found a grand total of three studies in the available literature, and the results are somewhat different from the animal studies above.

Although animal research has found lithium carbonate to be safe regarding male reproductive health, clinical studies have found that lithium does affect sperm health.

Two in vivo studies from the early 1980s found altered sperm viability in men taking lithium (2, 3), with one study reporting a reduction in sperm viability of around 25% (2). In contrast, a 1989 prospective study found that lithium treatment did not affect spermatogenesis in men with bipolar disorder (4).

Is it possible that men with depression or bipolar disorder have altered sperm viability regardless of medication?

It’s plausible, given the relationship between inflammation and bipolar disorder (read more about that here), as well as the link between inflammation and depression (5) and the deleterious effect of heightened inflammatory cytokines on sperm viability and male fertility (6).

However, it’s worthwhile to note that Levin et al. (1981) found no difference in sperm viability in men with depression not taking lithium vs. healthy controls.

Additionally, lithium has also been linked to sexual dysfunction. Grover et al. (2014) estimated that around 30% of patients taking lithium experience sexual dysfunction, and this was true for both men and women. For men, this was characterized by erectile dysfunction, difficulty in arousal, and reduced sex drive (7).

Lithium may affect brain regions involved in sexual function, including the HPA axis, serotonergic and dopaminergic transmission, and glutamatergic/NDMA receptor signaling (8).

Lithium and oxidative stress: a cause for concern for male fertility or Goldilocks effect?

Lithium toxicity may be due in part to the effect of lithium on mitochondria, a mechanism observed in in-vitro animal studies (9, 10).

A recent animal study investigating how lithium affects spermatogenesis and male fertility found lithium alters mitochondrial function within Leydig cells (11).

“…mitochondrial membrane potential and ATP levels were significantly decreased in Li+-exposed LCs [Leydig cells]. Mitochondrial impairment could lead to an energy crisis. As the proper mitochondrial function is a critical factor for proper sperm function (e.g., sperm motility), any changes in mitochondrial function could lead to sperm abnormalities. Altogether, all these data indicate a role for OS and mitochondrial impairment in the pathogenesis of Li+-induced reproductive toxicity” (11).

While this is interesting, we must remember that animal studies can only sometimes be extrapolated to real-life conditions.

The million-dollar question is whether typical dosing of lithium carbonate is sufficient to induce this level of oxidative stress in humans.

And to make matters more confusing, lithium may be essential for sperm maturation in the epididymis (12).

If this seems counterintuitive to everything we’ve covered in this blog, let’s remember that lithium is naturally present in the human body, is found in water and food, and has been recognized as an essential trace nutrient. Lithium-deficient diets have been linked to adverse health effects, including mental illness and the risk of suicide (13).

But it gets more interesting—research shows lithium may protect against cadmium toxicity (14).

Cadmium is a highly toxic heavy metal that can have detrimental effects on reproductive health. You can read more about the harmful effects of cadmium here.

Even a small dose of lithium might be protective against cadmium-induced testicular damage due to oxidative stress (14). A study by Al-Azemi et al. used low doses of lithium in rodents (0.1 mg/100 gm body weight, or approximately 1/6th of the dose given to most human adults) but still found protective effects.

Ultimately, what do we know for sure about lithium and male fertility?

Perhaps some of the contradictory findings on lithium’s effect on sperm health and male hormones have more to do with the interaction of lithium with cadmium and other toxic substances, as opposed to lithium alone.

Since life isn’t a controlled experiment, one doesn’t always know exactly what the exposures are and how they interact with each other and with pharmaceuticals.

The variables of life can make it difficult to predict what the precise effect of lithium will be on individual male patients during the preconception period. Thankfully, you can take control of your reproductive health regardless.

Solutions: Dietary antioxidants might counteract potential oxidative stress from excess lithium

From what we’ve learned thus far, oxidative stress and impaired ATP synthesis are at the root of lithium carbonate’s potential adverse effects on male fertility.

With this knowledge, the next logical question is: could dietary antioxidants ameliorate lithium-induced oxidative stress in male reproductive organs?

Although this exact situation hasn’t been studied to my knowledge, there is evidence showing antioxidants benefit male fertility and ATP protection in spermatozoa. Additionally, antioxidant therapy can help those with bipolar disorder.

Several nutrients are known for their antioxidative effects and male fertility benefits:

Molecular hydrogen is a unique master antioxidant that maintains the delicate balance between oxidative stress and antioxidant protection. Emerging research shows that water enriched with molecular hydrogen improves male fertility and ATP production in sperm (15, 16, 17, 18).
Taurine is an amino acid studied for its potential to prevent mitochondrial dysfunction (19) and plays an essential part in male reproductive function (20). Several foods are rich sources of taurine, including scallops and fish, meat, and seaweed.
Alpha-lipoic acid (ALA) is an antioxidant and cofactor for ATP production. There is limited evidence on ALA and male fertility, but a small 2022 systematic review and meta-analysis concluded that ALA supplementation improves sperm motility, form, and volume in men (21). ALA is found in various plant and animal foods, including broccoli, potatoes, and red meat, and is available in supplemental form. An important note on ALA: it shouldn’t be taken by people with amalgam fillings because it acts as a mercury chelator. Unfortunately, this chelating action can promote the redistribution of mercury and thus potentially increase oxidative stress.

Are you looking for deeper support?

For me, bipolar disorder and its connection to reproduction is a personal issue.

Click here to schedule a time to talk if you or your family are looking for specific support for navigating fertility and reproduction with a bipolar diagnosis. I’m happy to answer any questions and see if we’re a good fit for working together.

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