"Miracle drug" metformin or birth defects that cause boys to have genitalia!

This article is reproduced from the "Lilac Academic" WeChat public account.

Introduction: There are several major "miracle drugs" in the scientific research community - aspirin, metformin, curcumin. Among them, metformin, with its various magical effects, has become one of the well-deserved "top streams". It can not only lower blood sugar, cure obesity, but also anti-aging, anti-cancer, cardiovascular protection, and every once in a while there will be a new role discovered by researchers.

Metformin was first approved for clinical treatment in the UK since 1957 and has been used to treat diabetes for more than 60 years and is a first-line drug for the treatment of diabetes. However, even metformin, which is called a "miracle drug", has some side effects, such as gastrointestinal adverse reactions that affect vitamin B12 absorption.

Nowadays, diabetes is increasingly occurring in people of childbearing age, and the use of metformin is not clinically recommended for women with diabetes who are planning to become pregnant or have become pregnant, but can be maintained at normal levels by insulin, thereby reducing the risk of fetal teratogenicity. However, there is no research evidence on whether diabetes drugs affect the reproductive health of men and the birth defects of offspring.

On March 28, 2022, researchers from the Universities of Southern Denmark and Stanford University published a research paper in annals of Internal Medicine, Annals of Internal Medicine (IF = 25.391). Through a large cohort study, the researchers found that babies born to men who took metformin during sperm development were at increased risk of birth defects, particularly in boys.

Figure 1 Research results (Source: Annals of Internal Medicine)

Data from birth registries, diabetic patients and drug prescriptions were statistically analysed in the study to assess whether there were differences in the risk of birth defects in the offspring of men who took insulin, metformin, sulfonylureas or other diabetic drugs before conception. The development of fully mature sperm, including from seminal cells to sperm cells, as well as further maturation in the epididymis, takes about 3 months. Therefore, if the father takes diabetes medication in the first 3 months of pregnancy, the offspring are considered to have been exposed to diabetes medication.

The researchers compared birth defects in infants who used different diabetes medications, birth defects in siblings whose babies were not exposed to the drug, and the effects of using the drug on offspring's birth defects at different times relative to sperm development.

After counting the development of 1,116,779 babies born in Denmark between 1997 and 2016, the study found that 3.3% (n = 36585) of infants in the control group (infants not exposed to diabetes drugs) had 1 or more major birth defects, and 51.4% were male. A total of 7029 offspring were exposed to diabetic drugs, including insulin (n = 5298), metformin (n = 1451), and sulfonylureas (n = 647). A small number of offspring are exposed to other diabetic drugs (n=276), so the effects of these drugs on birth defects are not further considered.

Infants born after insulin use by fathers were not at increased risk of birth defects compared to the control group, but infants born after metformin were at increased risk (5.2%). Offspring exposed to metformin are more likely to have reproductive defects, all of whom are boys. The incidence of major birth defects in the genitals and urinary tract was 3.39 times higher than in the control group. At the same time, the proportion of boys is lower (49.4 per cent). Offspring exposed to sulfonylureas also showed a correlation (5.1%) of increased birth defects, but lacked statistical significance and specificity for the birth defect category.

Fig. 2 Comparison of the risk of birth defects in infants taking and not taking metformin (Source: Annals of Internal Medicine)

At the same time, the findings suggest that taking metformin before and after sperm development does not increase the risk of birth defects. Siblings who were not exposed to metformin also did not have an increased risk of birth defects.

In fact, prior to this, there have been some animal-based research results that support the correlation between metformin and male reproductive health. Metformin can affect stem cell function and adhesion factors and has been associated with reduced apoptosis of testicular germ cells in rats. After pregnant mice take metformin, the size of the testicles of the fetus and newborn decreases, while the administration of metformin in vitro reduces the secretion of testosterone.

Dr. Germane M. BuckLouis, from George Mason University, published an editorial in response, saying there was an urgent need to confirm the reliability of this finding given metformin as a first-line treatment for type 2 diabetes, noting that a key limitation of the study was the lack of data on the amount of prescription medications taken by the men in the study.

Figure 3 Research results (Source: References[3])

This is the first study to suggest that metformin use in fathers may be linked to birth defects in their children and may offer new medication recommendations in the future for men with diabetes of childbearing age, but the researchers say it is too early to make any changes based on this data.

Michael Eisenberg, one of the researchers, said that if other studies confirm this finding, doctors may only begin to discuss with patients whether to switch to another treatment, weighing the risks and benefits of using metformin over other drugs.

Typography | Muzijiu

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Resources:

[1]https://www.acpjournals.org/doi/10.7326/M21-4389

[2]https://www.eurekalert.org/news-releases/947367

[3]https://www.acpjournals.org/doi/full/10.7326/M22-0770

[4] Bednar F, Simeone DM. Metformin and cancer stem cells: old drug, new targets. Cancer Prev Res (Phila).2012;5:351-4. [PMID: 22389436] doi:10.1158/1940-6207. CAPR-12-0026

[5] Romero R, Erez O, Hüttemann M, et al. Metformin, the aspirin of the 21st century: its role in gestational diabetesmellitus, prevention of preeclampsia and cancer, and the promotion oflongevity. Am J Obstet Gynecol. 2017;217:282-302. [PMID: 28619690]doi:10.1016/j. ajog.2017.06.003

[6] Ghasemnejad-Berenji M, Ghazi-Khansari M, Yazdani I, et al. Effect of metformin on germ cell-specific apoptosis, oxidative stress and epididymal sperm quality after testiculartorsion/detorsion in rats. Andrologia. 2018;50. [PMID: 28730645]doi:10.1111/and. 12846

[7] Tartarin P, Moison D, Guibert E, et al. Metformin exposure affects human andmouse fetal testicular cells. Hum Reprod. 2012;27:3304-14. [PMID: 22811314]doi:10.1093/humrep/des264