Table 2. Summary of metformin's effects on men's reproductive health: steroidogenesis.

Studies/comments	Main findings
Cellular studies	1. Metformin decreases testosterone secretion and mRNA expression with increased lactate production in human and NMRI mouse organotypic cultures (human testes more senstitive than mouse testes) [44].
Animal studies	1. Male fetal NMRI mice exposed to metformin in utero may have small testicular size resulting from decreased testosterone secretion because of lactate production induced by metformin [44].
	2. Metformin significantly reduces testicular weight, serum testosterone and sperm count, motility and viability in rabbits [46].
	3. Metformin protects testicular damages in male Sprague-Dawley rats [48]; and the effects are more remarkable when coadministered with Malaysian propolis [49].
	4. Co-administration of metformin and honey up-regulates testosterone in male Wistar rats [50].
	5. Diabetes-induced abnormal steroidogenesis and spermatogenesis can be normalized by metformin in male Wistar rats [51,52].
Human studies	1. Follow-up of boys born to mothers with gestational diabetes mellitus treated with either metformin or insulin in an open-label, randomized clinical trial conducted in Finland: pre-pubertal testicular sizes are not different [45].
	2. An interventional study in Italy shows that metformin increases serum level of testosterone and improves luteinizing hormone pulsatility in obese individuals with metabolic syndrome [53].
	3. Cross-sectional studies conducted in Iraq show that metformin use in men with type 2 diabetes mellitus is associated with a lower level of testosterone [32,33].
Author’s comments	1. Small testicular size as a result of in utero exposure to metformin is observed in an animal study, but not similarily seen in a human study.
	2. Animal studies suggest a protective effect of metformin on testicular damges and a beneficial effect of metformin on steroidogenesis.
	3. Except for one human cross-sectional study that suggests a potential harmful effect of metformin on testicular steroidogenesis, other human studies suggested a neutral or beneficial effect of metformin.
	4. Interested readers may refer to review articles by Bertoldo et al [17], Ferreira et al [24], Faure et al [22], and Alzain et al [23].

NMRI: Naval Medical Research Institute.