Metformin exposure affects human and mouse fetal testicular cells.
BACKGROUND
Metformin is a drug used in the treatment of diabetes and of some disorders related to insulin resistance, such as polycystic ovary syndrome. Gestational diabetes can cause complications for both mother and child, and some studies have shown a beneficial effect of metformin during pregnancy without an increase in perinatal complications. However, the effects on the gonads have not been properly studied. Here we investigated the effect of metformin administered during pregnancy on the development and function of the fetal testis.


METHODS
A dual approach in vitro and in vivo using human and mouse models was chosen. Cultures of human and murine organotypic testes were made and in vivo embryonic testes were analysed after oral administration of metformin to pregnant mice.


RESULTS
In human and mouse organotypic cultures in vitro, metformin decreased testosterone secretion and mRNA expression of the main factors involved in steroid production. In vitro, the lowest observed effect concentration (LOEC) on testosterone secretion was 50 µM in human, whereas it was 500 µM in mouse testis. Lactate secretion was increased in both human and mouse organotypic cultures with the same LOEC at 500 µM as observed in other cell culture models after metformin stimulation. In vivo administration of metformin to pregnant mice reduced the testicular size of the fetal and neonatal testes exposed to metformin during intrauterine life. Although the number of germ cells was not affected by the metformin treatment, the number of Sertoli cells, the nurse cells of germ cells, was slightly yet significantly reduced in both periods (fetal period: P = 0.007; neonatal period: P = 0.03). The Leydig cell population, which produces androgens, and the testosterone content were diminished only in the fetal period at 16 days post-coitum.


CONCLUSIONS
This study showed a potentially harmful effect of metformin treatment on the development of the fetal testis and should encourage future human epidemiological studies.
INRA UMR 85, Unité de Physiologie de la Reproduction et des Comportements, Nouzilly F-37380,  France.
P
P
Tartarin
D
D
Moison
E
E
Guibert
J
J
Dupont
R
R
Habert
V
V
Rouiller-Fabre
N
N
Frydman
S
S
Pozzi
R
R
Frydman
C
C
Lecureuil
P
P
Froment
D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation / Q000187:drug effects; D004622:Embryo, Mammalian / Q000187:drug effects / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D008687:Metformin / Q000009:adverse effects* / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009924:Organ Culture Techniques; D009929:Organ Size / Q000187:drug effects; D038081:Organogenesis / Q000187:drug effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000378:metabolism; D013737:Testis / Q000187:drug effects* / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism
D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D013739:Testosterone; D008687:Metformin