The Postnatal Offspring of Finasteride-Treated Male Rats Shows Hyperglycaemia, Elevated Hepatic Glycogen Storage and Altered GLUT2, IR, and AR Expression in the Liver

An important study demonstrating altered glucose transport and utilisation, predisposing to metabolic disease, in the offspring of Fin treated rats. The alteration of androgen signaling is associated with metabolic endpoints, and is expanded upon as the justification for the investigation and in the discussion:

Generally, testosterone is considered a key factor in gender related metabolic syndrome [19]. The lack of T in castrated rats causes symptoms similar to T2D or MetS, e.g., increased hepatic glucose synthesis (hyperglycaemia) as a consequence of inhibited insulin secretion, Akt phosphorylation, glucose uptake, glycogen synthase activity, GLUT-2 over-expression and glycogen phosphorylase activity in the liver. However, androgen concentration is not the only factor which influences glucose
homeostasis. A key role is also played by the androgen receptor (AR)—a target for T, DHT, and other androgens. Many studies indicate that AR deletion contributes to the development of late visceral obesity with leptin resistance, insulin resistance and increased lipogenesis in adipose tissue and the liver [14]. A lack of androgen receptors in males promotes insulin resistance that could promote T2D development. An experiment carried out on hepatic AR-knockout mice fed a HFD showed that male H-AR−/y (not female H-AR−/−) were overweight and were characterized by reduced sensitivity to insulin as a result of an increased expression of the protein-tyrosine phosphatase 1B (PTP1B), negative regulator of the insulin signaling pathway. So, the hepatic androgen receptor (as a positive factor), could also play an important role in avoiding insulin resistance development [31].

In our previous study on the same animal model, we showed that the offspring (F1:Fin) of rats exposed to finasteride had altered levels of serum androgens (T, DHT) and adverse changes in the morphology and physiology of testes and epididymides [32,33]. Given this trans-generational effect of finasteride on the male reproductive system and the aforementioned information on the role of androgens and AR in glucose metabolism, the aim of this study was to assess whether the androgen (T, DHT) imbalance in the F1:Fin generation of rats from males receiving finasteride can affect the accumulation of glycogen > in the liver (androgen-dependent organ), serum glucose concentration and the hepatic mRNAs and proteins, GLUT2, IR, and AR expression.

Androgens achieve the genomic effect via activation of nuclear receptors, followed by binding to a specific DNA region, known as the androgen response element (ARE) motif, localized in its target gene [41]. Testosterone replacement therapy restores GLUT-2 expression in castrated rat livers suggesting that testosterone may have a direct effect on GLUT-2 transcription and translation [20]. In the promoter region of the GLUT-2 gene, the presence of androgen response elements (ARE) has not been identified yet—this is probably why we did not observe any correlation between androgen concentration and GLUT-2 mRNA expression. However, according to McEwan et al. [42], AR acts as an independent ligand-activated transcription factor or it may bind to some other coactivators [43,44] to increase GLUT-2 expression. Androgens could also achieve a biological effect via a receptor associated with the plasma membrane of the cell, a mechanism that has not been thoroughly researched [13]. Although in our study F1:Fin rats in each age group had increased concentrations of circulating testosterone, the level of AR transcript was decreased, and adult rats in this group (90 PND) also had cytoplasmic immunoexpression of AR in some hepatocytes. This is in line with the conclusion of Shen et al. [13], who stated that “the integration of nongenomic effects via membrane receptor signaling and genomic effects via nuclear receptor signaling of sex hormones is critical to produce the final sex hormone cellular outcomes”.

The conclusion is clear and important:

It can be concluded that finasteride has trans-generational consequences and probably epigenetic side effects that could lead to some metabolic syndromes such as hyperglycaemia, insulin resistance, type 2 diabetes or a fatty liver in males. Moreover, finasteride should become the focus of research in the relatively new field of pharmacology— pharmacoepigenomics.

Owing to strong evidence of DHT/AR-mediated regulation of many epididymal functions, this group previously investigated and reported important findings on the transgenerational negative effects of finasteride on fertility related androgenic parameters in rats ​(Kolasa-Wolosiuk et al., 2015; Kolasa-Wołosiuk et al., 2018, 2019)​. Reduced androgen levels in the offspring of finasteride-treated adult male rats were noted as similar to those reported in studies exploring the effects of prenatal exposure to the antiandrogenic endocrine disruptors flutamide and vinclozolin ​(Kolasa-Wołosiuk et al., 2019).


So, adds a risk that our children will be fucked as well. That’s…wow


Even though it might feel bleak to see evidence of persistent biological changes from this drug, nothing is “added” in terms of the risk, scientifically or anecdotally, or any individual’s situation. It is evidence of heritable epigenetic metabolic effects in animal models, as has already been demonstrated with regards to fertility. It raises biological questions around persistent effects associated with the drug that are important to answer, in order to get effective clinical recognition and eventually help, should there be implications for PFS.

The literature review awor and I presented a year ago noted metabolic dysfunction, IR, and elevated triglycerides as alterations reported by PFS patients across the history of propeciahelp, and suggested evaluation in patients for this reason. We also reviewed significant scientific evidence on the critical role of androgen signaling in metabolic regulation. The risk and consequences were already apparent.

The dramatic metabolic changes some PFS patients experience is already well reported; No finding will change what has or hasn’t occurred for each individual, and those endpoints are hugely variable between patients. For many of us, the particular concern you raise can’t even be in the equation due to the severity of other harms from PFS…

Evidence of this sort is extremely beneficial and desperately necessary to conclusively move past the implication of “delusion” from irresponsible clinicians and the attribution of “negativity” to serious cases by individuals playing back-alley prescriber, both of which continue to delay accurate appreciation of this serious issue - which continues to cost lives.

This is a very positive thing for our issue, and strengthens the case for useful investigations rather than fiddling while Rome burns. Chin up! I’m optimistic for this year :slight_smile:


Wait a second. Does this mean that this trans generational effect can eventually be found not only in the offspring of PFS patients but in any Finasteride-treated patient?

Edit: not just hyperglicaemia, I mean the whole deal.

No it doesn’t. Unless your partner is giving birth to Wistar rats

that’s even worse than a milkman baby

Difficult to say, and likely difficult to assess. I suppose determining that to a point of certainty would require quite impractical studies…biopsy/assessment of the grown children of healthy men who were using fin for AGA at fertile age before conception, or long term monitoring to determine rate of development of metabolic diseases in a large cohort as compared to the general population. Rats have a much quicker lifespan than a human being, of course. It is certainly at least another thing that young men deserve the option of taking into account, especially considering the negative transgenerational fertility effects already demonstrated and mentioned.

It’s also of interest that development of metabolic disease in association with DHT deprivation has been a noted point of concern for a while:

Part of the abstract of " Health Risks Associated with Long-Term Finasteride and Dutasteride Use: It’s Time to Sound the Alarm", Traish 2020:

Thus, inhibition of 5α-reductases with finasteride or dutasteride to reduce 5α-DHT biosynthesis in the course of treatment of benign prostatic hyperplasia (BPH) or male pattern hair loss, known as androgenetic alopecia (AGA) my induces a novel form of tissue specific androgen deficiency and contributes to a host of pathophysiological conditions, that are yet to be fully recognized. Here, we advance the concept that blockade of 5α-reductases by finasteride or dutasteride in a mechanism-based, irreversible, inhabitation of 5α-DHT biosynthesis results in a novel state of androgen deficiency, independent of circulating testosterone levels. Finasteride and dutasteride are frequently prescribed for long-term treatment of lower urinary tract symptoms in men with BPH and in men with AGA. This treatment may result in development of non-alcoholic fatty liver diseases (NAFLD), insulin resistance (IR), type 2 diabetes (T2DM), dry eye disease, potential kidney dysfunction, among other metabolic dysfunctions.

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