Anabolic Androgenic Steroids and Hepatocellular Adenoma and Carcinoma: Molecular Mechanisms and Clinical Implications

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Overall the article is well documented and references. Tables 1 and 2 should be made more clear (rename the column "number" as it is not clear from the begining to what it referes). I suggest rephrasing some of the sentences, especially in the introduction, as the text seems not cursive and is a bit difficult to read.  

Comments on the Quality of English Language

Some minor spelling and grammer mistakes can be found throughout the text. 

Author Response

Dear Reviewer,

Thanks for your appreciated comments.
We re-named the column as "Lesion number" in order to let readers clearly understand what it refers.
We also performed English editing.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

In this manuscript, the authors summarized current knowledge on hepatocarinogenic roles of anabolic androgenic steroids (AAS) from molecular and clinical viewpoints. Although this manuscript has potential merit for readers of Gastroenterological Insights, there are several concerns that I would like the authors to address adequately.

 

1.       It is necessary to explain androgen receptor (AR), estrogen receptor (ER) and progesterone receptor (PGR) expression in hepatocytes and their gender difference.

2.       What about their expression in non-parenchymal cells?

3.       It should be elaborated why AAS have liver-specific carcinogenic effect. It should also be mentioned whether AAS promote or prevent the development of tumor in other tissues.

4.       Because oral contraceptives contain estrogen and progesterone, which one plays a central role in the development of HHA?

 

5.       3. Anabolic androgenic steroids: This section should be combined with the section 1.

Author Response

Dear Reviewer,

Thanks for your appreciated comments. We try to modified the manuscript as requested.

1 and 2. We added some information about these topics

3. Regarding the non-hepatic cancer risk associated to the use/abuse of AAS, there are not sufficient data to define an actual correlation. It as been postulated an increased risk of prostate cancer, but available data are inconclusive. Anyway, we added a sentence of this suggested topic.
Concerning the liver-specific carcinogenic effect, we have exposed different prooncogenic signaling pathways that involve AR activation. As we mentioned in the text, AAS exert their action by the binding to AR in different tissues, such as liver. These pre-clinic evidence (derived from in vitro and in vivo studies) justify the higher incidence of HCA and HCC in patients using AAS. 
In case you have further suggestions, we are pleased to receive them.

4. Thank you for this remark. Actually, in our paper we did not clarify this point. We mentioned the protective role of estrogens, but we did not specify progesterone action. It has been shown that progesterone induce abnormal proliferation and mitosis in liver cells. So, the increased risk of HCA development related to oral contraceptives (both estrogen-progestin and progestin-only) is related to progesterone. We added few lines on this topic.

5. As you correctly noticed, the section "Anabolic androgenic steroids" fits better after the introduction paragraph. We did not combine two section as suggested in order to avoid an extremely long introduction paragraph. So, we moved the entire paragraph as you can see in the updated draft.

We also performed English editing.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have adequately addressed my concerns and successfully improved the manuscript. I have no further concern.