Early Female Transgender Identity after Prenatal Exposure to Diethylstilbestrol: Report from a French National Diethylstilbestrol (DES) Cohort

Round 1

Reviewer 1 Report

Dear editors, thank you for offering me the opportunity to be a reviewer of this paper named ‘Early female transgender identity after prenatal exposure to DES: Report from a French national diethylstilbestrol (DES) cohort’. In this manuscript, authors described the presence of gender incongruence in 4 AMAB individuals exposed to this xenoestrogen during pre-natal period.

The manuscript addressed a very interesting and unexplored topic, with a high relevance, considering the increasing number of transgender people.

Based on my perception, the manuscript should be accepted after minor revision.

General considerations: many different terms are used in the whole text for transgender people (TG, female TG, transgender women, male to female, AMAB). I recommend to uniform the terminology.

Abstract

-        Please avoid the term transsexualism, which is no longer used, according to language recommendation of WPATH. As introduction, it would be preferable to use definition of gender incongruence.

-        Moreover, terms such as “diagnostic” “etiology” are considered pathologizing and should be avoided

-        Chromosomes are not part of the definition of trans men and women. Trans women (or, better, trans AMAB person) are individuals assigned male at birth (on the basis of external genitalia- not karyotype) with a different gender identity.

-        Please, change the word “etiology” into “biological basis of gender identity”

Introduction

Lines 42-43/70. It would be better not to use “female-to male” or “male-to-female”

Line 54. As in the introduction section, please refer to the development of gender identity, not “transgender etiology”.

Line 56. Literature on this topic has been recently summarized (doi: 10.3390/ijms21062123)

Line 72. May affect the “development of male gender identity and behaviour” would be better

More information regarding DES action would be helpful to the reader.

Materials and methods

Lines 97-98. Gender dysphoria does not present in pre-pubertal period. In this period of life, it would be better to talk about “gender variance”

Discussion

The order of different topic in the discussion section seems to be confusing. I suggest the authors to make some changes, in order to make the text more understandable and easier to follow to the reader.

Lines 170-172 these definitions should be reported in the introduction section

Lines 183-206 I don’t understand the reason for reporting diagnostic criteria of DSM. This part would rather benefit from a more extensive discussion of biological factors involved in the development of gender identity.

Lines 210-211 “diagnostic signs of transgender” should be avoided

Lines 232-233 It would be useful to detail evidences coming from animal studies

Lines 241 please do not use “gender identity disorders”. This them is obsolete and pathologizing

The authors did not report any limitations of the study. I recommend to implement this part. For example, gender identity has not been systematically assessed in the sample of people exposed to DES, and this could lead to an underestimation.

Minor editing of English language required

Author Response

Letter to the attention of Reviewer 1.

First, we would like to thank Reviewer 1 for the very precise corrections and suggestions. We have tried to answer most of them as much as possible.

Abstract:

We have modified the text of the abstract according to most of  the suggestions of Reviewer 1 but we have conserved the necessary medical term of 'diagnostic' and have added 'gender incongruence'.

Introduction

Lines 42-43/70. It would be better not to use “female-to male” or “male-to-female”: OK We removed it.

Line 54. As in the introduction section, please refer to the development of gender identity, not “transgender etiology”. OK, we changed it.

Line 56. -(85) Literature on this topic has been recently summarized (doi: 10.3390/ijms21062123): We have added the reference of Ristori et al (2020) in Int J Mol Sciand quoted it in the text. [Brain Sex Differences Related to Gender Identity Development: Genes or Hormones? Jiska Ristori¹, Carlotta Cocchetti ¹, Alessia Romani ¹, Francesca Mazzoli ¹, Linda Vignozzi ¹, Mario Maggi ², Alessandra Daphne Fisher ¹ Int J Mol Sci 2020 Mar 19;21(6):2123. doi: 10.3390/ijms21062123.] 

Line 72. May affect the “development of male gender identity and behaviour” would be better: OK, we changed it.

More information regarding DES action would be helpful to the reader: OK, We added more informations about DES effects.

“[22-26]. In addition, although less studied, in utero exposure to synthetic sex hormones, particularly DES, can cause psychological disorders, such as schizophrenia, bipolar disorders, eating disorders and suicidal behavior [27]. Interestingly, some studies in patients exposed in utero to DES and with psychotic disorders, identified methylome changes that affect the expression of ZFP57 and ADAMTS9, two genes implicated in neurodevelopment regulation [28], with potential multigenerational and transgenerational effects [29, 30].”

Materials and methods

Lines 97-98. Gender dysphoria does not present in pre-pubertal period. In this period of life, it would be better to talk about “gender variance”: OK , we changed it.

Discussion

The order of different topic in the discussion section seems to be confusing. I suggest the authors to make some changes, in order to make the text more understandable and easier to follow to the reader.

Lines 170-172 these definitions should be reported in the introduction section: OK we suppressed 'Transgender refers to a person whose sex assigned at birth, usually based on the external (or internal) genitalia, does not match the gender identity. It is often associated with gender dysphoria, which refers to psychological distress [27].'

Lines 183-206 I don’t understand the reason for reporting diagnostic criteria of DSM. This part would rather benefit from a more extensive discussion of biological factors involved in the development of gender identity : For a better information, we reported DSM criteria in the introduction section.

Lines 210-211 “diagnostic signs of transgender” should be avoided: OK we removed the term “diagnostic”

Lines 232-233 It would be useful to detail evidences coming from animal studies: OK We added effects on rat, mouse and quail. “In many animal studies, EDC exposure during development has been associated with changes in sex behavior, such as disruption of the normal social preference behavior (rats) and alteration of the differentiation of relevant sexually dimorphic pathways (mouse, Japanese quail) [42, 43].”

Lines 241 please do not use “gender identity disorders”. This them is obsolete and pathologizing: OK We changed it by risk of gender identity and incongruence.

The authors did not report any limitations of the study. I recommend to implement this part. For example, gender identity has not been systematically assessed in the sample of people exposed to DES, and this could lead to an underestimation.

Indeed, we added this sentence: “Similarly, our finding of four transgender women among 253 XY patients in utero exposed to DES (1.58%), a much higher rate than in the general population, and probably underestimated because no epidemiological investigation has been carried out on this subject, strongly suggests that DES plays a role in male to female transgender development. DES displays antiandrogenic activity in all assays used [53].”

Reviewer 2 Report

The associations of prenatal diethylstilbestrol (DES) exposure, a potent estrogen, with sexual orientation and gender identity are poorly investigated in literature. Scarce data report little support for the hypothesis that prenatal exposure to DES influences the psychosexual characteristics of adult men and women. This study firstly demonstrate a strong association between DES exposure and TGW evolution of male XY. 

The study fails to discuss how and why the low-medium dose of DES used during fetal life by mothers in this study may determine such brain alterations in siblings; they need to compare these results with data coming from literature whereas higher DES dosages used in the USA did not yield any TGW, as well. This is a critical point to explain the results and needs to be addressed within the  discussion

An English thorough revision is needed

Author Response

Letter to the attention of Reviewer 2.

First, we would like to thank Reviewer2 for suggestions. We have tried to answer most of them as much as possible.

The study fails to discuss :

 how and why the low-medium dose of DES used during fetal life by mothers in this study may determine such brain alterations in siblings; they need to compare these results with data coming from literature whereas higher DES dosages used in the USA did not yield any TGW, as well. This is a critical point to explain the results and needs to be addressed within the  discussion

Indeed, we added this sentence :

“Based on the study by Tournaire et al. [21, 31], the DES doses administered in France (4,050 mg< D < 7,300 mg) were lower than those administered in the United States (7,550 mg< D < 12,742 mg; doses varied in the different states). These authors investigated DES role in clear cell carcinoma development in DES daughters in France and proposed that the early fetal exposure (administration beginning during the first trimester of pregnancy) is more important than the dose. We think that this hypothesis is valid also for our four DES sons.”

Round 2

Reviewer 2 Report

I am satisfied with te response of the authors. I regret to tell them that I do not like the term TRANS AMAB within the entire manuscript. Thsi is not common in the medical community and need to be changed.

Please enter minor English modifications, i.e. trans amab

Author Response

We modified our text:

In abstract: Line 21 we replaced trans AMAB individuals by: transgender woman and line 30 by: female transgender.

Lines 238 and 244 transAMAB by:  female transgender

Words are highlighted in blue green.

Many thanks to the reviewer.