Reviewer ’s report  
 
Title:  Norethindrone is superior to combined oral contraceptive pills in short -term delay of 
menses and onset of br eakthrough bleeding: a randomized trial.  
 
Version: 0 Date: 11 Mar 2019 
 
Reviewer:  PEDRO ANTONIO  REGIDOR  
 
Reviewer’s report:  
 
Title  
 
Norethindrone is superior to combined oral contracepti ve pills in short -term delay of menses and 
onset of breakthrough bleeding: a ran domized trial.  
 
 
Reviewers comment  
 
This is a very interesting manuscript describing the possibilities to delay menstruation comparing 
a progestogen only pill (norethindrone) with a combined oral contraceptive containing 0,035 mg 
EE and 0.250 mg norgestima te in women with a wish for the delay of menstruation.  
 
All in all, the reviewer supports the publication of the manuscript.  
 
 
The authors should nevertheless add some points that are raised by the reviewer:  
 
1.) Why was this specific COC chosen for the trai l? Norgestimate has different pharmacological 
properties than norethindrone (also called norethisterone).  
 
There are available COC on the market containing noretistherone (also in the USA). 
Norgestimate as a por drug form of levonorgestrel, has a different half-life, a different receptor 
binding affinity to AR, PR, ER, receptors etc. and a different binding affinity to SHBG.  
 
Please discuss this.  
 
 
2.) Why a preparation with 0,035 EE was chosen? Why not a preparation containing E2 or 
dienogest or a vaginal rin g? 
 
Please discuss.  
 
 
2.) It is not clear at which day of the cycle exactly the tablets were ingested. Table 1 describes a 
mean start of the tablet intake at days 8.8 for NETA and 8,2 for the COC. It would improve the 
quality if the exact day of starting, in  relation to the number of patients, is described.  
 
Day 8 represents mid to late follicular phase of the menstrual cycle. Why was this phase chosen 
and not the early phase of the menstrual follicular phase (e.g. days 2 -6)? 
 
 
3.) Table 1 shows at the end and equality of both formulations. On one site the amount of 
breakthrough bleedings (please describe how you defined this; were these bleedings scheduled or 
unscheduled and at which day of the treatment did they occur?) was hig her in the COC group, on 
the other site the amount of side effects was higher in the group of norethindrone.  
 
 
4.) Therefore, I suggest changing the title in the sense to make a more balanced wording 
formulation.  
 
 
5.) Please describe in the chapter discussi on the possibilities of the use of long cycle products 
containing a combined regimen (e.g. COC like Seasonique, other COC in long cycle or the 
vaginal ring in long cycle) for the management in the induction of amenorrhea even when 
starting in the mid folli cular phase and discuss also these possibilities with other oral 
progestogens.  
 
Final decision: Recommend publication after changes in the manuscript  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include th e necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further 
assessment in your comments to the editors.  
 
I am able to asses s the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation that may in any way gain or lose financially from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisati on that may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this pape r? 
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare to have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included 
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to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal