Reviewer's report
Title:Does female sex hormone supplementation (FSHS), exercise or a
combination of both, improve pain and function in post-menopausal women with
greater trochanteric pain syndrome (GTPS)? A randomised controlled trial.
Version:3Date:14 December 2015
Reviewer: Nese Yuksel
Reviewer's report:
Thank you for the opportunity to review this manuscript. In this manuscript the
authors describe the design of a randomised controlled trial evaluating the
effectiveness of menopausal hormone therapy MHT) and exercise therapy in
postmenopausal women with greater trochanteric pain syndrome (GTPS). The
study is an interesting concept and the use of MHT and exercise is a novel
approach.
I have several suggestions that may assist the authors with further revisions.
Major Compulsary Revisions
General comment:
1)Use of term: Female sex hormone supplementation – suggest using the same
term throughout the text and tables to refer to hormone therapy (the authors
sometimes use different terms throughout the text/tables). One suggestion is to
use the term “menopausal hormone therapy (MHT)” – which is currently the
recommended term by the International Menopause Society (IMS) and North
American Menopause Society (NAMS). See Global Consensus Statement:
Villiers et al. Climacteric 2013;16:203–204
Methods:
Participants: Recruitment
2) How will they be recruited from medical practitioners and health care
professionals – do you mean at medical practitioners offices? What other health
care professionals will you be recruiting from?
Study procedure: Patient Screening and Table 1/Eligibility Criteria:
3) What is the age range of the postmenopausal women? What if the woman is
over 60 or 65 years of age or more than 10 years postmenopause – how will you
be handling these women?
4) You mention MHT supplementation in the last 12 weeks but what about
hormone contraception in the last 12 weeks as an exclusion (in case patients
were on CHC for perimenopausal symptoms and had remained on these)?
5) In regards to the definition of post-menopause, it indicates as “and/or” for
estradiol level and FSH levels. The concern I have is re the “or” as estradiol
levels and FSH levels alone are not diagnostic of postmenopause (in
perimenopause patients can see increased FSH levels and decreased estradiol
levels depending on where in the cycle levels taken). Suggest revising to be
specific for post-menopausal women.
6) Also the estradiol level – did you mean “<50” (it currently indicates as >50)
7) In regards to breast cancer – will you be looking at other risk factors such as
strong family history (ie 2 or more first degree relatives prior to menopause)?
Medical Assessment:
8) Will you be looking at the presence of other menopausal symptoms such as
vasomotor etc? How will this be captured?
9) Will you be including assessment of herbals or CAM use for menopausal
symptoms or for the GTPS?
10) Under “medication usage” will you be capturing other medications that could
be used to help with menopausal symptoms such as vasomotor etc ie
antidepressants, gabapentin
Interventions
Transdermal Cream
11) The application of the hormone therapy cream (rotated every 5 days in the
intervention) is a different application method compared to MHT guideline
recommendations from IMS or NAMS and what is currently done in practice. The
reference provided in the manuscript is from a textbook however can the authors
provide evidence from the primary literature to support the application in this
format?
12) Under the MHT intervention description make sure to indicate the duration of
the intervention.
Female sex hormone supplementation transdermal cream:
13) Has the MHT planned for use in the study (transdermal cream containing
estradiol and NETA) been tested as far as adequate absorption (especially with
the NETA component?). Is the cream comparable to the Estalis patch (with
regards to absorption patterns/pharmacokinetics etc?). What base will be used in
the cream to ensure adequate absorption? What is the exact dose that will be
used in the cream (it will not be the same as the patch as these are different
formulations). Please provide adequate references to these studies as the
references provided do not discuss this specific formulation that is being studied
(ie the cream application). Also a couple of the links (reference 53 and 54) were
not accessible directly from the manuscript. When accessed the “Estradiol
Topical” information (ref 53) - this information refers to commercial estradiol
topical products such as patches and gels.
14) In regards to the NETA – how do you know that the NETA provided in the
cream formulation provides the adequate protection for endometrial hyperplasia
(ie adequate absorption to do this? NETA has been studied with the Estalis patch
but how do you know this translates to the same benefits with the cream?)
15) Why did you choose the 50ug dose? How will adjustments in dose to the
MHT cream be made (ie what will you do if a woman has side effects)?
Adverse events:
16) How will adverse events be handled with patients on MHT? Some
breakthrough bleeding/spotting can occur when initiating MHT – how will this be
handled?
Discussion:
Paragraph 2:
17) In regards to the statement “A transdermal method of administering
hormones…as it combines the most efficacious…with the safest route of
administration”. The evidence is not there to say that the cream you are using is
the most efficacious (nor can we say this about transdermals in general as oral
agents can be efficacious as well).
18) 3rd sentence - Transdermal MHT may have a lower risk of VTE compared to
oral estrogens however this is at low or standard doses of transdermal MHT
(higher doses may still have a risk). This sentence should be revised to indicate
that the risk is lower than oral but not “lowers the risk of VTE”. Also it is from the
transdermal formulation not the “bioidentical”.
• Also NETA is not “bioidentical”.
Discretionary revisions:
Outcome measures:
20) Why are you not looking at menopause QOL as an outcome measure?
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests:
I declare that I have no competing interests