Relationship between circulating FSH levels and body composition and bone health in patients with prostate cancer who undergo androgen deprivation therapy: The BLADE study
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eLife assessment
The authors observed a positive correlation between FSH and fat mass, as well as a negative association with the appendicular lean mass/fat mass ratio. These valuable findings in male subjects within a hypogonadal setting following Degarelix treatment imply that FSH might function as a predictor, similar to observations in women. However, it's important to note that the analysis is incomplete, as other major confounding factors such as testosterone were not included.
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Abstract
Among its extragonadal effects, follicle-stimulating hormone (FSH) has an impact on body composition and bone metabolism. Since androgen deprivation therapy (ADT) has a profound impact on circulating FSH concentrations, this hormone could potentially be implicated in the changes of fat body mass (FBM), lean body mass (LBM), and bone fragility induced by ADT. The objective of this study is to correlate FSH serum levels with body composition parameters, bone mineral density (BMD), and bone turnover markers at baseline conditions and after 12 months of ADT.
Methods:
Twenty-nine consecutive non-metastatic prostate cancer (PC) patients were enrolled from 2017 to 2019 in a phase IV study. All patients underwent administration of the luteinizing hormone-releasing hormone antagonist degarelix. FBM, LBM, and BMD were evaluated by dual-energy x-ray absorptiometry at baseline and after 12 months of ADT. FSH, alkaline phosphatase, and C-terminal telopeptide of type I collagen were assessed at baseline and after 6 and 12 months. For outcome measurements and statistical analysis, t -test or sign test and Pearson or Spearman tests for continuous variables were used when indicated.
Results:
At baseline conditions, a weak, non-significant, direct relationship was found between FSH serum levels and FBM at arms ( r = 0.36) and legs ( r = 0.33). Conversely, a stronger correlation was observed between FSH and total FBM ( r = 0.52, p = 0.006), fat mass at arms ( r = 0.54, p = 0.004), and fat mass at trunk ( r = 0.45, p = 0.018) assessed after 12 months. On the other hand, an inverse relationship between serum FSH and appendicular lean mass index/FBM ratio was observed ( r = −0.64, p = 0.001). This is an ancillary study of a prospective trial and this is the main limitation.
Conclusions:
FSH serum levels after ADT could have an impact on body composition, in particular on FBM. Therefore, FSH could be a promising marker to monitor the risk of sarcopenic obesity and to guide the clinicians in the tailored evaluation of body composition in PC patients undergoing ADT.
Funding:
This research was partially funded by Ferring Pharmaceuticals. The funder had no role in design and conduct of the study, collection, management, analysis, and interpretation of the data and in preparation, review, or approval of the manuscript.
Clinical trial number:
clinicalTrials.gov NCT03202381 , EudraCT Number 2016-004210-10.
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Author Response
Reviewer #1 (Public Review):
In this analysis derived from the BLADE study, a Phase IV investigation using the LHRH antagonist Degarelix, the authors revealed additional insights into the relationship between FSH and body composition.
The primary strength of the study lies in its prospective nature and the utilization of human subjects.
We thank the reviewer for the positive evaluation.
However, some weaknesses exist in the study.
First, the authors presented results from a simple correlation study without accounting for potential confounding factors in fat metabolism. Particularly, readers may be intrigued to understand how testosterone or estradiol interact with FSH in relation to fat mass.
As for the evaluation of circulating levels of testosterone and estradiol, unfortunately the protocol did not include …
Author Response
Reviewer #1 (Public Review):
In this analysis derived from the BLADE study, a Phase IV investigation using the LHRH antagonist Degarelix, the authors revealed additional insights into the relationship between FSH and body composition.
The primary strength of the study lies in its prospective nature and the utilization of human subjects.
We thank the reviewer for the positive evaluation.
However, some weaknesses exist in the study.
First, the authors presented results from a simple correlation study without accounting for potential confounding factors in fat metabolism. Particularly, readers may be intrigued to understand how testosterone or estradiol interact with FSH in relation to fat mass.
As for the evaluation of circulating levels of testosterone and estradiol, unfortunately the protocol did not include the dosage for these hormones. The evaluation of testosterone, in particular, would have required mass photometry as the values of testosterone during therapy with degarelix are reduced below the sensitivity of the methods used in clinical practice. Therefore, the correlation/association analysis between testosterone and body composition would not have been reliable and would not have been useful for the study. All patients were considered to have hypogonadism due to the significant decrease in PSA values and the limited testosterone data available.
The inverse relationship between ALBI/FBM was previously documented in a paper by the same group (Palumbo et al, Prostate Cancer Prostatic Dis 2021). In that earlier publication, the authors reported no correlation between FSH and lean mass or ALBI, suggesting the significance of the correlation between FSH and ALBI/FBM arising from changes in fat body mass-a factor somehow not included in the prior paper, not necessarily from sarcopenia.
The referee is correct, as there is no correlation between lean mass and FSH, nor between lean mass variations and FSH variations. The correlation between ALMI/FBM and FSH is mostly due to the effect on fat mass. The text now includes a statement that emphasizes this concept (see Discussion page 8, lines 19-22).
Reviewer #2 (Public Review):
This manuscript reports the results of an ancillary study of a prospective trial assessing the effects of androgen deprivation therapy (ADT) with Dagarelix (a GnRH antagonist) on body composition in patients with prostate cancer. An interesting relationship between FSH levels, that were suppressed by Dagarelix treatment, and body composition parameters (particularly fat body mass) was described after 12 months of therapy. Therefore, the authors conclude that FSH could be a promising marker to monitor the risk of sarcopenic obesity and cardiovascular complications in prostate cancer patients undergoing ADT. As acknowledged by the Authors the main limitation of the study is the limited sample of patients. However, since testosterone levels were not assessed it is not possible to firmly establish whether the changes in fat mass observed with treatment are directly or indirectly associated with a reduction in FSH (and therefore in the latter case mediated by testosterone). Moreover, it is not clear whether the effect of the change in FSH levels during the study and the body composition parameters achieved at 12 months was evaluated (instead of assessing the relationship between FSH changes and changes in body composition parameters). Finally, tests on bone muscle mass and strength were not performed, so the hypothesis that variation of FSH levels in prostate cancer patients in ADT may affect sarcopenia remains speculative.
We appreciate the reviewer's positive assessment of our manuscript. We evaluated the correlation between FSH changes and body composition values after 12 months of Degarelix, as requested by the reviewer. No significant correlation was observed, see the attached table. Therefore we have decided not to insert this last statistical analysis in the revised paper.
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eLife assessment
The authors observed a positive correlation between FSH and fat mass, as well as a negative association with the appendicular lean mass/fat mass ratio. These valuable findings in male subjects within a hypogonadal setting following Degarelix treatment imply that FSH might function as a predictor, similar to observations in women. However, it's important to note that the analysis is incomplete, as other major confounding factors such as testosterone were not included.
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Reviewer #1 (Public Review):
In this analysis derived from the BLADE study, a Phase IV investigation using the LHRH antagonist Degarelix, the authors revealed additional insights into the relationship between FSH and body composition.
The primary strength of the study lies in its prospective nature and the utilization of human subjects
However, some weaknesses exist in the study.
First, the authors presented results from a simple correlation study without accounting for potential confounding factors in fat metabolism. Particularly, readers may be intrigued to understand how testosterone or estradiol interact with FSH in relation to fat mass.
The inverse relationship between ALBI/FBM was previously documented in a paper by the same group (Palumbo et al, Prostate Cancer Prostatic Dis 2021). In that earlier publication, the authors …
Reviewer #1 (Public Review):
In this analysis derived from the BLADE study, a Phase IV investigation using the LHRH antagonist Degarelix, the authors revealed additional insights into the relationship between FSH and body composition.
The primary strength of the study lies in its prospective nature and the utilization of human subjects
However, some weaknesses exist in the study.
First, the authors presented results from a simple correlation study without accounting for potential confounding factors in fat metabolism. Particularly, readers may be intrigued to understand how testosterone or estradiol interact with FSH in relation to fat mass.
The inverse relationship between ALBI/FBM was previously documented in a paper by the same group (Palumbo et al, Prostate Cancer Prostatic Dis 2021). In that earlier publication, the authors reported no correlation between FSH and lean mass or ALBI, suggesting the significance of the correlation between FSH and ALBI/FBM arising from changes in fat body mass-a factor somehow not included in the prior paper, not necessarily from sarcopenia.
-
Reviewer #2 (Public Review):
This manuscript reports the results of an ancillary study of a prospective trial assessing the effects of androgen deprivation therapy (ADT) with Dagarelix (a GnRH antagonist) on body composition in patients with prostate cancer. An interesting relationship between FSH levels, that were suppressed by Dagarelix treatment, and body composition parameters (particularly fat body mass) was described after 12 months of therapy. Therefore, the authors conclude that FSH could be a promising marker to monitor the risk of sarcopenic obesity and cardiovascular complications in prostate cancer patients undergoing ADT. As acknowledged by the Authors the main limitation of the study is the limited sample of patients. However, since testosterone levels were not assessed it is not possible to firmly establish whether the …
Reviewer #2 (Public Review):
This manuscript reports the results of an ancillary study of a prospective trial assessing the effects of androgen deprivation therapy (ADT) with Dagarelix (a GnRH antagonist) on body composition in patients with prostate cancer. An interesting relationship between FSH levels, that were suppressed by Dagarelix treatment, and body composition parameters (particularly fat body mass) was described after 12 months of therapy. Therefore, the authors conclude that FSH could be a promising marker to monitor the risk of sarcopenic obesity and cardiovascular complications in prostate cancer patients undergoing ADT. As acknowledged by the Authors the main limitation of the study is the limited sample of patients. However, since testosterone levels were not assessed it is not possible to firmly establish whether the changes in fat mass observed with treatment are directly or indirectly associated with a reduction in FSH (and therefore in the latter case mediated by testosterone). Moreover, it is not clear whether the effect of the change in FSH levels during the study and the body composition parameters achieved at 12 months was evaluated (instead of assessing the relationship between FSH changes and changes in body composition parameters). Finally, tests on bone muscle mass and strength were not performed, so the hypothesis that variation of FSH levels in prostate cancer patients in ADT may affect sarcopenia remains speculative.
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