Treatments given to cancer patients can cause negative side effects. For example, a treatment known as androgen deprivation therapy – which is used to reduce male sex hormone levels in prostate cancer patients – can lead to increased body fat percentage and decreased bone density. These adverse effects can have further negative impacts on patient health, such as increasing the risk of cardiovascular disease and fractures from falls from standing height or less, respectively. Understanding how androgen deprivation therapy contributes to these negative side effects may help clinicians better manage care and outcomes for patients with prostate cancer.

Follicle stimulating hormone (or FSH for short) has roles in male and female reproduction but has also been linked to changes in body composition. For example, elevated FSH levels are associated with higher total fat body mass in post-menopausal women. While androgen deprivation therapy is known to alter FSH blood levels, the impact of this change in prostate cancer patients was not well understood.

To investigate the effect of androgen deprivation therapy on FSH levels and body composition, Bergamini et al. used X-ray technology to measure total fat body mass in prostate cancer patients before and after undergoing 12 months of androgen deprivation therapy. The findings showed that patient FSH blood levels significantly decreased after 12 months of treatment. Higher FSH blood levels strongly correlated with increased total fat body mass after 12 months of treatment.

The findings of this clinical trial suggest that FSH blood levels impact the body composition of patients undergoing androgen deprivation therapy. As a result, FSH blood levels may be a suitable biomarker for identifying patients that are more likely to develop obesity and are therefore at greater risk of complications such as cardiovascular disease.

Recent preclinical and clinical studies have shown that follicle-stimulating hormone (FSH) exerts effects beyond those on gonadal tissue, which have been known for a long time (Lizneva et al., 2019). In the animal model, FSH has been observed to stimulate osteoclastic activity and therefore to exert a negative role on bone mass (Sun et al., 2006; Zaidi et al., 2023; Gera et al., 2022). Furthermore, FSH was found to have a positive action on adipocytes and the blockade of FSH induced by antibodies against FSH receptor caused an increase in bone mass and a reduction of body fat (Liu et al., 2017; Rojekar et al., 2023). These preclinical data were confirmed in clinical studies. Large epidemiologic data have shown significant reductions in bone mineral density (BMD) and high resorption rates 2–3 years prior to menopause, when FSH serum levels are increasing, which is also associated with increased body weight and visceral adiposity (Thurston et al., 2009; Senapati et al., 2014). A longitudinal study involving post-menopausal women has shown that increases in circulating FSH levels were associated with greater increases in the percentage of total body fat, total body fat mass, and subcutaneous adipose tissue (Mattick et al., 2022). Moreover, clinical studies have found that FSH is also involved in the modulation of lean mass. A large cohort study of perimenopausal women showed that increased FSH concentrations were associated with increasing fat mass and decreasing lean mass measured by bioelectrical impedance analysis (Sowers et al., 2007). Another recent prospective study showed that the indicators of sarcopenia were strongly associated with gonadotropins levels, especially in older men (Guligowska et al., 2021). The impact of FSH on body composition may at least partially explain the observed correlation between FSH levels and the risk of cardiovascular events (Munir et al., 2012; Silva et al., 2013; El Khoudary et al., 2016).

Studies clarifying the relationship among FSH, body composition measures, and BMD in prostate cancer (PC) patients are lacking. Likewise, the interaction between the variation of FSH serum levels and the modification of these parameters in PC patients undergoing androgen deprivation therapy (ADT) is not known.

We recently conducted the BLADE study (Bone mineraL mAss Dexa dEgarelix), a prospective phase IV study designed to obtain explorative information on dual-energy x-ray absorptiometry (DXA) measurement changes in lean body mass (LBM) and fat body mass (FBM) in patients with non-metastatic PC treated with degarelix, an LHRH (luteinizing hormone-releasing hormone) antagonist that has been developed to achieve effective long-term medical castration without the risk of testosterone surge and its associated flare. Data on changes in total LBM and FBM and on the impact of degarelix on BMD and bone turnover markers were recently published (Palumbo et al., 2021; Palumbo et al., 2022).

Here, we analyse the association of FSH with DXA-assessed FBM, LBM, and BMD and bone turnover markers at baseline and after degarelix administration in the patients enrolled in the BLADE study.

Twenty-nine patients were included in the BLADE study and their characteristics have been described elsewhere (Palumbo et al., 2022). The consort diagram is reported in supplementary material (Figure 1—figure supplement 1). An outlier value of FSH after 12 months was removed from the analysis. Mean FSH serum levels at baseline conditions were 11.9 UI/l (95% confidence intervals [CIs]: 7.6–16.3). Mean FSH serum levels significantly decreased to 1.45 UI/l (95% CIs: 1.01–1.89) after 6 months of degarelix treatment and to 2.4 UI/l (95% CIs: 1.4–3.4) after 12 months. The corresponding percent changes were −77.59% (95% CIs: −86.20 to −68.87) and −59.7% (95% CIs: −80.3 to −39.1, p < 0.001) (Figure 1). Data on changes in body composition parameters, BMD, and bone turnover markers have been published elsewhere (Palumbo et al., 2021; Palumbo et al., 2022; Dalla Volta et al., 2024). Correlations between FSH changes and changes in body composition parameters, BMD, and bone turnover markers were not statistically significant, so these data are not presented.

Figure 1 with 1 supplement see all

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Figure 1—source data 1

Data are from BLADE study database.

https://cdn.elifesciences.org/articles/92655/elife-92655-fig1-data1-v1.xls

Download elife-92655-fig1-data1-v1.xls

Relationship between FSH serum levels and body composition, BMD, and bone turnover markers after 12 months of degarelix treatment

The correlation between circulating FSH levels at 6 and 12 months, bone turnover markers evaluated at the same time, BMD and body composition parameters assessed after 12 months is shown in Table 2. FSH serum levels assessed after 6 months of degarelix administration showed a direct relationship with total FBM (r = 0.49, p = 0.008) and with fat mass evaluated at arms (r = 0.53, p = 0.004), trunk (r = 0.48, p = 0.009), and legs (r = 0.45, p = 0.015). In contrast, FSH serum levels after 6 months of treatment showed an inverse relationship with ALMI/FBM ratio (r = −0.58, p = 0.001). FSH measured after 12 months maintained a significant relationship with total FBM (r = 0.52, p = 0.006) (Figure 2a), fat mass at arms (r = 0.54, p = 0.004) (Figure 2b), and fat mass at trunk (r = 0.45, p = 0.018) (Figure 2c). The relationship between FSH and fat mass at legs lost the statistical significance (r = 0.33, p = 0.089), while the inverse relationship with ALMI/FBM ratio was confirmed (r = −0.64, p = 0.001) (Figure 2d).

Figure 2

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Table 2

FSH at 6 months			FSH at 12 months
	Correlation coefficient	p	Correlation coefficient	p
TOT BMD	−0.039	0.843	−0.107	0.595
BMD L2–L4	0.102	0.604	−0.040	0.844
BMD LEFT HIP	0.030	0.881	−0.044	0.829
CTX	0.051	0.796	0.055	0.785
BONE ALP	0.174	0.376	0.227	0.256
TOT fat (g)	0.490	0.008	0.518	0.006
Arm fat (g)	0.532	0.004	0.541	0.004
Leg fat (g)	0.454	0.015	0.328	0.089
Head fat (g)	0.187	0.341	0.093	0.644
Trunk fat (g)	0.483	0.009	0.452	0.018
TOT lean (g)	0.029	0.885	−0.036	0.859
Arm lean (g)	0.041	0.837	0.028	0.889
Leg lean (g)	−0.176	0.371	−0.285	0.149
Head lean (g)	0.086	0.663	−0.006	0.977
Trunk lean (g)	0.161	0.414	0.021	0.916
ALMI (appendicular lean/Ht2)	−0.229	0.241	−0.265	0.181
ALMI/FBM	−0.581	0.001*	−0.604	0.001*
Android/gynoid ratio	0.142	0.472	0.231	0.246

1. Data are Spearman R.

2. Bold values are those attaining statistical significance.

3. *

   Still significant after Bonferroni correction.

4. FSH: follicle-stimulating hormone; TOT: total; BMD: bone mineral density; CTX: C-terminal telopeptide of type I collagen; ALP: alkaline phosphatase; ALMI: appendicular lean mass index; Ht²: height squared; FBM: fat body mass.

ADT in PC patients leads to an increase in fat mass and to a decrease in lean mass, thus increasing the risk of sarcopenic obesity. In addition, ADT has also a negative impact on skeletal fragility, which increases the risk of fractures. During the recent years, there has been consistent evidence that alterations in body composition could contribute to determine skeletal fragility in patients under ADT, such as well demonstrated in other forms of male hypogonadism (Vena et al., 2023). However, the determinants of altered body composition in male hypogonadism and in ADTs have not been completely defined. As a matter of fact, low testosterone values do not seem to be the only determinant of sarcopenic obesity in males with hypogonadism. In this context, FSH values might play a role. In fact, among its extragonadal effects, FSH directly affects adipogenesis, lean mass and bone turnover (Liu et al., 2017; Rojekar et al., 2023; Zaidi et al., 2023; Gera et al., 2022).

As demonstrated in other studies prospectively evaluating circulating FSH levels after treatment with LHRH agonists and antagonists (Klotz et al., 2008), degarelix administration consistently reduced FSH values, although values might be variable among individuals under ADT. In this context, it is reasonable to hypothesize that variable values of FSH might directly influence body composition and skeletal fragility.

This ancillary analysis of the BLADE study shows that higher serum levels of FSH during degarelix treatment were significantly associated with higher total, limbs, and trunk fat mass. Moreover, higher FSH values under ADT were associated with lower ALMI/FBM ratio, a parameter that identifies patients at high risk for sarcopenic obesity. We can infer therefore that the effect was caused by the direct relationship of FBM since there was no correlation between lean mass and FSH in this study. These associations were not significant before starting degarelix, suggesting that sex hormones might counteract FSH effect on body composition at baseline conditions, whereas this effect becomes more evident after ADT. According to these data, small changes in FSH can result in significant changes in body composition in a condition of androgen and estrogen deprivation. However, since sex hormones were not measured in our patients, it was unclear whether the possible variability in testosterone values during degarelix treatment (Kamada et al., 2024) might have influenced the detrimental effects of FSH and body composition. Indeed, the protocol of BLADE study did not include measurement of testosterone values, since radioimmunoassay and chemiluminescence assay used in clinical practice could overestimate testosterone levels in majority of patients under ADTs, leaving a concern of misdiagnosing truly castrate patients as being inadequately treated (Tiwari et al., 2022).

It is known that one of the most noticeable differences of LHRH antagonists compared to LHRH agonists are FSH levels during therapy, which are mildly higher with LHRH agonists compared to LHRH antagonists. According to our data, PC patients treated with LHRH antagonists may experience less body composition changes due to lower FSH residual values (Klotz et al., 2008; Margel et al., 2019; Abufaraj et al., 2021).

Unlike other settings, FSH values before and after degarelix did not correlate with either BMD or bone turnover markers.

To our knowledge, this is the first study showing an association between circulating FSH levels and body composition in PC patients undergoing ADT. However, this study suffers from all the limitations of ancillary studies. Therefore, the results obtained are to be considered as hypothesis generating and cannot be generalized.

In conclusion, the findings of this study suggest that FSH serum levels after ADT could impact body composition – FBM in particular – in PC patients undergoing ADT.

Of course further investigation is required to establish the association between FSH serum levels, measured during ADT, and sarcopenic obesity risk in PC patients. However, this is an area of great interest.

FSH could be a promising marker in monitoring PC patients during ADT in order to identify those who are more vulnerable and at greater risk of alterations in body composition, which can be captured and measured reliably by DXA (Mazziotti et al., 2024).

All data generated or analysed during this study are included in the manuscript. Source data have been provided in an excel file labelled Source data 1.

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Author details

1. Marco Bergamini

   Medical Oncology Unit, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy

   Contribution

   Data curation, Investigation, Methodology, Writing – original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6161-707X

2. Alberto Dalla Volta

   Medical Oncology Unit, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy

   Contribution

   Data curation, Investigation, Methodology, Writing – review and editing

   For correspondence

   alberto.dallavolta@gmail.com

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8009-7663

3. Carlotta Palumbo

   Division of Urology, Department of Translational Medicine, University of Eastern Piedmont, Maggiore Della Carità Hospital, Novara, Italy

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

4. Stefania Zamboni

   Urology Unit, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

5. Luca Triggiani

   Radiation Oncology Unit, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

6. Manuel Zamparini

   Medical Oncology Unit, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy

   Contribution

   Data curation, Formal analysis

   Competing interests

   No competing interests declared

7. Marta Laganà

   Medical Oncology Unit, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy

   Contribution

   Investigation

   Competing interests

   No competing interests declared

8. Luca Rinaudo

   Tecnologie Avanzate S.r.l, Turin, Italy

   Contribution

   Validation, Investigation, Methodology

   Competing interests

   L Rinaudo is affiliated with Tecnologie Avanzate S.r.l. The author has no financial interests to declare

9. Nunzia Di Meo

   Radiology Unit, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy

   Contribution

   Investigation

   Competing interests

   No competing interests declared

10. Irene Caramella

    Medical Oncology Unit, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy

    Contribution

    Investigation

    Competing interests

    No competing interests declared

11. Roberto Bresciani

    Division of Biotechnology, Department of Molecular and Translational Medicine (DMTM), University of Brescia, Brescia, Italy

    Contribution

    Conceptualization, Writing – review and editing

    Competing interests

    No competing interests declared

12. Francesca Valcamonico

    Medical Oncology Unit, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy

    Contribution

    Investigation

    Competing interests

    No competing interests declared

13. Paolo Borghetti

    Radiation Oncology Unit, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy

    Contribution

    Investigation

    Competing interests

    No competing interests declared

14. Andrea Guerini

    Radiation Oncology Unit, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy

    Contribution

    Investigation

    Competing interests

    No competing interests declared

15. Davide Farina

    Radiology Unit, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy

    Contribution

    Conceptualization, Investigation, Methodology, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-4075-0001

16. Alessandro Antonelli

    Urology Unit, AOUI Verona, Department of Surgery, Dentistry, Pediatrics and Gynecology, University of Verona, Verona, Italy

    Contribution

    Investigation

    Competing interests

    No competing interests declared

17. Claudio Simeone

    Urology Unit, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy

    Contribution

    Conceptualization, Writing – original draft

    Competing interests

    No competing interests declared

18. Gherardo Mazziotti

    1. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Milan, Italy
    2. Endocrinology, Diabetology and Medical Andrology Unit, Metabolic Bone Diseases and Osteoporosis Section, IRCCS Humanitas Research Hospital,, Milan, Italy

    Contribution

    Conceptualization, Supervision, Writing – review and editing

    For correspondence

    gherardo.mazziotti@hunimed.eu

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-5458-701X

19. Alfredo Berruti

    Medical Oncology Unit, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy

    Contribution

    Conceptualization, Data curation, Supervision, Funding acquisition, Writing – review and editing

    Competing interests

    No competing interests declared

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