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© 2022 The Authors. Société Internationale d'Urologie Journal, published by the Société Internationale d'Urologie, Canada.

Key Words Competing Interests Article Information

Follicle-stimulating hormone, biomarker, 
androgen deprivation therapy, oncologic 
outcomes, prostate cancer

Paul Toren reports research funding from 
Bristol-Myers-Squibb and Janssen, as well 
as personal fees as a consultant from Sanofi, 
Ferring, Astellas, Bayer, and Abbvie.

Funding: This project was funded by a Fonds 
de Recherche du Québec – Santé Clinician-
Scientist Award (#32774) and a Prostate 
Cancer Canada Movember Discovery Grant 
(D2016-1393).

Received on August 6, 2021 
Accepted on September 7, 2021 
This article has been peer reviewed.

Soc Int Urol J. 2022;3(2):56–61

DOI: 10.48083/LWHQ7760

56 SIUJ  •  Volume 3, Number 2  •  March 2022 SIUJ.ORG

ORIGINAL RESEARCH

Follicle-Stimulating Hormone (FSH) Levels  
During Androgen Deprivation Therapy Are Not 
Associated With Survival or Development of 
Castration-Resistant Prostate Cancer
Kaleem Atchia,1 France-Hélène Joncas,1 Lily Summers Trasiewicz,2 Wei Phin Tan,3 Keyue Ding,2  
Brant A. Inman,3 Paul Toren1

1 Department of Surgery, Faculty of Medicine, Université Laval; Centre Hospitalier Universitaire (CHU) de Québec Research Centre, Oncology Division,  
Québec City, Canada  2 Canadian Cancer Trials Group (CCTG), Queen’s University, Kingston, Canada  3  Division of Urology, Duke Cancer Institute,  
Duke University, Durham, United States

Abstract

Background Follicle-stimulating hormone (FSH) dysregulation plays a potential role in prostate cancer progression. 
The objective of this study was to evaluate whether higher FSH levels during androgen deprivation therapy (ADT) for 
recurrent prostate cancer could predict the development of castration-resistant prostate cancer (CRPC), prostate 
cancer-specific survival (CSS), and overall survival (OS).

Methods Serum FSH levels were measured in cryopreserved samples of the continuous ADT arm of the PR.7 trial, 
supplemented with analogous samples from a large contemporaneous biobank. Univariate and multivariate analyses 
assessed the relationship between FSH tertiles and time to CRPC, as well as CSS, and OS.

Results A total of 172 patients were included in our analysis. Of these, 54 patients (31%) developed CRPC during 
the 9-year follow-up. Median FSH for the tertiles was 4.35, 6.13, and 11.32 mIU/mL. FSH tertiles were not significantly 
associated with the time to CRPC, or with CSS or OS. FSH levels were not a significant prognostic factor for these 
oncologic outcomes.

Conclusion As previously reported, the use of gonadotropin-releasing hormone (GnRH) antagonists for ADT 
has significantly more suppression of FSH levels than GnRH agonists. Our results do not suggest that differences in 
circulating FSH 1 year following ADT initiation influence long-term oncologic outcomes or development of CRPC.

Introduction

There is mounting evidence that follicle-stimulating hormone (FSH) dysregulation may play a role in prostate cancer 
development and progression[1]. Selective expression of FSH receptor by endothelial cells has been demonstrated 
in a wide range of tumors as well as in the majority of tumor metastases, including prostate cancer[2,3]. Higher 
preoperative levels of serum FSH have been linked with lower levels of testosterone, higher grade cancer, and 
extraprostatic extension[4,5]. In patients undergoing androgen deprivation therapy (ADT) for advanced prostate 

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cancer, an association between serum FSH levels and the 
time to the development of castration-resistant prostate 
cancer (CRPC) has been reported in a retrospective, 
single-center study[6].

ADT has also been associated with a higher risk of 
cardiovascular events[7,8]. Moreover, in the context of 
ADT, data suggest that FSH can promote cardiovascular, 
metabolic, and skeletal comorbidities through athero-
sclerotic plaque formation, metabolic syndrome, insu-
lin resistance, and bone resorption[9,10]. Of particular 
interest, recent reports have highlighted the differences 
in cardiovascular events between gonadotropin-releas-
ing hormone (GnRH) agonists and antagonists. For 
instance, a randomized phase II study by Margel et al. 
suggested that GnRH antagonist therapy, which lowers 
circulating FSH levels, is associated with an 18% abso-
lute risk reduction in major adverse cardiovascular and 
cerebrovascular events[11]. More recently, the random-
ized phase III HERO trial comparing leuprolide with 
the oral GnRH antagonist relugolix has shown a 54% 
relative risk reduction of major adverse cardiovascular 
events (MACE)[12].

An important difference between GnRH agonists 
and antagonists during ADT is superior suppression of 
serum FSH with antagonists, which has been a leading 
hypothesis in explaining the differences in cardiovas-
cular and other comorbidities. However, the role of FSH 
biology and its impact on clinical outcomes remains to 
be fully defined. The role of FSH suppression on clinical 
outcomes and safety has so far been researched mainly in 
studies comparing GnRH agonists with antagonists. In 
the CS21 trial, rapid decrease in PSA and more profound 
suppression of FSH was noted with degarelix compared 
with leuprolide, including upon crossover from leupro-
lide to degarelix[13]. Few studies have reported on the 
association of FSH levels before or during ADT, as an 
independent prognostic factor, on clinical outcomes. In 
a recent study, Kourbanhoussen et al. showed no signif-
icant association between FSH levels before prostatec-
tomy with biochemical recurrence, time to CRPC, time 
to metastasis, or occurrence of MACE[14]. In the context 
of ADT, it has been reported that FSH levels could 
predict time to the development of CRPC[6].

In this study, using cryopreserved serum samples 
from the PR.7 trial with long annotated clinical 
follow-up[15], we sought to evaluate whether higher 
FSH levels correlate with lower overall survival (OS) and 
cancer-specific survival (CSS), as well as a reduced time 
to development of CRPC.

Methods
Inst itut iona l resea rch et hics approva l for t his 
retrospective study was obtained from the CHU de 
Québec-Université Laval (2016-2835) and from the Duke 
University Institutional Review Board (Pro00044627).

For this analysis, we identified 163 patients with 
cryopreserved serum samples taken 12 months post 
randomization from the continuous androgen depriva-
tion (CAD) arm of the PR.7 trial for whom demographic 
information and long-term clinical follow-up were avail-
able in the Canadian Cancer Trials Group (CCTG) data-
base. Informed consent was obtained for the biobank for 
all participants in the PR.7 trial.

For 100 of those patients, serum samples taken 24 and 
36 months post randomization were also available and 
were included in our analysis. Details of the PR.7 trial 
are provided in the original publication[15]. Notably, all 
patients received GnRH agonists in this cohort.

To increase our statistical power, we included 9 addi-
tional contemporaneous cryopreserved serum samples 
from patients identified in a large biobank at Duke 
University with long clinical follow-up.

These patients also received continuous ADT follow-
ing PSA recurrence following radiotherapy and met the 
inclusion criteria of the PR.7 trial.

FSH levels were measured using 20 µL of plasma 
with immunoassays according to the manufacturer’s 
instructions (Cayman Chemicals, Ann Arbor, MI, US). 
Statistical analyses assessed the relationship between 
FSH levels and clinical outcomes such as OS, CSS, and 
time to CRPC. CRPC was defined as at least 2 rising 
PSA values or as new or progressing metastases despite 
castrate levels of testosterone (< 1.7 mmol/L). Patients 
were divided into tertiles based on FSH levels during 
CAD and Kaplan-Meier survival curves estimated OS, 
CSS, and time to CRPC for these tertiles. Cox multivari-
able proportional hazards analyses were performed for 
the same outcomes, with adjustment for baseline clini-
cal factors: age, Gleason score, baseline PSA, time since 
radiotherapy, and Eastern Cooperative Oncology Group 
(ECOG) status.

Results
A total of 172 patients were included in this study. The 
mean age was 73.4 years, and almost 80% of patients 

Abbreviations 
ADT androgen deprivation therapy
CRPC castration-resistant prostate cancer
CSS cancer-specific survival
FSH follicle-stimulating hormone
GnRH gonadotropin-releasing hormone
OS overall survival

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had a Gleason score ≤7 at diagnosis. The median FSH 
during ADT was 6.19 IU/mL (interquartile range: 4.82 
to 9.81). Median FSH for the tertiles was 4.35, 6.13, and 
11.32 mIU/mL. Only 10% of patients had prostatectomy 
before ADT. Over the 9 years of follow-up, 54 patients 
(31%) developed CRPC, and 48 patients (28%) died, of 
whom 20 (12%) died of prostate cancer. Demographic 
and clinical characteristics are outlined by FSH tertile 
and for the whole cohort in Table 1. Baseline patient 
characteristics were similar across all tertiles, except that 
Gleason scores were similar for tertiles 1 and 3, while 
tertile 2 had fewer patients with a score > 7.

Univariate and multivariate Cox regression analysis 
adjusted for age, Gleason score, baseline PSA, time since 
radiotherapy, and ECOG status found no significant 
association between FSH tertile and OS, CSS, or time to 
development of CRPC (Figure 1, Table 2).

For the subset of 100 patients with 3 annual FSH 
measurements after randomization, median and maxi-
mum FSH levels were similarly analyzed, but no statis-
tically significant association was found. Lastly, within 
the latter subset of patients, a comparison of patients 
with increasing FSH levels (≥ 30% from baseline) with 
those who had no increase (< 30%) yielded no significant 
association with the clinical outcomes.

Discussion
The role of FSH in prostate cancer clinical outcomes and 
comorbidities during ADT is not yet fully understood. 
In this analysis, we were not able to demonstrate a 
significant association between circulating FSH levels 
during ADT and OS, CSS, or time to development of 
CRPC.

Given that low testosterone levels before radical prosta-
tectomy have been associated with poor prognosis[16–19], 

TABLE 1. 

Demographic and clinical characteristics of patients according to FSH tertile 

FSH Tertile 1 FSH Tertile 2 FSH Tertile 3 All patients

Number of patients 56 59 57 172

Age–mean (SD) 73.2 (7.7) 73.1 (5.8) 74.0 (5.3) 73.4 (6.3)

Age–median (IQR) 74.95 (68.4, 78.9) 74.1 (69.8, 77.5) 74.6 (69.5, 77.2) 74.4 (69.2, 77.95)

Gleason score–n (%) 
 ≤ 7
 > 7 
 Not available

44 (78.6) 
9 (16.1) 
3 (5.3)

50 (84.7) 
6 (10.2) 
3 (5.1)

43 (75.4) 
11 (19.3) 
3 (5.3)

137 (79.7) 
26 (15.1) 
9 (5.2)

Baseline PSA–median (IQR), ng/mL 8.04 (5.45, 10.75) 7.53 (5.90, 13.90) 8.10 (6.40, 12.10) 7.96 (5.92, 12.05)

Baseline testosterone–median (IQR), 
nmol/L

12.55 (9.00, 16.75) 11.90 (8.90, 14.90) 12.20 (9.85, 16.10) 12.10 (9.30, 16.00)

Testosterone during ADT–median (IQR), 
nmol/L

0.50 (0.40, 0.92) 0.80 (0.50, 1.20) 0.70 (0.40, 1.00) 0.70 (0.40, 1.10)

FSH during ADT–median (IQR), mIU/mL 4.35 (3.82, 4.98) 6.13 (5.32, 7.13) 11.32 (9.85, 14.78) 6.19 (4.82, 9.81)

Prior prostatectomy – n (%)  
 No 
 Yes

 
48 (86)  
8 (14)

 
53 (90) 
6 (10)

 
53 (93) 

4 (7)

 
154 (90) 
18 (10)

CRPC during follow-up – n (%) 18 (32) 17 (29) 19 (33) 54 (31)

Cancer-specific mortality – n (%) 6 (11) 5 (8) 9 (16) 20 (12)

Overall mortality – n (%) 17 (30) 11 (18.6) 20 (35) 48 (28)

Baseline ECOG status – n (%) 
 0 
 1

45 (80) 
11 (20)

51 (86) 
8 (14)

44 (77) 
13 (23)

140 (81) 
32 (19)

FSH: follicle-stimulating hormone; SD: standard deviation; IQR: interquartile range; CRPC: castration-resistant prostate cancer

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59SIUJ  •  Volume 3, Number 2  •  March 2022 SIUJ.ORG

Follicle-Stimulating Hormone (FSH) Levels During Androgen Deprivation Therapy

100

80

 60

Pe
rc

en
ta

ge

100

20

1/3tertl 2/3tertl 3/3tertl
0

0186420

100

80

 60

Pe
rc

en
ta

ge

Time (years)

100

20

1/3tertl 2/3tertl 3/3tertl
0

0186420

100

80

 60

Pe
rc

en
ta

ge

100

20

1/3tertl 2/3tertl 3/3tertl
0

0186420

Overall Survival 

Development of CRPC 

Time (years)

Time (years)

FIGURE 1.

Kaplan-Meier curves for overall survival, cancer-specific survival, and development of CRPC by FSH tertile 

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it would be reasonable to hypothesize that physiologic 
feedback increase in FSH might also be a marker for 
adverse disease course. However, a recent retrospective 
study of 492 patients showed no association between 
FSH levels and long-term oncologic and cardiovas-
cular outcomes[14]. Although several studies found 
some evidence for preoperative FSH levels as a prog-
nostic marker for more aggressive disease in patients 
undergoing radical prostatectomy[4,5,20], we found no 
differences in long-term clinical outcomes for advanced 
prostate cancer under ADT. Few studies have directly 
investigated the prognostic value of FSH levels during 
ADT. For example, a prior study of patients treated 
with ADT reported that higher FSH levels may predict 
shorter time to development of CRPC[6]. Nonetheless, 
FSH measurement in this retrospective cohort occurred 
in less than a third of patients, raising the potential for 
selection bias. Our contradictory results feature a greater 
number of patients, a lower proportion of patients who 
later developed CRPC, and longer follow-up.

Our study has a reasonably sized, multi-centric 
cohort of patients with long-term clinical follow-up from 
a robust clinical trial. Limitations intrinsic to the cohort 
of the clinical trial are discussed elsewhere[21]. However, 
the limitations of this study include the fact that only 
one FSH measurement was available for the main analy-

sis 1 year into ADT and 3 measurements over 3 years for 
a subset of patients. There was also no standardization 
of the time of sampling during the day, which may have 
small effects on circulating FSH levels due to circadian 
rhythms. No details were available on whether patients 
had medical comorbidities that might have affected FSH 
production. Finally, the number of events limits the 
power to detect differences between the FSH tertiles.

Accumulating research comparing GnRH agonists 
with antagonists suggests GnRH antagonists are asso-
ciated with lower overall mortality and cardiovascular 
events[22]. Superior FSH suppression has been hypoth-
esized to play an important role in this comparison. 
Nonetheless, our results suggest FSH values following 
ADT with GnRH agonists do not predict survival. Thus, 
our results cast doubt on whether FSH levels are caus-
ative in any relationship between GnRH antagonists and 
cardiovascular outcomes. This is concordant with the 
recent report by Kourbanhoussen et al.[14].

In summary, this retrospective analysis does not 
suggest that circulating FSH levels during ADT for 
recurrent prostate cancer predict clinical outcomes. 
Further clinical research is warranted to better under-
stand the role of FSH level in prostate cancer patients.

TABLE 2.

Association between FSH tertile and long-term clinical outcomes 

Variable FSH Tertile 1, adjusted HR
FSH Tertile 2, adjusted HR 

(95% CI)
FSH Tertile 3, adjusted HR 

(95% CI)

Overall survival 1.00 0.544 (0.264–1.122) 1.106 (0.594–2.057)

Cancer-specific survival 1.00 0.639 (0.221–1.843) 1.250 (0.493–3.168)

Time to CRPC 1.00 0.739 (0.393–1.388) 1.089 (0.595–1.995)

FSH: follicle-stimulating hormone; CRPC: castration-resistant prostate cancer; HR: hazard ratio; CI: confidence interval

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