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ORIGINAL ARTICLE
1
Clomiphene citrate treatment for late onset hypogonadism:
rise and fall
_______________________________________________
Marcelo Marconi 1, Renato Souper 1, Jonathan Hartmann 1, Matías Alvarez 2, Ignacio Fuentes 3,
Francisco J. Guarda 3
1 Departamento de Urología de la Universidad Católica de Chile, Santiago, Chile; 2 Facultad de Medicina,
Universidad Católica de Chile, Santiago, Chile; 3 Departamento de Endocrinología, Universidad Católica
de Chile. Santiago, Chile
ABSTRACT ARTICLE INFO
______________________________________________________________ ______________________
Objective: Previous series have demonstrated that Clomiphene Citrate (CC) is an effec-
tive treatment to increase Total Testosterone (TT) in Late Onset Hypogonadism (LOH)
patients. However, what happens to TT levels after ending CC treatment is still debat-
able. The objective of this study is to evaluate TT levels 3 months after the discontinu-
ation of CC in patients with LOH who were previously successfully treated with the
same drug.
Materials and Methods: Twenty-seven patients with LOH that were successfully treated
(achieved TT levels >11nmol/l) with CC 50mgs daily for 50 days were prospectively
recruited in our Andrological outpatient clinic. CC was then stopped for 3 months and
TT levels were measured at the end of this period.
Results: Mean TT level before discontinuation of CC was 22.7±8.1nmol/L (mean±SD).
Three months after discontinuation, mean TT level significantly decreased in all pa-
tients, 10.2±3.9nmol/l (p<0.01). Twenty-one patients (78%) decreased TT levels under
11nmol/L. Six patients (22%) had TT levels that remained within the normal recom-
mended range (≥11nmol/l). No statistical significant differences were observed between
both groups.
Conclusion: In the short term LOH does not seem to be a reversible condition in most
patients after CC treatment. More studies with longer follow-up are needed to evaluate
the kinetics of TT in LOH.
Keywords:
Hypogonadism; Clomiphene;
Tes to st er on e; T he ra pe ut ic s
Int Braz J Urol. 2016; 42: XX-XX
_____________________
Submitted for publication:
February 21, 2016
_____________________
Accepted after revision:
April 14, 2016
INTRODUCTION
The exact prevalence of Late Onset Hypo-
gonadism (LOH) is a matter of debate (1-3); ho-
wever, there is consensus that it constitutes an
emerging problem (4). Testosterone Replacement
Therapy (TRT) using different formulations i.e. in-
tramuscular, transcutaneous and trans-mucosal-
-among others-is the most popular treatment stra-
tegy for LOH (5). Based in clinical experience and
following recommendations coming from guide-
lines, in most patients the indication of TRT may
be clear; however, in some cases it may be contro-
versial or even contraindicated. Examples of these
situations are patients who want to father a child
in the near future, in which TRT is contraindicated
(6), patients with LOH symptoms-i.e. decreased se-
xual interest, erectile dysfunction-and Total Tes-
tosterone (TT) levels that are under but very close
to the normal recommended range (11nmoL/L), in
Vol. 42 (x): 2016 July 4.[Ahead of print]
doi: 10.1590/S1677-5538.IBJU.2016.0112
IBJU | CLOMIPHENE TREATMENT FOR LATE ONSET HYPOGONADISM
2
whom the clinician may doubt whether the symp-
toms are really related to TT levels (7) or may be
related to other conditions-i.e. psychological is-
sues; and finally, men that may have transient
hypogonadism (8, 9), for example due to stress-
ful conditions (10). In these cases, but also in ty-
pical LOH patients, Clomiphene Citrate (CC) has
become an extremely interesting alternative (11).
Clomiphene Citrate blocks the estrogen receptor
in the hypothalamus and pituitary gland, incre-
asing FSH and LH levels and secondarily increa-
sing spermatogenesis and testosterone levels (11,
12). Even though, Clomiphene Citrate treatment is
not approved for men in many countries, it has
been used over-the-counter for decades, first to
improve sperm count and in the last 15 years it
has proved to be an effective and safe strategy to
increase testosterone levels in patients with LOH
(13, 14). Clomiphene Citrate has advantage of not
affecting fertility and not blocking the Hypotha-
lamus-Pituitary-Testis (HPT) axis. However, infor-
mation about CC treatment for LOH is still scarce,
especially regarding the kinetics of TT levels and
the potential recovery of HPT axis after treatment
discontinuation. Taking this information into ac-
count, the objective of this study is to evaluate TT
levels 3 months after the discontinuation of CC in
patients with LOH who were previously success-
fully treated with the same drug.
PATIENTS AND METHODS
Thirty patients (mean 50.1 years, range 32-
70) with LOH were prospectively recruited in our
Andrological outpatient clinic. Late Onset Hypo-
gonadism was defined according to previous con-
sensus definition (15):
-Symptoms: decreased sexual interest, de-
creased morning erections, erectile dys-
function.
-Total Testosterone <11nmol/l (in at le-
ast two different measurements) Regar-
ding symptoms, 13/27 patients complai-
ned of decreased sexual desire, 11/27 with
Erectile Dysfunction (ED), and 3/27 both
symptoms. The median IIEF-5 score of all
patients before treatment was 18 (range
11-24). In the subgroup that complained of
exclusively ED or decreased sexual interest
plus ED the median score was 15 (range
11-19).
To be eligible to be treated with CC, patients
had normal FSH and LH, no thyroid function ab-
normalities neither hyperprolactinemia. After a 50-
day treatment with 50mgs of CC daily, twenty-se-
ven patients achieved normal TT levels (>11nmol/l).
In this specific sub-group (n=27) CC was stopped
for 3 months and TT levels were evaluated at the
end of this period. Total testosterone was analyzed
using electrochemiluminescence inmuno assay
(Roche™). LH and FSH were measured using direct
chemiluminimetric inmuno assay (Siemens™). The
study was approved by the Research Ethical Com-
mittee of Pontificia Universidad Católica de Chile.
Statistical analysis
Data analysis was performed using
GraphPad™ software. Differences in TT levels be-
fore and after discontinuation of CC were analyzed
with paired t-test, considering statistical significan-
ce with a p<0.05. Results are shown as mean±SD.
RESULTS
Mean TT level at the time of diagnosis
(n=30) was 8.5±1.8nmol/L (mean±SD), with normal
range gonadotropins: FSH 5.1±4.9mIU/mL and LH
4.3±2.9mIU/mL. After a 50-day CC treatment, 27
patients achieved normal TT level. Mean TT level
in this group was significantly higher than pre-tre-
atment state, 22.7±8.1nmol/L, p<0.01 (Figure-1).
Three months after discontinuation of treatment,
mean TT level (n=27) was 10.2±3.9nmol/L. All pa-
tients (n=27) significantly decreased (p<0.01) TT
after discontinuation of CC (Figure-1). Twenty-one
(78%) patients decreased TT levels under 11nmol/L.
Six patients (22%) had TT levels that remained wi-
thin the normal recommended range (≥11nmol/L)
three months after discontinuation of CC. This sub-
group (n=6) was controlled six months after dis-
continuation of CC, in all cases TT decreased to
the pre-treatment levels (<11nmol/L). No statistical
significant differences were observed between the
group of patients who maintained TT levels within
the normal range (three months after discontinua-
IBJU | CLOMIPHENE TREATMENT FOR LATE ONSET HYPOGONADISM
3
tion) and those who decreased it (i.e. age, previous
TT levels). Regarding symptoms, after increasing
TT levels 38.5% (5/13) of patients who complained
of decreased sexual desire improved the symptom,
27.3% (3/11) improved ED rising their IIEF-5 score
(n=3) from a median of 18 (range 17-21) to 22 (21-
24), and 2/3 (66.7%) improved both.
DISCUSSION
Testosterone replacement therapy has sig-
nificantly increased in the last decade (16), howe-
ver, everyday practice concerns are multiple (17).
First: TRT is meant to be a lifelong treatment, so
the decision of starting therapy is considerable, es-
pecially regarding long term safety issues-i.e. car-
diovascular, oncological, etc., costs for the patient
and finally the fact that if the treatment is stopped,
testosterone levels will drop and may become even
lower than the one that motivated TRT due to HPT
axis blockade. Second: the two cardinal symptoms
that usually motivate TRT are decreased sexual de-
sire and ED. We know that the first is very sensitive
to TT levels (18), however, extremely subjective.
On the other hand, ED is associated with TT levels
much lower than the lower range in which TRT is
indicated (7, 18), so it may be incorrectly associated
with TT levels that are low, but not low enough to
explain the symptom. Third: TRT produces revers-
ible infertility, which constitutes a problem in pa-
tients who want to father a child. Fourth: we do not
know how many patients may present only a tran-
sient hypogonadism which could recover TT levels
after a “stimulation” treatment, meaning that an
undetermined number of LOH cases may not need
a chronic treatment but a short-term therapy or an
intermittent one (8, 9).
Taking all this information into account,
therapy with CC makes sense and evidence sup-
ports it. The results of our series demonstrate that
90% of men with LOH increased TT under treat-
ment which agrees with other reports showing
that in selected patients, CC is efficacious in a high
proportion of cases and has the advantages of not
blocking the HPT axis, not affecting fertility, not
producing polycythemia, and all with lower costs
Figure 1 - Total Testosterone (TT) levels at Day 0 (diagnosis), Day 50 (after Clomiphene Citrate (CC) treatment, 50mgs.
daily), and Day 140 (90 days after ending CC treatment).
*p<0.01 between day 0 and day 50. **p<0.01 between day 50 and day 140.
IBJU | CLOMIPHENE TREATMENT FOR LATE ONSET HYPOGONADISM
4
than TRT (8, 19-21). Even an isomer of CC, Enclo-
miphene (EC), has been introduced recently, having
the advantages of shorter half-life and theoretically
more specificity to increase LH and FSH (22). EC
has also demonstrated to increase testosterone le-
vels in a high proportion of cases (23). So if CC or
EC are such a good treatment, why not use it in
all cases? And, if patients recover TT levels after a
treatment with CC, is that recovery permanent once
the therapy is cancelled?
Regarding the first question, it seems that
one of the concerns would be the safety of the drug
in the long term. Evidence suggests that long term
CC treatment has no adverse effects and that effi-
cacy is maintained, however, in the longer studies
the follow-up does not exceed 46 months (14). In
our study no adverse effects were reported; howe-
ver, follow-up is too short to be conclusive.
The main objective of our study was to elu-
cidate if LOH could be reversed by a 50-day CC tre-
atment. Previous evidences were scarce, since most
of the studies did not report the kinetics of TT after
stopping CC treatment. We found three studies that
reported TT level after ending treatment. Lim and
cols. in 1976 reported in five hypogonadal uremic
men an increase in TT levels after CC treatment that
lasted for 12 months (24). Normal TT levels were
reported 4 months after ending therapy. Guay and
cols. in 2003 mentioned that in some patients with
LOH, CC can be stopped and normal TT levels can be
maintained (8). However, definitive data regarding
this asseveration is lacking in the manuscript (8).
Devoto and Aravena, reported that in a subgroup
of patients with functional hypogonadotropic hy-
pogonadism who respond to CC therapy, normal
TT levels were maintained six months after ending
treatment (9). On the other hand, Kaminetsky and
cols, and Wiehle and cols. reported that in patients
with secondary hypogonadism who responded to
EC therapy, once the treatment was stopped TT le-
vels decreased and returned to the pre-treatment
values (23, 25). Our results concur with the last
two authors since all patients decreased TT levels 3
months after discontinuation of CC treatment, 78%
of them under the normal range. The six cases in
which TT was in the normal range three months
after CC discontinuation also dropped TT levels (to
pre-treatment levels) six months after ending tre-
atment. We think that our results reveal that LOH
is a chronic irreversible condition in most cases.
Since all cases dropped TT levels to pre-treatment
levels we were not able to evaluate if certain pa-
tient characteristics (age, comorbidities, etc.) could
predict a permanent response to CC treatment. The
same occurred in the primary group (n=30) where
27 patients increased TT levels, making a compa-
rison between responders and non-responders not
statistically possible due to the small number of
non-responder cases (n=3).
Considering our results and previous re-
ports we think CC treatment would have three roles:
First, it is an excellent alternative when patients are
concerned about fertility, second, CC is an extraor-
dinary alternative for a therapeutic individual trial
in cases where we are not convinced that low tes-
tosterone is really the explanation to all its symp-
toms, especially when the TT level is very close to
the normal ranges. Finally, CC represents a good
alternative to TRT with the advantage of not blo-
cking HPT axis, but taking into account our results
and previous series (23, 25), it should be discussed
with the patient that treatment will be permanent
in most cases.
The main limitations of our study are: the
short follow-up and the absence of the evaluation
of estradiol and free testosterone. Regarding this
last point, all patients had TT values under the nor-
mal range associated with symptoms, according to
the guidelines in these cases TT would be enough
for evaluation (5). Also no specific questionnaire
was applied to the patients regarding LOH symp-
toms, however, these questionnaires are not recom-
mended by the guidelines since their specificity is
low and are not effective for case finding (5).
CONCLUSIONS
Late Onset Hypogonadism on men who suc-
cessfully respond to CC therapy in the short term do
not seem to reverse the condition after ending tre-
atment. More studies with longer follow-up are ne-
eded to evaluate the kinetics of TT in these patients.
CONFLICT OF INTEREST
None declared.
IBJU | CLOMIPHENE TREATMENT FOR LATE ONSET HYPOGONADISM
5
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_______________________
Correspondence address:
Marcelo Marconi, MD
Departamento de Urología
de la Universidad Católica de Chile, Santiago, Chile
Marcoleta 367
Santiago, 832-0000, Chile
Telephone: +56 9 7968-5115
Email: mmarconi@andro.cl
