Changes in hormonal profile and seminal parameters with use of aromatase inhibitors in management of infertile men with low testosterone to estradiol ratios
seminal parameters with use ofaromatase inhibitors in managementof infertile men with low testosteroneto estradiol ratios
Odysseas Gregoriou, M.D., Panagiotis Bakas, M.D., Charalampos Grigoriadis, M.D., Maria Creatsa, M.D.,Dimitrios Hassiakos, M.D., and Georgios Creatsas, M.D.
2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, University of Athens, Athens, Greece
Objective: To compare the effects of 2.5 mg letrozole with those of 1 mg anastrazole daily on the hormonal and semen proﬁles of a sub-set of infertile men with low T/E2 ratios.
Design: Prospective, nonrandomized study.
Setting: Reproductive medicine clinic.
Patient(s): The study group consisted of 29 infertile men with a low serum T/E2 ratio (<10).
Intervention(s): Patients were divided into two groups. Group A included 15 patients treated with 2.5 mg letrozole orally once daily for6 months, and Group B consisted of 14 patients treated with 1 mg anastrazole orally every day for 6 months.
Main Outcome Measure(s): Hormonal evaluation included measurement of serum FSH, LH, PRL, T, and E2. In all sperm analyses pre-treatment and posttreatment total motile sperm counts (ejaculate volume Â concentration Â motile fraction) were evaluated.
Result(s): The use of aromatase inhibitors (either letrozole or anastrazole) in cases of infertile men with low T/E2 ratios improved bothhormonal and semen parameters.
Conclusion(s): This study suggests that some men with severe oligospermia, low T levels, and normal gonadotropin concentration mayhave a treatable endocrinopathy. (Fertil SterilÒ 2012;98:48–51. Ó2012 by American Society for Reproductive Medicine.)Key Words: Aromatase inhibitors, male infertility, oligospermia, letrozole, anastrazole
Aromataseisacytochromep450 breastcancers,impairedspermproduc- anonsteroidal,selective,potentthird-
zole, also a nonsteroidal agent, represents
dione to E2 and estrone, respectively.
ized trial was to compare the effects of 2.5
Received November 28, 2011; revised and accepted April 4, 2012; published online May 11, 2012.
O.G. has nothing to disclose. P.B. has nothing to disclose. C.G. has nothing to disclose. M.C. has nothing
to disclose. D.H. has nothing to disclose. G.C. has nothing to disclose.
Reprint requests: Odysseas Gregoriou, M.D., Aretaieion Hospital, 2nd Department of Obstetrics and
Gynecology, Vas. Sophias 76 Av., Athens 11528, Greece (E-mail: ).
Review Board at the Aretaieion Hospi-tal, Athens. The study took place from
Fertility and Sterility® Vol. 98, No. 1, July 2012 0015-0282/$36.00
Copyright 2012 American Society for Reproductive Medicine, Published by Elsevier Inc.
infertile men with a low serum T/E2 ratio (<10). These patients
In all sperm analyses pretreatment and posttreatment
were divided into two groups. Group A consisted of 15
TFSF were evaluated. The mean TFSF value was used for com-
patients treated with 2.5 mg letrozole orally once daily for
parison from pretreatment to posttreatment. Additionally, in
6 months, and group B consisted of 14 patients treated with
all cases analyzed, volume of ejaculate (in milliliters), sperm
1 mg anastrazole orally every day for 6 months. Patients
concentration (in millions per milliliter), and motility (per-
were allocated to either group on an alternating basis by the
outpatient clinic. Informed consent was received from all
Group A was treated with 2.5 mg letrozole (Femara; No-
vartis Pharmaceuticals), and group B was treated with 1 mg
Liver function tests were performed every month, and se-
anastrazole (Arimidex; Zeneca Pharma International) orally,
rum hormones and semen parameters were assessed at the be-
ginning and at the end of treatment. The serum hormones and
Data were statistically analyzed using Medcalc statistical
semen parameters were compared before and after the
software (version 22.214.171.124). Results are presented as mean Æ
SE. Statistical analysis was performed using Student's t test
All men had a thorough history and underwent physical
to compare pre- and posttreatment sperm parameters, serum
examination, semen analyses, serum hormonal evaluation in-
hormone levels, and testicular volumes. All data are given
cluding FSH, LH, T, E2, PRL, and TSH, and karyotype analysis;
as mean Æ SE, and P< .05 was considered a statistically sig-
Y chromosome microdeletion and patients with a total sperm
count <1 Â 106 had genetic analysis for cystic ﬁbrosis. Pa-tients with abnormal results on karyotype analysis or Y chro-
mosome microdeletion assay were excluded from the study.
The results in all examined parameters of the two study
All patients had sperm concentrations <10 Â 106 sper-
groups (A and B) are presented in respectively.
matozoa/mL, T/E2 ratio of <10, and T levels <300 ng/dL. Tes-
Improvement was not seen in seminal parameters in 4 of
ticular volume was measured with the use of ultrasound using
15 patients in the letrozole group (26.6%) and in 3 of 14 pa-
the equation length Â height Â width Â 0.71
tients in the anastrazole group (21.4%).
Blood samples for hormonal evaluation were taken in the
Of the patients treated with letrozole, only one presented
early morning, between 7:00 and 8:00 AM. Initial hormonal
an asymptomatic mild increase in serum liver enzymes (serum
evaluation included assessment of serum FSH, LH, PRL, T,
glutamic oxaloacetic transaminase [SGOT] and serum gluta-
E2, and TSH, and all hormones were measured using a com-
mic pyruvic transminase [SGPT]), but it was transient, and
mercially available kit (Vidas, bioMerieux).
medication was continued. Additionally, two patients com-
The reference ranges of the assays used for FSH, LH, E2, T,
plained of transient weakness, 1 patient of nausea that lasted
PRL, and TSH were as follows: FSH, 0.1–110 mIU/mL; LH,
for 10 days, and 2 patients of mild headache. On the other
0.1–100 mIU/mL; E2, 9–3,000 pg/mL; T, 0.1–13 ng/mL;
hand, in two patients—from those who were treated with
PRL, 0–200 ng/mL; TSH, 0–60 mIU/mL.
anastrazole—an asymptomatic increase in serum liver en-
Idiopathic oligozoospermia was diagnosed on the basis of
zymes (alkaline phosphatase) was observed. One patient de-
FSH concentrations that were within the normal range of ref-
veloped mild diarrhea at 1 month of use, which lasted for 3
erence values; the average value from the two most recent se-
days and subsided on its own without further sequelae; two
men analyses being below normal according to the World
patients developed transient nausea and one patient mild
Health Organization classiﬁcation and the absence of
headache. No other complications were reported from the pa-
any abnormality that could be responsible for the impaired
tients of both groups. In summary, both drugs were well
semen values, such as infection, trauma, autoimmunity, var-
icocele, or epididymal factor; the negative results of the hor-monal and other investigations that the patients were
submitted to have been described above.
Semen samples were collected by masturbation after 2–4
Results of semen analysis and hormonal tests before and after 6
days of sexual abstinence and processed within 1 hour of
months of treatment with letrozole 2.5 mg/d.
ejaculation. All semen analyses were performed in the same
andrology laboratory according to World Health Organiza-tion criteria None of the participants had received any
medication as a therapeutic regimen for at least 3 months be-
fore the study, although occasional use of analgesics (e.g.,
The seminal values for the initial and 6th-month evalua-
tions are the means of two estimations.
As an overall index of seminal quantity and quality, the
total functional sperm fraction (TFSF, Â106) was estimated.
This term includes quantitative and qualitative factors of
the semen and has been calculated by multiplying the sperm
a TFSF was estimated by multiplying total sperm count (Â106) by motility (%) and by mor-
count (Â106) by motility (%) and by normal morphology (%)
Gregoriou. Aromatase inhibitors and male infertility. Fertil Steril 2012.
alone indicated an increased pregnancy rate compared with
the group without the addition of the aromatase inhibitor
Saylam et al. treated 27 infertile men with a low se-
Results of semen analysis and hormonal tests before and after 6
months of treatment with anastrazole 1 mg/d.
2 ratio (<10) with 2.5 mg letrozole orally once daily
for >6 months. They noted that T/E2 ratio, ejaculate volume,
sperm motility, and total motile sperm count (TMSC) signiﬁ-
cantly increased after the letrozole treatment. Additionally, 2
of 10 oligospermic men achieved spontaneous pregnancy. In
patients with azoospermia, 23.5% presented spermatozoa in
the ejaculate, and 76.5% remained azoospermic after letrozole
Patry et al. treated a 31-year-old man with primary
infertility, normal serum FSH levels, and pattern of nonob-
structive azoospermia, with use of the aromatase inhibitor le-
trozole orally for up to 4 months, and ﬁnal testicular biopsy
TFSF was estimated by multiplying total sperm count (Â106) by motility (%) and by mor-
Raman et al. treated 140 subfertile men with abnormal
Gregoriou. Aromatase inhibitors and male infertility. Fertil Steril 2012.
T/E2 ratios using either testolactone 100–200 mg or anastra-zole 1 mg daily. A comparison of the efﬁcacy of these twotherapies on both hormonal and semen parameters showed
Statistical comparison of TFSF for the letrozole and anas-
similar effects. Additionally, treatment with aromatase inhib-
trazole groups before and after treatment, using Student's t
itors has been used before testicular sperm extraction in Kli-
test for independent samples (because all samples follow nor-
neﬂeter's syndrome patients, with favorable results
mal distribution), showed that there was no statistically sig-
Clomiphene citrate was not used in these patients because
niﬁcant difference between TFSF of the letrozole group
there were published data suggesting development of azoo-
before treatment and TFSF of the anastrazole group before
spermia after treatment with clomiphene citrate in patients
treatment (P¼ .62), as well as TFSF of the letrozole group after
treatment and TFSF of the anastrazole group after treatment
Many infertile men with severe oligospermia can exhibit
(P¼ .81). Therefore, it could be said that both groups are com-
a decreased T/E2 ratio, and treatment with an aromatase in-
parable with respect to TFSF before and after treatment. Ad-
hibitor can normalize values and improve semen quality.
ditionally, the increase in average TFSF in the letrozole group
The ﬁndings of the present study suggest that some men
after treatment compared with the pretreatment value was
with severe oligospermia (<5 Â 106/mL), low T levels (<300
31.6%, and the increase in average TFSF in the anastrazole
ng/dL), a T (ng/dL) to E2 (pg/mL) ratio <10, and normal go-
group after treatment compared with the pretreatment value
nadotropins concentration may have a treatable endocrinop-
was 21.1%. To detect whether there is a statistically signiﬁ-
athy. Accordingly, the endocrine evaluation should perhaps
cant difference between the 31.6% increase of average TFSF
include an estimation of E2 and calculation of the T (ng/dL)
seen in the letrozole group in comparison with the 21.1% in-
to E2 (pg/mL) ratio. A ratio <10 identiﬁes those who might
crease of average TFSF seen in the anastrazole group, having
beneﬁt from treatment with an aromatase inhibitor to im-
a type I error of 0.05 and a type II error of 0.20, 273 patients
prove T levels and possibly the seminal parameters. The efﬁ-
cacy of letrozole and anastrazole in improving the seminalparameters was similar, and the nonresponse rate was26.6% in the letrozole group and 21.4% in the anastrazole
group. The T levels and the T/E2 ratio were improved in all pa-
Change of plasma E2 levels within the male physiologic range
tients in both groups. This was the reason why a control arm
could be associated with signiﬁcant change of LH levels in
was not used in this study. The side effects that were reported
plasma through an effect at the level of the pituitary gland
by the patients in both groups were considered well tolerated
. A decrease in E2 levels with the administration of an aro-
and subsided with time, and there was no signiﬁcant differ-
matase inhibitor is associated with an increase in levels of LH,
ence in the incidence and severity of side effects between
FSH, and T Although FSH release is mainly under the con-
the two groups. Therefore, it seems that both anastrazole
trol of inhibin, circulating E2 has a strong effect on FSH levels
and letrozole are equally effective in the improvement of T
levels and seminal parameters in patients with severe oligo-
Earlier studies using anastrozole or testolactone have
spermia (<5 Â 106/mL), low T levels (<300 ng/dL), and a T
shown evidence for a positive action on sperm concentration
(ng/dL) to E2 (pg/mL) ratio <10, and the presented side effects
and motility . However, another trial using
are mild, well tolerated, and subside with the time. There are
testolactone did not show a signiﬁcant improvement of sperm
no available data concerning possible risks about the long-
quality in men with oligospermia More recently, a study
term use of aromatase inhibitors in men, but from the
in which anastrozole was added to treatment with tamoxifen
available data from the use of aromatase inhibitors in post-
in men with idiopathic oligoasthenoteratozoospermia and
menopausal women with breast cancer it seems that the
a decreased T over E2 ratio after treatment with tamoxifen
main potential concerns are about the risk of development
of osteoporosis and a possible mild increase in cholesterol
Zavos PM, Wilson EA, Cohen MR. Total functional sperm fraction
levels at 5 years of use of letrozole The percentage of pa-
measurements in males of known fertility or infertility. Fertil Steril 1984;
tients taking letrozole and reporting osteoporosis was 6.9%,
Pitteloud N, Dwyer AA, DeCruz S, Lee H, Boepple PA, Crowley WF Jr, et al.
vs. 5.5% in the placebo group. Bisphosphonates, drugs to in-
Inhibition of luteinizing hormone secretion by testosterone in men requires
crease bone strength, were given to 21.1% of letrozole pa-
aromatization for its pituitary but not its hypothalamic effects: evidence
tients and 18.7% of placebo patients. However, there are no
from the tandem study of normal and gonadotropin releasing hormone-
available data as far as we know at 6 months' follow-up con-
deﬁcient men. J Clin Endocrinol Metab 2008;93:784–91.
cerning the risk of developing osteoporosis or increase in cho-
T'sjoen GG, Giagulli VA, Delva H, Crabbe P, De Bacquer D, Kaufman JM.
lesterol levels that could have an effect on the vascular
Comparative assessment in young and elderly men of the gonadotropinresponse to aromatase inhibition. J Clin Endocrinol Metab 2005;90:
Possible limitations of this study could be the relatively
Raven G, de Jong FH, Kaufman JM, de Ronde W. In men, peripheral estradiol
small numbers of participating patients in each group and
levels directly reﬂect the action of estrogens at the hypothalamo-pituitary
that there are no data about rates of IUI/IVF and pregnancy
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signiﬁcance of the improvement seen in semen parameters
Vandekerckhove P, Lilford R, Vail A, Hughes E. Clomiphene or tamoxifen for
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Clark RV, Sherins RJ. Treatment of men with idiopathic oligozoospermic in-
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CHAPTER 30 Pharmaceutical Products 1. This Chapter does not cover: (a) Foods or beverages (such as dietetic, diabetic or fortified foods, food supplements, tonic beverages and mineral waters)other than nutritional preparations for intravenous administration (Section IV); Plasters specially calcined or finely ground for use in dentistry (heading 2520); Aqueous distillates or aqueou