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  concentration  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.
doi: 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 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  height  width  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 level to inhibit gonadotropin secretion. J Clin Endocrinol Metab 2006;91: outcomes, which could give information about the clinical significance of the improvement seen in semen parameters Vandekerckhove P, Lilford R, Vail A, Hughes E. Clomiphene or tamoxifen for in terms of pregnancy achievement rates.
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A control arm was not used in the study given the previ- Clark RV, Sherins RJ. Treatment of men with idiopathic oligozoospermic in- ously published reports describing benefit of aromatase inhi- fertility using the aromatase inhibitor, testolactone. Results of a double bition in men with E2/T ratios >10:1 .
blinded, randomized, placebo-controlled trial with crossover. Andrology Further prospective, randomized, blinded, placebo- controlled studies are needed to clarify the role of aromatase inhibitors in the management of male infertility.
ratio in predicting the efficacy of tamoxifen citrate treatment in idiopathicoligoasthenoteratozoospermic men. Urol Int 2009;83:446–51.
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