- Email: [email protected]
DPP-IV inhibitor may affect spermatogenesis
diabetes research and clinical practice 93 (2011) e74–e75
Contents lists available at ScienceDirect
Diabetes Research and Clinical Practice jou rnal hom ep ag e: w ww.e l s e v i er . c om/ loca te / d i ab r es
Brief report
DPP-IV inhibitor may affect spermatogenesis§ Hatsuki Hibi a,*, Tadashi Ohori a, Yoshiaki Yamada b a b
Department of Urology, Kyoritsu General Hospital, Japan Department of Urology, Aichi Medical University, School of Medicine, Japan
article info
abstract
Article history:
A 39-year-old physician was diagnosed retrograde ejaculation due to diabetes and treated
Received 27 April 2011
with amoxapine. This treatment was effective; he could ejaculate. He began receiving DPP-
Accepted 28 April 2011
IV inhibitor (Sitagliptin 50 mg, daily), in lieu of insulin injection. Unusual effect on semen
Published on line 1 June 2011
quality was occurred following the administration of the drug. # 2011 Elsevier Ireland Ltd. All rights reserved.
Keywords: DPP-IV inhibitor Diabetes Retrograde ejaculation Azoospermia
1.
Case report
In January 2009, a 39-year-old physician (Dermatologist) was referred to our hospital due to lack of ejaculation. He and his spouse, a healthy 31-year-old, hoped for a baby. He has exhibited diabetes mellitus for nine years. His medical history included Kawasaki’s disease diagnosed at 5 years of age; however, no treatment was administered consequent to the absence of cardiovascular event. Diabetes was treated initially with insulin injection for one year, followed by oral antidiabetic agents for five years. Subsequently, insulin injection was re-initiated. Finasteride, which is an oral tablet incorporating a 5-alpha reductase inhibitor aid for alopecia, was prescribed from February 2007; however, it was discontinued in February 2009. Although the patient did not display erectile dysfunction, he noticed decreasing semen volume over approximately two years. Physical examination revealed normal testicular volume (22 ml for each testis) and normal genitalia. Consequent to his §
inability to ejaculate, semen analysis was not possible. Amoxapine (50 mg, daily), which is a tricyclic anti-depressant, was used in terms of tentative diagnosis of retrograde ejaculation due to diabetes. This treatment was effective; he could ejaculate one month later. Semen analysis demonstrated volume of 0.2 ml, sperm concentration of 213 106/ml and 53% motility. His wife did not conceive by intercourse; as a result, the couple underwent intra-uterine insemination (IUI) in August 2009. Unfortunately, conception was not achieved. He began receiving DPP-IV inhibitor (Sitagliptin 50 mg, daily), in lieu of insulin injection in November 2009; his hemoglobinA1c value decreased sharply to 6.1%. In February 2010, the couple decided to undergo a second IUI; however, semen analysis revealed no sperm. Endocrine panel examination disclosed no abnormalities with the exception of low free(LH/FSH = 1.80/3.68 mIU/ml; testosterone, testosterone 3.72 ng/ml; free-testosterone, 6.3 pg/ml). We recommended discontinuation of the DPP-IV inhibitor. In June 2010, his wife underwent a third IUI and conceived successfully. Semen
This paper was presented at the 10th Conference of Kanto Andrology held in Tokyo, 11th September, 2010. * Corresponding author at: Department of Urology, Kyoritsu General Hospital, Goban-cho, Atsuta-ward, Nagoya 456-8611, Japan. Tel.: +81 52 654 2211; fax: +81 52 651 7210. E-mail address: [email protected] (H. Hibi). 0168-8227/$ – see front matter # 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2011.04.022
diabetes research and clinical practice 93 (2011) e74–e75
analysis demonstrated volume of 0.3 ml, sperm concentration of 171 106/ml and 30% motility; in contrast, hemoglobin-A1c level increased to 9.1%. DPP-IV inhibitor was prescribed from late July 2010. In September 2010, semen analysis demonstrated volume of 0.3 ml, sperm concentration of 46 106/ml and 30% motility. In October 2010, semen analysis demonstrated volume of 0.2 ml, sperm concentration of 0.2 106/ml and 0% motility. Due to decreased semen quality, administration of the DPP-IV inhibitor was again terminated. In early January 2011, the patient’s semen quality returned to previous levels following a three-month discontinuation (volume, 0.5 ml; sperm concentration, 316 106/ ml; motility, 10%). Fortunately, a healthy girl was delivered in February 2011. Ejaculatory dysfunction, while relatively uncommon, is not a rare cause of infertility. Dysfunction of seminal emission is a manifestation of diabetic neuropathy affecting the sympathetic innervation of structures required for the emission process. Approximately 32% of diabetic men will exhibit evidence of ejaculatory dysfunction. Retrograde ejaculation (RE) is more common that total failure of emission [1]. Medical treatment of RE is based on either increasing the sympathetic tone of the bladder or decreasing parasympathetic activity. Anti-depressants such as tricyclic and monoamine oxidase inhibitors, e.g., imipramine hydrochloride, are used primarily. Recently, amoxapine demonstrated a high success rate in RE patients [2]. In the current case, amoxapine was effective for RE; the patient was able to ejaculate. In instances where medical treatment has failed, sperm collection methods including surgery for assisted reproductive technology (ART) should be considered. Drugs that inhibit dipeptidyl peptidase-IV (DPP-IV) are a new class of antidiabetogenic compounds proved in numerous clinical trials [3]. Clinical studies have evaluated the potential for DPP-IV inhibition to reduce glucagon levels, delay gastric emptying and stimulate insulin release [4]. However, no reports regarding spermatogenesis appear in the literature. We hypothesized that most patients receiving DDP-IV inhi-
e75
bitors are of relatively older age; thus, they are subject to lessened impact with respect to fertility-related problems. The semen quality of this patient deteriorated sharply following three-month DPP-IV inhibitor administration. Semen quality recovered upon discontinuation of the drug; subsequently, DPP-IV inhibitor was re-prescribed. Semen quality deteriorated again; fortunately, it recovered upon withdrawal of the drug. The reason for the decreased semen quality remains unknown; DPP-IV inhibitor may affect spermatogenesis in this clinical course. Careful attention is warranted when DPP-IV inhibitor is administered in young adults.
Acknowledgment The authors wish to thank Shigeo Hieda, MD, of the Yagoto Lady’s Clinic, who managed the IUI procedures at his clinic.
Conflict of interest The authors declare that they have no conflict of interest.
references
[1] Shaban SF, Seaman EK, Lipshultz LI. Treatment of abnormalities of ejaculation. In: Lipshultz LI, Howards SS, editors. Infertility in the male. 3rd ed., St. Louis: Mosby; 1997. p. 423–8. [2] Otani T. Ejaculatory dysfunction—treatment choice according to type of ejauculatory dysfunction. Jpn J Urol Surg 2007;20:655–61 (in Japanese). [3] Pratley RE, Salsali A. Inhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes. Curr Med Res Opin 2007;23:919–31. [4] Langley AK, Suffoletta TJ, Jennings HR. Dipeptidyl peptidase IV inhibitors and the incretin system in type 2 diabetes mellitus. Pharmacotherapy 2007;27:1163–80.
Contents lists available at ScienceDirect
Diabetes Research and Clinical Practice jou rnal hom ep ag e: w ww.e l s e v i er . c om/ loca te / d i ab r es
Brief report
DPP-IV inhibitor may affect spermatogenesis§ Hatsuki Hibi a,*, Tadashi Ohori a, Yoshiaki Yamada b a b
Department of Urology, Kyoritsu General Hospital, Japan Department of Urology, Aichi Medical University, School of Medicine, Japan
article info
abstract
Article history:
A 39-year-old physician was diagnosed retrograde ejaculation due to diabetes and treated
Received 27 April 2011
with amoxapine. This treatment was effective; he could ejaculate. He began receiving DPP-
Accepted 28 April 2011
IV inhibitor (Sitagliptin 50 mg, daily), in lieu of insulin injection. Unusual effect on semen
Published on line 1 June 2011
quality was occurred following the administration of the drug. # 2011 Elsevier Ireland Ltd. All rights reserved.
Keywords: DPP-IV inhibitor Diabetes Retrograde ejaculation Azoospermia
1.
Case report
In January 2009, a 39-year-old physician (Dermatologist) was referred to our hospital due to lack of ejaculation. He and his spouse, a healthy 31-year-old, hoped for a baby. He has exhibited diabetes mellitus for nine years. His medical history included Kawasaki’s disease diagnosed at 5 years of age; however, no treatment was administered consequent to the absence of cardiovascular event. Diabetes was treated initially with insulin injection for one year, followed by oral antidiabetic agents for five years. Subsequently, insulin injection was re-initiated. Finasteride, which is an oral tablet incorporating a 5-alpha reductase inhibitor aid for alopecia, was prescribed from February 2007; however, it was discontinued in February 2009. Although the patient did not display erectile dysfunction, he noticed decreasing semen volume over approximately two years. Physical examination revealed normal testicular volume (22 ml for each testis) and normal genitalia. Consequent to his §
inability to ejaculate, semen analysis was not possible. Amoxapine (50 mg, daily), which is a tricyclic anti-depressant, was used in terms of tentative diagnosis of retrograde ejaculation due to diabetes. This treatment was effective; he could ejaculate one month later. Semen analysis demonstrated volume of 0.2 ml, sperm concentration of 213 106/ml and 53% motility. His wife did not conceive by intercourse; as a result, the couple underwent intra-uterine insemination (IUI) in August 2009. Unfortunately, conception was not achieved. He began receiving DPP-IV inhibitor (Sitagliptin 50 mg, daily), in lieu of insulin injection in November 2009; his hemoglobinA1c value decreased sharply to 6.1%. In February 2010, the couple decided to undergo a second IUI; however, semen analysis revealed no sperm. Endocrine panel examination disclosed no abnormalities with the exception of low free(LH/FSH = 1.80/3.68 mIU/ml; testosterone, testosterone 3.72 ng/ml; free-testosterone, 6.3 pg/ml). We recommended discontinuation of the DPP-IV inhibitor. In June 2010, his wife underwent a third IUI and conceived successfully. Semen
This paper was presented at the 10th Conference of Kanto Andrology held in Tokyo, 11th September, 2010. * Corresponding author at: Department of Urology, Kyoritsu General Hospital, Goban-cho, Atsuta-ward, Nagoya 456-8611, Japan. Tel.: +81 52 654 2211; fax: +81 52 651 7210. E-mail address: [email protected] (H. Hibi). 0168-8227/$ – see front matter # 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2011.04.022
diabetes research and clinical practice 93 (2011) e74–e75
analysis demonstrated volume of 0.3 ml, sperm concentration of 171 106/ml and 30% motility; in contrast, hemoglobin-A1c level increased to 9.1%. DPP-IV inhibitor was prescribed from late July 2010. In September 2010, semen analysis demonstrated volume of 0.3 ml, sperm concentration of 46 106/ml and 30% motility. In October 2010, semen analysis demonstrated volume of 0.2 ml, sperm concentration of 0.2 106/ml and 0% motility. Due to decreased semen quality, administration of the DPP-IV inhibitor was again terminated. In early January 2011, the patient’s semen quality returned to previous levels following a three-month discontinuation (volume, 0.5 ml; sperm concentration, 316 106/ ml; motility, 10%). Fortunately, a healthy girl was delivered in February 2011. Ejaculatory dysfunction, while relatively uncommon, is not a rare cause of infertility. Dysfunction of seminal emission is a manifestation of diabetic neuropathy affecting the sympathetic innervation of structures required for the emission process. Approximately 32% of diabetic men will exhibit evidence of ejaculatory dysfunction. Retrograde ejaculation (RE) is more common that total failure of emission [1]. Medical treatment of RE is based on either increasing the sympathetic tone of the bladder or decreasing parasympathetic activity. Anti-depressants such as tricyclic and monoamine oxidase inhibitors, e.g., imipramine hydrochloride, are used primarily. Recently, amoxapine demonstrated a high success rate in RE patients [2]. In the current case, amoxapine was effective for RE; the patient was able to ejaculate. In instances where medical treatment has failed, sperm collection methods including surgery for assisted reproductive technology (ART) should be considered. Drugs that inhibit dipeptidyl peptidase-IV (DPP-IV) are a new class of antidiabetogenic compounds proved in numerous clinical trials [3]. Clinical studies have evaluated the potential for DPP-IV inhibition to reduce glucagon levels, delay gastric emptying and stimulate insulin release [4]. However, no reports regarding spermatogenesis appear in the literature. We hypothesized that most patients receiving DDP-IV inhi-
e75
bitors are of relatively older age; thus, they are subject to lessened impact with respect to fertility-related problems. The semen quality of this patient deteriorated sharply following three-month DPP-IV inhibitor administration. Semen quality recovered upon discontinuation of the drug; subsequently, DPP-IV inhibitor was re-prescribed. Semen quality deteriorated again; fortunately, it recovered upon withdrawal of the drug. The reason for the decreased semen quality remains unknown; DPP-IV inhibitor may affect spermatogenesis in this clinical course. Careful attention is warranted when DPP-IV inhibitor is administered in young adults.
Acknowledgment The authors wish to thank Shigeo Hieda, MD, of the Yagoto Lady’s Clinic, who managed the IUI procedures at his clinic.
Conflict of interest The authors declare that they have no conflict of interest.
references
[1] Shaban SF, Seaman EK, Lipshultz LI. Treatment of abnormalities of ejaculation. In: Lipshultz LI, Howards SS, editors. Infertility in the male. 3rd ed., St. Louis: Mosby; 1997. p. 423–8. [2] Otani T. Ejaculatory dysfunction—treatment choice according to type of ejauculatory dysfunction. Jpn J Urol Surg 2007;20:655–61 (in Japanese). [3] Pratley RE, Salsali A. Inhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes. Curr Med Res Opin 2007;23:919–31. [4] Langley AK, Suffoletta TJ, Jennings HR. Dipeptidyl peptidase IV inhibitors and the incretin system in type 2 diabetes mellitus. Pharmacotherapy 2007;27:1163–80.