Could Clomiphene Kindle Acute Manic Episode In A Male Patient? A Case Report Pallavi Sinha M.D., Amit Garg M.D. PII: DOI: Reference:
S0163-8343(14)00117-0 doi: 10.1016/j.genhosppsych.2014.05.011 GHP 6862
To appear in:
General Hospital Psychiatry
Received date: Revised date: Accepted date:
7 March 2014 10 May 2014 13 May 2014
Please cite this article as: Sinha Pallavi, Garg Amit, Could Clomiphene Kindle Acute Manic Episode In A Male Patient? A Case Report, General Hospital Psychiatry (2014), doi: 10.1016/j.genhosppsych.2014.05.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT TITLE PAGE MANUSCRIPT TYPE- CASE REPORT
RI P
T
TITLE: COULD CLOMIPHENE KINDLE ACUTE MANIC EPISODE IN A MALE PATIENT? A CASE REPORT KEY WORDS: CLOMIPHENE, MANIC EPISODE, MALE MANUSCRIPT WORD COUNT: 769
MA
NU
SC
FIGURES: 0 CONFLICT OF INTEREST DECLARED: NONE SOURCES OF SUPPORT: NONE THE MANUSCRIPT HAS BEEN READ AND APPROVED BY ALL THE AUTHORS AND EACH AUTHOR BELIEVES THAT THE MANUSCRIPT REPRESENTS HONEST WORK. THE MATERIAL SUBMITTED HAS NOT BEEN PUBLISHED ELSEWHERE, NOR IS IT UNDER CONSIDERATION FOR PUBLICATION ELSEWHERE.
CE
PT
ED
AUTHORS NAME AND AFFILIATIONS: 1. PALLAVI SINHA, M.D. SENIOR RESIDENT DEPARTMENT OF PSYCHIATRY I.H.B.A.S, DILSHAD GARDEN, DELHI. INDIA- 110095 PH. +91-11-22583322 FAX. +91-11-22599227 MOB. +91-9868396934 E-MAIL. [email protected]
AC
2. AMIT GARG, M.D. ASSISTANT PROFESSOR, DEPARTMENT OF PSYCHIATRY I.H.B.A.S, DILSHAD GARDEN, DELHI. INDIA- 110095 PH. +91-11-22583322 FAX. +91-11-22599227 MOB. +91-9650431525 E-MAIL. [email protected] CORRESPONDING AUTHOR AMIT GARG, M.D. ASSISTANT PROFESSOR, DEPARTMENT OF PSYCHIATRY I.H.B.A.S, DILSHAD GARDEN, DELHI. INDIA- 110095 PH. +91-11-22583322 FAX. +91-11-22599227 MOB. +91-9650431525, 9868396838 E-MAIL. [email protected] None
ACCEPTED MANUSCRIPT Abstract Psychiatric adverse effects associated with the use of clomiphene are relatively
T
uncommon. Though case reports link mood swings to be associated with clomiphene, it is
RI P
not known to be associated with a syndromal affective episode. Being a selective oestrogen receptor modulator, clomiphene affects the hypothalamus-pituitary-gonadal
SC
axis and can have potential neuropsychiatric effects in vulnerable persons. Herein we
NU
report a case of clomiphene induced manic episode in a known bipolar male patient.
ED
MA
Key words: Clomiphene, Manic episode, Male
PT
Introduction
Clomiphene citrate is a racemic mixture of zuclomiphene and enclomiphene acting as a
CE
selective oestrogen receptor modulator1. The cis-isomer zuclomiphene (38%) has
AC
primarily oestrogen receptor agonist properties, and the trans-isomer enclomiphene (62%) has mostly oestrogen receptor antagonistic properties2. Acting as an anti-oestrogen on the hypothalamus- pituitary-gonadal axis, it increases the pulse frequency and concentration of follicle stimulating hormone (FSH) and luteinizing hormone (LH), giving a moderate gonadotrophin stimulus. In males, enclomiphene isomer induces hypothalamic GnRH release, thus increasing serum testosterone levels2. Though long marketed as a drug to aid reproduction in females, clomiphene citrate has also been used off-label to treat men with adult-onset secondary hypogonadism for increasing sperm production. Enclomiphene2 is also an oral selective oestrogen receptor modulator in
ACCEPTED MANUSCRIPT phase II/III clinical stage being developed for the treatment of male hypogonadotropic hypogonadism.
studies have revealed mood swings and irritability as
RI P
uncommon though some
T
Psychiatric adverse effects associated with the use of clomiphene are relatively
psychological side effects of clomiphene therapy3. We report a case of patient with
SC
known bipolar disorder who developed a manic episode subsequent to administration of
NU
clomiphene citrate for the purpose of infertility secondary to oligozoospermia.
MA
Case
Mr. M, a 34 year old male on follow-up from the out-patient department of our hospital
ED
presented with complaints of euphoric mood, increased goal directed activities, increased
PT
talkativeness, increased libido and decreased need for sleep for the past 4 days. Patient was a known case of bipolar affective disorder with a total duration of illness of 6 years
CE
with one manic and one depressive episode in the past. He had been in remission for the
AC
past 4 years and had been maintaining on lithium carbonate 900mg/day with adequate adherence. Patient did not have any history of substance use and his family history was non-contributory. The patient and his spouse had also been undergoing evaluation for primary infertility and in the course of investigations, the patient was diagnosed with oligozoospermia. Hormonal screening revealed normal testosterone, follicle stimulating hormone and luteinizing hormone levels. Patient was started on clomiphene citrate 50mg three times a week for oligozoospermia. After 5 days of initiation of clomiphene therapy, patient’s manic symptoms emerged. On presentation, his mental status examination revealed overfamiliarity, increased psychomotor activity, elated affect, inflated self-
ACCEPTED MANUSCRIPT esteem and ideas of grandiosity with absent insight. A serum lithium level sent on the subsequent day of presentation was at 0.83 meq/litre and his thyroid function tests were
T
within normal limits. Clomiphene was discontinued for the patient and risperidone was
RI P
added at 2 mg per day along with lithium carbonate at 900mg per day. Lorazepam was given at 1 mg per day on an SOS basis for arousal symptoms and insomnia. The patient
SC
followed up after one week and showed significant improvement in symptoms. He
NU
eventually became asymptomatic over the next 3 weeks and has been continuing to
MA
maintain well since then.
ED
Discussion
PT
Given the close temporal relationship of the exposure (within 1 month) to clomiphene and the development of manic symptoms, we believe that the most likely explanation for
CE
this case is a medication-triggered manic episode. A re-challenge with clomiphene could
AC
have confirmed our hypothesis, but it was against the consent of the patient and his spouse and would also have been deemed unethical. Though mood changes have been noted with clomiphene treatment in women4-6, but to our knowledge, this is the first report of mania precipitated by clomiphene use in a male. Research over the years has implicated the hypothalamic-pituitary-gonadal axis in mood dysregulation. In the index patient, testosterone (and in turn estrogen) levels could have been modulated by clomiphene citrate. Clomiphene citrate has been shown to increase serum testosterone levels in both eugonadal7 and hypogonadal males2, 8. Testosterone may interact directly with androgen receptors or through aromatization to estrogen
ACCEPTED MANUSCRIPT metabolites in the brain to stimulate the mitogen activated protein kinase (MAPK) pathway9, a fundamental signaling pathway and critical regulator of emotional responses.
T
The irritable male syndrome10 is a behavioural state of nervousness, irritability, lethargy
RI P
and depression that occurs in adult male mammals following withdrawal of testosterone and hypoestrogenism is also associated with depressive symptoms11.
SC
Conversely, oestrogen and testosterone administration has been reported to have mood
NU
enhancing anti-depressant effect12,13 . Testosterone has also been linked in the past to manic episodes14. In a placebo-controlled, double-blind, crossover study15 of
MA
administration of supraphysiologic doses of testosterone cypionate to normal men, testosterone treatment significantly increased several measures of manic and aggressive
PT
ED
symptoms.
Conclusion and implications
CE
These pathways point to an exciting interaction of endocrinological influences on higher
AC
cognitive functions. An elevated testosterone levels could have led to elevated oestradiol levels as the latter is synthesized from testosterone using the enzyme aromatase. While both oestrogen and testosterone have been linked to mood symptoms, a simple causative explanation does not exist for them. A limitation in the index case was the absence of serum gonadotropin levels post clomiphene citrate administration. These would have allowed us some insight into the complex interactions between various gonadotropins leading to the development of affective symptoms. We could not entirely rule out the possibility of a breakthrough manic episode in this case but nevertheless the strong temporal correlation with the intake of clomiphene and the other case reports3,6
ACCEPTED MANUSCRIPT implicating clomiphene with mood symptoms suggest that this molecule requires further studies to profile its safety in populations vulnerable to psychiatric disorders.
T
This case suggests that the administration of hormone modulators like clomiphene may
RI P
kindle mania in susceptible individuals. As specialists treat an increasing number of patients with infertility, it is cardinal that they be familiar with the probable psychiatric
SC
adverse effects and exercise caution in prescribing clomiphene to individuals with a
NU
proclivity to affective switch.
MA
REFERENCES
1. Dickey RP, Holtkamp DE. Development, pharmacology and clinical experience with
ED
clomiphene citrate. Hum Reprod Update. 1996;2:483- 506.
PT
2. Hill S, Arutchelvam V, Quinton R. Enclomiphene, an estrogen receptor antagonist for the treatment of testosterone deficiency in men. IDrugs. 2009 Feb;12(2):109-19.
CE
3. Choi SH, Shapiro H, Robinson GE, Irvine J, Neuman J, Rosen B, Murphy J, Stewart
AC
D. Psychological side-effects of clomiphene citrate and human menopausal gonadotrophin. J Psychosom Obstet Gynaecol. 2005;26:93-100. 4. Blum M, Zacharovitch D, Pery J, Gilerowitch M: Estrogen replacement therapy (ERT) by a special regimen in the years following menopause. Clin Exp Obstet Gynecol. 1989;16:9–11. 5. Kapfhammer HP, Messer T, Hoff P: Psychotic illness during treatment with clomifen. Dtsch Med Wochenschr. 1990;115:936–939. 6. Blenner JL. Clomiphene-induced mood swings. J Obstet Gynecol Neonatal Nurs.1991;20:321–327.
ACCEPTED MANUSCRIPT 7. Rönnberg L. The effect of clomiphene citrate on different sperm parameters and serum hormone levels in preselected infertile men: a controlled double-blind cross-over study.
T
Int J Androl. 1980 Oct;3(5):479-86.
RI P
8. Shabsigh A1, Kang Y, Shabsign R, Gonzalez M, Liberson G, Fisch H, Goluboff E. Clomiphene citrate effects on testosterone/estrogen ratio in male hypogonadism. J Sex
SC
Med. 2005 Sep;2(5):716-21.
NU
9. Carrier N, Kabbaj M. Extracellular signal-regulated kinase 2 signaling in the hippocampal dentate gyrus mediates the antidepressant effects of testosterone. Biol
MA
Psychiatry. 2012 Apr 1;71(7):642-51
10. Lincoln GA. The irritable male syndrome. Reprod Fertil Dev. 2001;13(7-8):567-76.
ED
11. Toren P, Dor J, Rehavi M, Weizman A: Hypothalamic-pituitary- ovarian axis and
PT
mood. Biol Psychiatry. 1996;40:1051–1055. 12. Kanayama G, Amiaz R, Seidman S, Pope HG Jr. Testosterone supplementation for
CE
depressed men: current research and suggested treatment guidelines. Experimental and
AC
clinical psychopharmacology. 2007; 15:529–538. 13. Klaiber EL, Broverman DM, Vogel W, Peterson LG, Snyder MB. Individual differences in changes in mood and platelet monoamine oxidase (MAO) activity during hormonal replacement therapy in menopausal women. Psychoneuroendocrinology. 1996;21(7):575– 592 14. Weiss EL, Bowers MB, Mazure CM. Testosterone-Patch-Induced Psychotic Mania. Am J Psy. 1999;156:969-969. 15. Pope HG Jr, Kouri EM, Hudson JI. Effects of supraphysiologic doses of testosterone on mood and aggression in normal men: a randomized controlled trial. Arch Gen
ACCEPTED MANUSCRIPT Psychiatry. 2000;57:133-40.
T
Acknowledgement : none
RI P
Conflict of interest: none
AC
CE
PT
ED
MA
NU
SC
Financial disclosures: none
S0163-8343(14)00117-0 doi: 10.1016/j.genhosppsych.2014.05.011 GHP 6862
To appear in:
General Hospital Psychiatry
Received date: Revised date: Accepted date:
7 March 2014 10 May 2014 13 May 2014
Please cite this article as: Sinha Pallavi, Garg Amit, Could Clomiphene Kindle Acute Manic Episode In A Male Patient? A Case Report, General Hospital Psychiatry (2014), doi: 10.1016/j.genhosppsych.2014.05.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT TITLE PAGE MANUSCRIPT TYPE- CASE REPORT
RI P
T
TITLE: COULD CLOMIPHENE KINDLE ACUTE MANIC EPISODE IN A MALE PATIENT? A CASE REPORT KEY WORDS: CLOMIPHENE, MANIC EPISODE, MALE MANUSCRIPT WORD COUNT: 769
MA
NU
SC
FIGURES: 0 CONFLICT OF INTEREST DECLARED: NONE SOURCES OF SUPPORT: NONE THE MANUSCRIPT HAS BEEN READ AND APPROVED BY ALL THE AUTHORS AND EACH AUTHOR BELIEVES THAT THE MANUSCRIPT REPRESENTS HONEST WORK. THE MATERIAL SUBMITTED HAS NOT BEEN PUBLISHED ELSEWHERE, NOR IS IT UNDER CONSIDERATION FOR PUBLICATION ELSEWHERE.
CE
PT
ED
AUTHORS NAME AND AFFILIATIONS: 1. PALLAVI SINHA, M.D. SENIOR RESIDENT DEPARTMENT OF PSYCHIATRY I.H.B.A.S, DILSHAD GARDEN, DELHI. INDIA- 110095 PH. +91-11-22583322 FAX. +91-11-22599227 MOB. +91-9868396934 E-MAIL. [email protected]
AC
2. AMIT GARG, M.D. ASSISTANT PROFESSOR, DEPARTMENT OF PSYCHIATRY I.H.B.A.S, DILSHAD GARDEN, DELHI. INDIA- 110095 PH. +91-11-22583322 FAX. +91-11-22599227 MOB. +91-9650431525 E-MAIL. [email protected] CORRESPONDING AUTHOR AMIT GARG, M.D. ASSISTANT PROFESSOR, DEPARTMENT OF PSYCHIATRY I.H.B.A.S, DILSHAD GARDEN, DELHI. INDIA- 110095 PH. +91-11-22583322 FAX. +91-11-22599227 MOB. +91-9650431525, 9868396838 E-MAIL. [email protected] None
ACCEPTED MANUSCRIPT Abstract Psychiatric adverse effects associated with the use of clomiphene are relatively
T
uncommon. Though case reports link mood swings to be associated with clomiphene, it is
RI P
not known to be associated with a syndromal affective episode. Being a selective oestrogen receptor modulator, clomiphene affects the hypothalamus-pituitary-gonadal
SC
axis and can have potential neuropsychiatric effects in vulnerable persons. Herein we
NU
report a case of clomiphene induced manic episode in a known bipolar male patient.
ED
MA
Key words: Clomiphene, Manic episode, Male
PT
Introduction
Clomiphene citrate is a racemic mixture of zuclomiphene and enclomiphene acting as a
CE
selective oestrogen receptor modulator1. The cis-isomer zuclomiphene (38%) has
AC
primarily oestrogen receptor agonist properties, and the trans-isomer enclomiphene (62%) has mostly oestrogen receptor antagonistic properties2. Acting as an anti-oestrogen on the hypothalamus- pituitary-gonadal axis, it increases the pulse frequency and concentration of follicle stimulating hormone (FSH) and luteinizing hormone (LH), giving a moderate gonadotrophin stimulus. In males, enclomiphene isomer induces hypothalamic GnRH release, thus increasing serum testosterone levels2. Though long marketed as a drug to aid reproduction in females, clomiphene citrate has also been used off-label to treat men with adult-onset secondary hypogonadism for increasing sperm production. Enclomiphene2 is also an oral selective oestrogen receptor modulator in
ACCEPTED MANUSCRIPT phase II/III clinical stage being developed for the treatment of male hypogonadotropic hypogonadism.
studies have revealed mood swings and irritability as
RI P
uncommon though some
T
Psychiatric adverse effects associated with the use of clomiphene are relatively
psychological side effects of clomiphene therapy3. We report a case of patient with
SC
known bipolar disorder who developed a manic episode subsequent to administration of
NU
clomiphene citrate for the purpose of infertility secondary to oligozoospermia.
MA
Case
Mr. M, a 34 year old male on follow-up from the out-patient department of our hospital
ED
presented with complaints of euphoric mood, increased goal directed activities, increased
PT
talkativeness, increased libido and decreased need for sleep for the past 4 days. Patient was a known case of bipolar affective disorder with a total duration of illness of 6 years
CE
with one manic and one depressive episode in the past. He had been in remission for the
AC
past 4 years and had been maintaining on lithium carbonate 900mg/day with adequate adherence. Patient did not have any history of substance use and his family history was non-contributory. The patient and his spouse had also been undergoing evaluation for primary infertility and in the course of investigations, the patient was diagnosed with oligozoospermia. Hormonal screening revealed normal testosterone, follicle stimulating hormone and luteinizing hormone levels. Patient was started on clomiphene citrate 50mg three times a week for oligozoospermia. After 5 days of initiation of clomiphene therapy, patient’s manic symptoms emerged. On presentation, his mental status examination revealed overfamiliarity, increased psychomotor activity, elated affect, inflated self-
ACCEPTED MANUSCRIPT esteem and ideas of grandiosity with absent insight. A serum lithium level sent on the subsequent day of presentation was at 0.83 meq/litre and his thyroid function tests were
T
within normal limits. Clomiphene was discontinued for the patient and risperidone was
RI P
added at 2 mg per day along with lithium carbonate at 900mg per day. Lorazepam was given at 1 mg per day on an SOS basis for arousal symptoms and insomnia. The patient
SC
followed up after one week and showed significant improvement in symptoms. He
NU
eventually became asymptomatic over the next 3 weeks and has been continuing to
MA
maintain well since then.
ED
Discussion
PT
Given the close temporal relationship of the exposure (within 1 month) to clomiphene and the development of manic symptoms, we believe that the most likely explanation for
CE
this case is a medication-triggered manic episode. A re-challenge with clomiphene could
AC
have confirmed our hypothesis, but it was against the consent of the patient and his spouse and would also have been deemed unethical. Though mood changes have been noted with clomiphene treatment in women4-6, but to our knowledge, this is the first report of mania precipitated by clomiphene use in a male. Research over the years has implicated the hypothalamic-pituitary-gonadal axis in mood dysregulation. In the index patient, testosterone (and in turn estrogen) levels could have been modulated by clomiphene citrate. Clomiphene citrate has been shown to increase serum testosterone levels in both eugonadal7 and hypogonadal males2, 8. Testosterone may interact directly with androgen receptors or through aromatization to estrogen
ACCEPTED MANUSCRIPT metabolites in the brain to stimulate the mitogen activated protein kinase (MAPK) pathway9, a fundamental signaling pathway and critical regulator of emotional responses.
T
The irritable male syndrome10 is a behavioural state of nervousness, irritability, lethargy
RI P
and depression that occurs in adult male mammals following withdrawal of testosterone and hypoestrogenism is also associated with depressive symptoms11.
SC
Conversely, oestrogen and testosterone administration has been reported to have mood
NU
enhancing anti-depressant effect12,13 . Testosterone has also been linked in the past to manic episodes14. In a placebo-controlled, double-blind, crossover study15 of
MA
administration of supraphysiologic doses of testosterone cypionate to normal men, testosterone treatment significantly increased several measures of manic and aggressive
PT
ED
symptoms.
Conclusion and implications
CE
These pathways point to an exciting interaction of endocrinological influences on higher
AC
cognitive functions. An elevated testosterone levels could have led to elevated oestradiol levels as the latter is synthesized from testosterone using the enzyme aromatase. While both oestrogen and testosterone have been linked to mood symptoms, a simple causative explanation does not exist for them. A limitation in the index case was the absence of serum gonadotropin levels post clomiphene citrate administration. These would have allowed us some insight into the complex interactions between various gonadotropins leading to the development of affective symptoms. We could not entirely rule out the possibility of a breakthrough manic episode in this case but nevertheless the strong temporal correlation with the intake of clomiphene and the other case reports3,6
ACCEPTED MANUSCRIPT implicating clomiphene with mood symptoms suggest that this molecule requires further studies to profile its safety in populations vulnerable to psychiatric disorders.
T
This case suggests that the administration of hormone modulators like clomiphene may
RI P
kindle mania in susceptible individuals. As specialists treat an increasing number of patients with infertility, it is cardinal that they be familiar with the probable psychiatric
SC
adverse effects and exercise caution in prescribing clomiphene to individuals with a
NU
proclivity to affective switch.
MA
REFERENCES
1. Dickey RP, Holtkamp DE. Development, pharmacology and clinical experience with
ED
clomiphene citrate. Hum Reprod Update. 1996;2:483- 506.
PT
2. Hill S, Arutchelvam V, Quinton R. Enclomiphene, an estrogen receptor antagonist for the treatment of testosterone deficiency in men. IDrugs. 2009 Feb;12(2):109-19.
CE
3. Choi SH, Shapiro H, Robinson GE, Irvine J, Neuman J, Rosen B, Murphy J, Stewart
AC
D. Psychological side-effects of clomiphene citrate and human menopausal gonadotrophin. J Psychosom Obstet Gynaecol. 2005;26:93-100. 4. Blum M, Zacharovitch D, Pery J, Gilerowitch M: Estrogen replacement therapy (ERT) by a special regimen in the years following menopause. Clin Exp Obstet Gynecol. 1989;16:9–11. 5. Kapfhammer HP, Messer T, Hoff P: Psychotic illness during treatment with clomifen. Dtsch Med Wochenschr. 1990;115:936–939. 6. Blenner JL. Clomiphene-induced mood swings. J Obstet Gynecol Neonatal Nurs.1991;20:321–327.
ACCEPTED MANUSCRIPT 7. Rönnberg L. The effect of clomiphene citrate on different sperm parameters and serum hormone levels in preselected infertile men: a controlled double-blind cross-over study.
T
Int J Androl. 1980 Oct;3(5):479-86.
RI P
8. Shabsigh A1, Kang Y, Shabsign R, Gonzalez M, Liberson G, Fisch H, Goluboff E. Clomiphene citrate effects on testosterone/estrogen ratio in male hypogonadism. J Sex
SC
Med. 2005 Sep;2(5):716-21.
NU
9. Carrier N, Kabbaj M. Extracellular signal-regulated kinase 2 signaling in the hippocampal dentate gyrus mediates the antidepressant effects of testosterone. Biol
MA
Psychiatry. 2012 Apr 1;71(7):642-51
10. Lincoln GA. The irritable male syndrome. Reprod Fertil Dev. 2001;13(7-8):567-76.
ED
11. Toren P, Dor J, Rehavi M, Weizman A: Hypothalamic-pituitary- ovarian axis and
PT
mood. Biol Psychiatry. 1996;40:1051–1055. 12. Kanayama G, Amiaz R, Seidman S, Pope HG Jr. Testosterone supplementation for
CE
depressed men: current research and suggested treatment guidelines. Experimental and
AC
clinical psychopharmacology. 2007; 15:529–538. 13. Klaiber EL, Broverman DM, Vogel W, Peterson LG, Snyder MB. Individual differences in changes in mood and platelet monoamine oxidase (MAO) activity during hormonal replacement therapy in menopausal women. Psychoneuroendocrinology. 1996;21(7):575– 592 14. Weiss EL, Bowers MB, Mazure CM. Testosterone-Patch-Induced Psychotic Mania. Am J Psy. 1999;156:969-969. 15. Pope HG Jr, Kouri EM, Hudson JI. Effects of supraphysiologic doses of testosterone on mood and aggression in normal men: a randomized controlled trial. Arch Gen
ACCEPTED MANUSCRIPT Psychiatry. 2000;57:133-40.
T
Acknowledgement : none
RI P
Conflict of interest: none
AC
CE
PT
ED
MA
NU
SC
Financial disclosures: none
