eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Klinefelter Syndrome: Treatment & Medication

Author: Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, and Pathology, Director of Genetic Laboratory Services, Louisiana State University Medical Center
Contributor Information and Disclosures

Updated: Jun 10, 2009

Treatment

Medical Care

Early identification and anticipatory guidance are extremely helpful, although Klinefelter syndrome is rarely diagnosed in prepubertal males. Treatment should address 3 major facets of the disease: hypogonadism, gynecomastia, and psychosocial problems.

  • Androgen therapy 
    • Androgen therapy is the most important aspect of treatment. Testosterone replacement should begin at puberty, around age 12 years, and the dose should increase until it is sufficient to maintain age-appropriate serum concentrations of testosterone, estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). 
    • Androgen therapy is used to correct androgen deficiency, to provide appropriate virilization, and to improve psychosocial status. Regular testosterone injections can promote strength and facial hair growth; build a more muscular body type; increase sexual desire; enlarge the testes; improve mood, self-image, and behavior; and protect against precocious osteoporosis.
  • Speech and behavioral therapy
    • A multidisciplinary team approach can assist in improving speech impairments, academic difficulties, and other psychosocial and behavioral problems.
    • In children, early speech and language therapy is particularly helpful in developing skills in the understanding and production of more complex language.
    • Males with Klinefelter syndrome should receive a comprehensive psychoeducational evaluation to assess their areas of strengths and weaknesses. The information obtained from these evaluations may be helpful in planning appropriate resources and classroom placement.
  • Physical and occupational therapy
    • Physical therapy should be recommended in boys with hypotonia or delayed gross motor skills that may affect muscle tone, balance, and coordination.
    • Occupational therapy is advised in boys with motor dyspraxia.
  • Treatment for infertility
    • Men with Klinefelter syndrome were considered infertile until 1996. Over the last decade, developments in microsurgical techniques and advances in artificial reproductive technologies (ART) allowed more than 50% of patients with Klinefelter syndrome to have their own children through the combination of microsurgical testicular sperm extraction (TESE) and the use of freshly retrieved sperm for in-vitro fertilization (IVF).17,18,6,19 The fact that sperm can be found in the testes of men with Klinefelter syndrome has challenged the previous assumption that men with Klinefelter syndrome are always sterile. Viable spermatozoa can now be extracted from the testes via surgical biopsy, and a spermatozoon can be directly injected into an ovum.
    • More than 60 children have been born worldwide after successful intracytoplasmic sperm injection (ICSI) in couples in which the male partner has Klinefelter syndrome.
    • A minority of men with Klinefelter syndrome have viable sperm in their ejaculate and are able to provide sperm for cryopreservation for future pregnancies.
  • Genetic counseling
    • The recurrence risk is not increased above that in the general population.
    • Physicians should provide parents with information from unbiased follow-up studies of children with Klinefelter syndrome.
    • The best time to reveal the condition to an affected male is probably mid-to-late adolescence, when he is old enough to understand his condition.
  • Reproductive genetic counseling20
    • Sperm from patients with the nonmosaic 47,XXY karyotype has been used successfully in assisted reproduction.
    • Origin of the meiotic products of patients with the nonmosaic 47,XXY karyotype remains unclear. First, mosaicism cannot be excluded in the nonmosaic 47,XXY karyotype.21 Indeed, the presence of a normal XY germ cell line in the testis could explain the production of normal haploid sperm in these apparently nonmosaic patients. Nevertheless, lymphocyte karyotyping neither predicts the chromosomal constitution of the testis cells nor the presence or absence of spermatogenesis.22
    • ICSI per se is also associated with an increased risk of producing a chromosome anomaly in offspring.23 IVF is also associated with an increased risk for de-novo chromosomal aberrations, especially those involving the sex chromosomes.24,25
    • Reproductive genetic counseling of patients with the 47,XXY karyotype remains difficult. Some authors have recommended preimplantation or prenatal diagnosis after ICSI using sperm cells from patients with the 47,XXY karyotype.26,27,28,29 Arguments from authors who propose a preimplantation genetic diagnosis (PGD) include the increased risk of producing sex chromosomal-abnormal offspring (the unbalanced offsprings are 47,XXX or 47,XXY karyotypes).30,31,32,33,29
    • The genetic risk in the offspring of patients with 47,XXY karyotype remains unknown but is presumably low. This risk concerns sex chromosomal and autosomal aneuploidy. Genetic counseling should be reassuring, and management of the pregnancy should proceed with caution.20

Surgical Care

  • Mastectomy may be indicated for gynecomastia, which places considerable psychological strain on the patient and increases the risk of breast cancer.

Consultations

  • Clinical geneticist
  • Endocrinologist
  • Surgeon
  • Psychologist
  • Speech therapist

Diet

  • No special diet is needed.

Activity

  • No activity restrictions are required.

Medication

Androgen

Exogenous androgen (testosterone) is the treatment of choice for many aspects of Klinefelter syndrome.


Testosterone enanthate (Delatestryl) or cypionate (Depo-Testosterone)

Major therapeutic aims are to reduce serum gonadotropin concentrations to the upper limits of normal and to gradually induce virilization.

Adult

200 mg IM q2-3wk

Pediatric

Beginning at age 11-12 years: 50 mg IM qmo; increase dosage annually in accord with the patient's state of well-being, degree of virilization, growth, and serum gonadotropin levels, eventually reaching adult dose

Increases effects of warfarin; increases propranolol clearance

Documented hypersensitivity; severe renal, hepatic, or cardiac disease; prostate or breast cancer in males; hypercalcemia

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Initiation of therapy may be associated with priapism (rare); other adverse effects include salt and water retention with edema and hypertension, polycythemia, and transient or increased gynecomastia; large doses in older patients may produce prostatic hypertrophy, leading to acute bladder outlet obstruction

More on Klinefelter Syndrome

Overview: Klinefelter Syndrome
Differential Diagnoses & Workup: Klinefelter Syndrome
Treatment & Medication: Klinefelter Syndrome
Follow-up: Klinefelter Syndrome
Multimedia: Klinefelter Syndrome
References
[ CLOSE WINDOW ]

References

  1. Klinefelter HF Jr, Reifenstein EC Jr, Albright F. Syndrome characterized by gynecomastia aspermatogenesis without a-Leydigism and increased excretion of follicle-stimulating hormone. J Clin Endocr Metabl. 1942;2:615-624.

  2. Giedd JN, Clasen LS, Wallace GL, et al. XXY (Klinefelter syndrome): a pediatric quantitative brain magnetic resonance imaging case-control study. Pediatrics. Jan 2007;119(1):e232-40. [Medline]. [Full Text].

  3. Vorona E, Zitzmann M, Gromoll J, Schuring AN, Nieschlag E. Clinical, endocrinological, and epigenetic features of the 46,XX male syndrome, compared with 47,XXY Klinefelter patients. J Clin Endocrinol Metab. Sep 2007;92(9):3458-65. [Medline]. [Full Text].

  4. Seo JT, Lee JS, Oh TH, Joo KJ. The clinical significance of bone mineral density and testosterone levels in Korean men with non-mosaic Klinefelter's syndrome. BJU Int. Jan 2007;99(1):141-6. [Medline].

  5. Rovenský J. Rheumatic diseases and Klinefelter's syndrome. Autoimmun Rev. Nov 2006;6(1):33-6. [Medline].

  6. Paduch DA, Fine RG, Bolyakov A, Kiper J. New concepts in Klinefelter syndrome. Curr Opin Urol. Nov 2008;18(6):621-7. [Medline].

  7. Paduch DA, Bolyakov A, Cohen P, Travis A. Reproduction in men with Klinefelter syndrome: the past, the present, and the future. Semin Reprod Med. Mar 2009;27(2):137-48. [Medline].

  8. [Guideline] National Collaborating Centre for Women's and Children's Health. Fertility: assessment and treatment for people with fertility problems. Feb 2004;216. [Full Text].

  9. Lee YS, Cheng AW, Ahmed SF, Shaw NJ, Hughes IA. Genital anomalies in Klinefelter's syndrome. Horm Res. 2007;68(3):150-5. [Medline].

  10. Jacobs PA, Strong JA. A case of human intersexuality having a possible XXY sex-determining mechanism. Nature. Jan 31 1959;183(4657):302-3. [Medline].

  11. Thomas NS, Hassold TJ. Aberrant recombination and the origin of Klinefelter syndrome. Hum Reprod Update. Jul-Aug 2003;9(4):309-17. [Medline]. [Full Text].

  12. Lowe X, Eskenazi B, Nelson DO, Kidd S, Alme A, Wyrobek AJ. Frequency of XY sperm increases with age in fathers of boys with Klinefelter syndrome. Am J Hum Genet. Nov 2001;69(5):1046-54. [Medline]. [Full Text].

  13. Zitzmann M, Depenbusch M, Gromoll J, Nieschlag E. X-chromosome inactivation patterns and androgen receptor functionality influence phenotype and social characteristics as well as pharmacogenetics of testosterone therapy in Klinefelter patients. J Clin Endocrinol Metab. Dec 2004;89(12):6208-17. [Medline].

  14. Bojesen A, Gravholt CH. Klinefelter syndrome in clinical practice. Nat Clin Pract Urol. Apr 2007;4(4):192-204. [Medline].

  15. Wikstrom AM, Dunkel L. Testicular function in Klinefelter syndrome. Horm Res. 2008;69(6):317-26. [Medline].

  16. Mantovani V, Dondi E, Larizza D, et al. Do reduced levels of steroid 21-hydroxylase confer a survival advantage in fetuses affected by sex chromosome aberrations?. Eur J Hum Genet. Feb 2002;10(2):137-40. [Medline].

  17. Schiff JD, Palermo GD, Veeck LL, et al. Success of testicular sperm injection and intracytoplasmic sperm injection in men with Klinefelter syndrome. J Clin Endocrinol Metab. Nov 2005;90(11):6263-7. [Medline].

  18. Damani MN, Mittal R, Oates RD. Testicular tissue extraction in a young male with 47,XXY Klinefelter's syndrome: potential strategy for preservation of fertility. Fertil Steril. Nov 2001;76(5):1054-6. [Medline].

  19. Wikstrom AM, Painter JN, Raivio T, Aittomaki K, Dunkel L. Genetic features of the X chromosome affect pubertal development and testicular degeneration in adolescent boys with Klinefelter syndrome. Clin Endocrinol (Oxf). Jul 2006;65(1):92-7. [Medline].

  20. Tachdjian G, Frydman N, Morichon-Delvallez N, et al. Reproductive genetic counselling in non-mosaic 47,XXY patients: implications for preimplantation or prenatal diagnosis: Case report and review. Hum Reprod. Feb 2003;18(2):271-5. [Medline]. [Full Text].

  21. Tournaye H, Staessen C, Liebaers I, et al. Testicular sperm recovery in nine 47,XXY Klinefelter patients. Hum Reprod. Aug 1996;11(8):1644-9. [Medline]. [Full Text].

  22. Westlander G, Ekerhovd E, Granberg S, Hanson L, Hanson C, Bergh C. Testicular ultrasonography and extended chromosome analysis in men with non mosaic Klinefelter syndrome: a prospective study of possible predictive factors for successful sperm recovery. Fertil Steril. 2001;75:1102-1105. [Medline].

  23. Aboulghar H, Aboulghar M, Mansour R, Serour G, Amin Y, Al-Inany H. A prospective controlled study of karyotyping for 430 consecutive babies conceived through intracytoplasmic sperm injection. Fertil Steril. Aug 2001;76(2):249-53. [Medline].

  24. Van Opstal D, Los FJ, Ramlakhan S, et al. Determination of the parent of origin in nine cases of prenatally detected chromosome aberrations found after intracytoplasmic sperm injection. Hum Reprod. Apr 1997;12(4):682-6. [Medline]. [Full Text].

  25. Bonduelle M, Aytoz A, Van Assche E, Devroey P, Liebars I, VanSteirteghem A. Incidence of chromosomal aberrations in childrenborn after assisted reproduction through intracytoplasmic sperm injection. Hum Reprod. 1998;13:781-782. [Medline]. [Full Text].

  26. Staessen C, Coonen E, Van Assche E, et al. Preimplantation diagnosis for X and Y normality in embryos from three Klinefelter patients. Hum Reprod. Aug 1996;11(8):1650-3. [Medline]. [Full Text].

  27. Estop AM, Munne S, Cieply KM, Vandermark KK, Lamb AN, Fisch H. Meiotic products of a Klinefelter 47,XXY male as determined by sperm fluorescence in-situ hybridization analysis. Hum Reprod. Jan 1998;13(1):124-7. [Medline]. [Full Text].

  28. Reubinoff BE, Abeliovich D, Werner M, Schenker JG, Safran A, Lewin A. A birth in non-mosaic Klinefelter's syndrome after testicular fine needle aspiration, intracytoplasmic sperm injection and preimplantation genetic diagnosis. Hum Reprod. Jul 1998;13(7):1887-92. [Medline]. [Full Text].

  29. Rosenlund B, Hreinsson JG, Hovatta O. Birth of a healthy male after frozen thawed blastocyst transfer following intracytoplasmic injection of frozen thawed testicular spermatozoa from a man with nonmosaic Klinefelter's syndrome. J Assist Reprod Genet. Mar 2002;19(3):149-51. [Medline].

  30. Hinney B, Guttenbach M, Schmid M, Engel W, Michelmann HW. Pregnancy after intracytoplasmic sperm injection with sperm from a man with a 47,XXY Klinefelter's karyotype. Fertil Steril. Oct 1997;68(4):718-20. [Medline].

  31. Palermo GD, Schlegel PN, Sills ES, et al. Births after intracytoplasmic injection of sperm obtained by testicular extraction from men with nonmosaic Klinefelter's syndrome. N Engl J Med. Feb 26 1998;338(9):588-90. [Medline].

  32. Ron-El R, Raziel A, Strassburger D, Schachter M, Bern O, Friedler S. Birth of healthy male twins after intracytoplasmic sperm injection of frozen-thawed testicular spermatozoa from a patient with nonmosaic Klinefelter syndrome. Fertil Steril. Oct 2000;74(4):832-3. [Medline].

  33. Crüger D, Toft B, Agerholm I, Fedder J, Hald F, Bruun-Petersen G. Birth of a healthy girl after ICSI with ejaculated spermatozoa from a man with non-mosaic Klinefelter's syndrome. Hum Reprod. Sep 2001;16(9):1909-11. [Medline]. [Full Text].

  34. Aguirre D, Nieto K, Lazos M, et al. Extragonadal germ cell tumors are often associated with Klinefelter syndrome. Hum Pathol. Apr 2006;37(4):477-80. [Medline].

  35. Campbell WA, Price WH. Venous thromboembolic disease in Klinefelter's syndrome. Clin Genet. Apr 1981;19(4):275-80. [Medline].

  36. Anawalt BD, Bebb RA, Matsumoto AM, et al. Serum inhibin B levels reflect Sertoli cell function in normal men and men with testicular dysfunction. J Clin Endocrinol Metab. Sep 1996;81(9):3341-5. [Medline].

  37. Bagatell CJ, Bremner WJ. Androgens in men--uses and abuses. N Engl J Med. Mar 14 1996;334(11):707-14. [Medline].

  38. Bender BG, Harmon RJ, Linden MG, Robinson A. Psychosocial adaptation of 39 adolescents with sex chromosome abnormalities. Pediatrics. Aug 1995;96(2 Pt 1):302-8. [Medline].

  39. Bhasin S, Ma K, Sinha I, et al. The genetic basis of male infertility. Endocrinol Metab Clin North Am. Dec 1998;27(4):783-805, viii. [Medline].

  40. Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab. Feb 2003;88(2):622-6. [Medline].

  41. Chen H. Klinefelter syndrome. In: Atlas of Genetic Diagnosis and Counseling. Totowa, New Jersey: Humana Press; 2006:570-574.

  42. De la Chapelle A. Sex Chromosome Abnormalities. In: Emery AEH, Rimoin DL, eds. Principles and Practice of Medical Genetics. Vol 1. Edinburgh, England: Churchill Livingstone; 1990:273-299.

  43. Denschlag D, Tempfer C, Kunze M, Wolff G, Keck C. Assisted reproductive techniques in patients with Klinefelter syndrome: a critical review. Fertil Steril. Oct 2004;82(4):775-9. [Medline].

  44. Ferrier PE, Ferrier SA, Pescia G. The XXXY Klinefelter syndrome in childhood. Am J Dis Child. Jan 1974;127(1):104-5. [Medline].

  45. Friedler S, Raziel A, Strassburger D, Schachter M, Bern O, Ron-El R. Outcome of ICSI using fresh and cryopreserved-thawed testicular spermatozoa in patients with non-mosaic Klinefelter's syndrome. Hum Reprod. Dec 2001;16(12):2616-20. [Medline]. [Full Text].

  46. Greco E, Iacobelli M, Rienzi L, Fabris GF, Tesorio N, Tesarik J. Birth of a healthy boy after fertilization of cryopreserved oocytes with cryopreserved testicular spermatozoa from a man with nonmosaic Klinefelter syndrome. Fertil Steril. Apr 2008;89(4):991.e5-7. [Medline].

  47. Kamischke A, Baumgardt A, Horst J, Nieschlag E. Clinical and diagnostic features of patients with suspected klinefelter syndrome. J Androl. Jan-Feb 2003;24(1):41-8. [Medline]. [Full Text].

  48. Kleczkowska A, Fryns JP, Van den Berghe H. X-chromosome polysomy in the male. The Leuven experience 1966-1987. Hum Genet. Sep 1988;80(1):16-22. [Medline].

  49. Krausz C, Forti G. Sperm cryopreservation in male infertility due to genetic disorders. Cell Tissue Bank. 2006;7(2):105-12. [Medline].

  50. Linden MG, Bender BG, Robinson A. Sex chromosome tetrasomy and pentasomy. Pediatrics. Oct 1995;96(4 Pt 1):672-82. [Medline].

  51. Mandoki MW, Sumner GS, Hoffman RP, Riconda DL. A review of Klinefelter's syndrome in children and adolescents. J Am Acad Child Adolesc Psychiatry. Mar 1991;30(2):167-72. [Medline].

  52. Meschede D, Louwen F, Nippert I. Low rates of pregnancy termination for prenatally diagnosed Klinefelter syndrome and other sex chromosome polysomies. Am J Med Genet. Dec 4 1998;80(4):330-4. [Medline].

  53. Nielsen J, Pelsen B, Sorensen K. Follow-up of 30 Klinefelter males treated with testosterone. Clin Genet. Apr 1988;33(4):262-9. [Medline].

  54. Peet J, Weaver DD, Vance GH. 49,XXXXY: a distinct phenotype. Three new cases and review. J Med Genet. May 1998;35(5):420-4. [Medline].

  55. Ratcliffe SG, Bancroft J, Axworthy D, McLaren W. Klinefelter's syndrome in adolescence. Arch Dis Child. Jan 1982;57(1):6-12. [Medline].

  56. Robinson A, Bender BG, Linden MG. Prognosis of prenatally diagnosed children with sex chromosome aneuploidy. Am J Med Genet. Oct 1 1992;44(3):365-8. [Medline].

  57. Robinson A, Lubs HA, Nielsen J, Sorensen K. Summary of clinical findings: profiles of children with 47,XXY, 47,XXX and 47,XYY karyotypes. Birth Defects Orig Artic Ser. 1979;15(1):261-6. [Medline].

  58. Ron-El R, Strassburger D, Gelman-Kohan S, Friedler S, Raziel A, Appelman Z. A 47,XXY fetus conceived after ICSI of spermatozoa from a patient with non-mosaic Klinefelter's syndrome: case report. Hum Reprod. Aug 2000;15(8):1804-6. [Medline]. [Full Text].

  59. Schulte-Beerbuhl M, Nieschlag E. Comparison of testosterone, dihydrotestosterone, luteinizing hormone, and follicle-stimulating hormone in serum after injection of testosterone enanthate of testosterone cypionate. Fertil Steril. Feb 1980;33(2):201-3. [Medline].

  60. Schwartz ID, Root AW. The Klinefelter syndrome of testicular dysgenesis. Endocrinol Metab Clin North Am. Mar 1991;20(1):153-63. [Medline].

  61. Smith S. Index of suspicion. Case 1. Diagnosis: Klinefelter syndrome. Pediatr Rev. Nov 1992;13(11):435-6. [Medline].

  62. Smyth CM, Bremner WJ. Klinefelter syndrome. Arch Intern Med. Jun 22 1998;158(12):1309-14. [Medline].

  63. Swerdlow AJ, Higgins CD, Schoemaker MJ, et al. Mortality in patients with Klinefelter syndrome in Britain: a cohort study. J Clin Endocrinol Metab. Dec 2005;90(12):6516-22. [Medline].

  64. Swerdlow AJ, Schoemaker MJ, Higgins CD, Wright AF, Jacobs PA,. Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst. Aug 17 2005;97(16):1204-10. [Medline].

  65. Visootsak J, Graham JM Jr. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis. 2006;1:42. [Medline].

  66. Wattendorf DJ, Muenke M. Klinefelter syndrome. Am Fam Physician. Dec 1 2005;72(11):2259-62. [Medline].

  67. Yoshida A, Miura K, Nagao K, et al. Sexual function and clinical features of patients with Klinefelter's syndrome with the chief complaint of male infertility. Int J Androl. Apr 1997;20(2):80-5. [Medline].

  68. Zaleski WA, Houston CS, Pozsonyi J, Ying KL. The XXXXY chromosome anomaly: report of three new cases and review of 30 cases from the literature. Can Med Assoc J. May 28 1966;94(22):1143-54. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, and Pathology, Director of Genetic Laboratory Services, Louisiana State University Medical Center
Harold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Human Genetics, and Teratology Society
Disclosure: Nothing to disclose.

Medical Editor

Ian Krantz, MD, Department of Pediatrics, Assistant Professor, University of Pennsylvania and Children's Hospital of Philadelphia
Ian Krantz, MD is a member of the following medical societies: American Society of Human Genetics
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Margaret M McGovern, MD, PhD, Professor and Chair of Pediatrics, Stony Brook University, New York
Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics
Disclosure: Genzyme Grant/research funds PI

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.