Medical Care

Evaluation and therapy can usually be implemented on an outpatient basis. Inpatient evaluation and treatment may be necessary for patients with congenital heart disease or acute adrenocortical insufficiency.

All postpubertal-age patients with Kallmann syndrome and idiopathic hypogonadotropic hypogonadism are candidates for gonadal steroid replacement therapy in the absence of specific contraindications. Additional therapies to restore fertility can be implemented on request.

Behavioral modification and psychological counseling may benefit individuals with hypothalamic amenorrhea. Such approaches should be offered before estrogen replacement therapy.

Medical therapies are used to treat associated conditions, including osteoporosis, adrenocortical insufficiency, congenital heart disease, and neurologic disorders.

Surgical Care

Assisted reproductive technologies, including in vitro fertilization (IVF), zygote intrafallopian transfer (ZIFT), and gamete intrafallopian transfer (GIFT), have been used successfully when male patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism do not achieve adequate sperm counts on either GnRH or gonadotropin therapy.

Patients with Kallmann syndrome and congenital heart disease may need corrective surgery. A detailed description of the pertinent procedures is beyond the scope of this review.

Patients with cleft lip or palate also need surgical correction.

Consultations

Adult or pediatric specialists should be consulted, depending on the patient's age.

Consultations include the following:

Endocrinologist and reproductive endocrinologist
Cardiologist
Cardiothoracic surgeon and pediatric surgeon
Neurologist and psychiatrist
Otolaryngologist
Dermatologist

Diet

No dietary restrictions are required in the absence of congenital heart disease. Salt restriction (adult Na⁺ intake < 2 g/d) is advised for patients with congestive heart failure.

All patients must ensure an adequate calcium (1200-1500 mg/d) and vitamin D (800-1000 U/d) intake, especially if they are osteopenic. Dietary supplements may be necessary for patients to achieve these goals.

Activity

Routine activity restrictions are not necessary; however, patients with osteoporosis need to avoid high-impact sports and situations conducive to falls.

Activity restrictions are also appropriate in patients with certain forms of congenital heart disease or seizures.

Further outpatient care

Medications include gonadal steroid replacement (testosterone in males and estrogen-progestin in females) in postpubertal-aged patients.

Male and female patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism who desire fertility may choose between pulsatile gonadorelin (GnRH) infusion and gonadotropin therapy (the former is no longer available in the US). Clomiphene may be helpful in women with hypothalamic amenorrhea and should be tried first in this patient population after correction of the precipitating factors, if possible. Assisted reproductive technologies, including IVF, ZIFT, GIFT, and intracytoplasmic sperm injection (ICSI), have been used successfully when male patients do not achieve adequate sperm counts on GnRH or gonadotropin therapy.

Patients with primary adrenocortical insufficiency need glucocorticoid and mineralocorticoid replacement therapy.

Antiepileptic medications are needed in patients with seizures.

Patients with congenital heart disease may need pharmacologic therapy as well. Details of these therapies are beyond the scope of this review.

Patients with ichthyosis are treated with alpha-hydroxy acids, such as glycolic acid or lactic acid.

Further inpatient care

Admit patient for diagnostic testing and surgery as needed.

Transfer

Transfer may be indicated for specific diagnostic testing or surgery.

Inpatient and outpatient medications

Medications include gonadal steroid replacement (testosterone in males and estrogen-progestin in females) in postpubertal-aged patients.

Male and female patients with KS or IHH who desire fertility may choose between pulsatile gonadorelin (GnRH) infusion and gonadotropin therapy (the former is no longer available in the US). Clomiphene may be helpful in women with hypothalamic amenorrhea and should be tried first in this patient population after correction of the precipitating factors, if possible. Assisted reproductive technologies, including IVF, ZIFT, GIFT, and ICSI have been used successfully when male patients do not achieve adequate sperm counts on GnRH or gonadotropin therapy.

Patients with primary adrenocortical insufficiency need glucocorticoid and mineralocorticoid replacement therapy.

Antiepileptic medications are needed in patients with seizures.

Patients with congenital heart disease may need pharmacologic therapy as well. Details of these therapies are beyond the scope of this review.

Patients with ichthyosis are treated with alpha-hydroxy acids, such as glycolic acid or lactic acid.

Prevention

Patients at risk of osteoporosis should avoid high-impact sports and situations conducive to falls.

Patients with certain forms of congenital heart disease should avoid strenuous exercise.

Patients with recent seizures must refrain from certain activities and sports (such as diving) that would put them at risk if another seizure were to occur during participation.

Medication

Bonomi M, Libri DV, Guizzardi F, Guarducci E, Maiolo E, Pignatti E, et al. New understandings of the genetic basis of isolated idiopathic central hypogonadism. Asian J Androl. 2012 Jan. 14(1):49-56. [QxMD MEDLINE Link].
Dode C, Levilliers J, Dupont JM, et al. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet. 2003 Apr. 33(4):463-5. [QxMD MEDLINE Link].
Silveira LF, Latronico AC. Approach to the patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2013 May. 98(5):1781-8. [QxMD MEDLINE Link].
Pitteloud N, Quinton R, Pearce S, et al. Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J Clin Invest. 2007 Feb. 117(2):457-63. [QxMD MEDLINE Link]. [Full Text].
Monnier C, Dode C, Fabre L, et al. PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling-activity. Hum Mol Genet. 2008 Sep 29. [QxMD MEDLINE Link].
Abreu AP, Trarbach EB, de Castro M, et al. Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome. J Clin Endocrinol Metab. 2008 Oct. 93 (10):4113-8. [QxMD MEDLINE Link].
Pitteloud N, Zhang C, Pignatelli D, et al. Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A. 2007 Oct 30. 104(44):17447-52. [QxMD MEDLINE Link]. [Full Text].
Dode C, Teixeira L, Levilliers J, et al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet. 2006 Oct 20. 2(10):e175. [QxMD MEDLINE Link]. [Full Text].
Canto P, Munguía P, Söderlund D, et al. Genetic analysis in patients with Kallmann syndrome: coexistance of mutations in prokineticin receptor 2 and KAL1. J Androl. 2008 Aug 21. [QxMD MEDLINE Link].
Merke DP, Tajima T, Baron J, et al. Hypogonadotropic hypogonadism in a female caused by an X-linked recessive mutation in the DAX1 gene. N Engl J Med. 1999. 340(16):1248-52. [QxMD MEDLINE Link].
Clement K, Vaisse C, Lahlou N, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998 Mar 26. 392(6674):398-401. [QxMD MEDLINE Link].
Pralong FP, Gomez F, Castillo E, et al. Complete hypogonadotropic hypogonadism associated with a novel inactivating mutation of the gonadotropin-releasing hormone receptor. J Clin Endocrinol Metab. 1999 Oct. 84(10):3811-6. [QxMD MEDLINE Link].
Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003 Oct 23. 349(17):1614-27. [QxMD MEDLINE Link]. [Full Text].
Silveira LG, Latronico AC, Seminara SB. Kisspeptin and clinical disorders. Adv Exp Med Biol. 2013. 784:187-99. [QxMD MEDLINE Link].
Dhillo WS, Chaudhri OB, Patterson M, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab. 2005 Dec. 90(12):6609-15. [QxMD MEDLINE Link].
Gottsch ML, Cunningham MJ, Smith JT, et al. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology. 2004 Sep. 145(9):4073-7. [QxMD MEDLINE Link]. [Full Text].
Miura K, Acierno JS, Seminara SB. Characterization of the human nasal embryonic LHRH factor gene, NELF, and a mutation screening among 65 patients with idiopathic hypogonadotropic hypogonadism (IHH). J Hum Genet. 2004. 49(5):265-8. [QxMD MEDLINE Link].
Young J, Metay C, Bouligand J, Tou B, Francou B, Maione L, et al. SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development. Hum Reprod. 2012 May. 27 (5):1460-5. [QxMD MEDLINE Link].
Tornberg J, Sykiotis GP, Keefe K, Plummer L, Hoang X, Hall JE, et al. Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proc Natl Acad Sci U S A. 2011 Jul 12. 108 (28):11524-9. [QxMD MEDLINE Link].
Miraoui H, Dwyer AA, Sykiotis GP, et al. Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet. 2013 May 2. 92 (5):725-43. [QxMD MEDLINE Link].
Kim HG, Ahn JW, Kurth I, Ullmann R, Kim HT, Kulharya A, et al. WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet. 2010 Oct 8. 87 (4):465-79. [QxMD MEDLINE Link].
Salian-Mehta S, Xu M, Knox AJ, Plummer L, Slavov D, Taylor M, et al. Functional consequences of AXL sequence variants in hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2014 Apr. 99 (4):1452-60. [QxMD MEDLINE Link].
Pingault V, Bodereau V, Baral V, Marcos S, Watanabe Y, Chaoui A, et al. Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness. Am J Hum Genet. 2013 May 2. 92 (5):707-24. [QxMD MEDLINE Link].
Turan I, Hutchins BI, Hacihamdioglu B, Kotan LD, Gurbuz F, Ulubay A, et al. CCDC141 Mutations in Idiopathic Hypogonadotropic Hypogonadism. J Clin Endocrinol Metab. 2017 Jun 1. 102 (6):1816-1825. [QxMD MEDLINE Link].
Seminara SB, Hayes FJ, Crowley WF Jr. Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann''''s syndrome): pathophysiological and genetic considerations. Endocr Rev. 1998 Oct. 19(5):521-39. [QxMD MEDLINE Link]. [Full Text].
Trarbach EB, Silveira LG, Latronico AC. Genetic insights into human isolated gonadotropin deficiency. Pituitary. 2007. 10(4):381-91. [QxMD MEDLINE Link].
Seminara SB, Achermann JC, Genel M, et al. X-linked adrenal hypoplasia congenita: a mutation in DAX1 expands the phenotypic spectrum in males and females. J Clin Endocrinol Metab. 1999 Dec. 84(12):4501-9. [QxMD MEDLINE Link].
Beranova M, Oliveira LM, Bedecarrats GY, et al. Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2001 Apr. 86(4):1580-8. [QxMD MEDLINE Link].
Patil VA, Lila AR, Shah N, et al. Genetic spectrum of Kallmann syndrome: Single-center experience and systematic review. Clin Endocrinol (Oxf). 2022 Dec. 97 (6):804-13. [QxMD MEDLINE Link].
Caronia LM, Martin C, Welt CK, Sykiotis GP, Quinton R, Thambundit A, et al. A genetic basis for functional hypothalamic amenorrhea. N Engl J Med. 2011 Jan 20. 364(3):215-25. [QxMD MEDLINE Link]. [Full Text].
Fromantin M, Gineste J, Didier A, et al. [Impuberism and hypogonadism at induction into military service. Statistical study]. Probl Actuels Endocrinol Nutr. 1973 May 3. 16:179-99. [QxMD MEDLINE Link].
Filippi G. Klinefelter's syndrome in Sardinia. Clinical report of 265 hypogonadic males detected at the time of military check-up. Clin Genet. 1986 Oct. 30(4):276-84. [QxMD MEDLINE Link].
Sonne J, Lopez-Ojeda W. Kallmann Syndrome. StatPearls. 2023 Jan. [QxMD MEDLINE Link]. [Full Text].
Raivio T, Falardeau J, Dwyer A, et al. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med. 2007 Aug 30. 357(9):863-73. [QxMD MEDLINE Link]. [Full Text].
Fraietta R, Zylberstejn DS, Esteves SC. Hypogonadotropic hypogonadism revisited. Clinics (Sao Paulo). 2013. 68 Suppl 1:81-8. [QxMD MEDLINE Link]. [Full Text].
Nishio H, Mizuno K, Moritoki Y, Kamisawa H, Kojima Y, Mizuno H, et al. Clinical features and testicular morphology in patients with Kallmann syndrome. Urology. 2012 Mar. 79(3):684-6. [QxMD MEDLINE Link].
Swee DS, Quinton R, Maggi R. Recent advances in understanding and managing Kallmann syndrome. Fac Rev. 2021. 10:37. [QxMD MEDLINE Link]. [Full Text].
Quinton R, Duke VM, de Zoysa PA, et al. The neuroradiology of Kallmann's syndrome: a genotypic and phenotypic analysis. J Clin Endocrinol Metab. 1996 Aug. 81(8):3010-7. [QxMD MEDLINE Link]. [Full Text].
Raivio T, Wikstrom AM, Dunkel L. Treatment of gonadotropin-deficient boys with recombinant human FSH: long-term observation and outcome. Eur J Endocrinol. 2007 Jan. 156(1):105-11. [QxMD MEDLINE Link].

Media Gallery

MRI of the brain in patients with Kallmann syndrome (KS) and idiopathic hypogonadotropic hypogonadism (IHH). Panel A is a coronal T1-weighted image of a male with KS showing (abnormal) medially oriented olfactory sulci (black arrows) and normal appearing olfactory bulbs (white arrows). Panel B is an axial T1-weighted image of the same male with KS showing the presence of olfactory sulci (white arrows). Panel C is a coronal T1-weighted image of a female with IHH showing normal olfactory bulbs (large arrows) and sulci (small arrows). Panel D is a coronal T1-weighted image of a female with KS showing lack of olfactory bulbs with shallow olfactory sulci (arrows). (Images reproduced from Quinton R, et al: The neuroradiology of Kallmann's syndrome: a genotypic and phenotypic analysis. J Clin Endocrinol Metab 1996; 81: 3010-3017, with permission from the Endocrine Society).
This is a frequently sampled serum luteinizing hormone (LH) profile in a male patient with Kallmann syndrome (KS) in comparison with a healthy individual. It shows lack of LH pulsatility in the former.