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Kallmann syndrome

Kallmann syndrome is an example of hypogonadism (decreased functioning of the sex hormone-producing glands) caused by a deficiency of gonadotropin-releasing hormone (GnRH), which is created by the hypothalamus. Kallmann syndrome is also known as hypothalamic hypogonadism, familial hypogonadism with anosmia, or gonadotropic hypogonadism, reflecting its disease mechanism. more...

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Kallman syndrome was described in 1944 by Franz Josef Kallmann, a German geneticist. However, others had noticed a correlation between anosmia and hypogonadism before this such as the Spanish doctor Aureliano Maestre de San Juan 80 years previously.


Kallmann syndrome is characterized by:

  • Hypogonadotropic hypogonadism (a lack of the pituitary hormones LH and FSH)
  • Congenital (present from birth) anosmia (complete inability to smell) or hyposmia (decreased ability to smell).

It can also be associated with optic problems, such as color blindness or optic atrophy, nerve deafness, cleft palate, cryptorchidism, renal agenesis, and mirror movement disorder. However, it is not clear at this time how or if these other problems have the same cause as the hypogonadism and anosmia and these other problems are more often present in those without Kallmann syndrome.

Males present with delayed puberty and may have micropenis (although congenital micropenis is not present in the majority of male KS cases).

Females present with delayed puberty i.e.primary amenorrhea and lack of secondary sex characteristicd, such as breast development.


The diagnosis is often one of exclusion found during the workup of delayed puberty. The presence of anosmia together with micropenis in boys should suggest Kallmann syndrome (although micropenis alone may have other causes).


Under normal conditions, GnRH travels to the pituitary gland via the tuberoinfundibular pathway, where it triggers production of gonadotropins (LH and FSH). When GnRH is low, the pituitary does not create the normal amount of gonadotropins. The gonadotropins in turn affect the production of hormones in the gonads, so when they are low, the hormones will be low as well.

In Kallmann syndrome, the GnRH neurons do not migrate properly from the olfactory placode to the hypothalamus during development. The olfactory bulbs also fail to form or have hypoplasia, leading to anosmia or hyposmia.

Kallman syndrome can be inherited as an X-linked recessive trait, in which case there is a defect in the KAL gene, which maps to chromosome Xp22.3. KAL encodes a neural cell adhesion molecule, anosmin-1. Anosmin-1 is normally expressed in the brain, facial mesenchyme, mesonephros and metanephros. It is required to promote migration of GnRH neurons from the hypothalamus to the pituitary gland. It also allows migration of olfactory neurons from the olfactory bulbs to the hypothalamus.


Treatment is directed at restoring the deficient hormones -- known as hormone replacement therapy (HRT). Males are administered human chorionic gonadotropin (hCG) or testosterone. Females are treated with oestrogen and progestins.


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From Gale Encyclopedia of Medicine, 4/6/01 by J. Ricker Polsdorfer


Hypogonadism is the condition more prevalent in males in which the production of sex hormones and germ cells are inadequate.


Gonads are the organs of sexual differentiation--in the female, they are ovaries; in the male, the testes. Along with producing eggs and sperm, they produce sex hormones that generate all the differences between men and women. If they produce too little sex hormone, then either the growth of the sexual organs or their function is impaired.

The gonads are not independent in their function, however. They are closely controlled by the pituitary gland. The pituitary hormones are the same for males and females, but the gonadal hormones are different. Men produce mostly androgens, and women produce mostly estrogens. These two hormones regulate the development of the embryo, determining whether it is a male or a female. They also direct the adolescent maturation of sex organs into their adult form. Further, they sustain those organs and their function throughout the reproductive years. The effects of estrogen reach beyond that to sustain bone strength and protect the cardiovascular system from degenerative disease.

Hormones can be inadequate during or after each stage of development--embryonic and adolescent. During each stage, inadequate hormone stimulation will prevent normal development. After each stage, a decrease in hormone stimulation will result in failed function and perhaps some shrinkage. The organs affected principally by sex hormones are the male and female genitals, both internal and external, and the female breasts. Body hair, fat deposition, bone and muscle growth, and some brain functions are also influenced.

Causes & symptoms

Sex is determined at the moment of conception by sex chromosomes. Females have two X chromosomes, while males have one X and one Y chromosome. If the male sperm with the Y chromosome fertilizes an egg, the baby will be male. This is true throughout the animal kingdom. Genetic defects sometimes result in changes in the chromosomes. If sex chromosomes are involved, there is a change in the development of sexual characteristics.

Female is the default sex of the embryo, so most of the sex organ deficits at birth occur in boys. Some, but not all, are due to inadequate androgen stimulation. The penis may be small, the testicles undescended (cryptorchidism) or various degrees of "feminization" of the genitals may be present.

After birth, sexual development does not occur until puberty. Hypogonadism most often shows up as an abnormality in boys during puberty. Again, not every defect is due to inadequate hormones. Some are due to too much of the wrong ones. Kallmann's syndrome is a birth defect in the brain that prevents release of hormones and appears as failure of male puberty. Some boys have adequate amounts of androgen in their system but fail to respond to them, a condition known as androgen resistance.

Female problems in puberty are not caused by too little estrogen. Even female reproductive problems are rarely related to a simple lack of hormones, but rather to complex cycling rhythms gone wrong. All the problems with too little hormone happen during menopause, which is a normal hypogonadism.

A number of adverse events can damage the gonads and result in decreased hormone levels. The childhood disease mumps, if acquired after puberty, can infect and destroy the testicles--a disease called viral orchitis. Ionizing radiation and chemotherapy, trauma, several drugs (spironolactone, a diuretic and ketoconazole, an antifungal agent), alcohol, marijuana, heroin, methadone, and environmental toxins can all damage testicles and decrease their hormone production. Severe diseases in the liver or kidneys, certain infections, sickle cell anemia, and some cancers also affect gonads. To treat some male cancers, it is necessary to remove the testicles, thereby preventing the androgens from stimulating cancer growth. This procedure, still called castration or orchiectomy, removes androgen stimulation from the whole body.

For several reasons the pituitary can fail. It happens rarely after pregnancy. It used to be removed to treat advanced breast or prostate cancer. Sometimes the pituitary develops a tumor that destroys it. Failure of the pituitary is called hypopituitarism and, of course, leaves the gonads with no stimulation to produce hormones.

Besides the tissue changes generated by hormone stimulation, the only other symptoms relate to sexual desire and function. Libido is enhanced by testosterone, and male sexual performance requires androgens. The role of female hormones in female sexual activity is less clear, although hormones strengthen tissues and promote healthy secretions, facilitating sexual activity.


Presently, there are accurate blood tests for most of the hormones in the body, including those from the pituitary and even some from the hypothalamus. Chromosomes can be analyzed, and gonads can, but rarely are, biopsied.


Replacement of missing body chemicals is much easier than suppressing excesses. Estrogen replacement is recommended for nearly all women after menopause for its many beneficial effects. Estrogen can be taken by mouth, injection, or skin patch. It is strongly recommended that the other female hormone, progesterone, be taken as well, because it prevents overgrowth of uterine lining and uterine cancer. Testosterone replacement is available for males who are deficient.

Key Terms

Surgical removal of pieces of tissue for examination.
Refers to life before birth, specifically the first two months after conception.
The unborn person or animal, still in the womb.
Part of the brain just above the pituitary that stimulates pituitary gland function.
Ionizing radiation
X rays. Diagnostic x rays are too weak to do damage under normal circumstances, but x rays used to treat cancer must be used with great care.

Undescended testicle
A testicle that is still in the groin and has not made its way into the scrotum.

Further Reading

For Your Information


  • Carr, Bruce R. and Karen D. Bradshaw. "Disorders of the ovary and female reproductive tract." In Harrison's Principles of Internal Medicine. Edited by Kurt Isselbacher, et al. New York: McGraw-Hill, 1998, pp. 2097-2115.
  • Griffen, James E. and Jean D. Wilson. "Disorders of the testes." In Harrison's Principles of Internal Medicine. Edited by Kurt Isselbacher, et al. New York: McGraw-Hill, 1998, pp. 2092-2024.
  • Matsaumoto, Alvin M. "The Testes." In Cecil Textbook of Medicine. Edited by J. Claude Bennett and Fred Plum. Philadelphia: W. B. Saunders, 1996, pp. 1329-1341.
  • Nelson, Waldo E., et al., ed. "Hypofunction of the ovaries." In Nelson Textbook of Pediatrics. Philadelphia: W. B. Saunders, 1996, pp. 1635-1639.
  • Nelson, Waldo E., et al., ed. "Hypofunction of the testes." In Nelson Textbook of Pediatrics. Philadelphia: W. B. Saunders, 1996, pp. 1629-33.
  • Plymate, Stephen R. "Male hypogonadism." Principles and Practice of Endocrinology and Metabolism. Edited by Kenneth L. Becker, et al. Philadelphia: J. B. Lippencott Company, 1995, pp. 1056-1082.
  • Schimke, R. Neil. "Genetic diseases of endocrinology and metabolism." In Principles and Practice of Endocrinology and Metabolism. Edited by Kenneth L. Becker, et al. Philadelphia: J. B. Lippencott Company, 1995, pp. 1551-1553.


  • Rosenberg, M.J., T.D. King, and M.C. Timmons. "Estrogen-androgen for hormone replacement." Journal of Reproductive Medicine 42 (July 1997): 394-404.

Gale Encyclopedia of Medicine. Gale Research, 1999.

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