Kallmann syndrome

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Kallmann syndrome
Video explanation
Specialty endocrinology

Kallmann syndrome is a rare genetic disorder that affects the natural production of hormones that initiate and complete puberty. It also impairs the function and proper development of the olfactory bulb in a variety of ways, resulting in a defective sense of smell (anosmia). The anosmia may be partial or total. Some forms of Kallmann syndrome may also be associated with additional symptoms involving the ears, eyes, hands, kidneys, teeth or face (cleft palate). If left untreated, people with Kallmann syndrome will almost invariably be infertile.

Kallmann syndrome is a form of hypogonadotropic hypogonadism (HH). Apart from the sense of smell there is no difference in the diagnosis or treatment between a case of HH or a case of Kallmann syndrome.[1][2] Kallmann syndrome is predicated on the impairment of the hypothalamus to release the hormone GnRH. In normal circumstances a cascade of hormonal activity in the HPG axis initiates and completes puberty and maintains proper levels of testosterone, oestrogen and progesterone throughout life. Without the hormones LH and FSH, which are normally produced by the pituitary gland under the influence of GnRH, the ovaries and testes remain dormant with isolated exceptions.[3]

It is three to five times more common in males than females. Hypogonadotropic hypogonadism is estimated to affect between 1 in 4,000 and 1 in 10,000 males, of which about a half are Kallmann syndrome cases. It is unclear whether this is a true gender imbalance or whether it is due to under-diagnosis in females.[4][5] A 2011 estimate in the Finnish population was 1 in 48,000 people overall, with 1 in 30,000 for males and 1 in 125,000 for females.[6] Kallmann syndrome was described in a paper published in 1944 by Franz Josef Kallmann, a German-American geneticist.[7][8] The link between anosmia and hypogonadism had already been noted however, in particular by the Spanish doctor Aureliano Maestre de San Juan in 1856.[9]

Signs and symptoms[edit]

The features of Kallmann syndrome (KS) and congenital hypogonadotropic hypogonadism (CHH) can be split into two different categories; "reproductive" and "non reproductive". Not all symptoms will appear in every case of KS/CHH, not even amongst family members. Some of these features are linked to the gene defects known to cause KS/CHH, but in some cases it is still not clear why some of these features exist. It has been estimated that 60% of KS/CHH cases will show a non-reproductive symptom.

It is normally difficult to distinguish a case of KS/CHH from a straightforward constitutional delay of puberty. However, if puberty has not started by either age 14 (girls) or 15 (boys) and one of these non-reproductive features is present then a referral to reproductive endocrinologist might be advisable.[10]

Each KS/CHH case can show a different range of symptoms and a different severity of symptoms. Severity can range from total absence of puberty with anosmia to slightly delayed puberty with or without anosmia. Even family members will not always show the same degree of symptoms. In the same family with the same KS gene defect, some members may have complete KS with no sense of smell, others may have CHH with some sense of smell, and still others may have isolated anosmia and no hormone deficiencies.[11] Cases of KS/CHH can be separated into different categories depending on the gene mutation(s) involved.[12]

Non-reproductive features[edit]

Non reproductive features include:[1][13][14][2]

  • Total lack of sense of smell (anosmia) or markedly reduced sense of smell (hyposmia). This is the defining feature of Kallmann syndrome; it is not seen in other cases of HH. Approximately 50% of HH cases occur with anosmia and can be termed as Kallmann syndrome.
  • Cleft palate, hare lip or other midline cranio-facial defects.
  • Neural hearing impairment
  • Absence of one of the kidneys (unilateral renal agenesis)
  • Skeletal defects including split hand/foot (ectrodactyly) or shortened middle finger (metacarpal)
  • Controlateral synkinesis (mirror movements of hands)
  • Missing teeth hypodontia
  • Poor balance or coordination due to cerebral ataxia
  • Eye movement abnormalities

A fraction of cases may present with post-pubertal onset, which results in a phenotypically normal penis in men with subsequent testicular atrophy and loss of some secondary sex traits. These men generally present with sexual impairment and low libido. In women, late-onset HH can result in secondary amenorrhoea. Anosmia may or may not be present in these individuals.

Affected individuals with KS and other forms of CHH are almost invariably born with normal sexual differentiation; i.e., they are physically male or female. This is due to the human chorionic gonadotrophin (hCG) produced by placenta at approximately 12 to 20 weeks gestation (pregnancy) which is normally unaffected by having KS or CHH.

People with KS/CHH lack the surge of GnRH, LH, and FSH that occurs between birth and six months of age.[15] This surge is particularly important in infant boys as it helps with testicular descent into the scrotum. A small percentage of boys with KS/CHH will be born with micropenis (fewer than 5 to 10% of cases) and/or cryptorchidism (undescended testes; 30% of cases), which may be treated surgically in the first year of life. The surge of GnRH/LH/FSH in non KS/CHH children gives detectable levels of testosterone in boys and oestrogen & progesterone in girls. The lack of this surge can sometimes be used as a diagnostic tool if KS/CHH is suspected in a newborn boy, but is not distinct enough for diagnosis in girls.

Osteoporosis[edit]

One possible side effect of having KS/CHH is the increased risk of developing secondary osteoporosis or osteopenia. Oestrogen (females) or testosterone (males) is essential for maintaining bone density.[16] Deficiency in either testosterone or oestrogen can increase the rate of bone resorption while at the same time slowing down the rate of bone formation. Overall this can lead to weakened, fragile bones which have a higher tendency to fracture.

Even a short time with low oestrogen or testosterone, as in cases of delayed diagnosis of KS/CHH can lead to an increased risk of developing osteoporosis but other risk factors are involved so the risk of developing it will vary from person to person.

People with KS/CHH should have a bone density scan at least every five years, even if they are on constant hormone replacement therapy. This interval will be shortened to three years if the patient is already in the at-risk zone (osteopenia) or yearly if the patient has osteoporosis already.

The bone density scan is known as a dual energy X-ray absorptiometry scan (DEXA or DXA scan). It is a very simple straightforward test, taking less than 15 minutes to perform. It involves taking a specialised X-ray picture of the spine and hips and measuring the bone mineral density and comparing the result to the average value for a young healthy adult in the general population.[17]

Adequate calcium levels, and probably more importantly vitamin D levels are essential for healthy bone density. Some patients with KS/CHH will have their levels checked and may be prescribed extra vitamin D tablets or injections to try to prevent the condition getting worse. The role of vitamin D for general overall health is under close scrutiny at the moment with some researchers claiming vitamin D deficiency is prevalent in many populations and can be linked to other disease states.

Some people with severe osteoporosis might be prescribed bisphosphonates to preserve bone mass. Exercise, especially weight bearing and resistance exercise, is known to reduce the risk of osteoporosis.

Genetics[edit]

The structure of GNRH1
(from PDB: 1YY1​)

To date at least twenty five different genes have been implicated in causing Kallmann syndrome or other forms of HH through a disruption in the production or activity of GnRH. These genes involved cover all forms of inheritance and no one gene defect has been shown to be common to all cases which makes genetic testing and inheritance prediction difficult.[18][19]

The number of genes known to cause cases of KS / CHH is still increasing.[11] In addition it is thought that some cases of of KS / CHH are caused by two separate gene defects occurring at the same time.[20] Around 50% of cases have an unknown genetic origin.

Some of the genes known to be involved in cases of KS / CHH are listed in the Online Mendelian Inheritance in Man ((OMIM)) table at the end of this article.

OMIM Name Gene Locus Description
308700 KAL1 KAL1 (ANOS1) Xp22.3 Kallmann syndrome can be inherited as an X-linked recessive trait, in which case there is a defect in the KAL1 (ANOS1) gene, which maps at chromosome Xp22.3.[21][22]

This genetic form may include synkinesis and renal agenesis. ANOS1 encodes an extracellular matrix glycoprotein, anosmin-1, present in various embryonic tissues including the presumptive olfactory bulbs in the rostral forebrain. The protein is required to promote the embryonic migration of olfactory nerve fibres and GnRH neurons from the olfactory epithelium of the nose into the brain.[23][24]

147950 and 612702 KAL2 FGFR1 and FGF8 8p11.23 and 10q24.32 Autosomal dominant mutations of FGFR1, encoding fibroblast growth factor receptor 1, or FGF8, encoding one of its ligands (fibroblast growth factor 8), cause about 10% of KS/CHH cases. These genetic forms may include cleft lip and / or palate, hypodontia, hearing impairment, or ectrodactyly (FGFR1 mutations).[25][26][27]
244200 and 610628 KAL3 PROKR2 and PROK2 20p12.3 and 3p13 Mutations of PROKR2, encoding prokineticin receptor-2, or PROK2, encoding one of its ligands (prokineticin 2), are involved in autosomal recessive forms of KS (where both alleles of the gene are mutated), but most patients carrying mutations in either gene only have one mutated allele, suggesting that they carry at least one additional mutation in another, as yet unidentified in most cases, KS gene (oligogenic forms).[28]
616030 FEZF1 FEZF1 7q31.32 Mutations of FEZF1, encoding a (zinc finger)-domain containing protein, are involved in an autosomal recessive form of KS. The protein is required for the passage of growing olfactory nerve fibres and GnRH releasing neurones into the brain.[29]
612370 CHD7 CHD7 8q12.2 Mutations of CHD7 have first been reported in CHARGE syndrome, a severe developmental disease affecting multiple organs, which often includes KS. CHD7 encodes a transcriptional regulator that binds to enhancer elements in the nucleoplasm.[30][31]
611584 SOX10 SOX10 22q13.1 Mutations of SOX10 have first been reported in Waardenburg syndrome, which may include KS in addition to deafness. SOX10 encodes a transcription factor expressed by olfactory ensheathing cells, glial cells of neural crest origin that are permissive for the elongation and targeting of olfactory nerve fibres.[32]
614897 SEMA3A SEMA3A 7q21.11 Mutations of SEMA3A, encoding semaphorin 3A (ligand of plexin A1 receptor), involved in the guidance of olfactory nerve fibers into the brain, are thought to be involved in oligogenic forms of KS.[33]
614838 NELF NELF 9q34.3 Associated with the migration of the olfactory axons and GnRH neurones during development.
615271 FLRT3 FLRT3 20p12.1 Encodes fibronectin-like domain-containing leucine rich transmembrane protein 3. Protein associated with the function of the KAL2 genes (FGFR1 and FGF8) which allows for the migration of both olfactory axons and GnRH releasing neurones during early embryonic development.[34]
615270 FGF17 FGF17 8p21.3 Encodes fibroblast growth factor 17. Protein associated with the function of the KAL2 genes (FGFR1 and FGF8) which allows for the migration of both olfactory axons and GnRH releasing neurones during early embryonic development.[34]
615267 IL17RD IL17RD 3p14.3 Encodes interleukin receptor 17 D. Protein associated with the function of the KAL2 genes (FGFR1 and FGF8) which allows for the migration of both olfactory axons and GnRH releasing neurones during early embryonic development.[34]
615269 DUSP6 DUSP6 12q21.33 Encodes dual specificity phosphate-6. Protein associated with the function of the KAL2 genes (FGFR1 and FGF8) which allows for the migration of both olfactory axons and GnRH releasing neurones during early embryonic development.[34]
615266 SPRY4 SPRY4 5q31.3 Encodes sprouty, Drosphila, homolog of, 4. Protein associated with the function of the KAL2 genes (FGFR1 and FGF8) which allows for the migration of both olfactory axons and GnRH releasing neurones during early embryonic development.[34]
146110 and 614841 GNRHR and GNRH1 GNRHR and GNRH1 4q13.2 and 8p21.2 Biallelic mutations of GNRHR or GNRH1, encoding the GnRH receptor and the hormone GnRH1, respectively, cause normosmic CHH or partial CHH. Binding of GnRH1 to its receptor allows FSH/LH secretion by the pituitary gland.[35][36]
614837 and 614842 KISS1R and KISS1 KiSS-1 and KiSS-1R 19p13.3 and 1q32.1 Biallelic mutations of KISS1R or KISS1, encoding the kisspeptin receptor 1 and the ligand kisspeptin 1, respectively, cause normosmic CHH. Kisspeptin, produced in the hypothalamus, is essential for pulsatile GnRH secretion, and is thought to be involved in the timing of the onset of puberty.[37][38]
614840 and 614839 TACR3 and TAC3 TACR3 and TAC3 4q24 and 12q13.3 Biallelic mutations of TACR3 or TAC, encoding the receptor of neurokinin B and the ligand neurokinin B, respectively, cause normosmic CHH (usually severe HH with high incidence of micropenis). They are associated with a higher rate of reversible HH than mutations of other CHH genes. Neurokinin B, produced in the hypothalamus, is crucial for GnRH secretion.[39]
164160 LEP LEP 7q31.2 Encodes leptin, the ligand of the receptor LEPR. Involved in pulsatile GnRH secretion.
300200 DAX1/NROB1 DAX1 Xp21.2 Encodes a nuclear receptor with no known ligand. Known to be a transcription inhibitor. Mutations in DAX1 are thought to cause X-linked recessive forms of CHH in both males and occasionally females. Known to cause pubertal delay in females.

Pathophysiology[edit]

Shows the normal hormonal control of puberty from the hypothalamus down to the testes or ovaries and their negative feedback mechanisms. The negative feedback control allows just the right amount of hormone to be released according to the needs of the body at that time.
Shows the effect of the interruption of GnRH hormone release from the hypothalamus on the subsequent inability of the testes and ovaries to function correctly at puberty as seen in cases of KS/HH. In most cases of KS/HH the testes and ovaries are able to function correctly, but fail to do so because they have not had the correct hormonal signals.

This failure in GnRH production can either be due to the absence of the GnRH releasing neurones inside the hypothalamus [23] or the inability of the hypothalamus to release GnRH in the correct pulsatile manner to ensure LH and FSH release from the pituitary.[11] HH can occur as an isolated condition with just the LH and FSH production being affected or it can occur in combined pituitary deficiency conditions such as in CHARGE syndrome.

The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism

The term isolated GnRH deficiency (IGD) has increasingly been used to describe this group of conditions as it highlights the primary cause of these conditions and distinguishes them from other conditions such as Klinefelter syndrome or Turner syndrome which share some similar symptoms but have a totally different etiology.[40] The term hypogonadism describes a low level of circulating sex hormones; testosterone in males and oestrogen and progesterone in females. Hypogonadism can occur through a number of different mechanisms. The use of the term hypogonadotropic relates to the fact that the hypogonadism found in HH is caused by a disruption in the production of the gonadotropin hormones normally released by the anterior pituitary gland known as luteinising hormone (LH) and follicle stimulating hormone (FSH). LH and FSH have a direct action on the ovaries in women and testes in men. The absence of LH and FSH means that initially puberty will not commence at the correct time, and subsequently the ovaries and testes will not perform their normal fertility function with the maturation and release of eggs in women and the production of sperm in men alongside their role in producing the sex hormones.

Kallmann syndrome (KS) and other forms of hypogonadotropic hypogonadism (HH) are classed as pituitary or endocrine disorders. While the end result is a failure of puberty and the development of secondary sexual characteristics, the underlying cause of the disorder is located between the two endocrine glands located within the brain.

The hypothalamus gland and the pituitary gland can be seen as the control stations for all the hormonal activity throughout the body. These glands secrete a number of different hormones with various effects around the body. KS/HH results from the disruption in the communication between the hypothalamus and pituitary in regard to one set of hormones only. All the other actions of the hypothalamus and pituitary glands remain unaffected.

Normally the hypothalamus releases a hormone called gonadotropin releasing hormone (GnRH). GnRH is released by specialised nerve cells or neurones of the hypothalamus into the hypophyseal portal system in a pulsatile manner at set intervals throughout the day, and acts on the anterior pituitary gland, causing it to release two hormones called gonadotropins. These hormones are luteinising hormone (LH) and follicle stimulating hormone (FSH), which have a direct action on the testes in men and ovaries in women. LH and FSH are essential for stimulating the development of secondary sexual characteristics seen at puberty and for maintaining the normal sexual function of both men and women, including maintaining the correct levels of the sex steroids: testosterone in men and oestrogen and progesterone in women. In KS/CHH the release of GnRH is either absent or markedly reduced.

In the first 10 weeks of normal embryonic development the GnRH releasing neurones migrate from their original source in the nasal region and end up inside the hypothalamus. These neurones originate in an area of the developing head, called the olfactory placode, that will give rise to the nose; they then pass through the cribriform plate, along with the fibres of the olfactory nerves, and into the rostral forebrain. From there they migrate to what will become the hypothalamus. Any problems with the development of the olfactory nerve fibres will prevent the progression of the GnRH releasing neurones towards the brain.[41] If the GnRH releasing neurones are prevented from reaching the hypothalamus no GnRH will be released, so in turn no FSH or LH will be released which results in the failure of puberty and deficient production of testosterone in men, and oestrogen and progesterone in women. In KS the olfactory nerve fibres are interrupted in the frontonasal region, and the olfactory bulbs are missing or not fully developed, which gives rise to the additional symptom of lack of sense of smell (anosmia) or strongly reduced sense of smell (hyposmia). In other forms of CHH the olfactory nerves and olfactory bulbs develop correctly, so there is a normal sense of smell and the migration of the GnRH releasing neurones is not affected, but some hypothalamic defect prevents GnRH from being released, or alternatively, the hormone is released but cannot stimulate the cells of the pituitary gland because the hormone receptor is absent or not functional. The genes that have been implicated in KS or CHH play a part in the generation, migration, or activity of these GnRH releasing neurones, or in the ability of GnRH to stimulate FSH and LH production.

Diagnosis[edit]

The diagnosis is often one of exclusion found during the workup of delayed puberty.[4][42][43]

A paper published in 2012 by Prof. Jacques Young[44] highlights a typical example of the diagnostic work up involved in a suspected case of KS/CHH.

One of the biggest problems in the diagnosis of KS and other forms of CHH is the ability to distinguish between a normal constitutional delay of puberty and KS or CHH.[45]

The main biochemical parameters in men are low serum testosterone and low levels of the gonadotropins LH and FSH, and in women low serum oestrogen and low levels of LH and FSH.

For both males and females with constitutional delay of puberty, endogenous puberty will eventually commence without treatment. However a delay in treatment in a case of KS/HH will delay the physical development of the patient and can cause severe psychological damage. The "wait and see" approach applied to "late bloomers" is probably counterproductive to the needs of the patient whereas a step-by-step approach with hormone replacement therapy used with slowly increasing doses can be used as a diagnostic tool.

Post natal diagnosis of KS / CHH before the age of 6 months is sometimes possible. The normal post natal hormonal surge of gonadotropins along with testosterone or oestrogen is absent in babies with KS / CHH. This lack of detectable hormones in the blood can be used as a diagnostic indicator, especially in male infants.[46]

Normally testicular enlargement is the key sign for the onset of puberty in boys however the use of nighttime LH sampling can help predict the onset of puberty.

In females diagnosis is sometimes further delayed as other causes of amenorrhoea normally have to be investigated first before a case of KS/CHH is considered.[47] KS/CHH can still occur in females in cases when menstruation has begun but stopped after one or two menstrual bleeds. A study of GnRH deficient women in 2011[48] showed that 10% had experienced one or two bleeds before the onset of amenorrhoea.

In males, treatment with age-appropriate levels of testosterone can be used to distinguish between a case of KS/CHH from a case of delayed puberty. If just delayed the testosterone can "kick-start" endogenous puberty, as demonstrated by testicular enlargement, whereas in the case of KS/CHH there will be no testicular enlargement while on testosterone therapy alone. If no puberty is apparent, especially no testicular development, then a review by a reproductive endocrinologist may be appropriate. Dr Richard Quinton, a leading UK expert on KS/CHH, suggests that if puberty is not apparent by the age of 16 then the patient should be referred for endocrinological review.[49]

A full endocrine workup will be required to measure the levels of the other pituitary hormones, especially prolactin, to check that the pituitary gland is working correctly. There can be other general health issues such as being overweight or having an underlying chronic or acute illness which could cause a delay of puberty. This makes it essential for a patient to get a full endocrine review to distinguish between a case of KS/CHH and another cause for the pubertal delay.

Bone age can be assessed using hand and wrist X-rays. If the bone age is significantly lower than the chronological age of the patient, this could suggest delayed puberty unless there is another underlying reason for the discrepancy.

A karyotype may be performed to rule out Klinefelter syndrome and Turner syndrome, although the hormones levels would also rule out both these relatively common reasons for hypogonadism.

A magnetic resonance imaging (MRI) scan can be used to determine whether the olfactory bulb is present and to check for any physical irregularities of the pituitary gland or hypothalamus.

A standard smell test can be used to check for anosmia, but it must be remembered that even in total anosmia various substances (such as menthol and alcohol) can still be detected by direct stimulation of the trigeminal nerve.

Genetic screening can be carried out, but in light of the unknown genes involved in the majority of KS and CHH cases, a negative result will not rule out a possible diagnosis.

A review paper published in 2014[2] highlighted the need for doctors to be aware of the possible diagnosis of KS / HH if pubertal delay is found alongside associated "red flag" symptoms. The symptoms listed in the paper were split into two categories; reproductive symptoms associated with the lack of mini puberty seen between birth and six months of age and non-reproductive symptoms which are associated with specific forms of HH. As with other review papers the authors also warned against the "wait and see" approach when puberty appears to be delayed.

Treatment[edit]

Treatment for KS and other forms of HH can be divided into hormone replacement therapy and fertility treatments.[15][42][43][50]

Hormone replacement therapy[edit]

The aim for hormone replacement therapy (HRT) for both men and women is to ensure that the level of circulating hormones (testosterone for men and oestrogen/progesterone for women) is at the normal physiological level for the age of the patient. At first the treatment will produce most of the physical and psychological changes seen at puberty, with the major exception that there will be no testicular development in men and no ovulation in women.

After the optimum physical development has been reached HRT for men will continue to ensure that the normal androgen function is maintained; such as libido, muscle development, energy levels, hair growth, and sexual function. In women, a variety of types of HRT will either give a menstruation cycle or not as preferred by the patient. HRT is very important in both men and women to maintain bone density and to reduce the risk of early onset osteoporosis.

The fertility treatments used for both men and women would still include hormone replacement in their action.

There are a range of different preparations available for HRT for both men and women; a lot of these, especially those for women are the same used for standard HRT protocols used when hormone levels fall in later life or after the menopause.

For males with KS / CHH the types of delivery method available include daily patches, daily gel use, daily capsules, sub cutaneous or intramuscular injections or six monthly implants. Different formulations of testosterone are used to ensure both the anabolic and androgenic effects of testosterone are achieved.[1][2]

Testosterone undecanoate is commonly used worldwide, though less so in the US, for treating male KS / CHH patients and has proved to be effective in maintaining good testosterone levels with an increased injection period of up to 12 weeks.

The precise treatment method used and interval between injections will vary from patient to patient and may need to be adjusted to maintain a physiological normal level of testosterone over a longer period of time to prevent the mood swings or adverse effects that can occur if testosterone levels are too high or low. Some treatments may work better with some patients than others so it might be a case of personal choice as which one to use.

As an alternative human chorionic gonadotrophin (hCG) can also be used to stimulate natural testosterone production. It acts in the same way as LH; stimulating the Leydig cells in the testes to produce testosterone. hCG can be used as pre-cursor to male fertility treatments but it can be used in isolation just for testosterone production.

There are no specialist HRT treatments available just for women with KS/HH but there are multitude of different HRT products on the market including oral contraceptives and standard post-menopause products. Pills are popular but patches are also available. It may take some trial and error to find the appropriate HRT for the patient depending on how her body reacts to the particular HRT. Specialist medical advice will be required to ensure the correct levels of oestrogen and progesterone are maintained each month, depending on whether the patient requires continuous HRT (no-bleed) or a withdrawal option to create a "menstrual" type bleed. This withdrawal bleed can be monthly or over longer time periods depending on the type of medication used.

Fertility treatments[edit]

Fertility treatments for people with KS/HH will require specialist advice from doctors experienced in reproductive endocrinology. There is a good success rate for achieving fertility for patients with KS/HH, with some experts quoting up to a 70% success rate, if IVF techniques are used as well. However, there are factors that can have a negative effect on fertility and specialist advice will be required to determine if these treatments are likely to be successful.

Fertility treatments involve the administration of the gonadotropins LH and FSH in order to stimulate the production and release of eggs and sperm. Women with KS or HH have an advantage over the men as their ovaries normally contain a normal number of eggs and it sometimes only takes a few months of treatment to achieve fertility while it can take males up to two years of treatment to achieve fertility.

A new potential new form of fertility treatment underwent clinical trials in 2013 and 2014 by Merck Sharp & Dohme. The trial evaluated a longer acting form of FSH, in the form of corifollitropin alfa. Injections were taken fortnightly instead of the normal twice weekly it is hoped that this would induce sperm production within months rather than the two years it can take with currently available medications.[51]

Human chorionic gonadotrophin (hCG) is sometimes used to stimulate testosterone production in men and ovulation induction in women. For men it acts in the same way as LH; stimulating the Leydig cells in the testes to produce testosterone. Common trade names for hCG products include Pregnyl, Follutein, Profasi, or Choragon. Some men with KS or HH take hCG solely for testosterone production.

Human menopausal gonadotrophin (hMG) is used to stimulate sperm production in men and for multiple egg production and ovulation induction in women. It contains a mixture of both LH and FSH. In men the FSH acts on the sperm producing Sertoli cells in the testes. This can lead to testicular enlargement but can take anything from 6 months to 2 years for an adequate level of sperm production to be achieved. Common trade names for hMG products include Menopur, Menogon, Repronex, or Pergonal.

Purified forms of FSH are also available and are sometimes used with hCG instead of using hMG.

Females with KS / HH would normally require both hCG and FSH in order to achieve fertility. Other cases of female infertility can be treated with just FSH but females (and most males) with KS / CHH would require the use of both forms of gonadotropin injection.

Injections can be intramuscular but are normally taken just underneath the skin (subcutaneous) and are normally taken two or three times a week.

For both men and women, an alternative method (but not widely available), is the use of an infusion pump to provide GnRH (or LHRH) in pulsatile doses throughout the day. This stimulates the pituitary gland to release natural LH and FSH in order to activate testes or ovaries. The use of Kisspeptin delivered in the same pulsatile manner is also under evaluation as a possible treatment for fertility induction.

Prognosis[edit]

Reversal of symptoms have been reported in between 15% to 22% of cases.[3] The causes of this reversal are still under investigation but have been reported in both males and females.

Reversal appears to be associated with 14 of the known gene defects linked to KS/CHH. The study suggests no obvious gene defect showing a tendency to allow reversal. There is a suggestion that the TAC3 and TACR3 mutations might allow for a slightly higher chance of reversal, but the numbers involved are too low to confirm this. The ANOS1 mutations appear to be least likely to allow reversal with to date only one recorded instance in medical literature. Even male patients who previous had micro-phallus or cryptorchidism have been shown to undergo reversal of symptoms.

The reversal might not be permanent and remission can occur at any stage; the paper suggests that this could be linked to stress levels. The paper highlighted a reversal case that went into remission but subsequently achieved reversal again, strongly suggesting an environmental link.

Reversal cases have been seen in cases of both KS and normosmic CHH but appear to be less common in cases of KS (where the sense of smell is also affected). A paper published in 2016[52] agreed with the theory that there is a strong environmental or epigenetic link to the reversal cases. The precise mechanism of reversal is unclear and is an area of active research.

Reversal would be apparent if testicular development was seen in men while on testosterone therapy alone or in women who menstruate or achieved pregnancy while on no treatment. To date there have been no recorded cases of the reversal of anosmia found in Kallmann syndrome cases.

Epidemiology[edit]

The epidemiology of Kallmann's is not well understood. Individual studies include a 1986 report reviewing medical records in the Sardinian army found a prevalence of 1 in 86,000 men[53] and a 2011 report from Finland found a prevalence of 1:30,000 for males and 1:125,000 for females.[54]

There is 4 to 5:1 ratio of men to women among all people with Kallmann syndrome; in familial Kallmann the ratio is lower, at 2.5 to 1.[53][54]

Society and culture[edit]

Terminology[edit]

The terminology used when describing cases of HH can vary, other terms used to describe the condition include:

Patient perspective[edit]

Another aspect of Kallmann syndrome is social isolation. Since it is such a rare condition, many people with Kallmann syndrome have never met or talked with someone else with the condition. Doing so can help a person come to terms with having the condition.[56]

Research[edit]

Kisspeptin is a protein that regulates the release of GnRH from the hypothalamus, which in turn regulates the release of LH and to a lesser extent, FSH from the anterior pituitary gland. Kisspeptin and its associated receptor KISS1R are known to be involved in the regulation of puberty. Studies have shown there is potential for kisspeptin to be used in the diagnosis and treatment of conditions such as Kallmann syndrome and CHH in certain cases.[57][58]

References[edit]

  1. ^ a b c Boehm U, Bouloux PM, Dattani MT, et al. (2015). "Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and treatment". Nat Rev Endocrinol. 11 (Jul 21): 547–64. doi:10.1038/nrendo.2015.112. PMID 26194704. 
  2. ^ a b c d Dunkel L, Quinton R (2014). "Transition in endocrinology: induction of puberty". Eur J Endocrinol. 170 (6): R229–39. doi:10.1530/EJE-13-0894. PMID 24836550. 
  3. ^ a b Sidhoum VF, Chan YM, Lippincott MF, et al. (2013). "Reversal and Relapse of Hypogonadotropic Hypogonadism: Resilience and Fragility of the Reproductive Neuroendocrine System". J. Clin. Endocrinol. Metab. 99: 861–70. doi:10.1210/jc.2013-2809. PMC 3942233Freely accessible. PMID 24423288. 
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