Physiological and Pathophysiological Alterations of the Neuroendocrine Components of the Reproductive Axis

KAL 1 (ANOS 1) Mutation

The pathological association between IHH and olfactory dysfunction was originally recognized in the 19th century, but Kallmann and Schoenfeld first suggested a genetic basis for this group of patients in 1944. In 1989, Schwanzel-Fukuda and colleagues discovered a tangle of GnRH neurons on the surface of the cribriform plate in a human fetus with X-linked KS. The finding of the neurons in this location rather than in the typical location in the hypothalamus established defective GnRH neuronal migration as the cause of hypogonadotropic hypogonadism in KS. ^, Because the initial differentiation and migration were normal, research then focused on factors affecting axonal growth, path-finding, and maturation. The KAL1 gene on the X chromosome (Xp22.3) was subsequently identified in 1991 by two groups, and both deletions and point mutations have since been found in patients with KS. ^, The product of KAL1, anosmin-1, is transiently expressed in numerous tissues of the developing human fetus, including the OB and along the migratory pathway for GnRH neurons. In the absence of anosmin-1 (with the KAL1 mutation), OB differentiation and early olfactory axon navigation are impaired. Without olfactory nerve synaptogenesis in the OB, GnRH neurons have no migratory pathway to follow to the forebrain, resulting in the anosmia and hypogonadotropic hypogonadism typical of KS. KAL1 expression also occurs in the mesonephric tubules, ureteric bud, and corticospinal tract by 7 weeks of age, and in the retina and kidney by 11 weeks of age. This tissue-specific expression accounts for the high prevalence of renal, neurological, and midline facial abnormalities in patients with KS. Unilateral renal agenesis is believed to occur because of developmental failure of the collecting duct system in the absence of mesonephric tubule anosmin-1. Synkinesia (“mirror movements,” or the involuntary movements of one extremity when an individual is asked to perform rapid, repetitive motions with the other extremity) results from abnormal fast-conducting ipsilateral corticospinal tract projections. Absence of anosmin-1 expression in the facial mesenchyme leads to a high incidence of cleft palate in patients with KAL1 mutations. Renal agenesis and synkinesia were present in 31% and 85% of patients, respectively, of a British cohort of patients with KS. These abnormalities were not present in any patients with KS without the KAL1 mutation or in patients with normosmic IHH.

As is the case with all forms of hypogonadotropic hypogonadism, KS is much more common in males, with prevalence estimated at 1:7500 males versus 1:70,000 females. The KAL1 mutation accounts for only 3% to 15% of cases of anosmic IHH ^, and no more than one-third of familial cases of IHH, but it is highly penetrant. No cases of KAL1 mutations have been described in female patients or in normosmic males. Patients with KS usually do not undergo puberty, but a minority may have some degree of testicular growth or breast development, suggesting that GnRH deficiency is not always complete. Additional reproductive features may include cryptorchidism and microphallus. As is the case with other genetic defects discussed later, there is no clear genotype-to-phenotype relationship in those with a KAL1 mutation, illustrating the importance of modifier genes and environmental factors.

KAL 2 Mutation

Mutations in the gene encoding fibroblast growth factor receptor 1 (FGFR1), a tyrosine kinase receptor, also referred to as KAL2, appear to be inherited in an autosomal dominant pattern and are seen in 7% to 10% of individuals with KS. Fibroblast growth factor signaling is involved with the formation, growth, and shaping of a variety of tissues and organs, including the OB. Fibroblast growth factor (FGF) receptor-1 (FGFR1) has been detected in both the nasal placode and the developing OBs of mice as well as along the migratory pathway for GnRH neurons and in the mature hypothalamus. Studies in rodents with targeted abolition of FGFR1 signaling resulted in aplasia of the OB. Both FGFR1 and anosmin-1 are coexpressed in the olfactory placode of human embryos by 4.5 weeks’ gestation, and again at 8 weeks in the terminal nerve portion that guides GnRH neuronal migration to the hypothalamus. Studies suggest that FGFR1 is a ligand for anosmin-1. Loss-of-function mutations in the FGFR1 gene located on chromosome 8p11.2 can cause IHH, with or without anosmia. ^, At least 12 missense mutations have been identified in this gene thus far, and loss of function of the isoform FGFR1c is present in approximately 10% of male and female patients with KS. Isoform FGFR1c is also important for palate morphogenesis as well as olfactory development.

Unlike KAL1 mutations, KAL2 mutations are not always associated with a severe reproductive phenotype. A minority of patients may have delayed puberty or normal reproductive function, suggesting that the KAL2 mutation may not prevent GnRH migration entirely but may affect neuronal maturation in the hypothalamus. This variable expressivity of KAL2 suggests a role for other genes or the environment in modifying the phenotypic expression of this mutation. It also raises the possibility that KAL2 mutations account for other reproductive phenotypes associated with hypothalamic dysfunction, such as hypothalamic amenorrhea and delayed puberty.

Congenital hypogonadotropic hypogonadism (CHH) is less severe in patients with KAL2 mutations than in those with KAL1 mutations, and mean LH levels are significantly lower in KAL1 patients compared to KAL2 patients. Identification of KAL2 mutations and the relationship between FGF signaling and anosmin-1 may explain the male predominance of hypogonadotropic hypogonadism despite the low prevalence of the X-linked form of the disease. Females have two copies of the KAL1 gene and, therefore, higher levels of anosmin-1, which may compensate for inadequate FGFR1 function in the presence of a KAL2 mutation. Thus, women with KAL2 mutations often have a milder, if not a normal, reproductive phenotype. On the other hand, males have a lower level of KAL1 or anosmin-1 expression and are unable to compensate for impaired FGF signaling in the presence of a KAL2 mutation. Thus, their reproductive phenotypes tend to be more severe.

Other Candidate Genes

As is the case for IHH as a whole, most cases of KS are sporadic and cannot be traced to familial transmission. Autosomal recessive transmission of KS does exist, but the responsible gene has yet to be cloned. Multiple other candidate genes that may be involved in cases of anosmic IHH without KAL1 mutations have been identified in the past decade. Mutations of CHD7, which can cause CHARGE syndrome (coloboma, congenital heart disease, choanal atresia, mental and growth retardation, genital hypoplasia, and ear malformations or deafness), have been seen in KS patients. Heterozygous mutations in NELF have been reported in a few patients with KS; the murine form of NELF is involved in olfactory and GnRH neuronal migration. Mutations in Pkr2, which encodes a G-protein-coupled receptor critical for OB and reproductive organ development in mice. have been found, as have mutations in the heparan sulfate 6-O-sulfotransferase 1 (HS6ST1) gene. The enzyme is involved in the modulation of extracellular matrix components, such as heparin sulfate polysaccharides, thought to modulate cell-cell communication, which is required for neural migration. Heterozygous mutations of WD repeat domain 11 (WDR11) have been found in a small number of patients with Kallmann syndrome. The WDR11 gene encodes a protein that interacts with the transcription factor EMX1. The interaction between both factors is important for the development of olfactory neurons. FGF receptor mutations have also been identified in normosmic individuals with IHH, suggesting that anosmic IHH and normosmic IHH are part of a spectrum of disease rather than distinct clinical entities. ^,

GnRH Mutations

There are also patients with IHH manifesting with severe hypogonadism who do have isolated GnRH deficiency. It was not until 2009 that a homozygous frameshift mutation in the GnRH1 gene in such patients was reported. GnRH1 encodes the preprohormone of GnRH. These patients had severe hypogonadism, suggesting that isolated GnRH deficiency can be a rare cause of IHH. ^, Other etiologies for IHH have since been identified in this group of patients, in whom the frequency of cryptorchidism and nonreproductive phenotypes (synkinesia, palate abnormalities, hearing loss) is much less common than in anosmic IHH.

GnRH Receptor Mutations

Attempts to identify congenital defects that would explain normosmic IHH have led to the discovery of loss-of-function missense mutations in the gene encoding the GnRH receptor ( GnRH-R ) on chromosome 4q21.2. These mutations are transmitted in an autosomal recessive pattern. The GnRH receptor is a G-protein-coupled transmembrane receptor involved with signal transduction. Mutations in this protein were initially considered unlikely because patients with normosmic IHH showed increased FSH and LH secretion in response to exogenous GnRH stimulation. However, in the study by de Roux and colleagues, the index cases both had partial IHH and likely responded normally to GnRH stimulation because the exogenous dose was high enough to overcome their partial receptor defects. GnRH-R mutations are estimated to occur in 40% of autosomal recessive cases of normosmic IHH and in 10% to 15% of sporadic cases. ^, Heterozygotes are unaffected.

Identical mutations can produce different clinical phenotypes, suggesting that gonadotroph function depends on other genes as well. The clinical presentation of patients with GnRH-R mutations can include microphallus, cryptorchidism, gynecomastia, delayed puberty in males, and primary amenorrhea, incomplete thelarche, and delayed puberty in females. Phenotypes can also be milder, as in men with normal adult-sized testes as well as intact spermatogenesis but impaired LH-dependent Leydig cell testosterone secretion (“fertile eunuch syndrome”). It is now believed that GnRH secretion in these cases is sufficient to trigger enough Leydig cell testosterone production locally to maintain spermatogenesis and testicular growth but insufficient to generate systemic testosterone levels capable of achieving full virilization.

Screening for GnRH-R mutations at the time of diagnosis of IHH is not clinically useful unless fertility is an immediate treatment goal. In these cases, knowledge of a GnRH-R mutation would guide one toward gonadotropin therapy and away from pulsatile GnRH therapy, as the latter was less effective in restoring reproductive function. As with other confirmed genetic abnormalities, identification of a GnRH-R mutation would also allow screening and treatment of family members.

GPR54 Mutations

Homozygous deletions in the gene GPR54 on chromosome 19 (19p13) were first reported in 2003 in a large consanguineous family with multiple members affected by IHH but with normal GnRH receptors. GPR54 encodes an orphan G-protein-coupled receptor that is expressed widely across the reproductive axis, including the hypothalamus, pituitary, gonads, and placenta. The ligand for GPR54 is kisspeptin (formerly metastin), which is derived from kisspeptin-1. Kisspeptin was originally discovered because of its ability to inhibit metastatic melanoma and breast cancer cell lines. Continued study of this protein suggests that it may play an important role in regulating central puberty through its ability to signal through GPR54 and stimulate GnRH release. GPR54 mutations account for 2% to 5% of normosmic IHH. Both male and female GPR54- deficient mice had a hypogonadotropic hypogonadal phenotype (males with small testes, females with delayed vaginal opening and delayed follicular maturation), but had normal levels of hypothalamic GnRH and responded to exogenous GnRH. ^{, ,} Similarly, spermatogenesis and successful ovulation have been achieved in GPR54- deficient patients treated with exogenous GnRH. GPR54 does appear to have tissue-specific effects, because the in vitro administration of kisspeptin metastin did not have the same stimulatory effects on pituitary gonadotrophs as it did on the hypothalamus, and homozygous mutations in GPR54 did not affect spermatogenesis or ovarian steroidogenesis. The exact mechanism by which GPR54 regulates puberty remains the subject of ongoing investigation.

TAC3 Mutations

Homozygous mutations in tachykinin 3 (TAC3), which encodes neurokinin B and its heptahelical transmembrane G-protein-coupled receptor TACR3 , have been described in patients with normosmic IHH. Patients with this mutation have very low basal LH secretion with a nonpulsatile pattern, while pulsatile GnRH treatment normalizes LH release.

Gonadotropin Mutations

Both FSH and LH are composed of a common α subunit and a β subunit that is unique to FSH, LH, thyroid-stimulating hormone (TSH), and human chorionic gonadotropin (hCG). Alpha subunit mutations have not been reported and likely are not compatible with life. ^, However, beta subunit mutations in both the LH and FSH molecules have been identified and are associated with delayed puberty.

Pituitary Transcription Factor Mutations

Mutations in various homeobox transcription factors involved with normal adenohypophyseal development have been reported. Homozygous mutations in LHX3 have been described in two consanguineous families who presented with combined pituitary hormone deficiencies, including deficits in LH and FSH. LHX3 encodes a protein that is required for pituitary development and motor neuron specification. Mutations in PROP1 are also associated with variable degrees of FSH and LH insufficiency and other pituitary hormone deficiencies. ^, PROP1 has both DNA-binding and transcriptional activation ability. Its expression leads to the ontogenesis of homozygous and heterozygous mutations of HESX1 and has been implicated in some cases of septooptic dysplasia, a disease that includes optic nerve hypoplasia, pituitary gland hypoplasia, and midline CNS anomalies. Children with septooptic dysplasia can have either precocious puberty or pubertal failure.

A novel mutation in HESX1 has been described, which causes combined pituitary deficiency but no septooptic dysplasia phenotypes.

Hypogonadotropic Hypogonadism and Adrenal Failure

Normosmic hypogonadotropic hypogonadism can occur in association with adrenal failure due to loss-of-function mutations in DAX1 (adrenal hypoplasia congenital). DAX1 encodes an orphan nuclear receptor on chromosome Xp21 and is critical for the development and function of both the adrenal gland and the hypothalamic-pituitary-gonadal axis. In the presence of DAX1 mutations, adrenal failure usually presents in male infants or boys and is followed by impaired pubertal development due to failure of hypothalamic and pituitary gonadotropin production. Males with this mutation are often resistant to gonadotropin stimulation because of impaired spermatogenesis. Steroidogenic factor 1 (SF1), another nuclear receptor that regulates gene transcription in both the adrenal gland and the gonads, caused both adrenal and gonadal agenesis when knocked out in a murine model. Human SF1 mutations were associated with XY sex reversal and adrenal failure. It is now thought that DAX1 represses transcription of nuclear receptors, including SF1, and that loss of DAX1 function causes a variety of adrenal, pituitary, and hypothalamic abnormalities.

Hypogonadotropic Hypogonadism and Obesity Syndromes

Mutations in leptin and the leptin receptor have been identified in morbidly obese patients with normosmic IHH. It is leptin’s effects on the release of NPY that are likely responsible for its effects on GnRH secretion. Mutations in prohormone convertase 1 (PC1) also cause morbid obesity and hypogonadotropic hypogonadism, as well as hypocortisolemia (with elevated proopiomelanocortin) and hypoinsulinemia (with elevated proinsulin).

Adult-Onset Idiopathic Hypogonadotropic Hypogonadism

An acquired form of GnRH deficiency was described in 1997 in 10 men who presented with decreased libido, impotence, and infertility at a mean age of 35 years, after undergoing normal puberty. None had features of congenital GnRH deficiency (anosmia, synkinesia, cleft palate, or a family history of GnRH deficiency), and none had a tumor, a history of radiation, infection, or infiltrative disease that might have explained their abnormal gonadotropin and sex steroid levels. Treatment with pulsatile GnRH reversed the hypogonadism and restored fertility in the subset of men who received long-term therapy. Recent data show that some men with IHH carry a mutation in the FGF8 gene and have normal reproductive function before the onset of hypogonadism, suggesting a combination of genetic and environmental influences.

Diagnosis of Idiopathic Hypogonadotropic Hypogonadism

Hypogonadotropic hypogonadism should be included in the differential diagnosis for any patient with absent or incomplete pubertal development. In males, this can include microphallus, cryptorchidism, absence of facial hair, and small testes; and in women, incomplete or absent breast development, amenorrhea, or eunuchoid body habitus. Obtaining a family history can also be helpful when considering a diagnosis of IHH. Whereas the incidence of delayed puberty in the general population is less than 1%, the incidence of delayed puberty among relatives of a series of 106 patients with IHH was 12%. Because the GnRH pulse generator is quiescent until the onset of puberty (after an initial period of activation during infancy), the diagnosis of hypogonadotropic hypogonadism is usually not made until the age of 18 years, when such physical findings might prompt laboratory evaluation. Characteristic findings include low sex steroid levels (testosterone <100 ng/dL; E ₂ <20 pg/mL) in association with low or inappropriately “normal” gonadotropin levels. Assessment of other pituitary hormones should also be performed when hypogonadotropic hypogonadism is initially discovered. Other biomarkers for the diagnosis of hypogonadotropic hypogonadism also include inhibin, INSL3, AMH, and kisspeptin. To exclude structural causes of GnRH deficiency, magnetic resonance imaging (MRI) is indicated in the evaluation of such patients. When laboratory studies and negative findings on imaging studies offer no other explanation for hypogonadotropic hypogonadism, a diagnosis of IHH or isolated GnRH deficiency is appropriate.

Sarfati et al reported for the first time two cases due to KAL 1 and FGFR1 mutations in which the diagnosis was identified during fetal life on the basis of KS in the parents and noninvasive monitoring (fetal ultrasound).

Tumors

Craniopharyngioma

Craniopharyngiomas are rare, almost always benign, epithelial tumors arising from remnants of the craniopharyngeal duct that occur with an annual incidence of 0.13 cases per 100,000 person-years. ^, They are the most common lesions involving the hypothalamic-pituitary region in children and account for 5.6% to 15% of the intracranial neoplasms in this population (2%–5% in adults). ^, Craniopharyngiomas affect men and women at equal rates, and no genetic susceptibility has been identified. They are histologically benign lesions, usually cystic or mixed (84%–99%) rather than solid (1%–16%). Two subtypes have been identified: adamantinomatous and papillary. The adamantinomatous type is more common in children and often contains calcification. Although tumor margins are usually sharp, adamantinomatous craniopharyngiomas tend to generate significant reactive gliosis in the adjacent normal brain tissue, making complete surgical resection difficult. Cysts may be multiloculated and contain viscous fluid rich in desquamated squamous epithelial cells and cholesterol. Because of the sometimes brown-green appearance of this cystic fluid, the term “motor oil” has been used to describe it. A preliminary study showed that nuclear accumulation of b-catenin is present in adamantinomatous craniopharyngiomas but not in papillary craniopharyngiomas. The strong beta-catenin expression indicates the reactivation of the Wnt signaling pathway, which is involved in the development of several neoplasms. The papillary subtype is seen almost exclusively in adults and is rarely associated with calcification. Papillary craniopharyngiomas tend to be solid or mixed rather than purely cystic, and they are less likely to infiltrate surrounding normal brain tissue, making surgical resection easier. Papillary craniopharyngiomas usually lack the peripheral palisading of epithelial cells, cystic change, calcification, and the cholesterol depots found in the adamantinomatous type.

Recent genetic analysis has shown differences between these 2 subtypes of craniopharyngiomas in 60% to 96% of adamantinomatous craniopharyngiomas show mutations in B-catenin (CTNNB1), which is a downstream effector of the Wnt pathway which is involved in growth and development.

Papillary craniopharyngiomas have been discovered to frequently have a mutation of the BRAF gene, which plays a role in the mitogen-activated kinase pathway.

Craniopharyngiomas almost always have a suprasellar component and are rarely purely intrasellar, as shown by the images in Fig. 21.3 . Because of their proximity to vital neural structures and their significant size at the time of diagnosis (58%–76% are between 2 and 4 cm), they frequently present with headache, nausea, vomiting, visual disturbances, growth failure (in children), and hypogonadism (in adults), although the rate of tumor growth also determines the severity of symptoms. ^, Bitemporal hemianopsia is the most common visual complaint, occurring in almost 50% of cases. Hydrocephalus can be present, occurring more frequently in children than in adults for unclear reasons (41%–54% versus 12%–30%). With the exception of hydrocephalus and its associated symptoms, there was no difference in symptom duration or extent of hormone deficiency between children and adults with craniopharyngiomas.

Both computed tomography (CT) and MRI can be helpful in diagnosing craniopharyngiomas. CT can show calcification that is characteristic of the adamantinomatous subtype, whereas MRI with gadolinium enhancement provides better structural analysis. The appearance of the craniopharyngioma depends on the proportion of solid and cystic components and the content of the cyst. The solid tumor part is iso-or hypointense compared to the brain on precontrast T1 sequences and shows enhancement after contrast. On T2 sequences the signal is mixed, hypo- or hyperintense. The cystic component is hypointense on T1 and hyperintense on T2. If there is protein, cholesterol, or methemoglobin present, then there may be a high T1 and a low T2 signal. The cyst can show a peripheral contrast-enhancing rim in the T1 postcontrast images. When the findings of imaging studies are consistent with craniopharyngioma, surgical resection is usually the initial therapy, although radiation therapy (RT) has been used for small lesions not causing pressure-related visual, neurological, or endocrinological damage. The surgical approach depends on tumor size, location, degree of calcification, and the experience of the surgeon, but it often involves craniotomy and sometimes a two-stage process. Preoperative drainage of large cystic components in the days before surgery can relieve pressure-related symptoms and make surgical resection easier, although cyst cavities refill if surgery is delayed by weeks. Gross total resection is the goal in all cases, but it often cannot be achieved because of tumor size and adherence to vital neurovascular structures.

Unfortunately, craniopharyngiomas often recur even after gross total resection has been achieved and confirmed radiographically. Recurrence rates at 10 years vary from 0% to 62% but improve with use of adjuvant RT. Recurrence-free survival correlates best with the extent of surgical removal; age, sex, location (intrasellar versus suprasellar), and size of the tumor at the time of surgical resection do not predict recurrence. Some reports suggest that recurrent craniopharyngiomas show a higher microvessel density, lower levels of galectin-3 and macrophage migration inhibiting factor, and lower levels of retinoic acid receptor beta and higher levels of retinoic acid receptor gamma. Management of recurrent disease usually involves RT rather than repeated surgery because of the perioperative morbidity and mortality associated with the latter. In fact, surgery for recurrent disease is only recommended in the event of acute pressure-related symptoms. ^, The 10-year progression-free survival rate from the time of the first recurrence was 72% in a series of 25 patients who received RT. Other options for the management of recurrences include brachytherapy (for predominantly cystic lesions), bleomycin installation via an Ommaya reservoir, and stereotactic radiosurgery. ^{, , ,}

Some studies have demonstrated some response after systematic chemotherapy in pediatric patients after treatment with INF-alpha-2b (pegylated and nonpegylated) and offer hope for future therapies with lower side effect profiles.

The endocrine, visual, and neuropsychological morbidities associated with craniopharyngiomas are significant. At the time of presentation, 35% of the patients in Van Effenterre’s cohort had one to three hormone deficits. After treatment, the frequency of individual hormone deficits varies significantly across studies (88%–100% for growth hormone [GH], 80%–95% for FSH and LH, 55%–88% for adrenocorticotropic hormone [ACTH], 39%–95% for TSH, and 25%–86% for antidiuretic hormone [ADH]) and is not affected by the type of therapy. Unlike pituitary adenomas, it is very unusual for patients with pretreatment hormone deficits to experience restoration of those axes after treatment, but pituitary hormones can be replaced relatively easily. Visual defects (i.e., quadrantanopia or worse) are present in the majority of patients after surgery with or without adjuvant RT. Potentially more disabling are the consequences of hypothalamic damage that occur so commonly in patients with craniopharyngiomas. Obesity secondary to hyperphagia affects 26% to 61% of patients who undergo surgery with and without adjuvant RT. ^, Data by Bomer I et al suggest that the development of obesity in craniopharyngioma patients is associated with lower resting energy expenditure compared to obesity patients without craniopharyngioma, suggesting that factors independent of hyperphagia might play a role. Diabetes insipidus (DI), with an impaired sense of thirst resulting in water and electrolyte imbalances, was present in 14% of a pediatric cohort. Neuropsychological and cognitive functions often decline in patients with craniopharyngiomas. At follow-up 7 years after initial treatment, 16% of the adults and 26% of the children in Van Effenterre’s cohort were not living independently and had not returned to their previous jobs or schools. Mortality rates three to six times higher than those of the general population have been reported in patients with craniopharyngiomas.

Rathke Cleft Cyst (RCC).

RCCs are the most common incidentally discovered sellar lesion. They are found in 13% to 33% of normal pituitary glands. They are discovered usually later in life with a peak between the 4th and 6th decades, which is most likely due to their slow rate of growth, and symptoms occur later in life. RCC originates from embryonic remnants of the Rathke pouch, which extends cranially to form the craniopharyngeal duct. The pouch is derived from the ectodermal stomodeum (primitive oral cavity). The Rathke pouch cells proliferate and form the pars anterior of the pituitary and the cells from the posterior wall differentiate into the pars intermedia. The pouch involutes and the craniopharyngeal duct obliterates. If the obliteration of the lumen does not occur, then a cyst develops and the remnants in the craniopharyngeal canal develop into cystic lesions ranging from simple RCCs to complex craniopharyngiomas. RCCs are benign lesions that can range from a few millimeters to 5 cm. The content of the cyst is mostly thick and can consist of cholesterol and proteins. The cyst wall is lined by cuboid or columnar epithelium and occasionally with goblet cells secreting mucous into the cyst. RCCs and craniopharyngiomas have overlapping pathological features and are sometimes difficult to distinguish. The coexistence of RCCs with pituitary adenomas has been shown in 0.5% to 1.7%. Of these adenomas, GH secreting pituitary adenomas and prolactinomas are the most frequently described as coexisting with RCCs. The location of RCCs is usually in the pars intermedia, sometimes with suprasellar extension. Symptoms usually do not occur until the cyst is large enough to put pressure on the surrounding structures. The most common symptom includes headaches. The presence of headaches does not correlate with the cyst size but seems to be related to either high or isointense content on T1-weighed MRI, mucous cyst content, or cystic wall inflammation. Major visual field defects are present in up to 75% of cases and anterior pituitary hormone deficits are present in 19% to 81% of patients. Hypogonadism because of hyperprolactinemia is the most frequent hormonal manifestation. MRI often shows a hypointense lesion with rim enhancement and a hyperintense signal in the T2-weighted images. Hyperintensity on T1-weighted images and isointensity on T2-weighted images suggests mucoid material is present in the cyst; hyperintensity in both T1- and T2-weighted images suggest the presence of blood. Cysts with high protein content show a high T1 signal intensity. Only 13% of RCCs show calcification on CT. Asymptomatic, small RCCs are treated conservatively without surgery. If symptomatic, the aim is to drain the cyst content and remove as much of the capsule as possible. Radiation is usually not used routinely for treatment with the exception of recurrent cysts. The 4-year recurrence rate has been reported to be 48%; the presence of squamous metaplasia in the cyst wall is associated with a higher risk of recurrence.

A recent update of the Cochrane review comes to the conclusion that there are currently no well-powered RCTs to give recommendations for the use of bleomycin in the treatment of cystic craniopharyngiomas in children.

Infiltrating Diseases

Sarcoidosis

Sarcoidosis is a multisystem disease of activated T lymphocytes and noncaseating granulomas that commonly affects the lungs, lymph nodes, eyes, and skin but can involve the CNS and peripheral nervous system in 10% to 20% of cases. Neurological symptoms can be the presenting sign of disease in 50% of the latter group of patients and can increase morbidity and mortality. CNS lesions can appear as subdural plaques or infundibular plaques, infiltrating intraparenchymal pseudotumoral masses, or as multiple nodules in MRI studies. Although hypothalamic-pituitary lesions may not be evident on MRI, 25% to 33% of patients with neurosarcoidosis have DI, and autopsy studies in such patients show extensive granulomatous inflammation of the hypothalamus, with little pituitary involvement. DI results from vasopressin deficiency and destruction of neurons in the neurohypophysis, but damage to the osmoreceptor controlling thirst also contributes to polyuria and polydipsia. Other symptoms of hypothalamic disease include somnolence, body temperature dysregulation, hyperphagia, and obesity. ^, Impaired secretion of anterior pituitary hormones also occurs; GH and gonadotropin deficiencies occur more commonly than TSH or ACTH deficiency. In Murialdo and Tamagno’s Italian series of 91 patients, 39% had hypogonadotropic hypogonadism, and 59% of the women in the study ( n = 46) reported amenorrhea.

As with other forms of sarcoidosis, confirmation of neurosarcoidosis requires histological evidence of noncaseating granulomas and lymphocyte infiltration of affected tissue, but obtaining nervous system tissue can be difficult. However, a probable diagnosis can be made with the proper clinical picture and imaging studies (i.e., MRI; Fig. 21.4 ). PRL elevation can be a useful screen for hypothalamic involvement. Results of cerebrospinal fluid (CSF) analysis are abnormal in 80% of patients with CNS sarcoid and can include elevations in protein, lymphocytes, or angiotensin-converting enzyme levels.

Prednisone is the mainstay of treatment for neurosarcoidosis, as it is for other forms of the disease, although therapy is often intensified in CNS disease. RT is employed in patients who do not respond to oral medications. Unfortunately, anterior pituitary deficiencies usually are not restored, despite treatment. Dopaminergic agents can be used to decrease PRL levels, but they will not restore fertility if hypogonadotropic hypogonadism is also present.

Sarcoidosis can also infiltrate the epididymis and testes, resulting in painless epididymitis or a scrotal mass, both of which respond to glucocorticoids. Granulomatous involvement of the uterus and fallopian tubes has also been reported in women with sarcoidosis who present with amenorrhea or menorrhagia. Thus, reproductive dysfunction in patients with sarcoidosis can be both primary and secondary to CNS disease.

Langerhans Cell Histiocytosis

Langerhans cell histiocytosis (LCH) is another multisystem disease of unknown etiology that has a predilection for the hypothalamus and pituitary. It is characterized by the clonal accumulation and proliferation of abnormal dendritic histiocytes, with accompanying lymphocytes, eosinophils, and neutrophils. These cellular infiltrative lesions can destroy a variety of tissues, including skin, bone, lymph nodes, liver, spleen, lungs, and bone marrow. Known previously as Letterer-Siwe disease, Hand-Schüller-Christian disease, eosinophilic granuloma, and histiocytosis X, LCH primarily affects children between the ages of 1 and 3 years old. It can remit spontaneously or disseminate, even resulting in death in rare cases. Adults make up fewer than 30% of all reported cases of LCH, with an incidence of 1.8 cases per million people. LCH in adults more commonly affects the skin, lungs, and bones.

The hypothalamic-pituitary axis is involved in 5% to 50% of children with LCH, with 15% to 50% of these children presenting with DI. ^, The incidence of DI increases over time. It is usually seen within 5 years of diagnosis and occurs more often in the setting of multisystem disease. DI was also the earliest hormonal abnormality in the adult cohort reported by Kaltsas and colleagues, 33% of whom presented with DI. Anterior pituitary hormone deficiency occurs in approximately 20% to 35% of patients and is usually associated with DI. In a large pediatric cohort, the estimated 5- and 10-year risks of pituitary involvement with LCH were 22% and 24%, respectively. GH deficiency is the most common pituitary endocrinopathy, occurring in 10% of patients with LCH and increasing in frequency over time. Ear, nose, and throat involvement increases the risk of GH deficiency. GH deficiency in the absence of DI is unusual, but 54% of patients with DI who were followed for 10 years ultimately had GH deficiency. GH replacement effectively improves the final height in children with GH deficiency, although midparental height is usually not achieved because children have fairly severe growth restrictions at the time therapy is initiated. ^, Importantly, GH therapy did not increase the risk of LCH disease activity. GH replacement in adults with LCH has not been well studied.

Gonadotropin deficiency also occurs in LCH, almost always in association with other anterior pituitary hormone deficiencies. Because most patients are prepubertal at the onset of disease activity, those with gonadotropin deficiency require exogenous sex steroids to induce and maintain puberty. Fifty percent of the cohort of 12 patients reported by Kaltsas and colleagues had gonadotropin deficiency at a median of 7 years old after diagnosis of LCH, and exogenous gonadotropins successfully restored fertility in 1 male patient.

Findings on MRI are abnormal in the majority of patients with LCH and endocrinopathy. Loss of the posterior pituitary bright spot on T1-weighted images and infundibular enlargement are the most common abnormalities, with the former observed in 100% of patients with DI. As shown in Fig. 21.5 , other less common radiological abnormalities include a thickened infundibular stalk, a partially or completely empty sella, and lesions in the hypothalamus.

Both children and adults with LCH and DI are at high risk for anterior pituitary deficits and should be followed closely. Unfortunately, dynamic evaluation of pituitary function was not a useful predictor of later endocrinopathies. DI and other hormonal deficiencies tend to be permanent once established, despite treatment of LCH lesions with radiation therapy, chemotherapy, or both. RT may be helpful for controlling localized disease and mass effects, however. Chemotherapy was not helpful in long-term disease management in adults.

Other infiltrating diseases that can cause hypothalamic infiltration with resulting reproductive dysfunction include hemochromatosis (which more commonly affects the pituitary; discussed later in the chapter), leukemia, ^, lymphoma, and Wegener granulomatosis. Central DI is often the presenting feature, and treatment of the underlying condition sometimes results in resolution of this and other associated hormonal abnormalities. ^, When associated with malignancies (leukemia, lymphoma), hypothalamic involvement is a poor prognostic feature and usually does not respond to treatment.

Infections.

Infections are a rare cause of hypothalamic-pituitary disease affecting the reproductive axis. They usually present acutely with fever, headache, meningism, and change in mental status or seizure and can be identified using culture, polymerase chain reaction, or detection of antibodies to viral antigens. Tuberculosis and atypical mycobacterial infections, viral encephalitis, mycotic infections, and bacterial meningitis can all cause infiltration of the hypothalamus or pituitary and result in hormonal deficiencies. Box 21.1 summarizes the classification of infiltrative, infectious, and other nontumoral diseases involving the hypothalamus that can cause hypogonadotropic hypogonadism.