What is relationship between the medial preoptic area, the organum vasculosum of the lamina terminalis and Kallmann syndrome?

The medial preoptic area is a structure located in the hypothalamic anteroventral third ventricle region, and is closely related to the olfactory brain development and sexual differentiation of the brain. The medial preoptic area surrounds the organum vasculosum of the lamina terminalis, and both structures are the main areas where synthesis of gonadotropin-releasing hormone occurs in the brain. Neurons synthesizing gonadotropin-releasing hormone migrate from the medial nasal epithelium to the rostral brain and reach the organum vasculosum of the lamina terminalis and the medial preoptic area. Kallmann syndrome is a genetic disorder which combines hypogonadotropic hypogonadism and anosmia. Hypogonadism is characterized by the absence or reduced levels of gonadotropin-releasing hormone and anosmia due to olfactory bulb aplasia. This paper speculates on the connection between the development of the medial preoptic area, the organum vasculosum of the lamina terminalis and olfactory bulbs with Kallmann syndrome, since the anteroventral third ventricle region is crucial for the normal development of these structures and its connection with the olfactory nerves and sexual maturation.

Compound deficiencies in multiple fibroblast growth factor signalling components differentially impact the murine gonadotrophin-releasing hormone system.

Gonadotrophin-releasing hormone (GnRH) neurones control the onset and maintenance of fertility. Aberrant development of the GnRH system underlies infertility in Kallmann syndrome [KS; idiopathic hypogonadotropic hypogonadism (IHH) and anosmia]. Some KS patients harbour mutations in the fibroblast growth factor receptor 1 (Fgfr1) and Fgf8 genes. The biological significance of these two genes in GnRH neuronal development was corroborated by the observation that GnRH neurones were severely reduced in newborn transgenic mice deficient in either gene. In the present study, we hypothesised that the compound deficiency of Fgf8 and its cognate receptors, Fgfr1 and Fgfr3, may lead to more deleterious effects on the GnRH system, thereby resulting in a more severe reproductive phenotype in patients harbouring these mutations. This hypothesis was tested by counting the number of GnRH neurones in adult transgenic mice with digenic heterozygous mutations in Fgfr1/Fgf8, Fgfr3/Fgf8 or Fgfr1/Fgfr3. Monogenic heterozygous mutations in Fgfr1, Fgf8 or Fgfr3 caused a 30-50% decrease in the total number of GnRH neurones. Interestingly, mice with digenic mutations in Fgfr1/Fgf8 showed a greater decrease in GnRH neurones compared to mice with a heterozygous defect in the Fgfr1 or Fgf8 alone. This compounding effect was not detected in mice with digenic heterozygous mutations in Fgfr3/Fgf8 or Fgfr1/Fgfr3. These results support the hypothesis that IHH/KS patients with digenic mutations in Fgfr1/Fgf8 may have a further reduction in the GnRH neuronal population compared to patients harbouring monogenic haploid mutations in Fgfr1 or Fgf8. Because only Fgfr1/Fgf8 compound deficiency leads to greater GnRH system defect, this also suggests that these fibroblast growth factor signalling components interact in a highly specific fashion to support GnRH neuronal development.

[GnRH deficiency: new insights from genetics]. / Déficience en GnRH: le nouvel eclairage apporté par la génétique.

The acquisition of a sexually dimorphic phenotype is a critical event in mammalian development. Hypogonadotropic hypogonadism (HH) results from impaired secretion of GnRH. The patients display with delayed puberty, micropenis and cryptorchidism in the male reflecting gonadotropin insufficiency, and amenorrhea in the female. Kallmann's syndrome (KS) is defined by the association of HH and anosmia or hyposmia (absent smelling sense). Segregation analysis in familial cases has demonstrated diverse inheritance patterns, suggesting the existence of several genes regulating GnRH secretion. The X-linked form of the disease was associated with a genetic defect in the KALI gene located on the Xp22.3 region. KAL1 gene encodes an extracellular matrix glycoprotein anosmin-1, which facilitates neuronal growth and migration. Abnormalities in the migratory processes of the GnRH neurons with the olfactory neurons explain the association of HH with anosmia. Recently, mutations in the FGF recepteur 1 (FGFR1) gene were found in KS with autosomal dominant mode of inheritance. The role of FGFR1 in the function of reproduction requires further investigation. Besides HH with anosmia, there are isolated HH (IHH). No human GnRH mutations have been reported although hypogonadal mice due to a GnRH gene deletion exist. In patients with idiopathic HH and without anosmia an increasing number of GnRH receptor (GnRHR) mutations have been described which represent about 50% of familial cases. The clinical features are highly variable and there is a good relationship between genotype and phenotype. A complete loss of function is associated with the most severe phenotype with resistance to pulsatile GnRH treatment, absence of puberty and cryptorchidism in the male. In contrast, milder loss of function mutations causes incomplete failure of pubertal development. The preponderant role of GnRH in the secretion of LH by the gonadotrophs explains the difference of the phenotype between male and female with partial GnRH resistance. Affected females can have spontaneous telarche and normal breast development while affected males exhibit no pubertal development but normal testis volume, a feature described as "fertile-eunuch". High-dose pulsatile GnRH has been used to induce ovulation. Another gene, called GPR54, responsible for idiopathic HH has been recently described by segregation analysis in two different consanguineous families. The GPR54 gene is an orphan receptor, and its putative ligand is the product of the KISS-1 gene, called metastine. Their roles in the function of reproduction are still unknown.

Resonance in the menstrual cycle: a new model of the LH surge.

In vertebrates, ovulation is triggered by a surge of LH from the pituitary. The precise mechanism by which rising oestradiol concentrations initiate the LH surge in the human menstrual cycle remains a fundamental open question of reproductive biology. It is well known that sampling of serum LH on a time scale of minutes reveals pulsatile release from the pituitary in response to pulses of gonadotrophin releasing hormone from the hypothalamus. The LH pulse frequency and amplitude vary considerably over the cycle, with the highest frequency and amplitude at the midcycle surge. Here a new mathematical model is presented of the pituitary as a damped oscillator (pulse generator) driven by the hypothalamus. The model LH surge is consistent with LH data on the time scales of both minutes and days. The model is used to explain the surprising pulse frequency characteristics required to treat human infertility disorders such as Kallmann's syndrome, and new experimental predictions are made.

Kallmann's syndrome: skeletal and psychological aspects of late diagnosis.

We report a case of Kallmann's syndrome (KS) in a previously untreated 30-year-old Caucasian male, admitted to our Endocrinology Department, presenting with hypogonadotropic hypogonadism and hypoosmia, and reporting a history of rickets in early childhood and a rapid growth pattern. On admission, his main complaints were back-pain and a decreased tolerance to physical exercise. The patient gave no family history of hypogonadism or hypoosmia, and his case was assumed to be sporadic KS. On physical examination hypogonadism (micropenis, small testes, no puberty), hypoosmia and severe scoliosis, kyphosis and chest malformations were recorded. No facial hair growth was found nor past voice braking. His skeletal proportions were eunuchoidal, no mid-line defects were found. This case of KS was identified unusually late. Due to patient's anxiety that his physical appearance might change due to therapy, he was referred to a clinical psychologist who confirmed the patient's self-perception as a male. The risk of further bone malformations, progression of osteoporosis and consecutive pathological fractures were the main indications for commencing treatment. Psychological support was provided. Six months of treatment with low doses of hCG (500 IU given i.m. twice a week) had elevated his testosterone levels but they still remained below the lower values of the normal reference range for males. Additional treatment with vitamin D and calcium supplementation was continued. A certain improvement of bone density score was observed. The patient noted a marked pain relief and he willingly complied with the treatment. After six months of therapy hCG dose was increased to 2000 IU given twice a week. We conclude that even at such a late diagnosis of Kallmann's syndrome in a male who accepts his physical appearance and does not wish any treatment in this respect, hormonal therapy is necessary and should be introduced to reduce significant risk of osteoporosis and bone fractures, and also to offset slowly progressing skeletal malformations which result from the lack of epiphyseal fusion.

Hypothalamic dysfunction.

A pulsatile GnRH stimulus is required to maintain gonadotropin synthesis and secretion. The frequency and amplitude of GnRH pulses determine gonadotropin subunit gene expression and secretion of pituitary LH and FSH. Rapid frequency (more than 1 pulse per h) GnRH pulses favor LH while slower frequencies favor FSH secretion. During ovulatory cycles, an increase in GnRH frequency during the follicular phase favors LH synthesis prior to the LH surge, while following ovulation, luteal steroids slow GnRH pulses to favor FSH synthesis. Thus, a changing frequency of GnRH stimulation of the gonadotrope is one of the mechanisms involved in differential gonadotropin secretion during ovulatory cycles. In hypothalamic amenorrhea a majority of women exhibit a persistent slow frequency of LH (GnRH) pulses, which reflects excess hypothalamic opioid tone and can be temporarily reversed by opioid antagonists. At the other end of the spectrum, in polycystic ovarian syndrome, LH (GnRH) pulses are persistently rapid and favor LH synthesis, hyperandrogenism and impaired follicular maturation. Administration of progesterone can slow GnRH pulse secretion, favor FSH secretion and induce follicular maturation. Thus, the ability to change the pattern of GnRH secretion is an important factor in the maintenance of cyclic ovulation, and loss of this function leads to anovulation and amenorrhea.

Female hypogonadotropic hypogonadism. Hypothalamic amenorrhea syndrome.

The neuroendocrine-metabolic repertoire governing the reproductive cyclicity in women can be interrupted by a variety of social, environmental, nutritional, and psychological aberrations. Clinical conditions including exercise-related and psychogenic amenorrhea, and desynchronization of biological rhythms in the development of hypothalamic gonadotropin-releasing hormone dysfunction are discussed. Clinical and laboratory evaluations and modes of management are presented.

LHRH neurons: functions and development.

Examination of the properties of developing LHRH neurons, by in situ hybridization procedures or LHRH immunocytochemistry, showed that these cells (1) are unique among neuroendocrine cells in their origin from the epithelium of the medial olfactory pit, and (2) express LHRH mRNA. LHRH neurons, visualized by either method, tended to be clustered when seen along the migration route in the nasal mesenchyme. Neural cell adhesion molecule (NCAM) is present on the central processes of the olfactory, vomeronasal and terminalis nerves, which form the scaffold along which LHRH neurons migrate into the brain. Injection of a small amount (1 microliter) of antiserum to NCAM into the olfactory pits of 10-day-old embryonic mice, while not sufficient to break up the NCAM scaffolding, appeared to decrease the number of LHRH-immunoreactive cells in the epithelium of the medial olfactory pit, and retarded their migration in the nasal mesenchyme. This suggest that NCAM is important for LHRH cell migration. Never found actually colocalized with LHRH in the same neurons, NCAM nevertheless may be required for the migration of LHRH-expressing cells.