Kisspeptin-54 Accurately Identifies Hypothalamic Gonadotropin-Releasing Hormone Neuronal Dysfunction in Men with Congenital Hypogonadotropic Hypogonadism.

BACKGROUND: Hypogonadotropic hypogonadism (HH) is hypogonadism due to either hypothalamic or pituitary dysfunction. While gonadotropin-releasing hormone (GnRH) can directly test pituitary function, no specific test of hypothalamic function exists. Kisspeptin-54 (KP54) is a neuropeptide that directly stimulates hypothalamic GnRH release and thus could be used to specifically interrogate hypothalamic function. Congenital HH (CHH) is typically due to variants in genes that control hypothalamic GnRH neuronal migration or function. Thus, we investigated whether KP54 could accurately identify hypothalamic dysfunction in men with CHH. METHODS: Men with CHH (n = 21) and healthy eugonadal men (n = 21) received an intravenous bolus of either GnRH (100 µg) or KP54 (6.4 nmol/kg), on 2 occasions, and were monitored for 6 h after administration of each neuropeptide. RESULTS: Maximal luteinizing hormone (LH) rise after KP54 was significantly greater in healthy men (12.5 iU/L) than in men with CHH (0.4 iU/L; p < 0.0001). KP54 more accurately differentiated CHH men from healthy men than GnRH (area under receiver operating characteristic curve KP54: 1.0, 95% CI 1.0-1.0; GnRH: 0.88, 95% CI 0.76-0.99). Indeed, all CHH men had an LH rise <2.0 iU/L following KP54, whereas all healthy men had an LH rise >4.0 iU/L. Anosmic men with CHH (i.e., Kallmann syndrome) had even lower LH rises after KP54 than did normosmic men with CHH (p = 0.017). Likewise, men identified to have pathogenic/likely pathogenic variants in CHH genes had even lower LH rises after KP54 than other men with CHH (p = 0.035). CONCLUSION: KP54 fully discriminated men with CHH from healthy men. Thus, KP54 could be used to specifically interrogate hypothalamic GnRH neuronal function in patients with CHH.

Kallmann Syndrome with Syndactyly.

Kallmann syndrome is a rare genetic disorder marked by hypogonadotropic hypogonadism (HH) and anosmia, affecting 1 in 50,000 females. It is due to a defect of gonadotropin-releasing hormone (GnRH)-secreting neurons migration from the nasal olfactory epithelium to the basal hypothalamus. Non-reproductive, non-olfactory symptoms can also be present, depending on the genetic form of disease. The management includes hormone replacement therapy and fertility treatment. We report a case of Kallmann syndrome in an 18-year girl who presented with primary amenorrhea with poor, secondary sexual characteristics' development, poor sense of smell and syndactyly. The plasma levels of luteinising hormone, follicle stimulating hormone, and estradiol were very low, while chromosome analysis showed 46, XX karyotype. Pelvic MRI confirmed the presence of uterus and ovaries. MRI of brain was normal. Treatment was started with cyclic conjugated estrogen and progestin with good response. She is now on regular follow-up to monitor treatment.

Induction of puberty with human chorionic gonadotropin (hCG) followed by reversal of hypogonadotropic hypogonadism in Kallmann syndrome.

INTRODUCTION: Kallmann syndrome (KS) is a rare, congenital disorder combining hypogonadotropic hypogonadism (HH) due to GnRH-deficiency with anosmia. Traditionally thought to require lifelong therapy it turns out to be a reversible condition in some patients. CASE REPORT: We present a case of a 22-year old man with absent puberty due to KS, in whom genetic testing revealed heterozygosity for a mutation in the PROK2 gene. Pubertal development and virilisation was achieved by using human chorionic gonadotropin (hCG) injections followed by testosterone replacement. During the follow-up we observed reversal of hypogonadism allowing discontinuation of testosterone treatment. Normalisation of testicular volume as well as gonadotropin and inhibin B levels through a 2-year postreversal period was seen. CONCLUSIONS: Treatment with hCG is effective in inducing pubertal development and may have advantage over testosterone replacement due to a potential of gonadal maturation. A regular assessment of testicular volume and biochemical surveillance including measuring of serum inhibin B and gonadotropins are necessary for a timely detection of reversal of GnRH deficiency.

Anti-Müllerian Hormone and Ovarian Morphology in Women With Isolated Hypogonadotropic Hypogonadism/Kallmann Syndrome: Effects of Recombinant Human FSH.

CONTEXT: Isolated hypogonadotropic hypogonadism (IHH), characterized by gonadotropin deficiency and absent puberty, is very rare in women. IHH prevents pubertal ovarian stimulation, but anti-Müllerian hormone (AMH) and antral follicle count (AFC) have not been studied. OBJECTIVES: (1) To compare, in IHH vs controls, AMH, ovarian volume (OV), and AFC. (2) To compare, in IHH, ovarian responses to recombinant human follicle-stimulating hormone (rhFSH) and rhFSH plus recombinant human luteinizing hormone (rhLH). SUBJECTS: Sixty-eight IHH women; 51 matched healthy women. METHODS: Serum LH, FSH, sex steroids, inhibin B (InhB), AMH, and OV and AFC (sonography) were compared. Ovarian response during rhFSH administration was assessed in 12 IHH women with low AMH levels and low AFC and compared with hormonal changes observed in six additional IHH women receiving rhFSH plus rhLH. RESULTS: InhB was lower in IHH than in controls. AMH levels were also significantly lower in the patients, but two-thirds had normal values. Mean OV and total, larger, and smaller AFCs were lower in IHH than in controls. Ovarian stimulation by rhFSH led to a significant increase in serum estradiol and InhB levels and in the number of larger antral follicles. AMH and smaller AFC increased early during rhFSH stimulation but then declined despite continued stimulation. rhFSH plus rhLH stimulation led to a significantly higher increase in estradiol levels but to similar changes in circulating InhB and AMH than with rhFSH alone. CONCLUSIONS: IHH women have both low AMH levels and low AFC. However, their decrease can be reversed by follicle-stimulating hormone. Serum AMH and AFC should not serve as prognostic markers of fertility in this population.

Bone involvement in males with Kallmann disease.

BACKGROUND: Kallmann syndrome (KS) is a rare genetic condition characterized by congenital early-onset hypogonadotropic hypogonadism and anosmia or hyposmia. Male subjects are more frequently affected and present absent/delayed puberty, low testosterone levels with higher risk for osteoporosis. Therefore, to maintain normal levels of sex steroids and prevent bone loss, male KS needs life-long hormonal replacement therapy (HRT). AIMS: The objective of our study is to assess bone involvement in subjects with KS currently treated with HRT. METHODS: In our retrospective study, we analyzed data from medical records of patients with KS treated with HRT (either gonadotropins or testosterone preparations), including clinical history, biochemical parameters, and the following outcome measures: the bone mineral density (BMD) at the lumbar spine (LS), femoral neck (FN), and total body less head (TBLH); and the Vertebral Fracture Assessment (VFA) by Dual Energy X-ray Absorptiometry (DXA). RESULTS: Clinical and instrumental data of 32 patients with KS were evaluated; their mean age was 30.32 (± 10.09) years, their mean body mass index (BMI) was 25.71 (± 3.23) kg/m(2). Four patients (12.5%) had a LS BMD Z score below the expected range for age. Five patients had vertebral deformities observed at VFA. Duration of HRT was related to bone health parameters: BMD at all measured sites were higher in patients receiving adequate HRT for more than 2 years compared with the patients treated for less than 6 months. A deficient vitamin D status was found in 43% of cases and it was prevalent in patients with shorter HRT. DISCUSSION AND CONCLUSION: Early starting and adequate duration of HRT are related to bone health parameters in patients with congenital hypogonadotropic hypogonadism due to KS. Restoring vitamin D sufficiency might also be advisable in this condition.

Pulsatile GnRH Is Superior to hCG in Therapeutic Efficacy in Adolescent Boys With Hypogonadotropic Hypogonadodism.

CONTEXT: We investigated the efficacy and safety of two different treatments that have not been evaluated in peripuberty boys with hypogonadotropic hypogonadism (HH). OBJECTIVE: The objective of the study was to assess the effectiveness and safety of GnRH or human chorionic gonadotropin (hCG) treatment in adolescent boys with HH. DESIGN: Twelve patients received 8-10 µg of GnRH, sc injected every 90 minutes using a pump. Another 22 patients received hCG, injected im as follows: for the first 3 months, 1000 IU of hCG was injected two times per week and then once every other day for the next 3 months. The dose of hCG was increased to 2000 IU after a 6-month treatment and the above cycle was repeated for another 6 months. All patients were treated for 12-14 months and followed up every 3 months. SETTING: Thirty-five participants were chosen from Beijing Children's Hospital from 2008 to 2014. Twenty-three patients with Kallmann syndrome and 12 with normosmic idiopathic hypogonadotropic hypogonadism. The age ranged from 10 to 16 years. INTERVENTION(S): Twelve patients were treated with pulsatile pump GnRH (group 1), and 22 patients were treated with im hCG (group 2). One patient was treated successively with hCG and GnRH, which was removed in data analysis. MAIN OUTCOME MEASURE(S): Testicular volume was measured by an orchidometer. The levels of T, LH, and FSH serum were measured with a chemiluminesent immunoassay. Bone age was measured by x-ray. RESULTS: Patients treated with GnRH showed larger testes than those treated with hCG. Patients in both groups showed a significantly increased length of penis and T levels. But the difference of the two groups was not statistically significant. There was no significant difference in side effects in both groups. CONCLUSIONS: Boys with HH may be effectively treated with GnRH. We suggested that GnRH exhibits higher efficacy in treating adolescent boys with HH than hCG.

Plasma kisspeptin levels in male cases with hypogonadism.

The hypothalamic hormone kisspeptin (metastin) regulates human reproduction by modulating gonadotropin-releasing hormone (GnRH) secretion. Kisspeptin is detected in peripheral blood, although GnRH is not. In this study, we measured plasma kisspeptin levels in four male cases with hypogonadism and seven normal male controls using enzyme immunoassay (EIA) to elucidate the clinical implications of kisspeptin levels in male hypogonadism. The results showed a variety of plasma kisspeptin levels: 6.0 fmol/mL in a male with isolated hypogonadotropic hypogonadism (IHH), 43.2 fmol/mL in a male with Kallmann's syndrome, 40.7 fmol/mL in a male with azoospermia, 323.2 fmol/mL in a male with hypergonadotropic hypogonadism, and 12.3 ± 2.5 fmol/mL (mean ± SD) in seven normal controls. Except for the case with IHH, the plasma kisspetin levels were elevated in the three cases with Kallmann's syndrome, azoospermia, and hypergonadotropic hypogonadism. The reason why the three cases had high values was their lesions were downstream of the kisspeptin neuron in the hypothalamic-pituitary-gonadal axis, suggesting that elevated kisspeptin levels were implicated in hypothalamic kisspeptin secretion under decreased negative feedback of gonadal steroids. The result that the plasma kisspeptin levels were decreased by gonadotropin therapy in the case with Kallmann's syndrome supported this hypothesis. In conclusion, to measure plasma kisspeptin levels could be useful for better understanding of male hypogonadism.

Biochemical and MRI findings of Kallmann's syndrome.

Kallmann's syndrome is a neuronal migration disorder characterised by anosmia/hyposmia and hypogonadotropic hypogonadism. We present a case of a 21-year-old man who was unable to sense smell since birth and who displayed non-development of secondary sexual characteristics for the past 10 years. Blood investigations showed low basal levels of serum follicle stimulating hormone (FSH), serum luteinising hormone (LH) and serum testosterone. After a gonadotropin releasing hormone challenge test there was a slight increase in serum FSH and serum LH, and after a human chorionic gonadotropin (HCG) challenge test the patient's serum testosterone level increased to 34 times that of his basal level. MRI of the brain showed absence of bilateral olfactory bulbs and sulcus with an apparently normal appearing pituitary gland, and bilateral loss of distinction between the gyrus rectus and medial orbital gyrus, thus confirming the diagnosis. The patient is on treatment with injection of HCG 2000 IU deep intramuscular twice a week and is on follow-up.

Insulin-like peptide 3 (INSL3) in men with congenital hypogonadotropic hypogonadism/Kallmann syndrome and effects of different modalities of hormonal treatment: a single-center study of 281 patients.

CONTEXT: Insulin-like factor 3 (INSL3) is a testicular hormone secreted during fetal life, the neonatal period, and after puberty. OBJECTIVE: To measure INSL3 levels in a large series of men with congenital hypogonadotropic hypogonadism (CHH)/ Kallmann syndrome (KS), in order to assess its diagnostic value and to investigate its regulation. PATIENTS: We studied 281 CHH/KS patients (91 untreated, 96 receiving T, and 94 receiving combined gonadotropin therapy [human chorionic gonadotropin, hCG, and FSH]) and 72 age-matched healthy men. METHODS: Serum INSL3 was immunoassayed with a validated RIA. RESULTS: Mean (±SD) INSL3 levels (pg/mL) were 659 ± 279 in controls and lower (60 ± 43; P < .001) in untreated CHH/KS patients, with no overlap between the two groups, when the threshold of 250 pg/mL was used. Basal INSL3 levels were lower in both untreated CHH/KS men with cryptorchidism than in those with intrascrotal testes and in patients with testicular volumes below 4 mL. Significant positive correlations between INSL3 and both serum total T and LH levels were observed in untreated CHH/KS. Mean INSL3 levels remained low in T-treated CHH/KS patients and were significantly higher in men receiving combined hCG-FSH therapy (P < .001), but the increase was lower cryptorchid patients. FSH-hCG combination therapy or hCG monotherapy, contrary to T and FSH monotherapies, significantly increased INSL3 levels in CHH/KS. CONCLUSIONS: INSL3 is as sensitive a marker as T for the evaluation of altered Leydig cell function in CHH/KS patients. INSL3 levels correlate with LH levels in CHH/KS men showing, together with the rise in INSL3 levels during hCG therapy, that INSL3 secretion seems not constitutively secreted during adulthood but is dependence on pituitary LH.

Congenital hypogonadotropic hypogonadism during childhood: presentation and genetic analyses in 46 boys.

BACKGROUND: The majority of the patients reported with mutations in isolated hypogonadotropic hypogonadism (HH) are adults. We analysed the presentation and the plasma inhibin B and anti-müllerian hormone (AMH) concentrations during childhood and adolescence, and compared them to the genetic results. METHODS: This was a retrospective, single-center study of 46 boys with HH. RESULTS: Fourteen (30.4%) had Kallmann syndrome (KS), 4 (8.7%) had CHARGE syndrome and 28 (60.9%) had HH without olfaction deficit nor olfactive bulb hypoplasia. Eighteen (39%) had an associated malformation or syndromes. At diagnosis, 22 (47.8%) boys were aged

Circulating antimüllerian hormone levels in boys decline during early puberty and correlate with inhibin B.

OBJECTIVE: To investigate peripheral levels of inhibin B and antimüllerian hormone (AMH) in boys during peripuberty and in patients with congenital hypogonadotropic hypogonadism (HH). DESIGN: Randomized, placebo-controlled trial (peripubertal boys); and cross-sectional clinical study (males with HH). SETTING: University central hospital. PATIENT(S): Twenty-eight peripubertal boys with idiopathic short stature (ISS), 19 males with Kallmann syndrome. INTERVENTION(S): Letrozole (2.5 mg/day) or placebo in boys with ISS for 2 years. MAIN OUTCOME MEASURE(S): Longitudinal follow-up observation of serum AMH and its relationship with inhibin B during early puberty and the influence of high (letrozole-treated boys) and low (males with HH) gonadotropin exposure on circulating AMH. RESULT(S): In boys with ISS receiving placebo, the decrease in AMH levels and the increase in inhibin B levels were correlated. The serum AMH level had already declined before a clinically significant increase in testis volume or serum testosterone occurred. Letrozole did not appear to modulate the decline in AMH. The AMH levels were lower in boys and young adults with Kallmann syndrome and prepubertal testes (mean: 20.9 ± 4.7 ng/mL, n = 6) as compared with prepubertal ISS boys (102.3 ± 11.9 ng/mL). CONCLUSION(S): The gonadotropin-mediated early pubertal increase in inhibin B is tightly coupled to decrease in AMH levels and may reflect androgen-mediated differentiation of Sertoli cells. Profound gonadotropin deficiency is associated with low AMH levels, suggesting impaired development of the Sertoli cell population.

Normal inhibin B levels suggest partial preservation of gonadal function in adult male patients with anorexia nervosa.

INTRODUCTION: The impact of undernutrition on endocrine and exocrine gonadatrope function is poorly known in male anorexia nervosa (AN) patients. AIM: The aim of this study was to compare the pituitary-gonadal function of male AN subjects with that of healthy controls, Kallmann syndrome (KS) patients, and female AN subjects. METHODS: Observational monocentric cross-sectional study performed in 31 male and 25 female subjects with restrictive-type AN, 22 male and 20 female controls, and nine male KS patients. MAIN OUTCOME MEASURES: Hormonal parameters are as follows: follicule stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin, estradiol, testosterone, inhibin B, thyroid hormones, growth hormone (GH), insulin-like growth factor 1 (IGF-1), cortisol, adrenocorticotropic hormone (ACTH), dehydroepiandrosterone sulfate, and leptin. RESULTS: Similar abnormalities of free T3, GH, IGF-I, cortisol, and leptin were found in men as in AN women with equivalent undernutrition status when compared with corresponding controls. Low levels of LH, FSH were found in both male and female AN patients. In male AN, total testosterone was found lower than in controls but higher than in KS, while a lack of estradiol was noticed in AN women. Sex hormones variations were directly related to weight gain only in AN men. No relationship was found between sex hormones and leptin variation for both sexes. In AN men, inhibin B levels were similar to that of controls and did not correlate with testosterone levels. CONCLUSIONS: Significant differences of undernutrition impact on gonadal status were noticed between male and female AN subjects, including partial preservation of testosterone release and probable preservation of exocrine function, according to the normal inhibin B levels.

[Kallmann syndrome]. / Kallmann-Syndrom.

The Kallmann syndrome is a very rare congenital association of gonadotropin-releasing hormone deficiency and hyposmia or anosmia. Clinically it is characterized by low serum concentrations of testosterone and inadequate low levels of luteinizing hormone and follicle-stimulating hormone as well as incomplete sexual maturation, lack of secondary sexual features (facial and body hair growth, deepening of the voice), micropenis and sometimes even cryptorchidism. The reduced or absent sense of smell is typical for the Kallmann syndrome and distinguishes this syndrome from other causes of hypogonadotropic hypogonadism. Additional findings may include synkinesia, hearing loss, unilateral renal aplasia, brachy- or syndactyly, agenesis of corpus callosum, cleft palate and dental agenesis. A 19-year-old man presented to our male infertility clinic with delayed sexual maturation, eunuchoid habitus, micropenis, cryptorchidism, erectile dysfunction and absence of ejaculation, anemia and osteoporosis as well as low serum concentrations of luteinizing hormone, follicle-stimulating hormone and testosterone in combination with hyposmia.

An unusual case of autonomous hyperparathyroidism in a patient with X-linked hypophosphatemic rickets and Kallmann syndrome.

We are reporting an unusual patient who presented to our medical center at 18 years of age for evaluation of disabling bilateral lower extremity deformity and delayed puberty. Extensive clinical, laboratory, and radiologic evaluation confirmed the coexistence of 2 X-linked inherited disorders, X-linked hypophosphatemic rickets (XLH) and Kallmann syndrome (KS). Treatment with oral phosphate and calcitriol along with intramuscular testosterone injections was initiated. Despite a dramatic response, the course of treatment was complicated by secondary hyperparathyroidism and, 13 years later, by the development of an autonomous parathyroid adenoma that was surgically resected. Furthermore, the coexistence of XLH and KS has not been reported before. We believe that the proximity of the KAL-1 gene (Xp 22.3), involved in the pathogenesis of KS, to the phosphate regulating endopeptidase on the X chromosome gene (Xp 22.1-22.2), involved in XLH, might be responsible for this association.

Two cases of Kallmann syndrome associated with empty sella.

Kallmann syndrome (KS) is a developmental disease characterized by the association of isolated hypogonadotropic hypogonadism and anosmia/hyposmia. We report an unusual presentation of two females with KS and empty sella. These females, aged at 20 and 29-year-old, presented primary amenorrhea with prepubertal estradiol and low gonadotropin levels. No other significant clinical signs were observed. Empty sella was observed on MRI in both cases. Sequencing of FGFR1 gene, recently implicated in autosomal form of KS, was performed and one splicing mutation (IVS14 + 1G > A) was identified in one patient.

Reversal of idiopathic hypogonadotropic hypogonadism.

BACKGROUND: Idiopathic hypogonadotropic hypogonadism, which may be associated with anosmia (the Kallmann syndrome) or with a normal sense of smell, is a treatable form of male infertility caused by a congenital defect in the secretion or action of gonadotropin-releasing hormone (GnRH). Patients have absent or incomplete sexual maturation by the age of 18. Idiopathic hypogonadotropic hypogonadism was previously thought to require lifelong therapy. We describe 15 men in whom reversal of idiopathic hypogonadotropic hypogonadism was sustained after discontinuation of hormonal therapy. METHODS: We defined the sustained reversal of idiopathic hypogonadotropic hypogonadism as the presence of normal adult testosterone levels after hormonal therapy was discontinued. RESULTS: Ten sustained reversals were identified retrospectively. Five sustained reversals were identified prospectively among 50 men with idiopathic hypogonadotropic hypogonadism after a mean (+/-SD) duration of treatment interruption of 6+/-3 weeks. Of the 15 men who had a sustained reversal, 4 had anosmia. At initial evaluation, 6 men had absent puberty, 9 had partial puberty, and all had abnormal secretion of GnRH-induced luteinizing hormone. All 15 men had received previous hormonal therapy to induce virilization, fertility, or both. Among those whose hypogonadism was reversed, the mean serum level of endogenous testosterone increased from 55+/-29 ng per deciliter (1.9+/-1.0 nmol per liter) to 386+/-91 ng per deciliter (13.4+/-3.2 nmol per liter, P<0.001), the luteinizing hormone level increased from 2.7+/-2.0 to 8.5+/-4.6 IU per liter (P<0.001), the level of follicle-stimulating hormone increased from 2.5+/-1.7 to 9.5+/-12.2 IU per liter (P<0.01), and testicular volume increased from 8+/-5 to 16+/-7 ml (P<0.001). Pulsatile luteinizing hormone secretion and spermatogenesis were documented. CONCLUSIONS: Sustained reversal of normosmic idiopathic hypogonadotropic hypogonadism and the Kallmann syndrome was noted after discontinuation of treatment in about 10% of patients with either absent or partial puberty. Therefore, brief discontinuation of hormonal therapy to assess reversibility of hypogonadotropic hypogonadism is reasonable. (ClinicalTrials.gov number, NCT00392756 [ClinicalTrials.gov].).

Doubtful descent, dilemma and diagnosis: a case of Kallmann syndrome.

A 16-year-old boy with a diagnosis of bilateral cryptorchidism was referred for preoperative evaluation. He had diminished hearing and difficulty in vision since birth, with inattentiveness, poor school performance and delayed milestones. He was previously operated on for cleft lip. General survey revealed bilateral short fourth metacarpals and an operative scar mark over the left nostril and upper lip. He had a micropenis, small soft testes with anosmia, and sensory-motor deafness. The hormonal assay was consistent with hypogonadotrophic hypogonadism. Magnetic resonance imaging of the brain and computed tomography cisternography revealed almost hypoplastic olfactory bulb with an ill-defined olfactory tract and sulci, supporting the clinical diagnosis of Kallmann syndrome.

Coexistence of Kallmann syndrome and complete androgen insensitivity in the same patient.

Kallmann syndrome (KS) is a developmental disease that combines hypogonadotropic hypogonadism and anosmia/hyposmia. Other congenital abnormalities may also coexist. This present report describes two sisters, aged 13 and 12 years, born from Lebanese consanguineous parents. The two sisters have complete androgen insensitivity (normal female appearance and an XY karyotype) due to a novel mutation, a C-to-G transversion in intron 2 of the androgen receptor gene, resulting in an aberrant splicing leading to an insertion of 66 nucleotides in the mRNA. In addition, the older sister has KS, together with synkinesia and multiple skeletal abnormalities, mainly kyphosis, vertebral abnormalities, and short right hand and feet. Her testosterone, FSH and LH levels were very low compared with her younger sister. No mutation in the KAL1 and FGFR1/KAL2 genes were found. This unique report raises the possibility of an autosomal recessive or X-linked form of KS with new phenotypic expression.