Melatonin hypersecretion in male patients with adult-onset idiopathic hypogonadotropic hypogonadism.

Increased melatonin secretion observed in male patients with congenital isolated hypogonadotropic hypogonadism and its normalization during testosterone treatment had suggested that melatonin and the reproductive hormones are inter-related. Since these patients have a congenital form of hypogonadism, it is likely that hypermelatoninemia is the consequence of hypogonadism. To further study the relations between the pineal and the reproductive axis in humans, we evaluated melatonin secretion in two men (aged 35 and 50 yrs.) with acquired adult-onset hypogonadotropic hypogonadism. The diagnosis was based on the findings of normal testicular volume, azoospermia, low serum testosterone, normal LH and FSH levels, but apulsatile LH secretion, and intact anterior pituitary hormones secretion, normal findings on skull radiographic imaging, prior sexual maturation and paternity. Melatonin secretion was assessed as urinary 24 h 6-sulphatoxymelatonin excretion (aMT6s) prior to and during the administration of 250 mg testosterone enanthate per month for 4 months. Pretreatment melatonin production was markedly increased in both patients: 427-915 ng/kg/24 h vs. 204+/-81 [mean+/-SD] in 16 age-matched male controls. During testosterone treatment, aMT6s levels were normalized in one patient (range: 81-287 ng/kg/24 h) and remained elevated in the other patient (range: 830-1280 ng/kg/24 h). These data indicate that male patients with acquired GnRH deficiency have increased melatonin secretion. Melatonin hypersecretion in these patients may reflect a functional association.     

GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism

Idiopathic hypogonadotropic hypogonadism (IHH) is a condition characterized by failure to undergo puberty in the setting of low sex steroids and low gonadotropins. IHH is due to abnormal secretion or action of the master reproductive hormone gonadotropin-releasing hormone (GnRH). Several genes have been found to be mutated in patients with IHH, yet to date no mutations have been identified in the most obvious candidate gene, GNRH1 itself, which encodes the preprohormone that is ultimately processed to produce GnRH. We screened DNA from 310 patients with normosmic IHH (nIHH) and 192 healthy control subjects for sequence changes in GNRH1. In 1 patient with severe congenital nIHH (with micropenis, bilateral cryptorchidism, and absent puberty), a homozygous frameshift mutation that is predicted to disrupt the 3 C-terminal amino acids of the GnRH decapeptide and to produce a premature stop codon was identified. Heterozygous variants not seen in controls were identified in 4 patients with nIHH: 1 nonsynonymous missense mutation in the eighth amino acid of the GnRH decapeptide, 1 nonsense mutation that causes premature termination within the GnRH-associated peptide (GAP), which lies C-terminal to the GnRH decapeptide within the GnRH precursor, and 2 sequence variants that cause nonsynonymous amino-acid substitutions in the signal peptide and in GnRH-associated peptide. Our results establish mutations in GNRH1 as a genetic cause of nIHH.     

Osteoporosis in men with idiopathic hypogonadotropic hypogonadism

To assess the effect of testosterone deficiency on skeletal integrity in men, we determined bone density in 23 hypogonadal men with isolated gonadotropin-releasing hormone deficiency and compared those values with ones from controls. Cortical bone density, as assessed by single-photon absorptiometry of the nondominant radius, ranged from 0.57 to 0.86 g/cm2 (mean +/- SE, 0.71 +/- 0.02) in patients with fused epiphyses and from 0.57 to 0.67 g/cm2 (mean, 0.61 +/- 0.01) in patients with open epiphyses, both of which were significantly (p less than 0.001) lower than normal. Spinal trabecular bone density, as assessed by computed tomography, was similarly decreased (p less than 0.0001) and ranged from 42 to 177 mg K2HPO4/cm3 (mean, 112 +/- 7). Cortical bone density was at least 2 SD below normal in 16 of 23 men, and 8 men had spinal bone densities below the fracture threshold of 80 to 100 mg K2HPO4/cm3. Osteopenia was equally severe in men with immature and mature bone ages, suggesting that abnormal bone development plays an important role in the osteopenia of men with idiopathic hypogonadotropic hypogonadism.     

男性特发性低促性腺激素性性功能减退症

男性特发性低促性腺激素性性功能减退症是由于基因异常引起下丘脑分泌促性腺激素释放激素（GnRH）功能障碍导致睾丸功能低下的遗传性疾病，主要临床表现为第二性征发育不全，性功能低下和不育。诊断主要根据临床表现和血卵泡刺激素、黄体生成素和睾酮水平均明显降低，且除外体质性青春发育延迟和后天获得性低促性腺激素性性腺功能减退症。目前尚无根治措施，仅限于替代治疗。雄激素替代治疗可以促进第二性征的发育和维持性功能，使用促性腺激素或GnRH脉冲治疗可诱导精子生成，使部分患者实现生育愿望。早期诊断和恰当的治疗策略是治疗成功的关键。     

Antipituitary antibodies in adults with apparently idiopathic growth hormone deficiency and in adults with autoimmune endocrine diseases

The role of antipituitary antibodies (APA) in autoimmune pituitary diseases still needs to be clarified. The aim of this study was 2-fold: first, to investigate the presence of APA in adults with idiopathic or acquired GH deficiency (GHD) and in adults with autoimmune endocrine diseases; and second, to evaluate whether in autoimmune endocrine patients APA titer is correlated to the pituitary function and particularly to GH secretion. We studied 12 adults with isolated and apparently idiopathic GHD who were treated with recombinant GH in childhood (group 1a), 14 patients with adult GHD secondary to surgery for pituitary and parasellar tumors (group 1b), and 180 patients with organ-specific autoimmune diseases (group 2). APA were evaluated by indirect immunofluorescence. In all APA-positive patients and in 20 APA-negative patients of group 2, GH secretion was investigated by testing its response to insulin-induced hypoglycemia (insulin tolerance test) and, when impaired, also to arginine. APA were found (at high titers) in 4 of 12 patients of group 1a (33.3%) but were absent in all patients in group 1b. APA were also found in 40 of 180 patients of group 2 (22.2%), 35 of them at low titers (group 2a) and 5 at high titers (group 2b). Twenty of the 140 autoimmune endocrine APA-negative patients studied (group 2c) and all APA-positive patients at low titers (group 2a) had normal pituitary function. Conversely, all APA-positive patients at high titers (groups 1a and 2b) had a severe isolated GHD. An inverse correlation between APA titers and GH peak serum response to insulin tolerance test in autoimmune endocrine patients was observed. Our results suggest that APA, when detected at high titers, may be considered a good diagnostic tool to highlight the possible occurrence of GHD in adults with autoimmune endocrine diseases. Moreover, they may indicate an autoimmune pituitary involvement in adults with apparently idiopathic GHD, suggesting that the prevalence of autoimmune GHD is much higher than that so far considered.     

Cat-eye syndrome with isolated idiopathic hypogonadotropic hypogonadism

A 34-year-old Japanese man diagnosed as having cat-eye syndrome (CES) with isolated idiopathic hypogonadotropic hypogonadism (IHH) was treated at our university. He showed preauricular pits/tags, downward slanting palpebral fissures, ocular hypertelorism, and strabismus. However, ocular coloboma and anal atresia, major characteristic features of CES, were negative. Chromosomal analysis revealed malformation in chromosome 22 and eunuchoid features and a low grade development of secondary sexual characteristics were also evident. Endocrinological examinations revealed that this patient was in a state of isolated IHH. Although CES with IHH is extremely rare, endocrine disorders should be given due attention.     

Alpha-subunit secretion in men with idiopathic hypogonadotropic hypogonadism

We studied the regulation of glycoprotein hormone alpha-subunit secretion in four men with idiopathic hypogonadotropic hypogonadism due to presumed GnRH deficiency. Immunoreactive alpha-subunit was present at low but usually detectable levels in blood samples drawn at 10- to 20-min intervals for 12-24 h; however, no characteristic pattern of pulsatile alpha-subunit secretion was found. Serum from each man was examined by gel filtration chromatography. Each sample tested contained an immunoreactive alpha-subunit peak with a slightly lower elution volume than [125I]hCG alpha, as we had previously found in serum from normal men. To determine if this peak represented TSH alpha, two men were treated with 0.3 mg L-T4 daily for 7-14 days. Serum TSH levels decreased to less than 1.5 mU/L, and neither TSH nor alpha-subunit levels increased after the iv administration of 500 micrograms TRH. An alpha-subunit peak that eluted before [125I]hCG alpha was again found in the serum of T4-treated men. We conclude that glycoprotein hormone alpha-subunit is present in the serum of men with idiopathic hypogonadotropic hypogonadism in whom TSH secretion is completely suppressed by L-T4. The gonadotrophs represent the most likely source of this alpha-subunit. The finding of more normal alpha-subunit than LH secretion in these men indicates that the production of the gonadotropin subunits is differentially regulated in man and supports the hypothesis that factors in addition to GnRH regulate alpha-subunit gene expression.     

The effects of gonadotropin treatment on the immunological features of male patients with idiopathic hypogonadotropic hypogonadism

There is a significant line of evidence for a role of androgens in the modulation of the immune system. However, little is known about immunological features of male patients with idiopathic hypogonadotropic hypogonadism (IHH) and the potential effects of gonadotropin treatment. Thus, the objective of this study was to evaluate the levels of selected soluble immune parameters [IgA, IgG, IgM, C3c, C4, interleukin-2 (IL-2), and IL-4], the CD4+/CD8 ratio, and counts of total lymphocyte and some subpopulation of lymphocytes (CD3+, CD4+, CD8+, and CD19+ cells) before and after gonadotropin treatment in men with IHH. Twenty-nine IHH patients and 19 age-matched healthy controls were included in the study. The patients were treated with human menopausal gonadotropin/hCG for 6 months. The pretreatment levels of serum Igs, C3c, IL-2, and IL-4 in the patients were significantly higher than those in the controls (P<0.001 for all). After treatment, all Igs (P<0.001), C3c (P<0.01), and IL-2 and IL-4 levels (P<0.005) were decreased significantly compared to pretreatment levels. Pretreatment lymphocyte counts (P<0.05); the percentages of CD3+ cells (P<0.001), CD4+ cells (P< 0.001), and CD19+ cells (P<0.001); and the CD4/CD8+ ratio in the patient group were significantly higher (P<0.05) than those in the controls. After treatment, the lymphocyte count (P<0.001); CD3+ (P<0.01), CD4+ (P<0.001), and CD19+ (P<0.005) cells; and the CD4-/CD8+ ratio (P<0.001) were decreased, but CD8+ cells were increased significantly (P<0.001). In summary, lack of testosterone action results in the enhancement of cellular and humoral immunity. The results of this study allowed us to conclude that testosterone deficiency affects both cell-mediated and humoral immunity, and these may be modulated with gonadotropin therapy in male patients with IHH.     

Plasma ghrelin levels in males with idiopathic hypogonadotropic hypogonadism

It has recently been shown that ghrelin is a pleitropic modulator with effects on diverse biological functions, such as energy homeostasis and reproduction. In this study, ghrelin levels and its relationship between metabolic and biochemical parameters were investigated in male subjects with idiopathic hypogonadotropic hypogonadism (IHH). Patients in the study were composed of 33 men with IHH, and controls were composed of 36 healthy age-matched men. The patients' group had significantly higher waist/hip ratio (WHR), and lower testis volume, luteinizing hormone (LH), follicle stimuling hormone (FSH) and total testosterone (TT) levels when compared with controls. Plasma total ghrelin levels were significantly lower in patients than in controls (96.4 +/- 29.1 ng/ml vs. 146.1 +/- 28.9 ng/ml, P < 0.001, respectively). No correlation of ghrelin was found with body mass index, waist/hip ratio, homeostasis model assessment insulin resistance index, testis volume, LH, FSH and TT levels in both patients and controls. The present study showed that ghrelin levels were significantly lower in men with IHH than in controls. However, further studies are needed to better understand the relationships between ghrelin, and metabolic and reproductive systems.     

特发性低促性腺激素性性腺功能减退症的遗传学研究进展

特发性低促性腺激素性性腺功能减退症( idiopathic hypogoandotropic hypogonadism,IHH)是一种复杂的寡基因疾病.其中60％的患者伴嗅觉缺如或减退,又称Kallmann综合征.通过遗传学及分子生物学手段研究,目前已发现十余个IHH的致病基因.     

Neonatal gonadotropin therapy in male congenital hypogonadotropic hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) causes pubertal failure and infertility in both women and men due to partial or total secretory failure of the two pituitary gonadotropins lutropin (LH) and follitropin (FSH) during periods of physiological activation of the gonadotropic axis. Men and women with CHH frequently seek treatment for infertility after hypogonadism therapy. Some etiologies, such as autosomal dominant or X-linked Kallmann syndrome, raise the question of hereditary transmission, leading to increasing demands for genetic counseling and monitoring of medically assisted pregnancies. Diagnosis and treatment of newborn boys is, therefore, becoming an increasingly important issue. In male individuals with complete forms of CHH, the antenatal and neonatal gonadotropin deficit leads to formation of a micropenis and cryptorchidism, which could undermine future sexual and reproductive functions. Standard treatments, usually started after the age of puberty, often only partially correct the genital abnormalities and spermatogenesis. The aim of this Review is to examine the possible additional benefits of neonatal gonadotropin therapy in male patients with CHH. Encouraging results of neonatal therapy, together with a few reports of prepubertal treatment, support the use of this novel therapeutic strategy aimed at improving sexual and reproductive functions in adulthood.     

Approach to the male patient with congenital hypogonadotropic hypogonadism

The term "congenital hypogonadotropic hypogonadism" (CHH) refers to a group of disorders featuring complete or partial pubertal failure due to insufficient secretion of the pituitary gonadotropins LH and FSH. Many boys (or their parents) will seek medical consultation because of partial or absent virilization after 14 yr of age. Small testes are very frequent, but height is generally normal. Laboratory diagnosis of hypogonadotropic hypogonadism is relatively simple, with very low circulating total testosterone and low to low-normal gonadotropin and inhibin B levels. This hormone profile rules out a primary testicular disorder. Before diagnosing CHH, however, it is necessary to rule out a pituitary tumor or pituitary infiltration by imaging studies, juvenile hemochromatosis, and a systemic disorder that, by undermining nutritional status, could affect gonadotropin secretion and pubertal development. Anterior pituitary function must be thoroughly investigated to rule out a more complex endocrine disorder with multiple hormone deficiencies and thus to conclude that the hypogonadotropic hypogonadism is isolated. The most likely differential diagnosis before age 18 yr is constitutional delay of puberty. Apart from non-Kallmann syndromic forms, which are often diagnosed during childhood, the two main forms of CHH seen by endocrinologists are Kallmann syndrome, in which CHH is associated with impaired sense of smell, and isolated CHH with normal olfaction. Anosmia can be easily diagnosed by questioning the patient, whereas olfactometry is necessary to determine reliably whether olfaction is normal or partially defective. This step is important before embarking on a search for genetic mutations, which will also be useful for genetic counseling. The choice of a particular hormone replacement therapy protocol aimed at virilizing the patient will depend on age at diagnosis and local practices.     

Distribution of gene mutations associated with familial normosmic idiopathic hypogonadotropic hypogonadism

Objective: Normosmic idiopathic hypogonadotropic hypogonadism (nIHH) is characterized by failure of initiation or maintenance of puberty due to insufficient gonadotropin release, which is not associated with anosmia/hyposmia. The objective of this study was to determine the distribution of causative mutations in a hereditary form of nIHH. Methods: In this prospective collaborative study, 22 families with more than one affected individual (i.e. multiplex families) with nIHH were recruited and screened for genes known or suspected to be strong candidates for nIHH. Results: Mutations were identified in five genes (GNRHR, TACR3, TAC3, KISS1R, and KISS1) in 77% of families with autosomal recessively inherited nIHH. GNRHR and TACR3 mutations were the most common two causative mutations occurring with about equal frequency. Conclusions: Mutations in these five genes account for about three quarters of the causative mutations in nIHH families with more than one affected individual. This frequency is significantly greater than the previously reported rates in all inclusive (familial plus sporadic) cohorts. GNRHR and TACR3 should be the first two genes to be screened for diagnostic purposes. Identification of causative mutations in the remaining families will shed light on the regulation of puberty.     

Increases in bone density during treatment of men with idiopathic hypogonadotropic hypogonadism

To assess the effects of gonadal steroid replacement on bone density in men with osteoporosis due to severe hypogonadism, we measured cortical bone density in the distal radius by 125I photon absorptiometry and trabecular bone density in the lumbar spine by quantitative computed tomography in 21 men with isolated GnRH deficiency while serum testosterone levels were maintained in the normal adult male range for 12-31 months (mean +/- SE, 23.7 +/- 1.1). In men who initially had fused epiphyses (n = 15), cortical bone density increased from 0.71 +/- 0.02 to 0.74 +/- 0.01 g/cm2 (P less than 0.01), while trabecular bone density did not change (116 +/- 9 compared with 119 +/- 7 mg/cm3). In men who initially had open epiphyses (n = 6), cortical bone density increased from 0.62 +/- 0.01 to 0.70 +/- 0.03 g/cm2 (P less than 0.01), while trabecular bone density increased from 96 +/- 13 to 109 +/- 12 mg/cm3 (P less than 0.01). Cortical bone density increased 0.03 +/- 0.01 g/cm2 in men with fused epiphyses and 0.08 +/- 0.02 g/cm2 in men with open epiphyses (P less than 0.05). Despite these increases, neither cortical nor trabecular bone density returned to normal levels. Histomorphometric analyses of iliac crest bone biopsies demonstrated that most of the men had low turnover osteoporosis, although some men had normal to high turnover osteoporosis. We conclude that bone density increases during gonadal steroid replacement of GnRH-deficient men, particularly in men who are skeletally immature.     

特发性低促性腺激素性性腺功能减退症合并1型糖尿病一例

本文中报道一例因“糖尿病酮症酸中毒”就诊的26岁男性患者,查体发现患者消瘦,外生殖器未发育。实验室检查显示糖化血红蛋白10.7%,C肽0.38 ng/ml。谷氨酸脱羧酶抗体阳性。促卵泡激素、促黄体生成素、睾酮均低于正常。骨龄14岁。染色体核型分析为46,XY。诊断为特发性低促性腺激素性性腺功能减退症(IHH)合并1型糖尿病。基因检测示成纤维细胞生长因子受体1错义杂合突变。IHH合并1型糖尿病非常少见,发生机制不明,基因检测结果相关性有待进一步研究。