A novel loss of function mutation in exon 10 of the FSH receptor gene causing hypergonadotrophic hypogonadism: clinical and molecular characteristics

BACKGROUND: Inactivating mutations of the FSH receptor (FSHR) are a rare cause of hypergonadotrophic hypogonadism in women. Only one patient with primary amenorrhoea due to an FSHR gene mutation has been reported outside of Finland, where the prevalence of Ala189Val mutations is particularly high. METHODS AND RESULTS: Here, we describe the clinical, molecular genetic and functional characteristics associated with a novel inactivating mutation in exon 10 of the FSHR gene identified in a patient who presented with primary amenorrhoea at 17 years of age. The C to G transversion found at nucleotide 1043 causes a Pro348Arg substitution in the extracellular region of the FSHR and results in a mutant FSHR that is completely inactive in functional studies and that does not bind FSH. The proband exhibits apparent homozygosity for this recessive mutation. Her father is heterozygous for the mutation while analysis of exon 10 of the FSHR gene from her mother revealed only wild-type sequence. Chromosome painting was used to exclude deletions or rearrangements of 2p, and microsatellite markers did not show paternal uniparental isodisomy for this region. These findings suggest that the proband is hemizygous, with an inherited or de-novo microdeletion, or alternatively a de-novo gene conversion, of the accompanying FSHR allele. CONCLUSIONS: This case confirms the importance of the FSHR in female pubertal development and reproduction, and supports a relationship between phenotype and function for FSHR mutations.     

Infant feeding with soy formula milk: effects on puberty progression, reproductive function and testicular cell numbers in marmoset monkeys in adulthood

BACKGROUND: This marmoset study addresses concerns about feeding human male infants with soy formula milk (SFM). METHODS: From age 4 to 5 days, seven male co-twin sets were fed standard formula milk (SMA) or SFM for 5-6 weeks; blood samples were subsequently collected at 10-week intervals. Testes from co-twins killed at 120-138 weeks were fixed for cell counts. RESULTS: SFM- and SMA-fed twins showed normal weight gain; puberty started and progressed normally, based on blood testosterone measurements. Body weight, organ weights (prostate, seminal vesicles, pituitary, thymus and spleen) and penis length were comparable in co-twins. All SMA- and 6/7 SFM-fed males were fertile. Unexpectedly, testis weight (P = 0.041), Sertoli (P = 0.025) and Leydig cell (P = 0.026) numbers per testis were consistently increased in SFM-fed co-twins; the increase in Leydig cell numbers was most marked in males with consistently low-normal testosterone levels. Seminiferous epithelium volume per tubule showed a less consistent, non-significant increase in SFM-fed males; raised germ cell numbers per testis, probably due to increased Sertoli cells, conceivably resulted in larger testes. Average lumen size, although greater in SFM-fed group, was inconsistent between co-twins and the difference was not significant. CONCLUSIONS: Infant feeding with SFM has no gross adverse reproductive effects in male marmosets, though it alters testis size and cell composition, and there is consistent, if indirect, evidence for possible 'compensated Leydig cell failure'. Similar and perhaps larger changes likely occur in adult men who were fed SFM as infants.     

GPR54 and kisspeptin in reproduction

Kisspeptins, the peptide products of the KiSS-1 gene, were identified in 2001 as natural ligands of the previously orphan G protein-coupled receptor, GPR54. They include, among others, metastin and kisspeptin-10. The known biological functions of kisspeptins were initially restricted to their ability to suppress tumour metastasis, hence the name of metastin. However, in late 2003, two groups independently reported that loss-of-function mutations of the GPR54 gene are linked to absence of puberty onset and hypogonadotrophic hypogonadism in humans--a phenotype that was reproduced in GPR54-null mice. Those seminal observations revealed a totally unexpected, fundamental role of the KiSS-1/GPR54 system in control of puberty and reproductive function and boosted an extraordinary interest for the characterization of these novel facets of kisspeptin physiology. Indeed, in the last 2 years, metastin and kisspeptin-10 have been demonstrated as very potent stimulators of the gonadotrophic axis, in a number of species and through different routes of administration. In addition, the hypothalamic KiSS-1/GPR54 system has been proven as an essential gatekeeper of GnRH neurons, involved in their activation at puberty and their regulation by gonadal steroids and (probably) metabolic factors. This review comprehensively examines the experimental evidence obtained to date supporting a pivotal role of kisspeptins and GPR54 in the control of reproduction.     

Growth pattern in the Apert syndrome

In this paper, we demonstrate that a discernible and unique growth pattern characterizes the Apert syndrome. The keys to understanding Apert newborn measurement values are brain size and cranial configuration. Both true megalencephaly and coronal synostosis are present at birth. Thus, the head is unusually heavy and the cranium is disproportionately high. Mean newborn length and weight are above the normal 50th centile. Of our newborn patients, 16% exceeded 4,000 g in weight. Preterm infants were appropriate or slightly large for gestational age. A biphasic linear growth pattern was found. In childhood, deceleration of linear growth occurs so that most values fall between the 5th and 50th centiles. From adolescence to adulthood, deceleration becomes more pronounced. This 2-step linear growth deceleration results in large measure from rhizomelic shortness of the lower limbs. Puberty takes place within the normal time frame. Although a disproportionate amount of the megalencephaly accounts for the dramatic increase in head height, the widely patent midline calvarial de fect, allowing the brain to expand anteriorly into the metopic area, and some increase in the head breadth permit the mean head circumference at birth to normalize slightly above the 50th centile. During the growth period, the head circumference was studied in surgically unoperated Apert patients from the 1960s and earlier. The natural history of the growing cranium consists of gradual deceleration in head circumference from slightly above the 50th centile at birth to within or at ?2 SD later on. © 1993 Wiley-Liss, Inc.     

下丘脑错构瘤的MR诊断与临床表现

目的：分析下丘脑错构瘤的MRI表现,探讨其临床表现、病理及MRI表现的关系,以提高对本病的认识。方法：回顾性分析了14例下丘脑错构瘤的MR及临床资料,其中男6例,女8例,年龄1～37岁。均进行了MR常规扫描和增强扫描,均经病理证实。结果：14例病灶中以宽基底附于第三脑室底部、灰结节和乳头体者6例,有＂蒂＂错构瘤6例,1例位于鞍背后方,1例异位于视交叉上方,所有病例均呈等T1WI信号,等或稍长T2WI信号,信号较均匀,边界较清晰。结节状或类圆形者9例,不规则形5例。直径〈15mm者10例,〉15mm者4例,最大直径2.9cm。2例有明显占位效应,向上压迫三脑室,向前压迫垂体柄或视交叉。结论：当患者出现性早熟和（或）痴笑样癫痫为主的临床表现,MRI显示灰结节和乳头体肿块并典型信号改变且无明显强化时,应首先考虑本病。     

Recent Discoveries on the Control of Gonadotrophin‐Releasing Hormone Neurones in Nonhuman Primates

Since Ernst Knobil proposed the concept of the gonadotrophin‐releasing hormone (GnRH) pulse‐generator in the monkey hypothalamus three decades ago, we have made significant progress in this research area with cellular and molecular approaches. First, an increase in pulsatile GnRH release triggers the onset of puberty. However, the question of what triggers the pubertal increase in GnRH is still unclear. GnRH neurones are already mature before puberty but GnRH release is suppressed by a tonic GABA inhibition. Our recent work indicates that blocking endogenous GABA inhibition with the GABA_A receptor blocker, bicuculline, dramatically increases kisspeptin release, which plays an important role in the pubertal increase in GnRH release. Thus, an interplay between the GABA, kisspeptin, and GnRH neuronal systems appears to trigger puberty. Second, cultured GnRH neurones derived from the olfactory placode of monkey embryos exhibit synchronised intracellular calcium, [Ca²⁺]_i, oscillations and release GnRH in pulses at approximately 60‐min intervals after 14 days in vitro (div). During the first 14 div, GnRH neurones undergo maturational changes from no [Ca²⁺]_i oscillations and little GnRH release to the fully functional state. Recent work also shows GnRH mRNA expression increases during in vitro maturation. This mRNA increase coincides with significant demethylation of a CpG island in the GnRH 5′‐promoter region. This suggests that epigenetic differentiation occurs during GnRH neuronal maturation. Third, oestradiol causes rapid, direct, excitatory action in GnRH neurones and this action of oestradiol appears to be mediated through a membrane receptor, such as G‐protein coupled receptor 30.     

Primary hypothyroidism presenting as ovarian tumor and precocious puberty in a prepubertal girl

We report a case of a prepubertal girl with juvenile primary hypothyroidism presenting as ovarian cysts and precocious puberty. The 7-year-old female was referred to our clinic because of a pelvic/abdominal mass and vaginal bleeding. Besides these findings, on physical examination we noticed the thyroid gland globally increased and the presence of secondary sexual characteristics. Based upon the clinical profile and investigations, the patient was diagnosed with juvenile primary hypothyroidism due to autoimmune thyroiditis. The cysts and precocious puberty resolved spontaneously after the simple replacement of thyroid hormone. It is important to bear in mind hypothyroidism in cases of girls presenting ovarian cysts and precocious puberty in order to avoid unnecessary surgery on the ovaries.     

Melatonin and human reproduction: Shedding light on the darkness hormone

Melatonin, N-acetyl-5-methoxytryptamine, is a molecule with diverse physiological functions. This neuro-hormone affects reproductive performance in a wide variety of species. In most animals, but not exclusively all, melatonin has an antigonadotrophic effect. The seasonal changes in the number of hours per day that melatonin is secreted mediate the temporal coupling of reproductive activity to seasonal changes in day-length. These observations stimulated a search for a role for the pineal gland and melatonin in human reproduction. Clinical experience related to this issue has yielded inconclusive and sometimes conflicting results. This article reviews the current available evidence concerning the effects of melatonin on human reproductive processes (e.g., puberty, ovulation, pregnancy, and fertility). Possible reasons for the vagueness and elusiveness of the clinical effects are discussed.     

A longitudinal study from prepuberty to puberty of gingivitis

Abstract A longitudinal study of 24 subjects progressing normally from prepuberty to puberty was undertaken to evaluate the effects of sex hormone levels on clinical and microbiologic parameters and on serum antibodies. During elementary school, at the beginning of the longitudinal monitoring, 2 groups, 12 subjects with gingivitis and 12 gingivitis-free subjects, were selected and observed through puberty. Bone ages and self-assessment of secondary sex characteristics were used to confirm puberty. A statistically significant increase in the proportions of Prevotella intermedia including Prevotella nigrescens and serum antibody levels against P. intermedia was seen in gingivitis group throughout the longitudinal study. Serum levels of testosterone in boys and estradiol and progesterone in girls was positively correlated with levels of P. intermedia and P. nigrescens. In puberty, a slight but significant increase in GI scores over prepuberty has been shown; however, there was no significant change in PII from prepuberty to puberty. Our study confirmed that there was a statistically significant increase in gingival inflammation and in the proportion of P. intermedia and P. nigrescens in puberty relative to the baseline value, except in the gingivitis-free male group. Our findings suggest that these increases are correlated with elevation in systemic levels of the sex hormones.     

Evaluation of pubertal and pathological gynaecomastia in children: A single-center experience

Gynaecomastia in adolescents is a benign glandular proliferation of the male breast. Secondary causes of gynaecomastia in adolescents are relatively rare and may result from a wide variety of rare pathological conditions. Among these, klinefelter syndrome, complete androgen resistance, adrenal tumours and oestrogen-secreting testicular tumours, hypogonadism, hyperthyroidism, kidney disease and medications play a role in aetiology. The aim of our study is to review the demographic characteristics, hormone profile, aetiological characteristics of paediatric gynaecomastia patients admitted to a single center and to determine the frequency of pathological gynaecomastia. Forty-three male patients with gynaecomastia who applied to the paediatric endocrinology outpatient clinic were included in our study. Demographic characteristics, physical examination findings, hormone profile, breast ultrasonography and karyotype results of the patients were recorded. There were 43 male patients in our study. Thirty-six (83.7%) of the patients were pubertal gynaecomastia, 7 (16.2%) were pathological gynaecomastia. Three of the patients with pathological gynaecomastia were prepubertal gynaecomastia, 2 had klinefelter syndrome, 1 had hypergonadotropic hypogonadism after acute lymphoblastic leukaemia treatment and 1 had gynaecomastia after spirololactone use. Careful evaluation of patients with gynaecomastia is especially important in detecting pathological types. We reported the rare prepubertal gynaecomastia and klinefelter frequency in our study.