Luteinizing Hormone-releasing Hormone Test Research Articles

Idiopathic central precocious puberty in a Klinefelter patient: highlights on gonadotropin levels and pathophysiology

BackgroundIdiopathic central precocious puberty (ICPP) is supposed to be non-existent in a context of testicular destruction that is typically present in Klinefelter syndrome (KS). Herein, we describe a rare case of ICPP in a Klinefelter patient (47,XXY) with 2 maternal X chromosomes. Moreover, we highlight the differences in gonadotropin levels in comparison to males with ICPP and a normal karyotype.Case presentationAn 8 years old boy with a history of cryptorchidism was evaluated for precocious puberty (Tanner staging: P2/G3). Both testes measured 25x35mm. His hormonal profile confirmed a central origin of precocious puberty with high serum testosterone (4.3 ng/ml), luteinizing hormone [LH (3.5 UI/l)] and follicle stimulating hormone [FSH (7.7 UI/l)] levels. Luteinizing hormone-releasing hormone (LHRH) test amplified LH and FSH secretion to 24 and 14 UI/l respectively. Brain magnetic resonance imaging (MRI) was normal. No MKRN3 mutation was detected. He was treated for ICPP for two years. During puberty, he suffered from hypergonadotropic hypogonadism leading to the diagnosis of KS (47,XXY karyotype). Chromosomal analysis by fluorescent multiplex polymerase chain reaction (PCR) using X chromosome microsatellite markers identified 2 maternal X chromosomes.Analysing 8 cases of KS developing ICPP (our reported case and 7 other published cases) revealed that these KS patients with ICPP have higher LH and FSH levels during ICPP episode than in ICPP patients with a normal karyotype (ICPP with KS vs ICPP with a normal karyotype: LH levels 9.4 ± 12 vs 1.1 ± 0.6 UI/l; FSH levels 23.1 ± 38.5 vs 2.7 ± 1.5 UI/l). Furthermore, their response to gonadotropin-releasing hormone (GnRH) stimulation is characterized by excessive LH and FSH secretion (LH levels post-GnRH: 58 ± 48 vs 15.5 ± 0.8 UI/l; FSH levels post-GnRH: 49.1 ± 62.1 vs 5.7 ± 3.9 UI/l).ConclusionsICPP in boys is extremely rare. The pathophysiology of ICPP in KS is unknown. However, maternal X supplementary chromosome and early testicular destruction may play a significant role in the initiation of ICPP, in part explaining the relative “overrepresentation of ICPP in KS. Thus, karyotype analysis could be considered for boys suffering from ICPP, especially if testicular size is smaller or gonadotropins are significantly elevated.

Changes in Body Mass Index in Girls with Idiopathic Central Precocious Puberty under Gonadotropin-Releasing Hormone Analogue Therapy: The Spanish Registry

Background: The influence of gonadotropin-releasing hormone analogue (GnRHa) treatment on body mass index (BMI) evolution in girls with idiopathic central precocious puberty (CPP) is unclear. Hence, we aimed to evaluate the effect of GnRHa treatment on BMI-standard deviation score (SDS) from diagnosis of idiopathic CPP until adult height. Methods: An observational study of girls diagnosed with CPP in Spain was carried out between January 2008 and December 2014. A computer program was designed to process clinical and biological data from patients treated in 55 departments of pediatric endocrinology throughout the country. The inclusion criteria were (1) girls diagnosed with CPP before 8 years of age; (2) born after 1992; (3) with a difference between bone and chronological age of at least 1 year, and (4) with a luteinizing hormone peak >7 U/l during luteinizing hormone-releasing hormone testing. The influence of GnRHa treatment on BMI-SDS evolution was analyzed. Results: Data from 333 girls (22.2% adopted) were evaluated. We report follow-up data at 6, 12, 24, 36, 48 and 60 months and adult height from 269, 232, 198, 153, 105, 56 and 49 girls, respectively. During treatment, there was an increase in BMI-SDS of 0.43 ± 1.17 (95% CI: 0.20-0.64). At adult height (n = 49), BMI-SDS was 1.51 ± 1.38, which was 0.60 ± 1.09 higher than at diagnosis (95% CI: 0.43-0.75). Conclusions: During treatment with GnRHa, girls experience a significant increase in BMI-SDS that persists after therapy is stopped and adult height has been reached.

Mutational analysis of KISS1 and KISS1R in idiopathic central precocious puberty

The genetic background of idiopathic central precocious puberty (ICPP) is not well understood. The genetic activation of pubertal onset is thought to arise from the effect of multiple genes. Familial ICPP has been reported suggesting the existence of monogenic causes of ICPP. Kisspeptin and its receptor are found to be involved in gonadotropin-releasing hormone (GnRH) secretion and puberty onset. Mutations in their genes, KISS1 and KISSR, have been suggested to be causative for ICPP. ICPP was defined by pubertal onset before 8 years of age in girls, and a pubertal luteinizing hormone (LH) response to GnRH testing. Twenty-eight girls with ICPP were included in the study [age at diagnosis was 5.72±2.59, with a mean bone age advancement of 1.4 years (-0.1 to 2.8). Height at onset of therapy in SD score was 0.90±1.48 for age]. Luteinizing hormone-releasing hormone test was performed in all subjects, and all of them had a pubertal response (LH 20.35±32.37 mIU/mL; FSH 23.32±15.72 mIU/mL). The coding regions of KISS1 and KISS1R were sequenced. No rare variants were detected in KISS1 or KISS1R in the 28 subjects with ICPP. We confirmed that mutations in KISS1 and KISS1R are not a common cause for ICPP.

First case of a Japanese girl with Myhre syndrome due to a heterozygous SMAD4 mutation

This article reports the first case of a Japanese girl with molecularly confirmed Myhre syndrome (MS). The patient was 9 years old at her first visit, and she had been diagnosed with unknown skeletal dysplasia. Her phenotype fulfilled the clinical and radiological criteria for MS, such as typical facies with prognathism, hearing impairment, short stature, square body shape, and limited joint mobility. The thick calvarium and thick skin were clues to the clinical diagnosis of MS. A heterozygous mutation in the mothers-against-DPP homolog 4 (SMAD4) gene has been reported to cause MS. We sequenced SMAD4 using standard PCR-based technique and identified a recurrent mutation (p.Ile500 Thr). She attained menarche before 11 years of age; however, she developed oligomenorrhea after a few years of 40-day cycles, necessitating hormone replacement therapy. The luteinizing hormone-releasing hormone (LHRH) tests suggested abnormalities related to hypothalamo-hypophyseal malfunction. Previous reports on MS described early menarche in girls and early or delayed puberty and cryptorchidism in boys. Therefore, we recommend performing an endocrinological evaluation of the hypothalamo-hypophyseal-gonadal axis in patients with MS to clarify whether hormonal abnormalities are associated with the syndrome.

Successful pregnancy after the treatment of primary amenorrhea in a patient with non‐classical congenital adrenal hyperplasia

We describe a case of non-classical congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency in a 30-year-old Japanese woman who achieved pregnancy after treatment of primary amenorrhea. Hirsutism and clitoromegaly were present. Ultrasound examination showed polycystic appearance of the ovary. Luteinizing hormone-releasing hormone (LH-RH) test resulted in exaggerated LH response, showing a polycystic ovary syndrome (PCOS) pattern. The diagnosis was based on the elevated intial levels of 17-hydroxyprogesterone (55 ng/mL) and dihydroepiandosterone (7780 ng/mL). The first withdrawal bleeding occurred within 6 weeks after treatment with hydrocortisone (20 mg/day) combined with conjugated estrogens (1.25 mg/day) and medroxyprogesterone acetate (10 mg/day), which were continued for five courses. The bleeding remained cyclic every 28 days with maintenance doses of hydrocortisone. Subsequently, ovulation was induced using clomiphene citrate (100 mg/day). Pregnancy was achieved at the second attempt of ovulation induction and was within 10 months after initial presentation. Continuing hydrocortisone, the patient delivered a healthy baby at term.

Luteinizing hormone-releasing hormone (LH-RH) treatment for inducing clomiphene response in anovulatory patients with hypogonadotropic hypogonadism.

LH-RH was administered to anovulatory patients with hypogonadotropic hypogonadism to convert them to clomiphene responders. This synthetic decapeptide was injected intramuscularly in doses of 100 μg twice a week for six weeks. Diagnostic tests of progestin, LH-RH and gonadotropin were performed before and after LH-RH treatment. Seven out of nine patients became clomiphene or clomiphene-hCG responders after one course of treatment. One patient became a clomiphene-hCG responder after one additional course of treatment. One patient with hypothyroidism did not respond to clomiphene citrate with two courses of treatment. The results of the progestin test and gonadotropin test and the basal E2 levels after this treatment were correlated with the ovulatory response to clomiphene therapy or to clomiphene-hCG therapy after LH-RH treatment. But basal gonadotropin levels and the mode of gonadotropin responses of the LH-RH test were not necessarily correlated with the ovulatory response to clomiphene or clomiphene-hCG therapy after LH-RH treatment.

Clinical evaluation of the luteinizing hormone-releasing hormone (LH-RH) test in cases with anatomically verified disorders of the hypothalamo-pituitary region.

The effect of slow intravenous infusion of luteinizing hormone-releasing hormone (LH-RH) on serum LH was studied in 58 patients with anatomically verified hypothalamo-pituitary disorders as well as in control groups. Normal responses to the LH-RH test were found in 15 out of 15 cases with intrasellar pituitary tumours and in five out of six cases after transsphenoidal surgery for an intrasellar pituitary tumour. Twenty-one out of 25 patients where a pituitary tumour with both supra- and intrasellar extension had been removed had pathological responses to the test. All eight patients with hypothalamic disorders, mainly tumours not directly influencing the pituitary, gave normal responses to the LH-RH tests. Out of four patients with hypothalamopituitary malformations a pathological response to the LH-RH infusion was found in three cases and a normal response in one case. The increase of serum LH after LH-RH infusion was pronounced and rather constant in males and post-menopausal women. It was more difficult to evaluate a “normal” test response in women of fertile ages because of the great variations during the different menstrual phases. It is concluded that the LH-RH test may be of importance in the investigation of patients with suspected tumours of the pituitary as well as for differential diagnosis between hypothalamic and pituitary disorders of gonadotropin secretion.

Evaluation of Semen Quality, Endocrine Profile and Hypothalamus-Pituitary-Testis Axis in Male Patients With Homozygous β-Thalassemia Major

The endocrine profile, hypothalamus-pituitary-testis axis and semen quality were evaluated in male patients with homozygous beta-thalassemia major. A total of 168 male patients 18 years or older with homozygous beta-thalassemia major were enrolled in the study and 84 healthy age matched male volunteers served as controls. All subjects provided a medical history and underwent physical examination and routine semen analysis. Two blood samples were drawn from each participant at 20-minute intervals to determine the resting levels of certain hormones, including luteinizing hormone, follicle-stimulating hormone, prolactin, testosterone, estradiol, insulin-like growth factor-1 and insulin like growth factor binding protein-3. The hypothalamus-pituitary-testis axis was also assessed using the luteinizing hormone-releasing hormone test. The prevalence of hypogonadotropic hypogonadism was 76.2% (128 patients). Of the studied patients with homozygous beta-thalassemia major 75 (44.6%) were short. Compared with normal controls the patients with homozygous beta-thalassemia major had lower serum luteinizing hormone, follicle-stimulating hormone, insulin-like growth factor-1, insulin-like growth factor-1 binding protein-3 and testosterone. In addition, there were decreased luteinizing hormone and follicle-stimulating hormone responses to luteinizing hormone-releasing hormone in patients with homozygous beta-thalassemia major compared to those in normal controls. Total sperm count, sperm motility and percent normal sperm morphology were lower in patients with homozygous beta-thalassemia major than in controls. Most subjects with beta-thalassemia major have hypogonadotropic hypogonadism state, impairment fertility and growth retardation. Further studies are warranted to better clarify the causes and consequences of hypogonadotropic hypogonadism in patients with homozygous beta-thalassemia major.

Two novel GnRHR gene mutations in two siblings with hypogonadotropic hypogonadism

Mutations in the gonadotropin-releasing hormone receptor (GnRHR) gene are the cause of isolated hypogonadotropic hypogonadism (HH). We describe the molecular investigations of the GnRHR gene in two siblings affected by HH and their clinical course. The female was referred at age 14 for pubertal delay with no secondary sexual signs, whereas the male had been followed since prepuberty. Hormonal evaluation showed very low levels of gonadotropins, luteinizing hormone-releasing hormone test (LHRH test) and sexual steroids in both patients, suggesting a possible defect in the mechanism of action of the GnRH gene on its receptor. The GnRHR gene of the two siblings and their parents were analyzed by PCR followed by direct sequencing. Two new single nucleotide substitutions resulting in the T104I and the Y108C substitutions in the first extracellular loop (ECL1) were identified in both siblings. The molecular analysis confirmed the carrier status of the parents. We identified two new missense mutations in the GnRHR gene in two siblings with HH. The nature of the substitutions lying in the ECL1 involved in the ligand-receptor interaction, as well as the high conservation of the two residues in all mammalian GnRHR, are suggestive of some implications in the phenotype observed.

Persistent neonatal hypoglycaemia as a result of hypoplastic pituitary gland

An Indonesian female infant developed hypoglycaemia shortly after delivery by lower segment caesarean section. Following admission to the neonatal intensive care unit, she continued to have episodes of hypoglycaemia despite adequate glucose intake of up to a maximum of 12 mg/kg/minute. During the episodes of hypoglycaemia, repeated measurement of her blood samples revealed persistently low levels of serum insulin of <2 IU/ml, serum free thyroxine of 4.78 pmol/litre, thyroid stimulating hormone of 0.31 uIU/ml and growth hormone of 0.27 mIU/litre, all suggesting a diagnosis of hypopituitarism. Empirical replacement therapy with hydrocortisone (10 mg four times daily) was started at 26 days. However, her hypoglycaemic attacks ceased only with commencement of additional hormone replacement therapy of growth hormone (0.1 mg once daily for 6 days per week) and thyroxine (50 μg once daily). The hydrocortisone dose was gradually tailed to a maintenance dose of 2.5 mg twice daily. Stimulatory tests such as adrenocorticotropic hormone and luteinizing hormone-releasing hormone tests and posterior pituitary function were not performed at that time as the infant developed Klebsiella pneumoniae and coagulase negative staphylococcus sepsis which may have affected the test results. A magnetic resonance imaging (MRI) scan of her brain at 1 month of age showed a hypoplastic pituitary gland with a shallow pituitary fossa (Figure 1). The posterior lobe of the gland was undescended, lying ectopic at the base of the third ventricle with an absent pituitary stalk (Figure 2). The rest of the MRI was normal with no associated anomalies of the midline forebrain structures. No abnormalities were detected in detailed opthalmological examination of her eyes excluding the possibility of septo-optic dysplasia. When followed up at 8 months of age, she remained well with improved hormonal profiles and normal levels of serum urea and electrolytes. Her weight, height and occipito-frontal circumference were all below the third percentile.

Ovarian cysts and tumors as the cause of isosexual pseudoprecocious puberty

Precocious puberty in girls is generally defined as appearance of secondary sexual characteristics before eight years of age. Menarche before the ninth birthday may serve as an additional criterion. Precocious puberty is divided in central precocious puberty and pseudoprecocious puberty. Central precocious puberty (GnRH dependent) occurs because of premature activation of hypothalamic-pituitary-gonadal axis and activity of gonadotrophins. Pseudoprecocious puberty (GnRH independent) is caused by activity of sexual steroids that are not the result of gonadotrophin activity. Objective of our study was to examine the etiology, clinical and laboratory manifestations of isosexual pseudoprecocious puberty in girls. In the period between 1995 and 2004, clinical and laboratory sings of 34 girls with precocious puberty were studied at the Endocrine Department of the Institute of Mother and Child Health Care of Serbia. Initial evaluations included height measurement, staging of puberty, bone age assessment and pelvic ultrasound. Important diagnostic sonographic parameters of precocious puberty were the volumes of ovaries and uterus as well as ovarian structure. The initial hormonal evaluation included measuring of plasma oestradiol, luteinizing hormone (LH) and follicle stimulating hormone (FSH). The luteinizing hormone releasing hormone (LHRH) stimulation test was used to evaluate LH and FSH responsiveness (60 microg/m2 LHRH-Relefact LHRH, Ferring). Blood samples were collected at 0, 20 and 60 minutes. Basal and GnRH stimulated LH and FSH were determined by immunoradiometric assay. Estradiol concentration was measured using the fluoroimmunometric assay. Thirty-four girls aged 6 months to 9 years (mean age 4.5 years) with precocious puberty were studied during the period of 9 years. Eleven girls presented with breast development, six with vaginal bleeding and seventeen with signs of puberty. On the basis of clinical signs, bone age, estradiol levels and LHRH test, premature thelarche was diagnosed in eleven patients (32.4%), premature menarche in six (17.6%) and central precocious puberty in ten girls (29.4%). Seven girls (20.6%) presented with pseudoprecocious puberty. Pelvic ultrasound examination revealed unilateral ovarian cysts in six patients and granulosa cell tumor in one. Elevated estrogen serum levels and failure of gonadotropin responses after gonadotropin releasing hormone were the classical findings in patients with isosexual pseudoprecocious puberty during the acute period of disease. In four patients, the cyst decreased spontaneously after several months, while in two patients, the cyst was removed by laparotomy. Surgical treatment was performed in a patient with granulosa cell tumor. Our work demonstrates that autonomous functional ovarian follicle cyst is the most often cause of isosexual pseudoprecocious puberty. Short period of observation is suggested because the cyst can resolve spontaneously. On the other hand, juvenile granulosa cell tumor, as highly malignant tumor, should be removed as soon as diagnosis is established.

P181 - Pseudo-pubertés précoces révélatrices d’un corticosurrénalome malin

Trente huit enfants ont été traités pendant au moins 2 ans pour une puberté précoce par un analogue retard du LH-RH. Ce traitement a été bien toléré. Il entraîne une régression des caractères secondaires, une diminution de la vitesse de croissance, un ralentissement de la maturation osseuse, une inhibition de la sécrétion des gonadotrophines hypophysaires et une normalisation des stéroïdes sexuels. La normalisation du rapport âge statural/âge osseux fait espérer une amélioration de la taille définitive.Chronic administration of luteinizing hormone-releasing hormone (LH-RH) is currently considered as the most appropriate therapy of precocious puberty. A delayed release preparation of D-Trp-6-LH-RH (Décapeptyl ® in microcapsules) designed to release the agonist for 28 days after intramuscular injection of 60 μg/kg body wt was given to 12 boys and 26 girls with precocious puberty. Plasma levels of gonadotropins and sex steroids were suppressed to prepubertal levels within 3 weeks, whilst pituitary responses to LH-RH test were almost abolished within 7 weeks.A significant improvement of secondary sex characteristics, as well as gonadal size, was observed within 6 months. Growth velocity (cm/yr, mean ± SD) was reduced in boys and girls from 9.9 ± 3.4 and 9.6 ± 3.3 respectively before treatment to 5.2 ± 1.0 and 5.3 ± 1.3 respectively during the third year of treatment. The mean ratio height age/bone age was just before treatment 0.91 in boys and 0.88 in girls and increased to 1 after 3 yr of treatment. This study shows that Decapeptyl in microcapsules induced a prolonged suppression of gonadal function and a relative blockade of bone maturation. A significant improvement of adult height relative to the effect of conventional treatments should be expected.

Hypogonadotropic hypogonadism and hematologic phenotype in patients with transfusion-dependent beta-thalassemia.

To determine the prevalence and risk factors of hypogonadotropic hypogonadism in transfusion-dependent patients with thalassemia. The authors examined 29 patients with thalassemia major aged 15 years or older. Luteinizing hormone-releasing hormone tests were performed and beta-thalassemia mutations were analyzed by direct sequencing. The prevalence of hypogonadotropic hypogonadism was 72%. Failure of puberty was observed in 5 of 11 (45%) boys and 7 of 18 (39%) girls. Arrested puberty was noted in two boys (18%) and five girls (28%). Ten girls (56%) did not menstruate, two (11%) had regular menstrual cycles, one (6%) had irregular menstrual cycles, and five (28%) developed secondary amenorrhea. Twenty-one and eight patients had the beta 0/beta 0 and beta 0/beta+ hematologic phenotypes, respectively. beta 0-thalassemia mutation alleles involved IVS II-654 (C-T), codons 41/42 (-TCTT), codons 27/28 (+C), and codons 17 (A-T). beta+-thalassemia mutations alleles were -28 (A-G) and HbE (codons 26(GAG-AAG)). Hematologic phenotype (odds ratio, 28.50; P = 0.002) was the only risk factor identified in the logistic regression analysis. In patients with thalassemia major, genetic differences may influence their susceptibility to hypogonadotropic hypogonadism, possibly as a result of differences in the amounts of blood transfused and/or their vulnerability to free radical damage. The hematologic phenotype is a main determinant of the severity of thalassemia major; hence, it may influence the need for and frequency of blood transfusion and the patient's iron-overload status.

Effects of Long-Term Erythropoietin Therapy on the Hypothalamo–Pituitary–Testicular Axis in Male Capd Patients

Gonadal dysfunction has been recognized for a long time in uremic male patients. The present study assesses the hypothalamo-pituitary-testicular axis and growth hormone status in male continuous ambulatory peritoneal dialysis (CAPD) patients, before and after recombinant human erythropoietin (rHuEPO) therapy. Single-center prospective study. Ten anemic male patients with chronic renal insufficiency, and 11 healthy volunteers with normal renal function, matched for age, were included in the study. All patients were on CAPD therapy and none had received rHuEPO treatment previously. Blood samples were collected between 0800 and 0900 hr from all patients for the determination of basal follicle stimulating hormone (FSH), luteinizing hormone (LH), and growth hormone (GH) levels. A luteinizing hormone-releasing hormone (LH-RH) stimulation test was carried out using LH-RH 100 microg intravenous as a bolus injection. Blood for FSH, LH, and GH determinations was drawn every 30 minutes during the 3-hour test period. Human chorionic gonadotropin (hCG) test was performed after 48 hours. After estimations of basal serum total and free testosterone levels, 2000 IU hCG was administered intramuscularly and repeated 48 hours later. Total and free testosterone levels were measured in blood samples collected before and 48 hours after two injections of hCG. After improvement in anemia with exogenous rHuEPO, LH-RH and hCG tests were repeated. Baseline FSH concentrations before and after rHuEPO treatment were slightly higher in CAPD patients than in healthy volunteers (p = 0.85 and p = 0.70, respectively). Areas-under-the-curve (AUCs) for FSH secretion before and after rHuEPO treatment were also slightly higher in patients than in healthy volunteers (p = 1.00 and p = 0.75, respectively). The pretreatment basal LH levels in patients were significantly higher than in controls (p < 0.001). After the improvement in anemia with rHuEPO, serum LH levels declined significantly (p < 0.05). The AUCs for LH secretion before and after rHuEPO treatment were significantly higher in patients than in controls (p < 0.05). All patients had elevated basal levels of GH with paradoxical response to LH-RH. Baseline GH levels in patients were significantly higher than those in healthy subjects (p < 0.001) before rHuEPO treatment. After treatment with rHuEPO, basal GH levels declined but did not normalize, and baseline levels of free testosterone increased significantly (p < 0.05). Anemic uremic male patients on CAPD have normal levels of testosterone with normal response to hCG administration, elevated basal levels of GH, and elevated basal levels of LH, with exaggerated response to LH-RH administration. Improvement in anemia with rHuEPO reduced the basal levels of LH and GH, but exaggerated the LH response; paradoxical GH response to LH-RH administration persisted. These results indicate a defect at the level of the hypothalamus and pituitary gland in uremic male patients undergoing CAPD, and that the improvement in anemia with rHuEPO partially restores some of these endocrine abnormalities.

Prolonged activation of the hypothalamus– pituitary–gonadal axis in a child with X‐linked adrenal hypoplasia congenita

X-linked adrenal hypoplasia congenita (AHC) is a rare developmental disorder of the human adrenal cortex that is caused by a mutation of the DAX-1 gene, a member of the nuclear hormone receptor superfamily. Hypogonadotrophic hypogonadism is frequently associated with this disease and the DAX-1 mutation is known to impair gonadotrophin production by acting at both the hypothalamic and pituitary levels. However, three recent studies reported that the hypothalamic-pituitary-gonadal axis was active in six infants with AHC, suggesting that a difference exists in the central regulation of hypothalamic-pituitary-gonadal activity between infant boys and pubertal boys. To determine the effect of the DAX-1 gene mutation on the axis in early childhood, we measured testosterone, LH, and FSH and performed LH-releasing hormone tests on a boy with AHC from birth to 3 years of age. Surprisingly, our findings showed that the axis was active from the infantile period to 3 years of age. This delayed initiation of the prepubertal pause, or prolonged activation of the axis, indicates that the DAX-1 gene is related to the control mechanism of the prepubertal restraint of gonadotrophin secretion.

The roles of insulin sensitivity, insulin-like growth factor I (IGF-I), and IGF-binding protein-1 and -3 in the hyperandrogenism of African-American and Caribbean Hispanic girls with premature adrenarche.

Recent reports indicate that girls with premature adrenarche are at risk of developing functional ovarian hyperandrogenism and polycystic ovarian syndrome (PCOS). As insulin and insulin-like growth factors (IGFs) have been implicated in the pathogenesis of PCOS, we hypothesize that they may also have a role in the hyperandrogenism of premature adrenarche. Thirty-five prepubertal girls (23 Caribbean Hispanics and 12 Black African-Americans) underwent a 60-min ACTH and LH-releasing hormone test. Insulin sensitivity (S(I)) was assessed using the frequently sampled i.v. glucose tolerance test with tolbutamide. Fasting levels of IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, sex hormone-binding globulin, and free testosterone (T) were also obtained. The mean age of the patients was 6.8 yr, and bone age was 8.0 yr. Twenty-five patients had a family history of noninsulin-dependent diabetes mellitus and 19 patients had acanthosis nigricans. The mean S(I) for the entire group was 6.78 +/- 5.21 x 10(-4) min/microU x mL (normal prepubertal S(I), 6.5 +/- 0.54 x 10(-4) min(-1) x microU(-1) x mL(-1)). However, 15 of the 35 girls had an S(I) that was more than 2 SD below the mean reported for normal prepubertal children. Of these 15 patients, 13 were obese, and 14 had acanthosis nigricans. For the entire group of girls, the mean ACTH-stimulated levels of 17-hydroxypregnenolone (17OHPreg), dehydroepiandrosterone (DHEA), androstenedione (AS), 17-hydroxyprogesterone (17OHP), and T and the ACTH-stimulated ratios of 17OHPreg/17OHP, 17OHPreg/DHEA, 17OHP/AS, and DHEA/AS did not differ from the levels reported for Tanner stage II-III pubertal girls. The girls were divided into two groups based on their S(I) (group I, S(I) >2 SD below the mean for age; group II, normal S(I)). The group I girls with a reduced S(I) had significantly higher ACTH-stimulated levels of 17OHPreg (group I, 760 +/- 87.84 ng/dL; group II, 428.9 +/- 46.28 ng/dL; P = 0.002), 17OHPreg/17OHP ratio (group I, 3.95 +/- 0.36; group II, 2.96 +/- 0.35; P = 0.05), 17OHPreg/DHEA (group I, 2.06 +/- 0.21; group II, 1.4 +/- 0.13; P = 0.01), and free T (group I, 1 +/- 0.23 ng/dL; group II, 0.49 +/- 0.19 ng/dL; P = 0.014). Levels of sex hormone-binding globulin were lower in the group I girls. Furthermore, for the entire group of girls, the S(I) correlated inversely with ACTH-stimulated levels of 17OHPreg, DHEA, and AS and the ACTH-stimulated ratio of 17OHPreg/17OHP. IGF-I correlated inversely with S(I) (r = -0.94; P < 0.001) and correlated directly with the ACTH-stimulated levels of 17OHPreg (r = 0.8; P < 0.001) and AS (r = 0.63; P < 0.05). IGF-I also correlated with the ACTH-stimulated ratios of 17OHPreg/17OHP (r = 0.61; P < 0.05), 17OHPreg/DHEA (r = 0.9; P < 0.001), 17OHP/AS (r = 0.79; P < 0.001), and DHEA/AS (r = 0.96; P < 0.001). IGFBP-1 correlated inversely with the ACTH-stimulated levels of 17OHPreg (r = -0.38; P < 0.05) and DHEA (r = -0.36; P < 0.05). To summarize, the ACTH-stimulated delta5-steroid levels were higher in prepubertal girls with premature adrenarche and reduced S(I). There was a significant inverse correlation among ACTH-stimulated hormone levels, S(I), and IGFBP-1, whereas IGF-I correlated directly with ACTH-stimulated androgens. These findings support the hypothesis that insulin and IGFs may have a role in the hyperandrogenism of premature adrenarche just as they do in PCOS. Hence, in certain girls with premature adrenarche, hyperandrogenism may be the first presentation of PCOS and/or insulin resistance.

Persistence of Autonomous Ovarian Activity After Discontinuation of Therapy for Precocious Puberty in McCune-Albright Syndrome

ObjectiveThe aim of this study was to evaluate the possibility of persistence of autonomous ovarian activity in girls with McCune-Albright syndrome (MAS) after withdrawal of medroxyprogesterone therapy administered for precocious puberty. Design, Setting, and ParticipantsFive girls with MAS were followed-up 1.2 to 8.5 years after the end of treatment. The girls underwent luteinizing hormone-releasing hormone (LH-RH) tests, estradiol (E2) basal measurement, and pelvic ultrasound two times in the follow-up period. ResultsMenses resumed in four of five girls, 1.4±0.9 years after the end of treatment, at chronologie age of 11.3±1.3 years. Cycles for all girls were irregular. Three patients presented inadequate E2 levels (from 56 to 320pg/mL) associated with low or absent gonadotropin response to LH-RH tests. The pelvic ultrasoundshowed ovarian cysts at the time of the study. ConclusionThese hormonal and ultrasonographie findings provide evidence of persistenceof autonomousovarian activity in some young women with MAS.

Long-term administration of pulsatile gonadotropin-releasing hormone for exploration of pituitary functionality in amenorrheic patients

Differentiation between hypothalamic and pituitary amenorrhea is generally based on the luteinizing hormone-releasing hormone (LHRH) test (whether as a single dose, two consecutive doses, or pulsatile over 5- 10 days), together with high-resolution imaging (computed tomography or magnetic resonance) of the sellar region. Long-term administration of gonadotropin-releasing hormone (GnRH) is generally used only for ovulation induction, and not for diagnostic purposes. Here, wereport the results of long-term administration of GnRH to 19 women initially diagnosed as suffering from hypothalamic amenorrhea on the basis of LHRH testing and computed tomography imaging. During treatment, subjects received 20-μg pulses of GnRH every 90 min, subcutaneously from a portable infusion pump. Fourteen subjects responded (i.e. ovulated) during the first treatment cycle; one subject menstruated but did not ovulate during the first cycle, and then dropped out of the study; the remaining four subjects did not ovulate or menstruate despite at least three treatment cycles. Magnetic resonance imaging of the sellar region of these four subjects revealed pituitary lesions (partially empty sella in three cases, microadenoma in one case) which had not been detected by computed tomography. By contrast, no such abnormalities were detected in the nine responders who agreed to undergo magnetic resonance imaging. These findings suggest that long-term administration ojGnRHis of value not onlyforovulation induction but also for diagnostic purposes. Specifically, an initial diagnosis of hypothalamic amenorrhea is confirmed if there is a positive ovulation response after two GnRH treatment cycles; otherwise, pituitary amenorrhea should be suspected. Our results also suggest that magnetic resonance imaging is more effective than computed tomography for the detection of partially empty sella.

Gonadotropin therapy in males with hypogonadotropic hypogonadism: factors affecting induction of spermatogenesis after gonadotropin replacement.

Sixteen patients with hypogonadotropic hypogonadism received gonadotropin replacement therapy. Two patients treated with HCG alone showed induction of spermatogenesis 2 and 12 months after the start of treatment. Three subjects receiving combination therapy showed sperm appearance 6-28 months after treatment. The patients showing sperm appearance, whose testicular volume was > or = 4 ml, showed a higher sperm count and impregnated their partners, although no relationship was found between pretreatment testicular volume and sperm appearance. The response to HCG test correlated with sperm appearance after gonadotropin therapy. Sperm appearance was not observed in any subject except for one who showed no response to luteinizing hormone-releasing hormone (LH-RH) test and none of the patients without response of FSH to LH-RH demonstrated any induction of spermatogenesis. In conclusion, the responses to LH-RH test and possibly to HCG test could predict the induction of spermatogenesis after gonadotropin replacement therapy, and a large testicular volume is associated with post-treatment fertility.

LHRH Test in the Assessment of Puberty in Normal Children

We compared the performance of a sensitive immunoradiometric assay for luteinizing hormone (LH) with a standard radioimmunoassay and assessed the utility of a single LH determination after a standard dose of LH-releasing hormone (LHRH) in distinguishing pubertal from prepubertal state. Nocturnal integrated LH concentration and LH response to a standard LHRH test were assessed in 56 normal children aged 6-17 years. For each assay we examined sensitivities at fixed specificities and areas under the receiver-operator characteristic curves. The results show that: (1) the immunoradiometric assay exhibits better test performance; (2) a single blood sample 30, 45, or 60 min after LHRH administration is as useful to distinguish pubertal from prepubertal state in normal children as the peak LH estimated by multiple blood sampling, and (3) a single cutoff level for IRMA LH can be applied to these time points.