LH-RH and HCG studies in a Turner phenotype male (Noonan's syndrome). A case report.

LH-RH and HCG stimulation tests were performed in a prepubertal 13-year-old boy with Noonan's syndrome. The basal plasma LH (0.8 mIU/ml) was normal and FSH (2.5 mIU/ml) high, with an elevated response of both LH (8.3 mIU/ml) and FSH (9.6 mIU/ml) to LH-RH, as seen in primary hypogonadism. However, the patient had a normal testosterone response to HCG (437 ng%). These conflicting test results illustrate the difficulty of predicting potential for fertility in patients with Turner phenotype male.     

Puberty in 24 patients with Klinefelter syndrome

Twenty four boys with Klinefelter syndrome, 18 of whom were diagnosed prepubertally, were observed until adulthood. Onset of puberty, as judged from testicular enlargement and pubic hair development, occurred between 11 to 14 years in the above 18 patients. By the age of 17 pubic hair, penile length and height had reached the adult stage in all patients, but arrest of testicular growth was noted at midpuberty, 13 years, with maximal mean (±SD) volume attained being 3.5±1.5 ml. The first conscious ejaculation was reported to have occurred between 13 to 16 years in 10 patients and in the remaining 4 between 17 to 18 years of age. Sperm counts obtained after the age of 18 revealed azospermia or severe oligospermia in all patients except one, who had a sperm count of 30×10⁶/ml. The hypothalamic-pituitary-gonadal axis, assessed by LH-RH and hCG stimulation tests, was found to be normal in prepuberty and during early pubertal stages. From mid-puberty the basal levels of plasma FSH and the response to LH-RH showed a gradual increase above the normal. Towards late puberty (>15 years) basal and peak levels of LH were above normal with a concomitant decrease in the basal level of testosterone and its response to hCG.These findings indicate that during childhood and early puberty function of the hypothalamic-pituitary-gonadal axis is normal in Klinefelter syndrome, allowing the onset of pubertal signs at the appropriate age, and that until late puberty there is a relative preservation of function in the testicular Leydig cells, permitting the normal sequential development of the androgen-dependent pubertal signs. The measurement of testicular testosterone reserve by means of hCG stimulation constitutes a useful aid in determining when and if testosterone replacement therapy should be instituted.     

Effect of synthetic luteinizing hormone-releasing hormone on the release of gonadotropins in hypophysogonadal disorders of children and adolscents. VII. Constitutional delay of puberty in males.

Serum gonadotropins (LH and FSH) were measured by radioimmunoassay before and after intravenous injection of 0.1 mg/m2 of synthetic luteinizing hormone-releasing hormone in 20 male patients, aged 15 to 18 years, with constitutional delay of puberty. Basal plasma levels of LH and FSH were in the prepubertal range. After administration of LH-RH, the increase in LH was significantly high than in prepubertal control subjects, aged 1 to 13 years; the difference between test patients and pubertal control subjects was not significant. The increase in FSH was in the prepubertal range, significantly lower than that in pubertal control subjects. This discrepancy between LH and FSH responses to LH-RH is similar to that observed in normal boys at the late prepubertal stage and suggests that an elevation of readily releasable pituitary stores of LH correlates with the first step of pubertal onset in males, even if puberty is delayed.     

Father-to-son transmission of hypogonadism with anosmia: Kallmann's syndrome.

Gonadal and olfactory features of Kallmann's syndrome, usually considered to be inherited as an X-linked recessive trait, were found in a father and son who both had cryptorchidism, hypogonadism, and hyposmia. The father's fertility had been induced with chorionic gonadotropin, leading to the birth of three children. Olfactory and gonadal functions were normal in the mother and two siblings. The father had low basal plasma testosterone and subnormal follicle stimulating hormone (FSH) response to luteinizing hormone-releasing hormone (LH-RH). The affected son and his healthy brother were prepubertal. Their basal plasma total and free testosterone, serum FSH and luteinizing hormone (LH), and response to LH-RH were similar. The clinical presentation and formal olfactory function studies were considered most helpful for the suggestive diagnosis of Kallmann's syndrome in children. The occurrence of this syndrome in this family is consistent with autosomal dominant inheritance.     

Gonadotrophin response to LH-RH in boys with delayed growth and adolescence.

Plasma luteinising hormone (LH) and follicle-stimulating hormone (FSH) concentrations were measured before and after intravenous luteinising hormone-releasing hormone (LH-RH) in 33 boys with growth delay. Eighteen were prepubertal and 15 pubertal. Basal LH and FSH levels were low in both groups with mean increments after LH-RH of 3.2 +/- 0.8 U/l (mean +/- SEM) and 2.6 +/- 0.4 U/l respectively in the prepubertal and 7.4 +/- 0.7 U/l and 2.0 +/- 0.3 U/l in the pubertal boys. The LH increment showed a positive correlation with increasing bone age (r = 0.71, P less than 0.001); FSH did not. The LH-RH response thus appeared normal in relation to the stage of maturity.     

Primary gonadal failure and precocious adrenarche in a boy with Prader-Labhart-Willi syndrome

A 7-year-old boy with Prader-Labhart-Willi syndrome who had precocious adrenarche was found to have primary gonadal failure, as evidenced by appropriate laboratory investigations: elevated basal levels of plasma FSH and LH with exaggerated responses to LH-RH stimulation and unresponsiveness of plasma testosterone to repeated hCG stimulations. The elevated values of plasma DHEA which were found indicate an early activation of the adrenal gland. This patient demonstrates the varibility of pubertal development in the Prader-Labhart-Willi syndrome, with the unusual association of primary gonadal failure and precocious adrenarche.     

Activity of the hypophyso-gonadal axis in premature boys

Postnatal evolution of testosterone, LH and FSH plasma levels was studied in 30 premature boys. Increase in LH and testosterone levels at the age of 2 months was found in these children as in full-term children; both parameters were positively correlated. Activation of hypophysogonadal function in premature seems to depend on postnatal age and not on gestational age.     

A comparison of patients with premature thelarche and idiopathic true precocious puberty in the initial stage of illness

A comparative study of patients with premature thelarche and patients with idiopathic true precocious puberty was conducted. The age at the first visit tended to be lower for those with precocious puberty. In comparison with normative data for children, the frequency of low birthweight and small for date (SFD) status was greater in the 55 patients with premature thelarche, but SFD was also frequent in the 18 patients with precocious puberty. The height, weight and Kaup's index were all within the normal range for these two groups. The ratios for bone age/chronologic age and bone age/height age tended to be high in both groups. In the patients with premature thelarche, the blood luteinizing hormone (LH) level showed a normal response, and the blood follicle stimulating hormone (FSH) level a hyper-response, to stimulation with luteinizing hormone-releasing hormone (LH-RH). In contrast, both the blood LH and FSH levels showed a normal response to LH-RH stimulation in most of the patients with precocious puberty, and a hyper-response was rare among them. Although the blood estradiol (E2) level was higher in patients with precocious puberty than in those with premature thelarche, about 50% and 90% of the patients in the respective groups had normal levels. These results suggest that normal responses of blood LH and excessive responses of blood FSH to LH-RH loading may be useful in some patients for diagnosing premature thelarche at an early stage.     

Premature thelarche--natural history and sex hormone secretion in 68 girls

Data obtained during long-term follow-up of 68 girls with premature thelarche were analysed. In 85% onset was before the age of 2 years, in 30.8% being present at birth. In 44.1% there was a regression after 3 2/12 +/- 2 8/12 years (SD). Basal levels of plasma FSH and response to LH-RH were significantly higher than prepubertal controls (1.93 +/- 1.56 vs. 0.8 +/- 0.1 mU/ml and peaks 12.3 +/- 5.4 vs. 7.9 +/- 1.0 mU/ml respectively; p less than 0.001). Twenty-seven of 52 patients tested had increased plasma estradiol and in 27 of 40 patients tested, urocytograms or vaginal smear showed estrogenization. Basal levels of LH and response to LH-RH were prepubertal. The girls with premature thelarche were significantly taller than normal controls of the same age (p less than 0.001). These results suggest that premature thelarche is an incomplete form of precocious sexual development probably due to derangement in the maturation of the hypothalamo-pituitary-gonadal axis which results in a higher than normal secretion of FSH, as well as a defect in the peripheral sensitivity to the sex hormones.     

Testicular function after combination chemotherapy in childhood for acute lymphoblastic leukaemia.

We have assessed testicular function with luteinising hormone-releasing hormone (LH-RH) and human chorionic gonadotrophin stimulation tests in 44 boys previously treated with, or currently receiving, chemotherapy for acute lymphoblastic leukaemia (ALL). At the same time a testicular biopsy was performed in each boy and the morphology was studied. Histologically the chemotherapy appeared to damage the tubular system in particular, and the degree of damage was assessed by estimating the tubular fertility (TF) index which is defined as the percentage of seminiferous tubules containing identifiable spermatogonia. The mean TF index in all 44 biopsies was 51%. Only 2 of the 44 boys showed an absent or blunted testosterone response to human chorionic gonadotrophin. This suggests that Leydig cell function is rarely impaired by such chemotherapy and that most of the boys, similarly treat for ALL, will undergo normal pubertal maturation. Apart from the basal luteinising hormone (LH) levels in the prepubertal group which could not be compared, the median basal serum follicle-stimulating hormone (FSH), LH, and testosterone concentrations, the median peak FSH and LH responses to LH-RH, and the mean plasma testosterone responses to human chorionic gonadotrophin stimulation did not differ between the prepubertal, early pubertal, and late pubertal groups compared with normal boys of similar pubertal maturation. Three of 32 prepubertal ALL boys, and 5 of 12 pubertal ALL boys showed abnormalities of gonadotrophin secretion. The increased frequency of abnormalities of FSH secretion in the pubertal ALL boys compared with the prepubertal ALL boys could not be explained by more severe tubular damage in the former group. We conclude that moderately severe damage to the tubular system of the testis unassociated with Leydig cell impairment may not be detected in the prepubertal boy with current tests of testicular function.     

Premature Thelarche–Natural History and Sex Hormone Secretion in 68 Girls

ABSTRACT. Data obtained during long-term follow-up of 68 girls with premature thelarche were analysed. In 85 % onset was before the age of 2 years, in 30.8 % being present at birth. In 44.1 % there was a regression after 3^2/12±2^8/12 12years (SD). Basal levels of plasma FSH and response to LH-RH were significantly higher than prepubertal controls (1.93± 1.56 vs. 0.8±0.1 mU/ml and peaks 12.3±5.4 vs. 7.9±1.0 mU/ml respectively; p <0.001). Twenty-seven of 52 patients tested had increased plasma estradiol and in 27 of 40 patients tested, urocytograms or vaginal smear showed estrogenization. Basal levels of LH and response to LH-RH were prepubertal. The girls with premature thelarche were significantly taller than normal controls of the same age ( p <0.001). These results suggest that premature thelarche is an incomplete form of precocious sexual development probably due to derangement in the maturation of the hypothalamo-pituitary-gonadal axis which results in a higher than normal secretion of FSH, as well as a defect in the peripheral sensitivity to the sex hormones.     

The LH and FSH responses to LH-releasing hormone (LH-RH) in girls with true precocious puberty treated with cyproterone acetate

Ten girls with precocious puberty ranging in age from 7 to 10 7/12 years who were treated with oral cyproterone acetate on a long term basis, were subjected to LH-RH tests, prior to and 3 to 16 months after the institution of therapy. Cyproterone acetate was given in doses from 60 to 153 mg/m², which proved to be clinically effective, as evidenced by the slowing down of sexual maturation.The basal levels of LH were found to be unaffected by therapy and corresponded to the pubertal stages of the individual girls. The peak increment of LH after LH-RH stimulation was markedly suppressed by the therapy. FSH secretion and its responsiveness to LH-RH was not affected by cyproterone acetate. The basal levels of FSH were higher during therapy than before, but the peak FSH increment remained the same. An escape phenomenon in the LH peak response was evident in 2 patients upon retesting after prolonged therapy. It is possible that the antigonadotrophic action of cyproterone acetate is due to its progestational nature.Supported in part by a Grant from the Harry C. Bernard Fund     

Assessment of the gonadotrophin-gonadal axis in androgen insensitivity syndrome.

OBJECTIVE: To study the value of measuring serum luteinising hormone (LH), follicle stimulating hormone (FSH), testosterone, and dihydrotestosterone (DHT) in androgen insensitivity syndrome (AIS). DESIGN: Retrospective study of patients on a nationwide register of AIS. PATIENTS: Sixty one cases of AIS with androgen receptor (AR) dysfunction (abnormalities of the AR gene and/or abnormal AR binding) were divided into three age groups: infants, < 1 year old; children, 1-13 years old; and postpubertal, > 13 years old. MEASUREMENTS: Age, dose of human chorionic gonadotrophin (hCG) stimulation, pre-hCG and post-hCG serum testosterone values, serum DHT values, and serum LH and FSH values before and after LH releasing hormone (LHRH) stimulation. RESULTS: In 23 of 30 infants testosterone was within age related reference ranges; six were above this range. The median testosterone rise following variable dosage of hCG was 9.5 times the basal value. The increment was not related to the hCG dose, age, or basal concentration of testosterone. The median basal and stimulated testosterone:DHT ratios were 2.5 and 6.1, respectively. The median increment in DHT was 2.2-fold. Seventeen of 18 FSH and 11 of 19 LH measurements were within age related ranges in infants; in seven patients LH values were above the range. LHRH stimulation performed in 39 patients showed an exaggerated LH in all age groups. The FSH response was not exaggerated in children. CONCLUSION: Although a positive hCG test excludes biosynthetic defects of testosterone, an inadequate response does not exclude AIS. Basal LH and testosterone may not be raised during early infancy. An LHRH stimulation test might be useful for evaluating cases of suspected AIS presenting in mid-childhood.     

GONADAL DYSFUNCTION IN PATIENTS WITH ATAXIA TELANGIECTASIA

ABSTRACT. Two males and three females with ataxia telangiectasia aged from 4 6/12; to 23 years were subjected to an i.v. LH-RH test. All were found to have elevated basal levels of FSH and three had elevated basal levels of LH. In all the response of FSH to LH-RH was supranormal. In the pubertal and adult females the basal levels of estradiol were low. The laboratory and clinical findings in these patients as well as data reported by others indicate that the primary gonadal failure is an integral part of AT.     

Gonadal dysfunction in patients with ataxia telangiectasia.

Two males and three females with ataxia telangiectasia aged from 4 6/12 to 23 years were subjected to an i.v. LH-RH test. All were found to have elevated basal levels of FSH and three had elevated levels of LH. In all the response of FSH to LH-RH was supranormal. In the pubertal and adult females the basal levels of estradiol were low. The laboratory and clinical findings in these patients as well as data reported by others indicated that the primary gonadal failure is an integral part of AT.     

Multiple associated endocrine abnormalities in a patient with pseudohypoparathyroidism type 1a

A girl with type 1a pseudohypoparathyroidism (PHP) presented several hormonal abnormalities. Although she had eluded neonatal thyroid screening, she was diagnosed as having hypothyroidism at the age of 5 months. Thereafter, a diagnosis of PHP was made on the basis of skeletal features of Albright osteodystrophy and lack of both cyclic adenosine monophosphate (c-AMP) and phosphaturic responses after parathyroid hormone (PTH) infusion. The basal levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) were higher than normal and showed exaggerated responses to luteinizing hormone-releasing hormone (LH-RH). There was no growth hormone (GH) response to arginine infusion, and the prolactin (PRL) response after thyrotropin-releasing hormone (TRH) infusion was also impaired. The stimulating guanine nucleotide-binding protein (Ns) activity of the erythrocytes was reduced to 66.9%. The skeletal age was not delayed at the age of 5 months in spite of the hypothyroid state, and it advanced following thyroxine and vitamin D treatments.Abbreviations PHP pseudohypoparathyroidism - c-AMP cyclic adenosine monophosphate - PTH parathyroid hormone - LH luteinizing hormone - FSH follicle-stimulating hormone - LH-RH luteinizing hormone-releasing hormone - GH growth hormone - PRL prolactin - TRH TSH-releasing hormone - Ns stimulating guanine nucleotide-binding protein - TSH thyroid stimulating hormone - Pi/cr phosphate/creatinine ratio     

HYPOPHYSO-GONADAL FUNCTION IN THE DIABETIC CHILD

ABSTRACT. 14 diabetic boys (five with a family history of diabetes and nine without) and 29 "short normal" boys were studied. A gonadal function test (2.000 IU of hCG i.m. for 3 days and plasma testosterone assay before and after the hCG administration) as well as an LH-RH test (50 μg i.v.) were carried out. While basal testosterone level turned out to be similar in the two groups of children, it was significantly lower ( p <0.01) after hCG than the mean value of the control group. This difference was mainly observed in those patients with a family history of diabetes. In the diabetic children, basal LH level was normal and the pituitary LH reserve was lower than in the control group. Both basal FSH level and FSH pituitary reserve were lower than in normal children. These data show that an alteration in the hypothalamus-pituitary-gonadal function is already evident in the diabetic child.     

Hypophyso-gonadal function in the diabetic child.

14 diabetic boys (five with a family history of diabetes and nine without) and 29 "short normal" boys were studied. A gonadal function test (2.000 IU of hCG i.m. for 3 days and plasma testosterone assay before and after the hCG administration) as well as an LH-RH test (50 microgram i.v.) were carried out. While basal testosterone level turned out to be similar in the two groups of children, it was significantly lower (p less than 0.01) after hCG than the mean value of the control group. This difference was mainly observed in those patients with a family history of diabetes. In the diabetic children, basal LH level was normal and the pituitary LH reserve was lower than in the control group. Both basal FSH level and FSH pituitary reserve were lower than in normal children. These data show that an alteration in the hypothalamus-pituitary-gonadal function is already evident in the diabetic child.     

Endocrine studies in Blackfan-diamond anemia: Evidence for hypothalamic-pituitary dysfunction under frequent transfusion therapy

A 13 year old boy with Blackfan-Diamond anemia treated with frequent transfusions was investigated for endocrine abnormalities. Prepubertal plasma LH and FSH values, lack of sleep-related hormone rhythms of the gonadotropins, as well as prepubertal responses of LH and FSH to acute stimulation with LHRH strongly suggests that a hypothalamic-pituitary abnormality is the cause of the hypogonadotropic hypogonadism observed in this patient. As a result of impaired stimulation of the gonads plasma testosterone was prepubertal. A three-to fourfold increase of basal plasma PRL values was found without any signs of a typical sleep-dependent increase. Values obtained ranged between 21 ng/ml and 24 ng/ml (normal range 5–8 ng/ml). A normal response to TRH stimulation was found.These results suggest that hemosiderosis may responsible for the hyperprolactinemia as a result of hypothalamic-pituitary dysfunction. Furthermore, dysfunction is demonstrated by prepubertal responses of LH and FSH to LHRH stimulation.Abbreviations LH luteinizing hormone - FSH follicle-stimulating hormone - PRL prolactin - LHRH luteinizing-hormone-releasing hormone - TRH thyrotropin releasing hormone - PIF prolactin inhibiting factor     

Serum levels of LH and FSH in patients with adreno-genital syndrome (AGS) (author's transl)]

Serum levels of LH, FSH, testosterone and 17beta-estradiol were estimated by radioimmunoassay in 13 children suffering from AGS. Hormone levels were determined during and after substitution therapy and were compared with values registered in normal subjects. After therapy was stopped a statistically significant rise of testosterone and 17beta-estradiol was observed, but no changes in the serum levels of LH and FSH was noted. The discrepancies between the two observations are discussed.