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Research Notes: Endocrinological Aspects of Prader-Willi Syndrome (PWS)See also:
Horm Res. 2007. BACKGROUND: In boys with Prader-Labhart-Willi syndrome (PWS), hypogonadism causes pubertal arrest and reduces pubertal muscle growth. Formerly, it was assumed that therapy with gonadal hormones accentuates behaviour abnormalities in PWS. Our aim was to assess the clinical effects of human chorionic gonadotropin (hCG) therapy on pubertal development, muscle mass and behaviour in adolescents with PWS. METHODS: 6 peripubertal boys with PWS undergoing long-term treatment with growth hormone were examined 6-monthly for at least 2 years before and after pubertal arrest (13.5 +/- 0.3 years, mean +/- SEM) and the beginning of hCG therapy (500-1,500 IU twice weekly, intramuscularly). Height, weight, pubertal stage, bone age, body composition (by dual-energy X-ray absorptiometry), testosterone levels and behaviour abnormalities (obtained from parents) were assessed. RESULTS: Testicular volume and lean mass were reduced in pubertal boys with PWS. During hCG therapy, testosterone levels and lean mass significantly increased (at the beginning and after 2 years of hCG therapy: 2.3 +/- 0.9 and 10.7 +/- 1.3 nmol/l, -3.1 +/- 0.3 and -1.4 +/- 0.6 SD, respectively), and fat mass stabilized at 38%. The characteristically observed PWS-associated problems, mood instability, aggressiveness and difficulties in social interaction, did not deteriorate during therapy. CONCLUSION: In the present study, timely application of hCG to treat hypogonadism in boys with PWS promoted virilization and normalized muscle mass without detrimental effects on behaviour. Larger studies comparing hCG therapy with testosterone replacement would be useful. J Clin Endocrinol Metab. 2006 Mar. CONTEXT: The specific form of hypogonadism in Prader-Labhart-Willi syndrome (PWS), central or peripheral, remains unexplained. OBJECTIVES: The objectives of this study were to investigate the cause of hypogonadism in PWS and determine whether human chorionic gonadotropin (hCG) treatment can restore pubertal development. DESIGN: This was a clinical follow-up study, divided into two samples, over a duration of 1.5 and 4.5 yr. PATIENTS: Eight male infants and six peripubertal boys (age at start of observation, 0.06-0.93 and 8.1-10.8 yr, respectively) with genetically confirmed PWS were studied. INTERVENTION: hCG (500-1500 U twice weekly) was given from age 13.5 yr to the present. MAIN OUTCOME MEASURES: Serum FSH, LH, inhibin B, and testosterone levels and pubertal development were the main outcome measures. RESULTS: Infants with PWS presented normal LH (2.3 +/- 0.7 U/liter) and testosterone (2.5 +/- 0.9 nmol/liter) levels (mean +/- sem at 5 months) compared with the reference range. However, two thirds of the boys displayed cryptorchidism. Inhibin B levels were at the lowest level of the normal range and decreased significantly between infancy and puberty (at 13 yr, 72 +/- 17 pg/ml), whereas FSH secretion increased (9.9 +/- 2.6 U/liter). Pubertal maturation stopped at an average bone age of 13.9 yr. hCG therapy increased testosterone (11 +/- 2 nmol/liter) and reduced FSH (at 16 yr, 1.1 +/- 0.9 U/liter) levels. Testicular volume (5.6 +/- 1 ml) and inhibin B (26.5 +/- 11.9 pg/ml) remained low. CONCLUSION: Children with PWS display a specific form of combined hypothalamic (low LH) and peripheral (low inhibin B and high FSH) hypogonadism, suggesting a primary defect in Sertoli and/or germ cell maturation or an early germ cell loss. hCG therapy stimulates testosterone production and virilization. From the full text article: Hypogonadism leading to hypogenitalism and early pubertal arrest is a central feature of PWS and is generally attributed to hypothalamic dysfunction. In male patients with PWS, some degree of gonadotropin deficiency was suggested by several reports of reduced gonadotropic function (3, 6, 7, 8, 9, 10, 11) in the presence of prepubertally normal testicular histology (12, 13, 14). In addition, some patients may have primary hypogonadism with elevated basal and stimulated gonadotropin levels (13, 15, 16, 17, 18, 19, 20, 21, 22) as well as abnormalities in testicular histology (6, 15, 17). These findings are usually interpreted as gonadal failure due to cryptorchidism and/or surgical intervention and indicate that gonadotropin deficiency is not complete in PWS (7, 20, 22). However, the absence of spermatogenesis was also described in descended testes (23), without indicating the origin of the testicular damage. The conflicting data on the pathophysiology of gonadal dysfunction in male individuals with PWS has still not been resolved. Furthermore, it remains unknown to what extent GH deficiency contributes to impaired gonadal function. GH substitution was shown to potentiate the Leydig cell response to human chorionic gonadotropin (hCG) in patients with hypopituitarism (24, 25) or hypogonadotropic hypogonadism (26). Nevertheless, an arrest of gonadal development is observed in all boys at pubertal age despite otherwise efficacious GH treatment (27, 28, 29, 30). The aim of this study was to investigate the origin of hypogonadism in boys with PWS and to determine whether hCG treatment started at the time of pubertal arrest can restore Leydig cell function as well as pubertal development. We examined the pituitary-testicular axis in male infants with PWS as early as the diagnosis was established, because gonadal stimulation in boys during the first months of life is associated with subsequent testicular maturation (31, 32) and is reduced in congenital hypogonadotropic hypogonadism (33). ... In the present study we longitudinally analyzed levels of the hormones of the pituitary-testicular axis in boys with PWS during infancy and puberty. According to our data, at the age of 5 months infants with PWS have normal LH and testosterone and slightly elevated FSH levels, revealing sufficient gonadotropic stimulation and normal Leydig cell function during infancy. Inhibin B levels are significantly decreased in PWS from infancy onward, suggesting a primary testicular defect affecting the tubular compartment. This decrease in inhibin B is associated with increased FSH, but not LH, secretion. Midpubertal LH levels do not rise, and pubertal maturation stops. hCG therapy promotes pubertal development through an increase in serum testosterone levels and reduces FSH levels, whereas inhibin B secretion does not increase. These findings question the traditional assumption of a hypothalamic defect as the unique cause of hypogonadism in PWS and imply that there is an additional important peripheral defect in gonadal development at puberty. The levels of FSH, LH, and testosterone in PWS infants were well within the normal range. Because in most infants with PWS, the diagnosis was made only after the expected peak of gonadotropin secretion, which occurs during the second month of life, early postnatal gonadotropin secretion could not be analyzed in most of our patients. However, one infant with complete testicular descent was nevertheless investigated from the first month on and displayed a fully normal gonadotropin surge. In addition, four boys at the age of 4 months showed serum testosterone levels compatible with a possible residual elevation after the postnatal gonadotropin peak. In contrast, inhibin B levels gradually decreased in the presence of normal or even increased FSH levels. These data suggest that the formerly assumed gonadotropin deficit in infants with PWS is not complete and, above all, does not involve FSH secretion. The findings in our patients with PWS differ from the situation in infants with hypogonadotropic hypogonadism (33) or cryptorchidism as well as from infants with Klinefelter’s syndrome. In infants with prenatal diagnosis of Klinefelter’s syndrome, levels of FSH and inhibin B were normal, but testosterone was decreased (36). In boys with cryptorchidism, hormonal data, including inhibin B, were in the normal range (39, 40). The normal androgen levels observed in the present study during infancy explain neither the high incidence (67%) of cryptorchidism in boys with PWS nor the hypogenitalism found in other children with the syndrome. The lack of abdominal pressure in the presence of the extreme muscle hypotonia might be an alternative explanation for disruption of testicular descent in PWS (41). Bone maturation before puberty is generally slightly advanced in children with PWS due to obesity-related endocrine alterations (42, 43), with a slight elevation of adrenal androgens. As a consequence, boys with PWS entered puberty at an adequate or even early age with normal levels of LH and testosterone, but bone maturation and testicular development slowed down after BA 13 yr, as it is typical for hypothalamic hypogonadism (44). hCG therapy was started when pubertal arrest was recognized. Leydig cells responded to hCG therapy. Testosterone rose, although levels remained in the lower normal range, and LH secretion decreased. In the long term, testosterone levels dropped below the normal range again and did not correlate with the dose of hCG. This therapy induced complete testicular descent in one boy with undescended testes. However, testicular volume, on the average, did not increase to more than 6 ml, probably because of the lack of spermatogenetic activity (45, 46). The steep decline in FSH levels during hCG treatment confirmed a previous anecdotal report (18) and was similar to that found in boys with cryptorchidism after hCG administration. It was explained to be mediated by the increase in testosterone secretion and subsequent aromatization to estrogens (39). These data suggest that in PWS, the hypothalamic-pituitary negative feedback of the FSH and LH axes works. In contrast, levels of inhibin B were low not only during childhood, but were further decreased during puberty in our patients with PWS. It is assumed that during puberty in healthy boys, high intratesticular testosterone levels activate germ cells and initiate inhibin B production (32, 37, 39, 47). In the present study inhibin B remained invariably decreased despite the significant rise of testosterone during hCG therapy. The lack of inhibin B response to hCG as well as the low basal inhibin B levels from infancy imply some form of Sertoli cell hypofunction, a primary defect of the tubular epithelium (32), and/or a disturbed interaction between Sertoli and germ cells. Cryptorchidism does not seem to be exclusively responsible for this damage, because inhibin B levels are normal in healthy boys with cryptorchidism (39, 40) and, in the infants of the present study, independent of testicular descent. Furthermore, the hypothesis of a primary gonadal defect in PWS is substantiated by the findings of absent germ cells in gonadal biopsies of descended testes of adult males with PWS (15) even in descended testes (23). Nevertheless, there is no doubt that the hypothalamic defect is responsible for the absence of the pubertal LH rise in PWS. This suggests that the two axes (FSH and LH) are dissociated in this syndrome at puberty, with FSH reflecting a peripheral and LH a central hypogonadism. hCG treatment and subsequent testosterone increase were well tolerated without behavioral side effects. In male adolescents with PWS, a substitution with sex hormones seems mandatory to induce normal pubertal development, prevent osteoporosis, and improve body composition. A typical male appearance is important to avoid additional stigmatization due to high voice, gynecomastia, and other signs of eunuchoidism. Because testosterone deficiency in males with PWS further aggravates the inborn decrease in lean mass, it represents an additional factor for reducing energy expenditure and enhancing fat accumulation. Hypogonadism in PWS children should be treated at puberty. hCG administration can be controlled and adapted on a short-term basis, preventing significant fluctuations in testosterone levels. However, Sertoli cell/tubular function is not restored by this treatment. In summary, children with PWS display a specific form of combined (central and peripheral) hypogonadism involving deficiency of LH and testosterone secretion at puberty and primary damage of the tubular compartment, resulting in reduced inhibin B levels and FSH elevation. Furthermore, the response of testosterone to hCG therapy is inadequate. This condition may be caused by a defect in Sertoli cell maturation and/or germ cell depletion. In adolescents with PWS, hCG therapy ensures male appearance without side effects, but testicular volume remains subnormal, and fertility is not achieved. Am J Med Genet A. 2004 Jan 15. Individuals with Prader-Willi syndrome (PWS) generally survive into adulthood. Common causes of death are obesity related cor pulmonale and respiratory failure. We report on a case series of eight children and two adults with unexpected death or critical illness. Our data show age-specific characteristics of PWS patients with fatal or life-threatening illnesses. Under the age of 2 years, childhood illnesses in general were associated with high fever and rapid demise or near-demise. Hypothalamic dysfunction likely plays a role in exaggerated fever response, but also perhaps in central regulation of adrenal function. Below average sized adrenal glands were found in three children, which raises the possibility of unrecognized adrenal insufficiency in a subset of individuals with PWS and emphasizes the vital role of autopsy. The tub drowning death of an adult patient could be related to central hypersomnia [or cataplexy?], which has been reported in PWS. We suggest that increased risk for critical illness be considered in the discussion of anticipatory guidance for the care of infants with PWS. Since a number of children died while hospitalized, particularly close observation of PWS children who are ill enough to warrant hospital admission is recommended. Eur J Pediatr. 2003 May. Genital abnormalities and disorders of pubertal development such as hypogonadism are common in Prader-Willi Syndrome (PWS). Depending on age, PWS patients present genital hypoplasia and delayed or incomplete gonadal maturation. Nevertheless, only a few evaluations have been made of these findings in this syndrome; in the cases previously reported the diagnosis of PWS has often been based only on clinical criteria and not confirmed by genetic analysis. In this paper we describe both external genital findings and spontaneous pubertal development in 84 patients aged from 2.1 to 35.4 (42 males, 42 females) affected by PWS. Diagnosis was made using the Holm and Cassidy criteria and was confirmed by genetic analysis (methylation test and/or FISH). We evaluated the presence of cryptorchidism, scrotal development, length of penis and volume of testis in males and outlook of labia minora and/or clitoris, age of menarche and features of menses (when present) in females; in both sexes we also evaluated the onset of puberty. All recruited males showed cryptorchidism, which was bilateral in 36 out of 42 patients (86%); 38 patients (90%) underwent orchidopexy. Small testes and scrotal hypoplasia were present in 76% and 69% of cases, respectively. In 76% of females, hypoplasia or absence of labia minora and/or clitoris was described. Spontaneous menarche occurred only in 14/32 cases (44%) over the age of 15 years, but menstrual cycles were often a periodical vaginal spotting. Primary amenorrhea was diagnosed in 56% of cases. Isolated premature pubarche was present in six males and in six females (14% of cases) while one male and two females were affected by precocious puberty (3.6%). Conclusion: Hypogonadism represents a common clinical feature in PWS, confirming the importance of such a major diagnostic criterion. Cryptorchidism was consistently present in all our cases. Patients with PWS commonly fail to spontaneously complete puberty, although some patients may have early pubarche or, more rarely, precocious puberty. In older subjects, hormonal replacement therapy is not always necessary and it must be reserved for selected patients. Horm Res. 2002. Background/Aim: Since hyperandrogenism in simple obesity is assumed to arise from hyperinsulinism and/or increased insulin-like growth factor I (IGF-I) or leptin levels, we examined how in patients with Prader-Willi syndrome (PWS), the most frequent form of syndromal obesity, the accelerated adrenarche can be explained despite hypothalamic-pituitary insufficiency with low levels of insulin and IGF-I. Methods: In 23 children with PWS and a mean age of 5.6 years, height, weight, fat mass, fasting insulin concentration, insulin resistance (by HOMA-R; see text), and leptin and IGF-I levels were determined to test whether they explain the variance of the levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), of androstenedione, and of cortisol before and during 42 months of therapy with growth hormone. Results: The baseline DHEAS, DHEA, and androstenedione concentrations were increased as compared with age-related reference values, whereas the cortisol level was always normal. During growth hormone treatment, the DHEA concentration further rose, and the cortisol level decreased significantly. The insulin and IGF-I concentrations were low before therapy, while fat mass and leptin level were elevated. The hormonal covariates provided alone or together between 24 and 60% of the explanation for the variance of adrenal androgen levels, but the anthropometric variables did not correlate with them. Conclusions: In children with PWS, elevated androgen levels correlate with hormones that are usually associated with adiposity. However, the lack of direct correlations between disturbed body composition and androgen levels as well as the increased sensitivity to insulin and IGF-I are abnormalities specific to PWS, potentially caused by the underlying hypothalamic defect. Endocr Rev. 2001 Dec. Prader-Willi syndrome is a genetic disorder occurring in 1 in 10,000-16,000 live-born infants. In the general population, approximately 60 people in every 1,000,000 are affected. The condition is characterized by short stature, low lean body mass, muscular hypotonia, mental retardation, behavioral abnormalities, dysmorphic features, and excessive appetite with progressive obesity. Furthermore, morbidity and mortality are high, probably as a result of gross obesity. Most patients have reduced GH secretory capacity and hypogonadotropic hypogonadism, suggesting hypothalamic-pituitary dysfunction. Replacement of GH and/or sex hormones may therefore be beneficial in Prader-Willi syndrome, and several clinical trials have now evaluated GH replacement therapy in affected children. Results of GH treatment have been encouraging: improved growth, increased lean body mass, and reduced fat mass. There was also some evidence of improvements in respiratory function and physical activity. The long-term benefits of GH treatment are, however, still to be established. Similarly, the role of sex hormone replacement therapy needs to be clarified as few data exist on its efficacy and potential benefits. In summary, Prader-Willi syndrome is a disabling condition associated with GH deficiency and hypogonadism. More active treatment of these endocrine disorders is likely to benefit affected individuals. Eur J Pediatr. 2001 Jan. Premature adrenarche/pubarche in male patients with Prader-Labhart-Willi syndrome may be associated with increased growth velocity and bone age acceleration. Biomed Pharmacother. 1999 Dec. Diabetes mellitus is not a diagnostic criterion for Prader-Willi syndrome (PWS), but it is often found in PWS patients. The etiology for diabetes mellitus in PWS may be related to the morbid obesity and consequent insulin resistance, because a decrease of oxytocin neurons and leptin resistance in PWS may cause hyperphagia, inducing obesity. However, treatment with growth hormone (GH) is beneficial for the majority of GH-deficient PWS children, because relative decreased fat mass and increased fat-free mass could prevent obesity and concomitant insulin resistance. Hypogonadism is thought to be due to hypogonadotrophic hypogonadism in a majority of PWS patients. Hypergonadotrophic hypogonadism secondary to cryptorchidism and its treatment is shown in other cases. Low luteinizing hormone and high follicle-stimulating hormone levels in PWS cases in young men with idiopathic oligospermia or in the early stages of puberty is less frequently reported. Acta Paediatr. 1999 Nov. Intern Med. 1998 Dec. A 21 -year-old man with Prader-Willi syndrome (PWS) was hospitalized due to hyperglycemia. After diet therapy and transient insulin administration, his blood glucose levels improved. Based on the fact that his urinary C-peptide levels increased, the diabetes mellitus may have been due to insulin resistance with obesity. In addition, his testes had become atrophied. Testosterone levels remained low even after human chorionic gonadotropin (HCG) administration. Luteinizing hormone (LH) levels were also low after LH releasing hormone (LHRH) administration. The LH response increased slightly after daily LHRH administration, indicating hypothalamic hypogonadism. Follicle stimulating hormone (FSH) levels were, however, high and increased after LHRH administration. The selective FSH elevation may have been due to the accompanying idiopathic oligospermia. Acta Paediatr Suppl. 1997 Nov. Disturbances of the hypothalamic-pituitary-gonadal axis are reviewed in patients with Prader-Willi syndrome, and a brief account is given of thyroid function, adrenal function and glucose metabolism in such patients. Cryptorchidism, hypoplastic external genitalia and delayed or incomplete pubertal development in most patients with Prader-Willi syndrome suggest dysfunction of the hypothalamic-pituitary-gonadal axis. Decreased levels of gonadotrophins, consistent with hypogonadotrophic hypogonadism, have been found in some patients, whereas others appear to have hypergonadotrophic hypogonadism secondary to cryptorchidism and its treatment. Gonadal function is normal in a small number of patients with the syndrome. Although most clinicians agree that cryptorchidism should be corrected in early childhood, in practice the surgery is often not performed. In addition, most patients do not receive sex hormone replacement therapy. It is therefore suggested that more aggressive endocrine treatment strategies for hypogonadism are warranted in both children and adults with Prader-Willi syndrome. Both thyroid function and adrenal function appear to be normal in most patients, and glucose metabolism is similar to that in normal obese individuals. Endocrinol Jpn. 1990 Feb. We report an adolescent patient with Prader-Willi syndrome accompanying suppressible hypergonadotropism. The subject is an 18-year-old female. She was obese (body mass index: 35.7) and hypomyotonic with mental retardation. On endocrinological examination, a high serum LH concentration and hyperresponsiveness of luteinizing hormone (LH) to intravenously administered LH-Releasing Hormone (LH-RH) were observed, while the basal follicle stimulating hormone level was within the normal range. In addition, serum dehydroxyepiandrosterone sulfate (DHEA-S) was also increased. Following 2 mg dexamethasone administration for 7 days, serum LH and DHEA-S were almost normalized and hyperresponse of LH to LH-RH completely disappeared. The present study provides evidence that altered responsiveness to adrenal steroid may be involved in the establishment of hypergonadotropinism in an adolescent patient with Prader-Willi syndrome. Am J Med Genet. 1987 Dec. We have studied steroid sulfate conjugates in serum samples from 17 children with Prader-Willi syndrome (PWS) by extraction, enzymatic hydrolysis and chromatography of the hydrolysed, free steroids. The chromatograms in patients with PWS can be divided into 2 classes. Ten (4 with the deletion on chromosome 15 and 6 without) of 17 had a normal pattern with dehydroepiandrosterone (DHEA) as the only steroid detected. However, 7 out of 17 (3 with the deletion and 4 without) had a very different pattern. The chromatogram derived from these hydrolysates had 5 major peaks. One of these was DHEA; a second peak was tentatively identified as 16 alpha-hydroxy-DHEA on the basis of column retention time and immunoreactivity. The remaining 3, more polar, compounds have not yet been identified. The presence of unusual steroid sulfoconjugates in serum may correlate with other features of PWS and may be the basis for dividing PWS into two separate disease states: a) PWS-1 associated with DHEA-S as the only sulfo-conjugate and b) PWS-2 associated with unusual sulfo-conjugates. One interesting possibility is that these sulfo-conjugates may have a hormonal function, even though no function has yet been recognized for DHEA-S. Then, PWS may be the common clinical manifestation of a variety of different defects in the sulfo-conjugate metabolic pathway. Helv Paediatr Acta. 1984 Oct. Exp Clin Endocrinol. 1983 Jul. In two girls (14 and 16 years) and one boy (19 years) with PLW-syndrome and pronounced obesity (240, 210 and 77% overweight) endocrine function tests were carried out. Growth hormone secretion was decreased but normalized after reduction of weight. Thyroxin levels as well as basal and TRH stimulated TSH concentrations were normal. HCG application in the boy induced no rise of the normal basal testosterone levels. Oral glucose tolerance test demonstrated an increased stimulation of insulin in two cases, no other symptoms of diabetes mellitus were found. In the LHRH test an insufficient rise of gonadotropins was found. However, after two weeks of pernasal application of an LHRH analogue (D-Leu6-des-Gly10-EA) the gonadotropin stimulation was distinctly improved and onset of puberty was induced in the male patient. These results are indicative of a hypothalamic disturbance in patients with PLW-syndrome. Eur J Pediatr. 1982 Nov. 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 variability of pubertal development in the Prader-Labhart-Willi syndrome, with the unusual association of primary gonadal failure and precocious adrenarche. Minerva Pediatr. 1982 Feb 28. No abstract available. Minerva Pediatr. 1981 Mar 15. No abstract available. Klin Padiatr. 1981 Mar. At least in boys hypogenitalism is a constant feature of the Prader-Labhart-Willi Syndrome. Our patient, a 16 10/12 years old girl had the characteristic symptoms of the syndrome and precocious puberty. Menarche had occurred at the age of 8 6/12 years. Precocious puberty does not exclude the diagnosis of a Prader-Labhart-Willi syndrome. Clin Endocrinol (Oxf). 1980 Jan. Hypothalamic, pituitary and gonadal function was studied in five male and three female patients with the Prader-Willi syndrome. All were clinically hypogonadal: all males had low circulating testosterone levels, although in two females basal plasma oestradiol was within the normal range for the early follicular phase of the menstrual cycle. Basal gonadotrophin levels were low and the response to the intravenous ater 10 days and 6 weeks treatment with oral clomiphene (200 mg daily) was followed by a normal rise in luteinizing hormone (LH) and follicle stimulating hormone (FSH) in four out of five patients tested. All five males were tested with human chorionic gonadotrophin (hCG) and the rise in plasma testosterone was subnormonal in four. Treatment with hCG was continued for 6 weeks in these four patients, but in only one did testosterone levels rise (transiently) to the normal adult male range. In one female patient studied no rise in plasma oestradiol was detected in response to human menopausal gonadotrophin (hMG). These results suggest that the hypogonadism in the Prader-Willi syndrome is due to combined hypothalamic and primary gonadal abnormalities. Acta Paediatr Scand. 1978 Nov. The sexual maturation in the Prader-Labhart-Willi (PLW) syndrome was investigated in 14 patients, 10 females and 4 males. A wide variability in the pattern of pubertal development was found including delayed puberty in 5 patients and normal puberty in 4 patients; sexual precocity was also observed in 5 patients, true precocious puberty in one patient and incomplete sexual precocity in the form of precocious pubarche in 4 patients. In 5 patients, 3 of them with precocious pubarche, the appearance of the pubertal signs was followed by a delay or arrest in their future development. An LH-RH stimulation test was performed in 11 patients. In the 6 patients who eventually developed normal puberty, the basal levels and the peak responses of both LH and FSH were within the range of those observed in normal controls of the same pubertal stage. In 4 patients showing marked delay or arrest of puberty, the basal levels were normal or low and the responses of LH and FSH to LH-RH were blunted. Priming with repeated LH-RH stimulation in one of the male patients led to an augmented LH response, suggesting a hypothalamic hypogonadotrophism. It is concluded that the lack of uniformity in the pattern of sexual maturation in the PLW syndrome is due to a variability in the location and extent of a hypothalamic lesion, which may comprise an active process continuing beyond the perinatal period. Rev Clin Esp. 1976 Dec 15. No abstract available. J Clin Endocrinol Metab. 1975 Aug. Two women with the Prader-Labhart-Willi syndrome are presented. The gonadotropin response to LH-RH administration was studied prior to, immediately following, and 6 months after a 6-week trial of clomiphene citrate, 200 mg per day for 21 days in divided doses, followed by 100 mg for 21 days in divided doses, followed by 100 mg per day for 14 days in divided doses, and followed by 50 mg per day in a single dose for an additional 14 days. During therapy, the basal gonadotropin and estradiol concentrations rose from prepubertal levels to those of mature women in midmenstrual cycle. However, 6 months after cessation of treatment, the basal gondadotropin and estradiol levels had returned to the prepubertal range. The initial response to LH-RH in the 2 patients differed in that one was clearly prepubertal and the other indistinguishable from the broad range of the adult normal response. The LY and FSH responses to LH-RH administration was greater after 6 weeks of clomiphene citrate therapy than they were either before (both patients) or 6 months after treatment (1 patient). We conclude that there is heterogeneity in the response to LH-RH administration in the Prader-Labhart-Willi Syndrome, just as there is in other syndromes of hypogonadotropic hypogonadism. A normal adult response of gonadotropins to the administration of LH-RH was acheived during clomiphene citrate therapy. J Clin Endocrinol Metab. 1974 Dec. No abstract available. Dtsch Med Wochenschr. 1974 May 31. No abstract available. Rev Invest Clin. 1974 Jan-Mar. Neuroendocrinology. 1974. No abstract available. Acta Med Iugosl. 1974. No abstract available. |