Successful Diagnoses and Remarkable Metabolic Disorders in Patients With Solitary Hypothalamic Mass: A Case Series Report.

Background: Solitary intracranial hypothalamic mass occurs rarely. The etiological diagnosis of solitary hypothalamus lesion is challenging and often unachievable. Although previous studies indicated that lesions affecting the hypothalamus often cause significant metabolic disorders, few reports about the metabolic disturbances of patients with solitary hypothalamic mass have been reported. Method: Twenty-five patients with solitary hypothalamus lesions who had been evaluated and treated in Huashan Hospital from January 2010 to December 2020 were retrospectively enrolled. The clinical manifestations, radiological features, endocrine and metabolic disorders, and pathology were analyzed. Results: The male to female ratio was 5/20. The median age of onset was 22 (19, 35) years old. The most common initial symptom was polydipsia/polyuria (19/25, 76.0%) and amenorrhea (9/20, 45.0%). A high prevalence of hypopituitarism of different axes was found, with almost all no less than 80%. Central hypogonadism (21/22, 95.5%) and central diabetes insipidus (19/21, 90.5%) were the top two pituitary dysfunctions. Conclusive diagnoses were achieved by intracranial surgical biopsy/resection or stereotactic biopsy in 16 cases and by examining extracranial lesions in 3 cases. The pathological results were various, and the most common diagnoses were Langerhans cell histiocytosis (7/19) and hypothalamitis (5/19). The mean timespan from onset to diagnosis in the 19 cases was 34 ± 26 months. Metabolic evaluations revealed remarkable metabolic disorders, including hyperlipidemia (13/16, 81.3%), hyperglycemia (10/16, 62.5%), hyperuricemia (12/20, 60%), overweight/obesity (13/20, 65.0%), and hepatic adipose infiltration (10/13, 76.6%). Conclusion: Either surgical or stereotactic biopsy will be a reliable and relatively safe procedure to help to confirm the pathological diagnosis of solitary hypothalamic mass. Metabolic disorders were severe in patients with solitary hypothalamic mass. The management of such cases should cover both the treatment of the primary disease, as well as the endocrine and metabolic disorders.

Sudden onset of sleep caused by hypothalamic infarction: a case report.

BACKGROUND: Hypothalamic lesions, such as tumors and demyelinating diseases, reportedly cause abnormal sleepiness. However, stroke involving the hypothalamus has rarely been described. Here, we report a patient with infarction restricted to the hypothalamus who presented with sudden onset of sleep. CASE PRESENTATION: A 42-year-old woman with a history of migraine without aura presented with irresistible sleepiness and developed several episodes of sudden onset of sleep. Neurological examinations were unremarkable except for partial left Horner syndrome. Brain magnetic resonance imaging (MRI) revealed a high-intensity lesion restricted to the left hypothalamus on diffusion-weighted and fluid-attenuated inversion recovery MRI images. Cerebrospinal fluid (CSF) orexin-A levels obtained on hospital day 3 after her sleepiness had resolved were normal (337 pg/mL; normal > 200 pg/mL). Serum anti-nuclear and anti-aquaporin 4 (AQP4) antibodies and CSF myelin basic protein and oligoclonal band were negative. A small hypothalamic infarction was suspected, and the patient was treated with intravenous edaravone and argatroban, as well as oral clopidogrel. Three months later, there had been no clinical relapse, and the hypothalamic lesion had almost disappeared on follow-up MRI. No new lesion suggestive of demyelinating disease or tumor was observed. CONCLUSION: Hypothalamic stroke should be considered a cause of sudden onset of sleep.

Revised criteria for PCOS in WHO Group II anovulatory infertility - a revival of hypothalamic amenorrhoea?

OBJECTIVE: To evaluate revised criteria for polycystic ovarian morphology (PCOM) in the diagnosis of polycystic ovary syndrome (PCOS) in anovulatory infertility. DESIGN: Prospective cohort study. PATIENTS: WHO Group II anovulatory infertile women (n = 75). MEASUREMENTS: Clinical, sonographic and endocrine parameters, including anti-Müllerian hormone (AMH). RESULTS: The Rotterdam criteria for PCOM (antral follicle count (AFC) ≥12 and/or ovarian volume >10 ml) were fulfilled in 93% of the women. The PCOM prevalence was 68% when increasing the threshold to AFC >20 and 76% according to an AMH-based threshold of >35 pmol/l. The most recently proposed AFC ≥ 25 threshold reduced the PCOM prevalence to 52% (n = 39), leaving 48% (n = 36) without features of PCOM. Comparing the 36 women with non-PCOM with the 39 women in the PCOM group according to AFC ≥ 25, 22% vs 59% (P = 0·001) had serum LH >10 IU/l, 11% vs 41% (P = 0·003) had an LH/FSH ratio >2 and 19% vs 41% (P = 0·04) had hirsutism and/or elevated total testosterone, free testosterone, and/or androstenedione. The non-PCOM group included significantly more women with secondary infertility. The median AMH in the non-PCOM group was 47 pmol/l, which was twofold lower than in the PCOM group but above the upper limit of normo-ovulatory women. CONCLUSIONS: According to a revised threshold of 25 follicles, almost half the anovulatory infertile women do not have PCOM. The characteristics of these women may be compatible with hypothalamic anovulation, but according to AMH levels, the ovaries remain multifollicular. PERSPECTIVES: A better distinction between hypothalamic amenorrhoea and PCOS could improve treatment strategies for anovulatory infertility.

The absence of GH signaling affects the susceptibility to high-fat diet-induced hypothalamic inflammation in male mice.

GH is important in metabolic control, and mice with disruption of the gene encoding the GH receptor (GHR) and GH binding protein (GHR-/- mice) are dwarf with low serum IGF-1 and insulin levels, high GH levels, and increased longevity, despite their obesity and altered lipid and metabolic profiles. Secondary complications of high-fat diet (HFD)-induced obesity are reported to be associated with hypothalamic inflammation and gliosis. Because GH and IGF-1 can modulate inflammatory processes, our objective was to evaluate the effect of HFD on hypothalamic inflammation/gliosis in the absence of GH signaling and determine how this correlates with changes in systemic metabolism. On normal chow, GHR-/- mice had a higher percentage of fat mass and increased circulating nonesterified free fatty acids levels compared with wild type (WT), and this was associated with increased hypothalamic TNF-α and phospho-JNK levels. After 7 weeks on a HFD, both WT and GHR-/- mice had increased weight gain, with GHR-/- mice having a greater rise in their percentage of body fat. In WT mice, HFD-induced weight gain was associated with increased hypothalamic levels of phospho-JNK and the microglial marker Iba-1 (ionized calcium-binding adapter molecule 1) but decreased cytokine production. Moreover, in GHR-/- mice, the HFD decreased hypothalamic inflammatory markers to WT levels with no indication of gliosis. Thus, the GH/IGF-1 axis is important in determining not only adipose tissue accrual but also the inflammatory response to HFD. However, how hypothalamic inflammation/gliosis is defined will determine whether it can be considered a common feature of HFD-induced obesity.

Hyperleptinaemia rather than fasting hyperinsulinaemia is associated with obesity following hypothalamic damage in children.

BACKGROUND: Obesity following hypothalamic damage is often severe and resistant to lifestyle changes. Disruption of hypothalamic feedback mechanisms that maintain energy homeostasis may be responsible for this intractable obesity. Adipocytokines including insulin and leptin are also known to be important regulators of appetite and weight. OBJECTIVE: To investigate the role of insulin, leptin, adiponectin and resistin in the aetiology of hypothalamic obesity (HO). DESIGN: This was a cross-sectional study of three groups of children, those with HO, congenital hypopituitarism (CH) and simple obesity (SO). RESULTS: A total of 69 children (HO=28, CH=18, SO=23) had leptin, resistin, adiponectin and insulin measured. Although fasting hyperinsulinaemia and insulin resistance were demonstrated, no differences in insulin or insulin resistance were seen between the groups. The HO group, however, had higher levels of leptin, adiponectin and resistin, which persisted even after adjusting for fat mass, compared with the other groups (P<0.05). CONCLUSION: No differences in fasting hyperinsulinaemia or insulin resistance were seen between the groups; however, leptin levels are elevated, even after adjusting for fat mass, suggesting that an element of leptin resistance is associated with HO. This is consistent with the inability of leptin to act on the hypothalamus, either due to transport across the blood-brain barrier or dysfunctional receptors. The lack of response to leptin may be more important in the development of obesity in these individuals, and the fasting hyperinsulinaemia is a result of the increased adipose tissue rather than the cause of the weight gain.

Hypothalamic hamartoma secreting corticotropin-releasing hormone. Case report.

The authors describe a unique case of a 2-year-old boy with a hypothalamic hamartoma secreting corticotropin-releasing hormone (CRH). The patient presented with a history of behavioral disturbances progressing over 12 months. His neurological status was intact. Magnetic resonance imaging demonstrated a 1.8 x 1.6 x 1.2-cm isointense, nonenhancing hypothalamic lesion. Endocrinological workup revealed elevated serum CRH and adrenocorticotropic hormone levels, nonsuppression with low-dose dexamethasone, and partial suppression with high-dose dexamethasone. He underwent tumor resection via a right frontotemporal craniotomy. Pathological examination of the tissue confirmed a hypothalamic hamartoma with CRH immunostaining. Postoperatively, his hormone levels normalized and his behavioral disturbances abated. The radiographic and clinical characteristics of hypothalamic hamartomas are reviewed and therapeutic considerations discussed.

Gonadotrophin and prolactin secretory dynamics in girls with normal puberty, idiopathic precocious puberty and precocious puberty due to hypothalamic hamartoma.

OBJECTIVE: This study was designed to test the hypothesis that hypothalamic hamartoma causes precocious puberty through a different neuroendocrine mechanism than that of normal puberty or of idiopathic precocious puberty. DESIGN AND PATIENTS: We compared the pattern of gonadotrophin secretion among 4 girls with precocious puberty due to hypothalamic hamartoma, 27 girls with idiopathic precocious puberty, and 14 girls with normal puberty. All subjects were breast stage 3 or 4. Blood samples were obtained every 20 min for 4 h during the day (1.000 hours to 1400 h) and night (22.00 hours to 0200 h). MEASUREMENTS: LH, FSH, and prolactin were measured in each blood sample. Girls also underwent LHRH-stimulation with measurement of LH and FSH before and after stimulation. RESULTS: There were no significant differences in mean LH level, LH peak amplitude, or LH or FSH peak frequency during either the day or the night among the three diagnostic groups. However, the mean +/- SD LHRH-stimulated peak LH levels were greater in girls with hypothalamic hamartoma than in girls with normal puberty or with idiopathic precocious puberty (194 +/- 142 vs 85 +/- 60 or 66 +/- 54 IU/l, respectively, P < 0.05). The LHRH-stimulated peak FSH level in girls with hypothalamic hamartoma exceeded the level for the normal pubertal girls (31 +/- 19 vs 17 +/- 7 IU/l, P < 0.05), but not the level for the girls with idiopathic precocious puberty (25 + 12 IU/l). The peak LH to peak FSH ratio in the girls with hypothalamic hamartoma exceeded the ratio for the girls with idiopathic precocious puberty (7.3 +/- 3.9 vs 2.6 +/- 3.0 IU/l, P < 0.05), but not the ratio for the normal pubertal girls (5.0 + 2.9). There were no significant differences in mean prolactin level, peak amplitude or frequency, or in the ratio of mean night to mean day prolactin, among the 3 diagnostic groups. CONCLUSIONS: We conclude that spontaneous gonadotrophin and prolactin secretion are similar among girls with hypothalamic hamartoma, idiopathic precocious puberty, or normal puberty. However, the increased LHRH-stimulated peak LH in the girls with hypothalamic hamartoma suggests subtle differences in neuroendocrine regulation that may underlie their more rapid pubertal maturation.

Evaluation of amenorrhea.

Pregnancy is the most common cause of amenorrhea and must be ruled out before proceeding with diagnostic evaluation. A careful history and physical examination may reveal evidence of androgen excess, estrogen deficiency or other endocrinopathies. Serum prolactin and thyroid-stimulating hormone (TSH) levels should be checked in all women who are not pregnant. Galactorrhea by history or on examination and/or an elevated prolactin level should be investigated with an imaging study to rule out a pituitary adenoma. If serum prolactin and TSH levels are normal, a progesterone challenge test should be performed to determine outflow tract patency and estrogen status. In women with hypoestrogenic amenorrhea, indicated by a negative challenge test and a competent outflow tract, serum gonadotropin, follicle-stimulating hormone and luteinizing hormone levels may be measured to determine whether amenorrhea represents ovarian failure or pituitary or hypothalamic dysfunction. Hypothalamic amenorrhea is common in women with a history of weight loss, stress or vigorous exercise. Amenorrheic women with adequate estrogen levels should receive cyclic progesterone. Hormonal therapy and calcium supplementation in hypoestrogenic amenorrhea.

Naloxone stimulation test in women with hypothalamic amenorrhea: a preliminary report.

We researched the possibility of the induction of ovulation by means of chronic opioid receptor blockade in 4 women with hypothalamic amenorrhea. Daily 4 mg naloxone were given as a bolus injection intravenously. By means of continuous determination of LH, FSH, 17-beta-estradiol (E2) and progesterone as well as of sonographic folliculometry follicular growth and subsequent ovulation should have been proved. Neither we found alterations of the basal values of LH, FSH, E2 and progesterone, nor we observed a follicular growth. These results lead us to the conclusion to put a naloxone stimulation test before further therapy. In this way opioid mediated hypothalamic ovarian insufficiencies can be registered and a therapy optimum can be reached early.

Immunoreactive corticotropin-releasing hormone present in human plasma may be derived from both hypothalamic and extrahypothalamic sources.

Immunoreactive CRH concentrations were determined in human plasma using an immunoaffinity chromatographic extraction procedure and sensitive RIA. Immunoreactive CRH was detectable in the plasma of all normal subjects (mean +/- SD, 6.2 +/- 2.4 pg/mL; n = 15). Basal (0800-1000 h) plasma immunoreactive CRH levels were significantly lower in patients with Cushing's syndrome due to adrenal (2.8 +/- 1.1 pg/mL; n = 4) or pituitary adenomas (2.9 +/- 0.8 pg/mL; n = 5), in patients with hypothalamic hypopituitarism (3.2 +/- 0.9 pg/mL; n = 5), and in glucocorticoid-treated patients (3.9 +/- 1.9 pg/mL, n = 8). Basal plasma CRH levels were also low in patients with acromegaly (2.8 +/- 0.8 pg/mL; n = 14) and insulin-treated diabetic patients whose pituitary-adrenal function was normal (3.6 +/- 1.0 pg/mL; n = 12). In normal subjects plasma CRH levels increased after insulin-induced hypoglycemia; this response was abolished by the prior administration of dexamethasone. In contrast, basal plasma CRH levels were not affected by prior administration of metyrapone or dexamethasone. No evidence for diurnal variation in plasma immunoreactive CRH was found in normal subjects. In addition, in normal subjects oral glucose administration elicited a significant increase in plasma CRH (basal, 7.3 +/- 0.9 pg/mL; peak 30 min after glucose, 16.7 +/- 5.8 pg/mL; n = 5; P less than 0.05) without concomitant changes in ACTH. Gel filtration of extracts of pooled plasma from normal subjects revealed a major component of immunoreactive CRH in the position of synthetic rat CRH. Immunoreactive CRH-sized material had the same retention time as authentic rat CRH in a reverse phase high pressure liquid chromatography system. The content of immunoreactive CRH in human placenta, pancreas, and adrenal gland was much larger than that in hypothalamus. These findings suggest that immunoreactive CRH is present in peripheral plasma; the increase in plasma immunoreactive CRH after insulin-induced hypoglycemia may reflect stimulation of hypothalamic CRH release; the increase in plasma immunoreactive CRH after glucose administration may reflect extrahypothalamic CRH release; and the lack of diurnal variation in plasma immunoreactive CRH together with the lack of suppression of CRH by dexamethasone suggest that basal plasma CRH is of extrahypothalamic origin.

L-dopa stimulates release of hypothalamic growth hormone-releasing hormone in humans.

A sensitive RIA for human GH-releasing hormone-(1-44)-NH2 [hGHRH-(1-44)-NH2] was developed which allows its measurement in human plasma extracts. The assay did not detect hGHRH-(1-37)-OH or hGHRH-(1-40)-OH. A method to extract hGHRH from plasma was developed using silicic acid and acid-acetone, by which recovery of synthetic hGHRH-(1-44)-NH2 from plasma averaged 74.3%. Serial dilutions of plasma extracts gave an inhibition curve parallel with that of synthetic hGHRH-(1-44)-NH2 in the RIA system. On Sephadex G-50 columns, hGHRH-like immunoreactivity (hGHRH-LI) in plasma extracts eluted as a single peak corresponding to hGHRH-(1-44)-NH2. This hGHRH-LI peak, when subjected to reverse phase HPLC, emerged at the position where hGHRH-(1-44)-NH2 was eluted. hGHRH-LI was detectable in the peripherally circulating plasma of all subjects tested. The mean basal level of plasma hGHRH-LI in normal subjects was 9.4 +/- 0.7 (+/- SE) pg/ml (n = 22; range, 2.8-18.1 pg/ml), comparable to the basal plasma hGHRH-LI concentration in patients with hypothalamic lesions (11.3 +/- 1.1 pg/ml; n = 7). Oral administration of L-dopa (0.5 g) caused a significant increase in both plasma hGHRH-LI and GH levels in normal subjects, and the plasma hGHRH-LI peak slightly preceded or coincided with that of plasma GH in individual subjects. There was also a significant correlation between plasma hGHRH-LI and the GH rises after L-dopa administration when their net increments were compared. All of the patients with hypothalamic lesions had significant increases in plasma GH after hGHRH-(1-44)-NH2 injection (1 microgram/kg BW, iv), indicating the presence of functioning somatotrophs in their pituitaries. When L-dopa was orally administered to these patients, neither plasma hGHRH-LI nor GH concentration changed throughout a 120-min observation period. These findings suggest that 1) hGHRH, immunologically and chromatographically indistinguishable from synthetic hGHRH-(1-44)-NH2, is detectable in peripheral plasma in humans; 2) L-dopa stimulates the release of hypothalamic hGHRH, alterations of which are reflected in changes in peripheral levels; and 3) the source of circulating hGHRH is not restricted to the hypothalamus, since hGHRH-LI is present in the peripheral plasma of patients with hypothalamic lesions in amounts similar to those found in normal subjects.