Pubertal timing predicts adult psychosexuality: Evidence from typically developing adults and adults with isolated GnRH deficiency.

Evidence suggests that psychosexuality in humans is modulated by both organizational effects of prenatal and peripubertal sex steroid hormones, and by activational effects of circulating hormones in adulthood. Experimental work in male rodents indicates that sensitivity to androgen-driven organization of sexual motivation decreases across the pubertal window, such that earlier puberty leads to greater sex-typicality. We test this hypothesis in typically developing men (n = 231) and women (n = 648), and in men (n = 72) and women (n = 32) with isolated GnRH deficiency (IGD), in whom the precise timing of peripubertal hormone exposure can be ascertained via the age at which hormone replacement therapy (HRT) was initiated. Psychosexuality was measured with the Sexual Desire Inventory-2 (SDI-2) and Sociosexual Orientation Inventory-Revised (SOI-R). In both sexes, earlier recalled absolute pubertal timing predicted higher psychosexuality in adulthood, although the magnitude of these associations varied with psychosexuality type and group (i.e., typically developing and IGD). Results were robust when controlling for circulating steroid hormones in typically developing participants. Age of initiation of HRT in men with IGD negatively predicted SOI-R. We discuss the clinical implications of our findings for conditions in which pubertal timing is medically altered.

Brief Behavioral Intervention for Disruptive Behavior in a Child with a Hypothalamic Hamartoma: A Case Report.

Most children with hypothalamic hamartoma (HH) manifest symptoms of epilepsy and associated cognitive deficits and behavioral difficulties as well as central precocious puberty (CPP). However, there is little to no research examining behavioral difficulties in children with HH without epilepsy, nor is there research examining treatments to address the behavioral difficulties of patients with HH without epilepsy. In the current case report, the authors implemented a validated parent management training program [the Brief Behavioral Intervention (BBI)], to treat symptoms of ADHD and disruptive behavior in a 6-year-old female patient with HH and CPP. The family participated in six BBI sessions over a period of 8 weeks. Parent behavioral ratings suggested significant reductions of symptoms of ADHD and disruptive behaviors to the normal range. The current case report demonstrates the effectiveness of the BBI program in the treatment of behavioral difficulties in a patient with HH and CPP. Further, the present study explores behavioral manifestations rarely explored in patients with HH without epilepsy.

Psychiatric comorbidity with hypothalamic hamartoma: Systematic review for predictive clinical features.

OBJECTIVE: We conducted a systematic review of the English-language literature to identify clinical features associated with a higher risk of psychiatric symptoms (aggression and rage behaviors) in patients with hypothalamic hamartoma (HH) and epilepsy. METHODS: Two publicly-accessible databases (PubMed and Cochrane Library) were searched for Hypothalamic Hamartoma AND Epilepsy. We identified peer-reviewed original research publications (case reports or clinical series; N=19) in which clinical data was provided on an individual basis. Subjects were cohorted into those with (N=51) and without (N=68) behavioral aggression. Multiple clinical features were collated and subjected to univariate analysis to determine possible differences between these two cohorts. RESULTS: The presence of aggression significantly correlated with 1) male gender, 2) younger age at time of first seizure onset, 3) the presence of intellectual disability, and 4) the presence of multiple seizure types (versus gelastic seizures only). For those patients undergoing surgical treatment, aggression also correlated with younger age at the time of surgical intervention. CONCLUSION: Possible predictive clinical features for the presence of aggression and rage behaviors in patients with hypothalamic hamartoma and epilepsy are identified. These results may contribute to the complex treatment decisions that are unique to this population.

Improved Behavior and Neuropsychological Function in Children With ROHHAD After High-Dose Cyclophosphamide.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare, generally progressive, and potentially fatal syndrome of unclear etiology. The syndrome is characterized by normal development followed by a sudden, rapid hyperphagic weight gain beginning during the preschool period, hypothalamic dysfunction, and central hypoventilation, and is often accompanied by personality changes and developmental regression, leading to substantial morbidity and mortality. We describe 2 children who had symptomatic and neuropsychological improvement after high-dose cyclophosphamide treatment. Our experience supports an autoimmune pathogenesis and provides the first neuropsychological profile of patients with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation.

ADHD-like behavior in a patient with hypothalamic hamartoma.

We report a male patient with hypothalamic hamartoma (HH) who manifested central precocious puberty (CPP) at 4 years of age. Gonadotropin-releasing hormone (GnRH) analogue treatment was started at 6 years of age and his pubertal signs were suppressed. At 9 years of age, the patient was emotionally unstable, aggressive, and antisocial. He had severe attention deficit hyperactivity disorder (ADHD)-like behavior and conduct disorder. No seizure activity was observed. GnRH analogue treatment was discontinued for 8 months from 9 years and 4 months of age due to his mother's illness. During this period sexual urges were observed. Treatment with daily methylphenidate markedly improved his behavioral problems. However, his sexual urges were not suppressed until 3 months after the GnRH analogue treatment was restarted. The present case is unique because the patient's behavioral problems were observed despite the parahypothalamic type of HH and absence of seizures. This case is also rare because behavioral problems were observed without seizures, and no ADHD cases with hamartoma have been reported previously. Recently, clinical studies have described an association between psychiatric morbidity, including ADHD, and hyperandrogenism disorders. Our patient's ADHD-like symptoms might be due to hyperandrogenism. In such cases, GnRH analogue with methylphenidate could be effective for improving ADHD-like symptoms.

Psychopathological traits of adolescents with functional hypothalamic amenorrhea: a comparison with anorexia nervosa.

BACKGROUND: Functional hypothalamic amenorrhea (FHA) is a form of anovulation, due to the suppression of hypothalamic-pituitary-ovarian axis, not related to identifiable organic causes. Like adolescents with anorexia nervosa (AN), subjects with FHA show dysfunctional attitudes, low self-esteem, depressive mood, anxiety and inability to cope with daily stress. The aim of the study is to examine similarities and differences between FHA and AN in terms of clinical profiles and psychological variables. METHODS: 21 adolescents with FHA, 21 adolescents with anorexia nervosa, and 21 healthy adolescents were included in the study. All the teenagers completed a battery of self-administered psychological tests for the detection of behaviors and symptoms attributable to the presence of an eating disorder (EDI-2), depression (CDI), and alexithymia (TAS-20). RESULTS: Different from healthy controls, subjects with FHA and with AN shared common psychopathological aspects, such as maturity issues, social insecurity and introversion, a tendency to depression, excessive concerns with dieting, and fear of gaining weight. Nevertheless, adolescents with AN presented a more profound psychopathological disorder as observed at test comparisons with subjects with FHA. CONCLUSIONS: Results show a clinical spectrum that includes AN and FHA and suggest the necessity to treat FHA with a multidisciplinary approach for both organic and psychological aspects.

Neuroendocrine recovery initiated by cognitive behavioral therapy in women with functional hypothalamic amenorrhea: a randomized, controlled trial.

OBJECTIVE: To determine whether cognitive behavior therapy (CBT), which we had shown in a previous study to restore ovarian function in women with functional hypothalamic amenorrhea (FHA), could also ameliorate hypercortisolemia and improve other neuroendocrine and metabolic concomitants of in FHA. DESIGN: Randomized controlled trial. SETTING: Clinical research center at an academic medical university. PATIENT(S): Seventeen women with FHA were randomized either to CBT or observation. INTERVENTION(S): CBT versus observation. MAIN OUTCOME MEASURE(S): Circulatory concentrations of cortisol, leptin, thyroid-stimulating hormone (TSH), total and free thyronine (T(3)), and total and free thyroxine (T(4)) before and immediately after completion of CBT or observation. (Each woman served as her own control.) RESULT(S): Cognitive behavior therapy but not observation reduced cortisol levels in women with FHA. There were no changes in cortisol, leptin, TSH, T(3), or T(4) levels in women randomized to observation. Women treated with CBT showed increased levels of leptin and TSH, but their levels of T(3) and T(4) remained unchanged. CONCLUSION(S): In women with FHA, CBT ameliorated hypercortisolism and improved the neuroendocrine and metabolic concomitants of FHA while observation did not. We conclude that a cognitive, nonpharmacologic approach aimed at alleviating problematic attitudes not only can restore ovarian activity but also improve neuroendocrine and metabolic function in women with FHA. CLINICAL TRIAL REGISTRATION NUMBER: NCT01674426.

Decreased quality of life in children with hypothalamic hamartoma and treatment-resistant epilepsy.

We evaluated health-related quality of life in patients with hypothalamic hamartoma, to see how it differs from that of children with more common neurologic disorders. We used the PedsQL 4.0, along with the Child Behavior Checklist, Hague Seizure Severity Scale, and Side Effects Scale, to evaluate presurgical patients with hypothalamic hamartoma and epilepsy (n = 21). The results were compared with those of age-matched cohorts with migraine (n = 19) and Benign Epilepsy with Central Temporal Spikes (n = 11). In comparison with the migraine group, the patients with hypothalamic hamartoma had decreased health-related quality of life across all domains of the PedsQL 4.0. Compared with the benign epilepsy group, the hypothalamic hamartoma cohort has a significantly lower score in School Function. Comorbid psychomotor retardation was predictive of lower quality of life. Research examining the efficacy of recently developed surgical treatments for hypothalamic hamartoma should include health-related quality of life as an outcome measure.

Hypothalamic-pituitary-thyroid axis function in women with a menstrually related mood disorder: association with histories of sexual abuse.

INTRODUCTION: We previously reported a unique hypothalamic-pituitary-thyroid (HPT) axis profile in women with a menstrually related mood disorder (MRMD) who also had a history of sexual abuse (SA). In the present study, we sought to extend that work by examining the association of an SA history with HPT-axis disturbance in both women with MRMD and women without MRMD. METHODS: Fifty-seven women met the prospective criteria for MRMD (23 with an SA history), and 52 women were non-MRMD (18 with an SA history). Thyroid-stimulating hormone, thyroxin (T4; total and free), and triiodothyronine (T3; total and free) were evaluated in serum, together with thyroid hormone ratios reflecting T4 to T3 conversion. RESULTS: Women with MRMD, compared with women without MRMD, had elevated T3/T4 ratios (p values ≤ .01; reflecting increased conversion of T4 to T3) and lower free and total T4 concentrations (p values = .01). Higher T3/T4 ratios and lower T4 concentrations predicted more severe premenstrual symptoms in all women. An SA history, irrespective of MRMD status, was associated with elevated thyroid-stimulating hormone concentrations (p = .03). However, in women with MRMD, an SA history was associated with elevated T3 concentrations (p = .049), whereas in women without MRMD, an SA history was associated with decreased T3 concentrations (p = .02). CONCLUSIONS: An MRMD and an SA history are associated with independent and interactive effects on the HPT axis. The evidence that an MRMD moderates the influence of SA on T3 concentrations contributes to a growing body of work suggesting that an SA history may identify a distinct subgroup of women with MRMD.

Effect of growth hormone replacement therapy on the quality of life in women with growth hormone deficiency who have a history of acromegaly versus other disorders.

OBJECTIVE: To compare the response in quality of life (QoL) to growth hormone (GH) replacement in women with GH deficiency (GHD) and a history of acromegaly with that in women with GHD of other causes. METHODS: Fifty-five women with GHD were studied: 17 with prior acromegaly and 38 with other causes of GHD. We compared two 6-month, randomized, placebo-controlled studies of GH therapy in women with hypopituitarism conducted with use of the same design-one in women with a history of acromegaly and one in women with no prior acromegaly. QoL was assessed with the following questionnaires: the QoL-Assessment of Growth Hormone Deficiency in Adults (AGHDA), the Symptom Questionnaire, and the 36-Item Short-Form Health Survey (SF-36). RESULTS: The 2 groups had comparable mean pretreatment age, body mass index, and QoL scores and comparable mean GH dose at 6 months (0.61 ± 0.30 versus 0.67 ± 0.27 mg daily). After 6 months of GH replacement therapy, women with GHD and prior acromegaly demonstrated a greater improvement in AGHDA score, four SF-36 sub-scales (Role Limitations due to Physical Health, Energy or Fatigue, Emotional Well-Being, and Social Functioning), and the Somatic Symptoms subscale of the Symptom Questionnaire than did women with GHD of other causes. Poorer pretreatment QoL was associated with a greater improvement in QoL after administration of GH. CONCLUSION: In this study, GH replacement therapy improved QoL in women with GHD and a history of acromegaly but not in women with GHD due to other hypothalamic and pituitary disorders. Further studies are needed to determine the long-term risks versus benefits of GH replacement in patients who develop GHD after definitive treatment for acromegaly.

Neurochemical and behavioral analyses of the lateral hypothalamic syndrome: a look back.

Philip Teitelbaum is one of the great physiological psychologists of his generation. His early research clarified key issues regarding the effects of electrolytic lesions of the ventromedial or ventrolateral hypothalamus on food intake in rats, a subject of paramount interest during the 1950s and 1960s. Perhaps best known were his extensive studies of the lateral hypothalamic syndrome in rats, which focused on the complex and changing array of symptoms after experimental brain damage. It soon became clear from later work that his research interests were not in the brain's control of food intake but in the effects of lesions to fragment behavior and thereby allow investigators to view its components. He was the foremost proponent of the use of exquisite behavioral analysis to reveal details in movement that allowed insights into brain function, and that approach - old fashioned physiological psychology made modern and at its finest - has infiltrated the entire field of experimental psychology, including studies of ingestive behavior, even while the new field of behavioral neuroscience emerged. He extended his analytic approach to neurological issues such as autism in humans, a promising arena that fully occupied his attention during the later phases of his career. But his influence on his scientific colleagues went well beyond his careful and powerful thinking; his articles and books have been models of clarity and concision. I write in behalf of a grateful field to salute his many great contributions.

Mood disorders and sexual functioning in women with functional hypothalamic amenorrhea.

OBJECTIVE: To investigate the sexual function of women with functional hypothalamic amenorrhea (FHA) and to test the mediating effects of depression and anxiety on the sexual functioning of women with FHA. DESIGN: In this cross-sectional study, participants completed questionnaires on sexual function, depression, and anxiety. SETTING: Tertiary care university hospital. PATIENT(S): Women with (n=41) and without (n=39) FHA recruited from a gynecologic endocrinology unit. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The McCoy Female Sexuality Questionnaire assessed sexual function, and the Zung Scale measured depression and anxiety. RESULT(S): Women with FHA experienced more sexual function problems and significantly higher depression and anxiety compared to women without menstrual dysfunction. In addition, depression offered a significant explanation for the sexual problems experienced by women with FHA. CONCLUSION(S): The psychologic symptoms that contribute to the onset of FHA partially mediate the relationship between FHA and sexual dysfunction.

Hypercortisolemia is associated with severity of bone loss and depression in hypothalamic amenorrhea and anorexia nervosa.

CONTEXT: Anorexia nervosa (AN) and functional hypothalamic amenorrhea (HA) are associated with low bone density, anxiety, and depression. Women with AN and HA have elevated cortisol levels. Significant hypercortisolemia, as in Cushing's disease, causes bone loss. It is unknown whether anxiety and depression and/or cortisol dysregulation contribute to low bone density in AN or HA. OBJECTIVE: Our objective was to investigate whether hypercortisolemia is associated with bone loss and mood disturbance in women with HA and AN. DESIGN AND SETTING: We conducted a cross-sectional study in a clinical research center. PARTICIPANTS: We studied 52 women [21 healthy controls (HC), 13 normal-weight women with functional HA, and 18 amenorrheic women with AN]. OUTCOME MEASURES: Serum samples were measured every 20 min for 12 h overnight and pooled for average cortisol levels. Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry (DXA) at anteroposterior and lateral spine and hip. Hamilton Rating Scales for Anxiety (HAM-A) and Depression (HAM-D) were administered. RESULTS: BMD was lower in AN and HA than HC at all sites and lower in AN than HA at the spine. On the HAM-D and HAM-A, AN scored higher than HA, and HA scored higher than HC. Cortisol levels were highest in AN, intermediate in HA, and lowest in HC. HAM-A and HAM-D scores were associated with decreased BMD. Cortisol levels were positively associated with HAM-A and HAM-D scores and negatively associated with BMD. CONCLUSIONS: Hypercortisolemia is a potential mediator of bone loss and mood disturbance in these disorders.

Hypothalamic--pituitary-- adrenal axis dysregulation in women with irritable bowel syndrome in response to acute physical stress.

Irritable bowel syndrome (IBS) supports the concept of a dysregulated hypothalamic-pituitary-adrenal (HPA) axis. This study investigates the neuroendocrine and psychological responses to the acute physical stress of a lumbar puncture (LP) in women with diarrhea-predominant IBS by assessing central and peripheral HPA activity and affective measures. Blood samples have been collected at baseline and immediately post- and 1 hr following LP from 13 women with IBS and 13 controls. Plasma adrenocorticotropic hormone (ACTH), cortisol, epinephrine, and norepinephrine levels are analyzed. A single measure of cerebrospinal fluid (CSF) concentrations of corticotropin-releasing factor (CRF(CSF)) and norepinephrine(CSF) is noted. Affective assessments are used to rate anxiety and depression with the Hospital Anxiety and Depression Scale (HADS) and acute mood state is rated using the Stress Symptom Rating questionnaire (stress, anxiety, anger, arousal). The women with IBS display blunted ACTH and cortisol responses to the LP along with a profile of affective responsiveness suggestive of chronic psychosocial stress, although no CRF(CSF) differences between groups are observed.

Stereotactic disconnection of hypothalamic hamartoma to control seizure and behavior disturbance: case report and literature review.

An 18-year-old boy with refractory epilepsy and aggressiveness associated to a hypothalamic hamartoma was submitted to a stereotactically guided lesion by thermocoagulation. The target was based on magnetic resonance (MR) images merged with computed tomography scan images taken on the day of surgery while patient was on a stereotactic frame. In order to reveal structures not discernible in MR images, the Schaltenbrand digital brain atlas was merged onto the patient's images. Target and trajectory of the depth electrode were chosen based on three-dimensional imaging reconstructions. A surgical plan was devised to disconnect the hypothalamic hamartoma from the hypothalamus, medial forebrain bundle, fasciculus princeps, and dorsal longitudinal fasciculus. Our target was placed at the inferior portion of the posterolateral component of the hamartoma, bordering the normal hypothalamus. The patient evolved with marked lessening of aggressiveness. Seizure frequency was reduced from several seizures per day to less than one tonic-clonic seizure during sleep per month and only two episodes suggestive of partial complex seizures during daytime. These results have remained consistent over a 24-month postoperative follow-up. Functional neuroanatomy of hypothalamic connections involved in seizure propagation and aggressive behavior was reviewed.

Gelastic seizures: not always hypothalamic hamartoma.

Gelastic seizures are often associated with hypothalamic hamartomas. However, focal cortical dysplasias can also cause "laughing seizures", and such cases can be difficult to localize with EEG. This case report presents a 29-year-old woman who was successfully rendered free of gelastic seizures after resection of a frontal cortical dysplasia, localized through MRI and SPECT imaging.[Published with video sequences].

Sexual symptoms in endocrine diseases: psychosomatic perspectives.

BACKGROUND: Not only the most frequent causes of endocrine sexual dysfunction, such as hypogonadism and hyperprolactinemia, but almost all extragonadal endocrinopathies (hyper- and hypothyroidism, hyper- and hypocortisolism, steroidal secreting tumors, etc.) may have a greater or lesser effect on sexual function. METHODS: We analyzed scientific literature on the correlations between hormones and sexual behavior, analyzing the most important issue from a practical point of view. The aim of this review article was thus to summarize the sexual symptoms that may be observed with endocrine diseases. RESULTS: Hormones directly or indirectly regulate all human sexual functions (desire, erection/lubrication, ejaculation, orgasm). Some sexual symptoms may occur as a psychosomatic consequence of hormonal impairment. However, in other cases, endocrine failure may be generated by the psychosomatic involvement. CONCLUSIONS: The endocrinologist, as an expert in body chemistry, is ideally positioned to identify and evaluate the full range of medical, physical, and psychiatric problems disrupting sexual function.

Endocrine profiles and neuropsychologic correlates of functional hypothalamic amenorrhea in adolescents.

OBJECTIVE: To determine trigger factors and neuropsychologic correlates of functional hypothalamic amenorrhea (FHA) in adolescence and to evaluate the correlations with the endocrine-metabolic profile. DESIGN: Cross-sectional comparison of adolescents with FHA and eumenorrheic controls SETTING: Academic medical institution PATIENT(S): Twenty adolescent girls with FHA (aged <18 years) and 20 normal cycling girls INTERVENTION(S): All subjects underwent endocrine-gynecologic (hormone) and neuropsychiatric (tests and interview) investigations. A separate semistructured interview was also used to investigate parents. MAIN OUTCOME MEASURE(S): Gonadotropins, leptin, prolactin, androgens, estrogens, cortisol, carrier proteins (SHBG, insulin-like growth factor-binding protein 1), and metabolic parameters (insulin, insulin-like growth factor 1, thyroid hormones) were assayed in FHA and control subjects. All girls were evaluated using a test for depression, a test for disordered eating, and a psychodynamic semistructured interview. RESULT(S): Adolescents with FHA showed a particular susceptibility to common life events, restrictive disordered eating, depressive traits, and psychosomatic disorders. The endocrine-metabolic profile was strictly correlated to the severity of the psychopathology. CONCLUSION(S): Functional hypothalamic amenorrhea in adolescence is due to a particular neuropsychologic vulnerability to stress, probably related to familial relationship styles, expressed by a proportional endocrine impairment.

Psychiatric comorbidity in adult patients with hypothalamic hamartoma.

The objective was to investigate the prevalence of psychiatric comorbidity in adults with hypothalamic hamartoma (HH). A standardized clinical interview and assessment scales were used to assess for depression, anxiety, personality, and sexual behavior, based on previous findings in the pediatric population. We found a high prevalence of mood and anxiety disorders, with Major Depressive Disorder and Social Anxiety Disorder being the most common. "Anxious" personality types were the most common. Symptoms of Asperger syndrome were high in males versus females. We concluded that depression and anxiety are common in adult patients with HH. Remission of cognitive, behavioral, and autistic symptoms has been reported with surgical tumor resection. Whether this can correct the psychiatric disturbances remains to be investigated. The need for adjunctive psychiatric treatment may nevertheless remain.