Kisspeptin in functional hypothalamic amenorrhea: Pathophysiology and therapeutic potential.

Functional hypothalamic amenorrhea (FHA) is one of the most common causes of secondary amenorrhea, resulting in anovulation and infertility, and is a low estrogen state that increases the risk of cardiovascular disease and impairs bone health. FHA is characterized by acquired suppression of physiological pulsatile gonadotropin-releasing hormone (GnRH) release by the hypothalamus in the absence of an identifiable structural cause, resulting in a functional hypogonadotropic hypogonadism. FHA results from either decreased energy intake and/or excessive exercise, leading to low energy availability and weight loss-often in combination with psychological stress on top of a background of genetic susceptibility. The hypothalamic neuropeptide kisspeptin is a key component of the GnRH pulse generator, tightly regulating pulsatile GnRH secretion and the downstream reproductive axis. Here, we review the physiological regulation of pulsatile GnRH secretion by hypothalamic kisspeptin neurons and how their activity is modulated by signals of energy status to affect reproductive function. We explore endocrine factors contributing to the suppression of GnRH pulsatility in the pathophysiology of FHA and how hypothalamic kisspeptin neurons likely represent a final common pathway through which these factors affect GnRH pulse generation. Finally, we discuss the therapeutic potential of kisspeptin as a novel treatment for women with FHA.

Analysis of the effects of eating and emotions on reproductive axis function in patients with functional hypothalamic amenorrhea.

Objective: To investigate the effects of eating and emotions on reproductive axis function in patients with functional hypothalamic amenorrhea (FHA).Methods: A retrospective cohort study was conducted to summarize the clinical and endocrine characteristics of 58 patients with FHA at initial diagnosis and to follow up the recovery of ovulation and spontaneous menstruation in the patients to investigate these biochemical indicators and their effects on recovery outcomes.Results: Among patients with FHA, 13.8% (8/58) and 15.5% (9/58) had above moderately severe depressive and severe anxiety symptoms respectively, and 25.9% (15/58) were at high risk for eating disorders. 34.5% (20/58) were included assessed as having recovered. The non-recovered group had higher scores on the Patient Health Questionnaire (PHQ-9) (p = .022) and higher scores on the Eating Attitude Test-26 (EAT-26) (p = .03) as well as bulimia and food preoccupation (p = .041). Follicle diameter >5 mm at initial diagnosis was an independent factor influencing recovery of reproductive axis function (odds ratio = 7.532; 95% confidence interval, 1.321-42.930; p = .023).Conculsions: Mood disorders and a certain risk of eating disorders were present in FHA.These, together with weight loss, endocrine and follicle size, could influence the outcome.

Chorio-retinal vessel density in women affected by functional hypothalamic amenorrhea: a monocentric observational cross-sectional study to evaluate the impact of hypoestrogenism on chorio-retinal vascularization.

PURPOSE: Functional hypothalamic amenorrhea (FHA) is characterized by an estrogen deficiency which in turn can cause vascular dysfunction. The aim of this study is to evaluate any changes in the chorio-retinal circulation in patients affected by FHA. 24 patients with FHA and 24 age-matched controls underwent a gynecological evaluation and an OCT angiography (OCTA) to study chorio-retinal vascularization. RESULTS: OCTA in FHA patients showed an increase in vessel density in the choriocapillaris (CC) layer (both in the fovea area, at 5% p value = 0.037 and in the whole area, at 5% p value = 0.028) and an increase in vascular density in the deep fovea (DVP) (at 10% p value = 0.096) in the whole district compared to controls. Simple linear regressions show a significant negative association between CC vessel density and insulin (p = 0.0002) and glucose values (p = 0.0335) for the fovea district and a negative association between DVP vessel density and endometrial thickness (at 10%, p value: 0.095) in the whole district. CONCLUSION: Our study shows that CC vessel density is increased in women affected by FHA. This could represent a compensation effort to supply the vascular dysfunction caused by estrogen deficiency. We also found an increasing trend in vascular density in DVP associated with the decrease of endometrial thickness, an indirect sign of estrogenization. Considering that these changes occur in absence of visual defects, they could be used as a biomarker to estimate hypoestrogenism-induced microcirculation changes before clinical appearance.

An Unusual Case of Hypothalamic Hamartoma With Nongelastic Seizures and Posterior Cortex Connectivity.

BACKGROUND: To describe a rare seizure semiology originating from a hypothalamic hamartoma in a child, along with unusual ictal onset and connectivity pattern, and provide a review of the pathophysiology of epilepsy associated with hypothalamic hamartoma and management. METHODS: A detailed retrospective chart review and literature search were performed using Pubmed and Embase. RESULTS: We present a case of a three-year-old male who presented with dyscognitive seizures with onset at age 22 months. Stereoelectroencephalography exploration confirmed the onset in hypothalamic hamartoma with rapid propagation to the temporal-parietal-occipital association cortex and precuneus. The patient's epilepsy was cured with laser ablation of the hamartoma. CONCLUSION: Published literature mostly describes a more anterior frontal or temporal epileptic network with primarily gelastic seizures being the hallmark type of seizures associated with hypothalamic hamartoma. We highlight a rare posterior cortex network with an atypical presentation of focal nonmotor seizures with impaired awareness in the setting of a hypothalamic hamartoma. Stereotactic laser ablation of the hamartoma rendered seizure freedom. Early diagnosis and appropriate treatment can lead to seizure freedom.

Intraoperative changes in large-scale thalamic circuitry following laser ablation of hypothalamic hamartomas.

BACKGROUND AND OBJECTIVES: Gelastic seizures due to hypothalamic hamartomas (HH) are challenging to treat, in part due to an incomplete understanding of seizure propagation pathways. Although magnetic resonance imaging-guided laser interstitial thermal therapy (MRgLITT) is a promising intervention to disconnect HH from ictal propagation networks, the optimal site of ablation to achieve seizure freedom is not known. In this study, we investigated intraoperative post-ablation changes in resting-state functional connectivity to identify large-scale networks associated with successful disconnection of HH. METHODS: Children who underwent MRgLITT for HH at two institutions were consecutively recruited and followed for a minimum of one year. Seizure freedom was defined as Engel score of 1A at the last available follow-up. Immediate pre- and post- ablation resting-state functional MRI scans were acquired while maintaining a constant depth of general anesthetic. Multivariable generalized linear models were used to identify intraoperative changes in large-scale connectivity associated with seizure outcomes. RESULTS: Twelve patients underwent MRgLITT for HH, five of whom were seizure-free at their last follow-up. Intraprocedural changes in thalamocortical circuitry involving the anterior cingulate cortex were associated with seizure-freedom. Children who were seizure-free demonstrated an increase and decrease in connectivity to the pregenual and dorsal anterior cingulate cortices, respectively. In addition, children who became seizure-free demonstrated increased thalamic connectivity to the periaqueductal gray immediately following MRgLITT. DISCUSSION: Successful disconnection of HH is associated with intraoperative, large-scale changes in thalamocortical connectivity. These changes provide novel insights into the large-scale basis of gelastic seizures and may represent intraoperative biomarkers of treatment success.

Chorioretinal biomarkers in hypothalamic amenorrhea.

PURPOSE: The aim of our study was to evaluate changes in the retinal and choriocapillaris circulations in patients with hypothalamic amenorrhea. METHODS: Prospective, cross-sectional observational study on 25 patients (50 eyes) diagnosed with hypothalamic amenorrhea and 25 age-matched healthy women. Optical coherence tomography angiography (OCTA) was used to evaluate the vessel density (VD) of superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris VD layers in whole 6.4 × 6.4-mm image and in fovea grid-based image. In patients' group, systemic parameters were collected: body mass index (BMI), endometrial rhyme thickness, follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, insulin, and cortisol. RESULTS: SCP and DCP did not show any statistical difference when comparing patients and controls (all p > 0.05). Differently, choriocapillaris VD in the whole region showed a non-significant tendency toward higher values in the patients group in both eyes (p = 0.038 for right eye [RE], p = 0.044 for left eye [LE]). Foveal choriocapillaris VD was higher in hypothalamic amenorrhea women vs. healthy controls (66.0 ± 2.4 vs. 63.7 ± 6.6%, p = 0.136 for RE; 65.0 ± 2.4 vs. 61.6 ± 7.0%, p = 0.005 for LE). Focusing on correlation with systemic parameters, SCP and DCP foveal density had a medium/high effect size with endometrial rhyme, along with DCP in the fovea area vs. cortisol and SCP in the whole area vs. FSH. CONCLUSION: When comparing hypothalamic amenorrhea patients to healthy subjects, OCTA detected changes in the choriocapillaris layer, showing increased VD in the early stage of the systemic pathology, suggesting that microvascular "compaction" could be a first phase of hypoestrogenism adaptation.

Neuroinflammation and Hypothalamo-Pituitary Dysfunction: Focus of Traumatic Brain Injury.

The incidence of traumatic brain injury (TBI) has increased over the last years with an important impact on public health. Many preclinical and clinical studies identified multiple and heterogeneous TBI-related pathophysiological mechanisms that are responsible for functional, cognitive, and behavioral alterations. Recent evidence has suggested that post-TBI neuroinflammation is responsible for several long-term clinical consequences, including hypopituitarism. This review aims to summarize current evidence on TBI-induced neuroinflammation and its potential role in determining hypothalamic-pituitary dysfunctions.

Sleep-disordered breathing, respiratory patterns during wakefulness and functional capacity in pediatric patients with rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation syndrome.

OBJECTIVE: To characterize the clinical presentation of sleep-disordered breathing and respiratory patterns at rest and during a 6-min walk test (6MWT) in children with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome. METHODS: Retrospective study of children with ROHHAD who had a diagnostic baseline polysomnography, daytime cardiorespiratory monitoring at rest and a 6MWT. Polysomnography data were also compared with body mass index-, age-, and sex-matched controls. RESULTS: Of the eight children with ROHHAD, all eight (100%) had obstructive sleep apnea (OSA) and 2/8 (25%) had nocturnal hypoventilation (NH) on their baseline polysomnography. Comparing the ROHHAD group to the control group, there were no significant differences in the median (interquartile range [IQR]) obstructive apnea-hypopnea index (11.1 [4.3-58.4] vs. 14.4 [10.3-23.3] events/h, respectively; p = .78). However, children with ROHHAD showed a significantly higher desaturation index compared to the control group (37.9 [13.7-59.8] vs. 14.7 [4.3-27.6] events/h; p = .05). While awake at rest, some children with ROHHAD experienced significant desaturations associated with central pauses. During the 6MWT, no significant desaturations were observed, but two children showed moderate functional limitation. CONCLUSIONS: Among children with ROHHAD, respiratory instability may be demonstrated by a significant number and severity of oxygen desaturations during sleep in the presence of OSA, with or without NH, and oxygen desaturations with central pauses at rest during wakefulness. Interestingly, during daily activities that require submaximal effort, children may not experience oxygen desaturations. Early recognition of respiratory abnormalities and targeted therapeutic interventions are important to limit associated morbidity and mortality in ROHHAD.

Significance of the electrophysiological border between hypothalamic hamartomas and the hypothalamus for the target of ablation surgery identified by intraoperative semimicrorecording.

OBJECTIVE: Ablation surgery has become the first line of treatment for hypothalamic hamartomas (HHs). For effective treatment, optimum targeting of ablation is mandatory. The present study aimed to evaluate the correspondence between the electrophysiological features of HHs and morphological targeting by semimicrorecording during stereotactic radiofrequency thermocoagulation (SRT). METHODS: Eighty HH patients who underwent SRT were involved. Semimicrorecording was performed on the first trajectory. The distance from the center of the target at the morphological border (TMB) determined by magnetic resonance imaging, differences in discharge patterns, and area potentials (APs) were measured. RESULTS: The electrophysiological border (EB) between the HH and hypothalamus was detected by semimicrorecording in 73 (91.3%), AP increase (API) in the HH was detected in 31 (38.8%), and spike discharges (SDs) of the HH were detected in 56 patients (70.0%). Semimicrorecording showed significantly different APs among structures passing through the trajectory, except between API and SDs. The median distances from the center of the TMB to the EB, API, SDs, and AP decline were -3.50, -2.49, -1.38, and +2.00 mm, respectively. SIGNIFICANCE: The electrophysiological features of HHs were shown by semimicrorecording during SRT. The EB corresponded to the morphological border. The electrophysiologically active area of HHs was located near the border. Ablation surgery should focus on disconnection at the border between the HH and the hypothalamus to maximize its effectiveness, as well as to reduce complications.

Hypothalamic hamartomas: A comprehensive review of the literature - Part 1: Neurobiological features, clinical presentations and advancements in diagnostic tools.

Hypothalamic hamartomas (HH) are rare, non-neoplastic heterotopic tissues which contains normal neurons and glia including oligodendrocytes and fibrillary astrocytes but in an abnormal distribution. They arise from the floor of the third ventricle, tuber cinereum, or mammillary bodies. Estimated incidence ranges from 1 in 50,000-1 in 1,000,000. Hypothalamic hamartomas are associated with different clinical presentations including various types of seizures, most characteristically; the gelastic seizures, precocious puberty, cognitive impairment, and behavioral changes. In this review, the authors discuss advancements in different diagnostic elements of hypothalamic hamartoma; including clinical features, EEG findings, and neuroimaging techniques. Moreover, different classifications described in the literature will be discussed.

Craniopharyngioma treatment: an updated summary of important clinicopathological concepts.

INTRODUCTION: Craniopharyngiomas (CPs) are benign histological tumors that may develop at different positions along the hypothalamic-pituitary axis. Their close, heterogenous relationship to the hypothalamus makes surgical removal challenging even though this remains the primary treatment strategy. AREAS COVERED: This article presents a critical overview of the pathological and clinical concepts regarding CPs that should be considered when planning treatment. Thus, we have performed a comprehensive review of detailed CP reports published between 1839 and 2020. EXPERT OPINION: CP surgery should pursue maximal tumor resection while minimizing the risk of injuring the hypothalamus. Therefore, surgical strategies should be individualized for each patient. Accurate assessment of presenting symptoms and preoperative MRI has proven useful to predict the type of CP-hypothalamus relationship that will be found during surgery. CPs with dense and extensive adhesions to the hypothalamus should be highly suspected when MRI shows the hypothalamus positioned around the mid-third of the tumor and an amputated upper portion of the pituitary stalk. Symptoms related to functional impairment of the infundibulo-tuberal area of the third ventricle floor, such as obesity/hyperphagia, Fröhlich's syndrome, diabetes insipidus, and/or somnolence, also indicate risky CP-hypothalamic adhesions. In these cases, limited tumor removal is strongly advocated followed by radiation therapy.

Diagnosis, Background, and Treatment of Hypothalamic Damage in Craniopharyngioma.

Craniopharyngiomas (CP) are rare brain tumors managed primarily with surgery and radiotherapy. There are 2 phenotypes of CP, i.e., one with a rather good outcome without hypothalamic damage and another with hypothalamic damage. With hypothalamic damage, progressive disease with recurrent operations and additional cranial radiotherapy often result in hypothalamic obesity, an affected psychosocial life, and cognitive dysfunction. The morbidity and mortality are increased for particularly cerebrovascular diseases. Preoperative hypothalamic involvement to predict hypothalamic damage is important for decision making for hypothalamus-sparing surgery. Also a postoperative hypothalamic damage evaluation with the use of hypothalamus volume measurement can predict hypothalamic obesity, which is important for early treatment options. The morbidity of CP includes cognitive dysfunction with attention deficits and impaired episodic memory and processing speed. Again patients with hypothalamic damage are more affected. Treatment options of hypothalamic obesity in the chronic phase are scarce and not convincingly successful. The most optimal situation is to try to hinder or stop the evolution of hypothalamic obesity. Prevention of hypothalamic damage is recommended, with special regard to hypothalamus-sparing therapeutic approaches that respect the integrity of essential nuclei located in both the medial and the posterior hypothalamic areas.

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.

Gelastic seizures: a retrospective study in five tertiary hospital centres.

This study aimed to characterize, clinically and neurophysiologically, a series of patients with gelastic seizures (GS), including both adults and children. We retrospectively collected patients with GS from epilepsy clinics of five tertiary hospital centres within a single country. Patients were selected through relatives'/caregivers' descriptions, home video and/or video-EEG monitoring. GS were identified through ictal semiology. Thirty-five patients were enrolled; 62.9% had initial GS in infancy, 14.3% in adolescence and 22.8% at adult age. Twenty-six had abnormal MRI: eight presented with hypothalamic hamartoma (HH) and 16 non-HH lesions that included different structural aetiologies and genetic, metabolic and immune aetiologies. All patients with HH had their first GS in infancy or adolescence. For the remaining aetiologies, GS started in infancy in 59.3%, in adolescence in 11.1% and at adult age in 29.6%. Video-EEG data was available for analysis in 11 patients, including seven patients with a non-HH MRI lesion. The ictal onset topography on scalp video-EEG was usually concordant with the MRI lesion (in 6/7 patients) and the most frequent ictal onset was fronto-temporal. In two patients, both video-EEG and MRI suggested a parietal and occipital epileptogenic zone. Aetiologies and patterns of affected topography unrelated to HH are common in patients with GS, and all age groups may manifest with this type of ictal semiology. This ictal manifestation has no lateralizing value and, despite a clear preponderance for hypothalamic, frontal and temporal lobe origins, other brain areas, namely the parietal and occipital lobes, should be considered.

Electrophysiological properties and seizure networks in hypothalamic hamartoma.

OBJECTIVE: Little is known about the intrinsic electrophysiological properties of hypothalamic hamartoma (HH) in vivo and seizure network since only few cases using stereoelectroencephalography (SEEG) electrodes exploring both cortex and HH have been published. To elucidate these issues, we analyzed simultaneous SEEG recordings in HH and cortex systematically. METHODS: We retrospectively investigated data from 15 consecutive patients with SEEG electrodes into the HH for the treatment purpose of radiofrequency thermocoagulation treatment. Additional SEEG electrodes were placed into the cortex in 11 patients to assess extra-HH involvement. Interictal discharges within the HH and anatomo-electroclinical correlations during seizures of each patient were qualitatively and quantitatively analyzed. RESULTS: Overall, 77 electrodes with 719 contacts were implanted, and 33 spontaneous seizures were recorded during long-term SEEG monitoring. Interictally, distinct electrophysiological patterns, including isolated intermittent spikes/sharp waves, burst spike and wave trains, paroxysmal fast discharges, periodic discharges, and high-frequency oscillations, were identified within the HH. Notably, synchronized or independent interictal discharges in the cortex were observed. Regarding the ictal discharges, the electrical onset pattern within the HH always started with abrupt giant shifts superimposed on low-voltage fast activity across patients. The gelastic seizure network mainly involved the HH, orbitofrontal areas, and cingulate gyrus. Seizures with automatisms and impaired awareness primarily propagated to mesial temporal lobes. Moreover, independent ictal discharges arising from the mesial temporal lobe were detected in three out of nine patients. INTERPRETATION: This study comprehensively reveals intrinsic electrophysiological patterns and epileptogenic networks in vivo, providing new insights into the mechanisms underlying cortical and subcortical epileptogenesis.

Discriminating hypothalamic oligomenorrhea/amenorrhea from hyperandrogenic oligomenorrhea/amenorrhea in exercising women.

The mechanism underlying oligo/amenorrhea in exercising women is often presumed as hypothalamic inhibition secondary to energy deficiency; however, hyperandrogenism may provide an alternative mechanism in some exercising women. Our purpose was to compare reproductive, metabolic, and androgen profiles of exercising women with eumenorrheic, ovulatory menstrual cycles (n = 91), oligo/amenorrhea without evidence of hyperandrogenism (Oligo/Amen; n = 83), and oligo/amenorrhea with evidence of hyperandrogenism (Oligo/Amen-HA; n = 17), and determine the prevalence of oligo/amenorrhea with evidence of hyperandrogenism in exercising women. Self-reported menstrual history and quantification of daily estrogen and progesterone urinary metabolites determined reproductive status. Resting energy expenditure, body composition, and metabolic hormone concentrations determined metabolic status. Serum androgens and calculated free androgen index (FAI) determined androgen status. Groups were similar in age (22.4 ± 0.3 years), height (165.1 ± 0.5 cm), resting energy expenditure (1198.4 ± 12.0 kcal/day), and total triiodothyronine (85.0 ± 1.5 ng/dL) concentration. Oligo/Amen-HA had greater weight (60.0 ± 1.6, 56.1 ± 0.7 kg), body mass index (22.3 ± 0.4, 20.6 ± 0.2 kg/m2), percentage body fat (27.3% ± 1.4%, 24.4% ± 0.6%), fat mass (16.2 ± 1.0, 13.8 ± 0.4 kg), insulin (5.8 ± 0.7, 4.2 ± 0.3 µIU/mL), leptin (12.2 ± 2.3, 6.6 ± 0.7 ng/mL), FAI (6.1 ± 0.3, 1.7 ± 0.1), and luteinizing hormone/follicle-stimulating hormone (1.9 ± 0.3, 1.3 ± 0.2) compared with Oligo/Amen, respectively. In our sample, 17% of those with oligo/amenorrhea had concurrent hyperandrogenism. This study supports that oligo/amenorrhea in some exercising women is related to hyperandrogenism. Novelty Caution must be utilized when discriminating hypothalamic oligo/amenorrhea from hyperandrogenic oligo/amenorrhea. In our sample, 17% of those with presumed hypothalamic oligo/amenorrhea had concurrent hyperandrogenism. Exercise and/or mild energy deficiency may be protective against developing severe hyperandrogenic symptoms.

Hypothalamic hamartomas in adulthood: Clinical spectrum and treatment outcome-A unicenter experience.

INTRODUCTION: Clinical manifestations of the hypothalamic hamartoma-epilepsy syndrome (HH-ES) in adulthood are variable. Efficacy of therapeutic options and outcome are diverse. METHODS: Retrospective study of adult patients diagnosed with a HH in magnetic resonance imaging and epilepsy who attended our tertiary Epilepsy Unit between 2003 and 2018. We report the clinical and electroencephalographic features of a series of adult patients with HH and related epilepsy seen in our center together with the treatments and seizure outcome. RESULTS: We describe a series of eight patients. Five males (62.5%), median age at evaluation was 28.5 years (IQR: 15.5). Clinical manifestations included focal with preserved and impaired awareness emotional seizures (gelastic seizures [GS]) in six patients (75%), focal tonic, atonic with impaired awareness and focal to bilateral tonic-clonic seizures. Mild GS were the only symptom in one patient. Three patients (37.5%) had endocrinological disturbances such as obesity and hypothyroidism. Fifty percent of the patients showed psychiatric comorbidity such as anxiety disorder and aggressiveness, and two patients had psychomotor delay. Seven patients (87.7%) had drug-resistant seizures and three of them were treated with radiosurgery. Out of the treated group, only one (33.3%) became seizure-free 2 years after surgery but developed psychiatric problems. The other two patients had an Engel IV outcome and received a vagal nerve stimulation (VNS) implant. VNS did not lead to changes either in intensity nor in seizure frequency. CONCLUSIONS: Hypothalamic hamartoma-epilepsy syndrome clinical manifestations in adult patients are as variable as at pediatric age. Outcome of therapeutic options such as radiosurgery or VNS may be poorer at this stage.

Advances in the management of craniopharyngioma in children and adults.

Background Childhood and adult-onset craniopharyngioma is a rare embryogenic tumor of the sellar, suprasellar, and parasellar region. Survival rates are high; however, tumor location and treatment sequalae including endocrine deficits, visual impairment, metabolic complications, cognitive and psychosocial deficits can significantly impair patient's quality of life. There is considerable controversy regarding the optimal management of craniopharyngiomas. Subtotal resection of the tumor followed by targeted irradiation to avoid further hypothalamic damage is currently indicated. Novel insights in the tumor's molecular pathology present the possibility for targeted therapy possibly decreasing the rate and severity of treatment-associated morbidity. Conclusions Craniopharyngioma should be seen as a chronic disease. To achieve optimal outcomes a multidisciplinary team of specialized neurosurgeons, neuro-radiologists, neuro-oncologists, pathologists and endocrinologists should be involved in the diagnosis, planning of the surgery, irradiation and long-term follow-up.

Opioids and reproduction.

More than 40years ago, the endogenous opioids were first described. Their role as important neuromodulators of pain and their influence on a variety of neuroendocrine control systems within the central nervous system has been recognized. More recently, endogenous opioids and their receptor have been identified in a variety of reproductive and non-reproductive tissues outside the central nervous system. What role the opioid system plays in these peripheral tissues and organs is not completely understood and thus the subjects of current research. In the central nervous system, endogenous opioids inhibit pulsatile Gonadotropin Releasing Hormone (GnRH) release, affecting the release of gonadotropins from the pituitary, and thus mediating stress response within the central nervous-pituitary-gonadal axes in both women and men-Peripherally, endogenous opioids have been demonstrated to be present-among other organs-in the pancreas and in the ovary, where they are produced by granulosa cells and may influence oocyte maturation. In men, endogenous opioids play a role in sperm production within the testis. Opioid antagonists such as naltrexone have been used to restore cyclicity in women through improvement in insulin resistance, GnRH-pulsatility and hyperandrogenemia stemming from specific pathophysiological conditions such as hypothalamic amenorrhea, polycystic ovarian syndrome, hyperinsulinemia, ovarian hyperstimulation syndrome. Opioid antagonists have also been used to treat male sexual disorders and male infertility. In summary, endogenous opioids exert a variety of actions within the reproductive system which are reviewed in this chapter.