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Alessandro D Genazzani - One of the best experts on this subject based on the ideXlab platform.

  • acetyl l carnitine alc administration positively affects reproductive axis in hypogonadotropic women with functional Hypothalamic Amenorrhea
    Journal of Endocrinological Investigation, 2011
    Co-Authors: Alessandro D Genazzani, P Monteleone, Federica Ricchieri, Chiara Lanzoni, Susanna Santagni, Erika Rattighieri, Elisa Chierchia, V M Jasonni
    Abstract:

    Background: Hypothalamic Amenorrhea (HA) is characterized by neuroendocrine impairment that, in turn, negatively modulates endocrine function, mainly within the reproductive axis. HA presents with hypo-LH, hypoestrogenism and, until now, a definite therapeutic strategy has not yet been found. The aim of the following study was to test the efficacy of acetyl-L-carnitine (ALC) administration in HA-affected subjects. Population: Twenty-four patients affected by stress-induced HA were divided into two groups according to LH plasma levels: group A, hypo-LH (LH≤3 mIU/ml; no.=16), and group B, normo-LH (LH>3 mIU/ml; no.=8), were treated with ALC (1 g/day, per os) for 16 weeks. Design: Patients underwent baseline hormonal assessment, pulsatility test (for LH and FSH), naloxone test (for LH, FSH and cortisol) both before and after 16 weeks of treatment. Results: Under ALC administration hypo-LH patients showed a significant increase in LH plasma levels (from 1.4±0.3 to 3.1 ±0.5 mIU/ml, p<0.01 ) and in LH pulse amplitude (p<0.001). No changes were observed in the normo-LH group. LH response to naloxone was restored under ALC therapy. Maximal LH response and area under the curve under naloxone were significantly increased (p<0.05 and p<0.01, respectively). No changes were observed in the normo-LH patients. Conclusions: Our data support the hypothesis of a specific role of ALC on counteracting the stress-induced abnormalities in hypo-LH patients affected by Hypothalamic Amenorrhea.

  • Acetyl-1-carnitine as possible drug in the treatment of Hypothalamic Amenorrhea
    Acta Obstetricia et Gynecologica Scandinavica, 2011
    Co-Authors: Alessandro D Genazzani, Felice Petraglia, Ivana Algeri, Mario Gastaldi, M Calvani, G Botticelli, Andrea R Genazzani
    Abstract:

    Several neuroendocrine disregulations have been demonstrated in patients with Hypothalamic Amenorrhea, but a definite therapeutic strategy has not yet been found. Since acetyl-1-carnitine (ALC) has been reported to have a specific effect on central cholinergic, serotoninergic, dopaminergic and opioidergic systems, 20 patients with Hypothalamic Amenorrhea were treated with ALC (2 g/day, per os). Both the clinical efficacy and the endocrine parameters were evaluated after 6 months. The patients were subdivided in two groups according to their LH plasma levels: A) hypogonadotropic: 10 subjects with plasma LH 3 mIU/ml. All subjects underwent: 1) a pulsatility study (4 h sampling every 10 min), 2) GnRH test (two bolus injections of 10 mg at time 0 and ±120), 3) TRH test (200 mg). These parameters were evaluated before and after 6 months of ALC administration. The occurrence of a spontaneous menstruation was observed in 6 out of 10 hypogonadotro...

  • diagnostic and therapeutic approach to Hypothalamic Amenorrhea
    Annals of the New York Academy of Sciences, 2006
    Co-Authors: Alessandro D Genazzani, Federica Ricchieri, Chiara Lanzoni, Claudia Strucchi, V M Jasonni
    Abstract:

    Abstract: Hypothalamic Amenorrhea (HA) is a secondary Amenorrhea with no evidence of endocrine/systemic causal factors, mainly related to various stressors affecting neuroendocrine control of the reproductive axis. In clinical practice, HA is mainly associated with metabolic, physical, or psychological stress. Stress is the adaptive response of our body through all its homeostatic systems, to external and/or internal stimuli that activate specific and nonspecific physiological pathways. HA occurs generally after severe stressant conditions/situations such as dieting, heavy training, or intense emotional events, all situations that can induce Amenorrhea with or without body weight loss and HA is a secondary Amenorrhea with a diagnosis of exclusion. In fact, the diagnosis is essentially based on a good anamnestic investigation. It has to be investigated using the clinical history of the patient: occurrence of menarche, menstrual cyclicity, time and modality of Amenorrhea, and it has to be exclude any endocrine disease or any metabolic (i.e., diabetes) and systemic disorders. It is necessary to identify any stressant situation induced by loss, family or working problems, weight loss or eating disorders, or physical training or agonist activity. Peculiar, though not specific, endocrine investigations might be proposed but no absolute parameter can be proposed since HA is greatly dependent from individual response to stressors and/or the adaptive response to stress. This article tries to give insights into diagnosis and putative therapeutic strategies.

  • increased adrenal steroid secretion in response to crf in women with Hypothalamic Amenorrhea
    The Journal of Steroid Biochemistry and Molecular Biology, 2001
    Co-Authors: Alessandro D Genazzani, Stefano Luisi, Felice Petraglia, Franca Fruzzetti, Chiara Bersi, Barbara Malavasi, M Luisi, Andrea R Genazzani
    Abstract:

    Abstract Objective: To evaluate adrenal steroid hormone secretion in response to corticotropin-releasing factor (CRF) or to adrenocorticotropin hormone in women with Hypothalamic Amenorrhea. Design: Controlled clinical study. Setting: Department of Reproductive Medicine and Child Development, Section of Gynecology and Obstetrics, University of Pisa, Italy. Patient(s): Fifteen women with Hypothalamic Amenorrhea were enrolled in the study. Eight normal cycling women were used as control group. Intervention(s): Blood samples were collected before and after an injection of ovine CRF (0.1 μg/kg iv bolus) or after synthetic ACTH (0.25 mg iv). Main outcome measure(s): Plasma levels of ACTH, 17-hydroxypregnenolone (17OHPe), progesterone (P), dehydroepiandrosterone (DHEA), 17-hydroxyprogesterone (17OHP), cortisol (F), 11-deoxycortisol (S) and androstenedione (A). Result(s): Basal plasma concentrations of ACTH, cortisol, 11-deoxycortisol, DHEA and 17OHPe were significantly higher in patients than in controls, whereas plasma levels of progesterone and 17-OHP were significantly lower in patients than in controls. In amenorrheic women the ratio of 17-OHPe/DHEA, of 17-OHPe/17-OHP and of 11-deoxycortisol/cortisol were significantly higher than in controls, while a significant reduction in the ratio of 17-OHP/androstenedione, of 17-OHP/11-deoxycortisol was obtained. In response to corticotropin-releasing factor test, plasma levels of ACTH, cortisol, 17-OHP, 11-deoxycortisol, DHEA and androstenedione were significantly lower in patients than in controls. In response to adrenocorticotropin hormone, plasma levels of 17-OHP, androstenedione and androstenedione/cortisol were significantly higher in patients than in controls. Conclusions: Patients suffering for Hypothalamic Amenorrhea showed an increased activation of hypothalamus-pituitary-adrenal (HPA) axis, as shown by the higher basal levels and by augmented adrenal hormone response to corticotropin-releasing factor administration. These data suggest a possible derangement of adrenal androgen enzymatic pathway.

  • Pivagabine decreases stress-related hormone secretion in women with Hypothalamic Amenorrhea.
    Journal of Endocrinological Investigation, 2000
    Co-Authors: Stefano Luisi, M Santuz, Felice Petraglia, M Stomati, Chiara Bersi, M Fedalti, G Esposito, Alessandro D Genazzani
    Abstract:

    Stress-induced neuroendocrine activities influence the regulation of endocrine glands and axes. Weight loss-related Hypothalamic Amenorrhea is a typical stress-induced physiopathological condition. It is characterized by increased adrenal cortex activation and by reduced GH, LH, FSH and gonadal steroid hormone levels. The aim of the present study was to investigate the effects of pivagabine, a neurotropic drug (1800 mg/day for 7 days) or placebo administration on ACTH, cortisol, GH, LH, FSH and PRL plasma levels in patients with Hypothalamic Amenorrhea related to weight loss. Hormonal parameters and the pulsatile release of cortisol (6-hour pulsatility, sampling every 10 minutes) were evaluated before and after 7 days of treatment. Pivagabine administration significantly reduced mean plasma ACTH (from 21.7±1.7 to 15.4±1.2 pg/ml, p

Christos S Mantzoros - One of the best experts on this subject based on the ideXlab platform.

  • bone metabolism in anorexia nervosa and Hypothalamic Amenorrhea
    Metabolism-clinical and Experimental, 2017
    Co-Authors: Sharon H Chou, Christos S Mantzoros
    Abstract:

    Abstract Anorexia nervosa (AN) and Hypothalamic Amenorrhea (HA) are states of chronic energy deprivation associated with severely compromised bone health. Poor bone accrual during adolescence followed by increased bone loss results in lifelong low bone density, degraded bone architecture, and higher risk of fractures, despite recovery from AN/HA. Amenorrhea is only one of several compensatory responses to the negative energy balance. Other Hypothalamic-pituitary hormones are affected and contribute to bone deficits, including activation of Hypothalamic-pituitary-adrenal axis and growth hormone resistance. Adipokines, particularly leptin, provide information on fat/energy stores, and gut hormones play a role in the regulation of appetite and food intake. Alterations in all these hormones influence bone metabolism. Restricted in scope, current pharmacologic approaches to improve bone health have had overall limited success.

  • leptin therapy in women with Hypothalamic Amenorrhea
    2015
    Co-Authors: Sharon H Chou, Christos S Mantzoros
    Abstract:

    Hypothalamic Amenorrhea is caused by dysfunction of the Hypothalamic–pituitary–gonadal axis associated with chronic energy deficiency from excessive exercise, psychological stress, or insufficient nutritional intake. In addition to Amenorrhea, these women are also noted to have abnormalities in other neuroendocrine axes (e.g., cortisol excess, decreased thyroid hormones, growth hormone resistance), low bone turnover and bone mineral density, and low lymphocyte counts. Hypoleptinemia in these women has been proposed to signal a state of energy deficiency and set off these energy-conserving processes. In the context of two clinical trials studying the effects of recombinant leptin in women with HA, leptin administration in replacement doses has been shown to restore reproductive function, decrease cortisol levels, increase triiodothyronine levels, increase insulin-growth factor-1 levels, improve bone mineral density, and increase CD4+ and CD8+ T-cell counts. If circulating leptin reaches supraphysiological levels in response to leptin administration, loss of weight and fat mass ensues; this is reversible however by decreasing the dose to achieve physiological levels. The potential use of leptin in HA needs to be further studied.

  • leptin is an effective treatment for Hypothalamic Amenorrhea
    Proceedings of the National Academy of Sciences of the United States of America, 2011
    Co-Authors: Sharon H Chou, John P Chamberland, Giuseppe Matarese, Rianna Stefanakis, Mary Brinkoetter, Huizhi Gong, Kalliopi M Arampatzi, Christos S Mantzoros
    Abstract:

    Hypothalamic Amenorrhea (HA) is associated with dysfunction of the Hypothalamic-pituitary-peripheral endocrine axes, leading to infertility and bone loss, and usually is caused by chronic energy deficiency secondary to strenuous exercise and/or decreased food intake. Energy deficiency also leads to hypoleptinemia, which has been proposed, on the basis of observational studies as well as an open-label study, to mediate the neuroendocrine abnormalities associated with this condition. To prove definitively a causal role of leptin in the pathogenesis of HA, we performed a randomized, double-blinded, placebo-controlled trial of human recombinant leptin (metreleptin) in replacement doses over 36 wk in women with HA. We assessed its effects on reproductive outcomes, neuroendocrine function, and bone metabolism. Leptin replacement resulted in recovery of menstruation and corrected the abnormalities in the gonadal, thyroid, growth hormone, and adrenal axes. We also demonstrated changes in markers of bone metabolism suggestive of bone formation, but no changes in bone mineral density were detected over the short duration of this study. If these data are confirmed, metreleptin administration in replacement doses to normalize circulating leptin levels may prove to be a safe and effective therapy for women with HA.

  • recombinant human leptin in women with Hypothalamic Amenorrhea
    Obstetrical & Gynecological Survey, 2005
    Co-Authors: Corrine Kolka Welt, Jean L Chan, John Bullen, Robyn Murphy, P C Smith, Alex M Depaoli, Aspasia Karalis, Christos S Mantzoros
    Abstract:

    Hypothalamic Amenorrhea, characterized by absent menstrual cycles and low estrogen levels, reportedly accounts for more than 30% of all cases of Amenorrhea in women of reproductive age. Infertility and bone loss are possible consequences. Functional Hypothalamic Amenorrhea occurs when, for any reason, there is a relative energy deficit. Leptin levels are low in these patients, and the normal diurnal variation in leptin levels is absent. To determine whether low leptin levels cause neuroendocrine and reproductive dysfunction, 8 women with Hypothalamic Amenorrhea resulting from low body weight or strenuous exercise prospectively received recombinant human leptin for 2 to 3 months. Six control women received no treatment. Participants self-administered 0.08 mg/kg of recombinant human leptin subcutaneously each day, 40% of it in the morning and 60% in the evening. Serum leptin levels increased during treatment and body weight decreased slightly. Food intake and resting metabolic rate did not change appreciably. Three of 8 women had an ovulatory menstrual cycle while receiving leptin. Two others had a preovulatory follicle but did not ovulate. Leptin treatment significantly increased maximum follicle diameter, the number of dominant follicles, ovarian volume, and endometrial thickness. Mean levels of luteinizing hormone (LH) increased during treatment, and LH pulse patterns improved or became normal in 6 of 8 women. Thyroid hormone levels increased but remained within the normal range. Markers of bone formation, including bone alkaline phosphatase and osteocalcin, rose significantly during leptin treatment. There was no significant change in urinary N-telopeptides, a marker of bone resorption. Total bone density did not change significantly. No adverse effects were noted. Patients reported decreased appetite but felt well. In this prospective study, leptin treatment of women with Hypothalamic Amenorrhea normalized reproductive hormone levels, follicle development, and menstrual cyclicity. The findings suggest that leptin, which reflects the adequacy of stored energy, is necessary for normal neuroendocrine and reproductive functioning.

  • recombinant human leptin in women with Hypothalamic Amenorrhea
    The New England Journal of Medicine, 2004
    Co-Authors: Corrine Kolka Welt, Jean L Chan, John Bullen, Robyn Murphy, P C Smith, Alex M Depaoli, Aspasia Karalis, Christos S Mantzoros
    Abstract:

    Background Disruptions in Hypothalamic–gonadal and other endocrine axes due to energy deficits are associated with low levels of the adipocyte-secreted hormone leptin and may result in Hypothalamic Amenorrhea. We hypothesized that exogenous recombinant leptin replacement would improve reproductive and neuroendocrine function in women with Hypothalamic Amenorrhea. Methods Eight women with Hypothalamic Amenorrhea due to strenuous exercise or low weight were studied for one month before receiving recombinant human leptin and then while receiving treatment for up to three months. Six control subjects with Hypothalamic Amenorrhea received no treatment and were studied for a mean (±SD) of 8.5±8.1 months. Results Luteinizing hormone (LH) pulsatility, body weight, ovarian variables, and hormone levels did not change significantly over time in the controls and during a one-month control period before recombinant leptin therapy in the treated subjects. In contrast, recombinant leptin treatment increased mean LH lev...

Felice Petraglia - One of the best experts on this subject based on the ideXlab platform.

  • Acetyl-1-carnitine as possible drug in the treatment of Hypothalamic Amenorrhea
    Acta Obstetricia et Gynecologica Scandinavica, 2011
    Co-Authors: Alessandro D Genazzani, Felice Petraglia, Ivana Algeri, Mario Gastaldi, M Calvani, G Botticelli, Andrea R Genazzani
    Abstract:

    Several neuroendocrine disregulations have been demonstrated in patients with Hypothalamic Amenorrhea, but a definite therapeutic strategy has not yet been found. Since acetyl-1-carnitine (ALC) has been reported to have a specific effect on central cholinergic, serotoninergic, dopaminergic and opioidergic systems, 20 patients with Hypothalamic Amenorrhea were treated with ALC (2 g/day, per os). Both the clinical efficacy and the endocrine parameters were evaluated after 6 months. The patients were subdivided in two groups according to their LH plasma levels: A) hypogonadotropic: 10 subjects with plasma LH 3 mIU/ml. All subjects underwent: 1) a pulsatility study (4 h sampling every 10 min), 2) GnRH test (two bolus injections of 10 mg at time 0 and ±120), 3) TRH test (200 mg). These parameters were evaluated before and after 6 months of ALC administration. The occurrence of a spontaneous menstruation was observed in 6 out of 10 hypogonadotro...

  • Patients with functional Hypothalamic Amenorrhea are characterized by low serum inhibin B concentrations
    Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego, 2010
    Co-Authors: Agnieszka Podfigurna-stopa, Stefano Luisi, Blazej Meczekalski, Lucia Lazzeri, Valentina Ciani, Felice Petraglia
    Abstract:

    UNLABELLED: Functional Hypothalamic disturbances may be the cause of secondary Amenorrhea and are related to aberration in both the pattern of pulsatility and amplitude in the release of gonadotropin-releasing hormone (GnRH) in hypothalamus. Inhibin B, as an ovarian peptide plays a crucial role in reproduction function throughout regulation of folliculotropin (FSH) pituitary production and inhibiting GnRH secretion during the menstrual cycle. THE AIM OF THE STUDY: To measure and estimate serum inhibin B concentration in patients with functional Hypothalamic Amenorrhea. Material and methods. The study included 41 women suffering from functional Hypothalamic Amenorrhea. Secondary Amenorrhea was defined as the lack of menstruation lasting at least 90 days not due to pregnancy, characterized by low serum concentrations of lutropin (LH < 5 mIU/ml)) and typical for functional Hypothalamic disturbances anamnestic investigation. The control group consists of 40 healthy women with normal menstrual cycles and Body Mass Index (BMI between 18.5- 24.9 kg/m2). Medical history, examination and laboratory analysis of LH, FSH, estradiol (E), prolactin, testosterone and inhibin B were performed (ELISA--enzyme-linked immunosorbent assay). RESULTS: There are statistically lower serum inhibin B, FSH, LH, estradiol and prolactin concentrations in patients with functional Hypothalamic Amenorrhea in comparison to healthy women. Positive correlation between serum concentration of inhibin B and estradiol concentration was found in patients with functional Hypothalamic Amenorrhea. CONCLUSIONS: Patients with functional Hypothalamic Amenorrhea are characterized by statistical significant decrease in serum inhibin B concentration in comparison to the control group.

  • increased adrenal steroid secretion in response to crf in women with Hypothalamic Amenorrhea
    The Journal of Steroid Biochemistry and Molecular Biology, 2001
    Co-Authors: Alessandro D Genazzani, Stefano Luisi, Felice Petraglia, Franca Fruzzetti, Chiara Bersi, Barbara Malavasi, M Luisi, Andrea R Genazzani
    Abstract:

    Abstract Objective: To evaluate adrenal steroid hormone secretion in response to corticotropin-releasing factor (CRF) or to adrenocorticotropin hormone in women with Hypothalamic Amenorrhea. Design: Controlled clinical study. Setting: Department of Reproductive Medicine and Child Development, Section of Gynecology and Obstetrics, University of Pisa, Italy. Patient(s): Fifteen women with Hypothalamic Amenorrhea were enrolled in the study. Eight normal cycling women were used as control group. Intervention(s): Blood samples were collected before and after an injection of ovine CRF (0.1 μg/kg iv bolus) or after synthetic ACTH (0.25 mg iv). Main outcome measure(s): Plasma levels of ACTH, 17-hydroxypregnenolone (17OHPe), progesterone (P), dehydroepiandrosterone (DHEA), 17-hydroxyprogesterone (17OHP), cortisol (F), 11-deoxycortisol (S) and androstenedione (A). Result(s): Basal plasma concentrations of ACTH, cortisol, 11-deoxycortisol, DHEA and 17OHPe were significantly higher in patients than in controls, whereas plasma levels of progesterone and 17-OHP were significantly lower in patients than in controls. In amenorrheic women the ratio of 17-OHPe/DHEA, of 17-OHPe/17-OHP and of 11-deoxycortisol/cortisol were significantly higher than in controls, while a significant reduction in the ratio of 17-OHP/androstenedione, of 17-OHP/11-deoxycortisol was obtained. In response to corticotropin-releasing factor test, plasma levels of ACTH, cortisol, 17-OHP, 11-deoxycortisol, DHEA and androstenedione were significantly lower in patients than in controls. In response to adrenocorticotropin hormone, plasma levels of 17-OHP, androstenedione and androstenedione/cortisol were significantly higher in patients than in controls. Conclusions: Patients suffering for Hypothalamic Amenorrhea showed an increased activation of hypothalamus-pituitary-adrenal (HPA) axis, as shown by the higher basal levels and by augmented adrenal hormone response to corticotropin-releasing factor administration. These data suggest a possible derangement of adrenal androgen enzymatic pathway.

  • Pivagabine decreases stress-related hormone secretion in women with Hypothalamic Amenorrhea.
    Journal of Endocrinological Investigation, 2000
    Co-Authors: Stefano Luisi, M Santuz, Felice Petraglia, M Stomati, Chiara Bersi, M Fedalti, G Esposito, Alessandro D Genazzani
    Abstract:

    Stress-induced neuroendocrine activities influence the regulation of endocrine glands and axes. Weight loss-related Hypothalamic Amenorrhea is a typical stress-induced physiopathological condition. It is characterized by increased adrenal cortex activation and by reduced GH, LH, FSH and gonadal steroid hormone levels. The aim of the present study was to investigate the effects of pivagabine, a neurotropic drug (1800 mg/day for 7 days) or placebo administration on ACTH, cortisol, GH, LH, FSH and PRL plasma levels in patients with Hypothalamic Amenorrhea related to weight loss. Hormonal parameters and the pulsatile release of cortisol (6-hour pulsatility, sampling every 10 minutes) were evaluated before and after 7 days of treatment. Pivagabine administration significantly reduced mean plasma ACTH (from 21.7±1.7 to 15.4±1.2 pg/ml, p

  • Hypothalamic Amenorrhea with normal body weight acth allopregnanolone and cortisol responses to corticotropin releasing hormone test
    European Journal of Endocrinology, 2000
    Co-Authors: Blazej Meczekalski, Stefano Luisi, Felice Petraglia, M Stomati, M Luisi, F Bernardi, A Tonetti, P Monteleone, Andrea R Genazzani
    Abstract:

    Objective: Hypothalamic Amenorrhea (HA) is a functional disorder caused by disturbances in gonadotropin-releasing hormone (GnRH) pulsatility. The mechanism by which stress alters GnRH release is not well known. Recently, the role of corticotropin-releasing hormone (CRH) and neurosteroids in the pathophysiology of HA has been considered. The aim of the present study was to explore further the role of the Hypothalamic‐pituitary‐adrenal axis in HA. Design: We included 8 patients (aged 23.16 6 1.72 years) suffering from Hypothalamic stress-related Amenorrhea with normal body weight and 8 age-matched healthy controls in the follicular phase of the menstrual cycle. Methods: We measured basal serum levels of FSH, LH, and estradiol and evaluated ACTH, allopregnanolone and cortisol responses to CRH test in both HA patients and healthy women. Results: Serum basal levels of FSH, LH, and estradiol as well as basal levels of allopregnanolone were significantly lower in HA patients than in controls (P < 0.001) while basal ACTH and cortisol levels were significantly higher in amenorrheic patients with respect to controls (P < 0.001). The response (area under the curve) of ACTH, allopregnanolone and cortisol to CRH was significantly lower in amenorrheic women compared with controls (P < 0.001, P < 0.05, P < 0.05 respectively). Conclusions: In conclusion, women with HA, despite the high ACTH and cortisol levels and, therefore, hypothalamus‐pituitary‐adrenal axis hyperactivity, are characterized by low allopregnanolone basal levels, deriving from an impairment of both adrenal and ovarian synthesis. The blunted ACTH, allopregnanolone and cortisol responses to CRH indicate that, in Hypothalamic Amenorrhea, there is a reduced sensitivity and expression of CRH receptor. These results open new perspectives on the role of neurosteroids in the pathogenesis of Hypothalamic Amenorrhea.

Andrea R Genazzani - One of the best experts on this subject based on the ideXlab platform.

  • skeletal status and body composition in young women with functional Hypothalamic Amenorrhea
    Gynecological Endocrinology, 2012
    Co-Authors: Agnieszka Podfigurnastopa, Andrea R Genazzani, Pawel Pludowski, Maciej Jaworski, R Lorenc, Blazej Meczekalski
    Abstract:

    Context: Functional Hypothalamic Amenorrhea (FHA) related to hypoestrogenism and hormonal status may influence skeletal homeostasis and body composition. The study aimed to evaluate hormones concentrations, body composition and bone strength in FHA cases. Patients and methods: Total body scans using DXA method (DPX-L, GE Lunar) were performed in a group of 27 women aged 21.8 years ± 3.9 with FHA related to weight loss. References of healthy control subjects were used to calculate Z-scores (age and gender matched), SD-scores (height and gender matched), and SDs-scores (weight and gender matched). Whole skeleton bone mineral content (TBBMC, g) and density (TBBMD, g/cm2), lumbar spine (L2–L4) bone mineral density (SBMD; g/cm2), lean body mass (LBM, g) and fat mass (FM, g) were investigated. Relative bone strength index was calculated as the TBBMC/LBM ratio. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, testosterone, and prolactin (PRL) concentrations were assayed to character...

  • Acetyl-1-carnitine as possible drug in the treatment of Hypothalamic Amenorrhea
    Acta Obstetricia et Gynecologica Scandinavica, 2011
    Co-Authors: Alessandro D Genazzani, Felice Petraglia, Ivana Algeri, Mario Gastaldi, M Calvani, G Botticelli, Andrea R Genazzani
    Abstract:

    Several neuroendocrine disregulations have been demonstrated in patients with Hypothalamic Amenorrhea, but a definite therapeutic strategy has not yet been found. Since acetyl-1-carnitine (ALC) has been reported to have a specific effect on central cholinergic, serotoninergic, dopaminergic and opioidergic systems, 20 patients with Hypothalamic Amenorrhea were treated with ALC (2 g/day, per os). Both the clinical efficacy and the endocrine parameters were evaluated after 6 months. The patients were subdivided in two groups according to their LH plasma levels: A) hypogonadotropic: 10 subjects with plasma LH 3 mIU/ml. All subjects underwent: 1) a pulsatility study (4 h sampling every 10 min), 2) GnRH test (two bolus injections of 10 mg at time 0 and ±120), 3) TRH test (200 mg). These parameters were evaluated before and after 6 months of ALC administration. The occurrence of a spontaneous menstruation was observed in 6 out of 10 hypogonadotro...

  • functional Hypothalamic Amenorrhea current view on neuroendocrine aberrations
    Gynecological Endocrinology, 2008
    Co-Authors: Blazej Meczekalski, Agnieszka Podfigurnastopa, A Warenikszymankiewicz, Andrea R Genazzani
    Abstract:

    Functional Hypothalamic Amenorrhea (FHA) is defined as a non-organic and reversible disorder in which the impairment of gonadotropin-releasing hormone (GnRH) pulsatile secretion plays a key role. There are main three types of FHA: stress-related Amenorrhea, weight loss-related Amenorrhea and exercise-related Amenorrhea. The spectrum of GnRH–luteinizing hormone (LH) disturbances in FHA is very broad and includes lower mean frequency of LH pulses, complete absence of LH pulsatility, normal-appearing secretion pattern and higher mean frequency of LH pulses. Precise mechanisms underlying the pathophysiology of FHA are very complex and unclear. Numerous neuropeptides, neurotransmitters and neurosteroids play important roles in the physiological regulation of GnRH pulsatile secretion and there is evidence that different neuropeptides may be involved in the pathophysiology of FHA. Particular attention is paid to such substances as allopregnanolone, neuropeptide Y, corticotropin-releasing hormone, leptin, ghrelin...

  • increased adrenal steroid secretion in response to crf in women with Hypothalamic Amenorrhea
    The Journal of Steroid Biochemistry and Molecular Biology, 2001
    Co-Authors: Alessandro D Genazzani, Stefano Luisi, Felice Petraglia, Franca Fruzzetti, Chiara Bersi, Barbara Malavasi, M Luisi, Andrea R Genazzani
    Abstract:

    Abstract Objective: To evaluate adrenal steroid hormone secretion in response to corticotropin-releasing factor (CRF) or to adrenocorticotropin hormone in women with Hypothalamic Amenorrhea. Design: Controlled clinical study. Setting: Department of Reproductive Medicine and Child Development, Section of Gynecology and Obstetrics, University of Pisa, Italy. Patient(s): Fifteen women with Hypothalamic Amenorrhea were enrolled in the study. Eight normal cycling women were used as control group. Intervention(s): Blood samples were collected before and after an injection of ovine CRF (0.1 μg/kg iv bolus) or after synthetic ACTH (0.25 mg iv). Main outcome measure(s): Plasma levels of ACTH, 17-hydroxypregnenolone (17OHPe), progesterone (P), dehydroepiandrosterone (DHEA), 17-hydroxyprogesterone (17OHP), cortisol (F), 11-deoxycortisol (S) and androstenedione (A). Result(s): Basal plasma concentrations of ACTH, cortisol, 11-deoxycortisol, DHEA and 17OHPe were significantly higher in patients than in controls, whereas plasma levels of progesterone and 17-OHP were significantly lower in patients than in controls. In amenorrheic women the ratio of 17-OHPe/DHEA, of 17-OHPe/17-OHP and of 11-deoxycortisol/cortisol were significantly higher than in controls, while a significant reduction in the ratio of 17-OHP/androstenedione, of 17-OHP/11-deoxycortisol was obtained. In response to corticotropin-releasing factor test, plasma levels of ACTH, cortisol, 17-OHP, 11-deoxycortisol, DHEA and androstenedione were significantly lower in patients than in controls. In response to adrenocorticotropin hormone, plasma levels of 17-OHP, androstenedione and androstenedione/cortisol were significantly higher in patients than in controls. Conclusions: Patients suffering for Hypothalamic Amenorrhea showed an increased activation of hypothalamus-pituitary-adrenal (HPA) axis, as shown by the higher basal levels and by augmented adrenal hormone response to corticotropin-releasing factor administration. These data suggest a possible derangement of adrenal androgen enzymatic pathway.

  • Hypothalamic Amenorrhea with normal body weight acth allopregnanolone and cortisol responses to corticotropin releasing hormone test
    European Journal of Endocrinology, 2000
    Co-Authors: Blazej Meczekalski, Stefano Luisi, Felice Petraglia, M Stomati, M Luisi, F Bernardi, A Tonetti, P Monteleone, Andrea R Genazzani
    Abstract:

    Objective: Hypothalamic Amenorrhea (HA) is a functional disorder caused by disturbances in gonadotropin-releasing hormone (GnRH) pulsatility. The mechanism by which stress alters GnRH release is not well known. Recently, the role of corticotropin-releasing hormone (CRH) and neurosteroids in the pathophysiology of HA has been considered. The aim of the present study was to explore further the role of the Hypothalamic‐pituitary‐adrenal axis in HA. Design: We included 8 patients (aged 23.16 6 1.72 years) suffering from Hypothalamic stress-related Amenorrhea with normal body weight and 8 age-matched healthy controls in the follicular phase of the menstrual cycle. Methods: We measured basal serum levels of FSH, LH, and estradiol and evaluated ACTH, allopregnanolone and cortisol responses to CRH test in both HA patients and healthy women. Results: Serum basal levels of FSH, LH, and estradiol as well as basal levels of allopregnanolone were significantly lower in HA patients than in controls (P < 0.001) while basal ACTH and cortisol levels were significantly higher in amenorrheic patients with respect to controls (P < 0.001). The response (area under the curve) of ACTH, allopregnanolone and cortisol to CRH was significantly lower in amenorrheic women compared with controls (P < 0.001, P < 0.05, P < 0.05 respectively). Conclusions: In conclusion, women with HA, despite the high ACTH and cortisol levels and, therefore, hypothalamus‐pituitary‐adrenal axis hyperactivity, are characterized by low allopregnanolone basal levels, deriving from an impairment of both adrenal and ovarian synthesis. The blunted ACTH, allopregnanolone and cortisol responses to CRH indicate that, in Hypothalamic Amenorrhea, there is a reduced sensitivity and expression of CRH receptor. These results open new perspectives on the role of neurosteroids in the pathogenesis of Hypothalamic Amenorrhea.

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  • heightened cortisol response to exercise challenge in women with functional Hypothalamic Amenorrhea
    American Journal of Obstetrics and Gynecology, 2017
    Co-Authors: Kristen M Sanders, Jennifer F Kawwass, Tammy L Loucks, Sarah L Berga
    Abstract:

    Background Functional Hypothalamic Amenorrhea is characterized by anovulation caused by reduced gonadotropin-releasing hormone drive and is associated with hypercortisolemia that has been linked to heightened Hypothalamic-pituitary-adrenal reactivity to common psychological and metabolic challenges. Objective We hypothesized that women with functional Hypothalamic Amenorrhea would display greater cortisol responses to exercise challenge than ovulatory women with eumenorrhea. Study Design We completed a cross-sectional comparison of 9 women with functional Hypothalamic Amenorrhea and 11 women with eumenorrhea who were of reproductive age, who weighed 90–110% ideal body weight, who did not exercise excessively, and who had no formal psychiatric diagnosis. Subjects completed a 20-minute submaximal exercise challenge using a cycle ergometer in a research exercise laboratory. Heart rate and circulatory cortisol, glucose, and lactate were measured at 10-minute intervals before, during, and after the exercise challenge. Results Baseline (t= –10 minutes) cortisol, glucose, lactate, and heart rate were comparable between groups. Glucose levels rose modestly during exercise by 2.9% in women with eumenorrhea (P=.4) but declined by 10.6% in functional Hypothalamic Amenorrhea (P Conclusion The heightened cortisol response to exercise in women with functional Hypothalamic Amenorrhea was associated with a decline in blood glucose level that was not observed in women with eumenorrhea. Women with functional Hypothalamic Amenorrhea appear to be more reactive at the endocrine level to the metabolic demand of exercise. Submaximal challenge unmasks underlying stress sensitivity in women with functional Hypothalamic Amenorrhea and highlights the importance of the use of psychological interventions for stress reduction in this population.

  • functional Hypothalamic Amenorrhea an endocrine society clinical practice guideline
    The Journal of Clinical Endocrinology and Metabolism, 2017
    Co-Authors: Catherine M Gordon, Sarah L Berga, Madhusmita Misra, Kathryn E Ackerman, Jay R Kaplan, George Mastorakos, Hassan M Murad, Nanette Santoro, Michelle P Warren
    Abstract:

    Cosponsoring Associations: The American Society for Reproductive Medicine, the European Society of Endocrinology, and the Pediatric Endocrine Society. This guideline was funded by the Endocrine Society. Objective: To formulate clinical practice guidelines for the diagnosis and treatment of functional Hypothalamic Amenorrhea (FHA). Participants: The participants include an Endocrine Society-appointed task force of eight experts, a methodologist, and a medical writer. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society committees and members and cosponsoring organizations reviewed and commented on preliminary drafts of this guideline. Conclusions: FHA is a form of chronic anovulation, not due to identifiable organic causes, but often associated with stress, weight loss, excessive exercise, or a combination thereof. Investigations should include assessment of systemic and endocrinologic etiologies, as FHA is a diagnosis of exclusion. A multidisciplinary treatment approach is necessary, including medical, dietary, and mental health support. Medical complications include, among others, bone loss and infertility, and appropriate therapies are under debate and investigation.

  • use of cognitive behavior therapy for functional Hypothalamic Amenorrhea
    Annals of the New York Academy of Sciences, 2006
    Co-Authors: Sarah L Berga, Tammy L Loucks
    Abstract:

    Behaviors that chronically activate the Hypothalamic-pituitary-adrenal (HPA) axis and/or suppress the Hypothalamic-pituitary-thyroidal (HPT) axis disrupt the Hypothalamic-pituitary-gonadal axis in women and men. Individuals with functional Hypothalamic hypogonadism typically engage in a combination of behaviors that concomitantly heighten psychogenic stress and increase energy demand. Although it is not widely recognized clinically, functional forms of Hypothalamic hypogonadism are more than an isolated disruption of gonadotropin-releasing hormone (GnRH) drive and reproductive compromise. Indeed, women with functional Hypothalamic Amenorrhea display a constellation of neuroendocrine aberrations that reflect allostatic adjustments to chronic stress. Given these considerations, we have suggested that complete neuroendocrine recovery would involve more than reproductive recovery. Hormone replacement strategies have limited benefit because they do not ameliorate allostatic endocrine adjustments, particularly the activation of the adrenal and the suppression of the thyroidal axes. Indeed, the rationale for the use of sex steroid replacement is based on the erroneous assumption that functional forms of Hypothalamic hypogonadism represent only or primarily an alteration in the Hypothalamic-pituitary-gonadal axis. Potential health consequences of functional Hypothalamic Amenorrhea, often termed stress-induced anovulation, may include an increased risk of cardiovascular disease, osteoporosis, depression, other psychiatric conditions, and dementia. Although fertility can be restored with exogenous administration of gonadotropins or pulsatile GnRH, fertility management alone will not permit recovery of the adrenal and thyroidal axes. Initiating pregnancy with exogenous means without reversing the hormonal milieu induced by chronic stress may increase the likelihood of poor obstetrical, fetal, or neonatal outcomes. In contrast, behavioral and psychological interventions that address problematic behaviors and attitudes, such as cognitive behavior therapy (CBT), have the potential to permit resumption of full ovarian function along with recovery of the adrenal, thyroidal, and other neuroendocrine aberrations. Full endocrine recovery potentially offers better individual, maternal, and child health.

  • increased cortisol in the cerebrospinal fluid of women with functional Hypothalamic Amenorrhea
    The Journal of Clinical Endocrinology and Metabolism, 2006
    Co-Authors: Benedetta Brundu, Judy L Cameron, Lauri J Adler, Tammy L Loucks, Sarah L Berga
    Abstract:

    Context: The proximate cause of functional Hypothalamic Amenorrhea (FHA) is reduced GnRH drive. The concomitant increase in circulating cortisol suggests that psychogenic stress plays an etiologic role, but others have argued for a strictly metabolic cause, such as undernutrition or excessive exercise. Indeed, our finding that the cerebrospinal fluid (CSF) concentration of CRH was not elevated in FHA cast doubt about the extent of Hypothalamic-pituitary-adrenal activation in FHA and, therefore, we wondered whether central cortisol levels were elevated. Objective: We tested the null hypothesis that CSF cortisol levels would be comparable in FHA and eumenorrheic women (EW). Design: The study is a cross-sectional comparison. Setting: The study was set in a general clinical research center at an academic medical center. Participants: Fifteen women with FHA who were of normal body weight and 14 EW participated. Intervention: Blood samples were collected at 15-min intervals for 24 h, followed by procurement of ...

  • treatment of functional Hypothalamic Amenorrhea with hypnotherapy
    Fertility and Sterility, 2003
    Co-Authors: Walter Tschugguel, Sarah L Berga
    Abstract:

    Abstract Objective: To determine the effects of hypnotherapy on resumption of menstruation in patients with functional Hypothalamic Amenorrhea (FHA). Design: Uncontrolled clinical study. Setting: Academic clinical care center. Patient(s): Twelve consecutive women with FHA were selected. Intervention(s): A single 45- to 70-minute session of hypnotherapy was administered, and patients were observed for 12 weeks. Main outcome measure(s): Patients were asked whether or not menstruation resumed and whether or not well-being and self-confidence changed. Result(s): Within 12 weeks, 9 out of 12 patients (75%) resumed menstruation. All of the patients, including those who did not menstruate, reported several beneficial side effects such as increased general well-being and increased self-confidence. Conclusion(s): Hypnotherapy could be an efficacious and time-saving treatment option that also avoids the pitfalls of pharmacological modalities for women with FHA.