Biomedical subjects

A R Genazzani

Publications and source records attributed to A R Genazzani.

At least 73 records · Page 4Linked to original sources

PubMed2001

Neuroendocrine effects of raloxifene hydrochloride in postmenopausal women.

Raloxifene is a selective estrogen modulator able to exert an estrogen-like action on some target tissues and a specific antiestrogenic action on the uterus and breast. In ovariectomized rats, it has been shown to stimulate the beta-endorphin and allopregnanolone concentrations of the anterior and neurointermediate pituitary lobes, the hypothalamus and the hippocampus. The present study aimed to evaluate, in 12 healthy postmenopausal women, the effect of 60 mg/day raloxifene hydrochloride administration for 6 months on plasma beta-endorphin and allopregnanolone levels, and on the dynamic changes of both beta-endorphin and allopregnanolone secretion after the administration of: (1) clonidine, an alpha 2-presynaptic adrenergic agonist; (2) naloxone, an opioid receptor antagonist; and (3) fluoxetine, a serotonin selective reuptake inhibitor. The administration of raloxifene significantly increased both circulating beta-endorphin and allopregnanolone concentrations, at both the third and sixth months of treatment (p < 0.01). Clonidine, fluoxetine and naloxone administration before therapy was not able to stimulate the release of beta-endorphin, but the response was completely restored after raloxifene administration. Before therapy, clonidine and naloxone tests were accompanied by a significant rise in allopregnanolone secretion; the same changes were observed after raloxifene administration, but with significantly higher allopregnanolone concentrations at each time considered. While the fluoxetine test before therapy failed to increase the release of allopregnanolone, the same test after 6 months of raloxifene administration was characterized by a significant release of allopregnanolone at 60 and 90 minutes. The present data indicate that raloxifene has an estrogen-like effect on neuroendocrine pathways in postmenopausal women.

Adrenergic alpha-Agonists↗

PubMed2000

Estrogens and glucocorticoids inhibit endothelial vascular cell adhesion molecule-1 expression by different transcriptional mechanisms.

The antiatherogenic effect of estrogen is mediated, in part, by inhibitory effects on endothelial vascular cell adhesion molecule-1 (VCAM-1) expression. To determine the mechanism by which estrogen regulates VCAM-1 expression, we compared the effect of 17beta-estradiol (E(2)) and of the glucocorticoid dexamethasone (Dex) on lipopolysaccharide (LPS)-induced VCAM-1 expression in human endothelial cells. E(2) decreased LPS-induced VCAM-1 mRNA and protein expression to a greater extent than Dex. Dex, but not E(2), stabilized VCAM-1 mRNA. This correlated with inhibition of monocytoid U937 cell adhesion to endothelial cells. Transfection of endothelial cells with a functional VCAM-1 promoter construct showed that E(2) inhibited LPS-induced VCAM-1 gene transcription more potently than did Dex. However, using a truncated construct containing only the nuclear factor-kappaB (NF-kappaB)-responsive elements but lacking the consensus sequences for activator protein-1 (AP-1) and GATA, E(2) and Dex had similar inhibitory effects. Consistently, gel-shift assays showed that E(2) and Dex comparably inhibit LPS-induced activation of NF-kappaB, whereas E(2) inhibited LPS-induced activation of AP-1 and GATA to a greater extent than Dex. E(2) inhibition of NF-kappaB after LPS treatment was associated with decreased inhibitor kappaB (IkappaB) kinase activity and with a stabilization of the NF-kappaB inhibitor IkappaBalpha. These results indicate that E(2) decreases VCAM-1 gene expression through the inhibition of NF-kappaB, AP-1, and GATA and suggest novel mechanisms for the antiatherogenic effect of estrogen on the vascular wall.

Animals↗

PubMed2000

Tibolone inhibits leukocyte adhesion molecule expression in human endothelial cells.

Tibolone is a synthetic steroid with mixed estrogenic and progestogenic/androgenic activity used for post-menopausal hormone replacement therapy. Since its cardiovascular effects are still not clear, and no data have been published on possible direct actions on the vessel wall, we studied the effects of tibolone and its metabolites on lipopolysaccharide (LPS)-induced expression of leukocyte adhesion molecules on human endothelial cells. Tibolone and its two estrogenic 3alpha-OH and 3beta-OH metabolites, but not the progestogenic/androgenic Delta(4)-isomer, concentration-dependently decreased LPS-induced vascular cell adhesion molecule-1 protein expression. This effect was estrogen receptor dependent, since it was completely blocked by the pure estrogen receptor antagonist ICI 182780. Furthermore, only tibolone, the 3alpha-OH and the 3beta-OH metabolites decreased endothelial expression of E-selectin, while none of the compounds changed the levels of intercellular adhesion molecule-1. These findings were associated with parallel changes in mRNA levels for the three adhesion molecules. Our data show that tibolone and its estrogenic metabolites exert direct actions on the vascular wall, decreasing the expression of endothelial-leukocyte adhesion molecules, thus producing potentially important direct anti-atherogenic effects.

Arteriosclerosis↗

PubMed2000

Activin A stimulates insulin secretion in cultured human pancreatic islets.

Activin A is a dimeric glycoprotein showing a high sequence homology with transforming growth factor-beta (TGF-beta) and playing autocrine/paracrine actions in reproductive tissues. However, since the synthesis of activin is ubiquitous it may have a role in regulating cell growth and differentiation in several tissues. Previous studies showed that activin A is expressed by insulin-positive B cells of human pancreatic islets, and women with gestational diabetes have higher serum activin A levels than healthy pregnant women at the same gestational age. The present study aimed to evaluate the effect of activin A on insulin secretion from cultured human pancreatic islets. With this purpose human pancreatic islets were incubated with varying concentrations of activin A (0.1 to 10.0 nM). In absence of glucose, activin A did not modify insulin secretion at the different concentrations used. In absence of activin A, 8.3 mM and 16.7 mM glucose significantly increased insulin secretion, with a dose-dependent pattern. In presence of a non stimulatory concentration of glucose (3.3 mM), activin A significantly increased insulin secretion starting from low concentration (0.1 nM). Furthermore, the addition of activin A to 8.3 mM and 16.7 mM glucose induced an additional effect of the dose-dependent glucose-mediated insulin secretion (p<0.001). The present data could support a role for activin A in human endocrine pancreas in modulating insulin response to different glucose concentrations.

Activins↗

PubMed2000

Pivagabine decreases stress-related hormone secretion in women with hypothalamic amenorrhea.

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<0.05) and cortisol levels (from 12.2+/-0.7 to 9.7+/-0.7 ng/ml, p<0.05) and increased GH levels (from 1.4+/-0.5 to 3.0+/-0.9 ng/ml, p<0.05). A significant reduction of cortisol pulse amplitude was observed (p<0.01) while no change in pulse frequency occurred. No changes were observed in placebo-treated subjects. LH, FSH and PRL levels were not modified by placebo or pivagabine administration. In conclusion, in patients with hypothalamic amenorrhea related to weight loss pivagabine induced a significant decrease of cortisol secretion and an increase of GH release by pivagabine administration, suggesting that this drug exerts a specific neuroendocrine modulatory role.

Adrenocorticotropic Hormone↗

PubMed2000

Longitudinal evaluation of perimenopausal femoral bone loss: effects of a low-dose oral contraceptive preparation on bone mineral density and metabolism.

To characterize the pattern of biochemical markers of bone metabolism and femoral bone mineral density in eumenorrheic and oligomenorrheic perimenopausal women, and assess the effects of a low-dose oral contraceptive (OC) on bone metabolism and femoral bone density, bone biochemical markers and femoral bone density (measured at the neck, Ward's triangle and trochanter regions) were evaluated in a longitudinal 2-year follow-up study. The study was conducted in healthy, normally menstruating perimenopausal women (n = 18), perimenopausal oligomenorrheic women (n = 18), and perimenopausal oligomenorrheic women treated with an OC containing 20 microg ethinylestradiol plus 0.15 mg desogestrel (n = 19). The results were analyzed by factorial or repeated measures analysis of variance, as appropriate. During the observation period, in normally menstruating women there were no changes in the menstrual cycle, plasma FSH and estradiol levels, biochemical markers of bone turnover or femoral bone density. In oligomenorrheic untreated women an increase in cycle length with a concomitant decrease in plasma estradiol and an increase in plasma FSH levels were found (p < 0.05). In this group a significant increase in urinary excretion of hydroxyproline and in plasma osteocalcin levels with a concomitant significant decrease in femoral bone density (p < 0.05) occurred. In OC-treated women, osteocalcin plasma levels and urinary excretion of hydroxyproline significantly (p < 0.05) decreased, leading to a significant (p < 0.05) increase in femoral bone density. It is concluded that perimenopausal OC administration can avoid the increase in bone turnover and the decrease in femoral bone density due to the perimenopausal impairment of ovarian function.

Absorptiometry, Photon↗

PubMed2000

The use of a combined regimen of GnRH agonist plus a low-dose oral contraceptive improves the spontaneous pulsatile LH secretory characteristics in patients with polycycstic ovary disease after discontinuation of treatment.

PURPOSE: The fertility rate in women with polycystic ovary disease (PCOD) is influenced by the type of treatment received. The present study evaluated the possible correlation between treatment and pulsatile release of gonadotropins. METHODS: Spontaneous episodic secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and hormonal parameters were monitored before and after 1, 3, and 6 months after treatments suspension. Twenty-four PCOD patients were randomly divided into two groups of 12 subjects. Group A was treated with gonadotropin-releasing hormone (GnRH)-analogue plus oral contraceptive (OC). Group B was treated only with OC. Both groups were treated for 6 months and followed up for 6 months. RESULTS: In all subjects the therapeutic regimens reduced the androgenic milieau and the gonadotropin plasma levels. Spontaneous pulsatile secretion of LH and FSH was significantly modified in both groups, but patients who received the combined regimen showed a significantly greater reduction of LH plasma levels and a significantly greater decrease of LH pulse amplitude throughout the 6 months after treatment suspension. Ferriman-Gallway score and ovarian volumes were significantly reduced in patients who received the combined treatment than in the OC-treated patients. CONCLUSIONS: These data support the evidence of a higher efficacy of the combination of GnRH-a + OC than OC alone in restoring a normal and adequate spontaneous episodic gonadotropin discharge and in decreasing Ferriman-Gallway score and ovarian volumes in patients with PCOD.

17-alpha-Hydroxyprogesterone↗

PubMed2000

Controversial issues in climacteric medicine I. Cardiovascular disease and hormone replacement therapy. International Menopause Society Expert Workshop. 13-16 October 2000, royal society of medicine, London, UK.

The clinical benefits of HRT are clearly established for the relief of menopausal symptoms, improving quality of life and the prevention of osteoporosis. Although research on the impact of HRT (oral, transdermal, tibolone, etc.) and on the effects of raloxifene on CVD is still ongoing, with certain unresolved controversies, studies using a variety of different HRT formulations have shown a clear benefit on surrogate markers of CHD and epidemiological and clinical, although not randomized, studies have demonstrated a CHD reduction in HRT-treated women. Today, HRT may be used for the primary prevention of CVD. Conversely, there is no clear reason to commence HRT solely or primarily to confer an immediate cardiovascular benefit in postmenopausal women with established CHD. Equally, there is no compelling evidence for discontinuing--or indeed not initiating--HRT in women without CVD because of concern about cardiovascular risk. In any case, all medical interventions should be individualized to the specific woman's age, characteristics and needs. The ultimate effects of different dosages, schedules and type of hormones used should be clarified, avoiding inferring the effects of one form of HRT to others. The importance of increased attention to life-style factors such as healthy diet, exercise and cessation of smoking should be underlined since these can confer specific benefits also to menopausal women. For women with known risks for CVD, HRT may contribute to the beneficial effects of life-style improvements and well-established therapies (including blood pressure control, cholesterol-lowering drugs, aspirin, etc.). New strategies, including lower dosages, new estrogens, progestins, and new estrogen-like substances may be designed to target specific needs.

Coronary Artery Disease↗

PubMed2000

Increased HLA-DR homozygosity associated with pre-eclampsia.

It is generally accepted that maternal recognition of paternally derived fetal antigens occurs during normal pregnancy and may be beneficial for implantation and maintenance of gestation. Thus, we have investigated the human leukocyte class II DR antigens (HLA-DR), whose role in self and non-self recognition is well known, in women with pre-eclampsia, their partners and in control couples. The HLA-DR antigens were tested in 70 pre-eclamptic primigravidae women and their partners and 70 healthy control couples using the serological Terasaki technique. Our results did not show any particular HLA-DR antigen to be correlated with pre-eclampsia, but a statistically significant increase of only one identifiable HLA-DR antigen, which was presumed to express homozygosity at the HLA-DR locus, in the pre-eclamptic women and their partners: 67.1 versus 7. 9% in the control couples (P < 0.000001). The analysis of HLA-DR compatibility between pre-eclamptic women and their partners showed a statistically highly significant increase of the female-to-male compatibility (P = 0.0003) and a lower but significant male-to-female compatibility in comparison with controls (P = 0.014). From our results, it emerges that HLA-DR homozygosity and reduced antigenic disparity seem to be associated to a major risk for pre-eclampsia, which consequently appears to be a 'couple's disease'.

Case-Control Studies↗

PubMed2000

Progesterone, progestagens and the central nervous system.

Oestrogen, progestagens and androgens are able to modulate several brain functions. Receptors for gonadal steroids have been identified in several brain areas: amygdala, hippocampus, cortex, basal forebrain, cerebellum, locus coeruleus, midbrain rafe nuclei, glial cells, pituitary gland, hypothalamus and central grey matter. The mechanism of action of sex steroids at this level is similar to that observed in the peripheral target organs, including both genomic and non-genomic effects. The increased use of sex steroid hormone derivative therapies has lead to study of the biochemical and metabolic properties of the different progestin molecules available in hormonal therapies. In particular, experimental and clinical studies focused the attention of researchers on interactions between oestrogens and progestins in the neuroendocrine control of the brain functions and its clinical implications. Moreover, steroids are also synthesized de novo in the brain or may be derived from the conversion of blood-borne precursors, suggesting that the brain is also a source of steroids, named neurosteroids. Neurosteroids exert non-classical rapid actions as allosteric agonists of gamma-aminobutyric acid receptor A (GABA(A)) and also modulate classic neurotransmitters in the brain. In addition, progesterone derivatives, e.g. pregnanolone, and 3alpha 5alpha-OH THP (allopregnanolone) are synthesized de novo by astrocytes and oligodendrocites starting from cholesterol. Physiological or pathological modifications of the synthesis and release of neurosteroids play a relevant role in the control of brain function.

Animals↗

PubMed2000

High concentrations of the vascular endothelial growth factor and interleukin-8 in ovarian endometriomata.

Patients with endometriosis are characterized by the ability of the endometrium to implant and by the peritoneal response to the tissue; angiogenic factors may play a significant role in the aetiology of endometriosis supporting the implantation of ectopic endometrial cells. Vascular endothelial growth factor (VEGF) is a mitogen, morphogen and chemoactractant for endothelial cells and, in vivo, it is a powerful mediator for vessel permeability. Interleukin-8 (IL-8) is a chemoatractant for neutrophils and is a potent angiogenic factor. Women (n = 20) with ovarian endometriomata and 10 women with follicular cysts were enrolled in this study to investigate the role of VEGF and IL-8 in the development and maintenance of ovarian endometriomata. Cystic fluids were collected by laparoscopy, immediately centrifuged and stored until the enzyme-linked immunosorbent assays were performed. The VEGF and IL-8 concentrations were found to be significantly higher in the fluids of the ovarian endometriomata than in those of the follicular cysts of controls (P < 0.001 and P < 0.001 respectively); in addition, a significant inverse correlation between the VEGF cystic fluid concentrations and the diameter of the endometriotic adnexal masses was found (r = -0.56, P = 0.01). The evidence that the high concentrations of VEGF and IL-8 are present in the ovarian endometriomata indicates that angiogenesis could be a specific event both for the progression and maintenance of such cysts.

Adult↗

PubMed2000

Direct vascular effects of estrogens and selective estrogen receptor modulators.

The aim of this review is to provide an update on the latest advancements in the field of the action of estrogens on the cardiovascular system, and particularly on the molecular mechanisms of the direct effects of these hormones and of some of the new synthetic selective estrogen receptor modulators on the vascular wall.

Cardiovascular Diseases↗

PubMed2000

Neuropeptides, neurotransmitters, neurosteroids, and the onset of puberty.

Puberty results from withdrawal of the "gonadostat" mechanisms and from increased gonadotropin sensitivity to GnRH. It has been hypothesized that GnRH release may be modulated by a non-steroid-mediated mechanism. Modifications of neuropeptides, neurotransmitters, and neurosteroids may underlie the onset of pubertal processes. Neuropeptides mainly involved in the control of GnRH release are opioids, neuropeptide Y (NPY), galanin, and corticotropin-releasing factor (CRF), whereas neurotransmitters are noradrenaline, dopamine, serotonin, melatonin and gamma-aminobutyric acid (GABA). Norepinephrine, epinephrine, and dopamine stimulate GnRH, whereas the effect of serotonin on hypothalamic-pituitary-ovarian axis seems to be norepinephrine-mediated. Neurosteroids are steroid hormones that bind to the GABA-A receptor, synthesized in the brain de novo or from blood-borne precursors. DHEA, a GABA-A antagonistic neurosteroid, and allopregnanolone, a GABA-A agonistic neurosteroid, may be important in the onset of gonadarche. In conclusion, the onset of puberty derives from the complex interplay among neuropeptides, neurotransmitters, and neurosteroids that occurs in the awakening of hypothalamic-pituitary-ovarian axis.

Animals↗

PubMed2000

Effects of estradiol and raloxifene analog on brain, adrenal and serum allopregnanolone content in fertile and ovariectomized female rats.

Allopregnanolone is a neuroactive steroid synthesized in rat gonads, adrenal cortex, and central nervous system. It has been suggested that sex steroid hormones might influence allopregnanolone concentrations but no clear data have ever been reported. The aim of the present study was to investigate the effects of administration of 17beta-estradiol (17beta-E2), the raloxifene analog LY-117018 or their combination on allopregnanolone levels in fertile and ovariectomized (OVX) rats. Thirteen groups of 12 Wistar female rats each received either 17beta-E2 (0.1 or 1 microg/day) or LY-117018 (25, 250, and 1,250 microg/day), or 17beta-E2 1 microg/day plus LY-117018: 25, 250, and 1,250 microg/day for 14 days. The rats were then sacrificed and allopregnanolone content was assessed in the hypothalamus, hippocampus, pituitary, adrenals, and serum. Ovariectomy determined a significant decrease in allopregnanolone content in the hypothalamus, hippocampus, pituitary, and serum, while increasing it in the adrenals (p<0.01). In OVX rats, the administration of either 17beta-E2 or LY- 117018 restored ovariectomy-induced allopregnanolone changes. The administration of LY-117018 in addition to 17beta-E2 to OVX animals suppressed the increase in allopregnanolone levels determined by 17beta-E2 in the hippocampus, hypothalamus, and pituitary, but not in the adrenals and serum. In fertile rats, the administration of LY-117018 reproduced the effects of ovariectomy. This study shows that the raloxifene analog LY-117018 has an estrogen-like action on the central nervous system of OVX rats when administered alone, while it acts as an antiestrogen in the presence of 17beta-E2, both in OVX animals treated with 17beta-E2 and in fertile rats. A different effect was observed in the adrenal glands. The mechanism of action of this compound has still to be clarified.

Adrenal Glands↗

PubMed2000

Serum allopregnanolone levels in pregnant women: changes during pregnancy, at delivery, and in hypertensive patients.

Allopregnanolone is a neuroactive steroid measurable in peripheral circulation. The aim of the present study was to investigate the presence and the possible changes in serum allopregnanolone and progesterone levels in pregnant women during gestation, at delivery, and in patients with chronic hypertension, with or without superimposed preeclampsia. We also evaluated allopregnanolone in cord blood. Three groups of pregnant women were studied: 1) healthy controls followed longitudinally throughout gestation (n = 14); 2) at vaginal or cesarean delivery (n = 66); and 3) with chronic hypertension (n = 12), with (n = 7) or without (n = 5) superimposed preeclampsia. Allopregnanolone and progesterone levels were measured in maternal and cord serum by RIA. In healthy pregnant women, serum allopregnanolone and progesterone levels progressively increased throughout gestation. Whereas no changes were found at vaginal delivery, serum allopregnanolone and progesterone levels were significantly lower at delivery by emergency cesarean section (P < 0.01). Umbilical cord serum allopregnanolone and progesterone levels in emergency cesarean were significantly lower than those found at vaginal delivery (P < 0.01). Patients with chronic hypertension, with or without superimposed severe preeclampsia, showed serum allopregnanolone levels significantly higher than those of healthy women at the same gestational age (P < 0.01). In conclusion, maternal serum allopregnanolone levels increased during normal gestation were lower in women who underwent emergency cesarean and higher in patients with chronic hypertension, with or without preeclampsia. Because allopregnanolone is active on the central nervous system and in the control of systemic blood pressure, an involvement of this neurosteroid in the adaptive processes induced by pregnancy is suggested.

Adult↗

PubMed2000

Raloxifene acutely stimulates nitric oxide release from human endothelial cells via an activation of endothelial nitric oxide synthase.

Raloxifene is a selective estrogen receptor modulator (SERM) clinically effective for the prevention of postmenopausal osteoporosis. Estrogen's effect on cardiovascular diseases is mainly dependent on direct actions on the vascular wall. Since raloxifene has an endothelium-dependent relaxing effect, we studied the effects of this molecule on nitric oxide (NO) release from cultured human umbilical vein endothelial cells. Clinically effective concentrations of the compound triggered a rapid and dose-dependent release of NO from endothelial cells. Raloxifene-induced NO production was dependent on an estrogen receptor-mediated mechanism, since it was abolished by the pure estrogen receptor antagonist ICI 182,780. Treatment of endothelial monolayers with raloxifene was not associated with changes in endothelial nitric oxide synthase (eNOS) messenger RNA or protein, showing that raloxifene does not increase NO release through a transcriptional increase of eNOS. Indeed, raloxifene-induced NO production is due to an estrogen receptor-dependent acute stimulation of eNOS enzymatic activity. In conclusion, raloxifene activates eNOS in human endothelial cells, exerting a potentially important direct vasculo-protective effect stimulating endothelial NO production.

Cells, Cultured↗

PubMed2000

Allopregnanolone concentrations and premenstrual syndrome.

OBJECTIVE: To evaluate basal allopregnanolone and progesterone in both phases of the menstrual cycle in women suffering from premenstrual syndrome (PMS) and their response to a GnRH test. DESIGN: We selected 56 women (28 patients with PMS and 28 controls) aged between 18 and 32 years. Blood samples were drawn in both follicular and phases. Twenty-eight women (14 patients with PMS and 14 controls) underwent a GnRH test in the luteal phase. METHODS: We evaluated allopregnanolone by RIA, using a specific antibody. Serum progesterone and oestradiol were determined using a commercially available RIA kit. RESULTS: Luteal phase allopregnanolone concentrations were significantly lower in patients with PMS than in controls. Progesterone concentrations were significantly lower in patients with PMS in both the follicular and the luteal phase. Serum oestradiol concentrations were in the normal range in both groups of women, although slightly greater in those with PMS. Allopregnanolone and progesterone responses to a GnRH test were significantly blunted in women with PMS. CONCLUSIONS: Diminished concentrations of allopregnanolone and progesterone, its precursor, and a blunted response to the GnRH test lead us to hypothesise that patients with PMS may suffer from an inadequate production of ovarian neuroactive steroids, especially in the luteal phase. This would lead to an impaired anxiolytic GABA(A)-mediated response in stressful physiological and psychological conditions, and may in part explain various psychoneuroendocrine symptoms that arise during PMS.

Adult↗

PubMed2000

Hypothalamic amenorrhea with normal body weight: ACTH, allopregnanolone and cortisol responses to corticotropin-releasing hormone test.

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+/-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.

Adrenocorticotropic Hormone↗