naloxone and Amenorrhea

Functional hypothalamic amenorrhea are very probably due to a decrease of the frequency of the secretory pulses of LH, ie of GnRH. This decrease could be the consequence of a chronic hypersecretion of the corticotropin releasing hormone (CRH). CRH seems to act on the hypotalamic pulse generator of GnRH through the effect of the endogenous opioid peptides of the central nervous system. Opioid receptor antagonists restore normal pulse frequency of LH in most cases. Research is being done to try to elucidate the cause of the failure to such treatment: dopamine in among other mechanisms, supposed to play an essential role.

Topics: Amenorrhea; Corticotropin-Releasing Hormone; Female; Gonadotropin-Releasing Hormone; Humans; Hypothalamic Diseases; Luteinizing Hormone; Melatonin; Metoclopramide; Naloxone; Prolactin

This paper reviews recent experimental evidence which supports a role for endogenous opioid peptides in the control of gonadotropin function. In primates, cell bodies containing endogenous opioid peptides have been located within the hypothalamus in areas rich in gonadotropin-releasing hormone (GnRH) and dopamine. The release of beta-endorphin from these hypothalamic neurons is influenced by gonadal steroids, maximal release being observed when both estradiol and progesterone are present. beta-Endorphin has been shown to decrease LH secretion, and naloxone, an opiate antagonist, reverses this action. The LH-releasing activity of naloxone parallels variations in hypothalamic beta-endorphin secretory activity, so that maximal effects are seen during the luteal phase of the cycle. Present evidence indicates that opiates exert their effect on LH via a hypothalamic site. It is concluded that increased opioid inhibition of the GnRH-LH axis is responsible for the decline in LH pulse frequency during the luteal phase. The studies provide evidence for a chemical basis rationalizing relationships between reproductive function and stress, and have further implication on other forms of amenorrhea.

Topics: Amenorrhea; Animals; Arcuate Nucleus of Hypothalamus; beta-Endorphin; Brain Chemistry; Corticotropin-Releasing Hormone; Endorphins; Female; Follicle Stimulating Hormone; Haplorhini; Humans; Hypothalamus, Middle; Luteinizing Hormone; Menstrual Cycle; Naloxone; Pituitary Hormone-Releasing Hormones; Pro-Opiomelanocortin; Prolactin; Stress, Psychological

Topics: Adolescent; Adult; Amenorrhea; Arthritis, Infectious; Bone Diseases; Chemical and Drug Induced Liver Injury; Coma; Endocarditis, Bacterial; Extremities; Female; Fetal Growth Retardation; Hepatitis, Viral, Human; Heroin Dependence; Humans; Infant, Newborn; Ischemia; Male; Naloxone; Neurologic Manifestations; Pregnancy; Pregnancy Complications; Respiratory Tract Diseases; Sepsis; Skin Manifestations; Tetanus

To characterize the neuroendocrine patterns of abnormal GnRH secretion in hypothalamic amenorrhea (HA), 49 women with primary and secondary HA underwent frequent sampling of LH in a total of 72 baseline studies over 12-24 h. A subset of women participated in more than one study to address 1) the variability of LH pulse patterns over time; and 2) the impact of modulating opioid, dopaminergic, and adrenergic tone on LH secretory patterns. The frequency and amplitude of LH secretion was compared with that seen in the early follicular phase (EFP) of normally cycling women. The spectrum of abnormalities of LH pulses was 8% apulsatile, 27% low frequency/low amplitude, 8% low amplitude/normal frequency, 43% low frequency/normal amplitude, 14% normal frequency/normal amplitude. Of patients studied overnight, 45% demonstrated a pubertal pattern of augmented LH secretion during sleep. Of patients studied repeatedly, 75% demonstrated at least 2 different patterns of LH secretion, and 33% reverted at least once to a normal pattern of secretion. An increase in LH pulse frequency was seen in 12 of 15 subjects in response to naloxone (opioid receptor antagonist). Clonidine (alpha-2 adrenergic agonist) was associated with a decrease in mean LH in 3 of 3 subjects. An increase in LH pulse frequency was seen in 4 of 8 subjects in response to metoclopramide (dopamine receptor antagonist), but the response was not statistically significant. Baseline abnormalities in LH secretion did not appear to influence response to neurotransmitter modulation.. 1) HA represents a spectrum of disordered GnRH secretion that can vary over time; 2) LH pulse patterns at baseline do not appear to influence the ability to respond to neurotransmitter modulation; 3) Opioid and adrenergic tone appear to influence the hypothalamic GnRH pulse generator in some individuals with HA.

Topics: Adolescent; Adrenergic alpha-Agonists; Adult; Amenorrhea; Clonidine; Dopamine Antagonists; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Hypothalamic Diseases; Longitudinal Studies; Luteinizing Hormone; Metoclopramide; Naloxone; Narcotic Antagonists; Neurosecretory Systems; Neurotransmitter Agents; Sleep

To evaluate whether the efficacy of naltrexone administration in patients with hypothalamic amenorrhea correlates to the response to an acute naloxone test.. Thirty patients with hypothalamic amenorrhea associated with weight loss were studied. After naloxone test (4 mg in bolus IV) patients were divided into two groups: group A, nonresponsive (n = 15) and group B, responsive (n = 15). Group A underwent two cycles of hormonal replacement therapy with E2 patches and medroxyprogesterone acetate. Then all patients were administered naltrexone at the dosage 50 mg/d orally for 6 months. A third group of 10 amenorrheic patients were treated with oral placebo with the same schedule.. Plasma gonadal steroid levels increased in all patients and in 24 of 30 patients the menstrual bleeding occurred within 90 days from the beginning of treatment. After 6 months from naltrexone discontinuation, 18 of 24 patients still showed the occurrence of menstrual cycles. Luteinizing hormone plasma levels and LH pulse amplitude increased after 3 months of treatment and remained unchanged 6 months after naltrexone suspension. Plasma FSH levels did not show any change in any patient. The body mass index increased after 3 months in all patients who menstruated. Patients treated with placebo did not show any significant change in gonadotropins and gonadal steroid plasma levels.. The present study supports the efficacy of naltrexone therapy for patients with hypothalamic amenorrhea either responsive or nonresponsive to naloxone test.

Topics: Administration, Oral; Amenorrhea; Body Mass Index; Dose-Response Relationship, Drug; Estrogen Replacement Therapy; Estrogens; Female; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Menstrual Cycle; Naloxone; Naltrexone; Narcotic Antagonists; Progestins; Weight Loss

In anorexia nervosa alterations in the hypothalamic-pituitary-gonadal unit were previously thought to have been connected to an increase of endogenous opiate tone. The authors tried to prove that the replacement of normal endogenous steroid levels could restore the functional coupling between opiatergic and luteinizing hormone-releasing hormone (LH-RH) neurons in patients with anorexia nervosa. Pulsatile LH-RH therapy has been used to achieve normal ovarian activity. The authors studied gonadotropin levels before and during intravenously (IV) pulsatile LH-RH therapy (50 to 100 ng/kg body weight/90 to 120 minutes) in three anorexia nervosa and two weight loss amenorrhea patients, during both placebo and naloxone administration (2 mg IV bolus plus 4 mg infusion lasting 120 minutes). Before therapy, naloxone administration did not significantly change gonadotropin levels in three out of five patients, while a decrease in gonadotropin levels was observed in the other two subjects. During LH-RH therapy, normal pituitary-gonadal activity was demonstrated and ovulatory cycles were found in all patients. Naloxone administration did not change gonadotropin release during LH-RH therapy. Data could support the hypothesis of either a primitive impairment of LH-RH neurons, or an alteration in central regulation of LH-RH pulsar in anorexia nervosa.

Topics: Adolescent; Adult; Amenorrhea; Anorexia Nervosa; Body Weight; Estrogens; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Naloxone; Progesterone

Anorexia nervosa is a primarily psychiatric syndrome of self-induced weight loss due to an intense fear of becoming obese. Numerous endocrine abnormalities occur in anorexia nervosa patients, and in many respects these alterations reflects the endocrinology of reduced energy intake. However, the basic mechanisms of those alterations are far from being understood. In an attempt to understand the disrupted mechanisms of the hypogonadotropic hypogonadism of the anorectic state, we studied 10 anorectic women in the acute phase of their illness; all met the DSM III criteria. On each patient, two tests were performed with either saline as control or infusion of the opioid antagonist naloxone, and both LH and FSH levels were measured. Four mg of naloxone as bolus was used, followed by a naloxone infusion of 2 mg/h for 4 h. Compared with the pattern of normal women, naloxone did not increase in the anorectic patients either LH or FSH levels nor pulsatility. This result suggests that endogenous opioid peptides are not implicated in the low gonadotropic situation of anorexia nervosa. An alternative explanation could be that the low estrogenic "milieu" of these patients could mask the opioid action. To test this second possibility, another group of 7 anorectic women after partial weight recovery were challenged with estrogen administration. Compared with the pattern of normal women volunteers, all the anorectic patients but one presented an abnormal response in both LH and FSH levels after estrogen administration. In fact, the negative feedback and the delayed positive feedback of LH after estrogen were absent in these patients. Interestingly enough, the only patient with near-normal LH response to estrogen was considered fully recovered by the Psychiatric Unit. Several alterations in the hypothalamic-pituitary-adrenal axis has been reported in anorexia nervosa. Seven anorectic patients and 7 aged-matched women were challenged by ACTH 1-24, 250 micrograms (i.v.) and the ratio of increments in adrenal steroid products to precursors monitored. ACTH-induced increments in cortisol with respect to increments in 17-OH-progesterone was similar in anorectics and controls. On the contrary, the ratio of increments of androstenedione with respect to increments in 17-OH-progesterone were greater in anorexia nervosa than controls. These results suggest that in anorexia nervosa the 11-beta-21-alpha-hydroxylase system is normal but a deficient 17-20 desmolase system is present. Fi

Topics: Amenorrhea; Anorexia Nervosa; Corticotropin-Releasing Hormone; Cosyntropin; Endorphins; Estradiol Congeners; Feedback; Female; Gonadotropin-Releasing Hormone; Growth Hormone-Releasing Hormone; Humans; Hypothalamo-Hypophyseal System; Hypothalamus; Naloxone; Ovary; Pituitary Hormones, Anterior; Pituitary-Adrenal System

In order to assess a possible influence of endogenous opioids upon gonadotrophin secretion in women, we examined the effects of i.v. administration of 10 mg naloxone, a specific opiate antagonist, in ten normal menstruating women, in thirteen women with amenorrhoea and/or hyperprolactinaemia and in two women with putative deficiency of gonadotrophin-releasing hormone (GnRH). In thirteen subjects, a saline vehicle control study (randomized order of administration) was also performed. In the normal women, naloxone failed to elicit changes in serum gonadotrophin levels when administered during the early follicular phase of the menstrual cycle. However, significant increments of LH were observed from 30 to 165 min following naloxone administration during the late follicular phase. Similar LH responses occurred in the amenorrhoeic and hyperprolactinaemic women. There was a tendency towards a concomitant increment in FSH levels, which reached statistical significance variably from 60 to 105 min post-naloxone. The LH response to naloxone in individual subjects showed a significant (P less than 0.01) quadratic (U-shaped) relationship to the log basal oestradiol concentration. No response to naloxone was observed in the two patients with GnRH deficiency despite a brisk response to an exogenous GnRH bolus. Taken together, these data suggest that central nervous system inhibitory opioid pathways may be involved in the regulation of LH secretion in normal women and that excessive production of endogenous opioids may play a role in the pathophysiology of some amenorrhoeic conditions.

Topics: Adult; Amenorrhea; Endorphins; Estradiol; Female; Follicle Stimulating Hormone; Humans; Hypothalamic Diseases; Hypothalamic Hormones; Luteinizing Hormone; Menstruation; Naloxone; Pituitary Hormone-Releasing Hormones; Prolactin

To determine whether the opioidergic system is involved in the modulation of leptin secretion in healthy and amenorrheic subjects.. Prospective study.. Department of Obstetrics and Gynecology, University of Modena, Modena, Italy.. Healthy subjects (n = 8) and patients with hypothalamic amenorrhea (n = 17) or hyperandrogenism (n = 7) and low body mass index (BMI).. Acute infusion of naloxone (4-mg bolus) and blood sampling 15 minutes before infusion; at time of infusion; and 15, 30, 45, 60, 75, 90, and 120 minutes after infusion.. Plasma leptin, LH, FSH, E2, and cortisol concentrations.. Plasma leptin concentrations were lower (P <.01) in both hypothalamic and hyperandrogenic amenorrheic subjects than in healthy controls. In all groups of subjects, no significant changes in leptin levels were observed after infusion of naloxone. A significant correlation was found between leptin concentrations and BMI when all subjects were considered together (P <.05) but was not found in the single groups.. The present data do not support the hypothesis that opioidergic receptors are involved acutely in the modulation of leptin release in healthy and amenorrheic women.

Topics: Amenorrhea; Body Mass Index; Case-Control Studies; Female; Humans; Hyperandrogenism; Hypothalamic Diseases; Infusions, Intravenous; Leptin; Naloxone; Narcotic Antagonists; Proteins; Secretory Rate

The purpose of this study was to evaluate the role of the opioid system and the estrogen environment in the nocturnal secretion of melatonin in women with secondary amenorrhea (SA). Nocturnal melatonin concentrations in patients with SA were significantly higher than in normal women (p < 0.01 vs. women with normal menstrual cycles). There were significant negative correlations between cumulative melatonin levels (between 8 p.m. and 8 a.m.) and serum estradiol-17 beta (r = -0.561, p < 0.01) and between peak serum melatonin values and serum estradiol-17 beta concentrations (r = -0.608, p < 0.01) in SA. Intravenous administration of a conjugated estrogen (Premarin 20 mg) significantly suppressed nocturnal melatonin secretion (p < 0.05), but a continuous intravenous infusion of naloxone (1.6 mg/h from 8 p.m. to 6 a.m.), an opiate antagonist, did not affect nocturnal melatonin secretion in SA. Our findings suggest that elevated nocturnal melatonin secretion may be related to low estrogen levels, but that it is not mediated by the opioid system.

Topics: Adolescent; Adult; Amenorrhea; Circadian Rhythm; Endorphins; Estradiol; Estrogens, Conjugated (USP); Female; Humans; Melatonin; Naloxone; Reference Values

Within an ovulation induction study, we investigated the activity and reactivity of the hypothalamic-pituitary-adrenal axis in women suffering from hypothalamic amenorrhea by using naloxone.. The central opioid receptors were blocked by means of a naloxone bolus injection of 4 mg i.v. daily.. Before and after receptor blockade, the cortisol secretion showed diverse results independently from the hypothalamic opioid tone. The cortisol levels were not elevated. Also, the basal secretion of cortisol and DHEAS was nonspecific among the various responder groups.. It seems that there is no close relationship between central opioid tone and adrenal function in hypothalamic amenorrhea.

Topics: Adult; Amenorrhea; Dehydroepiandrosterone; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Injections, Intravenous; Luteinizing Hormone; Naloxone; Narcotic Antagonists; Ovulation Induction; Pituitary-Adrenal System; Receptors, Opioid; Treatment Outcome

Hyperprolactinaemic amenorrhoea is associated with disturbances of pulsatile gonadotrophin secretion. The underlying mechanism remains unclear and the aim of this study was to investigate the 24-hour secretory pattern of gonadotrophins in women with hyperprolactinaemic amenorrhoea. The effect of opioid blockade using naloxone infusion on LH secretory pattern was also studied.. The secretory patterns of LH, FSH, PRL and their responses to naloxone infusion were studied by serial blood samples collected at 10-minute intervals for 24 hours. On the following day, naloxone was infused at a dose of 1.6 mg per hour for 4 hours.. Eight women with hyperprolactinaemic amenorrhoea, two women hyperprolactinaemic but with normal ovarian cycles, and nine control subjects in the early follicular phase of menstrual cycle.. Concentrations of LH, FSH and PRL were measured in plasma samples obtained at 10-minute intervals for 24 hours. In one woman, concentrations of urinary oestrone glucuronide were measured daily during treatment with pulsatile GnRH.. The number of LH pulses per 24 hours was significantly fewer in women with hyperprolactinaemic amenorrhoea than in those with hyperprolactinaemia with normal cycles or control subjects (mean +/- SEM 4.5 +/- 2.4 vs 13.5 +/- 2.5 vs 17.3 +/- 0.8, P < 0.001). The magnitude of each episode of secretion was significantly higher in the hyperprolactinaemic amenorrhoeic women (P < 0.05) so the overall mean concentrations of LH throughout the 24-hour period was similar in the three groups (5.2 +/- 1.1, 4.8 +/- 0.8 and 5.2 +/- 0.4 U/l respectively). In women with hyperprolactinaemic amenorrhoea there was no significant change in the pattern of LH secretion during sleep in contrast to the control women in whom there was a slowing in the LH pulse frequency during the night. There was no significant change in the mean concentrations of LH, FSH and PRL during the naloxone infusion. There were also no significant changes in the LH pulse frequency in response to naloxone infusion when compared with an equivalent period of time in the previous 24 hours. In one hyperprolactinaemic amenorrhoeic woman, follicular development, ovulation and pregnancy were induced when gonadotrophin releasing hormone (GnRH) was infused in a pulsatile manner at a dose of 5 micrograms every 90 minutes.. The suppression of normal ovarian cycles in women with hyperprolactinaemic amenorrhoea is due to a significant reduction in frequency of LH (GnRH) secretion which is not due to an increase in hypothalamic opioid activity. As normal ovarian cycles can occur or be induced by exogenous GnRH in hyperprolactinaemia, it is unlikely that a high level of prolactin by itself inhibits follicular development and ovulation.

Topics: Adult; Amenorrhea; Circadian Rhythm; Estrone; Female; Follicle Stimulating Hormone; Follicular Phase; Humans; Hyperprolactinemia; Luteinizing Hormone; Naloxone; Secretory Rate

To evaluate the activity of the hypothalamic-pituitary-adrenal axis (HPA) in patients with hypothalamic amenorrhea.. Amenorrheic women with a history of emotional stressful events and eumenorrheic women as control group were studied.. Pulsatile cortisol (F) secretion over a 4-hour period of time and plasma F responses to various neuroendocrine tests (naloxone, fenfluramine, corticotropin-releasing hormone [CRH], adrenocorticotropic hormone) were investigated.. Women with hypothalamic amenorrhea showed a F secretory pattern higher than normal women. In addition, the lack of naloxone or fenfluramine-induced release of F and a blunted F response to CRH test were observed.. The increased activity of HPA in patients with hypothalamic amenorrhea is associated with an impaired activity of some central pathways (opioids and serotonin), suggesting multiple alterations in the hypothalamic control of pituitary-adrenal axis in amenorrheic women.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Amenorrhea; Corticotropin-Releasing Hormone; Female; Fenfluramine; Humans; Hydrocortisone; Hypothalamic Diseases; Hypothalamo-Hypophyseal System; Naloxone; Pituitary-Adrenal System

The role of dopamine and opiates in the suckling-induced suppression of gonadotrophin secretion and prolactin release was investigated during lactational amenorrhoea in fully breastfeeding women at 12 weeks post-partum. A total of 26 women, 20 using non-steroidal methods of contraception and six using the progestogen-only pill, Noriday (POP), breastfed their babies on demand at a frequency of 3.6 +/- 0.2 suckling episodes during the 8 h study period while blood samples were collected at 10-min intervals. Five hours after the start of sampling six women were given the dopamine antagonist metoclopramide (10 mg, i.m.) while four women received saline. In a second experiment, six women using nonsteroidal contraception and three women on the POP received an i.v. infusion of the opiate antagonist naloxone (1.6 mg/h) for 2 h, while four women using non-steroidal contraception and three women on the POP were infused with saline. Two hours after the i.m. injection or start of infusion all women were given an i.v. injection of 10 micrograms gonadotrophin releasing hormone (GnRH) and samples were collected for a further 1 h. All samples were assayed for luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin. Plasma concentrations of oestradiol were < 60 pmol/l in all women and they remained amenorrhoeic for at least 10 weeks after the study. Pulsatile release of LH was only observed over the 5 h pre-treatment period in 10 of the 20 non-steroid taking women (1-3 pulses/5 h), and in one of the six women (1 pulse/5 h) on POP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amenorrhea; Breast Feeding; Dopamine; Dopamine Antagonists; Endorphins; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Luteinizing Hormone; Metoclopramide; Naloxone; Postpartum Period; Prolactin; Secretory Rate

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

Topics: Adult; Amenorrhea; Estradiol; Female; Follicle Stimulating Hormone; Humans; Hypothalamic Diseases; Hypothalamus; Injections, Intravenous; Luteinizing Hormone; Naloxone; Ovarian Follicle; Ovary; Ovulation Induction; Progesterone; Receptors, Opioid; Ultrasonography

The physiological amenorrhea occurring in suckled females has been associated with both hypopulsatile gonadotropin secretion and hyperprolactinemia. To test whether these phenomena are opiate mediated and whether these effects are dependent on the presence of ovaries, we studied six suckled, lactating cynomolgus monkeys, three with intact ovaries and three that were ovariectomized 14 days postpartum. Frequent blood sampling (every 15 min) was performed at approximately monthly intervals using chronic venous catheters accessed remotely via a jacket and tether system. Each monkey was administered saline or naloxone (2 mg bolus then 2 mg/h) by constant infusion, in alternating 6-h blocks. During saline infusions, PRL concentrations varied markedly in a diurnal pattern with concentrations varying from 30-70 micrograms/L during the day and from 100-200 micrograms/L during the night. In both gonadal intact and ovariectomized groups of monkeys naloxone dramatically suppressed and maintained PRL concentrations at less than 20 micrograms/L irrespective of the time of day or the order of administration. The effects of naloxone on gonadotropin concentrations were much less dramatic. In gonadal-intact monkeys, no effect of naloxone was seen on pulse frequency of either FSH or LH, or on mean LH concentration, and only a slight increase was noted in mean FSH concentrations. In ovariectomized monkeys, naloxone was also without effect on pulsatile LH secretion, although mean LH concentrations were slightly higher during naloxone infusions than during saline infusions (P less than 0.05). From these results, we conclude that opiate peptides are released in response to the suckling stimulus in the cynomolgus monkey and that they mediate the effects of suckling on PRL secretion in both gonadal-intact and agonadal cynomolgus monkeys. The lack of effect of opiate blockade on gonadotropin concentrations suggests that multiple pathways may be involved with the inhibition of the GnRH pulse generator during lactational anovulation.

Topics: Amenorrhea; Animals; Animals, Suckling; Anovulation; Endorphins; Female; Longitudinal Studies; Luteinizing Hormone; Macaca fascicularis; Naloxone; Ovariectomy; Pregnancy; Prolactin; Puerperal Disorders; Weaning

Within the study we treated 6 women suffering from hypothalamic amenorrhea with 4 mg naloxone intravenous daily. The duration of the study was at most 30 days. The estimation of hormonal baseline and changes occurs daily, furthermore everyday sonographic folliculometry. In 2 patients the chronic opiate receptor blockade leads to a drastic stimulation of gonadotropin secretion. One of these women (responder in Naloxone-Test) has a long standing elevation of LH and FSH resulting in an ovulation 2 days past end of the therapy. The other women (non-responder in Naloxone-Test) reaches a follicular growth till 17 mm follicle diameter following in preterm atresia during therapy. In another woman (minimal-responder in Naloxone-Test) occurs a short and weak elevation of gonadotropins without any basic stimulation of the hypothalamic-pituitary-ovary axis. The results of this study show that: 1. it's possible to discern an opioid mediated hypothalamic amenorrhea and 2. a Naloxone-Test or Naloxone-Stimulation-Test should be put before starting a therapy with opiate antagonists in hypothalamic amenorrhea.

Topics: Adult; Amenorrhea; Female; Gonadotropin-Releasing Hormone; Humans; Naloxone; Ovarian Follicle; Ovulation; Ovulation Induction; Receptors, Opioid; Ultrasonography

We hypothesized that menstrual disturbances in female athletes arise from opioid-induced abnormalities in gonadotropin and/or prolactin (PRL) secretion. To investigate this hypothesis, we measured luteinizing hormone, follicle-stimulating hormone, and PRL levels in eumenorrheic and amenorrheic athletes during thyrotropin-releasing hormone and gonadotropin-releasing hormone tests at baseline, after naloxone infusions, after exercise to exhaustion, and after similar exercise during naloxone infusions. Contrary to our hypothesis, amenorrheic runners did not have significant alterations in basal, postexercise, or stimulated hormone levels compared with eumenorrheic runners. In addition, opioid blockade by naloxone did not enhance gonadotropin release by amenorrheic athletes.

Topics: Adult; Amenorrhea; Endorphins; Estradiol; Exercise; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Naloxone; Progesterone; Prolactin; Thyrotropin-Releasing Hormone

The ability to change the frequency and amplitude of pulsatile GnRH secretion may be an important mechanism in maintaining regular ovulatory cycles. Hyperprolactinemia is associated with anovulation and slow frequency LH (GnRH) secretion in women. To assess whether the slow frequency of LH (GnRH) secretion is due to increased opioid activity, we examined the effect of naloxone infusions in eight amenorrheic hyperprolactinemic women (mean +/- SE, serum PRL, 160 +/- 59 micrograms/L). After a baseline period, either saline or naloxone was infused for 8 h on separate days, and LH was measured in blood obtained at 15-min intervals. Additional samples were obtained for plasma FSH, PRL, estradiol, and progesterone. Responses to exogenous GnRH were assessed at the end of the infusions. LH pulse frequency increased in all subjects from a mean of 4.0 +/- 0.5 pulses/10 h (mean +/- SE) during saline infusion to 8.0 +/- 1.0 pulses/10 h during naloxone infusion (P less than 0.01). LH pulse amplitude did not change, and mean plasma LH increased from 7.4 +/- 0.8 IU/L (+/- SE) to 11.2 +/- 1.5 IU/L during naloxone (P less than 0.01). A small but significant increase was seen in mean plasma FSH. Plasma PRL, estradiol, and progesterone were unchanged by naloxone infusion. These data suggest that elevated serum PRL reduces the frequency of LH (GnRH) secretion by increasing hypothalamic opioid activity and suggest that the anovulation in hyperprolactinemia is consequent upon persistent slow frequency LH (GnRH) secretion.

Topics: Adult; Amenorrhea; Circadian Rhythm; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Hyperprolactinemia; Luteinizing Hormone; Naloxone; Pituitary Neoplasms; Prolactin

Exercise of sufficient intensity during daylight hours has been demonstrated to result in an acute elevation of circulating melatonin levels. The possibility that repeated elevations of daytime melatonin secretion may result in alterations of the nocturnal maxima of the circadian rhythm in highly trained athletic women with and without amenorrhea was investigated. Twenty-four-hour melatonin profiles in matched cyclic sedentary (CS; n = 10) women, cyclic athletic (CA; n = 10) women, and amenorrheic athletic (AA; n = 8) women were compared. The roles of endogenous opioids and dopamine as potential modulators of melatonin secretion were also evaluated by comparing the melatonin profiles during sequential 24-h infusions of saline, followed by either naloxone or metoclopramide (both at 30 micrograms/kg.h). Elevated (P less than 0.05) mean daytime (1000-1700 h) melatonin levels were observed in both groups of athletic women compared to sedentary women. In contrast, nocturnal melatonin levels in sedentary and athletic cycling women were indistinguishable, while amenorrheic athletic women displayed a marked increase in nocturnal peak amplitude (P less than 0.001 vs. CS and CA) and a 2-h delay in offset (P less than 0.001 vs. CS and CA), which yielded a 2-fold amplification of the integrated nocturnal melatonin secretion (P less than 0.001 vs. CS and CA). The onset of the nocturnal rise did not differ among the three groups. Opioidergic and dopaminergic blockade with naloxone and metoclopramide at the doses used did not alter any parameter of melatonin secretion in any of the three groups of women. In conclusion, athleticism in women is associated with an elevation of daytime melatonin levels independent of menstrual status. AA women, but not CA women, display a 2-fold amplification of nocturnal melatonin secretion with a 2-h delay of offset, which does not seem to be linked to athleticism per se. The significance and neuroendocrine basis for the expanded melatonin secretion in athletic amenorrheic women remains to be elucidated.

Topics: 2-Methyl-4-chlorophenoxyacetic Acid; Adult; Amenorrhea; Circadian Rhythm; Dopamine Antagonists; Exercise; Female; Hormones; Humans; Melatonin; Menstrual Cycle; Naloxone; Narcotic Antagonists; Reference Values

To better understand the pathophysiology of hypothalamic amenorrhea (HA), the frequency of luteinizing hormone (LH) pulsatility and the LH response to gonadotropin-releasing hormone (GnRH) was assessed before and after clomiphene citrate (CC) in 18 women with HA and 10 normal women in the early follicular phase (EFP). The HA women showed a greater acceleration of LH pulsatility after CC than EFP women but there was a decrease in their LH response to GnRH. Naloxone caused an increase in LH pulsatility in HA but not EFP women, although this effect was less than that seen with CC. We conclude that, in HA women, the GnRH pacemaker, but not the pituitary, is inhibited by increased sensitivity to the negative feedback effect of estradiol and increased opiate tone.

Topics: Adult; Amenorrhea; Clomiphene; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Hypothalamus; Luteinizing Hormone; Naloxone

We investigated the possibility of induction of ovulation by means of chronic opioid receptor blockade with naloxone. Daily 4 mg were given as an intravenous bolus injection in 4 women suffering from hypothalamic amenorrhea till the 30th day of therapy. A possible maturation of ovarian follicles and a subsequent ovulation should be proved by means of daily determination of LH, FSH, estradiol and progesterone as well as of a sonographic folliculometry. The day prior to and the first day of naloxone treatment we took blood samples every 10 minutes during 4 hours for determination of LH pulse frequency and amplitude. Neither we found any alteration of the basal values of LH, FSH and estradiol, nor we observed a follicular growth. These results lead us to the conclusion to introduce a naloxone stimulation test as a further diagnostic step. In this way opioid mediated hypothalamic ovarian insufficiencies could be registered and a sufficient therapy could be reached.

Topics: Amenorrhea; Drug Administration Schedule; Estradiol; Female; Humans; Hypothalamic Diseases; Injections, Intravenous; Luteinizing Hormone; Naloxone; Ovulation Induction; Progesterone; Receptors, Opioid

The cause of the amenorrhea that occurs in patients with hyperprolactinemia is unknown. The involvement of endogenous opioid peptides in the inhibition of GnRH release as a central factor leading to the hypogonadotropic state has been recently described. This study analyzed the LH response to opiate receptor blockade by naloxone (4 mg, iv) in groups of subjects with amenorrhea due to hyperprolactinemia of different etiologies. Patients presenting with a PRL-secreting pituitary adenoma (n = 7), idiopathic hyperprolactinemia (n = 9), or hyperprolactinemia during pharmacological treatment for schizophrenia (n = 5) were studied. Furthermore, to evaluate whether high circulating PRL levels influence the activity of the opioid system after the menopause, a group of seven postmenopausal subjects was tested before and 1 week after the administration of metoclopramide (10 mg, three times a day), a dopamine receptor antagonist. Normal premenopausal women (n = 6) served as controls. Naloxone significantly increased plasma LH levels in both prolactinoma and idiopathic hyperprolactinemic patients (P less than 0.01 vs. basal and placebo). In neither of those groups was a significant correlation found between the plasma LH response to naloxone and basal plasma PRL levels. In contrast to pathological hyperprolactinemia, blockade of opiate receptors did not significantly change LH secretion in either amenorrheic women with pharmacologically induced hyperprolactinemia or postmenopausal women. These results suggest that the effect of hyperprolactinemia on opioid modulation of LH secretion is related to the nature of the hyperprolactinemic state, supporting the existence of increased opioid inhibition of LH levels in pathological hyperprolactinemia.

Topics: Adenoma; Adult; Amenorrhea; Antipsychotic Agents; Dopamine Antagonists; Endorphins; Female; Humans; Hyperprolactinemia; Iatrogenic Disease; Luteinizing Hormone; Menopause; Metoclopramide; Naloxone; Pituitary Neoplasms; Schizophrenia

The pattern of pulsatile GnRH secretion is abnormal in some women with hypothalamic amenorrhea (HA) consequent to previous exercise or weight loss. Both diminished frequency pulsatile LH secretion, and by inference GnRH secretion, and normal LH pulsatility have been reported. We assessed whether the patterns of GnRH secretion varied with time by measuring plasma LH every 15 or 20 min for 24 h on 1-3 occasions during a 10-month period in 14 women with HA (a total of 24 studies). During the day, mean LH pulse frequency [1.0 +/- 0.1 (+/- SE) pulses/8 h] was lower than that in normal women in the early follicular phase of their cycles (5.1 +/- 0.6), and the frequency in individual HA patients was lower than early follicular phase values in 16 of 17 studies. The slow daytime LH pulse frequency also was a consistent finding, in that the values in repeat studies varied by less than 2 pulses/8 h in all but 1 patient. LH pulse frequency (2.0 +/- 0.4 pulses/8 h) was higher and more variable during sleep, and normal early follicular phase frequencies were found in 20% of patients with HA. The mechanisms whereby GnRH pulse frequency is reduced are not known. alpha-Adrenergic agonist drugs stimulate GnRH pulsatile secretion in rodents, but administration of the alpha 2-agonist clonidine (0.15 mg, orally, at 0800 and 2000 h) did not increase the frequency of LH pulses in 7 women (1.7 +/- 0.4 pulses/8 h). In contrast, administration of naloxone (1 mg/m2 X h, iv) for 8 h during the day to 14 patients, increased LH pulse frequency (3.3 +/- 0.5 pulses/8 h). In 8 of these 14 women, LH pulse frequency (4.9 +/- 0.4 pulses/8 h) increased into the range found during the normal early follicular phase, while in the other 6 women pulse frequency was not significantly increased (1.4 +/- 0.4 pulses/8 h). Plasma estradiol levels were similar in naloxone-responsive and unresponsive women, but spontaneous LH pulse frequency was higher at night in naloxone-responsive patients (2.9 +/- 0.6 vs. 1.4 +/- 0.3 pulses/8 h). The presence of nocturnal LH pulses did not predict responsiveness to naloxone, however, and LH pulse frequency was less than 2 pulses/8 h in 4 of the women who responded to naloxone. These data indicate that slow frequency GnRH secretion is a common finding during the day in women with HA. GnRH secretion is more variable at night, suggesting that the mechanisms involved in reducing pulsatile GnRH secretion are less effective during sleep.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adolescent; Adrenergic alpha-Agonists; Adult; Amenorrhea; Circadian Rhythm; Clonidine; Estradiol; Female; Humans; Hypothalamic Diseases; Luteinizing Hormone; Naloxone

This study evaluated the activity of central opiate receptors modulating luteinizing hormone (LH) secretion before and during treatment with human menopausal gonadotropin (n = 8) or purified human urinary follicle-stimulating hormone (n = 6) in 14 patients with hypogonadotropic hypogonadism (n = 6) or secondary amenorrhea (n = 8). LH response to saline infusion and naloxone administration (4 mg intravenously) was assessed. As control, 6 normal ovulating women were studied. Before therapy, all amenorrheic patients showed no LH increase after naloxone injection. Gonadotropin treatment restored the naloxone-induced LH response at preovulatory and midluteal phases in ovulating patients with secondary amenorrhea. The same response was present in spontaneously ovulating women but was absent in the hypogonadotropic hypogonad patients, despite the gonadotropin therapy's efficiency. In conclusion, when the alteration of gonadotropin-releasing hormone synthesis and/or release is reversible, the opioid system actively participates in the regulation of the hypothalamus-pituitary-gonadal axis.

Topics: Adult; Amenorrhea; Female; Follicle Stimulating Hormone; Humans; Hypogonadism; Luteinizing Hormone; Menotropins; Naloxone; Ovulation Induction; Pituitary Hormone-Releasing Hormones; Receptors, Opioid; Sodium Chloride; Stimulation, Chemical

Along with 51 amenorrheic patients the pituitary reactional situation was checked by means of an Gn-RH-stimulation test. Simultaneously to all these women the opiate antagonist Naloxone was infused in a further test series. In 7 from 51 women a significant increase of the LH was demonstrated in comparison to the basic values. Comparing the kinetics of the pituitary gland it was evident, that in all cases the gonadotropin emanation was detective respectively missing after the second Gn-RH-bolus, which followed immediately after the first one. The findings seem to proof the thesis that the endorphins mainly influence the gonadotropin reserve capacity. In cases, where it was possible to objectify the influence--the second pool was missing as well.

Topics: Amenorrhea; Female; Follicle Stimulating Hormone; Humans; Infertility, Female; Luteinizing Hormone; Naloxone; Pituitary Hormone-Releasing Hormones

The effect of improving diabetic control on secondary hypogonadotropic amenorrhea was investigated in patients with insulin-dependent diabetes mellitus (IDDM). Second, the hypothesis that increased central (hypothalamic) opiate inhibition may have been responsible for the suppression of gonadotropin-releasing hormone (GnRH) was tested by observing the effect of a four-hour naloxone infusion (1.4 mg/hour) on serum gonadotropin levels. All known causes of secondary amenorrhea were excluded before patients were eligible for the study. The median duration of amenorrhea was six years, and median body weight was 101 percent of ideal. After six months of improved metabolic control (n = 5) using intensified conventional therapy or continuous subcutaneous insulin infusion, the level of glycosylated hemoglobin dropped from 11.8 +/- 0.9 percent to 8.5 +/- 0.5 percent (p less than 0.005), and body weight increased from 60.5 +/- 1.8 kg to 64.7 +/- 1.4 kg (p less than 0.02). Menses did not, however, return in any patient. There was no significant change in serum levels of estradiol, progesterone, dihydroxyepiandrosterone, testosterone, prolactin, basal or GnRH-stimulated luteinizing hormone, or follicle-stimulating hormone. There was no change in the levels of luteinizing hormone or follicle-stimulating hormone during the naloxone infusion either during poor metabolic control or after six months of improved metabolic control. In conclusion, a form of secondary hypogonadotropic amenorrhea was identified in patients with IDDM that did not remit with sustained improvements in metabolic control. It did not appear to be mediated through increased central opiate tone.

Topics: Adult; Amenorrhea; Body Weight; Diabetes Mellitus, Type 1; Female; Gonadotropins, Pituitary; Humans; Naloxone; Pituitary Hormone-Releasing Hormones

With the aim of examining central opioid influences on the control of luteinizing hormone (LH) secretion, we evaluated the LH response to naloxone, an opioid receptor antagonist, in patients affected by normo-, hyper-, and hypogonadotropic amenorrhea, polycystic ovarian disease and hyperprolactinemia. The results indicate that opioid influences are altered in well-defined pathologic conditions (hyperprolactinemia, obesity), in addition to being modified by gonadal steroids.

Topics: Adenoma; Adolescent; Adult; Amenorrhea; Body Weight; Female; Gonadotropin-Releasing Hormone; Humans; Hypothalamo-Hypophyseal System; Luteinizing Hormone; Menstruation Disturbances; Naloxone; Oligomenorrhea; Ovary; Pituitary Neoplasms; Prolactin

12 mg of Naloxone were given using an intravenous pulsatile pump at the rate of 0.4 mg/minute every 8 minutes over a period of 4 hours in a woman of 28 years of age who had secondary amenorrhea of hypothalamic origin. The levels of L.H., F.S.H. and Prolactin were calculated every half hour during and after the perfusion. These was a progressive rise in the amplitude of L.H. peaks but no changes in F.S.H. and Prolactin levels. Intermittent inhibition of endogenous opioids seems to re-establish the pulsatile secretions of the hypothalamo-pituitary axis.

Topics: Adult; Amenorrhea; Female; Follicle Stimulating Hormone; Gonadotropins; Humans; Hypothalamic Diseases; Luteinizing Hormone; Naloxone; Prolactin

Topics: Amenorrhea; Female; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Naloxone; Pituitary Hormone-Releasing Hormones

The effects of opiate antagonism [naloxone infusion, 1 mg/(m2 X h)] on gonadotropin secretion were examined in four children (one female and three males: two late prepubertal and two pubertal; chronologic age, range 11.8-15.9 yr; bone age, range 8.5-13.5 yr) and in four women with hypothalamic amenorrhea (two at normal body weight and two at low body weight). Naloxone had no effect on daytime gonadotropin secretion in three children who were biologically the youngest in the group, two late prepubertal and one early pubertal [plasma luteinizing hormone (LH) means +/- SE: control day, 1.2 +/- 0.1; control night, 4.5 +/- 0.4; and naloxone day, 1.3 +/- 0.1 mIU/ml]. In contrast, opiate blockade produced a slight but discernible increase in plasma LH in the child whose hypothalamic-pituitary-gonadal axis was the most mature, a boy at mid-puberty. Naloxone produced a striking increase in plasma LH in the amenorrheic women at normal body weight (LH, means +/- SE: control day, 3.4 +/- 0.3; control night, 7.0 +/- 1.0; and naloxone day, 7.4 +/- 0.7 mIU/ml) as well as in those at low body weight (LH, means +/- SE: control day, 3.5 +/- 0.3; control night, 2.8 +/- 0.2; naloxone day, 4.9 +/- 0.4; and naloxone night, 6.7 +/- 0.5 mIU/ml). Antagonism of endogenous opiate activity increased LH pulse frequency in all four women.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Amenorrhea; Child; Female; Follicle Stimulating Hormone; Gonadotropins, Pituitary; Humans; Luteinizing Hormone; Male; Naloxone; Narcotic Antagonists; Pituitary Hormone-Releasing Hormones; Prolactin; Receptors, Opioid

We have examined temperature regulation in eight amenorrheic runners and gonadotropin response to an opioid antagonist in seven amenorrheic runners, 18 to 29 years of age, running 20 to 70 miles a week. Following equilibration, oral temperature was measured continuously, first in a cold room at 39 degrees F and then in a sauna at 172 degrees F in eight amenorrheic runners, in eight eumenorrheic runners, and in eight control subjects in the early follicular phase of the menstrual cycle. Studies were terminated if a subject's temperature fell below 94 degrees F or rose above 102 degrees F, and all studies were conducted in the afternoon. The rates of temperature change, calculated from total net temperature change divided by elapsed time in the test chamber, were not significantly different among the three groups of women. Seven other amenorrheic runners failed to have any significant changes in luteinizing hormone or follicle-stimulating hormone levels in response to the opioid receptor antagonist naloxone administered as an intravenous infusion at 1.6 mg/hour for 4 hours. If opioids inhibit gonadotropin secretion in exercise-associated amenorrhea, an increase in gonadotropins in response to naloxone would have been anticipated. Although it is possible that the dose of naloxone selected was inappropriate and that temperature responses under other conditions might differ from those of normal women, these data suggest that endogenous opiates do not play a direct role in the amenorrhea associated with exercise and that temperature regulatory centers in the hypothalamus are intact in this disorder, compared with other causes of amenorrhea such as anorexia nervosa. Further studies of hypothalamic function are warranted to test these possibilities.

Topics: Adolescent; Adult; Amenorrhea; Body Temperature Regulation; Estradiol; Estrone; Female; Follicle Stimulating Hormone; Humans; Hypothalamus; Luteinizing Hormone; Naloxone; Prolactin; Running

Naloxone is antagonistic to endogenous opioids. Giving it shows that these opioids act as controlling mechanisms in the secretion of LH and FSH by the hypothalamic, pituitary system and probably of Gn-RH by the hypothalamus. Endogenous opioids and particularly beta endorphin, which is itself under the control of oestradiol, play an inhibitory role on the secretion of Gn-RH and alter the pulsatile mode of Gn-RH secretion. We could not demonstrate PRL action which has been described by other authors.

Topics: Amenorrhea; Estradiol; Female; Follicle Stimulating Hormone; Humans; Injections, Intravenous; Luteinizing Hormone; Naloxone; Prolactin; Time Factors

Endogenous opiates are involved in the control of pituitary gonadotrophin and PRL secretion, and possibly of food intake. Both hyperprolactinaemia and weight loss (especially in anorexia nervosa) are frequently associated with amenorrhoea and an absence of gonadotrophin pulsatility. Since it has been suggested that increased endogenous opiate tone may operate in both conditions, we infused high-doses of naloxone into twelve patients with amenorrhoea of whom five had hyperprolactinaemia and seven had weight-loss related amenorrhoea. Eleven of the twelve patients had low levels of oestradiol (less than 50 pmol/l). Naloxone induced a marked rise in both LH and FSH levels in all of the five hyperprolactinaemic patients. In contrast, the patients with weight-loss amenorrhoea responded to naloxone with only a small or no rise in gonadotrophins. There was no consistent change in PRL in either group of patients. It is concluded that in hyperprolactinaemia, but not weight-loss amenorrhoea, there is an important endogenous opiate-mediated tonic inhibition of secretion of hypothalamic gonadotrophin releasing hormone.

Topics: Adolescent; Adult; Amenorrhea; Anorexia Nervosa; Estradiol; Female; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Naloxone; Prolactin

The functional activity of endogenous opioids and dopamine (DA) was assessed by analyzing gonadotropin and prolactin responses to DA receptor antagonist (metoclopramide) and the opioid receptor antagonist (naloxone) in selected patients with hypothalamic hypogonadotropic amenorrhea and in normal cycling women. 8 amenorrheic and 9 normal women during the low estrogen (early follicular) phase of menstrual cycle were studied. Simultaneous blood sampling and agent infusion was performed via 2 indwelling catheters after an overnight fast. Those receiving metoclopramide (10 mg intravenous bolus) and those receiving naloxone (1.6 mg/h for 4 hours) had blood samples withdrawn at various intervals. The 8 amenorrheic patients weighed significantly less (P .01) and had significantly lower mean basal serum luteinizing hormone (LH) (P .0001) and prolactin (P .01) than normal women. Metoclopramide administered to normal women induced no significant changes in pituitary gonadotropin levels. In contrast, 4 of 8 hypogonadotropic amenorrhea patients responded to metoclopramide with a significant mean net change of LH (P .05); a concomitant rise in follicle stimulating hormone (FSH) was also seen but was not statistically significant. The other 4 showed no response, as in normal women. Prolactin response to metoclopramide was reduced uniformly in all 8 patients, independent of LH responders or nonresponders. Naloxone in normal women showed no response. However, a clear increment of mean LH in response to naloxone was observed in the same 4 hypogonadotropic amenorrhea patients who also responded to metoclopramide. Mean LH nearly doubled; FSH levels showed no significant changes. Those other 4 patients who had no response to metoclopramide also had no response to naloxone. The 4 LH nonresponders with significantly (P .01) lower mean basal prolactin levels compared with normal women showed greater than l00% increase in prolactin levels by Hour 3 of naloxone infusion; in contrast, the LH responders showed no changes in prolactin levels in response to naloxone infusion.

Topics: Adult; Amenorrhea; Dopamine; Estrogens; Female; Follicle Stimulating Hormone; Humans; Hypogonadism; Hypothalamus; Kinetics; Luteinizing Hormone; Metoclopramide; Naloxone; Prolactin; Receptors, Opioid

Three amenorrheic runners of normal body weight, in whom organic disease had been excluded, were found to exhibit: (1) normal body composition, (2) low baseline concentrations of serum LH and normal concentrations of FSH, (3) normal to hyper-responsiveness of LH and FSH to GnRH testing, and (4) normal and possibly increased frequency of LH pulsations. In one of the 3 runners, the administration of naloxone was followed by a pronounced increase in the amplitude of the LH pulsations.

Topics: Adolescent; Adult; Amenorrhea; Body Composition; Endocrine System Diseases; Estradiol; Female; Follicle Stimulating Hormone; Humans; Hypothalamus; Luteinizing Hormone; Naloxone; Pituitary Hormone-Releasing Hormones; Running; Sports Medicine