Studies using releasing factors in Klinefelter's Syndrome: The responses of LH and FSH to luteinizing hormone-releasing hormone and of prolactin and TSH to thyrotropin-releasing hormone before and after testosterone

(1) During an investigation of their pituitary function, the TSH prolactin (PRL) and gonadotropin, (LH, FSH) response to TRH was measured in four patients with documented euthyroid Klinefelter's syndrome. (2) In all four patients, the serum testosterone was low, the gonadotropins were elevated and thyroid antibodies undetectable. (3) The identical study was repeated after each patient had received intramuscular testosterone cypionate 200 mg bi-weekly for three doses. This raised the serum testosterone at least four-fold. (4) Basal TSH was normal in all four patients but its response to TRH was blunted (mean peak TSH 9.6 μU/ml), compared with normal controls (mean peak TSH 18 μU/ml). Following testosterone this response to TRH was further suppressed to a mean peak of 3.4 μU/ml TSH. (5) Basal PRL levels were also normal and the mean peak response to TRH, 28 ng/ml. When repeated after testosterone, TRH produced a mean peak PRL of 58 ng/ml. (6) LH and FSH, both elevated basally, did not change with TRH administration, but both were stimulated by LHRH 100 μg i.v., LH briskly, FSH more variably. (7) FSH was suppressed sharply but LH only partially with testosterone therapy. (8) Our studies indicate that the TSH response to TRH in Klinefelter's syndrome is blunted and further suppressed with short term testosterone replacement. The PRL response to TRH under these same circumstances, however, is enhanced. Previous reports of abnormal LH feedback control are confirmed. (9) Klinefelter's syndrome is associated with subtle abnormalities in hypothalamic pituitary regulation not expected in typical primary hypogonadism.     

Gonadal steroid and gonadotropin response to dexamethasone: A study in sexual dysfunction and normal controls

Summary Numerous investigations have reported an alteration of hormonal response to dexamethasone in depressive disorder. No such data are available in psychogenic sexual dysfunction. Pre- and postdexamethasone levels of testosterone, estradiol, LH and FSH were studied in 20 male patients with sexual dysfunction and 20 male healthy controls. Dexamethasone had no influence on testosterone, estradiol, LH and FSH in normal controls. The patients showed an increase in testosterone and LH but not in FSH levels in the morning after dexamethasone administration. When compared with basal levels, the increase in postdexamethasone levels in sexual dysfunction was significant for testosterone (T) but not for LH (LH). The altered gonadal steroid and gonadotropin response to dexamethasone in sexual dysfunction might be due to disturbances of dexamethasone metabolism and glucocorticoid receptor density comparable to similar findings in depressive disorder.     

Hormonal changes in cerebral infarction in the young and elderly

Fifty-one patients with CCT verified cerebral infarction were submitted to serum and CSF radioimmunoassay of FSH, LH, estradiol (E2), progesterone, testosterone, cortisol and T4. The results were compared to those of 82 matched controls. Our findings suggest that (1) high serum E2 is a risk factor of stroke in males; (2) low serum T4 is a risk factor in males; (3) serum testosterone is reduced in acute stroke in males confirming that it is stress sensitive; (4) serum LH was higher in hypertensive thrombotic males when compared to normotensive ones, and (5) FSH, LH, E2 and T4 are undetectable in CSF of patients and controls.     

Effects of Carbamazepine on the Hypothalamic-Pituitary-Gonadal Axis in Male Patients with Epilepsy: A Prospective Study

The effects of carbamazepine (CBZ) monotherapy on serum sex hormone levels and on pituitary responsiveness to various stimuli were evaluated in a prospective study with 21 male patients with epilepsy. The serum levels of testosterone (T), free testosterone (FT), sex hormone binding globulin (SHBG), estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), and dehydroepiandrosterone sulfate (DHEAS) were assayed, and the free androgen index (FAI) values were calculated for each patient before and after 2-month CBZ treatment. The pituitary PRL, LH, and FSH responses to luteinizing hormone-releasing hormone (LH-RH), thyrotropin-releasing hormone (TRH), and metoclopramide (MC) were also measured before and after CBZ treatment. The baseline serum hormone and SHBG levels were measured and the FAI values calculated in 16 healthy male control subjects of similar age. The mean E2 level was higher in patients before CBZ treatment than in control subjects, and untreated patients had greater variances for FAI values, PRL levels, and LH levels than control subjects. No other significant differences were found between untreated patients and control subjects. The FAI values and DHEAS levels of patients decreased during 2-month treatment with CBZ. The PRL response to MC was higher after CBZ treatment than before. The baseline levels of other hormones and SHBG, as well as the LH and FSH responses to LH-RH, remained unaltered. The results indicate that during the first 2 months of CBZ treatment the androgen balance in male epileptic patients changes: Serum DHEAS levels and FAI values decrease, although FT levels remain unchanged. The clinical relevance of these hormonal changes is obscure.     

Hypothalamic-pituitary-gonadal axis in major depressive disorders

The baseline LH, FSH and testosterone levels and the LH and FSH response to TRH-LHRH administration (delta LH, delta FSH) were investigated in 28 patients meeting the RDC criteria for an acute major depressive disorder, and in 20 healthy persons. Twenty-two patients were also reinvestigated in a state of complete or partial clinical remission. Cross-sectional and longitudinal comparisons were made between the groups divided according to sex and menopausal status. After mathematical correction for age differences, the depressed males with an abnormal DST response showed significantly (P less than 0.03) higher delta FSH in the acute state compared to the controls. No relation could be established between the HPG axis hormone levels and the nocturnal serum melatonin levels or the PRL or TSH response to TRH-LHRH administration. In the longitudinal part of the study, the depressed males with an abnormal DST response showed decreased (P less than 0.03) testosterone levels and increased delta FSH (n.s.) in the acute state compared to remission, in contrast to the males with a normal DST. The present results do not support a hypothesis regarding a stimulus-induced down-regulation of the pituitary LHRH receptors in our patients. The possible mechanisms by which HPA axis activation (as revealed by an abnormal DST response) could influence the HPG axis in depressed patients remain to be elucidated.     

Testosterone implants into the lateral septum of male rats, a positive effect on LH and FSH secretion

After two days, testosterone implanted into the lateral septum increased serum levels of LH and FSH in male Wistar rats. As measured by RIA, LH in animals with testosterone implanted in them in comparison to those with an empty cannula was 0.220 +/- 0.015 vs. 0.111 +/- 0.019 ng/ml; p less than 0.001 and FSH was 3.20 + 0.21 vs. 1.50 + 0.21 ng/ml; p less than 0.001. Serum testosterone was not increased to a statistically significant extent by the implants (4.12 +/- 0.54 vs. 2.87 +/- 0.42 ng/ml; ns). It was concluded that testosterone or possibly one of its metabolites acting in the lateral septum facilitates the release of LH and FSH.     

Estrogen positive feedback on LH secretion in transsexuality

In order to test the hypothesis whether there is variation in hormonal levels or response to hormonal manipulation that could permit a distinction between heterosexuals and transsexuals, we designed the following protocol: Six male-to-female (m-to-f) transsexuals, six heterosexual control females and six female-to-male (f-to-m) transsexuals were given estradiol benzoate (E2B) (4.5 micrograms/kg/12 hr) for five days. In the female population, E2B treatment was initiated on day 5 of the menstrual cycle. In all the subjects blood luteinizing hormone (LH) and follicle stimulating hormone (FSH), estradiol-17 beta (E2) and testosterone (T) levels were measured twice daily. Additionally, LH and FSH responses to LHRH (100 micrograms iv) stimulation prior to and on day 5 of the E2B treatment were evaluated. In the m-to-f transsexuals, T levels decreased sharply and progressively during estrogen treatment, along with a fall in LH and FSH levels. The magnitude of the LH and FSH responses to LHRH stimulation also decreased following estrogen administration. In the heterosexual female controls and in the f-to-m transsexuals, estrogen administration increased LH levels to a minimum of 100% above initial values from day 3 onwards. Interestingly, the magnitude of the LH increase in the f-to-m transsexuals was greater than that of the heterosexual female controls. In both groups, LHRH stimulation resulted in a greater LH response compared to that prior to estrogen treatment. Our present observations, based on blood hormonal levels and responses to hormonal manipulations do not permit a distinction between heterosexual females and f-to-m transsexuals. There was no convincing evidence for the existence of a positive estrogen feedback on LH secretion in m-to-f transsexuals. These results contradict some of the reported hypotheses concerning hormonal alterations in these individuals.     

Effects of clomiphene citrate administraiton on the hypothalamo-pituitary-gonadal axis of male chronic schizophrenics.

The clomiphene citrate stimulation test was performed in 16 adult male chronic hebephrenic schizophrenics (10 off therapy from 3 months to 1 year and six on therapy with phenothiazines or haloperidol) and in five normal controls, matched for age. Clomiphene citrate was given orally at a daily dose of 150 mg, divided into three doses, for 8 days. FSH, LH and testosterone levels were assayed before the administration of clomiphene citrate and after 4 and 8 days of treatment. Schizophrenics showed normal increase of FSH levels during the clomiphene administration, while LH and testosterone responses were blunted. Phenothiazines or haloperiodol had no effect on the test.     

Effects of ECT on prolactin, LH, FSH and testosterone in males with major depressive illness

Fourteen males with major depressive illness (DSM-III) received a course of electroconvulsive therapy (ECT). Serum prolactin (PRL), luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone (T), were measured 15 minutes before and 15 minutes after each treatment. The severity of depression was assessed with the Hamilton Rating Scale for Depression (HRSD) two to three days before the first and two to three days following the last treatment. Post-ECT levels of PRL and LH were significantly higher than pre-ECT levels across every treatment. Changes in FSH and testosterone were not significant. There were no relationships between hormone levels (first versus last ECT) and severity of depression, including sexual functioning. It is argued that the relatively greater increases of LH than FSH is due to an acute antidopaminergic action of ECT which acts selectively on the secretion of the former. The blunted testosterone response to the increase of gonadotropins may be due to ECT-induced hyperprolactinemia.     

Sex hormones, sexual activity and plasma anticonvulsant levels in male epileptics.

Testosterone, LH, FSH, PRL, and sex hormone binding globulin (SHBG) were measured in 72 male epileptic patients on chronic anticonvulsant drug regimes. Sexual activity was estimated and plasma anticonvulsants measured. Total testosterone (TT), LH, FSH, PRL, and SHBG were increased; free testosterone (FT) was decreased. Sexual activity appeared diminished particularly in relation to reduced FT.     

Antidopaminergic-lnduced Hypothalamic LHRH Release and Pituitary Gonadotrophin Secretion in 12 Day-Old Female and Male Rats

In previous studies we have shown that the developing rat provides an interesting physiologic model in which the dopaminergic control of both LH and FSH is well defined in contrast to the controversial results obtained in adult rats. We wished to establish the role of testosterone in antidopaminergic induced gonadotrophins release in 12 day-old male and female rats, and evaluate the effect of antidopaminergic drugs at the hypothalamic level during this developmental stage. Haloperidol, an antidopaminergic drug, increased both LH and FSH in female 12 day-old rats but not in male littermates. The effect was blocked by bromocriptine and not by phentolamine indicating that haloperidol acted on the dopaminergic receptor, and that unspecific stimulation of the noradrenergic system was not involved. Haloperidol was ineffective when female rats were previously ovariectomized and injected with testosterone propionate at 9 days of age. If females were treated on the day of birth with testosterone propionate, haloperidol-induced FSH and LH release was also abolished. In control males haloperidol had no effect on the release of LH or FSH. But if males were orchidectomized at birth or at 9 days of age, haloperidol released both LH and FSH during the infantile period. In an attempt to establish the site of action of antidopaminergic drugs on gonadotrophin release, hypothalami (mediobasal and preoptic-suprachiasmatic area) from 12 day-old infant female rats were perfused with either haloperidol or domperidone (2±10^?6 M). Both drugs increased LHRH release into the perifusate. Besides haloperidol did not modify the release of LH or FSH from adenohypophyseal cells incubated in vitro. We therefore conclude that antidopaminergic-induced gonadotrophins release is modulated by serum testosterone concentrations, and that the site of action is probably the LHRH-secreting neuron of the hypothalamus.     

Luteinizing hormone sensitivity to naloxone in maturing male chimpanzees.

We have systematically investigated the involvement of endogenous opioids in gonadotropin secretion during primate sexual maturation by examining LH/FSH responses to gonadotropin-releasing hormone (GnRH) and changes in LH secretion during infusions of saline or naloxone, an opiate antagonist, in ten male chimpanzees between one and nine years of age. Animals were anesthetized with ketamine (10 mg/kg) and injected or infused IV with GnRH, naloxone or saline. Circulating levels of serum LH were elevated to the same extent (approximately 400%) in response to GnRH (100 micrograms) in animals 1-5 years old (juvenile) and in animals 6-9 years old (pubertal). No differences were noted between the two groups in GnRH-stimulated levels of serum FSH. During treatment with naloxone (0.14 mg/kg bolus followed by 0.2 mg/kg/h maintenance infusion for 3 h), serum LH levels in pubertal animals were significantly (p less than 0.05) elevated by as much as 95% over LH levels found during treatment with saline. Juvenile animals, on the other hand, failed to demonstrate significant increases in serum LH following naloxone at the doses tested. A strong correlation (r = .84) was found between circulating testosterone and serum LH levels during naloxone treatment. These data indicate that opioid inhibition of LH secretion can be reversed by naloxone only when puberty is reached in chimpanzees and suggest an alteration in opioid regulation of GnRH near the time of puberty. The strong correlation between testosterone levels and LH responses to naloxone suggests that steroids may participate in the maturation of opioid control of LH during puberty of nonhuman primates.     

The endocrine status in anorexia nervosa (author's transl)

Alterations in the secretion of iodothyronines, cortisol, testosterone and growth hormone have previously been described in anorexia nervosa. We have studied prolactin and gonadotropins secretion in 23 cases of anorexia nervosa. Prolactin secretion was normal. Modifications in gonadotropins release were observed. However they could not be always related to weight loss since amenorrhea could either precede weight loss or still be present after return of the weight to normal. In all cases, FSH release after LHRH stimulation was normal. No increase in LH levels was observed after LHRH injection when the weight was 70% below the ideal weight. With increasing weight, LH release progressively recovered and normal LHRH-induced LH release was obtained when the weight was above 90% of the ideal weight. At normal weight, the ratio of LH/FSH was normal in patients menstruating less than 3 months after the test, while the ratio was low in non-menstruating females. In conclusion, when the weight was insufficient basal levels of FSH and LH and responses after LHRH stimulation corresponded to a prepuberal stage. An increase in the LH/FSH ratio and a normal LH/FSH ratio preceeded the recovery of menstruations. In about 1/3 of the cases, such an evolution was not observed without any satisfactory explanation. Other factors than weight may be involved, especially when the amenorrhea persists after weight recovery.     

Predominant suppression of follicle-stimulating hormone β-immunoreactivity after long-term treatment of intact and castrate adult male rats with the gonadotrophin-releasing hormone agonist deslorelin

Gonadotrophin-releasing hormone (GnRH) agonists are used to treat gonadal steroid-dependent disorders in humans and to contracept animals. These agonists are considered to work by desensitising gonadotrophs to GnRH, thereby suppressing follicle-stimulating hormone (FSH) and luteinising hormone (LH) secretion. It is not known whether changes occur in the cellular composition of the pituitary gland after chronic GnRH agonist exposure. Adult male Sprague-Dawley rats were treated with a sham, deslorelin, or deslorelin plus testosterone implant for 41.0 ± 0.6 days. In a second experiment, rats were castrated and treated with deslorelin and/or testosterone. Pituitary sections were labelled immunocytochemically for FSHβ and LHβ, or gonadotrophin α subunit (αGSU). Deslorelin suppressed testis weight by two-thirds and reduced plasma FSH and LH in intact rats. Deslorelin decreased the percentage of gonadotrophs, although the effect was specific to the FSHβ-immunoreactive (-ir) cells. Testosterone did not reverse the deslorelin-induced reduction in the overall gonadotroph population. However, in the presence of testosterone, the proportion of gonadotrophs that was FSHβ-ir increased in the remaining gonadotrophs. There was no effect of treatment on the total LHβ-ir cell population, although the loss of FSHβ in bi-hormonal cells increased the proportion of mono-hormonal LHβ-ir gonadotrophs. The castration-induced plasma LH and FSH increases were suppressed by deslorelin, testosterone or both. Castration increased both LH-ir and FSH-ir without increasing the overall gonadotroph population, thus increasing the proportion of bi-hormonal cells. Deslorelin suppressed these increases. Testosterone increased FSH-ir in deslorelin-treated castrate rats. Deslorelin did not affect αGSU immunoreactivity, suggesting that the gonadotroph population per se is not eliminated by deslorelin, although the ability of gonadotrophs to synthesise FSHβ is compromised. We hypothesise that the FSH dominant suppression may be central to the long-term contraceptive efficacy of deslorelin in the male.     

Correlation between testosterone, gonadotropins and prolactin and severity of negative symptoms in male patients with chronic schizophrenia

The aim of this study was to evaluate the relationship between plasma levels of testosterone, FSH, LH and prolactin and the severity of negative symptoms in patients with chronic schizophrenia. Fifty-four male inpatients with chronic schizophrenia participated in this cross-sectional study. Twenty-five age-matched men without a history of psychiatric disorders or endocrine illnesses were used as controls. All patients were on risperidone 4 mg/day or haloperidol 10 mg/day and anticholinegic medication, biperidine 3 mg/day. The patients were assigned to groups with predominant negative and nonpredominant negative symptoms on the basis of their scores on the Positive and Negative Syndrome Scale (PANSS). Plasma levels of testosterone and free testosterone in the patients with predominant and nonpredominant negative symptoms were significantly lower than those in normal controls. Furthermore, plasma levels of FSH and LH, in the patients with predominant negative symptoms but not in the nonpredominant negative symptoms, were significantly lower than those in the normal controls. In contrast, plasma level of prolactin in the predominant negative symptoms group but not in the nonpredominant negative symptoms group was significantly higher than the aged matched normal males. Significant inverse correlation between negative subscale scores of PANSS and plasma levels of testosterone and free testosterone in the patients with predominant negative symptoms were detected. There was also a positive correlation between prolactin plasma levels and negative subscale scores. The present study indicates that assessment of sex hormones and function of hypothalamic-pituitary-gonadotropin axis could be an important biological marker for the severity of negative symptoms in schizophrenia and these findings may change the present pharmacotherapy for negative symptoms based on neuroendocrinology profiles of patients with schizophrenia.     

Plasma testosterone in male patients with Huntington's disease: relations to severity of illness and dementia

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms and by a progressive loss among other, of dopaminergic receptors in striatum, cortex, and hypothalamus. Central dopaminergic activity has been implicated in the regulation of sex hormones. Several features of testosterone deficiency, such as reduced muscle mass, depressive mood, and cognitive impairment, are often present in HD patients, but data on their testosterone levels are lacking. We assessed plasma levels of testosterone, LH, and FSH in 42 male patients with HD, confirmed by molecular genetic analysis, and searched for differences from age-matched healthy male subjects and for relations to CAG repeat number, age, age range, 26 to 76 (mean, 50.7 +/- 12.3) years; duration of illness range, 1 to 23 (mean, 6.7 +/- 6.3) years; and CAG repeat numbers from 40 to 65 (45.1 +/- 3.8). Disease symptomatology was assessed using the Unified Huntington's Disease Rating Scale. Testosterone and LH levels of the patients were significantly lower compared to the levels of 44 age-matched (mean age, 48.9 +/- 13.0, range, 26-76 years) healthy men. Severity of illness was negatively related to plasma testosterone levels. Further, low testosterone levels were associated with dementia but not with depression or psychotic features. Clinical studies with selected HD patients are needed to evaluate possible beneficial effects of androgen substitution therapy on cognitive functions, depression, muscle mass and strength, general well-being, and, eventually, neuroprotective effects.     

Neuroendocrine aspects of primary endogenous depression VIII. Pituitary-gonadal axis activity in male patients and matched control subjects

To determine the extent of hypothalamo-pituitary-gonadal (HPG) axis dysfunction in endogenous depressed men, we measured nocturnal and diurnal serum luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), and estradiol (E2) concentrations, and their responses to gonadotropin releasing hormone (LHRH) and dexamethasone administration, in 16 Research Diagnostic Criteria primary, definite endogenous male depressives and 16 individually matched male normal controls. Compared to their controls, the patients showed no differences in basal nocturnal or diurnal gonadotropin or gonadal steroid hormone concentrations, and no differences in hormone concentrations either post-LHRH or post-dexamethasone. Age was negatively correlated with baseline serum T in the patients but not in the controls, and it was modestly positively correlated with baseline serum LH in both groups of subjects. In the patients, the presence of DSM-III melancholia was modestly negatively correlated with baseline and post-LHRH concentrations of both LH and FSH and was positively correlated with baseline serum T, but it bore no relation to serum E2. None of the other subject characteristics or specific dimensions of depressive symptomatology were significantly related to the HPG axis measures. The HPG axis measures also were unrelated to pre- and post-dexamethasone cortisol concentrations in both groups of subjects. The results of this study suggest that, in contrast to the hypothalamo-pituitary-adrenal cortical and thyroid axis abnormalities frequently found in endogenous depressives, HPG axis function in male depressives is relatively normal.     

Effects of Carbamazepine on Pituitary Responsiveness to Luteinizing Hormone-Releasing Hormone, Thyrotropin-Releasing Hormone, and Metoclopramide in Epileptic Patients

Pituitary responsiveness to luteinizing hormone-releasing hormone (LH-RH), thyrotropin-releasing hormone (TRH), and metoclopramide (MC) was studied in 40 epileptic patients (24 men and 16 women) receiving carbamazepine (CBZ) treatment and in 29 (20 men and 9 women) untreated epileptic patients. Mean basal concentration of serum LH was significantly lower in the CBZ-treated female patients than in untreated female patients. The response of LH to LH-RH was also blunted in CBZ-treated female patients. No differences were found in basal or stimulated LH levels between the two groups of male patients. Nevertheless, the mean basal concentration of serum prolactin (PRL) was lower and the response of PRL to TRH was higher in male patients treated with CBZ. No differences were found in serum levels of follicle-stimulating hormone (FSH) or in responses of FSH to LH-RH between the CBZ-treated and untreated patients. These results indicate that CBZ has effects on pituitary responsiveness.     

Effect of naloxone on gonadotropin secretion before and after testosterone in Klinefelter's syndrome

A study was performed on eight subjects with Klinefelter's syndrome to assess the relation between gonadal hormones and opioid inhibition of gonadotropin secretion through comparison of their gonadotropin response to naloxone (NAL) (0.3 mg/kg; 1/3 bolus iv. at time 0 and 2/3 iv. for 120 min) before and after testosterone propionate (TP) 100 mg/day im. for 5 days. Under basal conditions, NAL failed to induce a significant change in LH levels. After TP, however, despite unchanged basal LH levels (mean +/- S.E.M.: 27.0 +/- 3.4 vs 21.2 +/- 3.21 microU/ml), LH significantly increased in response to NAL. FSH did not respond to NAL either before or after TP administration, though FSH levels were significantly reduced by TP. These findings suggest that in man, as in animals, gonadal hormones regulate opioid inhibition of LH secretion. The negative feedback of testosterone and its ability to activate opioid inhibiting tone may be dissociated, in keeping with the view that gonadal hormones control gonadotropin secretion through the activation of distinct, albeit concomitant, mechanisms.     

男性癫痫患者服用抗痫药物后血清性激素水平改变及其临床意义

目的 研究抗痫药物对男性癫痫患者性激素水平的影响。方法 应用放射免疫分析法和免疫放射测定分析法测定应用多种ＡＥＤｓ治疗和未经治疗的男性癫痫患者及健康对照组血清睾酮,游离睾酮,性激素结合球蛋白,雌二醇,间质细胞刺激素,滤泡刺激素的水平。结果未治疗组与正常对照组相比,各项指标均无显著差异。各治疗组与对照组相比,ＦＴ水平均显著降低,ＳＨＢＧ水平显著升高;苯妥英钠治疗组的Ｅ２水平升高;而ＴＴ,ＬＨ,ＦＳ