leuprolide and Hypogonadism

Chronic sex steroid deficiency has effects on adipose fatty acid (FA) storage mechanisms and fat oxidation, but the chronology of events are not well understood.. The objective of the study was to examine the acute effects of female sex steroid suppression on cellular mechanisms affecting abdominal and femoral subcutaneous adipose tissue FA storage.. This study had a randomized, longitudinal, parallel study design.. The study was conducted at the Mayo Clinic Clinical Research Unit.. Thirty-eight nonsmoking premenopausal women aged 18-50 years participated in the study.. The intervention included randomization to receive one of the following: 1) no treatment (control), 2) 3.75 mg of Lupron, or 3) 3.75 mg of Lupron and estrogen, but not progesterone, replacement for 49 days, resulting in at least 4 weeks of sex steroid suppression.. Body composition, fat cell size, postprandial chylomicron and nonchylomicron triglyceride concentrations, adipose tissue meal FA storage, direct free fatty acid storage, lipoprotein lipase, acyl CoA synthetase, and diacylglycerol acyltransferase activities, and CD36 content were measured.. Compared with the control group, the fed state femoral lipoprotein lipase activity was reduced in women taking Lupron and those taking Lupron and estrogen replacement. In addition, we observed significantly greater postprandial chylomicronemia in the Lupron group than in the other two groups. There were no differences in overall fat storage and oxidation. Depending on the mode of data expression (per unit lipid vs per 1000 adipocytes), there were modest changes in acyl CoA synthetase, diacylglycerol acyltransferase, and CD36 in response to acute sex hormone suppression.. Our results suggest estrogen and progesterone may have different effects on the regulation of FA metabolism and that acute sex steroid deficiency in women does not alter fat storage and oxidation.

Topics: Adipose Tissue; Adolescent; Adult; Body Composition; CD36 Antigens; Chylomicrons; Coenzyme A Ligases; Diacylglycerol O-Acyltransferase; Estrogens; Fatty Acids, Nonesterified; Female; Fertility Agents, Female; Humans; Hypogonadism; Leuprolide; Lipoprotein Lipase; Longitudinal Studies; Middle Aged; Postprandial Period; Young Adult

How sex steroids modulate glucocorticoid feedback on the hypothalamic-pituitary-corticotrope (HPC) unit is controversial in humans. We postulated that testosterone (T) in men and estradiol (E2) in women govern unstressed cortisol-mediated negative feedback on ACTH secretion. To test this hypothesis, 24 men and 24 women age 58 ± 2.4 yr were pretreated with leuprolide and either sex steroid (E2 in women, T in men) or placebo addback. Placebo or ketoconazole (KTCZ) was administered overnight to inhibit adrenal steroidogenesis during overnight 14-h intravenous infusions of saline or cortisol in a continuous versus pulsatile manner to test for feedback differences. ACTH was measured every 10 min during the last 8 h of the infusions. The main outcome measures were mean ACTH concentrations, pulsatile ACTH secretion, and ACTH approximate entropy (ApEn). ACTH concentrations were lower in women than men (P < 0.01), and in women in the E2+ compared with E2- group under both continuous (P = 0.01) and pulsatile (P = 0.006) cortisol feedback, despite higher cortisol binding globulin and lower free cortisol levels in women than men (P < 0.01). In the combined groups, under both modes of cortisol addback, ACTH concentrations, pulsatile ACTH secretion, and ACTH secretory-burst mass correlated negatively and univariately with E2 levels (each P < 0.005). E2 also suppressed ACTH ApEn (process randomness) during continuous cortisol feedback (P = 0.004). T had no univariate effect but was a positive correlate of ACTH when assessed jointly with E2 (negative) under cortisol pulses. In conclusion, sex steroids modulate selective gender-related hypothalamic-pituitary adrenal-axis adaptations to cortisol feedback in unstressed humans.

Topics: Adrenocorticotropic Hormone; Age Factors; Aging; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Enzyme Inhibitors; Estradiol; Feedback, Physiological; Female; Humans; Hydrocortisone; Hypogonadism; Hypothalamo-Hypophyseal System; Infusions, Intravenous; Ketoconazole; Leuprolide; Male; Middle Aged; Pituitary-Adrenal System; Prospective Studies; Protein Binding; Serum Albumin; Serum Albumin, Human; Sex Factors; Testosterone; Time Factors; Transcortin

Low testosterone (T) levels in men have been shown to predict development of the metabolic syndrome, but the effects of T on lipid metabolism are incompletely understood. In a randomized, double-blind, placebo-controlled, crossover study, 12 healthy, young males received gonadotropin-releasing hormone agonist treatment 1 month prior to 3 of 4 trial days to induce castrate levels of T. On trial days, T gel was applied to the body containing either high or low physiological T dose or placebo. On the 4th trial day, participants constituted their own eugonadal controls. Each study comprised a 5-h basal period and a 3-h hyperinsulinemic-euglycemic clamp. Short-term hypogonadism did not affect VLDL triglyceride (TG) secretion, nor did it affect VLDL-TG concentrations. It was, however, characterized by lower total lipid oxidation. In addition, acute rescue with high physiological T increased VLDL-TG secretion during both basal and clamp conditions. These data show that T can act through fast nongenomic pathways in the liver. In addition, the early hypogonadal state is characterized by decreased total lipid oxidation, but whether these changes represent early hypogonadal metabolic dysfunction warrants further investigations. T is not a major determinant of resting VLDL-TG kinetics in men.

Topics: Administration, Cutaneous; Adult; Androgens; Carbon Radioisotopes; Cross-Over Studies; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Gonadotropin-Releasing Hormone; Hormone Replacement Therapy; Humans; Hypogonadism; Kinetics; Leuprolide; Lipolysis; Lipoproteins, VLDL; Liver; Male; Testosterone; Triglycerides; Triolein; Young Adult

During conditions of ovarian suppression, women with premenstrual dysphoria (PMD) experience abnormal behavioral responses to physiological levels of ovarian steroids. Although hypothalamic-pituitary-adrenal (HPA) axis dysregulation frequently accompanies depression, and ovarian steroids regulate HPA axis responsivity, the role of HPA axis dysregulation in PMD is not known. We hypothesized that women with PMD would show abnormalities of HPA axis function analogous to those reported in depressive illness, and that ovarian steroids would differentially regulate HPA axis function in women with PMD compared with asymptomatic controls (AC).. Our objective was to characterize the HPA axis response to physiological levels of estradiol and progesterone in women with PMD and AC.. We conducted an open-label trial of the GnRH agonist depot Lupron with ovarian steroid replacement administered in a double-blind crossover design in an outpatient clinic.. Forty-three women (18 with prospectively confirmed PMD and 25 AC) participated.. Women received Lupron for 6 months. After 3 months of hypogonadism, women received 5 wk each of estradiol (100-μg patch daily) or progesterone (suppositories 200 mg twice daily). During each condition, combined dexamethasone-suppression/CRH-stimulation tests and 24-h urinary free cortisol levels were performed.. Plasma cortisol and ACTH levels were evaluated.. HPA axis function was similar in PMD compared with AC. In all, progesterone significantly increased the secretion of cortisol compared with estradiol [area under the curve (t(74) = 3.1; P < 0.01)] and urinary free cortisol (t(74) = 3.2; P < 0.01) and ACTH compared with hypogonadism [area under the curve (t(74) = 2.4; P < 0.05)].. HPA axis regulation is normal in PMD, suggesting that the pathophysiology of PMD differs from major depression. As observed previously, progesterone but not estradiol up-regulates HPA axis function in women.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Corticotropin-Releasing Hormone; Cross-Over Studies; Dexamethasone; Drug Therapy, Combination; Estradiol; Female; Fertility Agents, Female; Glucocorticoids; Gonadotropin-Releasing Hormone; Humans; Hydrocortisone; Hypogonadism; Hypothalamo-Hypophyseal System; Leuprolide; Middle Aged; Pituitary-Adrenal System; Premenstrual Syndrome; Progesterone; Young Adult

To determine if intermittent, low-dose, short-acting gonadotropin-releasing hormone agonist (GnRH-agonist) administration sufficiently up-regulates pituitary-gonadal function in gonadotropin deficiency to be of diagnostic or therapeutic value.. Case-control study.. General clinical research center.. Normal adult volunteers and gonadotropin-deficiency patients.. Low-dose leuprolide acetate administered subcutaneously at 4- to 5-day intervals up to 1 year.. Levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex steroid responses.. In normal men and women, low-dose GnRH-agonist repetitively transiently stimulated gonadotropins in a gender-dimorphic manner. In congenitally gonadotropin-deficient men (n = 6) and women (n = 1), none of whom had a normal LH response to an initial GnRH-agonist test dose, this regimen consistently stimulated LH to the normal baseline range within 2 weeks. Long-term GnRH-agonist administration to a partially gonadotropin-deficient man did not alleviate hypogonadism, however. Women with hypothalamic amenorrhea (n = 2) responded normally to a single GnRH-agonist injection; however, repeated dosing did not seem to induce the normal priming effect.. The subnormal LH response to GnRH-agonist in patients with congenital gonadotropin deficiency normalized in response to repetitive intermittent GnRH-agonist administration but not sufficiently to improve hypogonadism. Hypothalamic amenorrhea patients lacked the priming response to repeated GnRH-agonist but otherwise had normal hormonal responses to GnRH-agonist. We conclude that intermittent administration of a short-acting GnRH-agonist is of potential diagnostic value in distinguishing hypothalamic from pituitary causes of gonadotropin deficiency.

Topics: Adolescent; Adult; Dosage Forms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Hypogonadism; Leuprolide; Male; Periodicity; Predictive Value of Tests; Prognosis; Young Adult

Somatostatin (SS), GHRH, GH-releasing peptide (GHRP), and the sex-steroid milieu regulate GH secretion.. To test whether GHRH and GHRP remain effective secretagogs in the face of short-term hypogonadism.. Prospective, randomized double-blind.. Healthy young men (n=24) received a GnRH agonist twice 3 weeks apart followed by placebo (n=13, Pl) or testosterone (n=11, testosterone) addback.. were then given consecutive i.v. infusions of l-arginine (to restrain SS outflow) and a maximally effective dose of GHRH or GHRP-2 (to test corresponding secretagog pathways).. GH secretion stimulated by l-arginine/GHRH and by l-arginine/GHRP-2 was unaffected by combined testosterone/estradiol (E(2)) depletion. The low testosterone/E(2) milieu decreased basal (nonpulsatile) GH secretion (P=0.038), without altering fasting pulsatile GH secretion or IGF1 or IGF-binding protein (IGFBP)-3 concentrations. IGFBP-1 (P<0.0001) and abdominal visceral fat (AVF, P=0.017) correlated negatively with fasting basal GH secretion. By contrast, IGF1 (P=0.0012) and IGFBP-3 (P=0.015) correlated positively with fasting pulsatile GH secretion. AVF (P=0.0024) was a negative determinant, and IGF1 a positive determinant (P=0.018), of GHRH-driven GH pulses. Responses to GHRP-2 were unrelated to any of these factors.. l-arginine/GHRP-2 appears to be an especially robust stimulus of GH secretion, since efficacy is unmodified by profound short-term hypogonadism, a range of AVF estimates, and a spectrum of IGF1, IGFBP-1, and IGFBP-3 concentrations. Whether robustness also applies to chronic hypogonadism is not known.

Topics: Adult; Arginine; Cohort Studies; Double-Blind Method; Estradiol; Follicle Stimulating Hormone; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; Hypogonadism; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Leuprolide; Luteinizing Hormone; Male; Oligopeptides; Prospective Studies; Serum Albumin; Sex Hormone-Binding Globulin; Testosterone; Young Adult

Studies fail to find uniform effects of age-related or induced hypogonadism on human sexual function. We examined the effects of induced hypogonadism on sexual function in healthy men and women and attempted to identify predictors of the sexual response to induced hypogonadism or hormone addback. The study design used was a double-blind, controlled, crossover (self-as-own control). The study setting was an ambulatory care clinic in a research hospital, and the participants were 20 men (average+/-SD age=28.5+/-6.2 years) and 20 women (average+/-SD age=33.5+/-8.7 years), all healthy and with no history of psychiatric illness. A multidimensional scale assessing several domains of sexual function was the main outcome measure. Participants of the study received depot leuprolide acetate (Lupron) every 4 weeks for 3 months (men) or 5 months (women). After the first month of Lupron alone, men received (in addition to Lupron) testosterone enanthate (200 mg intramuscularly) or placebo every 2 weeks for 1 month each. Women received Lupron alone for 2 months, and then, in addition to Lupron, they received estradiol and progesterone for 5 weeks each. The results of the study: in women, hypogonadism resulted in a significant decrease in global measures of sexual functioning, principally reflecting a significant decrease in the reported quality of orgasm. In men, hypogonadism resulted in significant reductions in all measured domains of sexual function. Testosterone restored sexual functioning scores in men to those seen at baseline, whereas neither estradiol nor progesterone significantly improved the reduced sexual functioning associated with hypogonadism in women. Induced hypogonadism decreased sexual function in a similar number of men and women. No predictors of response were identified except for levels of sexual function at baseline. In conclusion, our data do not support a simple deficiency model for the role of gonadal steroids in human sexual function; moreover, while variable, the role of testosterone in sexual function in men is more apparent than that of estradiol or progesterone in women.

Topics: Adult; Affect; Dihydrotestosterone; Estradiol; Female; Humans; Hypogonadism; Leuprolide; Male; Middle Aged; Orgasm; Progesterone; Sex Characteristics; Sexual Behavior; Sexual Dysfunction, Physiological; Testosterone

The results of several recent studies suggest that estrogen and testosterone play an important role in the modulation of mood and cognitive function in women, and preliminary evidence indicates that these hormones may also modulate the levels of beta-amyloid (Abeta), a 4 Kilo Dalton peptide that is likely to be involved in the pathogenesis of Alzheimer's disease. However, the physiological and clinical effects of reversible castration remain unclear and no systematic data is currently available for men. We designed the present study to investigate the effects of reversible chemical castration on the mood and cognitive performance of men treated for prostate cancer, as well as its impact on the levels of plasma Abeta. Forty men with prostate cancer were clinically treated with androgen blockade therapy (flutamide and leuprolide) for 36 weeks and subsequently followed up for another 18 weeks after treatment was discontinued. All subjects received a comprehensive clinical, neuropsychological and biochemical evaluation that included the use of the Beck Depression (BDI) and Anxiety Inventories (BAI), several subtests of the Wechsler Memory and Intelligence Scales (Word Lists-WL, Verbal Paired Associates-VPA, Visual Reproduction-VR and Block Design-BD), and biochemical monitoring of changes in estrogen, testosterone and Abeta levels. Chemical castration was associated with a rapid and marked decline in the levels of testosterone and estradiol, and significant increase in plasma Abeta levels. Treatment was associated with increased BDI (p = 0.004) and BAI scores (p < 0.001), although such changes were of questionable clinical significance (i.e., few subjects had scores > or = 13). CAMCOG (p = 0.046) and WL recall total scores (p < 0.001) improved significantly after androgen blockade treatment was discontinued, but visuospatial abilities, as assessed by BD, was not influenced by the introduction or discontinuation of treatment. There was a significant negative correlation between changes in Abeta levels and subjects' WL total score change between weeks 36 and 54 (r = -0.452, p = 0.012). The results of this naturalistic study indicate that chemical castration is associated with a significant rise in the plasma levels of Abeta and, clinically, with increased depression and anxiety scores. The discontinuation of treatment is associated with better cognitive performance, most noticeably of verbal memory. The performance of subjects on the WL test was negatively corr

Topics: Adult; Affect; Aged; Aged, 80 and over; Amyloid beta-Peptides; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Anxiety Disorders; Cognition; Depressive Disorder; Estradiol; Flutamide; Follow-Up Studies; Humans; Hypogonadism; Leuprolide; Male; Memory; Middle Aged; Multivariate Analysis; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

The effects of declining androgen secretion on mood regulation and the potential psychotropic efficacy of androgen replacement in men are largely undetermined.. To examine the effects on mood of the acute suppression of testosterone secretion.. A double-blind, placebo-controlled, crossover (self-as-own-control) study.. An ambulatory care clinic in a research hospital.. Thirty-one healthy adult men with no history of psychiatric illness or substance or anabolic steroid abuse.. Men received depot leuprolide acetate (Lupron, 7.5 mg intramuscularly) every 4 weeks for 3 months. After the first month of Lupron alone, all men received (in addition to Lupron) testosterone enanthate (200 mg intramuscular) or placebo (sesame oil as color-matched vehicle) every 2 weeks for 1 month each in a crossover design. The order of administration of testosterone and placebo was randomly assigned and counterbalanced.. Mood and behavior rating scores (self-report and rater administered).. With the exceptions of hot flushes, libido, and the feeling of being emotionally charged, none of the symptoms measured showed a significant difference across eugonadal, Lupron plus placebo, and Lupron plus testosterone conditions. Despite the absence of a uniform effect of Lupron plus placebo on mood, 3 men experienced clinically relevant mood symptoms during this induced hypogonadal condition. High baseline levels of sexual functioning predicted the greatest decline in sexual function during Lupron plus placebo.. These data, the first to describe the effects on mood of induced hypogonadism in healthy young men, suggest that short-term hypogonadism is sufficient to precipitate depressive symptoms in only a small minority of younger men. The predictors of this susceptibility remain to be determined.

Topics: Adult; Affect; Case-Control Studies; Cross-Over Studies; Delayed-Action Preparations; Double-Blind Method; Health Status; Hormone Replacement Therapy; Humans; Hypogonadism; Leuprolide; Libido; Male; Middle Aged; Placebos; Sexual Behavior; Sexual Dysfunctions, Psychological; Testosterone

Studies of the effects of gender and gonadal steroids on serotonergic activity in humans are few in number and often contradictory. We examined the neuroendocrine and core temperature response to a serotonergic stimulus, m-chlorophenylpiperazine (m-CPP) (0.08 mg/kg body weight, IV), in asymptomatic female and male volunteers during induced hypogonadism (leuprolide acetate) and hormone replacement (estradiol (E2) or progesterone (P4) in women; testosterone (T) in men). Compared with the hypogonadal state, basal prolactin (PRL) secretion was significantly higher during both P4 and E2 replacement (p <.05) in women and during T replacement in men (p <.05). m-CPP stimulated PRL secretion was significantly greater only during P4 (p <.05) but not E2 (women) or T (men) replacement, compared with hypogonadism. Basal but not stimulated plasma growth hormone (GH) levels were significantly higher during P4 in women and T in men (p <.05), and no significant differences in basal or m-CPP stimulated plasma levels of ACTH or cortisol were observed. Finally, basal core temperatures were significantly higher during P4 replacement compared with either E2 replacement or the hypogonadal condition (p <.01) in women, with no differences observed in men. Comparisons of measures by gender (and matched for baseline plasma T levels) revealed that during the hypogonadal state m-CPP-stimulated GH secretion was significantly greater (p <.01) and m-CPP-stimulated ACTH (p <.05) and cortisol (p <.01) significantly less in women compared with men. Although our data are limited to those components of the central serotonergic system influenced by m-CPP administration, our findings suggest the following: the regulatory effects of gonadal steroids on serotonergic function are modest in humans during leuprolide-induced hypogonadism; menstrual cycle phase effects of serotonergic agents on PRL secretion may reflect both the effects of P4 and E2; the effects of P4 in humans may occur without E2 priming of the progesterone receptor; and gender differences in GH secretion occur independent of the presence of gonadal steroids.

Topics: Adult; Analysis of Variance; Area Under Curve; Body Temperature; Double-Blind Method; Estradiol; Female; Gonadal Steroid Hormones; Humans; Hypogonadism; Hypothalamo-Hypophyseal System; Leuprolide; Male; Piperazines; Pituitary-Adrenal System; Progesterone; Sex Characteristics

Hypogonadism is associated with osteoporosis in men. GnRH- agonist-induced hypogonadism increases bone turnover and bone loss in men, but the mechanism underlying these changes is unknown. To determine whether gonadal steroid deprivation increases the skeletal sensitivity to PTH or blunts the ability of PTH to promote 1,25-dihydroxyvitamin D formation, we infused human PTH-(1-34) at a dose of 0.55 U/kg.h for 24 h, in 11 men (ages, 50-82 yr) with locally advanced, node-positive, or biochemically recurrent prostate cancer but no evidence of bone metastases. PTH infusions were performed before initiation of GnRH agonist therapy (leuprolide acetate, 22.5 mg im, every 3 months) and again after 6 months of confirmed GnRH agonist-induced hypogonadism. Serum osteocalcin (OC), bone- specific alkaline phosphatase (BSAP), N-telopeptide (NTX), whole-blood ionized calcium, and 1,25-dihydroxyvitamin D were measured at baseline and every 6 h during each PTH infusion. Urinary NTX and free deoxypyridinoline (DPD) were assessed on spot morning samples before PTH infusion and on 24-h samples collected during the PTH infusions. Sex steroid levels were lowered to the castrate range in all subjects. Baseline serum NTX levels (drawn before PTH infusion) increased from 9.1 +/- 3.7 before leuprolide therapy to 13.9 +/- 5.0 nmol bone collagen equivalents (BCE)/L after leuprolide therapy (P = 0.003). Spot urine NTX collected before PTH infusion increased from 28 +/- 8 before leuprolide therapy to 49 +/- 17 nmol BCE/mmol creatinine after leuprolide therapy (P < 0.001), and urinary DPD increased from 4.7 +/- 1.1 to 7.4 +/- 1.8 nmol BCE/mmol creatinine (P < 0.001). Baseline serum OC and BSAP levels drawn before each PTH infusion did not change before vs. after leuprolide therapy. Serum NTX levels increased significantly during PTH infusion pre-GnRH agonist therapy (P < 0.001), and the rate of increase was greater after 6 months of GnRH agonist-induced hypogonadism (P < 0.01 for the difference in rates of change before and after GnRH agonist administration). Serum OC and BSAP levels decreased during PTH infusion (P < 0.001 for OC and P = 0.002 for BSAP), but the rates of decrease did not differ before or after leuprolide therapy (P = 0.45 for OC and P: = 0.19 for BSAP). Whole-blood ionized calcium levels increased during PTH infusion (P < 0.001), and the rate of increase was greater after GnRH agonist-induced hypogonadism (P = 0.068). Serum 1,25-dihydroxyvitamin D levels increased in r

Topics: Aged; Aged, 80 and over; Alkaline Phosphatase; Amino Acids; Antineoplastic Agents, Hormonal; Biomarkers; Bone and Bones; Calcitriol; Calcium; Collagen; Collagen Type I; Diphosphonates; Humans; Hypogonadism; Leuprolide; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Osteocalcin; Pamidronate; Peptides; Prostatic Neoplasms; Teriparatide; Time Factors

Endocrine factors are purported to play a role in the etiology of postpartum depression, but direct evidence for this role is lacking. The authors investigated the possible role of changes in gonadal steroid levels in postpartum depression by simulating two hormonal conditions related to pregnancy and parturition in euthymic women with and without a history of postpartum depression.. The supraphysiologic gonadal steroid levels of pregnancy and withdrawal from these high levels to a hypogonadal state were simulated by inducing hypogonadism in euthymic women-eight with and eight without a history of postpartum depression-with the gonadotropin-releasing hormone agonist leuprolide acetate, adding back supraphysiologic doses of estradiol and progesterone for 8 weeks, and then withdrawing both steroids under double-blind conditions. Outcome measures were daily symptom self-ratings and standardized subjective and objective cross-sectional mood rating scales.. Five of the eight women with a history of postpartum depression (62.5%) and none of the eight women in the comparison group developed significant mood symptoms during the withdrawal period. Analysis of variance with repeated measures of daily and cross-sectional ratings of mood showed significant phase-by-group effects. These effects reflected significant increases in depressive symptoms in women with a history of postpartum depression but not in the comparison group after hormone withdrawal (and during the end of the hormone replacement phase), compared with baseline.. The data provide direct evidence in support of the involvement of the reproductive hormones estrogen and progesterone in the development of postpartum depression in a subgroup of women. Further, they suggest that women with a history of postpartum depression are differentially sensitive to mood-destabilizing effects of gonadal steroids.

Topics: Adult; Affect; Cross-Sectional Studies; Depression, Postpartum; Estradiol; Female; Humans; Hypogonadism; Leuprolide; Middle Aged; Mood Disorders; Personality Inventory; Placebos; Progesterone; Psychiatric Status Rating Scales; Substance Withdrawal Syndrome

In a double-blind, placebo controlled study, ipriflavone (600 mg/day, T.D.D.) or identical placebo tablets were given with 500 mg/day of calcium to patients treated with the gonadotropin hormone-releasing hormone agonist (Gn-RH-A) leuproreline acetate, 3.75 mg every 30 days for 6 months. In placebo-treated subjects (n = 39), urinary hydroxyproline excretion and plasma osteocalcin levels showed a significant (P < 0.01 and P < 0.05, respectively) increase, whereas spine bone density and total body bone density significantly (P < 0.001 and P < 0.05, respectively) decreased after 3 and 6 months of GnRH-A administration. Conversely, in the ipriflavone-treated group (n = 39), no significant difference in bone markers and bone density was evidenced. These data indicate that ipriflavone can restrain the bone remodeling processes and prevent the rapid bone loss that follows medically induced hypogonadism.

Topics: Absorptiometry, Photon; Analysis of Variance; Antineoplastic Agents, Hormonal; Bone Density; Bone Remodeling; Female; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; Isoflavones; Leiomyoma; Leuprolide; Lumbar Vertebrae; Menopause; Metrorrhagia; Osteoporosis, Postmenopausal; Treatment Outcome; Uterine Neoplasms; Uterus

Despite well-established sex differences in the performance on tests of several cognitive domains (e.g., visuospatial ability), few studies in humans have evaluated if these sex differences are evident both in the presence of circulating sex hormones and during sex steroid hormonal suppression. Sex differences identified in the relative absence of circulating levels of estradiol and testosterone suggest that differences in brain structure or function exist independent of current hormonal environment and are more likely a reflection of differing developmental exposures and/or genetic substrates.. To evaluate cognitive performance in healthy eugonadal men and women before and again during GnRH agonist-induced hypogonadism.. Men (n=16) and women (n=15) without medical or psychiatric illness were matched for IQ. Cognitive tests were performed at baseline (when eugonadal) and after 6-8 weeks of GnRH agonist-induced gonadal suppression. The test batteries included measures of verbal and spatial memory, spatial ability, verbal fluency, motor speed/dexterity, and attention/concentration. Data were analyzed using repeated-measures models.. During both eugonadism and hypogonadism, men performed significantly better than women on several measures of visuospatial performance including mental rotation, line orientation, Money Road Map, Porteus maze, and complex figure drawing. Although some test performances showed an effect of hormone treatment, the majority of these differences reflected an improved performance during hypogonadism compared with baseline (and probably reflected practice effects).. The well-documented male advantage in visuospatial performance, which we observed during eugonadal conditions, was maintained in the context of short-term suppression of gonadal function in both men and women. These findings suggest that, in humans, sex differences in visuospatial performance are not merely dependent on differences in the current circulating sex steroid environment. Thus sex differences in visuospatial performance in adulthood could reflect early developmental effects of sex steroid exposure or other environmental exposures differing across the sexes as our data confirm that these differences are independent of circulating estradiol or testosterone levels in men and women.

Topics: Adult; Estradiol; Female; Humans; Hypogonadism; Injections, Intramuscular; Leuprolide; Male; Middle Aged; Neuropsychological Tests; Orientation; Outcome Assessment, Health Care; Perceptual Disorders; Photic Stimulation; Psychiatric Status Rating Scales; Radioimmunoassay; Sex Characteristics; Space Perception; Testosterone; Young Adult

The relationship between depression and estrogen withdrawal remains controversial. The authors examined the effects of gonadotropin-releasing hormone agonist-induced ovarian suppression on mood, sleep, sexual function, and nighttime hot flushes. They focused on whether participating women experienced clinically significant depressive symptoms and whether specific symptoms associated with hypogonadism (nighttime hot flushes and disturbed sleep) increased susceptibility to depression.. Participants were 72 healthy premenopausal women, ages 19-52 years, with no current or past axis I psychiatric diagnosis or gynecological or other medical illness. After 2 months of baseline screening, women received monthly injections of leuprolide acetate (3.75 mg) for 2-3 months. Outcomes were measured using the Beck depression inventory (BDI) and a daily rating scale measuring the severity of several affective and behavioral symptoms. Data were analyzed by repeated-measures analysis of variance using PROC MIXED (for mixed models).. BDI scores ≥10 were reported in four of the 72 women (5.6%). Relative to baseline, induced hypogonadism was associated with significantly decreased sexual interest, disturbed sleep, and more severe nighttime hot flushes, but no significant change in any mood-related symptom score. Hot flush severity was significantly correlated with disturbed sleep.. These data demonstrate that clinically significant depressive symptoms were rare accompaniments of short-term estradiol withdrawal and induced hypogonadism in healthy premenopausal women. Additionally, neither nighttime hot flushes nor disturbed sleep were sufficient to cause depressive symptoms in hypogonadal women.

Topics: Adult; Affect; Depression; Estradiol; Female; Fertility Agents, Female; Hot Flashes; Humans; Hypogonadism; Leuprolide; Middle Aged; Psychiatric Status Rating Scales; Sexual Behavior; Sleep; Women's Health

Gynecology clinic-based studies have consistently demonstrated that induced hypogonadism is accompanied by a decline in cognitive test performance. However, a recent study in healthy asymptomatic controls observed that neither induced hypogonadism nor estradiol replacement influenced cognitive performance. Thus, the effects of induced hypogonadism on cognition might not be uniformly experienced across individual women. Moreover, discrepancies in the effects of hypogonadism on cognition also could suggest the existence of specific risk phenotypes that predict a woman's symptomatic experience during menopause. In this study, we examined the effects of induced hypogonadism and ovarian steroid replacement on cognitive performance in healthy premenopausal women. Ovarian suppression was induced with a GnRH agonist (Lupron) and then physiologic levels of estradiol and progesterone were reintroduced in 23 women. Cognitive tests were administered during each hormone condition. To evaluate possible practice effects arising during repeated testing, an identical battery of tests was administered at the same time intervals in 11 untreated women. With the exception of an improved performance on mental rotation during estradiol, we observed no significant effects of estradiol or progesterone on measures of attention, concentration, or memory compared with hypogonadism. In contrast to studies in which a decline in cognitive performance was observed in women receiving ovarian suppression therapy for an underlying gynecologic condition, we confirm a prior report demonstrating that short-term changes in gonadal steroids have a limited effect on cognition in young, healthy women. Differences in the clinical characteristics of the women receiving GnRH agonists could predict a risk for ovarian steroid-related changes in cognitive performance during induced, and possibly, natural menopause.

Topics: Adult; Attention; Case-Control Studies; Cognition; Estradiol; Female; Follow-Up Studies; Gonadotropin-Releasing Hormone; Hormone Replacement Therapy; Humans; Hypogonadism; Injections, Intramuscular; Leuprolide; Memory; Ovary; Premenopause; Progesterone; Psychiatric Status Rating Scales

Leuprorelin acetate is an agonist of gonadotropin-releasing hormone, used as a first choice treatment in patients with prostate carcinoma. The impact of leuprorelin therapy in liver function and metabolism is largely unknown. We report about a patient who had been treated for 32 months with leuprorelin acetate, who developed a nonalcoholic fatty liver disease (NAFLD), associated with a focal lesion at the IV hepatic segment where histologic features appeared to be more severe. The patient, in addition to NAFLD, presented a marked iatrogenic hypotestosteronemia and full-criteria meeting the diagnosis of metabolic syndrome, including insulin resistance. The radiologic and clinical findings, the histopathologic features, and the absence of any hepatic abnormalities before treatment, support a causal role of leuprorelin in inducing metabolic derangement that, most likely secondary to androgen-deprivation, were, in turn, responsible for the development of NAFLD. In conclusion, this is the first case report of NAFLD with focal fatty liver associated with leuprorelin therapy. Patients in leuprorelin should be carefully monitored for the development of liver disease.

Topics: Aged; Antineoplastic Agents, Hormonal; Carcinoma; Fatty Liver; Humans; Hypogonadism; Insulin Resistance; Leuprolide; Liver; Male; Prostatic Neoplasms; Testosterone

Controversy and a notable paucity of published clinical data best characterize the current knowledge of testosterone-replacement therapy (TRT) for hypogonadism after treatment for early, localized prostate cancer. The objective of this study was to assess the risk of biochemical failure with TRT after treatment of early prostate cancer with permanent transperineal brachytherapy with or without external beam therapy in patients with low serum levels of testosterone and clinical symptoms of hypogonadism.. Patients who underwent prostate brachytherapy from 1996 to 2004 and received subsequent TRT for symptomatic hypogonadism were reviewed to detail cancer characteristics and treatment as well as pre- and post-TRT serum testosterone and prostate-specific antigen (PSA) values.. Thirty-one men received TRT after prostate brachytherapy for 0.5 to 8.5 years (median, 4.5 years), with a follow-up that ranged from 1.5 years to 9.0 years (median, 5.0 years) postbrachytherapy. TRT was started from 0.5 years to 4.5 years (median, 2.0 years) after brachytherapy. Serum total testosterone levels ranged from 30 ng/dL to 255 ng/dL (median, 188 ng/dL) before TRT and rose to 365 ng/dL to 1373 ng/dL (median, 498 ng/dL) on TRT. Transient rises in PSA were observed in 1 patient. The most recent PSA level was <0.1 ng/mL in 23 patients (74.2%), <0.5 ng/mL in 30 patients (96.7%), and <1 ng/mL in 31 patients (100%). No patients stopped TRT because of cancer recurrence or documented cancer progression.. For patients with low serum testosterone levels and symptoms of hypogonadism, TRT may be used with caution and close follow-up after prostate brachytherapy.

Topics: Aged; Antineoplastic Agents, Hormonal; Brachytherapy; Disease-Free Survival; Goserelin; Hormone Replacement Therapy; Humans; Hypogonadism; Leuprolide; Male; Middle Aged; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Treatment Outcome

Although the behavioral effects of high-dose androgen administration may involve alterations in serotonergic activity, few studies have investigated the impact of androgen withdrawal on the central nervous system in humans.. To examine the effects of pharmacologically induced hypogonadism on several cerebrospinal fluid (CSF) systems that could mediate the behavioral concomitants of hypogonadism.. Double-blind assessment of the effects of the short-term induction of hypogonadism and subsequent replacement with testosterone and placebo in a crossover design.. National Institutes of Health, Bethesda, Md.. Twelve healthy male volunteers.. We administered the gonadotropin-releasing hormone agonist leuprolide acetate (7.5 mg intramuscularly every 4 weeks) to the healthy male volunteers, creating a hypogonadal state, and then either replaced testosterone (200 mg intramuscularly) or administered a placebo every 2 weeks for 1 month.. Mood and behavioral symptoms were monitored with daily self-ratings, and lumbar punctures were performed during both hypogonadal (placebo) and testosterone-replaced conditions for CSF levels of steroids and monoamine metabolites.. The CSF testosterone, dihydrotestosterone, and androsterone levels were significantly lower during hypogonadism (P=.002, .04, and .046, respectively), but no significant changes were observed in CSF measures of 5-hydroxyindoleacetic acid, homovanillic acid, dehydroepiandrosterone, or pregnenolone. Decreased sexual interest was observed during the hypogonadal state compared with both baseline and testosterone replacement (P=.009) and correlated significantly with CSF measures of androsterone during both hypogonadism and testosterone replacement (r = -0.76 and -0.81, respectively; P<.01). Moreover, the change in severity of decreased sexual interest correlated significantly with the change in CSF androsterone levels between testosterone replacement and hypogonadism (r = -0.68; P<.05). The CSF 5-hydroxyindoleacetic acid and homovanillic acid levels did not correlate significantly with any behavioral or CSF measure.. These data suggest that the neurosteroid androsterone contributes to the regulation of sexual function in men.

Topics: Adolescent; Adult; Affect; Androsterone; Cross-Over Studies; Dihydrotestosterone; Double-Blind Method; Estradiol; Humans; Hypogonadism; Injections, Intramuscular; Leuprolide; Male; Middle Aged; Radioimmunoassay; Sexual Behavior; Spinal Puncture; Testosterone

To assess if leuprolide acetate stimulation discriminates between hypogonadotropic hypogonadism (HH) and constitutional delay of puberty (CDP) in males.. Case-control study.. Patients attending an academic research environment.. Only male patients were studied: 10 with HH (group 1, age 16.5 +/- 6.0 years), 8 prepubertal with CDP (group 2, age 14.3 +/- 1.2 years), 6 healthy prepubertal (group 3, age 9.5 +/- 3.3 years), and 8 healthy late-pubertal (group 4, age 15.1 +/- 3.1 years).. Blood samples were obtained after an overnight fast. Leuprolide acetate was then administered SC, and blood samples were drawn at 0, 30, 60, 120, 180 minutes, and 6 and 24 hours after stimulation.. Clinical follow-up evaluations of data and serum levels of LH, FSH, 17-hydroxyprogesterone, and testosterone.. Basal LH levels were similar in groups 1 through 3 and differed significantly from those in group 4. Peak serum LH levels were significantly higher in CDP compared with HH (8.9 +/- 1.4 vs. 1.4 +/- 0.2 IU/L). Baseline FSH levels were significantly higher only in pubertal boys (versus the HH group); peak levels did not differ among the groups. Basal and peak testosterone levels were significantly higher only in the control pubertal group when compared to the other groups; peak 17-hydroxyprogesterone concentrations were significantly higher in pubertal controls compared with HH and CDP.. Peak LH responses clearly discriminate HH from CDP. Timing for blood sampling should be fixed at 0, 60, 120, 180 minutes after stimulation.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adult; Case-Control Studies; Child; Diagnosis, Differential; Follicle Stimulating Hormone; Humans; Hypogonadism; Leuprolide; Luteinizing Hormone; Male; Puberty, Delayed; Regression Analysis; Testosterone

The impact of estrogen deficiency on bone has been extensively studied in the female; however, the effects of androgen deficiency on calcium fluxes in males have been less well characterized. We investigated the effect of short-term, severe androgen deficiency on measures of calcium absorption and kinetics as well as on markers of bone turnover in males. To accomplish this, 11 healthy male volunteers were recruited (mean age 23.3 +/- 0.5 years [SEM], body mass index 25.3 +/- 0.8 kg/m2). They consumed a weight maintenance diet for at least 3 days prior to admission to our Research Unit, with a calcium intake of approximately 1200 mg/day. At baseline (D1), subjects received 42Ca intravenously as well as 44Ca PO mixed with milk or juice. A 29-h urine collection was begun and blood samples collected at frequent intervals for the measurement of the isotopic enrichment of 42Ca and 44Ca using thermal ionization mass spectrometry. Twice daily urine samples were collected for 5 days after the administration of the isotopes. A gonadotropin-releasing hormone agonist (Lupron) was given after D1, again 3 weeks later, and studies repeated identically 4 weeks (D2, n = 6) and 10 weeks from baseline (D3, n = 7) (two subjects completed three studies). Testosterone concentrations were markedly suppressed on both D2 and D3 (-95%, p < 0.006), whereas there were no detectable changes in growth hormone and insulin-like growth factor-1 concentrations. Urinary calcium excretion increased significantly after 4 weeks (43%, p = 0.0007) and 10 weeks (73%, p = 0.003) of sustained hypogonadism. Using a multicompartmental kinetic model, the contribution of oral calcium to the urinary losses was decreased by D3 (-41%, p = 0.01), yet the contribution of bone calcium to urine losses increased by 10 weeks (+11%, p = 0.01). There was a 21% decrease in bone calcium deposition (Vo+) by D3 (p < 0.05) with no significant change in bone resorption rates (Vo-). There was a significant correlation between the decrease in testosterone concentration and the increase in urinary calcium excretion, especially at 10 weeks (R2 = 0.84, p = 0.004). These kinetic changes were accompanied by a decrease in osteocalcin concentrations on D2, with improvements by D3. Urinary N telopeptide, a measure of bone resorption, also increased during the studies. In summary, profound hypogonadism in young males is associated with marked increases in urinary calcium losses, with a greater contribution of bone calcium to tho

Topics: Adult; Bone Density; Bone Remodeling; Calcium; Female; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; Kinetics; Leuprolide; Male; Models, Biological; Osteocalcin; Testosterone

The possible role of gonadal steroids in regulating sleep and circadian rhythms in humans has received relatively little attention despite the importance of the topic to several clinical syndromes. Pharmacologically induced hypogonadism, with and without gonadal steroid replacement, provides an opportunity to examine these questions within a controlled experimental design. We used leuprolide acetate, with and without testosterone replacement, to study the role of testosterone in the regulation of sleep and of melatonin, PRL, and TSH secretion in men. Results from 10 men revealed significant decreases in 24-h PRL levels and in the percentage and time of stage 4 sleep in the hypogonadal state compared with testosterone replacement. There were no differences in melatonin or TSH secretion or in the timing or duration of sleep between the two hormonal conditions. These results indicate that testosterone has relatively specific and discrete effects on sleep and hormonal rhythms in men.

Topics: Adolescent; Adult; Body Temperature; Circadian Rhythm; Hormones; Humans; Hypogonadism; Leuprolide; Male; Melatonin; Middle Aged; Prolactin; Sex Characteristics; Sleep; Testosterone; Thyrotropin

The significance of stress-induced hypogonadism remains unclear. Since plasma testosterone and LH have renotropic activity that is other than reproductive, we hypothesize that stress-induced hypogonadism is an adaptive response to protect the kidney. To examine this hypothesis, we prepared hypogonadal male rats with different levels of LH and testosterone through orchiectomy (castration), through chronic treatment with a slowly secreted form of gonadotropin-releasing hormone agonist (GnRHA; GnRHA pretreatment), or through both treatments concomitantly (castration with GnRHA pretreatment). Castrated rats had undetectable plasma testosterone and high plasma LH. GnRHA-pretreated rats had low plasma testosterone and normal plasma LH. Castrated rats with GnRHA pretreatment had undetectable plasma testosterone and normal plasma LH. We compared their sensitivity to HgCl2 nephrotoxicity and found that, when a low dose of HgCl2 (1.5 mg/kg body weight (BW)) was injected s.c. to induce acute renal failure, endogenous creatinine clearance (Ccr) decreased from 390 +/- 30 to 94 +/- 17 ml/h per kg BW in intact (unpretreated) rats. Such a decrease in Ccr was completely prevented in castrated rats (388 +/- 30 ml/h per kg BW) and partially prevented in GnRHA-pretreated rats (216 +/- 40 ml/h per kg BW). When a high dose of HgCl2 (2.25 mg/kg BW) was injected, half of the eight intact rats died but castrated rats and GnRHA-pretreated rats survived (P < 0.05). The elevated resistance in castrated rats was reduced when plasma LH was reduced with GnRHA pretreatment, but was restored by additional pretreatment with ovine LH (40 micrograms/day), as evidenced by changes in Ccr. Elevated resistance in castrated rats was also reduced by the administration of testosterone propionate. In conclusion, hypogonadism activated the preventive and defensive mechanisms that protect the kidney through both decreased plasma testosterone and high or even normal plasma LH.

Topics: Acute Kidney Injury; Adaptation, Physiological; Animals; Creatinine; Gonadotropin-Releasing Hormone; Hypogonadism; Kidney; Leuprolide; Luteinizing Hormone; Male; Mercuric Chloride; Metabolic Clearance Rate; Orchiectomy; Rats; Rats, Wistar; Stress, Psychological; Testosterone

A 43-year-old woman with a history of 5 years of amenorrhea sought help in achieving a pregnancy. Her gonadotropins were found to be elevated and thus she was diagnosed as having ovarian failure. She was made to ovulate on many occasions by suppressing her gonadotropins first with estrogen, then stimulating her ovaries with hMG. However, she became refractory to this therapy and she was switched from estrogen to LA to suppress gonadotropins. The woman ovulated three times just with leuprolide therapy before any hMG was added. A possible hypothesis is that, on the way down to subnormal levels of LH and FSH, a critical level of gonadotropins was attained where they were still high enough to stimulate the follicles, but low enough to allow restoration of gonadotropin receptors, which previously had been down-regulated by the elevated gonadotropin levels.

Topics: Adult; Female; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; Leuprolide; Menotropins; Ovulation

Plasma LH, FSH and endogenous LHRH were determined by radioimmunoassay (RIA) when 100 micrograms of LHRH superanalogue, des-Gly10-[D-Leu6]-LHRH ethylamide (leuprolide) was intranasally administered to both 7 healthy subjects aged 22 to 63 years and 6 patients with various hypogonadism aged 22 to 43 years [2 with anorexia nervosa, 3 with hypophysial hypogonadism and 1 with isolated gonadotropin (Gn) deficiency]. The response of plasma LH after the intranasal administration of leuprolide was observed to be 814 +/- 236 (mean +/- SE)% in the healthy subjects at 2 to 10 hours, and 528 +/- 183% in the patients with hypogonadism at 2 to 4 hours. These elevations were observed until 24 hours after administration in both groups. The response of plasma FSH was observed to be 449 +/- 99% in the healthy subjects at 3 to 8 hours, and 593 +/- 238% in the patients with hypogonadism at 2 to 6 hours. These elevations were observed until 24 hours in the healthy subjects and until 12 hours in the patients with hypogonadism. Furthermore, these responses tended to be higher than those after 100 micrograms intravenous administration of LHRH; LH responded up to 386 +/- 50% in the healthy subjects and up to 390 +/- 91% in the patients with hypogonadism, and FSH up to 282 +/- 38%, 343 +/- 90%, respectively. The elevation of plasma immunoreactive LHRH which was determined using RIA having no immunocrossreactivity with leuprolide (less than 0.01%) was observed at 6 hours after the administration of leuprolide in the healthy subjects (789 +/- 497%).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Intranasal; Adult; Anorexia Nervosa; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Hypogonadism; Leuprolide; Male; Middle Aged

The chemical structure of luteinizing-hormone-releasing hormone (LHRH) was discovered in 1971 after more than a decade of intensive effort. Subsequent physiologic studies in primates and humans showed that the biologic activity of LHRH depends on the way in which the hormone is administered. Pulsatile administration of LHRH, which mimics the natural secretory pattern, causes sustained secretion of the gonadotrophins. This method of administration has been used to induce ovulation in women with hypothalamic amenorrhea and to induce puberty and spermatogenesis in men with hypogonadotrophic hypogonadism. Continuous infusion, however, produces only transient stimulation of gonadotrophin secretion, followed by a "desensitization" response in which gonadotrophin secretion is inhibited. Thus, LHRH can either augment or inhibit gonadotrophin secretion depending on the mode of administration. Recently, long-acting synthetic analogs of LHRH have been shown to desensitize the pituitary gland and inhibit gonadotrophin release when administered as a single daily subcutaneous injection. These LHRH analogs have proved highly effective in the treatment of prostatic carcinoma and central precocious puberty. They are also being studied as a new approach to contraception and to the treatment of endometriosis and polycystic ovary syndrome.

Topics: Animals; Child; Contraceptive Agents, Male; Endometriosis; Estrogens; Female; Follicle Stimulating Hormone; Genital Diseases, Female; Genital Diseases, Male; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; Hypothalamic Diseases; Infertility; Leuprolide; Luteinizing Hormone; Male; Neoplasms, Hormone-Dependent; Ovulation Induction; Polycystic Ovary Syndrome; Prostatic Neoplasms; Puberty, Precocious; Spermatogenesis; Time Factors; Triptorelin Pamoate

Topics: Adult; Aged; Child; Child, Preschool; Cryptorchidism; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Testosterone