Administration Of Luteinizing Hormone-releasing Hormone Research Articles

Psoas mass index at the level of the third lumbar vertebra on computed tomography is a prognostic predictor for metastatic castration-sensitive prostate cancer.

Computed tomography-defined low skeletal muscle mass is associated with oncological outcomes in patients with prostate cancer. However, its association with the outcomes of hormone-treated metastatic castration-sensitive prostate cancer remains unclear. We aimed to determine the association between metastatic castration-sensitive prostate cancer and psoas muscle parameters. We retrospectively reviewed 121 patients with N1 and/or M1 metastatic castration-sensitive prostate cancer who underwent primary androgen deprivation therapy between 2005 and 2021, either by administration of luteinizing hormone-releasing hormone agonist/antagonist or by surgical castration accompanied by bicalutamide, a first-generation antiandrogen. Before treatment administration, the psoas muscle index at the level of the third lumbar vertebra (psoas muscle area [cm2]/height2 [m2]) and the mean Hounsfield units of the psoas muscle were evaluated using non-contrast computed tomography and in relation to oncological outcomes. The median follow-up was 56.9months. Furthermore, during follow-up, 82 (67.7%) and 53 (43.8%) patients progressed to castration-resistant prostate cancer and died, respectively. Multivariate analysis of castration-resistant prostate cancer-free survival and overall survival showed significant differences in the Gleason score, clinical N-stage, and psoas muscle index (median cutoff: 3.044 cm2/m2). Pretreatment psoas muscle index is an independent predictor of poor castration-resistant prostate cancer-free survival and overall survival in patients with N1 and/or M1 metastatic castration-sensitive prostate cancer.

Low-dose every-second-day LHRH treatment following bilateral orchidopexy in children with bilateral cryptorchidism may improve their fertility outcome

Currently the standard treatment for bilateral cryptorchidism is bilateral surgical orchidopexy. Whether a hormonal treatment should be routinely administered postoperatively to increase fertility is debatable. Low-dose postoperative luteinizing hormone releasing hormone (LHRH) can increase spermatogonial numbers, but the effect of native LHRH (Kryptocur®) on adult fertility is unclear. To determine if low-dose every-second-day postoperative LHRH administration in children with bilateral cryptorchidism improves fertility in adulthood and if Nistal testicular histological grading could guide the decision to administer LHRH. All patients, actually at least 16yr of age, that underwent a bilateral orchidolysis and orchidopexy for bilateral cryptorchidism (surgery between 1997 and 2018) were contacted and offered a clinical exam, hormone levels, sperm analysis, and a scrotal ultrasound. At the original surgery, testicular biopsy was performed (if 60% of the tubuli contain >1 spermatogonia, this is normal=Nistal-1, if 30-60% filled=Nistal-2, if <30%=Nistal-3 and if Sertoli only=Nistal-4) and if in at least one testis impaired. A low dose native LHRH treatment was offered to the patients, as this treatment is known to increase the number of spermatogonia in a short term. Kryptocur® (LHRH, Gonadorelin, Hoechst®) was prescribed and dosed at 200μg (one spray in one nostril) every other day for 6-8 months. Forty-two men were eligible for this study. 20/42 accepted the invitation for a clinical and hormonal evaluation. 16/20 men accepted the invitation for an additional sperm analysis. Fourteen of 20 men received low-dose LHRH postoperatively in a nonrandomized manner. Three men had Nistal grade 1, eight grade 2, seven grade 3, and two had grade 4. Inhibin B levels were higher in men with Nistal 1 and 2 compared with Nistal 3 and 4P≤0.037). Severe oligospermia/azoospermia (<1×106/ejaculate) was observed in 33% of the treated group vs 67% of the untreated group (P≤0.036.) DISCUSSION AND CONCLUSIONS: Low-dose every-second-day postoperative LHRH treatment improves fertility outcome in bilateral cryptorchidism. Histological analysis of prepubertal testes according to Nistal grading cannot be used as a predictive diagnostic test for LHRH treatment.

Primary Hepatic Vascular Neoplasm in a Houston Toad (Anaxyrus houstonensis)

An 11-year-old captive, female Houston toad (Anaxyrus houstonensis) became lethargic and reluctant to move. This toad had been administered human chorionic gonadotropin (HCG) and luteinizing hormone-releasing hormone (LHRH) annually as part of a hormone-assisted captive propagation programme for 8 years. Due to poor prognosis, euthanasia was elected. At necropsy, the liver was moderately enlarged, diffusely dark red and had a nodular superficial appearance. Microscopically, the hepatic nodules consisted of poorly demarcated, non-encapsulated, paucicellular infiltrative neoplastic growths. These consisted of spindle cells, similar to sinusoidal endothelial cells, that formed irregular blood-filled vascular channels resembling sinusoids separated by thin bands of collagen and reticulin fibres. Neoplastic cells dissected through and replaced hepatic cords and bile ducts. Based on the cytohistomorphological features and analogy with vascular neoplasms in other vertebrates, a diagnosis of low-grade angiosarcoma was made. To the best of our knowledge, this is the first record of primary hepatic vascular neoplasia in an amphibian. It is not known if the long-term administration of HCG and LHRH had any oncogenic role in this animal. Vascular neoplasia should be included in the differential diagnosis of hepatomegaly and non-specific lethargy and health decline in amphibian species.

BPI19-009: Late Administration of Luteinizing Hormone-Releasing Hormone (LHRH) Agonists and Testosterone Levels &gt;50NG/DL in Prostate Cancer

Background: Achieving and maintaining effective testosterone (T) suppression is key to treatment of advanced prostate cancer (PCa), for which LHRH agonists are standard of care. Increasing evidence suggests maintaining very low T levels to &lt;20 ng/dL with androgen deprivation therapy (ADT) is desirable and correlates with disease-specific survival in patients with advanced PCa. Consistent drug delivery is important in providing continuous T suppression throughout the course of treatment without T rising above castrate level (T breakthrough). However, T breakthrough may occur between administrations, especially if a subsequent dose is delayed. Contributing factors to late administrations may include scheduling challenges, shortage of available appointments, and increasing number of patients. While FDA approvals for ADT drugs are based on a 28-day month, insurers may mandate full calendar months between doses for reimbursement. This study explored timeliness of subsequent LHRH agonist administrations and its relationship with T breakthrough. Methods: A retrospective review of electronic medical records from January 1, 2007 and June 30, 2016 of 85,030 LHRH agonist administrations for PCa treatment was conducted to evaluate the percentage of late subsequent dosing and impact on frequencies of T breakthrough, defined as T&gt;50 ng/dL. Late administrations were defined as those on or after day 33, 98, 129, and 195 for 1, 3, 4, and 6 month formulations, respectively. Results: 26.9% of all subsequent LHRH agonist administrations were late: 14.4% were ≤1 week late, 3.1% were between 1–2 weeks late, and 9.4% were &gt;2 weeks late. While only 4% of T values exceeded 50 ng/dL when doses were administered early/on time, 21% of T values exceeded 50 ng/dL when administrations were late. Conclusions: Over a quarter of subsequent administrations were defined as late, leading to &gt;20% incidence of T values exceeding 50 ng/dL. Considering the clinical benefits of maintaining effective T suppression throughout a course of ADT, clinicians should administer treatments within approved dosing instructions, routinely monitor T levels, and consider prescribing treatments with proven efficacy through the dosing interval to maintain T at castrate levels.

Late administration of luteinizing hormone-releasing hormone (LHRH) agonists and the impact on testosterone suppression in the real-world management of prostate cancer.

149 Background: LHRH agonists are standard for androgen deprivation therapy (ADT) for advanced prostate cancer (PCa). Increasing evidence suggests maintaining very low testosterone (T) levels is desirable and correlate with disease-specific survival. However, T levels may rise above castrate level between administrations, especially if the next dose is delayed. A previous publication showed that subcutaneously-administered leuprolide acetate (LA) provided a longer duration of action than intramuscularly-administered LA past the dosing interval. This study evaluated the timeliness of LHRH agonist administrations and subsequent rate of T breakthroughs in PCa patients. Methods: A retrospective review of electronic medical records from 1/1/07-6/30/16 of 85,030 LHRH agonist administrations for PCa treatment was conducted to evaluate the percentage of late subsequent administrations and T tests with T &gt; 50 ng/dL. A late administration was defined as occurring on or after day 33 (1 mo formulation), 98 (3 mo), 129 (4 mo), or 195 (6 mo). Descriptive statistics were used. Results: 26.9% of all subsequent LHRH agonist administrations were late: 14.4% were ≤ 1 week late, 3.1% were between 1 and 2 weeks late, and 9.4% were &gt; 2 weeks late. 21% of T tests demonstrated T &gt; 50 ng/dL when administrations were late, in contrast to only 4% of measured T levels exceeded 50 ng/dL when LHRH agonists were administered early or on time. Conclusions: Across LHRH agonists, greater than a quarter of subsequent administrations were defined as late. Among late administrations, about half were &gt; 1 week late, and more than a third were &gt; 2 weeks late. Late administrations were correlated with inadequate castration over 20% of the time. Considering the clinical benefits of maintaining effective T suppression during ADT, clinicians should administer treatments within approved dosing instructions, include routine monitoring of T levels, and consider prescribing treatments with proven prolonged effect through the dosing period to achieve T suppression to castrate levels.

Recovery of Serum Testosterone Levels and Sexual Function in Patients Treated With Short-term Luteinizing Hormone-releasing Hormone Antagonist as a Neoadjuvant Therapy Before External Radiotherapy for Intermediate-risk Prostate Cancer: Preliminary Prospective Study.

External beam radiation therapy (EBRT) with short-term androgen deprivation therapy is the standard of care for intermediate-risk prostate cancer patients. However, no study to date has evaluated the hormonal kinetics or sexual and hormonal function recovery after cessation of short-term luteinizing hormone (LH)-releasing hormone (LHRH) antagonist treatment. Ten intermediate-risk prostate cancer patients (mean age, 69.9 years) were included. All patients received 4 months of LHRH antagonist (degarelix) treatment followed by EBRT. The testosterone, luteinizing hormone (LH), follicle-stimulating hormone, and prostate-specific antigen levels were measured and Expanded Prostate Cancer Index Composite questionnaires were completed before LHRH antagonist therapy at baseline; 1, 2, 3, and 4 months after the first injection of LHRH antagonist treatment; and every 2 months thereafter until 18 months. The testosterone levels were at the castration level at 1 month after the first LHRH antagonist injection. The median interval to recover a normal testosterone level (> 7.2 nmol/L) was 7 months after the last LHRH antagonist administration. The LH and follicle-stimulating hormone levels decreased but had increased more than twice above baseline at 15 months after the last LHRH antagonist injection. The sexual function and hormonal bother subdomain scores and sexual and hormonal domain scores decreased once after LHRH antagonist treatment but had significantly recovered thereafter (P< .05). In most patients, the testosterone level had normalized within 9 months after the last LHRH administration. Sexual and hormonal function recovered after short-term LHRH antagonist administration for neoadjuvant therapy before EBRT.

Abstract CT109: Adjuvant ovarian suppression in high risk premenopausal breast cancer: ten-year follow-up of a phase I-II study

Abstract Background: Two randomized studies have shown the benefit of ovarian suppression in the adjuvant treatment of high risk premenopausal breast cancer, both with estrogen receptor positive (ER+) (Pagani et al. N Engl J Med 2014) and estrogen receptor negative (ER-) (Moore et al. N Engl J Med 2015). Nevertheless the median follow-up of these studies was limited to 68 and 49 months, respectively. Here we present the results of a large, phase I-II study, of adjuvant ovarian suppression in ER+ and in ER- patients, after a median follow-up of 123 months (range 93-223). Two hundred patients were enrolled between 06-1997 and 06-2007. The primary end point of the study was to find the best dose and schedule of a luteinizing hormone releasing hormone (LH-RH) analogue given to prevent ovarian failure in premenopausal patients treated with adjuvant chemotherapy. Secondary end points were disease free survival (DFS) and overall survival (OS). Methods: One week before chemotherapy, a LH-RH analogue was administered, 3.75 mg every 28 days for 1 year to the first cohort of 64 patients. The same monthly dose was given, for 2 years, to the second cohort of 36 patients. Because we had observed a decrease of 31% in the recurrence rate for the longer administration of LH-RH analogue, the 11.25 mg dose every 84 days, for 5 years, was chosen for the remaining 100 patients. The treatment consisted of: a- LH-RH analogue; b- Breast conserving (74%) and radical surgery (26%); c- Tailored systemic therapy concurrent with radiation therapy; d- Aromatase inhibitor in ER+ patients. Results: The median age was 43 years (range 26-45), the mean number of positive axillary nodes was 3.2 (range 1-25), including 20 patients with &amp;gt;10 positive nodes. 71% of patients were ER+ and/or progesterone receptor positive (PGR+), 29% were ER - and PGR-, 21% of patients were c-ErbB-2 positive. The median KI-67 was 30% (range 15% -100%). Ovarian failure rate was 10% in patients younger than 40 years and 44% in patients older than 40 years. The 15-year DFS and OS rate were 64% and 73%, respectively. 15-year DFS rate of ER+ and ER- patients were 74% and 44% respectively (P&amp;lt;0.005), while the 15-year OS rate were 74% and 75%, respectively (P&amp;gt;0.005). The usual pattern of toxicity of chemotherapy was observed. Hot flashes and G1 osteopenia occurring after LH-RH analogue administration were temporary and receded after the cessation of therapy. Conclusions: LH-RH administration, concurrent with chemotherapy is tolerable and useful. Five full term pregnancies were observed. The long-term recurrence and survival rate for ER+ and ER-patients were similar, with different patterns: ER+ patients had disease recurrences even after 13 years, while ER- patients had late new primaries, but no recurrence after 5 years. Citation Format: Francesco Recchia, Giampiero Candeloro, Massimo Bratta, Michele Rosselli, Silvio Rea. Adjuvant ovarian suppression in high risk premenopausal breast cancer: ten-year follow-up of a phase I-II study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT109.

Neoadjuvant luteinizing-hormone-releasing hormone agonist plus low-dose estramustine phosphate improves prostate-specific antigen-free survival in high-risk prostate cancer patients: a propensity score-matched analysis

The optimal treatment for high-risk prostate cancer (Pca) remains to be established. We previously reported favorable biochemical recurrence-free survival (BRFS) in high-risk Pca patients treated with a neoadjuvant therapy comprising a luteinizing-hormone-releasing hormone (LHRH) agonist plus low dose estramustine phosphate (EMP) (LHRH+EMP) followed by radical prostatectomy (RP). In the present study, we used a retrospective design via propensity score matching to elucidate the clinical benefit of neoadjuvant LHRH+EMP for high-risk Pca. The Michinoku Urological Cancer Study Group database contained data for 1,268 consecutive Pca patients treated with RP alone at 4 institutions between April 2000 and March 2011 (RP alone group). In the RP alone group, we identified 386 high-risk Pca patients. The neoadjuvant LHRH+EMP group included 274 patients with high-risk Pca treated between September 2005 and November 2013 at Hirosaki University. Neoadjuvant LHRH+EMP therapy included LHRH and EMP administration at a dose of 280 mg/day for 6 months before RP. The outcome measures were overall survival (OS) and BRFS. The propensity score-matched analysis indicated 210 matched pairs from both groups. The 5-year BRFS rates were 90.4 and 65.8 % for the neoadjuvant LHRH+EMP and RP alone groups, respectively (P < 0.0001). The 5-year OS rates were 100 and 96.1 % for the neoadjuvant LHRH+EMP and RP alone groups, respectively (P = 0.110). Although the present study was not randomized, neoadjuvant LHRH+EMP therapy followed by RP appeared to reduce the risk of biochemical recurrence. A prospective randomized study is warranted to determine the clinical implications of the neoadjuvant therapy described here.

988 The effects of long-term androgen deprivation therapy on penile length in patients with prostate cancer: A single-center, prospective, open label, observational study

Introduction. The adverse effects of long-term drug therapy for prostate cancer (PCa) can dramatically impact patient quality of life and are considered to be important factors when selecting treatment. Aim. To assess stretched penile length before and after long-term androgen deprivation therapy (ADT) for treatment of PCa. Methods. From January 2008 to June 2010 at a single institution, 39 consecutive patients without distant metastases who were elected to receive ADT as initial therapy for PCa were prospectively enrolled. Exclusion criteria were history of penile anomalies and/or trauma, and prior radical prostate surgery or radiation therapy. Erectile functions were evaluated at baseline according to the International Index of Erectile Function (IIEF). Vertically stretched penile length was measured every 3 months from the pubopenile junction to the meatus with a spring scale. Main Outcome Measure. After ADT, significant 3-month interval changes in stretched penile length were noted for up to 15 months (P < 0.001). The relationship between potency and penile shortening was not significant (P = 0.45). Results. The mean patient age was 67.1 years. Before therapy, the mean stretched penile length was 10.76 cm. After 24 months of ADT, mean penile length had decreased to 8.05 cm. However, these changes plateaued after 15 months. Normal erectile function (EF) was reported by 41% of patients before therapy, while 10.5% reported normal EF at the 24-month follow-up. The relationship between potency and penile shortening was not significant. However, patients who preserved their potency tended to experience less penile shortening. Conclusions. The administration of luteinizing hormone-releasing hormone (LHRH) agonists induced significant decreases in penile length for only up to 15 months in the absence of the confounding effects of surgery and radiation. Park KK, Lee SH, and Chung BH. The effects of long-term androgen deprivation therapy on penile length in patients with prostate cancer: A single-center, prospective, open label, observational study. J Sex Med 2011;8:3214-3219.

The Effects of Long‐Term Androgen Deprivation Therapy on Penile Length in Patients with Prostate Cancer: A Single‐Center, Prospective, Open‐Label, Observational Study

The adverse effects of long-term drug therapy for prostate cancer (PCa) can dramatically impact patient quality of life and are considered to be important factors when selecting treatment. To assess stretched penile length before and after long-term androgen deprivation therapy (ADT) for treatment of PCa. From January 2008 to June 2010 at a single institution, 39 consecutive patients without distant metastases who were elected to receive ADT as initial therapy for PCa were prospectively enrolled. Exclusion criteria were history of penile anomalies and/or trauma, and prior radical prostate surgery or radiation therapy. Erectile functions were evaluated at baseline according to the International Index of Erectile Function (IIEF). Vertically stretched penile length was measured every 3 months from the pubopenile junction to the meatus with a spring scale. After ADT, significant 3-month interval changes in stretched penile length were noted for up to 15 months (P < 0.001). The relationship between potency and penile shortening was not significant (P = 0.45). The mean patient age was 67.1 years. Before therapy, the mean stretched penile length was 10.76 cm. After 24 months of ADT, mean penile length had decreased to 8.05 cm. However, these changes plateaued after 15 months. Normal erectile function (EF) was reported by 41% of patients before therapy, while 10.5% reported normal EF at the 24-month follow-up. The relationship between potency and penile shortening was not significant. However, patients who preserved their potency tended to experience less penile shortening. The administration of luteinizing hormone-releasing hormone (LHRH) agonists induced significant decreases in penile length for only up to 15 months in the absence of the confounding effects of surgery and radiation.

Influence of surgical and chemical orchidectomy on weight and distribution of AChE-nerve fibres in thymuses of adult rats

The thymus is a crossroad between the immune and neuroendocrine systems. As such, it is innervated by acetylcholinesterase (AChE)-positive fibres of the vagus, the recurrent laryngeal and the phrenic nerves. It is well know, that the innervations density of the thymus increases with age. In our study, adult rats were orchidectomized (surgically and chemically by the application of a luteinizing hormone-releasing hormone). The density of AChE-positive nerve fibres in thymuses, as well as the weight of thymuses was examined. The authors found that both surgical and chemical orchidectomy result in macroscopic and microscopic regeneration of the atrophied thymuses. In regenerated rat’s thymuses after orchidectomy the density of AChE-positive nerve fibres was markedly higher in comparison with the control animals. The distribution, as well as the density of AChE-positive nerve fibres in regenerated thymuses after orchidectomy evokes the images of its innervations like in young animals before age-related involution. The authors also found a markedly higher weight of thymuses of orchidectomized rats in comparison with the control groups. In recent study the authors proved that after 8 weeks surgical orchidectomy leads to the regeneration of thymic AChE-positive innervation and chemical orchidectomy by administration of luteinizing hormone-releasing hormone after 4 weeks of adult rats.

Testicular steroid response to continuous and pulsatile intravenous luteinizing hormone-releasing hormone administration in normal men.

In 18 healthy normal men Leydig cell response was examined following intravenous luteinizing hormone-releasing hormone (LH-RH) administration under standardized conditions. The same total amount of LH-RH was administered for 3 hours both in a continuous (1 microgram/min; C (1,1)) and in a pulsatile fashion, by giving a 20 micrograms dose at 20 minutes intervals, P (20, 20), and a 60 micrograms dose at 60 minutes intervals, P (60, 60). Following the different modes of LH-RH administration which all caused 3-4 fold elevations of the mean endogenous luteinizing hormone (LH) concentrations and 1.7-2 fold elevations of the mean follicle-stimulating hormone (FSH) serum levels, an overt increase of the mean testosterone (T) levels was noticed up to 1.5 X the baseline value. No difference was observed in the total amount of T release among the investigated groups. The patterns of the T response, however, clearly differed from one another with a rapid increase, during the C (1, 1) and the P (20, 20) LH-RH administration, and a delayed but persistent T increase in the P (60, 60) experiment. The mean 17-hydroxyprogesterone (17-OHP) concentrations demonstrated a similar course to T in the P (60,60) experiment, while significant increases of the oestradiol (E 2) levels were never observed in all three experiments. In view of the comparable LH and FSH increments in response to LH-RH administration in either experiment the differences in T responses may be explained by assuming a direct effect of LH-RH on Leydig cell steroidogenesis in the men.

Long-term, pulsatile, low dose, subcutaneous luteinizing hormone-releasing hormone administration in men with idiopathic oligozoospermia. Failure of therapeutic and hormonal response.

In four normal men with a history of long standing infertility, severely disturbed sperm qualities (determined in at least three spermiograms), normal serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels (measured over a time period of 90 minutes), and lack of evidence of further andrological or other obvious endocrine disorders the effectiveness of luteinizing hormone-releasing hormone (LH-RH) treatment was investigated. LH-RH was administered subcutaneously with a portable, comterized infusion pump (Zyclomat) for 3 months, with administration intervals of 90 minutes and bolus dosages of 5 micrograms (three patients) and 20 micrograms (one patient). Semen qualities during and after LH-RH treatment, as compared to pretreatment values, showed no improvement in volume of ejaculate, number of sperms per milliliter and motility. During or at the end of the treatment period no evident differences were observed in serum LH, FSH and testosterone levels (measured over a 90 minutes period) compared with hormonal values before LH-RH therapy, nor at the low-dose (5 micrograms) neither at the high-dose (20 micrograms) administration schedule. It is concluded that pulsatile subcutaneous LH-RH treatment in normogonadotropic, oligozoospermic men does not seem to improve the therapeutical arsenal.

Intravenous luteinizing hormone‐releasing hormone has no effect on serum N‐terminal pro‐brain natriuretic peptide in children and adolescents

Little is known about the acute effects of i.v. luteinizing hormone-releasing hormone (LHRH) on the heart function, therefore the aim of the present study was to measure N-terminal pro-brain natriuretic peptide (N-BNP) in children, who underwent a diagnostic work up for short stature or delayed puberty. N-BNP was measured in 52 children before and after administration of LHRH. Serum N-BNP obtained from 255 healthy children and adolescents (aged birth-18.3 years) served as a reference. There was no significant difference between baseline N-BNP of children who underwent the LHRH diagnostic test and their healthy peers. There was no significant serum N-BNP level change before or after administration of LHRH (59 +/- 36 pg/mL vs 58 +/- 34 pg/mL). N-BNP fell from 399 +/- 425 pg/mL in newborns and reached 44 +/- 36 pg/mL in children aged 12-18 years. Short stature or delayed puberty had no effect on heart function determined by serum N-BNP; i.v. LHRH does not acutely influence the level of serum N-BNP.

Function of the hypothalamic–pituitary–gonadal axis in long-term survivors of hematopoietic stem cell transplantation for hematological diseases

Gonadal dysfunction in adult long-term survivors of hematopoietic stem cell transplantation (HSCT) is an adverse effect of conditioning regimens consisting of chemotherapy and total body irradiation (TBI). The impact of conditioning regimens consisting of chemotherapy alone on the function of the hypothalamic–pituitary–gonadal (HPG) axis was evaluated in a series of 41 female and 31 male patients who had undergone either autologous or allogeneic bone marrow/peripheral blood stem cell transplantation; mean age at transplantation was 32.6 years and mean time interval from transplantation was 1.5 years (range 0.2–9.8 years). Provocative testing of the HPG axis by administration of luteinizing hormone-releasing hormone was included in the first endocrinological evaluation. The follow-up period extended to three consecutive years. Gonadal dysfunction was not reported by any of the patients prior to their underlying illness. Hypergonadotrophic hypogonadism was observed in 97% of female and 19% of male patients. Leydig cell strain (normal testosterone, high luteinizing hormone levels) was evident in 32% and spermatogenesis damage (high follicle-stimulating hormone levels) in 68% of the male population. At the conclusion of the study four women (10%) had regained spontaneous menses and all hypogonadal men had resumed normal testosterone levels. Our results indicate a high incidence of gonadal dysfunction due to target organ failure in HSCT recipients not treated by TBI.

P181 - Pseudo-pubertés précoces révélatrices d’un corticosurrénalome malin

Trente huit enfants ont été traités pendant au moins 2 ans pour une puberté précoce par un analogue retard du LH-RH. Ce traitement a été bien toléré. Il entraîne une régression des caractères secondaires, une diminution de la vitesse de croissance, un ralentissement de la maturation osseuse, une inhibition de la sécrétion des gonadotrophines hypophysaires et une normalisation des stéroïdes sexuels. La normalisation du rapport âge statural/âge osseux fait espérer une amélioration de la taille définitive.Chronic administration of luteinizing hormone-releasing hormone (LH-RH) is currently considered as the most appropriate therapy of precocious puberty. A delayed release preparation of D-Trp-6-LH-RH (Décapeptyl ® in microcapsules) designed to release the agonist for 28 days after intramuscular injection of 60 μg/kg body wt was given to 12 boys and 26 girls with precocious puberty. Plasma levels of gonadotropins and sex steroids were suppressed to prepubertal levels within 3 weeks, whilst pituitary responses to LH-RH test were almost abolished within 7 weeks.A significant improvement of secondary sex characteristics, as well as gonadal size, was observed within 6 months. Growth velocity (cm/yr, mean ± SD) was reduced in boys and girls from 9.9 ± 3.4 and 9.6 ± 3.3 respectively before treatment to 5.2 ± 1.0 and 5.3 ± 1.3 respectively during the third year of treatment. The mean ratio height age/bone age was just before treatment 0.91 in boys and 0.88 in girls and increased to 1 after 3 yr of treatment. This study shows that Decapeptyl in microcapsules induced a prolonged suppression of gonadal function and a relative blockade of bone maturation. A significant improvement of adult height relative to the effect of conventional treatments should be expected.

Constitutionally Tall Stature with Morphological Abnormality of the Pituitary Gland

We describe two male pubertal cases of constitutionally tall stature (CTS) with an enlarged pituitary gland or pituitary microadenoma. Both patients' basal serum growth hormone (GH) levels were normal. Neither had oversecretion of any other pituitary hormones. However, their serum GH levels were paradoxically increased in response to an intravenous administration of thyrotropin-releasing hormone (TRH). A later GH response to an intravenous administration of luteinizing hormone-releasing hormone (LHRH) was also found in one patient. In addition, oral glucose loading (OGL) caused a late increase in serum GH at 180 min in both patients. Our present findings suggest that endocrinological and morphological abnormalities of the pituitary gland are found in some subjects with CTS during puberty. It is speculated that these paradoxical GH responses are associated with dysregulation of GH secretion. Finally, it is important to investigate whether tall children with morphological abnormalities of the pituitary gland such as our patients are preacromegalic, in which case, given that overproduction of GH secretion may occur in the future, further observation is necessary.

Effect of oxytocin on nitric oxide activity controlling gonadotropin secretion in humans.

Previously described inhibitory effects of the nitric oxide synthase (NOS) inhibitor L-NAME on luteinizing hormone-releasing hormone (LH-RH)-induced LH and follicle stimulating hormone (FSH) secretion in humans suggested modulation by nitric oxide (NO) of the gonadotropin-releasing action of LH-RH. In order to establish whether oxytocin (OT) participates in this regulatory mechanism, 10 normal men were treated with LH-RH (100 micro g as an i.v. bolus) given alone or in the presence of L-NAME (40 micro g kg-1 injected plus 50 micro g kg-1 infused i.v. for 60 min), OT (2 IU injected plus 4 IU infused i.v. for 60 min) or a combination of both drugs. The administration of OT was unable to change the gonadotropin responses to LH-RH. In contrast, L-NAME significantly reduced both FSH and LH increments induced by LH-RH. When L-NAME was given in the presence of OT, the LH and FSH responses to LH-RH were similar to those observed after the administration of LH-RH alone. These data suggest antagonistic actions of OT and L-NAME in the control of NOS activity in regulation of gonadotropin secretion induced by LH-RH.

Effects of Long-Term Erythropoietin Therapy on the Hypothalamo–Pituitary–Testicular Axis in Male Capd Patients

Gonadal dysfunction has been recognized for a long time in uremic male patients. The present study assesses the hypothalamo-pituitary-testicular axis and growth hormone status in male continuous ambulatory peritoneal dialysis (CAPD) patients, before and after recombinant human erythropoietin (rHuEPO) therapy. Single-center prospective study. Ten anemic male patients with chronic renal insufficiency, and 11 healthy volunteers with normal renal function, matched for age, were included in the study. All patients were on CAPD therapy and none had received rHuEPO treatment previously. Blood samples were collected between 0800 and 0900 hr from all patients for the determination of basal follicle stimulating hormone (FSH), luteinizing hormone (LH), and growth hormone (GH) levels. A luteinizing hormone-releasing hormone (LH-RH) stimulation test was carried out using LH-RH 100 microg intravenous as a bolus injection. Blood for FSH, LH, and GH determinations was drawn every 30 minutes during the 3-hour test period. Human chorionic gonadotropin (hCG) test was performed after 48 hours. After estimations of basal serum total and free testosterone levels, 2000 IU hCG was administered intramuscularly and repeated 48 hours later. Total and free testosterone levels were measured in blood samples collected before and 48 hours after two injections of hCG. After improvement in anemia with exogenous rHuEPO, LH-RH and hCG tests were repeated. Baseline FSH concentrations before and after rHuEPO treatment were slightly higher in CAPD patients than in healthy volunteers (p = 0.85 and p = 0.70, respectively). Areas-under-the-curve (AUCs) for FSH secretion before and after rHuEPO treatment were also slightly higher in patients than in healthy volunteers (p = 1.00 and p = 0.75, respectively). The pretreatment basal LH levels in patients were significantly higher than in controls (p < 0.001). After the improvement in anemia with rHuEPO, serum LH levels declined significantly (p < 0.05). The AUCs for LH secretion before and after rHuEPO treatment were significantly higher in patients than in controls (p < 0.05). All patients had elevated basal levels of GH with paradoxical response to LH-RH. Baseline GH levels in patients were significantly higher than those in healthy subjects (p < 0.001) before rHuEPO treatment. After treatment with rHuEPO, basal GH levels declined but did not normalize, and baseline levels of free testosterone increased significantly (p < 0.05). Anemic uremic male patients on CAPD have normal levels of testosterone with normal response to hCG administration, elevated basal levels of GH, and elevated basal levels of LH, with exaggerated response to LH-RH administration. Improvement in anemia with rHuEPO reduced the basal levels of LH and GH, but exaggerated the LH response; paradoxical GH response to LH-RH administration persisted. These results indicate a defect at the level of the hypothalamus and pituitary gland in uremic male patients undergoing CAPD, and that the improvement in anemia with rHuEPO partially restores some of these endocrine abnormalities.

Ultrastructural changes in granulosa cells and plasma steroid levels after administration of luteinizing hormone-releasing hormone in the Western painted turtle, Chrysemys picta

In this study we investigated the effects of treatment by luteinizing hormone-releasing hormone (LHRH) on the morphology and steroid release of ovarian tissues in the Western painted turtle, (Chrysemys picta). In Experiment I, four adult female turtles were injected with synthetic mammalian LHRH (i.p., 500pg/g bodyweight) and four with saline 2–3 weeks prior to ovulation. Granulosa cells from LHRH-treated turtles vs controls contained both preovulatory follicles (16–20mm in diameter) and small follicles (0.5–1.00mm in diameter) with increased RER, free ribosomes and mitochondria with swollen cristae. An increase in the amount of cytoskeletal material (microfilaments) was observed in granulosa cells of the experimental turtles compared to the controls. Cytoplasmic extensions of the oocyte and granulosa cells were longer in the small follicles of treated animals, accounting for the observed increase in the thickness of the zona pellucida (ZP) over the controls. In Experiment II, administration of LHRH (i.p.) to 10 turtles during the same period triggered a substantial increase in plasma progesterone and estradiol-17β levels over the 10 saline-injected controls. This supports the idea that in this species, as in mammals, steroidogenic activity in the ovarian follicles are under the control of the hypothalamic–pituitary axis. The ultrastructure and hormonal levels of the experimental animals were typical of untreated turtles just prior to ovulation. In this species the development of follicles and steroidogenesis can be stimulated prematurely by a releasing hormone from a nonreptilian origin.