The effect of methadone on the hypothalamic pituitary gonadal axis and sexual function: A systematic review.

BACKGROUND: Opioid abuse is a public health crisis. As opioid misuse worsens, efforts are being made to increase access to medication-assisted treatments. Methadone is a medication-assisted treatment used to treat opioid dependence and chronic pain. While methadone is beneficial in the treatment of opiate abuse and chronic pain, side effects of the medication include hormonal and sexual function changes. The purpose of this report is to review the effects of methadone on the hypothalamic pituitary gonadal axis hormones and sexual functioning in males and females. METHODS: A search of PubMed was conducted using pre-defined criteria, resulting in the evaluation of 295 articles. A total of 72 articles, including 52 human studies and 20 animal studies, met the selection criteria and were reviewed. The included studies examined the effects of methadone on the hypothalamic pituitary gonadal axis and/or sexual function. RESULTS: There was evidence of methadone-induced hormonal changes, disruptions in the hypothalamic pituitary gonadal axis, and sexual dysfunction, although there was some variability in the results of the reviewed studies. Differences in methadone dose and length of exposure to treatment appears to influence the variability in the results. Much of the literature examines the effects of methadone in males, with very limited research examining the effects in females. CONCLUSIONS: Despite its effectiveness for opiate abuse and chronic pain treatment, methadone has disruptive effects on the hypothalamic pituitary gonadal axis and sexual function. Further research is warranted to better define potential methadone-induced endocrine consequences and to further examine the effects of methadone in females.

Toward a multi-country monitoring system of reproductive health in the context of endocrine disrupting chemical exposure.

BACKGROUND: Worrying trends regarding human reproductive endpoints (e.g. semen quality, reproductive cancers) have been reported and there is growing circumstantial evidence for a possible causal link between these trends and exposure to endocrine disrupting chemicals (EDCs). However, there is a striking lack of human data to fill the current knowledge gaps. To answer the crucial questions raised on human reproductive health, there is an urgent need for a reproductive surveillance system to be shared across countries. METHODS: A multidisciplinary network named HUman Reproductive health and Global ENvironment Network (HURGENT) was created aiming at designing a European monitoring system for reproductive health indicators. Collaborative work allowed setting up the available knowledge to design such a system. Furthermore we conducted an overview of 23 potential indicators, based upon a weight of evidence (WoE) approach according to their potential relation with EDC exposure. RESULTS: The framework and purposes of the surveillance system are settled as well as the approach to select suitable reproductive indicators. The indicators found with the highest scores according to the WoE approach are prostate and breast cancer incidence, sex ratio, endometriosis and uterine fibroid incidence, indicators related to the testicular dysgenesis syndrome, precocious puberty incidence and reproductive hormone levels. CONCLUSION: Not only sentinel health endpoints, but also diseases with high burdens in public health are highlighted as prior indicators in the context of EDC exposure. Our work can serve as a basis to construct, as soon as possible, the first multi-country reproductive monitoring system.

Endocrinologic Consequences of Pediatric Posterior Fossa Tumours.

Intracranial tumors are the second most frequent malignancies in children and posterior fossa is a common location for these neoplasias during childhood. Recent advances in surgical techniques, radiotherapy and chemotherapy resulted in dramatic increase in the survival rates of these children, however they are still source of a significant morbidity and mortality. Endocrinological complications and late sequelae of childhood posterior fossa tumours are common among the survivors of these tumours and include growth retardation, hypothyroidism, pubertal disorders, gonadal dysfunction and osteopenia. These complications have significant impact on the quality of life of the survivors of childhood posterior fossa tumours. In this paper, the frequency, etiology, and management of these complications will be reviewed.

Gonadal function of beta-thalassemics following stem cell transplantation conditioned with myeloablative and reduced intensity regimens.

Gonadal dysfunction is a complication following stem cell transplantation (SCT). There have been no reports of gonadal function in stem-cell-transplanted thalassemic survivors who received a reduced intensity conditioning regimen (RIC). We evaluated gonadal function in 47 ß-thalassemic patients following SCT with either myeloablative or reduced intensity regimen. Thirty-six patients received a myeloablative regimen, the remaining 11 patients had an RIC regimen. Their median (range) age was 13.2 (5.9-25.8) years. There were 29 patients (62%) with gonadal dysfunction (26 with primary gonadal dysfunction and three with gonadotropin deficiency). Comparisons between patients who received myeloablative and RIC regimens, revealed no differences in gonadal dysfunction (56% vs. 82%, p=0.113, respectively). In conclusion, our study demonstrated high frequency of gonadal dysfunction in these patients. Even after receiving RIC, gonadal dysfunction was very common. To our knowledge, this study is the first to report gonadal function in children and adolescents with ß-thalassemia disease who were pre-transplanted with RIC.

Long-term endocrine side effects of childhood Hodgkin's lymphoma treatment: a review.

BACKGROUND Since childhood cancer survival has increased, long-term effects of treatment have gained interest. Childhood Hodgkin's lymphoma has been treated successfully for decades now. We provide an overview of the literature on long-term endocrine side effects, such as gonadal dysfunction and growth retardation, as a result of childhood Hodgkin's lymphoma treatment. METHODS A comprehensive search of the Pubmed database was performed. RESULTS We identified 16 studies (10 studies: 298 male survivors and 6 studies: 230 female survivors) about gonadal dysfunction. In survivors treated with alkylating agents or pelvic radiotherapy, severe gonadal damage is described. Recovery was rarely described. Seven studies (481 survivors) about bone mineral density (BMD) and growth were identified. The effects on BMD appear to be small. Data on growth are scarce, but show that radiotherapy in a dose of >30 Gy including the spine, especially in pre-pubertal children, results in reduced height. We included 10 studies (4012 survivors) about thyroid complications. Hypothyroidism is the most common thyroid disorder after radiotherapy. There is also a significant incidence in thyroid carcinoma after low-dose radiation. In survivors treated with chemotherapy only, hypothyroidism and thyroid cancer have not been reported. CONCLUSIONS The severity of endocrine toxicity after childhood Hodgkin's lymphoma depends on the type of treatment. Gonadal dysfunction seems to be the most severe endocrine long-term effect, especially after treatment with alkylating agents or pelvic radiotherapy. The knowledge obtained in specific follow-up programmes for paediatric cancer survivors will help to find the optimal balance between curability and long-term side effects.

Regulation of circulating leptin and its soluble receptor during pubertal development in the male rhesus monkey (Macaca mulatta).

In humans, circulating leptin levels are low in early childhood and rise until puberty, whereas the reverse occurs for the soluble leptin receptor (sOB-R). In women, leptin remains high and sOB-R remains low, but in men leptin declines after adolescence and sOB-R increases. These observations suggest that leptin may regulate the production of sOB-R, and that the increased testosterone in adolescent boys may be responsible for the gender differences in leptin and sOB-R. To test this hypothesis, leptin was administered continuously to agonadal juvenile male monkeys for 16 days. No change in sOB-R was observed. Intact juvenile male monkeys were given pulsatile doses of gonadotropins for a period of 7 weeks to induce precocious puberty and assess the effect on plasma testosterone, leptin, and sOB-R. By 4 weeks testosterone had reached adult levels. No changes were observed in leptin, but by week 4, sOB-R was higher than pretreatment values and remained higher at week 7. These data suggest that leptin may not play a significant role in regulating the production of sOB-R and that gender differences in sOB-R in humans may be driven by the increased production of testosterone at puberty in males.

Drug-induced endocrine and metabolic disorders.

Complex interactions exist amongst the various components of the neuroendocrine system in order to maintain homeostasis, energy balance and reproductive function. These components include the hypothalamus-pituitary- adrenal and -gonadal axes, the renin-angiotensin-aldosterone system, the sympathetic nervous system and the pancreatic islets. These hormones, peptides and neurotransmitters act in concert to regulate the functions of many organs, notably the liver, muscles, kidneys, thyroid, bone, adrenal glands, adipocytes, vasculature, intestinal tract and gonads, through many intermediary pathways. Endocrine and metabolic disorders can arise from imbalance amongst numerous hormonal factors. These disturbances may be due to endogenous processes, such as increased secretion of hormones from a tumour, as well as exogenous drug administration. Drugs can cause endocrine abnormalities via different mechanisms, including direct alteration of hormone production, changes in the regulation of the hormonal axis, effects on hormonal transport, binding, and signalling, as well as similar changes to counter-regulatory hormone systems. Furthermore, drugs can affect the evaluation of endocrine parameters by causing interference with diagnostic tests. Common drug-induced endocrine and metabolic disorders include disorders of carbohydrate metabolism, electrolyte and calcium abnormalities, as well as drug-induced thyroid and gonadal disorders. An understanding of the proposed mechanisms of these drug effects and their evaluation and differential diagnosis may allow for more critical interpretation of the clinical observations associated with such disorders, better prediction of drug-induced adverse effects and better choices of and rationales for treatment.

Female puberty: clinical implications for the use of prolactin-modulating psychotropics.

During puberty, girls may present with psychiatric illness necessitating treatment with psychotropic medications. Pubertal girls are especially vulnerable to medication-associated adverse events. Atypical antipsychotics and antidepressants have the potential to elevate prolactin levels, altering pubertal progression. Selection of prolactin-sparing atypical antipsychotics is recommended, as is treatment with the lowest effective dose of selective serotonin reuptake inhibitors. Monitoring of serum prolactin levels may be necessary.

Biomarkers of reproductive toxicity.

A biomarker can be broadly defined as any biological index capable of being measured, which is associated with or indicative of a defined biological endpoint such as a developmental or disease stage. Identification and verification of anatomical, endocrine, cellular and molecular biomarkers is crucial for successful clinical diagnosis and treatment of toxicity and disease, as well as basic toxicological, epidemiological and other research. Various biomarkers of reproductive development and health have been identified, including those associated with pubertal development, adult reproductive health and pregnancy outcome. Herein we discuss those in situ biomarkers which have been more closely associated with toxicant action on the reproductive system. Biomarkers of toxicant exposure and susceptibility are addressed, but the majority of the review focuses on those biomarkers which may prove useful for determining current pathophysiological status or predicting future adverse outcomes. In males these are primarily associated with altered spermatogenesis and sperm parameters, and in females with altered endocrine function. We conclude that although few robust in situ biomarkers are currently available which are specific for toxicant exposure, susceptibility or effect in reproductive systems, there is expectation that post-genomic technologies offer a new paradigm for identifying and verifying such biomarkers as may exist.

Decreasing the number of MOPP courses reduces gonadal damage in survivors of childhood Hodgkin disease.

BACKGROUND: Children treated for Hodgkin disease are at risk for gonadal damage. Since most children were treated with radiotherapy (RT) in combination with chemotherapy, the presumed detrimental effect of MOPP (mustine, vincristine, procarbazine, and prednisone) (in contrast to schemes with less or without alkylating agents) could not be discerned completely from the effects of RT. PROCEDURES: Children with Hodgkins disease treated without RT were included in sequential protocols containing six courses of MOPP (n = 24), six courses of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) (n = 17), or three courses of MOPP/ABVD (n = 35). Of these 76 patients, 48, who had completed treatment and had reached puberty, were investigated for gonadal damage. RESULTS: Of the male patients, 81% of MOPP treated patients had increased follicular stimulating hormone (FSH) values, in 23% luteinizing hormone (LH) values were abnormal. In ABVD treated patients, no elevated levels of FSH or LH were noted. In 30% of patients treated with MOPP/ABVD, FSH values were abnormal, but no abnormal LH values were found. Median testicular volume per group decreased in relation to a higher number of MOPP courses. Sperm analysis revealed azoospermia in nearly all MOPP treated patients. In ABVD and MOPP/ABVD treated patients both oligospermia and azoospermia were noted. The number of sperm samples were too less to make any sound conclusions. Menarche occurred in all females, however in some at a relatively later age. One female patient treated with MOPP/ABVD had a normal pregnancy. CONCLUSIONS: Limitation of MOPP therapy to three courses, in children treated without any RT, results in less gonadal damage as compared with six MOPP courses. From our data, MOPP damages Sertoli cells and may also damage Leydig cells as suggested by the higher LH values in conjunction with normal testosterone levels.

Minimising the long-term adverse effects of childhood leukaemia therapy.

Malignancies in childhood occur with an incidence of 13-14 per 100,000 children under the age of 15 years. Acute lymphoblastic leukaemia with an incidence of 29% is the most common paediatric malignancy, whereas acute myeloid leukaemias account for about 5%. The treatment of acute leukaemias consists of sequential therapy cycles (induction, consolidation, intensification, maintenance therapy) with different cytostatic drugs over a time period of up to 1.5-3 years. Over the last 25 years of clinical trials, a significant rise in the rate of complete remissions as well as an increase in long-term survival has been achieved. Therefore, growing attention is now focused on the long-term effects of antileukaemic treatment. Several cytostatic drugs administered in the treatment of acute leukaemia in childhood are known to cause long-term adverse effects. Anthracyclines may induce chronic cardiotoxicity, alkylating agents are likely to cause gonadal damage and secondary malignancies and the use of glucocorticoids may cause osteonecrosis. Most of the long-term adverse effects have not been analysed systematically. Approaches to minimising long-term adverse effects without jeopardising outcome have included: the design of new drugs such as a liposomal formulation of anthracyclines, the development of anthracycline-derivates with lower toxicity, the development of cardioprotective agents or, more recently, the use of targeted therapy;alternative administration schedules like continuous infusion or timed sequential therapy; and risk group stratification by the monitoring of minimal residual disease. Several attempts have been made to minimise the cardiotoxicity of anthracyclines: decreasing concentrations delivered to the myocardium by either prolonging infusion time or using liposomal formulated anthracyclines or less cardiotoxic analogues, or the additional administration of cardioprotective agents. The advantage of these approaches is still controversial, but there are ongoing clinical trials to evaluate the long-term effects. The use of new diagnostic methods, such as diagnosis of minimal residual disease, which allow reduction or optimisation of dose, offer potential advantages compared with conventional treatment in terms of reducing the risk of severe long-term adverse effects. Most options for minimising long-term adverse effects have resulted from theoretical models and in vitro studies, but only some of the modalities such as the use of dexrazoxane, the continuous infusion of anthracyclines or timed sequential therapy, have been evaluated in prospective, randomised studies in patients. Future approaches to predict severe toxicity may be based upon pharmacogenetics and gene profiling.

Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide.

A recent case of iatrogenic Cushing's syndrome and complete suppression of the pituitary-adrenal-axis in a patient with cystic fibrosis (CF) and allergic bronchopulmonary aspergillosis treated with itraconazole as an antifungal agent, and budesonide as an anti-inflammatory agent led to a systematic assessment of this axis and gonadal function in all patients treated with itraconazole in the authors' CF centre. Itraconazole can inhibit CYP3A, thus interfering with synthesis of gluco- and mineralocorticoids, androgens and oestradiol as well as the metabolism of budesonide. The aim of this study was to evaluate adrenal and gonadal function in patients treated with itraconazole with or without budesonide. An adrenocorticotrophic hormone (ACTH) test (250 microg tetracosactid) was performed in 25 CF patients treated with both itraconazole and budesonide, and in 12 patients treated with itraconazole alone (six patients with CF and six with chronic granulomateous disease). Mineralocorticoid and gonadal steroid function were evaluated by measurements of plasma-renin, follicle stimulating hormone, luteinising hormone, progesterone, oestradiol, testosterone, serum-inhibin A and B. ACTH tests performed as part of a pretransplantation programme in an additional 30 CF patients were used as controls. Eleven of the 25 patients treated with both itraconazole and budesonide had adrenal insufficiency. None of the patients on itraconazole therapy alone nor the control CF patients had a pathological ACTH test. Mineralocorticoid and gonadal insufficiency was not observed in any of the patients. Only one patient with an initial pathological ACTH-test subsequently normalised, the other 10 patients improved but had not achieved normalised adrenal function 2-10 months after itraconazole treatment had been discontinued. Suppression of the adrenal glucocorticoid synthesis was observed in 11 of 25 cystic fibrosis patients treated with both itraconazole and budesonide. The pathogenesis is most likely an itraconazole caused increase in systemic budesonide concentration through a reduced/inhibited metabolism leading to inhibition of adrenocorticotrophic hormone secretion along with a direct inhibition of steroidogenesis. In patients treated with this combination, screening for adrenal insufficiency at regular intervals is suggested.

Getting the problem of endocrine disruption into focus: the need for a pause for thought.

The study of chemically-induced endocrine disruption in mammals is a relatively new field of endeavour, and it has been assailed by an unusual level of disagreement among investigators regarding the developmental effects produced by chemicals in animals. This article discusses the several sources of uncertainty in endocrine toxicity studies, and the intrinsic variability of many of the key experimental parameters. It is concluded that current uncertainties are due to the absence of an extensive agreed control database for the developmental parameters under study, coupled to the established intrinsic variability of these parameters between strains/species of test animals and test protocols. Only when these factors are generally accepted and well studied will it be possible to design studies capable of distinguishing the possible subtle endocrine toxicity of chemicals and chance observations that cannot be independently reproduced.