Louise Bath

Ovarian and uterine characteristics after total body irradiation in childhood and adolescence: response to sex steroid replacement

Objective To study the effect of total body irradiation (14.4 Gray) in childhood and adolescence on ovarian and uterine characteristics, and to investigate the response to physiological sex steroid serum concentrations.

Non-DNA binding, dominant-negative, human PPARγ mutations cause lipodystrophic insulin resistance

Summary PPARγ is essential for adipogenesis and metabolic homeostasis. We describe mutations in the DNA and ligand binding domains of human PPARγ in lipodystrophic, severe insulin resistance. These receptor mutants lack DNA binding and transcriptional activity but can translocate to the nucleus, interact with PPARγ coactivators and inhibit coexpressed wild-type receptor. Expression of PPARγ target genes is markedly attenuated in mutation-containing versus receptor haploinsufficent primary cells, indicating that such dominant-negative inhibition operates in vivo. Our observations suggest that these mutants restrict wild-type PPARγ action via a non-DNA binding, transcriptional interference mechanism, which may involve sequestration of functionally limiting coactivators.

Radiation damage to the uterus — Review of the effects of treatment of childhood cancer

At the present time approximately 1 in 1000 young people aged between 16 and 35 years will have been cured of cancer in childhood and some of the treatment regimens used will have predictable effects on their future fertility prospects. In young women who have been exposed to radiotherapy below the diaphragm, the reproductive problems include the risk of ovarian failure and significantly impaired development of the uterus. The magnitude of the risk is related to the radiation field, total dose and fractionation schedule. Premature labour and low birth weight infants have been reported after flank abdominal radiotherapy. Female long-term survivors treated with total body irradiation and marrow transplantation are also at risk of ovarian follicular depletion and impaired uterine growth and blood flow, and of early pregnancy loss and premature labour if pregnancy is achieved. Despite standard oestrogen replacement, the uterus of these young girls is often reduced to 40% of normal adult size. Uterine volume correlates with the age at which radiation was received. Regrettably, it is likely that radiation damage to the uterine musculature and vasculature adversely affects prospects for pregnancy in these women. It has been demonstrated that, in women treated with total body irradiation, sex steroid replacement in physiological doses significantly increases uterine volume and endometrial thickness, as well as re-establishing uterine blood flow. However, it is not known whether standard regimens of oestrogen replacement therapy are sufficient to facilitate uterine growth in adolescent women treated with total body irradiation in childhood. Even if the uterus is able to respond to exogenous sex steroid stimulation, and appropriate assisted reproductive technologies are available, a successful pregnancy outcome is by no means ensured. The uterine factor remains a concern and women who are survivors of childhood cancer and their carers must recognize that these pregnancies will be at high risk.

Late effects of the treatment of childhood cancer on the female reproductive system and the potential for fertility preservation

One in 600 children will develop cancer in the first 15 years of life. Unlike the majority of adult cancers, most paediatric cancers are curable using multi-agent chemotherapy in combination with surgery and radiotherapy. The incidence of childhood cancer is 110 to 130 per million children per year and the relative frequencies of paediatric cancers as follows: leukaemia 34%; brain/spinal 24%; embryonal 15%; lymphona 11%; soft tissue 6%; bone 5%; others 5%. Over the last three decades there has been a sustained improvement in survival for most forms of childhood cancer. In the 1960s, acute lymphoblastic leukaemia, the most common childhood malignancy, had a five-year survival rate of less than 10%. Today, 70% of these children may now be cured. Following the demonstration in the 1950s that actinomycin was an effective agent in the treatment of Wilms’ tumour, there has been steady progress in the development of multi-agent chemotherapy regimens for the majority of childhood haematological and solid tumours. Radiotherapy is highly effective in the treatment of many malignancies but the increasing recognition of the morbidity for children from the late effects of radiation exposure has limited its therapeutic benefit. The majority of children with cancer are treated in specialised paediatric oncology centres according to nationally and often internationally agreed protocols. At the start of the 21 century, one in 1000 young adults in their third decade is a survivor of childhood cancer. The number of long term survivors is increasing year by year. The major challenge for this generation of children’s cancer specialists is to sustain the significant improvement in survival rates while at the same time minimising the treatment-induced late effects. The risk of late effects is directly related to the nature of the treatment received. The anticipation of late effects and their detection is important, as they may be amenable to prevention or treatment. The reproductive system is an important site of late effects of anti-cancer treatment. Natural pubertal progression, fertility and successful pregnancy outcome depend on normal hypothalamic, pituitary, ovarian and uterine function. Potential adverse effects on reproductive function in the female may be mediated through the hypothalamo–pituitary–ovarian axis, the ovary or the uterus. One of the more commonly recognised adverse effects of anti-cancer treatments is ovarian failure as a result of depletion of the numbers of primordial follicles leading to a premature menopause. The late effects of the treatment on reproductive function are difficult to predict with certainty. The patient or parents may expect discussion of these potential late effects before treatment commences. Options to preserve reproductive potential are limited in the case of young women and are experimental. Physicians need to be aware of the potential problems so that therapeutic prevention strategies and late effects can be openly discussed with the aim of cure at least cost.

Cardiovascular effects of physiological and standard sex steroid replacement regimens in premature ovarian failure

Current hormone replacement therapy may not optimize cardiovascular health in women with premature ovarian failure. We compared the effects of physiological and standard sex steroid replacement regimens on cardiovascular health in these women. In an open-label, randomized, controlled crossover trial, 34 women with premature ovarian failure were randomly assigned to 4-week cycles of physiological (transdermal estradiol and vaginal progesterone) and standard (oral ethinylestradiol and norethisterone) therapy for 12 months. Cardiovascular health was assessed by 24-hour ambulatory blood pressure, arterial stiffness, and renal and humoral factors. Eighteen women (19 to 39 years of age) completed the 28-month protocol. Both regimens caused similar suppression of luteinizing hormone and follicle-stimulating hormone and provided symptom relief. In comparison with the standard regimen, physiological sex steroid replacement caused lower mean 24-hour systolic and diastolic blood pressures throughout the 12-month treatment period (ANOVA; P≤0.0001 for both): systolic blood pressure was 7.3 mm Hg (95% CI: 2.5 to 12.0 mm Hg) and diastolic was 7.4 mm Hg (95% CI: 3.9 to 11.0 mm Hg) lower at 12 months. Although there were no differences in arterial stiffness, physiological sex steroid replacement reduced plasma angiotensin II (ANOVA; P=0.007) and serum creatinine (ANOVA; P=0.015) concentrations without altering plasma aldosterone concentrations. In comparison with a standard regimen, physiological sex steroid replacement in women with premature ovarian failure results in lower blood pressure, better renal function, and less activation of the renin-angiotensin system. These findings have major implications for the future cardiovascular health of young women who require long-term sex steroid replacement therapy.

Quantification of human urinary exosomes by nanoparticle tracking analysis

•  Exosomes are vesicles that are released from the kidney into the urine. They contain RNA and protein from the cell of origin and can track changes in renal physiology non‐invasively. •  Current methods for the identification and quantification of urinary exosomes are time consuming and only semi‐quantitative. •  In this study, we applied nanoparticle tracking analysis to human urine and identified particles with a range of sizes, including a subpopulation of characteristic exosomal size that labelled positively with antibodies to exosome proteins. •  Nanoparticle tracking analysis was able to track an increase in exosomal aquaporin 2 concentration following desmopressin treatment of a kidney cell line, a rodent model and a patient with central diabetes insipidus. •  With appropriate sample storage, nanoparticle tracking analysis has potential as a tool for the rapid characterization and quantification of exosomes in human urine. This new method can be used to develop urinary extracellular vesicles further as a non‐invasive tool for investigating human renal physiology.

Physiological versus standard sex steroid replacement in young women with premature ovarian failure: effects on bone mass acquisition and turnover

Background  The aim of this exploratory study was to establish whether we could improve skeletal health with a physiological regimen of SSR in young women with premature ovarian failure (POF).

Hydroxybutyrate near-patient testing to evaluate a new end-point for intravenous insulin therapy in the treatment of diabetic ketoacidosis in children

Background:  The aim of this study was to assess the clinical application of a near‐patient testing (NPT) device for capillary blood hydroxybutyrate (HOB) measurement in evaluating a new end‐point for intravenous insulin therapy in the treatment of diabetic ketoacidosis (DKA) in children.

OBESITY IN LEUKEMIA SURVIVORS: The Familial Contribution

A high prevalence of obesity in survivors of acute lymphoblastic leukemia (ALL) has been described, but genetic and social influence in obesity has not been analyzed in this group of patients. The authors studied a population of 33 long-term (25 females, 8 males) in first remission who had reached their final height. All patients received cranial irradiation as part of their central nervous system (CNS)-directed therapy and no patient received growth hormone. The body mass index (BMI: weight/height2) of patients and their biological parents was calculated and submitted to statistical analysis. Obesity was defined as BMI greater than the 85th centile. No excessive obesity was found among the males at final height. Fifty-six percent of the females were obese. In this group of 14 obese female survivors 59% had obese mother, but only 14% had obese fathers. The results indicate a significant maternal predisposition to obesity.

Is inhibin B a potential marker of gonadotoxicity in prepubertal children treated for cancer

background and objective Chemotherapy treatment of childhood cancer may impair gonadal function, which may be manifested only in adulthood as permanent sterility. Detection of gonadal dysfunction in prepubertal children has been hampered by the absence of a sensitive marker. Inhibin B is secreted by small antral follicles and Sertoli cells in females and males, respectively, and may be a marker of gonadal function in prepubertal children. The aim of this pilot study was to evaluate inhibin B in relation to sensitive measurements of gonadotrophins as markers of the early gonadotoxic effects of chemotherapy in prepubertal children treated for cancer.