Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin‐releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor ...1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β‐Klotho (KLB), the obligate co‐receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH. Genetic screening of 334 CHH patients identified seven heterozygous loss‐of‐function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction.
Synopsis
Defects in FGF21/KLB/FGFR1 signaling contribute to GnRH deficiency in both humans and mice. This signaling pathway is a novel link between metabolism and reproduction.
Heterozygous loss‐of‐function mutations in KLB are found in patients with congenital hypogonadotropic hypogonadism.
Klb‐deficient mice delayed sexual maturation and impaired fertility with decreased gonadotropins due to a hypothalamic defect.
Klb is expressed in the postnatal hypothalamus including GnRH neurons.
FGF21 reaches GnRH neurons via fenestrated capillaries in the hypothalamus in vivo and enhances GnRH release in median eminence explants in vitro.
Defects in FGF21/KLB/FGFR1 signaling contribute to GnRH deficiency in both humans and mice. This signaling pathway is a novel link between metabolism and reproduction.
Pituitary disease is associated with increased mortality predominantly due to vascular disease. Control of cortisol secretion and GH hypersecretion (and cardiovascular risk factor reduction) is key ...in the reduction of mortality in patients with Cushing’s disease and acromegaly, retrospectively. For patients with acromegaly, the role of IGF-I is less clear-cut. Confounding pituitary hormone deficiencies such as gonadotropins and particularly ACTH deficiency (with higher doses of hydrocortisone replacement) may have a detrimental effect on outcome in patients with pituitary disease. Pituitary radiotherapy is a further factor that has been associated with increased mortality (particularly cerebrovascular). Although standardized mortality ratios in pituitary disease are falling due to improved treatment, mortality for many conditions are still elevated above that of the general population, and therefore further measures are needed. Craniopharyngioma patients have a particularly increased risk of mortality as a result of the tumor itself and treatment to control tumor growth; this is a key area for future research in order to optimize the outcome for these patients.
Pituitary disease is associated with increased mortality. This review discusses epidemiological data and factors associated with increased mortality in patients with pituitary disorders. Although standardized mortality ratios (SMRs) in pituitary disease are falling due to improved treatment, SMRs for many conditions are still elevated above that of the general population and as such further research is required to optimise outcome in these patients.
Pituitary dysfunction is a recognised, but potentially underdiagnosed complication of traumatic brain injury (TBI). Post-traumatic hypopituitarism (PTHP) can have major consequences for patients ...physically, psychologically, emotionally and socially, leading to reduced quality of life, depression and poor rehabilitation outcome. However, studies on the incidence of PTHP have yielded highly variable findings. The risk factors and pathophysiology of this condition are also not yet fully understood. There is currently no national consensus for the screening and detection of PTHP in patients with TBI, with practice likely varying significantly between centres. In view of this, a guidance development group consisting of expert clinicians involved in the care of patients with TBI, including neurosurgeons, neurologists, neurointensivists and endocrinologists, was convened to formulate national guidance with the aim of facilitating consistency and uniformity in the care of patients with TBI, and ensuring timely detection or exclusion of PTHP where appropriate. This article summarises the current literature on PTHP, and sets out guidance for the screening and management of pituitary dysfunction in adult patients with TBI. It is hoped that future research will lead to more definitive recommendations in the form of guidelines.
ContextUp to 3% of US and UK populations are prescribed glucocorticoids (GC). Suppression of the hypothalamo–pituitary–adrenal axis with the potential risk of adrenal crisis is a recognized ...complication of therapy. The 250 μg short Synacthen stimulation test (SST) is the most commonly used dynamic assessment to diagnose adrenal insufficiency. There are challenges to the use of the SST in routine clinical practice, including both the staff and time constraints and a significant recent increase in Synacthen cost.MethodsWe performed a retrospective analysis to determine the prevalence of adrenal suppression due to prescribed GCs and the utility of a morning serum cortisol for rapid assessment of adrenal reserve in the routine clinical setting.ResultsIn total, 2773 patients underwent 3603 SSTs in a large secondary/tertiary centre between 2008 and 2013 and 17.9% (n=496) failed the SST. Of 404 patients taking oral, topical, intranasal or inhaled GC therapy for non-endocrine conditions, 33.2% (n=134) had a subnormal SST response. In patients taking inhaled GCs without additional GC therapy, 20.5% (34/166) failed an SST and suppression of adrenal function increased in a dose-dependent fashion. Using receiver operating characteristic curve analysis in patients currently taking inhaled GCs, a basal cortisol ≥348 nmol/l provided 100% specificity for passing the SST; a cortisol value <34 nmol/l had 100% sensitivity for SST failure. Using these cut-offs, 50% (n=83) of SSTs performed on patients prescribed inhaled GCs were unnecessary.ConclusionAdrenal suppression due to GC treatment, particularly inhaled GCs, is common. A basal serum cortisol concentration has utility in helping determine which patients should undergo dynamic assessment of adrenal function.
We conducted a survey of UK endocrine clinicians between June 2022 and August 2022 to understand current practices regarding GH treatment discontinuation in adults with growth hormone deficiency.
...Using Survey Monkey®, a web-based multiple-choice questionnaire was disseminated to the UK Society for Endocrinology membership. It consisted of 15 questions on demographics, number of patients receiving GH and current practice on GH treatment discontinuation.
In total, 102 endocrine clinicians completed the survey. Of these, 65 respondents (33 endocrinologists and 32 specialist nurses) indicated active involvement in managing patients with growth hormone deficiency. In total, 27.7% of clinicians were routinely offering a trial of GH discontinuation to adults receiving long-term GH therapy. Only 6% had a clinical guideline to direct such practice. In total, 29.2% stated that GH discontinuation should be routinely offered as an option to patients on long-term treatment, whilst 60% were not clearly in favour or against this approach but stated that it should probably be considered, and 9.2% were against. During the GH withdrawal period, most clinicians monitor signs and symptoms (75.4%), measure IGF-1 (84.6%), and complete a quality-of-life assessment (89.2%).
The practice of offering a trial of GH discontinuation in growth hormone deficiency adults on long-term GH therapy is highly variable, reflecting the lack of high-quality evidence. Around a quarter of clinicians offer GH withdrawal for a number of reasons, but only a few have a local clinical guidance. A further 60% of clinicians stated they would probably consider such an approach. Methodologically sound studies underpinning the development of safe and cost-effective guidance are needed.
In this UK survey of endocrine clinicians managing adults with growth hormone deficiency on long-term GH therapy, we explored for the first-time current practice and views on offering GH treatment discontinuation. In total, 27.7% of clinicians were routinely offering this option for a variety of reasons. Only 6% have local clinical guideline available to direct their practice on this. The majority of clinicians (60%), were not clearly in favour or against this approach but indicated it should probably be considered. In the absence of robust evidence on consequences of GH withdrawal, clinicians proposed monitoring of various clinical, biochemical and quality-of-life parameters during the period of discontinuation. Methodologically sound studies that will underpin the development of a safe, cost-effective guidance are needed.
Context:
Historically, Cushing's disease (CD) was associated with a 5-yr survival of just 50%. Although advances in CD management have seen mortality rates improve, outcome from transsphenoidal ...surgery (TSS), the current first-line treatment, varies significantly between centers.
Objectives:
The aim of the study was to define outcome including mortality in a cohort of CD patients treated with TSS over 20 yr.
Design:
We conducted a retrospective cohort study of 80 patients who underwent TSS to treat CD between 1988 and 2009. In 72 cases, data on clinical features and outcomes were collected from medical records. In eight patients, records were unavailable, but in all cases mortality data were obtained from National Health Service (NHS) registries and recorded as standardized mortality ratio.
Setting:
The study was conducted in a United Kingdom tertiary referral center.
Patients or Other Participants:
Adult patients confirmed to have CD participated in the study.
Interventions:
All patients underwent TSS.
Main Outcome Measure:
Patients were subdivided into groups based on disease response after initial treatment. Mortality according to subgroup was also assessed.
Results:
Median follow-up for clinical data was 4.6 yr. Three outcome groups were identified: cure, 72% (52 of 72); persistent disease, 17% (12 of 72); and disease recurrence, 11% (eight of 72). Median time to recurrence after initial remission was 2.1 yr (interquartile range, 1.3–3.1 yr). Mean follow-up for mortality was 10.9 yr. Thirteen of 80 patients had died: five of 52 in the cure group, two of eight in the disease recurrence group, two of 12 with persistent disease, and four of eight of those followed up by NHS registry search only. Overall, the standardized mortality ratio was 3.17 95% confidence interval (CI), 1.70–5.43, whereas in the cure group it was 2.47 (95% CI, 0.80–5.77), and it was 4.12 (95% CI, 1.12–10.54) for disease recurrence/persistent disease groups.
Conclusions:
We report long-term cure rates in excess of 70%. Mortality is increased in CD and may be higher in patients with persistent/recurrent disease compared to patients cured after initial treatment.
Survivors of childhood cancer are at high risk of chronic conditions, but few studies investigated whether this translates into increased health care utilization. We compared health care service ...utilization between childhood cancer survivors and the general British population and investigated potential risk factors.
We used data from the British Childhood Cancer Survivor Study, a population-based cohort of 17,981 individuals diagnosed with childhood cancer (1940-1991) and surviving ≥ 5 years. Frequency of talks to a doctor, hospital outpatient visits, and day-patient and inpatient hospitalizations were ascertained by questionnaire in 10,483 survivors and were compared with the General Household Survey 2002 data by using logistic regression.
Among survivors, 16.5% had talked to a doctor in the last 2 weeks, 25.5% had attended the outpatient department of a hospital in the last 3 months, 11.9% had been hospitalized as a day patient in the last 12 months, and 9.8% had been hospitalized as an inpatient in the last 12 months. Survivors had talked slightly more often to a doctor than the general population (odds ratio OR, 1.2; 95% CI, 1.1 to 1.3) and experienced increased hospital outpatient visits (OR, 2.5; 95% CI, 2.3 to 2.8), day-patient hospitalizations (OR, 1.4; 95% CI, 1.3 to 1.6) and inpatient hospitalizations (OR, 1.9; 95% CI, 1.7 to 2.2). Survivors of Hodgkin's lymphoma, neuroblastoma, and Wilms tumor had the highest ORs for day-patient care, whereas survivors of CNS tumors and bone sarcomas had the highest OR for outpatient and inpatient care. The OR of health care use did not vary significantly with age of survivor.
We have quantified how excess morbidity experienced by survivors of childhood cancer translates into increased use of health care facilities.
Growth hormone release and IGF-I synthesis decrease with increasing age. The regulation of the GH/IGF-I system is dependent on the integrity of the hypothalamus, pituitary and liver. During aging ...there are several changes which contribute to the decline in GH/IGF-I including changes in signal to the somatotrophs from growth hormone releasing hormone, somatostatin and other factors such as body composition, exercise, diet and sleep. All of these factors are discussed in detail within this review. The phenotypic similarities between aging and adult growth hormone deficiency syndrome combined with this decrease in GH/IGF-I with aging have prompted the question whether aging is a GH deficient state. The advent of recombinant growth hormone has led to a number of studies treating elderly patients with GH alone or in combination with sex steroids or exercise. The results of these studies would not back up the use of GH in elderly non-hypopituitary patients as they did not show efficacy, showed high rates of adverse events and there is also some evidence associating GH/IGF-I and risk of neoplasia. If GH therapy is to be used in this cohort of patients further long term efficacy and safety studies are required.
This single-center prospective observational study aims to describe the prevalence of vitamin D deficiency (VDD) in the traumatic brain injury (TBI) population and identify any relationship between ...vitamin D and severity of head injury or quality of life. One hundred twenty-four TBI patients had serum vitamin D (25-OHD) levels measured at the local post-TBI endocrine screening clinic over 20 months. Quality of Life after Brain Injury questionnaires were completed by the patient concurrently. A multivariate regressional analysis was performed, controlling for age, season, ethnicity, time since injury, TBI severity, and gender. A total of 34% (n = 42) of the cohort were vitamin D deficient (25-OHD <25 nmol/L), with a further 23% (n = 29) having insufficient levels (25-OHD 25-50 nmol/L). Vitamin D was significantly lower in patients with severe TBI than in patients with mild TBI (n = 95; p = 0.03; confidence interval CI 95% -23.60 to -1.21; mean effect size 12.40 nmol/L). There was a trend for self-reported quality of life to be better in patients with optimum vitamin D levels than in patients with deficient vitamin D levels, controlling for severity of injury (n = 81; p = 0.05; CI 95% -0.07 to 21.27). This is the first study to identify a significant relationship between vitamin D levels and severity of head injury. Clinicians should actively screen for and treat VDD in head-injured patients to reduce the risk of further morbidity, such as osteomalacia and cardiovascular disease. Future research should establish the natural history of vitamin D levels following TBI to identify at which stage VDD develops and whether vitamin D replacement could have a beneficial effect on recovery and quality of life.
Context:
Uncertainty exists whether the long-term use of ergot-derived dopamine agonist (DA) drugs for the treatment of hyperprolactinemia may be associated with clinically significant valvular heart ...disease and whether current regulatory authority guidelines for echocardiographic screening are clinically appropriate.
Objective:
Our objective was to provide follow-up echocardiographic data on a previously described cohort of patients treated with DA for lactotrope pituitary tumors and to explore possible associations between structural and functional valve abnormalities with the cumulative dose of drug used.
Design:
Follow-up echocardiographic data were collected from a proportion of our previously reported cohort of patients; all had received continuous DA therapy for at least 2 years in the intervening period. Studies were performed according to British Society of Echocardiography minimum standards for adult transthoracic echocardiography. Generalized estimating equations with backward selection were used to determine odds ratios of valvular heart abnormalities according to tertiles of cumulative cabergoline dose, using the lowest tertile as the reference group.
Setting:
Thirteen centers of secondary/tertiary endocrine care across the United Kingdom were included.
Results:
There were 192 patients (81 males; median age, 51 years; interquartile range IQR, 42–62). Median (IQR) cumulative cabergoline doses at the first and second echocardiograms were 97 mg (20–377) and 232 mg (91–551), respectively. Median (IQR) duration of uninterrupted cabergoline therapy between echocardiograms was 34 months (24–42). No associations were observed between cumulative doses of dopamine agonist used and the age-corrected prevalence of any valvular abnormality.
Conclusion:
This large UK follow-up study does not support a clinically significant association between the use of DA for the treatment of hyperprolactinemia and cardiac valvulopathy.
This follow up study examined the theoretical link between DA therapy at doses used for the treatment of lactotroph adenomas and the development of cardiac valve disease and found no increased risk.
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