Transsphenoidal pituitary adenoma resection: do early post-operative cortisol levels predict permanent long-term hypocortisolism?

Transsphenoidal surgery provides a minimal invasive treatment for pituitary adenoma. Our aim is to evaluate the endocrinological outcomes after adenoma resection focusing on the corticotroph function, and to identify prognostic factors for an impaired hypothalamic–pituitary–adrenal-axis function (HPA) and the reliability of postoperative early morning serum cortisol measurements. We performed a retrospective analysis of all patients treated for pituitary adenoma from April 2006 to January 2019 in our neurosurgical department. Pituitary function was assessed pre- and postoperatively as well as at 6 weeks to 12 weeks and at 1-year follow-up. Two hundred eleven patients were included. Nine percent of the patients recovered from a preoperative adrenal insufficiency, 10.4% developed a new need for hormone substitution, and a long-term deficiency of the hypothalamic–pituitary–adrenal-axis was observed in 30.9%. Cortisol measurements 5 days after surgery had a lower area under the curve (AUC) than cortisol levels detected after 6 to 12 weeks (AUC 0.740 vs. AUC 0.808) in predicting an intact corticotrope function. The cut-off value determined for cortisol measured after 6 weeks was 6.95 µg/dl (sensitivity of 94%, specificity of 68%). Postoperative early morning cortisol levels seem to be less sensitive and specific in predicting long-term corticotroph function than measurements after 6 weeks and 1 year, emphasizing the importance of endocrine follow-up testing.

ESE Clinical Practice Guideline on functioning and nonfunctioning pituitary adenomas in pregnancy

Pregnancies are rare in women with pituitary adenomas, which may relate to hormone excess from secretory subtypes such as prolactinomas or corticotroph adenomas. Decreased fertility may also result from pituitary hormone deficiencies due to compression of the gland by large tumours and/or surgical or radiation treatment of the lesion. Counselling premenopausal women with pituitary adenomas about their chance of conceiving spontaneously or with assisted reproductive technology, and the optimal pre-conception treatment, should start at the time of initial diagnosis. The normal physiological changes during pregnancy need to be considered when interpreting endocrine tests in women with pituitary adenomas. Dose adjustments in hormone substitution therapies may be needed across the trimesters. When medical therapy is used for pituitary hormone excess, consideration should be given to the known efficacy and safety data specific to pregnant women for each therapeutic option. In healthy women, pituitary gland size increases during pregnancy. Since some pituitary adenomas also enlarge during pregnancy, there is a risk of visual impairment, especially in women with macroadenomas or tumours near the optic chiasm. Pituitary apoplexy represents a rare acute complication of adenomas requiring surveillance, with surgical intervention needed in some cases. This guideline describes the choice and timing of diagnostic tests and treatments from the pre-conception stage until after delivery, taking into account adenoma size, location and endocrine activity. In most cases, pregnant women with pituitary adenomas should be managed by a multidisciplinary team in a centre specialised in the treatment of such tumours.

P–706 Impaired fibrinolysis during estrogen substitution in relation to frozen-thawed embryo transfer

Study question Is the clot lysis time prolonged in women undergoing estrogen substitution in artificial cycle during frozen-thawed embryo transfer (AC-FET)? Summary answer Women receiving AC-FET have a prolonged clot lysis time that could result in increased venous thromboembolic risk during estrogen substitution. What is known already High doses of estrogen are used for women treated with AC-FET; this in contrast to women treated with natural cycle frozen-thawed embryo transfer (NC-FET). Based on previous research on hormone replacement therapy in other settings, estrogen substitution is probably associated with an increased risk of thromboembolism. Moreover, it has formerly been shown that pregnant women followed assisted reproductive technology (ART) treatment as compared to natural fertilization, has an increased risk of thrombosis. However, changes in fibrinolysis has never been examined in women undergoing estrogen substitution during treatment with AC-FET. Study design, size, duration Prospective cohort study of women receiving AC-FET with oestrogen/progesterone substitution or NC-FET. Blood samples were obtained four times: 1) prior to hormone substitution (baseline), 2) confirmation of biochemical pregnancy, 3) gestational week 8 and 4) gestational week 13 (5 weeks after cessation of hormone substitution). Inclusion criteria: women aged > 18 years assigned for FET. Exclusion criteria: egg donor recipients, known bleeding disorders, indication for thromboprophylaxis and treatment with anti-platelet medication or non-steroid-anti-inflammatory drugs. Participants/materials, setting, methods We included women at the Department of Obstetrics and Gynaecology, Horsens Fertility Clinic, Denmark, from August 2019 – November 2020. In total, 34 participants were included: 19 women treated with AC-FET and 15 women receiving NC-FET. We examined fibrinolysis measured by a dynamic fibrin clot lysis assay that can assess the capacity for fibrin formation and fibrinolysis. This detailed information of the fibrinolytic activity are used as a surrogat marker of thromboembolic risk. Main results and the role of chance Our results showed a significantly longer lysis time (908 ± 234 vs 1157 ± 218) (p < 0.001) within the AC-FET group after hormone substitution compared to baseline. Moreover, we found a higher area under the curve (AUC) (919 ± 305 vs 1167 ± 391) (p = 0.006) within the AC-FET group. However, we observed no changes in mean lag phase or maximum absorbency after estrogen substitution within the AC-FET group. Since we observed a significantly higher AUC within the AC-FET group after estrogen substitution, this is probably due to the prolonged lysis time, indicating hypofibrinolysis. No significant changes was found comparing the NC-FET group with the AC-FET group. Limitations, reasons for caution Our data are based on a small study population. Additionally, we cannot exclude that the coagulation parameters could be affected by estrogen prior to study enrollment as we had no wash out period. Wider implications of the findings: Our findings indicate prothrombotic changes in the AC-FET group. It is relevant to individually consider the indication for AC-FET and restrict the use of unnecessary hormone exposure. These data should be followed by a populations-based study to clarify how this potentially increased venous thromboembolic risk will manifest itself clinically. Trial registration number NCT04359576

Povidone Iodine Disinfection Associated with Hypothyroidism and Potentially Contributing to Prolonged Kidney Failure

Objectives. To report a case of povidone-iodine (PVP-I, Iso-Betadine®) disinfection of lower leg fasciotomy wounds resulting in iodide absorption and possibly contributing to hypothyroidism and prolonged kidney injury. Design. Case report. Setting. Pediatric intensive care unit (PICU), university hospital. Patients. A 13-year-old patient presenting with prolonged oligoanuric kidney failure and unexplained primary hypothyroidism three weeks after severe abdominal sepsis with multiple organ dysfunction and major rhabdomyolysis due to bilateral lower leg compartment syndrome, necessitating moderate size fasciotomies, disinfected daily with PVP-I. Interventions. Interruption of PVP-I exposure and initiation of thyroid hormone substitution. Measurements and Main Results. Hypothyroidism was revealed during diagnostic work-up for persistent hypertriglyceridemia. Thyroxine (T4) (4.0 mg/L) and tri-iodothyronine (T3) (64 ng/L) were moderately low, yet thyroid stimulating hormone (TSH) (16.8 mIU/L) was fourfold the maximal normal range value. This pattern, atypical for prolonged critical illness-related hypothyroidism, prompted interruption of PVP-I exposure and initiation of thyroid hormone substitution. Urinary production and creatinine clearance recovered during the following days, and one week later, intermittent renal replacement therapy could be terminated, suggesting that PVP-I toxicity and/or hypothyroidism may have contributed to the persistent renal failure three weeks after resolved septic shock and rhabdomyolysis. Elevated serum and urinary anion gap normalized simultaneously, but this evolution of rather nonspecific indices could be multifactorial. Conclusion. PVP-I is a commonly used broad-spectrum antimicrobial agent for prevention and treatment of wound infections. Toxic complications due to PVP-I absorption, after disinfection of extended thermal injuries larger than 20% of the body surface, have been described. In critically ill children, however, toxic effects of PVP-I may occur due to repeated disinfection of less extended wounds. Proposed screening strategies include: monitoring of the volumes of PVP-I applied daily; of the thyroid function, the serum, and/or urinary anion gap and the urinary iodide concentrations. These strategies, however, remain to be validated. This case report should be a wake-up call for daily integration of wound management in the clinical evaluation of critically ill patients.

Long-Term Corticotroph Function Following Cure of Cushing’s Syndrome

Introduction: Hyper- and hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis in Cushing’s syndrome (CS) and Addison’s disease (AD) is associated with disturbances of classical feedback mechanisms. Time to recovery of adrenal function after CS remission depends on the etiology of CS and is longest after adrenal CS. To date there are no data on the recovery of corticotroph function following CS remission, and the synacthen test is recommended for testing adrenal function in patients with hypopituitarism. Aim Here we aim to test corticotroph function after long-term cure of Cushing’s syndrome following bilateral adrenalectomy (BADx), compared to patients with primary glucocorticoid deficiency due the presence of 21-hydroxylase antibodies or adrenoleucodystrophy, a pathophysiological model of glucocorticoid and mineralocorticoid deficiency. Methods: We retrospectively evaluated data from patients with CS and AD attending our endocrine department between 2000 and 2020, using the following inclusion criteria: BADx performed for pituitary/ectopic/adrenal or occult CS or primary adrenal insufficiency confirmed either by the presence of 21-hydroxylase antibodies or genetically in adrenoleucodystrophy. Results: Full data were available for 93 patients: 43 patients with BADx due to CS (18 patients with pituitary CS, 14 patients with adrenal CS and 11 patients with ectopic/occult CS, F:M 29:14, mean age at BADx 45.4 years age range 13-74 years) and 50 patients with AD (47 cases with positive 21-hydroxylase antibodies, 3 cases with adrenoleucodystrophy, F:M ratio 27:23, mean age at diagnosis 35 years, age range 6-57 years). The observation period was 537.5 patient-years after BADx (mean 12.5 years, range 1-38 years) and 647 patient-years following AD diagnosis (mean 14.2 years, range 1-46 years). At the last visit, there were no differences between the hormone substitution regimes between the groups. ACTH concentrations during the whole observation period and also at the last visit were lowest in patients with adrenal CS (56.5 pg/ml) when compared to patients with AD (487 pg/ml, p<0.001), or with patients with pituitary CS (377.5 pg/mL, p=0.011). ACTH values in patients with AD in long-term follow-up were significantly higher when compared to all patients with CS (141 pg/mL, p<0.001). Conclusion: These data highlight a long-term defective corticotroph function in patients with CS following BADx. Low ACTH concentrations long term after BADx for adrenal CS corroborate that corticotroph function fails to recover after CS cure. In the light of these findings, the utility of the synacthen test for excluding secondary/tertiary adrenal insufficiency following CS remission is disputable and remains to be evaluated in future studies dedicated to CS cohorts.

Photosensitive Epilepsy and Polycystic Ovary Syndrome as Manifestations of MERRF

Objectives. Although endocrinologic involvement and epilepsy are frequent features of myoclonic epilepsy with ragged-red fibers (MERRF), polycystic ovary syndrome (PCOS) and photosensitive epilepsy have not been reported. Case Report. A 32-year-old female was diagnosed with MERRF at age 19 y upon presence of the four canonical features and the variant m.8344A > G in MT-TK (tRNA (Lys)) (blood heteroplasmy rate: 50%). She experienced recurrent photosensitive focal and generalised seizures since age 19 y, which could be triggered by flickering light or by looking at small stones, leaves, or dirty snow on the ground. Since the last 42 months, she was seizure-free upon levetiracetam (4000 mg/d), clonazepam (1.5 mg/d), and topiramate (25 mg/d). Additionally, she suffered from secondary amenorrhoea since adolescence. She was married between ages 19 y and 25 y but did not get pregnant. PCOS was diagnosed and treated with desogestrel plus estradiol. Nonetheless, the course was progressive, particularly with regard to ataxia, myocloni, and myopathy. Conclusions. The phenotypic spectrum of MERRF is broader than anticipated and may additionally include PCOS and photosensitive epilepsy. PCOS in MERRF may respond to hormone substitution and photosensitive epilepsy to levetiracetam, clonazepam, and topiramate.

Patient-reported use of marijuana and cannabinoid (CBD) oil in patients with renal cell carcinoma undergoing systemic therapy.

5084 Background: The use of cannabis and cannabinoid related products has become increasingly common among cancer patients. We sought to gather independent data from online kidney cancer patient communities to assess frequency of use of marijuana and CBD-oil and estimate influence on treatment duration and side-effects. Methods: The KCCure online survey was performed between August 1, and September 30, 2019. Descriptive statistics were used to characterize patients who self-report using marijuana, their systemic treatments, and interactions with their oncologists. Results: Out of 1,136 patients responding, 411 patients were on systemic therapy with a median age of 57 years (28-86). Of the 441 patients with systemic therapy, 223 patients (54%) were male. There was no difference in gender distribution or race among patients who reported using or not using marijuana and or CBD oil. 93 patients (21%) reported using marijuana or CBD oil and 35 patients (8.5%) reported using both. Patients using marijuana and/or CBD oil had a median age of 55.7 +/- 1.1 years compared with patients not using (65.1 +/- 6.9 years). The median treatment duration was 23.9+/-2.4 months for patients using marijuana and/or CBD oil versus 26.4+/- 1.9 months for patients not using these supplements (p=0.437). Patients using marijuana and/or CBD oil were more likely to have bothersome side effects from therapy (p=0.001) and were less likely to talk to their doctor about their situation (p=0.044). The median NCCN distress score in patients using marijuana and/or CBD oil was 49.5+/-25.7 versus 51.4+/-24.0 (p n.s.). No correlation was seen with the use of steroids, anti-diarrhea drugs, anti-nausea-drugs, hormone substitution or other drugs used to manage side effects. Conclusions: Marijuana and/or CBD oil are used by a significant number of patients. No benefit/harm on treatment duration and use of concomitant drugs to control side effects and severity was seen. Patients using marijuana and/or CBD oil were more likely to report bothersome treatment related side effects and were more willing to report their side effects to their provider. As cannabinoids become more mainstream and legal in a number of states, more research is needed to better understand the impact these supplements may have on patients.

Estrogen modulation of pain perception with a novel 17β-estradiol pretreatment regime in ovariectomized rats

Estrogen plays substantial roles in pain modulation; however, studies concerning sex hormones and nociception often yield confusing results. The discrepancy could be a result of lack of consensus to regard estrogen as a variable when working with animal models; thus, the influence of hormones’ fluctuations on nociception has continually been neglected. In the present study, we designed a novel hormone substitution model to aid us to evaluate the effects of estrogen’s long-term alterations on ovariectomy (OVX)-induced mechanical hyperalgesia and the expression of estrogen receptors(ERs). OVX rats were implanted with slow-release estrogen pellets at differently arranged time points and doses, such that a gradual elevation or decrease of serum estrogen levels following a relatively stable period of estrogen replacement was achieved in rats. Our results demonstrated that gradual estrogen depletion rather than elevation following the stable period of estrogen substitution in OVX rats alleviated OVX-induced mechanical hyperalgesia in a dose-independent manner, and the opposite estrogen increase or decrease paradigms differently regulate the expression of spinal ERs. Specifically, in rats rendered to continuously increased serum estrogen, the early phase estrogen-induced anti-nociception effect in OVX rats was eliminated, which was accompanied by an over-activation of ERα and a strong depression of ERβ, while in the OVX rats subject to gradual decrease of estrogen replacement, both ERα and ERβ increased modestly compared with the OVX group. Thus, the present study demonstrated that estrogen increase or decrease modulate nociception differently through change of spinal ERs.

Effect of delayed diagnosis and treatment of congenital hypothyroidism on intelligence and quality of life: an observational study

BACKGROUND Congenital hypothyroidism is one of the most prevalent, albeit preventable causes of intellectual disability. This study determined the intellectual outcome and health-related quality of life (QoL) in children and adolescents clinically diagnosed with congenital hypothyroidism and the associations among age of starting thyroid hormone treatment, current free thyroxine (FT4) level, intelligence quotient (IQ), and QoL.METHODS Intelligence (Wechsler scales) and QoL (PedsQLTM 4.0 parent proxy-report) tests were administered to 25 patients with congenital hypothyroidism in the pediatric clinic of Cipto Mangunkusumo Hospital, Jakarta. Nineteen patients underwent thyroid ultrasonography or scintigraphy to determine the etiology of congenital hypothyroidism.RESULTS A total of 25 patients with the median age of 9 (5.5–12.5) years were recruited. Eighteen patients had a total IQ of <70. The age of treatment initiation did not correlate with full scale IQ (FSIQ) (r = −0.261, p = 0.071) and verbal IQ (VIQ) (r = −0.232, p = 0.265). The late initiation of treatment was correlated with lower performance IQ (PIQ) (r = −0.325, p = 0.025). The higher current FT4 levels was correlated with higher scores ofFSIQ (r = 0.314, p = 0.046) and PIQ (r = 0.320, p = 0.043). The late initiation of treatment (r = 0.006, p = 0.980) and higher current FT4 levels (r = 0.246, p = 0.310) were not correlated with QoL. Hemiagenesis of thyroid gland was the most common etiology.CONCLUSIONS The late initiation of thyroid hormone substitution in patients with congenital hypothyroidism negatively affects intellectual abilities.