Predictors of bone mineral density in patients receiving glucocorticoid replacement for Addison's disease.

PURPOSE: Patients receiving long-term glucocorticoid (GC) treatment are at risk of osteoporosis, while bone effects of substitution doses in Addison's disease (AD) remain equivocal. The project was aimed to evaluate serum bone turnover markers (BTMs): osteocalcin, type I procollagen N-terminal propeptide (PINP), collagen C-terminal telopeptide (CTX), sclerostin, DKK-1 protein, and alkaline phosphatase (ALP) in relation to bone mineral density (BMD) during GC replacement. METHODS: Serum BTMs and hormones were assessed in 80 patients with AD (22 males, 25 pre- and 33 postmenopausal females) on hydrocortisone (HC) substitution for ≥3 years. Densitometry with dual-energy X-ray absorptiometry covered the lumbar spine (LS) and femoral neck (FN). RESULTS: Among BTMs, only PINP levels were altered in AD. BMD Z-scores remained negative except for FN in males. Considering T-scores, osteopenia was found in LS in 45.5% males, 24% young and 42.4% postmenopausal females, while osteoporosis in 9.0%, 4.0% and 21.1%, respectively. Lumbar BMD correlated positively with body mass (p = 0.0001) and serum DHEA-S (p = 9.899 × 10-6). Negative correlation was detected with HC dose/day/kg (p = 0.0320), cumulative HC dose (p = 0.0030), patient's age (p = 1.038 × 10-5), disease duration (p = 0.0004), ALP activity (p = 0.0041) and CTX level (p = 0.0105). However, only age, body mass, ALP, serum CTX, and sclerostin remained independent predictors of LS BMD. CONCLUSION: Standard HC substitution does not considerably accelerate BMD loss in AD patients and their serum BTMs: CTX, osteocalcin, sclerostin, DKK-1, and ALP activity remain within the reference ranges. Independent predictors of low lumbar spine BMD, especially ALP activity, serum CTX and sclerostin, might be monitored during GC substitution.

Increased Resting-State Functional Connectivity in Patients With Autoimmune Addison Disease.

CONTEXT: Individuals with autoimmune Addison disease (AAD) take replacement medication for the lack of adrenal-derived glucocorticoid (GC) and mineralocorticoid hormones from diagnosis. The brain is highly sensitive to these hormones, but the consequence of having AAD for brain health has not been widely addressed. OBJECTIVE: The present study compared resting-state functional connectivity (rs-fc) of the brain between individuals with AAD and healthy controls. METHODS: Fifty-seven patients with AAD (33 female) and 69 healthy controls (39 female), aged 19 to 43 years were scanned with 3-T magnetic resonance imaging (MRI). RESULTS: Independent component and subsequent dual regression analyses revealed that individuals with AAD had stronger rs-fc compared to controls in 3 networks: the bilateral orbitofrontal cortex (OFC), the left medial visual and left posterior default mode network. A higher GC replacement dose was associated with stronger rs-fc in a small part of the left OFC in patients. We did not find any clear associations between rs-fc and executive functions or mental fatigue. CONCLUSION: Our results suggest that having AAD affects the baseline functional organization of the brain and that current treatment strategies of AAD may be one risk factor.

On Primary Adrenal Insufficiency with Normal Concentrations of Cortisol - Early Manifestation of Addison's Disease.

Primary adrenal insufficiency (AI) is an endocrine disorder in which hormones of the adrenal cortex are produced to an insufficient extent. Since receptors for adrenal steroids have a wide distribution, initial symptoms may be nonspecific. In particular, the lack of glucocorticoids can quickly lead to a life-threatening adrenal crisis. Therefore, current guidelines suggest applying a low threshold for testing and to rule out AI not before serum cortisol concentrations are higher than 500 nmol/l (18 µg/dl). To ease the diagnostic, determination of morning cortisol concentrations is increasingly used for making a diagnosis whereby values of>350 nmol/l are considered to safely rule out Addison's disease. Also, elevated corticotropin concentrations (>300 pg/ml) are indicative of primary AI when cortisol levels are below 140 nmol/l (5 µg/dl). However, approximately 10 percent of our patients with the final diagnosis of primary adrenal insufficiency would clearly have been missed for they presented with normal cortisol concentrations. Here, we present five such cases to support the view that normal to high basal concentrations of cortisol in the presence of clearly elevated corticotropin are indicative of primary adrenal insufficiency when the case history is suggestive of Addison's disease. In all cases, treatment with hydrocortisone had been started, after which the symptoms improved. Moreover, autoantibodies to the adrenal cortex had been present and all patients underwent a structured national education program to ensure that self-monitored dose adjustments could be made as needed.

Major immunophenotypic abnormalities in patients with primary adrenal insufficiency of different etiology.

Introduction: Patients with primary adrenal insufficiency (PAI) suffer from increased risk of infection, adrenal crises and have a higher mortality rate. Such dismal outcomes have been inferred to immune cell dysregulation because of unphysiological cortisol replacement. As the immune landscape of patients with different types of PAI has not been systematically explored, we set out to immunophenotype PAI patients with different causes of glucocorticoid (GC) deficiency. Methods: This cross-sectional single center study includes 28 patients with congenital adrenal hyperplasia (CAH), 27 after bilateral adrenalectomy due to Cushing's syndrome (BADx), 21 with Addison's disease (AD) and 52 healthy controls. All patients with PAI were on a stable GC replacement regimen with a median dose of 25 mg hydrocortisone per day. Peripheral blood mononuclear cells were isolated from heparinized blood samples. Immune cell subsets were analyzed using multicolor flow cytometry after four-hour stimulation with phorbol myristate acetate and ionomycin. Natural killer (NK-) cell cytotoxicity and clock gene expression were investigated. Results: The percentage of T helper cell subsets was downregulated in AD patients (Th1 p = 0.0024, Th2 p = 0.0157, Th17 p < 0.0001) compared to controls. Cytotoxic T cell subsets were reduced in AD (Tc1 p = 0.0075, Tc2 p = 0.0154) and CAH patients (Tc1 p = 0.0055, Tc2 p = 0.0012) compared to controls. NKCC was reduced in all subsets of PAI patients, with smallest changes in CAH. Degranulation marker CD107a expression was upregulated in BADx and AD, not in CAH patients compared to controls (BADx p < 0.0001; AD p = 0.0002). In contrast to NK cell activating receptors, NK cell inhibiting receptor CD94 was upregulated in BADx and AD, but not in CAH patients (p < 0.0001). Although modulation in clock gene expression could be confirmed in our patient subgroups, major interindividual-intergroup dissimilarities were not detected. Discussion: In patients with different etiologies of PAI, distinct differences in T and NK cell-phenotypes became apparent despite the use of same GC preparation and dose. Our results highlight unsuspected differences in immune cell composition and function in PAI patients of different causes and suggest disease-specific alterations that might necessitate disease-specific treatment.

Primary adrenal insufficiency induced by immune checkpoint inhibitors: biological, clinical, and radiological aspects.

Immune checkpoint inhibitors (ICI) have become a cornerstone in medical oncology, with evolving therapeutic strategies and applications. These monoclonal antibodies, designed to enhance immune responses, have revealed a spectrum of immune-related adverse events (irAEs). While many irAEs exhibit favorable responses to corticosteroid or immunosuppressive therapy, most ICI-related endocrinopathies necessitate lifelong replacement therapy and pose significant clinical challenges. Adrenal insufficiency (AI), a noteworthy endocrine irAE, can manifest as primary AI (PAI) or secondary AI (SAI), resulting from adrenal or pituitary gland dysfunction, respectively. ICI-induced AI, albeit relatively infrequent, occurs in 1-2% of patients receiving single-agent anti-Programmed Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) or Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) therapies and in a higher range of 4-9% when ICIs are used in combinations. Recognizing and addressing ICI-induced PAI is crucial, as it often presents with acute and potentially life-threatening symptoms, especially considering the expanding use of ICI therapy. This review provides an updated overview of ICI-induced PAI, exploring its clinical, diagnostic, and radiological aspects.

Pulsatile Subcutaneous Hydrocortisone Replacement in Primary Adrenal Insufficiency.

Pulsatile endogenous cortisol secretion is critical for physiological glucocorticoid gene signaling. Conventional glucocorticoid replacement therapy does not mimic endogenous cortisol pulsing in primary adrenal insufficiency. In an open-labeled, two-week, nonrandomized cross-over study of five patients with adrenal insufficiency (Addison's disease in two, bilateral adrenalectomy in one, and congenital adrenal hyperplasia in two patients) we compared pulsatile and continuous cortisol pump treatment and conventional oral glucocorticoid therapy with respect to 24-h serum corticosteroid levels and plasma adrenocorticotropic hormone (ACTH). Pulsed pump restored ultradian rhythmicity as demonstrated by five peaks of serum (all patients) and subcutaneous tissue cortisol (four patients). Morning subcutaneous cortisol and cortisone were higher in continuous and pulsed pump treatment than in oral therapy despite nearly similar serum cortisol levels in all treatment arms. ACTH was within the physiological range during pulsed pump treatment in all patients except for slightly elevated levels in the morning hours 04:00-08:00 h. During oral therapy, ACTH was very high in patients with Addison's disease and suppressed in patients with congenital adrenal hyperplasia. In conclusions, mimicking endogenous cortisol rhythmicity by ultradian subcutaneous infusion of cortisol is feasible. It was superior to both continuous pump and oral therapy in maintaining normal ACTH levels throughout the 24-h cycle. Our results demonstrate a low free cortisol bioavailability on thrice daily oral replacement therapy compared to both types of subcutaneous infusion.

Acute Mania in a Patient With Primary Adrenal Insufficiency Due to Autoimmune Adrenalitis: A Case Report.

We describe a rare case of acute mania in the setting of autoimmune adrenalitis. A 41-year-old male with no previous psychiatric diagnoses presented with impulsivity, grandiosity, delusions of telepathy, and hyperreligiosity following a previous hospitalization for an acute adrenal crisis and 2 subsequent days of low-dose corticosteroid treatment. Workups for encephalopathy and lupus cerebritis were negative, raising concern that this presentation might represent steroid-induced psychosis. However, discontinuation of corticosteroids for 5 days did not resolve the patient's manic episode, suggesting that his clinical presentation was more likely new onset of a primary mood disorder or a psychiatric manifestation of adrenal insufficiency itself. The decision was made to restart corticosteroid treatment for the patient's primary adrenal insufficiency (formerly known as Addison disease), coupled with administration of both risperidone and valproate for mania and psychosis. Over the following 2 weeks, the patient's manic symptoms resolved, and he was discharged home. His final diagnosis was acute mania secondary to autoimmune adrenalitis. Although acute mania in adrenal insufficiency is quite rare, clinicians should be aware of the range of psychiatric manifestations associated with Addison disease so that they can pursue the optimal course of both medical and psychiatric treatment for these patients.

Steroid supplementation before minor oral surgical procedures in patients taking long-term glucocorticoids: A triple-blinded, randomized, placebo-controlled trial.

BACKGROUND: Patients undergoing long-term glucocorticoid therapy are administered additional glucocorticoids before minor dental procedures, although this is not supported by evidence. The authors designed this study to validate the hypothesis that routine blanket glucocorticoid supplementation is unnecessary during minor oral surgical procedures under local anesthesia. METHODS: The authors recruited 270 patients into 3 groups (1:1:1 allocation) from the dental outpatient department. Primary outcomes were changes in hemodynamic parameters and frequency of adverse events among the 3 groups. The secondary outcome was the association of preprocedural stress and procedural pain with periprocedural adverse events in the long-term glucocorticoid therapy group (groups I and II). RESULTS: No clinically relevant changes in hemodynamic parameters among the 3 groups were found. The authors also found low periprocedural adverse events in all 3 groups combined (n = 1), so they did not explore the secondary outcomes further. CONCLUSIONS: Among patients undergoing long-term glucocorticoid therapy for indications other than primary adrenal insufficiency, elective minor oral surgical procedures can be performed safely with only their daily dose of glucocorticoid when their medical conditions are optimized. Routine additional glucocorticoid supplementation appears unnecessary. The results of the study also revealed opportunities for value addition by means of integrating oral health care with medical follow-up for patients with multiple co-occurring medical conditions. PRACTICAL IMPLICATIONS: Routine blanket glucocorticoid supplementation among patients taking a long-term glucocorticoid for indications other than primary adrenal insufficiency appears unnecessary before minor oral surgical procedures under local anesthesia. This clinical trial was registered at Clinical Trial Registry-India. The registration number is CTRI/2017/02/007779.

Clinical features and long-term management of cats with primary hypoadrenocorticism using desoxycorticosterone pivalate and prednisolone.

BACKGROUND: Primary hypoadrenocorticism (PH) is rare in cats and knowledge about treatment is sparse. OBJECTIVE: To describe cats with PH with a focus on long-term treatment. ANIMALS: Eleven cats with naturally occurring PH. METHODS: Descriptive case series with data on signalment, clinicopathological findings, adrenal width, and doses of desoxycorticosterone pivalate (DOCP) and prednisolone during a follow-up period of >12 months. RESULTS: Cats ranged from 2 to 10 years (median 6.5); 6 cats were British Shorthair. Most common signs were reduced general condition and lethargy, anorexia, dehydration, obstipation, weakness, weight loss, and hypothermia. Adrenal glands on ultrasonography were judged small in 6. Eight cats could be followed for 14 to 70 months (median: 28). Two were started on DOCP doses ≥2.2 mg/kg (2.2; 2.5) and 6 < 2.2 mg/kg (1.5-2.0 mg/kg, median 1.8) q28 days. Both high-dose cats and 4 low-dose cats needed a dose increase. Desoxycorticosterone pivalate and prednisolone doses at the end of the follow-up period were 1.3 to 3.0 mg/kg (median: 2.3) and 0.08 to 0.5 mg/kg/day (median: 0.3), respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Desoxycorticosterone pivalate and prednisolone requirements in cats were higher than what is currently used in dogs; thus, a DOCP starting dose of 2.2 mg/kg q28 days and a prednisolone maintenance dose of 0.3 mg/kg/day titrated to the individual need seems warranted. Small adrenal glands (width < 2.7 mm) on ultrasonography in a cat suspected of hypoadrenocorticism can be suggestive of the disease. The apparent predilection of British Shorthaired cats for PH should be further evaluated.

Coronary artery disease in a patient with Addison's disease: a case report and literature review.

BACKGROUND: Addison's disease which is due to dysfunction of the adrenal gland, with abnormal secretion of glucocorticoids and mineralocorticoids, is rare. By inducing inflammation and disorders of water and electrolyte metabolism, Addison's disease may accelerate progression of co-existed cardiovascular diseases. Addison's disease combined with cardiovascular disease is infrequent, only 10 cases in the literature. CASE PRESENTATION: We reported a 51-year-old male patient with unstable angina pectoris and hypotension. Changes on coronary angiography within 2 years suggested rapid progression of coronary artery disease in a patient with low cardiovascular risk. An additional clue of skin hyperpigmentation, fatigue and further examination confirmed the diagnosis of Addison's disease caused by adrenal tuberculosis. After hormone replacement treatment, the frequency and severity of the angina pectoris were alleviated significantly, as were hypotension, hyperpigmentation and fatigue. CONCLUSIONS: The combination of Addison's disease and coronary artery disease in one patient is rare. Addison's disease can induce inflammation and disorders of water and electrolyte metabolism, which may further accelerate the course of coronary artery disease. Meanwhile, the hypotension in Addison's disease may affect the coronary blood flow, which may result in an increased susceptibility to unstable angina in the presence of coronary stenosis. So, we should analyze comprehensively if the coronary artery disease progress rapidly.

Renin and electrolytes indicate the mineralocorticoid activity of fludrocortisone: a 6 year study in primary adrenal insufficiency.

CONTEXT: Fludrocortisone (FC) is the mineralocorticoid (MC) replacement treatment for patients with primary adrenal insufficiency (PAI). OBJECTIVE: To explore the dose of FC treatment and its relationship with glucocorticoid therapy, sodium, potassium, renin and clinical parameters. SETTING: Monocentric cohort. PATIENTS: Data of 193 patients with PAI (130 autoimmune) were collected during baseline (T0), intermediate (T1) and last follow-up visit (T2, respectively, after a mean of 38 and 72 months). MAIN OUTCOME MEASURE: Utility of endocrine and clinical parameters to titrate FC dose. RESULTS: FC dose (50-75 µg/daily) was stable in the follow-up in half patients. The MC activity of FC was dose-dependent: we observed a reduced but significant positive linear correlation between FC dose and sodium (r = 0.132) and negative linear correlation between FC and potassium (r = - 0.162) or renin (r = - 0.131, all p < 0.01). An overall reduction in the FC dose was observed at T2 in the group with longer follow-up (> 60 months, p < 0.05). Higher doses of FC were observed in patients with low-normal renin, especially in autoimmune PAI (86 vs 65 µg/daily, p < 0.05). On the contrary, reduced sodium and increased potassium levels were observed in patients with high renin at T2. The number of cardiovascular events (15 in the whole cohort) was similar in patients sorted by renin levels or FC dose. CONCLUSIONS: Renin and electrolytes can indicate the MC activity of FC treatment: they should be routinely evaluated and used to titrate its dose that can be reduced in the long-term follow-up.

Intractable vomiting as a presentation of adrenal insufficiency - a case report.

An array of pathophysiological processes can lead to chronic nausea and vomiting, including gastrointestinal and non-gastrointestinal disorders. Initial symptoms of adrenal insufficiency are usually non-specific, but intractable nausea and vomiting are infrequently associated, posing a diagnostic dilemma for clinicians. Here we present such a patient, who responded to glucocorticoid replacement with complete improvement.

[Hyperpigmentation reveals Addison's disease in a pregnant woman].

A 31-year-old woman was admitted to the local department of endocrinology for control of known anti-TPO positive hypothyroidism during pregnancy. The clinician noticed a remarkable hyperpigmentation. Primary adrenal insufficiency was diagnosed and treatment with cortico- and mineralosteroids commenced. Diagnosis of primary adrenal insufficiency during pregnancy is challenging as many symptoms overlap with normal symptoms of pregnancy. The usual diagnostic criteria cannot be used due to the altered hormone concentrations during pregnancy.

Broad Complex Tachycardia, Addison's disease, and Ascending Flacid Paralysis: An Interesting Case on Cardiology Floor.

Broad complex tachycardia is a common presentation in the cardiology emergency room but is not always due to ventricular tachycardia, especially in a young patient who has other important medical illnesses and with no underlying cardiac illness. We present a case of a 40-year male who was admitted with complaints of palpitation associated with rapidly progressive weakness of lower limbs progressing to quadriparesis in about 10 hours. His clinical presentation was due to hyperkalemia and weakness due to Addison's disease. The patient was treated with drugs to lower potassium levels and steroids. His muscle power improved dramatically as potassium levels normalized and he recovered completely. Key Words: Acute flaccid paralysis, Hyperkalemia, Broad complex tachycardia.

[Just Anorexia?] / Alles Anorexie?

Just Anorexia? Abstract. We report the case of a 30-year-old woman presenting with fatigue, loss of weight, nausea, emesis and hyponatremia. The evaluation proved Addison's disease due to an autoimmune polyendocrine syndrome type 2 with Hashimoto thyreoiditis. Under substitution with hydrocortisone and fludrocortisone all the symptoms subsided completely.

Impact of hydrocortisone replacement on bone mineral density and bone turnover markers in patients with primary adrenal insufficiency.

Objective. The study was aimed to assess the effect of hydrocortisone (HC) replacement therapy on bone mineral density (BMD) and bone turnover markers in patients with primary adrenal insufficiency (PAI). METHODS: A cross-sectional study was conducted in 37 PAI patients treated with HC. BMD and selected bone turnover markers (ß-crosslaps and osteocalcin) were measured. A stepwise binary logistic regression model was applied to determine the independent variables associated with low BMD. RESULTS: Osteoporosis was noted in 14.3% and osteopenia in 34.3% of cases. These patients were older (p=0.01) and received higher daily HC dose compared to patients with normal BMD (p=0.01). BMD values in the lumbar spine and the femoral neck were negatively correlated with daily HC dose (r=-0.36, p=0.03 and r=-0.34, p=0.05, respectively). Plasma osteocalcin was negatively correlated with disease duration (r=-0.38, p=0.02) and cumulative HC dose (r=-0.43, p<0.01). In multivariate analysis, a daily HC dose ≥12 mg/m2/day was independently associated with a higher risk of osteopenia/osteoporosis [OR (95% CI), 9.0 (1.1-74.6); p=0.04]. CONCLUSIONS: Impaired bone mineralization in patients with PAI is correlated with HC dose. A daily HC dose ≥12 mg/m2/day was associated with an increased risk of osteopenia and osteoporosis in these patients.

New-Onset Primary Adrenal Insufficiency and Autoimmune Hypothyroidism in a Pediatric Patient Presenting with MIS-C.

INTRODUCTION: There is emerging speculation that the inflammatory state associated with SARS-CoV-2 infection may trigger autoimmune conditions, but no causal link is established. There are reports of autoimmune thyroiditis and adrenal insufficiency in adults post-COVID-19. We describe the first pediatric report of adrenal insufficiency and autoimmune hypothyroidism after COVID-19. CASE PRESENTATION: A 14-year-old previously healthy girl, with vitiligo, presented in shock following 1 week of fever, lethargy, diarrhea, and vomiting. Three weeks prior, she had congestion and fatigue and known familial exposure for COVID-19. Labs were remarkable for sodium 129 mmol/L, K 4.3 mmol/L, creatinine 2.9 mg/dL, hemoglobin 8.3 g/dL, and positive COVID-19 PCR and SARS-CoV-2 IgG. She was resuscitated with normal saline and required pressor support. EKG showed abnormal repolarization presumed secondary to myocarditis. She met the criteria for multisystem inflammatory syndrome in children (MIS-C), received intravenous immune globulin and IL-1R antagonist and was admitted for intensive care. Persistent hypotension despite improved inflammatory markers and undetectable cortisol led to initiation of hydrocortisone. She was then able to rapidly wean off pressors and hydrocortisone within 48 h. Thereafter, tests undertaken for persistent bradycardia confirmed autoimmune hypothyroidism with TSH 131 µU/mL, free T4 0.85 ng/dL, and positive thyroid autoantibodies. Basal and stimulated cortisol were <1 µg/dL on a standard 250 µg cosyntropin stimulation test, with baseline ACTH >1,250 pg/mL confirming primary adrenal insufficiency. Treatment was initiated with hydrocortisone, levothyroxine, and fludrocortisone. Adrenal sonogram did not reveal any hemorrhage and anti-adrenal antibody titers were positive. The family retrospectively reported oligomenorrhea, increased salt craving in the months prior, and a family history of autoimmune thyroiditis. The cytokine panel was notably different from other cases of MIS-C. CONCLUSION: This is the first pediatric report, to our knowledge, of primary adrenal insufficiency and hypothyroidism following COVID-19, leading to a unique presentation of autoimmune polyglandular syndrome type 2. The initial presentation was attributed to MIS-C, but the subsequent clinical course suggests the possibility of adrenal crisis. It remains unknown if COVID-19 had a causal relationship in triggering the autoimmune adrenal insufficiency and hypothyroidism.

Adrenal crises in adolescents and young adults.

PURPOSE: Review the literature concerning adrenal insufficiency (AI) and adrenal crisis (AC) in adolescents and young adults. METHODS: Searches of PubMed identifying relevant reports up to March 2022. RESULTS: AI is rare disorder that requires lifelong glucocorticoid replacement therapy and is associated with substantial morbidity and occasional mortality among adolescents and young adults. Aetiologies in this age group are more commonly congenital, with acquired causes, resulting from tumours in the hypothalamic-pituitary area and autoimmune adrenalitis among others, increasing with age. All patients with AI are at risk of AC, which have an estimated incidence of 6 to 8 ACs/100 patient years. Prevention of ACs includes use of educational interventions to achieve competency in dose escalation and parenteral glucocorticoid administration during times of physiological stress, such as an intercurrent infection. While the incidence of AI/AC in young children and adults has been documented, there are few studies focussed on the AC occurrence in adolescents and young adults with AI. This is despite the range of developmental, psychosocial, and structural changes that can interfere with chronic disease management during this important period of growth and development. CONCLUSION: In this review, we examine the current state of knowledge of AC epidemiology in emerging adults; examine the causes of ACs in this age group; and suggest areas for further investigation that are aimed at reducing the incidence and health impact of ACs in these patients.

Effect of Recombinant Gonadotropin on Testicular Function and Testicular Sperm Extraction in Five Cases of NR0B1 (DAX1) Pathogenic Variants.

Background: NR0B1 pathogenic variants can cause congenital adrenal hypoplasia or primary adrenal insufficiency in early childhood usually associated with hypogonadotropic hypogonadism. NR0B1 is necessary for organogenesis of the adrenal cortex and to maintain normal spermatogenesis. In humans, restoration of fertility in patients carrying NR0B1 pathogenic variants is challenging. Objective: The aim of the study was to investigate the clinical, hormonal, histological, spermiological, and molecular genetic characteristics of a cohort of patients with NR0B1 pathogenic variants, monitored for fertility preservation. Patients: We included five patients, including four teenagers, with NR0B1 pathogenic or likely pathogenic variants. They all had primary adrenal insufficiency and were receiving replacement therapy with glucocorticoids and mineralocorticoids. Patients received recombinant follicle-stimulating hormone and recombinant human chorionic gonadotropin in order to induce spermatogenesis. Combined gonadotropin treatment was initiated between 13 years and 15 years and 6 months for the four teenagers and at 31 years and 2 months for the only adult. Physical and hormonal assessments were performed just before starting gonadotropin treatment. After 12 months of gonadotropin treatment, physical examination and hormonal assessments were repeated, and semen analyses were performed. If no sperm cells were observed in at least 2 semen collections at 3-month interval, testicular biopsy for testicular sperm extraction was proposed. Results: Bilateral testicular volume increased from 8 ml (interquartile range, 6-9) to 12 ml (10-16) after gonadotropin treatment. Inhibin B levels were relatively stable: 110 ng/L (46-139) before and 91 ng/L (20-120) at the end of gonadotropin treatment. Azoospermia was observed in all semen analyses for all cases during gonadotropin treatment. Three patients agreed to testicular biopsy; no mature sperm cells could be retrieved in any. Conclusion: We characterized a cohort of patients with NR0B1 pathogenic or likely pathogenic variants for fertility preservation by recombinant gonadotropin treatment, which began either at puberty or in adulthood. No sperm cells could be retrieved in semen samples or testicular biopsy even after gonadotropin treatment, indicating that gonadotropin treatment, even when started at puberty, is ineffective for restoring fertility.

Autoimmune Thyroid Disorders in Autoimmune Addison Disease.

CONTEXT: Autoimmune thyroid disease is the most common endocrine comorbidity in autoimmune Addison disease (AAD), but detailed investigations of prevalence and clinical course are lacking. OBJECTIVE: This work aimed to provide comprehensive epidemiological and clinical data on autoimmune thyroid disorders in AAD. METHODS: A nationwide registry-based study including 442 patients with AAD and autoimmune thyroid disease were identified through the Norwegian National Registry of Autoimmune Diseases. RESULTS: Of 912 registered AAD patients, 442 (48%) were diagnosed with autoimmune thyroid disease. A total of 380 (42%) had autoimmune hypothyroidism. Of the 203 with available thyroid function tests at time of diagnosis, 20% had overt hypothyroidism, 73% had subclinical hypothyroidism, and 7% had thyroid levels in the normal range. Negative thyroid peroxidase antibodies was found in 32%. Ninety-eight percent were treated with levothyroxine, 5% with combination therapy with liothyronine or thyroid extracts, and 1% were observed without treatment. Seventy-eight patients (9%) were diagnosed with Graves disease (GD), of whom 16 (21%) were diagnosed with autoimmune hypothyroidism either before onset or after remission of GD. At the end of follow-up, 33% had normal thyroid hormone levels without antithyroid-drugs or levothyroxine treatment. The remaining had either active disease (5%), had undergone ablative treatment (41%), or had developed autoimmune hypothyroidism (21%). CONCLUSION: The true prevalence of hypothyroidism in AAD is lower than reported in the current literature. Careful consideration of the indication to start thyroxin therapy is warranted. Long-term remission rates in GD patients with AAD are comparable to recent reports on long-term follow-up of patients without AAD.