Heterozygous variants in SIX3 and POU1F1 cause pituitary hormone deficiency in mouse and man.

Congenital hypopituitarism is a genetically heterogeneous condition that is part of a spectrum disorder that can include holoprosencephaly. Heterozygous mutations in SIX3 cause variable holoprosencephaly in humans and mice. We identified two children with neonatal hypopituitarism and thin pituitary stalk who were doubly heterozygous for rare, likely deleterious variants in the transcription factors SIX3 and POU1F1. We used genetically engineered mice to understand the disease pathophysiology. Pou1f1 loss-of-function heterozygotes are unaffected; Six3 heterozygotes have pituitary gland dysmorphology and incompletely ossified palate; and the Six3+/-; Pou1f1+/dw double heterozygote mice have a pronounced phenotype, including pituitary growth through the palate. The interaction of Pou1f1 and Six3 in mice supports the possibility of digenic pituitary disease in children. Disruption of Six3 expression in the oral ectoderm completely ablated anterior pituitary development, and deletion of Six3 in the neural ectoderm blocked the development of the pituitary stalk and both anterior and posterior pituitary lobes. Six3 is required in both oral and neural ectodermal tissues for the activation of signaling pathways and transcription factors necessary for pituitary cell fate. These studies clarify the mechanism of SIX3 action in pituitary development and provide support for a digenic basis for hypopituitarism.

Hypopituitarism.

Partial or complete deficiency of anterior or posterior pituitary hormone production leads to central hypoadrenalism, central hypothyroidism, hypogonadotropic hypogonadism, growth hormone deficiency, or arginine vasopressin deficiency depending on the hormones affected. Hypopituitarism is rare and likely to be underdiagnosed, with an unknown but rising incidence and prevalence. The most common cause is compressive growth or ablation of a pituitary or hypothalamic mass. Less common causes include genetic mutations, hypophysitis (especially in the context of cancer immunotherapy), infiltrative and infectious disease, and traumatic brain injury. Clinical features vary with timing of onset, cause, and number of pituitary axes disrupted. Diagnosis requires measurement of basal circulating hormone concentrations and confirmatory hormone stimulation testing as needed. Treatment is aimed at replacement of deficient hormones. Increased mortality might persist despite treatment, particularly in younger patients, females, and those with arginine vasopressin deficiency. Patients with complex diagnoses, pregnant patients, and adolescent pituitary-deficient patients transitioning to adulthood should ideally be managed at a pituitary tumour centre of excellence.

High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency.

Pituitary hormone deficiency occurs in ∼1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated individuals with hypopituitarism that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant-negative loss of function. Using a high-throughput splicing reporter assay, we tested 1,070 single-nucleotide variants in POU1F1. We identified 96 splice-disruptive variants, including 14 synonymous variants. In separate cohorts, we found two additional synonymous variants nominated by this screen that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in POU1F1.

Creating a SNOMED CT reference set for common endocrine disorders based on routine clinic correspondence.

BACKGROUND: Routine clinical coding of clinical outcomes in outpatient consultations still lags behind the coding of episodes of inpatient care. Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) offers an opportunity for standardised coding of key clinical information. Identifying the most commonly required SNOMED terms and grouping these into a reference set will aid future adoption in routine clinical care. OBJECTIVE: To create a common endocrinology reference set to standardise the coding for outcomes of outpatient endocrine consultations, using a semi-automated extraction of information from existing clinical correspondence. METHODS: Retrospective review of data from an adult tertiary outpatient endocrine clinic between 2018 and 2019. A total of 1870 patients from postcodes within two regional areas of NHS Grampian (Aberdeen City and Aberdeenshire) attended the clinic. Following consultation, an automated script extracted each problem statement which was manually coded using the 'disorder' concepts from SNOMED CT (UK edition). RESULTS: The review identified 298 relevant endocrine diagnoses, 99 findings and 142 procedures. There were a total of 88 (29.5%) commonly seen endocrine conditions (e.g., Graves' disease, anterior hypopituitarism and Addison's disease) and 210 (70.5%) less commonly seen endocrine conditions. Subsequently, consultant endocrinologists completed a survey regarding the common endocrine conditions; 28 conditions have 100% agreement, 25 have 90%-99% agreement, 31 have 50%-89% agreement and 4 have less than 59% agreement (which were excluded). CONCLUSION: Automated text parsing of structured endocrine correspondence allowed the creation of a SNOMED CT reference set for common endocrine disorders. This will facilitate funding and planning of service provision in endocrinology by allowing more accurate characterisation of the patient cohorts needing specialist endocrine care.

Beyond the bias! Sex distribution in paediatric growth hormone deficiency reexamined.

OBJECTIVES: Various biases pertaining to stature account for a male sex predominance in growth hormone deficiency (GHD) cases diagnosed by endocrinology clinics. This manuscript will assess the sex distribution when biases are minimised. METHODS: Retrospective chart review was conducted on patients diagnosed with GHD between 3 and 16 years of age. The sex distribution of cases was ascertained according to: (1) peak GH (pGH) by groups; based on growth hormone provocative testing, (2) pituitary gland imaging results, and (3) isolated GHD (IGHD) versus multiple pituitary hormone deficiencies (MPHD). The relative frequency of each sex was compared according to these subgroups with significance evaluated at α = .05 level. RESULTS: Of the 5880 clinic referrals for short stature, there were 3709 boys (63%) and 2171 girls (37%). Of these, 20% of boys (n = 745) and 15.3% of girls (n = 332) underwent provocative testing for GHD. Of those tested, 39.2% of boys (n = 292) and 32.2% of girls (n = 107) were diagnosed with GHD, all p < .001. There was a male predominance in GHD cases based on pGH or GHD severity. Though not significant, girls were more likely than boys to have MPHD (p = .056), even across pGH groups (p = .06). Both boys and girls had a similar distribution of imaging abnormalities. CONCLUSION: Stratifying by sex, we found similar percentages of pituitary imaging abnormalities (including tumours) and the number of pituitary hormone deficiencies in boys and girls as the cause of GHD. For these classifications, we did not find the historically reported male sex predominance.

Bone mineral density, turnover, and microarchitecture assessed by second-generation high-resolution peripheral quantitative computed tomography in patients with Sheehan's syndrome.

Sheehan's syndrome (SS) is a rare but well-characterized cause of hypopituitarism. Data on skeletal health is limited and on microarchitecture is lacking in SS patients. PURPOSE: We aimed to explore skeletal health in SS with bone mineral density (BMD), turnover, and microarchitecture. METHODS: Thirty-five patients with SS on stable replacement therapy for respective hormone deficiencies and 35 age- and BMI-matched controls were recruited. Hormonal profile and bone turnover markers (BTMs) were measured using electrochemiluminescence assay. Areal BMD and trabecular bone score were evaluated using DXA. Bone microarchitecture was assessed using a second-generation high-resolution peripheral quantitative computed tomography. RESULTS: The mean age of the patients was 45.5 ± 9.3 years with a lag of 8.3 ± 7.2 years prior to diagnosis. Patients were on glucocorticoid (94%), levothyroxine (94%), and estrogen-progestin replacement (58%). None had received prior growth hormone (GH) replacement. BTMs (P1NP and CTX) were not significantly different between patients and controls. Osteoporosis (26% vs. 16%, p = 0.01) and osteopenia (52% vs. 39%, p = 0.007) at the lumbar spine and femoral neck (osteoporosis, 23% vs. 10%, p = 0.001; osteopenia, 58% vs. 29%, p = 0.001) were present in greater proportion in SS patients than matched controls. Bone microarchitecture analysis revealed significantly lower cortical volumetric BMD (vBMD) (p = 0.02) at the tibia, with relative preservation of the other parameters. CONCLUSION: Low areal BMD (aBMD) is highly prevalent in SS as compared to age- and BMI-matched controls. However, there were no significant differences in bone microarchitectural measurements, except for tibial cortical vBMD, which was lower in adequately treated SS patients.

Progress, challenges and perspectives in the management of hypopituitarism.

Hypopituitarism is a rare endocrine disorder characterized by insufficient hormone secretion from the pituitary gland. This condition leads to deficient production of one or more pituitary hormones, including growth hormone (GH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), adrenocorticotropic hormone (ACTH), and antidiuretic hormone (ADH), also called arginine vasopressin (AVP). Symptoms vary widely and are often not, late recognized.Diagnosis typically involves a thorough clinical evaluation, hormone level assessments, and neuroimaging studies to identify underlying causes. Treatment aims to replace deficient hormones and address the underlying cause and related complications when possible. In this special issue we address diagnosis, comorbidities, and management of hypopituitarism. We hope that it will help healthcare professionals to manage their patients.

Pitfalls in the lab assessment of hypopituitarism.

The diagnostic approach to hypopituitarism involves many disciplines. Clinical symptoms rarely are specific. Imaging techniques are helpful but cannot prove the specific functional defects. Therefore, the definitive diagnosis of pituitary insufficiency is largely based on laboratory tests. However, also laboratory methods come with inherent limitations, and it is essential for the clinician to know and recognize typical pitfalls. Most factors potentially impairing the quality of hormone measurements are introduced in the preanalytical phase, i.e. before the hormones are measured by the laboratory. For example, the timing of blood drawing with respect to circadian rhythm, stress, and medication can have an influence on hormone concentrations. During the actual analysis of the hormones, cross-reactions with molecules present in the sample presenting the same or similar epitopes than the intended analyte may affect immunoassays. Interference can also come from heterophilic or human anti-animal antibodies. Unexpected problems can also be due to popular nutritional supplements which interfere with the measurement procedures. An important example in this respect is the interference from biotin. It became only clinically visible when the use of this vitamin became popular among patients. The extreme serum concentrations reached when patients take it as a supplement can lead to incorrect measurements in immunoassays employing the biotin-streptavidin system. To some extent, hormone analyses using liquid chromatography mass spectrometry (LCMS) can overcome problems, although availability and cost-effectiveness of this method still imposes restrictions. In the post-analytical phase, appropriateness of reference intervals and cut-offs with respect to the specific analytical method used is of outmost importance. Furthermore, for interpretation, additional biological and pharmacological factors like BMI, age and concomitant diseases must be considered to avoid misinterpretation of the measured concentrations. It is important for the clinician and the laboratory to recognize when one or more laboratory values do not match the clinical picture. In an interdisciplinary approach, the search for the underlying cause should be initiated.

Diagnosis and therapeutic approach to bone health in patients with hypopituitarism.

The results of many studies in recent years indicate a significant impact of pituitary function on bone health. The proper function of the pituitary gland has a significant impact on the growth of the skeleton and the appearance of sexual dimorphism. It is also responsible for achieving peak bone mass, which protects against the development of osteoporosis and fractures later in life. It is also liable for the proper remodeling of the skeleton, which is a physiological mechanism managing the proper mechanical resistance of bones and the possibility of its regeneration after injuries. Pituitary diseases causing hypofunction and deficiency of tropic hormones, and thus deficiency of key hormones of effector organs, have a negative impact on the skeleton, resulting in reduced bone mass and susceptibility to pathological fractures. The early appearance of pituitary dysfunction, i.e. in the pre-pubertal period, is responsible for failure to achieve peak bone mass, and thus the risk of developing osteoporosis in later years. This argues for the need for a thorough assessment of patients with hypopituitarism, not only in terms of metabolic disorders, but also in terms of bone disorders. Early and properly performed treatment may prevent patients from developing the bone complications that are so common in this pathology. The aim of this review is to discuss the physiological, pathophysiological, and clinical insights of bone involvement in pituitary disease.

Diagnosing and treating anterior pituitary hormone deficiency in pediatric patients.

Hypopituitarism, or the failure to secrete hormones produced by the anterior pituitary (adenohypophysis) and/or to release hormones from the posterior pituitary (neurohypophysis), can be congenital or acquired. When more than one pituitary hormone axis is impaired, the condition is known as combined pituitary hormone deficiency (CPHD). The deficiency may be primarily due to a hypothalamic or to a pituitary disorder, or concomitantly both, and has a negative impact on target organ function. This review focuses on the pathophysiology, diagnosis and management of anterior pituitary hormone deficiency in the pediatric age. Congenital hypopituitarism is generally due to genetic disorders and requires early medical attention. Exposure to toxicants or intrauterine infections should also be considered as potential etiologies. The molecular mechanisms underlying the fetal development of the hypothalamus and the pituitary are well characterized, and variants in the genes involved therein may explain the pathophysiology of congenital hypopituitarism: mutations in the genes expressed in the earliest stages are usually associated with syndromic forms whereas variants in genes involved in later stages of pituitary development result in non-syndromic forms with more specific hormone deficiencies. Tumors or lesions of the (peri)sellar region, cranial radiation therapy, traumatic brain injury and, more rarely, other inflammatory or infectious lesions represent the etiologies of acquired hypopituitarism. Hormone replacement is the general strategy, with critical periods of postnatal life requiring specific attention.

Diagnosing and treating the elderly individual with hypopituitarism.

Hypopituitarism in the elderly is an underestimated condition mainly due to the non-specific presentation that can be attributed to the effects of aging and the presence of comorbidities. Diagnosis and treatment of hypopituitarism often represent a challenging task and this is even more significant in the elderly. Diagnosis can be insidious due to the physiological changes occurring with aging that complicate the interpretation of hormonal investigations, and the need to avoid some provocative tests that carry higher risks of side effects in this population. Treatment of hypopituitarism has generally the goal to replace the hormonal deficiencies to restore a physiological balance as close as possible to that of healthy individuals but in the elderly this must be balanced with the risks of over-replacement and worsening of comorbidities. Moreover, the benefit of some hormonal replacement therapies in the elderly, including sex hormones and growth hormone, remains controversial.

Morbidities and mortality among hospitalized patients with hypopituitarism: Prevalence, causes and management.

Hypopituitarism is a highly heterogeneous multisystem disorder that can have a major impact on long-term morbidity and mortality, but even more so during acute medical conditions requiring hospitalization. Recent studies suggest a significant in-hospital burden with prolonged length of stay, increased rate of intensive care unit (ICU) admission, and initiation of mechanical ventilation - all of which may lead to an increased risk of in-hospital mortality. On the one hand, patients with hypopituitarism are often burdened by metabolic complications, including obesity, hypertension, dyslipidemia, and hyperglycemia, which alone, or in combination, are known to significantly alter relevant physiological mechanisms, including metabolism, innate and adaptive immune responses, coagulation, and wound healing, thereby contributing to adverse in-hospital outcomes. On the other hand, depending on the extent and the number of pituitary hormone deficiencies, early recognition of hormone deficiencies and appropriate management and replacement strategy within a well-organized multidisciplinary team are even stronger determinants of short-term outcomes during acute hospitalization in this vulnerable patient population. This review aims to provide an up-to-date summary of recent advances in pathophysiologic understanding, clinical implications, and recommendations for optimized multidisciplinary management of hospitalized patients with hypopituitarism.

Cognition and psychological wellbeing in hypopituitary patients.

Hypopituitarism (HP) frequently occurs in patients presenting with sellar masses and despite recent advances in therapeutic options, HP patients consistently suffer from impaired quality of life due to psychological distress and cognitive dysfunction. These neurocognitive complications tend to persist in spite of surgical or biochemical remission of the disease making it especially challenging to segregate the effect of HP per se from other comorbidities such as the effect of tumour, surgery, radiation therapy, or complications caused by excess hormone production. Regardless, there is ample evidence to suggest that receptors for various pituitary hormones are abundantly expressed in key areas of central nervous system that are associated with memory and behaviour function and HP is also associated with poor sleep which can further exacerbate neurocognitive dysfunction. There is also evidence that hormonal replacement in HP patients partially restores these neurocognitive functions and improves sleep disorders. However, there is a need for creating better awareness among healthcare providers interacting with HP patients to enhance an earlier recognition of these disorder and their impact on quality of life despite initial remission. Importantly, there is a need to not only develop better and more cost-effective replacement therapies that would closely mimic the physiological hormonal release patterns, but also develop coping strategies for HP patients suffering from these complications.

Special features on insulin resistance, metabolic syndrome and vascular complications in hypopituitary patients.

Pituitary hormone deficiency, hypopituitarism, is a dysfunction resulting from numerous etiologies, which can be complete or partial, and is therefore heterogeneous. This heterogeneity makes it difficult to interpret the results of scientific studies with these patients.Adequate treatment of etiologies and up-to-date hormone replacement have improved morbidity and mortality rates in patients with hypopituitarism. As GH replacement is not performed in a reasonable proportion of patients, especially in some countries, it is essential to understand the known consequences of GH replacement in each subgroup of patients with this heterogeneous dysfunction.In this review on hypopituitarism, we will address some particularities regarding insulin resistance, which is no longer common in these patients with hormone replacement therapy based on current guidelines, metabolic syndrome and its relationship with changes in BMI and body composition, and to vascular complications that need to be prevented taking into account the individual characteristics of each case to reduce mortality rates in these patients.

Androgen deficiency in hypopituitary women: its consequences and management.

Women with hypopituitarism have various degrees of androgen deficiency, which is marked among those with combined hypogonadotrophic hypogonadism and secondary adrenal insufficiency. The consequences of androgen deficiency and the effects of androgen replacement therapy have not been fully elucidated. While an impact of androgen deficiency on outcomes such as bone mineral density, quality of life, and sexual function is plausible, the available evidence is limited. There is currently no consensus on the definition of androgen deficiency in women and it is still controversial whether androgen substitution should be used in women with hypopituitarism and coexisting androgen deficiency. Some studies suggest beneficial clinical effects of androgen replacement but data on long-term benefits and risk are not available. Transdermal testosterone replacement therapy in hypopituitary women has shown some positive effects on bone metabolism and body composition. Studies of treatment with oral dehydroepiandrosterone have yielded mixed results, with some studies suggesting improvements in quality of life and sexual function. Further research is required to elucidate the impact of androgen deficiency and its replacement treatment on long-term outcomes in women with hypopituitarism. The lack of transdermal androgens for replacement in this patient population and limited outcome data limit its use. A cautious and personalized treatment approach in the clinical management of androgen deficiency in women with hypopituitarism is recommended while awaiting more efficacy and safety data.

Alterations in Serum miR-126-3p Levels over Time: A Marker of Pituitary Insufficiency following Head Trauma.

INTRODUCTION: Traumatic brain injuries (TBIs) pose a high risk of pituitary insufficiency development in patients. We have previously reported alterations in miR-126-3p levels in sera from patients with TBI-induced pituitary deficiency. METHODS: To investigate why TBI-induced pituitary deficiency develops only in some patients and to reveal the relationship between miR-126-3p with hormone axes, we used mice that were epigenetically modified with miR-126-3p at the embryonic stage. These modified mice were subjected to mild TBI (mTBI) according to the Marmarou's weight-drop model at 2 months of age. The levels of miR-126-3p were assessed at 1 and 30 days in serum after mTBI. Changes in miR-126-3p levels after mTBI of wild-type and miR-126-3p* modified mouse lines validated our human results. Additionally, hypothalamus, pituitary, and adrenal tissues were analyzed for transcripts and associated serum hormone levels. RESULTS: We report that miR-126-3p directly affects hypothalamus-pituitary-adrenal (HPA) axis upregulation and ACTH secretion in the acute phase after mTBI. We also demonstrated that miR-126-3p suppresses Gnrh transcripts in the hypothalamus and pituitary, but this is not reflected in serum FSH/LH levels. The increase in ACTH levels in the acute phase may indicate that upregulation of miR-126-3p at the embryonic stage has a protective effect on the HPA axis after TBI. Notably, the most prominent transcriptional response is found in the adrenals, highlighting their role in the pathophysiology of TBI. CONCLUSION: Our study revealed the role of miR-126-3p in TBI and pituitary deficiency developing after TBI, and the obtained data will significantly contribute to elucidating the mechanism of pituitary deficiency development after TBI and development of new diagnostic and treatment strategies.

Partial hypopituitarism with ACTH deficiency as the main manifestation as a complication of hemorrhagic fever with renal syndrome.

Hypopituitarism is a relatively rare complication of hemorrhagic fever with renal syndrome. However, almost all available reported cases were total anterior pituitary hypofunction, isolated growth-hormone deficiency, or isolated gonadotropin deficiency. Here, we firstly describe a patient with partial hypopituitarism with ACTH deficiency as the main manifestation as a complication of hemorrhagic fever with renal syndrome.

Unique case of lymphocytic hypophysitis with normal pituitary hormone serology mimicking a non-functioning pituitary adenoma.

BACKGROUND: Lymphocytic hypophysitis is a rare autoimmune condition that usually presents during pregnancy and causes inflammation of the pituitary gland. Although the pathophysiology is not well understood, it often presents with headaches, visual disturbances, and symptoms of hypopituitarism. However, not all cases may present with hypopituitarism which can make this rare disease with an incidence of ~ 1 in 9 million much more difficult to diagnose. CASE PRESENTATION: We present a 35-year-old G4P4 woman with progressive vision loss and intermittent frontal headaches during her first trimester through 2 months postpartum. She presented with no symptoms of hypopituitarism and her hormone panel only showed elevated prolactin, possibly due to her breastfeeding. She was treated with a right pterional craniotomy with decompression of both optic nerves, partial resection of the suprasellar mass, and glucocorticoid therapy for headaches and visual disturbances. CONCLUSION: This case is notable for a presentation of lymphocytic hypophysitis without symptoms of hypopituitarism. This is important for outpatient providers to be aware of, especially those that care for pregnant patients so that unfavorable outcomes can be avoided.

Hypopituitarism with secondary adrenocortical insufficiency and arginine vasopressin deficiency due to hypophysitis after COVID-19 vaccination: a case report.

BACKGROUND: Although vaccination against coronavirus disease (COVID-19) has several side effects, hypopituitarism due to hypophysitis has rarely been reported. CASE PRESENTATION: An 83-year-old healthy woman, who had received her fourth COVID-19 vaccine dose 2 days before admission, presented to the emergency department with difficulty moving. On examination, impaired consciousness (Glasgow Coma Scale: 14) and fever were observed. Computed tomography and magnetic resonance imaging of the head revealed swelling from the sella turcica to the suprasellar region. Her morning serum cortisol level was low (4.4 µg/dL) and adrenocorticotropic hormone level was normal (21.6 pg/mL). Central hypothyroidism was also suspected (thyroid stimulating hormone, 0.46 µIU/mL; free triiodothyronine, 1.86 pg/mL; free thyroxine, 0.48 ng/dL). Secondary adrenocortical insufficiency, growth hormone deficiency, delayed gonadotropin response, and elevated prolactin levels were also observed. After administration of prednisolone and levothyroxine, her consciousness recovered. On the 7th day of admission, the patient developed polyuria, and arginine vasopressin deficiency was diagnosed using a hypertonic saline test. On the 15th day, the posterior pituitary gland showed a loss of high signal intensity and the polyuria resolved spontaneously. On the 134th day, the corticotropin-releasing hormone loading test showed a normal response; however, the thyrotropin-releasing hormone stimulation test showed a low response. The patient's disease course was stable with continued thyroid and adrenal corticosteroid supplementation. CONCLUSIONS: Herein, we report a rare case of anterior hypopituitarism and arginine vasopressin deficiency secondary to hypophysitis following COVID-19 vaccination.

Successful treatment of medically and surgically refractory lymphocytic hypophysitis with fractionated stereotactic radiotherapy: a single-center experience and systematic literature review.

PURPOSE: To explore the potential role of focused radiotherapy in managing the lymphocytic hypophysitis (LH) refractory to medical therapy and surgery. METHOD: A systematic literature review was conducted following PRISMA guidelines to identify the studies on radiation treatment for hypophysitis, along with the experience in our institution. RESULTS: The study included eight patients, three from our institution and five from existing literature. The age at presentation ranged from 37 to 75 years old, with a median age of 58. The presenting symptoms involved headache in seven patients and diplopia in two patients. Pre-radiation visual field defects were noticed in four patients. All patients exhibited variable degrees of hypopituitarism before radiation, with oral corticosteroids being the initial medical treatment. Immunosuppressive therapy was attempted in two patients prior to radiation. Seven patients had a history of transsphenoidal surgery with a histologically confirmed LH. Three patients underwent stereotactic radiosurgery (SRS), while the remaining received FSRT, with a mean irradiation volume of 2.2 cm3. A single-session total dose of 12 -15 Gy was administered in the SRS group. In the FSRT group, doses ranged from 24 to 30 Gy with a median dose of 25 Gy, delivered in 2 Gy fractions. Four patients achieved a resolution of visual field defects, while another two patients demonstrated improvement in their associated focal neurologic deficits. No change in pre-existing endocrine status was shown after radiation, except in one patient. Clinical response was achieved in seven patients after a single course of radiation, while one patient required the second course. Six patients remained stable on low-dose glucocorticoid during at least a 12-month follow-up period, and one discontinued it entirely without experiencing relapse. Three patients demonstrated a complete radiologic response, while the remaining showed a partial radiologic response. CONCLUSIONS: Focused radiation, including FSRT, can play a role in symptomatic relief, effective mass shrinkage, and minimizing radiation exposure to critical surrounding structures in patients with refractory LH. However, further research efforts are necessary to better clarify its effects and optimal dose planning.