Analysis of patients with iatrogenic hypopituitarism after cranial irradiation

Introduction

Radiotherapy is one of the modern and effective methods for treating brain tumors. Cranial irradiation targets malignant cells; however, it inevitably poses a risk of radiation exposure to healthy brain tissue [1, 2].

Radiation therapy has been advancing rapidly in oncology. Nevertheless, cranial irradiation frequently leads to complications affecting healthy tissue structures, including damage to the hippocampus, white matter, and microvascular reactions. Exceeding the threshold of sensitivity to the total radiation dose, radiation toxicity results in long-term consequences that often manifest years after treatment [2–4].

The hypothalamic-pituitary region is relatively tolerant to radiation, which paradoxically increases the risk of iatrogenic hypopituitarism.

The pathological mechanism underlying this condition involves degenerative changes in the vessels of the pituitary gland and hypothalamus: endothelial cell death, increased permeability, thinning of the basal membrane, and enhanced fibroblast activity. These processes lead to obliteration of small vessels and subsequent tissue necrosis, particularly at high radiation doses [3, 5].

Ionizing radiation also induces degenerative changes in glial cells, reducing their trophic support for neurons of the hypothalamus and other CNS regions, thereby triggering demyelination [5].

It is also hypothesized that the immune system may act as a mediator of neuroendocrine dysfunction following cranial radiotherapy. Anti-hypothalamic and anti-pituitary antibodies, which are normally absent in healthy individuals, have been detected in children after radiotherapy [5].

Numerous clinical studies have confirmed that the somatotropic function of the pituitary gland is the most sensitive to radiation. Different pituitary axes likely exhibit variable radiosensitivity. Long-term follow-up data from patients who completed radiotherapy indicate that somatotropic deficiency occurs at a frequency of approximately 93%, ACTH deficiency at 38±6%, and TSH deficiency at 23±4% [1].

Radiation damage to the pituitary gland leads to tropic hormone deficiencies. The extent of the resulting insufficiency, including the risk of hypogonadism, depends on the severity of the damage.

In addition to hormonal deficiencies, long-term toxic effects of radiotherapy include cerebrovascular disturbances, brain tissue necrosis, cognitive impairment, cataracts, glaucoma, hearing loss, and alopecia [2, 6].

Cranial irradiation not only damages the hypothalamic-pituitary system but also affects the thyroid gland. Direct thyroid dysfunction occurs much more frequently than central hypothyroidism, even though a significant portion of the radiation dose targets the posterior cranial fossa. Furthermore, primary gonadal damage is a common consequence of radiotherapy [1].

Somatotropic deficiency can arise even with low radiation doses; thus, isolated growth hormone (GH) deficiency is the most frequent manifestation. Panhypopituitarism develops when total doses exceed 45 Gy [2, 7].

The severity of post-radiation hypopituitarism depends not only on the total radiation dose but also on the patient's age. Currently, there are no precise data on the effect of age on radiation response, so this issue remains debated. However, observations suggest that children irradiated at a young age are more vulnerable to radiation, even at low doses, and are more likely to develop GH deficiency than those treated at an older age [4, 6, 8–11].

The frequency of GH deficiency can reach 50–100% within 3–5 years after cranial irradiation. These findings underscore the need to assess the hormonal profile of children both during and after radiotherapy to prevent long-term treatment sequelae. Follow-up of children after cranial irradiation has helped define criteria for further evaluation, including physical assessment, assessment of pituitary hormone function, and, when indicated, stimulation tests to determine GH deficiency. Growth dynamics should be evaluated every 6–12 months until final height is achieved [2, 4, 7, 12].

Clinical evaluation, baseline pituitary hormone assessment, and dynamic testing for GH and ACTH deficiency should begin one year after cranial radiotherapy [2, 4].

Current evidence suggests that the risk of hypothalamic-pituitary dysfunction resulting from radiation therapy may be reduced by using novel irradiation techniques. Protecting healthy tissues from radiation-induced damage remains a pressing concern. Emerging radiation technologies may in the future provide effective control of primary brain tumors without causing long-term complications [4, 6, 13, 14].

Clinical case 1

Patient I., 15 years 7 months old. Primary diagnosis: hypopituitarism with growth hormone deficiency following radiotherapy, chemotherapy, and surgical treatment for medulloblastoma of the fourth ventricle. Comorbidities: organic brain damage (status post combined treatment – surgery, radiotherapy, chemotherapy – for fourth ventricle medulloblastoma at age 3 years 4 months). Hypothyroidism. Cervical spine dysplasia. Thoracolumbar scoliosis grade I–II. Thoracic spine dysplasia. Juvenile osteochondrosis. Flat feet. Bilateral sensorineural hearing loss grade I. Post-radiation cataract. Mild myopia of both eyes. Gilbert's syndrome.

Medical history: the child is from the first pregnancy, which was unremarkable. Delivery at 39 weeks. Apgar score 8/10. Birth weight 3820 g, birth length 52 cm. Breastfed until 3.5 months. Growth and development were age-appropriate. Vaccinated according to the National Immunization Schedule. Under dispensary follow-up by an endocrinologist, oncologist, ophthalmologist, audiologist, and cardiologist.

Past illnesses: recurrent viral infections, chickenpox, chronic gastroduodenitis. No history of allergies. No family history of endocrine disorders. Maternal height 175 cm, paternal height 190 cm. At age 3 years 4 months, according to the mother, the child developed recurrent vomiting without apparent cause. Later, gait instability, lethargy, and drowsiness appeared. Brain CT revealed a mass in the fourth ventricle. The boy was admitted to the N.N. Burdenko Neurosurgery Institute. Two months later, he underwent surgical treatment with total tumor resection. Histological examination: medulloblastoma, classic variant with areas of large-cell architecture.

The boy was referred to the R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation for further therapy. He received two courses of radiotherapy as craniospinal irradiation (total focal dose up to 36 Gy, followed by a boost to the posterior cranial fossa up to 54 Gy). After completing radiotherapy, he received 4 courses of high-dose polychemotherapy with autologous hematopoietic stem cell transplantation.

At age 9 years, hypopituitarism was suspected, and the patient was referred for evaluation. Radiography of the wrist joints showed bone age corresponding to chronological age (9–9.5 years). Thyroid function testing (TSH 14.1 µIU/mL, free T4 9.8 pmol/L) led to a diagnosis of primary hypothyroidism. Levothyroxine sodium was prescribed at 50 µg/day (1.5 µg/kg/day).

The patient was evaluated on an outpatient basis, with dynamic assessment of anthropometric parameters and adjustment of levothyroxine dose based on thyroid profile.

He first presented to the endocrinology department of the Clinic of Saint Petersburg State Pediatric Medical University at age 11 years 8 months. Based on physical and laboratory findings (height 140 cm, –1.02 SDS; IGF-1 level below –2 SDS; bone age corresponding to chronological age), an insulin tolerance test was performed, which revealed a peak GH response of 1.14 ng/mL. Consequently, replacement therapy with recombinant human growth hormone (rhGH) was initiated at 0.033 mg/kg/day.

After starting GH therapy, the patient was annually hospitalized at the Clinic of Saint Petersburg State Pediatric Medical University for safety and efficacy monitoring.

Given persistently low IGF-1 levels, the replacement therapy dose was systematically adjusted.

At age 13 years, ophthalmologic examination revealed bilateral post-radiation cataracts. At age 15 years 5 months, grade I sensorineural hearing loss was diagnosed.

During the most recent hospitalization at age 15 years 7 months, recombinant somatotropic hormone was discontinued at the growth-stimulating dose due to epiphyseal plate closure. Brain and pituitary MRI showed no signs of disease recurrence, but features of developing empty sella turcica and heterogeneity of the pituitary structure were noted.

The efficacy of the prescribed replacement hormonal therapy was analyzed based on physical, laboratory, and instrumental examinations. Assessment of sexual development revealed no signs of hypogonadism; sexual development was age-appropriate.

The patient was advised to continue dynamic monitoring of LH, FSH, ACTH, and TSH levels, and to undergo routine brain MRI. Current therapy includes recombinant GH at a metabolic dose and levothyroxine sodium replacement.

Table 1. Laboratory results

Table 2. Growth dynamics

Fig. 1. MRI of the brain and pituitary gland with contrast (Patient I., 15 years 7 months)

Clinical case 2

Patient O., 16 years 4 months old. Primary diagnosis: hypopituitarism with growth hormone deficiency. Comorbidities: status post surgery for pleomorphic xanthoastrocytoma (PXA) of the right frontal lobe. Organic brain damage. Structural epilepsy. Cognitive impairment. Mixed psychiatric disorder. Complicated radiation cataract of the left eye. Aphakia. Concomitant divergent strabismus of the right eye. Subclinical hypothyroidism. Overweight. Cervical spine dysplasia. Thoracolumbar scoliosis grade I–II, posture abnormality – increased thoracic lordosis, lumbar lordosis. Thoracic and lumbosacral spine dysplasia. Flat-valgus feet.

Medical history: the girl is from the fifth pregnancy, which was complicated by threatened miscarriage at 22 weeks, edema at 36–37 weeks; the second of twins, spontaneous delivery. Born at 38 weeks of gestation. Birth weight 2550 g, length 46 cm, head circumference 34 cm, chest circumference 31 cm. Apgar score 7/8.

At age 3 years 11 months, after dinner at kindergarten, she developed vomiting, which recurred several days later. Suspected helminthic infestation was treated without effect. Vomiting frequency increased to 4–5 times per day. To verify neurological pathology, brain MRI was performed. The scan revealed a well-defined mass in the right frontal lobe, and she was admitted to the Professor A.L. Polenov Russian Research Neurosurgery Institute.

Emergency bone-plastic craniotomy in the right frontal region with subtotal resection of the medial portions of the right frontal lobe was performed. Subsequently, the patient received radiotherapy (40 Gy).

At age 4 years 8 months, after an episode of loss of consciousness, brain MRI revealed signs of massive tumor enlargement with compression of surrounding tissues. A second operation was performed: right frontal craniotomy for tumor resection with external ventricular drainage. Radiotherapy was continued.

At approximately age 8 years, the parents noted poor weight and height gain, especially compared to the twin sister, and consulted a pediatric endocrinologist.

At age 8 years 4 months, ophthalmologic examination revealed bilateral radiation cataracts as a complication of radiotherapy.

Evaluation around the same age led to a diagnosis of secondary hypothyroidism, and levothyroxine sodium replacement therapy was initiated.

At age 14 years 11 months, during routine examination at the Clinic of Saint Petersburg State Pediatric Medical University, an insulin tolerance test for GH revealed a peak response of 0.09 ng/mL. Based on this result, replacement therapy with recombinant human growth hormone was initiated at a starting dose of 0.033 mg/kg/day.

Table 3. Growth and weight dynamics

Discussion

Since diagnosis, both patients have undergone regular evaluation to assess the efficacy and safety of the therapy based on physical and instrumental examinations.

In both patients, the initial endocrine manifestation was growth hormone deficiency that developed after radiotherapy.

Post-radiation complications also included radiation cataracts and hearing loss, which were identified during follow-up.

Replacement hormonal therapy resulted in positive growth dynamics, achievement of predicted height, and compensation of the thyroid profile. Hormonal therapy was systematically adjusted based on laboratory data.

To reduce the risk of tumor recurrence, patients routinely underwent brain MRI with dynamic assessment; at the time of the study, no deterioration after tumor removal or structural brain changes were observed.

Conclusion

Cranial irradiation is a modern treatment modality for brain tumors; however, a well‑established complication of this therapy is hypothalamic‑pituitary dysfunction with progressive deficiency of anterior pituitary hormones.

Radiation induces vascular and neuronal damage. The severity of hypopituitarism depends on the radiation dose received and the patient's age.

To improve patients' quality of life, timely assessment of hypothalamic‑pituitary function is essential, particularly monitoring weight and height dynamics in children, as the somatotropic axis is the most sensitive to radiation therapy.

Novel irradiation techniques are currently being developed. Following a comprehensive analysis of modern radiotherapy methods, their use may reduce or even eliminate the risks of long-term complications by lowering the radiation dose and decreasing the volume of healthy tissue exposed [9–11].