Long-Term Outcomes of Patients with Acromegaly - A Report from the Swedish Pituitary Register

Objective: To describe treatment and long-term outcomes of patients with acromegaly from all health-care regions in Sweden. Design and Methods: Analysis of prospectively reported data from the Swedish Pituitary Register of 698 patients (51% females) with acromegaly diagnosed from 1991-2011. The latest clinical follow-up date was December, 2012, while mortality data were collected for 28.5 years until June, 2019. Results: The annual incidence was 3.7/million; 71% of patients had a macroadenoma, 18% had visual field defects, and 25% had at least one pituitary hormone deficiency. Eighty-two percent had pituitary surgery, 10% radiotherapy and 39% medical treatment. At the 5- and 10-year follow-ups, IGF-I levels were within the reference range in 69% and 78% of patients, respectively. In linear regression the proportion of patients with biochemical control including adjuvant therapy at 10 year follow-up increased over time with 1.23 % per year. The SMR (95% CI) for all patients was 1.29 (1.11-1.49). For patients with biochemical control at the latest follow-up, SMR was not increased, neither among patients diagnosed 1991-2000, SMR 1.06 (0.85-1.33) or 2001-2011, SMR 0.87 (0.61-1.24). In contrast, non- controlled patients at the latest follow up from both decades had elevated SMR, 1.90 (1.33-2.72) and 1.98 (1.24-3.14), respectively. Conclusions: The proportion of patients with biochemical control increased over time. Patients with biochemically controlled acromegaly have normal life expectancy while non-controlled patients still have increased mortality. The high rate of macroadenomas and unchanged age at diagnosis illustrates the need for improvements in the management of patients with acromegaly.

Fertility Preservation Methods in Childhood and Adolescence Cancers: A Review.

In childhood and adolescence cancers; survival rates increase with the use of treatment options such as chemotherapy, radiotherapy and hematopoietic stem cell transplantation. One of the long-term effects of primary disease and cancer treatment is the irreversible damage to gonadal tissues, resulting in impaired fertility. Especially chemotherapeutic drugs; causes germ cell defect, affects the secretion of pituitary hormone, and also damages the anatomical structures of internal genital structures such as the uterus. Gonadal preservation methods are limited in prepubertal male patients. It is a good option to place the testicles in a different area before radiotherapy. Before chemotherapy or whole body irradiation, freezing of testicular tissue and ensuring pregnancy from frozen tissue is still in the experimental stage. After the ejaculation begins, obtaining and storing sperm is successfully done. A limited number of pregnancies were obtained oocytes frozen ovaries in the prepubertal girls. It is possible to freeze oocytes after puberty begins. In addition, recently, as a noninvasive method, gonadotropin-releasing hormone (GnRH) analogues have been used successfully, as it suppresses the hypothalamic-pituitary-gonadal axis and protects germ cells from cytotoxic effects. This article aims to provide information on fertility preservation methods in patients receiving childhood cancer treatment.

Hypogonadism in Women with Prader-Willi Syndrome—Clinical Recommendations Based on a Dutch Cohort Study, Review of the Literature and an International Expert Panel Discussion

Prader-Willi syndrome (PWS) is a rare neuroendocrine genetic syndrome. Characteristics of PWS include hyperphagia, hypotonia, and intellectual disability. Pituitary hormone deficiencies, caused by hypothalamic dysfunction, are common and hypogonadism is the most prevalent. Untreated hypogonadism can cause osteoporosis, which is already an important issue in PWS. Therefore, timely detection and treatment of hypogonadism is crucial. To increase understanding and prevent undertreatment, we (1) performed a cohort study in the Dutch PWS population, (2) thoroughly reviewed the literature on female hypogonadism in PWS and (3) provide clinical recommendations on behalf of an international expert panel. For the cohort study, we retrospectively collected results of a systematic health screening in 64 female adults with PWS, which included a medical questionnaire, medical file search, medical interview, physical examination and biochemical measurements. Our data show that hypogonadism is frequent in females with PWS (94%), but is often undiagnosed and untreated. This could be related to unfamiliarity with the syndrome, fear of behavioral changes, hygienic concerns, or drug interactions. To prevent underdiagnosis and undertreatment, we provide practical recommendations for the screening and treatment of hypogonadism in females with PWS.

An Update on Silent Corticotroph Adenomas: Diagnosis, Mechanisms, Clinical Features, and Management

With the introduction of 2017 World Health Organization (WHO) classification of endocrine tumors, T-PIT can serve as a complementary tool for identification of silent corticotroph adenomas (SCAs) in some cases if the tumor is not classifiable by pituitary hormone expression in pathological tissue samples. An increase of the proportion of SCAs among the non-functioning pituitary adenomas (NFPAs) has been witnessed under the new rule with the detection of T-PIT-positive ACTH-negative SCAs. Studies of molecular mechanisms related to SCA pathogenesis will provide new directions for the diagnosis and management of SCAs. A precise pathological diagnosis can help clinicians better identify SCAs. Understanding clinical features in the context of the pathophysiology of SCAs is critical for optimal management. It could provide information on appropriate follow-up time and aid in early recognition and treatment of potentially aggressive forms. Management approaches include surgical, radiation, and/or medical therapies.

Hypoglycemia Induces Vascular Endothelial Dysfunction in Subjects With Normal Glucose Tolerance

This prospective study determined the effects of hypoglycemic stimulation on vascular endothelial function in non-diabetic patients using reactive hyperemia peripheral arterial tonometry (RH-PAT). The study included non-diabetic patients who were hospitalized for an insulin tolerance test (ITT) for the diagnosis of hypoadrenocorticism or hypopituitarism. Vascular endothelial function was assessed using the reactive hyperemia index (RHI) measured by the RH-PAT. We also measured the levels of anterior pituitary hormone, adrenaline, noradrenaline, and dopamine at the time of hypoglycemia. The primary endpoint was a change in the RHI at 120 minutes after insulin administration. The study included 27 patients. ITT was associated with significant increases in systolic blood pressure, pulse rate, and the blood levels of adrenocorticotropic hormone, cortisol, growth hormone, adrenaline, noradrenaline, and dopamine. RHI significantly decreased after ITT from 2.24±0.51 to 1.71±0.42. A significant inverse correlation was observed between the change in RHI and change in adrenaline (r=-0.670, p=0.012). We concluded that hypoglycemic stimulation altered vascular endothelial function, as measured by RH-PAT, even in patients free of glucose intolerance. The observed deterioration in vascular endothelial function correlated with increases in catecholamine levels during hypoglycemia.Trial registration: UMIN000033244

Rathke’s Cleft Cyst Abscess—An Unusual Guest in The Sella

Abscess formation within a Rathkes’s cleft cyst (RCC) is extremely rare, particularly at a young age. We report the case of a young girl with abscess formation in RCC. A 21-year-old female presented with headache, vomiting, visual deterioration and features suggestive of hypopituitarism. She had bitemporal hemianopia with impairment of visual acuity. MRI revealed a cystic lesion in the sella with suprasellar extension and peripheral rim enhancement. On the basis of history and imaging, this was indistinguishable from more commonly encountered pituitary pathology. She underwent transsphenoidal decompression, which revealed yellowish purulent material that when cultured grew Staphylococcus epidermidis. Histological examination revealed numerous neutrophils and cyst wall lining with features characteristic of RCC. Postoperatively, she received antibiotics and replacement therapy for hypopituitarism. Three months later, she experienced deterioration in visual fields. Considering persistent disease, she underwent redo surgery which revealed similar findings. Postsurgery, pituitary MRI revealed an empty sella syndrome. Thereafter, follow-up for 1 year was stable with permanent diabetes insipidus and multiple pituitary hormone deficiency on supplementation. Although uncommon, we recommend considering RCC abscess as a differential diagnosis of a pituitary mass lesion, as predicting its presence can be difficult preoperatively. Persistent or recurrent disease is common in these cases, so timely diagnosis and adequate surgical drainage leads to lower morbidity and mortality.

Acute Sheehan’s syndrome manifesting initially with diabetes insipidus postpartum: a case report and systematic literature review

Purpose Acute Sheehan’s syndrome is a rare, but potentially life-threatening, obstetric event that can be complicated by diabetes insipidus. Little information on the diagnosis and treatment of Sheehan’s syndrome with diabetes insipidus is available. We report on a 28-year-old patient who developed acute Sheehan’s syndrome with diabetes insipidus after giving birth, and on a systematic review of similar cases. Methods We performed a systematic review of the literature cataloged in PubMed and Google Scholar using the keywords “Sheehan syndrome” OR “Sheehan's syndrome” AND “diabetes insipidus” to identify relevant case reports published between 1990 and 2021. Eight Reports met the inclusion criteria (English-language abstracts available, onset in the puerperium, information about the day of the onset). Results In the present case, postpartum curettage was necessary to remove the residual placenta. The total amount of blood loss was severe (2500 ml). On the second day postpartal, the patient developed polyuria. Laboratory analysis revealed hypernatremia with increased serum osmolality and decreased urinary osmolality. Hormone analysis showed partial hypopituitarism involving the thyroid, corticotropic, and gonadotropic axes. The prolactin level was elevated. Brain magnetic resonance imaging showed pituitary gland infarction. Desmopressin therapy was initiated and resolved the polyuria. Hormone replacement therapy was administered. Four months later, the patient was well, with partial diabetes insipidus. The literature review indicated that this case was typical in terms of symptoms and disease onset. Most reported cases involve hypotension and peripartum hemorrhage, but some patients without hemorrhage also develop Sheehan’s syndrome. Elevated prolactin levels are uncommon and associated with poor prognosis in patients with Sheehan’s syndrome. Conclusion Acute Sheehan’s syndrome with diabetes insipidus involves nearly all pituitary hormone axes, indicating severe disease. Prolactin elevation could suggest that a case of Sheehan’s syndrome is severe.

Septo-Optic Dysplasia Diagnosed in a Newborn Infant with Normoglycemia: The Importance of Thorough Physical Examination

A newborn male infant was admitted to the neonatal intensive care unit due to suspected sepsis. He was clinically stable with normal electrolyte levels on admission. However, he was noted to have micropenis and bilateral nonpalpable testes. Ultrasound imaging confirmed the presence of both gonads in the inguinal canal, with no Müllerian structures visualized. Laboratory examination revealed an undetectable random plasma cortisol level; subsequent ACTH stimulation testing confirmed adrenal insufficiency. Further testing revealed additional pituitary hormone deficiencies, and the infant was started on multiple hormone replacement therapies. Magnetic resonance imaging identified absent septum pellucidum, pointing of the frontal horns, and optic nerve hypoplasia. A diagnosis of septo-optic dysplasia was made based on this combination of findings. This case highlights the importance of thorough physical examination in newborn infants, which may reveal the only sign of underlying pathology in the absence of other concerning findings.

Hypothesis and Theory: Evaluating the Co-Evolution of the Melanocortin-2 Receptor and the Accessory Protein MRAP1

The melanocortin receptors (MCRs) and the MRAP accessory proteins belong to distinct gene families that are unique to the chordates. During the radiation of the chordates, the melancortin-2 receptor paralog (MC2R) and the MRAP1 paralog (melanocortin-2 receptor accessory protein 1) have co-evolved to form a heterodimer interaction that can influence the ligand selectivity and trafficking properties of MC2R. This apparently spontaneous interaction may have begun with the ancestral gnathostomes and has persisted in both the cartilaginous fishes and the bony vertebrates. The ramifications of this interaction had profound effects on the hypothalamus/anterior pituitary/adrenal-interrenal axis of bony vertebrates resulting in MC2R orthologs that are exclusively selective for the anterior pituitary hormone, ACTH, and that are dependent on MRAP1 for trafficking to the plasma membrane. The functional motifs within the MRAP1 sequence and their potential contact sites with MC2R are discussed. The ramifications of the MC2R/MRAP1 interaction for cartilaginous fishes are also discussed, but currently the effects of this interaction on the hypothalamus/pituitary/interrenal axis is less clear. The cartilaginous fish MC2R orthologs have apparently retained the ability to be activated by either ACTH or MSH-sized ligands, and the effect of MRAP1 on trafficking varies by species. In this regard, the possible origin of the dichotomy between cartilaginous fish and bony vertebrate MC2R orthologs with respect to ligand selectivity and trafficking properties is discussed in light of the evolution of functional amino acid motifs within MRAP1.

Growth Hormone Deficiency and Treatment in Childhood Cancer Survivors

Growth hormone (GH) deficiency is a common pituitary hormone deficiency in childhood cancer survivors (CCS). The identification, diagnosis, and treatment of those individuals at risk are important in order to minimize associated morbidities that can be ameliorated by treatment with recombinant human GH therapy. However, GH and insulin-like growth factor-I have been implicated in tumorigenesis, so there has been concern over the use of GH therapy in patients with a history of malignancy. Reassuringly, GH therapy has not been shown to increase risk of tumor recurrence. These patients have an increased risk for development of meningiomas, but this may be related to their history of cranial irradiation rather than to GH therapy. In this review, we detail the CCS who are at risk for GHD and the existing evidence on the safety profile of GH therapy in this patient population.