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Open access

Yotsapon Thewjitcharoen, Veekij Veerasomboonsin, Soontaree Nakasatien, Sirinate Krittiyawong and Thep Himathongkam

Summary

Primary amenorrhea could be caused by disorders of four parts: disorders of the outflow tract, disorders of the ovary, disorders of the anterior pituitary, and disorders of hypothalamus. Delay in diagnosis and hormone substitution therapy causes secondary osteoporosis. Herein, we report a case of a 23-year-old phenotypical female who presented with primary amenorrhea from 46, XX gonadal dysgenesis but had been misdiagnosed as Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome or Mullerian agenesis. The coexistence of gonadal dysgenesis and MRKH was suspected after laboratory and imaging investigations. However, the vanishing uterus reappeared after 18 months of hormone replacement therapy. Therefore, hormone profiles and karyotype should be thoroughly investigated to distinguish MRKH syndrome from other disorders of sex development (DSD). Double diagnosis of DSD is extremely rare and periodic evaluation should be reassessed. This case highlights the presence of estrogen deficiency state, the uterus may remain invisible until adequate exposure to exogenous estrogen.

Learning points:

  • An early diagnosis of disorders of sex development (DSD) is extremely important in order to promptly begin treatment, provide emotional support to the patient and reduce the risks of associated complications.
  • Hormone profiles and karyotype should be investigated in all cases of the presumptive diagnosis of Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome or Mullerian agenesis.
  • The association between 46, XX gonadal dysgenesis and Mullerian agenesis has been occasionally reported as a co-incidental event; however, reassessment of the presence of uterus should be done again after administration of exogenous estrogen replacement for at least 6–12 months.
  • A multidisciplinary approach is necessary for patients presenting with DSD to ensure appropriate treatments and follow-up across the lifespan of individuals with DSD.
Open access

Isabella Lupi, Alessandro Brancatella, Mirco Cosottini, Nicola Viola, Giulia Lanzolla, Daniele Sgrò, Giulia Di Dalmazi, Francesco Latrofa, Patrizio Caturegli and Claudio Marcocci

Summary

Programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte antigen 4/B7 (CTLA-4/B7) pathways are key regulators in T-cell activation and tolerance. Nivolumab, pembrolizumab (PD-1 inhibitors), atezolizumab (PD-L1 inhibitor) and ipilimumab (CTLA-4 inhibitor) are monoclonal antibodies approved for treatment of several advanced cancers. Immune checkpoint inhibitors (ICIs)-related hypophysitis is described more frequently in patients treated with anti-CTLA-4; however, recent studies reported an increasing prevalence of anti-PD-1/PD-L1-induced hypophysitis which also exhibits slightly different clinical features. We report our experience on hypophysitis induced by anti-PD-1/anti-PD-L1 treatment. We present four cases, diagnosed in the past 12 months, of hypophysitis occurring in two patients receiving anti-PD-1, in one patient receiving anti-PD-1 and anti-CTLA-4 combined therapy and in one patient receiving anti-PD-L1. In this case series, timing, clinical presentation and association with other immune-related adverse events appeared to be extremely variable; central hypoadrenalism and hyponatremia were constantly detected although sellar magnetic resonance imaging did not reveal specific signs of pituitary inflammation. These differences highlight the complexity of ICI-related hypophysitis and the existence of different mechanisms of action leading to heterogeneity of clinical presentation in patients receiving immunotherapy.

Learning points:

  • PD-1/PD-L1 blockade can induce hypophysitis with a different clinical presentation when compared to CTLA-4 blockade.
  • Diagnosis of PD-1/PD-L1 induced hypophysitis is mainly made on clinical grounds and sellar MRI does not show radiological abnormalities.
  • Hyponatremia due to acute secondary adrenal insufficiency is often the principal sign of PD-1/PD-L1-induced hypophysitis and can be masked by other symptoms due to oncologic disease.
  • PD-1/PD-L1-induced hypophysitis can present as an isolated manifestation of irAEs or be in association with other autoimmune diseases
Open access

Misaki Aoshima, Koji Nagayama, Kei Takeshita, Hiroshi Ajima, Sakurako Orikasa, Ayana Iwazaki, Hiroaki Takatori and Yutaka Oki

Summary

Patients treated with immunosuppressive drugs, especially methotrexate (MTX), rarely develop lymphoproliferative disorders (LPDs), known as MTX-related LPD (MTX–LPD). The primary site of MTX–LPD is often extranodal. This is the first reported case of MTX–LPD in the pituitary. A 65-year-old woman was admitted to our hospital with symptoms of oculomotor nerve palsy and multiple subcutaneous nodules. She had been treated with MTX for 11 years for rheumatoid arthritis. Computed tomography showed multiple masses in the orbit, sinuses, lung fields, anterior mediastinum, kidney, and subcutaneous tissue. Brain magnetic resonance imaging revealed a sellar mass. She was diagnosed with hypopituitarism and central diabetes insipidus based on endocrine examination. Although pituitary biopsy could not be performed, we concluded that the pituitary lesion was from MTX–LPD, similar to the lesions in the sinuses, anterior mediastinum, and subcutaneous tissue, which showed polymorphic LPD on biopsy. MTX was discontinued, and methylprednisolone was administered to improve the neurologic symptoms. After several weeks, there was marked improvement of all lesions, including the pituitary lesion, but the pituitary function did not improve. When pituitary lesions are caused by MTX–LPD, the possibility of anterior hypopituitarism and central diabetes insipidus needs to be considered. Further studies are needed to investigate the effectiveness of early diagnosis and treatment of MTX–LPD in restoring pituitary dysfunction.

Learning points

  • Pituitary lesions from MTX–LPD may cause hypopituitarism and central diabetes insipidus.
  • Pituitary metastasis of malignant lymphoma and primary pituitary lymphoma, which have the same tissue types with MTX–LPD, have poor prognosis, but the lesions of MTX–LPD can regress only after MTX discontinuation.
  • In cases of pituitary lesions alone, a diagnosis of MTX–LPD may be difficult, unless pituitary biopsy is performed. This possibility should be considered in patients treated with immunosuppressive drugs.
  • Pituitary hypofunction and diabetes insipidus may persist, even after regression of the lesions on imaging due to MTX discontinuation.
Open access

Charlotte Delcourt, Halil Yildiz, Alessandra Camboni, Eric Van den Neste, Véronique Roelants, Alexandra Kozyreff, Jean Paul Thissen, Dominique Maiter and Raluca Maria Furnica

Summary

A 26-year-old woman presented with persistent headache and tiredness. Biological investigations disclosed a moderate inflammatory syndrome, low PTH-hypercalcemia and complete anterior hypopituitarism. A magnetic resonance imaging (MRI) of the pituitary gland was performed and revealed a symmetric enlargement with a heterogeneous signal. Ophthalmological examination showed an asymptomatic bilateral anterior and posterior uveitis, and a diagnosis of pituitary sarcoidosis was suspected. As the localization of lymphadenopathies on the fused whole-body FDG-PET/computerized tomography (CT) was not evoking a sarcoidosis in first instance, an excisional biopsy of a left supraclavicular adenopathy was performed showing classic nodular sclerosis Hodgkin’s lymphoma (HL). A diagnostic transsphenoidal biopsy of the pituitary gland was proposed for accurate staging of the HL and surprisingly revealed typical granulomatous inflammation secondary to sarcoidosis, leading to the diagnosis of a sarcoidosis–lymphoma syndrome. The co-existence of these diseases constitutes a diagnostic challenge and we emphasize the necessity of exact staging of disease in order to prescribe adequate treatment.

Learning points:

  • The possibility of a sarcoidosis–lymphoma syndrome, although rare, should be kept in mind during evaluation for lymphadenopathies.
  • In the case of such association, lymphoma usually occurs after sarcoidosis. However, sarcoidosis and lymphoma can be detected simultaneously and development of sarcoidosis in a patient with previous lymphoma has also been reported.
  • An accurate diagnosis of the disease and the respective organ involvements, including biopsy, is necessary in order to prescribe adequate treatment.
Open access

Ilan Rahmani Tzvi-Ran, Judith Olchowski, Merav Fraenkel, Asher Bashiri and Leonid Barski

Summary

A previously healthy 24-year-old female underwent an emergent caesarean section without a major bleeding described. During the first post-operative days (POD) she complained of fatigue, headache and a failure to lactate with no specific and conclusive findings on head CT. On the following days, fever rose with a suspicion of an obstetric surgery-related infection, again with no evidence to support the diagnosis. On POD5 a new-onset hyponatremia was documented. The urine analysis suggested SIADH, and following a treatment failure, further investigation was performed and demonstrated both central hypothyroidism and adrenal insufficiency. The patient was immediately treated with hydrocortisone followed by levothyroxine with a rapid resolution of symptoms and hyponatremia. Further laboratory investigation demonstrated anterior hypopituitarism. The main differential diagnosis was Sheehan’s syndrome vs lymphocytic hypophysitis. Brain MRI was performed as soon as it was available and findings consistent with Sheehan’s syndrome confirmed the diagnosis. Lifelong hormonal replacement therapy was initiated. Further complaints on polyuria and polydipsia have led to a water deprivation testing and the diagnosis of partial central insipidus and appropriate treatment with DDAVP.

Learning points:

  • Sheehan’s syndrome can occur, though rarely, without an obvious major post-partum hemorrhage.
  • The syndrome may resemble lymphocytic hypophysitis clinically and imaging studies may be crucial in order to differentiate both conditions.
  • Hypopituitarism presentation may be variable and depends on the specific hormone deficit.
  • Euvolemic hyponatremia workup must include thyroid function test and 08:00 AM cortisol levels.
Open access

Chloe Broughton, Jane Mears, Adam Williams and Kathryn Lonnen

Summary

Pituitary adenomas can be classified as functioning or non-functioning adenomas. Approximately 64% of clinically non-functioning pituitary adenomas are found to be gonadotroph adenomas on immunohistochemistry. There are reported cases of gonadotroph adenomas causing clinical symptoms, but this is unusual. We present the case of a 36-year-old female with abdominal pain. Multiple large ovarian cysts were identified on ultrasound requiring bilateral cystectomy. Despite this, the cysts recurred resulting in further abdominal pain, ovarian torsion and right oophorectomy and salpingectomy. On her 3rd admission with abdominal pain, she was found to have a rectus sheath mass which was resected and histologically confirmed to be fibromatosis. Endocrine investigations revealed elevated oestradiol, follicle-stimulating hormone (FSH) at the upper limit of the normal range and a suppressed luteinising hormone (LH). Prolactin was mildly elevated. A diagnosis of an FSH-secreting pituitary adenoma was considered and a pituitary MRI revealed a 1.5 cm macroadenoma. She underwent transphenoidal surgery which led to resolution of her symptoms and normalisation of her biochemistry. Subsequent pelvic ultrasound showed normal ovarian follicular development. Clinically functioning gonadotroph adenomas are rare, but should be considered in women presenting with menstrual irregularities, large or recurrent ovarian cysts, ovarian hyperstimulation syndrome and fibromatosis. Transphenoidal surgery is the first-line treatment with the aim of achieving complete remission.

Learning points:

  • Pituitary gonadotroph adenomas are usually clinically non-functioning, but in rare cases can cause clinical symptoms.
  • A diagnosis of a functioning gonadotroph adenoma should be considered in women presenting with un-explained ovarian hyperstimulation and/or fibromatosis.
  • In women with functioning gonadotroph adenomas, the main biochemical finding is elevated oestradiol levels. Serum FSH levels can be normal or mildly elevated. Serum LH levels are usually suppressed.
  • Transphenoidal surgery is the first-line treatment for patients with functioning gonadotroph adenomas, with the aim of achieving complete remission.
Open access

E Bahaeldein and M J Brassill

Summary

Postmenopausal hyperandrogenism is a relatively rare diagnosis resulting from excess androgen production from the adrenals or ovaries. The exclusion of malignant causes is a priority. Laboratory tests and imaging are utilised to help differentiate the source of excess androgens. We report two cases of postmenopausal hyperandrogenism in women aged 75 and 67 years. Both cases presented with clinical features suggestive of hyperandrogenism which had developed gradually over the previous 2 years. Laboratory investigations confirmed a significant elevation in their serum testosterone levels. In both cases, imaging did not reveal any abnormality of the adrenals or ovaries. To help differentiate an adrenal vs ovarian source a single-dose GnRH analogue was given with measurement of testosterone and gonadotrophin levels pre and post. The reduction in gonadotrophins achieved by the GnRH analogue resulted in suppression of testosterone levels which suggested an ovarian source. Both patients proceeded to bilateral oophorectomy. Histology revealed a benign hilus cell tumour in one case and a benign Leydig cell tumour in the other.

Learning points:

  • A key part of the work-up of postmenopausal hyperandrogenism is to differentiate between an adrenal or an ovarian source of excess androgens;
  • Imaging may not identify small ovarian tumours or hyperthecosis and may also identify incidental adrenal masses which are non-functioning;
  • Current guidelines suggest ovarian and adrenal venous sampling when imaging is inconclusive but this requires technical expertise and has a high failure rate;
  • GnRH analogue use can successfully confirm ovarian source and should be considered as a diagnostic tool in this setting.
Open access

Yew Wen Yap, Steve Ball and Zubair Qureshi

Summary

The coexistence of primary hypothyroidism and thyroid-stimulating hormone (TSH)-stimulating pituitary macroadenoma can be a rare occurrence and can make diagnosis very challenging. We describe a case of a 44-year-old female with a history of fatigue, poor concentration, weight gain and amenorrhoea together with biochemical evidence of primary autoimmune hypothyroidism. Her initial TSH levels were elevated with low normal free thyroxine (T4) levels. Levothyroxine treatment was initiated and the dose was gradually titrated to supraphysiologic doses. This led to the normalisation of her TSH levels but her free T4 and triiodothyronine (T3) levels remained persistently elevated. This prompted a serum prolactin check which returned elevated at 2495 µ/L, leading onto pituitary imaging. A MRI of the pituitary gland revealed a pituitary macroadenoma measuring 2.4 × 2 × 1.6 cm. Despite starting her on cabergoline therapy with a reduction in her prolactin levels, her TSH levels began to rise even further. Additional thyroid assays revealed that she had an abnormally elevated alpha subunit at 3.95 (age-related reference range <3.00). This corresponded to a thyroid-secreting hormone pituitary macroadenoma. She went on to have a transphenoidal hypophysectomy. Histology revealed tissues staining for TSH, confirming this to be a TSH-secreting pituitary macroadenoma. This case highlighted the importance of further investigations with thyroid assay interferences, heterophile antibodies, alpha subunit testing and anterior pituitary profile in cases of resistant and non-resolving primary hypothyroidism.

Learning points:

  • Levothyroxine treatment in primary hypothyroidism can potentially unmask the presence of a latent TSH-secreting pituitary macroadenoma, which can make diagnosis very challenging.
  • A high index of suspicion should prompt clinicians to further investigate cases of primary hypothyroidism which despite increasing doses of levothyroxine treatment with normalisation of TSH, the free T4 and T3 levels remain persistently elevated.
  • Clinicians should consider investigating for adherence to levothyroxine, thyroid assay interference, heterophile antibodies, TSH dilution studies, alpha subunit and anterior pituitary profile testing to further clarity the diagnosis in these patients.
  • Although coexistent cases of TSHoma with primary hypothyroidism are rare, it should always be in the list of differential diagnoses in cases of unresolving primary hypothyroidism.
Open access

Laura Hamilton Adams and Derick Adams

Summary

Co-secreting TSH and growth hormone pituitary adenomas are rare. We present a case of a 55-year-old woman who presented with symptoms of neck fullness. Ultrasound revealed multiple thyroid nodules and examination revealed several clinical features of acromegaly. She was found to have a co-secreting TSH and growth hormone pituitary macroadenoma. She underwent surgical resection followed by gamma knife radiation, which resulted in complete remission of her TSH and GH-secreting adenoma.

Learning points:

  • TSH-secreting pituitary adenomas are rare and about one-third co-secrete other hormones.
  • Thyroid nodules are common in acromegaly and can be the presenting sign of a growth hormone-secreting pituitary adenoma.
  • In the workup of acromegaly, assessment of other pituitary hormones is essential, even in the absence of symptoms of other pituitary hormone dysfunction.
  • Complete remission of co-secreting GH and TSH pituitary macroadenomas is possible with surgery and radiation alone.
Open access

Daniela Regazzo, Marina Paola Gardiman, Marily Theodoropoulou, Carla Scaroni, Gianluca Occhi and Filippo Ceccato

Summary

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem hereditary cutaneous condition, characterized by multiple hamartomas. In rare cases, pituitary neuroendocrine tumors (PitNETs) have been described in patients with TSC, but the causal relationship between these two diseases is still under debate. TSC is mostly caused by mutations of two tumor suppressor genes, encoding for hamartin (TSC1) and tuberin (TSC2), controlling cell growth and proliferation. Here, we present the case of a 62-year-old Caucasian woman with TSC and a silent gonadotroph PitNET with suprasellar extension, treated with transsphenoidal endoscopic neurosurgery with complete resection. Therapeutic approaches based on mTOR signaling (i.e. everolimus) have been successfully used in patients with TSC and tested in non-functioning PitNET cellular models with promising results. Here, we observed a reduction of cell viability after an in vitro treatment of PitNET’s derived primary cells with everolimus. TSC analysis retrieved no disease-associated variants with the exception of the heterozygous intronic variant c.4006-71C>T found in TSC2: the computational tools predicted a gain of a new splice site with consequent intron retention, not confirmed by an in vitro analysis of patient’s lymphocyte-derived RNA. Further analyses are therefore needed to provide insights on the possible mechanisms involving the hamartin-tuberin complex in the pathogenesis of pituitary adenomas. However, our data further support previous observations of an antiproliferative effect of everolimus on PitNET.

Learning points:

  • Pituitary neuroendocrine tumors (PitNET) in patients with tuberous sclerosis complex (TSC) are rare: only few cases have been reported in literature.
  • Therapeutic approach related to mTOR signaling, such as everolimus, may be used in some patients with PitNETs as well as those with TSC.
  • We reported a woman with both non-secreting PitNET and TSC; PitNET was surgically removed and classified as a silent gonadotroph tumor.
  • Everolimus treatment in PitNET’s-derived primary cells revealed a significant decrease in cell viability.
  • Considering our case and available evidence, it is still unclear whether a PitNET is a part of TSC or just a coincidental tumor.