Pituitary immune-related adverse events induced by programmed cell death protein 1 inhibitors in advanced lung cancer patients: A report of 3 cases / 北京大学学报(医学版)

Pituitary immune-related adverse events induced by programmed cell death protein 1 inhibitors in advanced lung cancer patients: A report of 3 cases SUMMARY Programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1) have been widely used in lung cancer treatment, but their immune-related adverse events (irAEs) require intensive attention. Pituitary irAEs, including hypophysitis and hypopituitarism, are commonly induced by cytotoxic T lymphocyte antigen 4 inhibitors, but rarely by PD-1/PD-L1 inhibitors. Isolated adrenocorticotropic hormone(ACTH) deficiency (IAD) is a special subtype of pituitary irAEs, without any other pituitary hormone dysfunction, and with no enlargement of pituitary gland, either. Here, we described three patients with advanced lung cancer who developed IAD and other irAEs, after PD-1 inhibitor treatment. Case 1 was a 68-year-old male diagnosed with metastatic lung adenocarcinoma with high expression of PD-L1. He was treated with pembrolizumab monotherapy, and developed immune-related hepatitis, which was cured by high-dose methylprednisolone [0.5-1.0 mg/(kg·d)]. Eleven months later, the patient was diagnosed with primary gastric adenocarcinoma, and was treated with apatinib, in addition to pembrolizumab. After 17 doses of pembrolizumab, he developed severe nausea and asthenia, when methylprednisolone had been stopped for 10 months. His blood tests showed severe hyponatremia (121 mmol/L, reference 137-147 mmol/L, the same below), low levels of 8:00 a.m. cortisol (< 1 μg/dL, reference 5-25 μg/dL, the same below) and ACTH (2.2 ng/L, reference 7.2-63.3 ng/L, the same below), and normal thyroid function, sex hormone and prolactin. Meanwhile, both his lung cancer and gastric cancer remained under good control. Case 2 was a 66-year-old male with metastatic lung adenocarcinoma, who was treated with a new PD-1 inhibitor, HX008, combined with chemotherapy (clinical trial number: CTR20202387). After 5 months of treatment (7 doses in total), his cancer exhibited partial response, but his nausea and vomiting suddenly exacerbated, with mild dyspnea and weakness in his lower limbs. His blood tests showed mild hyponatremia (135 mmol/L), low levels of 8:00 a.m. cortisol (4.3 μg/dL) and ACTH (1.5 ng/L), and normal thyroid function. His thoracic computed tomography revealed moderate immune-related pneumonitis simultaneously. Case 3 was a 63-year-old male with locally advanced squamous cell carcinoma. He was treated with first-line sintilimab combined with chemotherapy, which resulted in partial response, with mild immune-related rash. His cancer progressed after 5 cycles of treatment, and sintilimab was discontinued. Six months later, he developed asymptomatic hypoadrenocorticism, with low level of cortisol (1.5 μg/dL) at 8:00 a.m. and unresponsive ACTH (8.0 ng/L). After being rechallenged with another PD-1 inhibitor, teslelizumab, combined with chemotherapy, he had pulmonary infection, persistent low-grade fever, moderate asthenia, and severe hyponatremia (116 mmol/L). Meanwhile, his blood levels of 8:00 a.m. cortisol and ACTH were 3.1 μg/dL and 7.2 ng/L, respectively, with normal thyroid function, sex hormone and prolactin. All of the three patients had no headache or visual disturbance. Their pituitary magnetic resonance image showed no pituitary enlargement or stalk thickening, and no dynamic changes. They were all on hormone replacement therapy (HRT) with prednisone (2.5-5.0 mg/d), and resumed the PD-1 inhibitor treatment when symptoms relieved. In particular, Case 2 started with high-dose prednisone [1 mg/(kg·d)] because of simultaneous immune-related pneumonitis, and then tapered it to the HRT dose. His cortisol and ACTH levels returned to and stayed normal. However, the other two patients' hypopituitarism did not recover. In summary, these cases demonstrated that the pituitary irAEs induced by PD-1 inhibitors could present as IAD, with a large time span of onset, non-specific clinical presentation, and different recovery patterns. Clinicians should monitor patients' pituitary hormone regularly, during and at least 6 months after PD-1 inhibitor treatment, especially in patients with good oncological response to the treatment.

Quiste de bolsa de Rathke e hiperprolactinemia, una causa infrecuente de amenorrea primaria / Rathke cleft cysts and hyperprolactinemia, an uncommon cause of primary amenorrhea

El quiste de la bolsa de Rathke es una lesión epitelial benigna de la región selar, formada a partir de remanentes embrionarios. La mayoría de los casos son asintomáticos, aunque pudiera presentarse con cefalea, disfunción hipofisaria y trastornos visuales, muy infrecuentemente como apoplejía hipofisaria. Se presenta el caso de una paciente que, habiendo presentado amenorrea primaria, se le realiza el diagnóstico de quiste de la bolsa de Rathke con hiperprolactinemia, logrando menarquia luego del tratamiento con cabergolina.

Rathke's cyst is a benign epithelial lesion of the sellar region, formed from embryonic remnants. Most cases are asymptomatic although it could present with headache, pituitary dysfunction and visual disorders, very infrequently as pituitary stroke. We present the case of a patient who, having presented primary amenorrhea, is diagnosed with Rathke's cyst with hyperprolactinemia, achieving menarche after treatment with cabergoline.

Relación entre la prolactina y la retinopatía diabética / Relation between prolactin and diabetic retinopathy

La retinopatía diabética, como forma de microangiopatía, se caracteriza por la pérdida de los pericitos y de las células endoteliales, lo que conlleva a una alteración de la permeabilidad de los capilares retinianos. El factor de crecimiento del endotelio vascular estimula directamente el desarrollo de la vasculatura interna y externa del ojo, y actúa además como un factor de permeabilidad vascular. Por lo general, en condiciones naturales, existe un equilibrio entre las moléculas promotoras y las inhibidoras de la angiogénesis; sin embargo, cuando estas condiciones son alteradas, como sucede durante los episodios de hipoxia o inflamación, este equilibrio se rompe, e inclina la balanza hacia la formación de vasos anormales que se extienden y sangran dentro del vítreo, y pueden provocar el desprendimiento de la retina, con la consiguiente pérdida de la visión. Se han desarrollado algunos medicamentos antiangiogénicos que reducen la expresión del factor de crecimiento del endotelio vascular y del factor de crecimiento del tejido conectivo en las células del epitelio retiniano expuestas al estrés oxidativo. Se ha avanzado también en el desarrollo de otros medicamentos con acción antiangiogénica, con gran efectividad en su uso, solos o combinados con fotocoagulación láser y cirugía, pero son muy costosos, solo disponibles en centros muy especializados, y la vía de administración es intravítrea. En la actualidad se conoce que la hormona hipofisaria prolactina, puede prevenir la progresión y promover la regresión de la retinopatía diabética a través de su conversión proteolítica a vasoinhibinas, en particular, la fracción de menor peso molecular (16 kDa-Prolactina), con importante acción antiangiogénica, bloqueando la estimulación de la angiogénesis inducida por varios factores, como el factor de crecimiento del endotelio vascular, y el factor de crecimiento fibroblástico en la proliferación de las células endoteliales, lo cual abre la esperanza de nuevos medicamentos para el tratamiento de la retinopatía proliferativa, aspectos sobre los que trata la presente revisión(AU)

Diabetic retinopathy, as a form of microangiopathy, is characterized by loss of pericytes and of endothelial cells, which causes alteration of the permeability of the retinal capillaries. The growth factor of the vascular endothelium directly stimulates the development of the internal and external vasculature of the eye, and additionally acts as a vascular permeability factor. In general, under natural conditions, there is a balance of promoting and inhibitory cells of angiogenesis. However, if these conditions are changed -as it happens during the hypoxia or inflammation episodes- this balance breaks and this tips the balance in favor of the formation of abnormal vessels that spread over and bleed into the vitreous, an event that may cause the retinal detachment and the resulting loss of vision. Some antiangiogenic drugs have been developed to reduce the expression of the vascular endothelium growth factor and of the connective tissue growth factor in the retinal epithelium cells under oxidative stress. Advances have also been made in the development of other antiangiogenic drugs of high effectiveness when they are used alone or combined with laser photocoagulation and surgery, but they are very expensive, available only in highly specialized centers and with intravitreal administration. Nowadays, it is known that hyphophysial hormone called prolactin can prevent the progress and encourage the regression of diabetic retinopathy through its proteolytic conversion to vasoinhibins, particularly, the lowest molecular weight fraction (16 kDa-prolactin). This fraction has an important antiangiogenic action since it blocks the stimulation of angiogenesis induced by several factors such as the vascular endothelium growth factor and the fibroblastic growth factor in the proliferation of the endothelial cells, all of which brings the possibilities of new drugs for the treatment of proliferative retinopathy. These are the aspects addressed in the present review(AU)

Principios básicos en la evaluación y el tratamiento de la amenorrea / Basic principles in the evaluation and treatment of amenorrhea

El embarazo y la lactancia son las dos causas más comunes de amenorrea entre las mujeres que se hallan en edad reproductiva. Sin embargo, la amenorea puede ser el primer síntoma de diversos trastornos orgánicos y funcionales. En esta revisión se analizarán las principales causas patológicas de amenorrea así como se diseñarán unas pautas sencillas para enfocar un diagnóstico y proponer el tratamiento adecuado. La amenorrea no es un diagnóstico sino un síntoma que indica un trastorno anatómico, genético o neuroendocrino. Clásicamente se ha clasificado la amenorrea como primaria o secundaria según el momento de su aparición. Si bien este criterio es ampliamente utilizado en la clínica, la experiencia demuestra que la ubicación prematura de una paciente en alguna de estas categorías puede originar diagnósticos erróneos y acabar en procedimientos innecesarios y costosos...

Effect of estrogen, progesterone and prolactin on cell proliferation in three brest cancer cell lines

Os hormônios esteróides e peptídicos desempenham papel fundamental na proliferaçäo do parênquima mamário. O objetivo deste estudo foi avaliar a influência de hormônios em linhas celulares estabelecidas a partir de neoplasias mamárias humanas. De acordo com o descrito na literatura, escolheram-se linhas celulares consoante a expressäo de receptores de estrogêneo e progesterona, tendo sido cultivadas em meio adequado, suplementado com 10 por cento FBS. Os hormônios testados foram: estrógeno (2µl/5ml), progesterona (5µl/5ml) e prolactina (1µl/5ml), tendo sido fornecidos quer isoladamente, quer nas diferentes combinaçöes entre si. No 30§ dia do tratamento hormonal, as células foram colhidas e fixadas em álcool. Por proliferaçäo celular foi avaliada pelo índice de MIB-1. O perfil imunocitoquímico das linhas celulares näo se alterou com os diversos tratamentos hormonais, mas se observaram alteraçöes consistentes no índice proliferativo: quando tratadas somente com prolactina, observaram-se reduçöes de 70,4 por cento, 70,7 por cento e de 25,2 por cento no índice de MIB-1 nas linhas T47D (RE-/RP+), Hs578T (RE-/RP-) e ZR-75-1 (RE+/RP+), respectivaente. Todos os tratamentos levaram à diminuiçäo da proliferaçäo nas linhas celulares ZR-75-1 e T47D. De acordo com nossos achados, o uso de prolactina pode representar uma estratégia de modulaçäo da proliferaçäo das células neoplásticas, mas säo necessários estudos in vivo para fundamentar esta hipótese

Resposta da prolactina ao hormonio liberador de tireotropina (TRH) em mulheres com osteoporose / Prolactin response to thyrotropin releasing hormone (TRH) in osteoporotic women

Se a prolactina tem ou näo algum efeito sobre o metabolismo de calcio ainda näo esta bem estabelecido. Alguns autores mostraram que mulheres com hiperprolactinemia desenvolvem uma forma particular de osteoporose e estudos mais recentes mostraram que mulheres com osteoporose apresentam niveis basais de prolactina mais baixos que o grupo controle. O presente estudo objetivou avaliar a resposta da prolactina após estimulo com TRH em mulheres com osteoporose...

Prolactina en pacientes con trastornos endocrinos y de fertilidad

Se analizan 926 historias clínicas de la consulta externa de las de endocrinología ginecológica e infertilidad para conocer la frecuencia en los niveles de prolactina (PRL) en las pacientes que asistieron al Instituto Materno Infantil de Bogotá en el período del 1§ de enero de 1984 al 31 de marzo de 1989. De los 926 casos se les solicitó PRL a 210 (22.6 por ciento), de estos, 152(72.4 por ciento) reportó niveles normales y elevada mayor de 20 ng/ml en 58 pacientes(27.6 por ciento), distribuidos así; oligomenorrea 16(27.5 por ciento),Amenorrea 2 RIA 11(18.9 por ciento),galactorrea 9 (15.5 por ciento), polimenorrea 8 (13.8 por ciento), amenorrea-galactorrea 4 e infertilidad 4 para (6.8 por ciento). Los niveles de PRL de acuerdo al motivo de consulta presentó los siguientes niveles: amenorrea-galactorrea 225.3 ng/ml, amenorrea IRIA 128.0 ng/ml, oligomenorrea 58.14 ng&ml, galactorrea 53.5ng/ml , polimenorrea 37.5 ng/ml. En los casos de hiperprolactinemia de 21 sillas turcas analizadas 9 (19.3 por ciento) fueron anormales, de 15 campimetrías 4 (26.7 por ciento) presentaron alteraciones y de 9 TAC 3 resultaron con alteración a nivel hipofisiario. La etiología no fue posible determinarla en 39 casos (53.5 por ciento), debida a hipotiroidismo 5 (8.6 por ciento), microadenoma 4 (6.9 por ciento), de origen farmacológico 4 (6.9 por ciento), síndrome de ovario poliquístico 3 (5.2 por ciento),macroadenoma 1 (1.7 por ciento). Recibieron inductores de ovulación. El seguimeinto promedio de las pacientes con tratamiento farmacológico fue de 19.1 meses dismunuyendo los niveles de PRL y mejoría de su disfunción ovárica. Estos resultados confirman que en pacientes con alteraciones del ciclo e infertilidad debe descartarse una hiperprolactinemia