The Study On The Diagnosis,treatment And Prognosis Of Autoimmune Hypophysitis

Objective.Autoimmune hypophysitis(AH)is a rare disease caused by inflammatory infiltration in the pituitary,resulting in pituitaiy insufficiency and/orspace-occupying effects.AH is often evaluated in a small case series or case reports.This study reviewed the diagnosis,treatment,and follow-up of 71 hypophysitis patients and aimed to delineate the characteristics of hypophysitis in a large single-center series.Also we aimed to describe the diagnosis and treatment of primai*y lymphocytic hypophysitis(LYH)in the largest cohort in China,and analysed the correlation of the management therapy and the prognoses.Meanwhile,we presented the experience of the clinical diagnosis of hypophysitis at pregnancy or postpartum and the results of different management of surgery and medication for these individuals.Methods.A retrospective cross-sectional analysis was conducted on 71 autoimmune hypophysitis patients at Peking Union Medical College Hospital(PUMCH)from 1999 to 2016.The medical records of the clinical,endocrine,pathological,imaging findings,diagnosis,treatment,and follow-up data werereviewed.Ordinal logistic regression analysis was used to evaluate the association between the clinical parameters and outcomes(e.g.,improvements in pituitary function,regression of lesion size on MRI,and disease recurrence)for primary LYH.Results.The spectrum of the disease included primary(81.7%)and secondary hypophysitis(18.3%).Central diabetes insipidus(CDI)(77.5%)was the most frequently observed symptom among AH and primary LYH.Among AH patients with hypopituitarism,hypogonadotropic hypogonadism(HH)was the most common symptom(53.8%),whereas adrenal insufficiency was the least common(35.0%).While,among the primary LYH patients,and Hypogonadotropic hypogonadism(HH)was the most frequently observed(60.0%)manifestation of anterior pituitary dysfunction;adrenal insufficiency was the third most common(26.0%)manifestation;and IGF-1 axis defects were the least frequent(22.0%).Thickening of the pituitary stalk was the most frequent imaging finding among AH(78.5%)and primary LYH.Among the primary LYH patients 78.0% of them exhibited both intrasellar and suprasellar expansion.Pharmacological dose of Glucocorticoid therapy solely was the major therapy used in 52.0% of the primary LYH patients,and partial improvement of anterior pituitary function was observed in 40.9% of the patients,and the recurrence rate was 46.2%.Pharmacological dose of glucocorticoids was identified to be significantly associated with increased odds of anterior pituitary fiinction improvement among primary LYH patients,amd no observed covariates were significantly associated with improvement of CDI and recurrence for primary LYH.Surgery was performed for primary granulomatous hypophysitis and xanthomatous hypophysitis.Immunosuppressive agents were administered for treatment of IgG4 related hypophysitis.Conclusion.The spectrum of AH is broad,with a variety of etiologies and the diagnosis and differential diagnosis for AH was pivotal.In our cohort,CDI was the most common symptom observed.Among AH patients with hypopituitarism,HH was the most common symptom,whereas adrenal insufficiency was the least common.Glucocorticoid therapy was effective for patients with primary LYH,and it also exhibited efficacy for hypophysitis due to germinoma;however,secondary hypophysitis experienced rapid recurrence.The sequence of anterior pituitary deficiencies in Chinese primary LYH patients was inconsistent with the previous findings(LH/FSH > TSH > ACTH > IGF-1 axis deficiency).A pharmacological dose of glucocorticoids was significantly associated with the improved anterior pituitary insufficiency.Objective.Functioning gonadotrophic adenomas(FGA)is rare and latent,prone to be misdiagnosed or delayed,and it is necessary to strengthen the understanding of the disease.In addition,FGA can lead to serious clinical symptoms due to its autocrine of biologically-active gonadotropins(follicle-stimulating hormone(FSH)and luteinizing hormone(LH).Clinical manifestations of FGA include sexual precocity in children;female menstrual disorders and ovarian hyperstimulation syndrome;testicular enlargement,but sexual dysfunction in men;eventually leading to infertility.Nonfunctioning pituitary adenomas(NFPA)is the most common type of pituitary macroadenoma.NFPA does not secrete hormones or secretes hormones in trace dose,but FSH/LH or its subunit(alpha or beta)can be detected in blood or mRNA levels in about75%-80% of NFPA patients.Also FSH/LH or their sub-units were pathologically positive by iimnunohistochemical staining,suggesting that its cell origin was gonadotropin cell line.FGA and the NFPA in which the gonadotropins or their sub-units are immunohistochemically-positive(NFGA)share the same manifestation in morphology,but their secretion is significantly different,and the mechanism is unclear."Hypothalamus-pituitary-gonad(HPG)axis" is an important neural-endocrine regulation system: hypothalamus produces gonad hormone release hormone(GnRH),GnRH promotes FSH/LH secretion by pituitary,and FSH/LH has effects on the targeted organs,as gonads,which produce sex hormone(e.g.ovarian produces estrogen and progestin;testicle produces testosterone).In turn,female hormones have negative or positive feedback on HPG axis.Kisspeptins secreted by KISS1 neurons on hypothalamus and its receptor(GPR54),are now well recognized as a potent stimulator of GnRH secretion when they combine together.There are no reports on the effects of kisspeptins and its receptor onthe pathogenesis of FGA by now.And the studies about Kisspeptins and its receptors in pituitary adenoma(PA)focused on whether they had inhibitory effects on tumor metastasis,but not on their effects on the secretion of PA.The present study aimed at exploring whether kisspeptins and its receptor KISS1 R were associated with the differenceof secretory function between FGA and NFPA.Methods.A total of 18 clinically and histologically verified PA tissues(3 FGA,12 NFPA with FSH or LH immunohistochemistry-staining positive in histology and 3 NFPA with FSH and LH negative in histology)were collected and used in this study.We detected the Kisspeptin/GPR54,GnRH,GnRHR,ESRi mRNA of the PA tissues through quantitative evaluation of RT-qPCR;GPR54 plus ESR protein expression through Western-blotting(WB)in the tissues above;and detected mutations in GPR54 by first-generation DNA sequencing.Meanwhile,we evaluated the quantitative levels of serum GnRH by ELISA method among the 18 PA patients and normal control subjects with the gender and age matched.Results.Our study found that KISS-1 R mRNA was significantly different among FGA and FSH/LH immunohistochemistry-staining positive or negative NFPA,highest level in FGA;followed by FSH/LH staining-positive NFPA;and FSH/LH negative NFPA(control NFPA group)lowest,as well as the KISS-1R protein level was frequently up-regulated in FGA group than the other two groups.No mutations of KISS1 R were found in 3 FGA patients.No significant differences of ESR1 mRNA were seen between FGA and FSH and/or LH immunohistochemical-staining positive NFPA,and the level in each of them was significantly higher than that of control NFPA group.No significant differences of KISS-1,GnRH,and GnRHR mRNA were observed among the three groups.In addition,the average level of GnRH in serum among patients with PA were significantly higher than that in the normal controls,and the average level of GnRH in FGA group and FSH and/orLH immunohistochemical-staining positive group were significantly higher than that in control NFPA group.Conclusion.Automatic secretion of FSH/LH by FGA might be associated with the hyper-expression KISS1 R gene and its regulation for their secretion.The expression of KISS1R might need to be increased to a certain level(threshold)that could cause the breakthrough in secretion ability of PA and induce clinical symptoms.Whether the hyper-expression of KISS1 R gene in FGA was related with the changes of methylation in the promoter region should be verified in the future.