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Anterior pituitary is critical for endocrine systems. Its hormonal responses to positive and negative regulators are indispensable for homeostasis. For this reason, generating human anterior pituitary tissue that retains regulatory hormonal control in vitro is an important step for the development of cell transplantation therapy for pituitary diseases. Here we achieve this by recapitulating mouse pituitary development using human embryonic stem cells. We find that anterior pituitary self-forms in vitro following the co-induction of hypothalamic and oral ectoderm. The juxtaposition of these tissues facilitated the formation of pituitary placode, which subsequently differentiated into pituitary hormone-producing cells. They responded normally to both releasing and feedback signals. In addition, after transplantation into hypopituitary mice, the in vitro -generated corticotrophs rescued physical activity levels and survival of the hosts. Thus, we report a useful methodology for the production of regulator-responsive human pituitary tissue that may benefit future studies in regenerative medicine. It is difficult to generate functional human anterior pituitary tissues in vitro . Here, Ozone et al. generate human anterior pituitary from embryonic stem cells by recapitulating in vivo development, and demonstrate this tissue secretes hormones and rescues hypopituitarism when grafted into mice.

Silent corticotroph adenomas (SCAs) are clinically nonfunctioning pituitary adenomas (NFPAs) with positive staining for corticotropin (ACTH) by immunohistochemistry. Whether SCAs behave more aggressively than NFPAs without ACTH immunoreactivity (ACTH negative) remains controversial. To compare characteristics and outcomes of SCAs with ACTH-negative NFPAs and to identify predictors of aggressive outcome. Primary composite endpoint included the first of any of the following events: progression, recurrence, or death. We reviewed all cases of SCAs and all ACTH-negative macroadenomas operated on between April 1995 and December 2007 by 1 neurosurgeon. Our retrospective cohorts included 33 SCAs followed for 42.5 months (median) (range, 6.7-179.0 months) and 126 ACTH-negative patients followed for 42 months (range, 6-142 months). SCA were younger (mean ± SD; 49.6 ± 14.1) than ACTH-negative patients (55.6 ± 12.8, P = .02). Tumor diameter was similar (2.8 ± 1.0 cm); cavernous sinus invasion was present in 45.5% of SCAs and 30.2% of ACTH-negative NFPAs (P = .09). Postoperative tumor residual was detected in 53.1% of SCAs and 49.6% of ACTH-negative patients. Radiation was administered in 40.6% of SCAs at 16 months (range, 3-149 months) and 33.3% of ACTH-negative patients at 13 months (range, 3-94) postoperatively. Progression of residual tumor occurred in 24.2% of SCAs and 11.1% of ACTH-negative patients (P = .08); recurrence was similar (6.0% SCAs vs 5.5% ACTH-negative patients). Cumulative event-free survival rates were not significantly different between the 2 groups (P = .3). Age, sex, tumor size, cavernous sinus invasion, or SCA subtypes were not associated with outcome. SCA patients were younger, but exhibited similar postoperative tumor regrowth rates as ACTH-negative macroadenomas while using a similar adjuvant radiation protocol. Long-term follow-up is warranted because predictors of regrowth are currently lacking.

Abstract BACKGROUND: O-6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that counteracts chemotherapeutic cytotoxicity of alkylating agents such as temozolomide. Low levels of MGMT expression have been shown to correlate with longer survival in glioma patients treated with temozolomide. The same is true in pituitary adenomas. OBJECTIVE: We investigated the immunohistochemical expression of MGMT in a variety of corticotroph adenoma subtypes to determine the potential utility of temozolomide as a therapeutic agent. METHODS: The tumors consisted of 40 cases of adrenocorticotropin-secreting pituitary tumors in Cushing disease, 12 Crooke cell adenomas, and 7 subtype I silent corticotroph adenomas. Staining for MGMT was assessed by light microscopy; nuclear reactivity was estimated semiquantitatively as present in < 10%, 10% to 25%, 25% to 50%, 50% to 75%, and > 75% of cells. RESULTS: Immunoexpression showed no correlation with patient age, sex, tumor size, invasiveness, or recurrence in patients with Cushing disease. Among adrenocorticotropin-secreting adenomas associated with Cushing disease, most invasive (60%) and recurrent (86%) tumors showed low MGMT immunopositivity, defined as < 25%. Most (75%) Crooke cell adenomas exhibited an MGMT immunoreactivity of ⩽ 50%. All subtype I silent corticotroph adenomas showed < 10% MGMT staining. CONCLUSION: Our descriptive findings of low MGMT expression in adrenocorticotropin-producing pituitary adenomas, particularly aggressive tumors, suggest that they may be suitable candidates for temozolomide therapy.