Helen Turner

Craniopharyngiomas in children and adults: systematic analysis of 121 cases with long-term follow-up.

Background  Craniopharyngiomas account for 2–5% of all primary intracranial tumours. Despite their benign histological appearance, they are often associated with an unfavourable prognosis and their optimal treatment remains controversial.

Undetectable postoperative cortisol does not always predict long-term remission in Cushing's disease: a single centre audit.

objective An undetectable postoperative serum cortisol has been regarded as a definition of cure in Cushing’s disease. However, we noted disease recurrence amongst patients with Cushing’s disease despite undetectable postoperative cortisol levels, and this led us to audit our data. We have also previously assessed surgical outcome for acromegaly and microprolactinoma for a single surgeon. The aims of this study were two‐fold: (i) to investigate the treatment and surgical outcome of patients with Cushing’s disease. In particular, we wished to compare the data with outcome for other pituitary tumours in our centre; and (ii) to determine whether undetectable cortisol following surgery is predictive of long‐term cure for Cushing’s disease.

Do the limits of serum prolactin in disconnection hyperprolactinaemia need re-definition? A study of 226 patients with histologically verified non-functioning pituitary macroadenoma

Background  The differentiation of a pituitary non‐functioning macroadenoma from a macroprolactinoma is important for planning appropriate therapy. Serum PRL levels have been suggested as a useful diagnostic indicator. However, values between 2500 and 8000 mU/l are a grey area and are currently associated with diagnostic uncertainty.

Antiangiogenic effects of somatostatin analogues

Inhibition of angiogenesis has become a target for antineoplastic therapy and for treatment of retinal neovascularization. The presence of somatostatin receptors on tumour cells and on the proliferating vascular endothelium has led to several in vitro and in vivo studies to investigate the antiproliferative and antiangiogenic effects of somatostatin analogues. Currently available data suggest that somatostatin analogues might inhibit angiogenesis directly through somatostatin receptors present on endothelial cells and also indirectly through the inhibition of growth factor secretion such as IGF‐I and vascular endothelial growth factor (VEGF) and reducing monocyte chemotaxis. However, beneficial effects on inhibition of neovascularization have been questioned by some studies. More work is therefore required to firmly establish the role of somatostatin analogues as potential antiangiogenic therapy. The currently available somatostatin analogues have high affinity for somatostatin receptor subtype 2 (sst2) and, to a lesser extent, sst5 and sst3. However, because vascular endothelial cells express several types of somatostatin receptors, it will be important to investigate somatostatin analogues with different receptor subtype affinities, which might increase the spectrum of available therapy for tumours.

Gonadal function in men with chronic illness

Normal testicular hormonal and spermatogenic function depend not only on the testis itself, but also on the integrity of the hypothalamus and anterior pituitary, which form a closed loop functional axis with negative feedback. Systemic disease has been shown to influence male gonadal function in a variety of ways, leading to reduced libido and erectile impotence, infertility, osteoporosis and decreased physical stamina and muscle mass. The effects of systemic disease may occur directly at the testicular level: reduced Leydig cell function will lead to androgen deficiency, while diseases affecting spermatogenesis may lead to male infertility. Alternatively, acute and chronic illness may interfere with the hypothalamic-pituitary axis and so lead to reduced testicular function. Hypogonadism may be defined as reduction in the functional activity of the testis, and may be primary (due to testicular disease) or secondary (due to hypothalamic-pituitary disease). Biochemical criteria in terms of testosterone levels are difficult to specify because there is a wide range of normality in the general population. Primary hypogonadism is easier to define biochemically as in general there will be lowered testosterone levels associated with elevations in gonadotrophins, however, secondary hypogonadism is more difficult to define as testosterone levels may be at the lower end of the normal range and associated with normal levels of gonadotrophins. While there may be an evolutionary or biological advantage of a low testosterone level in chronic illness as reduced sex drive and fertility will enable conservation of energy for recovery from illness and might also prevent ill males from reproducing, there are situations where low testosterone levels may not be ideal; for example leading to reduced muscle bulk in neurological conditions or respiratory failure. Severe illness of any kind may produce hypogonadotrophic hypogonadism. In a group of 30 male in-patients on a general medical ward, mean testosterone levels were found to be reduced to 49% of control values ( P<0.001) (Sempleet al., 1987). Duration of illness and whether it was acute or chronic did not significantly influence the actual level of testosterone, although testosterone values were slightly but nonsignificantly lower in those with chronic illness compared with those who were acutely ill. Follicle stimulating hormone (FSH), luteinising hormone (LH) and prolactin levels were not significantly different between the two groups. Changes in thyroid hormone levels with illness are common – ‘sick euthyroidism’, although many suggest this to be a misnomer and that the term nonthyroidal illness syndrome would be more appropriate (Chopra, 1997). In the Semple study, tri-iodothyronine (T3) and testosterone levels showed some correlation ( r 1⁄4 0.423, P< 0.05) but there was no correlation between testosterone and T4 (Semple t al., 1987). Unlike the thyroid abnormalities associated with chronic illness, neither changes in binding proteins nor abnormalities of peripheral conversion are seen in male hypogonadism associated with illness. Altered LH secretion or LH biological activity have been implicated as important in pathogenesis (Semple et al., 1987). This review will consider ageing and critical illness in addition to specific chronic illnesses, but will not consider diseases specific to the testis which affect gonadal function.

GH replacement does not increase the risk of recurrence in patients with craniopharyngioma

Background  A significant number of patients with craniopharyngioma are GH deficient. The safety of GH replacement in these subjects has not been established.

Surgical debulking of pituitary macroadenomas causing acromegaly improves control by lanreotide

Background  Macroadenomas causing acromegaly are cured surgically in only around 50% of patients. Primary medical treatment with somatostatin analogues has been suggested to be a means of treating patients with a potentially poor surgical outcome. Previous retrospective studies have also suggested that surgical debulking of pituitary tumours causing acromegaly improves control by somatostatin analogues. No prospective study using lanreotide has been carried out thus far to assess whether this is the case.

Proliferation, bcl-2 expression and angiogenesis in pituitary adenomas: relationship to tumour behaviour

The prediction of pituitary tumour behaviour, in terms of response to treatment from which can be derived optimal management strategies, is a challenge that has been approached using several different means. Angiogenesis in other tumour types has been shown to be correlated with poor response to treatment and tumour recurrence. The aim of this paper is to assess the role of measurements of cell proliferation and angiogenesis in predicting pituitary tumour behaviour. The proliferative capacity of the tumour was assessed using the Ki-67 labelling index (LI) while bcl-2 expression was used to assess anti-apoptotic pathways. The microvessel density (MVD) was assessed using antibodies to CD31 and factor VIII-related antigen, and with biotinylated ulex europaeus agglutinin I. There was no difference between Ki-67 LI and MVD of functionless tumours that recurred and those that did not, but bcl-2 expression was significantly lower in tumours that subsequently regrew. Macroprolactinomas had significantly higher LI than microprolactinomas and than all other tumours. Cell proliferation and angiogenesis were not related, showing that both processes are under different control mechanisms in pituitary tumours. In contrast there was a positive relationship between markers of angiogenesis and bcl-2 expression in prolactinomas, GH-secreting tumours and non-recurrent functionless tumours with higher levels of bcl-2 expression being found in the more vascular tumours. These findings may suggest that angiogenesis is related to the ability of tumour cells to survive rather than their proliferative activity.

Are Markers of Proliferation Valuable in the Histological Assessment of Pituitary Tumours

The prediction of tumour behaviour and response to treatment has led to interest in the assessment of the proliferative potential of tumours. Pituitary tumours are usually histologically benign but are capable of aggressive growth and local invasion, although distant metastasis is limited to the very rare pituitary carcinoma. These differences in tumour behaviour may determine both the prognosis and also the effectiveness of treatment whether it be surgery, drugs or radiotheraphy. Immunohistochemistry using antibodies to Ki-67 and proliferating cell nuclear antigen (PCNA) which are expressed in cells that have entered the cell cycle, can be used to assess the proportion of the cells from a tumour that are proliferating. The percentage of positively stained nuclei (labelling index (LI)) may be helpful in predicting appropriate management, as there is a relationship in many tumours between labelling index, invasiveness and tumour recurrence. This has been shown to be true for pituitary tumours, although there may be significant overlap such that low LI may be seen in the rare, aggressive, metastatic pituitary carcinomas, and high LI in indolent tumours. Thus although assessment of proliferation may be helpful in arousing suspicion as to subsequent tumour recurrence or invasiveness, this technique also demonstrates that there are other important and as yet unidentified processes that determine pituitary tumour behaviour.

Expression analysis of cyclins in pituitary adenomas and the normal pituitary gland.

The molecular events involved in pituitary tumour development are still poorly understood. The cyclins play an important role in the control of the cell cycle during cell proliferation and over‐expression of the cyclins has been shown in many different tumour types. The aim of this study was to investigate whether, in comparison to the normal gland, ectopic expression of cyclins occurs in pituitary tumours, and whether differences in cyclin expression are seen with different pituitary tumour types or in association with different tumour behaviour. In contrast to work on cyclin D there are no published data on cyclin B, A and E in human pituitary tumours.