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FAMILIAL ACROMEGALY   1 Jun 2007 

Maria Gueorguiev and Ashley B. Grossman,
Department of Endocrinology, St Bartholomew’s Hospital, London, UK 

    Familial acromegaly accounts for less than 5% of all acromegaly cases. This entity has been reported in the context of MEN-1 syndrome (due to mutations in the MEN1 gene revealed by a loss of heterozygosity at the 11q13 locus), or more rarely as part of the Carney complex (loss of heterozygosity at chromosomes 17q22-24 or 2p16, and to germline mutations in the PRKAR1A gene), or as part of the McCune-Albright syndrome (associated with Gsα gene mutations or mosaicism) (for review (1).
    Familial acromegaly can also be hereditary in the setting of conditions variously described as isolated familial somatotrophinomas (IFS), low-penetrance pituitary adenoma predisposition (PAP) or as familial isolated pituitary adenomas (FIPA), in the absence of other endocrinopathies, and where no mutations have been detected in the MENIN gene (1-3). In particular, familial somatotrophinomas can be homogeneously present within the family or be associated with prolactinomas or (possibly) mixed tumours in members of the same family. Isolated familial somatotrophinomas are characterised by and earlier age of onset (two third of subjects are affected before the age of 30 years),  larger tumours (macroadenomas), and show more invasive behaviour than the sporadic tumours.
    Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene (located at chromosome 11q13) resulting in a truncated protein have been reported in several families harbouring mainly somatotrophinomas, but also GH-PRL-secreting pituitary adenomas (4-6). The prevalence of AIP mutations in these families was reported to be about 15%, and even where present seems to have a penetrance <50% (4). Germline mutations of AIP, however, do not seem to be a common cause in apparently sporadic acses of acromegaly, and somatic mutations of this gene are also not a feature of sporadic tumours. It therefore seems likely that there are probably other susceptibility genes predisposing to familial acromegaly around the 11q13 locus, and these may coexist with other neoplasms. Indeed, a recent report described a patient with acromegaly related to a pituitary adenoma (with negative genetic screening for mutations in the previously described genes) in association with other clinical features such as colonic polyposis, lipomatosis, lentigines, renal carcinoma and familial testicular germ cell cancer, thus raising the suspicion of a putative new syndrome (7).  A germline mutation and a 19 bp duplication leading to a truncated protein in the CDKN1B/p27Kip1 gene have been reported in patients with MEN-1-like features and acromegaly (8,9), but these remain very rare. However, while the fuction of p27 as a cyclin-dependent kinase inhibitor is weel studies, the putative function of AIP remains completely obscure at present. While it has been suggested that genetic screening for germline AIP mutations is a reasonable course for at least some patients with acromegaly (10), most would not recommend this route at the present time.  

References

1.   Melmed, S. Aryl hydrocarbon receptor interacting protein pituitary tumorigenesis:  another interesting protein. 
 J. Clin. Endocrinol. Metab. 2007;92:1617-9

2.   Frohman, L.A., Eguchi, K.  Familial acromegaly. Growth Horm. IGF Res. 2004;14:       S90-S96

3.   Soares, B.S., Eguchi, K., Frohman, L.A.  Tumor deletion mapping on chromosome
      11q13 in 8 families with isolated familial somatotropinomas and in 15 sporadic
      somatotropinomas. J. Clin. Endocrinol. Metab. 2005; 90: 6580-7

4.   Vierimaa, O.; Georgitsi, M.; Lehtonen, R. et al. Pituitary adenoma predisposition

      caused by  germline mutations in the AIP gene. Science 2006; 312: 1228-30

5.   Daly, A.F.; Vanbellinghen, J.F.; Khoo, S.K. et al. Aryl hydrocarbon receptor 
      interacting protein gene mutations in familial isolated pituitary  adenomas: analysis
      in 73 families. J. Clin. Endocrinol. Metab. 2007; 92: 1891-6
6.   Toledo, R.A., Lourenço-Jr, D.M., Liberman, B. et al. Germline mutation in the aryl
      hydrocarbon interacting protein (AIP) gene in familial somatotropinoma. J. Clin.
      Endocrinol. Metab. 2007; 92: 1934-7

7.   Mai, P.L., Korde, L., Kramer, J. et al. A possible new syndrome with growth-

      hormone secreting pituitary adenoma, colonic polyposis, lipomatosis, lentigines and

      renal carcinoma in association with familial testicular germ cell malignancy: a

      case report. J. Medical Case Report 2007;1: 9-14

8.   Pellegata, N.S., Quintanilla-Martinez, L., Siggelkow, H. Et al. Germ-line  mutations
      in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. 
      Proc. Natl. Acad. Sci. U S A. 2006;103:15558-63
9.   Georgitsi, M., Raitila, A., Karhu, A. et al. Germline CDKN1B/p27Kip1 mutation in
      multiple endocrine neoplasia. J. Clin. Endocrinol. Metab. 2007, In Press
10. Georgitsi, M., Raitila, A., Karhu, A. et al. Molecular diagnosis of pituitary adenoma
      predisposition caused by Aryl hydrocarbon receptor interacting protein gene
      mutations Proc. Natl. Acad. Sci. U S A. 2007, In Press

 

NELSON’S SYNDROME      15 April 2007
Maria Gueorguiev and Ashley B. Grossman
Department of Endocrinology, St Bartholomew’s Hospital, London EC1A 7BE, UK

 Corticotroph Tumor Progression after Adrenalectomy in Cushing’s Disease: A Reappraisal of Nelson’s Syndrome

Guillaume Assie´, He´le`ne Bahurel, Joe¨l Coste, Ste´phane Silvera, Miche`le Kujas, Marie-Annick Dugue´, Foued Karray, Bertrand Dousset, Je´roˆme Bertherat, Paul Legmann, and Xavier Bertagna Departments of Endocrinology (G.A., F.K., J.B., X.B.), Biophysics and Hormonology (M.-A.D.), and Digestive and Endocrine Surgery (B.D.), Cochin Hospital, Faculte´ Rene´ Descartes, Paris 5 University, Centre de Re´fe´rence des Maladies Rares de la

Surre´nale, and Department of Radiology A (H.B., S.S., P.L.), Statistics and Medical Informatics (J.C.), and Department of Endocrinology-Metabolism-Cancer (G.A., J.B., X.B.), Institut National de la Sante´ et de la Recherche Me´dicale U567 and Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Cochin Institute, 75014 Paris, France; and Department of Neuropathology (M.K.), Laboratoire R. Escourolle, Pitie´ Salpe´trie`re Hospital, Paris 6 University, 75013 Paris, France

 Context: Adrenalectomy is a radical treatment for hypercortisolism in Cushing’s disease. However, it may lead to Nelson’s syndrome, originally defined by the association of a pituitary macroadenoma and high plasma ACTH concentrations, a much feared complication.
Objective: The objective of the study was to reconsider Nelson’s syndrome by investigating corticotroph tumor progression based on pituitary magnetic resonance imaging scan and search for predictive factors.
Design: This was a retrospective cohort study.
Setting: The complete medical records of Cushing’s disease patients at Cochin Hospital were studied.
Patients: Patients included 53 Cushing’s disease patients treated by adrenalectomy between 1991 and 2002, without previous pituitary irradiation.
Measurements: Clinical data, pituitary magnetic resonance imaging data, and plasma ACTH concentrations for all patients and pituitary gland pathology data for 25 patients were recorded. Corticotroph tumor progression-free survival was studied by Kaplan-Meier, and the influence of recorded parameters was studied by Cox regression.
Intervention: There was no intervention.
Results: Corticotroph tumor progression ultimately occurred in half the patients, generally within 3 yr after adrenalectomy. A shorter duration of Cushing’s disease (adjusted hazard ratio: 0.884/yr), and a high plasma ACTH concentration in the year after adrenalectomy [adjusted hazard ratio per 100 pg/ml (22 pmol/liter): 1.069] were predictive of corticotroph tumor progression. In one case, corticotroph tumor progression was complicated by transitory oculomotor nerve palsy. During follow-up, corticotroph tumor progression was associated with the increase of corresponding ACTH concentrations (odds ratio per 100 pg/ml of ACTH variation: 1.055).
Conclusion: After adrenalectomy in Cushing’s disease, one should no longer wait for the occurrence of Nelson’s syndrome: modern imaging allows early detection and management of corticotroph tumor progression. (J Clin Endocrinol Metab 92: 172–179, 2007)

COMMENT-A major challenge in the evolution of Cushing’s disease following therapeutic bilateral adrenalectomy is the occurrence of Nelson’s syndrome. In this retrospective series of 53 patients with Cushing’s disease from the Cochin Hospital (Paris), none treated with previous radiotherapy, Nelson’s syndrome, i.e. progression of a pituitary corticotroph macroadenoma after bilateral adrenalectomy seems to occur in a significant proportion of patients – 39% at 1 year and 47% at 7 years (median time of recurrence of 3 years) after adrenalectomy. This suggests that Nelson’s syndrome is indeed more frequent than previously reported in the literature (prevalence of 8%-29% in the largest published series with a variable interval after adrenalectomy, 0.5 to 24 years) probably because it was sought very carefully and because of the availability of imaging techniques with higher resolution than previously. In this study including 25 patients with complete clinical and biochemical records and investigations, two main predictive factors appeared: a shorter duration of Cushing’s disease (adjusted hazard ratio 0.884/yr) and elevated plasma ACTH levels in the year following the adrenalectomy (adjusted hazard ratio 100 pg/ml, 22 pmol/l: 1.069), both factors probably related to pituitary adenomas with more aggressive behaviour and larger size ab initio. The presence of visible pituitary adenoma on the MRI was also of prognostic value. These prognostic factors should be used to guide investigation in patients treated following bilateral adrenalectomy, and thus at risk of Nelson’s syndrome, at an early stage, in order to ensure early detection and an adequate therapeutic approach. Nelson’s syndrome often is assocaited with particularly aggressive pituitary tumours whch are not infrequently lethal. Furthermore, we would also propose, based on our own clinical observations, that the prudent endocrinologist should always consider the possibility of underlying an corticotroph carcinoma, particularly in cases which are difficult to control and with extremely high plasma ACTH levels. This highly unpleasant condition may be associated with either local CSF-spread tumour or even distant metastases

 

 

 

SCREENING AND TREATMENT OF GROWTH HORMONE DEFICIENCY IN ADULTS: NEW GUIDELINES -   21 December 2006
Maria Gueorguiev and Ashley B. Grossman
Department of Endocrinology, St Bartholomew’s Hospital, London EC1A 7BE

    Primarily prescribed for children with short stature, growth hormone (GH) replacement is currently also recommended for use in GH deficient states in adults under certain circumstances. In the majority of adult cases, growth hormone deficiency (GHD) is acquired and secondary to a pituitary or hypothalamic lesion or to its subsequent treatment, or to trauma. In a number of cases, GHD is of childhood-onset, due to genetic mutations (isolated GHD or multihormonal pituitary deficiencies, MPHD) or, less frequently, is associated with structural pathologies, and is usually irreversible. Transient isolated GHD in childhood remains possible, but in a number of children the probable final diagnosis is constitutional delay in growth and puberty rather than isolated idiopathic GHD. Adult-onset idiopathic GHD is very rare, in general preceding multiple pituitary hormonal deficiency. 
    The assessment of adult GH deficiency by provocative testing is challenging. Two tests are currently recommended (1) because of their higher reliability (using an immunochemiluminescent two-site assay) (2). The insulin tolerance test (ITT), which with a cutoff of 5.1 μg/L for GH has 96% sensitivity and 92% specificity. As an alternative when the ITT is contraindicated or not well tolerated, the GHRH-arginine test can be used with a cutoff of 4.1 μg/L for GH, showing 95% sensitivity and 91% specificity (although one cannot exclude hypothalamic GHD for which arginine alone can be used with GH cutoff of 1.4 μg/L )(2).  In the context of MPHD and serum IGF-1 levels less than 84 ng/ml, the specificity of this IGF-1 value as predictive for GHD was reported to be similar to any of the GH provocative tests used (3), and GH testing is therefore unnecessary in this situation (although not all funding agencies agree with this) (1). In all young adults with childhood-onset GHD (other than of known cause), reassessment and reconfirmation of the diagnosis should be carried out (1). GHD may be reversible in some cases, and also GH secretion declines with ageing. GH responsivity to testing may be within the normal reference range for adults although considered insufficient during childhood. If the diagnosis of permanent GHD of childhood-onset is probable, a low IGF-1 level when at least one month off GH treatment is sufficient to confirm this status.
    Treatment adjustments (1) should be performed individually based on serum IGF-1 levels (adjusted for age and gender) rather than weight-adjusted (4,5), and titrated to the appropriate level. Women, especially on oral oestrogen replacement, usually require higher doses of GH than men in order to obtain similar therapeutic effects (6,7). GH replacement during the transition from childhood and adolescence to adulthood is controversial, as peak bone mass is achieved several years after the final height is reached (1). However, many  believe that the evidence is sufficiently strong to recommend its continuation to at east 25 years of age. The thyrotroph and corticotroph axes should also be monitored on GH therapy. Thyroxine replacement doses should be adjusted, as GH may lower serum free T4 levels by enhancing T4 deiodination (8). Glucocorticoid replacement should be started if necessary, since GH may interfere with the conversion of cortisone to cortisol, and may therefore unmask a central adrenocorticotrophin deficiency (9).
    While there may be major benefits provided by GH treatment (reduction of cardiovascular risk and mortality related to hypopituitarism, improvement in the quality of life), it may also induce insulin resistance, type 2 diabetes and benign intracranial hypertension. While there is little evidence that GH is associated with an increase in any cancer risk (although see (10)), this therapy is contraindicated in the context of any active malignancy. 

1. Molitch ME, Clemmons DR, Malozowski S et al. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2006;91:1621-34

2. Biller BM, Samuels MH, Zagar A et al. Sensitivity and specificity of six tests for the diagnosis of adult growth hormone deficiency. J Clin Endocrinol Metab 2002;87:2067-79

3. Hartman ML, Crowe BJ, Biller MBK et al. Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency? J Clin Endocrinl. Metab 2002;87:477-85

4. Johansson G, Rosen T, Bengtsson BA. Individualized dose titration of growth hormone (GH) during GH replacement in hypopituitary adults. Clin. Endocrinol 1997;47:571-81

5. Hoffman AR, Strasburger CJ, Zagar A et al. Efficacy and tolerability of an individualized dosing regimen for adult growth hormone replacement therapy in comparison with fixed body weight-based dosing. J Clin Endocrinol Metab 2004;89:3224-33

6. Cook DM, Ludlam WH and Cook MB. Route of estrogen administration helps to determine growth hormone (GH) replacement dose in GH-deficient adults. J Clin Endocrinol Metab 1999;84:3956-3960

7. Burman P, Johansson G, Siegbahn A et al. Growth hormone (GH)–deficient men are more responsive to GH replacement than women. J Clin Endocrinol Metab 1997;82:550-5

8. Poretti S, Giavoli C, Ronchi C et al. Recombinant human GH replacement therapy and thyroid function in a large group of adult GH-deficient patients: when does L-T(4) therapy become mandatory? J Clin Endocrinol Metab 2002;87:2042-5

9. Giavoli C, Libé R, Corbetta S et al. Effect of recombinant human growth hormone (GH) replacement on the hypothalamic-pituitary-adrenal axis in adult GH-deficient patients. J Clin Endocrinol Metab 2004;89:5397-401

10.Swerdlow AJ, Higgins CD, Adlard P and Preece MA. Risk of cancer in patients treated with human pituitary GH in the UK, 1959-85: a cohort study. Lancet 2002;360:273-7

 

 

COMBINED THERAPY OF ACROMEGALY WITH PEGVISOMANT AND SOMATOSTATIN ANALOGUES
Maria Gueorguiev and Ashley B. Grossman
Department of Endocrinology, St Bartholomew’s Hospital, London EC1A 7BE 

Although treatment of acromegaly with somatostatin analogues produces significant tumour shrinkage in up to 50% of patients, and this is probably more effective if given as primary therapy, a small number of patients still remain with poorly-controlled and active disease (1,2). For cases resistant or intolerant to somatostatin analogues, and particularly where impaired glucose metabolism or overt diabetes mellitus is a relevant consideration, the growth hormone receptor antagonist, pegvisomant, is a useful therapeutic option (3,4). Serum IGF-1 levels normalise in 90% to 97% of cases under pegvisomant daily injections (doses up to 40 mg), while GH levels initially increase then stabilise, usually to around double their pre-treatment levels (5,6); the drug is well tolerated but remains extremely expensive. It is possible that less frequent dosing may maintain efficacy with decreased costs, but in one trial alternate-day treatment with pegvisomant 10 mg alone failed to normalise serum IGF-1 levels in 7 out of 10 patients with acromegaly (7)

Now, two recent studies have shown improved therapeutic efficacy for the combination of pegvisomant with a somatostatin analogue. The association of daily pegvisomant at lower doses (10 -15 mg) with Sandostatin LAR 30 mg im monthly normalised serum IGF-1 levels in 91% of patients (10 out of 11 patients)  (8). The combination of long-acting somatostatin analogues (30 mg long-acting octreotide or 120 mg of lanreotide autogel) with weekly pegvisomant (median dose 60 mg, range 40-80 mg/week) achieved normalisation of biochemical parameters - serum IGF-1 levels in 95% (18 out of 19 patients at 42 weeks of treatment, 81% of patients already at 18 weeks with pegvisomant 50 mg or more) and no tumour re-growth in 19 patients at 6 months follow up (even in the absence of previous radiotherapy, n = 18) (9). We might also anticipate a reduction in GH levels and therefore preserved negative feedback on the tumour and thus decreased risk of tumoral re-growth. A few cases of apparent tumour progression have been documented with pegvisomant monotherapy, with an estimated rate of tumour progression of 1.6-2.9%, probably due to cessation of intercurrent octreotide therapy and/or absence of prior radiotherapy (5,6,10,11). This new combined therapeutic regimen may seem attractive as it may improve patients compliance and allow a significant reduction in the therapeutic cost of the pegvisomant, although detailed economic analyses remain to be performed.

Finally, it will be of major interest to carry out the future studies focusing on the combination of pegvisomant with the new somatostatin analogue pasireotide (SOM230, Novartis, Basel, Switzerland). With its broader receptor affinity spectrum, the association may achieve improved therapeutic outcome with reduced pegvisomant doses.
1. Bevan, J.S. (2005) Clinical review: The antitumoral effects of somatostatin analog therapy in acromegaly. J. Clin. Endocrinol. Metab. 90, 1856-63.
2. Melmed, S., Sternberg, R. , Cook, D. et al. (2005) A critical analysis of pituitary tumor shrinkage during primary medical therapy in acromegaly. J. Clin. Endocrinol. Metab. 90, 4405-10.
3. Vance, M.L. and Laws, E.R. (2005) Role of medical therapy in the management of    acromegaly. Neurosurgery 56: 877-85.
4. Paisley, A.N., Trainer, P.J. and Drake, W.M. (2004) The place of pegvisomant in the acromegaly treatment algorithm. Growth Horm. & IGF Res.;14: S101-6.
5. van der Lely, A.J., Hutson, R.K., Trainer, P.J. et al. (2001a) Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet 24, 1754-9.
6. Trainer, P.J., Drake, W.M., Katznelson, L. et al. (2000) Treatment of acromegaly with the growth hormone- receptor antagonist pegvisomant. N. Engl. J. Med. 342, 1171-7.
7. Jehle, S., Reyes, C.M., Sundeen, R.E. and Freda, P.U. (2005) Alternate-day administration of pegvisomant maintains normal serum insulin-like growth factor-I levels in patients with acromegaly. J. Clin. Endocrinol. Metab. 90, 1588-93.
8. Jorgensen, J.O.L., Feldt-Rasmussen, U., Frystyk, J. et al. (2005) Cotreatment of acromegaly with a somatostatin analog and a growth hormone receptor antagonist. J. Clin. Endocrinol. Metab. 90, 5627-31.
9. Feenstra, J., de Herder, W.W., ten Have, S.M.T.H. et al. (2005) Combined therapy with somatostatin analogues and weekly pegvisomant in active acromegaly. Lancet 365, 1644-6.
10. van der Lely, A.J., Muller, A., Janssen, J.A. et al. (2001b) Control of tumor size and disease activity during cotreatment with octreotide and the growth hormone  receptor antagonist pegvisomant in an acromegalic patient. J. Clin. Endocrinol. Metab. 86, 478-81.
11. Besser, G.M., Burman, P. and Daly, A.F. (2005) Predictors of rates of treatment- resistant tumor growth in acromegaly. Eur. J. Endocrinol.  153, 187-93.

 

CUSHING’S SYNDROME AND PREGNANCY: DIAGNOSTIC AND THERAPEUTIC CHALLENGES (6 March 2006)
Maria Gueorguiev and Ashley B. Grossman---Department of Endocrinology, St Bartholomew’s Hospital, London EC1A 7BE 

    Cushing’s syndrome (CS) is rare during pregnancy, with less than 150 cases being reported in the literature. Its presenting features, biochemical investigation and therapeutic approaches, have recently been reviewed in two publications from the NIH (Lindsay et al., 2005a,b). Cushing’s disease (CD) represents only about 33% of the causes of CS in pregnancy compared to 58-70% in the general population, as reported in a recent review including 136 cases (Lindsay et al., 2005a). Conversely, adrenal adenomas constitute the majority (40-50%) of cases during pregnancy compared to only 15% in non pregnant women. Some of these cases may be due to abnormal expression of ectopic adrenal receptors for LH/human chorionic gonadotrophin (Wy et al., 2002; Lacroix et al., 1999). Ectopic ACTH secretion remains rare during the gestational period, probably because of the severe impairment of gonadotroph axis.  The hypercortisolism being usually more pronounced in the late stages of gestation, and the limited experience, contribute to making the diagnosis of CS difficult. Establishing the correct diagnosis early and offering appropriate treatment should improve maternal and fetal morbidity and mortality (2% maternal deaths and about 5% spontaneous abortion/ intrauterine death) (Lindsay et al., 2005a).
    Clinical features, mainly weight gain, hypertension and alterations in glucose metabolism are all similarly observed in both CS an pregnancy, while muscle weakness and larger purple striae are suggestive of CS. The subtlety of these clinical changes contributes to the fact that CS is often detected and diagnosed late, during the second and third trimester of gestation (Lindsay et al., 2005b). In addition, CS may be cyclical (Miyoshi et al., 2005).
    Variations in circadian cortisol rhythm are preserved during pregnancy, in particular the midnight nadir level, although this is reset to a higher concentration – this is not the case for CS/CD during pregnancy (Lindsay et al., 2005b). However, it should be emphasised that at least part of this apparent increase in nocturnal levels may relate to estrogen-induced increases in cortisol binding globulin (CBG). Late-night salivary cortisol seems to be a reliable non-invasive screening test with relatively low variability and excellent reproducibility. Although a cut-off of 6.1 nmol/l (0.22 μg/dl) was shown to have a sensitivity and specificity of 100%, the specificity decreases to 75% during late pregnancy (Viardot et al., 2005). Physiologically, urinary free cortisol (UFC) increases from concentrations within the normal range during first trimester of gestation, up to 3 times the upper limit of the normal during the last two trimesters. The diagnosis of CS in a pregnant woman should be considered only if there is more than 3-fold increase of the upper limit of the normal during the second and third trimesters, while a mean of an 8-fold increase has been reported (Lindsay et al., 2005a).
    The hypothalamo-pituitary-adrenal (HPA) axis response to exogenous dexamethasone is blunted during pregnancy: several studies have shown different degrees of suppression, and these changes may persist even up to 3 weeks postpartum (Greenwood et al., 1984; Owens et al., 1987). A few mechanisms have been advanced to explain this decreased suppressibility to exogenous glucocorticoids: CBG effects on cortisol, tissue refractoriness to glucocorticoids, or resetting of maternal HPA feedback probably resulting from a reduced cortisol feedback due to competition between progesterone and cortisol at the glucocorticoid  receptor (Odagiri et al., 1988; Dorr et al., 1989). ACTH and CRH of placental origin may also have a role. A suppression of about 40% of plasma cortisol and UFC after 1 mg dexamethasone is observed during the second and third trimesters of gestation, as compared to 78% in non-pregnant controls (Odagiri et al., 1988), resulting in a higher rate of false-positive tests. The suppression can be more important (~60%) when a higher dose of dexamethasone is administered (4 mg iv) during the second trimester or up to 90% following 12 mg in divided dose (Charnvises et al., 1985).
    Once increased cortisol production has been documented, a few tests are indicated to determine the etiology. Plasma ACTH levels may not always be suppressed in adrenal lesions during pregnancy, possibly due non suppressed placental CRH secretion or placental ACTH secretion. Thus, the recommended classical threshold values for ACTH cannot be applied during gestation (Arnaldi et al., 2003). The overnight or high dose (HDDST) suppression test with 8 mg dexamethasone may be useful in distinguishing pituitary (CD) from adrenal forms of CS, but its efficacy is unknown in differentiating ectopic ACTH secretion during pregnancy because of the small number of cases and the variable degree of cortisol response for each diagnosis. The CRH test has not been often used during pregnancy. Reduced responses of plasma ACTH to human CRH at 1 μg/kg have been observed during the third trimester of normal pregnancy (Schulte et al., 1990). Despite a small number of reports, a significant rise (+44-130%) of plasma cortisol (and ACTH) after CRH was found in 5 patients with surgically-confirmed CD during pregnancy (Ross et al., 1995; Mellor et al., 1998; Pinette et al., 1994) without adverse effects.
    Inferior petrosal sinus sampling (IPSS), with or without CRH, is the gold standard in distinguishing pituitary (CD) form other causes of CS, but has been used with success in only a few cases during gestation (Ross et al., 1995; Lindsay et al., 2005a). The interpretation of the results may not be easy: there is lack of knowledge of the degree of suppression of pituitary ACTH among pregnant patients with adrenal disease (Lindsay et al.; 2005b). This is an invasive method and the risks of irradiation during pregnancy contribute restriction in its use to mainly difficult cases. In pregnant patients with confirmed CS and borderline levels of ACTH, Lindsay et al. (2005b) recommend performing dynamic testing with HDDST and CRH stimulation in order to determine the source of ACTH secretion. IPSS may be performed in the case of discordant biochemical results and imaging. If ACTH levels are low and suggestive of an adrenal lesion, then ultrasound (lower sensitivity for smaller lesions) of the adrenals or preferablly MRI should be undertaken. Pituitary MRI (without gadolinium) is not routinely used during gestation but is considered safe after the first trimester. The interpretation of imaging should be cautious as the pituitary gland increases its volume up to 2-fold by the third trimester, and a greater proportion of incidentalomas could be identified during pregnancy.
    Therapeutic management, which is often instituted late during gestation, is associated with a more favorable outcome even if in some cases maternal and fetal complications may still occur: in the absence of active treatment 76% live births were documented, increasing to 89% if treatment was provided at a mean of 20 weeks (Lindsay et al., 2005a). These authors (Lindsay et al., 2005a and b) recommend a surgical approach (transsphenoidal surgery or adrenalectomy respectively) as first-line treatment, except during the very late stage of the third trimester. Medical treatment represents a  second choice because of the theoretical teratogenic or other adverse effects of available drugs. The use of metyrapone, which is safer, is probably restricted as it has been associated with fetal adrenal insufficiency in one case, and there also seems to be an increased risk of hypertension and preeclampsia. Ketoconazole has been  recommended if there is metyrapone intolerance, but experience is limited.
    In conclusion, there is clear need to establish cut-off values for interpreting adequately the different diagnostic tests during pregnancy. Early suspicion and diagnosis of CS, and establishing guidelines for appropriate therapeutic approach, will certainly contribute to improved maternal and foetal outcome.
References
1.  Lindsay, J.R., Jonklaas, J., Oldfield, E.H. and Nieman, L.K. Cushing’s syndrome during pregnancy: personal experience and review of the literature. J Clin  Endocrinol Metab 2005a; 90:3077-3083.
2.  Wy, L.A., Carlson, H.E., Kane, P. et al. Pregnacy-associated Cushing’s syndrome condary to a luteinizing hormone/human chorionic gonadotropin receptor-positive adrenal carcinoma. Gynecol Endocrinol 2002; 16:413-417.
3.  Lacroix, A., Hamet, P. and Boutin, J.M. Leuprolide acetate therapy in luteinizing hormone-dependent Cushing’s syndrome. N Engl J Med 1999; 341:1577-1581.
4.  Lindsay, J.R. and Nieman, L.K. The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment. Endocrine Rev 2005b; 26:775-799.
5.  Miyoshi, T., Otsuka, F., Suzuki, J. et al. Periodic secretion of adrenocorticotropin  in a patient with Cushing’s disease manifested during pregnancy. Endocrine J 2005; 52:287-292.
6.  Viardot, A., Huber, P., Puder, J.J. et al. Reproducibility of nighttime salivary cortisol and its use in the diagnosis of hypercortisolism compared with urinary free cortisol and overnight dexamethasone suppression test. J Clin Endocrinol Metab  2005; 90 (10): 5730-5736.
7.  Greenwood, J. and Parker, G. The dexamethasone suppression test in the puerperium. Aust NZ J Psychiatry 1984; 18:282-282.
8.  Owens, P.C., Smith, R., Brinsmead, M.W. et al. Postnatal disappearance of the  pregnancy-associated reduced sensitivity of plasma cortisol to feedback inhibition. Life Sci 1987; 41:1745-1750.
9.  Odagiri, E., Ishiwatari, N., Abe, Y. et al. Hypercortisolism and resistance to   dexamethasone suppression during gestation. Endocrinol Jpn 1988; 35:685-690.
10. Dorr, H.G., Heller, A., Versmold, H.T. et al. Longitudinal study of progestins,      mineralocorticoids, and glucocorticoids throughout human pregnancy. J Clin       Endocrinol Metab 1989; 68: 863-868.
11. Charnvises, S., Fencl, M.D., Osathanondh, R. et al. Adrenal steroids in maternal       and cord blood after dexamethasone administration at midterm. J Clin Endocrinol       Metab 1985; 61:1220-1222.
12. Arnaldi, G., Angeli, A., Atkinson, A.B. et al. Diagnosis and complications of       Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 2003;      88:5593-5602.
13. Shulte, H.M., Weisner, D. and Allolio, B. The corticotrophin releasing hormone       test in late pregnancy: lack of adrenocorticotrophin and cortisol response. Clin       Endocrinol 1990; 33:99-106.
14. Ross, R.J., Chew, S.L., Perry, L. et al. Diagnosis and selective cure of Cushing’s       disease during pregnancy by selective transsphenoidal surgery. Eur J Endocrinol       1995; 132:722-726.
15. Mellor, A., Harvey, R.D., Pobereskin, L.H. et al. Cushing’s disease treated by       trans-sphenoidal selective adenomectomy in mid-pregnancy. Br J Anaesth 1998;       80:850-852.
16. Pinette, M.G., Pan, Y.Q., Oppenheim, D. et al. Bilateral inferior petrosal sinus       corticotropin sampling with corticotropin-releasing hormone stimulation in a       pregnant patient with Cushing’s syndrome. Am J Obstet Gynecol 1994; 171:563-      564.

 

Bilateral inferior petrosal sinus sampling in Cushing’s disease: differences between children and adults  5 Dec 2005

 Maria Gueorguiev and Ashley Grossman, Department of Endocrinology, St Bartholomew’s Hospital, London EC1A 7BE

 Cushing’s disease (CD) always represents a diagnostic and therapeutic challenge. Despite being technically difficult and a somewhat invasive procedure, bilateral inferior petrosal sinus sampling (BIPSS) is commonly used to overcome the limitation of conventional imaging techniques (CT scanning, MRI) in experienced centres: BIPSS allows the confirmation of the pituitary source of an ACTH-dependent lesion  (the most sensitive test for excluding ectopic ACTH secretion), but also to a certain extent helps to localize the corticotroph (micro)adenoma within the pituitary, which is of crucial importance for the surgical approach. However, a recent paper from the NIH group seems to indicate a significantly lower sensitivity in children than in adults, in opposition to data from the UK.

 The diagnostic sensitivity of BIPSS in differentiating between an pituitary-dependent Cushing’s syndrome and an ectopic source, based on the inferior petrosal sinus central to peripheral (IPS/P) gradient, is reported to vary between 81% and 90% with a specificity between 90% and 100% in the largest adult patient series (1-4). The CRH-stimulated IPS/P gradient increases the sensitivity to 85%-97% (with a specificity remaining at ~100%). In a subgroup with contradictory responses to the high-dose dexamethasone test (HDDST) or to peripheral CRH testing, the sensitivity was a little lower at 76% (3;5). However, if a cut-off of 2 or 2.15 (instead of 3) for the post-CRH IPS/P gradient is used, the sensitivity rises to 93%-97% (2;4). The sensitivity for correctly lateralising the pituitary adenoma (based on the inter-petrosal sinus gradient (IPSG) was reported to be 83% (2).

 However, in two recent reviews British (6) and US (7) groups have analysed the data from 21 (out of 27) and 94 (out of 141) children respectively with CD who underwent BIPSS (performed under general anaesthesia in a large number of patients in the US study). In the first review centralisation of ACTH secretion was documented in 76%, and lateralisation of the microadenoma (2-4 mm) was observed in 81% of patients, 3 of which were obtained from catheterisation of the high jugular vein (2 showed also central secretion of ACTH), while the remaining (4 cases) had no lateralisation (suggestive of mid-line adenoma). For the NIH study, the reported diagnostic sensitivity for CD was 90% (basal) and 97% post-CRH (no ectopic tumours were identified). Nevertheless, while lateralisation of a microadenoma was found in a similar proportion of cases in the two series, the remaining having apparent mid-line lesions, the overall concordance with location of the adenoma at surgery was 81% for the UK series but only 58% for the NIH study.

 A number of factors can potentially interfere with the accuracy of BIPSS: these include anatomic/morphologic anomalies such as asymmetric venous drainage of the pituitary or a hypoplastic inferior petrosal sinus, or an unusual location of the microadenoma (i.e. in the sphenoidal sinus) (8-10); operator-dependent technical skills and experience: correct catheter positioning in the inferior petrosal sinuses, although high jugular vein catheter (risk of dilution factor) and cavernous sinus catheterisation have shown various results (6;8;9;11-16); and variation in ACTH secretion by the adenoma basally, as in cyclic disease (17),  with possible reversal of the inter-petrosal sinus gradient post-CRH stimulation (2;9;18;19). However, these considerations apply to adults as well as children. Among the unique parameters that could potentially explain the discrepancies in diagnostic sensitivity of BIPSS between the two groups (adults and children) are:

-          technically more difficult catheterisation in children due to smaller anatomical structures)

-          the smaller size of corticotroph microadenomas in children, often less than 2 mm in size (20;21)

-          a mid-line position of the microadenoma, as seen  in one third of the cases in the NIH study (7), although this was not noted in the British study (6).

However, none of these factors can readily explain the differences between the two series. It may be relevant that the US group generally used a general anaesthetic, but this was not thought necessary by the UK group. Even then, it is difficult to see how such a change in procedure could cause a loss of the lateral differential, although a general lowering of ACTH levels may have led to a ‘flattening’ of the absolute levels and hence a diminution in lateralisation. Whatever the case, BIPSS has generally been extremely helpful in the investigation of ACTH-dependent Cushing’s syndrome, and these results emphasise the importance of referring patients to specialised centres where the requisite expertise is readily available (22).

 Reference list

1.      Oldfield EH, Doppman JL, Nieman LK et al. Petrosal sinus sampling with and    without corticotrophin-releasing hormone for the differential diagnosis of    Cushing’s syndrome. N Engl J Med 1991; 325 (13):897-905.

2.      Kaltsas GA, Giannulis MG, Newell-Price JD et al. A critical analysis of the   value of simultaneous inferior petrosal sinus sampling in Cushing’s disease and       the occult ectopic adrenocorticotropin syndrome. J Clin Endocrinol Metab 1999;      84(2):487-492.

3.      Invitti C, Pecori GF, de Martin M, Cavagnini F. Diagnosis and management of       Cushing’s syndrome: results of an Italian multicentre study. Study group of       Italian Society of Endocrinology on the Pathophysiology of the Hypothalamic-      Pituitary-Adrenal Axis. J Clin Endocrinol Metab 1999; 84(2):440-448.

4.      Colao A, Faggiano A, Pivonello R, Pecori GF, Cavagnini F, Lombardi G.       Inferior petrosal sinus sampling in the differential diagnosis of Cushing’s       syndrome: results of an Italian multicentre study. Eur J Endocrinol 2001;       144(5):499-507.

5.      Invitti C, Pecori GF, Cavagnini F. Inferior petrosal sinus sampling in patients       with Cushing’s syndrome and contradictory responses to dynamic testing. Clin       Endocrinol (Oxf) 1999; 51(2):255-257.

6.      Storr HL, Afshar F, Matson M et al. Factors influencing cure by transphenoidal       selective adenomectomy in paediatric Cushing’s disease. Eur J Endocrinol              2005; 152(6):825-833.

7.      Batista D, Gennari M, Riar J et al. An assessment of  petrosal sinus sampling for  localisation of a pituitary microadenomas in children with Cushing’s disease. J  Clin Endocrinol Metab 2005 In press.

8.      Doppman JL, Chang R, Oldfield EH, Chrousos G, Stratakis CA, Nieman LK.       The hypopplastic inferior petrosal sinus: a potential source of false-negative       results in petrosal sampling Cushing’s disease. J Clin Endocrinol Metab 1999;       84(2):440-448.

9.      Lefournier V, Martinie M, Vasdev A et al. Accuracy of bilateral inferior petrosal       or cavernous sinuses sampling in predicting the latheralization of Cushing’s       disease pituitary microadenoma: influence of catheter position and anatomy of       venous drainage. J Clin Endocrinol Metab 2003; 88(1):196-203.

10.  Miller K et al. Diagnostic errors after inferior petrosal sinus sampling. J Clin       Endocrinol Metab 2004; 89(8):3752-3763.

11.  Flitsch J, Ludecke DK, Knappe UJ, Grzyska U. Cavernous sinus sampling in       selected cases of Cushing’s disease. Exp Clin Endocrinol Diabetes 2002;       110(7):329-335.

12.  Mamelak AN, Dowd CF, Tyrrell JB, McDonald GM. Venous angiography is needed to interpret inferior petrosal sinus and cavernous sinus sampling data for lateralizing adrenocorticotropin-secreting adenomas. J Clin Endocrinol Metab 1996; 81(2):475-481.

13.  Oliverio PJ, Monsein LH, Wand GS, Debrun GM. Bilateral simultaneous cavernous sinus sampling using corticotrophin-releasing hormone in the evaluation of Cushing’s disease. Am J Neuroradiol 1996; 17(9):1669-1674.

14.  Graham KE, Samuels MH, Nesbit GM et al. Cavernous sinus sampling is highly accurate in distinguishing Cushing’s disease from the ectopic adrenocorticotropin syndrome in predicting intrapituitary tumor location. J Clin Endocrinol Metab 1999; 84(5):1602-1610.

15.  Teramoto A, Yoshida Y, Sanno N, Nemoto S. Cavernous sinus sampling in patients with adrenocorticotrophic hormone-dependent Cushing’s syndrome with emphasis on inter- and intracavernous adrenocorticotrophic hormone gradients. J Neurosurg 1998; 89(5):762-768.

16.  Liu C, Lo JC, Dowd CF et al. Cavernous and inferior petrosal sinus sampling in       the evaluation of ACTH-dependent Cushing’s syndrome. Clin Endocrinol (Oxf)       2004; 61(4):478-486.

17.  Yamamoto Y, Davis DH, Nippoldt TB, Young WF, Jr., Huston J, III, Parisi JE. False-positive inferior petrosal sinus sampling in the diagnosis of Cushing’s disease. Report of two cases. J Neurosurg 1995; 83(6):1087-1091.

18.  Miller DL, Doppman JL, Nieman LK et al. Petrosal sinus sampling: discordant lateralization of ACTH-secreting pituitary microadenomas before and after stimulation with corticotrophin-releasing hormone. Radiology 1990; 176(2): 429-431.

19.  de Herder WW, Uitterlinden P, Pieterman H et al. Pituitary tumor localization       with Cushing’s disease by magnetic resonance imaging. Is there a place for      petrosal sinus sampling? Clin Endocrinol (Oxf) 1994; 40(1): 87-92.

20.  Magiakou MA, Mastorakos G, Oldfield EH et al. Cushing’s syndrome in children and adolescents. Presentation, diagnosis, and therapy. N Engl J Med 1994; 331(10):629-636.

21.  Kunwar S, Wilson CB. Pediatric pituitary adenomas. J Clin Endocrinol Metab 1999; 84(12):4385-4389.

22.  Moshang T, Jr. Cushing’s disease, 70 years later. And the beat goes on. J Clin Endocrinol Metab 2003; 88(1):31-33.

  

TUMOR SHRINKAGE WITH SOMATOSTATIN ANALOGS IN ACROMEGALY
Gueorguiev, M. and Grossman, A.B.
Department of Endocrinology, St Bartholomew’s Hospital, London EC1A 7BE, UK
 Following the wide availability of somatostatin analogs for treating GH-secreting pituitary adenomas in the mid-1980s , their use has partially shifted from purely adjuvant therapy following incomplete surgery to primary therapy in certain situations(1-5). Figure 1 summarises the complexity and diversity of intracellular signalling pathways activated upon ligand binding to somatostatin receptors sstr1 to sstr5(6-9). Two recent elegant reviews have assessed the therapeutic results of the two major  somatostatin analogs (mainly with affinity for sst 2 and sst 5 receptor subtypes) in terms of their ability to shrink somatotroph tumors, and particularly in relation to primary therapy, despite difficulties in evaluating disparate imaging techniques and a lack of control studies   (7;10).

In the first one(7), John Bevan  has reviewed 36 published studies where short-acting and long-acting octreotide (LAR) or lanreotide, were evaluated as primary or adjuvant therapy for acromegaly: significant tumour shrinkage was defined as 10-25% decrease in tumor volume based on pituitary imaging (MRI or CT) before and after treatment. Considering all studies together (921 patients), without distinction between analog type or formulation, 42% of patients showed a reduction in tumor size, with observed an mean volume decrease of 50%. However, the proportion of patients with significant tumor shrinkage was more greater in the group of primary therapy (without prior surgery or radiotherapy but some following drug therapy) than among those treated as adjuvant therapy (52% vs. 21%). Considering the type of formulation, octreotide-induced reduction of the adenoma occurred in a larger number of patients either for overall analysis (45%-57% for short-acting octreotide/LAR vs. 24% for lanreotide medium-length SR formulation), or separately for primary therapy (51%-80% vs. lanreotide SR 31%) or for adjuvant therapy (27%-28% vs 9% respectively).

In a complementary review   review: 10), Shlomo Melmed and colleagues analysed 15 studies (447 patients; a number of which had been included in the Bevan review) where somatostatin analogs were used as primary therapy alone (possible previous dopamine agonists or somatostatin analogs) or preceding surgery or radiotherapy. Overall, 36.6% of 424 acromegalic patients showed significant tumor shrinkage of >10% (there was no significant difference in the percentage of patients treated with short-acting octreotide/lanreotide or long-acting preparations, 37.8% vs. 34%). The results were much more modest with dopamine agonists alone as primary therapy: only 4-5% of patients obtained a reduction in tumor size. Overall, significant tumor reduction of a weighted mean of 49.8% was obtained, and this value remains the same regardless of the octreotide formulation used (short-acting 49.5% vs. LAR 50%).

 In both studies, the major predictive factor for a better therapeutic response in terms of tumor shrinkage was the absence of previous surgery or radiotherapy (52% of patients for primary therapy vs. 20% as secondary adjuvant therapy (7). In the report by Melmed and colleagues (10), probably due to the selection criteria (patients with shrinkage of 50%) the initial tumor size prior to treatment was also a determining factor for reduction of tumor volume.
It is clear that significant tumor shrinkage can be expected in around 50% of patients treated with somatostatin analogs such as octreotide; the results with lanreotide appear less sanguine, but it is possible that the newer lanreotide autogel preparation will be more effective. These reports are exciting in that they highlight the tumoristatic effects of these fascinating compounds.

                1.             Colao A, Ferone D, Marzullo P et al. Long-term effects of depot long-acting somatostatin analog octreotide on hormone levels and tumor mass in acromegaly. J Clin Endocrinol Metab 2001; 86(6):2779-2786.
     2.    Newman CB, Melmed S, George A et al. Octreotide as primary therapy for acromegaly. J Clin Endocrinol Metab 1998; 83(9):3034-3040.
     3.    Bevan JS, Atkin SL, Atkinson AB et al. Primary medical therapy for acromegaly: an open, prospective, multicenter study of the effects of subcutaneous and intramuscular slow-release octreotide on growth hormone, insulin-like growth factor-I, and tumor size. J Clin Endocrinol Metab 2002; 87(10):4554-4563.

     4.    Battershill PE, Clissold SP. Octreotide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in conditions associated with excessive peptide secretion. Drugs 1989; 38(5):658-702.

     5.    Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ. Octreotide. N Engl J Med 1996; 334(4):246-254.

     6.    Murray RD, Kim K, Ren SG, Chelly M, Umehara Y, Melmed S. Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis. J Clin Invest 2004; 114(3):349-356.

     7.    Bevan JS. Clinical review: The antitumoral effects of somatostatin analog therapy in acromegaly. J Clin Endocrinol Metab 2005; 90(3):1856-1863.

     8.    Dasgupta P. Somatostatin analogues: multiple roles in cellular proliferation, neoplasia, and angiogenesis. Pharmacol Ther 2004; 102(1):61-85.

     9.    Garcia dlT, Wass JA, Turner HE. Antiangiogenic effects of somatostatin analogues. Clin Endocrinol (Oxf) 2002; 57(4):425-441.

  10.    Melmed S, Sternberg R, Cook D et al. A critical analysis of pituitary tumor shrinkage during primary medical therapy in acromegaly. J Clin Endocrinol Metab 2005; 90(7):4405-4410. 

Figure 1: Upon ligand binding, somatostatin receptors activate a variety of  intracellular signalling systems, depending of the isoform and the target tissue. Pitiuitary adenoma shrinkage results from direct and indirect effects. Antiproliferative activity on tumour cells and endothelial cells (inhibition of angiogenesis) comprises cell cycle arrest and induction of apoptosis. Inhibition of release of hormones, growth factors, and modulation of the immune system represent indirect effects.
Abreviations: bFGF basal fibroblast growth factor, EGF epidermal growth factor, PDGF platelet-derived growth factor, VEGF vascular endothelial growth factor, IGF-1 insulin-like growth factor, AC adenylate cyclase, PTP protein tyrosine phosphatase, MAPK mitogen-activated protein kinase, ERK 1/2, eNOS endothelial nitric oxyde synthase, nNOS neuronal nitric oxyde synthase                                                   


 

Figure 1