It has been difficult to identify factors that affect the risk of cancer, but we know that people are at higher risk as they get older, or if they have a strong family history of cancer. The potential influence of environmental and behavioral factors remains poorly understood. Early population-based and case–control studies suggested that higher serum levels of IGF1 could be associated with increased cancer risk. Since GH therapy increases IGF1 levels, concern has been raised regarding its potential role as a cancer initiation factor. Experimental evidence and some clinical studies showed that when GH/IGF1 secretion or action was inhibited, a decreased incidence and rate of progression of cancers occurred. However, human populations comprise a garden variety of genotypes that respond differently to the same kind of exposures. Human population studies frequently reveal only very small effects to these exposures. So, are GH and cancer guilty by association? After more than 20 years, leukemia, a major safety issue initially believed associated with GH treatment in children with GH deficiency (GHD), has not been confirmed but the risk of second malignancies in patients previously treated with irradiation has been detected or confirmed through the National Cooperative Growth Study. Overall, this large study confirmed the favorable overall safety profile of GH therapy in children with GHD, and also highlighted specific populations at potential risk. The risk of secondary malignancy following radiotherapy is surely related to radiotherapy more than GH therapy that may increase growth but is less likely to start the oncogenic process. In GH-deficient adults treated with GH, observational studies (KIMS, HypoCCS) have shown that when IGF1 levels were targeted within normal age-related reference ranges, the occurrence of malignancies was not higher than in the general population.
Sandra Pekic and Vera Popovic
Sandra Pekic and Vera Popovic
Hypopituitarism is defined as one or more pituitary hormone deficits due to a lesion in the hypothalamic–pituitary region. By far, the most common cause of hypopituitarism associated with a sellar mass is a pituitary adenoma. A high index of suspicion is required for diagnosing hypopituitarism in several other conditions such as other massess in the sellar and parasellar region, brain damage caused by radiation and by traumatic brain injury, vascular lesions, infiltrative/immunological/inflammatory diseases (lymphocytic hypophysitis, sarcoidosis and hemochromatosis), infectious diseases and genetic disorders. Hypopituitarism may be permanent and progressive with sequential pattern of hormone deficiencies (radiation-induced hypopituitarism) or transient after traumatic brain injury with possible recovery occurring years from the initial event. In recent years, there is increased reporting of less common and less reported causes of hypopituitarism with its delayed diagnosis. The aim of this review is to summarize the published data and to allow earlier identification of populations at risk of hypopituitarism as optimal hormonal replacement may significantly improve their quality of life and life expectancy.
Helene Holmer, Vera Popovic, Bertil Ekman, Cecilia Follin, Ann Britt Siversson, and Eva Marie Erfurth
Data on bone mineral density (BMD) are lacking in adults with childhood onset (CO)–craniopharyngioma (CP) with hypothalamic damage from the tumor. In patients with CO GH deficiency, BMD increases during GH treatment.
The aims were to evaluate BMD in adults with CO–CPs on complete hormone replacement, including long-term GH and to evaluate the impact of hypothalamic damage on these measures.
Design and participants
BMD (dual-energy X-ray absorptiometry), markers of bone turn over, physical activity and calcium intake were assessed in 39 CO–CP adults (20 women), with a median age of 28 (17–57) years, in comparison with matched population controls.
Late puberty induction was recorded in both genders, but reduced androgen levels in females only. Only CP women had lower BMD (P=0.03) at L2–L4, and reduced Z-scores at femoral neck (P=0.004) and L2–L4 (P=0.004). Both genders had increased serum leptin levels (P=0.001), which significantly correlated negatively with BMD at L2–L4 (P=0.003; r=−0.5) and 45% of CP women had Z-score levels ≤−2.0 s.d. Furthermore, 75% of those with a Z-score ≤−2.0 s.d. had hypothalamic involvement by the tumor. Calcium intake (P=0.008) and physical activity (P=0.007) levels were reduced in CP men only. Levels of ostecalcin and crossLaps were increased in CP men only.
Despite continuous GH therapy, low BMD was recorded in CO–CP females. Insufficient estrogen and androgen supplementation during adolescence was the main cause, but hypothalamic involvement with consequent leptin resistance was also strongly associated with low BMD in both genders.
Jacqueline Trouillas, Pia Burman, Ann McCormack, Stephan Petersenn, Vera Popovic, Olaf Dekkers, and Gerald Raverot
The European Society of Endocrinology (ESE) survey reported on the largest cohort of 125 aggressive pituitary tumours (APT) and 40 pituitary carcinomas (PC). Whilst the survey focused on treatment effectiveness, all pathological data were not explored in detail. Here, we comment on some interesting pathological findings, notably the difference between APT and PC.
Helene Holmer, Bertil Ekman, Jonas Björk, Carl-Henrik Nordstöm, Vera Popovic, AnnBritt Siversson, and Eva-Marie Erfurth
Craniopharyngioma patients without GH therapy are at an increased cardiovascular disease (CVD) risk and particularly concerning women. No previous study on long-term GH therapy in adults with childhood onset (CO) craniopharyngioma was identified.
To investigate CVD risk in adults with CO craniopharyngioma on complete hormone replacement, including long-term GH therapy, and to investigate the impact of disease-related factors on CVD risk.
Design and participants
In a cross-sectional study of operated CO craniopharyngiomas (1958–2000) from a defined area of Sweden (2.5 million), we enrolled 42 patients (20 women) with a median age of 28 years (range 17–57) and assessed CVD risk of 20 (4–40) years after first operation. Comparisons were made with matched controls and between patients with tumor growth into the third ventricle (TGTV) versus non-TGTV. GH therapy was 10–12 years in women and men.
In comparison with controls, both male and female patients had increased body mass index, fat mass, insulin, and leptin levels. Overall, while not significantly increased in male patients, 55–60% of female patients had a medium–high CVD risk, compared with 10–20% in controls. An increased CVD risk (all P<0.05) and higher levels of fat mass and insulin were recorded in the TGTV group versus the non-TGTV group. Late puberty induction and lack of androgens were shown in female patients.
Adult patients with CO craniopharyngioma, especially those with TGTV, have persistently increased CVD risk. Conventional hormone substitution, including GH, is insufficient to normalize CVD risk, suggesting an important role for irreversible hypothalamic dysfunction.
Gerald Raverot, Pia Burman, Ann McCormack, Anthony Heaney, Stephan Petersenn, Vera Popovic, Jacqueline Trouillas, Olaf M Dekkers, and The European Society of Endocrinology
Pituitary tumours are common and easily treated by surgery or medical treatment in most cases. However, a small subset of pituitary tumours does not respond to standard medical treatment and presents with multiple local recurrences (aggressive pituitary tumours) and in rare occasion with metastases (pituitary carcinoma). The present European Society of Endocrinology (ESE) guideline aims to provide clinical guidance on diagnosis, treatment and follow-up in aggressive pituitary tumours and carcinomas.
We decided upfront, while acknowledging that literature on aggressive pituitary tumours and carcinomas is scarce, to systematically review the literature according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. The review focused primarily on first- and second-line treatment in aggressive pituitary tumours and carcinomas. We included 14 single-arm cohort studies (total number of patients = 116) most on temozolomide treatment (n = 11 studies, total number of patients = 106). A positive treatment effect was seen in 47% (95% CI: 36–58%) of temozolomide treated. Data from the recently performed ESE survey on aggressive pituitary tumours and carcinomas (165 patients) were also used as backbone for the guideline.
(i) Patients with aggressive pituitary tumours should be managed by a multidisciplinary expert team. (ii) Histopathological analyses including pituitary hormones and proliferative markers are needed for correct tumour classification. (iii) Temozolomide monotherapy is the first-line chemotherapy for aggressive pituitary tumours and pituitary carcinomas after failure of standard therapies; treatment evaluation after 3 cycles allows identification of responder and non-responder patients. (iv) In patients responding to first-line temozolomide, we suggest continuing treatment for at least 6 months in total. Furthermore, the guideline offers recommendations for patients who recurred after temozolomide treatment, for those who did not respond to temozolomide and for patients with systemic metastasis.
Christian J Strasburger, Peter Vanuga, Juraj Payer, Marija Pfeifer, Vera Popovic, László Bajnok, Miklós Góth, Veˇra Olšovská, L‘udmila Trejbalová, Janos Vadasz, Eyal Fima, Ronit Koren, Leanne Amitzi, Martin Bidlingmaier, Oren Hershkovitz, Gili Hart, and Beverly M K Biller
Growth hormone (GH) replacement therapy currently requires daily injections, which may cause distress and low compliance. C-terminal peptide (CTP)-modified growth hormone (MOD-4023) is being developed as a once-weekly dosing regimen in patients with GH deficiency (GHD). This study’s objective is to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of MOD-4023 administered once-weekly in GHD adults.
54 adults with GHD currently treated with daily GH were normalized and randomized into 4 weekly dosing cohorts of MOD-4023 at 18.5%, 37%, 55.5% or 123.4% of individual cumulative weekly molar hGH dose. The study included 2 stages: Stage A assessed the effectiveness and PK/PD profiles of the 4 dosing regimens of MOD-4023. Stage B was an extension period of once-weekly MOD-4023 administration (61.7% molar hGH content) to collect further safety data and confirm the results from Stage A.
Dose-dependent response was observed for both PK and PD data of weekly MOD-4023 treatment. Insulin-like growth factor I (IGF-I) SDS levels were maintained within normal range. The 18.5% cohort was discontinued due to low efficacy. MOD-4023 was well tolerated and exhibited favorable safety profile in all dose cohorts. The reported adverse events were consistent with known GH-related side effects.
Once-weekly MOD-4023 administration in GHD adults was found to be clinically effective while maintaining a favorable safety profile and may obviate the need for daily injections. Weekly GH injections may improve compliance and overall outcome. The promising results achieved in this Phase 2 study led to a pivotal Phase 3 trial, which is currently ongoing.
Daniele Cassatella, Sasha R Howard, James S Acierno, Cheng Xu, Georgios E Papadakis, Federico A Santoni, Andrew A Dwyer, Sara Santini, Gerasimos P Sykiotis, Caroline Chambion, Jenny Meylan, Laura Marino, Lucie Favre, Jiankang Li, Xuanzhu Liu, Jianguo Zhang, Pierre-Marc Bouloux, Christian De Geyter, Anne De Paepe, Waljit S Dhillo, Jean-Marc Ferrara, Michael Hauschild, Mariarosaria Lang-Muritano, Johannes R Lemke, Christa Flück, Attila Nemeth, Franziska Phan-Hug, Duarte Pignatelli, Vera Popovic, Sandra Pekic, Richard Quinton, Gabor Szinnai, Dagmar l’Allemand, Daniel Konrad, Saba Sharif, Özlem Turhan Iyidir, Brian J Stevenson, Huanming Yang, Leo Dunkel, and Nelly Pitteloud
Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood.
We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders.
Exome sequencing data were used to identify rare variants in known genes in CHH (n = 116), CDGP (n = 72) and control cohorts (n = 36 874 ExAC and n = 405 CoLaus).
Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%, P = 7.6 × 10−11) or controls (18%, P = 5.5 × 10−12). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%, P = 0.002) and controls (2%, P = 6.4 × 10−7).
Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.
Jens Sandahl Christiansen, Philippe F Backeljauw, Martin Bidlingmaier, Beverly M K Biller, Margaret C S Boguszewski, Felipe F Casanueva, Philippe Chanson, Pierre Chatelain, Catherine S Choong, David R Clemmons, Laurie E Cohen, Pinchas Cohen, Jan Frystyk, Adda Grimberg, Yukihiro Hasegawa, Morey W Haymond, Ken Ho, Andrew R Hoffman, Jeff M P Holly, Reiko Horikawa, Charlotte Höybye, Jens Otto L Jorgensen, Gudmundur Johannsson, Anders Juul, Laurence Katznelson, John J Kopchick, K O Lee, Kuk-Wha Lee, Xiaoping Luo, Shlomo Melmed, Bradley S Miller, Madhusmita Misra, Vera Popovic, Ron G Rosenfeld, Judith Ross, Richard J Ross, Paul Saenger, Christian J Strasburger, Michael O Thorner, Haim Werner, and Kevin Yuen
The Growth Hormone (GH) Research Society (GRS) convened a workshop to address important issues regarding trial design, efficacy, and safety of long-acting growth hormone preparations (LAGH).
A closed meeting of 55 international scientists with expertise in GH, including pediatric and adult endocrinologists, basic scientists, regulatory scientists, and participants from the pharmaceutical industry.
Current literature was reviewed for gaps in knowledge. Expert opinion was used to suggest studies required to address potential safety and efficacy issues.
Following plenary presentations summarizing the literature, breakout groups discussed questions framed by the planning committee. Attendees reconvened after each breakout session to share group reports. A writing team compiled the breakout session reports into a draft document that was discussed and revised in an open forum on the concluding day. This was edited further and then circulated to attendees from academic institutions for review after the meeting. Participants from pharmaceutical companies did not participate in the planning, writing, or in the discussions and text revision on the final day of the workshop. Scientists from industry and regulatory agencies reviewed the manuscript to identify any factual errors.
LAGH compounds may represent an advance over daily GH injections because of increased convenience and differing phamacodynamic properties, providing the potential for improved adherence and outcomes. Better methods to assess adherence must be developed and validated. Long-term surveillance registries that include assessment of efficacy, cost-benefit, disease burden, quality of life, and safety are essential for understanding the impact of sustained exposure to LAGH preparations.
Pia Burman, Jacqueline Trouillas, Marco Losa, Ann McCormack, Stephan Petersenn, Vera Popovic, Marily Theodoropoulou, Gerald Raverot, Olaf M Dekkers, and
To describe clinical and pathological characteristics and treatment outcomes in a large cohort of aggressive pituitary tumours (APT)/pituitary carcinomas (PC).
Electronic survey August 2020–May 2021.
96% of 171 (121 APT, 50 PC), initially presented as macro/giant tumours, 6 were microadenomas (5 corticotroph). Ninety-seven tumours, initially considered clinically benign, demonstrated aggressive behaviour after 5.5 years (IQR: 2.8–12). Of the patients, 63% were men. Adrenocorticotrophic hormone (ACTH)-secreting tumours constituted 30% of the APT/PC, and the gonadotroph subtypes were under-represented. Five out of 13 silent corticotroph tumours and 2/6 silent somatotroph tumours became secreting. Metastases were observed after median 6.3 years (IQR 3.7–12.1) from diagnosis. At the first surgery, the Ki67 index was ≥3% in 74/93 (80%) and ≥10% in 38/93 (41%) tumours. An absolute increase of Ki67 ≥ 10% after median of 6 years from the first surgery occurred in 18/49 examined tumours. Tumours with an aggressive course from outset had higher Ki67, mitotic counts, and p53. Temozolomide treatment in 156/171 patients resulted in complete response in 9.6%, partial response in 30.1%, stable disease in 28.1%, and progressive disease in 32.2% of the patients. Treatment with bevacizumab, immune checkpoint inhibitors, and peptide receptor radionuclide therapy resulted in partial regression in 1/10, 1/6, and 3/11, respectively. Median survival in APT and PC was 17.2 and 11.3 years, respectively. Tumours with Ki67 ≥ 10% and ACTH-secretion were associated with worse prognosis.
APT/PCs exhibit a wide and challenging spectrum of behaviour. Temozolomide is the first-line chemotherapy, and other oncological therapies are emerging. Treatment response continues to be difficult to predict with currently studied biomarkers.