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Open access

11-Oxygenated androgens are not secreted by the human ovary: in-vivo data from four different cases of hyperandrogenism

Matthias K Auer, James M Hawley, Christian Lottspeich, Martin Bidlingmaier, Andrea Sappl, Hanna F Nowotny, Lea Tschaidse, Marcus Treitl, Martin Reincke, Brian G Keevil, and Nicole Reisch

Objective

Differentiation of an adrenal from an ovarian source of hyperandrogenemia can be challenging. Recent studies have highlighted the importance of 11-oxygenated C19 steroids to the androgen pool in humans. The aim of this study was to confirm the origin of 11-oxygenated androgens in females and to explore their potential use in the diagnostics of hyperandrogenic disorders.

Methods

We measured testosterone and its precursors (dehydroepiandrosterone-sulfate and androstenedione) and 11-oxygenated androgens (11β-hydroxyandrostenedione (11-OHA4) and 11-ketotestosterone (11-KT)) in the periphery, adrenal and ovarian veins in four different cases of hyperandrogenism in females (polycystic ovary syndrome (PCOS), primary bilateral macronodular adrenal hyperplasia, Sertoli–Leydig cell tumor and ovarian steroid cell tumor).

Results

Two patients demonstrate excessive testosterone secretion in neoplastic ovarian tumors which was not paralleled by a significant secretion of 11-oxygenated androgens as determined by adrenal and ovarian vein sampling. In androgen-secreting bilateral adrenal macronodular hyperplasia, steroid profiles were characterized by elevated 11-KT and 11-OHA4 concentrations in adrenal veins and the periphery. In the patient with PCOS, peripheral 11-KT concentrations were slightly elevated in comparison to the other patients, but the 11-KT and 11-OHA4 concentrations were comparable in ovarian veins and in the periphery.

Conclusion

This study confirms that 11-OHA4 and 11-KT are not biosynthesized by the ovary. We propose that the testosterone/11-KT ratio as well as 11-OHA4 could help identify predominant adrenal androgen excess and distinguish neoplastic and non-neoplastic ovarian androgen source.

Significance statement

This study confirms that 11β-hydroxyandrostenedione (11-OHA4) and 11-ketotestosterone (11-KT) are not biosynthesized by the human ovary. We propose that the testosterone/11-KT ratio as well as 11-OHA4 could help to identify predominant adrenal androgen excess and distinguish neoplastic and non-neoplastic ovarian androgen source.

Open access

MOD-4023, a long-acting carboxy-terminal peptide-modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults

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

Objective

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.

Design

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.

Results

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.

Conclusions

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.

Open access

Patient-reported outcomes of parenteral somatostatin analogue injections in 195 patients with acromegaly

Christian J Strasburger, Niki Karavitaki, Sylvère Störmann, Peter J Trainer, Ilonka Kreitschmann-Andermahr, Michael Droste, Márta Korbonits, Berit Feldmann, Kathrin Zopf, Violet Fazal Sanderson, David Schwicker, Dana Gelbaum, Asi Haviv, Martin Bidlingmaier, and Nienke R Biermasz

Background

Long-acting somatostatin analogues delivered parenterally are the most widely used medical treatment in acromegaly. This patient-reported outcomes survey was designed to assess the impact of chronic injections on subjects with acromegaly.

Methods

The survey was conducted in nine pituitary centres in Germany, UK and The Netherlands. The questionnaire was developed by endocrinologists and covered aspects of acromegaly symptoms, injection-related manifestations, emotional and daily life impact, treatment satisfaction and unmet medical needs.

Results

In total, 195 patients participated, of which 112 (57%) were on octreotide (Sandostatin LAR) and 83 (43%) on lanreotide (Somatuline Depot). The majority (>70%) of patients reported acromegaly symptoms despite treatment. A total of 52% of patients reported that their symptoms worsen towards the end of the dosing interval. Administration site pain lasting up to a week following injection was the most frequently reported injection-related symptom (70% of patients). Other injection site reactions included nodules (38%), swelling (28%), bruising (16%), scar tissue (8%) and inflammation (7%). Injection burden was similar between octreotide and lanreotide. Only a minority of patients received injections at home (17%) and 5% were self-injecting. Over a third of patients indicated a feeling of loss of independence due to the injections, and 16% reported repeated work loss days. Despite the physical, emotional and daily life impact of injections, patients were satisfied with their treatment, yet reported that modifications that would offer major improvement over current care would be ‘avoiding injections’ and ‘better symptom control’.

Conclusion

Lifelong injections of long-acting somatostatin analogues have significant burden on the functioning, well-being and daily lives of patients with acromegaly.

Open access

11-Oxygenated C19 steroids are the predominant androgens responsible for hyperandrogenemia in Cushing’s disease

Hanna F Nowotny, Leah Braun, Frederick Vogel, Martin Bidlingmaier, Martin Reincke, Lea Tschaidse, Matthias K Auer, Christian Lottspeich, Stefan A Wudy, Michaela F Hartmann, James Hawley, Joanne E Adaway, Brian Keevil, Katharina Schilbach, and Nicole Reisch

Background

Symptoms of hyperandrogenism are common in patients with Cushing’s disease (CD), yet they are not sufficiently explained by androgen concentrations. In this study, we analyzed the contribution of 11-oxygenated C19 steroids (11oxC19) to hyperandrogenemia in female patients with CD.

Methods

We assessed saliva day profiles in females with CD pre (n  = 23) and post (n  = 13) successful transsphenoidal surgery, 26 female controls, 5 females with CD treated with metyrapone and 5 treated with osilodrostat for cortisol, cortisone, androstenedione (A4), 11-hydroxyandrostenedione (11OHA4), testosterone (TS), 11-ketotestosterone (11KT), as well as metabolites of classic and 11-oxygenated androgens in 24-h urine. In addition, morning baseline levels of gonadotropins and estradiol, sex hormone-binding globulin, cortisol and dehydroepiandrosterone sulfate (DHEAS) in serum and adrenocorticotrophic hormone in plasma in patients and controls were investigated.

Results

Treatment-naïve females with CD showed a significantly elevated area under the curve of 11OHA4 and 11KT in saliva throughout the day compared to controls (11OHA4 mean rank difference (mrd) 18.13, P = 0.0002; 11KT mrd 17.42; P = 0.0005), whereas A4, TS and DHEAS were comparable to controls. Gonadotropin concentrations were normal in all patients with CD. After transsphenoidal surgery, 11oxC19 and their metabolites dropped significantly in saliva (11OHA4 P < 0.0001; 11KT P = 0.0010) and urine (11-oxo-androsterone P = 0.0011; 11-hydroxy-androsterone P < 0.0001), treatment with osilodrostat and metyrapone efficaciously blocked 11oxC19 synthesis.

Conclusion

Hyperandrogenemia in CD is predominantly caused by excess of 11oxC19 steroids.

Open access

A randomised, open-label, parallel group phase 2 study of antisense oligonucleotide therapy in acromegaly

Peter J Trainer, John D C Newell-Price, John Ayuk, Simon J B Aylwin, Aled Rees, William Drake, Philippe Chanson, Thierry Brue, Susan M Webb, Carmen Fajardo, Javier Aller, Ann I McCormack, David J Torpy, George Tachas, Lynne Atley, David Ryder, and Martin Bidlingmaier

Objective

ATL1103 is a second-generation antisense oligomer targeting the human growth hormone (GH) receptor. This phase 2 randomised, open-label, parallel-group study assessed the potential of ATL1103 as a treatment for acromegaly.

Design

Twenty-six patients with active acromegaly (IGF-I >130% upper limit of normal) were randomised to subcutaneous ATL1103 200 mg either once or twice weekly for 13 weeks and monitored for a further 8-week washout period.

Methods

The primary efficacy measures were change in IGF-I at week 14, compared to baseline and between cohorts. For secondary endpoints (IGFBP3, acid labile subunit (ALS), GH, growth hormone-binding protein (GHBP)), comparison was between baseline and week 14. Safety was assessed by reported adverse events.

Results and conclusions

Baseline median IGF-I was 447 and 649 ng/mL in the once- and twice-weekly groups respectively. Compared to baseline, at week 14, twice-weekly ATL1103 resulted in a median fall in IGF-I of 27.8% (P = 0.0002). Between cohort comparison at week 14 demonstrated the median fall in IGF-I to be 25.8% (P = 0.0012) greater with twice-weekly dosing. In the twice-weekly cohort, IGF-I was still declining at week 14, and remained lower at week 21 than at baseline by a median of 18.7% (P = 0.0005). Compared to baseline, by week 14, IGFBP3 and ALS had declined by a median of 8.9% (P = 0.027) and 16.7% (P = 0.017) with twice-weekly ATL1103; GH had increased by a median of 46% at week 14 (P = 0.001). IGFBP3, ALS and GH did not change with weekly ATL1103. GHBP fell by a median of 23.6% and 48.8% in the once- and twice-weekly cohorts (P = 0.027 and P = 0.005) respectively. ATL1103 was well tolerated, although 84.6% of patients experienced mild-to-moderate injection-site reactions. This study provides proof of concept that ATL1103 is able to significantly lower IGF-I in patients with acromegaly.

Open access

Growth Hormone Research Society perspective on the development of long-acting growth hormone preparations

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

Objective

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).

Participants

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.

Evidence

Current literature was reviewed for gaps in knowledge. Expert opinion was used to suggest studies required to address potential safety and efficacy issues.

Consensus process

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.

Conclusions

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.

Open access

Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: a consensus statement

Margaret C S Boguszewski, Cesar L Boguszewski, Wassim Chemaitilly, Laurie E Cohen, Judith Gebauer, Claire Higham, Andrew R Hoffman, Michel Polak, Kevin C J Yuen, Nathalie Alos, Zoltan Antal, Martin Bidlingmaier, Beverley M K Biller, George Brabant, Catherine S Y Choong, Stefano Cianfarani, Peter E Clayton, Regis Coutant, Adriane A Cardoso-Demartini, Alberto Fernandez, Adda Grimberg, Kolbeinn Guðmundsson, Jaime Guevara-Aguirre, Ken K Y Ho, Reiko Horikawa, Andrea M Isidori, Jens Otto Lunde Jørgensen, Peter Kamenicky, Niki Karavitaki, John J Kopchick, Maya Lodish, Xiaoping Luo, Ann I McCormack, Lillian Meacham, Shlomo Melmed, Sogol Mostoufi Moab, Hermann L Müller, Sebastian J C M M Neggers, Manoel H Aguiar Oliveira, Keiichi Ozono, Patricia A Pennisi, Vera Popovic, Sally Radovick, Lars Savendahl, Philippe Touraine, Hanneke M van Santen, and Gudmundur Johannsson

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.