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Martin Reincke

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Anna Riester and Martin Reincke

Primary aldosteronism (PA) is the most common cause of secondary hypertension. In this review, we discuss the diagnosis and management of PA during pregnancy based on the literature. As aldosterone and renin are physiologically increased during pregnancy and confirmation tests are not recommended, the diagnosis of PA during pregnancy relies on a repeatedly suppressed plasma renin level. Mineralocorticoid receptor antagonists (MRAs) are the most effective drugs to treat hypertension and hypokalemia in patients with PA. However, spironolactone (FDA pregnancy category C) might lead to undervirilization of male infants due to the anti-androgenic effects. Although data in the literature are very limited, treatment with spironolactone is not recommended. Eplerenone (FDA pregnancy category B) is a selective MRA without anti-androgenic potential. If MRA treatment is required in pregnancy, eplerenone appears to be a safe and effective alternative, although symptomatic treatment with approved antihypertensive drugs and supplementation with potassium is the first choice. In case of aldosterone-producing adenoma, laparoscopic adrenalectomy is a therapeutic option in the second trimester of pregnancy.

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Tracy Ann Williams and Martin Reincke

The syndrome of primary aldosteronism (PA) is characterized by hypertension with excessive, autonomous aldosterone production and is usually caused by either a unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia. The diagnostic workup of PA is a sequence of three phases comprising screening tests, confirmatory tests and the differentiation of unilateral from bilateral forms. The latter step is necessary to determine the optimal treatment approach of unilateral laparoscopic adrenalectomy (for patients with unilateral PA) or medical treatment with a mineralocorticoid receptor antagonist (for patients with bilateral PA). Since the publication of the revised Endocrine Society guideline 2016, a number of key studies have been published. They challenge the recommendations of the guideline in some areas and confirm current practice in others. Herein, we present the recent developments and current approaches to the medical management of PA.

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Marily Theodoropoulou, Martin Reincke, Martin Fassnacht, and Masayuki Komada

Cushing's disease (CD) arises from pituitary-dependent glucocorticoid excess due to an ACTH-secreting corticotroph tumor. Genetic hits in oncogenes and tumor suppressor genes that afflict other pituitary tumor subtypes are not found in corticotrophinomas. Recently, a somatic mutational hotspot was found in up to half of corticotrophinomas in the USP8 gene that encodes a protein that impairs the downregulation of the epidermal growth factor receptor (EGFR) and enables its constitutive signaling. EGF is an important regulator of corticotroph function and its receptor is highly expressed in Cushing's pituitary tumors, where it leads to increased ACTH synthesis in vitro and in vivo. The mutational hotspot found in corticotrophinomas hyper-activates USP8, enabling it to rescue EGFR from lysosomal degradation and ensure its stimulatory signaling. This review presents new developments in the study of the genetics of CD and focuses on the USP8-EGFR system as trigger and target of corticotroph tumorigenesis.

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Martin Reincke, Michael Peter, Wolfgang G Sippell, and Bruno Allolio


Recent reports have shown an exaggerated response of 17-hydroxyprogesterone in up to 70% of patients with incidentally detected adrenal adenomas ('incidentalomas'). This has been explained by pre-existing 21-hydroxylase deficiency which may be a pathogenetic factor in the development of adrenal tumours. However, other defects in steroidogenesis, such as mild 11β-hydroxylase deficiency, could also result in increased 17-hydroxyprogesterone secretion. We therefore studied the glucocorticoid and mineralocorticoid pathways in patients with adrenal 'incidentalomas' by measuring multiple adrenal steroids before and after 1–24 ACTH stimulation. Twenty patients with adrenal 'incidentalomas' (14 females, 6 males) and 27 healthy controls (14 females, 13 males) were studied. All subjects underwent a 1–24 ACTH stimulation test (250 μg i.v.) with determination of progesterone, 11-deoxycorticosterone, corticosterone, 17-hydroxyprogesterone, 11-deoxycortisol and cortisol at O and 60 min. All steroids were measured by RIA after extraction and HPLC. Patients with 'incidentalomas' had higher stimulated concentrations of 17-hydroxyprogesterone (21·6 ± 8·4 vs 4·2 ± 0·3 nmol/l; P ≤ 0·001), 11-deoxycortisol (8·1 ± 1·2 vs 3·6 ± 0·3 nmol/l; P ≤ 0·001), progesterone (8·28 ± 2·82 vs 1·08 ± 0·15 nmol/l; P ≤ 0·001), and 11-deoxycorticosterone (2·1 ± 0·39 vs 0·78 ± 0·12 nmol/l; P = 0·002) compared with controls. In contrast, cortisol and corticosterone concentrations were not different. There was evidence for impairment of 11β-hydroxylase activity by an increased 11-deoxycortisol/cortisol ratio (0·012 ± 0·003 vs 0·005 ± 0·001 in controls; P = 0·002) and 11-deoxycorticosterone/corticosterone ratio (0·04 ± 0·003 vs 0·015 ± 0·003; P = 0·003). The conclusions reached were that patients with adrenal 'incidentalomas' have increased responses of precursors of the mineralocorticoid and glucocorticoid pathway including 17-hydroxyprogesterone after stimulation with ACTH. This seems to be caused by impairment of 11β-hydroxylase activity rather than by impaired 21-hydroxylase activity in these tumours.

European Journal of Endocrinology 136 196–200

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Nicole Reisch, Marc Slawik, Oliver Zwermann, Felix Beuschlein, and Martin Reincke

Objective: Adrenocorticotropic hormone (ACTH) is the primary secretagogue stimulating secretion of adrenal androgens (AA). Yet, genetic and environmental factors are assumed to play a determining role in the regulation of their biosynthesis and thus might explain the high variability of AA levels. Here we investigate the influence of an ACTH receptor promoter polymorphism affecting ACTH receptor gene transcription on ACTH-dependent dehydroepiandrosterone (DHEA) secretion.

Design: We recently reported a polymorphism within the transcription initiation site of the ACTH receptor gene promoter that alters the consensus sequence from CTC to CCC at −2 bp. This results in lower promoter activity in vitro and is associated with impaired cortisol response to ACTH stimulation in vivo. We now studied 14 normal, lean volunteers aged 20–35 years (eight CTC/CTC and six CCC/CCC carriers) in a 6-h ACTH stimulation test.

Methods: After overnight dexamethasone suppression, ACTH1-24 was administered continuously in each subject with hourly increasing doses (120–3840 ng/m2 body surface area/h) within a 6-h period. On a separate day, baseline DHEA samples were collected.

Results: In the 6-h ACTH stimulation test, CTC/CTC carriers showed a significantly higher DHEA response than CCC/CCC carriers (area under the curve: 19 367 ± 2919 vs 11 098 ± 1241 nmol/l per min; P < 0.04, Mann–Whitney U-test). In contrast, baseline DHEA concentrations did not differ between groups.

Conclusion: These data demonstrate that genetic variations within the ACTH receptor promoter result in decreased DHEA secretion. Thus, we might have identified one of the genetic factors responsible for variation in ACTH-dependent DHEA secretion.

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Guido Di Dalmazi, Renato Pasquali, Felix Beuschlein, and Martin Reincke

Subclinical hypercortisolism (SH), defined as alterations of the hypothalamus–pituitary–adrenal axis in the absence of clinical signs or symptoms related to cortisol secretion, is a common finding in patients with adrenal incidentalomas. The clinical correlates of this pathological condition have become clearer over the last few years. The aim of this review is to summarize the co-morbidities and the clinical outcomes of patients with SH. According to the analysis of the results of the studies published within the last 15 years, hypertension and type 2 diabetes are a common finding in patients with SH, occurring roughly in 2/3 and 1/3 of the patients respectively. Moreover, several additional cardiovascular and metabolic complications, like endothelial damage, increased visceral fat accumulation and impaired lipid metabolism have been shown to increase the cardiovascular risk of those patients. Accordingly, recent independent reports investigating the natural history of the disease in a long-term follow-up setting have shown that patients with SH have a higher incidence of cardiovascular events and related mortality. Moreover, longitudinal studies have also shown increased incidence of osteoporotic vertebral fractures. Future research is needed to improve the diagnostic performance of hormonal tests, by assessment of the complete steroid profile with more accurate assays, and to define the efficacy of surgical vs medical treatment in a randomized-controlled setting.

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Oliver Zwermann, Dominik M Schulte, Martin Reincke, and Felix Beuschlein

Objectives: Although several lines of evidence suggest that the overall effects of the ACTH receptor, melanocortin 2 receptor (MC2-R), mediated signal transduction on adrenocortical growth and tumorigenesis are anti-proliferative, activation of MC2-R induces mitogens like jun, fos, and myc and activates the MAPK pathway. In vivo, potential effects of endogenous ACTH on adrenal tumori-genesis can not be separated from effects of other POMC derived peptides.

Methods: Murine adrenocortical tumor cells that lack MC2-R expression (Y6pcDNA) and Y6 cells stablely transfected with MC2-R (Y6MC2-R) were generated. Presence of functional MC2-R was demonstrated by RT-PCR and Western blot using an antibody for phosphorylated CREB. As a syngenic tumor model, LaHeF1/J mice simultaneously received 107 Y6MC2-R and Y6pcDNA subcutaneously, giving rise to MC2-R positive and negative tumors within the same animal. Animals were treated for 3 weeks in groups of 12 according to the following schedule: group A, control animals receiving saline injection; group B, animals receiving 5.7 ng/injection of a slow release formula of ACTH 1-24 administered i.p. three times a week (aiming at a low physiologic dose); and group C, animals receiving 57 ng/injection of ACTH 1-24 (high physiological dose).

Results: Twenty days of ACTH 1-24 treatment did not significantly affect corticosterone levels, endogenous ACTH levels or adrenal and thymus weight compared with saline injection. However, ACTH 1-24 treatment of group B and C mice significantly reduced tumor weight in MC2-R positive tumors in a dose dependent manner (P = 0.03), while no significant difference in tumor mass was observed in MC2-R negative tumors. PCNA and TUNEL staining, together with morphological characterization, demonstrated that these in vivo effects were due to reduced proliferation, while apoptosis and cellular hypertrophy within the tumor remained unchanged.

Conclusion: MC2-R expression is associated with a less aggressive adrenal tumor phenotype and anti-proliferative effects can be amplified through stimulation with physiological doses of ACTH.

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Bruno Allolio, Martin Oremus, Martin Reincke, Hans-Jörg Schaeffer, Werner Winkelmann, Georg Heck, and Heinrich M Schulte

Allolio B, Oremus M, Reincke M, Schaeffer H-J, Winkelmann W, Heck G, Schulte HM. High-dose progesterone infusion in healthy males: evidence against antiglucocorticoid activity of progesterone. Eur J Endocrinol 1995;133:696–700. ISSN 0804–4643

High concentrations of unbound cortisol in late pregnancy have been explained by the antiglucocorticoid activity of high progesterone levels. To further test this hypothesis we studied the effect of high-dose progesterone on baseline and corticotrophin-releasing hormone (CRH)-induced hormone secretion in humans. In a double-blind crossover study eight healthy male volunteers received either progesterone (0.714 mg · kg−1 · h−1 for 60 min followed by a dose of 0.45 mg · kg−1 · h−1 over a total infusion time of 315 min) or vehicle as a continuous intravenous infusion. At 210 min a CRH test (0.1 μg/kg body weight as bolus iv) was performed. Within 30 min after the start of progesterone administration the serum progesterone level increased to 454 ± 31 nmol/l and remained in the range of third trimester pregnancy concentrations throughout the infusion period. During vehicle infusion the progesterone level remained in the normal range for healthy males and demonstrated a small but significant increase after CRH (1.52 ± 0.23 vs 0.74 ± 0.14 nmol/l; p < 0.01). However, baseline and CRH-stimulated serum cortisol and plasma adrenocorticotrophic hormone remained unaffected by high-dose progesterone. Moreover, unbound salivary cortisol also was not affected by progesterone, suggesting that there is no significant competition for transcortin binding sites. In conclusion, no antiglucorticoid activity was found after short-term administration of progesterone in males. These findings cast doubts on the concept that the alterations of the pituitary–adrenal axis in late pregnancy are induced by the antiglucocorticoid activity of high progesterone concentrations.

Bruno Allolio, Medizinische Universitätsklinik Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany