Systemic therapy of Cushing’s syndrome

Cushing’s disease (CD) in a stricter sense derives from pathologic adrenocorticotropic hormone (ACTH) secretion usually triggered by micro- or macroadenoma of the pituitary gland. It is, thus, a form of secondary hypercortisolism. In contrast, Cushing’s syndrome (CS) describes the complexity of clinical consequences triggered by excessive cortisol blood levels over extended periods of time irrespective of their origin. CS is a rare disease according to the European orphan regulation affecting not more than 5/10,000 persons in Europe. CD most commonly affects adults aged 20–50 years with a marked female preponderance (1:5 ratio of male vs. female). Patient presentation and clinical symptoms substantially vary depending on duration and plasma levels of cortisol. In 80% of cases CS is ACTH-dependent and in 20% of cases it is ACTH-independent, respectively. Endogenous CS usually is a result of a pituitary tumor. Clinical manifestation of CS, apart from corticotropin-releasing hormone (CRH-), ACTH-, and cortisol-producing (malign and benign) tumors may also be by exogenous glucocorticoid intake. Diagnosis of hypercortisolism (irrespective of its origin) comprises the following: Complete blood count including serum electrolytes, blood sugar etc., urinary free cortisol (UFC) from 24 h-urine sampling and circadian profile of plasma cortisol, plasma ACTH, dehydroepiandrosterone, testosterone itself, and urine steroid profile, Low-Dose-Dexamethasone-Test, High-Dose-Dexamethasone-Test, after endocrine diagnostic tests: magnetic resonance imaging (MRI), ultra-sound, computer tomography (CT) and other localization diagnostics. First-line therapy is trans-sphenoidal surgery (TSS) of the pituitary adenoma (in case of ACTH-producing tumors). In patients not amenable for surgery radiotherapy remains an option. Pharmacological therapy applies when these two options are not amenable or refused. In cases when pharmacological therapy becomes necessary, Pasireotide should be used in first-line in CD. CS patients are at an overall 4-fold higher mortality rate than age- and gender-matched subjects in the general population. The following article describes the most prominent substances used for clinical management of CS and gives a systematic overview of safety profiles, pharmacokinetic (PK)-parameters, and regulatory framework

Efficacy and Complications of Pituitary Irradiation

Radiation therapy is widely used in the management of intracranial (including sellar and parasellar) and systemic disorders. Although in many cases the irradiation aims to prevent the growth or regrowth and to control the hormonal hypersecretion of a pituitary tumor, in many others it adversely affects the hypothalamo-pituitary function simply because this area receives significant doses of radiation delivered for non-hypothalamo-pituitary disorders. The main long-term complications include hypopituitarism, optic neuropathy, cerebrovascular morbidity, and second brain tumors. Radiation technique and schedule are important determinants of these adverse effects

Clinical evidence of the effect of bisphosphonates on pregnancy and the infant

Bisphosphonates (BPs) are potent inhibitors of osteoclast mediated bone resorption. These drugs are widely used in the management of osteoporosis and other diseases, characterized by high bone turnover. The effect of BPs on gestation and lactation, when they are used as therapeutic agents in premenopausal women, is yet unknown. We conducted a detailed literature review and identified the cases of BPs use in young women, as well as, the effects of this therapy on the gestation and the embryo. The published data, regarding the use of BPs in premenopausal women and their effects on the pregnancy outcome, are limited. However, we could identify the outcomes of 40 pregnant women, who had received BPs prior to or during pregnancy, that have been documented in the literature. All women had valid indications to receive BPs for serious bone metabolism conditions. We could not identify any prospective trials, which focus on pregnancy outcomes following after the in-utero exposure to BPs. In total, no serious adverse effects were reported. Problems related to the offspring, such as hypocalcemia and a tendency for low body weight (LBW), were self-resolving. In addition, no serious adverse outcomes were reported for women having completed pregnancy. Nevertheless, follow-up was limited for both outcomes suggesting the necessity of national and international registries. © 2019 Walter de Gruyter GmbH, Berlin/Boston 2019

The management of head-and-neck paragangliomas.

Paragangliomas (PGLs) are tumours originating from neural crest-derived cells situated in the region of the autonomic nervous system ganglia. Head-and-neck PGLs (HNPGLs) originate from the sympathetic and parasympathetic paraganglia, most frequently from the carotid bodies and jugular, tympanic and vagal paraganglia, and are usually non-catecholamine secreting. Familial PGLs are considered to be rare, but recently genetic syndromes including multiple PGLs and/or phaeochromocytomas have been more thoroughly characterised. Nowadays, genetic screening for the genes frequently implicated in both familial and sporadic cases is routinely being recommended. HNPGLs are mostly benign, generally slow-growing tumours. Continuous growth leads to the involvement of adjacent neurovascular structures with increased morbidity rates and treatment-related complications. Optimal management mostly depends on tumour location, local involvement of neurovascular structures, estimated malignancy risk, patient age and general health. Surgery is the only treatment option offering the chance of cure but with significant morbidity rates, so a more conservative approach is usually considered, especially in the more difficult cases. Radiotherapy (fractionated or stereotactic radiosurgery) leads to tumour growth arrest and symptomatic improvement in the short term in many cases, but the long-term consequences are unclear. Early detection is essential in order to increase the chance of cure with a lower morbidity rate. The constant improvement in diagnostic imaging, surgical and radiation techniques has led to a safer management of these tumours, but there are still many therapeutic challenges, and no treatment algorithm has been agreed upon until now. The management of HNPGLs requires a multidisciplinary effort addressing the genetic, surgical, radiotherapeutic, oncological, neurological and endocrinological implications. Further progress in the understanding of their pathogenesis will lead to more effective screening and earlier diagnosis, both critical to successful treatment

Clinical review: Functioning gonadotroph adenomas.

CONTEXT: Functioning gonadotroph adenomas (FGAs) are pituitary tumors secreting biologically active gonadotropins. The published literature includes only small case series or individual case reports. This review summarizes the published data on this rare entity and, based on them, suggests guidance on the follow-up of these patients. EVIDENCE ACQUISITION: A review of articles in English retrieved from the PubMed up to December 2013 was conducted. The following terms were used for the search: "functioning gonadotroph adenomas," "FSH secreting adenomas," "LH secreting adenomas," "gonadotroph adenomas," "ovarian hyperstimulation," "macroorchidism," "testicular enlargement," and "precocious puberty." EVIDENCE SYNTHESIS: All reported cases of FGA were assessed, and information on presenting manifestations, management approaches, and long-term outcome was reviewed. CONCLUSIONS: FGAs cause distinct manifestations and, based on the limited published literature, they are mostly macroadenomas. Their pathogenesis remains enigmatic. Systematic series on their optimal management are lacking, but the primary therapy remains surgical excision of the adenoma. Given the risk of recurrence, long-term clinical and imaging follow-up is needed, and radiotherapy may be required. There is little evidence that medical therapies are particularly helpful, certainly in terms of tumor control. Central registration would enhance our insight regarding their pathology and optimal management