Neurokinin 3 receptor antagonists - prime time?

Vasomotor symptoms (hot flushes, flashes, night sweats) occur in the majority of menopausal women, and are reported as being of the highest symptom priority as they often persist over many years and can be highly disruptive. Hormone therapy is the most effective available treatment but is not without risk if taken long term, and is sometimes contraindicated; for example, in women with a personal or family history of breast cancer, which is the most common female cancer worldwide. Other treatment alternatives are not as efficacious, can cause side effects, and/or are not widely available. A new, effective, targeted treatment could therefore benefit millions of women worldwide. This became possible to investigate after accumulated evidence from both animal and human models implicated heightened signaling of a hypothalamic neuropeptide together with its receptor (neurokinin B/NK3R) in the etiology of sex-steroid-deficient vasomotor symptoms. Four clinical trials of three chemically distinct oral NK3R antagonists for the treatment of menopausal flushes have since completed and published, which consistently demonstrate efficacy and tolerability of these agents. These suggest great promise to change practice in the future if ongoing further larger-scale studies of longer duration confirm the same; as, estrogen exposure will no longer be required to effectively and safely treat vasomotor symptoms.

Neurokinin 3 receptor antagonism - the magic bullet for hot flushes?

Hot flushes affect 70% of menopausal women and are reported as being the most bothersome symptom by the majority. Hormone replacement therapy and other currently available alternative therapies are not without side-effects and/or have variable efficacy, and so an effective novel therapy could be practice-changing. Over the last 20 years, numerous studies in animal and human models have implicated neurokinin B, a hypothalamic neuropeptide, together with its receptor (NK3R) in the etiology of menopausal hot flushes. Most recently, a randomized, placebo-controlled trial of an NK3R antagonist in symptomatic menopausal women has proven concept suggesting a new therapeutic that can safely and effectively reduce hot flush frequency, severity, bother, and interference without the need for estrogen exposure. Here we review the physiology and neurocircuitry of the reproductive axis, hot flushes, and the evidence that supports this potential new therapeutic approach.

Using kisspeptin to assess GnRH function in an unusual case of primary amenorrhoea.

SUMMARY: Primary amenorrhoea is defined as the failure to commence menstruation by the age of 15 years, in the presence of normal secondary sexual development. The potential causes of primary amenorrhoea extend from structural to chromosomal abnormalities. Polycystic ovarian syndrome (PCOS) is a common cause of secondary amenorrhoea but an uncommon cause of primary amenorrhoea. An early and prompt diagnosis of PCOS is important, as up to 30% of these women are predisposed to glucose intolerance and obesity, with the subgroup of women presenting with primary amenorrhoea and PCOS displaying a higher incidence of metabolic dysfunction. We describe a case of an 18-year-old female presenting with primary amenorrhoea of unknown aetiology. Although initial investigations did not demonstrate clinical or biochemical hyperandrogenism or any radiological evidence of polycystic ovaries, a raised luteinising hormone (LH) suggested a diagnosis of PCOS. If PCOS was the correct diagnosis, then one would expect intact hypothalamic GnRH and pituitary gonadotropin release. We used the novel hormone kisspeptin to confirm intact hypothalamic GnRH release and a GnRH stimulation test to confirm intact pituitary gonadotroph function. This case highlights that kisspeptin is a potential unique tool to test GnRH function in patients presenting with reproductive disorders. LEARNING POINTS: Polycystic ovarian syndrome (PCOS) can present with primary amenorrhoea, and therefore, should be considered in the differential diagnosis.PCOS is a heterogeneous condition that may present in lean women with few or absent signs of hyperandrogenism.GnRH stimulation tests are useful in evaluating pituitary function; however, to date, we do not have a viable test of GnRH function. Kisspeptin has the potential to form a novel diagnostic tool for assessing hypothalamic GnRH function by monitoring gonadotropin response as a surrogate marker of GnRH release.Confirmation of intact GnRH function helps consolidate a diagnosis in primary amenorrhoea and gives an indication of future fertility.

Delayed presentation of late-onset cerebrospinal fluid rhinorrhoea following dopamine agonist therapy for giant prolactinoma.

UNLABELLED: Therapeutic shrinkage of prolactinomas with dopamine agonists achieves clinical benefit but can expose fistulae that have arisen as a result of bony erosion of the sella floor and anterior skull base by the invasive tumour, resulting in the potential development of cerebrospinal fluid (CSF) rhinorrhoea, meningitis, and rarely pneumocephalus. Onset of symptoms is typically within 4 months of commencing therapy. The management is typically surgical repair via an endoscopic transnasal transsphenoidal approach. A 23-year-old man presented to the Emergency Department with acute left limb weakness and intermittent headaches. Visual fields were full to confrontation. Immediate computed tomography and subsequent magnetic resonance imaging (MRI), demonstrated a 5 cm lobular/cystic mass invading the right cavernous sinus, displacing and compressing the midbrain, with destruction of the bony sella. He was referred to the regional pituitary multidisciplinary team (MDT). Serum prolactin was 159 455 mIU/l (7514.37 ng/ml) (normal ranges 100-410 mIU/l (4.72-19.34 ng/ml)). Cabergoline was commenced causing dramatic reduction in tumour size and resolution of neurological symptoms. Further dose titrations were required as the prolactin level plateaued and significant residual tumour remained. After 13 months of treatment, he developed continuous daily rhinorrhea, and on presenting to his general practitioner was referred to an otolaryngologist. When next seen in the routine regional pituitary clinic six-months later he was admitted for urgent surgical repair. Histology confirmed a prolactinoma with a low proliferation index of 2% (Ki-67 antibody). In view of partial cabergoline resistance he completed a course of conventional radiotherapy. Nine months after treatment the serum prolactin had fallen to 621 mIU/l, and 12 months after an MRI showed reduced tumour volume. LEARNING POINTS: CSF rhinorrhoea occurred 13 months after the initiation of cabergoline, suggesting a need for vigilance throughout therapy.Dedicated bony imaging should be reviewed early in the patient pathway to assess the potential risk of CSF rhinorrhoea after initiation of dopamine agonist therapy.There was a significant delay before this complication was brought to the attention of the regional pituitary MDT, with associated risk whilst left untreated. This demonstrates a need for patients and healthcare professionals to be educated about early recognition and management of this complication to facilitate timely and appropriate referral to the MDT for specialist advice and management. We changed our nurse-led patient education programme as a result of this case.An excellent therapeutic response was achieved with conventional radiotherapy after limited surgery having developed partial cabergoline resistance and CSF rhinorrhoea.

Phaeochromocytoma [corrected] crisis.

Phaeochromocytoma [corrected] crisis is an endocrine emergency associated with significant mortality. There is little published guidance on the management of phaeochromocytoma [corrected] crisis. This clinical practice update summarizes the relevant published literature, including a detailed review of cases published in the past 5 years, and a proposed classification system. We review the recommended management of phaeochromocytoma [corrected] crisis including the use of alpha-blockade, which is strongly associated with survival of a crisis. Mechanical circulatory supportive therapy (including intra-aortic balloon pump or extra-corporeal membrane oxygenation) is strongly recommended for patients with sustained hypotension. Surgical intervention should be deferred until medical stabilization is achieved.