Abstract
The prospect of a novel treatment modality for the management of menopausal symptoms is an exciting one. We know many women suffer with menopausal symptoms but are unable to utilise the current treatment options, either due to medical contraindication or due to concerns about the risks involved. Are neurokinin 3 receptor (NK3R) antagonists the answer?
Prague et al. published the details of a phase two randomised controlled trials (RCT) exploring an oral NK3R antagonist (MLE4901) as a treatment for menopausal symptoms in the Lancet. 1 This was a single-centre crossover study in which study participants received either 40 mg MLE4901 BD or placebo for four weeks followed by a two-week washout before switching. A total of 28 participants completed the trial, which demonstrated a reduction in the number of hot flushes per week by 45 percentage points (95% CI: 22–67) with MLE4901 when compared with the placebo. However, long-term safety remains a question, as raised liver transaminases were seen in three of the participants.
The use of NK3R antagonists has been prompted by substantial advances in our understanding of the regulation of gonadotrophin-releasing hormone (GnRH) secretion. Two hypothalamic neuropeptides (kisspeptin and neurokinin B) appear to be involved in the regulation of the hypothalamic-pituitary-gonadal axis, with NK3R blockade leading to suppression of luteinising hormone (LH) secretion in patients with polycystic ovarian syndrome (PCOS). A recent study by Skorupskaite et al. has also demonstrated a reduction in LH secretion and an associated reduction in hot flush frequency in patients taking a NK3R antagonist. 2 This is an exciting development as it supports a link between LH/GnRH pulsatility and vasomotor symptoms, which may open the door to a new therapeutic approach for managing menopausal symptoms.
At a recent meeting, the question – ‘with the prospect of neurokinin receptor antagonist do you think hormone replacement therapy (HRT) will still be necessary?’ – was raised. An insightful question but clearly the answer had to be ‘yes’, as there will remain a clear indication for hormone replacement in certain patients, even if clinical trials into neurokinin receptor antagonists allow a license to be granted for the management of vasomotor symptoms.
As the authors of these papers highlight, vasomotor symptoms are a significant problem for the menopausal population with 70% affected and 10% experiencing intolerable side effects. However, these are by no means the only menopausal symptoms managed with conventional HRT. If NK3R antagonists become available, they may suit patients whose predominant symptoms are hot flushes and night sweats but those wanting to optimise their bone health or cardiovascular risk may still prefer estrogen replacement. Therefore, it is important we consider the systemic benefits of HRT as well as the potential side effects when evaluating the utility of these new compounds.
This new development highlights the need for a tailored and evidence-based approach to managing the menopause, and we hope Post Reproductive Health continues to provide useful guidance and information for clinicians as they guide their patients through the treatment options available. One of the key areas of concern for both clinicians and patients considering HRT is the risk of breast cancer. This discussion and the consideration of risk become much more complex in patients who have had breast cancer treatment and are now struggling with side effects of treatment or menopausal symptoms. We have a collection of interesting articles in this edition exploring this topic – symptom prediction on aromatise inhibitors and use of transvaginal ultrasound in assessing patients with post-menopausal bleeding whilst on Tamoxifen. In addition, the ‘Tales from the Clinic’ gives some excellent examples of how to approach hormone replacement in breast cancer patients.
We are all looking forward to the BMS annual conference on 5 and 6 July at the Royal College of Physicians and hope many of you will be joining us.