Successful pregnancy and delivery in a woman with panhypopituitarism

To The Editor: Pregnancy after a complete loss of hypophyseal function is rare. Lack of growth hormone (GH), adrenocorticotropin (ACTH) and thyroid-stimulating hormone (TSH) in childhood may result in malfunction of different organ systems, affecting fertility. Complete lack of ovarian stimulation by FSH and LH results in anovulation and ovarian atrophy. We present a patient with panhypopituitarism who has achieved pregnancy and delivered through in vitro fertilization (IVF) and embryo transfer (ET). This 35 year-old woman underwent four trans-sphenoidal hypophysectomies at 12, 13, 23 and 26 years of age, for recurrent neuroectodermal cysts (embryonic remnant). Her second operation was complicated by panhypopituitarism with severe diabetes insipidus, treated with adequate doses of hydrocortisone, L-thyroxine and desmopressin. At age 21, cyclic substitution therapy with estrogen and progesterone was given for primary amenorrhea. Two years later, GH therapy was added. At age 33, she requested fertility treatment. GH, cyclic estrogen, and progesterone therapy were stopped, and she underwent ovulation induction, with gonadotropins, followed by IVF and ET, resulting in a successful dichorionic twin pregnancy. She was followed regularly at a combined antenatal clinic. No changes in steroid, desmopressin, or thyroxine doses were required, and the antenatal period was uneventful. An elective caesarean section was performed at 37 weeks gestation, and healthy twin boys (weighing 3.0 and 3.14 kg) were delivered. Clinical course during puerperium was normal.Conception and uncomplicated pregnancy in patients with hypopituitiarism are rare [1,2]. Well-timed substitution of missing hormones enables normal physical development. Stimulation therapy with gonadotropins can induce adequate follicular maturation. IVF-ET may be a useful treatment for infertility in patients with hypopituitarism as it may reduce the incidence of multiple pregnancies associated with higher risk in GH deficient patients

Action of MK‐7264 (Gefapixant) at human P2X3 and P2X2/3 receptors and in vivo efficacy in models of sensitisation

Background & Purpose The P2X3 receptor is an ATP‐gated ion channel expressed by sensory afferent neurons, and is as a target to treat chronic sensitisation conditions. The first‐in‐class, selective P2X3 and P2X2/3 receptor antagonist, the diaminopyrimidine MK‐7264 (Gefapixant), has progressed to Phase III trials for refractory or unexplained chronic cough. We have used patch‐clamp to elucidate the pharmacology and kinetics of MK‐7264 and rat models of hypersensitivity and hyperalgesia to test efficacy in these conditions. Experimental Approach Whole‐cell patch‐clamp of 1321N1 cells expressing human P2X3 and P2X2/3 receptors was used to determine mode of MK‐7264 action, potency and kinetics. The analgesic efficacy was assessed using paw withdrawal threshold and limb weight distribution in rat models of inflammatory, osteoarthritic and neuropathic sensitisation. Key Results MK‐7264 is a reversible allosteric antagonist at human P2X3 and P2X2/3 receptors with IC50 values of 153 and 220nM, respectively. Experiments with the slowly desensitising P2X2/3 heteromer revealed concentration and state‐dependency to wash‐on, with faster rates and greater inhibition when applied before agonist compared to during agonist application. Wash‐on rate (τ value) for MK‐7264 at maximal concentrations was 19s and 146s when applied before and during agonist application, respectively. In vivo, MK‐7264 (30 mg/kg) displayed efficacy comparable to naproxen (20 mg/kg) in inflammatory and osteoarthritic sensitisation models, and gabapentin (100 mg/kg) in neuropathic sensitisation models, increasing paw withdrawal threshold and decreasing weight bearing discomfort. Conclusions and Implications MK‐7264 is a reversible and selective P2X3 and P2X2/3 antagonist, exerting allosteric antagonism via preferential activity at closed channels. Efficacy in rat models supports clinical investigation of chronic sensitisation conditions

Visualisation of Airway Nerves in Chronic Cough: Towards the Identification of the Human Cough Receptor

<p>Immunochemical features of nerves identified in human airways</p