News Round Up: July 21, 2014

Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization

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Abstract

BACKGROUND. Patients with mutations that inactivate kisspeptin signaling are infertile. Kisspeptin-54, the major circulating isoform of kisspeptin in humans, potently stimulates reproductive hormone secretion in humans. Animal studies suggest that kisspeptin is involved in generation of the luteinizing hormone surge, which is required for ovulation; therefore, we hypothesized that kisspeptin-54 could be used to trigger egg maturation in women undergoing in vitro fertilization therapy.

METHODS. Following superovulation with recombinant follicle-stimulating hormone and administration of gonadotropin-releasing hormone antagonist to prevent premature ovulation, 53 women were administered a single subcutaneous injection of kisspeptin-54 (1.6 nmol/kg, n = 2; 3.2 nmol/kg, n = 3; 6.4 nmol/kg, n = 24; 12.8 nmol/kg, n = 24) to induce a luteinizing hormone surge and egg maturation. Eggs were retrieved transvaginally 36 hours after kisspeptin injection, assessed for maturation (primary outcome), and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos.

RESULTS. Egg maturation was observed in response to each tested dose of kisspeptin-54, and the mean number of mature eggs per patient generally increased in a dose-dependent manner. Fertilization of eggs and transfer of embryos to the uterus occurred in 92% (49/53) of kisspeptin-54–treated patients. Biochemical and clinical pregnancy rates were 40% (21/53) and 23% (12/53), respectively.

CONCLUSION. This study demonstrates that a single injection of kisspeptin-54 can induce egg maturation in women with subfertility undergoing in vitro fertilization therapy. Subsequent fertilization of eggs matured following kisspeptin-54 administration and transfer of resulting embryos can lead to successful human pregnancy.

TRIAL REGISTRATION. ClinicalTrials.gov NCT01667406.

FUNDING. Medical Research Council, Wellcome Trust, and National Institute for Health Research.

Authors

Channa N. Jayasena, Ali Abbara, Alexander N. Comninos, Gurjinder M.K. Nijher, Georgios Christopoulos, Shakunthala Narayanaswamy, Chioma Izzi-Engbeaya, Mathini Sridharan, Alexina J. Mason, Jane Warwick, Deborah Ashby, Mohammad A. Ghatei, Stephen R. Bloom, Anna Carby, Geoffrey H. Trew, Waljit S. Dhillo

A “kiss” before conception: triggering ovulation with kisspeptin-54 may improve IVF

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Abstract

A 30-year-old primigravid (G1P000) female with infertility secondary to her partner’s oligospermia and her chronic anovulation presented 13 days after an oocyte retrieval for in vitro fertilization (IVF) with a positive home pregnancy test, abdominal distention, a 5-pound weight gain, nausea, shortness of breath, and reduced urinary frequency. Her IVF cycle included the usual cocktail for gonadotropin stimulation and was uncomplicated, except for excessively stimulated ovaries that led to a peak estradiol level of 6,000 pg/ml and the retrieval of 30 oocytes. Her past history was relevant only for anovulation due to polycystic ovarian syndrome (PCOS), though her preprocedure body mass index was normal at 21 kg/m². Pelvic ultrasound revealed abundant ascites and enlarged ovaries, at 8 cm average diameter. Serum human chorionic gonadotropin (hCG) concentration was 200 mIU/ml; she was hemoconcentrated (hemoglobin 16 g/dl), with normal liver function and coagulation testing. An ultrasound guided, transvaginal paracentesis removed 4 liters of straw-colored fluid, resulting in significant short-term symptom relief.

Authors

Steven L. Young

Network modulation following sham surgery in Parkinson’s disease

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Abstract

Patient responses to placebo and sham effects are a major obstacle to the development of therapies for brain disorders, including Parkinson’s disease (PD). Here, we used functional brain imaging and network analysis to study the circuitry underlying placebo effects in PD subjects randomized to sham surgery as part of a double-blind gene therapy trial. Metabolic imaging was performed prior to randomization, then again at 6 and 12 months after sham surgery. In this cohort, the sham response was associated with the expression of a distinct cerebello-limbic circuit. The expression of this network increased consistently in patients blinded to treatment and correlated with independent clinical ratings. Once patients were unblinded, network expression declined toward baseline levels. Analogous network alterations were not seen with open-label levodopa treatment or during disease progression. Furthermore, sham outcomes in blinded patients correlated with baseline network expression, suggesting the potential use of this quantitative measure to identify “sham-susceptible” subjects before randomization. Indeed, Monte Carlo simulations revealed that a priori exclusion of such individuals substantially lowers the number of randomized participants needed to demonstrate treatment efficacy. Individualized subject selection based on a predetermined network criterion may therefore limit the need for sham interventions in future clinical trials.

Authors

Ji Hyun Ko, Andrew Feigin, Paul J. Mattis, Chris C. Tang, Yilong Ma, Vijay Dhawan, Matthew J. During, Michael G. Kaplitt, David Eidelberg

A brain network response to sham surgery

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Abstract

Evaluation of potential therapies for neurological disease has been challenging due to beneficial responses in patients receiving the sham/placebo treatment. Placebo effects are especially prominent in Parkinson’s disease (PD), which has become a useful model for studying the neurobiology of placebo responses. In this issue of the JCI, Ko and colleagues identify a neural circuit associated with the placebo response in a PD patient cohort. The observed placebo effect–associated pattern involved metabolic activity increases that corresponded with long-term motor improvements after sham surgery. Presurgery activity in this network was inversely related to sham response, suggesting that this network has potential for identifying sham responders and thus reducing placebo-related variance in surgical trials.

Authors

Mariya V. Cherkasova, A. Jon Stoessl