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Several different immunoassays have been used in the commercial pharmaceutical development of serelaxin. These assays have been well validated for submission of GLP preclinical and clinical studies to the FDA and EU regulatory bodies. The requirements for these assays exceed that of most research assays commonly developed in academic research but have been and are currently available to academic researchers. Additionally, many human relaxin immunoassays are commercially available from a variety of vendors. Validation procedures for immunoassays are well understood and documented, however validation of these assays is often lacking or completely absent. The data derived from these assays must be questioned if the investigator does not supply information on the validation of the assay used, either from the supplier or through their own efforts. Many recent papers on determination of serum relaxin in clinical settings have recently been published. The assay used for this determination varies but generally is one of two commercially available. These manuscripts and the assay used is discussed. Direct comparisons of assays are lacking but some general conclusions can be drawn by comparing results from similar studies using different assays. There is disagreement among the results of the concentrations of serum relaxin from the use of different assays that raise questions on assay reliability. The differences in the quality of immunoassays used for detection of serum relaxin should be part of the decisions making process in choosing an assay. While the end user bears the ultimate responsibility to demonstrate the assay is valid for the stated claims, reviewers and editors also share responsibility for quality of published results.

Introduction Moving teeth rapidly and avoiding posttreatment relapse are fundamental goals of orthodontic treatment. In-vitro and animal studies suggest that the human hormone relaxin might increase the rate of movement and the stability through its effect on the periodontal ligament. The purpose of this study was to compare relaxin and a placebo with regard to tooth movement and stability in human subjects. Methods A single-center, blinded, placebo-controlled, randomized clinical trial was used to examine the effect of relaxin on tooth movement and stability. Forty subjects were randomized 1:1 and received weekly injections of 50 μg of relaxin or a placebo for 8 weeks. Aligners programmed to move a target tooth 2 mm during treatment were dispensed at weeks 0, 2, 4, and 6. Movement was measured weekly on polyvinyl siloxane impressions that were scanned and digitized. The subjects were followed through week 12 to assess relapse. Results Tooth movement over the 8-week treatment period did not differ by treatment group ( P = 0.995). By using an intent-to-treat analysis, we found that the mean tooth movement for both groups was 0.83 mm (SE, 0.08 for relaxin and 0.09 for the placebo). Relapse from weeks 8 to 12 was the same in both groups ( P = 0.986), and the mean was −0.75 (SE, 0.07 for relaxin and 0.08 for theplacebo). Conclusions No differences in tooth movement over 8 weeks of treatment or relapse at 4 weeks posttreatment were detected when comparing subjects who received weekly injections of relaxin with those who received a placebo. In both groups, an average of less than half of the programmed tooth movement was obtained after 8 weeks of treatment. The local doses of relaxin might have been too low to affect tooth movement or short-term relapse.

Objective To characterize the hourly profiles of hCG secretion in blood during conceptive cycles that ended in successful pregnancy. Design Prospective study. Setting University fertility clinic and research laboratories. Patient(s) Healthy spontaneously ovulating women with regular menses, no history of infertility, and either no male partner or an azospermic partner. Intervention(s) Frequent blood samples were collected daily from 11 spontaneously ovulating women during 11 cycles of artifical insemination with donor semen. The concentrations of hCG, LH, and FSH were measured in the blood by immunoassay. Main Outcome Measure(s) The concentration of hCG in the frequent blood samples and the rate that the concentration of hCG changed during the period of frequent sampling. Result(s) For the conceptive cycles resulting in successful pregnancies analyzed, hourly hCG concentrations were observed to increase in a consistent nonpulsatile manner. Conclusion(s) These data provide the first characterization of the hourly secretion profile of hCG in early pregnancy as well as provide further evidence that individual daily blood samples are sufficient for the accurate assessment of pregnancy.

BAS Medical is investigating the use of relaxin to improve ortho-dontic treatments. Relaxin is well known for its effects on remodeling soft tissue, and we believe relaxin will be clinically useful in speeding tooth movement and preventing relapse. We investigated the use of relaxin in preventing relapse in a dog model. Dog maxillary second incisors were orthodontically rotated an average of 42 degrees, and then relaxin was administered by gingival injection to relieve the rotational memory in the connective tissues. Teeth were retained for 30 days to allow fibers to reform. Teeth then were released and relapse was measured by a series of impressions. Animals receiving relaxin gingival injections (n = 8) were compared with placebo-treated animals (n = 8) (exhibiting high relapse) and gingival fiberotomies (n = 8) (low relapse). Gingival fiberotomy is a surgical procedure to cut the gingival connective tissues away from the tooth and has been shown to be effective in preventing relapse clinically and in animal models. There was a significant difference in relapse between the fiberotomy and the placebo control groups, and the relaxin-treated group had an intermediate response between the two groups (nonsignificant). Dose and treatment optimization may improve the response in future studies. To study the underlying mechanisms, we have localized relaxin receptors on gingival and periodontal ligament fibroblasts in tissue slices and cell cultures. Relaxin was found to stimulate collagenase production by relaxin in human gingival fibroblast cultures. Taken together, the data support a role for relaxin therapy to speed tooth movement and prevent relapse in orthodontic practice.

These studies were designed to identify 1) a regimen of a third generation GnRH antagonist that abolishes primate luteal function, and 2) the amount of LH replacement required to maintain the structure and functional life span of the corpus luteum of the menstrual cycle after GnRH antagonist treatment. A single injection of antide at 3 or 5 mg/kg BW on day 6 of the luteal phase suppressed serum progesterone levels within 1 day of treatment, but levels recovered within 4 days. Administration of antide (3 mg/kg) for 3 days (luteal days 6–8) reduced (P < 0.05) serum progesterone below 1 ng/mL and maintained these low levels for the entire sampling period; in subsequent experiments, all monkeys received this antide regimen. Fixed doses (5, 10, or 20 IU) of recombinant human LH administered at 8-h intervals during and after antide treatment stimulated progesterone production in a dose-dependent manner; these monkeys menstruated earlier than controls regardless of treatment group. Replacement with an escalating dose regimen (5–20 IU) of LH resulted in typical serum progesterone and relaxin levels throughout a luteal phase of normal length. Corpora lutea removed on day 10 from monkeys treated with antide alone had decreased wet weight (P < 0.05) and few large luteal cells; coadministration of the escalating dose regimen of LH maintained luteal structure similar to that seen in time-matched controls. Antide-only treatment increased progesterone receptor (PR) messenger ribonucleic acid, but decreased PR immunostaining in luteal tissue; the escalating dose regimen of LH maintained PR messenger ribonucleic acid and immunostaining similar to those in controls. This study indicates that during GnRH antagonist administration, an escalating dose regimen of LH replacement is optimal for maintenance of the structure and functional life span of the primate corpus luteum.

Total concentrations of follicle stimulating hormone (FSH) were evaluated in daily urine samples from conceptive and nonconceptive menstrual cycles by measurement of the FSH beta subunit following treatment of the samples to dissociate the FSH heterodimer. Samples were self-collected by normal subjects during cycles in which daily blood samples also were obtained. Daily blood and urine specimens were collected prospectively from 10 subject in conceptive cycles, which led to normal pregnancies, and from 10 subjects with bilateral tubal ligations to provide control samples form nonconceptive cycles. Mean serum and urinary FSH concentration profiles wer parallel in both groups following ovulation and during he first 9 days of the luteal phase. Mean values for both serum and urinary FSH rose significantly above the postovulatory baseline by 10-12 days following the midcycle luteinizing hormone (LH) peak in nonconceptive cycles, but did not rise at any time following ovulation during conceptive cycles. Following regression analysis of the changing FSH concentration between days 9-14 post-LH surge in conceptive cycles, a slope of

Objective We determined the ovarian response to human chorionic gonadotrophin (hCG) in terms of relaxin and progesterone secretion during the peri-implantation period of normal and failing pregnancies. We wished to test the hypotheses that relaxin production in failing pregnancies is different from that in normal pregnancies, that relaxin is a reliable, quantitative indicator of the biological activity of endogenous hCG, and that relaxin is a useful predictor of peri-implantation spontaneous abortions. Design Daily blood samples were collected in a prospective longitudinal study from insemination patients. Patients Women undergoing artificial insemination in natural cycles with non-frozen donor semen at a University clinic. Measurements Serum LH, hCG, relaxin and progesterone were measured and the relationship between hCG and the ovarian hormones was evaluated in the peri-implantation period of normal pregnancies and spontaneous abortions. Results Nine of 23 conceptive cycles resulted in a spontaneous abortion between 16 and 70 days after the LH peak. In all normal and failing pregnancies there was a close qualitative relationship between hCG secretion and relaxin production. Six of nine failing pregnancies were associated with abnormally low hCG secretion. Six of the spontaneous abortions were associated with rates of relaxin secretion which were higher than the mean of 14 normal pregnancies. No such alterations in progesterone concentrations were observed. In cases where hCG was extremely low, the quantitative relationship between hCG and relaxin was different from that in cases of normal hCG concentrations. Conclusions There is a close temporal relationship between the secretion of trophoblastic hCG and ovarian secretion of relaxin in the peri-implantation period of normal and failing pregnancies. In failing pregnancies there is substantial variability in the quantitative relationship between relaxin and hCG, indicating that relaxin is not a reliable quantitative indicator of hCG bioactivity. Contrary to previous reports, relaxin concentrations in failing pregnancies tended to be higher than or equal to concentrations in normal pregnancies until the loss was imminent. Because of this relaxin is not a useful predictor of peri-implantation spontaneous abortions.

Relaxin has previously been tested in rodent wound healing models and been shown to promote angiogenesis and to speed healing. However, pigs have been shown to be a better model for human skin in dermatology studies, so juvenile pigs were selected for a study of scar reduction and cosmetic appearance. Twelve 20- by 6-mm excisional wounds were created on the backs of all animals. Topical formulations of relaxin with 0, 0.5, or 2.5 mg/mL were applied twice daily for weeks 2-3 and then daily for weeks 3-6 in all animals. In addition, some animals received systemic relaxin, which was administered via infusion pumps at a rate of 125 microg/kg of body weight/day. Assessments of healing and cosmetic appearance were made by a dermatologist at weeks 2, 4, and 6. Wound sites were collected at 6 weeks and evaluated histologically for granulation tissue, inflammation, and collagen organization. Wounds in animals receiving systemic relaxin had an improved appearance with less redness, reduced granulation tissue, and lower amounts of inflammation. They showed a more-well-knit collagen structure compared to controls. Wounds treated with topical formulations did not show improvement over controls. The topical formulation used was found to have a short residence time, which likely limited penetration of relaxin. Reformulated relaxin preparations with improved penetration might be useful as a topical treatment for wounds to prevent or reduce scarring.

Mild pulmonic stenosis in the dog, where right ventricular peak systolic pressure was increased approximately 150% at the time of sacrifice, induced 100% or more increase in right ventricular free wall weight by 3 weeks postoperative. Accompanying cardiac hypertrophy at these postoperative times, there was a decrease in both tissue PO2 levels and cAMP concentrations in the hemodynamically stressed ventricle, the right ventricle. Myosin ATPase activity was elevated as well as the velocity of contractile element shortening. The hemodynamically nonstressed left ventricle did not hypertrophy at these early postoperative times.