Pregnancy Hormone Relaxin Shows CV, Stroke Benefits

Nancy A. Melville

July 05, 2012

July 5, 2012 — Relaxin, a naturally occurring hormone best known for its properties in causing pelvic expansion and relaxation during pregnancy, shows efficacy as a novel therapy not just for improving functional recovery after stroke but also in treating peripheral artery disease, according to several studies presented here at ENDO 2012: the Endocrine Society 94th Annual Meeting.

In 1 study, said to be the first of its kind to evaluate relaxin in stroke patients, 36 poststroke patients were randomly assigned into 2 groups of 18 patients each, with 1 group receiving rehabilitation in addition to oral porcine relaxin (Vitalaxin Plus, Sky BioHealth), 40 mg/day, and the other group receiving only rehabilitation.

In the relaxin group and the rehabilitation group, patients were 56% and 50% male, respectively; the average age was 64 to 78 years. There were no baseline differences between the 2 groups in terms of risk factors or stroke syndromes.

Analyses performed at baseline and at 20 and 40 days showed that patients who received relaxin had greater improvements in general conditions and rehabilitation exercises.

Scores on Functional Independent Measures (FIM) for daily activity between the 2 groups were no different at 20 days. However, after 40 days, patients in the relaxin group showed significantly greater improvements in recovery in FIM score (96 vs 75; P < .001).

The relaxin group also showed greater improvements in cognitive function, assessed by Trail Making Test scores, at 20 days (3.5 vs 2; P < .002) and more improvement at 40 days (4 vs 2; P < .001).

In addition, global function, assessed by modified Ranking Scale score, was improved in the relaxin group at 20 days (2.5 vs 3.0; P < .001) and 40 days (2.0 vs 3.0; P < .001).

"This is the first trial with relaxin on stroke patients," said coauthor Mario Bigazzi, MD, an internist with the Prosperius Institute, in Florence, Italy. "I think this could prove to be an incredible tool in improving function in these patients."

Relaxin for Peripheral Artery Disease

In another study, Dr. Bigazzi and colleagues hypothesized that relaxin could be effective in the treatment of peripheral artery disease for various reasons.

"Relaxin may be a novel therapy in cardiovascular disease because it induces microvessel dilation, blood flow increase, platelet inhibition and neoangiogenesis, mainly through nitric oxide release," the researchers write.

They randomly assigned 20 patients with peripheral artery disease (mean age, 67 years) into 2 groups, 1 receiving oral porcine relaxin, 20 mg b.i.d. for 12 weeks, and the other a placebo.

The percent of increase in pain-free walking distance after 3 weeks in the relaxin group compared with the placebo group was 74% ± 16% vs 23% ± 9% (P < .01); at 12 weeks, the improvement was 168% ± 28% vs 65% ± 17% (P < .001); and at 3 months, it was 122% ± 15% vs 35% ± 4% (P < .001).

Maximum walking distance in the relaxin group also improved significantly compared with the group receiving placebo at all time points (each P < .001).

The therapeutic action of relaxin extended up to 3 months after withdrawal, and patients reported improved physical and mental status. There were no adverse events related to the treatment.

The authors speculated that the improvements may have resulted from "hemodynamic improvement as well as positive vascular remodelling."

"[This is] suggested by the long-lasting effects, as well as by the evidence of arterial neoformation with relaxin long-term therapy in a peripheral artery disease patient, described by us as a case report," they write.

The case report they refer to described a 30-year-old man who presented with obliterative peripheral arterial disease and recurrent thrombophlebitis in 2004. The patient was described as having occlusion of the popliteal artery and intermittent claudication, and he was scheduled for amputation of the left leg.

Instead of moving ahead with the amputation, however, the researchers tried treatment with 2 subcutaneous injections of 1.8 mg relaxin per day for 6 months, and then twice-yearly cycles of 3 months until 2006. Since then, the patient has been treated with 3-month cycles of oral porcine relaxin twice a year.

After the first 4 months, the researchers observed that the skin on the left foot, which had been pale, cold, and ulcerous, showed rapid improvement and healing of the ulcers.

Dramatic improvement was also seen in dyschromia and collateral arterial circulation of the leg. The patient had no further episodes of thrombophlebitis and showed "clearcut amelioration of intermittent claudication."

After 4 years, he showed further progressive improvement and, to the researchers' surprise, had new artery formation connecting deep femoral to tibial arteries.

The patient has exhibited no adverse effects from the treatment.

"We started injectable relaxin just to try to avoid the amputation," Dr. Bigazzi told Medscape Medical News. "After 36 hours, there was some improvement, after 10 days it was even better, and after 4 months, we saw circulation, no more ulcers.

"After he continued the therapy after 4 years, there was a new artery," he said. "It was amazing. This has never been seen before."

Dr. Bigazzi noted that the patient sometimes experiences claudication, but typically only in cold weather and at the beginning of heavy exercise.

"He should have been amputated 8 years ago. Instead, now he's playing sports and tennis. Sometimes in winter he has pain, but then he just stops exercising for a while."

Research on relaxin is currently under way for various other indications, including fibromyalgia, and researchers in Poland are conducting a clinical trial to evaluate the effect of a recombinant form of human relaxin on patients with acute heart failure.

Dr. Bigazzi and his team have even speculated that relaxin's cardiovascular mechanisms could help explain why women live longer than men.

Although safety concerns such as bleeding or edema clearly need to be well evaluated, owing to the known blood vessel effects of relaxin, the findings nevertheless appear promising on several levels, Bart L. Clarke, MD, who was a poster judge for the session, told Medscape Medical News.

"If this pans out, it could be a very big deal because if you might be able to reverse atherosclerosis or at least open the diameter of blood vessels where there is a blockage, that would be better than surgery or stents or balloon angioplasty," said Dr. Clarke, of the Mayo Clinic's Division of Endocrinology and Metabolism, in Rochester, Minnesota.

"Doctors can do things like bypass surgery or procedures to open blocked arteries right now, but if you have more than a discrete blockage or an artery with a longer distance of blockage, you can't always open it up. So this sort of medication would have potentially great application for those types of patients with more diffuse disease, which is common in people with diabetes."

Clinicians have known about relaxin since it was discovered in 1926 by renowned zoologist and reproductive endocrinologist Frederick Hisaw, but Dr. Clarke noted that sometimes it just takes the ingenuity of considering a property completely out of its established context to discover new potential.

"When we think about the way a hormone works, it's usually within the context of some disease or organ, but our hormones are probably doing plenty of other things — or are capable of doing things that are just not well described yet," he said.

"With relaxin, we know it relaxes smooth muscle during pregnancy and helps dilate the uterus so the baby could pass through, so it makes sense that theoretically it could affect smooth muscles in blood vessel walls."

Neurologist Brett Kissela, MD, said that although he was not familiar with relaxin as a potential therapy, other medications that have been explored to enhance stroke recovery have so far failed to show resounding success.

"There is a literature about using stimulants suggesting some benefit, but this is controversial, (and) literature about using dopamine agonists after stroke to help with language recovery, again, has not led to universal acceptance," said Dr. Kissela, a professor of neurology and codirector of the Neurology Residency Program at the University of Cincinnati, in Ohio.

Adverse effects in the vulnerable population of stroke patients are also a concern with any poststroke medications, he told Medscape Medical News.

"Lots of medications that are given after stroke can have a harmful effect on recovery, and yet this is understudied, and the adverse effects are not well appreciated."

In an effort to better understand those and a host of other issues surrounding relaxin, researchers have established an entire conference: the International Conference on Relaxin and Related Peptides, which holds its 6th gathering this October, in Florence, Italy.

The conference is sponsored by the Foundation for Research on Relaxin in the Cardiovascular Diseases and Other Pathologies, which Dr. Bigazzi founded.

"Considering the present clinical results and our previous experimental studies, we believe that relaxin is a very important, if not the most important, cardiovascular hormone,: he said.

The authors, Dr. Clarke, and Dr. Kissela have disclosed no relevant financial relationships.

ENDO 2012: The Endocrine Society Annual Meeting. Abstracts MON-155, MON-690, MON-689. Presented June 25, 2012.


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