Relaxin: Its Role in the Pathogenesis of Fibromyalgia

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Clinical Medical Director, HealthEast Pain Clinic HealthEast Bethesda Lutheran Hospital & Rehabilitation Center, St. Paul, Minnesota

Fibromyalgia is a debilitating disorder that is estimated to affect 2% (5 million) of the population of the United States. The ratio of female to male is approximately 9:1. It is also estimated that fibromyalgia costs the U.S. economy 9.2 billion dollars annually. Symptoms accompanying this disorder include widespread muscular and joint pain, spasm and diffuse tenderness in most areas of the body, unrefreshing sleep, fatigue and emotional distress. The Arthritis Foundation describes fibromyalgia as a form of soft tissue and muscular rheumatism. It is frequently associated with disorders such as irritable bowel, chronic fatigue and myofascial pain syndrome. Diagnosis of fibromyalgia is made by clinical elimination. Patients with no known diagnosis but with widespread pain, muscle spasm and fatigue of greater than three months duration; examination of specific sites of the body revealing 11 of the 18 sites on both sides of the body are painful on palpation, the diagnosis of fibromyalgia is made. These specific sites are at the base of the occiput, the cervical anterior, the trapezius, the supraspinatus, the second rib, the epicondyle on the elbow region, the greater trochanter, the gluteus and the fat pad on the knee. Chronic fatigue is often associated with fibromyalgia as well as many other disorders. These disorders include irritable bowel and bladder, panic disorder, amnesia disorder, allergic rhinitis, blurred vision, muscle fasciculation, myasthenia, interstitial cystitis, sleep disorder, headache, bruxism, TMJ syndrome, alopecia, thermal regulatory dysfunction, lymphadenalgia, dyspnea, chemical sensitivity, endometriosis, PMS, heart palpitation, photophobia, vertigo, Raynaud's phenomenon and dysmenorrhea. The etiology of fibromyalgia is unclear and unknown, and there is no effective curative treatment. Current therapy is directed primarily to alleviation of symptoms and management of pain. Therefore, management using nonprescription medication, prescription a nti-inflammatory drugs, injection of local anesthetic agents, physical therapy and exercise all are used to reduce symptoms related to the problems mentioned above. Medications such as tricyclic antidepressants are commonly prescribed to promote deeper sleep, which sometimes reduce symptoms. However, almost all current therapies are limited to reducing the severity of symptoms rather than treating the cause of the symptoms.

Over the course of many years I have observed fibromyalgia patients and have come to some rather interesting observations. Female fibromyalgia patients seem to have increased severity of their symptoms one week before and one week during menstruation on a regular basis. Further, many fibromyalgia patients' symptoms appear to be greatly aggravated during menopause between their fourth and fifth decades, or prematurely through surgically induced menopause. One other interesting observation I have made during these years was that many fibromyalgia patients reported remission of their symptoms when they were pregnant, and the return of their S/S almost within one to two months after delivery. At about the same time, I began to utilize botulinum toxin in many patients with myofascial pain syndrome. I also found that many fibromyalgia patients with cervical neck pain or headaches responded to botulinum toxin injections to the musculature surrounding the cervical neck. This indicated to me that somehow the musculature on these patients is shortened and contracted, and that the tonicity of the muscles must play a part in the pathogenesis of their symptoms. These observations gave me insight to begin searching for any agent or hormone within our body that would have an effect on the collagen of connective tissues. This agent must have effect on the contraction or the shortening of the muscle through the effect on collagen, resulting in spasm and spasticity of the musculature.

It was through this search that I came to a little known pregnancy hormone called relaxin which is produced ten times higher during pregnancy in most mammals. Relaxin has a diverse range of effects, including the production and remodeling of collagen, increase in elasticity and relaxation of muscles, tendons and ligaments during pregnancy, particularly in the pelvis. It is this hormone that is responsible for the remodeling of the pelvic region in preparation for descent of the fetus. The physiology of relaxin has been well documented in the literature regarding its structure, function and property. It is a polypeptide very similar to insulin and is secreted in females in the ovaries, and in males in the seminal tubules. Relaxin hormone has been prepared from animal form, particularly the pregnant sow, and had been used quite extensively in the 50's and 60's as an agent for shortening of labor, ripening of the cervix and the treatment of scleroderma and peripheral vascular disease. More than three thousand people have been treated with relaxin with various degrees of response to the porcine relaxin. Human form of relaxin has been prepared synthetically by recombinant DNA method and is presently produced by Connetics Corporation in Palo Alto, California as an investigational drug for treatment of scleroderma. Although much is known about the natural production of relaxin in pregnancy related functions, until recently little was known about its active sites in nonpregnancy related tissues. Significant information has been discovered and reported that involves specific relaxin binding cells in the cervix, mammary glands, nipples, small intestines, and skin of the pregnant pig. The study on humans indicated relaxin is secreted in a pulsatile nature in females. This usually is measurable in the blood stream approximately at the menstrual mid-cycle surge of the luteinizing hormone or approximately seven to ten days after ovulation. In the male, the level of relaxin is extremely low and is difficult to measure with current methods. However, the male relaxin level is measurable in the seminal fluid where it can reach approximately 200 nanograms per ejaculation in the normal male. It is postulated that retrograde pulsatile release of relaxin is possible in males. Because of its association with pregnancy, relaxin is well known as the third major pregnancy hormone along with progesterone and estrogen. Relaxin is well known as an agent for remodeling of the reproductive tract, collagen remodeling, thereby facilitating the birth process. Relaxin increases peripherally approximately seven to ten days after the mid cycle surge of luteinizing hormone and if conception occurs, continues to rise to over 800 picograms per ml by the third week. During pregnancy, relaxin peaks at the 10th week and is maintained at about 500 picograms per ml for the remainder of the pregnancy. Relaxin remodels the reproductive tract, including ripening of the cervix, thickening of the endometrium, increases the vascularization of the uterus and affecting collagen synthesis to cause ligaments and connective tissues to elongate and relax. It has also been observed that Raynaud's phenomenon completely disappeared during early pregnancy. Patients who have fibromyalgia and associated symptoms reported remission of their symptoms when they were pregnant, and there appears to be a direct correlation between the rise of relaxin level during pregnancy and the remission of their symptoms.

It is postulated by this author that the genesis of fibromyalgia is related to systemic deficit of relaxin hormone, or inability of the body to utilize the existing hormone (receptor site pathology and/or auto-immune antibodies to the circulating relaxin). The microscopic amount of pulsatile release of relaxin hormone is necessary in order to maintain the integrity of collagen and connective tissues of one's body. Further, through its direct effect on many of the documented receptor sites and its indirect effect on collagen, relaxin does exert its effects on many of the systemic structures. The direct effect is stimulation of the receptor sites to produce the desired functions and indirect effect through collagen remodeling, resulting in elastic and flexible collagen, which is the building block for all connective tissues. The combined direct and indirect effects can be broken down into the following (Figure 1): striated muscles; smooth muscles; central nervous system; autonomic nervous system; connective tissues in the form of skin, ligament, tendon and cartilage; and lastly, the cardiac muscles. Therefore, the hormone has both direct and indirect effects that affects the individual patient as a whole, affecting almost all parts of the body through these two routes of mechanism of action. All symptoms suffered from fibromyalgia can be explained by the lack of the hormonal effect on these six areas outlined in Figure 1. It is therefore postulated that restoration with daily supplemental replacement of relaxin on these patients will eliminate all the symptoms of fibromyalgia. Attempts will not be made to explain how each area is restored with relaxin hormonal supplementation. Readers are asked to read the attached schema for details.

Striated Muscles: It is this author's postulation that relaxin will release the sustained muscle contracture or spasm on many fibromyalgia patients. The etiology of how relaxin directly affects the striated muscle is unclear at the present time. Animal models have shown that striated muscles have no receptor site for relaxin. Therefore, relaxin must either exert its effect on the central nervous system or on the receptor sites within the muscles that are too low to be detectable at this time. However, once the sustained muscle spasms or contractures are released, the associated chronic fatigue will be minimized. Therefore, many patients' abnormal muscular tone will be ablated; resulting in resolution of their tender points and muscle originated pain, spasm and fatigue. The control of the central nervous system to the striated muscles must then be facilitated to a point that abnormal muscle movements (fasciculation, twitches, etc) are also ablated. I believe this will be the mechanism by which fibromyalgia patients regain proper function of their musculature. There are many other areas that are not being addressed at this time, and I hope future research will delineate exactly how relaxin affects the individual component of the striated muscles and other areas of one's body. Muscle efficiency leads to better control of muscles by the central nervous system and decrease of tight muscle bands, eventually deactivating the trigger points, resulting in a normal musculature on these muscles. These are the direct and indirect effects on the striated muscles which appear to cause the problem of chronic muscle and joint pain in addition to chronic fatigue, that is commonly associated with fibromyalgia.

Smooth Muscles: This author also postulates that smooth muscle is directly affected by relaxin. The sustained smooth muscle contracture and spasm are released through direct effect of relaxin on the smooth muscles. Receptor sites in smooth muscles have been documented in animal models, therefore, relaxation of smooth muscles have been proven to be a direct effect of relaxin. Further, because of abnormal smooth muscle tone is released, the smooth muscle denervation effect as described by Dr. C. Chan Gunn will be eliminated. The ANS and CNS, therefore, can control the smooth muscles in an efficient manner without over or under compensation as seen in denervated organs. The denervation effect of smooth muscles in this instance is related to the delayed response of the smooth muscles and not the effect of denervation. The result, however, is the same and the four components of denervation (super-duration/delayed response, hyper-excitability, increased susceptibility and super-reactivity) are mimicked exactly by inelastic and inflexible smooth muscles. Relaxin imparts good quality collagen on smooth muscles allowing efficient and proper control of the organs by the central nervous system through the autonomic nervous system. Therefore, smooth muscles and organs are able to maintain the proper signals to the central nervous system, allowing a normal control and a normal signal to be transmitted to the central nervous system. Homeostasis is therefore properly maintained on these smooth muscles and its related organs.

Central nervous system: It has been shown in animal models that mice brain tissue contains receptor sites for human relaxin. Therefore, it can be assumed that human central nervous system contains receptor sites for human relaxin. The exact mechanism of how relaxin diffuses through the blood brain barrier is unclear, and polypeptides have been shown to be unable to cross this barrier. The implication of this assumed effect of relaxin on the CNS is rather significant. Nonrefreshing sleep (defective stage 4 sleep), cognitive dysfunction and affective dysfunction are some of the major CNS manifestation of patients who suffer from fibromyalgia. Pregnant fibromyalgia patients have reported the restoration of their sleep pattern. Therefore, relaxin must somehow restore the aberrant sleep pattern in these patients. It may also restore the affective dysfunction and cognitive dysfunction of the central nervous system. Circumstantial evidence indicated that this might have been the case. These evidences are the increased CNS component of dysmenorrhea S/S during menstruation, and increased CNS S/S during menopause corresponding to the decrease of relaxin level. Further, postpartum depression may be implicated as secondary to abrupt cessation of the high level of relaxin after delivery. In susceptible patients, affective and cognitive dysfunctions and sleep disturbance may develop into severe postpartum depression that may include psychosis. Therefore, in reverse, deficit of relaxin in normal patients might cause similar problems. The "ABC" (affective, behavioral and cognitive) part of our CNS functions might be directly affected by relaxin in addition to aberrant sleep pattern.

Relaxin has also been known to release growth hormone in animal model. Growth hormone secretion marker IGF-1 (somatomedian-C) has been found to be significantly lower in fibromyalgia patients. Secretary dysfunction of growth hormone has been hypothesized by Dr. RM Bennett of Oregon to be related to increased somatostatin tone (the major inhibitor of GH release in the pituitary) and defective stage 4 sleep. Supplemental relaxin may restore the normal secretary functions of the CNS at least as far as GH is concern. Whether relaxin has any direct function in releasing neurotransmitters within the CNS (particularly in the hypothalamus, the pituitary, the pineal gland and the brain stem) is unclear. Its main functions within the CNS may be regulatory effects on the secretary process of the neurotransmitters. The relative excess or deficit of many of the neurotransmitters is restored to homeostasis levels. The net results are restoration of many usual and unusual complains (headache, thermal regulatory dysfunction, etc.) of fibromyalgia patients related to the CNS.

The indirect effect of relaxin on the central nervous system is speculative. Relaxin improves integrity and quality of collagen within the nervous tissues. Normal conductivity and response of these nervous tissues are restored and facilitated. The overall CNS functions regain their former homeostasis, elimination of abnormal, excessive and aberrant responses and reestablishment of normal CNS activities. These effects of relaxin on the CNS are probably premature at this time and would need further studies in the future to delineate the exact route of mechanism on how relaxin exerts its indirect effect on the CNS.

Autonomic nervous system: The autonomic nervous system of most fibromyalgia patients is imbalance with predominate excessive sympathetic outflows. The term dysautonomia is often used to describe these patients' S / S related to the ANS. There are significant problems related to smooth muscle dysfunctions (see effect of relaxin on smooth muscles) and the control of these organs as alluded to in the beginning of this discussion. This has to do with imbalance of the relatively increased sympathetic or decreased parasympathetic tone of the ANS. The inability of the ANS to maintain a homeostatic level of control on the smooth muscles and sphincters of many of the inner organs results in the under/ over performance of these organs. I believe that the direct effect of relaxin on smooth muscles and the nervous tissues will cause the ANS to restore back to normal. The imbalance of the sympathetic and parasympathetic outflows is reversed. Therefore, homeostasis of the inner organs and control of the sphincters and smooth muscles of the organs will be facilitated by relaxin, thus restoring the autonomic dysfunction.

The indirect effect of relaxin to the ANS is as speculative as the CNS where the neural tissue conductivity is improved through the better integrity and elasticity of collagen. The net effect is facilitation of conduction of nervous impulses directly from the organs through the ANS to the CNS and back to the organ. Therefore, the efficient control of all inner organs by the ANS results in normal functioning of internal components of our body. Dysautonomia is reversed and the internal homeostasis is maintained.

Cardiac muscles: It has been shown that relaxin exerts inotropic and chronotropic effects on the cardiac muscles. There are relaxin receptor sites within the cardiac muscles that relaxes the cardiac muscles. The deficit of relaxin might be responsible for palpitations and arrhythmia that are so often felt by fibromyalgia patients. The cardiac function in these patients is not maintained in the most efficient state due to decreased pumping mechanism secondary to muscle inelasticity. The resting compliance of the heart is decreased, resulting in compensations through increase in heart rate. It is postulated by this author that relaxin will stabilize the cardiac function of many fibromyalgia patients resulting in decreased palpitations and arrhythmia, increased efficiency and pumping mechanism of the cardiac muscles.

The indirect result of relaxin on cardiac muscles would be further improvement of conductivity and pumping mechanism. In the presence of relaxin, better collagen is produced, conductivity and elasticity of the cardiac muscles improved, and resting compliance of the heart increased, and overall cardiac functions restored. The net result is an efficient pumping heart with ability to circulate the blood throughout the entire body.

Connective tissue: The direct effect of relaxin on the superficial connective tissues has only recently been discovered. It is documented that relaxin receptor sites are found in hair follicles and epidermal cells of the skin in the pig. Therefore, relaxin exerts its direct effect on dermal cells and hair follicles resulting in better growth rate of the hair and skin. Relaxin exerts its well-known indirect effect on tissue remodeling, particularly during pregnancy (pelvic remodeling). This increases the flexibility and elasticity of the pelvic floor to facilitate childbirth. In combination with the direct and indirect effects of relaxin on the other 5 systems mentioned in this discussion, it is no wonder that pregnant fibromyalgia patients often reported remission of their overall S/S.

Therefore, the pathogenesis of fibromyalgia may be a direct result of overall deficit of relaxin, or inability of the receptor sites to bind with circulating relaxin (defective receptor sites, autoimmune antireceptor or antirelaxin antibodies?). The hypothesis, however, must account for the pathogenesis of various subgroups as in juvenile fibromyalgia, fibromyalgia from stress, trauma or illness-related difficulties, and fibromyalgia during menopausal time. Further, the explanation must also include why males have fibromyalgia.

Juvenile fibromyalgia: It is interesting to this author that fibromyalgia does not occur below a certain age. For example, it is unusual to find fibromyalgia below ten years of age. Therefore, since the reproductive organs in both males and females only produce relaxin during the second growth phase, the pathogenesis of fibromyalgia according to relaxin deficit can only occur during the second growth phase. Any patient who carries fibromyalgia symptoms before the second growth phase must be examined carefully in order to avoid labeling these patients as having fibromyalgia.

It is interesting to see that in juvenile fibromyalgia, young females and males have a much closer ratio, 6:4. It is also interesting to see that many of these female juvenile fibromyalgia patients have significant symptomatology related to dysmenorrhea and irregular menstruation. Such symptoms are indicative of decreased availability of the pulsatile relaxin. Insufficient relaxin at the critical growth stage of these patients results in poor quality and inelastic collagen for the rapid growth. Growth pain and fibromyalgia symptoms begin to appear. Further, since females develop second growth phase sooner than males, growing pains and fibromyalgia symptoms occur younger in females than males and is related to the relatively inadequate relaxin supply when the body demands a huge quantity of collagen for rapid growth. Therefore, duration of growing pains during this rapid growth phase may be a predictor of ability of a person to outgrow their early fibromyalgia S/S. If deficit of relaxin persists, then many of these young teenagers would eventually develop fibromyalgia. In male juvenile fibromyalgia, growth is usually adequately addressed as their rapid growth phase diminishes and the supply of relaxin and the production of collagen are balanced. It is this author's belief that male juveniles outgrow their fibromyalgia state more often than females because of the cyclical nature of the female reproductive functions. Further, because of difficulty with menstruation, many of these young females are placed on BCP (birth control pills) early to chronically suppress their reproductive functions and to reduce S/ S related to menstruation and dysmenorrhea. The use of BCP for this purpose might compound the issue of inadequate or deficit of relaxin on these female patients. Therefore, with increasing use of birth control pills at a younger age and extending to include their normal productive age from the 20-30's to 40's, the incidence of fibromyalgia at a younger age, parti cularly in woman, will increase significantly in the future. The slow shift of higher incidence of younger female population of fibromyalgia in the last 20-30 years may be linked to the introduction and popularity of oral BCP in the last 30-40 years. Epidemiological studies are necessary to confirm this possible causal observation.

In the adult fibromyalgia population one sees two different types of pathogenesis that leads to the development of fibromyalgia. It is this author's belief that primary fibromyalgia should be reserved for patients who develop fibromyalgia during the second growth phase whereas secondary fibromyalgia is related to iatrogenic or environmental causes. This author does see two types of fibromyalgia (fast vs slow onset) that begin their onset at adult time.

Fast onset fibromyalgia usually occurs in patients who had their relaxin level or reproductive organs abruptly eliminated or removed. A good example of this would be oophorectomy and hysterectomy so often performed on young women in their 30's and 40's. The onset often began after oophorectomy and hysterectomy, depending on the constitutional susceptibility of each individual patient. On some patients it was almost immediate, and within four to five months after removal of the ovaries a full-blown picture of fibromyalgia would develop. Others would take a few years from the time of removal of the ovaries before fibromyalgia became a presenting problem (probably related to the availability of secondary source of relaxin). Patients who had myofascial pain syndrome and rapidly progress to fibromyalgia must be evaluated with sudden deficit of relaxin in mind. Rapid onset type of fibromyalgia also occurs during menopause where many women develop symptoms due to natural cessation of ovarian functions.

It is believed there are secondary sources of relaxin in our body. Chronic suppression of primary ovarian or prostate source of relaxin (e.g. BCP in female and prostate diseases in male) will quickly exhaust the secondary source of relaxin. If recovery of the primary source of relaxin is not possible, rapid onset of fibromyalgia will develop as a consequence. Therefore, in susceptible patients who have primary source of relaxin but minimal secondary sources, deficit of relaxin from the primary source will rapidly progress to fibromyalgia. This may occur anytime during the early womanhood to menopausal time in female and the entire adulthood in male.

Slow onset fibromyalgia may be related to the gradual deficit of relaxin on a long-term basis. The symptoms are often precipitated by small traumatic events, stress in the individual or family, minor or major illness/surgeries which all serve as the nidus to precipitate fibromyalgia. This type of deficit is easily explained in women where one can definitely gauge the ovarian function. The gradual cessation of their ovarian function results in irregular menstruation, resulting in gradual decrease of relaxin production. S/S of fibromyalgia slowly develop over time until full blown picture of fibromyalgia emerged. This may be the hallmark for the diagnosis of slow-onset secondary fibromyalgia in women.

In a poster presented at the 1996 Annual Meeting of the American Academy of Pain Management, this author addressed the issue of low level of testosterone in male patients who complained of persistent musculoskeletal pain. Blood samples of these male patients (including several juveniles) indicated that >70% have low or below normal level of testosterone. The relationship between low level of testosterone and development of fibromyalgia is definitely significant. The probable causal relationship is as follows: low level of testosterone indicates lower reproductive secreting function implicating low secretion of relaxin in the seminal tubules. Therefore, low normal or below normal level of testosterone during teenager and early adulthood may be a predictor of the likelihood that particular individual male may develop fibromyalgia during his lifetime.

It is somewhat difficult to apply the sequence of events, slow or rapid onset fibromyalgia, in the juvenile male patient. Good hypotheses that apply to the female must somehow equally apply to the male. Male fibromyalgia patients definitely exist and it is this author's opinion that there are more male fibromyalgia patients than is presently diagnosed. The ratio of 9:1 will change once the public and physicians are aware that the male fibromyalgia patients do exist. Since it is difficult to measure the functional relaxin level in males, this author has attempted to measure testosterone as a function of male reproductive capabilities. This author also postulates that low level of testosterone in the male can imply that the relaxin level is also low in these patients. No conclusion can be drawn with a normal testosterone level. With this in mind, I began measuring testosterone levels in all males who presented to the Pain Clinic in the last two to three years. The testosterone level is presented in figure 2, and out of these male patients who presented to the Pain Clinic with musculoskeletal pain, almost 60 to 70% had an abnormal level of testosterone. Many of these patients appear to carry a diagnosis of fibromyalgia by definition alone. However, many of these male patients also have had multiple back surgeries, cervical neck surgeries, shoulder and knee surgeries without much help in reduction of pain. Some have been labeled as failed back syndrome, chronic cervical neck pain and spasm or arachnoiditis. The underlying etiology may not be of spinal or other surgical reasons but may be from fibromyalgia and its associated S/S. Prostatitis and various difficulties with their reproductive functions also appear to be more common in this male population. I postulate that males who carry a low level of testosterone have low levels of relaxin. Circulating relaxin through retrograde ejection of relaxin through the seminal tubule to the systems may be insufficient to exert the systemic effects and to produce good quality collagen, resulting in fibromyalgia. Besides age-related degeneration of the reproductive function, many illnesses, stress, trauma, surgeries and other factors that precipitate fibromyalgia in males must also be evaluated as to the effect these events exert on the reproductive organ; e.g., the impact of major surgery (as in cardiac bypass) on the function of the reproductive organ of the male patient is unclear, nor has it been studied. Therefore, all male pain patients' reproductive function must be evaluated and the testosterone level measured in order to eliminate fibromyalgia as a diagnosis. Once these evaluations are completed, male fibromyalgia conforms nicely to the hypothesis that deficit of relaxin may be the cause of juvenile, rapid and slow onset fibromyalgia. Decrease of relaxin level in the male may be reflected in the decreased level of testosterone, whereas decreased relaxin level in females may be better reflected in the reproductive cycles, and the associated S/S within these cycles.

Therefore, it is the postulation of this author that lack of relaxin is the pathogenesis of fibromyalgia. Further, replacement of this hormone may alleviate all the symptoms related to fibromyalgia and that the replacement is not of a curative nature but in control of the disease, as in insulin being able to control adult-onset diabetes. Treatment for these patients may require daily infusion or injection of 12 to 16 weeks of relaxin. This will allow the body to restore all the abnormal symptoms that are associated with the direct effect of relaxin deficit, to restore and remodel the body's inflexible and inelastic collagen. A maintenance dose of relaxin, lasting several days on biweekly or monthly basis would then be sufficient to maintain the health of these patients. A small subset of fibromyalgia patients may not respond to the daily supplemental replacement of relaxin since the pathology may be related to antibody formation to the receptor sites or relaxin. Animal relaxins with different molecular structures but similar agonist effect may provide some therapeutic effect when human relaxin fails.

The result of a pilot study of human relaxin on fibromyalgia conducted by this author is inconclusive. However, a further double blind study with longer longitudinal time frame and a larger sample size will eliminate the placebo effect. This will determine whether relaxin is effective in reducing the patients' sign and symptoms related to fibromyalgia. If the hypothesis related to the deficit or relaxin is proven to be sound from such a study, the exact mechanism of how this hormone effects individual suffering from fibromyalgia must be meticulously studied, and the hypothesis refined and reconfirmed. It is through these types of observations and studies that this devastating disease might be eliminated and controlled

Possible Side Effects from Relaxin Tablets

(Possible duration 7-10 days):

Morning sickness (nausea/vomiting/dizziness)

Diarrhea

Anxiety

Nose bleeding

Breast tenderness

Increase in menstrual flow

Acne

Possible Beneficial Side Effects:

Faster and more lustrous hair flow

Body hair growth

Faster and stronger nail growth

Translucent facial complexion

More elastic & smoother skin

Increase libido and sensation

Changes to be Observed

Improved memory

Clarity of cognitive function

Calmer exterior

Increased motivation

Restoration of sensory function (smell & taste)

Restoration of thermal regulatory function

Improved blood circulation

Deeper and more refreshing sleep

Increased energy

Shorter recuperation time ([up arrow] stamina)

[down arrow] Irritable bowel

[down arrow] Irritable bladder and [up arrow] control

Decreased muscle spasms and pain

Improvement in tremors, tic & pseudoseizure disorders

Dosage: Female

Start with 1 tablet in PM for 2-3 days. If you notice no side effects, increase to 1 tablet in AM and 1 in PM for 2-3 days. If you still notice no side effects, increase to I in AM and 2 in PM for 2-3 days, then to 2 tablets in AM and 2 tablets in PM. Maintain 2 tablets twice a day until your physician gives you further instructions.

Dosage: Male

Start with I tablet in PM for 2-3 days. If you notice no side effects, increase to I tablet in AM and i in PM. Maintain I tablet twice a day until further instruction by physician.

Correspondence:

Raymond M. Suen For Your Health, Inc. 13758 Lake City Way NE Seattle, Washington need zip USA

206-365-8488/800-456-4325

Fax 206-363-8790

Articles on Relaxin Review, CNS

1. The emerging concept of relaxin as a centrally acting peptide hormone with hemodynamic actions. (Geddes BJ; J Neuroendocrinol, 1995 Jun)
2. Relaxin: a pleiotropic hormone. (Bani D; Gen Pharmacol, 28(1):13-22 1997 Jan)

Binding Site

3. Identification of specific relaxin-binding cells in the human female. (Kohsaka T, et al.; Biology of Reproduction 59, 991-999, 1998)

Cancer Issues

* 4. Relaxin, a potent microcirculatory effector, is not angiogenic. (Norrby K; Int J Microcirc Clin Exp, 1996 Sep-Oct)
* 5. Relaxin influences the growth of MCF-7 breast cancer cells. Mitogenic and antimitogenic action depends on peptide concentration. (Bigazzi M; Cancer, 1992 Aug 1)
* 6. Relaxin influences growth, differentiation and cell-cell adhesion of human breast-cancer cells in culture. (Sacchi TB; Int J Cancer, 1994 Apr 1)

Collagen

* 7. The effect of relaxin on tissue expansion.(Kibblewhite D; Arch Otolaryngol Head Neck Surg, 1992 Feb)
* 8. Relaxin modulates synthesis and secretion of procollagenase and collagen by human dermal fibroblasts. (Unemori EN; J Biol Chem, 1990 Jun 25)
* 9. Stimulation of collagen secretion by relaxin and effect of oestrogen on relaxin binding in uterine cervical cells of pigs. (Huang C; J Reprod Fertil, 1993 May)
* 10. Relaxin binds to and elicits a response from cells of the human monocytic cell line, THP-1. (Parsell DA; J Biol Chem, 1996 Nov 1)

Insulin-Like Growth Factor, Prolactin, Growth Hormone

* 11. Relaxin-induced deoxyribonucleic acid synthesis in porcine granulosa cells is mediated by insulin-like growth factor-I. (Ohleth KM; Biol Reprod, 1995 Dec)
* 12. Relaxin stimulates prolactin secretion from anterior pituitary cells. (Sortino MA; Endocrinology, 1989 Apr)
* 13. The effect of relaxin infusion on prolactin and growth hormone secretion in monkeys. (Bethea CL; J Clin Endocrinol Metab, 1989 Nov)

Nitric Oxide Pathway

* 14. Relaxin-induced increased coronary flow through stimulation of nitric oxide production. (Bani-Sacchi T; Br J Pharmacol, 1995 Sep)
* 15. Relaxin inhibits histamine release from mast cells: involvement of nitric oxide production. (Masini E; Inflamm Res, 1995 Apr)
* 16. Relaxin activates the L-arginine-nitric oxide pathway in vascular smooth muscle cells in culture. (Bani D; Failli P; Bello MG; Thiemermann C; Bani Sacchi T; Bigazzi M; Masini E, Hypertension, 31(6):1240-7 1998 Jun)

Cardiovascular

Central hemodynamic effects of recombinant relaxin in the isolated, perfused rat heart model. (Coulson CC; Obstet Gynecol 1996 April)

Relaxin enhances the coronary outflow in perfused guinea-pig heart: correlation with histamine and nitric oxide. (Di Bello MG; Inflamm Res, 1995 Apr)

The cardiovascular effects of porcine relaxin in Brattleboro rats. (Parry LJ, et al. Endocrine. 1998 Jun;8(3):317 -22)

Evidence for a novel source of relaxin: atrial cardiocytes. (Taylor MJ; J Endocrinol, 1994 Nov)

Pressor and bradycardic effects of centrally administered relaxin in conscious rats. (Yang RH; Am J Hypertens, 1995 Apr)

The effect of relaxin on myocardial ischaemia-reperfusion injury and histamine release in vitro and in vivo. (Masini E; Inflamm Res, 1996 Mar)

Relaxin increases rat heart rate by a direct action on the cardiac atrium. (Ward DG; Biochem Biophys Res Commun, 1992 Jul 31)

Note: Articles on Cardiovascular will be available at a later date.

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By Samuel K. Yue

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