Painful bladder syndrome/interstitial cystitis (PBS/IC) affects women of all races, ethnic and socio-economic backgrounds. It is prevalent among 40 to 60 year old women. The symptoms vary with the person and from time to time in the same person. In severe cases, the intense pain can persist 24/7 for more than 2 years.
Living with PBS/IC is extremely difficult because of pain and suffering, staying home, social isolation, emotional troubles, sexual intimacy problems, depression and sleep deprivation. About 7.9% of all women may have early symptoms of PBS/IC. The disease comes with very high economic burden. For example, total annual medical costs per person can exceed $ 7,000, not counting the income loss from missed work.
PBS/IC is diagnosed by an exclusion of urinary tract infections and overactive bladder. Urothelial cells are damaged in PBS/IC, which was thought to be due to defective protective glycosaminoglycan layer of bladder mucosa. The damage cells do not get replaced, because of antiproliferative factors that the damaged cells seem to produce. However, the nature of these factors is unknown. Potassium particles and other toxic substances in urine that leak into damaged bladder mucosa, cause inflammation, irritation, scarring and stiffening of bladder wall. The stiffening reduces the bladder capacity to hold urine and can contribute to bladder pain during urine accumulation and emptying.
Many factors such as, bladder trauma from pelvic surgery, bladder over distension, dysfunctional pelvic floor muscles, autoimmunity, infections, primary neurogenic inflammation, spinal cord trauma, etc, are thought to cause PBS/IC . Multiple therapies that exist can only provide a symptomatic relief. Moreover, they do not work for everyone and the symptoms usually return after few months. Most of the orally taken pentosan polysulfate sodium (PPS) is mostly eliminated in the feces due to lack of absorption. It is also available for bladder instillations and they are effective against pain, urgency and frequency, but not nocturia. Although the mechanisms of PPS action are not known, it is believed to coat bladder’s urothelial cell lining, protecting it from the harmful effects of toxic substances in the urine. Because, it is a weak blood thinner, its use can increase the risk of bruising/bleeding from the nose and gums. The other common side effects include diarrhea, nausea, upset stomach, bloody stools, headache, hair loss, rash, and dizziness.
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Uterus and urinary bladder are homologous organs because of their common embryological origin, hollow nature and overlapping cellular and molecular networks. The shared gene networks include human chorionic gonadotropin (hCG)/luteinizing hormone (LH) receptors and parathyroid hormone – related protein genes. The latter is a stretch induced gene. Among these two, hCG/LH receptor gene is relevant to PBS/IC, because of its overexpression in urothelial cells, the sites of damage in PBS/IC, and the potential ability of hCG to repair the cellular damage.
The epithelial (urothelium) cells contain higher hCG/LH receptor levels than detrusor muscle and blood vessels of the bladder. The urothelial cells from bladder dome and trigone contain a similar receptor level. The urothelial cells from younger and older women contain the receptors, with higher levels in pre-menopausal than in post-menopausal bladders.
The following observations suggested that hCG may have a therapeutic value against PBS/IC.
1. The symptoms of PBS/IC seem to improve during pregnancy and during infertility treatments with hCG.
2. hCG has pleiotropic actions in uterine epithelial cells, which are the homologs of urothelial cells. This makes it possible for hCG to also regulate urothelial cells. In fact, treatment of porcine urothelial cells with hCG results in an increase in cyclic AMP levels and an upregulation of cyclooxygenase (COX)-2 , but not COX-1, gene expression.
3. The receptors for hCG to regulate urothelial cells are overexpressed as compared with the other bladder cell types.
4. As a member of cystine-knot growth factors superfamily, hCG can be expected to have pleiotropic actions in cells that it targets. Such actions could heal and/or replace damaged urothelial cells.
hCG will have minor side effects, if any, when administered by intramuscular (IM) injections. These side effects do not often require medical attention. hCG can also be administered as an oral medication in the form of lozenges or as a bladder instillations. It is also possible to develop stable hCG analogs, mimetics and nanoparticle delivery, etc, which can lower the dose and the frequency of treatment. Among these treatment modalities, perhaps bladder hCG instillations will be more interesting to explore, because they will deliver the hormone where it is most needed. In addition, any minor side effects that are associated with IM injections become obsolete. The possible consequences of chronic hCG administration such as an interruption of cycles, abnormal bleeding, short term infertility, etc are a small price to pay in exchange for the potential gain of treatment benefits against this painful disease.
In a trial setting, hCG instillations should be compared with similar instillation of dimethyl sulfoxide and PPS. The combination instillations may work better than single instillations, due to possible differences in their mode of action. In addition, hCG inclusion can reduce the toxicity, doses and cost of other drugs. hCG may not replace other therapies but it can complement them. Finding a cure for PBS/IC is a daunting task. Any therapeutic agent or a combination of them that can prevent cell damage, repair or replace the damaged cells in urothelial cell lining will provide a cure. It remains to be seen whether an introduction of hCG in the therapeutic regimen can improve the chances of coming close to accomplishing this goal. hCG is already cheap and can even be made cheaper by scaling up the production of recombinant hormone.
Men also can get PBS/IC, albeit less frequently than women. Although hCG/LH receptor’s presence in male urothelial cells is not known, it is likely that they are present, therefore, worth considering hCG therapy for men as well.
As others, PBS/IC is a multifactorial disease. Consequently, no single therapy works for every patient. hCG therapy, as the others, will be no exception. Thus, hCG therapy will not be a panacea, but it has a potential worth investigating for the treatment of PBS/IC patients.
C.V. Rao, Ph.D.
Departments of Cellular Biology and Pharmacology, Molecular and Human Genetics and Obstetrics and Gynecology, Reproduction and Development Program, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, 33199, USA.