Progesterone as a Bronchodilator
Russell Roby, JD, MD
5000 Bee Caves Rd, Suite 100
Patricia Q. Richardson, PhD
University of Texas at Austin
Richard H Richardson, PhD
Professor of Integrative Biology
University of Texas at Austin
Shilpa Shah, PhD
Breach Candy Hospital Trust
Background The effects of estrogen and progesterone on asthma have been well documented.8 In this paper we report that patients can experience rapid relief of breathing difficulties after receiving sublingual dilutions of progesterone which appear to act as progesterone antagonists.
Methods Using sublingual progesterone as a bronchodilator, we performed spirometric studies on sixteen patients with a previous diagnosis of severe asthma. We analyzed changes over time of the forced expiratory volume in one second (FEV?), the forced vital capacity (FVC), and the peak expiratory flow (PEF). For each patient we measured lung function three times: (1) before treatment, (2) after sublingual normal saline treatment (3) after sublingual progesterone treatment.
Results After treatment with sublingual progesterone, twelve of the sixteen patients (75%) experienced a significant bronchodilator effect (greater than 12% increase) in either FEV? or FVC. Eight (50%) experienced significant increase in both FEV? and FVC. Eight (50%), had an increase of 27% or greater in PEF.
Conclusion Sublingual progesterone acts as a progesterone antagonist and has a significant bronchodilator effect. This may be due to hormone allergy.1
Keywords progesterone, progesterone antagonist, estrogen, hormone allergy, hormone antibodies, IgE, IgM, IgG, asthma, premenstrual asthma, pain, sublingual, antigen, nitric oxide, Th1, Th2, cytokines, arginase, mast cells, NANC.
Asthma has long been associated with hormones.2,3,4,5,6 Increases in asthma symptoms have been associated with menstrual variances.7,8 Pre-menstrual asthma has been noted in the literature since the early l960’s.2,5 Some studies from as early as 1921 have suggested an allergic reaction to hormones.9,10
Progesterone was used in intradermal testing and treatment in l973 and again in1982, with similar results to ours.11,12 Our results are nearly identical with those of Miller and Mabray except that they administered the progesterone by injection and we used sublingual solutions. Heckel in l953 reported positive skin whealing in approximately two thirds of patients with common disorders relating to ovarian function.13 In 1949, Phillips reported many symptoms, including asthma, responded to hormonal treatment.14 We have used hormones as antigens since 1995. In particular we have found progesterone to act as a significant antigen in many types of clinical problems including pain and asthma.
We have analyzed changes in FVC, FEV? and PEF in sixteen patients to demonstrate the impact of sublingual progesterone on lung function.
Sixteen females who had a previous diagnosis of severe asthma and who used albuterol by nebulizer on a daily basis were selected for the study. This study was approved by the RCRC ethics committee of Austin, Texas. Written informed consent was obtained from each patient.
In three spirometric examinations, FEV?, FVC, and PEF were measured with a Vitalograph spirometer (model N2120, Vitalograph Inc., 8347 Quivira Road, Lenexas, Kansas 66215, U.S.A.), which was calibrated daily with a ?-liter syringe. After at least one trial blow, three values were obtained. As a criterion for correct performance of the procedure, at least two measurements of FVC, and FEV?, differing by less than 5 percent had to be produced. Data on FVC, FEV?, and PEF are reported both as absolute values and as percentages of predicted values.15
A baseline was established with the first test. Before the second test each subject was given 0.10ml of normal saline, sublingually. After the second test we placed 0.10ml of progesterone diluted to 0.05mcg, sublingually in each patient. If there was no change in shortness of breath, or incomplete relief within 30 seconds, we added 0.10ml of progesterone diluted to 5mcg, sublingually. If there was no change in the shortness of breath, or incomplete relief of those symptoms, within 30 seconds, we added progesterone 0.5mg, sublingually. If at any time the symptoms were reported to be gone, or after the last of the three dilutions were administered sublingually, we performed the last examination.
Table 1 shows the spirometric changes in these patients. There was no significant change between tests one and two. After the sublingual progesterone was administered, twelve of the sixteen subjects (75%) experienced greater than 12% increase in FVC or FEV?. Eight of the subjects (50%) experienced greater than 12% increase in both FVC and FEV?. Eight of the subjects (50%) experienced an increase of 27% or greater, in PEF.
Of those subjects responding, there was a mean increase in FVC of 28%, in FEV? of 43%, and in PEF of 71%.
The most extreme case involved an MS patient with severe asthma. These values are not averaged into the results, because the changes were far outside the rest of the results. After the sublingual progesterone she experienced a 269% increase in FVC. There was an increase of 356% in FEV?, and an increase of 400% in PEF.
Since 1995, we have been testing patients for hormone allergy. The response to intradermal and sublingual testing, using hormones, has been positive. We used progesterone in this study because in our experience it resulted in more positive skin reactions and greater changes in symptoms than any other hormone or conventional antigen. Because the progesterone seemed to have an antigen effect we performed several hundred tests for antibodies to progesterone and estrogen. We found nearly half of our patients were high in IgE, IgM, and IgG antibodies to progesterone and estrogen.1
(i) The ‘high dilution’ effects: The question whether and how highly diluted substances may have pharmacological effects needs to be discussed. An important point is to distinguish between very low dose and high-dilution effects. Dilution is a mathematical-mechanical process for the reduction, according to scale, of a substance to a state of physical solubility, physiological assimibility and therapeutic activity. When the diluted substance comes across other body substances, the greater the dilution faster is the velocity of reaction due to higher degree of ionization. It is like dilutions leading to transmissions. It is reported that the water, deprived of solute by means of serial dilutions, retains a specific activity that can be suppressed by physical treatments that do not have any effect on the solute itself 16. Maupertuis law of the least quantity explains the action and efficiency of infinitesimal dilutions. The principle is that the quantity of action necessary to effect any change is least possible 17. It is accepted in science as a fundamental principle of the universe. The decisive moment is always a minimum, an infinitesimal. The least possible, in our study, is the dilution sufficient to affect the result and bring about reaction.
(ii) The mode of action of the sublingual progesterone dilutions: The route of administration may have a strong influence on the efficacy of the treatment since the distribution and concentration of the hormone at the tissue level varies considerably 18. Sublingual administering of progesterone dilutions results in rapid absorption via the blood vessels under the tongue 19. The multiple locations of progesterone hormone receptors suggests that these hormones might locally bind to receptor of a cell and trigger a response by the cell, in various tissues including trachea, lungs, brain, and brainstem 20-24.
Progesterone is a potent respiratory stimulant 25. Sublingual progesterone dilutions plausibly have potential to activate the L-arginine-nitric oxide (NO) pathway 26. Nitric oxide is endogenously synthesized from the amino acid L-arginine by a family of enzymes, the nitric oxide synthases are released in the airways. L-arginine responses are reported to increase by progesterone, and antiprogesterone treatment decreases the same 27. L-arginine can also be catabolized by arginase. Nitric oxide synthase (NOS) and arginase activities are regulated by T-helper 1 (Th1) and Th2 cytokines, respectively. Allergy is considered to be a Th2-mediated disease, and indeed, arginase activity is increased after allergic sensitization 28. Progesterone strongly inhibits or even reverses arginase activity 29. Since L-arginine is the only physiological substrate for NOS; regulation of L-arginine availability could determine cellular rates of NO production 30. These suggest that progesterone by increasing the amount of substrate for NO can increase the formation of endogenous NO. Besides, progesterone is reported to augment NOS activity 31. The NOS enzyme system is active in airway epithelial cells, macrophages, neutrophils, mast cells, autonomic neurons, smooth muscle cells, fibroblasts, and endothelial cells. The chemical products of NOS in the lung vary with disease states, and are involved in pulmonary neurotransmission, host defense, and airway and vascular smooth muscle relaxation 32. Functionally, NOS exists in constitutive (cNOS) and inducible (iNOS) forms. cNOS seems to protect airways from bronchoconstriction and within seconds releases pM concentrations of NO upon receptor stimulation. iNOS has a modulatory role and releases large quantities (nM concentrations) of NO several hours after exposure 33. Further, Ricciardolo et al 34 have reported that a deficiency of local NO, probably of cNOS derived NO, may be responsible for the increased AHR in asthma. Since our study subjects showed an immediate improvement in pulmonary function we infer that on treatment with the progesterone dilution, cNOS might be getting stimulated.
(iii) Bronchodilation: All our study subjects had a marked improvement in their pulmonary functions within 30 seconds of sublingual progesterone dilution treatment. This finding gets supported by the fact that NO is an endogenously synthesized small, diffusible, highly reactive messenger molecule that can regulate various biological functions within seconds. Its velocity is faster than that of blood circulation time 35. It has a short half life (1–5 s) and one unpaired electron, making it a free radical that reacts with other molecules such as oxygen, superoxide radicals, or transition metals (such as iron bound within haemoproteins). It typically functions in paracrine fashion; NO synthesized in one cell acts on an adjacent cell to bring about a biological response such as smooth muscle relaxation involved in vasodilation 35. Increasing evidence also points to an important role for NO in the regulation of pulmonary function and in pulmonary disease 36,37. The ability of NO to relax smooth muscle has been described in multiple models and muscle types, including airway smooth muscle 38. Sasaki et al 39 have reported that endogenous endothelial NO significantly influences acetylcholine-induced bronchovascular dilation. A recent study on asthma has concluded that NO is a major mediator in providing the most potent physiological protection against airway narrowing in human subjects, namely, the bronchodilation and bronchoprotection after a deep inspiration 40. In addition, NO acts also as a neurotransmitter of the inhibitory nonadrenergic noncholinergic (NANC) nerves. In human central and peripheral airways in vitro, NO appears to account for the bronchodilator NANC response 41. Therefore, administering progesterone dilutions sublingually might modulate the endogenous release of NO and activate molecular mechanisms that induce airway smooth muscle relaxation.
(iv) Self-antidote phenomenon: The self-antidote phenomenon means that study subject who showed worsening at one dilution of sublingual progesterone, showed complete reversal of symptoms and significant improvement in breathing at a higher dilution of the same. This can be explained with respect to the concentration of release of endogenous NO. According to Mark & Timothy42 “supramaximal” doses of nitric oxide were associated with worsening of oxygenation. These observations imply that the optimal dose of inhaled nitric oxide must be determined by titration against the therapeutic target in each patient. That is exactly what we have done in our study when we individually checked several progesterone dilutions on each of our patients, in order to find out the specific right dilution with therapeutic effect for each of them.
(v) Safety of sublingual progesterone dilution therapy: None of the study subjects reported any discomfort or side effects or medical emergencies hence; the therapy was found to be completely safe for the patients. This could be because epithelium-derived NO is reported to be crucial in mediating a protective feedback mechanism. It reversibly suppresses the proliferation of activated human Th1 and Th2 cells, triggered through IFN-? release by Th1 CD4+ T cells down-regulating both Th1 and Th2 responses 43, 44. Thus providing a robust mechanism for local control of the exuberance of all forms of local T cell responses. In conclusion, progesterone dilutions are candidate drugs for the treatment of bronchial asthma. The fact that bronchial smooth muscle may be sensitive to high dilutions of progesterone is interesting because of the close relationships between the immune and neuroendocrine systems. Our study might have important implications for the development of a novel, safe, non-invasive treatment strategy against bronchial asthma and some forms of bronchoconstriction.
Acknowledgements, Conflicts of Interest
Acknowledgements All funding was provided by Russell Roby, MD. No other source of funding was used. Dr. Roby is in private practice as an allergist and all the tests were performed after obtaining an IRB permit and after obtaining an approved consent.
Conflicts of Interest Dr. Roby is in private practice and not affiliated with any outside medical or pharmaceutical entity. Dr. Patricia Richardson is doing research at the University of Texas at Austin and Professor R H Richardson is in the Department of Integrative Biology at the University of Texas at Austin. None of the authors have any conflict of interest. Dr. Shilpa Shah is a research scientist in Mumbai, India.
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* This treatment is not approved by the FDA