The Oxygen Model of Hormonal Disorders – Majid Ali, M.D.

Hormone Replacement Therapy (HRT) or Hormonal Receptor Restoration Therapy

Majid Ali, M.D.

Menstrual and menopausal disorders respond well to non-hormonal oxystatic therapies. For nearly a decade, I have considered those disorders to be caused fundamentally by disruptions of oxygen signaling.1,2 Oxygen orchestrates the biosynthesis of cholesterol—the queen mother of all steroids—as well as all of steroids derived from cholesterol. Oxygen also preserves the functional and structural integrity of hormone receptors. I intended this to be the main point of this column. However, I recognized this view would be considered a large leap of faith by readers. They have not likely encountered it in print or spoken word. As I began writing this column, I struggled with the best way to make my case in a single article. Frustrated with initial and clumsy attempts to succinctly state that case, I picked up Baynes and Dominiczak’s Medical Biochemistry and chanced upon the following sentence, “Most of the enzymes involved in converting cholesterol into steroid hormones are cytochrome P450 proteins that require oxygen and NADPH. In its simplest form, this enzyme complex catalyzes the replacement of a carbon-hydrogen bond with a carbon-hydroxyl bond: hence, the collective term mono-oxygenase.”3

Then I recalled the traditional teaching that the monoxygenase reaction inserts one atom of oxygen into an organic substrate while the other oxygen atom is reduced to water. In that scenario, oxygen is seen as a passive substrate and the enzyme is the primary mover. Then came the eureka moment. In a flash, I saw a role reversal in which oxygen was the principal actor and the enzymes responded to its cues on the stage of human biology—meaning, oxygen signaling transforms enzyme structures and functions. In my vision, diatomic oxygen lends its one arm to bring life to cytochrome enzymes, while with its second arm it produces water to create aqueous conditions to sustain the enzymes it activates. Enzymes fold and unfold—changing their functionalities as their structures are altered—in response to oxygen signals. In that instant, I conceived the format in which I would weave the established facts of oxygen signaling, receptor integrity, and steroid chemistry with my clinical observations and laboratory data to present the tapestry of the “Unifying Dysox Model of Hormone Dysfunctions.”

In the hours following my eureka moment, I wondered if I could come up with simple analogies to illustrate the central role of disrupted oxygen signalling in my hypothesis. I saw three possibilities: (1) a scenario of a sheep farmer with his dogs and sheep; (2) an image of oxygen as the master “membrane detergent”; and (3) a picture of “cytochrome steal.” Before I describe those analogies, I will describe some aspects of hormone receptor and selected case studies to illustrate crucial aspects of the Dysox Model. I will follow that with a brief review of the central role of oxygen signalling in steroidogenesis to provide a framework for my “oxygen view” of hormones.

The Age of Hormone Receptor Burn-Out

Hormone receptors are proteins with complex and malleable structures, some traversing the cell membranes multiple times, and some anchored to cell innards.4,5 Nature conferred remarkable malleability and resilience on hormone receptors—that resilience, however, is not enough to withstand the onslaught of chemicals presently soaking human habitat. Among the consequences of that global chemicalization is the age of hormone receptor burn-out, which has brought forth epidemics of menstrual and menopausal disorders—severe menstrual syndrome, too much flow, scant flow with clots, anovulatory state, endometriosis, polycystic ovarian syndrome, and what may be designated as “pseudomenopause”—a state of presumed menopause in which menstruation resumes with robust non-hormonal integrative managment plans and remains regular for years to come.

The hormone receptors can be viewed as crank-shafts that are turned by hormone molecules working as cranks. The turning of those crank-shafts transmits information to various hormonal pathways which, in turn, activate specific enzymes, hormone response elements (pre-genes), and genes. In this context, I use the term receptor burn-out for a state of receptor unresponsiveness caused by being disfigured, twisted, jammed, clogged, or otherwise rendered dysfunctional. There is an enormous number of environmental pollutants with strong structural homology with natural hormones. Some of those compounds have a greater affinity for hormone receptors than the hormones themselves. Those compounds either jam or disarm hormone receptors. Such endocrine disruptions cause reproductive dysfunctions in humans and animals on an unprecedented scale.6-8

Reversing Amenorrhea and Pseudomenopause With RRT

In 1998, I put forth the oxidative model of menstrual disorders.1 That model evolved during my work with patients with fibromyalgia, chronic fatigue syndrome, and related energy-deficit disorders who developed polymenorrhea, oligomenorrhea, and amenorrhea lasting for more than six months. In that long-term clinical outcome study of 35 women with amenorrhea, oligomenorrhea, and pseudomonas treated with non-hormonal, oxystatic therapies. Menstrual cycles were normalized completely in 12 out of 14 amenorrheic women (with improvements in the remaining two) and in 19 of 21 women with oligomenorrhea. The pertinent data for the 29 patients in the oligomenorrhea/ polymenorrhea subgroup are displayed in Tables 1 and 2. Those clinical observations led me to the formulation of the hypothesis of the Oxidative Menstrual Dysfunction (OMD) model, which essentially link cellular chemicalization with disrupted oxygen signaling causing menstrual abnormalities.1

Table 1. Data for 21 Patients with Oligomenorrhea and Polymenorrhea. Reference 1

Average Age (Range: 17 to 48)


Duration of menstrual dysfunction (months )


Predominantly oligomenorrheic


Predominantly polymenorrheic


Table 2. Outcome Data for 21 Patients with Oligomenorrhea and Polymenorrhea. Reference 1

Complete restoration to monthly menstrual cycles


Near-complete restoration


Incomplete restoration


RRT Versus HRT

In 1998, I also recognized that the hormone receptor restoration therapy (RRT) is superior to the prevailing hormone replacement therapy (HRT), whether HRT is given with synthetic or the so-called bioidentical hormones.2 Specifically in the RRT model, the following seven aspects of hormone/habitat were explored: (1) hormone-receptor-gene dynamics; (2) age of synthetic estrogen and xenoestrogen overload; (3) the association of menstrual and menopausal derangements with oxidative and dysox states; (4) quality of life issues concerning the control of menopausal symptom-complexes with non-hormonal therapies; (5) the impact of RRT vs. HRT approaches on health parameters of postmenopausal women; (6) the pros and cons of RRT vs. HRT in the prevention of coronary heart disease, stroke, and osteoporosis; and (7) the risk of breast, uterine, and other cancers with synthetic estrogens. Arguments were marshalled for the view that the optimal management of peri- and postmenopausal syndromes requires robust efforts to effectively address relevant bowel and liver issues. In that article, I also focused on supporting the thyroid/adrenal/pancreas trio with non-gonadal endocrine therapies was also addressed.

Illustrative Case Studies

Below, I include three case studies to illustrate three core aspects of the Unifying Dysox Model of Hormone Disorders. Each case sheds light on the clinical significance of the model.

Case 1: Polymenorrhea Treated With the RRT Model

In June 2006, a 43-year-old woman presented with twice-monthly periods, symptomatic autonomic intolerance, and persistent fatigue. The integrative RRT plan for her focused on robust bowel and liver detox therapies, antioxidants, redox-restorative therapies, antigen immunotherapy for IgE-mediated responses, and 15 mg of Armour thyroid extract. No synthetic hormone or phytofactor remedies with hormonal effects were included in her program between January 2007 and June 2007. Pertinent laboratory and clinical outcome data of this case are presented in Table 3. Note that she had serious hypocholesterolemia which improved modestly during the period of integrative management.

During the June 2007 visit, the patient spoke the following words, “My periods became normal in frequency and amount of flow within three months of following the treatment plan [June to September 2006]. I took 15 mg of Armour thyroid. You told me I could double up on the dose because it is a small dose. But I didn’t need to. Then in April [2007] I ran out of Armour. I did not have a period for seven weeks. This was the longest I went without a period. Can a small dose of Armour make a difference like that?” Her menstruation was restored with reintroduction of 15 mg of thyroid extract.

Table 3. Case 1. Polymenorrhea and Dysautonomia

in a 43-Year-old Woman Treated Successfully With RRT

June 2006 June 2007

Laboratory Data

Cholesterol 133 147

Estradiol 105 116

Progesterone 0.3 1.5

Testosterone N/A 38

FSH 7.88 22.1

Clinical Outcome*

Overall symptoms -3 +2

Dysautonomia -3 +2

Sleep -3 +4

*Clinical outcome scale: -4 to +4

Case 2: Control of the Postmenopausal Syndrome With the RRT Model

A 51-year-old, six-year postmenopausal patient was seen in 2003 for severe hot flashes, myalgia, gastroesophageal reflux disorder, and chronic fatigue. Serum C-reactive protein value was 11.3 mg/L. The last menstrual period was in 1997). In 2004, she bought a bakery business, which required her to work 12 to 16 hours a day, and brought heavy exposure to flour dust and molds. The data for business stress and changes in serum estradiol levels are correlated in Table 4. She responded well to the integrative plan, and then was absent for follow-up. She returned in March 2007 with a severe relapse of postmenopausal symptoms, persistent fatigue, and myalgia. The significant rises in the serum levels of IgE antibodies with specificity for four molds are shown in Table 5. The integrative RRT plan for her focused on robust oxystatic therapies, bowel and liver detox regimens, antioxidants, redox-restorative agents, and hydrogen peroxide foot soaks. No hormone therapy was administered between January 2007 and June 2007. Her program compliance was good, and she reported a near-complete relief of her symptoms.

Table 5. Case 2. A 51-Year-Old Woman With Stress-Induced Fall in Estradiol Levels Followed by Improvement With RRT. Scale of stress: 1 to -4

2003 2004 2005 2006 3/2007 5.2007

Estradiol pg/mL 56.9 27.7 N/A N/A zero 26

Stress 1 2 3 4 3 1

Table 5. Case 2. Increased Mold Exposure between Years 2004 and 2007 Is Indicated by Rising Levels of Allergen-Specific IgE Antibodies.

Specific IgE               2004            2007

Alternaria                  127           192

Epicoccum                 163            203

Fusarium                   127            167

Penicillium                  55            132

Case 3: Treatment of Amenorrhea with the RRT Model After the Failure of High-Dose Synthetic Hormone Therapy

A 36-year-old presented with a four-year history of Type I diabetes and chronic fatigue syndrome. Following menarche at age 13, she had regular menstrual cycles for nineteen years. Within several months of the onset of diabetes and chronic fatigue, she developed oligomenorrhea for which her gynecologist prescribed combined estrogen and progesterone therapy without success. A diagnosis of “hypothalamic brain suppression” was made by her gynecologist. She was treated with large doses of Provera and Premarin without benefit. Other symptoms included troublesome memory difficulties, episodes of palpitations, abdominal bloating and cramps, and chronic constipation. Prior to the age of 32, she suffered from acne, some nasal allergy and some “food reactions.” She received multiple amalgam fillings, but otherwise considered herself an athletic individual who lifted weight and ran regularly. She developed chronic knee pain which she attributed to overexercising. She was prescribed Naprosyn and given steroid injections for pain without much benefit. She received multiple courses of antibiotics for upper respiratory infections. Her weight had been stable at 120 lbs.

On physical examination, she appeared weak, dehydrated, and anxious. She weighed 132 lbs with a pulse of 66/min and blood pressure of 110/80. Her abdomen was bloated and deep tenderness was elicited in both lower quadrants. Multiple deeply situated myofascial trigger points were detected in soft and periarticular tissues in limbs and torso.

An individualized integrated management program was initiated following the general guidelines described later in this article, with a focus on restoring the bowel, blood, and liver ecosystems. Her synthetic hormone prescriptions were discontinued. Instead, she was put on initial doses of 10 mg of soybean-derived progesterone and 10 mg of pregnenolone in daily doses, and 15 drops daily of tinctures of black cohosh, licorice, dong quai, and red raspberry. Her menstrual flow resumed, first irregularly and scantily, later with increasing regularity within eight months. At fourteen months, she reported “regular” menstrual flows at 26-29 days, lasting for four to five days. Her serum hormone assay data are given in Table 6.

Table 6. Case 3. A 36-Year-Old Wman With Amenorrhea Corrected 14 Months With a Receptor Restoration Therapy (RRT) Approach. Sequential Serum Hormone Levels Obtained at 5, 8, and 11 Months Are Displayed.


5 Months

8 Months

11 Months

Estradiol pg/mL




Progesterone ng/mL




Testosterone ng/mL












Prolactin Units ng/mL




* All values were determined with blood samples drawn during the early third week of the menstrual cycle.

Case 4: Estrogen Abuse Prevented with the RRT Model

In April 2004, a 58-year-old woman was seen for incapacitating fibromyalgia, tachycardia, episodes of hot flashes, sweating, anxiety, multiple soft tissue trigger points,and episodes of vaginal spotting. In 2002, her gynecologist prescribed 0.625 mg of Premarin and 10 mg of Provera for control of hot flashes. Her symptoms recurred after an initial period of relief. The hormone doses were increased progressively when her symptom recurred after each increase. Despite incremental doses, her symptom-complex worsened. An endometrial biopsy showed endometrial hyperplasia with atypical changes. Table 7 shows sequential changes in serum estradiol levels establishing the existence of a serious and persistent estrogenic overdrive that caused endometrial hyperplasia during 2004. A robust integrative program addressing all relevant issues of the Dysox Model was implemented in April 2004 while the doses of synthetic hormones were decreased until such therapies were discontinued. A dose of 30 mg transdermal progesterone and 1.25 mg estradiol was included in her program. Her symptom-complexes were markedly relieved by year 2006 when her serum estradiol levels was 71 pg/mL.

Table 7. Case 4. A 58-Year-Old Woman With Fibromyalgia, Tachycardia, Severe Menopause Syndrome and Endometrial Hyperplasia Caused by Estrogenic Abuse. Her Symptom-Complexes Were Markedly Reduced With the Clinical Application of the Dysox Model. Scale of Overall Symptom Score 0-4+


Estradiol pg/mL

Symptom Score


Estradiol pg/mL

Symptom Score








































*Stress caused by husbands hospitalization for a serious illness. ** Note a rapid drop in serum estradiol level following that stress.

This case illustrates a crucial clinical aspect of the Dysox Model: large doses of synthetic hormones—notwithstanding the symptom relief with each increment in dose—not only fail to yield long-term benefits but also set the stage for the development of endometrial hyperplasia and cancer. What is required in such cases is an intelligent application of the Dysox Model.

Oxygen Orchestrates the Biosynthesis of Cholesterol and Steroidal Hormone

A brief outline of the cytochrome P450 system is necessary to show how oxygen orchestrates the biosynthesis of cholesterol and of gonadal hormone derived from cholesterol. Cytochrome P450s (CYPs, P450s, or CYP450s) are a superfamily of iron-containing proteins found in bacteria, archaea and eukaryotes (more than 6400 distinct CYP sequences as of October 2006). A measure of the genetic diversity of this superfamily is that humans have 57 genes and more than 59 pseudogenes divided among 18 families of cytochrome P450 genes and 43 subfamilies.9-12

In general, members of this family occur as components of multicomponent electron transfer chains, called P450-containing systems, which are involved in metabolism of a wide range of exogenous and endogenous compounds, including drugs, industrial compounds, synthetic hormones, and xenohormones. The main importance of the CYP450 family in the present context is that the most common reaction catalyzed by them is monooxygenase reaction (insertion of one atom of oxygen into an organic substrate while the other oxygen atom is reduced to water).

Animal CYPs are primarily membrane-associated enzymes found either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells. P450s play central roles in the biosynthesis of cholesterol, steroids (including estrogen and testosterone), and vitamin D metabolism. These enzymes are equally involved with further metabolic processing of both natural and synthetic estrogens and progestins.

According to the prevailing CYP nomenclature, genes encoding for CYP450 enzymes, and the enzymes themselves, individual member enzymes are given the designation of CYP, followed by an Arabic numeral indicating the gene family, a capital letter indicating the subfamily, and another numeral for the individual gene. For example, CYP11A1 (also known as P450scc) is involved with cholesterol side chain scission). CYP19A (P450arom, aromatase) occurs in the endoplasmic reticulum of ovaries, testes, brain, and fat catalyzes aromatization of androgens to estrogens.

The resting state of the P450 protein is as oxidized Fe3+. In the first step, the binding of a substrate initiates electron transport and oxygen binding—availability of functional oxygen, in the current context, brings to life the union of the enzyme and its substrate. It is noteworthy that electrons are supplied to the CYP by other proteins (cytochrome P450 reductase, ferredoxins, or cytochrome b5 to reduce the heme iron). Molecular oxygen (again in the prevailing view) responds to the then reduced iron. To complete the cycle, an iron-bound oxidant oxidizes the substrate to an alcohol or an epoxide, regenerating the resting state of the CYP.

My focus on oxygen here was drawn by my clinical observations. Specifically, I needed to understand the scientific basis of how bowel and liver detox procedures correct menstrual and menopausal disorders when the treatment plans do not include gonadal hormone therapies. Later I realized that the validity of my view is equally well supported by the utter simplicity of the model. I offer the following analogy of a shepherd and his sheep dogs and flock to illustrate my central point here.

Pro-inflammatory Roles of Estrogens and the Dysox Model

Oxygen governs the inflammatory response and adjudicates man-microbe conflicts. That was the title of my column of May 2005.13 Synthetic estrogens and xenoestrogens are potent pro-inflammatory agents. A clear understanding of the pro-inflammatory roles of synthetic estrogens, progestins, and androgens is key to understanding the Unifying Dysox Model of Hormone Dysfunctions. The following are major mechanisms by which synthetic estrogens, xenoestrogens, and synthetic androgens evoke and perpetuate pathologic inflammatory responses, and thereby set the stage for dysoxic hormonal disorders 14-18:

Postmenopausal hormone therapy (PHT) is associated with raised blood levels of a protein called CRP, a well established marker of inflammation.

PHT is also associated with raised blood levels of another well established marker of inflammation called IL-6.

PHT is associated with raised blood levels of a class of proteins found in the matrix—materials that hold cells together in tissues—called MMP-9. The increased levels of these proteins indicate an accelerated breakdown of the matrix substances.

PHT is associated with raised blood levels of a substance that anchors cells together called sICAM. Again, the raised levels of this substance indicate the presence of molecular inflammation and increased stress on normal cohesion among cells .

The case for pathologic proinflammatory effects of synthetic hormones becomes even stronger when the effects of controlled ovarian hyperstimulation (COH) caused by potent synthetic hormones used for in vitro fertilization (IVF) are carefully examined.

Oxygen, Hypoxia Inducible Factors, and Hormone Receptors

Protein systems in living tissues are dynamic. Proteins fold and unfold in response to cues in their molecular environment to assume various functions.19-21 Though well-protected by chaperons (which are proteins and so require their own chaperons), proteins misfold with excessive stress and become dysfunctional. The protein biosynthesis is closely matched with proteolysis to replace the disfigured or broken down units. The proteins that make up hormone receptors are not an exception to this protein order of human biology. It is well established that for a large number of proteins, proteolysis occurs in response to changes in the prevailing conditions of oxygen. In the following paragraph, I present some information about one family of proteins that display a high degree of responsiveness to oxygen signalling, which is of evident relevance to the Unifying Dysox Model of Hormone Dysfunctions.

Hypoxia-inducible factors (HIF) are a large family of proteins that display a high degree of responsiveness to oxygen signalling. I include here brief comments about one member of this family, hypoxia-inducible factor 1a (HIF-1a1) to shed light on one important aspect of the Unifying Dysox Model of Hormone Dysfunction. (HIF-1a is a basic helix-loop-helix transcription factor of the PAS superfamily. It plays a central role in cellular adaptation to diminished reduced oxygen availability.22,23 It senses and responds to oxygen deficit (becomes activated) and strives to restore oxygen homeostasis by: (1) inducing glycolysis, and angiogenesis to maintain cellular energetics; (2) inhibits cell proliferation and DNA repair to limit energy consumption; (3) activating a sleuth of its target genes, including those that encode erythropoietin, vascular endothelial growth factor, PGK1, and ARNT (also known as HIF-1ß)24); (4) recruiting the transcription co-activator p300/CBP25,26; (5) binding to the hypoxia-responsive element in the promoter27; (6) functionally antagonizing the oncogene Myc via protein-protein interactions; (7) up-regulating the CDKN1A/p21cip system; and (8) down-regulating MSH2 and MSH6 down-regulation.28 For all those, and probably others as yet unrecognized roles, HIF-1a has been designated as a master regulator of oxygen homeostasis for cell survival. Disruptions of all the above genetic and signaling pathways create the dysoxic conditions that set the stage—directly or indirectly—for the development of menstrual and menopausal disorders.

As mentioned earlier, oxygen seldom enters in descriptions of the biosynthesis and metabolism of cholesterol and steroidal hormones. Here is an interesting quote from Medical Biochemistry: “The exact mechanism by which this is achieved [reduction of HMG CoA reductase activity] remains unclear but may involve intracellular oxygenation of cholesterol to more potent enzyme inhibitors.29 In light of the facts of steroidal chemistry, pro-inflammatory effects of synthetic hormones, and oxygen-sensing molecular moieties presented above, below are the three analogies mentioned in the opening paragraphs of this column.

The Farmer With His Dogs and Sheep

A farmer’s dogs sleep in front of his ranch house. His sheep stay in the shed at the rear of the house. In the morning he makes his breakfast. The smell of his cooking wakes his dogs. Minutes later, the farmer appears at the door with food for his dogs. The dogs eat and then walk to the shed. The sheep get ready to be herded by the dogs, just as they have done for years.

Who starts the sheep? The farmer’s cooking? His appearance at the door? The dogs? Or the morning light? It is simply a case of Pavlovian conditioning, someone might say. Yes. That is true at one level. At another level, the sun created the conditions to form the planet Earth. The earth created the conditions to make farming possible. Now the earth spins to give the farmer its morning clues. The farmer creates the conditions for the dogs and the dogs for the sheep.

The sun created the oxygen conditions on the Earth which, in turn, created the conditions in which life began, differentiated, and grew into diverse life forms. The primordial cells evolved in the highly reducing ambient conditions on the Earth’s surface about three billion years ago when the atmosphere did not have appreciable amounts of free oxygen. The defining event in biology occurred when the primordial cells learned the ability to harness solar energy to split water into hydrogen and oxygen—hydrogen for chemical bond energy and oxygen to provide the organizing influence for the evolutionary surge that built highly complex energetic and metabolic molecular systems. Among the most sophisticated of those systems are thousands of P450 enzymes. Indeed, the P450 enzyme systems seemed to have evolved not only to provide for highly efficient electron transport protein systems for serving the growing energetic needs of cells but also to protect primordial cells from direct oxygen toxicity. So, today we have the oxygen-driven respiratory ATP generation system. I present this subject at length in Darwin, Dysox, and Oxystatic Therapies, the third volume of The Principles and Practice of Integrative Medicine. 30

Returning to my oxygen/monooxygenase hypothesis, ambient oxygen appeared on planet Earth long before the family of P450s did. The enzyme evolved in response to oxygen signaling, rather than the other way around. Thus, in the evolutionary context it is not tenable to hold that oxygen responds to enzyme signals.

Simply stated, the sheep farmer analogy allows us to consider the oxygen/monooxygenase dynamics at a deeper level. It illustrates the role reversal I saw in my eureka moment: oxygen is the principal actor and the enzymes respond to its cues on the stage of human biology, notwithstanding the traditional teaching in which the enzyme handles oxygen—inserts oxygen into organic compounds—to exert its enzymatic role. The core clinical point here is this: the oxygen view of enzyme functions in health and disease compels the clinician to recognize and address all relevant oxygen issues, regardless of the diagnostic label used in chronic illness.

Cytochrome Steal

I introduce the term cytochrome steal in this column to refer to a functional deficit of P450 enzyme systems required for the biosynthesis and breakdown of estrogens, progesterone, and testosterone. Such a deficit occurs in the body because the normal functions of these enzymes are being impaired by: (1) synthetic chemicals in the air, food, and water; (2) drugs; (3) industrial pollutants; (4) synthetic hormones; and (5) industrial pollutants with hormone-like activities (xenohormones). Since P450s are also recognized and important players in cellular energy generation, it should not come as a surprise that menstrual and menopausal syndromes are frequently associated with energy deficit states—the clinically observed phenomena that led me to the oxygen signaling hypothesis in the first place.1,2 The best known examples of energy deficit states are fibromyalgia, chronic fatigue syndrome, following chemotherapy for malignant diseases, and environmentally-induced disorders (9/11-related chronic illnesses and others).

The phenomenon of cytochrome steal—in my view—provides the scientific basis for the clinically-observed benefits in the menstrual and menopausal syndromes when the gonadal hormonal functions are restored with bowel and liver detox measures.

Oxygen: The Master Membrane Detergent

A cell membrane separates the internal order of a cell from external disorder. In 1987, I proposed the model of the oxidative leaky cell membrane state to draw attention to the clinical manifestation of cell membrane dysfunction and injury caused by incremental and cumulative oxidative stress.31 In 1998, I proposed that model of cell membrane dysfunction as a major pathogenetic component of menstrual and menopausal syndromes.1,2 In my May 2007 column, I wrote that I consider the abnormalities of insulin functions in hyperinsulinemia, the so-called metabolic syndrome, and Type 2 diabetes as the consequences of plasticized (chemicalized) and hardened cell membranes which immobilize the insulin receptors embedded in them.32 The image of oxygen as the “master membrane detergent” arose as I searched for an analogy to explain the expected consequences of chemicalized, hardened and “greasy” cell membranes. Specifically, how cell membranes in such states might interfere with the functionalities of hormone receptors embedded in them. And in the context of the Dysox Model, how oxygen-induced proteolysis (digestion and breakdown) of the membrane proteins might restore receptor functions. In an earlier section, I described the wide range of protein-modulating roles of oxygen mediated through altered dynamics of hypoxia-inducible factor 1a.

Simply stated, oxygen serves as a cell membrane detergent and restores hormone receptor function in menstrual and menopausal disorders. Just as oxygen is the keeper of white sand on a beach—it degrades and eliminates organic matter in it—so it is the keeper of cell membrane and degrades and clears up the greasy, proteinaceous materials on them.

I recognize there are elements of speculation in all three analogies described above. However, I believe the analogies are valid for their essential message when seen in light of the enormous body of available clinical, epidemiologic, and experimental data on the subject.

Clinical Implications of the Unifying Dysox Model of Hormone Dysfunction

Models in clinical medicine are put forth for two reasons: to enhance the understanding of complex issues and to offer workable simplicities in therapeutic efforts. Within these columns, and the eleven volumes of The Principles and Practice of Integrative Medicine, I continue to offer dysox models of various clinicopathologic entities because I believe they meet these two criteria. Specifically, I have attempted to show how the Unifying Dysox Model of Hormone Disorders sheds light on: (1) delineation of the links between the oxygen-driven enzymatic systems and detoxification pathways; (2) potent pro-inflammatory effects of synthetic estrogens and xenoestrogens; (3) the pathogenesis of menstrual and menopausal disorders within the context of oxygen signalling; (4) furnish sound scientific basis for the observed clinical superiority of the hormone receptor restoration (RRT) over the traditional hormone replacement therapy (HRT); and (5) provides clear scientific rationale for treating hormone dysfunctions with nutritional and detox therapies. In past columns, it has been explained how therapies that address issues of acid-alkali imbalance, oxidant/antioxidant regulation, and clotting-unclotting equilibrium serve as oxystatic (oxygen homeostatic) therapies.33-36 Such therapies focus on issues on the central roles bowel and liver detox therapies to address the matters of altered gut microbiota, mold allergy and mycotoxicosis, increased bowel permeability, and impaired liver detox. For additional information, I refer readers to Integrative Nutritional Medicine, the fifth volume of The principles and Practice of Integrative Medicine.37

Adjunctive Gonadal Hormone Therapies

I consider supplemental gonadal regimens for menstrual and menopausal disorders as adjunct therapies, and not the primary treatment . Such therapies are optimally used for limited periods of time only when nutrient, phytofactor, and detox measures fail to offer relief within weeks. It must be recognized that in a minority of patients with menstrual and menopausal disorders, the use of hormone replacement therapies becomes necessary despite the best efforts to address all relevant issues addressed in the Dysox Model. Those therapies are discussed at length in various articles in this issue of the Townsend Letter.

Closing Comments

In closing, I present a unifying Dysox Model of Hormone Disorders that has strong explanatory power for: (1) patterns of abnormal hormonal levels in various “non-hormonal” disease; (2) altered oxygen signalling that underlie those hormonal shifts; and (3) documented clinical superiority of RRT over HRT; and (4) improved clinical results in control of menstrual disorders when oxystatic, nutritional, and detox measures. I hope that the proposed model will be considered and put to test by others.


1. Ali M: Amenorrhea, oligomenorrhea, and polymenorrhea in CFS and fibromyalgia are caused by oxidative menstrual dysfunction (OMD-I) J Integrative Medicine 1998; 2:101-124.

2. Ali M: Oxidative menopausal dysfunction (OMD-II):hormone replacement therapy (HRT) or receptor restoration therapy (RRT)? J Integrative Medicine 1998;2:125-139.

3. Baynes J, Dominiczak MH. Medical Biochemistry, Mosby, New York 1999:197.

4. Darnell J, Lodish H, Baltimore D. Molecular Cell Biology. 1990. New York. Scientific American Books. Distribted by WH Freeman and Company. pp 784-802.

5. Ali M. The Principles and Practice of Integrative Medicine Volume I: Nature’s Preoccupation With Complementarity and Contrariety. 2005. New York. Canary 21 Press. 2nd edition.

6. Ali M: RDA:Rats, Drugs, and Assumptions. 1995. Denville, New Jersey, Life Span Books.

7. Robert J. Kavlock, George P. Daston, et al. Research Needs for the Risk Assessment of Health and Environmental Effects of Endocrine Disruptors: A Report of the U.S. EPA-Sponsored Workshop. Environmental Health Perspectives. 1996;104, Supp 4; 715-740

8. Ali endocrine disruptors

9 2003 UN Global Environment Outlook Year Book,

10. Shang E., et al. Environ. Sci. Technol., 40(9). 3118 – 3122 (2006).

11. International Union of Pure and Applied Chemistry. “cytochrome P450”. Compendium of Chemical Terminology Internet edition. Danielson P (2002). “The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans”. Curr Drug Metab 3 2002;6: 561-97.

12. Martin J. The Meaning of the 21st Century: A Vital Blueprint for Ensuring Our Future. 2006. UK. Eden Books.

13. Baynes J, Dominiczak MH. Medical Biochemistry. 1999. Mosby, New York. page 193

14. Cushman M. Effects of Estrogen and Selective Estrogen Receptor Modulators on Hemostasis and Inflammation. Annals of the New York Academy of Sciences. 2001;949:175.

15. Curb D, Prentice RL, Bray PF, et al. Venous thrombosis and conjugated equine estrogen in women without a uterus. Archives of Internal Medicine. 2006; 166:772-780.

16. Herrington DM, Reboussin DM, Brosnihan, KB, et al. Effects of Estrogen Replacement on the Progression of Coronary-Artery Atherosclerosis. N Eng J Med. 2000;343:522-529.

17. Elena F. Verdú, Yikang Deng et al. Modulatory effects of estrogen in two murine models of experimental colitis. Am J Physiol Gastrointest Liver Physiol. 2002;283:G27-G36.

18. Sano M. Cognitive effects of estrogens in women with cardiac disease: what we do not know. The American Journal of Medicine. 2005;7:612-613.

19. Zhong H, Angelo M. De Marzo, et al. Overexpression of Hypoxia-inducible Factor 1 in Common Human Cancers and Their Metastases. Cancer Research 1999;59, 5830-5835, November 15, 1999]

20. Hiraga T, Kizaka-Kondoh S, Hirota K, et al. Hypoxia and Hypoxia-Inducible Factor-1 Expression Enhance Osteolytic Bone Metastases of Breast Cancer. Cancer Res. 2007; 67:4157-4163.

21. Rezvani HR, Dedieu S, North S, et al. Hypoxia-inducible Factor-1{alpha}, a Key Factor in the Keratinocyte Response to UVB Exposure. J. Biol. Chem.2007; 282:16413 – 16422.

22. Bunn HF, Poyton RO. Oxygen sensing and molecular adaptation to hypoxia. Physiol Rev. 1996;76:839–885.

23 .Semenza GL. Regulation of mammalian. O 2 homeostasis by hypoxia-inducible factor 1. Annu. Rev. Cell Dev. Biol. 1999;.15:551–578.

24. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J. Biol. Chem. 1995;270:1230-1237.

25. Arany Z, Huang LE, Eckner R, et al. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription. Proc Natl Acad Sci U S A. 1996;93: 12969–12973.

26. Bhattacharya S, Michels CL, Leung MK, et al. Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev. 1999;13:64–75.

27. Wang GL, Semenza GL. Hypoxia-inducible Factor-1 Mediates Transcriptional Activation of the Heme Oxygenase-1 Gene. J Biol Chem. 1993;268:21513–21518.

28. Koshiji M, To KK, Hammer S, et al. Suppression of Hypoxia-inducible Factor 1 {alpha}(HIF-1 {alpha}) Transcriptional Activity by the HIF. Mol Cell. 2005;17:793–803.

29. Ali M. Leaky Cell Membrane Disorder (monograph). 1987. Teaneck, NJ, 1987.

30. Ali M. The Principles and Practice of Integrative Medicine Volume III: Dysoxygenosis and Oxystatic Therapies. 2005. New York. Canary 21 Press. 2nd edition.

31. Ali M. Juco J, Fayemi, A, et al. The dysox model of asthma and clinical outcome with integrated management plan. Townsend Letter-The examiner of Alternative Medicine. 2006;274:58-61. (May 2006)

32. Ali M. The dysox state and chronic parasitic infestations. Townsend Letter-The examiner of Alternative Medicine. 2006;276:82-84. (July 2006)

33. Ali M. Hurt human habitat and energy deficitHealing Through Restoration of Krebs cycle chemistry. Townsend Letter-The examiner of Alternative Medicine. 2006; 279:112-115.

34. Ali M. The dysox model of renal insufficieny and improved renal function with oxystatic therapies. Townsend Letter for Doctors and Patients.2005;267:101-108.

35. Ali Townsend diabetes

36. Ali M. Oxygen governs the inflammatory response and adjudicates the man-microbe conflicts. Townsend Letter for Doctors and Patients. 2005;262:98-103.

37. Ali M. The Principles and Practice of Integrative Medicine Volume V: Integrative Nutritional Medicine: Nutrition Seen Through the Prism of Oxygen Homeostasis. 2005. New York. Canary 21 Press. 1999. 2nd edition

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s