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The Unifying Oxygen Model of Gonadal Health

Majid Ali, M.D.

Oxygen is seldom, if ever, discussed in discussions of gonadal hormonal health, menstrual disorders, testosterone deficiency, and hormone replacement therapies. This, in my view, is a serious error. Women and men pay an enormous price for it in lost opportunities of not restoring gonadal health by addressing the issues of toxicities of foods, environments (both macro-ecologic and micro-ecologic aspects). Beyond that, they also lose opportunities of preventing a host of nutritional, environmental, autoimmune, infectious, and degenerative diseases.

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 links cellular chemicalization and grease buildup to disrupted oxygen signaling causing menstrual abnormalities.1 In this series of tutorials on gonadal health, I integrate these observations with additional clinical and research observations.

Unifying Dysox Model of Hormone Disorders

Menstrual disorders respond always well to effective non-hormonal oxystatic therapies. In many instances, such therapies are also effective for menopausal syndromes So I consider these disorders to be caused fundamentally by disruptions of oxygen signaling.1,2 To put this in a braoder context, I include here brief comments about adrenal and thyroid disorders. Functional adrenal deficits associated with clear laboratory evidence for adrenal disorders generally respond well to non-hormonal oxystatic therapies that include effective self-regulation, restoration of bowel ecology, and liver detoxification therapies. So I consider these disorders also to be caused fundamentally by disruptions of oxygen signaling.3,4 Thyroid disorders are ubiquitous in all regions of the world. Again, my clinical experience on this matter is unequivocal: the long-term clinical results are far superior when patients with hypothyroidism are managed with robust integrative programs that include thyroid extract preparations, rather than when they are prescribed synthetic thyroid agents. Most notably, as I documented with illustrative case histories in other publications, the thyroid function can be normalized in most patients with hyperthyroidism with integrative plans that do not include surgical resection of the gland or its destruction with radioactive iodine or with drugs in current use for that.

For those and other reasons, I focus on the hormone receptor dynamics as seen through the prism of oxygen homeostasis. The model of integrative endocrinology which emerged from those considerations is distinct from that the one prevailing in clinical medicine. In past writing, I have used the term Unifying Dysox Model of Hormone Disorders for my "oxygen view" of clinical endocrinology.

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. In the fall I intended this to be the main point of my Oxygen Homeostasis Column for one of the fall 2007 issue of the Townsend Letter. 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

 

Related Tutorials

* Amenorrhea, Oligomenorrhea, and Polymenorrhea in CFS and Fibromyalgia Are Caused by Oxidative Menstrual Dysfunction

* Oxidative Menopausal Dysfunction: Hormone Replacement Therapy (HRT) or

Receptor Restoration Therapy (RRT)?

 

The Eureka Moment

In the traditional teaching monoxygenase reactions are considered to insert 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

 

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

Average Age (Range: 17 to 48)

29

Duration of menstrual dysfunction (months )

17

Predominantly oligomenorrheic

15

Predominantly polymenorrheic

6

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

Complete restoration to monthly menstrual cycles

76%

Near-complete restoration

14%

Incomplete restoration

10%

 

Receptor Restoration Therapy (RRT) Versus Hormone Replacement Therapy (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.

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 Oxygen Model of Gonadal Health

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:

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

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

3. HRT 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.

4. HRT 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 .

5. 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.

Hormone Receptors, Oxygen, and Hypoxia Inducible Factors

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 Below I offer three analogies to be considered in light of the facts of steroidal chemistry, pro-inflammatory effects of synthetic hormones, and oxygen-sensing molecular moieties presented above.

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 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 brings the morning clues to the farmer to get ready for the day. The farmer creates the conditions for the dogs and the dogs for the sheep.

Returning to my oxygen hypothesis, the sun created the prevailing oxygen conditions on the Earth which, in turn, created the conditions in which thousands of P450 enzymes evolved over hundred of millions of years. Needless to say, ambient oxygen appeared on planet Earth long before the family of P450s did. The primordial cells evolved about three billion years ago when the Earth's atmosphere did not have appreciable amounts of free oxygen. Indeed, the P450 enzyme systems and related other complex electron transport protein systems evolved to protect primordial cells from direct oxygen toxicity, as well as to permit those cells to harness the solar energy in a far more efficient 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

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.

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 present context, how oxygen-induced proteolysis (digestion and breakdown) of the membrane proteins might restore receptor functions. In a companion tutorial, I describe 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.

My three analogies may seem far-flung to some readers. 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 Oxygen Model of Gonadal Health

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 signaling; (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 Immunology and Integrative Nutritional Medicine, the fourth and fifth volume of The principles and Practice of Integrative Medicine.37

Adjunctive Hormone Therapies

A core tenet of The Unifying Oxygen Model of Gonadal Health is that supplemental hormone regimens must never be considered to be the complete treatment of hormonal disorders. For example, it is common—and, in my view, a serious—mistake to prescribe synthetic hormones to treated the premenstrual syndrome among young girls. As for the for the menopausal syndrome, hormone replacement therapy with synthetic hormones can usually avoided with robust measures to restore hormone receptor function. Even when adjunct hormone therapies become necessary, they are optimally used for limited periods of time when nutrient, phytofactor, and detox measures fail to offer relief within weeks. In the case of chronic hypothyroidism, it is often necessary to administer long-term natural hormone It must be recognized that even in such cases, we need just as sharp a focus on nutritional, herbal, and detox therapies..

Closing Comments

In closing, I present a unifying Oxygen Model of Gonadal Health that has strong explanatory power for: (1) patterns of abnormal hormonal levels in various "non-hormonal" diseases; (2) altered oxygen signaling underlying those hormonal shifts; and (3) documented clinical superiority of RRT over HRT. I hope that the proposed model will be considered and put to test by others.

References

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 1999:338-339.

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, http://www.unep.org/geo/yearbook/yb2003/

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

List of Tutorials

The Unifying Oxygen Model of Gonadal Health

* Polycystic Ovary Syndrome - Part 1: A Body State of Evolution In Reverse

* Polycystic Ovary Syndrome _ Part 2: Surgical Removal of Cystic Ovaries

* Amenorrhea, Oligomenorrhea, and Polymenorrhea in CFS and Fibromyalgia Are Caused by Oxidative Menstrual Dysfunction

* Hormone Replacement Therapy (HRT) or Receptor Restoration Therapy (RRT)?

* Pro-inflammatory Roles of Estrogens

 

 

 

 

 Related Tutorials

The Unifying Oxygen Model of Gonadal Health

* Amenorrhea, Oligomenorrhea, and Polymenorrhea in CFS and Fibromyalgia Are Caused by Oxidative Menstrual Dysfunction

* Hormone Replacement Therapy (HRT) or Receptor Restoration Therapy (RRT)?

* Pro-inflammatory Roles of Estrogens

*Polycystic Ovary Syndrome - Part 1: A Body State of Evolution In Reverse

*Polycystic Ovary Syndrome _ Part 2: Surgical Removal of Cystic Ovaries