THE DYSOX MODEL OF ADRENAL HEALTH AND DISEASE

THE OXYGEN MODEL OF ADRENAL DYSFUNCTION

Majid Ali, M.D.

The intellectual disconnect between endocrinologists and the reality of adrenal dysfunction is breathtaking. In my columns, I strive hard not to subordinate ethics to ideology. Ethics, simply stated, is the study of the consequences of one’s action on others. Ethics is also the study of the consequences of one’s inaction on others when action is needed. If some endocrinologists are offended by my opening statement, I hope they will read this column and then decide if I have allowed ideology to subvert ethics.

All chronically individuals with dysfunctional oxygen metabolism (dysox) suffer clinically significant adrenal dysfunction. Dysox is the state of disrupted oxygen signaling and oxygen-driven bioenergetics.* This personal and clinical view of adrenal dysfunctions is at significant variance from the current thinking in endocrinology. Endocrinologists, with rare exception, continue to be preoccupied with named adrenal syndrome—Cushing’s syndrome, Addison’s disease, Conn’s syndrome, and Sheehan’s syndrome—as well as pituitary tumors and hypothalamic disorders. Such lesions account for an exceedingly small number of chronically ill individuals with objectively and quantifiably detected adrenal dysfunction. This, indeed, is one of the core messages of this column. My assertions in this column are based on extended clinical work with over 7,500 patients with chronic illness and on close analysis of over 900 profiles of the 24-hour urinary excretion of steroid compounds.

This column has nine other core points: First, the adrenal dysfunction of every individual requires individualized support for the gland. Second, the essential “adrenal question” is not what diagnostic label is chosen for someone with a dysfunctional gland—people everywhere are diminished by relentless habitat chemicalization and unrelenting stress, frustration, and anger—but how the adrenal function of that person can be assessed and restored. Third, the degrees of adrenal dysfunction are best assessed clinically, as well as with the measurement of 24-hour urinary excretion of adrenal and gonadal metabolites. Fourth, adrenal regeneration requires spiritual equilibrium and full restoration of oxygen homeostasis. Fifth, all disruptions of the bowel, blood, and liver ecosystems must be effectively addressed for adrenal homeostasis. Sixth, in my clinical experience, the direct short-term adrenal support is optimally provided with hydrocortisone, beginning with small doses of 2.5 mg twice daily to larger doses of ten to twenty mg daily. Seventh, the adrenal gland cannot be understood except through its inter-relationships with the hypothalamic-pituitary axis (HPA), gonadal output, insulin metabolism, energy economy of the body, the oxygen-driven bioenergetics, and chronic stress.

______________________________________________________________________________


The Cushinoid-Addisonian Epidemic

Eighth, there is a “Cushinoid-Addisonian” epidemic—most people with adrenal dysfunction pass from an initial hyperadrenergic (Cushing’s syndrome-like state) to a hypodrenergic (Addison’s disease-like) state. Ninth, an increasing number of young people are “gender-skewed”—females are “male-like” and males are “female-like,”so to speak—and the adrenals play crucial roles in the phenomenon of gender devolution. For an in-depth discussion of these subjects, I refer the readers to Darwin and Dysox Trilogy, the tenth, eleventh, and twelfth volumes of The Principles and Practice of Integrative Medicine.1-3 Before discussing the above issues, below is an illuminating historical footnote.


Rebecca Gerschman—An Unsung Hero

The unsung hero of the field of free radical pathobiology is Rebecca Gerschman, a physiologist at the University of Rochester. In the early 1950s, she investigated the relationships between oxygen toxicity and the adrenal gland, and proposed that oxygen toxicity was mediated by free radicals.4-7It is peculiar that Gerschman’s seminal contributions escaped the notice of most researchers and writers interested in the energetic-molecular basis of health and disease. She observed that adrenalectomy protected rats from oxygen toxicity. She was aware of a 1934 report of Ozorio de Almeida,8 which documented the histological similarity between testicular tissue injury caused by ionizing radiation and oxygen toxicity. Gerschman also knew of the universal theory of Michaelis,9 which held that free radicals were intermediates in oxidation processes. Examining the effect of adrenalectomy on certain types of acutely injured tissues, she observed that the procedure

exerted protective effects and deduced that adrenalectomy slowed the metabolic rate and consequently reduced the need for oxygen-driven reactions. Considering her findings in the larger context of the earlier work of de Almeida and Michaelis, she concluded that oxygen toxicity was mediated by free radicals.

The Cushinoid-Addisonina Transitions

I present the model of Cushnoid-Addisonian transitions to underscore an essential point: The adrenal glands regularly cope with environmental, nutritional, and anger-related stresses with an initial Cushinoid hyperactivity response, which is followed by Addisonian adrenal failure when decompensation occurs. Both the initial Cushinoid and subsequent Addisonian responses are quantifiable (Tables 1-3). Endocrinology textbooks and journals rarely, if ever, address the crucial issue of the adverse effects of toxic environment, toxic foods, and toxic thoughts on the adrenal structure and function. Nor does the endocrinology literature recognize the Cushinoid-Addisonian sequence occurring in people without any of the above-mentioned syndromes. Not surprisingly, endocrinologists act as if their patients are immune to all environmental, dietary, and anger-rnnelated toxicities. They limit their work to textual models of the Cushing’s syndrome, Addison’s disease, Conn’s syndrome, pituitary tumors, and hypothalamic disorders—entities which, as I show below, are exceedingly rare—and neglect adrenal dysfunctions that occurs in all chronically ill individuals.

The Cushing’s syndrome—adrenal hyperactivity caused by adrenal neoplasms and hyperplasia—is a rare disorder, with an incidence of 1 per 100.000 per year, with a female-to-male ratio of 5 to 1.10 The clinical features of the syndrome include: fatigue, excess adipose tissue (“buffalo torso”), protein deficit, facial edema and fat build-up (“moon face”), acne, hirsutism, skin striae, hypokalemia and muscle weakness, adrenal diabetes, osteoporosis, and failure to fight common infections due to immunosuppression.

The Addisons’s disease—adrenal failure putatively due to “primary atrophy,” autoimmunity, tuberculosis, and adrenal destruction by neoplasms—is also a rare disorder. There are no accurate statistics concerning the incidence of Addison’s disease in the United States. A British study reported the incidence of thirty-nine cases per million. The clinical features of the syndrome include: low blood sodium and chloride levels, excess potassium, acidosis, hypotension, hypoglycemia, dehydration, fatigue, and immunosuppression. Among the striking signs of adrenal deficiency in some instances are cutaneous and mucosal pigmentation.

The Conn’s syndrome (primary aldosteronism)—excess production of mineralocorticoid aldosterone due to hyperplasia or neoplasm of zona glomerulosa of the adrenal cortex—is also a rare disorder. Its clinical features include: retention of sodium and water, excessive loss of potassium, metabolic alkalosis, muscle cramps (due to neuronal hyperexcitability), muscle weakness (due to muscle cell hypoexcitability), headaches, and hypertension. In 1955, the prevalence of aldosteronism was estimated to be about one in 2,000 individuals with hypertension. Recently, substantially higher incidences of aldosteronism have been reported in hypertensive populations.12

I furnish the above synopsis is to make a point of crucial clinical significance: The Cushinoid-Addisonian transitions caused by toxicities of environment, diet, and anger produce all possible combinations of symptom-complexes seen in classical adrenal diseases. This is what endocrinologists refuse to accept. Their patients pay dearly for this ethical lapse.

Laboratory Evaluation of Cushnoid-to-Addisonian Transitions

The laboratory assessment of adrenal function presents four special problems: (1) The adrenal glands produce about 50 steroidal moieties by complex pathways and no single steroid can be relied upon for its functional assessment; (2) The adrenal steroidogenesis increases initially to cope with incremental demands followed by marked reductions, but not in any consistent pattern in the production of specific steroids or their metabolites; (3) Adrenal production of androgens, estrogens, and progesterone cannot be separated from gonadal production of these hormones; and (4) The laboratory range of some hormones is extremely wide—for instance the value for the urinary excretion of DHEA used by the Mayo Clinic laboratory is 21 to 2170 mcg/24 hour—making interpretation of the values of individual steroids difficult. Notwithstanding these problems, a suitable profile of steroids—the composition of my choice is shown in Table 1—is extremely valuable.

In cases of acute and severe demands on the adrenal glands, the glands mount a strong Cushnoid response with a marked increase in the urinary excretion of all hormones and their metabolites (Case 1, Table 1). The other end of the spectrum is the Addisonian depletion (complete adrenal failure) in which amazingly no steroids can be detected in the 24-hour urine samples (Case 6, Table 1). Between these two ends of the spectrum are seen examples of Cushinoid-to-Addisonian transitional stages representing varying patterns of overproduction of some and underproduction of other adrenal steroids (Cases 2 to 5, Table 1).

The problem of extremely wide laboratory reference ranges for individual steroids, as mentioned earlier, is tedious. I find it useful to consider the mid-point of the laboratory range for individual hormones and metabolites rather than merely accept the “high” and “low” designations in the report. The data in Table 2 clarifies this point by displaying the 24-hour urinary steroid excretion values for 26 chronically ill adult individuals. Note than when related to the midpoints of the laboratory reference ranges, the aggregate data for these patients were “low” for five, “normal” for one, and “high” for two steroid compounds. Without such an approach, the laboratory values for most patients are designated in error as “normal,” as was done by endocrinologists who reviewed the adrenal data of my patients.

Table 1. The Cushinoid-Addsonian Adrenal Dysfunction. The Initial Cushing’s Disease-Like Overdrive (Case 1*) Is Followed by Addison’s Disease-Like Adrenal Failure (Case 6#). Cases 2 to 5** Illustrate the Intermediate Stages in the Cushinoid-Addisonian Spectrum.

Adrenal Steroid

Case 1

Case 2

Case 3

Case 4

Case 5

Case 6

Pregnanediol

H

H

H

H

L

0

Androsterone

H

H

H

H

L

0

Etiocholalone

H

H

H

N

N

0

DHEA

H

H

N

L

N

0

Pregnanetriol

H

H

N

L

N

0

11-ketoandrosterone

H

N

L

N

L

0

11-ketoetiocholalone

H

N

L

L

L

0

11-OH-androsterone

H

L

L

N

L

0

*Case 1: 54-yr-old woman with hypertension, diverticulitis, palpitations, and severe Katrina-related stress.

#Case 6: 71-yr-old woman with long-standing severe marital stress, polymyalgia, polyarthralgia, and cystitis.

**Case 2: 47-yr-old woman single mom with fibrmyalgia. Case 3: 66-yr-old woman with history of chemotherapy for breast cancer, chronic fatigue syndrome, and allergy. Case 4: 42-old woman with sinusitis, hypothyroidism, and chronic stress. Case 5: 65-yr-old man with renal transplant rejection and hypertension.

The matter of the determination of serum or salivary cortisol levels for assessing adrenal function requires a comment. The results of such tests clearly represent snapshots of the adrenal gland function at the moment of obtaining samples. Such data inform little, if any, about the history of the struggle of the adrenal glands during the preceding years, For example, the serum cortisol levels fail to reveal the presence of increased cortisol turn-over in the body commonly seen in persons with central obesity.

Adrenal Support During a Program for Adrenal Functional Restoration

I do not treat adrenal diseases. I care for chronically unwell individuals with adrenal deficits. The crucial issues of spiritual equilibrium and the restoration of the bowel, blood, and liver ecosystems have been addressed in past columns.10-14 As for providing adrenal support until there is sufficient adrenal regeneration, there are two approaches: (1) direct support with hydrocortisone; and (2) indirect support with raw adrenal extract, phytofactors, and nutrients. Below, I relate how I concluded that direct adrenal support yields superior clinical results in most cases.

In the mid-1980s, I investigated the clinical benefits of bovine raw adrenal concentrate, as well as phytofactors and nutrients for adrenal support. Among the phytofactors, prescribed in combinations and rotations, were daily doses of roots of licorice (500 to 1,000 mg), rehmannia (500 to 750 mg), ashwargandha (100 to 200 mg), and Chinese yam (500 to 750 mg). Among the nutrients were daily doses of pantothenic acid (50 to 150 mg), pyridoxin (25 to 50 mg), riboflavin (10 to 20 mg), and ascorbic acid (1,000 to 2,000 mg). These adrenal factors were prescribed concurrently with antioxidants, minerals, and redox-restorative substances, such as glutathione, MSM, taurine, and others.

In the early 1990s, I compared the clinical benefits of the above factors with those of DHEA, pregnenolone, and androstenodione in daily doses of 25 to 50 mg each for men and for women half as much on alternate days. In the mid-1990s, I undertook a systematic study of hydrocortisone. Based on that experience, in my hands most patients with adrenal deficit respond best to direct adrenal support with hydrocortisone (daily doses of 5 to 20 mg). The short-term use of low-dose hydrocortisone is safe, effective, and without any adverse effects. It is widely misunderstood because it is confused with high-dose synthetic steroid therapy.

The subject of initial adrenal support with hydrocortisone creates unnecessary confusion in the minds of many people uninitiated in this therapy. They fail to see the difference between gentle adrenal support with low-dose hydrocortisone and massive synthetic steroid therapy in common use among the practitioners of pharmacologic medicine.


Adrenal failure, in the bioenergetics context, is but one face of evolution in reverse. To reverse it, we must recognize it as an “oxygen problem.” All oxygen problems can be corrected by oxystatic (oxygen-restoring) therapies.


Adrenal Regeneration and Recovery

The essential points are: (1) Clinical improvement in adrenal function is seen with optimal integrated and individualized plans within months in most cases; (2) Clinical indications of improved adrenal status precede normalization of laboratory values; (3) Some individuals with long-standing disabling illness and severe adrenal deficiency tolerate very low doses of hydrocortisone (1 to 3 mg daily) initially and take several months to accept larger doses (10 t 20 mg) until eventual adrenal recovery occurs in several months; and (4) Individuals with major depression and posttruamatic stress syndrome sometimes show poor clinical response despite robust efforts to support the gland.

Data in Table 3 illustrates the adrenal recovery pattern in a chronically ill 71-yr-old woman with abnormal urinary excretion of adrenal steroids.

Table. 2 Urinary Excretion of Adrenal and Gonadal Steroid Excretion in 26 Patients

With Chronic Illness and Adrenal Dysfunction

Adrenal Steroid

Range

Mid-Range

Mean

Males

Female

Pregnanetriol

47-790

371

306

473.5

H

278.2

L

Oxo-androsterone

8-87

39.5

47

H

36

L

52

H

Hydroxyetiocholalone

180-850

335

361

H

451

H

355

H

Hydroxyandrosterone

195-1500

652.5

640

L

749.1

H

624

L

Androsterone

150-2100

975

886

L

943.9

H

867.7

L

Etiocholalone

280-2100

910

763

L

Not done

Not done

DHEA

13-730

385.5

264

L

695.5

H

110.5

L

Table 3. A Profile of Adrenal Recovery in a 71-Yr-Old Woman with GERD, Episodes of Tachycardia, and Persisting Stress

Steroid

(Reference Range in mcg/gram creatinine)

Pre-Treatment

February 24, 2008

Posttreatment

July 21, 2008

Pregnanetriol (53-530)

132

N

172

N

Androsterone (150-2100)

229

L

943

N

Etiocholalone (280-2100)

243

L

834

N

DHEA (13-730)

31

N

41

N

11-ketoandrosterone (180-850)

1072

H

436

N

11-ketoetiocholalone (8-580)

916

H

300

N

The Adrenal, HPA, Insulin, Energy Economy, and Obesity

Glucocorticoids play crucial roles in the energy economy of the body—obesity is a classical feature of the Cushing’s syndrome—and involve the hypothalamic-pituitary-adrenal (HPA) axis in complex ways. In idiopathic obesity, cortisol turnover rate is increased 15,16 and the HPA axis reactivity is amplified17,18 even though the circulating cortisol concentrations are within the normal range. Interestingly, centrally obese women have lower awakening salivary cortisol levels and enhanced food-induced cortisol release, suggesting the possibility that this reflects enhanced adrenal sensitivity to ACTH. On the other hand, such women also show increased urinary cortisone-to-cortisol ratio—11-hydroxy steroid dehydrogenase type-2 activity is increased—and decreased sensitivity of monocytes to graded dexamethasone treatments in vitro. Their cortisol binding globulin affinity is low and correlates with: (1) higher waist-to-hip ratios; (2) increased plasma glucose and triglyceride levels; and (3) lower HDL cholesterol levels. Glucocorticoid receptor gene polymorphisms have been linked to obesity and hyperinsulinism; however, such effects are certainly less important than dietary and environmental factors, as evidenced by pandemic spread of childhood and teenage obesity rates.


ADRENAL GLAND AND GENDER DEVOLUTION


Our Fermenting Planet and Gender Devolution

Evolution differentiated humans into two genders slowly, over hundreds of millions of years. If the evolutionary differentiative influences, which produced women and men, were to be attenuated or abolished by environmental or genetic factors, one would expect a weakening or gender-defining influences. Such a change would gradually result in loss of gender differentiation, such that women and men become “gender-skewed”—females would become “male-like” and males would become “female-like,” so to speak. If some consistent patterns of such gender-skewing caused by environmental or genetic factors could be recognized, can a unifying model of “gender devolution”—evolution in reverse, so to speak—be proposed to explain a vast array of seemingly disparate observations concerning gender differentiation? In response to this question, I offer the following comments.

The TV ads for Viagra started with the senior citizen Robert Dole and within a few years focused on men in their late fifties. Recently, I noticed that pharmceutical ads for for erectile dysfunction show distressed faces of men in their early forties. That is not surprising. There is an epidemic of low blood testosterone levels and sperm counts in young men in thier late twenties and early thirties. In females of all ages, there are marked rises in the incidences of premature puberty, premenstrual syndrome, endometriosis, polycystic ovary syndrome, and pseudomenopause.

In little girls, gender devolution causes precocious puberty with the development of primary and secondary sexual characteristics, such as the premature appearance of pubic hair, breast enlargement, and menarche.22 In older girls, the phenotypic changes due to gender devolution include hirsutism, male-pattern baldness, alopecia, acne, anovulation, oligomenorrhea, and amenorrhea. In women, there is a higher incidence of premenstrual syndrome, endometriosis, and the Stein-Leventhal syndrome (polycystic ovary syndrome, PCOS).23,24 In older women, we may anticipate rising incidences of cancers of the breast, ovary, and other related organs. Now, let us consider the published data on these subjects. For example, in a study of 17,077 American girls, at age seven, 27.2% of African American and 6.7% of caucasian girls showed such secondary development; at age eight, the corresponding numbers were 48.3% and 14.7%.27 Amazingly, at age three, 3% of African-American girls and 1% of caucasian girls showed precocious developement with breast enlargement and/or appearance of pubic hair.

The Oxygen King Evolved Adrenals to Be Its Crisis Manager

The Oxygen King of human biology evolved the adrenal gland to serve as its primary crisis manager. It preserves the structural and functional integrity of adrenals in many ways. When adrenals falter, oxygen strengthens them by evoking homeostatic responses in other regulatory systems of the body. When the glands are exhausted, oxygen regenerates them. When the Oxygen King is besieged by toxic overloads and is unable to create conditions for adrenal regeneration, the glands fail, collapsing the entire crisis management functions of the body.

When survival is threatened, oxygen mounts a “total-body response” for the maximal effort to counter the threat. Oxygen directs the adrenal glands to release bursts of catecholamines to support the highest level of preparedness throughout the body. Catecholamines —epinephrine, norepinephrine, dopa, and others—are some of the most potent oxidizers in human biology and energize host defenses of all cell populations. Below are the aspects of oxyradical dynamics that support my evolutionary perspective of the oxygen-driven adrenal differentiation and function.

The biochemistry of catecholamines—epinephrine, norepinephrine, 6-hydroxydopamine, 6-aminodopamine, 3,4-dihydroxyphenylalanine (dopa), and dialuric acid—is well established.18-20 All these compounds participate in this state and contribute to oxidative fires of stress response via different pathways. Oxygen facilitates auto-oxidation of catecholamines and the generation of free radicals through several reactions. First, many such compounds undergo spontaneous oxidation (auto-oxidize) when exposed to diatomic oxygen to generate free radicals.24-26 Second, superoxides react directly with catecholamines to produce semiquinone radicals and hydrogen peroxide, the former feeds into many other oxidant chain reactions while the latter can mediate tissue injury by alkylative adduct formation or by redox cycling to produce other toxic oxidizing species. These reactions may be enhanced by redox-active metals such as iron, copper, and manganese, as well as by pro-oxidant toxic metals such as mercury. Third, catecholamines can be oxidized to organic free acids by superoxide produced by cytochrome P-450 activity. Removal of a single electron from such organic compounds can produce molecular species with unpaired electrons, which then enter cellular redox cycles, thus perpetuating free radical injury. Fourth, bursts of catecholamines potentiate many receptor-ligand functions during adrenergic hypervigilence, such as coronary vasoconstriction. The essential point here is that the core mechanism of such responses is oxidosis and is caused by a host of oxidant molecular species.

Closing Comments: Oxygen Is An Organizer, Not a Substrate

Chemistry and medical textbooks describe oxygen as a substrate in biologic reactions. For example, hemoglobin is described to pick up oxygen in the blood. Oxygenases are said to add oxygen in reactions catalyzed by them. Hypoxia-inducible factors (HIFs) are supposed to sense the presence of oxygen. Mitochondria are considered to utilize oxygen. Chemoreceptors are assigned the roles of recognizing the concentrations of oxygen in blood and cells.

I do not consider oxygen as a substrate for enzymes, sensing proteins, mitochondria, or chemoreceptor cells. Oxygen is an organizer, not just as a passive substrate. For reasons of crucial clinical significance in medicine, oxygen should be clearly seen for what it is: a mover, a shaker, an organizer. In this light, oxygen “rides” large protein complexes, such as hemoglobin. Oxygen re-arranges protein complexes, such as those included in the HIF family. Oxygen drives electron and protons chain reactions in cellular organelles mitochondria. Oxygen awakens cells: chemoreceptors. Oxygen activates cells, such as in glomus cells in aorta and the carotid arteries.

The crucial clinical importance of the Dysox Model of Adrenal Dysfunction is that it requires an unfaltering focus of all relevant issues of oxygen homeostasis regardless of the patient’s adrenal status on the CushinoidAddisonian spectrum—in the early Cushinoid overactivity phase, in the eventual Addisonian failure, or in the intervening states of overactivity or depletion. In clinical practice, I consider it imperative for creating conditions that foster adrenal functional restoration and recovery.

References

1. Ali M. The Principles and Practice of Integrative Medicine Volume X: Darwin, Oxygen Homeostasis, and Oxystatic Therapies. 3rd. Edi. New York. Insitute of Integrative Medicine Press.

2. Ali M. The Principles and Practice of Integrative Medicine Volume XI: Darwin, Dysox, and Disease. 2000. 3rd. Edi. 2008. New York. Insitute of Integrative Medicine Press.

3. Ali M. The Principles and Practice of Integrative Medicine Volume XII: Darwin, Dysox, and Integrative Protocols. 2008. New York. Insitute of Integrative Medicine Press.

4. Gerschman R, FennWo. Ascorbic acid content of the adrenal in oxygen poisoning. Am J Physiology. 1952;171:726.

5. Gerschman R, FennWo. Ascorbic acid content of the adrenal in oxygen poisoning. Am J Physiology. 1954;176:6-8.

6. Gerschman R, Gilbert DL, Nye SW, et al. Oxygen poisoning and x-irradiation: A mechanism in common. Science. 1954;119:623-626.

7. Gerschman R. Historical introduction to the “free radical theory” of oxygen toxicity. In: Oxygen and Living Processes: An Interdisciplinary Approach.1999. Ed: Gilbert DL. pp 44-46. Springer Verlag, Berlin, Germany.

8. Ozorio de Almeida A. Recherches sur l’action toxique des hautes pressions d’oxygene. CR Soc Biol 1934;116:1225-1227.

9. Michaelis L. Fundementals of oxidation and respiration. Am Sci 1946;34:573-596.

10. http://www.surgical-tutor.org.uk/system, August 24, 2008).

11. (www.nadf.us/diseases/addisons)

12. Shargorodsky M, Zimlichman, R. Primary Aldosteronism: The Most Frequent Form of Secondary Hypertension? IMAJ 2002;4:32-33.

13. Dunkelman SS, Fairhurst B, Plager J, et al. Cortisol metabolism in obesity. J Clin Endocrinol Metab. 1964;24: 832–841.

14. Hautanen A, Adlercreutz H. Altered adrenocorticotropin and cortisol secretion in abdominal obesity: implications for the insulin resistance syndrome. J Intern Med. 1993;234: 461–469.

15. Marin P, Darin N, Amemiya T, et al. Cortisol secretion in relation to body fat distribution in obese premenopausal women. Metabolism. 1992;41: 882–886.

16. Pasquali R, Cantobelli S, Casimirri F, et al. The hypothalamic-pituitary-adrenal axis in obese women with different patterns of body fat distribution. J Clin Endocrinol Metab. 1993;77: 341–346.

17. Syed AA, Weaver JU. Glucocorticoid Sensitivity: The Hypothalamic-Pituitary-Adrenal -Tissue Axis. Obesity Research. 2005;13, 1131–1133.

18. Selye H. Stress in Health and Disease. 1973. Butterworth, Boston.

19. Fuller RW. Control of epinephrine synthesis and secretion. Fed Pro. 1973;32:1772-1781.

20. Misra HP, Fridovich I. The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxidase dismutase. J Biol Chem 1972;247:3170-3175.

21. Cohen G, Heikkila RE. The generation of hydrogen peroxide, superoxide radical and hydroxyl radical by 6-hydroxydopamine, dialuric acid and related cytotoxic agents. J Biol Chem 1974;249:2447-2452.

22. Herman-Giddens ME, Slora EJ, Wasserman RC, et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics. 1997;99:505–512.

23. Nestler JE. Metformin for the Treatment of the Polycystic Ovary Syndrome. N Eng J Med. 2008;358:47-54.

24. de Muinich Keizer SM, Mul D. Trends in pubertal development in Europe. Hum Reprod Update.

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