It is proposed that amenorrhea, oligomenorrhea, and polymenorrhea in chronic fatigue syndrome (CFS) and fibromyalgia are aspects of an "oxidative menstrual dysfunction" (OMD-I) that occurs as a consequence of global oxidative damage to microecologic cellular and macroecologic tissue-organ ecosystems of the body. Thus, OMD-I is considered as one facet of the broad spectrum of accelerated oxidative injury to: (1) matrix, plasma membranes, and mitochondria (3M ecologies); (2) coagulation cascade, complement system, and capsases (3C pathways); (3) enzyme pathways involved with oxygen transport and utilization; (4) enzyme pathways involved with detoxification pathways; (5) enzyme pathways involved with synthesis of sex and non-sex hormones; (6) enzyme pathways involved in hormone receptor synthesis; and (7) regulatory hormone-receptor- gene dynamics. In support of the OMD-I model, clinical outcome data for 35 women is presented. Menstrual cycles were normalized completely in 12 of 14 amenorrheic women (and improved in the remaining two) and in 19 of 21 women with oligomenorrhea or polymenorrhea with therapies that addressed issues of redox homeostasis and damaged bowel, blood, and liver ecosystems, but did not employ synthetic estrogens or other hormones.
        Menstrual irregularities in CFS and fibromyalgia are common and are generally assumed to be due to gonadal insufficiency. The standard therapies for such disorders employ a variety of regimens of synthetic hormones to correct the putative estrogen deficiency. The OMD-I model challenges that view and proposes oxidative pathogenetic mechanisms for hormone-receptor-gene dysregulations in fibromyalgia and CFS. Furthermore, normalization of menstruation in such disorders with therapies that restore oxidatively damaged bowel, blood, and liver ecosystems provides a new insight into the relationship between pathophysiology of those organs and menstrual dysfunction. Some essential aspects of redox and hormonal homeostasis are reviewed to underscore the enormous complexities of the menstrual function, and to show that the prevailing use of synthetic hormones for menstrual dysregulation in fibromyalgia and CFS is neither rational on theoretical basis nor acceptable on empirical grounds.

The OMD-I model cannot be understood in the narrow context of primary or secondary ovarian failure leading to estrogenic insufficiency. Rather, it calls for a deeper understanding of redox homeostasis in the human microecologic cellular and macroecologic tissue-organ systems as well as a comprehensive view of redox-hormone-receptor-gene activation dynamics of the pathophysiology of menstruation. Indeed, dissociated from the broader context of oxidative ecologic injuries and efficacy of redox-normalizing therapies in fibromyalgia and CFS, the OMD-I model is reduced to mere conjecture. Specifically, the OMD-I model is presented, and its clinical significance defined, in light of the following considerations:

The details of individualized and integrative management are given after describing the case histories.

CASE STUDIES

Case 1

    A 20-year-old woman presented with severe fatigue, Hashimoto's disease, weight gain of 25 pounds, dryness of skin, lightheadedness, "spaciness", and amenorrhea of two years duration. Her sexual development was considered abnormal by her mother with delayed menarche at age 16 and poor mammary gland development. However, her menstrual cycles had been regular with normal flow until age 18 when she stopped having periods after a highly stressful school situation that lasted for several months. A month prior to coming to the Institute, she had undergone resection of a dermoid cyst of the ovary diagnosed during extensive endocrinologic work-up for amenorrhea. She had suffered from eczema in childhood. Her mother had suffered from Graves disease. Three months earlier she had undergone removal of a 1.5 cm mature cystic teratoma of the left ovary and a 3.5 cm benign mucinous cystadenoma of the right ovary. On physical examination, she was 63 and one-half inches tall and thin. Pharynx was injected with scant thin mucoid discharge. The thyroid gland showed mild diffuse enlargement without discrete nodules. The breasts were poorly developed. There was mild, poorly localized tenderness in the left lower quadrant of the abdomen. The remainder of the examination was non-contributory.
        The salient laboratory test results were as follows: WBC, 5,100; Hb, 13.9; platelet count, 240,000; ferritin, 25 mg/ml (12-156); cholesterol, 215 mg/dL; triglycerides, 282 mg/dL; HDL, 25 mg/dL; AST, 23 U/L (0-42); ALT, 21 U/L (0-48); vitamin B12, >2,000 pg/ml (>200); folic acid, 7.3 ng/ml (>1.9); thyroid antimicrosomal antibodies, markedly elevated at 477(<0.3); thyroglobulin antibodies, 15.3 U/ml (<1); LH, 4.7; ANA, <1:40) FSH, 4.6; estradiol, 0.9; prolactin, 8 U/ml; cortisol, 15mcg/dL (5-25 am); TSH, <0.1 (later 4.5 when on synthroid); T4, 4.7; T3U, 28.7%; triiodothyronine, 295 ng/dL (60-181); raised 24-hour urinary excretion of androsterones (see column #1 in Table 3 for details); and moderate to high levels of IgE antibodies with specificity for Alternaria, Aspergillus, Penicillium, Candida albicans, Hormodendrum, Cephalosporium, and Mucor.

Clinical Management and Outcome

The clinical management plan was individualized for the patient with special focus on restoring the bowel, blood and liver ecosystems. Over a period of eight months, she received eleven injections of Intramuscular 5 and 6 protocols (See Tables 11 and 12 for compositions of the protocols). Six months into the integrative program, she had a scant menstrual flow. Four months later, she reported having three monthly cycles similar to those she had before the onset of amenorrhea.

* Reference ranges. The letter H indicates values above the reference range.

Case 2

A 36-year-old presented with a four-year history of Type I diabetes and chronic fatigue syndrome. Her menstrual cycles became infrequent with sparse flow within months of the onset of diabetes and chronic fatigue syndrome. A diagnosis of "hypothalamic brain suppression" was made by her gynecologist. Her 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. A meniscus tear was suspected and she underwent arthroscopic knee surgery without relief of pain. She received multiple courses of antibiotics for upper respiratory infections. Her weight had been stable at 120 lbs.

At age 32, she developed disabling fatigue over a period of a few months, felt hungry at all times, craved breads and bagels, experienced blurred vision, and lost ten pounds in weight. A blood test showed a blood glucose level of 400 mg/dL and the diagnosis of Type I diabetes was made. Her diabetes regimen included metformin (500mg), Glucotrol (10mg b.i.d) and insulin (regular one to two units b.i.d and lente 15 to 20 units daily). She had no family history of diabetes.

Following menarche at age 13, she had regular menstrual cycles for nineteen years. Within several months of onset of diabetes and chronic fatigue, she developed oligomenorrhea for which her gynecologist prescribed combined estrogen and progesterone therapy without success. Several months later she experienced complete cessation of menstruation, which proved refractory to multiple attempts at hormonal manipulation (including Provera, synthetic estrogens, and later a daily dose of 100 mg of progesterone) and lasted for a period of about fourteen months till her initial visit to the Institute.

On physical examination, she appeared weak, dehydrated, and anxious. She weighed 132 lbs. Her pulse was 66/min and BP 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.

Salient laboratory data were as follows: WBC, 4,800; Hb, 13.1; platelets, 210,000; Hb A1C 5.6 percent; cholesterol, 174 mg/dL; triglycerides, 40 mg/dL; uric acid, 1.3 mg/dL; sodium, 132 mmol/L; potassium, 4.5 mmol/L; and glucose, 138 mg/dL; estradiol, 45 ng/L; 17-OH-progesterone, 1.0 ng/dL; testosterone, 23 ng/dL; prolactin, 5.2 mcg/L; LH, 2.1 U/L; FSH, 8.5 U/L; and DHEA, 772 ng/dL. Her plasma insulin levels were as follows: fasting, 3 units; 3 at 30 minutes after glucose load, 3 at one hour, 3.2 at two hours, 3 at three hours, and 3 at four hours. The fasting blood sugars ranged from 90 to 307 during the week preceding initial consultation.

Clinical Management and Outcome

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 4.

Case 4

A 43-year-old woman presented with Grave's disease of eight-week duration. Her symptoms included persistent heart palpitations, hand tremors, a "restless sleep pattern," memory difficulty, increased appetite, increased frequency of bowel movements, and "liver flushes." Her general health previous to the present illness had been "very good." Cardiology work-up had been negative.

She was prescribed a daily dose of 15 mg of Tapazole and 20 mg of propranolol by her endocrinologist prior to her initial consultation at the Institute for the purpose of substituting pharmacologic regimens with an herbal and nutritional program. She was put on an integrated management program with the following herbs: hawthorn berry extract, 2 ml twice daily; Lemon balm, passion flower, and motherwort.

Other pertinent laboratory data included: Radioactive iodine uptake at 5 hours was 31% and that at 24c hours, 54%; WBC, 4,600; Hb, 13.5; platelets, 172,000; serum testosterone level, 15 ng/dL; FSH, 25.9 mIU/ml; estradiol, 51 pg/ml; LH, 19.8 mIU/ml; prolactin, 9.1 ng/ml; vitamin B12, 541 pg/ml; ferritin, 34.9 ng/ml; folate, 16.2 ng/ml; MOST test (high-resolution microscopic oxidative stress test) showed 3+ oxidative coagulopathy, 2+ rouleaux formation, and diminished motility of WBCs.

Outcome

Clinical and laboratory normalization of the thyroid function was achieved in nine months. Her menstrual function was restored within six months of beginning the integrated program. Four months later, extreme family stress caused anxiety and depression, and she experienced some sweating and had a single episode of palpitations. However, she reported no change in her menstrual cycle.

Case 5

A 39-year-old woman presented with a seven month history of amenorrhea, chronic disabling fatigue, cognitive disorder, irritable bowel syndrome, inhalant allergy, atopic dermatitis, frequent upper respiratory infections, recurrent episodes of sore throat and sinusitis, daily headaches, sleep disorder, and chronic vaginitis. She had received multiple courses of antibiotics and steroid therapy for infectious and allergic symptamology.

The laboratory findings included the following: serum DHEA-sulfate, 49 mcg/dl (131-362); WBC, 4300; Hb, 13.7; serum bilirubin, 1.9 mg/dL; serum folate, 3.8 ng/mL; TSH, 2.5; T4, 8; T3, 30%; cholesterol, 150 mg/dL; triglycerides, 170 mg/dL; EBV VCA-IgG >170 AU; EBV NA-Abs 79 AU; high-resolution microscopy, 3+ primordial life forms; oxidative coagulopathy, 3+; granulocyte motility, 2+; serum aluminum level, 14.1 mcg/L; serum mercury 2.7mcg/L; moderate to high levels of allergen-specific IgE antibodies with specificity for Candida albicans, Aspergillus, Alternaria, Penicillium, Cephalosporium, Hormodendrum, Mucor, and epicoccum.

Follow-up

Thirteen months after beginning the program, the clinical outcome scores representing relief of symptoms (range: -4 to +4) were as follows: fatigue, -4 to +3; headache, -3 to +4; myalgia, 3+; memory loss, -3 to +2; and no episodes of URI and canker sores. The menstrual flow resumed on irregular basis after 14 months, and regular monthly menstrual flow on a 26-30 day cycle was established in 22 months.

Case 6

A 15-year-old with a four-year history of Crohn's disease presented with arrested growth and failure to develop secondary sexual characteristics. On the day of initial consultation, she weighed 55 pounds and measured 57 inches in height. She was a pale, emaciated young woman with severe and diffuse muscle wasting. She seemed exhausted and experienced visible difficulty just sitting up in the chair. Other details of the case, including the salient laboratory findings, have been previously detailed.

Clinical Management and Outcome

The individualized management plan included strong support for the antioxidant and enzyme defenses as well as for the bowel, blood, and liver ecosystems within the broad guidelines described later in the article. In addition, she received 11 injections of the intramuscular protocol and 19 infusions of the intravenous protocol over a period of twenty months.

Clinical Outcome

During the first 18 months of the program, she gained 4 1/2 inches in height and 26 pounds in weight (no gain in height or weight was observed during the first four months of the program). The use of steroids and other drugs was discontinued after about nine months of instituting the integrative plan. She was symptom free except for occasional cramps and loose BM. Her disabling chronic fatigue was relieved. She felt well enough to attend a summer camp after nearly four years of absence from the camp. She began development of secondary sexual organs. Five weeks prior to completing the manuscript of this article, she reported her first menstrual cycle lasting for three days.

Case 7

A pale, emaciated 16-year-old girl presented with a ten-year history of persistent and intractable Crohn's disease. She had received multiple courses of antibiotics and steroids, beginning with the first course administered to control acute colitis at the time of initial diagnosis established with a colonic biopsy. She had been on prednisone in doses of 30 to 5 mg during the preceding 18 months. On examination, she was obviously and severely malnourished, weighing 65 pounds and measuring 54 inches. Discrete and confluent lesions of pyoderma gangrenosum ranging in size from less than one centimeter to six centimeters and involving both lower legs and feet were observed. The ulceration of the skin and oozing of sanguinous discharge caused her socks and undergarments to stick to her skin in many areas. Other details of the case including laboratory test results, have been previously reported.

Clinical Management and Outcome

Her general condition improved steadily during the first four months of treatment. The use of steroids was discontinued. Her incapacitating chronic fatigue was relieved, and her skin ulcers healed. On most days, she was almost completely free of colitis symptoms. She began to develop secondary sexual characteristics (pubic hair and breasts), which had been arrested for almost two years. However, no gain in height or weight was observed during that period and in the following three months. After that time, she began to grow, gaining 17 pounds in weight and two and one-half inches in height during the following 15 months. Prednisone was discontinued. She received 21 weekly (or less frequently at some times due to scheduling difficulties) intravenous infusions over a period of 14 months. At the 20-month follow-up, she reported a gain of six inches in height and a "normal" regular menstrual flow every 26-29 days lasting for three to five days.

Case 8

A 37-year-old woman presented with a history of "pancolitis" for which she had been hospitalized once or twice yearly during the ten preceding years. She received broad-spectrum antibiotics on regular basis during those years. Other diagnoses made by her previous physicians included asthma (treated with Proventil, Maxair, Atrovent, and Aerobid), gastric ulcer with positive H. pylori antibody test, parasitic infestations (including E. hartmanni and Blastocystis hominis), rheumatoid arthritis, frequent canker sores, and episodes of light-headedness.

Two years prior to her initial visit at the Institute, she developed severe "flu" and was given antibiotics and steroids. Some weeks later, she developed severe nausea, palpitations and numbness following "bombing of her and her neighbor's apartments for bugs" by her landlord. An MRI scan ordered by her neurologist revealed demyelinating lesions.

She was an active, vigorous teenager. Following menarche at age 12, she had regular monthly menstrual flows for about 17 years when her periods became irregular, often coming at two-to-three month intervals. Her menstrual flow became scant. Eight months prior to her initial visit at the Institute, her menstruation ceased altogether.

The salient laboratory data were as follows: WBC, 6,000; Hb, 11.8; platelets, 267,000; cholesterol, 144 mg/dL; T4, 8.47 ug/dL; T3 1.07 uptake units; TSH, 1.91 IU/ml; bilirubin, 1.4 mg/dL; BUN, 9 mg/dL; urine pH, 6.0; sed. rate 62 mm; rheumatoid factor 1:256; vitamin B12 , 467 pg/ml; a normal CT scan of abdomen; 3+ score for primordial life forms on high-resolution microscopy of peripheral smears; low 24-hour urinary excretion values for 11-ketoetiocholanolone and undetectable amounts of 11-OH-etiocholanolone. Assay of IgE antibodies with specificity for nine molds, including Alternaria, Aspergillus, Mucor, Candida and Epicoccum, showed moderate to high levels. The presence of a non-obstructing left ureteral calculus was suspected on an IVP.

Clinical Management and Outcome

Like other patients included in this report, she was started on an individualized, integrated management protocol that focused on damaged bowel, blood, and liver ecosystems. The only hormonal support included in her program was 1/6th teaspoon of wild yam-derived progesterone cream applied to chest daily during the last weeks of the cycle and a daily dose of 12.5 mg of DHEA. No estrogen therapy was prescribed. She declined prescribed intramuscular vitamin injections.

At the five month follow-up, she reported dramatic clinical improvement in her chronic fatigue and colitis symptoms, a weight gain of 20 pounds, and near complete resolution of her headache. At 15 months, she reported regular periods at 28-29 day intervals with the flow "as it used to be." She returned three months later with a history of episodes of chest pain, arthralgia, memory difficulties, pericardial effusion diagnosed by echocardiography of several weeks duration, and a diagnosis of systemic lupus erythematosus. That illness began after the death of her grandmother, to whom she was very close.

Case 9

A 31-year-old woman presented with disabling chronic fatigue of four year duration which developed after highly stressful personal circumstances. She was an active, healthy teenager. Her menarche was at 15, and her menstrual cycles were regular during the first few years. She was prescribed an oral contraceptive (exact type unknown to the patient) for severe PMS after a negative laparoscopy for suspected endometriosis. One year after the onset of disabling fatigue, she developed speech difficulty and facial numbness one week after receiving dental braces. Her neurologic symptoms subsided six weeks later. However, an MRI scan showed early demyelinating lesions. She discontinued wearing the braces five months later and remained free of symptom for one year. Her personal life became highly stressful again. Her neurologic symptoms recurred after dental "bleaching." The diagnosis of multiple sclerosis was then established independently by two neurologists and she was prescribed variously neurontin, carbamazepine, betaserone and interon. Notwithstanding multiple attempts to control her progressive neurologic symptoms with drugs, her general condition deteriorated to a point that walking became very difficult, and she had frequent falls. Other pertinent features of her past history included recurrent episodes of sinusitis, chronic constipation, dizzy spells, and cognitive difficulties. feof right side hand, A significant element in ic . Soon after that her cycles became irregular, occurring every five to seven weeks, with some periods of amenorrhea.

The pertinent laboratory data included the following: WBC, 5800; Hb, 15 g/dL; estradiol, 46.45 pg/mL; FSH, 3.6 mU/mL; LH, 5.7 mU/mL; prolactin, 5.3 ng/mL (all hormone values represent 12th day of the cycle); testosterone, 53 ng/dL; serum potassium, 3.2 mEq/L; ALT, 56 IU/L; PLF, 3+; (1+ four months after beginning the program); antinuclear and Lyme antibodies, negative; T4, 6.7 ug/dL; T3 uptake, 1.02 uptake units; TSH, 1.12 uU/mL; cobalamine, 714 pg/mL; ferritin, 60.55 ng/mL; folate, 10.7 ng/mL.

A 24-hour urinary steroid analysis revealed markedly low to undetectable values of several metabolites. Table 7 shows the steroid profile before and eight months after beginning an integrative plan.

Clinical Management and Outcome

As a part of her individualized integrative program, her intravenous therapies included the following: 23 hydrogen peroxide infusions, each with an intramuscular injection ( IM6 or IM5 on alternate basis); 7 fatigue IV infusions; and 18 EDTA chelation infusions. After eighteen months of the program, she reported "near complete" control of her neurologic symptoms and disabling fatigue. Her premenstrual symptoms were markedly reduced and her cycles approached a monthly rate. Note that the value for androsterone excretion is higher after treatment.

Case 10

A 27-year-old woman presented with four-year history of fibromyalgia, CFS, depression, asthma, TMJ, chronic sinusitis, canker sores, recurrent yeast vaginitis, extensive and amenorrhea of one-year duration. Her menarche was at 12, and she had regular periods for three years with severe premenstrual symptoms. She attempted suicide at age 15, which was followed by menstrual irregularities. Surgery for chronic sinusitis offered her little benefit. Chronic stress of depression, fibromyalgia and related symptoms was compounded by a difficult divorce one year prior to her first visit to the Institute. Pertinent laboratory data were as follows: WBC, 4700; Hb, 13.7; platelets, 280,000; uric acid, 1.9; cholesterol, 204; albumin, 4.1; urinary steroids DHEA, 0; androsterone, 0; estradiol, 18; FSH, 5.1; LH, 4.97; prolactin, 5.1; PLFs, 4+; OC, 4+; erythrocyte membrane damage 3+.

Integrative Management and Outcome

Her menstrual cycle nearly normalized within four months of instituting the integrative plan.

Case 11

A 43-year-old woman presented with chronic fatigue syndrome of 5 year duration and migraine attacks of 22-year duration. Her menstruation had become increasingly irregular during the preceding two years. Her menstrual cycles stopped four months prior to her initial visit, and amenorrhea lasted for another four months during the early of management.

Pertinent laboratory data included the following: WBC, 7100; Hb, 12.9; cholesterol, 324 mg/dL (253 mg/dL four months after beginning the program without using cholesterol-lowering drugs); triglycerides, 116 mg/dL; PLF, 4+; T4, 4.48 ug/dL; T3 uptake, 0.9 uptake units; TSH, 4.75 uU/mL; cobalamine, 471 pg/mL; folate, 11.8 ng/mL; ferritin, 17.9 ng/mL; estradiol, 67.3 pg/mL; FSH, 2.05 mU/mL; LH, 7.3 mU/mL; prolactin, 26.6, ng/mL; (sample drawn in the third week of the menstrual cycle); 24-hour urinary lead excretion, 16 ug/g creatinine, cadmium, 2.3 ug/g markedly decreased or undetectable adrenal metabolites (see Table 9). PLFs, 3+; erythrocyte crenation, 3+.

Clinical Management and Outcome

Her menstrual cycles became regular after eight months of beginning the integrative program. She received 21 infusions of hydrogen peroxide and 12 of fatigue IV. Overall response 2-3+.

Case 12

A 38-yeas-old woman with amenorrhea of four month duration suffered headaches for many years, and debilitating CFS, insomnia and anxiety for four years. The pertinent laboratory data were as follows: WBC, 5400; Hb, 13.4; FSH, 93.2 U/L; LH, 45.8 U/L; estradiol, 28 ng/L; ANA, negative; Ig-E antibodies with specificity for the mold profile detected (9 of 9). A benign cyst was diagnosed with laparoscopic examination; High androsterone; TSH, 0.03; T4, 12.7 mcg/dL; T3 uptake, 34%.

The following quote describes her illness in her own words:

I'm frightened about CFS. I can't sleep. I have no periods now. I have restless leg syndrome. Breathing is an effort. My chest hurts all the time....as if I have been hit hard in my chest. For a long time I could not breathe deeply. Sleeping is an effort. The sleep specialist tells me I have restless leg syndrome and that's why I can't sleep. I was a runner, a very high energy level person, even as a child. Now I can't do anything. I have had panic attacks. The other day I went to give a speech, but thought I was going to collapse. I was a heavy coffee drinker, and a heavy drinker. My parents overdrank. I nearly killed myself from drinking once. I've seen Ayurvedic doctors, sleep specialists, pulmonary doctors, about 35 MDs in all. I have done trigger points, acupuncture, homeopathy. I saw 5 psychiatrists. One of them concluded I have ADD, gave me antidepressants. I tried all of them. Nothing worked. No one believes I have chronic fatigue. I will try until I get better or I die. My MD says I have a mental problem. I know I have become claustrophobic now.

She reported a menstrual cycle lasting for two days in the third month of her integrative management without the use of any hormones.

Case 13

A 30-year-old woman presented with a history of progressive chronic fatigue and myalgia of about 25 month duration. A year earlier, she divorced after an extremely stressful family life. She had become increasingly oligomenorrheic about 18 months previously after many years of "normal" menstrual cycles. Her menstruation ceased 6 months prior to her visit to the Institute.

At age 14, she was diagnosed to suffer from Crohn's disease. Three years later she underwent small bowel resection after medical management had failed. Recurrence of symptoms necessitated resection of an additional segments of small and large bowel. The two operations left her with a life time of abdominal bloating, diarrhea, and malabsorption. She also suffered from oxalate nephrolithiasis.

Pertinent laboratory data included the following: Hb, 10.9 gm/dL; WBC, 6900; cholesterol, 95 mg/dL; vitamin B12 , 173 pg/ml; FSH, 4.1 mIU/ml; prolactin, 10 ng/ml; estradiol, 83 pg/ml; T4, 5.4 mcg/dL; T3 uptake, 28%; and TSH, 2.7 mIU/ml; and moderate to high levels of IgE antibodies with specificity for eight of nine molds included in the profile.

Clinical Management and Outcome

An individualized integrated-ecologic management was instituted. She received two injections each of Intramuscular Protocols 5 and 6. At the 8-week follow-up (eight months after the onset of amenorrhea), she reported a menstrual period lasting for four days months.

Case 14

A 31-year-old woman presented with a four-year history of persistent fatigue, chemical sensitivity, headache, and abdominal bloating. Eighteen months earlier she was prescribed Elavil for depression by her psychiatrist. Six months prior to consultation, her menstruation ceased following several months of oligomenorrhea.

Pertinent laboratory data included the following: EBV VCA IgG, 775 EU/ml; EBV VCA IgM, 226 EU/ml (both elevated); CMV IgG, 850 elisa units (elevated); negative ANA; FSH, 3.9 mIU/ml; LH, 0.8 mIU/ml; prolactin, 6.6 ng/ml: estradiol, less than 20 pg/ml; progesterone, 0.15 ng/ml; and testosterone, less than 20 ng/dL. Blastocystis hominis trophozoites were found in the stool.

Clinical Management and Outcome

She reported a menstrual cycle lasting 3 days after two months of beginning an individualized integrative-ecologic management plan. At a follow-up visit four years later, she reported regular menstrual cycles at 26-day intervals.

INTEGRATIVE-ECOLOGIC REDOX-NORMALIZING PLAN FOR RESTORING MENSTRUAL FUNCTION

This clinical outcome study was conducted as an open trial of integrated therapies for reversing CFS and fibromyalgia. No attempt was made to narrowly define the management plans or to blind patients or any member of the team providing the care. Indeed, any attempt to set limits on the ecologic-integrative therapies employed or to establish placebo controls would have violated the spirit of integrative medicine. Furthermore, all such attempts would have been doomed to failure, since neither the clinicians nor the patients can be blinded to therapies such as those used for any length of time. Specifically, it was a considered decision not to employ synthetic hormone replacement therapy or phytoestrogens for normalizing menstruation.

Indeed, menstrual abnormalities were deliberately "defocused" during the initial months of instituting the integrated protocols designed to restore damaged bowel, blood, and liver ecosystems. Specifically, we focused on the following: (1) weakened antioxidant defenses; (2) impaired digestive and absorptive functions; (3) inadequate hepatic detoxification of the xenobiotic and endogenous toxins; (4) clinical evidence of compromised enzymatic energy pathways (of Krebs' cycle and others) in the form of "air hunger" and markedly diminished stamina; (5) damaged bowel, blood and liver ecosystems; (6) the "troubled trio" of thyroid, pancreas and adrenals; (7) food incompatibility reactions; (8) IgE-mediated mold and pollen allergy; (9) gentle, nongoal-oriented limbic exercise; and (10) stress, anxiety, and depression associated with chronic illness and arrested growth.

Details of such protocols have been described at length in several previous publications.41-53. The compositions of the oral nutrient and herbal formulations for restoring the damaged bowel, blood and liver ecosystems have been published.54,55 Compositions of the intramuscular and intravenous nutrient protocols used are given in Tables 11-14. Below, we include some brief comments about the components of our management program for the six patients in the present study.

1. Education

The educational focus was: (1) the core principles of integrative medicine; (2) the scientific basis of the management plans that emphasizes broad ecologic thinking rather than mere use of synthetic hormones to restore normal menstrual function; and (3) the oxidative phenomena that occur in the bowel, blood, and liver ecosystems that jeopardize human antioxidant, enzymatic, and immune defenses.

This was deemed essential for securing informed consents for prescribing ecologic-integrative therapies, including intramuscular and intravenous nutrient protocols. Under ordinary circumstances, this would have been a daunting task for any institution.

However, for over a decade, the Institute staff has focused heavily on issues of patient education and has prepared an extensive library of audio and videotapes, and books as well as organized seminars.41,42

The main components of our programs, the details of which have been published previously, included the following: (1) optimal hydration 43; (2) optimal breakfast to avoid swift glucose-insulin-adrenaline shifts (sugar roller coasters)44 ; (3) proper food choices in the kitchen45; (4) supplemental essential oils46 ; (5) nutrient supplementations47; (6) supportive herbal protocols for repairing damage to the bowel, blood and liver ecosystems48; (7) two or three effortless, odorless bowel movements every day49; (8) management of food incompatibility issues50; (9) diagnosis and management of IgE-mediated inhalant allergy51; (10) meditative, noncompetitive, nongoal-directed limbic exercise52 ; and (11) effective methods of stress control.53-55

2. Nutrition and Choices in the Kitchen

No attempt was made in this study to isolate the clinical benefits of individual foods, nutrient or herbal therapies.

Rather, clinicians writing the nutritional plans for individual patients relied on their past clinical experience with the use of various types of diets and nutrient supplementation.

Briefly, the subjects of the study were advised to: (1) drink 8-12 glasses of pure water with one-half teaspoon of sea salt (or herbal teas, excluding carbonated drinks and black tea) to maintain optimal hydration;(2) one to one and one-half tablespoons of partially hydrolyzed protein protocols containing 85-90% amino acids used to prevent undue stress on glucose-insulin dynamics (to avoid sugar roller coasters); (3) one or more tablespoons of one of the following cold-pressed oils: olive, flaxseed, sesame or pumpkin oil, to be taken cold with salad, uncooked vegetables, or other cold foods; (4) avoid foods with oxidized, denatured fats; (5) frequently consume food items such as ginger, onions, garlic and others that are empirically known to improve rheologic characteristics of blood; (6) take prescribed amounts of vitamins, minerals, redox restorative substances (RRS), sulfhydryl restorative substances (SRS), and others.

3. Nutrient Supplementation

In general terms, nutrients were prescribed in the following daily dose ranges: (1) magnesium, 750 to 1,500 mg; (2) potassium, 150 to 300 mg; (3) taurine, 500 to 1,500 mg; (4) ascorbic acid, 500 to 1,500 mg; (5) vitamin B complex, 25 to 50 mg of thiamine, riboflavin, niacin, pantothenic acid, pyridoxin; (6) glutathione and N-acetylcysteine, 200 to 600 mg each; (7) methylsulfonylmethane and alpha lipoic acid, 100 to 200 mg each; (8) selenium, molybdenum, and chromium, each from 200 to 600 mcg each; (9) zinc and copper, 25-50 mg and 2-5 mg respectively; and (10) freeze-dried probiotics such as Bifidobacterium and Lactobacillus in doses of one to three billion organisms. The scientific basis and/or rationale for such prescriptions have been discussed.47,54

4. Herbal Formulations

Herbal protocols for supporting battered bowel, blood, and liver ecologies were liberally prescribed for patients in this study as described previously.48

The compositions of two commonly prescribed herbal protocols are given inTables 4 and 5. Compositions of ten other empirically used bowel protocols employed have been published.48

5. Self-regulation

Women with amenorrhea, oligomenorrhea and menstrual irregularities suffer from considerable stress, and, in the case of young women, low self-esteem. We recognize that chronic, insidious adrenergic hyperactivity plays a critical role in the cause of clinical syndromes associated with menstrual disorders.

All patients were given training in effective previously described methods of self-regulation.53,54 Audiotapes for practice of such methods at home were provided to patients or their parents.

 6. Limbic Exercise

Impaired oxygen transport and oxygen utilization are hallmarks of CFS and fibromyalgia. Thus, patients suffering from those disorders cannot engage in even mild forms of traditional exercise with focus on increasing heart rate, respiration, and perspiration. In the author's experience, the Eastern methods of physical fitness that emphasize energy dynamics, fluidity and spontaneity of motion offer far superior results.

Thus, the program focused on meditative, slow, sustained, noncompetitive and nongoal-oriented exercise that is designated limbic exercise.43 Specifically, our purpose was to help our patients free their bodies from the performance demands of their analytical minds.

7. Special Steps for Hormonal Restoration: The Big Seven

Hormonal imbalances in most young women (PMS, irregular bleeding, and endometriosis) can be reversed with the following three-pronged approach: (A) therapies that restore injured cell membranes; (B) therapies that facilitate entry of natural hormones into the cells; and (C) therapies that enhance the function of hormones on their target cells. Specifically, the author's list of the big seven include the following:

1. Avoid synthetic hormones. As is evident from the cases presented in this report, synthetic hormones simply are not necessary for normalizing menstruation in CFS and fibromyalgia.

2. Eat soy products (learn from Asian women) who rarely develop breast cancer.

3. Maintain optimal hydration and learn about water therapies.

4. Take essential oils, including flaxseed oil

5. Repair injured cell membranes with nutrient and herbal protocols.

6. Restore battered bowel-blood-liver ecosystems with nutrients and herbs.

7. Consider plant-derived raw materials for hormones, such as wild yam, black cohosh, dong quai, macca, chaste tree, licorice, black haw,  hops, yarrow, and sarsaparilla. In many cases, use of plant-derived estrogens, progesterones and testosterone is advisable under medical supervision.

DISCUSSION

Deliberations of menstrual pathophysiology in fibromyalgia and CFS are usually limited to considerations of blood levels of estrogens, progesterone, and pituitary hormones, FSH, LH, and prolactin. Regrettably, this tendency begins with the traditional physiology taught in medical schools. Consider the following quote from the sixth (1997) edition of Human Physiology and Mechanisms of Disease:

The sexual and reproductive functions in the female can be divided into two major phases: first, preparation of the body for conception, and second, the period of gestation.56

So it is that students of medicine are lulled into an innocent belief that sex hormones exist only to prepare for conception and gestation. The above quote is all the more surprising in light of the following quote from the preface of the same textbook:

We hope, too, that he or she will understand that each individual living cell carries within its nucleus all the genetic information required to create an entirely new human being; yet, this same genetic pool serves as almost 100,000 separate intracellular control systems [italics added].57

An Integrated Redox-Hormone-Receptor-Gene Model of Menstrual Pathophysiology

In recent years, there has been an explosion of knowledge concerning multifunctionalities of gonadal hormones, their membrane receptors and nucleotide response elements, and diverse patterns of gene activation products.58-62

But from a clinical perspective, the complexities and intricacies of pathophysiology of menstruation has been all too evident for decades. For example, the prevailing and simplistic notions of functions of estrogens and progesterone have never satisfactorily explained the symptom-complexes of premenstrual syndrome; endometriosis; menopausal syndrome; oligomenorrhea and amenorrhea associated with endurance training; amenorrhea induced by chemotherapy and by immunosuppression with long-term steroid therapy; polymenorrhea that often accompanies acute and chronic stress syndromes, depressive episodes, or even prolonged travelling; and menstrual abnormalities seen in patients with damaged bowel, blood and liver ecosystems.

Menstrual irregularities in CFS and fibromyalgia are yet other examples of hormonal dysregulations that defy simple explanation of estrogen insufficiency. The most amazing aspect of this problem is how the fundamental aspects of redox dysregulation that influence all known homeostatic mechanisms have systematically been ignored in discussions of menstrual dysregulations. It is noteworthy in this context that in many instances, the hormone functions only to modify the behavior of the receptor, itself undergoing little, if any, bioenergetically or enzymatically useful change. Thus, the membrane receptors, which are components of the cell membrane and so are highly vulnerable to the vicissitude of oxidative stress on the membrane, are paid scant attention, to the detriment of clearer understanding of the role of redox dysregulation on redox-hormone-receptor-gene dynamics.

No Cell is an Island

In 1987, the concept of an oxidative leaky cell membrane dysfunction was introduced on teleological, experimental, and empirical grounds.1 Teleologically, no cell is an island. (Indeed, from a bioenergetic standpoint, no island is ever an island, since no island can exist except in dynamic equilibrium with whatever surrounds it and permits it the "island" designation).

A cell membrane exists only to separate internal order of the cell from external disorder. The membrane allows the cell to protect its internal organization against external randomness of thermodynamics. Such a primary gating function requires that the cell membrane be well equipped with a powerful arsenal to counter all bioenergetic threats, and, of course, the primary threat to it is free radical assault. Thus, the cell membrane has sophisticated antioxidant enzyme systems.47

Experimentally, the role of oxidative injury to cell and plasma membranes in the pathogenesis of cellular structural and functional dysfunctions can be easily demonstrated. Ample experimental evidence demonstrates that when the permeability of cell membranes increases by oxidative injury—the membranes are shot full of holes, so to speak—it allows leakage of intracellular elements (such as potassium, magnesium, taurine, and glutathione) and influx of predominantly extracellular elements (such as calcium, as well as heavy metals such as lead, mercury, and aluminum).

Empirically, the concept of oxidative leaky cell membrane dysfunction (and of the leaky cell dysfunction based on that) is fully supported by efficacy of redox-restorative therapies for a host of clinical entities characterized by accelerated oxidative stress, such as ischemic coronary artery disease,14 asthma,16 CFS,15 and fibromyalgia. The present study adds amenorrhea and oligomenorrhea in CFS and fibromyalgia to that list.

To fully appreciate the strength and explanatory power of the OMD-I model, some aspects of the redox-hormone-receptor-gene dynamics are presented in the following categories: (1) diversity of biologic functions of natural and synthetic sex hormones; (2) complexities of structure and function of hormone membrane receptors; (3) an ever-broadening range of patterns of gene activation by sex hormones; (4) the impact of xenoestrogens on menstrual function; (5) empirical evidence of functional interrelationships and interdependences of gonadal and nongonadal hormones; (6) empirical experience with hormonal manipulations versus nonhormonal ecologic management approaches; (7) unwarranted rejection of integrative therapies.

1. Diversity of Biologic Functions of Sex Hormones

Historically, estrogen and progesterone have been assigned clearly delineated roles in the menstrual functions, with estrogen given the responsibility for the proliferative endometrium phase of the menstrual cycle while secretory endometrial changes are attributed to progesterones. Such simplistic thinking is also extended to deliberation of "disorders" of sex hormones. For instance, progesterones are incriminated in the pathogenesis of premenstrual syndrome, while estrogens are believed to relieve symptoms. Both assumptions are patently unwarranted.63

Similarly, amenorrhea, oligomenorrhea, and other types of menstrual irregularities observed in women with fibromyalgia and chronic fatigue syndrome who previously had normal menstrual cycles are chalked up to gonadal failure without any objective evidence of gonadal involvement. It has recently been recognized that estrogens are as potent as progesterones in producing symptoms of premenstrual syndrome.64,65

Estrogens seldom deemed capable of affecting mood are now believed to influence mood and mentation in premenstrual and menopausal syndromes. Even a cursory look at the known inter-relationships and paradoxical effects of estrogens and progesterones on different tissues and under different conditions makes it clear that no specific therapeutic roles can be assigned to synthetic hormones in CFS and fibromyalgia with impunity.

2. Complexities of the Structure and Function of Hormone Membrane Receptors

It must be recognized at the outset that various cell types may have different sets of receptors for the same hormone, and the same receptors may induce different responses under different conditions. Alternatively, the same receptor may occur on a host of cell types. Furthermore, the binding of the hormone with its corresponding receptors may evoke different responses in various cell types.66 For example, estrogen and progesterone stimulate the production of egg white hormones in chickens and cellular proliferation in the hen oviduct. In women and mammals, estrogen stimulates endometrial proliferation and thickening in preparation of gestation (among many other roles). In insects and crustaceans, a-ecodysone, an estrogen-like hormone, is responsible for differentiation and maturation of larvae as well as induction of transcription of specific gene products.67

Gonadal hormones induce a variety of cellular responses by activating enzymes that cause rapid and short-lived increases in the intracellular concentrations of secondary messengers (intracellular signalling compounds), including 3'5'cyclic AMP (cAMP), 3'5'cyclic GMP (cGMP), inositol 1,4,5-triphosphate, 1,2-diacyglyerol, and calcium. Increased concentrations of secondary messengers, in turn, evoke responses from enzymes or nonenzymic proteins.68

Compared with most other hormones, hormonal regulation of menstruation is exceedingly complex. In addition to the well recognized regulatory positive and negative feedback mechanisms involving the pituitary and hypothalamic hormones, rising concentration of estrogen in the vesicular and mature follicles stimulates its own production by stimulating the proliferation of granulosa cells in its vicinity.

Prior to the discovery of a second estrogen receptor in 1997, the world of endocrinology held the simplistic belief that estrogens and estrogen receptors worked like keys and locks in an entirely predictable fashion.

Notwithstanding considerable clinical evidence supporting responsiveness of such organs as the prostate to estrogen influences (i.e., rising incidence of prostate cancer with increasing estrogenic activity in the environment), the dominant belief streadfastly held on the notion of immunity of prostatic parenchyma to estrogens. Then Jan-Ake Gustafsson et al. described a second estrogen receptor on the prostate gland and other tissues including the ovaries, organs which do not carry the first estrogen receptor.69,70 Then followed the discovery that although the second receptor (ERb) looked similar to its older sibling (Era), the two receptors differed much in their biologic functions, depending on the tissue or the ligand binding them. Specifically, the two molecules turned on different genes with different products of gene activation.71 Furthermore, it appears that there are more than one ER b. Different patterns of distribution of ERa and ERb were found in the brain. To add to the complexity, estrogen-receptor complexes require binding to certain DNA sequences for regulation of the expression of their specific genes.

Such DNA sequences have been dubbed estrogen response elements. A further layer of complexity is added by the role of the so-called reported genes that link response elements of either of the two estrogen receptors.

Studies with natural and synthetic estrogens as well as with antiestrogens (tamoxifen, raloxifene, and ICI 164384) showed significant differences in the functions of different receptors. That was soon followed by the discovery of estrogen receptors on the prostate and urinary bladder.

3. An Ever-Broadening Range of Patterns of Gene Activation by Sex Hormones

The mysteries of estrogen-receptor dynamics have deepened rather than become unravelled with recent observations. For example, until 1997 many tissues (including ovaries and urinary bladder) were not known to have estrogen receptors. Similarly, the prostate gland was not known to have estrogen receptors, even though synthetic estrogens have been used to control growth of prostate cancers for decades. Notwithstanding the recognized broad spectrum of activity of estrogens as well as some paradoxical effects of estrogen-like drugs, the simplistic view of using synthetic hormones for amenorrhea, oligomenorrhea, and polymenorrhea for patients with fibromyalgia and CFS continued.

As seen in the cases of patients in the present study, most such uses of synthetic estrogens are of limited short-term benefit. The long-term adverse consequences of such clinical uses of synthetic hormones are generally not known. It may be pointed out here that an increase of 43% more deaths from breast cancer has been recently reported in women receiving hormone replacement therapy.71,72

Some insights into the enormous complexity of gene regulation by estrogens are provided by recent studies that show that the two known estrogen receptors (ERa and ERb) play different roles in gene regulation involving sexual and nonsexual functions. Paech et.al.73 examined the transactivation properties of the two estrogen receptors with different ligands in the context of an estrogen response element and an AP1 element. (Estrogen response elements are DNA sequences to which an estrogen-receptor complex has to bind to regulate the expression of other genes.) ERa and ERb were found to signal in opposite directions when complexed with the natural hormone estradiol from an AP1 site. Specifically, with ERa, 17b-estradiol activated transcription, whereas with ERb, 17b-estradiol inhibited transcription. Interestingly, all three synthetic antiestrogens (tamoxifen, raloxifene, and ICI 164384) were observed to be potent transcriptional activators with ERb at an AP1 site.

4. The Impact of Xenoestrogens

Xenoestrogens (the chemicals with estrogen-like effects) are a major threat to women as well as their unborn babies. During the last 60 years, the incidence of breast cancer has risen steeply just as the use of synthetic estrogens and xenoestrogens has increased. The same holds for prostate cancer. Cancer of the uterus and breast has long been linked to high estrogenic activity.44,74,75

It seems safe to predict that future research will firmly establish the pandemics of breast and prostate cancers to be also directly related to the synthetic estrogens.

Steroidal natural estrogens as well as nonsteroidal synthetic estrogens (diethylstilbestrol [DES], diensterolm hexestrol) are carcinogenic compounds. Estrogens potentiate carcinogenic effects of other chemical compounds, such as 3-methylcholanthrene [MCA] and 7,12-dimethylbenzanthracene(DMDA), also enhance the carcinogenic influence of irradiation and X-rays.44,76,77

The proposed mechanisms of estrogens in carcinogenesis and promotion of tumor growth are many and include the following: DNA synthesis and gene expression, synthesis of growth factors, transformation of proto-oncogenes to oncogenes, increased production of free radicals (resulting from metabolism by monooxygenases), inhibition of cancer cell apoptosis, stimulation of certain enzymes such as cathepsin D), shifting dormant cells from Go to G1-S phase (estrogenic recruitment).

Synthetic estrogens and progesterones also appear to play critical roles in the pathogenesis of amenorrhea, oligomenorrhea, and polymenorrhea in clinical entities characterized by accelerated oxidative stress, such as CFS and fibromyalgia. In support of this viewpoint, some studies of the rising incidence of hormonal dysregulation in girls and animal experiments are cited.

Estrogen Overload In Young Girls

In a recent study of 17,077 American girls, at age three, 3% of African-American girls and 1% of white girls showed breast and/or pubic hair development. At age seven, 27.2% of the former and 6.7% of the latter showed such secondary development. At age eight 8, 48.3% of African American and 14.7% of white girls exhibit such development. Amazingly, three percent of three-year old girls also showed such precocious developemnt. This indicates a tremendous estrogenic overload and no one can predict what kind of trouble it spells for those girls.79

Estrogenic activities have been shown in chemicals in common use, including pesticides, plastics, petroleum products, polystyrene, and PAHs (polycyclic aromatic hydrocarbons).80,81 Chemical companies usually pooh-pooh the health hazards of their chemicals, claiming that minute amounts of are safe. However, in a recent study, some plastic compounds were shown to have hormonal activity at concentrations as low as two parts per billion. The author discussed this serious issue in his book RDA: Rats, Drugs and Assumptions.67

To complex layers of hormonal dysregulations must be added the impact of many environmental pollutants that often goes unrecognized. The studies of endometriosis in Rhesus monkey following chronic exposure to 2,3,7,8-tetrachlorodibenzo-e-dioxin by Rier et.al..82 are of special interest. Endometriosis occurs in Rhesus monkeys spontaneously and resembles its human counterpart, both pathologically and clinically.

Endometriosis is generally believed to be caused by estrogen dysregulation, and the role of environmental pollutants in its pathogenesis is rarely appreciated. Rier et al observed a direct dose-response correlation between chronic dioxin exposure and the incidence and severity of endometriosis in Rhesus monkeys. Specifically, they documented the presence of endometriosis with laparoscopy and biopsy in 71% of the exposed (25 ppt) monkeys while similar lesions were encountered in only 33% of control monkeys not exposed to dioxin. There are several target genes for the action of dioxin, including several growth regulatory genes involved in cell differentiation and inflammatory response. Notable among them are genes for cytochrome P-450, plasminogen activator inhibitor-2, and interleukin-1b.

In a related study, a higher incidence of endometriosis in humans was correlated with exposure to PCBs.83 Dioxin and PCBs belong to an ever-lengthening list of pesticides and industrial pollutants that have been clearly shown to cause a wide range of hormonal dysregulation in humans, mammals, birds and fish.84

It is noteworthy in this context that the World Health Organization in 1990 reported the average per person daily dioxin intake of 133 picograms (mainly thr