The Driven Researcher

Primary Ovarian Failure and HPV Vaccine

Posted by Celeste McGovern on Mar 6, 2017 10:18:00 AM

Dr. Orit Hamiel of Sheba Medical Center in Israel discusses HPV vaccination and subsequent primary ovarian failure, alternatively known as primary or premature ovarian insufficiency (POI), premature ovarian failure (POF) or diminished ovarian reserve (DOR). All these are names for a condition that causes women to experience menopause earlier in life than normal. About half of all women will experience menopause between the ages of 50 and 60, but menopause before the age of 40 is considered premature.

The triad of defining characteristics for POI is amenorrhea for at least four months in women under 40, low estrogen and levels of Serum Follicular Stimulating Hormone (FSH) levels of 40 international units per liter in two measures at least a month apart from each other. If the ovaries are not secreting high enough levels of estrogen, FSH hormone levels will elevate. Those require repetition in order for POI to be considered.

Overall, prevalence data on POI is minimal. However, the existing data suggests POI will affect approximately 1% of all women. POI is much rarer in younger women in their 20s than those in their late-thirties according to epidemiologic data from 1986.

More recently, an increase in POI has been noticed in adolescent girls between the years of 1998 and 2015. Of 15 total cases, some 13 cases occurred within the last five years of the study indicating a cluster. The researchers suggested further research into possible etiologies for this spike in incidence. However, very little is known about the causal factors for POI. Although a minority of cases has a known genetic, infectious, toxicological or autoimmune etiology, 90% of cases have no known cause. Genetic conditions such as Fragile X, autoimmune disorders such as celiac disease and type 1 diabetes, toxic exposures such as chemotherapy and radiation and infectious disease such as mumps are known causes.

However, causality does not need to be all environmental or all genetic. There could also be genetic susceptibility to an environmental insult. One possible trigger according to Dr. Hamiel is HPV vaccination.

HPV is an infection that is a cause of precancerous as well as cancerous lesions of the genitalia and oropharynx as well as the cause of genital warts. HPV causes nearly all cases of cervical cancer – the third most common cause of cancer in women worldwide and the fourth most common cause of cancer death in women. So there was much excitement in the medical community when the vaccine was introduced.

Currently, there are three licensed HPV vaccines in use – Cervarix made by GlaxoSmithKline and Gardasil and Gardasil 9 manufactured by Merck. Each vaccine also contains different adjuvants. Cervarix contains a lipid and aluminum hydroxide. Both Gardasil brands contain aluminum hydroxyphosphate sulfate (AAHS).

There are 12 vaccines licensed in America contain aluminum hydroxide. 23 contain other aluminum compounds, but only Gardasil and hepatitis b vaccines contain AAHS. Different aluminum adjuvants have different chemical as well as physical properties.

Aluminum phosphate, aluminum hydroxide and AAHS were all studied for their effects on the immunogenicity and formation of the HPV protein used in vaccinations. Both the adjuvants’ abilities to bind to the protein as well as their abilities to stimulate antibody responses were different depending on the adjuvant. AAHS stimulated much stronger antibody and T cell responses in mice than did the other adjuvants.

Going back to the potential of aluminum to cause POI, Dr. Hamiel describes two potential mechanisms. One is through a purely toxic effect and another is through an autoimmune dysfunction.

Aluminum toxicity has been associated with a series of problems such as encephalopathy, dementia, pneumoconiosis post-inhalation of aluminum particles and as well as allergy to aluminum adjuvant-containing vaccines. Chronic aluminum exposure can also lead to elevated aluminum levels in the reproductive system and has been correlated with the diminished ability of the ovaries to produce testosterone, estrogen and progesterone.

Autoimmune Inflammatory Syndrome induced by Adjuvants (ASIA Syndrome) is a series of conditions chronically stimulated by substances including aluminum vaccine adjuvants that can lead to Macrophagic Myofasciitis (MMF) and Gulf War Syndrome. 

Known symptoms of ASIA Syndrome already include fatigue, arthritis, myalgia, fever, dry mouth, cognitive deficits, chronic fatigue and sleep disorders. POI may be another symptom of ASIA.

Dr. Hamiel next presents information on several cases of adolescent POI, all of whom had normal menstrual cycles pre-vaccination. Two of those patients tested positive for viral-induced antibodies of the thyroid which puts them at increased risk of autoimmune disease.

Why this is so concerning is because in the clinical trial of Gardasil, Dr. Hamiel notes that subjects who received the vaccine were compared to a placebo group that received the AAHS adjuvant used in the vaccine. So any vaccine side-effects attributable to AAHS could not be reliably deduced.

Other methodological issues of the trial were that half the participants were lost to follow-up after just one year and any medical problems that occurred after seven months of receiving the vaccine were dismissed by the investigators as being unrelated. Many women were also using contraceptives which Dr. Hamiel warns may hide any effect on ovarian function since those drugs prevent menstruation.

However, 44,000 women and girls who received the vaccine were followed for three years in a post-licensure study, but it also concluded that no new safety concerns had arisen from the results. Yet it only measured emergency room visits and hospitalizations. POI cases arising from vaccination would not be enumerated from this method of data collection.

The US Vaccine Adverse Event Reporting System (VAERS) counts 200 reports of POI, menopause and amenorrhea associated with HPV2, HPV9 and HPV4 vaccination. Unfortunately, VAERS is inherently unreliable for measuring incidence since it is a database that relies entirely on passively reported events and is therefore susceptible to bias.

So there remains no long-term assessment of ovarian function in either clinical trials or post-marketing studies, even though 88% of VAERS reports involving POI, menopause and amenorrhea are associated with Gardasil. Yet doctors may still be largely ignorant of any association between Gardasil and POI.

Chronic Fatigue Syndrome Following Human Papilloma Virus Vaccination: Is Latent Epipharyngitis to Blame?

Dr. Osamu Hotta of Sendai Shakaihoken Hospital discusses cases of chronic fatigue syndrome that have occurred following HPV vaccination and possible underlying etiologies. It is speculated that chronic epipharyngitis is associated with autoimmune disease. In his talk, he goes over characteristics of epipharyngitis, epipharyngeal treatment and postulates epipharyngitis as a possible underlying mechanism for chronic fatigue triggered by HPV vaccines.

The surface of the epipharynx is coated with IgA immunoglobulins, and CD3+ (T) cells are also abundant in the epithelium and submucosa. White blood cells (T and B cells) are highly activated in the epipharynx compared to those in peripheral blood, even in healthy people.

The key characteristic of epipharyngitis is submucosal congestion. The epipharynx is prone to bleeding under these conditions by thick cotton-swabbing. The musculature of the epipharynx in normal conditions is recognized whereas in epipharyngitis it is not because of edema and congestion.

In an analysis of 41 patients who developed serious somatic symptoms post-HPV vaccination, 19 experienced discomfort of the pharynx. Those patients were treated with nasal and pharyngeal swabs dunked in diluted zinc chloride solution. Degree of epipharyngitis was determined by degree of bleeding soaked up by the swab. Severe bleeding was observed for all 41 patients with severe reactions following HPV vaccination, even though just 19 experienced pharyngeal symptoms. By contrast, severe bleeding was observed in only two of 39 comparable control subjects.

Of the patients with symptoms following vaccination, most showed some improvement or were cured of their symptoms following epipharyngeal zinc chloride treatment. He showed video footage of a woman who was initially confined to a wheelchair but was eventually able to stand and walk after enough days of epipharyngeal treatment and after no longer exhibiting epipharyngeal bleeding associated with epipharyngitis.

Dr. Hotta postulates a mechanism by which epipharyngitis can serve as the connection between HPV vaccination and chronic fatigue. He theorized that the vaccine or vaccine adjuvant could lead to epipharyngitis. This could lead directly to epipharyngeal symptoms but also more indirect disturbances such as altering the limbic system and hypothalamus. These can lead to sleep issues, pain, sensitivity to light, cognitive impairments and loss of memory. Dysautonomia can also occur leading to dizziness, numbness, involuntary spasms and irritable bowl. It can also lead to alteration of HPA axis leading to fatigue, disturbances in menstruation and muscular weakness.

He hypothesized an interaction between the epipharynx and HPA axis/limbic system, whereby pathologies affecting the epipharynx can lead to issues within the HPA axis and limbic system and vice versa. This can in turn lead to ASIA syndrome (autoimmune syndrome induced by adjuvants) and FSS (functional somatic syndrome), causing a long list of symptoms. This whole concept regarding chronic epipharyngitis and the relation to autoimmunity and autonomic neurological disturbances was originally proposed 50 years ago by the late Dr. Shinsaku Horiguchi, and which provides much of the basis of Dr. Hotta’s lecture.

Dr. Hotta concludes that Dr. Horiguchi’s theories about chronic epipharyngitis as it relates to such conditions may be correct and that the epipharyngeal condition may be important to consider with regard to such issues. Chronic epipharyngitis remains largely misunderstood, leaving open the possibility that it could have a strong role to play in patients suffering certain autoimmune and neurological dysfunction.

Severe Cases of ASIA Syndrome By Dr. Luis Javier Java of Hospital de Especialidades La Raza, Mexico

Dr. Java discusses severe cases of Autoimmune Syndrome Induced by Adjuvants (ASIA Syndrome). To give background, he notes that the syndrome ASIA was first proposed by Dr. Yehuda Schoenfeld in a 2011 paper published in the Journal of Autoimmunity. Among the conditions are siliconosis induced by silicone and Gulf War Syndrome, Macrophagis myofasciitis and post-vaccination phenomena associated with aluminum hydroxide. Other involved substances and heavy metals include mineral oil, guaiacol iodine gatital, mercury and titanium as well as sick building syndrome. These were all within the ASIA family.

Next Dr. Java presents criteria developed by Dr. Schoenfeld to qualify for an ASIA diagnosis. Major symptoms include muscular weakness, arthritis, chronic fatigue, neurological disorders, cognitive impairment and dry mouth. Minor criteria involve antibody response to adjuvant, irritable bowel, specific HLA or involvement of known autoimmune disease such as MS.

ASIA syndrome can include non-specific or specific pathologies of autoimmunity. ASIA can also involve any system in the human body. What all manifestations of ASIA have in common however are that they all involve the acceleration, prolonging and enhancement of disease by antigen-specific immune response-inducing substances, i.e. adjuvants.

Prior to Dr. Java’s talk 4000 ASIA cases and series of cases have been documented. Such severe cases have even included patient deaths.

Among the severe cases Dr. Java describes is that of a woman who first developed symptoms at age 49. She had received a cosmetic injection of mineral oil in the buttocks, but the next day developed fever and malaise. That woman dramatically improved with treatment for her symptoms, but over the following five years she developed subcutaneous nodules on specific areas throughout her body as well as episodes of fever. She was hospitalized at 54 for dysphagia, Raynaud’s phenomenon and abdominal and pelvic indurations. Biopsies of this woman’s skin reported fat necrosis, inflammation and vasculitis.

She was diagnosed with systemic sclerosis, panniculitis and depression. With treatment by prednisone, she did show partial improvement. However, she would be lost to follow-up after seven years of study.

Another such case involved a patient who was hospitalized with fever but without evidence of infection. That patient presented with severe skin abnormalities on the buttocks, genitalia and lumbar regions. However, that patient also improved on prednisone treatment.

Laboratory analysis in that patient showed calcifications in tissue, pulmonary fibrosis and infiltrates via chest x-ray, positivity for antinuclear antibodies and a chronic inflammatory reaction to foreign cells. These findings all point to adjuvant-related disease.

The patient required surgery to remove granulomas in her abdomen, during which she went into shock from bleeding and required blood transfusion.

The patient was discharged after five days, but re-admitted five days after that with severe anemia. Unfortunately despite substantial treatment, the patient’s condition deteriorated and she died. Among her host of diagnoses by the time of death were irreversible shock, severe autoimmune anemia and ASIA syndrome.

Next Dr. Java describes a patient who developed a severe adverse vaccine reaction within 48 hours of influenza vaccination. That same case qualified for ASIA after oil injection and progressive symptoms over 12 years. The oils reached the circulatory system triggering immune activation and eventually hemolysis.

To better understand severe ASIA cases, Dr. Java and his team conducted a meta-analysis of those cases. Meta-analysis of severe ASIA cases from 2011 to 2016 was done using all the major literature search engines – PubMed, MEDLINE, EMBASE and Cochrane. A systematic review was also conducted of severe ASIA where the diagnosis of which required involvement of major organs, life-threatening conditions, intense treatment, permanent disability and hospitalization. Patients who met criteria for ASIA had to either have two of the major criteria or one major criterion and two of the minor criteria.

From 2011 to 2016, 4480 ASIA cases were enumerated. Of these, 305 met criteria for severe ASIA include 11 patient deaths. The majority of severe ASIA cases were related to either HPV vaccination, influenza vaccination, mineral oil injection or silicone. The interval between exposure and outcome was highly variable – 2 days to 23 years. The majority of cases occurred last year- 2015. They were also predominantly female (93%).

Four of the deaths were associated with mineral oil injections. Those patients suffered liver failure, digestive bleeding and hypovolemic shock. Another seven deaths were associated with HPV vaccination, the manifestations of which were unspecified.

Although 57 million doses of the vaccine have been distributed worldwide from 2006 to 2013, only a few autoimmune cases from vaccination made it into the review. The vaccinations contained aluminum adjuvants, intended to stimulate an immune response to inoculate the patient against human papilloma virus.

Severe ASIA cases associated with HPV vaccination as reported in the US Vaccine Adverse Event Reporting System (VAERS) included – among other disorders – neuropsychiatric problems, premature menopause, thrombocytopenic purpura, acute cerebral ataxia, thyroiditis and autoimmune hepatitis.

Similarly, ASIA has also been associated with silicone implants. They have been used in heart valves, testicular prosthetics and breast implants. They have generally been considered inert, as the majority of women with breast implants do not suffer symptoms. 

However, a minority of patients have suffered from complications such as breast pain, infection and implant rupture. Very rarely, they have even associated with lymphoma.

65% of those patients have experienced symptoms indicative of autoimmune disease, including allergy, fatigue and morning stiffness. These issues may be caused by silicone or some other ingredient of breast implants.

Silicone implants – especially when ruptured inside the patient – have also been associated with ASIA. Of 130 cases of ASIA with silicone implants, 13 had severe ASIA. Eight of the 13 suffered silicone implant rupture and one committed suicide.

In presenting a systematic review of women with silicone breast implants who could be at increased suicide risk, women who underwent cosmetic breast augmentation between 1961 and 2014 had double or triple the risk of committing suicide. Many of these same patients also suffered from fibromyalgia, depression and anxiety.

Manifestations of ASIA associated with influenza vaccination include myocarditis, transverse myelitis and acute kidney failure. HPV vaccination has also been associated with serious side-effects.

Illegal injections of mineral oil are another major cause of ASIA, but such cases have mostly been reported in Mexico. Because this practice is often done in other Latin American countries as well and because of the sometimes lethal effects on consumers, the cases in Dr. Java’s review may represent only a small fraction of the real scope of the problem.

In wrapping up his presentation, Dr. Java notes that his study was the first review of all severe cases of ASIA that has been published. He further notes that the severe cases have included deaths, and severe cases have been associated with vaccination, silicone and mineral oil injections.

While Dr. Java stresses that associations between autoimmune disease and adjuvants does not necessarily mean a causal relationship, he urges more research to better understand such a relationship. There is an increase in ASIA cases, including those that threaten human life.

Vaccines, Adjuvants and Autoimmunity by Dr. Luisa Eca Guimarares of Centro Hospitalar, Portugal

Dr. Guimarares discusses vaccinations, adjuvants in vaccinations and the role they may play in autoimmunity and autoimmune disorders. She first presents the US infant vaccination schedule for 2015, noting similarities with the Portuguese schedule with few exceptions.

However, she stresses that both genetics and many environmental factors – such as smoking – may trigger an autoimmune disorder. Vaccine adjuvants are a possible cause of autoimmunity in previously healthy patients.

Vaccinations are not a patient-centered standard of care, but a disease-centered one. They are given not with regards to the individual patient but with regards to a disease being prevented even though different patient backgrounds may affect how likely they are to respond negatively to a given drug.

One example of patient-centered care is that doctors in Portugal document why they do not administer a treatment to a patient if not doing so deviates from accepted protocol. Such practice is the likely future of medical care, including vaccine administration.

There are a number of different types of adjuvants used in vaccines, such as xenobiotic adjuvants, oil-based emulsions and aluminum compound adjuvants. Among the ways they can induce autoimmunity is by translocating T cells to the lymph nodes. Another is enabling longer exposure to antigens through antigen protection, causing antigens to be stored leading to successive exposures to the immune system. Autoimmunity can also be stimulated locally at the injection site, as well as by stimulating release of inflammatory cytokines. Interaction to certain receptors, primarily “toll-like” receptors, is a fifth way. Altogether, these adjuvant pathways to autoimmunity are known as the “adjuvant effect.”

The way adjuvants are supposed to work in a vaccine is to stimulate an immune response to the vaccine. However, adjuvants such as aluminum could potentially cause side-effects. Aluminum is known to cross the blood-brain barrier into the central nervous system, remain in the brain for 8-11 years following exposure and trigger unwanted immune reactions. Yet it is common in many vaccines. The vast majority of vaccines given in the Israeli schedule, for example, contain aluminum adjuvants.

Both allergy and autoimmunity are known to be caused by metals. Those outcomes are both caused by abnormal immune responses and can lead to delayed hypersensitivity. One known example has been allergy to metal by people wearing earrings. Others include dental amalgam - removal of which has led to improved outcomes in patients who have suffered autoimmune disease.

Amalgam is comprised of copper, tin and mercury – a neurotoxic heavy metal. Exposure to mercury as well as to gold and nickel through different exposures can cause a variety of autoimmune side-effects. Silicone has been widely studied for its association with Autoimmune or Auto-inflammatory Syndrome induced by Adjuvants (ASIA Syndrome). Though silicone exposure by itself is insufficient to cause ASIA, silicone has been known to trigger the disorder in the presence of other risk factors. Patients have tested positive with anti-silicone antibodies and autoantibodies, and diseases can include such disorders as fibromyalgia.

The ideal prosthetic implant materials for avoiding autoimmunity would be those that are chemically inert, are not changed by bodily fluids, do not induce inflammatory reactions, maintain form, resist mechanical strains, can be sterilized and are non-carcinogenic. Unfortunately, silicone implants can degrade overtime. They can also cause a hypersensitive or inflammatory reaction by the body, whereby the tissue forms a capsule around the implant. Also, their carcinogenicity remains disputed.

There are a wide range of vaccines for measles, mumps, rubella, smallpox, yellow fever, hepatitis b, human papilloma virus, influenza, meningococcus, pneumococcus and tuberculosis that have all been described as having associations with autoimmune diseases. Despite reducing liver cancer in children, hepatitis b vaccination has also been associated with multiple sclerosis and myelitis. Other conditions described include thrombocytopenia, arthritis, vasculitis, neuropathy, juvenile dermatomyositis, Gillain-Barre Syndrome and MMF. Conditions described as being associated with vaccines generally include lupus, narcolepsy, fibromyalgia and ASIA syndrome.

To better understand these conditions requires study of vaccinomics – the interactions between patient genetics, vaccines and pathogens. Several problems with current vaccine safety studies are their short-term nature and use of placebos containing aluminum, which would mask any side-effects associated with aluminum.

Autoimmunity needs to be considered as well, not just the diseases but the phenomena behind them. Developing early screening methods may be useful, which a registry of ASIA cases may lead to. Discovering such phenomena may be key to developing good epidemiological research for otherwise hard-to-study conditions. Better, safer adjuvants are also recommended especially since vaccines are given to healthy patients who should remain healthy.

The Children’s Medical Safety Research Institute (CMSRI) is a medical and scientific collaborative established to provide research funding for independent studies on causal factors underlying the chronic disease and disability epidemic.

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