Study of thymus glands and estrogen as PCOS cause-PCOS is an immune disorder

Abstract

The aim of the present study was to investigate whether dietary advanced glycation end-products (AGEs) can be detected in the ovarian tissue of normal female rats and whether they can affect their metabolic or hormonal profile. Sixty normal rats (20 animals in each group) were randomly assigned to regular diet, either high (H-AGE) or low (L-AGE) in AGE content for 6 months. H-AGE rats demonstrated higher levels of fasting glucose (P < 0.001), insulin (P < 0.069), and serum AGEs (P < 0.001) than control and L-AGE rats. Additionally, the H-AGE group showed increased AGE localization in the theca interna cells of the ovarian tissue compared to control/L-AGE rats (P = 0.003). Furthermore, increased receptor for AGE (RAGE) staining was also observed in granulosa cells compared to control/L-AGE samples (P = 0.038). In the H-AGE group, plasma testosterone was higher than in control rats (P < 0.001) and in the L-AGE group (P < 0.001). However, H-AGE rats did not exhibit higher body weight compared with normal (P = 0.118) and L-AGE-fed rats (P = 0.35). These results demonstrate for the first time that administration of high AGE diet in female rats for a prolonged period is associated with increased deposition of AGEs in the theca cells and of RAGE in the granulosa and theca interna cells of the ovarian tissue compared with the corresponding ovarian compartments of the control and L-AGE-fed animals. The metabolic alterations in conjuction with the increased deposition in ovarian tissues of dietary glycotoxins and elevated levels of testosterone in H-AGE-fed animals compared to the controls suggest an impact of environmental factors on ovarian tissue and these findings need further exploration.

http://www.springerlink.com/content/g872k677v1114520/

First of all, we clearly see that PCOS is an autoimmune disease.

Before we go on any further, I need to go on a tangent. THIS STUDY WAS DONE IN ATHENS GREECE.

Greece is under attack by Wall Street through the use of Interest rate swaps and Credit default swaps. (My background isn't in medicine, it's in finance).

As we can clearly see here, Greece's bonds are way undervalued. This is incredibly sophisticated research, one that the researchers were free to conduct because they seemed to lack a conflict of interest between Big Pharma and doctors of medicine.

It was the Greeks who came up with the Hippocratic Oath.

The Modern Version:

I swear to fulfill, to the best of my ability and judgment, this covenant:

I will respect the hard-won scientific gains of those physicians in whose steps I walk, and gladly share such knowledge as is mine with those who are to follow.

I will apply, for the benefit of the sick, all measures [that] are required, avoiding those twin traps of overtreatment and therapeutic nihilism.

I will remember that there is art to medicine as well as science, and that warmth, sympathy, and understanding may outweigh the surgeon's knife or the chemist's drug.

I will not be ashamed to say "I know not," nor will I fail to call in my colleagues when the skills of another are needed for a patient's recovery.

I will respect the privacy of my patients, for their problems are not disclosed to me that the world may know. Most especially must I tread with care in matters of life and death. If it is given to me to save a life, all thanks. But it may also be within my power to take a life; this awesome responsibility must be faced with great humbleness and awareness of my own frailty. Above all, I must not play at God.

I will remember that I do not treat a fever chart, a cancerous growth, but a sick human being, whose illness may affect the person's family and economic stability. My responsibility includes these related problems, if I am to care adequately for the sick.

I will prevent disease whenever I can, for prevention is preferable to cure.

I will remember that I remain a member of society, with special obligations to all my fellow human beings, those sound of mind and body as well as the infirm.

If I do not violate this oath, may I enjoy life and art, respected while I live and remembered with affection thereafter. May I always act so as to preserve the finest traditions of my calling and may I long experience the joy of healing those who seek my help.

http://en.wikipedia.org/wiki/Hippocratic_Oath

Dioscorides was Greek.

Dioscorides wrote a five-volume book in his native Greek, Περὶ ὕλης ἰατρικής, known in English by its Latin title De Materia Medica ("Regarding Medical Materials") that is a "precursor to all modern pharmacopeias"."

http://en.wikipedia.org/wiki/Pedanius_Dioscorides

Apparently the grounds to develop mathematical, medical and scientific achievements, cures, etc. were only possible under a democratic reign. Greece was the inspiration to the Romans who adopted their culture in a Republic, and we adopted many of Greeces' concepts to build the modern world in the U.S.

Pray for Greece. Wall Street is attacking it with subprime derivatives to get their assets for cheap, I feel that I owe Greece a world of thanks for a genuine understanding of this horrible problem and hopefully a cure for it. Remember, money is just a bartering tool. Money can't cure people, doctors, God and you can.

This study was done in NY?

"An examination of the literature indicates a strong likelihood

of thymus involvement in estrogen and/or testosterone-

induced anovulation in other animal species. For

example, Kincl et al. [24,25] reported that anovulation in

E2- and T-injected female rats could be prevented by thymocyte

infusion. Notably, only thymocytes from adult

donors were effective. Thymocytes from 5-day-old animals

did not prevent anovulation. In primates the thymus

undergoes its final development prenatally [7]. Steroid

action would thus occur in utero. This could explain why

injections of testosterone propionate (TP) given to pregnant

rhesus monkeys on gestational day's 40–55, produces

anovulatory female offspring [26,27]. The female

offspring have enlarged ovaries with multiple small follicles;

an elevated LH/FSH ratio; and, high levels of serum

17αOH-progesterone and testosterone.

Additional evidence of steroid influence in utero is

detailed in reports of the consequences of using DES in

pregnant women [28-35]. Prescribed from the 1940s until

1971, DES was banned by the FDA due to the large

number of reproductive problems in daughters exposed in

utero. Problems included an increased rate of primary

infertility, oligomenhorrhea, amenorrhea, high levels of

androstenedione and testosterone, facial hirsutism, and

an elevated LH/FSH ratio. These symptoms are all associated

with the formation of cysts [36,37]. Notably, exposure

to DES on gestational weeks 9 through 12 produced

the highest rate of infertility [35]. This timeframe is coincident

with the final developmental stages of the thymus

[7].

The identity of the self-antigen(s) that CD8+

Autoreactive T

cells regard as nonself, is at present, a matter for conjecture.

MECs synthesize approximately 300 ectopic tissue

proteins [20]. At least two are involved in autoimmune

disease. A peptide epitope of insulin initiates CD8+

Autoreactive

T cell destruction of pancreatic β cells [38], and zona

pellucida glycoprotein 3 (ZP3) is implicated as the selfantigen

involved in ovarian dysgenesis [39]. Synthesized

in the ovary by the oocyte and granulosa cells [40], ZP3 is

a prime candidate for the self-antigen involved in the formation

of follicular cysts. Destruction of granulosa cells

by CD8+

Autoreactive T cells would seriously impair the follicle's

capacity to synthesize estrogen. Restoration of this

ability might explain why injections of FSH cause ovulation

in clomiphene-resistant PCOS women without intervention

by either exogenous LH or hCG [41].

In conclusion: we have proposed that follicular cysts

formed in a popular animal model of PCOS represent an

autoimmune disease initiated by steroid administration.

An increased incidence of autoimmune disease in DESexposed

women [42], lends further support for the

autoimmune nature of PCOS. As maternally derived

androgens and estrogens diffusing into the fetal area are

limited by the amnion [43], and are normally at nanogram

levels, it is unlikely that this source of steroid causes

PCOS. The reproductive problems observed with DES

came from milligram levels [44]. Potential sources of steroids

at this level are phytoestrogens, contained in food

supplements and ingested by some pregnant women. The

Centers for Disease Control and Prevention, for example,

report that 10% of representative samples of women in

the United States contain urinary levels in the milligram

range, of phytoestrogens found in flax seed [45]. Flax seed

and soy bean products cause reproductive problems in

female rats [46] and mice [47], and mice suffer thymocyte

loss and thymic atrophy when given genistein, the phytoestrogen

contained in soy beans [47]. Our future

research will determine whether or not phytoestrogens

cause anovulation and follicular cysts when administered

to female mice during the thymus' critical period. We will

also be investigating the impact of adrenal corticoids.

While the bulk of this paper has concentrated on the role

of gonadal steroids, the observation that adrenal steroids

diminish thymic/spleen weight and numbers of thymocytes/

splenocytes (Table 2), and can instigate cyst formation

[6], raises the possibility that severe stress during

pregnancy may be a factor in PCOS development."

http://www.rbej.com/content/pdf/1477-7827-7-47.pdf

High Levels of Oestrogen in Utero May Cause PCOS

Anne Seccombe

“We propose that in utero exposure to excessive levels of steroids such as estrogen has a long-term effect on the ability of the thymus to produce regulatory T cells. In female offspring this can lead to PCOS.”

Researchers from Binghamton University in New York published an article on 18 May 2009 in the Journal of Reproductive Biology and Endocrinology hypothesizing a new cause for PCOS.

Essentially they suggest, and their study supports, the theory that exposure of a foetus to high levels of steroids (such as eostrogen, testosterone or corticosteroids) whilst it is in utero may cause a cascade of auto-immune dysfunctions involving the thymus gland and it’s production of regulatory T-cells, eventually resulting in polycystic ovarian syndrome if the child is female. Sources of steroid exposure are likely to be from dietary phytoestrogens in the case of oestrogen or severe maternal stress whilst pregnant in the case of corticosteroids.

In the study, mice were injected with oestrogen at between 5 & 7 days old. This is known to cause anovulation and follicular cysts, a disease model that bears a similarity to PCOS in humans.

It is generally believed (but not proven) that this response is due to the hypothalamus responding to the excess oestrogen and a disruption in the GnRH delivery system.

This group of researchers, however, had a new idea which they sought to prove, namely that the anovulation and follicular cysts may be part of an immune response to the oestrogen and involving the thymus gland and it’s production of a specialised type of white blood cells called T cells and which help to fight infection or potential infection and also have a regulatory effect. High levels of oestrogen appear to prevent the thymus gland from producing fully developed regulatory T-cells. The absence of T-regulatory cells is known to cause a number of auto-immune diseases.

The researchers found that mice who had their thymus gland removed when they were 3 days old, prior to the injection of oestrogen, they did not develop follicular cysts and anovulation. When these mice later received an infusion from older mice who had been exposed to oestrogen, they found that the disease was transferable in a large percentage of the mice through the lymphocytes. Thus it would appear that the absence of regulatory T-cells is a prerequisite for the formation of follicular cysts.

The researchers concluded that exposure in utero to steroid hormones such as oestrogen or testosterone are unlikely to be derived from the mothers’ own hormones as these are usually only present in nanogram levels, whereas milligram levels are required to produce these effects. Therefore, the researchers hypothesize that it is more likely that these levels are achieved through the ingestion of phytoestrogens from the mothers’ diet, such as are found in soy and flaxseed products. Although it wasn’t covered in depth in the present study, the researchers highlighted that severe stress in pregnancy would raise levels of corticosteroids which are also known to negatively affect the spleen and thymus development of a foetus and the subsequent production of lymphocytes/thymocytes respectively.

http://pcosinfo.wordpress.com/news-research/elevated-oestrogen-in-utero/