Saturday, October 18, 2014
Estrogen as an antidepressant
"Estradiol appears to function as an antidepressant through mechanisms inherent in traditional psychotropics (Duman et al 1997; Manji et al 2001) in widespread regions of the cortex and limbic brain (Gundlah et al 2000). Estradiol promotes neurite outgrowth and neuronal survival in hypothalamus, amygdala, hippocampus, dopaminergic neurons, and prefrontal cortex (Lee and McEwen 2001). Pro-monoaminergic effects of estradiol include enhancement of norepinephrine, dopamine (McEwen and Alves 1999), cholinergic (Gibbs and Aggarwal 1998), and serotonin systems (Bethea et al 2000; Osterlund et al 2000; Pecins-Thompson and Bethea 1999). Estradiol also mitigates against oxidative stress, glutamateric excitotoxicity, and β-amyloid toxicity (Amantea et al 2005). A potential role for estradiol to modulate feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis (Cizza et al 1997) is yet another mechanism by which estradiol may act as a psychotropic." http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2782667/?report=reader
Metabolic changes due to low estrogen
Metabolic Dysfunction Under Reduced Estrogen Levels
When compared with age-matched men, premenopausal women have lower mortality, which is often thought to be caused by the protective effects of estrogens.[30] For a variety of reasons, most women must deal with the onset of decreased estrogen concentrations at some point in their lives. Reductions in circulating estrogens are associated most commonly with the onset of age-induced menopause. In addition, numerous clinical reasons may cause a woman to face loss of estrogen function before natural menopause. For example, oophorectomy is used clinically in women as a prophylactic approach to reduce the risk of genetically screened estrogen-positive cancers or for alleviating symptoms of chronic migraine.[16] In addition, using estrogen receptor antagonists as a treatment for estrogen-positive cancers also can result in ovarian failure. Finally, a small percentage of young women develop primary ovarian insufficiency, leading to abnormally low levels of circulating estrogens.[16] In this review, we define the loss of "estrogen function" as reductions in tissue-specific estrogen signaling caused by significant losses in circulating estrogens and/or pharmacological inhibition of the estrogen receptors.
Unfortunately, decreases in circulating estrogens in women result in increased risk for a number of clinical health issues that can lead to increased mortality. For example, reduced estrogen levels result in significant alterations in skeletal muscle, bone, cardiovascular, and brain functions,[30] with clinicians often prescribing estrogen or hormone therapy (HT) as a means to prevent or attenuate the onset of these symptoms. With the recent release of results from the Women's Health Initiative (WHI), there has been a substantial decline in the clinical use of HT because a portion of the data suggested that HT increased the risk of breast cancer and stroke.[8] The broad sweeping conclusions of the WHI have since been questioned for multiple reasons,[30] but these questions have not curtailed the reduction in HT prescription. Thus, the WHI has had a clear impact on the use of HT by clinicians in addressing issues on women's health, and it is important that appropriate alternative approaches be provided for women.
An important goal for women's health research is to define and understand mechanisms by which estrogens impact cell function across a variety of tissues. In women, estrogens encourage physiological mechanisms that prevent chronic disease; however, the loss of estrogen function results in the development of pathological function, indicating that estrogens are a key regulator of the cellular phenotype. Thus, if we can define the estrogen-regulated mechanisms that affect tissue function, we may be able to develop interventions to prevent the development of chronic disease in women with reduced levels of circulating estrogens. The goal of this review is to highlight recent findings concerning changes in metabolic function in adipose and hepatic tissue under conditions of reduced estrogen levels. In addition, we will explore the hypothesis that exercise training is an intervention that should be used as a primary approach to prevent the onset of metabolic disease in women who are experiencing a loss or decrease in estrogens.
Increases in visceral adiposity are of serious concern because of the significant link that exists between visceral fat storage, the development of metabolic disease, and increased mortality. The anatomical location of fat is a critical consideration, in that excess lipid storage in different anatomical fat depots has different consequences on glucose disposal. Fat storage in subcutaneous depots located in the lower half of the body typically is not associated with changes in insulin sensitivity, whereas excess lipid storage in the visceral region is associated with increases in peripheral insulin resistance. Based on the changes observed in visceral fat mass in women with reduced estrogen levels, it is clear that ovarian hormones, likely estrogens, play a critical role in the regulation of lipid metabolism in females.
For unknown mechanistic reasons, there is a clear association of lost of estrogen function with the onset of metabolic disease. For example, the OVX model exhibits a significant increase in visceral adiposity (Table), which is associated with increased peripheral insulin resistance.[31,32] These changes in visceral adiposity and insulin resistance are recapitulated in both the ARKO and the ERKO-[alpha] mouse models, suggesting that, regardless of the chosen animal model, loss of estrogen function leads to the development of metabolic disease.[12,15] It is clear that loss of female sex steroid function results in an increased risk of developing metabolic abnormalities, indicating that estrogens likely protect women from acute metabolic insults.
The observed alterations in lipolytic dynamics when ovarian function is compromised are accompanied by changes in protein content of key regulators of adipocyte lipolytic function. Specifically, OVX animals exhibit significant increases in visceral adipose tissue glycerol lipase (ATGL) protein (Fig. 2) and an increase in the interaction between ATGL and comparative gene idenfication-58 (CGI-58) compared with SHAM animals.[32] CGI-58 is a known activator of ATGL, thus suggesting that increased ATGL activation is a likely contributor to the higher basal lipolytic rates in the OVX animals. We also found decreases in perilipin (PLIN1) protein content in the OVX mice compared with that in SHAM mice (Fig. 2). PLIN1 is a lipid droplet coating protein that regulates both lipolytic rate by preventing unstimulated lipolysis and also by facilitating activated lipolysis.[2] Adipose tissue from knockout mice of PLIN1 exhibits increases in basal lipolysis,[2] which is similar to results seen in the OVX model. Together, these data suggest that loss of PLIN1 contributes to dysregulation of lipolysis in the OVX animals compared with the intact SHAM group. Our data also suggest that loss of PLIN1 content is paralleled by upregulation of another lipid droplet coating protein termed PLIN2 (ADRP).[31] Although PLIN2 retains some similarities to PLIN1, it does not provide the protective effect of PLIN1 in preventing unstimulated lipolytic attack,[2] which may also explain the increase in basal lipolyticrate seen in the OVX mice. In addition, overexpression of PLIN2 results in enhanced lipid storage,[2] thus suggesting that it may play a role in the increased lipid storage in the OVX mouse, which results in adipocyte hypertrophy. Surprisingly, when we gave the OVX animals access to voluntary running wheels, we failed to prevent this dysregulation in lipolytic function; however, supplementation of the OVX mice with 17β-estradiol was completely effective at preventing these changes from developing.[32] Our data also suggest that activation of lipolytic signaling mechanisms was impaired in an untrained OVX group in response to an acute bout of treadmill exercise compared with the SHAM group.[31] In response to the exercise bout, there was lower HSL phosphorylation (Fig. 2), which was likely a consequence of reduced PLIN1 content. Serine phosphorylation of PLIN1 in the protein kinase A consensus sequence is necessary for maximal lipolysis, which coincides with phosphorylation of HSL and direct interaction of HSL with PLIN1 in the PAT domain.[2] However, PLIN2 appears to lack the ability to support maximal rates of lipolysis induced by HSL, thus the upregulation of PLIN2 likely contributes to altered lipolytic response in the OVX animals. When compared with the intact female animals, OVX animals exhibit significant changes in key lipolytic signaling proteins that likely contribute to increases in the basal lipolytic rate.
The ability of the adipocyte to store lipid as TAG is limited, which was first demonstrated by the Czech lab that found significant down-regulation of fatty acid synthesis in large adipocytes.[5] The inability to store more lipid is referred to as the "overflow hypothesis," where the lipid droplet is unable to store more TAG, resulting in increased levels of FFA in circulation, an effect observed in the OVX animals. This loss of regulatory control of TAG dynamics would be expected to contribute to increased risk of developing lipotoxicity in peripheral tissues because of increased exposure to higher concentrations of circulating lipid. In the case of this review, lipotoxicity is defined as the excessive accumulation of cellular lipid that contributes to chronic cellular dysfunction. Indeed, we recently demonstrated that hepatic tissue is a likely target of this spillover because of the anatomical relationship of the liver with visceral tissue via the portal circulation.[14]
Women are not only inclined to the development of central obesity after menopause, but they also are susceptible to lipid accumulation in the liver. Obesity is often associated with the development of NAFLD.[22] NAFLD is the result of excess TAG storage in the liver, comprising a histological spectrum ranging from simple hepatic steatosis to advanced fibrosis and cirrhosis.[22] Intrinsically linked to the significant increases in lipid accumulation in the liver is a significant increase in the risk for developing insulin resistance and, ultimately, metabolic syndrome. Premenopausal women are at lower risk for developing NAFLD than age-matched men; however, when women become postmenopausal, there is a significant increase in risk for developing NAFLD.[17,28] Estrogens appear to protect against the development of NAFLD even under conditions (i.e., high-fat diet) that would accentuate lipid accumulation in the liver (Fig. 3).[4] As discussed above, we and others have shown that increases in basal lipolysis in OVX mice result in enhanced FFA release from the visceral depot likely into the portal vein, ultimately leading to increased lipid storage because of increased exposure of the hepatic tissue.[6,14,24,32] Thus, the explanation for the increased risk of NAFLD development in women under conditions of reduced estrogen levels is likely multifactorial.
Increases in hepatic lipid (i.e., TAG) content can be the result of alterations in a number of metabolic events. For example, increased TAG content can be a direct result of increased FFA influx or caused by increased synthesis of fatty acids via fatty acid synthase (FAS). In addition, TAG accumulation could result from decreased export of TAG via very low density lipoprotein or caused by decreased mitochondrial oxidation. In other words, a host of factors can contribute to changes in hepatic TAG content, and dysfunction of any of them can lead to significant increases in hepatic TAG content. In the OVX animals, significant increases in hepatic TAG content are often seen in the rat model. However, the data in the mouse OVX model are more equivocal, in that in the mouse, there is an increase in stored TAG; however, the increase does not reach the same magnitude as that in the rat.[14,21] What is critical to consider is that these increases in stored hepatic TAG are occurring even though the rodents are being maintained on a relatively low-fat diet. If the diet is changed to a high-fat diet, both mice and rats develop severe forms of NAFLD, indicating that the loss of estrogen exposure leads to a significant hypersusceptibility to NAFLD, which is often seen when fat exposure is increased. An additional complication to consider is the susceptibility of different strains of rodents to metabolic insults, which adds another layer of complexity to the interpretation of the published data. At this point, mechanisms within the hepatic tissue remain poorly defined, and only a few investigations have provided data to indicate potential mechanisms for why loss of estrogen might lead to increased susceptibility to NAFLD.
In our hands, we have found little indication of OVX mice increasing hepatic lipid storage because of increases in FAS or acetyl-Co carboxylase (ACC) protein content.[14] In contrast, D'Eon et al.[6] found significant decreases in hepatic FAS and ACC messenger ribonucleic acid (mRNA) expression in response to exogenous 17β-estradiol delivery to the OVX mouse, suggesting that estrogens may negatively regulate de novo synthesis of FA. However, it should be noted that the study design by D'Eon et al.[6] did not contain a SHAM control group, so it is impossible to determine if the OVX group had elevated levels of hepatic mRNA levels of FAS and ACC. In a follow-up study, Rogers et al.[24] found increased mRNA levels of hepatic FAS and ACC, coupled with histological indices of hepatic steatosis. The differences with our work are likely caused by the time of tissue collection, in that in our study, we collected tissue 8 weeks after OVX, whereas Rogers et al.[24] collected 10 weeks after surgery. Furthermore, OVX rats exhibit significant increases in hepatic ACC mRNA expression compared with intact cycling females.[21] Whereas further investigations are necessary to elucidate the mechanisms that link OVX to alterations in hepatic tissue, it appears that the level of activation of the FAS pathway may influence the severity of TAG accumulation in the OVX model and likely result in the development of NAFLD.
Our data in the OVX indicate that SCD-1 activation is higher under conditions of reduced estrogen concentrations (Fig. 4).[14] Similar results have been achieved in the ERKO mouse where SCD-1 mRNA expression was significantly elevated when compared with the wild-type mice, which was coupled with disruptions in glucose homeostasis.[3] Importantly, in a follow-up study, it was identified that estrogens negatively regulate the SCD-1 promoter, implicating that the loss of estrogens likely contributes to increased SCD-1 activation independent of obesity.[4] Albeit, it is very possible that development of the visceral adiposity additively increases SCD-1 promoter activation because the promoter is enhanced with FFA exposure,[13] again providing further evidence to the complexity of this phenotype. Regardless, treatment of obese animal models with 17β-estradiol or with estrogen receptor agonists attenuates or reverses the metabolic abnormalities induced by a variety of metabolic insults.[4,6,10] As a whole, the data clearly suggest that estrogens play a protective effect in preventing metabolic disease. Unfortunately, because of the complexity of the developing phenotype, it typically is unclear which targets truly are estrogen sensitive. It is critical that research continues to examine the mechanisms behind how estrogens contribute to the regulation of tissue function to determine where metabolic defects will develop during conditions of estrogen deficiency. However, it should be noted that if approaches are to be developed to prevent or reverse the effects of estrogen dysfunction they should be tested on clinically relevant models such as the OVX model and not just limited to genetically manipulated animal models. Ultimately, this will be critical because the WHI has resulted in a significant reduction in the use of the estrogen therapy as a means to treat women experiencing physiological changes caused by estrogen deficiency.
Wheel running also prevented the increase in hepatic 16:1 and 18:1 content of the OVX mice, which was associated with a lower desaturase index and reduced SCD-1 content when compared with those of the sedentary OVX mice (Fig. 4).[14] This finding is in agreement with that of others who found that in the OVX rat forced treadmill running prevented increases in hepatic SCD-1 mRNA and protein content when compared with the OVX sedentary group.[34] These data provide critical information indicating that loss of estrogenic function leads to increased SCD-1 activity that can be prevented by increasing the physical activity levels of the animal.
This would suggest that even small increases in wheel running completely prevented the metabolic changes in the OVX rodent, resulting in maintenance in hepatic phenotype that is similar qualitatively to the sedentary intact female mice. Furthermore, as suggested by others,[21] providing OVX rodents with the ability to exercise through wheel running or treadmill activity induces estrogen-like effects that induce a more favorable metabolic phenotype. However, it should be noted that the cellular mechanisms induced by exercise and estrogens likely are different. In addition, an important consideration is that decreases in the physical activity levels of the OVX model likely exacerbates the development of the metabolic disruptions seen within the animal.
http://www.medscape.com/viewarticle/771738
Exerc Sport Sci Rev. 2012;40(4):195-203.
http://www.medscape.com/viewarticle/771738When compared with age-matched men, premenopausal women have lower mortality, which is often thought to be caused by the protective effects of estrogens.[30] For a variety of reasons, most women must deal with the onset of decreased estrogen concentrations at some point in their lives. Reductions in circulating estrogens are associated most commonly with the onset of age-induced menopause. In addition, numerous clinical reasons may cause a woman to face loss of estrogen function before natural menopause. For example, oophorectomy is used clinically in women as a prophylactic approach to reduce the risk of genetically screened estrogen-positive cancers or for alleviating symptoms of chronic migraine.[16] In addition, using estrogen receptor antagonists as a treatment for estrogen-positive cancers also can result in ovarian failure. Finally, a small percentage of young women develop primary ovarian insufficiency, leading to abnormally low levels of circulating estrogens.[16] In this review, we define the loss of "estrogen function" as reductions in tissue-specific estrogen signaling caused by significant losses in circulating estrogens and/or pharmacological inhibition of the estrogen receptors.
Unfortunately, decreases in circulating estrogens in women result in increased risk for a number of clinical health issues that can lead to increased mortality. For example, reduced estrogen levels result in significant alterations in skeletal muscle, bone, cardiovascular, and brain functions,[30] with clinicians often prescribing estrogen or hormone therapy (HT) as a means to prevent or attenuate the onset of these symptoms. With the recent release of results from the Women's Health Initiative (WHI), there has been a substantial decline in the clinical use of HT because a portion of the data suggested that HT increased the risk of breast cancer and stroke.[8] The broad sweeping conclusions of the WHI have since been questioned for multiple reasons,[30] but these questions have not curtailed the reduction in HT prescription. Thus, the WHI has had a clear impact on the use of HT by clinicians in addressing issues on women's health, and it is important that appropriate alternative approaches be provided for women.
An important goal for women's health research is to define and understand mechanisms by which estrogens impact cell function across a variety of tissues. In women, estrogens encourage physiological mechanisms that prevent chronic disease; however, the loss of estrogen function results in the development of pathological function, indicating that estrogens are a key regulator of the cellular phenotype. Thus, if we can define the estrogen-regulated mechanisms that affect tissue function, we may be able to develop interventions to prevent the development of chronic disease in women with reduced levels of circulating estrogens. The goal of this review is to highlight recent findings concerning changes in metabolic function in adipose and hepatic tissue under conditions of reduced estrogen levels. In addition, we will explore the hypothesis that exercise training is an intervention that should be used as a primary approach to prevent the onset of metabolic disease in women who are experiencing a loss or decrease in estrogens.
Adipose Tissue Expansion Under Conditions of Reduced Estrogen Function
In females, a reduction in estrogens results in significant increases in fat mass in the visceral region; however, this change does not always equate to increases in overall body weight. In this review, we will use the term "lipid" to refer to fatty acid–based molecules, and the term "fat" will be used in an anatomical sense to describe adipose tissue. The impact of estrogen on adipose tissue is evident when comparing anatomical fat storage in males with that in females. Males tend to store excess lipid in the abdominal region (i.e., visceral fat), an android distribution pattern, whereas females with normal cycling estrogen patterns preferentially store lipid in the lower half of the body, a gynoid pattern of fat distribution. However, when estrogen levels are reduced chronically in women, there is an increase in visceral fat mass that results in a shift in body shape from a gynoid to an android pattern. With this increase in visceral fat mass, women are at an increased risk for developing metabolic and cardiovascular diseases.[30] The ovary secretes numerous hormones, but evidence suggests that loss of estrogen is critical because of its powerful effect on visceral adipose tissue function. For example, the use of HT in women can attenuate increases in visceral fat mass observed in women after the menopausal transition.[30] In a similar fashion, chronic 17β-estradiol treatment in animal models with estrogen deficiencies can prevent or even reverse the development of visceral adiposity.[32]Increases in visceral adiposity are of serious concern because of the significant link that exists between visceral fat storage, the development of metabolic disease, and increased mortality. The anatomical location of fat is a critical consideration, in that excess lipid storage in different anatomical fat depots has different consequences on glucose disposal. Fat storage in subcutaneous depots located in the lower half of the body typically is not associated with changes in insulin sensitivity, whereas excess lipid storage in the visceral region is associated with increases in peripheral insulin resistance. Based on the changes observed in visceral fat mass in women with reduced estrogen levels, it is clear that ovarian hormones, likely estrogens, play a critical role in the regulation of lipid metabolism in females.
Using Animals to Understand Metabolic Changes Induced by Reduced Estrogen Function
From a physiological standpoint, human studies of estrogen function in liver and adipose tissue in females are both experimentally feasible and informative. However, mechanisms are often hard to identify in human studies because of limitations of studying tissue biopsies that are small in size and not readily available. Study design and overall conclusions also are often affected by large variations in patient/subject characteristics. These difficulties have led to the use of different animal models to study the role of the ovary or estrogens in the regulation of tissue function. The ovariectomy model (i.e., bilateral surgical removal of the ovaries (OVX)) is one of the most commonly used animal models to study the role of female sex steroids in tissue function.[6,9–11,14,21,24,26,31,32] After OVX, circulating estrogen levels are reduced by approximately 70% to 90%,[11,26] a reduction comparable to that observed in females after natural or surgically induced menopause. Although the OVX model is often criticized for the abrupt nature of the onset, it still has provided critical information concerning women's health. In addition, OVX is relevant clinically because numerous premenopausal women undergo the same ovariectomy (i.e., oophorectomy) surgery for a variety of clinical reasons. Thus, it is unacceptable to discount the scientific importance of the OVX model because of the limitations it has in mimicking every aspect of age-related menopause when one considers the number of women who undergo oophorectomy before the onset of age-induced menopause. In addition, a number of genetic models are available that can be used to study estrogen function, including the estrogen receptor–knockout (ERKO) mouse and the aromatase-knockout (ARKO) mouse.For unknown mechanistic reasons, there is a clear association of lost of estrogen function with the onset of metabolic disease. For example, the OVX model exhibits a significant increase in visceral adiposity (Table), which is associated with increased peripheral insulin resistance.[31,32] These changes in visceral adiposity and insulin resistance are recapitulated in both the ARKO and the ERKO-[alpha] mouse models, suggesting that, regardless of the chosen animal model, loss of estrogen function leads to the development of metabolic disease.[12,15] It is clear that loss of female sex steroid function results in an increased risk of developing metabolic abnormalities, indicating that estrogens likely protect women from acute metabolic insults.
Adipocyte Hypertrophy Under Conditions of Reduced Circulating Estrogens
In addition to the visibly apparent changes in adipose tissue mass, alterations in fat cell (adipocyte) function occur when estrogen levels are compromised chronically. Changes in adipocyte function are caused by altered morphological changes in the fat pad, as well as to changes in key regulators of fat storage and breakdown. Morphologically, adipose tissue expansion may occur via an increase in adipocyte size and/or an increase in adipocyte number. When expansion occurs because of an increase in adipocyte number, peripheral insulin sensitivity often is preserved; whereas in contrast, when expansion is caused by an increased adipocyte size, metabolic consequences, such as reduced peripheral insulin sensitivity, commonly are observed.[27] In humans, a link between ovarian hormone status and visceral adipocyte size has been reported, with ovarian hormone–deficient women exhibiting significantly greater visceral adipocyte size compared with women with intact ovarian function.[29] We have found that OVX animals exhibit substantial increases in visceral adipocyte size compared with ovary-intact female (SHAM) animals (Fig. 1). The increase in adipocyte size develops over time, with substantially larger adipocytes readily apparent 8 wk after the OVX surgery (Fig. 1), without significant changes in adipocyte number (Wohlers LW and Spangenburg EE, unpublished data, 2012). The initial increase in the size of the adipocyte is visible 2 wk after the OVX surgery, with continued hypertrophy of the adipocyte visible for the next 6 wk (Wohlers LW and Spangenburg EE, unpublished data, 2012). Similar findings have been observed at later time points by other laboratories.[6,24]
Figure 1.
Ovariectomized (OVX) mice exhibit larger visceral adipocytes at various time points after surgery (2, 4, or 8) compared with SHAM animals. The OVX surgery was performed at 8 to 10 weeks of age, with the time points referring to point of tissue collection after the surgery. Isolated adipocytes are stained with BODIPY 493/503 and imaged with fluorescence microscopy. The scale bar equals 100 µm.
Adipocyte Dysfunction Under Conditions of Reduced Estrogen Levels
Unfortunately, because of the experimental difficulties in obtaining visceral fat biopsies from women, the mechanistic study of visceral adipocyte function as they relate to estrogen function is challenging. However, through the use of animals, we have gained substantial insight into the relationship between estrogens and adipocyte biology. Under normal physiological conditions, excess circulating free fatty acids (FFA) are stored efficiently as triacylglycerol (TAG), and lipolytic breakdown of TAG is initiated by stimuli such as starvation or exercise. However, in certain disease states, the regulatory mechanisms of TAG metabolism are disrupted, contributing to the onset of various metabolic diseases. OVX animals exhibit significant elevations in basal lipolysis in visceral adipose tissue; however, the visceral fat pad in OVX animals does not respond appropriately to stimuli that are expected to induce lipolysis.[6,31,32] We have found in OVX animals that increases in visceral adipocyte size are associated with increased basal lipolytic activation. After OVX, mice exhibit increases in basal lipolytic rate, as indicated by both elevated circulating serum glycerol and FFA levels, which are mimicked in organ bath and isolated adipocyte measures as well.[6,32] In addition, the in vitro stimulated lipolytic response of adipocytes isolated from OVX animals is impaired but is rescued in mice supplemented with estrogen.[6] OVX mice also exhibit impaired lipolytic signaling activation in response to an acute bout of running, a physiological stimulus of lipolysis.[31] At this point, it is unclear why stimulated lipolysis in visceral fat is blunted in OVX mice, but it is possible that basal lipolysis is upregulated to such an extent that the tissue becomes unresponsive to further stimulation.The observed alterations in lipolytic dynamics when ovarian function is compromised are accompanied by changes in protein content of key regulators of adipocyte lipolytic function. Specifically, OVX animals exhibit significant increases in visceral adipose tissue glycerol lipase (ATGL) protein (Fig. 2) and an increase in the interaction between ATGL and comparative gene idenfication-58 (CGI-58) compared with SHAM animals.[32] CGI-58 is a known activator of ATGL, thus suggesting that increased ATGL activation is a likely contributor to the higher basal lipolytic rates in the OVX animals. We also found decreases in perilipin (PLIN1) protein content in the OVX mice compared with that in SHAM mice (Fig. 2). PLIN1 is a lipid droplet coating protein that regulates both lipolytic rate by preventing unstimulated lipolysis and also by facilitating activated lipolysis.[2] Adipose tissue from knockout mice of PLIN1 exhibits increases in basal lipolysis,[2] which is similar to results seen in the OVX model. Together, these data suggest that loss of PLIN1 contributes to dysregulation of lipolysis in the OVX animals compared with the intact SHAM group. Our data also suggest that loss of PLIN1 content is paralleled by upregulation of another lipid droplet coating protein termed PLIN2 (ADRP).[31] Although PLIN2 retains some similarities to PLIN1, it does not provide the protective effect of PLIN1 in preventing unstimulated lipolytic attack,[2] which may also explain the increase in basal lipolyticrate seen in the OVX mice. In addition, overexpression of PLIN2 results in enhanced lipid storage,[2] thus suggesting that it may play a role in the increased lipid storage in the OVX mouse, which results in adipocyte hypertrophy. Surprisingly, when we gave the OVX animals access to voluntary running wheels, we failed to prevent this dysregulation in lipolytic function; however, supplementation of the OVX mice with 17β-estradiol was completely effective at preventing these changes from developing.[32] Our data also suggest that activation of lipolytic signaling mechanisms was impaired in an untrained OVX group in response to an acute bout of treadmill exercise compared with the SHAM group.[31] In response to the exercise bout, there was lower HSL phosphorylation (Fig. 2), which was likely a consequence of reduced PLIN1 content. Serine phosphorylation of PLIN1 in the protein kinase A consensus sequence is necessary for maximal lipolysis, which coincides with phosphorylation of HSL and direct interaction of HSL with PLIN1 in the PAT domain.[2] However, PLIN2 appears to lack the ability to support maximal rates of lipolysis induced by HSL, thus the upregulation of PLIN2 likely contributes to altered lipolytic response in the OVX animals. When compared with the intact female animals, OVX animals exhibit significant changes in key lipolytic signaling proteins that likely contribute to increases in the basal lipolytic rate.
Figure 2.
Immunoblotting for key lipolytic proteins in visceral adipose tissue from ovariectomized (OVX) and SHAM animals. Below each example is the percent difference in means that was determined in our previous publication (data from (31)). ATGL, adipose tissue glycerol lipase; PLIN, perilipin.
The ability of the adipocyte to store lipid as TAG is limited, which was first demonstrated by the Czech lab that found significant down-regulation of fatty acid synthesis in large adipocytes.[5] The inability to store more lipid is referred to as the "overflow hypothesis," where the lipid droplet is unable to store more TAG, resulting in increased levels of FFA in circulation, an effect observed in the OVX animals. This loss of regulatory control of TAG dynamics would be expected to contribute to increased risk of developing lipotoxicity in peripheral tissues because of increased exposure to higher concentrations of circulating lipid. In the case of this review, lipotoxicity is defined as the excessive accumulation of cellular lipid that contributes to chronic cellular dysfunction. Indeed, we recently demonstrated that hepatic tissue is a likely target of this spillover because of the anatomical relationship of the liver with visceral tissue via the portal circulation.[14]
Changes in Lipid Metabolism in Hepatic Tissue Under Chronic Conditions of Reduced Estrogen
Significant decreases in circulating estrogens induce adipocyte dysfunction that systemically exposes peripheral tissue to chronic increases in circulating FFA. In the case of visceral fat, FFA are released into the portal circulation and are first directed to the liver. In fact, 59% of stored hepatic TAG is derived from FFA in the portal circulation, 26% from de novo lipogenesis, and 15% from the diet.[7] Thus, an increase in FFA from portal circulation exposure would increase the risk of hepatic lipotoxicity. The development of fatty liver through the association of visceral adiposity is often referred to as the "portal vein hypothesis." Studies show that FFA released through visceral adipose tissue lipolysis are the predominant sources of hepatic lipids in patients with nonalcoholic fatty liver disease (NAFLD).[7] The risk of hepatic lipotoxicity likely is exacerbated if metabolic mechanisms within the exposed hepatocytes are compromised, preventing the cell from tolerating the increased flux of FFA. Here, we are proposing a two-hit hypothesis in that estrogens provide a multifactorial means for regulating metabolic function in women and that the loss of estrogens leads first to adipocyte dysfunction and second to a loss of mechanisms that would allow peripheral tissue to tolerate increases in lipid exposure. In the following paragraphs, we discuss data demonstrating that decreases in estrogens in women leads to metabolic dysfunction in hepatic cells that potentially could contribute to an increased risk for developing diabetes.Women are not only inclined to the development of central obesity after menopause, but they also are susceptible to lipid accumulation in the liver. Obesity is often associated with the development of NAFLD.[22] NAFLD is the result of excess TAG storage in the liver, comprising a histological spectrum ranging from simple hepatic steatosis to advanced fibrosis and cirrhosis.[22] Intrinsically linked to the significant increases in lipid accumulation in the liver is a significant increase in the risk for developing insulin resistance and, ultimately, metabolic syndrome. Premenopausal women are at lower risk for developing NAFLD than age-matched men; however, when women become postmenopausal, there is a significant increase in risk for developing NAFLD.[17,28] Estrogens appear to protect against the development of NAFLD even under conditions (i.e., high-fat diet) that would accentuate lipid accumulation in the liver (Fig. 3).[4] As discussed above, we and others have shown that increases in basal lipolysis in OVX mice result in enhanced FFA release from the visceral depot likely into the portal vein, ultimately leading to increased lipid storage because of increased exposure of the hepatic tissue.[6,14,24,32] Thus, the explanation for the increased risk of NAFLD development in women under conditions of reduced estrogen levels is likely multifactorial.
Figure 3.
Endocrine function of the ovary prevents excess adipose tissue expansion in the visceral region and release of excess free fatty acids (FFA) into the portal circulation.
Increases in hepatic lipid (i.e., TAG) content can be the result of alterations in a number of metabolic events. For example, increased TAG content can be a direct result of increased FFA influx or caused by increased synthesis of fatty acids via fatty acid synthase (FAS). In addition, TAG accumulation could result from decreased export of TAG via very low density lipoprotein or caused by decreased mitochondrial oxidation. In other words, a host of factors can contribute to changes in hepatic TAG content, and dysfunction of any of them can lead to significant increases in hepatic TAG content. In the OVX animals, significant increases in hepatic TAG content are often seen in the rat model. However, the data in the mouse OVX model are more equivocal, in that in the mouse, there is an increase in stored TAG; however, the increase does not reach the same magnitude as that in the rat.[14,21] What is critical to consider is that these increases in stored hepatic TAG are occurring even though the rodents are being maintained on a relatively low-fat diet. If the diet is changed to a high-fat diet, both mice and rats develop severe forms of NAFLD, indicating that the loss of estrogen exposure leads to a significant hypersusceptibility to NAFLD, which is often seen when fat exposure is increased. An additional complication to consider is the susceptibility of different strains of rodents to metabolic insults, which adds another layer of complexity to the interpretation of the published data. At this point, mechanisms within the hepatic tissue remain poorly defined, and only a few investigations have provided data to indicate potential mechanisms for why loss of estrogen might lead to increased susceptibility to NAFLD.
In our hands, we have found little indication of OVX mice increasing hepatic lipid storage because of increases in FAS or acetyl-Co carboxylase (ACC) protein content.[14] In contrast, D'Eon et al.[6] found significant decreases in hepatic FAS and ACC messenger ribonucleic acid (mRNA) expression in response to exogenous 17β-estradiol delivery to the OVX mouse, suggesting that estrogens may negatively regulate de novo synthesis of FA. However, it should be noted that the study design by D'Eon et al.[6] did not contain a SHAM control group, so it is impossible to determine if the OVX group had elevated levels of hepatic mRNA levels of FAS and ACC. In a follow-up study, Rogers et al.[24] found increased mRNA levels of hepatic FAS and ACC, coupled with histological indices of hepatic steatosis. The differences with our work are likely caused by the time of tissue collection, in that in our study, we collected tissue 8 weeks after OVX, whereas Rogers et al.[24] collected 10 weeks after surgery. Furthermore, OVX rats exhibit significant increases in hepatic ACC mRNA expression compared with intact cycling females.[21] Whereas further investigations are necessary to elucidate the mechanisms that link OVX to alterations in hepatic tissue, it appears that the level of activation of the FAS pathway may influence the severity of TAG accumulation in the OVX model and likely result in the development of NAFLD.
Decreases in Circulating Estrogens Leads to Increased Hepatic Stearoyl CoA Desaturase Activity
Although we did not find large increases in total TAG content, we did find significant changes in the composition of the fatty acids stored as TAG in the liver.[14] Significant changes in the composition of stored fatty acids can alter numerous physiological processes including signal transduction, insulin sensitivity, tissue metabolic rate, and fatty acid storage kinetics.[20] Specifically, we found a significant increase in the percentage of fatty acids in the monounsaturated form (16:1; 18:1) in the OVX mouse when compared with that in the SHAM mouse. Calculation of the desaturase index of the fatty acids stored as TAG in the liver demonstrated that there was a significantly greater amount of monounsaturated fatty acids (MUFA) than saturated fatty acids stored in OVX mice when compared with that in SHAM mice (Fig. 4). In the liver, the conversion of a saturated fatty acid (16:0, 18:0) to a MUFA (16:1, 18:1) is regulated enzymatically by the enzyme stearoyl CoA desaturase (SCD-1). In addition, we found a significant increase in the hepatic SCD-1 protein content in the OVX mice compared with that in SHAM mice (Fig. 4),[14] which also has been found by others at the mRNA and protein levels.[34] This finding was informative because MUFA are stored preferentially, as opposed to saturated fatty acids that are often favored for oxidation by the mitochondria.[20] SCD-1 is localized at the endoplasmic reticulum and plays a critical role in regulating cellular function across a variety of tissues; however, hyperactivation of SCD-1 can contribute to the development of metabolic disorders. Specifically, mice with global tissue deletion of SCD-1 conserve peripheral insulin sensitivity even while on a high-fat or high-carbohydrate diet (for detailed review, see).[20] In our hands, OVX mice develop visceral adiposity, glucose intolerance, and dysregulation of metabolic function in hepatic tissue while on a normal chow diet (70% carbohydrate; 10% fat, and 10% protein); thus, it is not unreasonable to suggest that hepatic SCD-1 may be a critical mediator of metabolic dysfunction in OVX mice. Finally, we found that SCD-1 content was correlated positively with blood glucose levels in SHAM and OVX mice (Fig. 4), suggesting that in the OVX model, there is a potential relationship between the increase in hepatic SCD-1 levels and the onset of glucose intolerance. These data conceptually provide evidence to our two-hit hypothesis idea in that the combination of events, visceral adipocyte dysfunction and increased hepatic SCD-1 content, would make individuals more susceptible to NAFLD and the development of overt metabolic disease.
Figure 4.
A. Sedentary ovariectomized (OVX) animals exhibited significant increases in the hepatic desaturase index (C18:1/C18:0) of extracted triacylglycerol (TAG) compared with SHAM animals, whereas exercise prevented any changes in the desaturase index in the OVX animals. †Statistically different from all other groups; *statistically different from sedentary SHAM (P < 0.05). B. Sedentary OVX animals exhibited significant increases in hepatic stearoyl CoA desaturase (SCD-1) content compared with all other groups. Exercise prevented the increase in hepatic SCD-1 content of the OVX mice. A representative blot of SCD-1 is shown beneath the graph. C. Hepatic SCD-1 protein content is correlated positively with blood glucose levels (4Y5 hours' fast) in sedentary OVX (
) and SHAM (
) animals. Data taken from our previous work (14).
Chicken or the Egg: Why is Metabolic Function in the Liver Altered?
Decreases in estrogen function that are induced by surgical, genetic, or pharmacological means lead to complex phenotypes throughout the animal. Specifically, because of the number of estrogen sensitive tissues, loss of estrogen signaling throughout the entire body leads to numerous pathological changes (i.e., obesity, insulin resistance, and physical inactivity) that often complicate the interpretation of the resulting data. It is often impossible to truly discern secondary effects versus primary effects of decreased estrogen function. For example, we have shown previously that OVX rats recover poorly from a bout of muscle atrophy when compared with intact females;[26] however, is this result caused by effects of estrogens specifically on the muscle, or is it complicated by the fact that the animals are obese and insulin resistant? Interestingly, changes found in the OVX, ERKO, and ARKO mice are similar qualitatively, thus, indicating that, regardless of how estrogen signaling is reduced, it results in substantial, but similar, physiological or metabolic deficiencies. Furthermore, exogenous delivery of 17β-estradiol can often prevent or reverse the metabolic dysfunction in the OVX and ARKO mice, suggesting the estrogens likely are the critical regulator and not another ovarian hormone. However, it should be noted that the delivery approaches generally are not physiological because they result in chronic doses of 17β-estradiol that are often on the upper levels of physiological concentrations rather than cyclic exposure of varying 17β-estradiol levels seen in females. The challenge remains for investigators to identify which effects are specific to the role estrogen plays in that tissue and which are secondary effects. Recently, two laboratories have shown elegantly that metabolic disruptions develop through specific genetic ablation of the estrogen receptor from myeloid cells or neurons within the hypothalamus showing the importance of tissue-specific estrogen signaling.[23,33] At this time, what is clear is that lost estrogen function leads to increased risk of numerous chronic health conditions, all of which are important critically to women's health; however, what is often not clear is which effects primarily are caused by lost estrogen function and which are secondary effects caused by changes elsewhere in the body.Our data in the OVX indicate that SCD-1 activation is higher under conditions of reduced estrogen concentrations (Fig. 4).[14] Similar results have been achieved in the ERKO mouse where SCD-1 mRNA expression was significantly elevated when compared with the wild-type mice, which was coupled with disruptions in glucose homeostasis.[3] Importantly, in a follow-up study, it was identified that estrogens negatively regulate the SCD-1 promoter, implicating that the loss of estrogens likely contributes to increased SCD-1 activation independent of obesity.[4] Albeit, it is very possible that development of the visceral adiposity additively increases SCD-1 promoter activation because the promoter is enhanced with FFA exposure,[13] again providing further evidence to the complexity of this phenotype. Regardless, treatment of obese animal models with 17β-estradiol or with estrogen receptor agonists attenuates or reverses the metabolic abnormalities induced by a variety of metabolic insults.[4,6,10] As a whole, the data clearly suggest that estrogens play a protective effect in preventing metabolic disease. Unfortunately, because of the complexity of the developing phenotype, it typically is unclear which targets truly are estrogen sensitive. It is critical that research continues to examine the mechanisms behind how estrogens contribute to the regulation of tissue function to determine where metabolic defects will develop during conditions of estrogen deficiency. However, it should be noted that if approaches are to be developed to prevent or reverse the effects of estrogen dysfunction they should be tested on clinically relevant models such as the OVX model and not just limited to genetically manipulated animal models. Ultimately, this will be critical because the WHI has resulted in a significant reduction in the use of the estrogen therapy as a means to treat women experiencing physiological changes caused by estrogen deficiency.
Increasing Physical Activity in OVX Mice Prevents Changes in Hepatic Tissue
In an effort to determine if the changes in hepatic SCD-1 protein content were preventable, we provided the mice with access to voluntary running wheels. We found that access to wheels resulted in attenuated increases in visceral mass and changes in hepatic TAG content in both the intact female mice and the OVX mice.[14,32] It should be noted that the intact control female mice ran a significantly greater amount of distance each night (~8200 km every 24 h) compared with the OVX mice (~2400 km every 24 h), which suggests that it only was necessary to slightly increase the activity levels to prevent the TAG accumulation. This is in agreement with others who found that treadmill running in OVX rats results in significant reductions in hepatic TAG content compared with sedentary groups.[21] Our evidence also suggested that increased physical activity caused by the wheel running resulted in decreased hepatic expression of diacylglycerolacyltransferase (DGAT1); however, the decrease was similar in the intact females and OVX mice. The decrease in DGAT1 is intriguing because DGAT1 represents the final regulatory step in the assembly of a TAG and may suggest that DGAT is sensitive to changes in activity levels. Barsalani et al.[1] demonstrated that treadmill running in OVX rats attenuated increases in DGAT2 compared with the OVX sedentary group. In addition, we indicated earlier that the FAS pathway may contribute to TAG accumulation in the liver. We found no effect of voluntary wheel running on hepatic FAS or ACC protein content in the OVX or intact female mice; however, others have found that forced treadmill running of OVX rats prevented increases in ACC mRNA expression.[21] Although the mechanism induced by exercise to prevent the hepatic TAG accumulation remains to be determined completely, it is clear that, like other models of obesity,[22] OVX rodents do not accumulate hepatic TAG significantly when they are given the opportunity to exercise.Wheel running also prevented the increase in hepatic 16:1 and 18:1 content of the OVX mice, which was associated with a lower desaturase index and reduced SCD-1 content when compared with those of the sedentary OVX mice (Fig. 4).[14] This finding is in agreement with that of others who found that in the OVX rat forced treadmill running prevented increases in hepatic SCD-1 mRNA and protein content when compared with the OVX sedentary group.[34] These data provide critical information indicating that loss of estrogenic function leads to increased SCD-1 activity that can be prevented by increasing the physical activity levels of the animal.
This would suggest that even small increases in wheel running completely prevented the metabolic changes in the OVX rodent, resulting in maintenance in hepatic phenotype that is similar qualitatively to the sedentary intact female mice. Furthermore, as suggested by others,[21] providing OVX rodents with the ability to exercise through wheel running or treadmill activity induces estrogen-like effects that induce a more favorable metabolic phenotype. However, it should be noted that the cellular mechanisms induced by exercise and estrogens likely are different. In addition, an important consideration is that decreases in the physical activity levels of the OVX model likely exacerbates the development of the metabolic disruptions seen within the animal.
Physical Activity is a Potential Intervention for Treating Women With Reduced Estrogen Function
If estrogen therapy is not considered a safe intervention, then it absolutely is critical that clinicians consider alternative approaches. The data are clear and compelling that decreases in estrogen levels or estrogen receptor function result in significant increases in risk for developing metabolic disease in women. When examining the metabolic changes induced by estrogen dysfunction, it is apparent why exercise or increases in the levels of physical activity would be so effective as an intervention. Loss of estrogen function leads to insulin resistance,[10] visceral adiposity,[31,32] hepatic dysfunction ([14,17]), and striated muscle dysfunction;[19,26] however, every one of these alterations can be prevented or reversed by increasing physical activity levels. Although the magnitude of studies done on women under conditions of reduced estrogen function is relatively low, there is indication that exercise training is an effective approach. For example, Ryan et al.[25] found that weight loss alone did not improve glucose utilization and insulin sensitivity in postmenopausal women; however, when weight loss was coupled with exercise training, it resulted in a significant improvement in both outcomes. Similar results were shown by You et al.,[35] who demonstrated that diet alone was not effective at reducing circulating inflammatory markers in postmenopausal women; however, when coupled with exercise training, there was a significant reduction in these same cytokines. These data suggest that exercise training is an intervention that is critical to women who clinically are experiencing reductions in estrogen function. Also, it is possible to extend beyond just metabolic dysfunction because recent data have shown that physical activity improves the survival rates of postmenopausal women with breast cancer.[18] In a qualitative fashion, the data indicate that longer duration bouts of exercise provide the most benefit; however, the intensity of activity did not seem to be critical.[18] Interestingly, we can extrapolate these findings to ours in that we found that very low levels of physical activity were effective in preventing the development metabolic disruptions in the hepatic tissue.[14] The ability of low-intensity exercise to be effective is critical because reductions in circulating estrogen levels are associated with reduced muscle force production[19] and, thus, a loss of muscle strength likely would hamper the individual from completing high-intensity exercise bouts. With both mechanistic and epidemiologic-based evidence demonstrating the importance of using physical activity as a means to improve health outcomes of women under conditions of reduced estrogen function, it seems that it will be necessary to analyze critically and determine scientifically appropriate approaches for using exercise as a therapeutic intervention in women.Overall Conclusions
The broader implication of these data is that physical activity may be an effective substitution for estrogen therapy in women, but it is unclear if physical activity as a clinical intervention is used in women who are experiencing reduced estrogen function. In addition, we feel that if the WHI is indicating that HT may not be a safe approach for women, then efforts must be made to define and promote alternative approaches for women. Thus, a critical next step would be conduction of more detailed human studies to determine the efficacy of using exercise training to prevent metabolic dysfunction in women who are experiencing reduced levels of estrogen or reduced estrogen receptor function. Considerations that need to be addressed would be the amount of necessary activity, intensity, and so on. Furthermore, we would predict that if loss of estrogenic function is caught early in women, then actual intervention might require only low levels of physical activity to prevent the accumulation of the metabolic defects. Conversely, we also suggest that it likely is more difficult (i.e., requires more strenuous exercise) to reverse a metabolic defect with exercise training, thus indicating that early screening by clinicians would be a critical aspect to consider. Overall, the numerous published data points indicate that we need to think carefully about the influence of sex steroids on tissue function and the interaction that appears to exist with physical activity.http://www.medscape.com/viewarticle/771738
Monday, October 13, 2014
Estrogen, hot flashes, and brain health
The aim of most hormonal treatments for endometriosis is to decrease estrogen. Over time this is not a good approach for our health in general. Here we see the affect of lowered estrogen in perimenopausal, menopausal women:
"Hot flushes, the classic symptom of menopause, are experienced by up to 85% of perimenopausal women.[11] (Perimenopause begins several years before menopause, when ovarian function starts to decline, and continues for several years after menopause, until ovarian function has reached its nadir.) A hot flush consists of a sudden sensation of heat in the upper body, often followed by perspiration and a chill. Peripheral vasodilation, tachycardia, decreased skin resistance, and sweating have all been documented to occur during a hot flush. Although poorly understood, the episodes certainly originate in the brain, most likely as a direct response to hypoestrogenism in the thermoregulatory center of the hypothalamus.[12]
It now appears that hot flushes are not merely symptoms of low estrogen levels; they may themselves lead to other neurologic problems. In oophorectomized women, hot flushes have been directly correlated with memory impairment.[13] In addition, single proton emission computed tomography (SPECT) of healthy menopausal women revealed decreased cerebral blood flow during hot flushes.[14] The greatest change occurred in the hippocampus, a center for memory and cognition. Regional patterns of cerebral blood flow during hot flushes resembled those characteristic of Alzheimer's disease. ERT resolved the hot flushes and restored normal patterns of cerebral blood flow.
Based on this evidence, reproductive biologists have hypothesized that hot flushes contribute to degenerative or aging changes in the brain.[15] Frequent vasoconstrictive episodes might lead to cerebral ischemia and free radical formation. The resulting damage may be analogous to that seen in the coronary arteries with plaque formation. The population of healthy neurons might be reduced, particularly in the hippocampus, leaving the brain with impaired ability to tolerate the neurodegenerative processes of aging and Alzheimer's disease.
Even in healthy older women, brain volume begins to decline as estrogen levels fall in the perimenopausal period.[16] This atrophy occurs particularly in the hippocampus and parietal lobe, areas primarily associated with memory and cognition. A similar loss in brain volume does not begin in men until a decade later (around age 60), most likely because male sex hormone production declines much more gradually with age. In fact, because of aromatization of testosterone to estrogen, men over the age of 60 have approximately three times more circulating estradiol than women of a similar age.[17]
In women, these cerebral changes may contribute to the frequent perimenopausal complaints of decreased mental clarity and short-term, verbal memory problems (see Table 1).[18] Studies of the effects of ERT on cognitive symptoms have generated inconsistent results, perhaps because dropouts and nonparticipants are more likely to be cognitively impaired.[19] A recent meta-analysis yielded only weak evidence that ERT improves cognition and prevents dementia.[20] However, many research groups have found a significant association between ERT and cognition, particularly in the area of verbal memory. For example, in one study of 727 postmenopausal women, history of estrogen use was associated with significantly higher scores on verbal memory and abstract reasoning tests.[21] " http://www.medscape.com/viewarticle/406718_2
"Hot flushes, the classic symptom of menopause, are experienced by up to 85% of perimenopausal women.[11] (Perimenopause begins several years before menopause, when ovarian function starts to decline, and continues for several years after menopause, until ovarian function has reached its nadir.) A hot flush consists of a sudden sensation of heat in the upper body, often followed by perspiration and a chill. Peripheral vasodilation, tachycardia, decreased skin resistance, and sweating have all been documented to occur during a hot flush. Although poorly understood, the episodes certainly originate in the brain, most likely as a direct response to hypoestrogenism in the thermoregulatory center of the hypothalamus.[12]
It now appears that hot flushes are not merely symptoms of low estrogen levels; they may themselves lead to other neurologic problems. In oophorectomized women, hot flushes have been directly correlated with memory impairment.[13] In addition, single proton emission computed tomography (SPECT) of healthy menopausal women revealed decreased cerebral blood flow during hot flushes.[14] The greatest change occurred in the hippocampus, a center for memory and cognition. Regional patterns of cerebral blood flow during hot flushes resembled those characteristic of Alzheimer's disease. ERT resolved the hot flushes and restored normal patterns of cerebral blood flow.
Based on this evidence, reproductive biologists have hypothesized that hot flushes contribute to degenerative or aging changes in the brain.[15] Frequent vasoconstrictive episodes might lead to cerebral ischemia and free radical formation. The resulting damage may be analogous to that seen in the coronary arteries with plaque formation. The population of healthy neurons might be reduced, particularly in the hippocampus, leaving the brain with impaired ability to tolerate the neurodegenerative processes of aging and Alzheimer's disease.
Even in healthy older women, brain volume begins to decline as estrogen levels fall in the perimenopausal period.[16] This atrophy occurs particularly in the hippocampus and parietal lobe, areas primarily associated with memory and cognition. A similar loss in brain volume does not begin in men until a decade later (around age 60), most likely because male sex hormone production declines much more gradually with age. In fact, because of aromatization of testosterone to estrogen, men over the age of 60 have approximately three times more circulating estradiol than women of a similar age.[17]
In women, these cerebral changes may contribute to the frequent perimenopausal complaints of decreased mental clarity and short-term, verbal memory problems (see Table 1).[18] Studies of the effects of ERT on cognitive symptoms have generated inconsistent results, perhaps because dropouts and nonparticipants are more likely to be cognitively impaired.[19] A recent meta-analysis yielded only weak evidence that ERT improves cognition and prevents dementia.[20] However, many research groups have found a significant association between ERT and cognition, particularly in the area of verbal memory. For example, in one study of 727 postmenopausal women, history of estrogen use was associated with significantly higher scores on verbal memory and abstract reasoning tests.[21] " http://www.medscape.com/viewarticle/406718_2
Tuesday, September 23, 2014
Rh negative blood assc w/ endo
"Results. We observed a higher proportion of Rh-negative women in the study group, as compared to healthy controls. Multivariate analysis showed that Rh-negative women are twice as likely to develop endometriosis (aOR = 1.90; 95% CI: 1.20-2.90). There was no significant difference in ABO group distribution between patients and controls. There was no difference when taking into account either the clinical forms (superficial endometriosis, endometrioma, and deep infiltration endometriosis) or the rAFS stages. Conclusion. Rh-negative women are twice as likely to develop endometriosis. Chromosome 1p, which contains the genes coding for the Rhesus, could also harbor endometriosis susceptibility genes." http://www.ncbi.nlm.nih.gov/pubmed/25243164
Thursday, September 11, 2014
Nerve fibers and pain in endometriotic lesions
[Relationship between pain and nerve fibers distribution in multiple endometriosis lesions].
[Article in Chinese]
Abstract
OBJECTIVE:
To investigate the relationship between the distribution of nerve fibers in multiple endometriosis lesions and pelvic pain.METHODS:
From Sept. 2007 to Sept. 2008, 120 endometriosis patients treated in Peking Union Hospital were enrolled in this study, which including 19 cases with stage I, 29 cases with stage II, 44 cases with stage III and 28 cases with stage IV. The pain symptom was evaluated by visual analogue scales (VAS) score and nerve fibers in multiple endometriosis lesions were detected by immunohistochemical staining.RESULTS:
The number of nerve fibers in multiple endometriosis lesions were (29.74+/-17.33)/mm2 in uterosacral ligament, (24.53+/-13.34)/mm2 in vaginal septum, (17.09+/-10.09)/mm2 in uterus rectum crux, (6.77+/-4.21)/mm2 in peritoneal endometriosis lesions, (0.07+/-0.25)/mm2 in endometriosis ovarian cyst wall. The number of nerve fibers in uterosacral ligament was mostly correlated with the degree of pain (r=0.56). The nerve fibers of uterus rectum crux and vaginal septum were correlated with defecation pain (r=0.58 and 0.41) and dyspareunia (r=0.82 and 0.67), which were significantly higher than those in endometriosis leision in peritoneum and ovary. There was no significant different number of nerve fibers among different stage disease (P>0.05).CONCLUSION:
There was significantly different distribution of nerve fibers in multiple endometriosis lesions, which was correlated with dysmenorrhea, anus pain, dyspareunia and chronic pelvic pain, not with clinical staging.http://www.ncbi.nlm.nih.gov/pubmed/20646536
____________________________________________________________________________________
Endometriosis-associated nerve fibers, peritoneal fluid cytokine concentrations, and pain in endometriotic lesions from different locations.
Abstract
OBJECTIVE:
To assess the relationship between endometriotic lesions with associated nerve fibers with both pain and peritoneal fluid (PF) cytokine concentrations based on lesion location.DESIGN:
An observational study.SETTING:
University hospital.PATIENT(S):
Premenopausal women undergoing laparoscopy.INTERVENTION(S):
The pain experienced by patients was recorded before surgery and ectopic endometrial tissue excised and matching PF collected during laparoscopy. Immunohistochemistry was performed on endometriotic tissue sections to identify nerve fibers and PF cytokine concentrations determined.MAIN OUTCOME MEASURE(S):
The pain experienced by women with endometriosis, the lesion locations, and the prevalence and proximity of nerve fibers to endometriotic lesions, as well as the PF concentrations of multiple cytokines.RESULT(S):
Lesions from the rectovaginal septum were significantly more likely to be associated with a nerve fiber and report more menstrual pain than lesions from other regions. The PF glycodelin concentrations were also significantly higher in samples with an endometriotic-associated nerve. In peritoneal endometriotic lesions significantly more menstrual pain was reported when endometriotic lesions were associated with nerve fibers, although no difference was observed between the cytokine concentrations. Ovarian endometriotic lesions were rarely associated with nerve fibers.CONCLUSION(S):
The presence of endometriosis-associated nerve fibers appear to be related to both the pain experienced by women with endometriosis and the concentration of PF cytokines; however, this association varies with the lesion location.http://www.ncbi.nlm.nih.gov/pubmed/22154765
____________________________________________________________________________________
Fertil Steril. 2011 Jun 30;95(8):2772-4. doi: 10.1016/j.fertnstert.2011.01.150. Epub 2011 Feb 19.
Nerve fibers and menstrual cycle in peritoneal endometriosis.
Abstract
There was no difference in the density of nerve fibers across the menstrual cycle in peritoneal endometriotic lesions. These findings may explain why patients with peritoneal endometriosis often have painful symptoms throughout the menstrual cycle.
Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
____________________________________________________________________________________
"
RESULTS:
The positive rate and density of PGP9.5-immunoreactive nerve fibers in peritoneal endometriotic leision were 62% (10/16) and (3.8+/-1.7)/mm2 in endometriosis patients with pain, which were significantly higher than 19% (3/16) and (1.7+/-0.5)/mm2 in endometriosis patients without pain (P<0.05) and 25% (5/20) and (1.3+/-0.6)/mm2 in peritoneal tissues in women without endometriosis (P<0.05). However, no differences were found between endometriosis patients without pain and women without endometriosis (P>0.05). Moreover, the density of PGP9.5-immunoreactive nerve fibers in peritoneal lesions in endometriosis patients with pain was positively correlated with the severity of pain (r=0.855, P<0.05). In addition, the density of PGP9.5-immunoreactive nerve fibers in peritoneal lesions was statistically higher in endometriosis patients with chronic pelvic pain and (or) dysmenorrhea than those in endometriosis patients with other type of pain (P<0.05), which was not associated with active lesion, site and staging (P>0.05).CONCLUSION:
It suggested that PGP9.5-immunoreactive nerve fibers might confer the mechanism of pelvic pain with endometriosis."http://www.ncbi.nlm.nih.gov/pubmed/20646535
___________________________________________________________________________________
"The nerve fiber density (mean +/- standard deviation/mm(2)) in peritoneal endometriotic lesions from hormone-treated women with endometriosis (10.6 +/- 2.2/mm(2)) was statistically significantly lower than in peritoneal endometriotic lesions from untreated women with endometriosis (16.3 +/-10.0/mm(2)). Nerve growth factor and nerve growth factor receptor p75 expression in peritoneal endometriotic lesions were slightly reduced in hormone-treated women with endometriosis compared with untreated women with endometriosis.
CONCLUSION(S):
Progestogens and combined oral contraceptives reduced nerve fiber density and nerve growth factor and nerve growth factor receptor p75 expression in peritoneal endometriotic lesions" http://www.ncbi.nlm.nih.gov/pubmed/18976764
Pelvic pain in women with ovarian endometrioma is mostly associated with coexisting peritoneal lesions.
Pelvic pain in women with ovarian endometrioma is mostly associated with coexisting peritoneal lesions.
Abstract
STUDY QUESTION:
Is the occurrence of pelvic pain in women with ovarian endometrioma associated with coexisting peritoneal lesions (PLs)?SUMMARY ANSWER:
Pelvic pain in women with ovarian endometrioma is usually associated with coexisting PLs. An increased tissue inflammatory reaction with elevated prostaglandin (PG) production may be responsible for the generation of pain.WHAT IS KNOWN ALREADY:
Severe pelvic pain in women with ovarian endometrioma is reported to be associated with deeply infiltrating endometriosis. However, information on pelvic pain in women with ovarian endometriosis with and without coexistent peritoneal superficial lesions is limited.STUDY DESIGN, SIZE AND DURATION:
Retrospective clinical study with case-controlled biological research using prospectively collected tissue samples derived from women with and without endometriosis and their retrospective evaluation.PARTICIPANTS/MATERIALS, SETTING, METHODS:
We performed a retrospective cohort study conducted in 2988 cases who had laparoscopic surgery for indications of ectopic pregnancy, tubal infertility and other benign gynecologic diseases. We analyzed the occurrence of pelvic pain in the cases with ovarian endometrioma according to the distribution of coexisting PLs and pattern of intrapelvic adhesions. Inflammatory reaction of eutopic and ectopic endometria was measured by immunoreaction to macrophage marker, CD68. The tissue expression of cyclooxygenase (COX) 2 was examined by immunohistochemistry and tissue concentrations of PG F2α were measured by ELISA.MAIN RESULTS AND THE ROLE OF CHANCE:
Among the 2988 surgical cases, 350 (11.7%) were found to have ovarian endometrioma at laparoscopy. Coexisting PLs were present in 269 of these women and in this group 85.4% of cases experienced pelvic pain and 14.6% had no pain. In contrast, among the 81 women with ovarian endometrioma only, 38.3% cases experienced pelvic pain and 61.7% cases had no pain and the difference between the groups was statistically significant (P < 0.01). The infiltration of CD68-immunoreactive macrophages was significantly higher in the eutopic and ectopic endometria of women with peritoneal endometriosis than in ovarian endometrioma. The tissue expression of COX2 and levels of PGF2α were significantly higher in both the eutopic and ectopic endometria derived from women with peritoneal endometriosis than in similar tissues derived from women with ovarian endometrioma.http://www.ncbi.nlm.nih.gov/pubmed/23108348
Tuesday, September 2, 2014
Symptoms and Physical and Surgical Findings
Synopsis of endo symptoms: "Typically, pelvic pain consists of dysmenorrhea, intermenstrual pain, and dyspareunia. Dysmenorrhea is the most commonly reported symptom and its severe form, although not entirely predictive, is highly suggestive of endometriosis.[43] Dyspareunia was found less frequently in ovarian endometriosis (77%) compared with peritoneal (88%) and rectovaginal (100%) forms of the disease.[44] Dysmenorrhea is usually progressive, with onset of pain often preceding the onset of menstrual flow. It usually continues throughout the menses and occasionally persists for several days afterward. The pain is most often localized in the low abdomen and deep pelvis; it is bilateral, often radiating to the back and thighs. It is often described as dull and aching and may be associated with rectal pressure, nausea, and episodes of diarrhea.[45] Intermenstrual pain may represent an extension of dysmenorrhea; in severe cases, patients may suffer from pain throughout the menstrual cycle. Intermenstrual pain has been reported in 57 to 68% of women with endometriosis and pain.[44] Endometriosis-related dyspareunia is usually positional and most intense upon deep penetration. It is most intense prior to menstruation, but in severe cases it may preclude vaginal intercourse throughout the month. Dyspareunia is usually associated with endometriosis of the cul-de-sac and rectovaginal septum.[47] Interestingly, dysmenorrhea and dyspareunia are more suggestive of endometriosis if the symptoms begin after years of relatively pain-free menses and coitus.[48]
Rarely, endometriosis may present as acute pelvic pain, typically perimenstrual, and usually in the context of hemoperitoneum and rupture or torsion of endometrioma.[58] Endometriosis has also been found in extrapelvic locations, giving rise to atypical symptoms. Nongynecologic organs most often affected by endometriosis include: the intestinal tract, the urinary tract, surgical scars, the lungs and thorax, peripheral nerves, and the central nervous system. Consequently, patients may present with a wide range of cyclic, menses-aggravated symptoms presumably reflecting cyclic bleeding and inflammation. About 0.1% of women who have undergone cesarean section may present with cyclic superficial pain, worsening when coughing and tensing the abdominal wall, that may resemble symptoms of a postoperative hernia.[59-61] Abdominal wall endometriomas are also found in abdominal scars following gynecologic surgeries and in the perineum after episiotomy. Surprisingly, cases of abdominal wall endometriosis have also been described in patients without previous surgical history.[62]
Women with gastrointestinal involvement may suffer from disturbed bowel function, dyschezia, cyclical hematochezia, or even bowel obstruction.[63-67] Hepatic endometriosis may present with cyclic right-sided subcostal pain.[68] Endometriosis of the urinary tract can cause hematuria, dysuria, urgency, and frequency. Bladder detrusor endometriosis presents with symptoms similar to those of interstitial cystitis, whereas renal involvement, although very rare, presents predominantly with abdominal pain and hematuria.[22,69-71] Involvement of the ureter may cause flank and iliac fossa pain due to partial or complete ureteric stenosis. Interestingly, ureteral endometriosis was found in 4.4% of patients with rectovaginal endometriosis.[72] Pulmonary and pleural endometriosis may be manifested by hemoptysis, chest pain, and shortness of breath resembling pulmonary embolism.[73-76] Women with diaphragmatic endometriosis may present with a wide spectrum of symptoms including chronic, cyclical shoulder tip pain.[77,78] Invasion of peripheral nerves can mimic common musculoskeletal problems and may result in cyclic pain such as sciatica, and cerebral endometriosis can lead to perimenstrual headaches or even seizures.[79-83]" http://www.medscape.com/viewarticle/460130_2
"Physical examination may provide a broad range of findings. In some cases, especially of mild endometriosis, the gynecologic examination may be entirely unremarkable. Ideally, the examination should be performed while the patient experiences at least some symptoms, preferably during menstruation, when it may be easiest to detect and localize areas suspected of harboring endometriosis.[84] A general physical examination is rarely rewarding unless the patient presents with focal cyclic symptoms suggestive of endometriosis in nongynecological organs. Abdominal examination often reveals tenderness, usually ill localized and deep. In rare instances of scar endometriomas, painful swelling and focal tenderness may mimic other lesions, such as hematomas, granulomas, or abscesses.
On pelvic examination, external genitalia and the vaginal surface are usually unremarkable. Speculum inspection may reveal bluish implants typical of endometriosis or red, hypertrophic lesions bleeding on contact, usually in the posterior fornix. In a recent retrospective analysis of 160 cases of histologically documented deeply infiltrative endometriosis, lesions were visible during speculum examination in only 14.4% and palpable during manual examination in 43.1% of patients.[85] Propst et al[86] described a new physical finding of lateral cervical displacement due to scarring of the ipsilateral uterosacral ligament that may be associated with endometriosis. The same group also reported an association between cervical stenosis (<4.5mm) and endometriosis in women with chronic pelvic pain.[87] Most commonly, positive physical signs are found on bimanual and rectovaginal examination of pelvic structures. Palpation of the uterus may reveal retroversion, decreased or absent mobility, and tenderness. Endometriomas may be detected as tender or nontender adnexal masses, often fixed to the uterus or to the pelvic sidewall. Tender masses, nodules, and fibrosis may be appreciated on palpation of the upper vagina, cul-de-sac, uterosacral ligaments, or rectovaginal septum. In a case-controlled study, the only signs of endometriosis in infertile patients were uterosacral nodularity and uterosacral tenderness.[88] Focal tenderness has been shown to correlate with the presence of endometriosis as well as the depth and volume of endometrial implants.[89] Koninckx and his associates[84] found that careful palpation during menstruation increases the detection rate of deep endometriosis, endometriomas, and cul-de-sac adhesions by over fivefold compared with a routine examination not timed to the menstruation.
However, a normal clinical examination does not rule out the diagnosis of endometriosis. When compared with surgical evaluation, pelvic examination showed poor sensitivity, specificity, and predictive values ( Table 1 ). A prospective study validating nonsurgical approaches to diagnosis of endometriosis found that pelvic examination was a reliable predictor of ovarian endometriomas but was not helpful in prediction of nonovarian lesions.[90]
It is essential to bear in mind that the physical signs listed here are not specific and none of the findings is diagnostic in and of itself of endometriosis. Caution should be exercised, and in the absence of conclusive evidence to the contrary, a differential diagnosis should include other conditions such as neoplasms or infections.
"Laparoscopic assessment in combination with histological examination of the excised lesions remains the gold standard for diagnosis of endometriosis. Knowledge of the most common locations of endometriosis is required for accurate visual inspection of the pelvic and abdominal cavities. Three different forms of endometriosis must be considered during laparoscopic visualization: peritoneal implants, endometriomas, and deep infiltrating lesions of the rectovaginal septum. An increased awareness of the variations in the appearance of endometriotic lesions has resulted in an almost twofold increase in the diagnosis of endometriosis at laparoscopy.[151]
The classic peritoneal implant appears as a bluish-black "powder burn" lesion with variable degrees of pigmentation and surrounding fibrosis. Typical dark coloration is the result of hemosiderin deposits from entrapped menstrual debris. However, the majority of peritoneal implants appear as nonpigmented, atypical (subtle) lesions, usually red or white. Jansen and Russell[154] have described the relationship between morphological and histological features of various endometriotic lesions. Lesions that were commonly endometriotic included areas of white opacification (81%), red flame-like lesions (81%), and glandular lesions (67%). Less frequently, histological confirmation of endometriosis was obtained in subovarian adhesions (50%), yellow-brown peritoneal patches (47%), and circular peritoneal defects (45%).[154]
As demonstrated by Nisolle and Donnez,[155] red lesions are highly vascularized and proliferative, usually representing an early stage of endometriosis. In contrast, white lesions contain fibrous tissue and are poorly vascularized. They are metabolically inactive and probably represent healed or latent lesions. Black, pigmented foci represent an advanced stage of the disease and the diagnosis of endometriosis has been histologically confirmed in 76 to 93% of these specimens.[156,157] Biochemical activity and clinical features of various lesions from infertile patients with minimal or mild endometriosis were assessed in a prospective study. White peritoneal implants were associated with less pain than black or red lesions, and both black and red lesions showed similar activity expressed in terms of prostaglandin F2![]()
production.[54] In a prospective study, changing patterns in activity of the peritoneal lesions were observed with no change in the stage of the disease when evaluated at laparoscopy before and 6 months after medical therapy.[158]
Redwine[159] proposed that endometrial peritoneal implants undergo a process of "natural evolution." This concept is supported by the observation that the frequency of red lesions and clear papules declines with patients' age and these implants appear to be replaced by black, and ultimately white, scarred lesions over a period of 7 to 10 years.[159] There is a significant overlap in the time course of the presentation of these defects, and all types of lesions may coexist in the same patient.
Endometriosis may also be detected in the lesions visible only under the microscope or scanning electron microscope.[152,160] The prevalence of endometriosis (including microscopic forms) in asymptomatic patients undergoing laparoscopy was estimated to be as high as 45 to 50%.[161] Novel techniques such as "peritoneal blood painting" and infusion of crystalloid into the cul-de-sac ("bubble test") were developed to improve the detection of subtle lesions.[162,163] However, the clinical significance of microscopic endometriosis remains uncertain. It is conceivable that microscopic endometriosis may be present in the majority of women and that a symptomatic disease may develop only in some.[161]
Because endometriotic implants vary in appearance, the experience and the expertise of the surgeon may greatly influence the selection of the biopsy area and hence the likelihood of a diagnosis of endometriosis. In a prospective study, Walter et al[164] correlated visual diagnosis of endometriosis at laparoscopy with final histological confirmation in 44 patients evaluated for chronic pelvic pain. Use of strict histological criteria resulted in lower rates of confirmed endometriosis because visually detected endometriosis was observed in 36% of cases but confirmed histologically in only 18% of cases.
Peritoneal endometriosis can be associated with other pathological changes such as general hypervascularization and adhesion formation. Adhesions should be evaluated for density (filmy, vascular, dense/fibrotic) and for the extent to which they limit mobility of pelvic organs. Assessment of the severity of periadnexal adhesions is of particular importance in infertile patients because the extent of adhesions is related to the prognosis.[165]"
http://www.medscape.com/viewarticle/460130_5
"Initial work on mapping of pain associated with the endometriosis lesions resulted in some thought-provoking findings. The classic black lesions were found to be painful in only 11% of patients when the lesion was touched. Similarly, white lesions were painful in 20% of patients with red lesions at 37%, and clear lesions at 32% were the most painful (Table 1). These results added further reason as to why initial therapy had such poor results. Surgeons would only “see” the black lesions and removed them, but these were the least painful lesions. The most painful clear lesions were not “seen” at laparotomy and therefore remained, as did the pain. What became apparent next, while mapping the patient, was the fact that the pain extended 28 mm beyond the visible border of the lesion onto what looked like “normal” peritoneum ((Figure 1). Therefore, if the surgeon only removed the lesion at its border, the microscopic disease in the previously identified normal looking peritoneum was left, and persistence or recurrence of the symptoms was encountered.
"Palpation of the lesions of endometriosis produced the cramps, not the uterus. Patients, postoperatively, reported that once they identified the cramps of endometriosis, they noticed that they were different than menstrual cramps. Furthermore, palpation of the endometriosis lesions on patients without a uterus and both ovaries removed reproduced the cramps of endometriosis. This confirmed the findings of other researchers who have concluded that a hysterectomy often does not change the course of the pain of endometriosis since it is the lesions, not the uterus, which are responsible for the cramp-like pain. The location of the lesion in relationship to the pelvis can, in most instances, reproduce the symptoms the patient experiences. Lesions on the utero-sacral ligament, when palpated, cause pain or cramps in the back. Palpation of lesions on the side wall of the pelvis result in pain or cramps radiating down the leg.
"What is most interesting is that right-left orientation of the pelvis does not exist in some patients.12 That is to say, palpation of a lesion of endometriosis on the left side of the pelvis may produce pain that the patient perceives as being on the right side of the abdomen, and the opposite is also true. How many times has a laparoscopy under general anesthesia been done on a patient complaining of right-sided pain where the surgeon saw a normal looking pelvis on the right—only to wake up the patient and tell her, “I saw nothing on the right side of your pelvis that would cause your pain.” It now becomes apparent why the results of the survey of the Endometriosis Association's members revealed that the average length of time from the onset of symptoms to the treatment of the endometriosis was 9.28 years and an average of 2.3 operations.
"As has been shown over the years, results of therapy, based only on what the physician sees, is marginal at best, especially in minimal endometriosis (ie, stage 1 and stage 2).
"The data revealing the failure of the approach of “treat and see,” based on what the surgeon observed at laparoscopy under general anesthetic, is strong and reveals that a new approach is needed. An approach based on patient confirmed diagnosis and patient-based analysis of the results of therapy needs to be looked at in greater detail. The only person who knows where the pain starts and ends is the patient herself. She is also the only one who can confirm when the pain is no longer present." http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3015350/
Video from Dr. David Redwine on the appearance of endometriosis:
http://vimeo.com/62247222
Rarely, endometriosis may present as acute pelvic pain, typically perimenstrual, and usually in the context of hemoperitoneum and rupture or torsion of endometrioma.[58] Endometriosis has also been found in extrapelvic locations, giving rise to atypical symptoms. Nongynecologic organs most often affected by endometriosis include: the intestinal tract, the urinary tract, surgical scars, the lungs and thorax, peripheral nerves, and the central nervous system. Consequently, patients may present with a wide range of cyclic, menses-aggravated symptoms presumably reflecting cyclic bleeding and inflammation. About 0.1% of women who have undergone cesarean section may present with cyclic superficial pain, worsening when coughing and tensing the abdominal wall, that may resemble symptoms of a postoperative hernia.[59-61] Abdominal wall endometriomas are also found in abdominal scars following gynecologic surgeries and in the perineum after episiotomy. Surprisingly, cases of abdominal wall endometriosis have also been described in patients without previous surgical history.[62]
Women with gastrointestinal involvement may suffer from disturbed bowel function, dyschezia, cyclical hematochezia, or even bowel obstruction.[63-67] Hepatic endometriosis may present with cyclic right-sided subcostal pain.[68] Endometriosis of the urinary tract can cause hematuria, dysuria, urgency, and frequency. Bladder detrusor endometriosis presents with symptoms similar to those of interstitial cystitis, whereas renal involvement, although very rare, presents predominantly with abdominal pain and hematuria.[22,69-71] Involvement of the ureter may cause flank and iliac fossa pain due to partial or complete ureteric stenosis. Interestingly, ureteral endometriosis was found in 4.4% of patients with rectovaginal endometriosis.[72] Pulmonary and pleural endometriosis may be manifested by hemoptysis, chest pain, and shortness of breath resembling pulmonary embolism.[73-76] Women with diaphragmatic endometriosis may present with a wide spectrum of symptoms including chronic, cyclical shoulder tip pain.[77,78] Invasion of peripheral nerves can mimic common musculoskeletal problems and may result in cyclic pain such as sciatica, and cerebral endometriosis can lead to perimenstrual headaches or even seizures.[79-83]" http://www.medscape.com/viewarticle/460130_2
"Physical examination may provide a broad range of findings. In some cases, especially of mild endometriosis, the gynecologic examination may be entirely unremarkable. Ideally, the examination should be performed while the patient experiences at least some symptoms, preferably during menstruation, when it may be easiest to detect and localize areas suspected of harboring endometriosis.[84] A general physical examination is rarely rewarding unless the patient presents with focal cyclic symptoms suggestive of endometriosis in nongynecological organs. Abdominal examination often reveals tenderness, usually ill localized and deep. In rare instances of scar endometriomas, painful swelling and focal tenderness may mimic other lesions, such as hematomas, granulomas, or abscesses.
On pelvic examination, external genitalia and the vaginal surface are usually unremarkable. Speculum inspection may reveal bluish implants typical of endometriosis or red, hypertrophic lesions bleeding on contact, usually in the posterior fornix. In a recent retrospective analysis of 160 cases of histologically documented deeply infiltrative endometriosis, lesions were visible during speculum examination in only 14.4% and palpable during manual examination in 43.1% of patients.[85] Propst et al[86] described a new physical finding of lateral cervical displacement due to scarring of the ipsilateral uterosacral ligament that may be associated with endometriosis. The same group also reported an association between cervical stenosis (<4.5mm) and endometriosis in women with chronic pelvic pain.[87] Most commonly, positive physical signs are found on bimanual and rectovaginal examination of pelvic structures. Palpation of the uterus may reveal retroversion, decreased or absent mobility, and tenderness. Endometriomas may be detected as tender or nontender adnexal masses, often fixed to the uterus or to the pelvic sidewall. Tender masses, nodules, and fibrosis may be appreciated on palpation of the upper vagina, cul-de-sac, uterosacral ligaments, or rectovaginal septum. In a case-controlled study, the only signs of endometriosis in infertile patients were uterosacral nodularity and uterosacral tenderness.[88] Focal tenderness has been shown to correlate with the presence of endometriosis as well as the depth and volume of endometrial implants.[89] Koninckx and his associates[84] found that careful palpation during menstruation increases the detection rate of deep endometriosis, endometriomas, and cul-de-sac adhesions by over fivefold compared with a routine examination not timed to the menstruation.
However, a normal clinical examination does not rule out the diagnosis of endometriosis. When compared with surgical evaluation, pelvic examination showed poor sensitivity, specificity, and predictive values ( Table 1 ). A prospective study validating nonsurgical approaches to diagnosis of endometriosis found that pelvic examination was a reliable predictor of ovarian endometriomas but was not helpful in prediction of nonovarian lesions.[90]
It is essential to bear in mind that the physical signs listed here are not specific and none of the findings is diagnostic in and of itself of endometriosis. Caution should be exercised, and in the absence of conclusive evidence to the contrary, a differential diagnosis should include other conditions such as neoplasms or infections.
"Laparoscopic assessment in combination with histological examination of the excised lesions remains the gold standard for diagnosis of endometriosis. Knowledge of the most common locations of endometriosis is required for accurate visual inspection of the pelvic and abdominal cavities. Three different forms of endometriosis must be considered during laparoscopic visualization: peritoneal implants, endometriomas, and deep infiltrating lesions of the rectovaginal septum. An increased awareness of the variations in the appearance of endometriotic lesions has resulted in an almost twofold increase in the diagnosis of endometriosis at laparoscopy.[151]
Peritoneal Implants
Peritoneal implants are most commonly localized in the uterosacral ligaments, cul-de-sac, ovarian fossa, and adjacent pelvic sidewalls. Less frequently, implants can also be found in the upper abdomen as well as on the surface of the bladder and the bowel (predominantly rectum, sigmoid colon, appendix, and cecum).[64,71] Hence careful and close inspection of the entire peritoneal cavity should be performed. Magnification obtained during laparoscopy depends on the distance between the laparoscope and the area inspected; for example, the magnification rate is approximately 3.2 and 1.7 from a distance of 10 and 20 mm, respectively.[152] Magnification allows the recognition of lesions as small as 400 µm for red and 180 µm for clear lesions.[151,153]The classic peritoneal implant appears as a bluish-black "powder burn" lesion with variable degrees of pigmentation and surrounding fibrosis. Typical dark coloration is the result of hemosiderin deposits from entrapped menstrual debris. However, the majority of peritoneal implants appear as nonpigmented, atypical (subtle) lesions, usually red or white. Jansen and Russell[154] have described the relationship between morphological and histological features of various endometriotic lesions. Lesions that were commonly endometriotic included areas of white opacification (81%), red flame-like lesions (81%), and glandular lesions (67%). Less frequently, histological confirmation of endometriosis was obtained in subovarian adhesions (50%), yellow-brown peritoneal patches (47%), and circular peritoneal defects (45%).[154]
As demonstrated by Nisolle and Donnez,[155] red lesions are highly vascularized and proliferative, usually representing an early stage of endometriosis. In contrast, white lesions contain fibrous tissue and are poorly vascularized. They are metabolically inactive and probably represent healed or latent lesions. Black, pigmented foci represent an advanced stage of the disease and the diagnosis of endometriosis has been histologically confirmed in 76 to 93% of these specimens.[156,157] Biochemical activity and clinical features of various lesions from infertile patients with minimal or mild endometriosis were assessed in a prospective study. White peritoneal implants were associated with less pain than black or red lesions, and both black and red lesions showed similar activity expressed in terms of prostaglandin F2
Redwine[159] proposed that endometrial peritoneal implants undergo a process of "natural evolution." This concept is supported by the observation that the frequency of red lesions and clear papules declines with patients' age and these implants appear to be replaced by black, and ultimately white, scarred lesions over a period of 7 to 10 years.[159] There is a significant overlap in the time course of the presentation of these defects, and all types of lesions may coexist in the same patient.
Endometriosis may also be detected in the lesions visible only under the microscope or scanning electron microscope.[152,160] The prevalence of endometriosis (including microscopic forms) in asymptomatic patients undergoing laparoscopy was estimated to be as high as 45 to 50%.[161] Novel techniques such as "peritoneal blood painting" and infusion of crystalloid into the cul-de-sac ("bubble test") were developed to improve the detection of subtle lesions.[162,163] However, the clinical significance of microscopic endometriosis remains uncertain. It is conceivable that microscopic endometriosis may be present in the majority of women and that a symptomatic disease may develop only in some.[161]
Because endometriotic implants vary in appearance, the experience and the expertise of the surgeon may greatly influence the selection of the biopsy area and hence the likelihood of a diagnosis of endometriosis. In a prospective study, Walter et al[164] correlated visual diagnosis of endometriosis at laparoscopy with final histological confirmation in 44 patients evaluated for chronic pelvic pain. Use of strict histological criteria resulted in lower rates of confirmed endometriosis because visually detected endometriosis was observed in 36% of cases but confirmed histologically in only 18% of cases.
Peritoneal endometriosis can be associated with other pathological changes such as general hypervascularization and adhesion formation. Adhesions should be evaluated for density (filmy, vascular, dense/fibrotic) and for the extent to which they limit mobility of pelvic organs. Assessment of the severity of periadnexal adhesions is of particular importance in infertile patients because the extent of adhesions is related to the prognosis.[165]"
http://www.medscape.com/viewarticle/460130_5
"Initial work on mapping of pain associated with the endometriosis lesions resulted in some thought-provoking findings. The classic black lesions were found to be painful in only 11% of patients when the lesion was touched. Similarly, white lesions were painful in 20% of patients with red lesions at 37%, and clear lesions at 32% were the most painful (Table 1). These results added further reason as to why initial therapy had such poor results. Surgeons would only “see” the black lesions and removed them, but these were the least painful lesions. The most painful clear lesions were not “seen” at laparotomy and therefore remained, as did the pain. What became apparent next, while mapping the patient, was the fact that the pain extended 28 mm beyond the visible border of the lesion onto what looked like “normal” peritoneum ((Figure 1). Therefore, if the surgeon only removed the lesion at its border, the microscopic disease in the previously identified normal looking peritoneum was left, and persistence or recurrence of the symptoms was encountered.
"Palpation of the lesions of endometriosis produced the cramps, not the uterus. Patients, postoperatively, reported that once they identified the cramps of endometriosis, they noticed that they were different than menstrual cramps. Furthermore, palpation of the endometriosis lesions on patients without a uterus and both ovaries removed reproduced the cramps of endometriosis. This confirmed the findings of other researchers who have concluded that a hysterectomy often does not change the course of the pain of endometriosis since it is the lesions, not the uterus, which are responsible for the cramp-like pain. The location of the lesion in relationship to the pelvis can, in most instances, reproduce the symptoms the patient experiences. Lesions on the utero-sacral ligament, when palpated, cause pain or cramps in the back. Palpation of lesions on the side wall of the pelvis result in pain or cramps radiating down the leg.
"What is most interesting is that right-left orientation of the pelvis does not exist in some patients.12 That is to say, palpation of a lesion of endometriosis on the left side of the pelvis may produce pain that the patient perceives as being on the right side of the abdomen, and the opposite is also true. How many times has a laparoscopy under general anesthesia been done on a patient complaining of right-sided pain where the surgeon saw a normal looking pelvis on the right—only to wake up the patient and tell her, “I saw nothing on the right side of your pelvis that would cause your pain.” It now becomes apparent why the results of the survey of the Endometriosis Association's members revealed that the average length of time from the onset of symptoms to the treatment of the endometriosis was 9.28 years and an average of 2.3 operations.
"As has been shown over the years, results of therapy, based only on what the physician sees, is marginal at best, especially in minimal endometriosis (ie, stage 1 and stage 2).
"The data revealing the failure of the approach of “treat and see,” based on what the surgeon observed at laparoscopy under general anesthetic, is strong and reveals that a new approach is needed. An approach based on patient confirmed diagnosis and patient-based analysis of the results of therapy needs to be looked at in greater detail. The only person who knows where the pain starts and ends is the patient herself. She is also the only one who can confirm when the pain is no longer present." http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3015350/
Video from Dr. David Redwine on the appearance of endometriosis:
http://vimeo.com/62247222
Subscribe to:
Posts (Atom)