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The first intimations that chronic fatigue syndrome might be associated with gynecological issues  came early in the history of the disorder.  In 1988 Dr. Komaroff co-authored a paper finding increased gynecological complications (endometriosis, ovarian cysts, polycystic ovaries, uterine fibroids, menstrual abnormalities and galactorrhea), in 149 women with ME/CFS. Similar findings (early menopause, hysterectomy) have been reported in fibromyalgia as well.

gender imbalance chronic fatigue syndrome

The gender imbalance has always suggested somethings up with the female hormones in ME/CFS. Three studies do as well.

The gender imbalance, the two-peak incidence pattern in ME/CFS occurring during times of hormonal fluctuations, the significant symptom reductions some women experience during pregnancy and the high rates of gynecological disorders found other functional syndromes all suggest female hormones must be involved in some way in both ME/CFS and FM.

That stimulating finding, however, went without followup for 23 years until in 2011  a CDC study found increased rates of endometriosis ovarian cysts, irregular periods, gynecologic surgical operations, and pelvic pain in women with ME/CFS.

The CDC jumped on their results. There would be no 20 year wait for another gynecological study. Three years later they had another study out.

Menopause. 2015 Feb 2. Early menopause and other gynecologic risk indicators for chronic fatigue syndrome in women. Boneva RS1Lin JMUnger ER

In the 2014 study 84 women diagnosed with chronic fatigue syndrome and 73 healthy controls took a gynecological history survey of 12 conditions (age at menarche, duration of menstrual cycle, excessive menstrual bleeding, bleeding between periods, missing periods, endometriosis, lower abdominal pain unrelated to menstrual periods, currently menopausal, age at menopause, gynecological surgical operations, hysterectomy, oophorectomy).  The women came from a population sampling effort in Georgia using the empirical definition.

Remarkably, every one of the 12 gynecological conditions assessed was significantly increased in the ME/CFS group. Abdominal pain unrelated to menstruation, currently menopausal, excessive menstrual bleeding and age at menopause, were the most highly significant findings (p < .007), with a  history of hysterectomy, endometriosis, gynecological surgeries and bleeding between periods coming in “second” with high significance factors (p <.004).

These were not small differences. Women with ME/CFS were four times more likely to have had a hysterectomy than women without ME/CFS. They also tended to have hysterectomies and/or oophorectomies (removal of the ovaries) at an earlier age plus the average age of menopause in ME/CFS was a full 10 years earlier than that of the healthy controls.

gynecological

The sex hormone – early menopause connection in chronic fatigue syndrome

A covariate model employing BMI, hysterectomy and age at menopause suggested that early age at menopause – possibly signifying reduced hormonal production – was a particularly significant factor. In fact over sixty percent of the early menopause found in the ME/CFS women, was associated with hysterectomy; i.e. the hysterectomy appears to have triggered early menopause. Hysterectomy often, through later ovarian failure, reduces sex hormone production.

The three gynecological history results suggest to the CDC that reduced levels of  female hormones (estrogen/progesterone) may play a role in ME/CFS. Early menopause, hysterectomy, menstrual bleeding and disturbed menstrual cycles are all associated with sex hormone depletion. Given that it was not surprising to see that the women with ME/CFS were significantly more likely to have been prescribed hormones than healthy controls.

The possible effects of reduced sex hormone production are manifold. Estrogen and progesterone are neuroprotective agents that effect sleep, cognition, inflammation, bone, muscle and joint health and pain sensitivity.

The Chicken Or The Egg?

Does chronic fatigue syndrome lead to hysterectomy and other problems or the opposite? Which is begetting which? It’s impossible to infer cause in these kinds of studies, but when both  hysterectomy and ME/CFS and/or fibromyalgia were present,  hysterectomy (ME/CFS (73%) / fibromyalgia (91%)) usually came first.

There’s no telling how important hysterectomy is to the development of ME/CFS or FM. It is, of course, a surgical procedure – a traumatic event – that also happens to affect sex hormone production. It’s possible that hysterectomy  and the sex hormone depletion it causes presents a kind of one-two punch that sets some women up for a major system reset at some point.

endometriosis

Immune sufficiency or autoimmunity may play a role in most common reason for hysterectomy – endometriosis.

The question is why early hysterectomies – the removal of the uterus and sometimes other organs – were so common in this group. Hysterectomy is not an uncommon procedure later in life – one in three women will ultimately undergo a hysterectomy at some point – but not so common earlier in life. It turns out that woman have hysterectomies for a variety of reasons – many of which involve pain relief. The most common reasons for hysterectomies are endometriosis followed by chronic pelvic pain, uterine fibroids, cancer and others.

The putative causes of endometriosis and chronic pelvic pain hover around those considered for ME/CFS. The roles autoimmune diseaseallergic reactions, and toxins are being examined in endometriosis. The roles stress-driven HPA axis dysfunction, neurogenic inflammation, and myofascial pain syndrome are being examined in chronic pelvic pain syndrome.

Pain Sensitization

Since increased pain sensitization appears to be a factor in all these disorders, it may be notable that increased pain is one possible outcome of female hormone dysregulation. High rates of pain associated with endometriosis and CPS could be driving higher rates of hysterectomies in these women. The high rates of abdominal pain that is not associated with menstruation found in the CDC’s CFS group smacks of the increased pain sensitivity occurring in three other disorders comorbid with ME/CFS  – vulvodynia, irritable bowel syndrome and interstitial cystitis.

Hysterectomies appear to set up women with fibromyalgia, for increased pain sensitivity. Pain sensitivity, stiffness and fatigue were substantially increased in a large study (n=813; 327 with hysterectomies) of women with FM and a history of hysterectomy.  The authors noted that the increased pain following a procedure designed to reduce pain suggested that misdiagnosis may be driving many women with FM to get unneeded and ultimately harmful hysterectomies. Their pelvic pain was due to fibromyalgia – not to structural problems. (In fact, studies finding increased rates of surgical procedures in FM relative to other rheumatological disorders, suggests that all too often FM pain is misdiagnosed as some sort of structural problem that surgery can fix – but which it ultimately makes worse.)

The estrogen – pain sensitization may be a critical one.  It was recently assessed in irritable bowel syndrome, another female dominated disorder (2x’s number of females/males). Estrogen receptors regulate both the transmission of pain signals from the body to the spinal cord and the filtering of pain signals at the dorsal horn of the spinal cord. In both cases they do this by modulating the activity of the ion channels, covered in a recent blog. Depending on the type of estrogen receptor in play, estrogen can either upregulate or down regulate pain sensitivity. In general, though, the ovarian hormones appear to have pain reduction properties.

Estrogen also appears to reduce sympathetic nervous system activity. Rice reported reduced estrogen levels may be tied to the increased levels of sensory nerve fibers he’s found in fibromyalgia patients hands.

Estrogen is in the mix. Some of the findings are tantalizing but there’s no clarity as yet to what role it’s playing.

 Natural Killer Cell Connection?

Natural killer cells serve dual purposes in the placenta: in their latent state they support placental growth, but if their cytotoxic properties are turned on, they can inhibit it as well. It’s intriguing, given the number of gynecological abnormalities CDC studies have found in women with ME/CFS, that natural killer cells are the most abundant immune cell during embryo implantation and early placental development. Could reduced NK cell functioning somehow be a factor in the gynecological problems in ME/CFS/FM?

Treatment

The treatment implications of these findings are obscure, at least to me. Anecdotal reports of ME/CFS patients responding to hormone replacement therapy do occur but they are hardly a mainstream therapy. Personally, I know of one person who responded very well to progesterone (and poorly to estrogen.) She gloamed onto the progesterone possibility by trawling the forums of other disease groups. Stories of the opposite reaction to female hormones can be found as well.

estrogen - chronic fatigue syndrome

Estrogen plays a role in pain sensitization as well as other symptoms and conditions.

Dr. Klimas is reported to support low dose estrogen in women going through menopause who do not demonstrate increased cancer risk. Why? Because she’s found that menopause can greatly exacerbate ME/CFS symptoms and therein lies the rub. Several factors suggest female and perhaps male hormones are involved in ME/CFS and probably FM, but exactly what role these complex factors play and how to manipulate them successfully, is another question entirely.

At the least, this study should alert physicians that some ME/CFS and FM patient’s flares may be due not to these disorders, per se, but to the entrance of early menopause – something they can do something about. At the most it will spur more research into the role sex hormones play in the genesis and perpetuation of ME/CFS and FM.

“CFS can take a tremendous toll on women’s lives at midlife and on our society and health care system. Being aware of the association of CFS and earlier menopause can help providers assist women in sorting out symptoms of CFS from symptoms of menopause,” Dr. Margery Gass

For now, hormonal treatments appear to be used as secondary factors to reduce symptoms, but who knows what the future may hold. If Broderick’s model is correct, hormone therapy in some form, may someday be part of a one – two- three punch protocol, designed to shift and ultimately tilt the system back to homeostasis.

Glaser restored T-cell cytotoxic activity and knocked down herpes simplex replication in stressed mice, using a beta blocker called nadolol and low dose mifeprestone, a natural killer enhancer used in abortions. The combination of a gynecologically active drug focused on natural killer cell functioning, and an autonomic nervous system affecting drug to fight off herpesvirus infection is, of course, intriguing. It may speak to the type of multi-systemic drug combination that ends up being effective in ME/CFS and FM.

Repurposing II: A Natural Killer Cell Enhancing Drug and Chronic Fatigue Syndrome 

The women in this study were a) from a randomly sampled population and b) identified using the empirical definition. The findings, may not, therefore, reflect those of patients seen in ME/CFS clinics. (Komaroff did, however, find increased rates of gynecological problems in a non-population-based study.) Hopefully, we’ll know more about the gynecological connection to ME/CFS as the CDC’s Multisite and the Chronic Fatigue Initiative’s epidemiological studies start rolling out.

Inquiry of the Day – What kinds of gynecological disorders, if any, have you been diagnosed with? Let us know on the ME/CFS and FM Gynecological Disorders poll on the Health Rising Forums

 

 

 

 

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