Some interesting new research is being reported on how progesterone – a hormone that forms part of the contraceptive pill – plays a role in the response to infection, as well as possibly helping to repair lung damage, writes ME Association medical adviser Dr Charles Shepherd.
Press report here:
Information from the MEA leaflet on research into female hormone status, the menopause and the use of hormonal drugs in ME/CFS:
Professor Tony Komaroff (1) et al in America examined whether menstrual and gynaecological abnormalities precede the onset of ME/CFS. They looked at 150 women with ME/CFS and 149 controls and used questionnaires on menstrual, reproductive and medical history.
The ME/CFS group reported increased gynaecological complications and a lower incidence of premenstrual symptomatology. Compared to controls, a greater number reported irregular menstrual cycles, periods of amenorrhoea (= no periods), and sporadic bleeding between periods.
Factors suggestive of abnormal ovarian function – e.g a history of polycystic ovary syndrome/PCOS, hirsuitism (= excessive hair growth) and ovarian cysts were also more common.
They concluded that frequent anovulatory (= no ovulation takes place) menstrual cycles due to hyperandrogenism (= polycystic ovary syndrome) or hyperprolactinaemia (= raised levels of the hormone prolactin) may increase the risk of ME/CFS. This is through the loss of the potential immunomodulatory effects of the female hormone progesterone in the presence of continued oestrogen production. They also hypothesised that frequent anovulatory menstrual cycles due to PCOS may help to explain the increased reporting of gynaecological complications and lowered premenstrual symptomatology in ME/CFS.
Boneva and colleagues from America (2) looked at 36 women with ME/CFS and 48 controls using a structured gynaecological history questionnaire. The ME/CFS group reported higher rates of pregnancy, gynaecological surgery, pelvic pain unrelated to menstruation, endometriosis, and periods of amenorrhoea. Menopause occurred about 4.4 years earlier in the ME/CFS group.
More women in the ME/CFS group reported having a hysterectomy and oophorectomy (= ovary removal) than controls. These findings stress the need to take a proper gynaecological history from women with ME/CFS.
Here in the UK, gynaecologists John Studd and Nicholas Panay reported in the Lancet (3) that an oestradiol patch and cyclical progestogen therapy may help women who have a premenstrual exacerbation of symptoms with low levels of serum oestradiol.
1) Harlow BL et al. Reproductive correlates of chronic fatigue syndrome. American Journal of Medicine, 1998, 105, 94S-99S.
2) Boneva et al. Gynaecological history in chronic fatigue syndrome. A population-based case study. Journal of Women's Health, 2011, 21 – 28.
3) Studd J and Panay N. Chronic fatigue syndrome. Lancet, 1996, 3478, 1384
And a still useful (2002) review of gynaecological problems in ME/CFS from my colleague Dr Rosemary Underhill:
<strong>Gynecological Concerns in Women with Chronic Fatigue Syndrome
By RosemaryUnderhill, MB, BS, MRCOG, United Kingdom
Women suffering from chronic fatigue syndrome (CFS) commonly have a bewildering array of symptoms that can occur in every body system, including the reproductive system. Diagnostic confusion sometimes occurs because some symptoms are common to both CFS and gynecological conditions such as premenstrual syndrome or menopause. These common gynecological conditions can also cause an exacerbation of CFS symptoms. The female reproductive hormone system might also play a part in the causation and persistence of CFS, since the illness occurs twice as often in women as men.(1)
Although scientific studies are few, a number of gynecological conditions have been found to occur more frequently in women with CFS. These conditions are usually associated with abnormal reproductive hormone levels, immune dysfunction and/or pain. Some of these conditions may even pre-date the onset of the CFS.(2,3) Why this should happen is open to conjecture. Endocrine and/or immunological changes may possibly be present in some CFS patients before the full-blown syndrome becomes manifest.
Gynecological symptoms in women with CFS should not be assumed to be merely part of the CFS symptomatology. Their investigation and treatment in patients with CFS should follow standard gynecological practice, and patients will benefit from relief of symptoms.
Low oestrogen states, menopause and osteoporosis
Many pre-menopausal CFS patients have scanty, irregular periods, inter-menstrual bleeding and sometimes periods of amenorrhea. These symptoms can predate the onset of CFS, are typical of anovulatory or oligoovulatory cycles and can be associated with a low oestrogen state. Hirsutism may be associated with oligomenorrhea. Researchers have found that ovarian hormone (estradiol) levels were low in some 25 percent of a small group of pre-menopausal women with CFS, in spite of normal follicle stimulating hormone (FSH) levels.4 The researchers suggested that a chronic oestrogen deficiency state is present in a subgroup of women with CFS.4 The normal FSH levels distinguish this condition from menopause where FSH levels are raised. At menopause, heavy irregular periods, scanty periods or amenorrhea can occur.
There are number of central nervous system symptoms associated with the low oestrogen state. They are tiredness, headaches, dizziness, lack of concentration, insomnia, depression and anxiety. When FSH levels are also raised at menopause, this can result in vasomotor instability, causing night sweats, feeling hot often and flushing of the face. All of these symptoms may be due to reproductive hormone changes, CFS or a combination of both. One point of difference is that vaginal dryness is usually present if oestrogen levels are low and less likely to be present if symptoms are due to CFS. Many women find that their CFS symptoms worsen at menopause.
In younger pre-menopausal women, the presence of a low oestrogen state can be confirmed by measuring blood estradiol levels (low) and FSH levels (not raised). In peri-menopausal women between 40 and 50, FSH levels may fluctuate, making serial measurements helpful. In women over 50, menopause is more likely and blood FSH is high.
Women with CFS who have had a low oestrogen state for some years are at risk for osteoporosis. A small study found that five of seven hypo-estrogenic pre-menopausal women with CFS had a low bone density.4 Other factors contributing to osteoporosis in CFS patients are exercise intolerance, because exercise exacerbates CFS symptoms, and lack of vitamin D, due to inability to go outside in the sunlight, as a result of weakness and photophobia. Calcium intake may also be low, if the patient avoids milk due to lactose intolerance, which is common in CFS. The diagnosis can be confirmed by bone density measurement.
Treatment considerations: In pre-menopausal patients, treatment to regularise periods is not necessary. But if oestrogen levels are low, the co-existing central nervous system symptoms can be much improved by hormone replacement therapy (HRT), although it will not cure symptoms due to CFS. In one uncontrolled trial, it was found that symptoms improved in 80 percent of patients with low oestrogen levels, following hormone treatment of estradiol patches and cyclical progesterone therapy.4 HRT is also helpful in menopausal patients. For example, insomnia associated with CFS is much improved if a menopausal patient is no longer woken several times each night by hot sweats.
Osteoporosis can be prevented and treated by use of HRT, calcium, magnesium, vitamin D supplementation, and weight-bearing exercise, if tolerated. Several pharmacological agents, which can reduce the incidence of fractures, have been approved for treatment of severe osteoporosis. With the exception of HRT, their effect on CFS patients has not been studied.
Premenstrual syndrome (PMS) occurs widely in the general population but is more common in CFS patients, occurring in more than 50 percent of them. PMS can pre-date the onset of CFS, although it is less common before the onset of the CFS than in controls.(2)
Symptoms start in the luteal phase of the menstrual cycle and improve within a day or two of the period. The most common symptoms include mood swings, irritability, depression, headache, insomnia, carbohydrate cravings, breast pain and tenderness, and abdominal bloating. Fluid retention may cause a weight gain of two or more pounds. In addition, CFS symptoms frequently worsen pre-menstrually.
The cause of PMS is disputed. It is thought to be hormonal in that it usually occurs in association with ovulatory cycles. Some recent research has found that it is linked to a deficiency in serotoninergic activity in the brain.(5)
Treatment considerations: Various treatments used in the past have been found to be no better than placebo. These include the use of progestogens, oestrogen's, vitamin B6 and evening primrose oil.(6) Recently, in several placebo controlled trials, serotoninergic antidepressants (SSRIs) such as fluoxetine 20 mg daily, or use on days 1428 of the menstrual cycle, were found to be successful, relieving PMS symptoms in up to 90 percent of patients,(7) but there are no specific studies in CFS patients. Side effects of treatment tended to improve with time.
About 15 percent of normal women suffer from dysmenorrhea, but at least 30 percent of CFS patients may suffer from it.8 Severe dysmenorrhea may occur on its own, or it can be a symptom of several gynecological conditions which are more common in CFS patients. These include endometriosis, fibroids, pelvic inflammatory disease and ovarian cysts. In all these conditions, menses may be heavy. If there is any abnormality found on examination, such as a pelvic mass, further gynecological investigation is indicated. Mild dysmenorrhea usually responds to analgesics such as aspirin or Tylenol, but NSAIDS may work better. Severe pain can be treated by suppressing ovulation with oral contraceptives.
Endometriosis is reported to occur in up to 20 percent of women with CFS. It can predate its onset.(2) Dysmenorrhea is the most frequent problem. It can be very severe even in apparently mild cases of the condition. Pain before the period, dyspareunia, pelvic pain and pain related to the bladder or bowel may also occur. There may be no symptoms, and the condition is only discovered during surgery for another condition, such as infertility, which is often associated with endometriosis.
In endometriosis, endometrial cells which line the uterus are also found in the pelvic cavity and sometimes elsewhere. Retrograde transport of endometrial fragments along the fallopian tubes occurs in many normal menstruating women, without signs of endometriosis. These endometrial cells are normally removed by immune system scavenger cells. In women with immune abnormalities such as CFS, the scavenging cells may be overwhelmed. With each menstrual cycle, the ectopic endometrial cells are shed, resulting in localised bleeding. This is painful and may lead to inflammation and scarring in the affected area.
A physical exam may be normal, but scarring may cause lack of mobility of the uterus and cystic enlargement of the ovaries may be present. This can be seen on an ultrasound scan. If symptoms are severe, the diagnosis can be confirmed and other conditions excluded by laparoscopy and biopsy. No abnormality may be seen on laparoscopy. The cause of pelvic pain can sometimes be difficult to find.
Women with endometriosis who do become pregnant are often much improved following delivery of the child. If severe pain caused by endometriosis does not respond to medication, surgery may be required as a last resort. It is very important to distinguish endometriosis pain from pain due to other problems before embarking on surgery.
Treatment considerations: The treatment of symptomatic endometriosis is by analgesics, such as NSAIDS, oral contraceptive pills or progestational agents. Also used are anti-estrogens with immune modulating effects, such as Danocrine, or the GnRH agonist Leuprolide acetate. These anti-estrogens all have side effects which may not be tolerated in CFS patients. For the treatment of infertility, there is no proof that the treatment of mild endometriosis by hormones is helpful.
Twenty percent of CFS patients have dysuria.9 Symptoms of pain, frequency and urgency of urination both by day and night may be present. Urine culture may show a bacterial infection which can be treated with antibiotics. However, sometimes the urine is sterile and symptoms may be due to interstitial cystitis, detruser instability, urethral syndrome or endometriosis. The patient should be referred for further investigation.
Interstitial cystitis is thought to be associated with some immune system abnormalities. An informal survey of patients with it found that 13.8 percent of them also suffered from CFS.10
Twenty-nine percent of a series of CFS patients complained of vaginal discharge.11 In all cases a swab should be obtained for diagnosis. There are many causes of vaginal discharge. A thick, creamy, irritating discharge may denote a vaginal infection with Candida albicans. The yeast organism is present in the vagina of many asymptomatic women, but overgrowth leading to symptoms may occur in patients who have had repeated courses of antibiotics, are pregnant, have diabetes or have abnormal immune function. There is disagreement as to whether vaginal candidiasis is more common than normal in women with CFS.
Some people believe that women with CFS suffer from a chronic multi-system yeast infection which exacerbates CFS symptoms. This has not been proven by culture and oral swabs are rarely positive for yeast. Vaginal yeast infection is normally a localised condition and only local treatment is indicated. There are several effective vaginal anti-fungal preparations. A short course of treatment may be adequate, but a longer two-week course may be necessary and may have to be repeated to clear symptoms.
Sexual dysfunction is present in up to 20 percent of CFS patients.9 Decreased libido is common and dyspareunia may also occur. Loss of libido can be associated with low reproductive hormone levels, or due to the severe fatigue, malaise and pain which are prominent in CFS. Dyspareunia may be caused by vaginal dryness from low oestrogen levels, or the presence of a pelvic condition such as endometriosis, interstitial cystitis, pelvic congestion syndrome or vulvodynia. For low oestrogen syndromes, a vaginal oestrogen cream or hormone replacement therapy may be helpful. Sexual problems put a severe strain on both patient and her partner. They may need counselling to help them save their relationship.
For contraception, an oral contraceptive pill or a hormonal implant can be used, if tolerated, but the intra-uterine contraceptive device (IUD) is not recommended because of an increased possibility of pelvic infection.12 The diaphragm, cervical cap or condom, while less effective as contraceptives, can be used. Surgical sterilisation carries anaesthetic risks in CFS patients and can cause a relapse.
Fibroids, ovarian cysts and hysterectomy
A history of ovarian cysts, including polycystic ovaries, and uterine fibroids was found in one study to be more common in CFS patients than in controls.(2) They often predated the onset of the CFS. There are no reports of any increase in ovarian cancer. If a pelvic mass is present, referral to a gynaecologist is indicated. Patients with CFS are significantly more likely than controls to have had a hysterectomy.(3) This may be associated with the increased numbers of patients with fibroids, ovarian cysts or endometriosis.
Rosemary Underhill, MB, BS, is a physician who specialises in obstetrics and gynaecology. Dr. Underhill served as a medical consultant for the New Jersey consensus manual for the primary care of CFS.
1) Jason LA, et al. A community-based Study of chronic fatigue syndrome. Arch Intern Med. 1999; 159:2129-2137.
2) Harlow BL, et al. Reproductive correlates of chronic fatigue syndrome. AJM. 1998; 105(3A): 94s-99s.
3) Reyes M, et al. Risk factors for CFS. J Chronic Fatigue Syndrome. 1996; 2(4):17-33.
4) Studd J and Panay N. Chronic fatigue syndrome. Lancet (letter). 1996; 348:1384.
5) Ashby CR, et al. Alteration of platelet serotonergic mechanisms and mono-amine oxidase activity in premenstrual syndrome. Biol Psych. 1988; 24(2): 225-233.
6) Manu P. The pharmacotherapy of common functional syndromes. The Haworth Press Inc. 2000; 229-257.
7) Stone AB, et al. Fluoxetine in the treatment of late luteal phase dysphoric disorder. J. Clin Psych. 1991; 52(7):290-293.
8) Jessop C. Clinical Features & Possible Etiology of CFIDS. CFIDS Chronicle. Spring 1991; 71.
9) Bell D. The Doctors Guide to Chronic Fatigue Syndrome. Addison-Wesley 1995;
10) Chalker L. Interstitial cystitis. CFIDS Chronicle. Summer 1996; 72.
11) Wookey C. Myalgic encephalomyelitis. Croom Helm. 1986; 21.
12) Shepherd C. Living with M.E. Cedar. 1993; 241.
Dr Charles Shepherd
Hon Medical Adviser, ME Association