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2011-03-17T00:32:00.000+07:00

Mysteries of endometriosis pain: Chien-Tien Hsu Memorial Lecture 2009

2011-03-08T16:13:00.001+07:00

Mysteries of endometriosis pain: Chien-Tien Hsu Memorial Lecture 2009
Ian S. Fraser
Article first published online: 4 FEB 2010

DOI: 10.1111/j.1447-0756.2010.01181.x

© 2010 The Author. Journal compilation © 2010 Japan Society of Obstetrics and Gynecology
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Journal of Obstetrics and Gynaecology Research
Volume 36, Issue 1, pages 1–10, February 2010
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Keywords:
endometriosis;endometrium;nerve fibers;pelvic pain

Abstract
The more that one looks at the condition endometriosis, the more one realises that it is a unique and complex condition exhibiting a bizarre range of deviations from normal endometrial and myometrial physiology, and presenting with a challenging range of pain-related symptoms. The changing nature of the pain is not well defined, and the molecular mechanisms leading to pain generation are far from clear. Recent research has begun to reveal some of these links between expression of unusual molecules in the eutopic endometrium and ectopic lesions, microanatomical changes in the pelvic nervous sytem, neuronal dysfunction and the later development of neuropathic pain. A better understanding of these mechanisms will undoubtedly lead to improved use of current medical and surgical treatments, and to the development of novel treatments in the future.

Introduction
This most prestigious lecture in Asian obstetrics and gynecology is given once every two years in honor of Professor Chien-Tien Hsu, one of the true legends of obstetrics and gynecology on this continent and one of the founders of the Asia and Oceania Federation of Obstetrics and Gynecology (AOFOG). Professor Hsu's clinical interests were primarily in oncology and reproductive endocrinology, and my illustrious predecessors as Chien-Tien Hsu Memorial lecturers have spoken exclusively on these themes.

Although I may appear to be departing from these themes in talking about the non-malignant condition of endometriosis, and indeed not even about its impact on fertility and endocrinology, this bizarre and variable condition exhibits many features which point towards a pseudo-malignant disease.1 Endometriosis exhibits loss of control of cellular proliferation, local infiltration and spread into adjacent deep tissues, disturbed angiogenesis, expression of proto-oncogenes, disturbed apoptosis, occasional distant spread and a tendency to recur after treatment – all being important features of malignancy. Nevertheless, these processes do not aggressively continue and inexorably progress, as in most true malignancies. Additionally, endometriosis is actually associated with a long-term risk of true ovarian malignancy, especially following recurrent ovarian endometriomas (with a relative risk of around 2.0).1

Yet, in many ways, the behavior of endometriosis is very different in the majority of sufferers. The keynote of the condition is variability (Table 1) and in most women the condition is unquestionably ‘benign’. It is only in a minority that the condition exhibits the features listed in the previous paragraph to the extent that the analogy with malignancy really holds. In many of these severely affected women, the intensity and persistence of pain is as difficult to deal with as in any case of bony metastases from cancer. Pain will be the central theme of this lecture.

Table 1. Endometriosis is a highly variable condition
High levels of variability in:
Age of onset of symptoms
Constellation of presenting symptoms
Types and severity of pain
Site and extent of pathology
Coexistence of other pathologies
Response to treatment
Rate of recurrence of symptoms and disease

Pain is the Central Challenge
Pelvic pain is universally recognized as the key symptom in endometriosis; the primary reason why the patient consults her doctor. Infertility is also a common symptom of endometriosis, but most of these patients will additionally complain of pain. Endometriotic pelvic pain may be well recognized, but many doctors, including gynecologists, think only in terms of the common triad of dysmenorrhoea, deep dyspareunia and pain with a bowel motion. Yet, there is now ample information to demonstrate that many women experience a much more complex range of pains, which are addressed in the next section. This lack of awareness of the variations in endometriotic pain may well be responsible for the distressing delays in diagnosis, which average 8–10 years from the onset of symptoms.2 These delays are even greater in those with onset of symptoms in early adolescence, a time of life during which many doctors still believe that endometriosis does not occur. A further factor contributing to a delay in diagnosis is the failure of patients to inform their doctor of pain symptoms. The decision to complain of pain to doctors, or failure to complain, are very personal decisions by individual patients, but it is clear that in most, if not all countries many women believe that their ‘endometriotic pains’ are a natural aspect of women's reproductive life, and hence they do not inform their doctor.

To be fair, for doctors attempting to manage endometriosis, it is one of the most variable of all gynecological conditions with consequent diagnosis challenges (Table 1). No other benign condition of the reproductive tract causes such troublesome or variable pain. Endometriosis is generally defined as the occurrence of tissue histologically similar to endometrium, but implanted outside the uterus. It is most usually found on the pelvic peritoneum, on the surface of the ovaries, bowel or bladder, on or in the utero-sacral ligaments, ovaries, recto-vaginal septum and rarely in other sites such as diaphragm, umbilicus, pleura, lungs, abdominal scars or elsewhere.

No other benign condition of the reproductive tract exhibits such a bizarre range of deviations from normal physiology of the endometrium. Indeed, there is increasing evidence to suggest that endometriosis is a disease originating from abnormalities of endometrial function.3,4 There is now highly convincing evidence of disturbances of multiple molecular systems involving structural, metabolic and immune systems.4–7 These include cytokeratins, integrins, vimentin, heat-shock proteins, smooth muscle actin, adhesion molecules, transcription factors, apoptosis proteins, aromatase enzyme expression, oxidative pathways and a wide range of angiogenic, lymph-angiogenic and neurogenic systems.

Symptoms of Pain in Endometriosis Sufferers
The classical symptoms of endometriosis, which should be recognized by all doctors, include secondary (congestive) dysmenorrhoea, deep dyspareunia, bowel motion pain, heavy menstrual bleeding and infertility. However, examination of the literature and focus groups indicate that menstrual cycle and menstruation-related pains are much more extensive and complex than this (Table 2). Indeed, the pains of endometriosis are only part of a unique but highly variable symptom complex (Table 3).

Table 2. Different types of pain associated with endometriosis8
1. Types of menstrual cycle pain
Premenstrual: general pelvic, back
Peri-menstrual: uterine and general, back
Mid-cycle: uterine and ovarian
Back, leg and loin pain: referred
Bowel pain: from closely located lesions
Peri- and post-micturition pain: from closely located peritoneal lesions, or from bladder
From other sites
2. Peri-menstrual pain (Dysmenorrhoea):
Dominant pain described as:
– intense, unbearable, miserable (89%)
– cramping, gnawing, crushing, pressing (88%)
Dominant sites of pain:
– central/low abdomen (92%)
– deep pelvic area (41%)
– lower back (50%)
– thighs, loins, rectal area, umbilicus
Much more severe than in women with no gynaecological disease
Worst on days 1–2 of menses, begins premenstrually when less severe
3. Nerve entrapment
Pain due to anatomical nerve distortion by scarred, but often active, endometriotic lesions
Recognised nerve entrapment:
– referred pain along the path of the trapped nerve, sometimes with associated functional disturbance (especially muscle)
– sciatic and obturator nerves
Postulated nerve entrapment:
– deep infiltrating lesions, especially in recto-vaginal septum (distortion of small nerve trunks in dense enteric and endometriotic nerve plexuses within highly fibrotic endometriosis lesions)
4. Neuropathic pains
– increasingly recognised as being a significant component of persistent endometriosis pain
– arises from damage to nerves (peripheral or central)
– may be exacerbated by repeated surgery
– therapies are often only partially successful
– Gabapentin; pregabalin (GABA analogues)
5. Other pains:
– hyperalgesia; allodynia
– Myofascial dysfunction (trigger points)
– lowered pain pressure threshold
– these are evidence of central nervous system sensitisation
Table 3. Clinical endometriosis: a highly variable symptom complex8 (endometriosis cases: n = 529; controls: n = 208)
Pain (92%); no pain (6–8%)
Extreme lethargy (97%)
Gastrointestinal symptoms (96%)
Urinary tract symptoms (44%)
Low resistance to infection (43%)
Low grade fever (42%)
Increased predisposition to autoimmune conditions
Genital tract bleeding:
– heavy menstrual bleeding (65%); premenstrual spotting (63%)
The characteristics of menstrual pain (dysmenorrhoea) are described by most women as intense, unbearable, miserable, cramping, gnawing, crushing or pressing.8 The dominant sites of pain are central and low abdomen (92% of women with dysmenorrhoea), deep pelvic area (41%), lower back (50%) and variously referred into thighs, loin, groin, rectal area and umbilicus.8 The severity of the pain was much greater than in a group of ‘control’ women,8 but interestingly the day of maximum severity of pain was day 1–2 in both endometriosis sufferers and the group of women with no specific gynecological complaint.

Painful gastrointestinal symptoms are often overlooked, but colicky pains and irritable bowel-type symptoms are experienced by 82% of women with endometriosis.8 It is said that the key difference between so-called irritable bowel syndrome and typical endometriosis-related bowel symptoms is that in irritable bowel syndrome the colic is relieved by a bowel motion, whereas in endometriosis it is not. Painful abdominal bloating is another overlooked endometriosis symptom, but one which can be terribly distressing in some women. Around 71% of women with endometriosis will experience painful bloating every cycle, while another 25% will sometimes experience it. Many of these women will possess two different wardrobes to accommodate the cyclical changes in abdominal girth, changes which can be objectively measured.9 Intermittent diarrhea (78%) and constipation (76%) are very frequent in the peri-menstrual stage, and pain with a bowel motion is also very common (67%) and exacerbated in the peri-menstrual stage. Bleeding from the bowel during menstruation is also more common than generally recognized (around 20%).

Nerve entrapment pain is a relatively rare type of endometriosis pain due to anatomical nerve distortion by active, fibrotic lesions, especially around the sciatic and obturator nerves.10,11 This pain is usually referred along the path of the trapped nerve, sometimes with associated functional disturbance, especially of muscle power. Postulated nerve entrapment occurs in the complex fibrous and hypertrophic deep invasive endometriotic lesions in the recto-vaginal septum, where distortion of nerve trunks appears to be occurring.12

Neuropathic and Other Types of Pain
Neuropathic pain is being increasingly recognized as a significant component of persistent endometriosis pain.13 Neuropathic pain arises from damage to peripheral or central nerve fibers, resulting in erratic or persistent axonal discharges. These persistent stimuli can set up abnormal neural circuits at a spinal cord or central level resulting in persistent, prolonged or intermittent signals to the central processing and perception centres. This may lead to persistent perception of pain, long after the original stimulus may have been removed.

A number of questionnaires have been designed to identify the neuropathic components of pain.14,15 One study suggests that neuropathic pain is uncommon in women with chronic pelvic pain,15 but there has been no comprehensive study on women with the persistent and debilitating types of endometriotic pain.

One concern about the consequences of pelvic surgery for endometriosis, especially repeated surgery, is that damage to nerve fibers, especially repeated damage, may trigger persistent, abnormal discharges from these plentiful, damaged and regenerating pelvic and endometriotic nerve fibers, leading to the development of neuropathic pain.

Other types of pain are also being reported in many women with endometriosis. These mainly involve altered perception of pain. Hyperalgesia involves the perception of pain as being more severe than expected from the stimulus, for example, a lowered pain threshold.16 Allodynia is the perception of pain from a stimulus that does not usually produce pain. In myofascial dysfunction there may be trigger points which produce a painful response when stimulated. All of these types of altered pain perception are evidence of sensitization at a central nervous system level.16

The Discovery of Endometrial Nerve Fibers
Several investigators have reported nerve fibers in ectopic endometriotic lesions12,17 and have described the presence of certain types of nerve fibers in some of the lesions. It was suggested that these may have a role in the mediation of pain. We decided to establish a series of investigations to comprehensively explore the innervation of the uterus and ectopic lesions in women with a range of endometriosis symptoms. We decided, in the first instance, to utilize a robust pan-neuronal marker, protein gene product 9.5 (PGP9.5), which was becoming the neurophysiologist's preferred immuno-histochemical marker for defining the presence of all nerve fibers in tissue sections. This antibody has minimal cross-reaction with other tissue types.18

This was followed up with a comprehensive investigation of a range of different immuno-histochemical markers recognizing autonomic, sensory and myelinated nerve fibers. Neurofilament was used to define myelinated nerve fibers, which were apparently sensory A-delta fibers. Substance P (SP) and calcitonin gene-related peptide (CGRP) were used to identify unmyelinated sensory C nerve fibers. Neuropeptide Y was used to identify adrenergic (sympathetic) nerve fibers and vasointestinal peptide identified cholinergic (parasympathetic) fibers. Growth associated protein-43 is expressed on growing nerve fibers. The situation is somewhat more complex than described above, and the accurate identification of nerve fiber types is quite difficult (Table 4).

Table 4. Identification of nerve fibre types in endometrium and endometriotic lesions
Fine nerve fibres in endometrium (functional layer)
Immuno-histochemical localisation with specific tissue markers for nerve fibres (antibodies for several molecules expressed by nerve fibres)
Pan-neuronal marker (protein gene product 9.5): specifically stains all nerve fibers
Stains for myelinated nerve fibers (neurofilament, stains A delta fibers)
Neurotransmitters and other markers for nerve fibers of different functions
Most of these nerve fibers are, in fact, unmyelinated C fibers
Sensory and autonomic C nerve fibers
These fine unmyelinated nerve fibers in the functional layer of eutopic endometrium expressed:
– vasointestinal peptide (cholinergic)
– neuropeptide Y (adrenergic)
– substance P (sensory)
– calcitonin gene-related peptide (sensory)
The first striking observation was that fine, unmyelinated nerve fibers are present in surprisingly high densities in both the functional and basal layers of endometrium of women with endometriosis, while virtually none are found in the endometrium of women with no endometriosis (Fig. 1).18 It became apparent that the functional layer of normal endometrium is one of the few – or perhaps the only – tissue in the body which is not normally innervated. Previous studies using less precise technologies have failed to agree on this conclusion.19,20 With careful scrutiny, small numbers of fine unmyelinated nerve fibers can be identified with PGP9.5 in the basal endometrium of some women without endometriosis, but rarely in the functional layer.18 In women with endometriosis, substantial nerve trunks can often be identified at the endometrial-myometrial interface. These are never seen in the absence of endometriosis.

Figure 1. Mean (±standard deviation) nerve fiber densities (protein gene product 9.5; per mm2) in the uterus, peritoneum and ectopic lesions in women with and without endometriosis.

Studies with multiple markers for different types of nerve fibers revealed that the unmyelinated nerve fibers in the endometrial functional layer were a mixture of sensory C, sympathetic and parasympathetic fibers.21 Myelinated sensory A-delta nerve fibers were occasionally seen in basal endometrium but never in the functional layer. In women with no endometriosis, myelinated nerve fibers were only found in myometrium.18 These nerve fibers are not homogeneously distributed through the endometrium but appear in clusters. Nerve fibers can be identified within a few microns of the luminal, epithelial layer of the endometrium.

The density of nerve fibers in myometrium is much lower than in endometrium, but women with endometriosis have much more densely innervated myometrium than women without endometriosis.18

Presumably, the high densities of nerve fibers present in endometrium and myometrium in women with endometriosis arise from the pre-existing innervation of the myometrium through a process of branching and proliferation. This explanation is supported by the observation of substantial nerve trunks at the endometrial-myometrial interface and the clustering of fine nerve fibers through the endometrium.

Nerve Fibers in Endometriotic Lesions
As others have described, nerve fibers can be identified within peritoneal,17 ovarian endometrioma22 and deep infiltrating endometriotic12 lesions. We have comprehensively analyzed and defined the innervation of these lesions23,24 and found densities in peritoneal lesions comparable to the eutopic endometrium (Fig. 1).23 These nerve fibers in lesions expressed all the markers we studied and included sensory C, sympathetic, parasympathetic and myelinated sensory A-delta fibers. Sometimes sizeable nerve trunks were identified passing though peritoneal lesions, something never seen in normal peritoneum.23

Somewhat surprising was the finding of a much greater density of nerve fibers in deep, infiltrating lesions (Fig. 1). The density in lesions of the uterosacral ligaments was more than double that found in peritoneal lesions, while densities in lesions infiltrating the rectal wall were even higher still.24 In several intestinal lesions densities of over 300 nerve fibers per mm2 were observed, compared with densities around 15 per mm2 in peritoneal lesions.23,24 It seems probable that the invading endometriosis bringing its own nerve supply links up with the intrinsic (enteric) nerve plexus of the bowel, resulting in excessive branching and proliferation of multiple nerve fibers. The density of the normal enteric plexus of the bowel is around 30 fibers/mm2.

These nerve fibers presumably arise from the normal local innervation of the peritoneum, endometrium or bowel through a branching and proliferation process.

Nerve Growth Factor and its Receptors
Why do these nerve fibers appear in eutopic endometrium and ectopic lesions? There must be some stimulus to local nerve growth, and nerve growth factor (NGF) seemed an obvious candidate. In fact, NGF is intensely expressed in the glands and stroma of the functional and basal layers of endometrium in women with endometriosis, whereas it is barely expressed at all (a trace in the basal layer) in women with no endometriosis.18 NGF is also intensely expressed in ectopic lesions.23 Other neurotrophins may also play a role.

NGF interacts with two specific receptors: TRK-A (a high affinity receptor) and p75 (a low affinity receptor). These receptors are barely detectable in normal endometrium, but are both intensely expressed in nerve fibers and stroma in eutopic endometrium.18 Similarly, they are intensely expressed in the stroma of ectopic lesions. It seems logical that this combination of up-regulated neurotrophin and its receptors would be a potent stimulus to branching and ingrowth of new nerve fibers.

Mechanisms of Pain Generation
This is the area of greatest mystery within the topic of endometriosis pain. It has generally been tacitly assumed that nerve fibers already present in the pelvis somehow become stimulated by the ectopic lesions, presumably by some substance which is released from the lesions at particular times during the menstrual cycle. Leading candidates for such specific substances include the prostaglandins, bradykinin and histamine, but little work has been carried out in this area in studying pelvic pain in women.

Pain signals in sensory nerve fibers are generated through receptors called nociceptors.25 They are responsive to ‘noxious’ stimuli which have the potential to do harm, and have the potential to trigger a reflex response. They send signals which initiate the sensation of pain. The fast signals travel in the myelinated, sensory A-delta fibers, and the slower, more persistent signals travel in the unmyelinated, sensory C nerve fibers. These signals are processed in the dorsal root ganglia and the lower spinal cord, before onward transmission of a modified signal to the thalamus, limbic system and higher centers, where pain is perceived and the emotional response is developed.

In visceral organs, nociceptors tend to respond to excessive pressure, excessive stretch, ‘inflammatory’ processes and a range of injurious chemical substances. The nociceptors in endometriotic lesions and eutopic endometrium have not been specifically studied, but it is known that pelvic nociceptors in adjacent organs are stimulated strongly by nerve growth factor and prostaglandin E2.26,27 They are also significantly sensitized by oestrogen. Bradykinin, histamine and interleukin-1 are probably also important sensitizers. In fact, the nociceptor is an incredibly complex organelle which can be stimulated, sensitized, inhibited or otherwise regulated by hundreds of extrinsic and intrinsic molecules, many of these arising in immune competent cells, such as mast cells, macrophages, dendritic cells, neutrophils, natural killer cells, plasma cells and probably others. The complexity may even rival the synapse, which is the most complex organelle in the body, with over 1500 synapse-associated proteins having been identified to date.

There is little doubt that immune cells will be shown to play important roles in pain generation in endometriosis, both in ectopic lesions and in the uterus. Macrophage numbers and function are greatly modified in ectopic lesions, peritoneal fluid and eutopic endometrium of women with endometriosis.28,29 In ectopic lesions, there is a direct relationship between the numbers of macrophages and the density of nerve fibers.30 There is also a substantial disturbance in the numbers of immature and mature dendritic cells in eutopic endometrium and in the ectopic lesions in women with endometriosis.31,32 Mast cells may have an interesting microanatomical and functional relationship with nerve fibers at the endometrial-myometrial interface where, in endometriosis, activated mast cells are abundant on the myometrial side, but in very low density in the endometrium.33

Another specialized feature of the eutopic endometrium in endometriosis, which may or may not relate to mechanisms of pain, is the significantly increased numbers of neuro-endocrine cells present in endometrial glands, compared to women without the disease.34 These neuro-endocrine cells have varied functions in different organs, but they have not been previously studied in the human uterus, let alone in endometriosis.

Implications of Abundant Nerve Fiber Presence
Many questions arise as to the new directions which will be required to understand the roles and functions of these eutopic and ectopic nerve fibers. How do the presence and function of the different types of nerve fibers react to the types and presence of symptoms? What is the role of nerve fibers in the pathogenesis of endometriosis? What happens to them during treatment? What is the potential for development and delivery of long-acting nociceptor blockers? What is the potential for development and delivery of NGF blockers? What is the potential for developing a less invasive means, than laparoscopy, for the diagnosis of endometriosis?

There is also the fascination of what may be happening to these nerve fibers during menstruation. Some nerve fibers lie very close to the epithelial surface of the endometrium, so are these fibers damaged and partially ‘shed’ during menstruation, then re-modeled and re-grew during the subsequent proliferative phase? Do these nerve fibers remain intact? Is there significant re-growth of these multiple nerve fibers every menstrual cycle? What do we know of plasticity of myometrial nerve plexus fibers during the normal menstrual cycle, and how does this change during endometriosis? Are the nociceptors in endometrium sensitized by the process of menstrual breakdown? Are there other examples in the body of regular, rapid re-modeling of nerve fibers under any similar circumstances? How does this damage to nerve fibers relate to symptoms? How does this damage and breakdown of nerve fibers relate to the pathophysiology of development of endometriosis? Do these nerve fibers in endometrium precede development of endometriosis lesions in the peritoneal cavity?

Potential for the Diagnosis of Endometriosis by an Endometrial Biopsy
It seemed to us that the presence of nerve fibers in endometrium was so predictable that it could be explored as the basis of a diagnostic test. In a pilot trial of endometrial biopsies collected from 20 women with proven endometriosis and 18 women with no endometriosis (for the detection of endometrial nerve fibers using PGP9.5) all of the women with endometriosis had detectable nerve fibers while none of the women without endometriosis had detectable nerve fibers.35 The sensitivity and specificity of 100% seemed to be too good to be true, and we immediately set up a double-blind trial with the aim of recruiting around 100 women.36

We recruited 99 women who presented with pelvic pain and/or infertility and were scheduled for diagnostic laparoscopy. The assessment of endometriosis at laparoscopy, carried out by one of five experienced gynecological endoscopists, was maintained in a separate database held separately from the laboratory assessment of endometrial nerve fibers. The databases were only brought together by a third person at the completion of the trial. Endometrial nerve fibers were detected in 63 of 64 women in whom endometriosis was surgically diagnosed (Table 5). A 43-year-old women with no endometrial nerve fibers visualized in the biopsy had clear evidence of stage IV endometriosis at laparoscopy.36

Table 5. Endometrial nerve fiber detection and identification in women presenting with pelvic pain or infertility
Identification of individual nerve fiber types is difficult
These endometrial nerve fibers are probably a combination of sensory C and autonomic C fibers
Sympathetic fibers strongly express neuropeptide Y, noradrenaline (adrenergic) and adenosine tri-phosphate; but sometimes also vasointestinal peptide and acetyl choline [ACh, sympathetic fibers are controlled by cell bodies in the thoracic and lumbar regions]
Parasympathetic fibers strongly express vasointestinal peptide (and co-express nitric oxide synthase) and ACh (cholinergic), but sometimes also neuropeptide Y [parasympathetic fibers are controlled by cell bodies in the cranial and sacral regions]
Sensory fibers express substance P and calcitorin gene-related peptide (but sometimes may also express neurofilament, vasointestinal peptide and neuropeptide Y)
Endometrial nerve fibers were not detected in 29 out of 35 women in whom endometriosis was excluded at laparoscopy. However, six women with no detected endometriosis had nerve fibers present in the endometrial biopsy. Four of these women had classic pelvic pain and infertility, while one had a single spot of adhesions in the Pouch of Douglas (not convincing of endometriosis) and one case had had endometriosis diagnosed 7 years previously, but no current visible lesions.36

These two studies offer promise that an endometrial biopsy can be used as a much less invasive and less expensive test for endometriosis than diagnostic laparoscopy carried out by an expert, and with equivalent reliability. Neither technique can be expected to provide 100% reliability for detection or exclusion, but both must be close. Endometrial biopsy can be carried out in an outpatient clinic, usually without local analgesia and offers the potential for much earlier diagnosis and more careful planning of future medical, surgical or infertility therapy. Even though this type of approach is an advance over laparoscopy, a reasonably reliable serum test would have even greater utility.

Effects of Hormonal Therapy on Nerve Fibers
In women with endometriosis who were being actively treated with oral progestogens or combined oral contraceptives, nerve fibers were no longer detectable in the majority.37 In three treated women out of 26, small numbers of nerve fibers were detected in the functional layer, but these only expressed vasointestinal peptide and neuropeptide Y (and hence were autonomic fibers) while none expressed the sensory nerve fiber markers SP and CGRP. This finding was accompanied by an almost complete loss of expression of NGF and its receptors. These combined findings implied that there should have been an almost complete inhibition of pain signals originating within the uterus itself.

By contrast, in women on hormonal treatment who were still experiencing sufficient symptoms to require a repeat laparoscopy all (18 out of 18) had nerve fibers still detectable in biopsies of their peritoneal lesions, albeit at a much reduced density.38 These nerve fibers still expressed weak staining for SP and CGRP suggesting that some sensory fibers were still present.

There are still many unanswered questions concerning the presence and function of nerve fibers during and after medical and surgical therapies and their relationship to persisting pain. It should also be appreciated that surgical excision is not always effective.39 There is a need to explore, much more actively, the place of progesterone receptor modulators40 and aromatase inhibitors,41 alone and in combination, and also the place of the long-acting progestogen delivery systems alone and in combination42–44

Conclusions
Women with endometriosis and pelvic pain almost always have fine, unmyelinated nerve fibers present in the functional layer of endometrium, and these nerve fibers are also greatly increased in the myometrium. Women without endometriosis almost never have these nerve fibers. These nerve fibers may also play a role in pain generation. The presence of these nerve fibers may allow reliable diagnosis of endometriosis without recourse to laparoscopy. The presence of these nerve fibers may predate the development of endometriotic lesions and symptoms. There may be important implications of nerve fiber presence for understanding of the impact of treatments and for evolving new treatments.

Endometriosis causes more recurrent distress through pelvic pain than any other gynecological condition in Western society. The mechanisms of development, triggering and persistence of this pain are very poorly understood, but some women with endometriosis have no pain – and this also is very poorly understood. The condition is highly variable and the diagnosis is often missed. Management is often unsatisfactory.

I believe that we, as gynecologists, have failed our patients. We have failed to understand the different types of pain. We have failed to understand the complexities or the factors which influence these pains. We have focused solely on lesions, we cut, burn and hope, and then repeat the surgery – later! We spend hours operating, but little time talking with the patient about their individual needs. We know that teaching pain-coping skills is critical, but is very difficult, and we as a profession put limited effort into the development of effective means of teaching pain-coping skills to women with chronic pelvic pain. We need to recognize the need for individualization of management.

Only when we recognize that this complex disease, endometriosis, is a systemic disease, with implications far beyond the reproductive tract and the recognizable lesions, will we be able to manage this disease most effectively.

Acknowledgments
The successful application of these fascinating investigations would not have been possible without the committed application of a cohesive team of collaborators, including Dr Robert Markham, Professor Peter Russell, Dr Natsuko Tokushige, Dr Frank Manconi, Dr Moamar Al-Jefout, Dr Georgina Luscombe, Dr Michael Cooper, Professor Janet Keast, Dr Sara ten Have, Dr Wang Guoyun, Associate Professor Alan Lam, Ms Cecilia Ng, Ms Lauren Schulke, Ms Marina Berbic, Ms Alison Hey-Cunningham, Mr Paul Tran, Ms Zaneta Kukeski and Mr Lawrence Young.

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Antioxidants for male subfertility

2011-02-04T15:01:00.000+07:00

[Intervention Review]
Antioxidants for male subfertility

Marian G Showell1, Julie Brown1, Anusch Yazdani2, Marcin T Stankiewicz3, Roger J Hart4

1Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand. 2Clinical Research and Development, Queensland Fertility Group, Woolloongabba, Australia. 3Reproductive Medicine, Flinders Reproductive Medicine, Bedford Park, Australia. 4School of Women's and Infants Health, The University of Western Australia, King Edward Memorial Hospital and Fertility Specialists of Western Australia, Subiaco, Australia

Contact address: Marian G Showell, Obstetrics and Gynaecology, University of Auckland, Park Road Grafton, Auckland, New Zealand. m.showell@auckland.ac.nz.

Editorial group: Cochrane Menstrual Disorders and Subfertility Group.
Publication status and date: New, published in Issue 1, 2011.
Review content assessed as up-to-date: 21 August 2010.

Citation: Showell MG, Brown J, Yazdani A, Stankiewicz MT, Hart RJ. Antioxidants for male subfertility. Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD007411. DOI: 10.1002/14651858.CD007411.pub2.

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Abstract

Background
Between 30% to 80% of male subfertility cases are considered to be due to the damaging effects of oxidative stress on sperm. Oral supplementation with antioxidants may improve sperm quality by reducing oxidative stress.

Objectives
This Cochrane review aimed to evaluate the effect of oral supplementation with antioxidants for male partners of couples undergoing assisted reproduction techniques (ART).

Search strategy
We searched the Cochrane Menstrual Disorders and Subfertility Group Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE, CINAHL, PsycINFO and AMED databases (from their inception until Febuary 2010), trial registers, sources of unpublished literature, reference lists and we asked experts in the field.

Selection criteria
We included randomised controlled trials comparing any type or dose of antioxidant supplement (single or combined) taken by the male partner of a couple seeking fertility assistance with placebo, no treatment or another antioxidant. The outcomes were live birth, pregnancy, miscarriage, stillbirth, sperm DNA damage, sperm motility, sperm concentration and adverse effects.

Data collection and analysis
Two review authors independently assessed studies for inclusion and trial quality, and extracted data.

Main results
We included 34 trials with 2876 couples in total.

Live birth: three trials reported live birth. Men taking oral antioxidants had an associated statistically significant increase in live birth rate (pooled odds ratio (OR) 4.85, 95% CI 1.92 to 12.24; P = 0.0008, I2 = 0%) when compared with the men taking the control. This result was based on 20 live births from a total of 214 couples in only three studies.

Pregnancy rate: there were 96 pregnancies in 15 trials including 964 couples. Antioxidant use was associated with a statistically significant increased pregnancy rate compared to control (pooled OR 4.18, 95% CI 2.65 to 6.59; P < 0.00001, I2 = 0%).

Side effects: no studies reported evidence of harmful side effects of the antioxidant therapy used.

Authors' conclusions
The evidence suggests that antioxidant supplementation in subfertile males may improve the outcomes of live birth and pregnancy rate for subfertile couples undergoing ART cycles. Further head to head comparisons are necessary to identify the superiority of one antioxidant over another.

Plain language summary

Antioxidants for male subfertility
Oxidative stress may cause sperm cell damage. This damage can be reduced by the body's own natural antioxidant defences. Antioxidants can be part of our diet and taken as a supplement. It is believed that in many cases of unexplained subfertility, and also in instances where there may be a sperm-related problem, taking an oral antioxidant supplement may increase a couple's chance of conceiving when undergoing fertility treatment. This review identified 34 randomised controlled trials involving 2876 couples. Pooled findings support increases in live births and pregnancy rates with the use of antioxidants by the male partner. Further work is recommended to confirm these findings.

Vitamin D supplementation for improving bone mineral density in children

2011-02-04T14:57:00.000+07:00

[Intervention Review]
Vitamin D supplementation for improving bone mineral density in children

Tania M Winzenberg1, Sandi Powell1, Kelly A Shaw2, Graeme Jones1

1Menzies Research Institute, University of Tasmania, Hobart, Australia. 2ASLaRC Aged Services Unit, Southern Cross University and Menzies Research Institute, University of Tasmania, Coffs Harbour, Australia

Contact address: Tania M Winzenberg, Menzies Research Institute, University of Tasmania, Private Bag 23, Hobart, TAS, 7001, Australia. tania.winzenberg@utas.edu.au.

Editorial group: Cochrane Musculoskeletal Group.
Publication status and date: New, published in Issue 10, 2010.
Review content assessed as up-to-date: 29 September 2009.

Citation: Winzenberg TM, Powell S, Shaw KA, Jones G. Vitamin D supplementation for improving bone mineral density in children. Cochrane Database of Systematic Reviews 2010, Issue 10. Art. No.: CD006944. DOI: 10.1002/14651858.CD006944.pub2.

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Abstract

Background
Results of randomised controlled trials (RCTs) of vitamin D supplementation to improve bone density in children are inconsistent.

Objectives
To determine the effectiveness of vitamin D supplementation for improving bone mineral density in children, whether any effect varies by sex, age or pubertal stage, the type or dose of vitamin D given or baseline vitamin D status, and if effects persist after cessation of supplementation.

Search strategy
We searched the Cochrane Central Register of Controlled Trials (CENTRAL Issue 3, 2009), MEDLINE (1966 to present), EMBASE (1980 to present), CINAHL (1982 to present), AMED (1985 to present) and ISI Web of Science (1945 to present) on 9 August 2009, and we handsearched key journal conference abstracts.

Selection criteria
Placebo-controlled RCTs of vitamin D supplementation for at least three months in healthy children and adolescents (aged from one month to < 20 years) with bone density outcomes.

Data collection and analysis
Two authors screened references for inclusion, assessed risk of bias, and extracted data. We conducted meta-analyses and calculated standardised mean differences (SMD) of the percent change from baseline in outcomes in treatment and control groups. We performed subgroup analyses by sex, pubertal stage, dose of vitamin D and baseline serum vitamin D and considered these as well as compliance and allocation concealment as possible sources of heterogeneity.

Main results
We included six RCTs (343 participants receiving placebo and 541 receiving vitamin D) for meta-analyses. Vitamin D supplementation had no statistically significant effects on total body bone mineral content (BMC), hip bone mineral density (BMD) or forearm BMD. There was a trend to a small effect on lumbar spine BMD (SMD 0.15, 95% CI -0.01 to 0.31, P = 0.07). There were no differences in effects between high and low serum vitamin D studies at any site though there was a trend towards a larger effect with low vitamin D for total body BMC (P = 0.09 for difference). In low serum vitamin D studies, significant effects on total body BMC and lumbar spine BMD were approximately equivalent to a 2.6% and 1.7 % percentage point greater change from baseline in the supplemented group.

Authors' conclusions
These results do not support vitamin D supplementation to improve bone density in healthy children with normal vitamin D levels, but suggest that supplementation of deficient children may be clinically useful. Further RCTs in deficient children are needed to confirm this.

Plain language summary

Vitamin D for improving bone density in children
This summary of a Cochrane Review, presents what we know from research about the effect of vitamin D supplements on bone density in children.

The review shows that in healthy children generally, vitamin D supplementation does not improve bone density at the hip, lumbar spine, forearm or in the body as a whole.

Some of the evidence suggests that vitamin D supplements may improve bone density in children who have low levels of vitamin D but this is uncertain.

We do not have precise information about side effects and complications but the available information suggests that vitamin D supplements are well tolerated.

What is osteoporosis and what is vitamin D?

Osteoporosis is a condition where bones are weak, brittle and break easily. The risk of osteoporosis and fractures (breaks) in later life depends on how much bone is built when a child and how much bone is lost when an adult. One way to prevent osteoporosis and fractures in later life is to build stronger bones when young. Vitamin D plays an important role in improving the body’s absorption of calcium from food, reducing losses of calcium from the body and getting calcium deposited into to bone to improve the quantity of bone developed. Therefore it is thought that if vitamin D levels in the body are low in childhood, less bone will be developed and that improving vitamin D levels by supplements would result in more bone being developed. Bone density is a major measure of bone strength and the amount of bone mineral present at different sites and so is used to measure the effects of interventions, like vitamin D supplementation, to improve bone health.

Association between Bell's palsy in pregnancy and pre‐eclampsia

2010-11-06T00:34:00.000+07:00

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Association between Bell's palsy in pregnancy and pre‐eclampsia

+ Author Affiliations

From the Department of Medicine, Sunnybrook and Women's College Health Science Centre, Toronto, Ontario, Canada

Received March 6, 2002.
Revision received March 12, 2002.

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Abstract

Background: Previous published case series have suggested an association between the onset of Bell's palsy in pregnancy and the risk of pre‐eclampsia and gestational hypertension.

Aim: To evaluate the period of onset of Bell's palsy in pregnancy and the associated risk of adverse maternal and perinatal events, including the hypertensive disorders of pregnancy.

Study design: Case series study of consecutive female patients.

Methods: Women presenting with Bell's palsy during pregnancy or the puerperium were identified by a hospital record review at five Canadian centres over 11 years. Information was abstracted about each woman's medical and obstetrical history, period of onset of Bell's palsy, and associated maternal complications, including pre‐eclampsia and gestational hypertension as well as preterm delivery and low infant birth weight (<2500>

Results: Forty‐one patients were identified. Mean onset of Bell's palsy was 35.4 weeks gestation (SD 3.9). Nine (22.0%, 95%CI 10.8–35.7) were also diagnosed with pre‐eclampsia and three (7.3%, 95%CI 1.4–17.1) with gestational hypertension, together (29.3%, 95%CI 16.5–43.9) representing nearly a five‐fold increase over the expected provincial/national average. There were three twin births. The observed rates of Caesarean (43.6%) and preterm (25.6%) delivery, as well as low infant birth weight (22.7%), were also higher than expected, although the rate of congenital anomalies (4.5%) was not.

Conclusions: The onset of Bell's palsy during pregnancy or the puerperium is probably associated with the development of the hypertensive disorders of pregnancy. Pregnant women who develop Bell's palsy should be closely monitored for hypertension or pre‐eclampsia, and managed accordingly.

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Introduction

In 1830, Sir Charles Bell described the association between idiopathic facial palsy (Bell's palsy) and pregnancy.¹ The prevalence rate of Bell's palsy in pregnancy is estimated at 45.1 cases per 100 000 women, considerably higher than in the non‐pregnant population.² In a systematic review, we observed that almost all cases of Bell's palsy were confined to the third trimester of pregnancy and the immediate postpartum period.³ Furthermore, there was a significantly higher rate of gestational hypertension and pre‐eclampsia (22.2%, 95%CI 12.5–36.4) among these cases, more than four times that found in the general obstetrical population.⁴

A limitation to previously published research into Bell's palsy in pregnancy is the absence of any systematic evaluation of important obstetrical and perinatal outcomes.³ Accordingly, these studies may have been biased toward underreporting of such events. We undertook this multi‐centre retrospective case series study with three principal objectives. First, to evaluate the timing of onset of Bell's palsy in pregnancy; second, to investigate the association between Bell's palsy and the hypertensive disorders of pregnancy; and third, to determine the prevalence of peripartum and perinatal outcomes among women who developed Bell's palsy during or immediately after pregnancy.

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Methods

We reviewed the hospital charts of women diagnosed with Bell's palsy in pregnancy between 1990 and July 2001. Participants were identified through the Medical Records Departments of five Ontario hospitals: the Hamilton Health Sciences Corporation and St Joseph's Hospital, both in Hamilton; and the Sunnybrook and Women's College Health Sciences Centre, University Health Network, and Mount Sinai Hospitals, all in Toronto. A search for these charts was made using the ICD‐9CM diagnostic codes related to Bell's palsy and any concurrent pregnancy within ±12 months of the diagnosis of Bell's palsy.

From each hospital chart, we abstracted information on maternal demographics, past medical history, maternal complications during the index pregnancy, and mode of delivery. Gestational hypertension was defined as a blood pressure >140/90 mmHg after 20 weeks gestation, and pre‐eclampsia was defined as a blood pressure >140/90 mmHg, with the additional presence of at least 2+ proteinuria on dipstick or >300 mg of proteinuria over a 24‐h period. Abstracted perinatal outcomes included neonatal gestational age at birth, birth weight and the presence of any fetal anomalies detected in utero or at birth. We attempted to corroborate the chart data by contacting each patient by telephone. Perinatal outcomes and delivery information for these women were compared to rates previously described for the province of Ontario or Canada.

Using the current study data, we updated our previous systematic review³ to better estimate the rate of gestational hypertension and pre‐eclampsia among women with Bell's palsy during pregnancy or the puerperium. The rates from all studies were pooled using a random effects model,⁵ and the presence of significant heterogeneity for the pooled estimate was defined at a p value <0.10 id="xref-ref-6-1" class="xref-bibr" href="http://qjmed.oxfordjournals.org/content/95/6/359.full#ref-6">⁶

All abstracted data were entered into Microsoft Excel version 5.0c. Calculation of the pooled estimate of pre‐eclampsia and gestational hypertension was done using Meta‐Analyst 0.988.⁷ Permission to conduct this study was obtained from the Ethics Review Board of each participating medical centre. Permission to contact the women was obtained from their family physicians or obstetricians, and once contacted, each woman provided informed consent before being administered the telephone questionnaire.

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Results

From the five hospitals, 41 women were diagnosed with unilateral Bell's palsy between 1990 and July 2001. The hospital charts were successfully reviewed for all 41 cases, and 19 women (46%) also had their information corroborated by telephone interview. For the remaining 22 women, either their telephone number was no longer in service, or written consent to contact them could not be obtained from their family physician or obstetrician.

The pre‐pregnancy characteristics of all 41 participants are listed in Table 1. The mean maternal age was 29.0 years (SD 6.0); the majority were nulliparous (36.6%) and there were three twin pregnancies. Few had a previous history of either chronic (one woman, 2.7%) or gestational hypertension (two women, 5.4%), and none (0%) had been diagnosed with pre‐eclampsia. One had experienced Bell's palsy previously, with a full recovery before the index pregnancy (Table 1).

The mean gestational age at the onset of Bell's palsy in the index pregnancy was 35.4 weeks gestation (SD 3.9). Only one woman (2.4%) presented before 27 weeks gestation, 33 (80.5%) between 27 and 42 weeks, four (9.8%) within the first week postpartum, while for three women (7.3%) the period of onset was not defined.

Nine women (22.0%, 95%CI 10.8–35.7) were diagnosed with pre‐eclampsia and three (7.3%, 95%CI 1.4–17.1) with isolated gestational hypertension. Thus, out of 41 women with Bell's palsy, 12 (29.3%, 95%CI 16.5–43.9) developed a hypertensive disorder, nearly five times the expected rate for Ontario/Canada (Table 2).

The overall mean neonatal birth weight was 3003.3 g (SD 873.8). The corresponding rates of Caesarean delivery (43.6%), preterm birth (25.6%) and low neonatal birth weight (22.7%) were comparably higher than expected (Table 2). Of the two neonates (4.5%) born with a detectable congenital anomaly, one had Down's syndrome and the other lethal fetal hydrops.

Using the current study data, in conjunction with those 11 studies included in our previous systematic review,³ the pooled rate of combined gestational hypertension or pre‐eclampsia was 25.0% (95%CI 8.3–55.2) among 203 women with Bell's palsy in pregnancy or the puerperium.

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View this table:

Table 1

Pre‐pregnancy characteristics of women with onset of Bell's palsy during the index pregnancy or puerperium

View this table:

Table 2

Maternal and perinatal outcomes among women with onset of Bell's palsy during the index pregnancy or puerperium, compared to those previously described within the general population

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Discussion

Of these 41 consecutive women, the majority presented with Bell's palsy during late pregnancy and the puerperium. They had an increased rate of the hypertensive disorders of pregnancy and operative delivery, while their infants experienced higher rates of preterm birth and low birth weight, compared to figures for the general population.

Study strengths and limitations

This study was probably biased by the retrospective collection of data, which was principally from the hospital charts of five large urban obstetrical centres. Since few clinicians were probably aware of the possible association between Bell's palsy and hypertension in pregnancy, it is unlikely that our estimates would have been much inflated by the presence of diagnostic suspicion bias, especially since we used objective definitions for the diagnosis of gestational hypertension and pre‐eclampsia. Although we included consecutive patients, and attempted to corroborate their chart data through telephone interviews, many could not be contacted, so some adverse perinatal events may have been missed or incorrectly recorded. In the absence of a concurrent control group, we had to rely upon national and provincial data to estimate the expected rates of adverse maternal and perinatal outcomes within the five participating centres. Such comparisons cannot account for possible differences between the women studied herein and those previously selected for large epidemiological studies. Finally, the presence of statistical heterogeneity for the pool estimate of pre‐eclampsia and gestational hypertension could be explained by the fact that previous investigators did not systematically assess for these events, or define them using standard criteria.³

Evidence for an association between Bell's palsy and pre‐eclampsia

Our results suggest that the vast majority of women who develop Bell's palsy in pregnancy had no known risk factors before pregnancy, including diabetes mellitus or chronic hypertension. As with previously published data, our findings support the hypothesis of an association between Bell's palsy and pre‐eclampsia.³ First, the observed rate of pre‐eclampsia was approximately five times higher than expected. Second, both disorders appeared late in pregnancy, and very rarely before the second trimester. Third, more women with Bell's palsy developed pre‐eclampsia (22%) than gestational hypertension (7.3%), suggesting that Bell's palsy and pre‐eclampsia may share a common pathway in their manifestation and pathogenesis, as outlined below.

Women in their third trimester of pregnancy may be predisposed to Bell's palsy due to the increase in maternal extracellular fluid volume during this period.¹² Other nerve compression syndromes, including carpal tunnel syndrome,¹³ are also seen more commonly in the latter part of pregnancy.¹⁴ An increase in perineural oedema, resulting in facial nerve impingement, may form the underlying basis for facial nerve palsy.¹⁵ Pre‐eclampsia often manifests with considerable oedema within both subcutaneous and nervous system tissues,¹⁶ probably creating a neuro‐compressive effect. A second possible explanation may be the presence of a hypercoagulable state associated with pre‐eclampsia, resulting in thrombosis of the vasa nervorum, thereby leading to nerve ischemia and paralysis.¹⁵ Since the aetiology of Bell's palsy remains unknown, but is probably multifactorial,¹⁷ these and other mechanisms may provide insight into the treatment and recovery of ‘idiopathic’ facial palsy in pregnancy.

Clinical and research recommendations

Regardless of its aetiology, the notion that Bell's palsy in pregnancy may be associated with impending pre‐eclampsia cannot be overlooked. For these women, we recommend heightening maternal and fetal surveillance for the remainder of pregnancy. Although our data do not permit us to comment on the recovery of Bell's palsy after delivery, others have observed nearly 100% recovery in women with incomplete palsy, but only a 52% satisfactory outcome in the presence of a complete facial paralysis.¹⁸ Thus, research is needed to better characterize the association between Bell's palsy and pre‐eclampsia, and the relative rate of recovery of facial palsy in such cases. Investigators might also consider whether certain drugs used in the treatment of pre‐eclampsia (e.g. magnesium sulphate) can worsen the recovery of Bell's palsy,¹⁹ as well as the benefit of other therapies, including corticosteroids.²⁰

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Footnotes

↵Address correspondence to Dr J.G. Ray. e‐mail: jray515445@aol.com

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QJM (2002) 95 (6): 359-362. doi: 10.1093/qjmed/95.6.359

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MMR vaccination and autism

2010-11-04T18:57:00.000+07:00

News & RSS | Hitting the Headlines Archive | Article

HITTING THE HEADLINES

06 Feb 2008

MMR vaccination and autism

There is no link between the MMR vaccination and autism, reported eight newspapers (5 February 2008). The newspaper reports were based on a well-conducted case-control study and were generally accurate. The study findings are likely to be reliable.

On 5 February 2008, eight newspapers (1-8) reported that there is no link between the MMR vaccine and autism.
The reports were based on a study published in the Archives of Disease in Childhood (9). The study compared 98 vaccinated children aged 10-12 years with autism spectrum disorders (ASD) to two control groups (also vaccinated) comprising 52 children with special educational needs but no ASD and 90 typically developing children within the same geographical area. There was no evidence of a differential response to measles virus or the measles component of the MMR between children with ASD, with or without regression, and controls who had either one or two doses of MMR.
Six of the papers accurately report the key findings from the study and in two there is no reporting of the study results (7-8). The study appears well conducted and the conclusions are likely to be reliable. The findings of the study are in line with previous epidemiological studies showing no association between MMR vaccination and the development of autism.

Evaluation of the evidence base for measles vaccination and antibody response in autism spectrum disorders

Where does the evidence come from?

The research was conducted by Professor G Baird and colleagues from Guy's & St Thomas' NHS Foundation Trust in London and various hospitals and research institutes in the UK. The study was funded by the Department of Health, the Wellcome Trust, the National Alliance for Autism Research (NAAR) and Remedi.

What were the authors' objectives?

To test the hypothesis that measles vaccination was involved in the pathogenesis of autism spectrum disorders (ASD) as evidenced by signs of a persistent measles infection or abnormally persistent immune response in children with ASD who had been vaccinated against MMR compared with controls.

What was the nature of the evidence?

A community based case-control study was conducted of 240 children aged 10-12 years. Children with a diagnosis of ASD were identified among a cohort of 56,946 children from 12 districts in the South Thames Region of the UK. Controls with a statement of special educational needs (SEN) but no ASD diagnosis were identified from the same cohort. A second control group comprised typically developing children born at the same time and in the same area as the ASD cases. Children whose blood samples showed that they had received at least one MMR vaccination were eligible for the study.

How did participants differ on their level of exposure to the factor of interest?

A total of 235 children had received the first MMR vaccination: 98 with ASD, 52 SEN controls, and 85 typically developing controls. Stage 2 MMR vaccination was received by 106 children: 35 children with ASD, 18 SEN controls and 53 typically developing controls. Five children with no evidence of at least one MMR vaccination were excluded from the analysis. The particular factors of interest were the detection of the measles genome or measles antibody concentrations and whether these differed between the ASD group and the control groups. An additional factor of interest was whether the presence of bowel symptoms (enterocolitis) differed between the groups.

What were the findings?

No difference was detected in the distribution of measles antibody or in measles virus in ASD cases and controls whether the children had received the first, second or both MMR vaccinations. When the analysis was restricted to ASD cases with a history of regression there remained no difference between the groups. Only one child, who did not have ASD or regression, had symptoms of possible enterocolitis.

What were the authors' conclusions?

There is no association between measles vaccination and ASD. In this cohort children were less likely to receive the second MMR vaccination after diagnosis of a developmental problem.

How reliable are the conclusions?

The research was a well-conducted case-control study, the largest of its type to be undertaken, and the conclusions are likely to be reliable. ASD cases and SEN controls were located by screening a large cohort of children likely to be representative of the general population. The selection of the patients, and allocation into study groups, was based on the use of standardised tools for the diagnostic assessment of autism. Rigorous methods were used to assess both exposure to MMR vaccine and the presence of measles virus or antibodies to the virus. The typically developing control group was not obtained from a randomised selection process and through inviting participation in the study it is possible that a biased group elected to participate. The findings of the study are in line with previous epidemiological studies showing no association between MMR vaccination and the development of ASD.

Systematic reviews

Information staff at CRD searched for systematic reviews relevant to this topic. Systematic reviews are valuable sources of evidence as they locate, appraise and synthesize all available evidence on a particular topic.

There was one related systematic review identified on the Cochrane Database of Systematic Reviews (CDSR) (10) and two on the Database of Abstracts of Reviews of Effects (DARE) (11,12).

References and resources

1. The research that 'disproves MMR jab link to autism'. The Daily Mail, 5 February 2008, p4.

2. MMR and autism link is dismissed. The Times, 5 February 2008, p18.

3. MMR vaccine does not cause autism, says study. The Daily Telegraph, 5 February 2008, p7.

4. MMR links to autism dismissed by huge study. The Guardian, 5 February 2008, p1.

5. No link between the MMR jab and autism. Daily Mirror, 5 February 2008, p26.

6. Parents' anger over new 'evidence' that the MMR jab is safe. Daily Express, 5 February 2008, p17.

7. MMR jab given OK. The Sun, 5 February 2008, p21.

8. Autism 'is not linked to MMR'. The Independent, 5 February 2008, p13.

9. Baird G, Pickles A, Simonoff E [et al.]. Measles vaccination and antibody response in autism spectrum disorders. Archives of Disease in Childhood. Online publication February 5 2008 doi:10.1136/adc.2007.122937.

10. Demicheli V, Jefferson T, Rivetti A, Price D. Vaccines for measles, mumps and rubella in children. The Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD004407. DOI: 10.1002/14651858.CD004407.pub2.

11. Jefferson T, Price D, Demicheli V, Bianco E, European Research Program for Improved Vaccine Safety. Unintended events following immunization with MMR: a systematic review. Vaccine 2003;21(25-26):3954-3960. [DARE Abstract]

12. Wilson K, Mills E, Ross C, McGowan J, Jadad A. Association of autistic spectrum disorder and the measles, mumps, and rubella vaccine: a systematic review of current epidemiological evidence. Archives of Pediatrics and Adolescent Medicine 2003;157(7):628-34. [DARE Abstract]

Consumer information

NHS - MMR the facts

Health Education Board for Scotland (HEBS) - MMR Information Centre

National Autistic Society

Previous Hitting the Headlines summaries on this topic

MMR not linked to autism: new study. Hitting the Headlines archive, 7 July 2006.

'Lingering fears of MMR-autism link dispelled'. Hitting the Headlines archive, 3 March 2005.

'Doctor's doubt on all-clear for MMR and autism link'. Hitting the Headlines archive, 11 October 2004.

MMR study finds no link with autism. Hitting the Headlines archive, 10 September 2004.

Bowel virus, autism and MMR. Hitting the Headlines archive, 13 January 2004.

'New research supports concern over MMR jab'. Hitting the Headlines archive, 16 December 2003.

Can mercury in jabs double the risk of autism? Hitting the Headlines archive, 19 November 2003.

The MMR vaccine and autism. Hitting the Headlines archive, 21 May 2003.

New study on MMR and autism. Hitting the Headlines archive, 7 November 2002.

'MMR may be linked to autism'. Hitting the Headlines archive, 9 August 2002.

Study finds no evidence of MMR and autism link. Hitting the Headlines archive, 12 &13 June 2002

What is the evidence for and against the MMR vaccine? Part 1. Hitting the Headlines archive, 7 February 2002.

What is the evidence for and against the MMR vaccine? Part 2. Hitting the Headlines archive, 7 February 2002.

Misreporting Measles Research. Hitting the Headlines archive, 6 February 2002.

The MMR vaccine debate. Hitting the Headlines archive, 24 September 2001.

Biggest study clears MMR jab. Hitting the Headlines archive, 12 January 2001.

Further information about Hitting the Headlines

Further information about Hitting the Headlines, together with selected relevant links, can be found at http://www.library.nhs.uk/hth/.

Publisher:
Centre for Reviews and Dissemination

Publication Date:
06 Feb 2008

Diagnosis and Treatment of Premenstrual Dysphoric Disorder

2010-06-23T18:20:00.001+07:00

Diagnosis and Treatment of Premenstrual Dysphoric Disorder

SUBHASH C. BHATIA, M.D., and SHASHI K. BHATIA, M.D.

Creighton University School of Medicine, Omaha, Nebraska

Am Fam Physician.�2002�Oct�1;66(7):1239-1249.

� Patient Information Handout

From 2 to 10 percent of women of reproductive age have severe distress and dysfunction caused by premenstrual dysphoric disorder, a severe form of premenstrual syndrome. Current research implicates mechanisms of serotonin as relevant to etiology and treatment. Patients with mild to moderate symptoms of premenstrual syndrome may benefit from nonpharmacologic interventions such as education about the disorder, lifestyle changes, and nutritional adjustments. However, patients with premenstrual dysphoric disorder and those who fail to respond to more conservative measures may also require pharmacologic management, typically beginning with a selective serotonin reuptake inhibitor. This drug class seems to reduce emotional, cognitive-behavioral, and physical symptoms, and improve psychosocial functioning. Serotoninergic antidepressants such as fluoxetine, citalopram, sertraline, and clomipramine are effective when used intermittently during the luteal phase of the menstrual cycle. Treatment strategies specific to the luteal phase may reduce cost, long-term side effects, and risk of discontinuation syndrome. Patients who do not respond to a serotoninergic antidepressant may be treated with another selective serotonin reuptake inhibitor. Low-dose alprazolam, administered intermittently during the luteal phase, may be considered as a second-line treatment. A therapeutic trial with a gonadotropin-releasing hormone agonist or danazol may be considered when other treatments are ineffective. However, the risk of serious side effects and the cost of these medications limit their use to short periods.

Millions of women of reproductive age have recurrent emotional, cognitive, and physical symptoms related to their menstrual cycles. These symptoms often recur discretely during the luteal phase of the menstrual cycle and may significantly interfere with social, occupational, and sexual functioning.

Premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome (PMS), is diagnosed by the pattern of symptoms. According to a report by the Committee on Gynecologic Practice of the American College of Obstetricians and Gynecologists,1 up to 80 percent of women of reproductive age have physical changes with menstruation; 20 to 40 percent of them experience symptoms of PMS, while 2 to 10 percent report severe disruption of their daily activities. Menstruation-related physical discomfort, such as dysmenorrhea, may begin with menarche. Often this condition is superseded by PMS in late adolescence or the early 20s. These syndromes generally remain stable over time.

Diagnosis

In the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV), PMDD is classified as “depressive disorder not otherwise specified” and emphasizes emotional and cognitive-behavioral symptoms.2� At least five of the 11 specified symptoms must be present for a diagnosis of PMDD (Table 1).2 These symptoms should be limited to the luteal phase and should not represent amplification of preexisting depression, anxiety, or personality disorder. In addition, they must be confirmed prospectively by daily rating for at least two consecutive menstrual cycles. A symptom-free period during the follicular phase of the menstrual cycle is essential in differentiating PMDD from preexisting anxiety and mood disorders.
TABLE 1
Research Criteria for Premenstrual Dysphoric Disorder

A. In most menstrual cycles during the past year, five (or more) of the following symptoms were present for most of the time during the last week of the luteal phase, began to remit within a few days after the onset of the follicular phase, and were absent in the week postmenses, with at least one of the symptoms being either (1), (2), (3), or (4):

1.

Markedly depressed mood, feelings of hopelessness, or self-deprecating thoughts
2.

Marked anxiety, tension, feelings of being “keyed up” or “on edge”
3.

Marked affective lability (e.g., feeling suddenly sad or tearful or increased sensitivity to rejection)
4.

Persistent and marked anger or irritability or increased interpersonal conflicts
5.

Decreased interest in usual activities (e.g., work, school, friends, hobbies)
6.

Subjective sense of difficulty in concentrating
7.

Lethargy, easy fatigability, or marked lack of energy
8.

Marked change in appetite, overeating, or specific food cravings
9.

Hypersomnia or insomnia
10.

A subjective sense of being overwhelmed or out of control
11.

Other physical symptoms, such as breast tenderness or swelling, headaches, joint or muscle pain, a sensation of “bloating,” or weight gain

B. The disturbance markedly interferes with work or school or with usual social activities and relationships with others (e.g., avoidance of social activities, decreased productivity and efficiency at work or school).

C. The disturbance is not merely an exacerbation of the symptoms of another disorder, such as major depressive disorder, panic disorder, dysthymic disorder, or a personality disorder (although it may be superimposed on any of these disorders).

D. Criteria A, B, and C must be confirmed by prospective daily ratings during at least two consecutive symptomatic cycles. (The diagnosis may be made provisionally prior to this confirmation.)

note:In menstruating females, the luteal phase corresponds to the period between ovulation and the onset of menses, and the follicular phase begins with menses. In nonmenstruating females (e.g., those who have had a hysterectomy), the timing of luteal and follicular phases may require measurement of circulating reproductive hormones.

Reprinted with permission from the American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, D.C.: American Psychiatric Association, 1994:717–8. Copyright 1994.

Researchers have developed a reliable and valid self-reporting scale called the Daily Symptom Report (see patient information handout).3 The report consists of 17 common PMS symptoms, including 11 symptoms from the DSM-IV PMDD diagnostic criteria. Patients rate each symptom on a five-point scale, from zero (none) to 4 (severe). The scale provides guidance for scoring the severity of each symptom and may be used in the office setting by primary care physicians for diagnosis and assessment of PMDD.

Etiology

Currently, there is no consensus on the cause of PMDD. Biologic, psychologic, environmental and social factors all seem to play a part. Genetic factors are also pertinent: 70 percent of women whose mothers have been affected by PMS have PMS themselves, compared with 37 percent of women whose mothers have not been affected.4 There is a 93 percent concordance rate in monozygotic twins, compared with a rate of 44 percent in dizygotic twins.4 Genetic influences mediated phenotypically through neurotransmitters and neuroreceptors seem to play a significant role in the etiology.

Features of PMDD and depressive disorders—specifically atypical depression—overlap considerably. Symptoms of atypical depression (i.e., depressed mood, interpersonal rejection hypersensitivity, carbohydrate craving, and hypersomnia) are similar to those of PMDD. Thirty to 76 percent of women diagnosed with PMDD have a lifetime history of depression,5 compared with 15 percent of women of a similar age without PMDD. A family history of depression is common in women diagnosed with moderate to severe PMS.6 There is significant comorbidity between depression and PMDD. Despite this relationship, many patients with PMDD do not have depressive symptoms; therefore, PMDD should not be considered as simply a variant of depressive disorder.7

The effectiveness of selective serotonin reuptake inhibitors (SSRIs), administered only during the luteal phase of the menstrual cycle,8–14 highlights the difference between PMDD and depressive disorder. Acute treatment with SSRIs increases synaptic serotonin without the down-regulation of serotonin receptors needed for improvement in overt depression. This finding suggests that PMDD is possibly caused by altered sensitivity in the serotoninergic system in response to phasic fluctuations in female gonadal hormone. Other studies also favor the serotonin theory as a cause of PMDD. In particular, the efficacy of l-tryptophan,15 a precursor of serotonin, and of pyridoxine,16 which serves as a cofactor in the conversion of tryptophan into serotonin, also favors serotonin deficiency as a cause of PMDD. Carbohydrate craving, often a symptom of PMDD, is also mediated through serotonin deficiency.

Because PMDD only affects women of reproductive age, it is reasonable to assume that female gonadal hormones play a causative role, possibly mediated through alteration of serotoninergic activity in the brain. Estrogen and progesterone seem to modulate levels of monoamines, including serotonin. Eliminating the effect of ovarian gonadal hormones through the use of a gonadotropin-releasing hormone (GnRH) agonist relieves PMDD symptoms.17 Subsequent administration of estrogen and progesterone causes symptoms to return in women with PMS but not in those without PMS symptoms.18

Treatment

The goals of treatment in patients with PMDD are (1) symptom reduction and (2) improvement in social and occupational functioning, leading to an enhanced quality of life. Available treatment options are summarized in Tables 2 through 6.

LIFESTYLE CHANGES

Lifestyle changes may be valuable in patients with mildly severe symptoms and benefit their overall health. Aerobic exercise and dietary changes often reduce premenstrual symptoms.19,20 Decreasing caffeine intake can abate anxiety and irritability, and reducing sodium decreases edema and bloating. Many patients prefer to try lifestyle changes and/or nutritional supplements as a first step in the treatment of PMDD.

NUTRITIONAL SUPPLEMENTS

Many of the nutritional supplements described in Table 24,15,16,19–22 have proven efficacy. A meta-analysis16 of nine randomized, placebo-controlled trials was conducted to ascertain the effectiveness of vitamin B6 in PMS management. The researchers concluded that vitamin B6, in dosages of up to 100 mg per day, is likely to benefit patients with premenstrual symptoms and premenstrual depression. In another study,21 research literature (from January 1967 to September 1999) was reviewed to evaluate the effectiveness of calcium carbonate in patients with PMS. The reviewers concluded that calcium supplementation in a dosage of 1,200 to 1,600 mg per day is a treatment option in women with PMS. Calcium supplementation (using Tums E-X) was found to reduce core premenstrual symptoms by 48 percent in 466 patients.22 Vitamin E, an antioxidant, seems to reduce the affective and physical symptoms of PMS.20 Tryptophan,15 a substrate for serotonin, may also benefit some patients.15
TABLE 2
Treatment Approaches to PMDD

Lifestyle changes

Regular, frequent, small balanced meals rich in complex carbohydrates and low in salt, fat, and caffeine19,20

Regular exercise19,20

Smoking cessation20

Alcohol restriction20

Regular sleep20

Nutritional supplements

Vitamin B6, up to 100 mg per day16

Vitamin E, up to 600 IU per day20

Calcium carbonate, 1,200 to 1,600 mg per day21,22

Magnesium, up to 500 mg per day20

Tryptophan, up to 6 g per day15

Nonpharmacologic treatments

Stress reduction and management20

Anger management4

Self-help support group20

Individual and couples therapy20

Cognitive-behavioral therapy23

Patient education20 about the cause, diagnosis, and treatment of PMS/PMDD

Light therapy20 with 10,000 Lx cool-white fluorescent light

PMDD = premenstrual dysphoric disorder; PMS = premenstrual syndrome.

Information from references 4,15,16, and 19 through 23.

NONPHARMACOLOGIC TREATMENTS

Almost invariably, psychosocial stressors should be addressed, either as a cause or a result of PMDD. Psychosocial stressors are known to alter brain neurochemistry and stress-related hormonal activity. Stress reduction, assertiveness training, and anger management can reduce symptoms and interpersonal conflicts. Women with negative views of themselves and the future caused or exacerbated by PMDD may benefit from cognitive-behavioral therapy.23 This kind of therapy can enhance self-esteem and interpersonal effectiveness, as well as reduce other symptoms.23 Educating patients and their families about the disorder can promote understanding of it and reduce conflict, stress, and symptoms.20

HERBAL THERAPIES

A recent study24� reviewed efficacy and safety data on herbal supplements marketed for women. The author concluded that two herbal products, evening primrose oil and chaste tree berry, have been effective in treating PMS (Table 3).24–26 Other researchers25 have arrived at variable conclusions about the efficacy of evening primrose oil. It is thought to provide the gamma-linolenic acid required for synthesis of prostaglandin E1,24 one of the anti-inflammatory prostaglandins. Chaste tree berry may reduce prolactin levels,24,25 thereby reducing symptoms of breast engorgement. These herbal therapies have not been approved by the U.S. Food and Drug Administration (FDA) for use in PMDD, and their safety in pregnancy and lactation has not been established. Moreover, manufacturing standards for herbal products are not uniform.
TABLE 3
Herbal Therapies for PMDD
Herbal product Dosage Use recommendation Comments

Evening primrose oil24,25

500 mg per day to 1,000 mg three times per day

Days 17 through 28 of menstrual cycle

Most-studied of all herbs used in treatment of PMS

May provide a precursor for prostaglandin synthesis

Benefits breast tenderness

Safety data in pregnancy and lactation lacking

Not approved for this use by the FDA

Chaste tree berry24–26

30 to 40 mg per day

Days 17 through 28 of menstrual cycle

May benefit breast symptoms

Inhibits prolactin production

Safety data lacking

Not approved for this use by the FDA

PMDD = premenstrual dysphoric disorder; PMS = premenstrual syndrome; FDA = U.S. Food and Drug Administration.

Information from references 24 through 26.

PHARMACOLOGIC INTERVENTIONS

Antidepressant and Anxiolytic Medications

The serotoninergic antidepressants are the first-line treatment of choice for severe PMDD (Table 4).8–14,27–37 Fluoxetine, in a dosage of 20 mg per day, has been shown to be superior to placebo, whether used only during the luteal phase12 or throughout the full menstrual cycle.27–29 In a review29 of seven controlled and four open-label clinical trials of fluoxetine, symptoms were significantly reduced in patients with PMDD.
TABLE 4
Pharmacologic Interventions: Antidepressant and Anxiolytic Medications
Agents Dosage Use recommendation Comments

SSRIs

Citalopram13,35

10 to 30 mgper day

Full cycle or luteal phase only

Benefits physical, cognitive, and emotional symptoms

Administration during luteal phase

Luteal-phase use is superior to continuous treatment

Not approved by FDA for this use

Fluoxetine12,27,29,35

20 mg per day

Full cycle or luteal phase only

Significant reduction of all symptoms

Decreased libido or delayed orgasm is most common side effect in long-term, continuous use

Approved by FDA for this use

Paroxetine30,35

10 to 30 mgper day

Full cycle

Benefits all symptoms

Transient GI and sexual side effects

Superior to maprotiline

Not approved by FDA for this use

Sertraline8–10,14,31–33,35

50 to 150 mg per day

Full cycle or luteal phase only

Benefits all symptoms

Transient GI and sexual side effects

Approved by FDA for this use

Other serotoninergic antidepressants

Clomipramine11,34

25 to 75 mgper day

Full cycle or luteal phase only

Benefits all symptoms

Anticholinergic and sexual side effects

Not approved by FDA for this use

Anxiolytics

Alprazolam28,36,37

0.375 to 1.5 mg per day

Luteal phase

Interrupted use during the luteal phase can reduce the risk of drug dependence

Use only if SSRIs are ineffective

Not approved by FDA for this use

SSRIs = selective serotonin reuptake inhibitors; FDA = U.S. Food and Drug Administration; GI = gastrointestinal.

Information from references 8 through 14, and 27 through 37.

In one placebo-controlled study,30 paroxetine in a dosage of 10 to 30 mg per day improved mood and physical symptoms in patients with PMDD. Paroxetine was more effective than the noradrenaline reuptake inhibitor maprotiline.30 Sertraline in a dosage of 50 to 150 mg per day was superior to placebo whether used during the full menstrual cycle31–33 or only during the luteal phase.8–10,14 Citalopram in a dosage of 10 to 30 mg per day was effective in one randomized, placebo-controlled trial.13 Interestingly, intermittent administration of citalopram during the luteal phase was found to be superior to continuous treatment. Clomipramine, a serotoninergic tricyclic antidepressant that affects the noradrenergic system, in a dosage of 25 to 75 mg per day used during the full cycle34 or intermittently during the luteal phase,11 significantly reduced the total symptom complex of PMDD.

In a recent meta-analysis35 of 15 randomized, placebo-controlled studies of the efficacy of SSRIs in PMDD, it was concluded that SSRIs are an effective and safe first-line therapy and that there is no significant difference in symptom reduction between continuous and intermittent dosing. Because fluoxetine, citalopram, clomipramine, and sertraline were effective if administered during the luteal phase only, these drugs may be used as first-line therapy and taken intermittently only during the luteal phase. Such an approach can reduce the risk of long-term side effects (e.g., weight gain), minimize discontinuation syndrome, and reduce the cost of care. SSRIs benefit the total symptom complex of PMDD, not only the mood-related symptoms. It should also be noted that fluoxetine and sertraline are the only two SSRIs with FDA approval for use in the treatment of PMDD.

Alprazolam, a high-potency benzodiazepine with mood-enhancing and anxiolytic effects, has been shown to be somewhat effective in patients with PMS.28,36,37 Because of the potential for drug dependence, alprazolam should be considered a second-line drug and used only if SSRIs fail to achieve an optimal response. Therapy should be limited to the luteal phase, and the agent should be given in low dosages—0.375 to 1.5 mg per day. The risk of drug dependence with alprazolam can be minimized by administering it only during the luteal phase of the menstrual cycle in patients without a history of substance abuse.

Hormonal Therapies

It has been shown that by inducing anovulation and amenorrhea, GnRH agonists, leuprolide, histrelin, and goserelin provide significant relief of symptoms in patients without comorbid depression.38–40 However, these medications can induce menopausal symptoms such as hot flushes, vaginal dryness, fatigue, irritability, cardiac problems, and osteopenia. In women with a history of PMDD, treatment of induced menopause with estrogen39 or estrogen plus progestational agents18 can induce recurrent symptoms of PMDD. This finding supports the theory of an etiologic role for female gonadal hormones in PMDD.

Danazol (Danocrine), a weak androgen prescribed for patients with endometriosis, fibrocystic breast disease, and hereditary angioneurotic edema, is sometimes used to treat PMDD. The typical dosage is 100 mg twice a day. Such treatment can reduce symptoms but may result in anovulation and masculinization, either of which may limit regular use.41 Because of the potential for serious side effects and significant costs, GnRH agonists and danazol should be tried as a last resort. These medications must be initiated during menstruation to prevent teratogenicity if there is an unintended pregnancy.

Although oral contraceptive pills (OCPs) suppress ovulation, they are not reported to be consistently effective in the treatment of PMDD (perhaps because the studies had variable samples). OCPs may not suffice if mood symptoms are prominent and, in some patients, these drugs may worsen dysphoria (a known side effect of some birth control pills) in many women without PMDD.

Efficacy studies of progesterone have shown limited benefits. One study42 found progesterone to be superior to placebo; however, another study43� reported efficacy equal to or less than that of placebo. Currently, ovarian gonadal hormones are thought to be of limited usefulness in the treatment of PMDD, and none of the drugs has FDA approval for this indication (Table 5).18,20,38–43
TABLE 5
Hormonal Therapies for PMDD
Drug Dosage Use recommendation Comments

Leuprolide depot38,40

3.75 mg IM per month

Up to six cycles

Pregnancy category X

Significant relief from symptoms but can induce menopausal syndrome

Leuprolide depot with ovarian hormone supplements18

3.75 mg IM per month with estrogen and progesterone

Can exceed six cycles

Less likely to induce menopause; PMDD symptoms may return, making this combination less effective

Goserelin with estrogen supplementation39

3.6 mg SC every 28 days with estrogen

Can exceed six cycles

Less likely to induce menopause; PMDD symptoms may return, making this combination less effective

Pregnancy category X

Use nonhormonal contraception during therapy and for 12 weeks after discontinuation of drug or until menses resume

Danazol41

100 mg twice a day

Up to six cycles

May cause masculinization from weak androgenic properties

Pregnancy category X

OCPs20

OCPs with varying amounts of estrogen and progesterone, once a day

Full cycle

Variable response; may not benefit patients with significant mood symptoms; in some patients, may make mood symptoms worse

Progesterone42,43

Vaginal suppositories, 200 to 400 mg per day

Not recommended for this use

Questionable efficacy

PMDD = premenstrual dysphoric disorder; IM = intramuscularly; SC = subcutaneously; OCPs = oral contraceptive pills.

Information from references 18,20, and 38 through 43.

Miscellaneous Pharmacologic Interventions

In a double-blind, placebo-controlled, crossover study,44 spironolactone in a dosage of 100 mg per day was more effective than placebo in reducing irritability, depression, somatic symptoms, feelings of swelling, breast tenderness, and craving for sweets. Bromocriptine in a dosage of up to 2.5 mg three times per day may be beneficial in patients with cyclic mastalgia,4,20 although in one study45 it was not found to be effective. Ibuprofen, in a dosage of up to 1,000 mg per day, can reduce breast pain, headaches, back pain, and other pain symptoms,20� but seems to have limited effect on mood symptoms (Table 6).4,20,44,45
TABLE 6
Miscellaneous Pharmacologic Interventions for PMDD
Agents Dosage Use recommendation Comments

Diuretics

Spironolactone44

100 mg per day

Luteal phase

Aldosterone antagonist

Potassium-sparing diuretic

Could improve physical and psychologic symptoms

Dopamine agonist

Bromocriptine4,20,45

Up to 2.5 mg three times per day

Days 10 through 26 of menstrual cycle

May relieve cyclic mastalgia; evaluate hepatic and renal functions before initiation

NSAIDs

Ibuprofen20

500 to 1,000 mg per day

Days 17 through 28 of menstrual cycle

Take with food May relieve mastalgia

PMDD = premenstrual dysphoric disorder; NSAIDs = nonsteroidal anti-inflammatory drugs.

Information from references 4,20,44, and 45.

Other Medical Interventions

Historically, surgical and radiation oophorectomies have been used to treat severe PMS, but these modalities have no role in the current management of PMDD.

Evidenced-based efficacy ratings of currently available treatments for PMS and PMDD are described in Table 7,8–16,19–25,28–39,41–45 while an algorithm for the management of these conditions is outlined in Figure 1.
TABLE 7
Efficacy Rating of Current Treatments for PMS/PMDD
Recommended treatment Efficacy in PMS/PMDD Efficacy rating* Comments/evidence

Lifestyle changes19,20

PMS or PMDD

G

Health benefits without risks

Vitamin B616

PMS or PMDD

B

Dosage > 100 mg per day may cause peripheral neuropathy

Vitamin E20

PMS or PMDD

E

Antioxidant without significant risk

Calcium carbonate21,22

PMS or PMDD

B

Placebo-controlled study supports benefits in moderate to severe PMS

Tryptophan15

PMS or PMDD

B

Supported by a placebo-controlled study

Cognitive-behavioral therapy23

PMS

A

Benefits documented; not many studies

PMDD

B

—

Herbal therapies24,25

PMS or PMDD

E

Safety in pregnancy and lactation not documented; not FDA-approved

Selective serotonin reuptake inhibitors8–10,12–14,29–33,35

Nonresponsive PMS or PMDD

A

Well-designed, randomized, placebo-controlled studies and metaanalyses

Clomipramine11,34

PMDD

B

Anticholinergic side effects

Alprazolam28,36–37

PMDD

B

Low-dose, luteal phase treatment; long-term use may cause tolerance

GnRH agonists or danazol18,38,39,41,42

PMDD

C

Menopausal syndrome/masculinization/cost limit its use

Spironolactone, bromocriptine, or ibuprofen41,44,45

PMS or PMDD

D

Symptom-focused efficacy; spironolactone efficacy supported by double-blind study

Oral contraceptives or progesterone42,43

PMDD

E

Anecdotal efficacy or not consistently effective

Surgical or radiation oophorectomy

PMDD

F

Not recommended

PMS = premenstrual syndrome; PMDD = premenstrual dysphoric disorder; FDA = U.S. Food and Drug Administration; GnRH = gonadotropin-releasing hormone.

*—Efficacy rating key: A = first line; B = second line; C = third line; D = symptomatic efficacy; E = efficacy anecdotal or not consistently effective; F = not recommended; G = general or adjunctive treatments.

Information from references 8 through 16,19 through 25,28 through 39, an d41 through 45.

Management of PMS/PMDD

FIGURE 1.

Algorithm for the management of PMS/PMDD. (PMS = premenstrual syndrome; PMDD = premenstrual dysphoric disorder; SSRI = selective serotonin reuptake inhibitor; GnRH = gonadotropin-releasing hormone.)

The Authors

SUBHASH C. BHATIA, M.D., is chief of the Mental Health and Behavioral Science Department at the Department of Veterans Affairs, Nebraska–Western Iowa Health Care System, Omaha. He is also professor of psychiatry at Creighton University School of Medicine and clinical associate professor at the University of Nebraska College of Medicine, both in Omaha. A medical graduate of Panjab University, Chandigarh, India, Dr. Bhatia received a graduate degree from the Postgraduate Institute of Medical Education and Research, also in Chandigarh, and completed a residency in psychiatry at Creighton University. Dr. Bhatia is board-certified in psychiatry, geriatric psychiatry, addiction psychiatry, and forensic psychiatry.

SHASHI K. BHATIA, M.D., is director of child and adolescent residency education and training at Creighton University School of Medicine, where she is also associate professor of psychiatry, child and adolescent psychiatry, and pediatrics. In addition, she serves as clinical associate professor at the University of Nebraska College of Medicine. A medical graduate of Panjab University, Dr. Bhatia completed a residency in obstetrics and gynecology at the Postgraduate Institute of Medical Education and Research and a residency in psychiatry and child psychiatry at Creighton University. Dr. Bhatia is board-certified in psychiatry, child and adolescent psychiatry, addiction psychiatry, and forensic psychiatry.

Address correspondence to Subhash C. Bhatia, M.D., Chief, Mental Health and Behavioral Science Department, Department of Veterans Affairs, Nebraska–Western Iowa Health Care System, 4101 Woolworth Ave., Omaha, NE 68105 (e-mail: subhash.bhatia@med.va.gov). Reprints are not available from the authors.

The authors thank Daniel Richard Wilson, M.D., Ph.D., Professor and Chair, Creighton University School of Medicine, Department of Psychiatry, for constructive suggestions for the manuscript.

Dr. Shashi Bhatia is a member of the speakers bureaus of Abbot Laboratories and Forest Pharmaceutical, Inc. Dr. Subhash Bhatia is a member of the speakers bureaus for Eli Lilly and Co., Pfizer US Pharmaceutical Group, and Forest Pharmaceutical, Inc. Sources of funding: none reported.

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32. Yonkers �KA, Halbreich �U, Freeman �E, Brown �C, Endicott �J, Frank �E, et al. �Symptomatic improvement of premenstrual dysphoric disorder with sertraline treatment. �JAMA. �1997;278:983–8.

33. Cohen �LS. �Sertraline for premenstrual dysphoric disorder. �JAMA. �1998;279:357–8.

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39. Leather �AT, Studd �JW, Watson �NR, Holland �EF. �The treatment of severe premenstrual syndrome with goserelin with and without ‘add-back’ estrogen therapy. �Gynecol Endocrinol. �1999;13:48–55.

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41. Hahn �PM, Van Vugt �DA, Reid �RL. �A randomized, placebo-controlled, crossover trial of danazol for the treatment of premenstrual syndrome. �Psychoneuroendocrinology. �1995;20:193–209.

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43. Vanselow �W, Dennerstein �L, Greenwood �KM, de Lignieres �B. �Effect of progesterone and its 5 alpha and 5 beta metabolites on symptoms of premenstrual syndrome according to route of administration. �J Psychosom Obstet Gynaecol. �1996;17:29–38.

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45. Meden-Vrtovec �H, Vujic �D. �Bromocriptine (Bromergon, Lek) in the management of premenstrual syndrome. �Clin Exp Obstet Gynecol. �1992;19:242–8.

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Where did viruses come from?

2010-06-21T21:12:00.000+07:00

March 27, 2008 | 26 comments
Where did viruses come from?

© ISTOCKPHOTO/SEBASTIAN KAULITZKI

Ed Rybicki, a virologist at the University of Cape Town in South Africa, answers:

Tracing the origins of viruses is difficult because they don't leave fossils and because of the tricks they use to make copies of themselves within the cells they've invaded. Some viruses even have the ability to stitch their own genes into those of the cells they infect, which means studying their ancestry requires untangling it from the history of their hosts and other organisms. What makes the process even more complicated is that viruses don't just infect humans; they can infect basically any organism—from bacteria to horses; seaweed to people.

Still, scientists have been able to piece together some viral histories, based on the fact that the genes of many viruses—such as those that cause herpes and mono—seem to share some properties with cells' own genes. This could suggest that they started as big bits of cellular DNA and then became independent—or that these viruses came along very early in evolution, and some of their DNA stuck around in cells' genomes. The fact that some viruses that infect humans share structural features with viruses that infect bacteria could mean that all of these viruses have a common origin, dating back several billion years. This highlights another problem with tracing virus origins: most modern viruses seem to be a patchwork of bits that come from different sources—a sort of "mix and match" approach to building an organism.

The fact that viruses like the deadly Ebola and Marburg viruses, as well as the distantly related viruses that cause measles and rabies, are only found in a limited number of species suggests that those viruses are relatively new—after all, those organisms came along somewhat recently in evolutionary time. Many of these "new" viruses likely originated in insects many million years ago and at some point in evolution developed the ability to infect other species—probably as insects interacted with or fed from them.

HIV, which is thought to have first emerged in humans in the 1930s, is another kind of virus, known as a retrovirus. These simple viruses are akin to elements found in normal cells that have the ability to copy and insert themselves throughout the genome. There are a number of viruses that have a similar way of copying themselves—a process that reverses the normal flow of information in cells, which is where the term "retro" comes from—and their central machinery for replication may be a bridge from the original life-forms on this planet to what we know as life today. In fact, we carry among our genes many "fossilized" retroviruses—left over from the infection of distant ancestors—which can help us trace our evolution as a species.

Then there are the viruses whose genomes are so large that scientists can't quite figure out what part of the cell they would have come from. Take, for instance, the largest-ever virus so far discovered, mimivirus: its genome is some 50 times larger than that of HIV and is larger than that of some bacteria. Some of the largest known viruses infect simple organisms such as amoebas and simple marine algae. This indicates that they may have an ancient origin, possibly as parasitic life-forms that then adapted to the "virus lifestyle." In fact, viruses may be responsible for significant episodes of evolutionary change, especially in more complex types of organisms.

At the end of the day, however, despite all of their common features and unique abilities to copy and spread their genomes, the origins of most viruses may remain forever obscure.

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AWAKENING DESIRE: UNDERSTANDING FEMALE SEXUAL DYSFUNCTION

2010-06-20T11:35:00.001+07:00

Interests:
AWAKENING DESIRE:
UNDERSTANDING FEMALE SEXUAL DYSFUNCTION
Jennifer Wider, MD
Society for Women's Health Research
June 8, 2010

Many women experience problems in the bedroom at one time or another. Female sexual dysfunction is not uncommon and although some women and healthcare providers have difficulty discussing it, it has been recognized by the medical community for decades. In fact, for the last twenty years, it has been listed in the Diagnostic and Statistical Manual of Mental Disorders, a manual published by the American Psychiatric Association, used to classify and diagnose psychological disorders.

Female sexual dysfunction (FSD) can develop at any age, but many women report sexual problems at times of hormonal fluctuation; for example: post-pregnancy or during menopause. FSD encompasses several conditions that can have an effect on a woman’s health and cause concern and suffering. These symptoms include:

The desire to have sex is low or absent.
An inability to maintain arousal during sexual activity, or become aroused despite a desire to have sex.
An inability to experience an orgasm.
Pain during sexual contact.
Hypoactive sexual desire disorder (HSDD) affects roughly 1 in 10 women and is the most common sexual dysfunction among women of all ages. It is sometimes difficult to diagnose because a woman’s sex drive varies tremendously from person to person. And the factors causing a lowered sex drive can range from psychological to biological. But some women underestimate what an important role sexual health plays in their overall health and well-being. And if the lack of desire becomes distressing in any way or interferes with her overall quality of life, she may have HSDD.

Many women suffer in silence and some even feel that a decline in sexual desire is a normal part of aging. According to Sheryl A. Kingsberg, PhD, a clinical psychologist and Professor in the Department of Reproductive Biology at Case Western Reserve University School of Medicine in Cleveland, Ohio: “Women should not be expected to accept a distressing loss of sexual desire any more than they should be expected to simply accept arthritis, acid reflux, or any other condition often associated with aging.”

Unfortunately, HSDD in women is not as well recognized as erectile dysfunction (ED) in men. There are many medications available for the treatment of ED, but currently, there are no US FDA approved medications for women with HSDD. “The problem is further compounded by a lack of attention and interest in women’s sexual satisfaction in many cultures,” says Kingsberg. And as a result, “some women may feel that it is not appropriate to seek help for a sexual problem.”

There are options available. An important step in getting help for FSD is realizing that there is a problem. Too many women ignore their symptoms or are unable to recognize that they have a treatable issue. Kingsberg suggests that: “Women should speak to their partners about the problem and (they may consider) seeing a professional for guidance; this professional may be a counselor, a sex therapist, a physician or nurse practitioner, or some other trusted person.”

Psychotherapy or sex therapy can be very effective in uncovering the different components that may contribute to the problem. There are a few medical treatments which include hormonal therapies that may help some women. “A number of other very exciting new approaches to the treatment of low sexual desire in women are under development,” say Kingsberg, “and may be available soon.”

###

The Society for Women’s Health Research (SWHR), a national non-profit organization based in Washington D.C., is widely recognized as the thought leader in women’s health research, particularly how sex differences impact health. SWHR’s mission is to improve the health of all women through advocacy, education and research. Visit SWHR’s website at swhr.org for more information.

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Vitamin C protects, maintains healthy bone mass

2010-06-18T20:56:00.001+07:00

Dipali Pathak
713-798-4710
pathak@bcm.tmc.edu
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Vitamin C protects, maintains healthy bone mass

HOUSTON -- (May 11, 2010) -- Vitamin C, or ascorbate, plays an important role in maintaining bone mass – promoting the balance between old bone resorption and new bone formation, said researchers from Baylor College of Medicine and Lexicon Pharmaceuticals in a report that appears online in the Journal of Biological Chemistry.

"The assumption is that everyone gets enough vitamin C in their diet," said Dr. Kenneth Gabbay, professor of pediatrics – molecular diabetes and metabolism at BCM. "However, multiple studies of large groups of people show that higher intakes of vitamin C are associated with higher bone mass and lower fracture rates. Our study shows that vitamin C or ascorbate is critical to maintaining the homeostasis necessary for healthy bone mass."

In particular, he referred to the Framingham Osteoporosis study and the Women's Health Initiative, both of which involved thousands of participants.

Gabbay and his colleagues built on the fact that mice can actually synthesize vitamin C, an ability that is lacking in humans. They identified two enzymes critical to this process by providing the building material for vitamin C – aldehyde reductase and aldose reductase. Aldehyde reductase is responsible for 85 percent of vitamin C production and aldose reductase, the remaining 15 percent. Mice bred to lack both enzymes cannot make any vitamin C and develop scurvy, a condition that affects many organ systems including bone.

However, if mice lack only aldehyde reductase, they and their skeletons develop and grow normally on the 15 percent ascorbate or vitamin X generated through aldose reductase until they face a stressor that requires more vitamin C, such as pregnancy or the loss of sex hormones that accompany menopause and aging.

"Then they fall off a cliff and develop early profound osteoporosis," said Gabbay.

Bone formation

His studies (in mice) show that ascorbate or vitamin C both suppresses osteoclasts, which promote bone resorption, and stimulates the development of osteoblasts that make new bone, thus enhancing new bone formation. The constant renewal of bone is crucial to healthy bone architecture.

Many treatments for osteoporosis, including bisphosphonates such as Fosamax and Actonel, suppress the function of osteoclasts, and hence blocks bone resorption and mechanisms of bone repair. Unfortunately, these treatments do not stimulate osteoblast formation and new bone is not made. Many anti-oxidants such as resveratrol (found in red wine) and pycnogenol do the same thing. Only vitamin C affects both sides of the equation – osteoclast suppression and osteoblast development, said Gabbay.

Important as vitamin D, calcium

Most experts recommend vitamin D, calcium, exercise and bisphosphonates to keep bones healthy, said Gabbay.

"Vitamin C is never mentioned, whereas it's likely an equally important element for maintaining strong healthy bones" he said. "Our studies necessitate formal studies in patients to evaluate the usefulness of vitamin C therapy in susceptible populations."

Others who took part in this work include: Kurt M. Bohren, Roy Morello, Terry Bertin, all of BCM, and Jeff Liu and Peter Vogel of Lexicon Pharmaceuticals in the Woodlands. Morello is now at the University of Arkansas for Medical Sciences in Little Rock, Ark.

Funding for this work came from the Harry & Aileen Gordon Foundation, the Jacob & Louise Gabbay Foundation, the Agar Organization, the U.S. Department of Agriculture and the Children's Nutrition Research Center at Baylor College of Medicine and Texas Children's Hospital. The authors also thank the Rolanette and Berdon Lawrence Bone Disease Program of Texas.