Thursday, August 24, 2017

ENDOMETRIOSIS-A CHRONIC PAINFUL CONDITION

Endometriosis is a chronic inflammatory condition, due to the presence of endometrium (normal lining of the uterus) outside the uterus; commonly behind the uterus, ovaries, tubes, pelvic peritoneum and also far off from the pelvis. Endometriosis of the lungs, kidneys and other far off places is also seen.  This endometrium undergoes menstruation with each menstrual cycle. Blood has nowhere to escape. It remains there and causes inflammation, and adhesions.  This blood clots quickly but still within normal time. It happens in 1 in 10 women, it is estimated that there are one and a half million women in the world suffering from this terrible condition, yet most governments give very little money for research on ENDO (Endometriosis). It can begin at any age after the start of the menstrual cycle. I have come across many young girls, as young as 12 years, and teenagers. They are often told you have to put up with it.  They miss school and are unable to participate in a normal life. ENDO causes very painful periods, painful sexual activity, painful bowel action, pain on passing urine, if bowel and bladder is involved which is often the case. It causes infertility in about 50% of women and excessive bleeding. Besides all this it also causes fatigue, depression, diarrhoea, constipation, nausea and often pain all the time. It is estimated that it often takes 8-10 Years before diagnosis of endometriosis is confirmed.  I feel that this may be due to a woman’s reluctance to undergo the diagnostic test, which a surgical procedure is called Laparoscopy. The diagnosis can be confused with irritable bowel syndrome, pelvic inflammatory disease, ovarian cysts; none of these conditions cause as much pain as Endo unless the ovarian cyst is twisted.

WHY DOES ENDO HAPPEN
1) It is believed that during the period, there is a backward flow (Retrograde flow) of blood in the abdominal cavity through the fallopian tubes, and if the blood is too much or for some reason the body is unable to clean it, it remains there with the endometrial cells. There is some genetic role if two close family members of the family have ENDO, you are more likely to have it.
There are many women who do not have a uterus, or how does ENDO go to the lungs, eyes or very distant organs.
2) There is another theory called, Transformation Syndrome or Induction Theory, which has a view that under the influence of hormones or immune factors the peritoneal cells transform into endometrial cells. 3) Embryonic cell theory, hormones may transform the remaining cells into endometrial cells.
4) Blood vessels, tissue fluids and Lymphatics, transplant the endometrial cells to other parts of the body.
5) Immune system disorders do not recognise the endometrial cells at funny places and therefore do not destroy them.
  6) Last but not the least there is the human factor,
  after an operation we inadvertently implant the
  endometrium on the scar. I have seen a few cases of
  Caesarean section scar endometriosis.
I feel in some cases more than one factor is at work. For argument sake in retrograde menstruation, the immune system is unable to clean all the blood.
SYMPTOMS OF ENDOMETRIOSIS
Endomertriosis is a nasty lifelong disease. There is really no cure for it; however we can relieve its symptoms and may be improve the quality of life to some extent. There are two main symptoms, pain and more pain and infertility in 30-50% women.
Pain is pelvic pain, dysparunia, dysmenorrhea, and chronic pelvic pain. Pain is not always cyclic pain; it is also not proportional to the severity of this disease. A small number of women are pain free. Unusual symptoms are bowel problems, and when the bowel is involved e.g. spasms, diarrhoea, constipation and rectal bleeding, it is very often confused with IBS. If the urinary bladder is involved the women get urgency, frequency, and haematuria (Blood in the Urine). Rarely if there is chest involvement women can get chest pains, air or fluid in the pleura (lining of the 
lungs).

DIAGNOSIS OF ENDOMETRIOSIS
One can suspect  ENDO from the history of pain , infertility and a family history, however the gold standard  for diagnosis is laparoscopy which is a surgical  procedure many women and mothers are reluctant to have this performed; hence the diagnosis of ENDO is often delayed. However many of us often start the treatment after fair clinical certainty. After taking the history a clinical pelvic examination is performed in females who are sexually active. Very young girls and teen agers often require a laparoscopy to conform the diagnosis. It is not disastrous to start them on oral contraceptives if their mothers agree, as they help with the pain of ENDO and keep the disease under control.
On clinical pelvic examination we may find a uterus with restricted mobility, stuck to the bladder or the rectum depending on the pathology of the ENDO. You may also find cysts on one or both ovaries which result from the ENDO of the ovaries. They are called endomeriomas or chocolate cysts. Further diagnosis is confirmed by ultrasound, this has to be a transvaginal or rectal ultrasound. In very young girls it can be vulval, often it is not required as the disease in very early stages, and you may not see much on ultrasound.  Ultrasound is good at detecting endometriomas they are low level echoes with a thick cyst wall, they have hyperchoic nodules and many other findings differentiate these from other cysts and, ovarian cancer. 

Doppler studies are also done. MRI further adds to elaborate the diagnosis of ENDO. MRI is very useful to make the diagnosis of extra pelvic endometriosis such as cervix, vagina, round ligament of the uterus, abdominal wall lesions, rectus muscles, deep infiltrating lesions. Any lesions on the abdominal wall bigger than 5 mm are considered deep infiltrating lesions. They are often very painful.
Adhesions Causing Pain

Deep infiltrating lesions are fibrous solid and thickened. It is difficult to diagnose the lesion on the nerves e.g.  Presacral nerves. If the rectum is cleansed before ultrasound we get a lot more information.      
Since laparascopy is a surgical procedure newer non invasive diagnostic tests are being investigated for the diagnosis of ENDO, these include CA125 (Blood Test for inflammation) and genetic data from endometrial tissue obtained from endometrial biopsy. With CA125 one has to be careful as a high value of CA125 is also used for screening of ovarian cancer. Cut off reference for ovarian cancer is 35 international units per ml. CA125 is tested in two phases of menstrual during menstruation and midcycle. If it is low during menstrual phase the probability of ENDO is low as normally it is high due to inflammation, desquamation of tissues and breakdown of haematological barrier. If high in both the phases it suggests a more severe type of ENDO. This is expressed as deep infiltrating endometriosis. It is very painful and more difficult to deal with as compared to endomeriomas. About 6% of cases of deep infiltrating endometriosis involve the appendix as well, this further contributes to infertility. This test CA125 can be useful if negative, it can help to exclude the diagnosis of ENDO.
The other non invasive test that is being tried is Gene expression. The investigators found different gene expressions, in the endometrium of the women suffering from endometriosis. Gene expression in different conditions showed different immune activation. The researchers are trying to further define these tests. It will be very simple then. A simple endometrial biopsy can give us the diagnosis of endometriosis.
STAGES OF ENDOMETRIOSIS
Stage 1 
Minimal superficial spots
Stage2
Appearance of more spots which appear within the deeper layers of the tissues
Stage 3
Moderate. It is present on one or both ovaries. It may also show thin adhesions. It may also have adhesions behind the uterus in the normal empty space (cul de sac)
Stage 4
Deep implants, Endometriomas, adhesions, bowel and bladder involvement, distortion in the shape of the uterus. Involvement of the peritoneum ; nodules bigger than 5 mm,on the peritoneum
Most severe pathology is deep infiltrating lesions and Endometriomas 

TREATMENT OF ENDOMETRIOSIS
At the present stage of our knowledge, there is no real treatment of endometriosis (ENDO) we try to control its progression, pain and help with infertility that it causes.
A fair bit of research is going on with several drugs, which interfere with oestrogen production without causing the total inhibition of ovarian function. Drugs that decrease the size of ENDO, immunological drugs that decrease the inflammatory reactions, thus helping with pain. It will be many years before these drugs will be available for human consumption. Let us see how we are helping them now. In milder types of ENDO, particularly in young girls we use combined oral contraceptives. This suppresses the ovarian function, thus the activity of ENDO, they can go to school or uni, and improve the quality of life. a pain killer such as nurofen can be added. The pill can be taken continuously for many months so that the period happens 3-4 months a year instead of every month.
Danazol is another drug that is useful. It is a derivative of testosterone, it helps by causing anovulation. Dose of Danazol is 600 -800mgm daily, at this dose it can cause masculising effects such as deepening of the voice and increased hair growth. Long term it can increase cholesterol and can cause liver damage. It is only a short term answer. It does not help in dosage lower than these. If by chance you get pregnant while on Danazol, the female foetus can become masculinised.
Progestational drugs are useful long term. They    have their own side effects. Medroxyprogesteron injection is effective. It is given as an injection of 150mgm every 3months. It causes complete absence of periods with very little pain. However the other side effects are breast tenderness, fluid retention, constipation, depression and above all loss of bone density. The other progesterone preparation which is commonly used is Dienogest (Visanne). It works by decreasing oestrogen production, decreases pain and also ENDO. This is about the best oral treatment available at this stage; it is shown to be very useful to prevent recurrence after operative treatment.This can cause asthma and allergic reactions. Do not take these drugs if you have risk factors for heart attack, stroke or DVT. The two other drugs that are being studied in animals are, letrozole and retinoic acid which decreases the size of ENDO and inflammation respectively. May prove to be very useful in human’s, in the future. They act by preventing cell proliferation apoptosis (Cell Death) and neovasculizition. They are anti oestrogen and are used in breast cancer treatment.  The other medical treatment which is very useful is GnRH agonists and GnRH antagonists.These can be used in different forms such as subcutaneous injections (1.8mgm once a month or 3.75mgm once every 3months or nasal spray, implants. These cause two main side effects; loss of bone density and menopausal symptoms; such as loss of sleep and hot flashes, and almost runs the whole gamete of menopausal symptoms. Add back HRT is used which is very helpful for both symptoms of menopause and loss of bone density. (These have been discussed in management of AUB). The other drug which has been found useful is GnRH antagonists. 3mgm of Centrirelix( is injected once a week for eight weeks.
This does not cause any menopausal symptoms, oestrogen level is maintained at the lower limit of normal and it does not cause any serious side effects. One study showed that 60% of cases showed a decrease in the degree of endometriosis.
There are three things in endometriosis which need treatment, the disease itself, intractable pain caused by the disease, and infertility. None of these problems are totally curable but we try and help them. The medical treatment which we have discussed is to help many women if the diagnosis is made early; they are treated and followed up forever.
SURGICAL PROCEEDURES DONE IN ENDOMETRIOSIS
The first procedure required in endometriosis, is a laparoscopic examination of the abdomen. At present this is the gold standard for confirming the diagnosis and extent of ENDO. This being an operative procedure is the reason why there is delay in the diagnosis of ENDO. As already mentioned there is fair bit of research going on to make the diagnosis of ENDO without laparoscopy. A simple laparoscopy if performed for diagnosis alone is a simple procedure. However we obtain consent from the women, that if we find ENDO, we will deal with it at the same time. All the possible complications are explained. It is a day procedure, performed under general anaesthetic. You are prepared for the theatre like any other operation.
To start with a tiny cut is made at the belly button. A small needle is inserted into the abdomen making sure it is moving freely. The abdomen is filled with a certain amount of carbon dioxide. A surgical telescope is passed inside the abdomen so that we can see all the organs. The ovaries, tubes, and the area behind the uterus, between it and the bowel called the cul de sac, along with the uterus itself. This is common place where ENDO starts. It can then involve the bowel, and also cause what we call deep infiltrating endometriosis (DIE). We also look at the
appendix, the bowel ,peritoneum(the covering of the abdominal cavity). Extra one or two small incisions are made to pass other instruments into the abdomen which we will use to operate. Scattered ENDO, is excised (sent for biopsy), or ablated by high energy heat source very carefully, so that the adjoining tissues are safe. In early stage disease both pain and infertility improve. Main problems with ENDO are:
1) Endometriomas , this is a collection of blood around the ovarian ENDO. This can be easily diagnosed by transvaginal ultrasound. If a woman is a virgin, vulval (just from outside) an ultra sound can be done or you have to do a Trans abdominal ultrasound. Endometriomas are unilocular cysts with a ground glass appearance. These when found on Ultrasound or laparoscopy should be removed. It is not good enough to drain them as infertility results are better when the endometriomas are removed completely; it will also not reoccur. Removing the cyst wall completely is the best treatment. One of the latest alternative suggestions or options is that cyst wall should be partially removed and the rest vaporised and sealed. This gives the best results for infertile women.
2) The second difficult problem is deep infiltrating endometriosis, when the nodes on the peritoneum are more than 5 mm it is considered deep. When the bowel is involved it can be upto10mm. For lesions deeper than 5 mm heat coagulation and laser ablation should not be done. For deep infiltrating ENDO, very experienced laparoscopic surgeons are necessary, often you have to have multiple speciality surgeons e.g. bowel surgeons, urologist, if urinary bladder or ureter is involved.  The complication rate for deep ENDO  treatment is high. It is often better to transfer them to a standalone ENDO centre . These cases can be studied in detail including using an MRI which can also identify ENDO outside the pelvic organs, and different specialists are on the spot. It is still debated whether it is best to dissect out the nodules on the bowel or do segmental resection (remove the involved bowel). The decision depends on individual cases and women’s involvement and the surgeon’s expertise. If it can be done it should be done, as it reduces pain, improves quality of life and improves chances of fertility. If not we try to help with hormone therapy to help pain and quality of life. The question often arises what is better laparoscopy or laparatomy (opening the abdomen). In my opinion laparoscopy is always better, but you have to have very good facilities, equipment and experienced laparoscopic surgeons. After laparoscopy you can recover sooner and invest less time in the hospital stay.
The other operations that are done with ENDO are:
1) Appendectomy, it is believed that if appendix is involved with ENDO, the chances of infertility are higher.
2) During laparoscopy it was frequent that the surgeons ablated the uterosacral ligaments (ligaments behind the uterus) hoping that the nerve supply of the area will be cut and this will help with the pain. However this did not help. This is being given up.
3) The group of nerve fibres that are cut are called presacral nurectomy. This helps with central abdomenal pain. You need an expert to do this.
4) Removal of adhesions that are formed in ENDO can often be an operation in itself.
Luckily the adhesion formation is less after laparoscopic surgery and when we finish the operation leave the cavity clean, rinse it and place a piece of protective material now available over the operated area. This material will prevent tissues rubbing against each other and prevent adhesions. This material will get absorbed by itself in due course.
The final operation for endometriosis is hysterectomy with removal of both tube and ovaries, as it is the ovaries which propagate ENDO.This can be vaginal, abdominal, normal or laparoscopic depending on the different situations. Most women will require hormone replacement treatment. They should we given both oestrogen and progesterone. Oestrogen alone can reactivate any residual ENDO. It can even run the risk of endometrial cancer. Endometriosis increases the risk of ovarian cancer by 1% compared to the population in general.
Currently many studies are being done and investigated to see if post operative treatment is useful, but it appears there is no benefit from hormone therapy within 6 months of operation.  However it is being tried for contraception, prevention of pain and reoccurrence. In women operated on for endometriosis and are not keen to have a baby LNG-IUS (Mirena) a long acting intrauterine device or a combined oral contraceptive is useful for secondary prevention of ENDO. Mirena can also be used as an initial treatment of ENDO.
Women who suffer from infertility due to ENDO do benefit from surgery. It is best to do laser ablation of ENDO at the time of laparoscopy; endometriomas should be removed not drained for better results for infertility. Hormonal treatment after surgery should be avoided if trying to help with infertility. Often it is useful to refer them to IVF for help from assisted reproductive technology. At our current stage of knowledge many woman still suffer from ENDO, with lifelong pain infertility and poor quality of life.

A lot of work is being done for early diagnosis by gene testing from simple endometrial biopsy. A lot of 
studying is required to know the role of the immune system on ENDO, and how to prevent  the
Inflammation, adhesion formation, pain and reoccurrence. We need to know what the best treatment for pain and infertility is to prevent recurrence of endometriomas and deep endometriosis. There is great need to make people aware of ENDO and its social impact so that early diagnosis is made while we are making every attempt to find easier ways to diagnose, than by laparoscopy. Public has to give up the dictum that you are a women so you have to suffer this period pain. How many teen agers suffer in silence from ENDO?
How many women remain infertile?
Recently in New Zealand, they have decided to discuss Endometriosis with teenagers so that they can discuss their menstrual problems with their health providers and it can be prevented from progressing. Then it does not become difficult to manage. This is very forward thinking in the management and education of Endometriosis. 

I hope that we can resolve and defeat some of these problems.

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