Endometriosis

These ectopic endometrial tissues may be found in the myometrium when it is called endometriosis internal or adenomyosis. More commonly, however, these tissues are found at sites other than uterus and are called endometriosis externa or generally referred to as endometriosis. Endometriosis is a disease of contrast. It is a benign but it is locally invasive, disseminates widely. Cyclic hormones stimulate growth but continuous hormones suppress it.[1]

During the last couple of decades, the prevalence of endometriosis has been increasing both in terms of real and apparent. The real one is due to delayed marriage, postponement of first conception and adoption of small family norm. The apparent one is due to increased use of diagnostic laparoscopy as well as heightened awareness of this disease complex amongst the gynaecologists. The prevalence is about 10 percent. However, prevalence is high amongst the infertile women (30–40%) as based on diagnostic laparoscopy and laparotomy.[1]

Sites:

• Abdominal
• Extra-abdominal
• Remote

Abdominal:

It can occur at any site but is usually confined to the abdominal structures below the level of umbilicus.

Extra-abdominal:

The common sites are abdominal scar of hysterotomy, caesarean section, tubectomy and myomectomy, umbilicus, episiotomy scar, vagina and cervix.[1]

still remains unclear and is full of theories. The principal ones are:

Retrograde Menstruation (Sampson’s theory)

There is retrograde flow of menstrual blood through the uterine tubes during menstruation. The endometrial fragments get implanted in the peritoneal surface of the pelvic organs (dependent sites, e.g., ovaries, uterosacral ligaments). Subsequently, cyclic growth and shedding of the endometrium at the ectopic sites occur under the influence of the endogenous ovarian hormones. Retrograde menstruation per se is unlikely to produce endometriosis. Probably, a genetic factor or favourable hormonal milieu is necessary for successful implantation and growth of the fragments of endometrium. While this theory can explain pelvic endometriosis, it fails to explain the endometriosis at distant sites.

Coelomic metaplasia (Meyer and ivanoff)

Chronic irritation of the pelvic peritoneum by the

menstrual blood may cause coelomic metaplasia which results in endometriosis. Alternatively, the Mullerian tissue remnants may be trapped within the peritoneum. They could undergo metaplasia and be transformed into endometrium. This theory can explain endometriosis of the abdominal viscera, the rectovaginal septum and the umbilicus.[1]

Direct implantation

According to the theory, the endometrial or decidual tissues start to grow in susceptible individual when implanted in the new sites. Such sites are abdominal scar following hysterotomy, caesarean section, tubectomy and myomectomy. Endometriosis at the episiotomy scar, vaginal or cervical site can also be explained with this theory. This theory however, fails to clarify endometriosis at sites other than mentioned.

Lymphatic theory (halban):

It may be possible for the normal endometrium to metastasize the pelvic lymph nodes through the draining lymphatic channels of the uterus. This could explain the lymph node involvement.

Vascular theory:

This is sound at least to explain endometriosis at distant sites such as lungs, arms or thighs. [1]

Genetic and immunological factors

Genetic basis of endometriosis probably accounts for less than 10 percent of the patients. There is 6–7 times increased incidence in first degree relatives. Multifactorial inheritance is thought of. However, a defect of local cellular immunity may be responsible for the ectopic tissue to grow in abnormal sites only in susceptible women. Peritoneal macrophages normally remove the menstrual debris by phagocytosis.

Pelvic endometriosis is associated with a subclinical peritoneal inflammation resulting in increase in peritoneal fluid. In patients with endometriosis, the activated macrophages secrete several factors like cytokines, interleukin–1, α TNF, integrins and angiogenic factors. These factors promote the growth of endometrial cells over the ectopic sites. Ectopic endometrium is more resistant to apoptosis. Furthermore, activated macrophages reduce sperm motility, increase sperm phagocytosis and interfere with fertilization.

Environment theory

suggests somatic mutations of cells due to environmental factors (pollutants, dioxins). Ovarian and deep infiltrating endometriotic lesions explain with this theory. Thus, it is certain that, not all cases of endometriosis at different sites can explain by a single theory.[1]

Pathology-

General Considerations

• The endometrium (glands and stroma) in the ectopic sites have got the potentiality to undergo changes under the action of ovarian hormones

• While proliferative changes constantly evidence, the secretory changes are conspicuously absent in many; may due to deficiency of steroid receptors in the ectopic endometrium
• Cyclic growth and shedding continue till menopause. The periodically shed blood may remain encysted or else, the cyst becomes tense and ruptures
• As the blood is irritant, there is dense tissue reaction surrounding the lesion with fibrosis. If it happens to occur on the pelvic peritoneum, it produces adhesions and puckering of the peritoneum
• If encysted, the cyst enlarges with cyclic bleeding.

chocolate cyst

The serum gets absorbed in between the periods and the content inside becomes chocolate coloured. Hence, the cyst call chocolate cyst which commonly locate in the ovary. Chocolate cyst may also due to haemorrhagic follicular or corpus luteum cyst or bleeding into a cystadenoma. For this reason, the term endometrial cyst or endometrioma prefer to chocolate cyst

• In spite of dense adhesions amongst the pelvic [1]

Patient Profile

The age is between 30–45. The patients are mostly nulliparous or have had one or two children long years prior to appearance of symptoms. Infertility, voluntary postponement of first conception until at a late age and higher social status are often related. Thus, it is more common in private than hospital patients. There is often family history of endometriosis. Outflow tract obstruction is an important cause when it is seen in teenagers (10%)

Symptoms

• About 25 percent of patients with endometriosis have no symptom, being accidentally discovered either during laparoscopy or laparotomy.
• Symptoms are not related with extent of lesion. Even when the endometriosis is widespread, there may not be any symptom; conversely, there may be intense symptoms with minimal endometriosis.
• Depth of penetration is more related to symptoms rather than the spread. Lesions penetrating more than 5 mm are responsible for pain, dysmenorrhea and dyspareunia.
• Non-pigmented endometriotic lesions compared to the classic pigmented “powder burns” lesions produce more prostaglandin F (PGF) and hence are more painful.
• The symptoms are mostly related to the site of lesion and its ability to respond to hormones. Midline lesions are more symptom producing. Degree of pain is not related to the severity of endometriosis.[1]

Dysmenorrhea (70%)

There is progressively increasing secondary dysmenorrhea. The pain starts a few days prior to menstruation; gets worsened during menstruation and takes time, even after cessation of period, to get relief of pain, (co-menstrual dysmenorrhea). Pain usually begins after few years pain-free menses. The site of pain is usually deep seated and, on the back, or rectum. Increased secretion of PGF 2α, thromboxane β2 from endometriotic tissue is the cause of pain.

Abnormal menstruation (20%):

Menorrhagia is the predominant abnormality. If the ovaries are also involved, polymenorrhagia or epimenorrhagia may be pronounced. There may be premenstrual spotting.

Infertility (40–60%):

Whether endometriosis causes infertility or infertility produces endometriosis is not clear. Endometriosis is found in 20–40 percent of infertile women, where as in about 40–50 percent patients with endometriosis suffer from infertility. The multiple factors involved in producing infertility [1]

Dyspareunia (20–40%)

The dyspareunia is usually deep. It may be due to stretching of the structures of the pouch of Douglas or direct contact tenderness. As such, it is mostly found in endometriosis of the rectovaginal septum or pouch of Douglas and with fixed retroverted uterus.

Chronic Pelvic Pain

The pain varies from pelvic discomfort, lower abdominal pain or backache. The cause may be multifactorial. These include—(i) Inflammation in the peritoneal implants and release of PGF, and also due to adhesions and ovarian cysts. (ii) Action of inflammatory cytokines released by the macrophages. (iii) Invasion of nerves or involvement of bladder and bowel. The pain aggravates during period.

Abdominal Pain

There may be variable degrees of abdominal pain

around the periods. Sometimes, the pain may be acute due to rupture of chocolate cyst.[1]

Other Symptoms

The symptoms are related to the organ involved.

• Urinary—frequency, dysuria, back pain or even

haematuria

• Sigmoid colon and rectum—painful defecation (dyschezia), diarrhea, constipation, rectal bleeding or even melena
• Chronic fatigue, perimenstrual symptoms (bowel, bladder)
• Hemoptysis (rarely), catamenial chest pain
• Surgical scars—cyclical pain and bleeding

Abdominal Examination:

Abdominal palpation may not reveal any abnormality. A mass may be felt in the lower abdomen arising from the pelvis— enlarged chocolate cyst or tubo-ovarian mass due to endometriotic adhesions. The mass is tender with restricted mobility.

Pelvic Examination

Bimanual examination may not reveal any pathology. The expected positive findings are—pelvic tenderness, nodules in the pouch of Douglas, nodular feel of the uterosacral ligaments, fixed retroverted uterus or unilateral or bilateral adnexal mass of varying sizes Speculum examination may reveal bluish spots in the posterior fornix. Rectal or rectovaginal examination is often helpful to confirm the findings.[1]

Clinical diagnosis

It is by the classic symptoms of progressively increasing secondary dysmenorrhea, dyspareunia and infertility. This corroborate by the pelvic findings of nodules in the pouch of Douglas, nodular feel of the uterosacral ligaments, fixed retroverted uterus and unilateral or bilateral adnexal mass. However, physical examination has poor sensitivity and specificity. Many patients have no abnormal findings on examination.

Serum marker CA 125—

A moderate elevation of serum CA 125 notice in patients with severe endometriosis. It is not specific for endometriosis, as it significantly raise in epithelial ovarian carcinoma. However, it is helpful to assess the therapeutic response and in follow up of cases and to detect any recurrence after therapy. Monocyte Chemotactic Protein (MCP-1) level is increased in the peritoneal fluid of women with endometriosis.

 Imaging

• Ultrasonography is not much helpful to the diagnosis. TVS can detect ovarian endometriomas.
• Transvaginal (TVS) and Endorectal ultrasound are Found better for rectosigmoid endometriosis.
• Magnetic Resonance Imaging (MRI) Is a diagnostic tool. There is a characteristic hyperintensity on T1 weighted images and a hypo intensity on T2 Weighted images.
• CT better compare to ultrasonography in the diagnosis. MRI Is useful for deep infiltrating endometriosis. Colonoscopy, recto sigmoidoscopy and cystoscopy done when respective organs are involved.[1]

Laparoscopy is the gold standard. Confirmation done by double puncture laparoscopy or by laparotomy.

 Other benefits are:

• Confirmation of the lesion with site, size and extent.
• Biopsy is take at the same time.
• Staging is do.
• Extent of adhesions is record.

Opportunity to do laparoscopic surgery if needed. The classic lesion of pelvic endometriosis describe as ‘powder burns’ or ‘match stick’ spots on the peritoneum of the pouch of Douglas. Findings may record on video or DVD (RCOG2006) Microscopically Some of these lesions contain endometrial glands, stroma and hemosiderin-laden macrophages. [1]

Biopsy confirmation of excised lesion is ideal but negative histology does not exclude it. None of the imaging techniques including ultrasound, can diagnose specifically the peritoneal endometriosis. Empiric medical treatment usually not recommend except for pain relief and to reduce menstrual flow.[1]

Endometriosis needs to treat as it is a progressive disease (30–60%).

• Preventive
• Curative

Preventive:

The following guidelines may prescribe to prevent or minimize endometriosis:

• To avoid tubal patency test immediately after curettage or around the time of menstruation
• Forcible pelvic examination should not done during or shortly after menstruation.
• Married women with family history of endometriosis encourage not to delay the first conception but to complete the family.[1]

Curative:

The objectives are i.e.:

• To abolish or minimize the symptoms—pelvic pain and dyspareunia to improve the fertility
• approaching menopause
• To prevent recurrence.

But it is difficult to achieve the objectives because of obscure aetiology and unpredictable life history. The results of treatment are difficult to evaluate because of lack of uniform staging or grading. The following facts are to be borne in mind.

• Asymptomatic in good number of cases.
• Subjective symptoms are not proportionate to objective signs.
• Frequent association with infertility.
• Remission during pregnancy and menopause. Prerequisites prior to therapy are accurate diagnosis with the help of laparoscopy along with staging and pictorial documentation.[1]

Treatment options for Pelvic Endometriosis:

Expectant treatment

Endometriosis is a progressive disease in about 30–60 percent of women. It is not possible to predict in which woman it will progress. Some form of treatment often need regardless of the clinical profile and to arrest the progress of the disease. However, in women with minimal to mild endometriosis role of any treatment is controversial. Cumulative pregnancy rate is similar when expectant treatment compare with conservative surgery. Case selection is important.

Protocols for Expectant Management

Observation with administration of non-steroidal anti-inflammatory drugs or prostaglandin synthetase inhibiting drugs use to relieve pain. Ibuprofen 800–1200 mg or mefenamic acid 150–600 mg a day is quite effective. The married women encourage to have conception. Pregnancy usually cures the condition. This is due to absence of shedding and decidual changes in the ectopic endometrium causing its necrosis and absorption.[1]

Hormonal treatment

The aim of the hormonal treatment is to induce atrophy of the endometriotic implants. It should consider suppressive rather than curative because of high recurrence rate. The mechanism of endometrial atrophy is either by producing ‘pseudopregnancy’ (combined oral pills) or by ‘pseudo menopause’ (Danazol) or by ‘medical oophorectomy’ (GnRH agonists). The hormonal use is gratifying in superficial peritoneal implants and endometriomas of less than 1 cm. The drugs used combine estrogenic and progestogen (oral pill), progestogens, danazol and GnRH analogues. All the drugs use continuously to produce amenorrhea and as such individualization of the dose require.

Combined oestrogen and progestogen

The low dose contraceptive pills may prescribe either in a cyclic or continuous fashion with advantages in young patients with mild disease who want to defer pregnancy. It causes endometrial Decidualization and atrophy. Pills may induce amenorrhea. It relieves dysmenorrhea. Anastrozole an aromatase inhibitor is found to reduce the growth and pain of endometriosis.[1]

Progestogens:

It causes decidualization of endometrium and atrophy. High doses may suppress ovulation and induce amenorrhea.

Oral route commonly use. Injectable preparations as depot form should withheld in patients wishing to conceive. Ovulation may remain suspended for several months following withdrawal of the therapy. The side effects are well tolerated. The Drug is comparatively cheaper than danazol. Progesterone Antagonists (Mifepristone 50–100 mg/day) has also been found effective.

Levonorgestrel-releasing-IUCD when used, found to reduce dysmenorrhea, pelvic pain, dyspareunia and menorrhagia significantly. It is especially useful for rectovaginal endometriosis.[1]

Danazol

Danazol therapy is to start from the day 5 of the menstrual cycle. The dose (600–800 mg daily) is variable and depends upon the extent of the lesions but should be adequate enough to produce amenorrhea. The patient should use barrier methods of contraception to avoid virilization of a female fetus in accidental pregnancy. Resolution of endometriotic lesions has seen in about 80% of cases but the recurrence rate is high (40%). The side effects are at times intense and intolerable to the extent of discontinuation of the therapy. A few often persist even after the therapy. The drug is costlier than progestogen. Gestrinone has got the same mechanism of action like that of danazol. The side effects are less than danazol. Administration is simple, twice a week.[1]

GnRh analogues

When used continuously act as medical oophorectomy, a state of hypoestrinism and amenorrhea. The goal to maintain a reduce level of serum oestrogen (30–45 pg/mL) so that growth of endometriosis suppress. The side effects are more tolerable than danazol. The drugs have got limited availability and costliest of all the drugs used. Long-term therapy (more than 6 months) should avoid.

Results:

The efficacy of the hormone therapy judge by relief of symptoms, reduction of the volume of the lesions as revealed by second look laparoscopy, improvement of fertility and prevention of recurrence. For Quick relief of symptoms and reduction of the volume of the lesion, GnRH Analogues are the best. Progestogens take some Time to achieve these objectives. Danazol place midway between the two. Taking every aspect together (pain relief, pregnancy rates, recurrence rates, costs and side effects), no single medical treatment is superior to others. Following medical suppression or other conservative surgery, residual endometriotic lesions may regenerate once the ovarian function re-establish. Overall recurrence rate is about 40 percent after 5 years.[1]

Surgical Management

Indications

• Endometriosis with severe symptoms unresponsive to hormone therapy.
• Severe and deeply infiltrating endometriosis to correct the distortion of pelvic anatomy.
• Endometriomas of more than 1 cm. [1]

Surgery may conservative or definitive.

Conservative Surgery:

Conservative surgery plan to destroy the endometriotic lesions in an attempt to improve the symptoms (pain, subfertility) and at the same time to preserve the reproductive function.

Laparoscopy

It commonly done to destroy endometriotic lesions by excision or ablation by electro-diatherapy or by laser vaporization. Conservative surgical treatment in minimal to mild endometriosis (ablation plus adhesiolysis) improves the fertility outcome. Laparoscopi-cutero sacral nerve ablation (LUNA) is done when pain is very severe. The advantage of laser is to cut the tissues precisely with least chance of damage to the underlying vital structures. Great deal of technical expertise is essential to avoid injury to the ureters. Surgical treatment improves fertility and symptoms in women with moderate and severe endometriosis.[1]

Homeopathic treatment base on individualization in which a doctor selects a medicine according to your/ patients constitution rather than matching only symptoms similarity, so before taking any homoeopathic medicine you have to firstly consult a homoeopathic physician for your concern problem’s, there are so many remedies are useful for this condition but some few therapeutic indications of homeopathic remedies in the cases of Endometriosis are as below.

Caulophyllum. [Caul]

The dysmenorrhea of Caulophyllum is essentially spasmodic in character; the pains are bearing down in character. It produces a continued spasm of the uterus simulating first stage of labor; the flow is mostly normal in quantity. The spasmodic intermittent pains which call for Caulophyllum are in the groins, a useful remedy in these spasmodic cases if given between the periods. to various part of the body.

Magnesia muriatic is also a remedy which may be studied in uterine spasm. Gelsemium is similar in many respects to Caulophyllum. It is very useful remedy in neuralgic and congestive dysmenorrhea when there is such bearing down. The pains are spasmodic and labor-like, with passages of large quantities of pale urine. It is one of the best given low in hot water. It will surely relieve the pains at the start.

Belladonna. [Bell]

The congestive forms of dysmenorrhea would call for Belladonna. There is pain preceding the flow and a sensation of heaviness as if everything would protrude from the vulva, relieved by sitting up straight. The pains come on suddenly and cease suddenly; the flow is offensive and clotted. The dysmenorrhea is intensely painful, the vagina is hot and dry and the pains are cutting through the pelvis in a horizontal direction, not around the body, as in Platinum and Sepia.

Veratrum viride is use with benefit in congestive dysmenorrhea, in plethoric women, accompany with strangury and preceded by intense cerebral congestion, also spasmodic dysmenorrhea at or near the climacteric. These are conditions in which the old school knows only Opium, yet these remedies are far superior to that drug, often curing permanently while Opium is only palliative.[2]

Viburnum opulus. [Vib]

This remedy produces a sudden pain in the region of the uterus before menstruation and much backache during menses. In neuralgic and spasmodic dysmenorrhea, it has achieved considerable reputation. Dr. Hale considers it specific in this form of painful menstruation. Its chief indications seem to be in the character of the pains, which are spasmodic. Spasmodic dysuria in hysterical subjects also calls for Viburnum.

Its keynotes, therefore, are bearing down, aching in sacral and pubic region, excruciating, cramp, colicky pains in hypogastrium, much nervousness, and occasional shooting pains in the ovaries. Like Sepia, Viburnum has pains going around the pelvis and also the empty, gone feeling in the stomach; but the bearing down is more violent, culminating in an intense uterine cramp. More indicated by clinical experience than by its pathogenesis.[2]

Xanthoxylum. [Xanth]

This remedy has about only one use in homoeopathic medicine, and that is in dysmenorrhea and uterine pains. It is useful where the pains are agonizing, burning, extending down thighs along the crural nerves with a feeling as if the limbs is paralyze, the menstruation is usually profuse and with it agonizing bearing down pains; chiefly left sided are the pains of Xanthoxylum, though it also affects the right ovary.

It corresponds closely to the neuralgic form of dysmenorrhea. Hale says that the neuralgic element must predominate to have the remedy efficacious. Some further symptoms may be headache over the left eye the day before the menses, and it seems to correspond to women of spare habits and of a delicate, nervous temperament.[2]

 Magnesia Phosphorica. [Mag-p]

Perhaps no remedy has achieved a greater clinical reputation in dysmenorrhea than has Magnesia Phosphorica. The pains calling for it are neuralgic and crampy preceding the flow, and the great indication for the use of this remedy is the relief from warmth and the aggravation from motion. In neuralgia of the uterus Magnesia Phosphorica vies with Cimicifuga. Uterine engorgements with the characteristic crampy pains will indicate the remedy. It has also been used successfully in membranous dysmenorrhea. We have very few remedies for this affection.

Borax is one, but it is often unsuccessful, there seems to be no very special characteristic for it, unless it be the fear of downward motion which might exist in some cases. Hale mentions Viburnum, Guaiacum and Ustilago, besides Borax, for membranous dysmenorrhea. Their indications are chiefly empirical. Colocynth, a useful remedy in dysmenorrhea, may be compared with Magnesia Phosphorica. The symptoms of Colocynth are severe left-sided ovarian pains, causing patient to double up; pains extend from umbilicus to genitals.[2]

Pulsatilla. [Puls]

Dysmenorrhea calls for Pulsatilla when the menses are dark in color and delayed; the flow will be fitful and the more severe the pains are the chillier the patient will get. The pains gripe and double the patient up. It is perhaps more useful when give between the periods, and in congestive dysmenorrhea, from wetting of the feet, it is compared with Aconite, but in Aconite the discharge is bright red instead of dark.

Chamomilla and Cocculus are two remedies which run along side by side with Pulsatilla in dysmenorrhea, and all need careful individualization. Chamomilla has also a dark flow, but it has such characteristic mental symptoms of crossness and incivility that it cannot be mistaken. It will relieve many cases (12X). Cocculus also has dark flow. It has a pain as if sharp stones were rubbing against each other in the abdomen from accumulation of flatus; the pains are worse at night, awaken the the patient and make her irritable. Menses come too early, sometimes nausea is an accompaniment. It also is said to be more efficacious given between the periods. The mental condition of Pulsatilla, if present, will always indicate the remedy. Further, if the pains shift about the indications of Pulsatilla are still stronger.[2]

Cocculus. [Cocc]

A most useful remedy in dysmenorrhea and scanty, irregular menstruation. Uterine cramps. Profuse discharge of clotted blood and severe headache accompanied by nausea; a heaving up and down of the stomach as in seasickness. It suits cases on the borderland between the neuralgic and congestive types of dysmenorrhea. Uterine cramps with suppressed irregular menstruation and a sero-purulent bloody discharge were favorite indications of Dr. Conrad Wesselhoeft. Gelsemium IX has also proved useful in the spasmodic form. Ignatia has dysmenorrhea with menstrual colic or bearing-down in the hypogastric region, hysterical labor-like pains relieved by pressure.[2]

To fight inflammation and pain caused by endometriosis, it’s best to consume a nutrient-dense, well-balanced diet that’s primarily plant-based and full of vitamins and minerals. Add these to your diet:

• fibrous foods, such as fruits, vegetables, legumes, and whole grains
• iron-rich foods, such as dark leafy greens, broccoli, beans, fortified grains, nuts, and seeds
• foods rich in essential fatty acids, such as salmon, sardines, herring, trout, walnuts, chia, and flax seeds
• antioxidant-rich foods found in colorful fruits and vegetables, such as oranges, berries, dark chocolate, spinach, and beets

Make sure you pay attention to how your body acts when you eat certain foods. Keeping a journal of the foods you eat and any symptoms or triggers you have may be helpful.

Consider meeting with a registered dietitian. They can help you plan meals that work best with you and endometriosis, as there’s no one-size-fits-all approach.[3]

Exercise:

Exercise may help with the management of endometriosis, too. This is because exercise can reduce estrogen levels and release “feel-good” hormones.

In addition to conventional methods of treatment, alternative treatments may be very helpful for women with endometriosis. For example, relaxation techniques may be beneficial. These can include:

• Meditation
• Yoga
• Acupuncture
• Massage [3]

What is Endometriosis?

Presence of functioning endometrium (glands and stroma) in sites other than uterine mucosa is called endometriosis.

Homeopathic Medicines used by Homeopathic Doctors in treatment of Endometriosis?

• Cimicifuga
• Caulophyllum
• Belladonna
• Viburnum opulus
• Xanthoxylum
• Magnesia
• Phosphorica
• Pulsatilla
• Cocculus

What causes Endometriosis?

• Retrograde Menstruation
• Coelomic metaplasia
• Direct implantation
• Lymphatic theory
• Genetic and immunological factors
• Environment theory

What are the symptoms of Endometriosis?

• Dysmenorrhea
• Abnormal menstruation
• Infertility
• Dyspareunia
• Chronic Pelvic Pain
• Abdominal Pain
• Dysuria
• Haematuria