The endometrium and its abnormalities

Question 1

Describe the menstrual cycle.

Answer 1

• At the end of one cycle, oestrogen and progesterone are at their lowest (in a natural cycle).
• Low levels of sex steroids mean there is no negative feedback, so the next cycle can begin.
• Hypothalamus releases GnRH in a pulsatile manner, which results in the release of gonadotrophins. Predominantly FSH produced in the first half of the cycle; stimulates follicle growth.
• Typically have one dominant follicle (dominant follicle selection occurs; presumably has more receptive FSH receptors)
• Granulosa cells of follicle produce oestrogen for endometrial proliferation. First half of the cycle is oestrogen dominated (almost no progesterone production) = unopposed oestrogen. Endometrium starts to proliferate again.
• Oestrogen negatively feeds back to switch off FSH; prevents more follicles from developing. Granulosa cells of the dominant follicle still produce oestrogen, so the endometrium will proliferate more.
• LH surge then causes ovulation. This is triggered by consistently high oestrogen levels for 48h. Negative feedback becomes positive. Changes the hypothalamic pulsation from fast + short to slow + long. This is probably caused by inhibin and activin; oestrogen is just the surrogate measure.
• Luteal phase is always 14 days; the other one is variable. Ovulation always occurs 14 days before menstruation.
• Egg ovulates and oestrogen levels decrease quickly. Remaining CL is yellow because of the cholesterol (main purpose is steroid production). Oestrogen is secreted again, as well as progesterone (pro-gestational = to get pregnant). Progesterone is the main steroid. It is unopposed oestrogen in the first half, but oestrogen and progesterone in the second half.
• An oestrogen-primed endometrium, which has proliferated, will now turn into a secretory endometrium (for pregnancy).
• Spiral arteries become tortuous. Lots of inflammatory infiltrate! Glands get bigger (more glandular), secrete mucus. Implant around day 5 after ovulation (around day 19 to 20 when the endometrium is getting to its thickest).
• The endometrium up to this point is maintained by oestrogen and progesterone. After this point, in the absence of pregnancy, there is a drop in steroid levels that triggers menstruation. To keep the endometrium, this must be stopped. If pregnant, menstruation does not occur; hCG will be produced (one amino acid different to LH; FSH, LH and hCG are all one amino acid apart). Binds to LH receptors on the CL. Saves the CL, so oestrogen and progesterone levels continue to increase (need both to preserve endometrium).
• At the beginning of the cycle, the endometrium is shed down to the basal level (functional parts removed) if pregnancy has not been achieved in previous cycle. The drop in steroid hormones causes the endometrial shed. In the absence of pregnancy, the CL undergoes programmed cell death (becomes corpus albicans = little, white body with no fat anymore and oestrogen levels fall quickly). This inevitable CL death, causes a rapid drop in steroid levels, triggering the events of menstruation. If pregnant, hCG will be produced (one amino acid different to LH). Binds to LH receptors on the CL. The CL is saved and continues producing oestrogen and progesterone, so levels stay high and there is a secretory endometrium.

Question 2

What are the four layers of the endometrium?

Answer 2

• The functional part is the compactum and spongiosum. Tend to have just compactum in the proliferative phase and get spongiosum in the secretory phase.
• Basal layer is the anchor underpinning it all (remains after menstruation).
• The endometrium is an epithelium and then immediately, there is the myometrium which is muscle. Just under the basal layer, there is a thin layer (seen with electron microscopy) called the junctional zone. It has partial epithelial properties, like the endothelium, and partial myometrial (muscular) properties. Two purposes = anchoring and regulation of the vessels that come through it.

Question 3

How does menstruation occur?

Answer 3

1) Initiated by withdrawal of E and P
2) Local mediators PG’s, PAF
3) Spiral artery vasoconstriction
4) Ischaemia and tissue damage
5) Spiral artery relaxation
6) Shedding of functional endometrium

• Initiated by the rapid drop in oestrogen and progesterone
• Most steroids direct cellular events (rather than having major direct effects)
• To get rid of the endometrium (down to the basal layer), the only biological way to do this naturally is to completely de-vascularise it. Can’t get rid of the vessels, but can change them. Key event is terminal branches of the uterine arteries (known as spiral arteries) becoming ischaemic and shedding.
• This drop in oestrogen and progesterone leads to a big change in inflammatory markers. The major player is prostaglandins.
  PG = prostaglandin
  PAF = platelet aggregating factor
• PAF is another inflammatory mediator. It makes platelets aggregate and it is related to coagulation.
• Another key note is that the overall effect of the release of PGs is on the smooth muscle in the spiral arteries to cause vasoconstriction. It causes intense vasoconstriction to the point where it completely occludes the vessels. The area that it is supplying becomes ischaemic and the spiral arteries fall apart (without affecting the vessels below the ischaemic level).
• Women bleed blood and the functional endometrium is released as little bits of tissue as well.
• Women can often predict their periods due to cramps, nausea, back ache; prostaglandins have lots of effect in the body. Also, ischaemic pain hurts. It is very common to have some degree of pain (usually manageable).

Question 4

How is menstruation controlled?

Answer 4

• Oestrogen and progesterone control everything
• PGs are a major contributor in the menstrual cycle and pregnancy
• There are four classes of PGs. (functionally, there are two). E and I class cause smooth muscle relaxation (vasodilatation) and stop the platelets from working.
  PG F2a and thromboxane (Tx) have the opposite effect. They cause vasoconstriction and make the platelets clump (stop bleeding). During the vasoconstriction part, F2a and Tx are predominant.
• During the secretory phase, there is an inflammatory infiltrate in the endometrium. All inflammatory cells come in to control implantation. In the absence of pregnancy, lots of interleukins will be produced (by lymphocytes for example). They have effects on platelets, blood vessels and the inflammatory cascade too
• TNF is another inflammatory mediator (classically produced by cancer). It is also a normal inflammatory mediator; TNF is proinflammatory and PAF is pro-coagulation (to stop bleeding)
• Most tissues in the body that turn over get remodelled, e.g. the endometrium every 28 days. Matrix metalloproteases are responsible for getting tissue integrity and modelling etc. Once activated, they start breaking down collagen and things that hold tissue together. When breaking things down and building it back up, the right balance is necessary.
• Women have to stop themselves bleeding. Once bleeding, the body naturally tries to correct this. The platelets are activated, clump blood vessels and clotting cascade. Clotting is controlled; when fibrin plugs are made by the clotting cascade, the fibrinolytic system opposes it (breaks fibrin clots down). This balance allows the right amount of bleeding.
• The spiral arteries must come through the junctional zone. As they have slightly muscular activity within that junctional zone, it is believed that it is about pinching them off to try and stop the bleeding.
• There is lots going on at the molecular level to cause bleeding, stop it and start the remodelling process.
• For normal menstruation, it is a correct balance and regulation of inflammation, coagulation and fibrinolysis in the endometrium. Most common problem is heavy bleeding.

Question 5

What are the clinical problems associated with menstruation?

Answer 5

1) Anything different from usual pattern
2) Too much bleeding - Menorrhagia
3) Bleeding too often = Polymenorrhoea. Most common problem
4) IMB / PCB; IMB = inter-menstrual bleeding (bleeding between problems), IMB is very common but is never normal. PCB = post-coital bleeding (after sex). Again, very common but never considered normal.
5) Chaotic bleeding = bleeding all over the place. More chaotic and unscheduled bleeding is always more concerning for serious pathologies.

Question 6

Nomenclature and classification of uterine bleeding.

Answer 6

• Abnormal uterine bleeding (AUB) can be divided into acute, intermittent or chronic. Consider frequency, regularity, duration and volume.
• There is either something structural (usually in the uterus) causing the abnormal bleeding or there is something functional (occurring at the molecular level; can’t be seen). If a patient presents with heavy bleeding, think PALM COEIN.
  1) Structural
  (PALM):
• Polyps are very common and can be completely benign
• Adenomyosis = endometrial tissue found in the myometrium (causes heavy periods).
• Leiomyoma = fibroids (benign tumours of smooth muscle in the uterus; most common tumour in the world). Around 50% chance of a Caucasian woman getting a fibroid and around 90% in a black woman. A lot of it is likely to be genetic, but it is very common. There are a certain subset of them that do cause problems, particularly heavy bleeding.
• Malignancy can either include a carcinoma in the cervix or in the endometrium. Malignancy will generally cause chaotic, unscheduled bleeding (easier to notice).
  2) Non-structural (COIEN):
• Clotting disorders. Often found when they first start having periods (may never have had a haemostatic challenge before), e.g. Von Willebrand’s disease.
• Ovulatory dysfunction. Regular periods mean ovulation is occurring like clockwork. Irregular periods mean the patient is either anovulatory or oligo-ovulatory (once in a while). Most common reason is PCOS. If not ovulating, there is no CL and progesterone will not be produced. Oestrogen will keep the endometrium proliferating and eventually cause heavy periods (no progesterone around to modify it).
• Iatrogenic = some drugs, e.g. warfarin (blood thinners) or anti-coagulants, extend the clotting time and then result in heavy bleeds.
• Birth control, particularly with progesterone-containing one causes no bleeding or erratic bleeding.
• Not otherwise classified

Question 7

What are the causes of abnormal vaginal bleeding?

Answer 7

• Pathological causes
  1) Fibroids – submucous. Fibroids are nearly always benign. The nature of them is not worrying, it is all about LOCATION. A lump on the outside of the uterus won’t affect periods. However, if it is poking into the cavity (submucosal fibroids), it will increase the surface area of the cavity massively and cause increased bleeding. Otherwise, intramural fibroids (in the lining of the wall rather than poking out/in) stretch and distort the cavity, making it bigger. Mainly interested in submucosal fibroids that distort and poke into the cavity. They can be inward facing or outward facing in the wall. Highly vascularised; will bleed a lot when menstruating.
  2) Adenomyosis = about 40-50% chance. Endometrial tissue is found in the myometrium. Mostly doesn’t cause a problem. The women who get it usually have children and it is thought to be an artefact of childbirth, e.g. endometrial tissue forced into myometrium during contractions. The problem can be that endometrial tissue in the muscle of the uterus can bleed into the muscle. This causes painful periods and lots of little bits of endometrium in the myometrium tend to extend the cavity and make the volume bigger,
  3) Endometrial pathology. There are three endometrial pathologies = benign adenomas or polyps (benign), hyperplasia (an overgrowth), carcinoma.
  4) Cervical pathology = polyps, carcinoma. Polyps on the cervix often cause funny bleeding. Often bleed when provoked, e.g. during sex.
  Cancer of the cervix is very different pathology to cancer of the endometrium. Cervical cancer is caused by HPV. and usually causes erratic bleeding
  5) Cervical infection - Chlamydia can cause intermenstrual/post-coital bleeding as well.
  6) Pregnancy!!! Pregnancy can cause funny bleeding. Always assume patient is pregnant until proven otherwise.
• DUB = diagnosis of exclusion. When there is funny bleeding and everything else has been ruled out, the patient must have dysfunctional uterine bleeding. Can’t find a cause because it is a molecular problem; everything looks normal, but it is not working properly.

Question 8

What is the importance of intrauterine structural abnormalities?

Answer 8

1) Submucous fibroids (leiomyomas) are associated with a threefold increased risk of abnormal bleeding – invariably menorrhagia. There is no doubt, however, that fibroids that poke into the cavity (submucous fibroids) are associated with a threefold increased risk of abnormal bleeding compared to women without. Most of the time, these fibroids would be causal and not casual findings.
2) Endometrial Polyps (adenomas) are more frequent in women with menstrual disorders. There is also no doubt that polyps are found more commonly in women with menstrual disorders. Less convinced whether they are causal or casual.

• Causal / casual – diagnostic bias?? Is it causing the problem or is it a casual find?

Question 9

What are the steps in approaching a patient presenting with abnormal bleeding?

Answer 9

1) Exclude pregnancy
2) Exclude cervical pathology. - If a patient has funny bleeding, the cervical pathologies can be excluded by examination.
3) Exclude focal benign intracavity pathology (polyps, submucous fibroids). For heavy bleeds, structural problems in the uterus need to be excluded.
4) Consider other endometrial pathology (>
40) . Actually over 45! This is when more serious abnormalities start to become a feature. Have to consider hyperplasia and occasionally cancer. Important to use the least invasive way of finding out.
5) Use the least invasive method to achieve this

Question 10

What are the potential endometrial abnormalities?

Answer 10

1) Dysfunctional uterine bleeding. Default is often DUB, but only after ruling out the others!
2) Endometrial polyps. Benign endometrial adenomas. Focal problem; rest of endometrium is normal.
3) Endometrial hyperplasia (Benign; It is overcrowded, there are too many glands, too busy compared to normal endometrium = hyperplastic. All of the cells look innocent. Can start to change its nature. The endometrium is still busy and some of the the nuclei of the cells look a bit strange = hyperplasia with atypia. This is when it is concerning, because they usually progress to cancer
4) Endometrial hyperplasia with atypia (mild – severe)
5) Endometrial adenocarcinoma. This can progress to adenocarcinoma (cancer). It is a spectrum of disorder.
- Of women presenting with menorrhagia 50- 60% will have NO structural or obvious pathological cause identifiable – it is a problem at the molecular level i.e. cellular dysfunction. Heavy periods are often DUB (cellular dysfunction; molecular problem)
- It is a diagnosis of exclusion

Question 11

What are dysfunctional uterine bleeding (DUB) causes?

Answer 11

1) PGs (E + I vs F2a + Tx). Too much E+I class = vasodilatation and platelets do not work; heavy bleeding. This is a molecular problem with PGs. Has been seen in many endometrial samples from women who report heavy bleeding (these PGs predominate when it should be the latter two in the normal state).
2) Interleukins (IL – 8, 13 +16). Not much can be done about ILs themselves. Again, it is known that again there are usually too many inflammatory mediators around. Seems to be an upgrading in the inflammatory response for unknown reasons.
3) Tissue Necrosis Factor (TNF) + Platelet Aggregating Factor (PAF) - Often too much TNF, which is proinflammatory; they all cascade each other. There is less PAF = less platelet plugging in vessels.
5) Matrix metallo-proteinases - Overexpression of MMPs = pro-breakdown environment = more bleeding
6) Coagulation / fibrinolysis. Clotting cascade produces fibrin. Plasminogen/plasmin is the opposite (fibrinolytic system) and breaks clots down. Women with excessive bleeding can have too much plasminogen action. They start making clots to stop themselves bleeding, but break them all down.
7) Junctional zone - It is known that there is dysfunction for some women with the junctional zone and it is probably to do with regulation of the vessels coming through. It is a real area of interest (also an area or interest for implantation and fertility issues).

• The two main areas implicated in excessive bleeding are prostaglandins and excessive fibrinolysis (breaking down clots)
• It is all about self-reporting; if a women finds her periods acceptable, they won’t be investigated. Usually reported when it is unacceptably heavy and interferes with daily life.

Question 12

What points are taken in a history when a patient presents with abnormal bleeding?

Answer 12

1) LMP – was it normal? Need to find out when the last period was to rule out pregnancy. Pregnancy is always the first consideration.
2) Regular or irregular periods
- Cycle control (ovulation vs anovulation). Regular periods mean ovulation is normal. Otherwise, the patient may be anovulatory or not ovulating often. This is a different problem. Want to quantify bleeding.
- Heavy - clots, flooding?
- with bleeding between (IMB)?
- post coital bleeding (PCB) IMB/PCB is very important; tends to point to the cervix.
- Pain
3) Medication, smoker, smear, operations
4) Contraception = hormonal vs non-hormonal. All progesterone-only methods cause erratic bleeding. Important to know whether it is a contraceptive issue or an ongoing problem,
e.g. a patient using condoms and nothing hormonal, then what is seen with their cycle is really the case. The combined pill has brilliant cycle control, but can cause breakthrough bleeding or bleeding in between. Progesterone-only pill causes erratic bleeding.
Mirena coil is progesterone as well (erratic bleeding). Copper coil can cause really heavy bleeding. It is a foreign body sitting in the endometrium, so the body attacks it. Results in sterile endometritis. It is an inflammatory response that results in heavy bleeding. May also stop using other forms of contraception, e.g. the pill, so light periods return to normal (already feels heavier), but the endometritis (inflammatory response to it) can cause heavier periods. The implant, like all progesterone-only methods, causes erratic bleeding.
5) BMI - Low BMI (<17), particularly in anorexia nervosa cases (with a BMI as low as 12), often causes amenorrhoea. When in a starvation state, the body is not fit to reproduce and switches off non-essential functions. Leptin is found in abundance in fat tissue (these patients don’t have much) and it is important in the initiation and maintenance of menstruation. High BMI (obese) often get very heavy bleeding. Lots of cholesterol = lots of steroids. Start converting androgens to oestrogen in the fat tissue peripherally. Hyperestrogen proliferates the endometrium. BMI has increased in the country in the last 20 years (in parallel to the increase in incidence of uterine cancer). This is oestrogen-driven. Following menopause, the ovaries have switched off and oestrogen can only be made in the fat.
6) Abdomen = Distension, scars, pain and especially masses
7) Cervic = polyps, suspect lesions. With erratic bleeding, the cervix is always examined (important for cervical cancer).
8) Bimanual = Uterine size, adnexal masses, pain

Question 13

What is a transvaginal sonography (TVS) used for?

Answer 13

1) Can assess the relationship of fibroids to the cavity. Can see whether it is causal or casual.
2) Has a high detection rate for polyps
3) Assess function – anovulatory cycles. Know what the state of the uterus and ovary should be depending on when the last period was.
4) Can reliably assess structures outside the uterus (tubal and ovarian pathology). Can also find cysts on ovaries, swollen tubes etc. which are important reproductively. Incidental findings but important nonetheless.

• Well accepted by patients. Not very comfortable but patients remain covered and tolerate it well; yields informative results about the pelvis (probe is immediately onto the structures, e.g. on the uterus and ovaries are close). Going through the abdomen does not produce as good an image.
• Relatively cheap with few complications
• Most important and informative test conducted

Question 14

What information is provided by TVS?

Answer 14

• Periovulatory endometrium is hard to hide pathology in – or immediately post menstrual to assess ET
• The thickness of the endometrium is measured. Depends on when the scan is being taken and there is still huge variation between individuals (even on the same day of the cycle). The upper limit of endometrial thickness is not known.
• Cut-off values for ET are arbitrary in premenopausal women - @ 6 mm post menstrual or 12 mm anytime in cycle
• 4 mm maximum thickness is for postmenopausal women (not women who are having periods) who should not be having anything occurring in the endometrium at all. It is thought to be ~12 mm, but thicker endometria have been seen without pathologies.
• Have to be careful in young women; a cut-off level can’t just be used.
• Ultrasound is ideal for focal pathology but not good for predicting endometrial pathology – a biopsy is still needed in many cases. Polyps are usually quite obvious. More global problems, like hyperplasia, usually require a biopsy to be sent to the lab for confirmation.

Question 15

What is hydrosonography?

Answer 15

• When looking at the uterus in a sagittal section, the front and back walls of the endometrium on top of each other can be seen as a double layer. Water can be squirted in to separate the layer.
• Hydrosonography (squirting water in to lift layers apart for a better visual) is being carried out less.

Question 16

When is a hysteroscopy used?

Answer 16

• Looking into the uterus with a scope through the cervix
• If TVS abnormal = If those ultrasound images showed a polyp or fibroid, it would be likely that they are causing the problem. Can then look in the uterus for two reasons; to confirm the diagnosis and to look into removing them.
• Non-response to medical therapy = When a patient goes to the GP with heavy bleeding, the GP is likely to perform an examination and provide medication. If this does not work, the diagnosis has to be reconsidered and can look in the uterus.
• Multiple risk factors for endometrial
  pathology = Concerned about women with hyperplasia and/or cancer. These are harmful pathologies and it is important to look into the uterus to rule them out.

Question 17

What is a hysteroscopy?

Answer 17

• This is the procedure. Scope is introduced through the vagina and into the cervix.
• Bubbles in the uterus portray the saline released through the scope to lift apart the layers for a better visual.

Question 18

What are the risk factors for significant endometrial abnormality?

Answer 18

• Obesity is probably the single biggest risk factor driving an abnormal endometrium. Excess cholesterol = high oestrogen levels. There is increased proliferation of the endometrium. The more proliferation that occurs, the more likely errors are. This is why abnormalities start to develop.
• Nulliparity = not having had children. Having children means spending a few years amenorrhoeic. Constant cycles allow an increased chance of errors occurring. Also, starting periods early and finishing late = higher exposure to oestrogen within a lifetime. Recently, this has actually been proven to be less important (small risk).
• Early menarche / late menopause – length
  of E2 exposure – weak facto
• Hypertension/diabetes
• Anovulation e.g. PCOS. Can be oligomennhorric or amennorohoeiac. No ovulation = no progesterone. This is similar to being overweight (they are often the same people as the phenotype is often being overweight). The insulin resistance can develop into diabetes.
• Genetics - FH breast / endometrial / colonic
  cancer – Lynch syndrome (HNPCC). In terms of cancers of the uterus (endometrium), about 5-10% are genetically determined (most of it is being overweight and related problems). Lynch syndrome (hereditary non-polyposis colorectal cancer) have mismatch repair gene problems (error in DNA repair mechanisms). It is a genetic disease of autosomal dominant inheritance, leading to generations of colorectal and uterine cancer. Therefore, some people can have a genetic predisposition. These women can take their uteri out as a preventative measure. They get certain types of cancers (tends to be endometrial and colonic, but can get other types). Most of it is sporadic (mainly related to BMI).

Question 19

What are the different types of endometrial hyperplasia?

Answer 19

1) Simple = too thick (thick endometrium causes heavy bleeding) , too many glands (glandular to stromal ratio is very high under the microscope), present with heavy bleeding/bleeding between periods/post-menopausal bleeding. Begins with simple hyperplasia where there is too much going on. Starts to get atypical.
2) Atypical = The cells start to de-differentiate and look abnormal. Not yet cancerous but it is heading there.
3) Carcinoma = Eventually, it will turn into a carcinoma. Since it is a glandular carcinoma, it will become an adenocarcinoma. Most of it will resemble endometrial tissue. It is called endometrioid adenocarcinoma (there are different types, but this is the most common one). It is driven by unopposed oestrogen.

Question 20

What are the causes of unopposed oestrogen?

Answer 20

1) Obesity – peripheral conversion of
androgen to oestrogen (aromatase). BMI most vital factor. The more adipose tissue, the more
conversion.
2) Chronic anovulation, e.g. PCOS. Unopposed oestrogen for a different reason, but the same problem. Follicular ovarian oestrogen production
continues. Progesterone only produced after ovulation. Unopposed oestrogen. Continual stimulation causes overgrowth. Over years leads to hyperplasia and
sometimes cancer.

Question 21

What treatments are available for polyps and fibroids?

Answer 21

1) Polyps
- Surgery TCRP = For focal problems, such as polyps and fibroids, surgery can be conducted to take them out.
- When a polyp is found, e.g. in the hysteroscopy images, a transcervical resection of the polyp (TCRP) is conducted. Can go through the cervix (transcervical) to see the polyp and zap it out.
2) Fibroids
- Medical Mirena IUS or Kyleena = If the fibroids are small and not too problematic, they can be managed medically. The best treatment is Mirena (releases levonorgestrel, which is a progestogen, locally into the endometrium). High, local levels of progesterone counteracts oestrogenic action and causes atrophy (thins out the endometrium). Mirena is good because it is a local, high dose; very little is absorbed into the bloodstream and the side effects from the progesterone are very low. Kyleena is a new coil of the same drug (levonorgestrel); lasts for four years (rather than five), but is smaller so easier to put in.
- Surgery TCRF/Myomectomy = If the fibroids are going to be removed, there are two options; can either go transcervical again (through the cervix) or open up the uterus (myomectomy)
- Hysterectomy = Can take the uterus out (hysterectomy as the last resort). There are a number ways of doing this. Depends on the size of the fibroids, previous history of surgery etc. By taking the uterus out, it won’t ever be a problem again. However, some people may want their uterus, e.g. if they are young/still want to have children.
• total/subtotal abdominal
• vagina

Question 22

How are polyps removed?

Answer 22

• Visualise the posterior wall using a hysteroscope.
• Loop that has been pushed through is powered by high-frequency electrical energy to cut through the fibroid (resection).
• Enter from below (transcervical, not through the abdomen); very neat and safe way of removing polyps and small fibroids in the cavity, can keep slicing to produce smaller pieces again.

Question 23

What is a hysterectomy?

Answer 23

• Removal of the uterus

- A hysterectomy is an option for fibroids rather than hyperplasia.

Question 24

What are the considerations when treating DUB?

Answer 24

• Does she need or want treatment? Some patients decide they can cope with the periods after ruling out serious pathologies.
• Does she need contraception/desire
  pregnancy? There are two routes to go down when treating heavy periods = hormonal and non-hormonal. If the patient is trying to get pregnant, they can’t use anything hormonal (it is all contraceptive). If the patient needs contraception, they can be treated and provided with contraception in one. To manipulate the problem using drugs, the diagnosis has to be specific.
• How much is the problem affecting her
  quality of life? The heavy bleeding, in particular, is usually very inconvenient. Excessive bleeding can cause anaemia. The body can compensate for blood loss by producing more red cells. However, the body needs iron to make red cells and excessive bleeding every month means the body uses up the stores in the liver. The patient will eventually become iron-deficient and can’t make more red cells. Blood count will then start to drop. Normal Hb levels are ~130 g/L. If pregnant, it drops by ~10-15. A patient who has been compensating for this blood loss for a prolonged period of time collapses and presents in the hospital with Hb of ~34 g/L and air hunger (couldn’t breathe). She can’t maintain oxygen saturation as there were not enough red cells going around her body and ended up needing a transfusion.

Question 25

What are the options for treating DUB?

Answer 25

1) Nothing (if they don’t want treatment)
2) Medical = The problems are caused by abnormal PGs and fibrinolysis, so this is what is treated!

• Non Hormonal (what is the dysfunction????)
  • Tranexamic acid - anti fibrinolytics 40-50%
  reduction in blood loss. Best treatment; stops plasminogen from working. As there is too much plasminogen action, it uses an anti-fibrinolytic mechanism to stop fibrinolysis. Have to time it properly, using it the first few heavy bleed days. Very safe. Clot properly and do not bleed as much (instead of breaking down clots too quickly and bleeding). Can cut the bleeding down by up to 50%. Corrects excessive fibrin breakdown in
  endometrium (affects plasminogen action)
  • Mefanamic acid 30% reduction in blood loss. Mefanamic acid is an NSAID. It takes out cyclooxygenase, which makes PGs in the final conversion pathways. It is an anti-PG. The way this particular non-steroidal anti-inflammatory works is by reducing E+ I (the excess PGs that affect the ratio). In terms of the biochemistry, it takes out the vasodilatory ones that stop the platelets from working in order to let the other PGs take control (restores the ration). NSAID – corrects PG imbalance to allow normal
  vasoconstriction and platelet aggregation. Good for pain also! Since it is a non-steroidal anti-inflammatory!
• Hormonal
  • Mirena IUS – 90% reduction blood loss. About 1 in 3 women do not bleed at all. Regardless of what is happening in the endometrium, Mirena just switches it off which can resolve many problems! 30% amenorrheic. Local high dose progestagen - thin endometrium (Anti-proliferative). Kyleena new 4 year option
  • COCP – 20 - 30% reduction in blood loss. Removes cyclical events – thin endometrium. Administering high does oestrogen and progesterone together, without allowing proliferation to begin with (proliferation occurs when there is unopposed oestrogen at the beginning of the cycle (granulosa cells produce oestrogen)), the net effect is atrophy. Therefore, the endometrium is very thin. Switches the cycle off and cuts down the amount of bleeding. Periods get lighter and usually less painful.
  • Progestagens less beneficial for volume loss. Oral progestogens can be used = medroxyprogesterone or norethisterone (synthetic progesterone). Use to control cycle length in anovulatory DUB. They are good for short-term switching everything off. Can use a high dose to switch the cycle off by negative feedback. The downside of them is the side effects of using a high dose. Progesterone is quite close to cortisol and aldosterone in the steroid pathway. Causes a significant amount of mineralocorticoid effects, e.g. fluid retention, vasodilatation (related to headaches). Mirena is good because it is a local, high dose; very little is absorbed into the bloodstream and the side effects from the progesterone are very low.

3) Surgery (for failed medical treatment). For surgery, there are a couple of options.
- Endometrial resection/ ablation = Once the patient no longer wants to reproduce, destroying the endometrium is a smaller surgery than removing the uterus. A probe can be inserted into the uterus (under anaesthetic) and energy can be applied to the endometrial cavity to destroy it. This works very well.
- Hysterectomy -vaginal/abdominal
- Remove ovaries

Question 26

What needs to be considered when treating patients?

Answer 26

1) How old is patient (< or >45) = Increased likelihood of a pathology with age
2) Is the cycle regular?
3) Is there erratic bleeding? (Inter-menstrual/post-coital/chaotic). The more erratic the bleeding is, the more concerning it is.
4) Do you need to investigate the endometrium?
5) If so, how?
6) Treatment?

Question 27

Case 1:

• 41 year old – heavy periods for 9 months
• Bleeds for 9 days every 28 reg (K= 9/28)
• Affecting ability to go to work
• NO IMB or PCB
• Smear 2 years ago – normal
• Contraception – condoms
• No other relevant medical or family history

Answer 27

• No reason to be worried (not likely to be cancer, hyperplasia etc.)
• Relatively young woman with no funny bleeding; regular cycle means she is probably ovulating (volume control problem rather than a cycle control problem)
• Heavy periods on scheduled
• No hormonal influences used/taken
• Is she likely to have a significant
  endometrial abnormality? Probably not
• Any other likely diagnoses? Likely a DUB - can only say this after ruling everything else out
• Investigations?

Results:
- TVS – normal – no polyps or fibroids
- Diagnosis = DUB, ovulatory (a molecular problem). There is nothing else going on; a simple scan shows everything looks normal structurally. This is a problem of bleeding volume control (not the cycle)
- Treatment – volume control. Simple to treat a dysfunctional endometrium, e.g. using medication
• Tranexamic acid
• Mefanamic acid
• Mirena IU (Switch it off). Depends on what she wants to do/her reproductive issues at this point.
- Don’t need to do anything else for her. Just observe how she responds.
- Not too concerning; it is just heavy periods, ovulatory (happens every single month), scheduled bleeding.

Question 28

Case 2:

• 43 year old
• Heavy periods K = 7-8 / 35 – 65days
• No IMB / PCB
• Contraception- condoms
• Smear 18/12 ago - normal
• No other relevant medical or family history

Answer 28

• Not ovulating very often (oligomenorrhea)
• Bleeds normally
• No IMB/PCB is good. When she comes on, she bleeds heavily.
• No hormonal influences
• Is she likely to have a significant endometrial abnormality? More likely than case 1 (still not concerning though) as she is not ovulating, so there is unopposed oestrogen.
  She will have a different stimulus to the woman in case 1 who has a regular cycle

Results:
- TVS – normal – no polyps or fibroids
- Endometrial biopsy – proliferative endometrium, no atypia or hyperplasia seen. As there is a slightly higher risk of a problem, an endometrial biopsy is carried out. The proliferation seen is expected due to the oestrogen exposure (and little progesterone likely to be around).
- Diagnosis = Anovulatory DUB
- Treatment; there are two problems here = volume control and cycle control
• Tranexamic acid
• Mefanamic acid
• Mirena IU
• COCP; If she is trying to get pregnant, she can only be offered bleeding (volume) control. Her bleeding can otherwise be taken out of the equation (controlled monthly by the pill or use Mirena to switch her endometrium off).
- Underlying cause is not concerning. This is just an anovulatory dysfunctional uterine bleeding at the moment (while case 1 was ovulatory).

Question 29

Case 3:

• 45 year old
• IMB for last 6 months
• K = 5 / 29 regular
• Contraception condoms
• Smear 1 year ago – normal
• No other medical history of note

Answer 29

• More worried; little bit older, - IMB (unscheduled/sporadic bleeding)
• However, cycle is regular
• Is she likely to have a significant endometrial abnormality? Yes; old (45+) with erratic bleeding = more likely than the previous cases
• Any other likely diagnoses?
• Investigations?

Results:

• TVS (ultrasound) = Fibroid is an incidental finding. It is not close to the cavity. Since she is 45, the chances of a fibroid are quire high (~50%)
• There is a white blob in the middle of the endometrial lining. This is an endometrial polyp.
• As fibroids are muscular, they appear dark. Polyps are endometrial so they appear light.
• Likely to explain the unusual bleeding (these can bleed)
• Diagnosis = endometrial polyp.
• Investigations? Hysteroscopy. Can chop it up to remove the problem

Question 30

Case 4:
- 51 year old 
- Heavy bleeding most days last 3 months
- Cycles used to be irregular (every 2-6 
months)
- Gynae history of PCOS
- Nulliparous
- Contraception - condoms
- Medical – obesity/NIDDM/ High BP

Answer 30

• Older
• Constant bleeding
• Lots of risk factors for serious endometrial pathology = very concerning
• Still menstruating (not menopausal yet), but has lots of risk factors for either hyperplasia or cancer. She may not have it, but she is behaving like it.
• Is she likely to have a significant endometrial abnormality? Yes
• Any other likely diagnoses?
• Investigations?

Results:

• TVS (Ultrasound) – thickened endometrium – no discrete polyp seen
• Ultrasound shows bright and thick endometrium; a discrete polyp can’t be seen.
• Need to take a biopsy
• Endometrial biopsy = endometrial adenocarcinoma poking down and invading into the muscle. It could have been hyperplasia, but it is actually more than that. When a patient has this type of history and abnormal endometrium, it is important to keep looking until a diagnosis is reached (for all the reasons discussed). Unlikely for the results to come back normal (expected to be hyperplasia or cancer which would then have to be treated).

Question 31

Summarise endometrial abnormalities.

Answer 31

• Most menorrhagia (heavy periods) is DUB and treatments
  reflect the dysfunction
• Exclude focal pathology – needs focal removal, i.e. polyps or fibroids
• Beware erratic bleeding – pathology much
  more likely. Abnormal bleeding/IMB/post-coital bleeding is always more concerning for more serious pathologies, e.g. hyperplasia and cancer.
• TVS and biopsy +/- hysteroscopy diagnosis
  in nearly all. Abnormal bleeding/IMB/post-coital bleeding is always more concerning for more serious pathologies, e.g. hyperplasia and cancer.
• Exam questions set are usually framed in a clinical context, e.g. discuss treatments of DUB and why they work. These abnormalities cause real clinical problems. What is going on molecularly and being more focal.