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Andrew M. Kaunitz, MD, from the Department of Obstetrics and Gynecology at the University of Florida, Jacksonville, explains how to diagnose and treat various patterns of abnormal uterine bleeding.
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Ed Livingston: Abnormal uterine bleeding is very common, affecting up to one third of all women. The diagnosis can be confusing unless it is approached in an organized way stratified by how the bleeding relates to a woman’s normal menstrual cycle. Treatments vary significantly based on the cause. For many causes of abnormal uterine bleeding, hormone therapy is both safe and very effective. There are many misconceptions about all this, so we asked Dr. Andrew Kaunitz, an expert on this topic to discuss how to diagnose and treat abnormal uterine bleeding.
EL: Dr. Andrew Kaunitz published a review on abnormal uterine bleeding in the June 4, 2019 issue of JAMA. Lets meet him.
AK: My name is Andrew Kaunitz, Professor and Associate Chairman in the Department of Obstetrics and Gynecology, University of Florida, College of Medicine, in Jacksonville.
EL: You have written an article for JAMA about uterine bleeding, and I just want to walk through the table, which I think is the best way to cover the topic. And that table is divided into two major categories. Cyclical, and non-cyclical bleeding. Could you define what those two entities are?
AK: So in referring to abnormal uterine bleeding, that is cyclical, here we are referring to ovulatory women, where bleeding is approximately monthly, or can be considered predictable. Heavy menstrual bleeding is ovulatory or predictable bleeding, but bleeding this is excess. For instance, more than 8 days in duration, or heavy enough to interfere with a woman's quality of life.
In contrast with cyclical AUB, or heavy menstrual bleeding, is the category, AUB-O, or bleeding associated with ovulatory dysfunction. And this would be unpredictable bleeding. The term oligomenorrhea has been used in the past. But AUB-O often associated with the common syndrome polycystic ovarian syndrome, or PCOS, is unpredictable. Bleeding may be infrequent, for instance, three to six episodes of bleeding a year. It could be continuous. But either way, this unpredictable pattern of bleeding can be referred to as AUB-O, or bleeding which is associated with ovulatory dysfunction.
EL: Let's start with cyclical bleeding. What are the causes of that?
AK: Okay, so the two most common causes of heavy menstrual bleeding, or HMB, would be structural problems involving the uterus itself. One common, well-recognized entity would be uterine fibroids, or leiomyomata. These are benign tumors of the myometrium which can cause heavy cyclical bleeding or HMB. Another less well-recognized but, in fact common entity that can also cause HMB is uterine adenomyosis. This is when there is growth of the endometrial tissue into the myometrium, resulting not only in heavy bleeding or prolonged bleeding, but in some women excess cramping or dysmenorrhea, or even continuous pelvic discomfort coming from the uterus.
EL: How do you make the diagnosis of those entities, fibroids and adenomyosis?
AK: So, a bimanual exam, which might suggest an enlarged, lobular uterus, certainly would make clinicians think that fibroids may be present. Fibroids are more common in women of African ethnicity, or if there is a family history of uterine fibroids, for instance, in a sister or mother. Women may not be aware that their first degree relatives specifically had uterine fibroids, but may report a history of heavy bleeding, or a hysterectomy performed for heavy bleeding. And often that will be a tip-off that uterine fibroids may be present. Adenomyosis may also cause the uterus to be enlarged. But often in a symmetric fashion. But adenomyosis is a diagnosis that we are less likely to make clinically and more likely to make with imaging, specifically vaginal ultrasound. And in fact, vaginal ultrasound should be considered the first line, or go to imaging procedure for all women with abnormal uterine bleeding. Fibroids have a very distinctive appearance with vaginal ultrasound.
So the diagnosis of uterine adenomyosis, although adenomyosis is, in fact, a prevalent condition, maybe more subtle or challenging than uterine fibroids. Fibroids have a very distinctive appearance with vaginal ultrasound, and as I mentioned, can cause characteristic findings on bimanual pelvic examination. And adenomyosis may be associated with a symmetrically enlarged uterus, but the clinical findings of adenomyosis may not be very clear-cut or evident. But a well interpreted vaginal ultrasound can suggest adenomyosis in many cases.
EL: Once you've made a diagnosis of say, fibroids, how do you treat that?
AK: Okay, well because the presenting symptom with fibroids is often heavy menstrual bleeding, it's important to make sure that anemia or iron deficiency is not present with blood work including a CBC and a ferritin level. And endometrial biopsy, sometimes called endometrial sampling may be appropriate, particularly in women over age 45 years or women who are obese. Where the prevalence of endometrial hyperplasia is higher. Once endometrial hyperplasia has been ruled out, and the patient has been evaluated for possible anemia, then we need to focus on treatment, and although many, many clinicians, many women for that matter, may jump to thoughts about surgery, particularly hysterectomy, in the setting of fibroids, a woman who is not interested in future pregnancies, in fact, medical management is often effective in addressing the heavy menstrual bleeding associated with both fibroids and adenomyosis.
If women are appropriate candidates for oral contraceptives, specifically if they don't have contraindications, such as being smokers, or hypertensive, over age 35, then a combination estrogen/progestin oral contraceptives can be very effective. If contraindications to estrogen that, for instance, those I guess mentioned are present, using oral high-dose continuous pregestational medications, such as norethindrone acetate, 5 mg tablets, can be very useful. And although over the short run may result in erratic or even continuous light bleeding, if women continue to use oral high dose progestins long-term, let's say more than two or three months, many of those women will experience either a reduction in bleeding or even become amenorrhoeic, which is particularly welcome in women who have been experiencing heavy menstrual bleeding, and perhaps anemia with that.
EL: Let's move on to the non-cyclic, unpredictable bleeding, and starting off with ovulatory dysfunction, which is, I guess, usually caused by polycystic disease. So could you tell us about how that presents, how you make that diagnosis, and how you treat it?
AK: Okay, so polycystic ovarian syndrome, or PCOS, is a most common endocrine disorder of young women. And often presents with erratic bleeding, sometimes infrequent bleeding, for instance, three to six menstrual cycles annually, and may often be associated with so-called hyperandrogenism, where the ovaries in women with PCOS produce excess amounts of testosterone resulting in adult acne, and hirsutism. For instance, bothersome facial hair, or excess hair in other parts of the body as well.
EL: And is there a definitive way to establish that diagnosis? Is it by ultrasound, or how do you know they have PCOS?
AK: So women, but clinicians also can be very frustrated. I'll back up and say women suffering symptoms of PCOS, including abnormal uterine bleeding or the hyperandrogenic signs I just mentioned, can be very frustrated because it's often years before the diagnosis of PCOS is correctly made. And in fact, there is no specific test for PCOS. However, the history as I mentioned can be characteristic, and in many cases, vaginal ultrasound can be useful because ovarian imaging indicates, for instance, 12 or more follicles per image of the ovary, or ovaries that are excess size in terms of dimensions or volume of the ovaries. So ultrasound can be useful. But the history is particularly helpful in making the diagnosis of PCOS.
A woman who used to have cyclical normal menses, perhaps she's gained weight, which can be a risk factor for developing PCOS, and now her menses have become unpredictable, infrequent, and accompanied by hyperandrogenic signs. This is highly characteristic of, and I would say diagnostic of PCOS. And then once the diagnosis is made, treatment will relate to women's fertility interests. If women with PCOS or other ovulatory disorders want to conceive, then infertility specific treatment becomes appropriate. However, if women with ovulatory disorders, including PCOS, are simply interested in addressing their symptoms, their bleeding, and hyperandrogenic symptoms, then hormonal management ends up being very effective and should be considered first line treatment.
Again, if there are no contraindications, oral contraceptives represent first line therapy for women with PCOS. And if contraindications are present, progestational only treatment, whether that be oral high-dose progestins, used continuously, or even the progestin-IUD, can be very helpful. Not necessarily helping with hyperandrogenic symptoms, but progestational therapy, whether it be oral or intrauterine can be very effective in reducing or eliminating bleeding, and also preventing the occurrence of endometrial hyperplasia, or even endometrial cancer, which can occur even in very young women with PCOS, or prolonged anovulation.
EL: One thing I missed is your discussion about-- for women who desire to conceive. How is that treated, when they have PCOS? Or how do you manage?
AK: So women with ovulatory disorders who wish to conceive need specific ovulation induction therapy after they've been appropriately evaluated. Classically the medication clomiphene sulfate has been used, and is effective. More recently an off-label: Aromatase inhibitors are used effectively to induce ovulation and address infertility in women with PCOS.
EL: Okay, I got that. Another category of-- or another cause of non-cyclical bleeding is iatrogenic, from contraceptive medications. Could you tell us what medications do that, and how you figure that out?
AK: So I think most commonly women using hormonal or intrauterine contraceptives can experience erratic, unpredictable, and bothersome bleeding. For instance, women starting injectable contraception, with depo-metroxyprogesterone acetate, long term, after 6 or 12 months of injections, and the injections are every three months in injectable contraceptive users, women will become amenorrhoeic. Bleeding will cease. However, over the short-term, when women start injectable contraception, irregular or even continuous light bleeding is common and it's important to be aware that this should resolve over time, if women hang in there with their injections. Likewise, women beginning IUDs, whether it be the non-hormonal copper IUD, or progestin IUDs, initially may experience erratic, unpredictable, and bothersome bleeding.
With the copper IUD, long-term cyclical ovulatory bleeding pattern will result, although with the copper IUD, menses may be somewhat longer, or somewhat more intense than prior to IUD use. In contrast, women initiating use of the progestin IUD may experience initial erratic light bleeding, but long-term, there will be a major or even profound reduction in menstrual blood loss. For instance, after six months of progestin IUD use, there can be an 80% or greater reduction in menstrual blood loss, so that long-term users of progestin IUDs will often become either amenorrhoeic, or just have occasional light bleeding or spotting episodes.
EL: Another category, category of causes for non-cyclical bleeding is intermenstrual, which can be caused by polyps, fibroids, or infections. Could you tell us how those present how they're diagnosed and treated?
AK: Certainly. So women who have an ovulatory, cyclical or predictable bleeding pattern, but also-- or also note intermenstrual bleeding, need evaluation specifically for conditions like cervicitis, which can cause post-coital bleeding, cervical polyps, which likewise can cause post-coital bleeding. It is also important to remember to make sure that women presenting with any type of abnormal uterine bleeding are up to date with their cervical cancer screening, which may include cervical cytology or Pap smears, as well as HPV testing. If there is no lower genital tract cause, such as cervical disease, that is identified with exam, specifically vaginal speculum examination, imaging becomes important, and vaginal ultrasound without fluid infusion, or so-called unenhanced vaginal ultrasound may suggest the presence of a fibroid inside the cavity and these are often called sub-mucosal fibroids, or may suggest the presence of an endometrial polyp.
However, a more definitive test for intercavitary fibroids, or endometrial polyps, would be fluid infusion sonogram, sometimes called saline infusion sonogram, or sonohistogram. And this is a brief, minimally invasive office procedure that uses saline to highlight the presence of inter-cavitary pathology. If a sub-mucosal fibroid or an endometrial polyp is identified in this setting, then hysteroscopic removal will address the problem very effectively.
EL: And endometritis, how does that present?
AK: So endometritis may present as heavy menstrual bleeding or irregular uterine bleeding, uterine tenderness may be present, but in the setting of chronic endometritis, as opposed to post-partum endometritis, which is associated with fever and uterine tenderness, in the GYN setting, a woman who has not recently been pregnant, chronic endometritis may not be associated with fever or uterine tenderness. And there, the diagnosis is best made with endometrial biopsy which will reveal definitive endometritis with histopathology, and then treatment, in that setting, with a broad-spectrum oral antibiotic, for instance, doxycycline, or perhaps doxycycline combined with metronidazole, to enhance anaerobic coverage, will be curative.
EL: How long do they need those antibiotics for in that setting.
AK: I would say a minimum of 10 to 14 days and some experts might say yes, even longer oral antibiotic therapy.
EL: Okay. The final category of causes for non-cyclical or unpredictable bleeding is post-coital. So could you explain that to us?
AK: So post-coital bleeding can overlap with intermenstrual bleeding, and it is important that clinicians ask explicit questions to try to sort this out. But when post-coital bleeding is present, as I mentioned earlier, it's important to first evaluate the lower genital tract with the vaginal speculum examination, make sure that cervical disease is not present. And if it's not, endometrial biopsy may be useful. Vaginal ultrasound may be useful, and looking for uterine structural problems, whether it be fibroids, or a specifically intercavitary pathology, endometrial polyps, or intercavitary fibroids, so-called submucosal fibroids, is useful and if identified, surgically treating intercavitary pathology, which involves hysteroscopic ambulatory surgery, is often curative.
And I'd like to also mention a less common iatrogenic cause of AUB. We talked about how common irregular bleeding, caused by hormonal and intrauterine contraceptives is...but clinicians should also recognize that women taking anticoagulants may experience heavy menstrual bleeding, and benefit from hormonal management. For instance, a progestin IUD. And one important scenario to mention would be a woman who has experienced a deep venous thrombosis, and now is on oral anticoagulant therapy, because she has a history of DVT, she's not a candidate for estrogen-containing contraceptives, like conventional estrogen/progestin. Oral contraceptives, or the patch contraceptive, or the vaginal ring contraceptive.
Because all of these increase the risk of thrombosis, and are considered contraindicated with a history of DVT. However, use of progestin-only contraceptives is safe and effective in this setting. And for instance, placement of a progestin IUD, whether or not the woman needs contraception, can be very helpful in effectively reducing or eliminate heavy menstrual bleeding in women taking anticoagulation. One other less common iatrogenic cause of AUB-O or irregular bleeding associated with anovulation, would involve women who are taking medications which elevate prolactin levels. Where the pituitary ends up secreting more prolactin than normal, and two common examples of such medications are medications used in psychiatric practice.
For instance, haloperidol, and risperidone. These medications are classic causes of hyperprolactinemia. Checking your prolactin level can be useful, and then assessing whether hormonal management makes sense or not would be an appropriate next step. If women need to continue these medications, then early hormonal management is going to be appropriate and indicated for reducing or eliminating this irregular bleeding, caused by hyperprolactinemia.
EL: Those are really great points. One other thing I wanted to cover here in terms of post-coital bleeding, one of the diagnoses is cervicitis. How do you make that diagnosis?
AK: So, cervicitis is a diagnosis made clinically during vaginal speculum exam. The cervix may appear erythematous, and friable. For instance, touching the cervix with a Q-Tip or a Pap smear spatula may cause excessive bleeding, and then when cervicitis is more severe, so-called mucopurulent changes, where you see actually muco-pus, and inflammatory appearing exudate coming from the cervix. Helps make that diagnosis that much more clear. Women with cervicitis need to be checked for STDs, specifically chlamydia, gonorrhea, and trichomonas, treated accordingly. But many women with cervicitis may end up screening negative for these sexually transmitted pathogens, but will still benefit from oral antibiotic therapy. And again, doxycycline is used for at least 10 days, and is very useful to treat cervicitis.
EL: Is there anything that you can think of that we didn't cover?
AK: Just wanted to emphasize that although clearly there is a role for surgery, whether it be endometrial ablation, minimally invasive procedure, or hysterectomy, which is, of course, definitive treatment for any type of abnormal uterine bleeding. Many, not all, but many women can be well managed with medical management alone, including oral hormone therapy and intrauterine, progestin-- excuse me, including hormonal therapy, whether that be oral therapy or intrauterine/progestin therapy in the form of a progestin-releasing IUD. One other procedure that is relevant for women with heavy menstrual bleeding caused by uterine fibroids, but in women who would either prefer to avoid surgery or who may have co-morbidities, which make them high risk for perioperative complications, the procedure performed by interventional radiologists, known as uterine artery embolization, can be very useful in women with heavy menstrual bleeding associated with fibroids, when medical management has not been helpful, but it may be appropriate to avoid definitive hysterectomy. That would be a patient who might benefit from consultation with an interventional radiologist, and consideration of the minimally invasive procedure, uterine artery embolization.
EL: So, I'm a general surgeon, and I was Chief of Surgery for a long time, and I came to the journal seven years ago full-time, but before I came here, that procedure was becoming very popular. And it was somewhat controversial, I think, when it was introduced. It's uterine artery embolization. So-called non-operative hysterectomy. Has that taken off? It seems like it never really got to be-- never got too popular?
AK: It's a great question. So I am referring fewer patients with fibroids and heavy menstrual bleeding refractory to medical management to my interventional radiology colleagues. This is despite the fact that uterine artery embolization remains very useful, and if anything is much better studied in the radiologists who specialize in interventional procedures, I think, have improved their knowledge of, and skills regarding, uterine artery embolization. I think one important reason why less women may be going in the direction of interventional radiology to treat their fibroids with heavy bleeding is the minimally invasive approach to hysterectomy, which has become so widespread, or really not represent standard of care in gynecological surgery practice.
With laparoscopic/robotic routes of hysterectomy, many women, including those with high BMI, morbid obesity, or co-morbidities, who 10 years ago, 15 years ago, may not have been considered safe surgical candidates, now may be safe surgical candidates. And so that has, perhaps, swung the pendulum a little bit away from uterine artery embolization. However, UA continues to represent a very useful treatment modality in the setting of a woman with a bulky fibroid uterus, failed medical management, and either wishes to avoid surgery or, due to co-morbidities should avoid surgery. IN fact, just this week, I referred such a patient to an interventional radiologist here in Jacksonville. And I'm hopeful that this will be the treatment that she needs, and that will cure her problem.
EL: I want to clarify one point on laparoscopic hysterectomy. There was a tremendous amount of discussion, continues to be a tremendous amount of discussion about the risk of women having fibrosarcoma, that get disseminated during the procedure, that phenomenon was related to morcellation and I'm assuming that morcellation is pretty much out of the picture these days? So that when you refer to laparoscopic hysterectomy, I'm assuming you mean doing the procedure, and removing the uterus as a whole specimen, not grinding it up. Is that true?
AK: So the issue of morcellation associated with minimally invasive surgery, you're right, has received a tremendous amount of attention and is certainly controversial. We've learned more about the epidemiology of sarcoma in women with fibroids, and we recognize that this is a rare condition fortunately. And it certainly is more prevalent in menopausal women, or older women with uterine fibroids, as opposed to younger women with fibroids. My expertise is not GYN surgery. It's more in medical management. But my colleagues, who spent a lot of time in the OR, are certainly doing fewer, if any cases of morcellation, and as you implied, are retrieving the uterine specimen intact, often using so-called bags, or other barriers, as opposed to the very prevalent use of morcellation earlier.
EL: Is there still a role for morcellation? I think if you were to ask minimally invasive surgical experts, they would say yes, but that role has diminished, and it would be much more in younger women with fibroids going to the operating room as opposed to older women. I guess the points that I want to make for the public at large, because a lot of non-physicians listen to these podcasts, is that it's not the laparoscopic hysterectomy that was dangerous, it's the morcellation.
EL: So if a woman is referred to a gynecological surgeon to have a lap hysterectomy, they shouldn't be worried about the sarcoma issues, because it would probably be done, with the entire specimen being taken out with it.
AK: I think a woman in that setting should talk about the controversy and the issue of morcellation in women with fibroids, and what is the gynecologist doing to attempt to exclude the presence of sarcoma preoperatively? For instance, endometrial sampling can be useful. Endometrial sampling has a moderate sensitivity in preoperative diagnosis of uterine sarcomas. It's certainly not-- nowhere close to 100% sensitive, but find out what the gynecologic surgeon is planning. I think women in this setting many times will, after talking with their surgeon, will be reassured that the surgeon is well aware of this issue and will be using a modality intraoperatively in which the uterine specimen is removed intact, rather than morcellated.
The other point that I don't know, if this gets discussed much in gynecology, but it certainly was in general surgery when lap colon resection was introduced. The criticisms of that procedure when it first came about was that you do this entirely complicated, and in those days, cumbersome laparoscopic dissection and then remove a colon, and then make an incision to take the colon out. An incision almost big enough to do the operation anyway. So in the early days, we thought, well why are we doing this? What's the benefit if you have to have an incision? But as it turned out, patients did way better with the laparoscopic dissection and that incision than they did from an open procedure. It was remarkable how much better they did.
And then with increasing experience, we see a parallel trend with minimally invasive GYN surgery. Instead of women ending up with a big laparotomy incision, ending instead having minimally invasive hysterectomy and being able to go home either the next day, or in some cases, particularly if there is good support at home, the same day as minimally invasive surgery. It's a major advance. There's less blood loss. There's less pain, and there is much shorter hospital stays. So I think minimally invasive hysterectomy is very much here to stay. And my colleagues in the operating room are getting more and more adept in the advantages of minimally invasive approaches, GYN as well as other surgical fields, I think are continuing to become more and more clear.
EL: Yeah, it's remarkable. Anything else you think we should cover?
AK: I think we've covered a lot of ground, and just, again, to underscore that treating abnormal uterine bleeding doesn't necessarily mean surgery. Surgery continues to play a very important role as we've discussed. But in most cases, initial management, and in many cases, the only management, should be medical as we've detailed here during this podcast, and surgery can be reserved for those patients who may have specific structural anatomic problems that don't respond well to medical management, such as a sub-mucosal fibroid, or endometrial polyp, a large, bulky fibroid uterus, where it's not just bleeding problems, but there is also bulk problems causing abdominal changes, sexual pain, those kinds of problems with an enlarged uterus can't be addressed with medical or hormonal management, and will require surgery. But I guess you want to emphasize that medical management can play a very important role in effectively treating many women with the common symptom of abnormal uterine bleeding.
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A very special thanks to today’s guest, Dr Andrew Kaunitz. And thanks to Lisa Hardin who scheduled him for the JAMA podcast. Today’s episode was produced by Daniel Morrow. Our audio team here at JAMA includes Michelle Kurzynski, Jesse McQuarters and Mike Berkwits, our Deputy editor for electronic media here at JAMA Network. Once again I’m Ed Livingston Deputy Editor for Clinical Reviews and Education for JAMA. Thanks for listening.
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