If they have adenomatous hyperplasia this is a little more severe and I will follow them a little closer. I will re-biopsy them in about three months to make sure we are getting improvement. If they have atypical adenomatous hyperplasia – and nowadays you’ll see this described as cystic hyperplasia with atypia, I think is what many of the pathologists are using now. This can be a very dangerous proposition. Thirty percent will become cancer within 10 years, 20% will already have a focal adenocarcinoma present. I think if you are going to treat with progestins you need to do something to evaluate the endometrium very thoroughly, such as a hysteroscopy or something like that before you fall back on this. You can reverse it with progestins but you have to follow it up very carefully.
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Hormone replacement therapy: a lot of people advocate biopsying them and then adjusting the estrogen/progestin balance as necessary if you are having trouble with spotting or breakthrough bleeding with these patients. For menopausal patients, if they are close to their menopause – within two years of cessation of their menses – I kind of tend to put them on a cyclic program for about a year to a year and a half because they may have some endometrium that is still there and it just hasn’t regressed all the way and if you start on both estrogen/progestin therapy then I feel that you may run into more spotting and breakthrough bleeding and end up doing more of these biopsies. Patients oftentimes don’t like biopsies, especially if I do them because I use about a 4 mm cannula on the end of a 60 cc syringe. I get rid of a lot of polyps and things that way too, but it is uncomfortable. I always fell though that if I don’t get anything when I biopsy them then there’s nothing there worth getting. A lot of people use pipelles which are very comfortable, very easy to use, but I don’t think they give you quite as good a specimen.
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Patients that are just becoming menopausal – say she quit menstruating three to six months about – and you want to know, should you biopsy her before you start her on estrogens. Does she have any endometrial growth? It’s perfectly acceptable for you to give her 10 days of Provera and see if she has a withdrawal bleed. If she doesn’t, then go ahead and start her on estrogen and progestin replacement therapy because she’s got no endometrium of any significance to cause a problem. If they are on hormone replacement therapy and you are having difficulty balancing estrogen/progestin levels, biopsy and see what’s happening. Sometimes you’ll get a proliferative report back which means that you don’t have enough progestin and you just need to bump the progestin up a little bit. If you get an atrophic pattern back then that means that you may need to bump the estrogen up a little bit to prevent them from being too thin and from getting oozing out of the capillaries.
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For patients on Depo-Provera , how long to I let them go without having a menstrual period if they become amenorrheic? Or when they don’t want to take Depo shots any longer, how long will I let them be amenorrheic before I’ll intervene? The thing about Depo-Provera is its effects last for a long time. About 50% of patients will still be anovulatory after their last shot at a six month time frame. Some of them as long as 18 months. You have two choices. The first thing I would is, if the patient wanted to get back to menstruating, I would give her Provera. Do a Provera withdrawal test. If she does not respond to that then she has not developed enough endometrium to start menstruating from. Then you are at the point where you could interfere by giving them estrogen and progestin and then start cycling them on that. My other choice would be, if they are interested in conception, is to give them Clomid to stimulate ovulation, to stimulate the ovaries to working again. I have seen patients go as long as 18 months without menses, without ovulation, after their last Depo-Provera shot. Depo-Provera is a very potent long-lasting drug and if you give it it’s going to be awhile before they get rid of the effects.
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How long will I let a smoking woman take oral contraceptives before I’ll take her off? I’ll let her go to menopause and long as she and I agree on a contract. I will discuss with her her increased risk of cardiovascular disease on the oral contraceptives, I will cut her back to like low estrin or Elise which are 20 mcg pills and I will see them every three to six months if I have any concern about their blood pressure or cardiac status. But I will very carefully follow them along as long as they agree that if they have chest pain, stomach discomfort or heartburn that doesn’t go away – pain in the neck, pain in the back. They will call me and either come to the ER or come to my office for me to see them.
Then on physical examination I inspect the vulva, the vagina, the cervix, any lesions, polyps. Do they have condyloma, any cervicitis, then the uterus for its size, shape, and on examination the adnexa. Also I try and correlate any bleeding they are having, any intermenstrual bleeding. Occasionally I’ll get a patient sent to me for uterine bleeding who’s having hemorrhagic cystitis. So if it’s only when they are emptying their bladder or something, you may think about doing a cath U/A for hemorrhagic cystitis, which can be interpreted as vaginal bleeding. CBC as I mentioned earlier, to evaluate anemia, platelets, possibility for infection. People with chronic PID will have normal differential and normal white count but may continue to have an increased sedimentation rate. Pregnancy test, as I teach my residents and students, Severson’s first rule of obstetrics is every patient is pregnant until proven otherwise. That will keep you out of a lot of trouble, especially with bleeding and spotting. Clotting factors, if they are indicated or if you suspect you may have an undiagnosed blood dyscrasia, and a Pap smear. Don’t forget the Pap smear. If she’s not bleeding, do a Pap smear. Make sure that you get a good one. If she is bleeding, make sure she doesn’t have large visible cervical lesion. If she does, just biopsy it. Just take a biopsy forceps, take a piece out of it, and then use some Monsel solution to tamponade the bleeding.
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Non-invasive tests that we have available are transvaginal ultrasound. We can perform those now. We can also perform sono-hysteroscopy where we infuse a little saline into the endometrial cavity, do a transvaginal ultrasound, and we can actually visibly identify polyps, submucous fibroids and pedunculated fibroids and tumors in the endometrial cavity without having to invade the cervix.
Invasive testing: endometrial biopsy. If you have any question at all, my tendency to do an endometrial biopsy is very great. I have a low tolerance for women that bleed because I’ve seen several 32-year-old patients with endometrial cancer. So if I have somebody that is not responding to treatment, who is young – I say young, I consider that under 35 – then I’ll biopsy them. If they are over 35 I strongly feel that you ought to go ahead and biopsy them before you start any treatment. That will at least give you a starting place and give you a pathologic diagnosis to help you with your case. D&C is really a blind procedure anymore. I favor a hysteroscopy and directed biopsies, which you have to do in the operating room. So a D&C you will only sample about 40% of the endometrium. You will miss polyps, you will miss submucous fibroids, so I think that the status of care in increasing and the standard in the future is going to be that patients will have hysteroscopies combined with either a D&C or a directed biopsy.
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Now, how can we treat the bleeding? We have treatment for ovulatory bleeding that may just require placing the patient on progestins where they just need to either have their progesterone levels boosted a little bit by taking a supplemental progestin and getting kind of a medical D&C performed on a monthly basis. I’ll treat those patients on days 14-23 of their cycle, with 10 mg of Provera a day. Or I’ll offer them oral contraceptives to take and to control their menstrual cycles. These are also the patients you can try on nonsteroidal antiinflammatories if they are for sure ovulatory. That may help by the mechanism of thromboxane production. Anovulatory patients, as I mentioned earlier, if they are not interested in pregnancy and we are not going to use Clomid and attempt to achieve a pregnancy, I offer them progestins either on a monthly basis – if they don’t want to do that – then every three months at a minimum. Oral contraceptives, I feel, are very good in helping to protract the hypothalamic pituitary axis. If we do an endometrial biopsy and we find a hyperplasia, as long as it’s a simple hyperplasia, treating it with progestins, Provera 10 mg a day for 15 days every month for six months and then re-biopsy them, would be my procedure of choice.
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Perimenopausal bleeding: this is usually physiologic and self limited. These menstrual disturbances are usually the rule as I’ve said earlier, but we must evaluate them to rule out cancer. Usually they have ovulatory then anovulatory cycles, or several anovulatory cycles in a row, get a little endometrial hyperplasia or an endometrial polyp, or have other lesions such as submucous fibroids or something like that. So you must evaluate these and rule out cancer. I had a patient earlier this year who was only 47 that was having menstrual irregularities. And we biopsied and biopsied and didn’t get anything and couldn’t control them. She’d been tried on various hormonal therapies prior to coming to see me. We ended up doing a hysterectomy and when we opened the uterine specimen she had 50% myometrial invasion by an endometrial carcinoma. So it does happen in younger people. But it’s unusual.
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Postmenopausal bleeding is never physiologic. Fifteen to twenty percent of them represent cancer. The etiology is unopposed estrogens, or peripheral conversion in fatty tissue to estrone. Sometimes they are given hormone replacement or exogenous estrogen for years at a time without any progestin to counteract it. Or they have a uterine or ovarian tumor. I’ve diagnosed several ovarian cancers by postmenopausal bleeding. The evaluation of the endometrium is mandatory in these patients. You must do something to evaluate them to rule out a cancer. And that’s in the postmenopausal. How do we evaluate them? Of course, our history, physical and laboratory are your beginnings. You can do non-invasive tests and invasive tests. If I have young patients who are having menometrorrhagia and we suspect they are becoming anemic, a CBC is helpful. Oftentimes you may want to do some bleeding studies, because up to 17% of patients in some studies have been shown to have a bleeding diaphysis that was unknown by the physician and unknown by the patient. So you might keep that in the back of your mind that you might want to do a PTT and a PT and a platelet count. I get a history about the number of pads and tampons, or both if they are using both. Some patients are flowing so heavily they are losing work because they are embarrassed to go out of the house. They are wearing tampons and pads and flooding through them in an hourly pattern. So how often are they changed. If the patient can’t remember the numbers, what I start asking them then is, “Okay, are you using pads and tampons?” If they are using both and they can’t remember how many, then I ask them “How many boxes do you use during a menstrual cycle?” They can remember boxes. Then I ask them, “Okay, how many are in the box that you buy?” And you can get a pretty accurate count that way of how many pads and tampons they are using. Ask them whether they are soaked or not, if they are flooding through them are they also flooding onto their clothes, are they passing any clots, how big are the clots – and most of them are passing quarter to half-dollar size clots. How long has this been going on, is this the same as usual for them or have their periods been getting longer, are they getting heavier days of flow, and you’d be surprised at how many patients will tell me, “Oh, I’ve been doing this now for two or three years. And they’ve been putting up with it for that long.
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Their heaviest days … usually most of them will start out with a fairly normal bleed and then all of a sudden it gets real heavy and passes clots and then after a couple of days they will get a little bit better. Then I find out, have we had any previous infections such as things I would suspect for PID or Chlamydia which may cause bleeding and problems. Have they had any treatments recently, are they taking any hormones or have they had any trauma. Then a history of any blood dyscrasias. Up to 17% can be involved. Any medications? Patients don’t think of aspirin and ibuprofen as being medications, or any of the other nonsteroidal antiinflammatories that will cause bleeding problems. In fact, it’s amazing the number of patients that I talk to that don’t think birth control pills are medications. So you have to ask them specifically about that.
Ovarian problems, such as polycystic ovarian cysts syndromes. My treatment for that, I offer the patient a couple of choices. One is to withdraw menses every three months or so with Provera 10 mg for ten days, or put them on birth control pills to protect their hypothalamic pituitary axis and protect their endometrium from over-stimulation.
Renal blastomas, granulosa and thecal cell tumors and hilus cell tumors are difficult or may be very difficult to diagnose, but can cause bleeding. Chronic pelvic inflammatory disease – because of the vasculitis in the endometrium and also in the region of the ovaries – will cause bleeding. Endometriosis can be found almost anywhere and can interfere with the normal function of the endometrium and may cause abnormal bleeding just by having endometrial implants in the vagina. I’ve diagnosed several patients by seeing something that didn’t look normal and just biopsying it. Comes back as endometriosis.
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Then premature menopause, which is menopause that occurs before the age of 45, can cause you to have anovulation and menstrual irregularities. Drugs that will affect your menstrual cycles: just about everything. Morphine, reserpine, phenothiazines, MAO inhibitors, anticholinergics, and then any steroid preparations you give, such as progesterones: Norplant, Depo-Provera are known to create a lot of problems with irregular spotting and bleeding. Some patients are placed on testosterones for libido. Adrenal androgens can be produced. Estrogens can be produced. The patients may be getting exogenous estrogens that you don’t know about. One of the great places that they find them now are in these health food stores in the malls. They can actually get phyto-estrogen’s and buy estrogen-containing products and take them without anybody monitoring this. The west coast, a lot of patients are having menstrual irregularities and problems from exogenous estrogens from eating tofu. So that’s another source. So you have to investigate dietary sources if you suspect that this patient is getting exogenous estrogens or something. And oral contraceptives can create menstrual problems as we all know and have experienced.
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Stress, emotional stress, excessive exercise, things like a change in habits – even as simple as flying from New York to Los Angeles, spending a couple of days in Los Angeles, back to New York – can throw off ovulation and create menstrual irregularities. The morbidly obese patient can produce too much exogenous estrone where the fat tissue is changing hormones into estrone, creates an endometrial hyperplasia and bleeding. We discussed anorexia nervosa and malabsorption syndrome. Not so much nutritional, but let’s talk about exercise for a minute. Patients who excessively exercise burn up their steroid hormones and will have menstrual problems. You might see this in some of the patients on oral contraceptives too. I have one young lady that I treat with oral contraceptives because of her thrombocytopenia, to control her menses. She was doing jut beautifully on her oral contraceptives and then in October called up. Needed an appointment because she was not spotting and bleeding and so forth. So she came in to see me and everything was normal and I was interviewing here – I interview my patients as I’m seeing them – and I said, “Well, are you doing anything different?” She said, “Oh, no. I’m doing all the same stuff.” I said, “Okay, well you’re in school now?” “Oh, yes.” “Well, are you involved in any sports?” “Oh, yes. I’m cross-country running now.” That was enough, just enough, to burn up her steroid hormones enough to give her menstrual irregularities. So in the younger patient they may think that this is completely normal to go out and start doing something as in sports and don’t effect it to affect hormonal therapy or replacement or something like that. So if it will happen to that patients being treated with oral contraceptives are on pharmacologic and not physiologic doses, if she’s a young woman on her own cycling and not on oral contraceptives and starts some strenuous physical program, she may have trouble with bleeding
The reasons many patients have the anovulatory type of bleeding, the endocrine problems we see with thyroid, pituitary. Ovarian problems: they may have polycystic ovaries. Drugs such as many of the psychiatric drugs will create problems, related back to endocrine. Many of the psychiatric drugs will raise the prolactin and cause problems. Stress can cause changes in it. We all know about nutritional problems, especially in the bulimic patients that create menstrual problems such as amenorrhea, total amenorrhea and so forth.
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Thyroid problems we see both in the hyper and hypo thyroid. If the patient has any other symptoms of either, such as hyperthyroid – if she’s one of those patients that can get all her housework done and have time to go shopping and all the rest of that, then I get suspicious. They may be a little hyperthyroid, and if they are not gaining weight slowly over the decades, and you should. Your metabolism changes by about 2% every five years so that the natural history is that we gain about 5 to 10 pounds every decade of life. So if she is not into that group and she is able to get all her housework done and everything else, she may be a little bit on the hyperthyroid side. I’ve also seen several patients who came in because of dysfunctional bleeding that were hypothyroid. Their doctors had put them on thyroid medication, had gotten them balanced, then they found if they self-medicated a little bit – gee, I feel a little bit better and I can do a little bit more. And I had one that had a TSH of 0.3 or something like that. It was hard to convince her to stop self-medicating but we finally got her to do it. Her menstrual periods straightened out, her bleeding problems corrected. Hypothyroid; I look for those patients, especially those that are having trouble with more weight gain than you would expect. Ones that just don’t have the energy to get things done and so forth. Thyroid testing is really easy to do with a TSH and a 3T4. Order discount Clearitol
Adrenal problems, hyperplasia and tumors, are things we see. Patients who have anovulatory cycling, doing laboratory testing for this is very easy. It’s a simple blood test to do and if it’s normal you can pretty well count out the adrenal tumors and so forth. The test is DHEA sulfate. And that’s a simple test to order. If it comes back normal, you don’t have adrenal problems. Hypothalamic pituitary problems; we see failures. The classic is Sheehan’s postpartum necrosis of the pituitary gland. Other ones we see failure in: had a very interesting patient yesterday that was totally amenorrheic since the age of 28 because of a pituitary tumor and had acromegaly because of excessive growth hormone and so forth. She was totally … had a total pituitary failure because of treatment but nobody had ever thought to put her on estrogen replacement therapy. They had essentially made her a postmenopausal patient by destroying her pituitary with surgery and radiation but hadn’t treated her with hormones, and set her up for osteoporosis and heart disease and so forth that are the hallmarks of the postmenopausal patient.
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Neoplasias of the hypothalamic gland; doing serum prolactins is easy. Try and draw them in the morning. That’s when they are going to be at their highest level. Hyperprolactinemia’s are fairly frequent. You need to be careful in treating them with bromocriptine because of seizures, but I’ve only seen one patient in the 15 years I’ve been using bromocriptine that had seizures. Diabetic patients also have trouble with their endocrinologic system and also with their bleeding and their menses. One point I want to put out, which I put out to all medical students, oral contraceptives in the diabetic are extremely good. They are extremely safe. JAMA and all the internal medicine articles that are written show that they have no increase, in diabetic patients, no increase in insulin requirements, not increase in retinopathy, no increase in neuropathy of anything. But then they’ll still tell the patient, “Oh, no, you are diabetic. You shouldn’t be on birth control pills.” There’s nothing worse than having a pregnancy diabetic because they are very difficult to control and take care of. So birth control pills are good in this group for menstrual problems and so forth.
The normal luteal phase, like I say, ovulation occurs. The corpus luteum cyst forms and produces both estrogen and progesterone and maintains the endometrium, makes it secretory, ready for a pregnancy. In discussing it with patients I will often times say, “Well, after you ovulate the endometrium becomes very thick and lush like a garden that has flowered and bloomed” and this is what we need to look for, especially when doing an endometrial biopsy. Now we can look at the phases of life as causing abnormal bleeding problems. They do occur in the pre-pubertal time, the reproductive time is when we see the most of them. There’s a fair amount of problems in the perimenopausal period, and this is because – for those of you who have been in practice since the advent of birth control pills – you’ll remember that during the 60’s, 70’s and early 80’s, we carried patients on birth control pills up until we figured they were in menopause and then we’d switch them over to hormone replacement therapy. Well, this changed out view of the perimenopausal period because their menses during the late 30’s and their 40’s were artificially controlled by the oral contraceptives. And we didn’t see the natural history. Nowadays we have more patients opting for sterilization procedures at a younger age. Then as these patients get into their 30’s, their late 30’s, get into their 40’s we start to see the natural hormonal fluctuations, occasional anovulatory cycles and so forth that then create irregular menstrual cycles, create menorrhagia and create menometrorrhagia, which is the natural history. If you go back and think about the patients in the 50’s and early 60’s that were in their late 30’s and their 40’s, many of them would have three, four or five D&C’s and then a hysterectomy for bleeding problems. And that’s the natural history in the perimenopausal patient. We can control that with oral contraceptives and did for years until somebody came out with the statement that every woman over 35 has got to come off birth control pills. I don’t know who started that rumor but it’s an ugly rumor and it’s untrue. In fact, oral contraceptives in this group of patients are extremely valuable in controlling menstrual cycles, in controlling the precursors of osteoporosis, because women start losing bone mass at the young age of 35. They already start going downhill and the oral contraceptives will prevent the loss of bone mass in that 35-50 year old age group before we put them on hormonal therapy. So I don’t know where it started, as I said, but it’s a dirty vicious rumor that you have to take women off birth control pills at the age of 35. You don’t do them any service. The last group, age-wise or lifestyle-wise, we see are the postmenopausal patients.
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Pre-pubertal causes usually, I think of foreign bodies because little girls and little boys explore themselves. Explore their genitalia. They like to put things …you always hear about them putting things in their nose. Little girls will put things in the vagina and they may have a foreign body. Very difficult to examine little girls, and probably there’s two easy ways to do it. Number one, if she’s a very good patient, you’ll have the mother lie down on the examining table and have the child lay on the mother’s abdomen with her knees up under her, sort of in a knee-chest position, you can sometimes spread the labia and with a light just look up the vagina to see if there’s anything up there. If I can’t get an exam done and the child is actually having bleeding and so forth, then my choice is to take them to the operating room, put them to sleep. You can do a good visual inspection and you can do a vaginoscopy with a cystoscope. It’s very simple, very easy. Sexual abuse is another thing that we think of and we look for signs of. Exogenous estrogen can be a problem. She may be picking up her mother’s birth control pills and having withdrawal menses because she takes a pill and after awhile, after a few pills that her mother didn’t happen to notice were gone, she stopped taking them and has some bleeding. Then of course we always worry about tumors, sarcoma botryoides, dysgerminomas and so forth.
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During the reproductive years: this is the group we see most frequently. Pregnancy and its complications is a frequent cause. Ovulatory problems only occur in maybe up to 25% of the patients. Anovulatory problems are the ones we deal with the majority of times. The patient is having either irregular anovulation or irregular ovulation, or is totally anovulatory. That can be 75% to 90% of the patients you see. And then anatomical problems in the reproductive years are usually fairly few and far between, although we do see a fair number of patients that have fibroids or cervical polyps or something like that, that are creating a problem. During the reproductive years the menarche usually occurs about the age of 12 now. It’s been dropping over the years. Ovulatory dysfunction is usually the problem with menarche and right after menarche. Inadequate endometrial response to estrogens, prolonged follicular phases, these young ladies are usually not ovulatory for the first year and a half to two years of their menses, so I kind of expect that many of these young ladies will have menstrual irregularities during the first year and a half to two years of their menstrual life. Like I say, anovulatory dysfunction is usually due to a failure to achieve ovulation. You have unopposed estrogens, endometrium keeps growing and growing but never matures, and then sloughs. We see extensive proliferation with inadequate stromal support when you do an endometrial biopsy.
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