New Learnings And A Question

[kjd111]

I know this has been discussed on some older threads but i couldn't find the exact one i was looking for, so thought i would start another. My daughter has NMH, with low catecholamines (vs. POTs). She has been sick for almost two years now following a moderately serious concussion. The medications she is on (dexedrine, midodrine, florinef, propranolol and indomethacin) have definitely helped some but she still continues to have a lot of fatigue and mysterious "water retention". What i have been told is that because her body doesn't have enough epinephrine and norepinephrine, her sympathetic tone is low and she is leaking fluid out of her capillaries into her tissues. Not surprisingly, this adds to her problems and she aches and is fatigued and has headaches even more when she is "swollen". For the longest time after her concussion, she didn't get a period. This May, she was put on Femara in an attempt to see if it would bring down some of the swelling in her breasts (tmi) because she retains a ton of fluid there and she found it uncomfortable and embarrassing (she went from a 'b' to a 'd' overnight - literally- 4 months after the concussion). The theory being, that the Femara would kill the estrogen.

And so, her chest did slowly come down over the summer but interestingly, she started to have periods again and has more or less had them regularly since June. I found this baffling. No estrogen ought to equal no period in my mind. Then, i noticed something else. From about day 7 to about day 16 of her cycle, she would be really swollen with fluid (ie. lots of leaky capillaries) and she felt horrible. Around day 18-20, she would get a massive diuresis and stay unswollen for anywhere from 7 to 14 days. This was a new thing. It still swells when she exercises or is hot, etc. but the baseline body weight was almost 10 pounds less during those two weeks - not insubstantial! I asked our endo about this. He said it was the opposite of what you would expect. Most women swell during this time. He didn't know. So this month i took her to our ob/gyn and asked if they would draw hormones for a month so i could see what was going on. They agreed and drew blood on day 5, day 12 and day 19. She was really swollen all the way until day 17 when in 2 hours, it plummeted. The results were interesting. Day 5 had high FSH, high LH, low estrogen and non-existent progesterone. Day 12 had lower levels of FSH and LH, estrogen of 101! and non-existent progesterone. Day 19, 2 days after she deswelled, had low estrogen (less than 10) and progesterone of 26.

I found this really interesting. First, I asked how it was possible to get a normal estrogen rise on Femara. And, if it was normal on Femara, then it must have been right up there big before she was on it. The ob thought perhaps she just was not on a high enough dose of femara. But, clearly, the progesterone seems to help. A lot. Maybe we didn't notice it before because.......she didn't ovulate, so, no progesterone. i did read that some folks on this board seem to do better in the back half of their cycles (and some don't). So, since i do a lot of research for a living, i...............researched. I found some articles mentioning estrogen is a dilator and progesterone a constrictor (and some mentioned the reverse), and i found some that said there is more aldosterone with the progesterone and so one retains more fluid in the back half of the cycle. My daughter also has zero aldosterone (again probably from the concussion), so i wasn't sure this was the mechanism that was helping. Then, I found an interesting article on Medscape that mentions that they found a difference in neuro-transmitters in the body depending on the stage of the menstrual cycle. The early follicular phase they called low GABA, low serotonergic and high sympathetic tones. The mid-cycle was high glutamatergic, low sympathetic and high serotonergic tones. The mid-luteal phase was high GABA, high sympathetic, low serotonergic tone. The late luteal was high sympathetic, low serotonergic and decreasing GABA. The following clip from it was interesting to me (probably because i'm a closet science geek):

"Basic science and clinical data would suggest that the activity of specific neurotransmitter systems varies during different phases of the menstrual cycle (Figure 7). During the mid-cycle (high estrogen, low progesterone), there is likely up-regulation of the serotonergic and glutamatergic systems and down-regulation of the sympathetic nervous system. During the mid-luteal phase (high estrogen/high progesterone), there is up-regulation of GABAergic and sympathetic systems and down-regulation of the serotonergic system. During the late luteal and early follicular phases, there is up-regulation of the sympathetic system and down-regulation of serotonergic and GABAergic systems." (Ovarian Hormones and Migraine Headache: Pathophysiology of Migraine Headache).

So, we have been having discussions with the ob/gyn. She thinks it might be worth trying to put her on a pill that is mostly progesterone to see if we can eradicate some of the really bad reactions she has during the mid-cycle timeframe. she's tossing around progestins vs. progesterone. She said the advantage of progestin, is it will completely kill the estrogen. The advantage of the progesterone, is its closer to what's going on now in her body - which we know has an effect. Since i am not at a point of needing hrt, i've no idea. Anyone been on either and have any thoughts?

Thanks!

Kate

[firewatcher]

Has she had her pituitary checked?

I found this:

The Fertility Effects Of Femara. World News Today, April 14, 2009

Fertility problems pester nearly one in every four women, regardless of age, health issues, and race. To help address this increasing issue, scientists have struggled to find the rootstock of the problem of infertility as well as medical ways to assist women in their desire to have children. The idea of Femara and fertility use is one of the most doggedly debated ideas in medical circles.

Femara and fertility treatments are constantly being revamped and reworked to gain a woman?s chances of becoming pregnant. There are two different instances in which fertility drugs can be useful: one, women who are not able to ovulate on their own can be medically stimulated to dream up and release an egg, and two, women that are already ovulating can be stimulated to have an increased chance of pregnancy by the release of multiple eggs during an ovulation return.

However, this change in hormonal levels because of fertility treatments does not always have the desired effects. For one, some women can have multiple births as the end result of taking medications like Gonal F and Follistim. And the increase in hormones can also be problematic for those women with a predisposition or a information of breast cancer. However, Femara and fertility treatments are not linked with increasing the hormonal levels, which makes the Femara a safer alternative for a larger group of women.

Women with breast cancer find that Femara and fertility concerns are congruent. Because Femara, also known as letrozole, is an aromatase inhibitor, it decreases the hull?s ability to produce the hormone estrogen, vital in the conception and pregnancy process. What Femara can do is work with conventional infertility treatments to regulate the amounts of estrogen that are in the body, allowing the woman to have an increased chance of pregnancy without the forebodings of too much estrogen in the body. Or it can be used by itself and naturally increase one?s chances of becoming pregnant.

Other advantages to Femara and fertility is the irritable metabolism of the chemical in the body, which allows it to work on the short term, rather than remaining in the body and affecting the resulting pregnancy as some super ovulation infertility treatment methods can do. In its methodology, Femara can help fertility by allowing the corpse to produce more of its own estrogen in a natural manner by the stimulation of the pituitary gland, rather than introducing additional estrogen in the treatment itself. When the enzyme in Femara suppresses the output of estrogen, rather than the estrogen receptors, this allows the pituitary gland to be activated.

There are some potential side effects to this reduction of estrogen, however, when using Femara and fertility treatments. Hot flashes, mamma tenderness, and minor headaches have all been reported with the use of Femara. Some studies have also shown that there is a risk of birth defects in those that are compelling Femara when they are already pregnant.

Femara and fertility treatments utilizing aromatase are shown to be significantly more impressive in women who have already failed with the use of traditional treatments: Clomid and Serophene, for example. In scientific studies, patients using Femara were capable to ovulate nine out of twelve months and of these twelve patients, three conceived while on the Femara.

Additional studies have shown that Femara and fertility are unmistakably linked. When patients have used Femara, there was an increase in the thickening of the uterine wall, which allowed for firmer egg implantation once the egg was fertilized. This event seems to allow for fewer miscarriages than the traditional fertility treatments. Treatment with Femara seems to be more effective in younger patients than in older women, however, the rates of good are high for those that have already failed with traditional treatments.

[kjd111]

Her pituitary has been checked and the results have been mixed. She has a small adenoma on the posterior part, but no one has told me its causing any problems. This part of the story belongs under the topic "frustration with doctors" i suppose. When she first fell, i took her right away to the ER. It was a serious fall and she was not lucid for almost an hour. It was very scary. Rather than be concerned with her head, the ER seemed more concerned with why she had passed out - did heart tests. I have no issue with that (and the tests showed no issues), but they just said "oh she might have a little concussion, she'll be fine". 3 days later, it was very clear she was not fine. Took her back and demanded a head CT - no bleeding. "She's fine", they said. But, she wasn't. It took almost 8 weeks for her to be better balance-wise and she had what we now know was diabetes insipidus. Our pediatrician is very nice, but ancient. He couldn't explain why her brain was foggy and she had to pee every hour. And, that's when she started passing out every morning when she got out of bed. It took me about 7 doctors and almost 15 months to find one who discovered that she had some sort of autonomic dysfunction. Her brain didn't clear for almost a year.

They drew FSH, LH and estrogen off and on during that time just to see if the pituitary was functional. She had levels in the mid-range and since she wasn't cycling, no one could tell us if they were good or bad. Her chest actually swelled so badly, that she got stretch marks. Between that and the fluid retention in her mid-section, i thought at one point she might have cushings. Her face was even flushed. We had that very carefully tested by someone who knows cushing's and she didn't have it. But she does have mild GH deficiency and is on a low dose replacement for that - and it does help. Her cortisol levels are low in the morning, average in the afternoon, and apparently do go down at night (tested at 11pm twice and they were under .5, but she doesn't have much ACTH. Her thyroid is average - average TSH, low average FT4 and low FT3. They put her on a really low dose of t3 and it helps a bit. But most of the response i have gotten is "she has pituitary hormones, the cortisol does go up a little in an ACTH stim test (went from 9 to 16) and she doesn't appear to have diabetes insipidus, so her pituitary must be fine". Its frustrating because her pituitary tests are all a little borderline, a little sluggish, but not zero - so apparently no one sees its a problem. In fact, we didn't get taken seriously at all until we got to our current endo, who found the orthostatic hypotension and started testing catecholamines. Hers are low/mid range lying down and didn't move at all upon standing. Then he found out she has zero aldosterone - but mid-range renin. He couldn't explain that and seemed surprised. That was the aha moment. So.....................long answer but for whatever reason, the femara helped a little. But she still produces estrogen. The estrogen seems to make her swell. The progesterone seems to make it quite a bit better. I am concerned about the concept of progestins however. I just don't know much about the difference between those and progesterone.

[firewatcher]

If she has confirmed DI, she has pituitary damage.

Concussion is a KNOWN cause for hypopituitarism and she seems to fit the critera. If that adenoma is swelling and receding it would cause crazy fluctuations in hormones. Did you take her to a pituitray endocrinologist? There can be delayed pituitary damage due to damaged blood flow. Have you asked her if she has any breast discharge? It may not be estrogen causing her breasts to swell, but prolactin.

just a couple thoughts...

[kjd111]

I absolutely appreciate all and any thoughts..............Our endocrinologist is an endo, i have no idea how much pituitary specialty he has though. He's meant to be one of the better ones in Dallas, and he discovered the autonomic dysfunction and orthostatic hypotension, which something like 7 other physicians failed to do. But, in his defense, my daughter had so much testing before we came to him, that he honed in on stuff we hadn't had tested. I think he thought maybe a lot of it had already been ruled out. The DI was confirmed retrospectively by looking at something in her urine counts from that time, but he felt it was past, since she's now retaining too much water. I had asked about too much anti-diuretic hormone but was told that she would have really low sodium which she doesn't have. I would love, love to find someone who really knows the pituitary stuff well. This guy has been great. The only thing that's baffled me is that 50% of his practice is reproductive endocrinology but he didn't have too much opinion on why she deswells for that back half of the cycle. I'm not a doctor, but it seemed clear that for some reason the progesterone was doing something - if in fact it was there. That's why i had it tested and its definitely there. The big question, is what to do with that information - do we just put her on progesterone? If so, what kind.............

[firewatcher]

There is a huge difference in the run of the mill endo and a pituitary endo. Most just deal with thyroid and diabetes, not pituitary issues. I am on HRT for low FsH, LH and Estradiol. I trialled Progesterone and it worsened me and did nothing to regulate my periods. You'll know fairly quickly once she's on it if it would help. Most docs will want you to try it for 5-10 days and stop to see if you get a period. I get grumpy/moody within a day or two. My OB/GYN wanted me on Prometrium to counteract the unopposed estrogen and give me a regular cycle, but it doesn't do that for me. Unfortunately when you deal with endocrine issues, it gets really complicated. Good luck!

[Heiferly]

I'm on Depo Provera, which is progestin I think, but I'm feeling too dense tonight to try to figure out how that might apply to the situation you're describing. :-/ My levels are wonky in different ways, and I haven't had some of mine tested that you have results for. I do "third space" fluids like you describe her doing, but not to the extent that you're describing. I don't know if my fluid retention would cycle with my menstrual cycles because on the Depo Provera I don't have menstrual cycles whatsoever, and I've actually been on the Depo since before I got dysauto (was put on it due to reproductive problems years ago after surgery on one of my ovaries).

If it's any help, if you DO find out that progestin is helpful and you consider Depo, I personally have been very happy with the Depo Provera injections. Not having menstrual cycles to muck up my dysauto has been *blissful* compared to what I hear other women going through with theirs. Also, it doesn't have interactions with other meds like a lot of oral hormones can, and it's a lot more convenient than taking something daily.

[juliegee]

I would think that it's worth giving the progesterone or progestin (either) a try just during the first half of her cycle- the back half sounds OK. Jennifer's onto something about finding a good pituitary endo. Your daughter's issues sound the exact opposite of most women.

For what it's worth, progesterone has worsened my issues. It gives me really, really low BP. You could start with a cream....

Let us know what you decide.

Julie

[kjd111]

So. The update out of the blue today..........they did a 24 hour urine test for cortisol two weeks ago. Results came back today. I think the range is 10-34 and hers was a 3! Now they want to put her on prednisone every other day. Yikes. Not sure about this. Is anyone else out there adrenal insufficient/Addisons? If so, can you share your experience with the steroids? The side effects sound terrible.

[juliegee]

So. The update out of the blue today..........they did a 24 hour urine test for cortisol two weeks ago. Results came back today. I think the range is 10-34 and hers was a 3! Now they want to put her on prednisone every other day. Yikes. Not sure about this. Is anyone else out there adrenal insufficient/Addisons? If so, can you share your experience with the steroids? The side effects sound terrible.

Whoa...that is out of the blue. I've been tested for Addisons repeatedly & my cortisol is always high. We had a member here DXed with Addison's & MCAD, but she hasn't been active in a while. This may be the answer to your daughter's problems. There's some evidence that the lack of cortisol is involved in fluid retention....

Addison's is quite serious with the risk of adrenal crisis. I would have the test repeated & have blood work done as well to confirm before beginning treatment. I think florinef is also used in Addison's. My internist had me on that when he thought I had Addison's and it did help for different reasons. If your daughter really has this, she will have to take many precautions to keep herself safe & healthy. It's unimaginable to me that she's been able to competitively skate with this deficit- she's one tough cookie! Let us know what you learn.

Julie

[sue1234]

A 24-hour urine is really not the "gold" standard for diagnosing Addison's. It is definitely used for diagnosis of Cushings. What they need to do is do a stimulation test. That is the "gold" standard for seeing what her baseline is and then how well she responds. I would push for that.

[kjd111]

"A 24-hour urine is really not the "gold" standard for diagnosing Addison's. It is definitely used for diagnosis of Cushings. What they need to do is do a stimulation test. That is the "gold" standard for seeing what her baseline is and then how well she responds. I would push for that."

Thanks so much everyone for the replies. I did push for the stim test actually and the only reason i didn't argue further was that our endo is very good - he's older but really knows his stuff and was the first (and only) doctor in almost 18 months of looking that even found the orthostatic hypotension. He also knew enough to test catecholamines and all the rest. I argued for about 10 minutes and then didn't want to tick him off. My real fear was that 24 hr urines are usually just too non-specific for Addison's (or so i've read). I was worried her result would be in the range, but low. Like a 7 or 8 or 9. What he told me was folks with Addison's will have 24 hr urines of like a 2 or 3. Well, that's what we ended up getting .....a 3.

My daughter did have a stim test almost 8 months after her concussion. The results were mixed. Her afternoon baseline cortisol was a 9 and she stimmed to a 16. According to the endo at the time, she said "as long as it goes up, she's fine". I always wondered about that since i had read the value should double and at a minimum go over 18 - which, clearly, it didn't do. They also allowed her to walk around the hospital for an hour and eat. Our endo here told me that was "flawed" technique and the stim test was "borderline". The bigger issue in my mind at the time, was that her morning cortisols were low and her afternoon ones were always almost the same value. That combined with the swelling and weight gain that went with the fluid retention, i thought for the longest time she might have cushings - since she had no diurnal variation. I even took her to a cushing's specialist in LA and we did do urinary cortisols, 10 hour cortisols and even 2 serum ones at 11pm at a local hospital (which took some doing). The 11pm ones were less than .5. The 24 hour urinary ones were usually between 10 and 16 with one at 26. But she still had not much variation in serum cortisol during the day and her morning cortisols were like 10's and her ACTH was always a little low too for 8am - like a 9, when the cortisol was an 8. That sort of thing.

When we got to our current endo in March, it took me a while to let go of the possible "cushings" thing. His belief was the afternoon cortisols were not lower than the am because her body was under so much strain from keeping itself upright due to the capillary leakage and OH. She had been on midodrine and florinef for about 6 days when we did our last 24 hour urine. It was a 7. So, i think he was probably right. He did do a serum draw before he ordered the 24 hr urine this time. He wanted to see what it was when she was stressed - she had just skated (sort of) and had a huge exam that day and was really stressed out. It was a 6. I asked him about the stim test and he said its a "sledgehammer" for the adrenals and won't tell him a thing about what is going on pituitary-wise. Sigh. She did start the 5mg of prednisone yesterday and while i don't think it did (or is going to do) much for the fluid leakage, her ability to exercise quite literally doubled. It was astonishing! She hasn't been able to skate for more than 35 or 40 minutes in almost 6 months. It did seem to make her a little more emotional, so i asked if we could drop the dosage. Its making her nervous because we both know about the side effects if you get too much of this thing. Additionally, our ob/gyn wants to put her on progestins since we have now definitively documented that her fluid retention almost vanishes around day 18 or her cycle and comes back up as her period starts. The endo wants to wait. I debated..............and finally decided to start the progestins as she was so swollen this week (week 1 of her cycle) and it makes her so sick. She did deswell some and that was a day before she started the prednisone and i didn't see much difference swelling-wise on the prednisone yesterday. Maybe it takes time.

What i may do, is send her files to another neuroendocrinologist just for a second opinion. Not because i don't trust our doctor, but just for a fresh set of eyes on what is clearly a wickedly complicated case. I actually found one in New York city who will do phone consults if you already have a ton of labs (and he usually orders more), so thought it wouldn't hurt. What i don't understand is .........if her ACTH is starting to fail and that's dropping her cortisol..........how does that happen 18 months to 24 months after her fall? That's quite a delay. And, ...................how do low and non-responsive to standing catecholamines tie in with that. Can failing cortisol cause autonomic dysfunction, complete with low catecholamines and a lot of the other physical problems that go with Pure Autonomic Failure (bowels and eyesight) that she has? or is the autonomic failure causing the cortisol to fail because she's used it all up trying to stay upright? I wish i were a doctor.........

[firewatcher]

Sometimes, pituitary death does not occur immediately. Necrosis can take a while; in some cases up to 30 years. Sheehan's syndrome is slow pituitary necrosis due to lack of bloodflow to the pituitary (most commonly after a severe drop in BP with childbirth.) If she had pituitary damage due to the concussion and a recurrent drop in BP from NMH, she may have ongoing pituitary damage from lack of circulation to her pituitary. If all her hormones are tanking you need to be careful, a crisis could happen very suddenly. Sheehan's is very rare, and most common in India. A US doc probably would not even think of it or consider it. Her neuroendocrinologist should suspect it or something like it given her pituitary damage.

My OB/GYN suspects this for me since my hormones are slowly dwindling after a huge drop in BP after the birth of my son (8 years ago.) I ended up in shock boots with a really annoying nurse stationed at my bedside.

Be vigilant! Don't accept: "It couldn't possibly be that...it's so rare..."

Good luck!

[sue1234]

I agree with Firewatcher--really watch all of it constantly!

With all that you've listed in your last post, it really does "sound" like she is low in cortisol. Her many tests seem on the verge, constantly, of being low. I don't think her stim. test was a "passing" test. From what I read all the time, either double or go above 20(?) or something like that.

I would consult with the NYC neuro. It couldn't hurt!