Tests and challenges in the diagnosis of spontaneous early menopause

The diagnostic criteria for POI, irregular periods or an absence of periods for a period of a few months combined with an FSH, Follicle-stimulating hormone, level which is in the menopausal range. If you find that on one occasion you repeat that test six weeks later. If the FSH is raised twice, at six weekly intervals, it’s very unlikely to be anything except ovarian insufficiency. One would then go on to investigate the other possible causes.

There are a limited number of causes for secondary amenorrhea and the common ones of course would be pregnancy, which you should never forget. Premature ovarian failure, polycystic ovarian syndrome, hyperprolactinemia, which is usually associated with galactorrhoea, milky discharge from the breasts, but not always. And then hypothalamic amenorrhea, which is the one most young women are accused of having.

So that’s whether you have an eating disorder, if you’re over-exercising, if you’re particularly stressed, and your hypothalamus is not working properly, so your periods go away. For most young women they’re stressed, they’re busy, they’re doing all sorts of things, and they’re exercising, and that’s very often what the family doctor or the local gynaecologist will say – “It’s nothing, go away.” But it’s not always the case.

So your first test is the history of menstruation, FSH twice, and then after that, prolactin levels, pregnancy tests, Anti-Mullerian hormone levels, which will tell you how many follicles are in fact there. Maybe a pelvic ultrasound to exclude the possibility of auto-immune ovarian cyst formation, and then later on – later on lots of other tests, cardiovascular tests, bone tests and so on. But staged.

Well, you know, first of all, I think premature menopause, once you exclude the other possibility, or other cause of it. So you know, you need to look at the… some of the endocrine area, the thyroid issue, if they have any autoimmune diseases. Family history sometimes is telling you, if they say that their parents have had that. But those people tend to be the ones [who are] more aware, because you know, somebody have had that experience in the house. And then you know, of course you check that everything else is okay, you know, and then you then will have to say, “It’s a spontaneous idiopathic,” not known why they suddenly have that.” So it will involve the blood test; the actual, you know, ultrasound, and all of those kind of things, to just make sure.

Some women have been through the experience of being told that there’s nothing wrong with them and I think they’re a bit frightened that they’re going to be told they’re stupid. …

It takes quite a while to get diagnosed often. And sometimes it is hard. Sometimes the symptoms are quite vague. They don’t always start just with hot flushes. So sometimes it does take a while.

Do you think there’s issues with the system as well, that diagnosis is so delayed for some people?

I think so. I think there’s probably a lack of appreciation of how relatively common it is and how you diagnose it, what the possible symptoms are. I think menopause has basically gone under the radar. So after publication of the Women’s Health Initiative everyone stopped using HRT. So then you got, you know, HRT was no longer taught really within general practice training. So there’s a whole lot of doctors who have never really used it. I think, unfortunately, the kind of – the fear around menopause and use of HRT in older women has translated into a sort of lack of knowledge of younger women as well, I think. But it’s hard to know.

A delay in diagnosis is the commonest problem, for sure, and that’s what we really have to address. We have to say over and over again, ‘Don’t be frightened to look and see what is going on early’ – and for women, for any woman who’s worried, ‘Don’t take ‘no’ for an answer.’ If you go to your doctor and your doctor says ‘You’re nuts,’ go to another doctor. Keep at it, don’t just surrender, because it’s such an important issue for you and for your long term health that it deserves to be investigated.

I suppose when it’s ovarian failure, you’ve got to go to the bottom of finding out what is the cause and whether there’s any other autoimmune conditions associated with… So that’s why you end up knowing these guys quite well because you get to see them every year at least and make sure that they haven’t got any other things cropping up including thyroid and autoimmune things.

The tree that you could draw of all the conditions that could cause early ovarian failure is huge, medically, so that’s where the puzzle is quite complicated … like someone with say galactosemia, they’ve known they’ve had it since they were a baby, so the parents are used to managing that. From the purposes of their other issues, which is all sorts of medical things. But the ovarian function stuff tends to then arise later in sort of late teens, early 20s.

Yeah, so people do need to know what base condition has caused the problem in the first place if there is something that you can find, and then other times it’s just you don’t know, you don’t have a particular reason, as long as you exclude the things that make a difference to their health otherwise. I mean there are some conditions where there’s going to be more osteoporosis for other reasons as well, or other issues with growth. Like there’s some young women who have big dramas with their permanent… their stature, say with Turners particularly, but not just Turners, there’s other genetic conditions that also have that problem and also muscle mass, things like that which are important, so yeah.

How do you actually diagnose the various primary ovarian failure, and then the premature ovarian insufficiency and then the…

That’s a very complicated question, because someone whose never had a period you’ve got to make sure it’s not… There’s different levels. So it may be coming from a brain, as in a pituitary gland thing, or a hypothalamic thing, or… Because there’s other conditions that can affect your inputs from the brain to the ovaries, including… There’s a myriad of things. Anyway, so you have to make sure it’s not coming from up there. And even you’ve got some girls who have anorexia nervosa. So there’s eating disorders in there, as well. Some girls who’ve never had periods that are just because they’re underweight or they’re exercising too much, and they don’t always necessarily seem to be at that skinny… that thin that they’re from the anorexia group. It’s just some of the girls who are doing intensive training for, say, swimming or gymnastics and stuff like that. So you’ve got to make sure it’s not that sort of thing.

Stress is another thing that can sometimes… Even, a whole bunch of Year 12s… I always see Year 11s, Year 12s who’ve got periods that are all over the shop because their stress levels are too high. And then you’ve got to make sure it’s not other organs causing it, so things like thyroid disease can double back and inhibit the ovarian function. So you sort of just do barrages of blood tests and things, and then you’ve got to make sure they’ve got a uterus and got ovaries, and then maybe you might do genetic tests.

There’s a whole bunch of tests, depending on which way the tree goes. Sort of like there’s a flowchart type thing. You can look those flow charts up and they’re very big. In fact, every time I get a new person with primary ovarian fail, as in early, early, not having a period ever, I often have to go back to the big flow chart and make sure I’ve checked off all of the different things because it’s really a bit complicated.

The women who are… had periods for a long time, then become amenorrhoeic or have no periods anymore, again, you sort of almost have to go through a little bit the same process. Obviously, they’ve still got a uterus and things, but to make sure there’s not another disease process that’s causing it. You do need to follow a sort of regime of a few tests.

What’s the link between sort of these autoimmune issues and early menopause?

We don’t, we don’t really understand it very well at all, and the markers we have now are very – I think – crude. In the future I think we’ll have better markers. So some markers, for example, one lady I’ve had recently has had just some positive thyroid antibodies which show that there’s an autoimmune response against the thyroid, but there was no other cause found. So I’ve said to her that this is probably an indication that this is an autoimmune process, this is probably what explains your ovaries not working very well, but we don’t have any other marker than that.

And sometimes that can be a little bit of a comfort. Because I think the worst thing is when there’s absolutely no cause and nothing that they can put their hand on because they feel very vulnerable, ‘Why did this happen to me?’ And to have a reason or a cause is very important for some women.

So the first thing is confirm it, because there are other conditions that can mimic menopause, and some other conditions can shut the ovaries off temporarily, and things like thyroid conditions and when women exercise too much, or have lost a lot of weight, or under extreme stress – that can sort of stun the pituitary a bit into turning off ovarian function. So it’s important to rule out those conditions to start with.

So for example I test thyroid, I test a hormone called prolactin, and you want to confirm that it is menopause, so you need to do an oestrogen level, which is estradiol, and an FSH which is a pituitary hormone that regulates the ovarian production of oestrogen, and then you want to confirm that later. So it’s a one-off test and you do need to repeat at least four weeks later that FSH and oestrogen level to confirm that it is menopause. Because sometimes you will be tricked.

The other issue is that peri-menopause can be tricky as well, so typically in the 40s those levels can be high, but then you might check them again and they might be normal. So there are criteria for the diagnosis of early and premature menopause, so you need to do that. So the diagnosis is the first thing, and I will usually do a gynaecological ultrasound as well to have a look at the ovaries, and that will really be looking at follicles or eggs.

To see, are there any eggs? Are the ovaries looking strange? Is there anything wrong with the uterus, is there anything else that might be causing this, endometriosis or whatever? So I normally do that. And then – so once diagnosis is made, that’s menopause, early or premature – then it’s a matter of finding a cause. So then I do do a whole lot of different, unusual tests, including autoimmune tests like looking for rheumatoid arthritis markers, looking for thyroid, looking for thyroid autoimmune markers, there’s a lot of these tests.

And I have a little guide for me because you can’t remember them all. And then usually they don’t turn up anything, but in a very few they’ll turn up something like Fragile X carrier status or something like that. Then you also need to look at consequences. So bone density, so I organise a DXA scan. And really that’s the majority of tests – you’re looking at diagnosis, you’re looking for causes, because that would be important for the lady and for family.

What I will always do when a lady first comes to me with suspected premature or early menopause, a whole lot of tests trying to find out if there’s an autoimmune, or if there’s some other cause, and in the majority of cases there just won’t be a cause found, which is very frustrating for some women. But at least if you’ve done all the tests then you can counsel their families.

I suppose the most common things I’ve found is that some of them have an autoimmune tendency, and some of them have for example some markers of autoimmune thyroid disease or other things like that, and some have Fragile X, which is a genetic condition whereby women can have a tendency to have an earlier or premature menopause. Because that can be carried through to children, or can have implications for children, and premature menopause if it’s not created medically can have implications for children – that’s why I do investigate when I first see them and make sure that there’s nothing that won’t be an implication for a future generation, or for fertility.

I mean, you must never make a diagnosis based on one – on one lot of testing.

You have to repeat it?

Yeah, and to complicate that, you know, most of – a lot of these young women I see, they go in and out. So, they’ll have a good month and a bad two months, and a good month and a bad two months.

Yes.

So, it’s a moveable – it’s very important, and I think a lot of the women I see, they’ve had this diagnosis made after one blood test, and, you know, it – you have to be really, really sort of monitoring – and, I guess in my situation, it’s easy to do that. I’m set up well to do that, but these women that come in and they want to have fertility, you know, they’ve got infertility and they’ve been told they’re in early menopause and they’ve got to go and use donor eggs, I mean, that’s when we begin a whole different level of evaluation and trying to sort of get some ovarian activity back again. So, I guess that’s part – that’s a big part of what I do.

So, sorry, I’m digressing, but it comes from when you make the diagnosis, you make the diagnosis, but that’s a sort of evolutionary thing. You keep trying, you keep doing different blood tests, because over 50% of the young people I see will actually go in and out, fairly frequently.

What does that reflect, that it’s – that they’re not menopausal yet, or?

Well, it reflects that they have extremely fragile ovarian function, and they have times of premature ovarian insufficiency, but if you really try your damndest, you might – or, actually, even irrespective of what you do, but if you’re around watching, there might be some little windows of opportunity for fertility or fertility preservation.