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New Treatments for Amenorrhea

The thing you have to remember about secondary amenorrhea is to go back to the basics; pregnancy test, TSH, prolactin and some assessment of endogenous estrogen. It is a big problem, about one percent per year overall - that is actually a large number of people, when you add up the number of women in this country of reproductive age with a missed period.

There is physiologic amenorrhea and obviously the number one thing you always check is a pregnancy test, beta hCG, the second the person comes in; there is no excuse not to have amenorrhea.

This is the general scheme that I have made nice and simple and it will keep popping up throughout the lecture because it is helpful to remember. All you see up here is beta hCG, prolactin, TSH, FSH possibly - usually, I end up doing it, but it is not necessary - and you have to do something to assess endogenous estrogen. Don't assume when someone comes to you with secondary amenorrhea that automatically she has high estrogen levels and she is just not ovulating that she has PCO. Even if she is obese and hirsute, it doesn't necessarily mean that she has PCO. You have to assess to see the reason why she is not bleeding. It could be that she has very high estrogen. It could also be that she has very low estrogen. The only way to assess that really well is either a progestin challenge or a vaginal smear and look with a Sedi stain for a amenorea.

Asherman's syndrome usually results from over-aggressive D&C's, but it can happen for other reasons, too. Post partum endometritis can lead to it; endometritis from any other source.

Other causes of secondary amenorrhea as a general laundry list include premature ovarian failure; hypogonadotropic hypogonadism; hypothalamic dysfunction, and PCO.

Hyperprolactinemia is clearly easy to treat. It is relatively common. It can be caused by lots of different things. There are a list of drugs that can cause this, including phenothiazines, most of the neuroleptics and people have started to say that Prozac can lead to mild hyperprolactinemia, although I personally have not seen this. Hypothyroidism is another possibility; the mechanism here is that in response to the decreased T4 with an elevated TRH - TRH comes from the hypothalamus, comes down the median eminence and stimulates the pituitary to produce prolactin.

Remember that prolactin is under the negative influence generally of dopamine. It is the only pituitary hormone that is under a negative influence chronically and TRH stimulates it. Hypothalamic lesions, of course, are a possibility. Pituitary lesions, and the classic ones being microadenomas or macroadenomas are included here. Growth hormone-secreting tumor are more rare, but are something to think about, particularly in the case of somebody who is amenorrheic, who may have some galactorrhea, but doesn't have an elevated prolactin on routine screen. It is a little more confusing, because if you remember basic embryology, you have mammotrophs, somatotrophs and then you have somatomammotrophs.

Workup is a TSH, because you are looking for hypothyroidism as a general rule; MRI usually with contrast of the hypothalamus and pituitary in particular, looking for anything that will compress the stalk and specifically adenomas of the anterior pituitary.

The big issue with hyperprolactinemia is actually hypoestrogenic state. These people are essentially menopausal from the point of view that they are hypogonadal. They are at risk for everything - the bone density decrement, cardiovascular disease.

Treatment is that you have to drop the prolactin and raise the estrogen levels up. You can do this simultaneously. Don't worry, for example that if you give somebody the pill that they are going to get a 6 or 7-cm tumor is going to become a big brain tumor - doesn't work that way. It is incredibly rare. So you can replete their estrogen and give them some dopamine agonist.

Various dopamine agonists, the classic one we all know being Parlodel, is a daily medication and the side effects are pretty significant. The number one side effect is orthostatic hypotension. You need to tell people that when they get up in the morning after they start taking this, to put their feet on the ground, sit up, get their bearing straight and don't just hop out of bed.

Does dopamine agonist make a difference? Absolutely. In two separate studies, one-hundred percent of them reduced their prolactins and a large percent of them ovulated and got pregnant.

Radiographic progression in idiopathic or small tumors is incredibly unusual, in terms of follow up. One study did report a thirty-seven percent normal to abnormal CT in three years.

So you can have no bleed, which could lead to Asherman's, in which case you would expect the FSH to be normal or low; you could have a bleed, in which case you would worry about things like PCO, which brings you over towards androgens; or you could have a high FSH after no bleed and that could be from premature ovarian failure. If you have no bleed and then you give the person estrogen for a month, followed by progesterone.

Premature ovarian failure has lots of different causes. This is of course a situation in which your gonadotropins are going to be elevated, FSH will be high, because there is no estrogen to suppress it. The most common cause is idiopathic, but it could be autoimmune, but it is clearly associated with people who have antimicrosomal antibodies with Hashimoto's disease or Graves' disease, chromosomal problems are very common, iatrogenic, radiation, environmental. There is no question that we have found mutations in people who have been whittled down in the funnel and everything has been ruled out. In very rare cases you find a mutation in FSH that is not bioactive but may be immunoactive, so you pick it up and see that everything is fine, but you study it and find out that it doesn't work; either it doesn't bind properly or it doesn't stimulate the FSH receptor properly, or the receptor itself might be messed up. Maybe it can bind, but it doesn't transduce the FSH signal and there is no estrogen. Other causes include chromosomal abnormalities and this is not insignificant - anywhere between ten and fifteen percent in most studies. Progestin withdrawal will cause premature ovarian failure.

Chromosomal abnormalities occur about ten to twenty percent of the time, so you should get a karyotype in anyone who has elevated gonadotropins and premature ovarian failure, particularly if they are less than 5 feet 3 inches. Anyone who is taller than that would likely not have a chromosomal mosaicism type picture, or Turneroid-looking picture on their chromosomes.