Let’s talk about hyperprolactinemia and
the different reasons as to why you might
then develop this.
A functioning lactotrophic… remember that
lactotrophic means prolactin.
Also keep in mind that a lactotroph is a somatomammotroph.
A prolactinoma due to overexpression… here
we go, if you haven’t memorized it already,
we have a pituitary tumour transforming gene,
Do not forget this, why?
Because a prolactinoma of all of the hormones
that come out of a functioning adenoma in
the anterior pituitary, prolactin’s number
Another reason or another cause of hyperprolactinemia
yet once again is primary hypothyroidism.
The question that I get often times from students
is, well, “Dr. Raj, why could this not be
Well, technically perhaps... and so, you think
if it was secondary hyperthyroidism, that
means that my anterior pituitary, decreased
TSH and you would have increased TRH thus
increase in prolactin.
One would think that there will be hyperprolactinemia.
However, in primary hypothyroidism, you have
combined, concerted effort, but TRH and TSH…
remember, all these cells within anterior
pituitary mixed up and so, therefore, there
is enough influence on that lactotroph to
release prolactin… primary hypothyroidism.
What else may cause hyperprolactinemia?
Whatever may then cause decreased dopamine
influence on your lactotrophs.
Damage to your dopaminergic neurons, drugs,
antipsychotics… remember, schizophrenia
means too much dopamine; antipsychotics is
a dopamine antagonist, may result in hyperprolactinemia,
look for galactorrhea in a female.
The stalk section that we talked about earlier.
If the stalk has been severed or lesioned
or you have a non-functioning adenoma compressing
the stalk, you’re not going to deliver dopamine
It will result in hyperprolactinemia.
Or benign, you might have a craniopharyngioma,
sometimes referred to in your sella as being
like crank oil in consistency.
May result in, once again, increased release
or lack of release of dopamine or delivery
thus increased prolactin.
Metastatic breast cancer, big one here in
which once again you’re causing decreased
delivery of dopamine.
Thus, what’s my topic for this section?
Do not forget about malignant, metastatic
We have something called PRLR mutation with
the amino acid histidine to arginine at codon
188 or 1-8-8, whatever you want to think of
PRLR is important, histidine to arginine.
Loss of Janus kinase-2/signal transduction
and therefore, resulting in, you probably
want to memorize, STAT 5.
So, up until this point, you probably have
learned about JAK2 stat.
JAK2 stat is dealing with what we talked about
earlier with WBC pathology and we talked about
myeloproliferative disorders such as Polycythemia
vera, such as essential thrombocythemia.
Now, this is JACK2 STAT 5.
Genes and genetics, they are huge in pathology
What else may cause hyperprolactinemia, but
this time physiologically?
How about nipple stimulation?
Estrogen binds to ER which in turn binds to
What the heck does this mean?
Okay, let me walk you through this.
Think about a pregnant lady, how often is
she running milk down her nipple?
Not very often at all.
My point is this that estrogen may then block
the release of milk from the breast.
This is during pregnancy.
What happens is that post-partum, all of a
sudden estrogen levels drop, the blockage
on the receptors for prolactin has been lifted
and therefore, now, the infant and the child,
newborn, is ready to then breastfeed.
Decreased prolactin clearance includes chronic
kidney injury or perhaps even a macroprolactin,
a macroprolactinoma type.
Chest wall trauma.
So, there’s a lot of things about the-the
chest region-chest region that we’ve talked
about in terms of interesting things.
Remember, chest in ADH we dealt with quite
a bit, didn’t we?
We talked about lung cancer, small cell of
the lung; we talked about chest trauma and
I talked and I walked you through a thoracic
disease or, excuse me, thoracic surgery and
a lot of interesting things about the chest
wall that seems to have a pretty direct effect
on what’s happening with hormonal levels.
Here, the serum prolactin concentration is
much higher in most patients who have a lactotroph
macroadenoma than in patients with any other
cause of hypoprolactinemia.
So, what this graph is then showing you in
great detail is the fact that hypoprolactinemia
is my topic and of all the various causes
of hypoprolactinemia that we walked through,
the highest levels of prolactin could be found
in those patients that tend to have a macroadenoma.
The symptoms of hypoprolactinemia.
Premenopausal women, this will be where there
would be headache, impaired vision and amenorrhea.
Infertility, menstrual cycle dysfunction,
there will be no ovulation; inhibition of
LH and FSH, why?
Remember prolactin inhibits GNRH, no LH and
Therefore, you would not have or she would
not have menses.
Amenorrhea secondary to hyperprolactinemia
show a lower spine and forearm bone density.
Lumbar and forearm, there seems to be an influence.
Once again, we talked about this earlier with
When compared to normal population with menses,
so there’s something here in terms of the
balance of estrogen that has been lost with
prolactin, look for lower bone density in
the spine, lower spine especially, and the
And with all these prolactin, you will for
sure have galactorrhea.
So, even though it might seem as though that
the female is fertile, she’s not; she’s
So, amenorrheic with galactorrheic.
This is called hypogonadotropic hypogonadism.
What does that even mean?
If it’s a male or a female, the gonad would
be testes/ovary respectively.
That is not functioning.
There is no disease in the ovaries and testes.
Were there in hypoprolactinemia?
So, that high level of prolactin is not affecting
the gonad directly, but it is affecting whom?
The hypothalamus, thus the anterior pituitary.
That access of the hypothalamus in the pituitary
is called hyp-… or it’s called gonadotropic.
In hypoprolactinemia, how much GNRH and how
much LH and FSH do you have?
So, my hypogonadism is caused by hypogonadotropic.
Thus, we call this hypogonadotropic hypogonadism.
The boards love this kind of questions, they
love this type of concept in which you have
to constantly think through what’s occurring.
This is a secondary hypogonadism… secondary
hypogonadism, not primary.
Erectile dysfunction, decreased libido, infertility,
This is a male on the right and this is the
Greek symbol for a male.
Notice here, we are not putting in amenorrhea
since we’re referring to a male.
The previous section was the Greek symbol
for a female.
What we have here is an important algorithm
We will dive into much greater detail with
this algorithm when we take a look at female
The reason that I’ve placed this here specifically
is so that you clearly see how to utilize
the test for hypoprolactinemia and when it
becomes important to you with steps of management.
So, let’s begin.
Our first order of this algorithm will be
to the right of this algorithm and what has
been put in a box here.
We are not touching the left wing of this
algorithm whatsoever at this juncture even
though it’s incredibly important for us
to, once again, dive into when we get into
female reproductive pathology.
But, our focus will be on the right side when
dealing with hypoprolactinemia and why.
Now, before we begin, let’s first start
thinking about when you would want to even
think about using this, who’s your patient
coming in through the door, what’s the question
she’s been asking you.
It’s a fact that she’s not having menses
and she’s not having menses for a three
month period during some time in her reproductive
So, maybe she started having menses at the
age of 14 and between age of 14 and let’s
say the average age of menopause is 50 years
of age in the US.
During that time span, between 14 and 50,
she is not having menses for three months.
That is the definition of secondary amenorrhea.
The most common cause of secondary amenorrhea
During pregnancy, obviously, she is not going
to have her menses.
The most common cause of secondary amenorrhea...
and so, when you read this box here and it
says secondary amenorrhea, understand who
your patient is walking through that door.
If the most common cause is pregnancy, obviously
the most important test to conduct here would
be a beta HCG.
Now, this beta HCG comes back to be negative,
then there’s something else that’s causing
her to be amenorrheic during her reproductive
What is it?
Well, maybe it’s primary hypothyroidism,
maybe she is eating a little bit of food.
“Hey doc, I’m eating a little bit of food,
but I’m gaining all these weight.
I even wake up at 5 o’clock in the morning
before I have to take my kids to school and
I exercise, I hit the gym and all I have is
a bowl of cereals and I’m still gaining
three pounds per week.”
Hmm, you check TSH, you find that to be elevated.
This is interesting.
So, now, at this point, your female reproductive
age, three months, she’s not having menses
and with those type of symptoms that I’ve
given you will be hypothyroidism.
You find an increase in TSH, obviously expect
there to be an increase in TRH.
Her T3/T4 low, this is then causing increase
in prolactin and this prolactin causes what?
Inhibition of gonadotropin releasing hormone
and your female is not having menses.
So, there might be thyroid disease associated
with secondary amenorrhea.
Let’s keep going.
Patient presents with secondary amenorrhea,
negative pregnancy test.
We said the most common cause of secondary
amenorrhea was in fact pregnancy, but that
comes back to be negative for beta HCG.
Next, you checked TSH and you find your TSH
levels to be elevated and you’re thinking
Aha, that is the cause of your secondary amenorrhea
and your female who is in her reproductive
Let’s move on.
Now, you check her beta HCG, negative; you
check her TSH, within normal limit; she is
27 years of age, she’s not having menses.
Now, what are you going to do?
Well, now, you’re thinking about prolactin.
If you’re thinking about prolactin and you
find that to be increased, now what I need
you to do always in pathology is to understand
the concept first then you memorize the value.
Not the other way around because you’ll
be wasting precious time.
You’re checking for secondary amenorrhea,
beta HCG is negative and you find your TSH
to be within normal limit.
Now, you find your prolactin to be elevated.
Now, if you want, memorize greater than 100
micrograms per millilitre.
So, now, you know this prolactin that’s
to be-that’s to be elevated and then you’re
doing MRI, next step of management.
So, I just walked you through three steps
of management for secondary amenorrhea and
when you would perhaps even think about using
prolactin or hypoprolactinemia in a case of
a female who is not having menses.
First step, beta HCG; second step, TSH; third
step, prolactin elevated; your next step of
management, aha, MRI of the head.
What are you going to find perhaps?
You’ll find a tumour.
You’ll find a functioning tumour that is
then causing perhaps what else maybe?
And maybe they’ll be nice; they usually
are, trust me.
And they’ll give you visual disturbances
and maybe headache.
But, isn’t it interesting that sometimes
you read a stem of a question and this…
the critical information goes right by you,
goes over your head and then you start figuring
things out and you go back to stem and, oh
my goodness, you know, you start seeing the
So, the more that you are exposed to your
clinical presentations, the more you’ll
notice what to look for and what to pick out
of the stems of your question.
This is the evolution of your boards.
Is that clear?
It’s very much a thinking exam.
That’s why things have dropped down to 44
questions per block now, right?
It was 52 once upon a time, then 46, now it’s
44… evolution of the exam.
You need to be able to think through it, I’m
helping you to do that.
Now, if that doesn’t happen then you consider
other causes, but for right now, that’s
Somewhere along the line of what I walked
you through, you’d find the answer.
The pitfalls – the hook effect and macroprolactin
and what that means following... is the following.
Every once in a while you can have...
Now, always ask yourself this question, “This
adenoma that I’m finding, this adenoma that
I’m finding within the-within the pituitary,
is it a functioning or non functioning adenoma?”
Always ask yourself that question.
So, evaluation of prolactin, then you find
that to be greater than 20 micrograms, then
at that point maybe it’s a macroprolactin.
History of pregnancy, meds, headaches, renal
disease will be all part of, of course, your
MRI of the pituitary may reveal the adenoma
that we talked about.
Large, non-secreting adenoma can elevate prolactin
via stalk compression, we talked about that
Therefore, inhibiting the release or delivery
of dopamine to the anterior pituitary.
And so, therefore, you might find elevated
levels of prolactin.
So, when you say non-functioning remember,
non-functioning meaning that you might disrupt
or inhibit the release of many other anterior
pituitary hormones, but you might cause inhibition
of dopamine delivery and therefore, increase
levels of prolactin… macro.
Hypoprolactinemia… first line, well, if
there’s too much prolactin and you want
to try and slow it down, you’ve heard of
drugs such as bromocriptine or cabergoline.
This is a dopamine agonist and so, therefore,
you are iatrogenically or exogenously mimicking
the action of endogenous dopamine.
Inhibition of prolactin secretion and amenorrhea,
galactorrhea, prolactin secreting tumours,
correction of female infertility secondary
So, these are indications in which you’re
thinking about giving your dopamine and a
lot of these we already talked about.
If the medications do not work then you start
getting into tran-transphenoidal surgery,
post-operative radiation therapy to prevent
regrowth of residual, but… but… but…
we got a couple of things here.
Transphenoidal debulking of lactotroph adenomas
that are resistant to cabergoline recur after
Now, the only problem is this, that anytime
that you are even thinking about giving your
patient, exposing your patient to radiation,
initially, there might be a hyper functioning
of that particular organ, but if radiation
is given abundantly or the tissue is so sensitive
that the radiation kills off the tissue excessively,
you might, and look for this, oftentimes go
from hyper to hypo.
We can say the same thing about Grave’s
disease of the thyroid and that is something
that you have seen over and over again, your
[Inaudible 00:19:22] therapy.
Upon treatment with radiation, you are destroying
excessive thyroid tissue going from Grave’s
disease to hypothyroidism.
The same kind of issue might also take…
might be taking place in other organs including
the anterior pituitary.
In order, we talked about drugs, transphenoidal,
last resort maybe post-operative radiation.