by Carlo Raj, MD

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    00:00 Let’s talk about hyperprolactinemia and the different reasons as to why you might then develop this.

    00:05 A functioning lactotrophic… remember that lactotrophic means prolactin.

    00:12 Also keep in mind that a lactotroph is a somatomammotroph.

    00:15 A prolactinoma due to overexpression… here we go, if you haven’t memorized it already, we have a pituitary tumour transforming gene, PTTG.

    00:25 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 one, PTTG.

    00:40 Another reason or another cause of hyperprolactinemia yet once again is primary hypothyroidism.

    00:46 The question that I get often times from students is, well, “Dr. Raj, why could this not be secondary hyperthyroidism?” 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.

    01:09 One would think that there will be hyperprolactinemia.

    01:12 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.

    01:36 What else may cause hyperprolactinemia? Whatever may then cause decreased dopamine influence on your lactotrophs.

    01:43 How? 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.

    02:01 The stalk section that we talked about earlier.

    02:03 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 effectively.

    02:13 It will result in hyperprolactinemia.

    02:16 Or benign, you might have a craniopharyngioma, sometimes referred to in your sella as being like crank oil in consistency.

    02:26 May result in, once again, increased release or lack of release of dopamine or delivery thus increased prolactin.

    02:35 Metastatic breast cancer, big one here in which once again you’re causing decreased delivery of dopamine.

    02:42 Thus, what’s my topic for this section? Hyperprolactinemia.

    02:48 Do not forget about malignant, metastatic breast cancer.

    02:52 Genetics.

    02:53 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 it as.

    03:09 PRLR is important, histidine to arginine.

    03:15 Loss of Janus kinase-2/signal transduction and therefore, resulting in, you probably want to memorize, STAT 5.

    03:23 So, up until this point, you probably have learned about JAK2 stat.

    03:29 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.

    03:44 Now, this is JACK2 STAT 5.

    03:48 Genes and genetics, they are huge in pathology nowadays.

    03:55 What else may cause hyperprolactinemia, but this time physiologically? How about nipple stimulation? Sure.

    04:04 Stress/exercise… hyperprolactinemia.

    04:08 Estrogen binds to ER which in turn binds to E-response elements.

    04:13 What the heck does this mean? Okay, let me walk you through this.

    04:18 Pregnancy.

    04:20 Think about a pregnant lady, how often is she running milk down her nipple? Not very often at all.

    04:27 My point is this that estrogen may then block the release of milk from the breast.

    04:36 This is during pregnancy.

    04:39 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.

    04:56 Decreased prolactin clearance includes chronic kidney injury or perhaps even a macroprolactin, a macroprolactinoma type.

    05:05 Chest wall trauma.

    05:07 So, there’s a lot of things about the-the chest region-chest region that we’ve talked about in terms of interesting things.

    05:16 Remember, chest in ADH we dealt with quite a bit, didn’t we? Remember SIADH? 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.

    05:42 Fascinating! 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.

    05:56 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.

    06:23 The symptoms of hypoprolactinemia.

    06:26 Premenopausal women, this will be where there would be headache, impaired vision and amenorrhea.

    06:34 Infertility, menstrual cycle dysfunction, there will be no ovulation; inhibition of LH and FSH, why? Remember prolactin inhibits GNRH, no LH and FSH.

    06:49 Therefore, you would not have or she would not have menses.

    06:57 Amenorrhea secondary to hyperprolactinemia show a lower spine and forearm bone density.

    07:06 Lumbar and forearm, there seems to be an influence.

    07:09 Once again, we talked about this earlier with prolactin.

    07:13 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 forearm.

    07:29 And with all these prolactin, you will for sure have galactorrhea.

    07:33 So, even though it might seem as though that the female is fertile, she’s not; she’s amenorrheic.

    07:41 So, amenorrheic with galactorrheic.

    07:46 This is called hypogonadotropic hypogonadism.

    07:51 What does that even mean? Watch.

    07:56 If it’s a male or a female, the gonad would be testes/ovary respectively.

    08:06 That is not functioning.

    08:08 Why? There is no disease in the ovaries and testes.

    08:13 Were there in hypoprolactinemia? No.

    08:17 So, that high level of prolactin is not affecting the gonad directly, but it is affecting whom? The hypothalamus, thus the anterior pituitary.

    08:31 That access of the hypothalamus in the pituitary is called hyp-… or it’s called gonadotropic.

    08:38 In hypoprolactinemia, how much GNRH and how much LH and FSH do you have? Not much.

    08:47 So, my hypogonadism is caused by hypogonadotropic.

    08:52 Thus, we call this hypogonadotropic hypogonadism.

    08:58 The boards love this kind of questions, they love this type of concept in which you have to constantly think through what’s occurring.

    09:09 This is a secondary hypogonadism… secondary hypogonadism, not primary.

    09:17 Erectile dysfunction, decreased libido, infertility, rarely galactorrhea.

    09:24 This is a male on the right and this is the Greek symbol for a male.

    09:29 Notice here, we are not putting in amenorrhea since we’re referring to a male.

    09:34 The previous section was the Greek symbol for a female.

    09:38 What we have here is an important algorithm for hypoprolactinemia.

    09:44 We will dive into much greater detail with this algorithm when we take a look at female reproductive pathology.

    09:53 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.

    10:07 So, let’s begin.

    10:10 Our first order of this algorithm will be to the right of this algorithm and what has been put in a box here.

    10:21 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.

    10:34 But, our focus will be on the right side when dealing with hypoprolactinemia and why.

    10:43 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.

    10:54 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 life.

    11:04 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.

    11:17 During that time span, between 14 and 50, she is not having menses for three months.

    11:25 That is the definition of secondary amenorrhea.

    11:29 The most common cause of secondary amenorrhea is pregnancy.

    11:35 During pregnancy, obviously, she is not going to have her menses.

    11:40 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.

    11:51 If the most common cause is pregnancy, obviously the most important test to conduct here would be a beta HCG.

    11:59 Now, this beta HCG comes back to be negative, then there’s something else that’s causing her to be amenorrheic during her reproductive life span.

    12:13 What is it? Well, maybe it’s primary hypothyroidism, maybe she is eating a little bit of food.

    12:22 “Hey doc, I’m eating a little bit of food, but I’m gaining all these weight.

    12:26 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.

    12:42 Oh, wow! This is interesting.

    12:46 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.

    12:56 You find an increase in TSH, obviously expect there to be an increase in TRH.

    13:01 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.

    13:14 So, there might be thyroid disease associated with secondary amenorrhea.

    13:19 Let’s keep going.

    13:21 Patient presents with secondary amenorrhea, negative pregnancy test.

    13:26 We said the most common cause of secondary amenorrhea was in fact pregnancy, but that comes back to be negative for beta HCG.

    13:34 Next, you checked TSH and you find your TSH levels to be elevated and you’re thinking thyroid disease.

    13:43 Aha, that is the cause of your secondary amenorrhea and your female who is in her reproductive age.

    13:51 Let’s move on.

    13:55 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.

    14:11 Now, what are you going to do? Well, now, you’re thinking about prolactin.

    14:16 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.

    14:30 Not the other way around because you’ll be wasting precious time.

    14:33 You’re checking for secondary amenorrhea, beta HCG is negative and you find your TSH to be within normal limit.

    14:40 Now, you find your prolactin to be elevated.

    14:42 Now, if you want, memorize greater than 100 micrograms per millilitre.

    14:48 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.

    14:55 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.

    15:09 First step, beta HCG; second step, TSH; third step, prolactin elevated; your next step of management, aha, MRI of the head.

    15:21 What are you going to find perhaps? You’ll find a tumour.

    15:25 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.

    15:34 And they’ll give you visual disturbances and maybe headache.

    15:36 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 light? 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.

    16:00 This is the evolution of your boards.

    16:04 Is that clear? It’s very much a thinking exam.

    16:06 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.

    16:18 You need to be able to think through it, I’m helping you to do that.

    16:22 Let’s continue.

    16:23 Now, if that doesn’t happen then you consider other causes, but for right now, that’s good enough.

    16:28 Somewhere along the line of what I walked you through, you’d find the answer.

    16:32 The pitfalls – the hook effect and macroprolactin and what that means following... is the following.

    16:39 Every once in a while you can have...

    16:41 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.

    16:55 So, evaluation of prolactin, then you find that to be greater than 20 micrograms, then at that point maybe it’s a macroprolactin.

    17:02 History of pregnancy, meds, headaches, renal disease will be all part of, of course, your hypoprolactinemia workup.

    17:10 MRI of the pituitary may reveal the adenoma that we talked about.

    17:15 Large, non-secreting adenoma can elevate prolactin via stalk compression, we talked about that earlier.

    17:21 Therefore, inhibiting the release or delivery of dopamine to the anterior pituitary.

    17:26 And so, therefore, you might find elevated levels of prolactin.

    17:29 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.

    17:49 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.

    18:00 This is a dopamine agonist and so, therefore, you are iatrogenically or exogenously mimicking the action of endogenous dopamine.

    18:10 Indications… Inhibition of prolactin secretion and amenorrhea, galactorrhea, prolactin secreting tumours, correction of female infertility secondary to hyperprolactinemia.

    18:20 So, these are indications in which you’re thinking about giving your dopamine and a lot of these we already talked about.

    18:29 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.

    18:42 Transphenoidal debulking of lactotroph adenomas that are resistant to cabergoline recur after surgery.

    18:48 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.

    19:16 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.

    19:25 Upon treatment with radiation, you are destroying excessive thyroid tissue going from Grave’s disease to hypothyroidism.

    19:34 The same kind of issue might also take… might be taking place in other organs including the anterior pituitary.

    19:42 In order, we talked about drugs, transphenoidal, last resort maybe post-operative radiation.

    About the Lecture

    The lecture Hyperprolactinemia by Carlo Raj, MD is from the course Pituitary Gland Disorders.

    Included Quiz Questions

    1. Prolactinoma
    2. Primary hyperthyroidism
    3. Sheehan's syndrome
    4. Non-functioning lactotrophic adenoma
    5. Lymphocytic hypophysitis
    1. Primary hyperthyroidism
    2. Damage to hypothalamic dopaminergic neurons
    3. Selective serotonin reuptake inhibitors
    4. Severed pituitary stalk
    5. Craniopharyngioma
    1. Lactotroph macroadenoma
    2. Metastatic breast cancer
    3. Prolactin receptor mutation
    4. Chronic kidney disease
    5. Primary hyperthyroidism
    1. Increased ovulation
    2. Amenorrhea
    3. Infertility
    4. Decreased bone density in the lumbar spine
    5. Galactorrhea
    1. Hypothyroidism
    2. Hypogonadotropic hypogonadism
    3. Pituitary adenoma
    4. Oral contraceptive use
    5. Chronic kidney disease
    1. A dopamine agonist
    2. A dopamine antagonist
    3. A prolactin receptor agonist
    4. A prolactin receptor antagonist
    5. Bromocriptine is not used in the treatment of hyperprolactinemia.

    Author of lecture Hyperprolactinemia

     Carlo Raj, MD

    Carlo Raj, MD

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    Very helpful
    By Julian P. on 19. November 2017 for Hyperprolactinemia

    Great walk through, the concepts are easy to understand and apply.