Diagnoses of Reproductive Hormone Disorders– Reproductive Pathology

by Carlo Raj, MD

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    00:01 Our topic here, reproductive hormonal pathologies and differentials. Another set of differentials and diagnoses that you need to make sure that you’re clear about. Students tend to get confused.

    00:12 I will walk you through this in an organized fashion in which you will then once again hear, pay attention to the genotype, phenotype, and ultimately the presentation. First and foremost, there are four major conditions here. Every one of these you need to know. Klinefelter, androgen insensitivity syndrome, used to be called testicular feminization syndrome. Get away from that; androgen insensitivity syndrome, premature ovarian failure, and polycystic ovarian syndrome.

    00:39 These four conditions, you need to make sure that you know. I’ll give you the most common presentation. If you want to read more about this on your own, you may please do so. But let me give you at least this much. Let’s begin with Klinefelter first. In this patient, the most common genetic issue or genetic pattern will be XXY, 69 XXY. With Klinefelter, let me first begin by telling you who your patient is and what they look like. They will be tall. The arm span might be as long as the leg span. However, the leg span usually is a lot longer. Most common presentation, arm span is almost as long as leg span. Those are long arms. Now XXY, your patient is tall. Difficult for me to say a male or female. The reason for this is following the characteristic or the description of Klinefelter’s eunuchoid. What does eunuchoid mean? Features of male, features of female. The features of the female will be the gynecomastia. The features of the male will be the jaw of a male. Eunuchoid .

    01:51 The gynecomastia could be problematic. We had a discussion, where gynecomastia if left untreated increases the risk of breast cancer in a Klinefelter patient. Also, in this patient with Klinefelter, they seem to be socially inept. So they attend a party or they’re in a social gathering and they really are awkward. At the workplace, maybe they have a cubicle in the office and they have a deadline that they never reach. So as far as work is concerned, there is suboptimal intelligence.

    02:26 I don’t mean ridiculously low IQ. They’ll get a job but they may not be the most efficient.

    02:32 They’re tall. There’s no way you can miss this patient by that description. We need to go into further detail though. So there is an XXY. The Y gives you what kind of gonad? Good, the testes.

    02:46 In the testes, you’re thinking about two layers of the cell. You have the outer Leydig if you remember and you have the inner Sertoli. That’s where you begin with the Sertoli cells. The Sertoli cells will be damaged. If not the Sertoli cell, what does the Sertoli cell - what lumen does it surround, the Sertoli cell? Seminiferous tubule. You put those two together and the Sertoli cell and maybe perhaps the vas and the seminiferous tubule might then become fibrosed. So now what happens to your Klinefelter patient? With this fibrosis and difficulty of passing the sperm into the seminal vesicle, your patient is going to be infertile. Those are the most common presentations.

    03:29 Now, the only thing that I wish to bring to your attention, use common sense. I've talked about physiology with you quite a bit now. If the Sertoli cells are not present, would you tell me as to what hormone it produces to give you feedback, the Sertoli cell? The hormone was inhibin, wasn’t it? If inhibin is not present because the Sertoli cell is not working properly, what hormone can you then expect to be increased? Very good, FSH. With all that said, let’s take a look at our patient. Growth factors in Klinefelter syndrome. Well, the growth factors might be affected. The loss of Sertoli cell results to loss of inhibin, thus increasing FSH.

    04:08 That increase in FSH is then going to bring about aromatization of your testosterone into estrogen.

    04:15 Hence, I told you about this patient exhibiting or expressing your gynecomastia. There's eunuchoid and the arm span could be as long as the leg span. Another stuff here that’s rather interesting that you need to make sure that you know for your boards. The infertility, by actually providing the testosterone in some of your patients, not all. There are many, many, many, many chromosomal patterns for Klinefelter. The one that’s most common that you need to know, 69 XXY. By giving testosterone, you might actually correct the infertility in this patient with Klinefelter.

    04:47 Amazing? Know that one. Let’s move on to androgen insensitivity syndrome. Know this big time.

    04:56 Now, with androgen insensitivity syndrome, remember, genotypically your patient here XY, male.

    05:03 Male pseudo-hermaphrodite is what we looked at with our algorithm in prior discussion.

    05:11 What is that Y chromosome going to give this patient? This once again begins with our normal physiology. It gives you your, remember? The testes and the Müllerian inhibiting factor.

    05:21 Müllerian inhibiting factor, let me walk you through this first and then I’ll walk you through the verbiage. You have the testes but they might not be descended properly. So where might they be? Maybe the abdomen but more commonly where? In the inguinal canal. Your patient now is at risk for what? A seminoma. It’s called cryptorchidism, right? So what’s your next step of management? It’s to take them out, orchiectomy. At least do orchiopexy. Orchiopexy is bringing it down but more importantly, you need to do an orchiectomy. Got to take these out. But even then, there’s no guarantee that your patient is not going to develop a seminoma. Why does the patient develop seminoma perhaps? The Y chromosome. Next, who’s your patient? The patient, the mother brings her daughter, her daughter to you, the clinician. Why? Amenorrhea. At the age of what? The daughter is let’s say, let’s just make it, let’s exaggerate the age and we'll say 15 or 16.

    06:20 At the age of 15 or 16, no menarche has taken place in her daughter. Pelvic exam is being done.

    06:29 Upon examination, you’d noticed there is a vagina. Her breasts have developed properly.

    06:36 Upon pelvic exam however, you don’t see a cervical os. What does that mean to you? No internal female structure, blind pouch. Does that ring a bell? It should. If not, then please know it. Why is there a blind pouch in this patient who’s genotypically a male and phenotypically is presenting as a female? When I say female, I mean a well-developed female phenotypically.

    07:05 The Tanner system of the breasts are well-developed. The vagina is present. The only thing is the uterus is not present. Why? The Y chromosome, no pun intended. The Y chromosome will give rise to or gives the patient Müllerian inhibiting factor, anti-Müllerian hormone.

    07:21 Ah, there you go. Well, if you don’t know what that’s saying, listen. The Müllerian structure gives rise to internal female structure. When I say internal female structure, do not begin with the ovaries. What gives you the gonads, the chromosome. What do the Y chromosome give your patient, testes. So, what do I mean by internal female structure, fallopian tube, uterus, cervix, and the upper portion of the vagina. That’s a normal Müllerian structure.

    07:52 In this patient, none of those exist, hence the blind pouch. Let me ask you something.

    07:59 So what exactly is insensitive and why in the world do the male structures not develop at all? There is no internal male structure, no seminiferous tubule, vas deferens and such.

    08:12 There is no no external male structure. You mean to say that the mother for 16 years thought that she had a daughter phenotypically. So, there’s absolutely no external male structure.

    08:25 No penis and no prostate. Why is this all taking place? So when you say insensitive, who's insensitive? Dr. Raj is insensitive. Okay, well that’s another story. But really what’s insensitive are the androgen receptors specifically the testosterone receptors. When? In a fetus. So, if the testosterone receptors aren’t present and by the way, would you tell me where the receptors are located for testosterone. Cytoplasm, on the other side of the membrane.

    08:56 But they are not sensitive to the testosterone. So therefore, the male fetus will not develop any internal male structures. I also said there’s no external. Understand please. You first have to get the testosterone in or has to bind to the receptor so that 5α-reductase can do its job to convert the testosterone into DHT. That is also not happening in a fetus.

    09:22 So therefore, there’s no internal male structure. There's no external male structure. What did you find? Just the distal portion of the vagina, distal 2/3 of the vagina, blind pouch. Anytime the receptor isn’t working, would you please tell me as to what your hormone level will be? Elevated, elevated, elevated, elevated. There you have it. Let’s take a look. Loss of testosterone receptor activity. The loss or complete loss of testosterone, meaning to say that there’s no internal male structure and this then include no vas deferens, no epididymis and no seminal vesicle.

    09:56 Please understand this much. Let’s move on to another patient. This is premature ovarian failure.

    10:04 In premature ovarian failure, now things become a little bit different. If you notice, Klinefelter and androgen insensitivity syndrome, both of these patients had a Y chromosome.

    10:15 In the premature ovarian failure, well here the genotype will be XX. Think of this as being, think of this as being menopause in a young female in her reproductive age. Female less than 40 presents with amenorrhea, menopause. What’s the number one hormone that you’re looking for during menopause? FSH. You should find that to be elevated. So what’s my problem? It’s the fact that you have an exhausted, exhausted loss of function of the entire ovary. In a premature ovarian failure, a girl, a female who should be in a reproductive age, perhaps she wishes to conceive but her ovaries are dead. That’s unfortunate. So now, if there’s no estrogen, what’s going to be elevated? FSH, FSH, FSH. This is a type of primary hypogonadism, a type of what’s known as your hypogonadotropic hypogonadism. Genotypically XX. Then we have polycystic ovarian syndrome.

    11:18 Start from the top. This is a patient who genotypically is XX. She walks through the door and she is obese. In addition, she has male hair-like distribution. So meaning to say, she might have a moustache. But genotypically, she is XX. She is obese. She has hirsutism and because she's obese, there’s every possibility that your patient has diabetes mellitus. Now what about this patient? Pretty straightforward in terms of presentation. The one that you want to know for sure and we’ve talked about this earlier. Remember polycystic ovarian syndrome is a risk factor for developing endometrial hyperplasia or carcinoma and also breast cancer. That means your patient has a lot of estrogen. Don’t forget that. That can actually be an answer choice. You begin with thinking increase in LH. Increase in LH, that’s where you go with this most commonly. Now you walk me through this. Genotypically XX. So, no problems in terms of her sexual development of her structures. That’s all perfect. She has a Müllerian. She developed her vagina. There is cervix.

    12:26 and so on and so forth. So, don’t worry about that so much. She is obese and she’s hirsutised.

    12:30 Why is she hirsutised? LH then works on your theca cell. The theca cell is going to give you testosterone. Ah, excess testosterone in this patient is going to give you hirsutism.

    12:42 Let’s get going. I said there was increase in estrogen and testosterone. She’s obese.

    12:48 What do you know about adipocytes? Oh yeah, it has aromatase so there’s going to be increased aromatization of your testosterone into estrogen. This increase in estrogen increase the risk of this female of perhaps developing cancers. Bottom line is this. Know your patient. Walk into that door. Number two, all labs are increased except FSH. That’s the most important point. Meaning to say, you’re going to have increase in LH, increase in testosterone, increase in estrogen at 2:1 or 3:1 increased ratio of LH to FSH. With that, you’re golden, you’re solid. You listen to what I've said for each one of these patients on this table. In the previous discussions, we talked about placental aromatase deficiency, 5α-reductase deficiency, those patients and Turners and such.

    13:38 We just walked through eight major diagnoses in which they can ask about pathology, physiology, biochemistry. You can understand these. These are fantastic. Get excited. Let’s talk more about Klinefelter. So now, you have a female and what about her? She has excess estrogen giving her increased female sexual characteristics. We’re talking about gynecomastia. Androgen insensitivity, you can’t convert the testosterone into DHT. So not only does your male not have the internal male structure but he also doesn’t have the external male structure, DHT. Look at this.

    14:17 We have your phallus and your prostate not present. Premature ovarian failure, interesting concept.

    14:23 Genotypically XX, the ovaries are dead in a female in a reproductive age. You’ll find this to be interesting physiology. It’s called a progesterone challenge test. Important, oh yeah.

    14:37 What’s the name of the first phase of the menstrual cycle, follicular, A.K.A. proliferative.

    14:44 What’s the major hormone in the follicular phase? Estrogen. And if you have all that proliferation and at the end of your menstrual cycle meaning right before menses, what’s going to happen with progesterone and estrogen? They’ll be withdrawn, sloughing off or apoptosis of your endometrium. Welcome to bleeding, right? Welcome to bleeding. In premature ovarian failure, the ovaries are dead. Tell me about estrogen level, decreased. So you don’t have massive proliferation of the endometrium. If you never had proliferation and if you were to somehow physiologically mimic this exam to remove the hormones then maybe you might see bleeding or not.

    15:34 In this case of premature ovarian failure, if there is no proliferation, if you withdrew the "hormone," don’t worry about how to do this. We call this a progesterone challenge test. In this case of of premature ovarian failure, negative for bleeding. I want you to compare this patient and that physiology scenario to polycystic ovarian syndrome. Before you get there though, here’s my testosterone being converted into estrogen and also the testosterone giving rise to hirsutism.

    16:05 Point being, let’s take a look at the last bullet point. Loss of estrogen, so tell me about the endometrium, thickened. So, if you were to do a progesterone challenge test on this patient, would you perhaps be able to see bleeding? Yes, you would. Yes, you would.

    16:22 Klinefelter, please pay attention to the arm span. Take a look at the jaw, male-like.

    16:30 Take a look at the chest, gynecomastia. That arm span seems to be as long as the leg span.

    16:37 You cannot miss this question. In the office, how well is the patient doing? How efficient is he with meeting deadlines? Not very good. Infertility, can you treat the infertility perhaps? Perhaps by giving testosterone. With androgen sensitivity, ultimately, take a look.

    17:02 Your patient is going to have the lower portion of the vagina and so therefore we’re talking about blind pouch. Take a look at this patient. Phenotypically, no wonder the mother thought that she had a daughter. Look. Phenotypically, Tanner’s, size, breasts, well-developed. You see the labial folds.

    17:26 The arm span is not as long as the leg span, not necessarily tall. The hair is like a female sexual characteristics. Pelvic exam and you find no cervical os in this patient. Genotypically, this patient is a male. You can’t tell by looking at this patient phenotypically. Do you understand that? Now beyond that in terms of management, well that’s more behavioral science and that is not my area of expertise. But that more goes along the line of family discussion and what they want to do in terms of my goodness, you’re a male genotypically and so on and so forth.

    18:06 So I am not touching that. Pathology is what I focus upon. Premature ovarian failure, here what you end up finding is the fact that you have dead ovaries. In polycystic ovarian sydrome, every single hormone is elevated except your FSH. With polycystic ovarian syndrome at the very bottom here, remember with polycystic ovarian syndrome, you don’t always have to have cyst in the ovary which makes it difficult for you to understand it. But just accept it at this point.

    18:42 There are criteria for polycystic ovarian syndrome. One of them includes oligomenorrhea.

    18:47 I’m giving you a patient walking in. She does not even have to have cysts in the ovary to diagnose polycystic ovarian syndrome. That is current day practice here because of the estrogen upon progesterone withdrawal or challenge, you will find bleeding. Most of your conditions if you’re thinking about a female pathology, the bleeding from progesterone challenge test will be negative like we just did earlier with premature ovarian failure.

    About the Lecture

    The lecture Diagnoses of Reproductive Hormone Disorders– Reproductive Pathology by Carlo Raj, MD is from the course Reproductive Hormone Disorders.

    Included Quiz Questions

    1. Male-pattern hair distribution
    2. Secondary sexual Characteristics start to appear after puberty.
    3. Decreased intelligence
    4. Infertility
    5. Long arm span
    1. Increased Inhibin
    2. None of the above
    3. Increased Estrogen
    4. Increased FSH
    5. Increased LH
    1. Usually discovered In Preschool Age
    2. No development of internal male organs
    3. Genotypic males
    4. They have testicles.
    5. Present as amenorrhea
    1. 29 year-old Female with amenorrhea.
    2. 32 year-old Female with multiple ovarian cysts and DM
    3. 35 year-old Female with dysmenorrhea
    4. 32 year-old Female with oligomenorrhea
    5. 51 year-old Female with amenorrhea
    1. Increased Inhibin
    2. None of the above
    3. Increased FSH
    4. Increased LH
    5. Decreased estrogen
    1. Low Testosterone
    2. Multiple ovarian cysts
    3. DM
    4. Hirsutism
    5. Amenorrhea
    1. Androgen insensitivity Syndrome
    2. None of the above
    3. Klinefelter Syndrome
    4. Premature Ovarian Failure
    5. PCOS
    1. Premature Ovarian Failure
    2. None of the above
    3. Klinefelter Syndrome
    4. Androgen insensitivity Syndrome
    5. PCOS

    Author of lecture Diagnoses of Reproductive Hormone Disorders– Reproductive Pathology

     Carlo Raj, MD

    Carlo Raj, MD

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