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.
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.
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 .
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.
I don’t mean ridiculously low IQ. They’ll get a job but they may not be the most efficient.
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.
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.
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.
That increase in FSH is then going to bring about aromatization of your testosterone into estrogen.
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.
Amazing? Know that one. Let’s move on to androgen insensitivity syndrome. Know this big time.
Now, with androgen insensitivity syndrome, remember, genotypically your patient here XY, male.
Male pseudo-hermaphrodite is what we looked at with our algorithm in prior discussion.
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.
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.
At the age of 15 or 16, no menarche has taken place in her daughter. Pelvic exam is being done.
Upon examination, you’d noticed there is a vagina. Her breasts have developed properly.
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.
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.
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.
In this patient, none of those exist, hence the blind pouch. Let me ask you something.
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.
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.
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.
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.
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.
Please understand this much. Let’s move on to another patient. This is premature ovarian failure.
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.
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.
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.
and so on and so forth. So, don’t worry about that so much. She is obese and she’s hirsutised.
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.
Let’s get going. I said there was increase in estrogen and testosterone. She’s obese.
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.
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.
We have your phallus and your prostate not present. Premature ovarian failure, interesting concept.
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.
What’s the name of the first phase of the menstrual cycle, follicular, A.K.A. proliferative.
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.
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.
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.
Klinefelter, please pay attention to the arm span. Take a look at the jaw, male-like.
Take a look at the chest, gynecomastia. That arm span seems to be as long as the leg span.
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.
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.
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.
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.
There are criteria for polycystic ovarian syndrome. One of them includes oligomenorrhea.
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.