S1E55 Polycystic Ovary Syndrome (PCOS)

the ovaries. So you might think that that's all this is, but in actuality, you don't even need to have polycystic overies to be diagnosed, and the fluid filled structures in the ovaries they're not even true cysts, but we'll talk more about that later. So PCOS is one of the most common endochronopothies in women of reproductive age. It effects between six point five and ten percent of all women of reproductive age. Let's go ahead and get started with

the patho first. So the patho is pretty complex, multifactorial, there's a lot going on, so we'll keep it focused on what you need to know. Some key concepts or trends that we typically see in patients with piacos. So starting with your LH levels. So PACOS patients have altered LH levels with relatively higher serum lutinizing hormone concentrations relative to FSH concentrations. This is just a small component of the whole picture, but I think is important to understand.

So let's do a quick review of a normal functioning hypothalamic pituitary ovariant axis. In a normal HPO axis, the hypothalamus releases GnRH in a pulsatile manner, stimulating the anterior pituitary to secrete LH and FSH. LH goes down and acts on the thika cells in the ovary, promoting androgen production primarily androstendon, while FSH stimulates granulosa cells to produce aromatase. Romatase is an enzyme that converts these androgens into estrogen,

specifically estradil. So as this process goes on, a dominant follicle develops. F SH stimulates the follicle to develop. Rising estrogen levels trigger positive feedback on the pituitary, leading to a surge in LH, which induces ovulation. Most of this you probably already know. After ovulation, progesterone from the corpus lutium provides negative feedback, slowing down GnRH pulses, reducing LH and FSH secretion to complete the cycle. It's a lot, but here's the part that you need to know and

p cosse. This balance is disrupted due in part two, a higher pulsatile frequency of g n rh which LH is more responsive to, leaving us with excessive amounts of LH relative to f SH levels. So it means those thikas cells which are stimulated by LH are now producing too many androgens and FSH can't keep up to convert them.

These elevated androgen levels, along with the relatively lower f SH levels, which normally stimulate follicular development, impair normal follicle maturation, resulting in anovulation and in accumulation of these immature follicles in the ovary, which lead to the classic appearance we'll see on ultrasound in some patients. Okay, so remember the increased LH to FSH ratio. One other part of the pathway I feel is important to understand is how insulin

resistance plays a role. So fifty to seventy percent of females with p costs demonstrate clinically measurable insulin resistance, So we have insulin resistance which leads to compensatory hyper insulinemia. So high levels of insulin in the body. But what do high levels of insulin have to do with androgen

excess and ovulatory to spunction. Well more than you'd think, So besides the obvious regulation of glucose that comes to mind when thinking of insulin, it does something else when in high levels, and that is to stimulate the THIKA cells of the ovaries to produce more androgens. So kind of like what we were talking about before with the effect of LH on the ovaries, insulin can stimulate steroidogenesis,

causing those THECA cells to crank out more androgens. And these increased levels of insulin also inhibit production of something known as SHBG, sex hormone binding globulin. This is a transport protein that binds to hormones like testosterone as well as others, and it regulates their access to certain tissues. When hormones like testosterone are bound to SHBG, though, and this is the important part, these hormones are rendered inactive,

meaning they can't do anything. So the fact that these high insulin levels inhibit production of SHBG means we have more of those androgens hanging out free in the bloodstream in their active state, able to unleash their hyper androgenic effects. High insulin levels even seem to override the ovara's natural resistance to LH, making them hyperresponsive, driving even more androgen production, all of which lead to some of the clinical manifestations

will go over all. Right, So that's a lot of info. May take away. Excess LH relative to FSH, excess insulin from insulin resistance. Remember those and let's move on to the clinical manifestations next. So this is a syndrome, so the clinical presentation can vary from person to person, and there's many potential clinical manifestations irregular menstrual cycles, hersutism, acne, obesity,

mood disorders, metabolic issues, cardiovascular issues, diabetes. But the two, the two I want you to remember that are also part of the diagnostic criteria will go over shortly is as follows. The first is menstrual dysfunction oligomenareea amenareea. So women with PA costs will have infrequent or absent menstrual cycles, which is caused by infrequent or absent ovulation. As a result.

Infertility is a common consequence of these menstrual regularities and is frequently one of the reasons women with pea costs will seek medical attention. So remember oligomenarea or amenarea and the potential for infertil Next, hyper androgenism, hersaitism, acne, female pattern hair loss. So these are the repercussions of those excess androgens like testosterone we mentioned earlier. So hersaitism which is a thick or pigmented body hair also known as

terminal hair and a male distribution pattern. So we can see dark hair growth on the upper lip, the chin, around the nipples, the perieriolar surface, as well as the lower abdomen. The linear alba acne is common as well. This can be on the face, back, chest as well as other areas of the body. And then finally, female pattern hair loss, so these women may start to have

thinning of the hair on their head. This diffuse alopecia. Okay, So menstrual dysfunction, oligo or a menorrhea, and hyper androgenism. Now these are the two I want you to focus on, but of course be aware there are other potential clinical manifestations metabolic issues like obesity, insulin resistance, but focus on the menstrual dysfunction, infertility and hyper androgenic features. Let's talk

about diagnosis next. So when we're talking about the diagnosis of PECOS, there is no no single lab or imaging study you can do to definitively diagnose this syndrome. So what we do to make the diagnosis is by using something known as the Rotterdam criteria. There are a few different criteria out there, but the Rotterdam criteria is the one most expert groups use and therefore it's the one you need to know. So what does the criteria entail?

So to make the diagnosis of PA costs, you need to have two out of the three based on the Rotterdam criteria. The first is oligoovulation or anovulation, which will generally manifest with menstrual regularity like we talked about before, so infrequent or absent menstrual cycles. The next is clinical and or biochemical signs of hyper androgenism. So this means either the patient has clinical signs of hyperandrogenism so hersitism,

actne et cetera. Or they have biochemical signs of hyper androgenism so you obtain labs and they have elevated testosterone levels. And then finally, the last criteria, which we haven't talked too much about yet is the ultrasound defindings. So the last criteria is polycystic ovaries by ultrasound. So let's talk

about the ultra findings. Like I mentioned before, the fluid filled structures in the ovary that we see in some women with PA costs are not cists, but rather these immature follicles that never developed during those failed ovulation events. So an ultrasound will see abnormally high numbers of small

follicles within these enlarged sclerotic ovaries. The small follicles are often located on the periphery of the ovary and sometimes they'll resemble a string of pearls and you'll sometimes hear them being referred to as that string of pearl sign when describing p COS ultrasound findings. So the Rotterdam criteria states a positive finding on ultrasound is twelve or more of these small follicles and either ovary measuring two to nine millimeters in diameter and or increased ovarian volume over

ten mL. Now, there are some groups that suggest revising this increasing to twenty or more follicles per ovary because of the improvements and resolution of pelvic ultrasound and the fact that a percentage of normal cycling women met the threshold without having PA costs. What that means to you is, don't memorize these numbers. If they can't agree on the criteria for the specifics here, they can't expect you to remember them or memorize that for an exam. So don't

worry so much about the specific number. But keep in mind, if the question is describing numerous small follicles and a big old plump ovary, they're probably describing pea cos all right. So that's the Rotterdam criteria. That's what you need to know. Irregular ovulation, hyper androgenism, and polycystic ovaries on ultrasound you need two out of a three, meaning if you have a patient with irregular mensis and hyper androgenic symptoms, you don't even need an ultrasound to diagnose. But there is

one last part we're missing, one very important component. Before you make the diagnosis based on the Rotterdam criteria, you absolutely have to rule out your differentials. Rotterdam criteria also require exclusion of other conditions that mimic pea costs, So peacos has some very sneaky impostors conditions that have many of the same or in some cases exactly the same clinical findings. So once you establish a patient fits the Rotterdam criteria, the next step is to rule out your

very important differentials. Now, there are a number of differentials. I'm not going to cover every single one, but the ones you need to know and the ones that will likely be tested on can all be found in your apartment. Your apartment as an APT what does that mean? Apartment APT stands for three important areas and those are adrenal, pituitary, and thyroid. So these are the differentials to roll out before making your diagnosis, and they can all be found

in your apartment. So starting with adrenal, the letter A, what I'm going to cover right now is the most important differential you need to know, and if they're going to give you a differential on an exam, it will very likely be this one. This is known as NCCAH non classic congenital adrenal hyperplasia. If you want to forget all of the other differentials, I'm going to go over

and just remember one. This is it. A patient with NCCAH can present with almost identical signs and symptoms as those with PECOS hyperindrogenism, olligo, manaia, polycystic overies, So you

don't want to miss this. So to screen for this, you obtain a serum seventeen hydroxy progesterone, which is also super high heal to know, I sometimes remember the as apartment seventeen just to help me remember this screening test because it's just so popular to be tested on, and I definitely got a question on this in school, So please remember this one and then the other. Adrenal differential is an adrenal tumor, so a patient with an adrenal

androgen secreting tumor or an adrenal cortical carcinoma. These patients can have clinical and biochemical manifestations of hyper androgenism like pa COS, but generally more severe. These patients usually have significant elevation of testosterone and or DHVAS levels way higher than PECOS patients, and usually will exhibit more severe signs of hersitism and even signs of virilization things like cliteromegaly, increased muscle mass, and deepening of the voice, which we

typically don't see in pea COS. Okay, so that's the a for apartment. Adrenal main takeaway, don't forget NCCAH screened with the seventeen hydroxy progesterone. Remember your apartment seventeen. Next letter in the apartment is P which stands for pituitary. Specifically, we're talking about hyper prolactinemia. So hyperperlactinemia, which is an elevation of prolactin levels from the pituitary, can lead to infertility, oligomenarea or a menareea, so this needs to be in

your workup. And then finally, the T stands for thyroid, so both hypo and hyperthiroidism can also lead to oligomenarea, so check a TSH as well. There are, of course other differentials Cushing syndrome, primary ovarian insufficiency, ovarian hyperthiicosis, pregnancy of course a very important cause of a menarea. But the ones I highlighted in your apartment those are the ones to remember as those will likely be tested on again.

Highlighting non classic congenital adrenal hyperplasia, which you screen for with a seventeen hydroxy progesterone. All right, next, let's talk about treatment. So treatment for PCOS is targeted at a number of different areas because of all of the complications associated with this condition. Remember we have oligomanarea, hyperindrogenism and fertilities, obesity, insulin resistance, dyslibidemia. So I'm breaking this down to highlight

the essentials. Let's start with what is considered the first line intervention for many women with peacos, and that is lifestyle changes diet exercise, weight reduction. Specifically in our overweight or obese patients with p costs, Diet, exercise and weight loss are very effective for improving insulin resistance, decreasing the hyperandrogenic symptoms, and some studies have found that modest weight loss five to ten percent reduction in body weight may

restore normal ovulatory cycles and improve pregnancy rates. Of course, this is also beneficial for managing the underlying metabolic abnormalities we talked about cardiovascular disease, type two diabetes, etc. So this should be the first step for all overweight and obese women with PA costs. The next step for treatment we're going to talk about. Our medications are pharmacologic therapy. We're going to break this down into two categories, women

pursuing pregnancy and those who are not pursuing pregnancy. So starting first with women not pursuing pregnancy, a patient who does not want to get pregnant, who has menstrual dysfunction and or androgen excess, which medication can we use? So the first line pharmacotherapy for most women will be with a combined oral contraceptive or a COC, which is a combination of estrogen and progestin. So the coeocs have a number of benefit for women with PCOS. First, they suppress

ovarian androgens, decreasing the hyper androgenic features. Obviously, provide contraception because even women with oligomenarrhea may still ovulate intermittently lead to unwanted pregnancy. And then finally, something that we may not be thinking about, but patients with chronic annovulation like in PECOS. These patients are at higher risk for endometril hyperplasia and even endometrial cancer. And that's because we have this chronic anovulatory state causing the endometrium to be exposed

to estrogen without the balancing effect of progesterone. We call this unopposed estrogen, and combined oral contraceptives help prevent this by providing daily progestin, which is a synthetic form of progesterone which counteracts the proliferative effects of estrogen on the endometrium and the second part of the combined oral contraceptive, the estrogen component reduces serum androgen concentrations by increasing SHBG concentration. Remember SHBG the guy who gives testosterone a big hug

and doesn't let go. So this in turn reduces the symptoms of acne or hersitism. Binding these in a CEOC helps you manage both hyper androgenism and menstrual dysfunction, and that's why these are generally considered first line pharmacologic treatment. Now, what about a patient with hyperandrogenic symptoms who's been on a COEC for many months with no improvement. What other medication do we have in our arsenal specifically for these

persistent hyperandrogenic symptoms. Well, the one you should know is spirinolactone. Spiralactone is a minerali cordiicoid receptor antagonist, and it is an effective treatment option for androgen excess as it blocks

androgen receptors and also decreases testosterone production. And spirinalactone falls under the women not pursuing pregnancy category because you do not want to get pregnant while taking this medication as it can actually feminize male fetuses, preventing development of their genitalia, so the patient needs to also be on a contraceptive

while taking this medication. There are some other options out there, such as finess, dride fluta, mind, but spirinalactone is the preferred agent compared to the other available options due to its efficacy. All right, next, let's talk about women who are pursuing pregnancy who are experiencing infertility and require treatment. So before we go over our meds and ovulatory women with peacos who are overweight oral beats should attempt to

weight loss prior to initiating ovulation induction therapy. In most cases, some older women or women whose testing shows diminished ovarian reserve sometimes they'll go straight to meds, but in general weight loss for navulatory women who are overweight oral beese weight loss is recommended first. If lifestyle changes and weight loss are not effective and medication is needed, the one you should know is in romatase inhibitor by the name

of lectrisol. Lectrosols should be first line treatment for ovulation induction in infertile analvieslory women with peacos. Now this has shifted over the years, as clomaphene used to be first line by per up to date and the twenty eighteen International evidence based guidelines, lectrosol is now the first line treatment option for ovulation induction in women with peacos, Like

a number of pea cost treatments. It's still not FDA approved for the syndication, so your patients need to be aware of that, And there are some alternatives clomaphene met foreman, although both of those are less effective for live birth rates compared to lectrozol, so I would just focus on lectrosol after weight loss in women pursuing pregnancy. So how does letrozol work for ovulation induction? While letrozol is in

aromatase inhibitor. Romatase, as we briefly discussed earlier during the path or review, is an enzyme that converts androgens into estrogen. So if we inhibit aromatase, less endrogens are converted to estrogen and we have much less estrogen in the body.

When we have less estrogen in the body, the hypothalamus and pituitary sense this say oh, crap we need to help out, and they produce more FSH, that hormone we have been lacking because LH took over the show, and with more FSH we have improved follicular development and improved ovulatory rates. Those are the mens I think you should know. There's plenty of others, but the ones I went over are the most commonly used and the ones you'll likely get tested on. All right, so that is p COS.

It's a lot, so you probably need a mnemonic. Now, before I tell you what the mnemonic is, I first want to be clear. This is just a memory tool. It's just a way to remember what you need to know about pa cos. In no way do I intend for this to be offensive to anyone with PCUS. It's just a simple little visualization that helped me remember. So PCUS or pa COS I used to remember in Seat

of Peacos as pea clause. Piacos is pea clause as in Santa Claus, and Santa Claus contains all of the high old things you need to know about peacos, including a Rotterdam criteria and the most important meds. So again, PACs is now pea clause as in Santa Claus. So when we visualize our Pea cos Santa Claus, you'll notice a few things about this version of him. First, in his right hand, he's holding a ball of lettuce, a lettuce ball. His left hand, he's holding a bottle of

Coca Cola. On his forehead is a big old pimple being popped with a spear. He's wearing a pearl necklace on the wall as a calendar with December twenty fifth circle, and of course has expected he has a big white beard, as we've all come to know him for now, what do all these things represent when it comes to Peacas. First, that ball of lettuce in his right hand, That lettuce ball helps remember the first line pharmacologic therapy for patients

pursuing pregnancy letrasol lettuce ball letrasol. And his left hand holds the clue for first line treatment for women not pursuing pregnancy, COC's or combined oral contraceptives with the first three letyers of Coca Cola highlighted coc What about the big pimple on his forehead being popped by a spear. Pimple represents your hyper androgenic symptoms like acne and the spear popping it helps you remember how you treat it

speir in a lactone, spear rhonolacton, speierronolactone. The anti androgen we used for patients with persistent hyperandrogenic symptoms despite coc monotherapy, is why beard helps you remember the hersaitism we can see in patients with peacos. The pearl necklace helps you remember the string of pearl sign remember those numerous follicles

on the periphery of the ovary. And then the calendar on the wall shows December twenty fifth circled, symbolizing infrequent or aps in periods like Sanna who only shows up once a year in his red suit. So there's a lot to remember in peacos. But I feel like if you can just remember Sanna and Apartment seventeen cement this crazy image in your brain, you should be just fine. Now that we have our mnemonic, let's do a few

quick questions to test your knowledge. Question one, a twenty nine year old woman presents to the office complaining of excessive hair growth on her upper lip, chin, lower abdomen, as well as irregular menstrual cycles. The patient is five feet five inches tall, weighs one hundred and thirty two pounds, and has a BMI of twenty two. On physical examination, there is terminal hair noted on the face and along

the line alba of the lower abdomen. She's not currently taking any medications, denies any known medical conditions, and is not planning on pregnancy at any point in the near future. She's interested in starting a medication to address the persistent hair growth on her face and abdomen and the absence of contraindications. Which of the following would be the most appropriate next step in management for the likely diagnosis A letrazol B spirriinalactone C met foreman D combined oral contraceptive

or E lifestyle changes, diet, exercise, weight reduction. So the correct answer is D combined oral contraceptive. So why is that the correct answer? So we have a twenty nine year old female presenting with hersaitism or regular metro cycles based on the Rotterdam criteria. She has pics. Of course, to definitively say that full work up to roll out your differentials would be needed, but that's not what this

question is asking. It's asking based on the likely diagnosis which treatment are you going to recommend to her hyper androgenic symptoms? So we know the medication we're going to prescribe as a coc or combined oral contraceptive. Remember that bottle of Coca Cola and Santa's left hand. Now, what about the other options? While letrozol would not be appropriate, this medication is used for ovulation induction in women pursuing pregnancy.

Spirinalactone could be used as an adjunct therapy for persistent hyperandrogenic symptoms, but it's generally not first line met foreman which at one time was used pretty frequently for peacs, is no longer recommended for hersaitism per the twenty eighteen Endercin Society guidelines, as it has been found to provide little or no benefit. And then finally, lifestyle would have been appropriate if this patient was overweight or obese, but this patient as a normal BMI of twenty two. Question two.

A twenty six year old woman presents to the clinic with concerns about difficulty becoming pregnant. She and her partner have been trying to conceive for several months without success. She reports only one to two menstrual cycles over the past year. It's not on any medications and has no significant past medical history. Physical examination reveals hersatism on the upper lip and lower abdomen. Her height is five foot four, weight is two hundred pounds BMI thirty four point three.

A transvaginal ultrasound reveals enlarged ovaries with multiple small follicles arranged peripherally. Differentials will rule DOWNT and the patient was diagnosed with PCOS. Which of the following is the most appropriate first step in managing her infertility? A clomiphene citrate, B letrasol, C met foreman D spirrinalactone E lifestyle change weight loss, So that is going to be E weight loss.

So this patient has a BMI of thirty four point three, so she is classified as obese and for younger women with PCOS and inovulatory infertility, attempts at weight loss should be attempted first. In those with obesity. If this does not restore ovulatory cycles, ovulation induction is attempted next, usually with letrasol. Question three. A twenty five year old woman presents to the clinic after noticing increasing facial hair growth

acne in irregular menstrual cycles over the past year. She reports that her periods now occur every two to three months. After researching the line, she believes she has polycystic ovary syndrome and requests treatment to help regulate her cycles and reduce the hair growth. She's otherwise healthy. Not taking any medication, denies galactoria, headaches, visual changes, heater, cold intolerance, or fatigue. Physical examination confirms hersaitism and reveals no other abnormalities. BMI

is twenty seven. Which of the following is the most appropriate next step in management of this patient. A initiate treatment with combined oral contraceptives. B prescribes sphere and lactone for hersuitism, C refer for laser hair removal. D conduct a diagnostic workup to exclude other causes of hyper androgenism and oligomenerrhea. Or E suggests lifestyle changes diet and exercise. So the correct answer is D conduct a diagnostic workup

to exclude other causes of hyper androgenism and oligomenarhea. While all of these are decent answers and may all be adequate treatment options at some point in the future for this patient. The first step before initiating any form of treatment for a patient with the expected PACs is the first ensured that they have piacos. And while she has some convincing symptoms based on the Rotterdam criteria, we can't forget that Rotterdam criteria also requires exclusion of other conditions

that mimic PACs before making the diagnosis. So we need to roll out our differentials to ensure we are treating the right thing. So start in the apartment for those differentials APT, adrenal, pituitary, thyroid, among others. Question four, a twenty nine year old woman with PCUS wishes to conceive. Over the past six months, she has attempted lifestyle modification, including dietary changes, increase physical activity, and has achieved modest

weight loss. Despite these efforts, he continues to experience and ovulatory cycles. According to current evidence, which is the most appropriate first line treatment option for ovulation induction for this patient A chlomiphene citrate, b letrazol, C met foreman D, gonadotropins E laparoscopic ovarian drilling. So the correct answer is

going to be b letrozol. So remember, let's tresol your lettuce ball in Santa's right hand is the first line ovulation induction agent over klomaphene citrate Answer A and met format Answer C, which are both less effective for live birth rates than electrosol and the other two options gonadotropins. Exogenous gonadotropin regimens are complex and expensive and considered second line, and of course laparoscopic ovarian drilling also referred to as

ovarian diathermy or electrocoagulation. This is a surgical option, meaning more invasive, and would generally only be utilize after the patient has tried and failed pharmacotherapy. All right, So that was picos. I hope that was helpful. Thank you so much for the support of the and best of luck in school.