Polycystic ovary syndrome in adolescents is common, has different diagnostic criteria from those of adult PCOS, and carries lifelong health implications. In this guide, pediatric endocrinologist Jennifer Olson, MD, FAAP, offers a clear path for PCPs suspecting the condition, covering questions to ask patients, tests to order and treatment options. Learn how to establish a management plan with individualized goals.
I like to share and I liked to receive questions. So I hope there's lots of them um at the end. Um So I'm going to talk about pcos or polycystic ovary syndrome and adolescence and try to provide some tips for primary care. Right? Let's see if I can. Um Oh there we go. Okay. I have nothing to disclose. So agenda today is to describe the pathogenesis of Pcos as currently understood to diagnose Pcos and adolescent females to identify comorbidities associated with PCOS to screen for metabolic complications and to choose appropriate treatment for adolescents with Pcos. Alright, so I always like to start with a case. Uh so we have some something to sort of focus on as we go through The talk. Um so this is a 15 year old female who presents to your office with secondary and gonorrhea. She reports that her monarchy was at the age of 11 And initially she had Menzies occurring every 2-3 months But for the past 12 months has not had a menstrual period at all. She's had no recent change in her weight. She walks about half a mile to school. That's her exercise. And she just says she gets a regular diet. She also waxes hair from her upper lip and she plucks hair from her chin. Family history is significant for type two diabetes and her dad. Alright so here is our patient. Um she is overweight. Her blood pressure is um is generous. Um You note that she has mild parasitism under her chin and that she has a can Thanasis Niagara cans around her neck and under both of her Zilla. She's fully developed 10 or five and there were no other remarkable findings. Okay, so what additional questions should you ask this patient? What laboratory studies should you order? What imaging studies if any? Should you order and what treatment or treatments should you offer this patient? So we're going to go through the um and try to answer these questions. Right, so polycystic ovary syndrome or pcos is the most common endocrine disorder in women. It affects about 10% of the general population and it's the most common cause of female infertility. So it's it's important to understand it. It frequently becomes manifest during adolescence and it has significant implications for morbidity throughout the lifespan. This includes metabolic syndrome and cardiovascular disease, type two, diabetes, depression and psychosocial dysfunction and endometrial carcinoma. The cause is unknown but it appears to be a complex trait that has both heritable and non heritable factors. It starts with the intra uterine environment and then is influenced by the extra uterine environment. It involves insulin resistance and obesity as the most common influencing factors. And it always involves ovarian dysfunction. Um in two forms an ovulation in androgen excess. The pathogenesis. Unfortunately it's not well understood. It's a can be a heterogeneous presentation and path of physiology. It seems to include a complex interaction between genes and the environment. There may be an autism. All dominant um presentation with variable penetrates and it seems as if there is a co primary pathogenesis. So there's two things going on at the same time. One is in the neuro endocrine system involving gonadotropin releasing hormone and LH lutin izing hormone. And the other is a separate um path of physiology going on in the ovaries leading to ovarian hyperandrogenism. So under normal circumstances I'm just going to go through a little bit of physiology here. Under normal conditions, the hypothalamus releases, going to add a trope in releasing hormone G. N. R. H. Which then leads the pituitary to release the appropriate amount of FSH and LH follicle stimulating hormone and scrutinizing hormone. These hormones stimulate the ovaries to produce estrogen estradiol, progesterone and testosterone. And again under normal conditions there is this nice feedback where testosterone is produced in the thick of cells and then feeds back um and down regulates its own production in the pathogenic state, leading to pcos. There is an increase in G. N. R. H. Release. This leads to a predominance of looting izing hormone or LH. And this leads in turn to an increase in testosterone and a loss of the internal regulation within the ovary itself and ultimately there's granule, Asus cell death which leads to the polycystic ovary appearance and um lack of feedback to the hypothalamus and so this continues unregulated. There are multiple organ systems involved in pcos and as I have mentioned the hypothalamic pituitary system is involved with increased production of gonadotropin releasing hormone leading to an increased ratio an increase ratio of LH. FSH. That's the first organ system. The ovary itself is also involved over producing testosterone. The adrenal glands are involved with an increased production of D. H. E. A. S. The liver is resistant to insulin. Um Do this. Um Fat cells are pro inflammatory, also produce estrogen and are resistant insulin. Uh And then the muscle cells are resistant to insulin as well. So the path of physiology can be different in different patients. Um 90% of individuals with pcos have functional ovarian hyperandrogenism where the ovaries overproduced testosterone 50% have hyper insulin ism 50% have LH excess. about 50% have obesity. Which is interesting because about 50% or so of individuals with pcos are not obese and then there's about 25 to 50% who have functional adrenal hyperandrogenism. So there's over production of androgens from the adrenal glands and then there's about 5% who have normal ovarian function but have isolated adrenal hyper and androgen isM. So it can be quite heterogeneous. How does insulin play into all of this? So there is a role for insulin in PCOS and um insulin in high levels, increases adrenal and ovarian production of male hormones or D. A. G. A. S. And testosterone at high insulin levels. Also decrease the synthesis of sex hormone binding globulin from the liver in turn leading to high levels of free testosterone. So the insulin resistance is also tissue specific the liver and the fat cells and the muscle cells are resistant to insulin. But the ovaries and the adrenals are still sensitive. High insulin levels also increase the risk for obesity and type two diabetes hypertension display video miA and nonalcoholic fatty liver disease. And these all increased risk for cardiovascular disease. So what are the risk factors for PCOS? So it's a biological process that acts throughout the lifespan and it begins in utero. So low birth weight babies small for gestational age are at higher risk for pcos. We call this metabolic programming. In addition, those fetuses exposed to maternal androgens from maternal pcos or congenital adrenal hyperplasia, for example, also have increased risk for developing pcos. Post natal rapid weight gain is a risk factor. And um Precocious adrianne, archy or early adrianne arche um which is the appearance of Pubic hair, axillary, hair, or body odor before the age of eight. and girls Can lead to a 2-fold increased risk for pcos and adolescents. Early age of puberty development is a risk factor and then obesity, which is the most common cause of insulin resistance. So first I'm going to briefly discuss the pcos phenotype is an adult. Before moving on to discussing how pcos is diagnosed in adolescence. So the diagnostic criteria for adults go back to 1990 and the NIH and these um criteria that that are based on regulatory dysfunction or polycystic ovary morphology um define our are defined um in these four studies. So the most familiar is actually the Rotterdam criteria. Um But after that came the androgen excess and pcos society with its criteria and then back to the NIH in 2000 and 12, which basically just reinforced the Rotterdam criteria. So all of these criteria involved a combination of either androgen excess and and ovulate Torrey dysfunction. Androgen excess and polycystic ovary morphology Um or all three. So what about pcos and adolescence? So in 2015 there was a consensus panel from the pediatric endocrine society that was convened and the concern was that adult criteria being used in adolescent females was problematic. And the main reason is that an oval atari cycles are normal in adolescence. And here statism can only be defined two years after monarchy. Acne is also common in adolescents and testosterone levels rise during an ambulatory cycles. There was a lack of reliable normal uh reference ranges for testosterone levels and adolescents. Um It was unclear if hyperandrogenism in adolescence predicts future hyperandrogenism and adulthood. Um And then if you look at ovaries on ultrasound polycystic ovary morphology is actually common finding in normal adolescence. So the the pediatric endocrine society consensus panel decided that it was important to develop separate criteria for adolescent pcos that was not based upon the adult criteria. So first it's important to understand um the definition of a Maria in um adolescence. So There's always ovulate Torrey dysfunction in Pcos. Um primary aim. Honoria is defined as lack of monarchy by 15 years or by three years after breast development. Secondary aim. Honoria is defined as going more than 90 days without a menstrual period after monarchy, and then Olive Go Maria is dependent upon years post monarchy. So in the first year post monarchy, oligarchy, gonorrhea is less than four periods of year, four periods per year, and then once the the regulatory cycle is considered mature, which is after six years post monarchy. Um then Olive Go minnery A would be fewer than nine periods per year. But it's important to know that um these definitions are all based upon the timing of monarchy. So excessive uterine bleeding is Um always define disciples that are shorter than 21 days or Um or one cycle less than 19 days in one year. And it's always abnormal to have cycles shorter than 21 days or to have fewer than um cycles every every three months More than 90 days. Okay, so what are the diagnostic criteria for pcos and adolescents. So in 2015, the panel Um agreed that two things were necessary. The first is ovulate Torrey dysfunction, which is age and puberty stage specific, which we just talked about. And the second is hyperandrogenism. These symptoms also need to be persistent and otherwise unexplained. So it's a diagnosis of exclusion, Obesity and insulin resistance are not essential to diagnosis even though they're comin and polycystic ovary morphology on ultrasound is not required for diagnosis. So no imaging is needed to make the diagnosis of pcos analysis. Okay, so how is androgen excess defined? It can be one of two ways it can be biochemical, which is a laboratory test showing persistent elevation in total and or free testosterone. Or it can be clinical. So 60-80% of patients with pcos have clinical signs of hyperandrogenism. Mostly it's your statism, but it can also be moderate to severe inflammatory acne that's unresponsive to therapy. Or it can be these here statism equivalents um said Maria hyperhidrosis, hydrogen dinosaur coritiba. These are similar to hear statism. So what's the differential diagnosis? So if you look at this pie, you will see the um in greene by far the most common ideology for hyperandrogenism is PCOS. And most other conditions in the differential diagnosis. There's a much smaller incidents, but they include non classic ch paralyzing tumor cushing's disease, Hyper protect anemia. Acromegaly, thyroid dysfunction. Um exogenous um causes from uh certain drugs uh and then there's an idiopathic, so how do you evaluate hyperandrogenism? So the serum free testosterone is going to be your most sensitive test And it is 50% more sensitive than total testosterone. So this is a very useful to remember um that a patient and adolescent can have a normal total testosterone level but can still have an elevated free testosterone testosterone total testosterone levels. Um Over 150 would increase the likelihood of an ovarian or an adrenal tumor. And um the reference ranges that are used for adolescents are the adult reference ranges. Sex hormone binding globulin is suppressed by hyperandrogenism anemia and by hyper insulin e. Mia. Um So these patients often have a low S. H. P. G. And then the D. A. G. A. S. Is the best marker for adrenal androgen production. And if your D. H. Es level is over 700 that would be a reason to consider adrenal imaging for a possible tur what is the evaluation for abnormal densities? So obviously you would want to rule out pregnancy. Um And then you also want to consider uh other causes of abnormal menstrual patterns. So chronic disease anemia um conditions that would cause chronic inflammation. Um So a said rate or a crp might be helpful a cmp to look at things like liver function, kidney function. Um LH and FSH are important labs. Uh Prolactin, high high prolactin can cause the main area and then thyroid conditions um Obviously also can affect the menstrual cycle. Um And then I always mentioned that mild elevations in TSH in the 5 to 10 range is common in obese individuals and it is one of the consequences of of obesity and not the cause of obesity. So what else causes hyper androgen androgen ism besides pcos. Um So the important thing is to rule out are non classic Ch. And you can do this with a 17 hydroxy progesterone that's drawn at eight a.m. Um And if it's over 1 70 then you would at least need to consider that it's non classic. Ch. And you would probably refer um So that an A. C. Th test could be done um D. H. E. A. S. We we talked about as being the most important adrenal androgen And a. level over 700 would be worrisome for a paralyzing adrenal tumor. Um cortisol an afternoon level under 10. Um Makes cushing syndrome unlikely. But you can definitely do a 24 hour urine collection for free cortisol. If you're worried about cushing's if there's other signs of cushing's um and then um gigantism or acromegaly um you can check an I. G. F. One level. So what is the role of older sound? So the consensus panel does not recommend ultrasound for diagnosis and the reason again is that there is a high frequency of polycystic comparing ovaries in normal adolescent females. The role for ultrasound is essentially to exclude an ovarian um Androgen producing tur so if the total testosterone is over 150 that would be a reason to do a pelvic ultrasound to look at the ovaries um If there are other signs of civilization like clitoral meagley um rapidly progressive here statism deepening of the voice. Um Or there's a poor response to treatment. Those would be all reasons to to image the um ovaries. So there are many comorbidities associated with PCOS is a metabolic disorder and it is associated with both insulin resistance and hyper insulin amia. It's associated with overweight and obesity. And many of the lipid disorders um associated with metabolic syndrome are also found in Pcos. So this is generally high triglycerides and high HD high LDL cholesterol with a low HDL. There can be impaired glucose tolerance. And about a third of patients with Pcos There's type two diabetes, there's obstructive sleep apnea as well. And these are all risk factors for cardiovascular disease to screen for cardiovascular comorbidities. Um It's a fasting lipid panel uh hemoglobin A one C. Um and then blood pressure um measurements. You can also do a two hour or a glucose tolerance test but I find a hemoglobin a one C. Two B. A much simpler test to obtain other comorbidities include fatty liver or non alcoholic fatty liver disease which is five times higher in pcos. It's manifested by an elevated A. L. T. Um It's important to to diagnose and to recognize this because metformin which is one of the treatments that we're going to talk about is contraindicated especially if there's very high um liver markers or liver failure. Um endometrial carcinoma carries a 2.7 fold risk in pcos compared to the general population. This is due to prolonged unopposed estrogen stimulation of the endometrium and then depression and mood disorders are very common and this can be due to the excessive weight gain that's associated uh here statism acne. Um And then even the menstrual irregularity and concerns about fertility can really um way on even um even young adolescents. So family members also need to be evaluated. The parents of these Um individuals and their siblings are also increased risk for metabolic syndrome and type two diabetes. Um And then their mothers and their sisters are at increased risk for PCOS. So um just like type two diabetes is a family disease. I also um council the entire family um when I'm talking to an adolescent with with PCOS. So what are the management goals? The number one thing to consider is the patient's concerns. So it's really important to ask the the young woman what what bothers you the most? What are you worried about? What don't you like? Um Because ultimately what you're trying to do is improve quality of life, improve long term health outcomes. Um Remember to to think of the comorbidities and understand that a multi drug therapy might be necessary to target all the aspects um and that it's a lifelong syndrome and it's um it can change over over the lifespan as well. So options for management. Um The first one is always going to be lifestyle modification if the patient is overweight, combined oral contraceptives for the menstrual irregularity. Progestin only contraceptives um or or treatment for a Maria spironolactone. Cosmetic hair removal. Metformin. Um And then I'll mention a few potential new therapies in addition. All right so lifestyle management because up to 80% of women with pcos are overweight or obese. Um it's important to just to reduce their sedentary behavior, increased physical activity and then um implement you know some form of calorie uh reduction. Um There isn't good evidence that a low fat diet or a low carb diet is better. Um But ultimately you do need to reduce calories. Um And then again this is really tends to be you know a family um Oriented disorder. Um many times you know parents have type two diabetes um or there's obesity and the siblings. And so it's really about how the whole family can be healthier. So even a modest amount of weight loss can improve Insulin sensitivity, decrease blood sugar levels, improved lipid profiles 5-10%. You can also reduce androgen levels with weight loss and you can improve menstrual function and as a as a result ultimately um fertility. Um And there is some research looking at the effects of bariatric surgery on decreasing um Type two diabetes hypertension prediabetes and display academia. So for menstrual irregularity combined oral contraceptive pills as sort of the cornerstone. Um But I will say that there is a significant amount of resistance um um among uh families and and patients um to use oral contraceptives because of the association with birth control. Um But they do reduce androgen production and as well as androgen excess by suppressing the endogenous hypothalamic pituitary ovarian access alright access and increasing sex hormone binding globulin. So they also prevent endometrial hyperplasia. And this decreases the risk for endometrial carcinoma. And they do provide contraception which uh you know can be useful. So it is the first choice for the regulation of of any irregular menstrual pattern. Um you can see an improvement in 2-3 months. The duration of treatment is not well defined but considering a trial off after a one or more years of therapy is reasonable. Um And of course you have to weigh the risk of a trial off with the risk for pregnancy. Um And uh some of the recommendations are to continue oral contraceptives until the patient is kind of psychologically mature. Which is defined as more than five years post monarchy. They work by decreasing LH and decreasing ovarian androgens and increasing S. Hbg which in turn decreases free testosterone. So that's the mechanism of action. Um they contain a combination of ethinyl estradiol generally 30-35 micrograms and then a progestin and I've listed the progestin is here in the order of um anti androgynous city. So um diese gestural and dress maradona are the most anti androgenic so they are the best um for parasitism and or acne. Um But they also carry a higher risk of vino venus thrombosis embolism. So this just compares the androgynous city of the progestin component versus um thrombosis bolic risk. And as you can see in the green um be as your androgynous city uh decreases. Um You can see in the blue the relative risk of venus from mombasa risk increases as you go from the first generation to the fourth generation progestin. I'm just listing here some common um oral contraceptive combinations. Um And again the progestin component is listed in order of androgynous city um along with the estrogen component and the brand name. Um I think it's important to sort of you know have one or two in your repertoire that you're comfortable prescribing and um and you know sort of go with go with uh you know your top you know 11 or two choices. Um The lower the ethinyl estradiol, the higher the risk for breakthrough bleeding is. Um So that's always something to consider as well. What are the adverse effects? Um So they increase insulin resistance. Um They can increase risk for blood clots or stroke. They increase LDL cholesterol, total cholesterol and they can raise blood pressure. um so there is a 4-fold increased risk of venus thrombosis thrombosis bolic events compared to non users and a 1.5 to 2 fold increased risk of stroke or myocardial infarction. Um Obviously you know these risks are lower and younger individuals who don't smoke, you don't have a family history. Um And then they can also affect glucose tolerance. So for the families or for the individuals who do not want to take a uh birth control pill or don't want to take a medication daily. Um Then there is a progestin only option. And um I have these patients taken oral progestin for 7-10 days every 1-3 months. And this is just to induce a withdrawal bleed, protect the uterine lining um and increase the risk for uterine cancer. And the reason I usually prescribe this every another month is to allow the patient to know if they're having spontaneous Menzies in between and if they do have a spontaneous Menzies then they can skip the following month. Um and only take the progestin if it's been two months without a period. Um So this is actually quite popular option. Um And it can be done with either pro vera or micro nyse progesterone, which is prom a tree. Um All right. Um So there is um less risk for cardiovascular disease but it's also important to note that this um form of protecting the uterine lining does not improve here statism or acne. Um And it does not provide contraception. Um Side effects can be depression or mood changes, bloating breast soreness. So what about here statism? So cosmetic hair removal is the cornerstone. So this can be done by shaving. Um Chemical agents waxing bleaching threading um And the goal is to either mask the hair or remove the excess hair. Um These forms of hair removal have immediate results and um you can repeat them. They're also relatively safe. They work relatively inexpensive and can be done without a prescription. There is a prescription cream um for hair removal. Um But it's only by prescription and it stops working when you stop using the cream. Mhm. So if the patient has here to hear statism combined, oral contraceptives are still the first line of medical therapy um But they work better if the hair is removed first. Um You can add an anti androgen which is essentially spironolactone after six months um Which reduces your citizen by 1/3 when used in combination with oral contraceptive pill. Um the maximum effect takes 9-12 months. So I always tell patients that they have to be patient. Um and then you need to take be taking at least 100-200 mg um divided b. i. d. It's important to know to check liver function in potassium after a few weeks of treatment. It is potassium sparing. Um And it's important that you start the oral contraceptives first because it's Terada genic. So metformin is also um Recommended in pcos and it is approved for type two diabetes in those over 10 years of age and it has been approved since 2000. Um It's recommended for patients with insulin resistance because it improves glucose metabolism um Can help lower B. M. I decrease like infosys. It can help the lipid profile. Um But it doesn't work by itself. It works along with lifestyle changes in terms of diet and exercise and then it can improve ovulation and about half of patients. So uh decreases testosterone and it has a little bit of an effect on hair statism. Um You need to get to a dose of 1000 mg a day. Um Generally I start at 500 then I titrate up. Side effects are pretty common include diarrhea, upset stomach decreased appetite. The maximum dose is 2000 mg a day. Um I also tend to stick to the extended release formulations uh whenever possible they're a little bit easier on the G. I. Um in terms of gi side effects. Um I always tell patients to take with food and then avoid if the liver function tests are extremely elevated more than three times normal. And then I counsel about the risk for lactic acidosis. And to avoid taking the medication if they have uh you know uh stomach flu or a G. And can't eat normally or if they're having a ct skin and need I. V. Contrast dye and not to use alcohol. Um I'll just mention like Arugula tide which is a tosa, it's a GLP one agonist. It has been approved for youth over 10 years of age with type two diabetes. Um It increases insulin and lowers glue pagan. It inhibits appetite and it's as effective as Metformin for weight loss in some randomized trials in obese women with Pcos. Um It does have significant side effects nausea, vomiting diarrhea. So I have found that it's not very well tolerated um vitamin deal just mentioned because it's pretty benign. There are some studies that suggest it can lower total testosterone. Um And there is some new evidence that there is an increased fracture risk and decreased bone mineral density in women with Pcos. So there's no reason not to optimize vitamin D. And calcium. Okay so I'm going to wrap up by going through back to our young women. Um And so what additional information? Um Well she has some feelings of depression. Um What laboratory studies um did you get? And what are the results? Um This is a very classic sort of profile for somebody with Pcos. Um The total testosterone is actually within the normal reference range but the free testosterone is almost twice normal. Um Sex hormone binding globulin is low LH is high. The LH FSH ratio is 3 to 1. The D. A. T. A. S. Is Elevated but it's it's not over 700. The A. One C. Is kind of in the prediabetes range lt mildly elevated triglycerides, mildly elevated LDL elevated And HDL cholesterol close. Um And you've already ruled out thyroid disease non classic ch hyper lacked in and uh the fasting glucose in the S. T. Those are those were all normal. Okay so what are you how are you going to treat her? Um You're going to recommend lifestyle modification, increase exercise, decrease calories. Um Get rid of all the sugary beverages. Simple carbohydrates, increase whole fruit, vegetables, fiber, lean protein and smaller portion sizes. Um You probably start by considering a combination oral contraceptive pill. Or you talk to her about matt foreman. Um You might add spironolactone for her hair statism and you might refer her for mental health support. So I'll just summarize Pcos and adolescents. Um it affects 10% of women. It's the most common cause of female infertility. It's a complex heterogeneous, poorly understood condition. The risk factors are genetic and environmental and begin in utero adult criteria should not be used to diagnose Pcos and adolescents. Multiple comorbidities are associated with Pcos. Um The treatment must be individualized based upon the patient's concerns. Treatment primarily addresses the symptoms and it's a lifelong condition. Um So diagnosis is made by menstrual irregularity or a memory a plus androgen excess. The laboratory evaluation I've summarized here. Um But we went through it in detail. Ultrasound is not required for diagnosis. It's used to exclude humourous um and treatment is lifestyle modification combined. Oral contraceptives, uh pills, um Metformin or both. Um Cosmetic hair removal from election Rivera. Um This is a resource for patients um that I often um provide um from the pediatric endocrine society? Um Pcos a guide for patients and parents and how to refer your patients to UCSF, mm hmm
