Laboratory Assessment in PCOS Diagnosis and Management

Laboratory assessment in PCOS diagnosis and management (PODCAST TRANSCRIPT)

Welcome to the Healthier World with Quest Diagnostics podcast. Our goal is to prompt action from insight as we keep you up to date on current clinical and diagnostic topics in cardiovascular, metabolic, endocrine, and wellness medicine. 

Polycystic ovary syndrome is a common and complex hormonal disorder that impacts millions of women across the globe. It's estimated that 5 to 6 million women in the US have PCOS. But in clinical practice, the diagnosis and management of this condition isn't always as easy as it may seem. One in three women with PCOS may spend more than two years and see or more than three healthcare professionals before the condition is diagnosed. It is estimated that 75% of individuals with PCOS remain undiagnosed. Making an accurate and timely diagnosis of PCOS is crucial for the near and long-term health of patients as these patients face adverse reproductive and cardiometabolic health impacts across the lifespan.

I'm Sarah Walsh, a physician assistant by training and an educator at heart. I'm a clinical specialist within Quest Diagnostics cardiovascular, metabolic, endocrine, and wellness clinical segment. Today, I'm joined by Dr Sanjay Dixit board certified endocrinologist, and one of Quest Diagnostics medical directors.  

Today, we're going to dive into the challenging diagnosis of PCOS. We'll talk through PCOS basics, PCOS diagnostic criteria and review a guideline-supported algorithm that provides a step-by-step method to diagnosing PCOS. In addition to ruling out other disease states that may be on your differential. Welcome Dr Dixit. Thank you so much for joining me today.

Thank you, Sarah. It's great to be here. 

Okay. Let's all start on the same page here. What is polycystic ovary syndrome or PCOS?

Polycystic ovary syndrome is a disorder defined by a combination of signs and symptoms of androgen excess and ovarian dysfunction.  

Note that PCOS is a diagnosis of exclusion, many other disease states can cause similar signs and symptoms that present in PCOS. Statistics vary from source to source, but it's estimated that PCOS affects between 5 and 18 percent of reproductive-age women. It's the most common endocrine disorder affecting reproductive-age females and also one of the most common causes of female infertility.

Okay. That's helpful. So not only defining the condition, but also giving a perspective of the prevalence here. Right? So you're looking at, you know, 5 to 18% of reproductive-age. Women and this being the most common endocrine disorder affecting reproductive-age females. 

Dr. Dixit, you mentioned PCOS is defined by a combination of signs and symptoms of androgen excess and ovarian dysfunction. But what does that look like from a patient presentation standpoint? What signs and symptoms or PCOS should providers be looking for in clinical practice?

Well, in terms of androgen excess, one would see in a patient things like hirsutism, androgenic alopecia, which is balding on the scalp, as well as facial acne. Ovulatory dysfunction refers to menstrual abnormalities. Two terms that you may hear are oligomenorrhea, which is when menstrual periods occur at intervals greater than 35 days with less than nine periods in a year, or amenorrhea, the complete lack of menses. Infertility would also qualify as ovulatory dysfunction. And then there are ultrasound findings, as the name suggests, polycystic ovaries. However, this is not required for the diagnosis. 

You know, I've always found the name of this condition. Interesting. Right. Polycystic ovary syndrome. But like you mentioned, you don't need polycystic, ovarian morphology to be diagnosed, which brings us to another area that I think as a primary care clinician, I've always found confusing the diagnostic criteria for PCOS. I know that there's multiple diagnostic criteria that exist, but would you mind reviewing the most common set of criteria used for PCOS and what those criteria are?

Absolutely, Sarah. The Rotterdam criteria are the most widely accepted criteria for the diagnosis of PCOS. In fact, the International Evidence Based Guidelines for the Assessment and Management of PCOS, which came out in late 2023, support the use of the Rotterdam Criteria. Now two of the following three characteristics need to be present when making a diagnosis of PCOS.

Number one, irregular menses, usually oligomenorrhea or amenorrhea, as I mentioned earlier. Number two, clinical or biochemical signs of hyperandrogenism. When I say clinical signs, I'm primarily talking about hirsutism. Now, what's hirsutism? It refers to dark coarse hairs in areas where women typically have little or no hair, such as the upper lip, chin, or mid portion of the chest. When I say biochemical hyperandrogenism, I'm talking about hyperandrogenism noted on a patient's labs. Number three polycystic ovarian morphology by ultrasound. Again, remember, this is a diagnosis of exclusion, and all recommendations and guidelines state that other causes of ovulatory dysfunction and hyperandrogenism must be excluded first before a diagnosis of PCOS can be established.

Awesome. That was a great review. So we're utilizing the Rotterdam criteria. You need at least two of the three criteria, which include ovulatory dysfunction, hyperandrogenism, biochemical, clinical or polycystic ovarian morphology. Also really helpful that you pointed out that there are other diagnoses that we need to exclude prior to the diagnosis of PCOS. So driving home the point that this is a diagnosis of exclusion. For our listeners, we'll jump into the laboratory testing related to excluding conditions later. But first I want to address laboratory assessment related to one of the specific criteria hyperandrogenism - where do I start here Dr. Dixit? What labs would I be utilizing or should I be utilizing in assessing biochemical hyperandrogenism? 

Yeah, it's a great question, Sarah. Per the guidelines that came out in late 2023 you'd start by checking a total and free testosterone to assess for biochemical hyperandrogenism, and the method really is very crucially important when checking androgens in females. 

The total testosterone should be of a liquid chromatography tandem mass spec assay. You might see this in written documents as LC-MS/MS. I will note that immunoassay use in women and the evaluation of PCOS for total testosterone is not appropriate. The free testosterone should be either of a reliable calculation or of equilibrium dialysis, and I will note that Quest offers both options. If the total and or free testosterone is not elevated, the provider could consider measuring two other androgens, androstenedione and DHEA sulfate. However, both of these have poorer specificity compared to total and free testosterone. 

I appreciate that you call out that method matters here in testing testosterone in women. Traditionally, this isn't something, you know, in my training that was ever really discussed. So really helpful to call that out that for assessing total testosterone in female, the preferred and guideline-recommended methodology is liquid chromatography mass spectrometry, And for free testosterone, you have the option of utilizing the gold standard, which is equilibrium dialysis. Or utilizing a reliable calculation to obtain free testosterone. 

Is that correct? 

That's absolutely correct.

Now are we checking androgens on everyone we have a suspicion of PCOS?

Not necessarily, Sarah. That's a good question as well. While the presence of hirsutism might be predictive of biochemical hyperandrogenism, one should remember, and I used to see this in practice, that self-treatment such as plucking or waxing limits the clinical assessment. And so checking androgens is really most important in patients with minimal or no clinical signs of hyperandrogenism, such as hirsutism. I will note a couple of things about androgen measurement. Repeating androgen measurements without a compelling reason is not recommended. And this is a frequent question that I used to get in practice. If a patient is taking a combined oral contraceptive pill, androgen should not be checked at that time. They should be discontinued for approximately three months, and if the oral contraceptive pill is being used for contraception, another method of contraception should be instituted in the interim.

Interesting points. Yeah. I didn't even consider all the procedures that we have to remove excess hair these days. Those features may not be present on exam making biochemical assessment of excess testosterone crucial. We mentioned earlier that PCOS was a diagnosis of exclusion. And I want to circle back to that. We know that we need to rule out a few conditions prior to the diagnosis of PCOS, but what are we ruling out here? Can we touch on and review the common conditions that clinicians need to exclude here and how clinicians should approach this from a laboratory testing perspective? 

Absolutely, Sarah. I think of the common disorders that need to be excluded as four. The first and possibly the most important, condition to exclude is pregnancy. Way to evaluate for that is with a HCG level. Second, hyperprolactinemia would be easily evaluated for with a serum prolactin level. Third, hypo and hyperthyroidism can cause menstrual abnormalities. And this is easily evaluated with a TSH, with or without free T4 and then a medical condition called non classic congenital adrenal hyperplasia can mimic a lot of signs and symptoms in PCOS. This is evaluated with an 8 am 17 hydroxy progesterone level. Now, I will note there are uncommon medical disorders that can also mimic certain signs and symptoms of PCOS. Things like acromegaly, which is growth hormone excess, cushings syndrome, which is cortisol hypersecretion, and then androgen secreting tumors, ovarian hyperthecosis. but I wanted to highlight the most common disorders to exclude first.

I want to confirm the why behind the need to exclude these conditions. Right. So you highlight the most common for conditions to exclude here. So pregnancy, hyperprolactinemia, thyroid abnormalities, non-classic congenital adrenal hyperplasia. We need to exclude these because they are all conditions that can present with similar signs of symptoms of PCOS - is that correct? 

That's absolutely correct.

Okay, so we've touched on where to start if we have a suspicion of PCOS for our patients from a laboratory perspective. Starting with total testosterone and free testosterone. We've talked about the appropriate methodologies that we should be utilizing and what needs to be excluded in the differential diagnosis here. The last laboratory assessment I want to discuss is the utilization of AMH or anti-malarian hormone in the workup for PCOS. I know the international update in 2023 AMH was mentioned, but I want to hear from you, what role does AMH have in this diagnosis and when should it be utilized? 

Well, as you mentioned, Sarah, AMH stands for anti-malarian hormone. It's a hormone that's expressed by the follicle pool in the ovaries. It's been noted that it's generally higher in women with PCOS compared to women with normal ovulation, and the recommendations from the 2023 guideline that I referenced earlier says that serum AMH could be used for defining polycystic ovarian morphology in adults. Now either the serum AMH or a transvaginal ultrasound are used to define polycystic ovarian morphology, but both of them should not be ordered. And as with the transvaginal ultrasound, AMH is not necessary for PCOS diagnosis. There are issues with AMH to consider, however There are variations in the different lab assays for AMH. There's an inverse relationship with body mass index and AMH and AMH can be suppressed by current or recent oral contraceptive pill use. AMH should not be checked in adolescence.

Great information on AMH. It sounds like a viable option from a laboratory perspective for providers or even for patients that may not be wanting to pursue a transvaginal ultrasound and likely we'll be hearing more and more about its utilization in the PCOS diagnosis. Now you mentioned the adolescent population when you were talking about AMH and thinking back traditionally, when you're working up PCOS, you're thinking a reproductive-age, female. PCOS can present itself at the beginning or even persist after reproductive-age, but are there any special considerations clinicians need to think about when evaluating an adolescent patient or a post-menopausal patient for PCOS? 

I'll speak to the adolescent question first. As we all know, irregular menstrual cycles can occur in a normal adolescent. So, it's a difficult diagnosis to pin down for that reason. However, if the PCOS diagnosis is being considered by the provider, it’s noted in the guidelines that I referenced earlier that if the adolescent has some PCOS features but doesn't meet the diagnostic criteria, the provider could consider the patient at increased risk and then reassessment is recommended at or before full reproductive maturity, which is eight years post menarche. One should also note that androgen levels reach adult ranges at 12 to 15 years of age. And as I noted earlier, AMH should not be checked in adolescence population. It's interesting in that when I was in training, it was considered that PCOS was not a diagnosis to give to a postmenopausal female. But we know that clinical, or biochemical hyperandrogenism can persist in the postmenopausal female. Now the diagnosis of PCOS can be established in a postmenopausal female retrospectively if a history of oligo or amenorrhea, hyperandrogenism, and or polycystic ovarian morphology occurred during the reproductive years, roughly ages 20 to 40. Why is this important after a female gone through menopause? It's important to try to evaluate a patient's cardiometabolic risk. 

When I started practicing in primary care, I always wondered what my role was in this diagnosis. And after walking through, today where we start from a laboratory perspective, what needs to be assessed and ruled out, I feel whole heck a lot more confident in the PCOS workup and I'm hoping other providers do too, but I want to circle back to something you mentioned in your last answer, when you mentioned the importance of establishing this diagnosis, as it plays into the patient's overall cardio-metabolic risk. When a patient is presenting with this diagnosis, are there additional conditions or lab assessments that primary care clinicians or women's health providers need to be thinking about? 

PCOS is not just an endocrine disorder. It's a true multidisciplinary condition and requires buy in from different specialties, including OBGYNs as well as primary care physicians. It's well known that women with PCOS are at increased risk of a whole slew of cardiometabolic conditions, such as cardiovascular disease, hypertension, metabolic syndrome, sleep apnea, metabolic dysfunction, associated fatty liver disease. For example, I'll talk about type 2 diabetes - and this statistic really floored me when I first read it. 50 percent of all women with PCOS will develop type 2 diabetes by the age of 40. And compared to age matched controls, women with PCOS are four times more likely to develop type 2 diabetes. The guidelines recommend a lipid panel in all females with PCOS at the time of diagnosis, as well as monitoring for glycemic status. The guidelines recommend an oral glucose tolerance test as the most accurate test to assess glycemic status in a female with PCOS. However, due to issues with oral glucose tolerance tests, the inconvenience, the time, one could also consider alternative testing, such as a fasting glucose, hemoglobin A1c, or insulin resistance panel with score.

That points out a huge role that primary care clinicians and women's health providers have within the PCOS diagnosis. You know, these patients often come with cardiometabolic risk that impacts across the lifespan. It's crucial when the PCOS diagnosis made or noted that we're thinking about these other cardiometabolic conditions that these women are at risk for lifelong. I know many listeners are probably wondering about additional resources. I, myself, you know, love a good cheat sheet algorithm. Anything that makes care more efficient and streamline nowadays is awesome. Can you speak about the algorithms that Quest has developed to assist providers in this area?

Yeah, who doesn't love a good algorithm, Sarah, right? Right, right? Right. Well, our team of medical experts throughout Quest have developed diagnostic algorithms that can simplify the path to a PCOS diagnosis and aligns medical society guidelines with our comprehensive endocrine test menu.

This is great news, always, like I said, appreciate an algorithm. So for our listeners today, note that the algorithm is linked in the podcast description. There are a few additional resources you'll see on there. There's a link to quest diagnostics, clinical focus on PCOS that takes a deeper dive than what time allowed us today. And for many providers that are wanting even more, we do have two recorded webinars on our clinical education center related to PCOS delivered by Dr. Andrea Dunaif, a PCOS expert at Mount Sinai health system. Thank you again so much Dr. Dixit for your time and expertise today, this has been really valuable. Any final takeaways for our listeners? 

You know, thinking about this podcast, I came away with three major points that I'd like our listeners to remember. First, a reproductive-age female should have regular menses most of the time. Females going months on end without a period is just not normal and deserves further investigation. Secondly, as we just discussed, this is not just an issue for OBGYNs and or endocrinologists. Due to the prevalence of PCOS in reproductive-age women, and because of the downstream cardiometabolic abnormalities in these same patients. All primary care providers need to be aware of this condition. Lastly, if you take away only one thing from today's podcast, remember that staggering statistic that 50 percent of females with PCOS will develop type 2 diabetes by the age of 40.

That statistic is definitely motivation to make sure that we're monitoring and screening these patients appropriately. Thanks again, Dr. Dixit. It was a pleasure.

Great to be here. Thank you. 

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