Pharmacological management of polycystic ovary syndrome

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Polycystic ovary syndrome, often abbreviated to PCOS, is a common endocrine disorder affecting about 1 in 8 women. Because it has such a broad range of symptoms and features, PCOS is often underdiagnosed. In 2023, an extensive evidence-based international guideline was released covering the assessment and management of PCOS.

As a GP, I, of course, have the 2023 guideline bookmarked, but I also really appreciate a snappy summary article written by guideline authors. And so today on the Australian Prescriber Podcast, I'm really lucky to be speaking with one of these very authors. Dr Jillian Tay is an endocrinologist at Monash Health and a research fellow based at Monash University. And Jillian, along with her colleague Dr Carolyn Ee, has written a great summary article for Australian Prescriber. It's all about the pharmacological management of PCOS. Jillian, thanks so much and welcome to the show.

I'm very happy to be here, Laura.

Great. And so before we jump into the actual pharmacological treatment options, let's define what we're speaking about today. And I guess one of the challenges of a syndromic condition is how variable each person's experience of this condition is going to be. And so just to start with, could you take us through the key concerns that women with PCOS face and how that does or maybe doesn't really align with the diagnostic criteria?

This is a very important question and thank you for bringing this up. We definitely know that PCOS is a multisystemic disorder and it has impact on the women's reproductive, cardiometabolic, and also the mental health aspects. According to the latest PCOS guideline diagnostic criteria, we have updated and improved the Rotterdam criteria, which now has specific diagnostic criteria for both the adults and the adolescent group.

I just want to highlight that the diagnosis criteria relies heavily on the reproductive features of PCOS. So for example, the menstrual irregularity, the hyperandrogenism, and the polycystic ovary morphology seen in the ultrasound, or it's now also can be replaced with elevated AMH [anti-Mullerian hormone] levels in the adult's population.

So you see that these features definitely do not take into account the women's concern about their cardiometabolic and mental health issues. And our group has previously performed international surveys on what are the priorities of women with PCOS, and while fertility is a main concern, other concerns that stood out are the long-term cardiometabolic risks, such as obesity, diabetes, and cardiovascular disease. Poor mental health also is not taken into consideration at all.

Thank you for reminding us of that. And certainly your article does cover the comorbidities and conditions for which PCOS is a risk factor, and you've taken us through those, which is great because when we come to the medications later, a lot of those are actually thinking about reducing those risk factors. It's great to see the new updated diagnostic criteria helpfully labelled in this article. It was interesting to see the new addition of an AMH [concentration], and so I was interested in how useful you find AMH as an extra option for diagnostic.

AMH is very, very new in the diagnostic guideline and there is a lot of controversy about that. So what the guideline was showing is that there is definitely evidence that elevated AMH levels can be a surrogate marker for polycystic ovary morphology that is seen in ultrasound. That is what the evidence has shown. And so we have to put that out because that is one of the priorities a lot of obstetricians and gynaecologists and women have –can they not do an ultrasound and use AMH levels as a surrogate marker? And the answer is yes, but how applicable that is would be different and highly dependent on local resources.

So it's important to note that we currently do not recommend using AMH in the adolescent group. Also, we do not recommend using the ultrasound in the adolescent group, and this is because during the puberty period it is very common to have immature follicles that is seen as polycystic ovary morphology. And the AMH levels also can be affected by women's ages. BMI [body mass index] and certain medications can also impact the levels.

So while the guideline shows that there is evidence that it [AMH concentration] can be a surrogate marker for polycystic ovary morphology, it currently does not give any definition on what is the normal range that women should be applying. And this will be heavily based on the local clinical labs[and] what they put in as their normal range.

And I also want to add, we currently do not recommend that we order both AMH levels and pelvic ultrasound at the same time concurrently because that is going to risk over-diagnosing PCOS. But I would suggest that we only use AMH level where the ultrasound cannot be performed in women. So for example, [when] the transvaginal approach is not available, because we know that [the] transvaginal approach is a lot more accurate compared to [the] transabdominal approach, or that an experienced sonographer in the area is not readily available.

At my introduction, I said I loved a snappy summary, and Table 1 in this article is a very snappy summary of the key symptoms of PCOS and the first, second, and third-line therapies. But I guess for our discussion, can we go through each of the medications or medication classes and just talk through how they're useful, for what, and some practical tips, rather than just going symptom by symptom?

Sure.

Great. Let's start off with the combined oral contraceptive pill. Does everyone need it and can it be any pill?

Not everybody needs the combined oral contraceptive pill. In management of PCOS, it is treatment of the symptoms. So you only prescribe a medication if a woman is complaining of a symptom that can be effectively managed with pharmacological treatment. So for the combined oral contraceptive pill, there is very good evidence that it helps with regulating the irregular periods. It helps with improving clinical hyperandrogenism, such as hirsutism and clinical acne.

So could it be any pill? Generally, yes, as per general population guidelines. Currently, there is no evidence to say that one formulation is better than the other. However, we do apply the general principles, which is starting with low-dose estrogen first and also avoid the cyproterone preparations because there has [been a] higher risk for liver dysfunctions, venous thromboembolic events, etc. Also, the general contraindications with starting combined oral contraceptive pills, such as migraines with aura, a breast cancer history, and personal history of thromboembolic disease.

It's great to hear that despite marketing, [with] any of the pills, [it is] very reasonable to start if there is a clinical indication and no contraindications. So it's great that we can go with the lower-dose PBS [Pharmaceutical Benefits Scheme]-subsidised pills. Can you talk us through the situations when progesterone-only pills are used for people with PCOS?

So again, the symptoms that the progesterone-only pills target are irregular menstrual cycles and endometrial protection. It has no effect on clinical hyperandrogenism as the combined oral contraceptive pills does. And I will only use progesterone-only pill if clinical hyperandrogenism is not a women's main concern and they want to regulate their menstrual cycles or they want endometrial protection. Otherwise, I will also use it when women cannot tolerate combined oral contraceptive pills or they have a direct contraindication to oral contraceptive pills. And for that, [the] main purpose of using the progesterone-only pill is for endometrial protection to prevent endometrial hyperplasia and cancer.

Great. And as we'll come to later, there are some other medications that might be used in PCOS for which you should not get pregnant on. If they're on a different medication that you can't get pregnant on, they might want a pill for that.

Yeah, they can use barrier contraception or any other forms of the long reversible hormonal contraceptions. That's totally reasonable.

And you mentioned that the combined pill is not needed for all women with PCOS, but what about metformin? It's listed as first-line for weight management and metabolic risk factors as well as second line for oligomenorrhea or irregular periods. Do you think most people who have PCOS should be on metformin or would get a benefit from it?

No. So I definitely don't prescribe metformin unless there is an indication. We know that for women who have a normal body weight and they're already doing lifestyle [modifications] and have regular periods or they're not worried about periods, they're not worried about fertility, there's no point in starting metformin for them. Or even if there is a woman who has irregular periods and the main concern is hirsutism, there's no point using metformin because it's not effective against that symptom.

So I will only use metformin as an adjuvant to lifestyle management if a patient has reached a plateau with weight loss with lifestyle management alone or they just want something to help them along. And also if they are wanting to conceive and they want to try metformin as a ovulation induction therapy, but there are obviously better medications that are more effective for ovulation induction rather than metformin.

And for those medications, we are referring early to our specialist colleagues to help with that. And just a practical question, clinician to clinician, how well tolerated is metformin in PCOS compared to how we're using it in type 2 diabetes?

So the main side effects are the gastrointestinal side effects, but the only thing is metformin is not TGA [Therapeutic Goods Administration] approved for PCOS. So they're all a private script.

However, metformin, it is an off-patent inexpensive drug. So as far as private scripts go, this tends not to be such a huge financial barrier.

Yes.

Okay. Now let's move on to the antiandrogens. What symptoms are we targeting, and which ones can we use, and how effective are they?

So the only indication for antiandrogens is for clinical hyperandrogenism. So I mean hirsutism, alopecia, or acne. But evidence is more available for hirsutism and not for the others.

It is currently recommended second-line after combined oral contraceptive pills because, number 1, 90% of women with hirsutism will respond to combined oral contraceptive pills, plus/minus some topical treatments such as waxing, shaving, threading, laser therapy, etc.

And also, combined oral contraceptive pills have other benefits on top of antiandrogens, such as regulating the menstrual cycles and having endometrium protection, etc. So given that most women do respond to combined oral contraceptive pills, we will only use antiandrogens for clinical hyperandrogenism if, number 1, a patient does not respond as well to combined oral contraceptive pills. And then you can use antiandrogens as an add-on therapy or as [the] only therapy if there is a contraindication or intolerance to combined oral contraceptive pills to target clinical hyperandrogenism. But because there is a risk of antiandrogens causing a male fetus to have under-virilisation, we do recommend that when you start a woman with PCOS with [an] antiandrogen, they need to be on some form of effective contraception.

And about how long does someone need to be taking say something like spironolactone to see a clinical improvement in their symptoms of hirsutism?

It is very important to manage the patient's expectations. I tend to tell patients you need to be patient and wait for at least 6 months before stopping the therapy because that is the duration of the life cycle of the hair follicle. If you stop at 3 months, you're not going to see an effect.

What about inositol? It doesn't need a script. And so sometimes I actually think I've missed having these conversations with patients. What kind of conversations do you have with patients around the evidence for inositol? Is it really expensive? I mean, I see it being marketed to patients. Tell me, how do you approach this?

I think they're expensive. The evidence on it is very, very mixed. So let's start with talking about the evidence. Currently inositol [products] are over-the-counter supplements and therefore, they are not under the strict regulations as any pharmacological therapy.

So therefore, there are many different kinds of formulations, different doses is available in the market. So it's really hard to get very convincing evidence to say that it works. So in the systematic review that we've done for the PCOS guideline, there is some low evidence that potentially inositol may help to improve metabolic measures such as glucose and insulin levels. But if you compare it to metformin, there's actually definitely more evidence that metformin works better than inositol for all these outcomes.

But the reason why inositol is on the guideline [is] because there is a very strong consumer voice that they're interested about supplements therapy and natural types of therapy for management of PCOS. And so given that there is also no evidence of potential harm with using inositol, such as there's also no significant adverse event, definitely side effects is much less compared to metformin in regards of the gastrointestinal side effects. So we do say that patient[s] can try inositol with informed consent so long as they know that this is what we know so far with the evidence.

And I guess whenever I have these conversations with patients, how expensive is this product for an unproven benefit? Often it does come up as part of our conversations that we have and the number of times I find myself on Google and trying to see how much is this costing you every month? That happens quite a lot, I will say, in my clinic.

But I think when patients come and ask me about it, they have already made up their mind whether they want to use it or not.

Excessive weight and associated comorbidities have clearly meant that attention has also turned to anti-obesity drugs when thinking about PCOS. So things like orlistat and of course the very popular GLP-1 [glucagon-like peptide-1] receptor agonists. What are the considerations for these medications specifically in PCOS?

I know this is not related to pharmacological treatment, but I want to emphasise that weight stigma is extremely prevalent in PCOS. So the guideline has now endorsed a weight-neutral approach. That is, we need to ask permission from patients to discuss weight management options with them. Also, lifestyle should definitely be the first-line treatment for weight management. And weight management goals could be either weight maintenance or weight loss if the patient wants to. So if we are considering pharmacological therapy for weight loss in women with PCOS, currently the general population guideline applies. So orlistat, phentermine, bupropion or naltrexone, topiramate and the GLP-1 analogues will be following the general population guidelines.

And I guess when we're considering these medications, these are also medications of which contraception is needed because pregnancy is not recommended while on these medications. And you make an important point also in this article that it's certainly not appropriate, especially in teenage patients. This article really highlights that often in those younger people within 8 years of menarche, we're probably actually not making a diagnosis of PCOS anyway based on an AMH [concentration] or a sonological appearance on ultrasound.

We can definitely diagnose PCOS in adolescents if they have concurrent irregular periods and also hyperandrogenism. If they only have either one of them and we won't assess AMH levels or the ultrasound pelvis until 8 years post-menarche, then these adolescents will be at risk of PCOS and we should evaluate later on.

And I do appreciate that the ‘Health at Every Size’ or a weight-neutral approach is something that is in the guidelines and certainly a really appropriate thing when speaking especially to young people about the shapes of their bodies.

Yes.

It's been great to be able to chat through the specifics of the pharmacological management of PCOS, and also to remind ourselves about their role alongside the really important non-pharmacological support for this condition. Thank you, Jillian, for your time today.

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The full article we spoke about today is available for free on the Australian Prescriber Podcast and includes details for the full 2023 guideline. The views of the hosts and guests on this podcast are their own and may not represent Australian Prescriber or Therapeutic Guidelines. Both authors of this article were authors on the International Evidence-Based Guideline for the Assessment and Management of Polycystic Ovary Syndrome 2023. Jillian Tay received research support from the NHMRC Centre for Research Excellence in Women's Health and Reproductive Life to develop the Polycystic Ovary Syndrome International Guideline. Registration fees for relevant annual scientific meetings were supported by the organisers to present on findings of the guideline. She's a member of the Endocrine Society, Endocrine Society of Australia, and the Androgen Excess and Polycystic Ovary Syndrome Society.