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Polycystic ovary syndrome (PCOS) is a common condition characterized by reproductive, hyperandrogenic and dysmetabolic features, and often becomes clinically manifest during adolescence, particularly with weight-gain. Thomas Barber discusses the heritability of PCOS and why it associates with obesity. Barber further speaks to challenges for the future.

Image courtesy of interviewee. November 27, 2023

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This video video discusses Polycystic Ovary Syndrome (PCOS), describing it as a common endocrine disorder affecting premenopausal women and characterized by reproductive, metabolic, and hyperandrogenic features. It affects approximately 5-7% of women of reproductive age and is the leading cause of female subfertility, primarily due to irregular ovulation and hormonal imbalances.

Key symptoms include irregular or absent menstrual periods, excessive hair growth (hirsutism), acne, and potential insulin resistance leading to type 2 diabetes, along with metabolic disturbances like obstructive sleep apnea. The genetic basis of PCOS is complex, with research indicating heritability around 70%, but many aspects remain unknown.

Current treatment focuses on weight loss to alleviate insulin resistance and related symptoms, with limited pharmaceutical options available. The speaker emphasizes the need for more targeted therapies and better understanding of the condition's pathogenesis. Additionally, they highlight the importance of psychological support for affected individuals, given the emotional and mental health challenges posed by PCOS, especially during adolescence.

This video video concludes by discussing the potential for new pharmacotherapies that could improve weight management in individuals with PCOS, specifically mentioning advancements in GLP-1 agonists, which may significantly benefit future treatment strategies. Overall, the text underscores the complexity of PCOS and the importance of compassionate, multi-disciplinary approaches to managing the condition and supporting those affected.

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X-TIMESTAMP-MAP:LOCAL=00:00:00.000,MPEGTS=900000

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It's a very common, condition.

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It's been, it's being called the endocrine

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equivalent of the common cold.

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Uh, it is in fact the commonest endocrine condition

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that we see, endocrine meaning hormonal problem.

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And it's a, it's a condition which affects women,

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more specifically premenopausal women.

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So women of reproductive age.

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Um, it affects between about five

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and 7% of the,

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of the female population within the age group.

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It's a condition which is typified by reproductive features.

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And what I mean by that is disturbances

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of menstrual functions.

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So periods. So it could either be irregular

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or absent periods, for example, so some women

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with PCOS might go for many months without a period,

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or may never have a period indeed,

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or they may just have some irregularity

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of the menstrual cycle.

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Um, and that's under underlied by, problems

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with the ovulation, so ovulation with the ovary,

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that becomes disturbed in PCOS.

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And so that then, leads to irregular periods.

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It's also a condition which, associates with,

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subfertility, in fact, it's the commonest cause

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of subfertility in women.

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Again, that's because of the, arrest of the development

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of the, of the follicles.

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So just before women ovulates the follicle, undergoes a,

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a process within the ovary,

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and that kind of developing follicle gets arrested at a

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certain, stage of that process.

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And it means that women, are less able to ovulate and

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therefore become less fertile.

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It's also a condition which associates

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with what's called hyper androgenic features.

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And what this means is, women can develop,

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clinical features related to excessive levels

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of testosterone and other, kind

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of androgenic hormones.

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And, and that translates with into kind of hershe,

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which is excessive hair growth in a male distribution.

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So, for example, excessive hair growth on, on the face,

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for example, or on the chest, is, is fairly common.

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Uh, and women often need to resort to shading, plucking

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or waxing, to, to, to manage this, this problem.

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Um, these hers can have a huge degree of, severity.

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Uh, it can, it can also manifest with acne

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and what we call androgenic alopecia,

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which is essentially hair loss in,

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in a male, distribution.

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So those are the kind of typical, classical features.

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But importantly, PCS also associates

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with metabolic disturbances and interesting resistance.

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And, and this means that women

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with PCOS are much more likely to have

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what we call dysglycemia or develop type two diabetes.

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And there's also an association with obstructive sleep apnea

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as well, and other metabolic problems.

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So, although the metabolic disturbances don't feature in the

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diagnostic criteria for PCOS, they are

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nonetheless a very important aspect, clinical, and,

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and biochemical feature of the, of the condition

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it typically develops in, adolescent girls.

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Okay. Adolescents is a time clearly of, of, of great change.

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Hormonally, great change.

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And this often, leads to

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what we call insulin resistant state.

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Uh, and that can, kind of contribute to the pathogenesis

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and development of PCOS

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and, often in the context of weight gain as well.

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So, although PCOS at its heart is a,

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is a genetic condition, it tends to,

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and in families, it's also a condition which tends

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to become manifest with weight gain

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and the development of overweight and,

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and obesity in, in both girls and women.

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Okay? So we, we, we, well, we know that we, we've done

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what we call genome wide association studies, for PCS.

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And, and what that means is you,

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you look at the entire genome, which,

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which contains about 22,000 genes, okay?

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And you look at the, what we call SNPs

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or single nucleotide polymorphisms,

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and you can essentially map out the genome, in PCS

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and compare it to women who don't have PCOS, and you can

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therefore look for associations of, certain alleles and,

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and variants within the genome, which associate with PCOS.

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And, and, and those cities have been very instructive.

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We've, we've, found a number of variants which associate

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with PCOS, and, which, so we can kind of map out some

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of the genetic architecture PCS,

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but I think it's important to state that

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actually despite these genome-wide studies,

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and we now have a number of them

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that have been published on many thousands of participants,

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we still only, know about a, a, a small minority

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of the kind of heritability of P two s.

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You know, the vast majority of it, is, we, we,

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we simply don't, we simply don't know.

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And it's possible that some of those, some of

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that heritability may be what we call epigenetic effects.

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And, and what this means is a,

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not necessarily a change in the genome structure itself,

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but in the proteins

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and histones, which attached to the genome

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and which affects the expression of genes.

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And that's a, you know, a very topical area in our,

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in medicine is the, is the epigenome.

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And, as you can probably appreciate, a lot

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of this is particularly relevant in tro.

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So there are a lot of epigenetic changes

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that occur in the developing fetus.

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Uh, and these, these are influenced

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by the maternal environment.

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And we know now that this is not even just a generational

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thing, but can actually be multi-generational.

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So, in other words, the environment that your

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grandparents experience can actually

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have a effect on the way in which your genes are expressed,

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which is, which is pretty incredible, isn't it?

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And, and that certainly could account for some of the ities.

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The problem, one of the problems with epigenomics is

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that it's incredibly difficult to, to study,

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because as you can imagine, there's thousands

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and thousands of these histones, and they're not static.

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They're kind of, dynamic in time,

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and they change over time.

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And so it's, it's a, it's an inherently

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very difficult thing to study.

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So, so that's one very important aspect.

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Uh, we know that heritability PCs is something about,

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70% or something like that from,

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from, you know, twin studies.

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Um, but in addition to that,

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and very importantly, there are, it, it is a,

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a weight related condition as well.

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So typically, PCS does tend to develop in women and,

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and adolescent girls who gain weight

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to become overweight and obese.

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It's not always the case.

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There are some, a minority of PCS that are lean,

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but the, the vast majority of women

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and girls with PCS do have a problem with their weight.

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And, and, and the reason, the main reason for that is

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because when we gain weight, this affects the

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sensitivity of the insulin receptor,

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and we develop something called insulin resistance.

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And what happens is that

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that insulin levels in the blood rise to compensate

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for the insulin resistance.

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And so-called hyper anemia then has other effects on

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the ovary, for example, to enhance, the production

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of androgens within the ovary,

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but also to arrest follicle development

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that we were talking about earlier.

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And there's various other effects

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of raised engine levels as well.

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Now, that's not the, the whole explanation,

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as you can probably appreciate pathogenesis

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of PCS is, is complex.

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It's in completely understood,

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but we think that a lot

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of it is mediated through that mechanism.

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And that's probably the main reason why obesity, is a,

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is a contributor to PCS, but it's not the whole story.

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And if you don't have the genetic underlying architecture

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to put you at increased risk of PCS,

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then weight gain on its own would not,

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would probably not result in, in manifestation

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of PCS, if that makes sense.

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Well, there's lots of things we dunno about PCOS.

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I mean, pathogenesis is one of those.

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And, and of course, genetics is a,

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and epigenetics is a huge, aspect of that.

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Um, I think also another huge area that we don't yet know,

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and we're not yet, you know, perhaps a,

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a deficiency is in our therapeutics for, for PCOS.

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I mean, currently the best treatment option is

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through weight loss, because we know that

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with effective weight loss, we can reverse the insulin

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resistance and we can alleviate many of the re many

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of the reproductive hyper antigenic

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and metabolic, features of this, condition.

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But any, any kind of,

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treatment strategy which results in weight loss,

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and that could be lifestyle, dietary change,

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bariatric surgery potentially,

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or even, pharmacotherapies, you know,

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could potentially have, you know, utility in, in PCOS.

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But we otherwise, we have therapies that have been around

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for years, if not decades.

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So the likes of metformin, for example, combined,

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contraceptive pill and various sort, the anti-androgens.

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But, but these, in my mind,

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they're really just sticking pluses.

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They don't really address the underlying, pathogenesis

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of this, condition that they're merely addressing some

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of the clinical features like irregular periods

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or, you know, excessive androgens and so on.

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And unfortunately, some of those therapies do also have,

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problems like that.

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There are, sometimes there can be a risk of clotting,

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for example, in certain, you know, combined

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or contraceptive pills, which of course can be an issue in,

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in, in obese women.

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Uh, there can also be side effects from some

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of the anti-androgen therapies as well.

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So I think, I think, you know, certainly,

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the development of more effective therapies

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and therapies which are really targeted towards the

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underlying problem in P two s,

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there's certainly a need for that.

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And I think in the future, I hope that, you know, pharma

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companies and so on will, will develop,

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some of those therapies.

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And clearly by getting a, a better,

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insights into the underlying pathogenesis, of course,

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that will facilitate more focused, therapeutics.

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You know, you can't have one without the other.

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And because we don't, fully understand the pathogenesis

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yet, then of course that obviously is a, is a bit

09:59.925 --> 10:02.205
of an issue, but hopefully with further GWAS studies

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and genetic insights and so on,

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and, you know, with potentially even future genetic

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therapies, you know, I think

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that is something for the future.

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I think, you know, the genome-wide studies will help us to,

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not just for PCOS,

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but to get insights into many, conditions.

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And I think, you know, although currently we don't really

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have many genetic focused therapies in, in,

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as treatment options generally in medicine, you know,

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this is certainly something which

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companies are very interested in.

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And I think in the future, this will feature a lot more.

10:31.355 --> 10:32.605
It's clearly much easier

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to develop a genetic therapy form monogenic condition.

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So whether there's just one defect in the genome,

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it's obviously relatively easy to, to address.

10:40.505 --> 10:42.645
But when you've got a complex condition like PCUS

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where there's, there's many alleles which may be,

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contributing, and some

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of those may be different in different patients,

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clearly it's much more of a challenge of, of course, PCOS is

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and always has been a, a, a,

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a very interesting area of research.

10:57.625 --> 10:59.485
And I think, mainly

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because it's, it's, it's,

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it's such a complex and fascinating condition.

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It's a very common condition.

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It's one where there are a lot of unknowns

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and a lot of questions and,

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and huge potential to, to help, patients.

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I think, we shouldn't lose sight of the fact that,

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you know, PCS is an incredibly,

11:16.235 --> 11:17.885
difficult condition to live with.

11:17.915 --> 11:20.725
It's been termed the thief of womanhood. Okay?

11:21.185 --> 11:23.125
Uh, we shouldn't underestimate the

11:23.865 --> 11:26.245
impact Hersch can have on a woman.

11:26.785 --> 11:28.565
It, it, it's hugely distressing.

11:29.225 --> 11:32.965
And I think, of course can associate with quite,

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you know, emotional impact and,

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and other mental health problems.

11:36.965 --> 11:38.885
And I think, we have to be,

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compassionate in our approach to,

11:40.905 --> 11:42.245
to managing this condition.

11:43.345 --> 11:47.005
And, and, and I think of, of course, there are,

11:47.065 --> 11:49.565
you know, potential potential for research,

11:49.665 --> 11:52.445
not just in the, you know, in the kind of genetics

11:52.445 --> 11:55.125
and the kind of scientific aspects of the condition,

11:55.125 --> 11:56.805
but also for the human aspect as well.

11:56.825 --> 11:59.405
And I think, you know, psychological research,

11:59.465 --> 12:02.645
how best can we help these patients, you know,

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emotionally, to deal with their problems?

12:05.025 --> 12:06.405
You know, you know,

12:06.405 --> 12:10.085
often I think certainly PCS management does certainly at

12:10.085 --> 12:13.645
times, merit a kind of MDT based approach.

12:13.805 --> 12:16.725
I mean, typically that's not usually done, I have to say it.

12:16.755 --> 12:20.325
Well, there may be some, kind of, collaboration

12:20.325 --> 12:22.325
between the endocrinologist

12:22.345 --> 12:24.845
and, a reproductive specialist, for example.

12:25.345 --> 12:27.765
Um, but in many sense, it's done either

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by an endocrinologist or a reproductive specialist,

12:30.865 --> 12:33.325
but at the place for a psychiatrist that, you know,

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traditionally or a psychologist

12:34.525 --> 12:36.005
that doesn't usually feature, right?

12:36.425 --> 12:39.005
Um, I mean, one of my roles is to, is

12:39.005 --> 12:40.725
to lead on the obesity serious wine base.

12:40.725 --> 12:43.685
So we have some excellent, clinical psychologists who,

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who contribute to the obesity side of it.

12:46.105 --> 12:48.525
And I think, certainly there's, there's,

12:48.645 --> 12:50.565
there's definitely a case for having, you know,

12:50.565 --> 12:52.285
psychological support,

12:52.545 --> 12:54.165
for these, for these women as well.

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These women and girls. Remember,

12:55.365 --> 12:57.565
it's a condition which often develops in adolescence,

12:57.565 --> 12:59.565
which obviously is a very difficult time

12:59.565 --> 13:00.725
of one's life anyway.

13:01.025 --> 13:04.245
And to have the PCS on top of that clearly is, is,

13:04.665 --> 13:06.005
it can be hugely distressing.

13:06.525 --> 13:09.925
I think one other area could be potentially be the, the,

13:09.925 --> 13:12.725
you know, the, the, kind of fertility aspects of PCS.

13:12.725 --> 13:14.725
We haven't really mentioned much about this,

13:14.785 --> 13:17.485
but this course, this condition is a, is,

13:17.545 --> 13:20.085
is literally the leading cause of sub fertility in women.

13:20.285 --> 13:22.525
I know in recent times there have been some great

13:22.525 --> 13:24.685
developments in reproductive,

13:25.135 --> 13:26.805
strategies and, and treatments.

13:26.865 --> 13:27.965
Uh, and that's fantastic.

13:28.545 --> 13:31.645
Uh, and obviously we, we, we work closely with, you know,

13:31.645 --> 13:34.525
with, our reproductive colleagues, who,

13:34.525 --> 13:36.245
who are involved in the fertility clinics

13:36.265 --> 13:37.965
and, you know,

13:38.385 --> 13:40.725
but there's always, you know, there's always potential

13:40.725 --> 13:41.885
for more research in that.

13:41.945 --> 13:44.845
And I think, I, I guess finally, I would probably say,

13:45.755 --> 13:47.935
as I kind of intimated earlier, you know, the,

13:47.935 --> 13:48.975
the focus on weight loss.

13:49.175 --> 13:52.455
I mean, we're literally on the eve now of, of a, of,

13:52.475 --> 13:55.855
of a new era of, pharmacotherapies for obesity.

13:56.075 --> 13:58.375
And these are based on the molecule called GLP one

13:58.375 --> 13:59.695
or glucagon light type one.

14:00.085 --> 14:01.255
This is an Linton hormone

14:01.255 --> 14:03.575
that's released from the distal ium.

14:03.995 --> 14:06.535
Uh, and we've been using it, I've been using it now

14:06.535 --> 14:09.255
for 15 years in the context of type two diabetes.

14:09.315 --> 14:10.855
But recently some

14:10.855 --> 14:12.455
of these therapies have been licensed for obesity.

14:12.635 --> 14:15.775
And there are now combinations of GLP one with GIP

14:15.795 --> 14:18.895
for example, other triple combinations

14:18.895 --> 14:20.055
with glucagon as well.

14:20.195 --> 14:23.935
And, molecules in development, which, which combined

14:23.935 --> 14:26.055
with PYY, which is an appetite suppressant,

14:26.055 --> 14:27.295
and some of the data that are coming

14:27.295 --> 14:29.015
through are truly remarkable.

14:29.355 --> 14:31.735
And I think, although the, the history

14:31.735 --> 14:33.975
of weight loss drugs have been quite checkered,

14:34.295 --> 14:35.975
I think the future is quite propitious.

14:35.995 --> 14:39.495
And I think we we're, we, you know, I think we, you know,

14:39.655 --> 14:41.655
given the efficacy of some

14:41.655 --> 14:43.855
of these therapies which are showing weight loss of,

14:44.035 --> 14:46.815
so in some cases in the mid 20%, if you can imagine

14:46.845 --> 14:50.775
that 26% weight loss in the case of Tze peptide, which is,

14:50.835 --> 14:55.005
Uh, dual GLP one GIP dual agonist, I mean, you know,

14:55.595 --> 14:57.165
when we apply that, we could apply

14:57.165 --> 14:58.885
that in weight related conditions like

14:59.005 --> 15:00.405
PCOS to very good effect.

15:00.945 --> 15:03.445
And I think that, you know, that certainly I think will

15:03.445 --> 15:05.285
feature much more, I think in future management.

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