"Understanding the Link Between PCOS and OSA" Yvonne Chu (04.07.2021)

April 18, 2021

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00:16All right, welcome everybody.
00:17We're going to get started.
00:19I am Lauren Tobias and I'd
00:21like to welcome you to our Yale
00:23Sleep Seminar this afternoon.
00:25A few brief announcements before
00:26we introduce the speaker for today,
00:28please first take a moment
00:30to ensure that you're muted.
00:32In order to receive CME
00:33credit for attendance,
00:34please see the chat room for instructions.
00:36You can chat.
00:37You can text the unique ID for this
00:39conference anytime until 3:15 and if
00:41you're not already registered with DLC Me,
00:43you will need to do that first.
00:45If you have any questions
00:46during the presentation,
00:47I encourage you to make use of the
00:49chat rooms throughout the hour and
00:51we will also encourage people to
00:53unmute themselves and ask their
00:54questions allowed at the end.
00:56We do have recorded versions
00:58of these lectures that are made
01:00available online within two weeks
01:01at the link provided in the chat.
01:03And finally,
01:04feel free to share announcements
01:06for weekly lecture series to anyone
01:08who you think might be interested.
01:10Or contact Debbie Lovejoy to
01:12be added to our email list.
01:14And before I turn it over to Janet
01:16Hilbert to introduce today's speaker,
01:19I just want to let everybody know
01:21about the talk for next week.
01:23It's one of our joint Yale Harvard
01:26conferences and the Speaker
01:27will be Jonathan Lipton,
01:29who is a persistent professor of
01:31neurology at Boston Children's
01:32Hospital and Harvard Medical School.
01:34And his talk is entitled exploring the
01:36cross talk between neuro development
01:38disorders and circadian clocks,
01:40so please plan to join us for that next week.
01:44And with that,
01:45I'll turn it over to Doctor Hilbert.
01:48OK, thank you doctor Tobias.
01:49So it is my pleasure to
01:52introduce Doctor Yvonne Chu,
01:53our speaker for today.
01:55Doctor Chu is a postdoctoral fellow
01:57in Sleep Medicine here at Yale.
01:59She did her undergraduate work
02:01at Cornell University and she
02:03received her MD degree from U Conn.
02:06She completed her internal medicine
02:08residency at Boston Medical
02:10Center and then she stayed on in
02:12Boston for another two years at
02:14BOS at Brigham and Women's where
02:16she investigated the genetic and
02:18molecular aspects of cell migration.
02:21She then came back to Connecticut Ann.
02:23She wasn't attending hospitalist at Yale.
02:25New Haven Hospital for the next few years.
02:28We were very fortunate to have her
02:30match with us and sleep and not only
02:32has she been a superb clinical fellow,
02:35she's really contributed to the
02:37sleep program and she's been
02:38very productive academically.
02:39She leads a quality improvement team,
02:41really focused on improving the process
02:43of care for our pregnant patients,
02:45who will refer to us at the
02:48sleep center and as part of that,
02:50she surveyed Obi-wan practitioners.
02:52Throughout the region regarding
02:54their screening practices in their
02:55knowledge base and that work,
02:57she's going to be presenting at the
02:59research meeting in April as well
03:02as at the sleep Meeting in June.
03:04She also authored a manuscript
03:05on obstructive sleep apnea and
03:07polycystic ovary syndrome.
03:08That's been very well received.
03:10So today she's going to be
03:12discussing understanding the link
03:13between obstructive sleep apnea
03:15and polycystic ovarian syndrome.
03:16So welcome Doctor Chu.
03:19Thank you for that introduction.
03:21Doctor Helbert welcome and
03:22good afternoon everyone.
03:23My talk today is on understanding the
03:26link between obstructive sleep apnea
03:28and polycystic ovarian syndrome.
03:30Before we begin,
03:31just a couple of housekeeping flies.
03:33I have no disclosures to make.
03:35And agree Cordier attendance
03:37and receive CME credit please.
03:39Texas ID number 21618.
03:41It will also appear in the
03:44in the text chat box.
03:46So here are the learning objectives.
03:48By the end of this hour,
03:50my hope is for the audience to be able
03:52to recognize the clinical presentation,
03:54diagnosis and complications of PCOS.
03:56Describe the prevalence
03:57of comorbid OSA and PCOS.
03:59Discuss the role of ***
04:01hormones in regulating,
04:02breathing,
04:03and to understand how this regulation
04:06of these hormones may play a role in
04:09the pathogenesis of OSA and PCOS.
04:11To understand how insulin resistance
04:13is a shared feature of these two
04:16disorders and finally to understand
04:18how treatment may modulate
04:20the outcomes of OSA in PCOS.
04:23So I want us to think back and
04:25I'm sure we can all recall a case
04:27in which we saw a young woman
04:29with PCOS present for evaluation
04:31of sleep disordered breathing.
04:32I will share with you a case I
04:35saw during the first couple of
04:37weeks of my fellowship.
04:39Let's give our patient the name SK.
04:42She's a 38 year old woman who
04:45presented with snoring for 20 years and
04:48recently worsened after a £15 weight gain.
04:50Also with symptoms of gassing awakenings,
04:53excessive daytime sleepiness with
04:55an effort score of 10 nocturia,
04:57and morning headaches.
04:58Her past medical history includes
05:00class 3 obesity,
05:02PCOS that was diagnosed at age 15 and
05:05has been untreated as well as depression.
05:09Esskay physical exam was notable for an
05:11elevated systolic blood pressure 131,
05:14elevated BMI of 46.5 and in large
05:17neck circumference of 19 1/2 inches
05:19as well as amount party of three.
05:22The remainder of her exam was unremarkable.
05:26Eskape Labs were notable for mild
05:30transaminated elevated total cholesterol.
05:32Would decrease HDL,
05:33increases LDL and increase
05:35triglycerides her a one see was also
05:38increased in the pre diabetic range.
05:40The rest of her labs including
05:44her serum bicarbonate were normal.
05:47Given the high pretest probability
05:48for OSA SK underwent home sleep apnea
05:51testing and this is her hypnogram.
05:53At the bottom,
05:54we can see she slept mostly on
05:56her right and left sides.
05:58This is consistent with her
06:00preference to avoid back sleeping.
06:03There were clusters of obstructive
06:05apneas in red here.
06:06As well as Hypotony is here in pink.
06:09On the top we can see associated
06:12the saturation.
06:13Her respiratory event Index
06:15came out to be 66 an hour,
06:17which is consistent with severe
06:19OSA along with a mean sad of
06:2292% and nature of 73%.
06:25Here's a closer view in a four
06:28minute window we see classic back
06:30to back obstructive respiratory
06:32events with associated cyclic.
06:34See saturation and heart rate variability.
06:38There is snoring scene in between
06:40the apneas and hypoxemia and during
06:42her recovery breath her oxygen
06:44saturation largely recovered
06:46back up to the mid 90s.
06:50Our impression was that SK at 38
06:53year old woman has severe OSA as
06:55supported by her symptoms of snoring,
06:58gasping awakenings,
06:59nocturia morning headaches,
07:00and excessive daytime sleepiness.
07:02Along with comorbid depression,
07:04an elevated blood pressure.
07:06And supported by her physical exam.
07:09Findings of the increased BMI in large
07:11neck circumference in a crowded airway.
07:14Anne supported by laboratory findings
07:16of insulin resistance and metabolic
07:17syndrome and then trans ammonite.
07:19If that was suggestive of possible
07:21non alcoholic fatty liver disease.
07:23And finally this is confirmed with the
07:26home sleep apnea test with an REI of 66.
07:33Now, being a new fellow in training at
07:36the time, I didn't think much about the
07:39patients PCOS that ending I was working
07:41with ask me what role does PCOS play?
07:44How does this support the diagnosis
07:46of OSA and how do we explain her
07:49various metabolic derangements
07:50in light of her PCOS an OSA?
07:53This led me to consider what is the
07:57relationship between OSA and PCOS.
08:00We will begin by discussing
08:02the clinical presentation,
08:03diagnosis and comorbidities of PCOS.
08:07PCOS is common with a strong
08:10genetic predisposition.
08:11It was first described in 1935 by
08:13sign in Leventhal as a condition of
08:17oligo operation and hyperandrogenism.
08:19Most it is the most common endocrinopathy
08:23affecting 7 to 13% of women internationally.
08:28Twin studies suggest strong familial
08:31contribution in PCOS development and this
08:33comes from data in over 1300 identical
08:35Twins and their Singleton siblings.
08:38Essentially,
08:38it's one of the identical Twins has
08:42PCOS or other twin is about twice
08:45as likely to have PCOS compared
08:47to their Singleton siblings.
08:50I'm going genetic studies are examining
08:52the specific genes involved in the
08:55biosynthesis and metabolism of androgens,
08:57pelicula, Genesis and secretion,
08:59and action of insulin.
09:02The broader dam criteria is the
09:04most inclusive and preferred
09:06diagnostic criteria for PCOS.
09:08This chart here shows the three most
09:11popular criteria used in the diagnosis
09:13of PCOS and they're to Rotterdam,
09:15NIH and androgen access criteria.
09:19The main features of PCOS are outlined here.
09:22They are clinical or biochemical
09:24evidence of hyperandrogenism,
09:26oligo, menorrhea,
09:27and polycystic ovaries on ultrasound.
09:30I will go through each of these in
09:31detail in the subsequent slides here.
09:33I just want you to know that you
09:35can have a combination of any two
09:37of two out of these three features
09:39to make the diagnosis of PCOS
09:41using the Rotterdam criteria.
09:43Now several of my upcoming slides will
09:45be referring to recommendations based on
09:48international evidence based guidelines
09:49for the assessment and management of PCOS.
09:52It was published in 1920 eighteen.
09:55Among the experts is that on this
09:57committee are the American Society
09:59for Reproductive Medicine and American
10:01Pediatric Society Endocrine Society.
10:03Now,
10:03here are their standardized goods used
10:05to indicate the societies grade for the
10:08recommendations here from one to four,
10:10with four being a strong recommendation
10:13in terms of the quality of evidence we
10:15see from 4 to one here with four here
10:19up there indicating very confident
10:21in the level of of the evidence.
10:25The first of the three key features
10:28of PCOS hyperandrogenism,
10:29which can be determined clinically
10:31or biochemically clinically.
10:32We can look for hirsutism,
10:34acne, male pattern, hair log,
10:36and this is the strong recommendation.
10:39Biochemically, we can use Calculator,
10:41free testosterone or the free androgen index,
10:44which is the total testosterone
10:45levels divided by this,
10:47the *** hormone binding globulin,
10:49and this also has a strong recommendation,
10:52but limited competence is level of evidence.
10:55Standardized visual scales are
10:57preferred when assessing hirsutism,
10:58and this is what a strong
11:00recommendation here is.
11:01The Fehrman Galway score,
11:03which was first introduced in 1961.
11:05Each of the nine body areas
11:07is most sensitive to androgen,
11:09is assigned a score from 0 being know
11:12her to floor, being lost, a pair,
11:14a score of 1 to 7 indicates focal
11:17hirsutism and is considered normal.
11:19Ace score of eight or more is
11:22considered generalized hirsutism.
11:23Ann is considered abnormal.
11:24It is important to note there are racial
11:28considerations when using this score.
11:30East Asian women have lower her citizen
11:32score cutoff whereas Middle Eastern,
11:34Hispanic and Mediterranean women have
11:36slightly higher hirsutism score cutoff.
11:39The next key feature is a
11:41legal menorrhea or amenorrhea.
11:43All common area is irregular
11:45menstrual cycle and an International
11:47Society most strongly recommends
11:48the use of this following criteria.
11:51A regular menstrual cycles are
11:52considered normal in the first
11:54year post monarchy as part of the
11:56pooper role transition between
11:57one to three years post monarchy.
11:59Less than 21 days or greater than
12:0145 days is consider a regular
12:03beyond three years post menarche
12:05all the way up to Perry Menopause.
12:08Less than 21 days or prison 35 days
12:10or less than eight cycles per year
12:12is considered a regular and then
12:14beyond the first year post meta arkie
12:17greater than 90 days for anyone
12:19cycle considering regular and then.
12:21Primary amenorrhea by age 15 or no
12:24menses by beyond three years post the Larkey,
12:27is considered amenorrhea.
12:29And when menstrual cycles are irregular,
12:32a diagnosis of PCOS should be considered,
12:35and this is what is strong recommendation.
12:39The last core feature here
12:41is polycystic ovaries.
12:42Which on ultrasound can support
12:46diagnosis of PCOS.
12:48In patients already with a legal
12:50memory and hyperandrogenism,
12:51an ovarian ultrasound is not necessary.
12:54Ultrasound should not be used
12:56for PCOS diagnosis.
12:58If lesson 8 years have
13:00elapsed after men are key.
13:02When typically the ovaries can
13:05demonstrate multi Poly tools and
13:07that that's common and normal.
13:10To make the diagnosis of polycystic ovaries,
13:12ultrasound will show bears and 20
13:15follicles or an ovarian volume gear
13:17is greater than or equal to 10 Mills.
13:20Here are pictures of what Paula cystic
13:22ovaries may look like on ultrasound.
13:24Some of us may remember from medical
13:26school that is sometimes referred to
13:28as a string of pearls appearance.
13:30And for comparison,
13:31we have here a cystic ovary and
13:33normal ovary with two antral
13:35follicles and one dominant follicle.
13:39Now, numerous comorbidities
13:40have been identified and PCOS,
13:42but the following ones recognized
13:45by the International Society.
13:46They include type 2 diabetes,
13:48gestational diabetes,
13:49and impaired fasting glucose
13:51will be city depression,
13:53anxiety, body image distress,
13:54a question of cardiovascular disease,
13:57as this is supported by limited data.
14:00OSA an enemy treil cancer.
14:02As you can see, some of these
14:05disorders are considered comorbidities.
14:07As with OSA as well.
14:10We now move on to discuss the
14:13prevalence of comorbid OSA in PCOS.
14:16Just to remind everyone,
14:17the prevalence of OSA increases
14:19as women get older and heavier,
14:22and this is supported by data from the
14:25famous Wisconsin Sleep Cohort from
14:27between the years of 1988 and 2011.
14:30This is the logic tunele study of over
14:341500 participants between the ages of
14:3630 to 60s selected from a Mail in survey.
14:3945% of the participants were females.
14:41The table here shows modeling data on
14:44aging and weight increase overtime.
14:46OSA is defined by an hi greater
14:49than equal to 5.
14:52In the 30 to 49 age group,
14:55estimated prevalence of OSA is
14:571.4% in women with normal BMI and
15:00we see this estimated prevalence
15:01increase all the way up to 43%.
15:04In those who have class 3 obesity,
15:07and among the 50 to 70 age group,
15:10estimated prevalence range from
15:129% in those are normal BMI all
15:14the way up to 68% in those women
15:17with the Class 3 obesity.
15:22Now we look at women with PCOS
15:24in a meta analysis of 17 studies
15:28with over 600 participants.
15:30The prevalence bull essay in PCOS is 35%
15:33with a confidence interval of 22 to 49%.
15:37Now it's important to remember that these
15:40studies typically included teenagers
15:42and excluded post menopausal women.
15:44Therefore the prevalence may seem lower
15:46compared to Wisconsin cohort data,
15:48which represents women across
15:50the entire lifespan.
15:52Problem OSA is higher in obese
15:55women compared to lean women with
15:58PCOS and the odds ratio is 3.8.
16:01Now what is very important to know
16:03is that after controlling for BMI.
16:06The risk for OSA is 5 to 10
16:09times higher in adults with PCOS
16:12compared to those without PCOS.
16:16Again, I cannot emphasize enough that
16:19obesity is not the sole driver in the
16:23pathophysiology of OSA and PCOS population.
16:25Now, this study here actually found
16:28that HIV is higher in PCOS after
16:31controlling for age and obesity.
16:34It's a case control study and there were 36
16:37participants have had PCOS and half do not.
16:39Table one shows that they were
16:41of similar age in the early 30s.
16:44And have exact same mean BMI of 36.9.
16:49Now obviously the waist to hip
16:51ratio and testosterone levels are
16:53significantly higher in the PCOS Group,
16:55as we would expect.
17:00Table 2 here summarizes
17:01sleepiness and PSG data.
17:03It shows that the PCOS PCOS group
17:07has significantly higher mean
17:09upward score of 9.5 would arrange
17:11between 4 to 18 compared to an
17:14average of 5.8 in the control group.
17:17The overall HI is significantly
17:20high under PCOS Group.
17:22With the average age of 22 range of 1
17:26to 102 compared to an average of 6.7.
17:30In the control group,
17:31this is a remarkable finding,
17:33considering that none of these women had
17:35been diagnosis OSA prior to the study.
17:40These next two slides,
17:41or these next two studies here,
17:43are highlighted to show that common sleep
17:46complaints in PCOS include insomnia
17:48and excessive daytime sleepiness.
17:50Both are community based studies comparing
17:53women with PCOS and women without PCOS.
17:56Women with PCOS had increased difficulty
17:59falling asleep with an odds ratio close
18:01to two increase awakening without causing
18:04an inability to resume sleep for greater
18:06than 15 minutes within office ratio.
18:09Also close to two.
18:11Increased severe tiredness with their
18:13relative risk ratio 11.5 and increases
18:16sleep difficulties within the last 12
18:18months when an author show close to 1.3.
18:21The authors concluded that targeted
18:24screening and management of sleep
18:26disturbances is warranted in PCOS.
18:29Now, according to the
18:30International Committee on PCOS,
18:32creating for OSA in PCOS is recommended.
18:36Their statements are US outlined here.
18:38Screening should only be
18:39considered for all I stay in PCOS.
18:42Identify and alleviate related
18:43symptoms such as snoring,
18:45waking,
18:45unrefreshing sleep,
18:46daytime sleepiness and the potential for
18:48fatigue to contribute to mood disorders.
18:51And this is with a strong recommendation.
18:53Screening should not be considered with
18:55the intention of improving cardiometabolic
18:57risk with the with inadequate evidence
19:00for metabolic benefits of OSA.
19:01Treatment in PCOS.
19:02Also, with a strong recommendation.
19:04Lastly, a simple screening questionnaire.
19:06Preferably, the Berlin tool,
19:08could be applied.
19:09It is positive referral to
19:11a specialist considered,
19:12and that's with a conditional recommendation,
19:14as currently there is not yet a
19:17screening tool validated in young
19:19women with and without PCOS.
19:21Disappointingly, in practice,
19:23screening rate is low.
19:25Perhaps this is due to the fact
19:27that there is little or no research
19:29on specific screening tools in
19:30the PCOS population.
19:31And this is the only study I found
19:34in regards to screening in the
19:36study of 50OBGYN and 29 endocrine
19:39practitioners caring for PCOS patients.
19:4237% reported that most of their
19:44patients had that Class 3 obesity.
19:4686% felt that their patients Nordin
19:49frequently and 92% refers less than
19:5125% of their patients for sleep study,
19:54and so to summarize and minority
19:57applied practitioners who treat
19:58PCOS are referring a minority of
20:01their patients for sleep evaluation.
20:03Despite the high prevalence of
20:04OSA in patients with PCOS,
20:06the lack of awareness of the
20:08link between PCOS and OSA may.
20:10It may also be a potential reason
20:12for the low rates of referral.
20:17We now move on to the key theories
20:19on the pathogenesis of OSA and PCOS.
20:22The purpose of this slide is to show what
20:25is known about the pathogenesis of PCOS.
20:28The main theory is that there is a
20:31disruption in GNRH release from the
20:33hypothalamus which leads to hyper secretion
20:36of LH from the pituitary gland resulting
20:39in an increase in the LH FSH ratio.
20:42This induces abula Tori dysfunction.
20:44Repeat a follicular arrested.
20:46What results in the polycystic ovary
20:49morphology we see on ultrasound?
20:51The increase in LH to FSH also promotes the
20:55hypersecretion of androgens and theca cells,
20:58which in turn reduces the inhibition
21:01of normal GNRH pulse frequency by
21:04progesterone and further promoting
21:06this development of PCOS.
21:08What is not shown here is that there's
21:11also an increased level of anti malarian
21:13hormone released in the follicles of PCOS,
21:16and that leads to reduce FSH
21:18sensitivity and blocks the conversion
21:20of androgens to estrogens,
21:22resulting in reduced overall estrogen levels.
21:26It will resistance arising from separate
21:28pathways that we will discuss later on.
21:31Also contribute to Abula Tori dysfunction.
21:36We will now segue into discussing
21:39the role of *** hormones in
21:41controlling breathing in normal women.
21:42Without PCOS, there's a balance
21:44between female hormones and male
21:46hormones on the one side we are.
21:48We have the female hormones
21:50estrogen and progesterone,
21:51which are protective in
21:52the development of OSA.
21:53On the other side are male
21:56hormones or androgens,
21:57among which include testosterone,
21:58which may promote the development of OSA.
22:01In PCOS we have a deficiency of
22:03female hormones and an excess of
22:06male hormones causing an imbalance.
22:07We no longer have the protective
22:09effects of female hormones and at
22:12the same time there is an excess
22:13of androgens when they which may
22:15promote development of OFA in the next
22:18several slides we will dive into the
22:21implications of this hormonal imbalance.
22:24We will start by talking about progesterone.
22:27Much of the research comes from
22:29studying the normal luteal phase in
22:31women where there is a surge and peak
22:33of progesterone activity which is
22:36associated with increased upper airway.
22:38Dilatory muscle activity reduce
22:40upper airway resistance and
22:42improved nocturnal ventilation.
22:43And just as a reminder,
22:45as you see here in the diagram,
22:48the normal,
22:48normal luteal phase occurs after ovulation,
22:51or the rupture of the follicules.
22:53What's left behind at the follicules
22:55becomes the corpus luteum.
22:56The corpus luteum is responsible
22:58for the release of progesterone,
23:00which will then stick in the lining
23:02of endometrium preparing for the
23:04implantation of the fertilized egg.
23:06Because operation is impaired in PCOS,
23:09the surge of progesterone does
23:11not occur and overall levels of
23:14progesterone remain low in PCOS.
23:17Four decades ago,
23:18this study came out in Java.
23:21Exogenous progesterone led to
23:23reduce obstructive apneas and
23:25improve daytime sleepiness in OSA.
23:27It was a small study with nine
23:30subjects with only one woman,
23:32an 8 of the subjects had obesity.
23:35Their average age is between 4070.
23:38The intervention was medroxyprogesterone,
23:4160 to 120 milligrams given
23:44daily in divided doses.
23:46The results here showed that
23:47there were four responders for
23:49represented by these building circles.
23:51Among the responders was the
23:53single woman enrolled in the study.
23:56Now the responder shows
23:57significant reduction.
23:58Hi,
23:58as well as improvement in daytime sleepiness,
24:01but that isn't shown here.
24:03The improvement in hi a curd
24:06during the intervention where they
24:08received madocks is progesterone.
24:10This is comparative before they
24:13receive this medication and compared
24:15to after they stopped the medication.
24:18Interesting Lee of note.
24:20The responders at baseline were also
24:23more hypoxemic on their wakeful ABG.
24:25The difference in PA.
24:27CO2 was, however,
24:28NASA tips to assist the Statistique
24:31Lee significant.
24:32The authors also noted that both
24:34responders and non responders showed
24:36improvements in their CO2 and O2
24:38levels during mid Roxy progesterone therapy.
24:40This speaks to the theory that
24:43progesterone may improve ventilation.
24:46We talked about normal menstrual
24:48cycle now will touch touch on
24:50pregnancy and pregnancy.
24:52Progesterone positively correlated
24:53suggest stational age negatively
24:55correlated with maternal weight and
24:58when adjusted for gestational age,
24:59maternal weight bearing,
25:01professional level is significantly
25:04lower in women
25:06with OSA. In menopause,
25:07there's a lot of progesterone and estrogen,
25:10and we all know that the prevalence
25:12of OSA increases post menopause.
25:14This is, however, impacted by other
25:16factors such as age and obesity.
25:19And to perhaps illustrate
25:20this point in one study,
25:23the administration of Luke Bronan healthy
25:25non obese young women to induce medical
25:28menopause did not result in sleep,
25:31fragmentation or clinically
25:33significant sleep disorder breathing.
25:35When we apply when we know
25:37about normal luteal phase.
25:39Pregnancy and menopause.
25:40The PCOS. We know that there are
25:43reduced levels of progesterone,
25:44estrogen, and PCOS.
25:46Therefore, this may predispose women to
25:48have increased upper airway collapsibility
25:51an reduce ventilla Tori drive and
25:54therefore increase the risk for OSA.
25:56We will now discuss and region.
25:59Androgen access is linked to central
26:01adiposity or Apple shaped body type.
26:03We see here.
26:05Studies have shown that 50 to 60%
26:08of women with PCOS have a nap.
26:10Dot abdominal distribution of
26:12body fat or central obesity.
26:14Regardless of their BMI.
26:17Central adiposity contributes to the
26:18pathogenesis and severity of OSA.
26:20Here, in this perspective study,
26:22looking at 36 women recruited
26:24from the sleep setting,
26:25the baseline age was 50s.
26:27BMI is in the low 30s.
26:29In the mean age I was 15.
26:32What was measured was the percentage
26:34of fat and lean body mass in different
26:37regions of the body using dexa.
26:40What was found was that Android or
26:43central distribution of fat was the
26:45best univariate predictor of hi in
26:48women with an R square value of 26%.
26:51These images here were taken from the
26:53publication to demonstrate what was
26:55considered Android versus gynoid fat.
27:00Furthermore, androgens,
27:01androgens and waist to hip ratio positively
27:04correlate with hi women with PCOS.
27:06This data is from this same
27:08case control study I referenced
27:10earlier in the presentation.
27:12Here we're looking at the 18 women
27:15with PCOS and not their control.
27:18The first figure shows a correlation
27:21between waist to hip ratio on
27:24the X axis and hi in the Y axis.
27:26We see a positive correlation
27:29within R = 0.51.
27:31The second figure shows a
27:33positive correlation between
27:34serum total cholesterol serum,
27:35total testosterone,
27:36an AHI with a positive correlation,
27:39R = 0.52. Again,
27:40these graphs only show women with PCOS.
27:43For those of you wondering,
27:45what about the control group?
27:47In this study,
27:48the women without PCOS but but control for
27:52age and BMI well in the control group.
27:55Hi was positively correlated
27:56with waist to hip ratio as well,
27:59and the R value was 0.5.
28:03Which arguably is a stronger correlation,
28:05and we see in the PCOS group.
28:07However,
28:08there was no significant correlation
28:10between serum testosterone
28:11and hi in the control group.
28:13This suggests that there are other
28:16factors contributing to central
28:17obesity besides androgen levels alone,
28:19and one of these factors is
28:21thought to be insulin resistance
28:24and elevated serum glucose levels.
28:26And that is segue into the next
28:29section on metabolic syndrome
28:30and insulin resistance in women
28:32with PCOS and OSA.
28:34Here's a visual to remind us
28:37what metabolic syndrome is.
28:38It consists of high triglycerides,
28:41low HDL, visceral obesity,
28:43insulin resistance and hypertension.
28:46When it was both PCOS and OSA have worse
28:50metabolic profile than women with only PCOS.
28:53In an observation ULL study
28:55of 28 Teen Agers with PCOS.
28:58Those with OSA had increased
29:00metabolic syndrome,
29:01increase insulin resistance,
29:02reduce HDL in increase in triglycerides.
29:05In another observation,
29:06ULL study of 103 teenagers with PCOS.
29:09Those with OSA hat increase
29:11homeostatic model assessment,
29:12which is essentially a method used
29:15to quantify insulin resistance as
29:17well as increase metabolic syndrome.
29:19Now,
29:19both of these studies did
29:22control her BMI an age.
29:27Insulin resistance is a key
29:29feature in both PCOS and OSA.
29:31In this diagram,
29:32we're looking at the pathogenesis
29:34from OSA to insulin resistance.
29:36In Type 2 diabetes,
29:37the two key elements of OSA are
29:39intermittent hypoxia and sleep fragmentation,
29:42and they have been linked to an
29:45increase in inflammatory aside,
29:46a time oxidative stress and the
29:49activation of sympathetic nervous system,
29:51and that all in turn leads to
29:53reduce insulin sensitivity at
29:55the target tissues as well as.
29:57Pancreatic beta cell dysfunction in
29:59the adipose tissue we see increased
30:02by policies increase inflammation,
30:04reduce insulin sensitivity.
30:05In the liver we see increased
30:08glucose production.
30:09The phenotype of non alcoholic fatty
30:12liver disease as well as increased
30:14inflammation in the muscles that
30:17decreases in efficiency of glucose
30:19uptake and then in the pancreas
30:21we see increased beta cells.
30:23Def Simple operation reduces one content
30:25reduce glucose induced insulin secretion.
30:28All of this results in insulin resistance,
30:31glucose intolerance and can potentially
30:33progressed to type 2 diabetes.
30:37Now I move the OSA figure aside
30:40and make room for the PCOS figure.
30:43We talked about earlier.
30:45We can see how untreated OSA
30:47may potentially feed into this
30:49insulin resistance pathway here
30:51that can further perpetuate
30:53abula Tori dysfunction in PCOS.
30:59All right, moving on,
31:00we're going to next talk about the
31:03treatment outcomes of OSA and PCOS.
31:06First, we're going to talk about this study
31:09that tries to answer the question what
31:11are the short term impacts of metformin
31:14on the metabolic and sleep parameters?
31:17This study included 90 adolescent
31:19females between the ages of 12 to 18,
31:22randomized into three groups.
31:23Control, untreated PCOS and
31:25PCOS plus metformin.
31:26The treatment was metformin 850
31:28milligrams twice daily for three months.
31:31Table one here shows the baseline
31:33characteristics of the three groups.
31:35The mean age is similar or about
31:3916 across the board.
31:41The mean BMI was normal at 21 in the
31:44control group and this is significantly
31:47different from the two PCOS group
31:49with the mean BMI of about 35.
31:52Here in here the BMI was not significantly
31:56different between the two PC LF groups.
31:58Now the fasting blood Glucose Tahoma
32:00index again that's the measurement
32:02of insulin resistance and hirsutism
32:04scores were all higher in two PCOS
32:06group compared to the control.
32:08But they were not significantly
32:10different between the two PCOS groups.
32:13Sleep disturbance Scale is a scale
32:15validated in adolescence and children,
32:17and it consists of 26 items
32:19with a score greater than 52,
32:21considered positive for sleep disorders,
32:23the mean score was 48 in the control group.
32:27Alright here and there were 75 in
32:30untreated PCOS soup and 78 in the PCOS.
32:32Plus plus metformin group again.
32:34No significant difference between
32:36the two PCOS groups and both of
32:39these groups have pathologic scores.
32:41And Lastly,
32:42the mean upwards of eight in
32:44the control group and very high,
32:46about 16 in each of the two PCOS group.
32:49Again,
32:50no difference between the two PCOS group.
32:54The results of metformin therapy
32:56were quite remarkable.
32:57Here we see in Table 2 the mean
33:00BMI in the PCOS plus metformin
33:03group decrease in 34 to 26.
33:07After just three months of metformin,
33:09mean body weight was 75 kilograms
33:12pretreatment and is now 57 kilograms,
33:15which is about £40 or 24% weight reduction.
33:19And for comparison,
33:20the untreated PCOS went up slightly from
33:2435 to 36 in their BMI and the control
33:29group BMI basically stayed normal.
33:32The fasting and postprandial glucose,
33:33as well as the home and index all
33:36decreased in the PCOS plus metformin group.
33:39Which was significantly different
33:40compared to the untreated PCOS group.
33:43Hirsutism score.
33:43Also decreasing the PCOS plasma
33:45form a group and download chart.
33:47All these fees here indicates significant
33:50difference compared to untreated group,
33:51whereas at baseline prior to
33:53treatment there was no difference
33:55between these two groups.
33:59Here in table three we see there is a
34:02significant decrease in Epworth score in
34:04the PCOS plus Metformin Group from 16 prior
34:07to treatment to all the way down to 12.
34:10The Edwards is now significantly different
34:13compared to the untreated group.
34:15The sleep disturbance core also decrease,
34:17but it does remain pathologic at above 52.
34:21So, to summarize,
34:23metformin therapy in PCOS reduces BMI,
34:27insulin resistance, hirsutism,
34:28and the Epworth score.
34:33In the prior study,
34:34we saw a weight reduction of 24%
34:37in the metformin treatment arm,
34:38which is a massive change.
34:40What we know is that a weight reduction
34:43of only 5 to 10% have beneficial
34:46results in both OSA and PCOS.
34:48We lost as a primary treatment
34:50in both of these conditions.
34:52In the general population and average
34:54weight loss of 10% of body weight can
34:57result in a modest reduction in Hi Ann
35:00and overall improvement in OSA severity.
35:03And PCOS a weight reduction of
35:055% can restore regular menstrual
35:08cycles and improve fertility.
35:10Other benefits of weight loss include
35:12decreased adipose and androgen levels,
35:15as well as an improvement
35:18in insulin resistance.
35:20Now let's review the current
35:22weight reduction recommendation.
35:23The American Thoracic Fest societies
35:26clinical practice guidelines recommend a
35:28comprehensive weight loss program for OSA.
35:31In all comers with OSA with a
35:34BMI greater than or equal to 25,
35:37a comprehensive lifestyle intervention
35:39program that includes a weight,
35:41reduced calorie diet,
35:42increase physical activity,
35:43and behavioral counseling
35:45is strongly recommended.
35:46And those of OSA,
35:48would it be in my greater than or
35:50equal to 27 but with no improvement?
35:53After a comprehensive weight
35:55loss program and antiobesity
35:56pharmacotherapy is recommended with
35:58the conditional recommendation.
35:59Those with OSA in a BMI greater than
36:02or equal to 35 but no improvement after
36:06comprehensive weight loss program.
36:08Referral for bariatric surgery
36:11evaluation is recommended conditionally.
36:13The international evidence based
36:15guidelines also recommend a comprehensive
36:17weight loss program for PCOS.
36:19Here third, two statements,
36:21healthy lifestyle behaviors
36:23encompassing healthy eating and
36:25regular physical activity should be
36:27recommended in those with PCOS to
36:29achieve an or maintain healthy weight
36:31and to optimize hormonal outcomes.
36:33General Health and quality of
36:35life across the life course with
36:38a strong recommendation.
36:39Lifestyle intervention,
36:40preferably including diet,
36:42exercise and behavioral strategies
36:44should be recommended in those
36:46with PCOS and excess weight
36:48for reductions in weight,
36:50central obesity and insulin resistance,
36:52and this has limited confidence
36:54in the level of evidence.
36:59They don't effective CPAP in
37:01PCOS are extremely limited.
37:03This is one of the only studies to date.
37:06It addresses the question what
37:08are the cardiometabolic effects of
37:11short term C pap therapy in PCOS?
37:13Here the intervention is
37:158 weeks of CPAP therapy.
37:17The measures include metabolic, hormonal,
37:19and cardiovascular assessments at
37:21baseline and after eight weeks of therapy.
37:24The subjects are 56 young women,
37:26young obese women with PCOS recruited
37:29from a University endocrine clinic.
37:31They were excluded if there was
37:33presence of diabetes, hypertension,
37:35or significant cardiovascular disease,
37:37and they must have been off any *** steroids,
37:41anti androgens or insulin lowering
37:43medications for eight weeks
37:45prior to the intervention.
37:4726 of them met,
37:48including criteria which
37:50includes a diagnosis of OSA.
37:517 dropped out among the 19 who
37:54completed this study study.
37:55Only nine were Papa here and.
38:00When we look at just those who
38:02were Papa here and graph A here
38:04shows a fitted regression values of
38:06the change in insulin sensitivity
38:08after CPAP as a function of BMI.
38:10There's a function that CPAP use.
38:13The dark line here represents a line of
38:16fit and the dotted lines represent the
38:1995th percentile constant confidence bands.
38:21Improvement in insulin sensitivity
38:23after C pap is greatest among
38:26women with lower BMI assist here.
38:28Anne was greater with more hours
38:30of CPAP used as we see here.
38:33Graph B shows modeling of change
38:35in insulin sensitivity expected
38:36after four hours,
38:376 hours and 8 hours of sleep apneas per
38:40night in an overly weight patient here
38:43with a BMI of 28 and an obese patient here.
38:46Would it be in my 35 predicted
38:48improvement in insulin sensitivity after
38:50treatment of OSA is more pronounced
38:52with longer hours of C pap used in
38:55a dose dependent manner and is of
38:57lesser magnitude in patients with higher BMI.
38:59Again,
39:00this is all modeling data here on the bottom.
39:05Another significant finding in
39:06this study was that short term pap
39:09therapy reduce norepinephrine levels.
39:11Here we see norepinephrine levels
39:13on the Y axis and the 24 hour day
39:16on the X axis potted along this
39:18continuum is the mean levels of
39:21norepinephrine before an after eight
39:23weeks to see pap therapy.
39:25The Gray bars indicate meals and the
39:28black bar here indicates that I'm in bed.
39:31See PAP treatment resulted
39:33in a 25% reduction.
39:34In the mean 24 hour plasma
39:37norepinephrine levels,
39:38it's interesting to note that affects
39:41extended beyond hours of CPAP use.
39:45I will mention that the authors
39:46did also look at cortisol,
39:48epinephrine, an left in levels,
39:50but there was no significant
39:52changes detected in those levels.
39:56Here the authors show the reduction in
39:58sympathetic activity after CPAP use.
40:00Segments of ECG recordings at these
40:03four time points, dinner, bedtime,
40:05breakfast and lunch or uses markers
40:07of cardiac autonomic function
40:09before and after C PAP treatment.
40:11The authors used spectral analysis
40:13of heart rate variability to
40:15measure autonomic activity.
40:17Here, the high frequency HF means
40:19normalized high frequency band is
40:21essentially a surrogate for vagal
40:23activity or parasympathetic activity.
40:25Bagel activity appears increased faster.
40:27The past few years, as you see here,
40:30the LM is normalized low frequency band,
40:33which is essentially a marker
40:34for sympathetic activity,
40:36and you see that decrease after CPAP use.
40:40The last chart here the L F2 HF ratios
40:44essentially index of cardio symptom.
40:46They go activity and that is
40:50also reduced after CPAP use.
40:53So again,
40:54the pickle method this year is
40:56that pap therapy seems to reduce
40:59sympathetic activity.
41:03And this is the last study
41:04I will highlight because it
41:06addresses an interesting question.
41:07CLOSE PCOS treatment prevent OSA.
41:11In a longitudinal study with peer
41:13she data at baseline and at three
41:16years follow up in 15 adolescent
41:18females with PCOS treated for
41:21hyperandrogenism and insulin resistance.
41:23We see here that.
41:27At baseline or their, their weight
41:29has not changed after three years.
41:32With treatment plan,
41:33it stayed around 32 for BMI and just
41:37just to kind of review that the
41:40treatment looking farther into this
41:43study was actually not standardized.
41:46It included either a comprehensive
41:48lifestyle intervention that only about
41:5150% of the participants took part in
41:53an in a combination of medications.
41:57So I follow up three of the girls
41:59were not on any medications.
42:01Two were taking Ocps,
42:03eight were taking an anti androgen drug
42:05called Diane 35 and one was taking OCP.
42:08Plus metformin was taking Diane
42:0935 plus performance.
42:10So as you can tell there was a
42:12lot of variability into treatment.
42:18So you know I, I just want to
42:20point out here that the weight
42:22and BMI were maintained after all,
42:24as opposed to increase after three years.
42:26And this was attributed to having
42:29some form of treatment for PCOS.
42:31And we don't see a in a significant
42:34difference here in the markers of glucose
42:37fasting glucose or insulin resistance,
42:39but that's perhaps this is the fact that very
42:43few of these teenagers were on metformin.
42:46And then we do see a significant
42:48reduction in free androgen index,
42:50and that's likely because many of them
42:53were on an anti androgen medication.
42:57With treatment Ann the Adolescents
43:00with PCOS had no changes in their AHI,
43:03which was normal and less than one per hour.
43:08At three years follow up as you see here,
43:10along with the other sleep parameters.
43:13I bring up this study because it
43:15suggests that early treatment of PCOS,
43:18particularly treatment that achieves
43:19weight maintenance and a slight
43:21reduction in free androgen index,
43:23may potentially prevent or at
43:25least delay the development of OSA
43:28in an otherwise high risk group.
43:31Now, of course,
43:32this study has its weaknesses.
43:33It was a small study.
43:35The subjects were still quite
43:37young that follow up.
43:38There was no standardized
43:39treatment as I mentioned,
43:41and no comparative data on adolescents.
43:43Untreated PCOS.
43:46So finally back to our
43:48case for our patient SK.
43:50The 38 year old patient with PCOS and OSA.
43:53Our recommendations for her which are in
43:55this shape app with close monitoring.
43:58Aim for five to 10% weight
44:00reduction with referrals.
44:01Weight management clinic.
44:03We encourage the patient to re
44:05establish care for PCOS and discuss
44:07referral between an endocrinologist or
44:09a reproductive specialist and decided
44:12on reproductive specialist because
44:13of her preference achieve fertility.
44:16We also discussed potentially restarting
44:18metformin to assist with weight reduction,
44:20improve sense insulin sensitivity,
44:22and potentially restore her menstrual cycles.
44:27So in summary,
44:28here are the take home bullet points.
44:30OSA has a high prevalence of
44:3235% among women with PCOS,
44:34controlling for BMI.
44:35The risk of OSA is 5 to 10 fold
44:38higher in adults with PCOS
44:41compared to those without PCOS.
44:43*** hormones play a role in the
44:46pathogenesis of OSA in PCOS.
44:49Insulin resistance is a key feature
44:51in both of these conditions.
44:53Metformin may reduce BMI,
44:55insulin resistance,
44:55and net worth C PAP therapy,
44:58or oh for OSA in PCOS may
45:01reduce cardiometabolic risk.
45:02Early treatment of PCOS may
45:05reduce the risk of developing OSA.
45:08I want to end with the comment that
45:10resources only skimmed the surface
45:12on the link between PCOS and OSA.
45:14We still have much more to learn
45:16about the role of *** hormones in the
45:19pathogenesis of OSA into feel less.
45:21It will also be interesting to see
45:23more longitudinal data regarding
45:25the treatment of OSA cinepax in
45:27PCOS as well as the treatment
45:29of PCOS is impacting OSA.
45:31And so hopefully I have accomplished
45:33the learning objectives in this hour
45:35and thank you all for your attention.
45:37I also want to thank all of
45:40the Yale faculty members,
45:41particularly this doctors,
45:42Tobias Hilbert,
45:43and minor for giving me feedback on
45:45my presentation and for Doctor Motion
45:47and for supervising me on the case of SK.
45:50And I will leave you with this image
45:53to remind us about the balance of
45:55*** hormones or just bounds in
45:57general and open the floor for
45:59up for any questions. Thank you.
46:03Thank you man, that was excellent really.
46:05A wonderful, wonderful overview.
46:06So what I would love is if people
46:09would like to either unmute
46:10themselves and ask their questions,
46:12or feel free to put questions in the
46:15chat and I will read them so that
46:18we don't look at them so we have one
46:21question from one of our former fellows.
46:23A great talk.
46:24What is the timeline from developing
46:26PCOS to developing OSA? What do
46:28we know about them?
46:30That's a great question.
46:31So what we know is that. Typically,
46:34women who develop PCOS develop it earlier,
46:38typically soon after their men are key an.
46:42There is typically a lapse of years
46:45later in the studies I found many of
46:50the adolescent studies 3rd to show OSA,
46:53appear in the in the late teens
46:57early 20s and there is definitely
47:00also a component of obesity that.
47:04That of course, the heavier the women,
47:07the more likely to they are to
47:09have OSA at an earlier age in PCOS,
47:13but definitely at a younger age than
47:15compared to the general female population.
47:19Great thank you.
47:20Alright where we have a couple
47:22of outstanding presentations.
47:23Great talk so it's always nice to see those
47:26people don't feel free to ask questions.
47:29You know doctor too.
47:31I was really struck by.
47:34Sort of similar to the to
47:36your pregnancy data.
47:37When you when you serve,
47:38aid OB GY and practitioners here,
47:40you know you presented that data
47:42about practitioners who take care of
47:44these women with PCOS all the time,
47:46but their referral rates for sleep
47:48evaluations seem right, extraordinary low.
47:50And so how do we? How do we change that?
47:53Like what would you?
47:54What would you suggest?
47:56Yeah, that's it. This is a great question,
48:00so I think a large factor in that
48:03is the lack of awareness of the the
48:06link between these two disorders,
48:09especially the lack of awareness.
48:12How early on in life that OSA may
48:15present in in these young out in the
48:19adolescents and young women with PCOS.
48:22So I think you know, to counteract that,
48:25I educational outreach too.
48:27You know, having collaboration between
48:29the sleep providers and endocrinologist,
48:32the reproductive specialist is key.
48:34Really an an as I found out from
48:37also just reaching out to the OBGYN
48:40practitioners on my research with pregnancy.
48:43Alot of them were very open and willing to,
48:47you know, attend any future you know.
48:50Educational session on just learning
48:53about how to screen for OSA.
48:55What symptoms to look for an?
48:58And you know what the treatment benefits are.
49:01They do want to know,
49:02and they're very interested in
49:04any educational opportunities.
49:05Terrific, right?
49:06So it sounds
49:07like it's really up to us as the sleep
49:10practitioners to really help educate and
49:12really teach them what they need to know.
49:14So that's terrific. Let me see.
49:16I'm just saying, oh, go ahead.
49:20Ivan, that was a wonderful twice really
49:22putting it all together nicely with the
49:25scientific background and all the clinical.
49:28So as you all heard is there is a wide open.
49:32Field at investigate.
49:33They buy directional relationship between
49:35this year's and OSA and and I'm sure
49:38it's going to make a huge impact if
49:41you have better understanding of the.
49:44Hormonal variations within PCOS population.
49:46Some of them may not have an actual
49:49increase in androgen levels,
49:52so trying to dissect out who are
49:55within that PCOS group actually
49:58at higher risk of developing OSA
50:00or an or metabolic syndrome.
50:03So maybe either current fellows
50:06or future fellows can actually
50:09get into this and do a kind of a
50:12translational and clinical
50:13correlation type of
50:15research. So it's going to be
50:17very fruitful, kind of the area
50:19to investigate absolutely absolutely.
50:21Yeah, the what we know.
50:23As I've mentioned in one of the slides,
50:26is that a lot of the data we know
50:28on the effect hormones role in PCOS
50:31and OSA development comes from,
50:33you know, studies looking at normal
50:35women's luteal phase, pregnant women.
50:37And so a lot of this. This.
50:40This is still not hashed out in PCOS.
50:43So I think really,
50:44diving in and looking at the role
50:47of *** hormones is important.
50:51Terrific so we have another
50:53question and this again revolves
50:54around treatment and you know this
50:57seems like limited data on C Pap's
50:59obviously to Doctor Most means point
51:01right areas fruitful for research.
51:03But a question of have you come
51:05across any information about the
51:07role of surgical weight loss?
51:08For for individuals who have PCOS and OSA?
51:12Yes, so the current recommendations
51:15in terms of surgical weight loss
51:19from the International Society on
51:22PCOS is is kind of it's conditional.
51:26There is not enough evidence to
51:30show that even bariatric surgery
51:33in PCOS is a strong recommendation
51:36or even a definitive potential
51:39definitive treatment for the.
51:43Hormonal imbalance or insulin
51:45resistance so they they are very,
51:48very cautious in that particular
51:51recommendation and also especially
51:54that a lot of these are young women so.
51:59And obviously,
52:00the weight comprehensive weight loss
52:02program is the initial approach.
52:05With these young women,
52:07and certainly I have not come over
52:11across any evidence regarding
52:13bariatric surgery.
52:15For these two conditions combined.
52:18Great thank you. Thank you.
52:20Alright so I think we have a few more
52:23minutes or maybe one more minute
52:25if anyone has another question.
52:27Ann wants to unmute themselves.
52:29I know we have a conference at three
52:31so I I'm mindful of. Yeah, I yeah,
52:34I'd like to make a very quick comment.
52:37Several years ago when I was still in Canada,
52:40I had a bunch of patients with PCOS and
52:43there was only at the time there was only
52:46one article about it in the literature,
52:48so I submitted my series.
52:50To this Journal to the main Journal
52:53of obstetrics and gynecology and
52:55I got an instantaneous rejection.
52:58And the and the rejection letter said.
53:00And this is a paraphrase.
53:02Our readers have no interest in sleep.
53:05I mean, this is like so, anyway,
53:07so I thought I I sort of throw that in that,
53:12and I think we might still be in that
53:15situation because, as you mentioned,
53:17Janet, we're not getting a whole
53:19lot of referrals from from,
53:21you know, from the gynecologists.
53:23Right, right I.
53:24But you know,
53:25as Doctor Chu mentioned,
53:26you know,
53:27I think that when we approached
53:28them an ask them questions about why
53:30aren't you screening and what are the
53:32barriers at its lack of knowledge.
53:34And yes,
53:35they are actually interested in learning
53:36so hopefully hopefully we've evolved.
53:38You know,
53:39since you got that rejection letter.
53:42So alright, well I would like to
53:44thank everybody for their attention,
53:46specifically Doctor Chu.
53:47This was outstanding and everyone for
53:49your comments and your questions.
53:50I think we will adjourn at this point,
53:53so thanks everyone. Have a great thank you.
53:56Bye bye great talk, Ivan.
53:57Great talk. Thank you so much.
53:59Thank
54:00you thank you, thank you everyone.