Joelle, a bubbly 25-year-old woman, arrived at the office exasperated, she had seen numerous clinicians, but was still struggling. She suspected PCOS, based on her signs and symptoms, including irregular & painful periods (for which she took oral contraceptive pills for two years during college), hirsutism, acanthosis nigricans, cystic acne and an elevated BMI with higher abdominal adiposity, not responsive to exercise. She also complained of marked anxiety.
Joelle started gaining weight and developed hirsutism in middle school, when she hit menarche. She developed acanthosis nigricans in high school. She was very self-conscious of these issues, and highly motivated to resolve them. Her testosterone was previously elevated, and she was diagnosed with pre-diabetes in 2011, but only a single cyst was identified on pelvic ultrasound and determined to be non-significant. Treatment for PCOS was therefore not pursued.
She had IBS, diarrhea alternating with constipation, and significant bloating, belching after most meals. She was previously prescribed digestive enzymes which she reported as helpful, but bloating continued nonetheless. She wasn’t a binge eater, but craved chocolate. She attempted to be “low carb-ish” and was mostly vegetarian and generally kept her diet “clean” and organic. She avoided gluten and dairy, albeit imperfectly, as she noted that both increased gas and bloating. Previous celiac serology was negative. Energy was fair; she reported generally “tanking” most afternoons. She kept a limited exercise schedule. In addition to digestive enzymes, she took vitamin D, 5000IU per day; and a probiotic.
Joelle was highly motived to begin a full functional program, as in six months’ time; she was headed overseas for graduate school. Her goals for treatment were: Weight loss, normalize hormone imbalances, optimize GI function and reduce/manage anxiety.
As usual, my baseline laboratory investigations were broad. I was looking carefully for signs of hormonal, metabolic, GI and nutrient imbalances.
Select significant baseline lab findings:
(L = Low; LN = Low-normal; H = High; HN = High-normal)
- Celiac genetics: HLADQ2 homozygous.
- Kidney and liver function tests: Normal
- Thyroid function tests: Normal/acceptable
- Thyroid antibody tests: Negative
- Fasting blood sugar: 82mg/dL
- HGB A1C: 5.1
- Fasting insulin: 15.5 HN (2-19.6 uIU/mL)
- Fasting lipids:
- HDL 45 L mg/dL (HDL large particles L)
- Triglycerides 95 HN mg/dL
- LDL 110 mg/dL (LDL small particles H)
- Lp(a) 156 nmol/L VH
- FSH: 7.6 L (35-250 mIU/mL, drawn at follicular phase)
- LH: 15.6 HN (0.5-16.9 mIU/mL, drawn at follicular phase)
- Sex hormone binding globulin: 18 LN (17-124 nmol/mL)
- 4-point urine sex hormones and cortisol measurements (all units are ng/mg creatinine):
- Testosterone 12.8 HN (4-14)
- Androsterone: 2318 VH (399-1364)
- Progesterone 1.6 VL (6-20)
- Estradiol: 3.2 (1.8-4.5)
- Cortisol, 4 point measurements: within normal/acceptable limits
- Testosterone 12.8 HN (4-14)
- SIBO breath test: Hydrogen: 64 VH; Methane: 7 (severe SIBO >33ppm)
- DNA stool test:
- Blastocystis hominis identified
- Bifidobacter spp: 7.9 E9 L (>8.9 E9)
- Elastase 203 LN (>200 mg/mL)
- IgG food sensitivities included: shrimp, salmon, gluten, casein (dairy), hazelnuts and peanuts
- Whole blood potassium: 82 L (90-111nmol/L)
- Vitamin D: 31 LN (RR 30-100 ng/mL)
- RBC Magnesium: 44 LN (34-63 ppm)
- Serum iodine: 49L (52-109ug/L)
Laboratory discussion: Research findings demonstrate that celiac genetics without positive serology, as was the case with my patient, has been associated with non-specific GI inflammation and gluten sensitivity. Thus, continuing gluten elimination was important.
Even using strict, functional laboratory interpretation, Joelle’s fasting blood sugar was fine, and her A1C was good. However, her fasting insulin was well above a functional reference range. As I’ve written about, The San Antonio Heart Study found increased risk for cardiovascular disease at fasting insulin levels above 5 (and incidentally, they found fasting insulin levels to be correlative with HOMA-IR). Dr. David Ludwig suggests that a fasting insulin should be 2 or lower in someone in peak metabolic shape. Thus, the currently employed standard reference range for insulin is insufficient for identifying early metabolic disease/insulin resistance. Employing a more sensitive, evidenced-based reference range allows for identifying metabolic imbalances that may be missed using A1C or fasting blood sugar alone. Furthermore, I find fasting insulin can often supplant the need for the dreaded glucose/insulin tolerance test, as I wrote about in this case study, where fasting insulin was a whopping 35, while fasting blood sugar and A1C were just 97 and 5.2, respectively.
Joelle’s lipid panel also suggests insulin resistance, with low total HDL and HDL particle size; and higher small LDL particles. Note that her triglyceride:HDL ratio, also predictive of metabolic disease, was >2.0.
Sex hormone findings were consistent with a PCOS/cardiometabolic picture. Testosterone, and more importantly, the potent testosterone metabolite, androsterone, was very elevated in Joelle, demonstrating aggressive 5-alpha reductase activity. Progesterone was markedly low, falling in postmenopausal range, whereas estradiol was well-within normal limits, suggesting relative estrogen dominance and increased aromatase activity (shunting some testosterone towards estrogen production)
Joelle’s luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were imbalanced, with LH higher and FSH lower. Normally found in about a 1:1 ratio, the 2:1 LH/FSH finding is consistent with PCOS. However, ovarian cysts were not identified. While I didn’t order an ultrasound as a part of my work-up (as perhaps I should have), a sensitive 3D transvaginal ultrasound allows for identification of smaller follicles, and may have been positive. That said, the NIH/NICHD diagnostic criteria doesn’t require the presents of cysts for the diagnosis of PCOS. From Tsilchorozidou, et al: “Ovarian morphological changes must be distinguished from the endocrine syndrome of PCOS and be considered as a sign rather and not a disease.”
Joelle’s breath test was positive for small intestinal bacterial overgrowth, and she had a fairly common Blastocystis hominis parasitic infection. IBS is a common finding in PCOS. Women with IBS/PCOS have higher BMI and body fat as compared to PCOS alone. Research suggests microbial imbalances play into metabolic changes, and can interrupt nutrient absorption.
Nutrient insufficiencies included vitamin D (commonly associated with PCOS), potassium and iodine (has been anecdotally associated with PCOS). Magnesium was considered low-normal by the reference ranges set forth by the laboratory. Magnesium (and calcium) imbalance may be found in PCOS.
In my experience, the most powerful intervention for PCOS is diet. Recall that Joelle was eager to see results quickly, requiring us to use an aggressive treatment approach. To that end, we used a layered ketogenic/ FODMAP/elimination plan. I always have an honest dialogue with patients around how long they are willing to be “impeccably adherent” to their therapeutic diet. Joelle agreed to six weeks. I was confident we would see sufficient changes within this time frame, which I suspected would encourage her to forge on longer as needed. From our nutrition team:
For her nutrition plan, we layered an organic, low-FODMAP, standard elimination plan, and IgG elimination with a ketogenic diet. We included hormone detox-supportive nutrients and potassium-rich foods (RBC potassium was low). [KF note: Yes, we actually do make these strict plans nutrient dense, and we employ a nutrient intake analysis as needed, leaning on supplemental vitamins/minerals if required. We employ these highly restrictive plans for the shortest time possible.] Joelle used keto strips as well as a food tracking app to help her hit the macronutrient targets for ketosis. Her main concerns initially were finding appealing options for breakfasts that were within the guidelines of her plan. We were able to achieve this with various forms of “breakfast bowls” using protein, good fats and low glycemic vegetables.
Within a month her GI symptoms were much improved. At the end of her 6 week elimination, Joelle had lost 16 lbs. We guided her through careful food challenges to determine any residual food sensitivities. Eggs were something she was particularly missing and so we started there, and she was able to reintroduce them without issue. FODMAPs challenges were similarly successful. Joelle was able to achieve and maintain a robust ketosis as measured by urine strips.
During the time we worked with Joelle, she’d moved to Europe to pursue a Master’s degree. This added another layer of complexity since she was continuing on her plan in a new environment and getting used to a new surroundings. This required some assistance from our nutrition team in planning for her international travel: We identified the primary areas of the plan that she should continue to focus on, and where she could introduce some flexibility to help her adjust. We planned international Skype calls to continue support.
Challenging salmon (an IgG-positive food) did prompt a return of symptoms and she therefore continued to avoid it. Likewise, gluten and dairy remained problematic for her and she was extremely motivated to keep out all sources.
At 10 weeks, Joelle had lost a total of 20 lbs. The speed of her weight loss was slowing (no bad thing as we prefer to keep weight loss steady rather than dramatic– fast weight loss can allow for the rapid release of toxins, among other issues). Her dress size had dropped from a 14 to an 8.
As her weight loss continued, we coached Joelle on how to cycle in and out of shorter term ketogenic states to sustain a gradual weight loss without having to stay ketogenic all the time.
For our supplement starting plan, I prioritized GI infections, normalizing PCOS-associated hormone imbalances and the underlying inflammatory drivers. Joelle preferred not to use pharmaceuticals. I used the botanical berberine, 2000mg in divided doses. Berberine is useful for normalizing blood sugar/insulin and lipids, and is a potent anti-microbial agent as well, with demonstrated activity against bacteria, fungi, protozoans and helminths. For some cases of SIBO, berberine alone isn’t enough, and isn’t often a first-line therapy. However, I was hopeful it would be sufficient when coupled with the highly restrictive diet we were employing. We also used 2500mg of EPA/DHA, and 3 grams of myo- plus D-chiro inositol; vitamin D 5000IU; a B complex, 500mg of magnesium glycinate and 500ug of iodine. Additional glycine, an amino acid with anxiolytic properties, was used PRN for anxiety. She was advised to continue digestive enzymes as needed.
12 week follow-up:
As the nutrition team noted above, IBS symptoms resolved, gas and bloating were at a minimum; weight loss-mostly abdominal- was at 20 pounds by week 10. Energy, anxiety and acne improved. Joelle began a committed workout schedule of Pilates, hiking and walking. Menstrual cycles were more regular, with minimal cramping. The acanthosis appeared to be resolving, but no obvious changes yet to hirsutism. She continued the diet, avoiding problem foods which included dairy, gluten and salmon.
First follow-up labs: Fasting blood sugar: 78 (was 82); A1C: 5.0 (was 5.1); fasting insulin: 3.6 (was 15.5); Vitamin D 48 (was 31); total testosterone was 8.4 (was 12.8); androsterone 1543 (was 2318); estradiol 1.7 (was 3.2). Lipids, hormones, nutrients and stool and breath tests to be repeated when she returned from Europe.
Needless to say, Joelle was thrilled with her progress. We will check-in again when she returns from Europe.
A word about the etiology of PCOS.
PCOS is an extremely common, complex endocrine/metabolic condition in women, the underpinnings of which are still being elucidated. Insulin resistance is often a fundamental driver of PCOS. Comorbidities include obesity, type II diabetes, gestational diabetes, infertility, hyperlipidemia, hypertension, cardiovascular disease, autoimmune thyroid disease; increased risk for breast, ovarian and endometrial cancers. There is clearly a genetic component, as sisters share a higher incidence of PCOS. That said, lifestyle factors (diet, exercise, stress) also play a very strong role in development of PCOS. And beyond the scope of this blog, we cannot overlook the all-important role that toxins play- especially endocrine disrupting organotoxins. Further, it has been proposed that premature androgenic alopecia (PAA) may be the male equivalent of PCOS, as a similar pattern of hormonal imbalances has been identified in a subset of men with PAA. For additional reading on PCOS, I’ve hyperlinked loads of materials throughout this case report.
Wonderful article-well referenced and enlightening sources! Very helpful clinical review!
Thank you for this. I enjoy this format as an MD…..as this is how I try and think through my patients care. The links are also very useful.
Thank you for providing this information. PCOS presents many challenges and I haven’t known where to begin: food, supplements, blood work, see a professional. This article is very informative and illustrates what working with someone who knows what they are dealing with can do for a patient. I’ve been to my primary doctor, gyno and endocrinologist and they only want to prescribe something, rather than look at the whole treatment plan.
Definitely look for a Functional Med doc in your area (see functionalmedicine.org for listing)! You can also consider working with us remotely- just reach out to Rhonda for details at email@example.com. Good luck & good health! You’re on the right track– DrKF
I would argue that weight loss alone was responsible for all of her clinical improvement. She felt better because she changed her diet and started exercising. That’s not rocket science.
The functional medicine hallmark barrage of labs and supplements likely had little to nothing to do with her improvement.
No doubt you’re right that diet and lifestyle changes were highly impactful in this case. While I find labs to be beneficial in guiding therapy and importantly- motivating to the patient in understanding their imbalances- they are certainly not a prerequisite to practicing functional medicine. Here’s a case example using a functional approach where no labs and minimal supplements were used: https://www.drkarafitzgerald.com/2015/06/05/the-rash-that-wouldnt-quit/
I think that adding in her D3 levels that improved were not exercise or even sun exposure induced. Only the supplement could have pushed D3 in that direction.
While weight loss with PCOS is very helpful, it’s not the whole picture, it’s so much more complex than just weight. I have PCOS, I have a strict lifestyle I follow. I thought losing weight was everything, it’s not! Without my supplements I hardly function as a person. With PCOS many vitamins, enzymes and such aren’t absorbed, utilized or produced. It’s an issue on a genetic level.
Summing up as weight loss being everything is very short sighted.
I wouldn’t say this was a barrage of labs. These were very prudent and focused; in fact they clearly revealed subtle facts about her chemistry that very well may have provided the patient the motivation to change her eating habits and thereby change her life. Also, I must note that the supplements were also focused, warranted and relatively affordable.
Thank you Dr. Fitzgerald. It’s a lot of work to put a case together like this with all of the hyperlinks for extended learning. I think this is a wonderful case of focused functional medicine successfully helping a young woman with PCOS who hadn’t previously found answers. I also have found fasting insulin helpful in assessments and believe this lab can be very motivating in patients who have signs of metabolic syndrome but have normal HgA1C. It can help them see why that may feel ill despite normal conventional labs.
As a functional psychiatrist I see this situation quite a bit. Very commonly the patient presents on oral birth control, an SSRI for “moodiness,” and often a stimulant or wellbutrin or a mood stabilizer. This amounts to a scattershot attempt at symptom control without addressing the ever-present dietary issues, insulin resistance, sluggish bowels and nutrients deficiencies (commonly B12, chromium, magnesium, zinc, D).
Regarding labs I might have added GGT to assess cysteine stores and oxidative overload (and add NAC to her supplements), B12 and urine methymalonic acid to assess B12 status (especially with the GI issues) and MTRR, MTR, MTRR, TCN2 analysis given the links to PCOS.
Dr. Becker, Thank you for your kind words. I am glad you like the case. Indeed, I did obtain a GGT, MMA and homocysteine, but opted not to include everything. DrKF
Really interesting case study, especially with the IgG sensitivity to Salmon which women with PCOS are usually encouraged to eat. Thanks for taking the time to write this up for a blog post.
Thanks Janine – appreciate your comment! Kara
Wonderful case study! Some questions: why strict ketogenic diet? what do you think about an autoimmune paleo protocol? Can you help with a link to the ketogenic and fodmap diet you use? Which sibo breath test would you recommend? Thank you for your help and advice!
Dr. Schmidt – thanks for your questions and comments! In this particular case, the patient was willing to put in extra effort for quicker rewards, and with the ketogenic diet we could get the biggest ‘bang for her buck’. Strict keto was only necessary short term, after which we can relax the macros, still keeping low carb. The autoimmune paleo protocol has merits, and we use variations and customizations of many of those diets in our treatment plans. SIBO breath test – we use Genova (make sure you’re testing methane as well as hydrogen and that test prep is good). We have our own in-house developed Keto/FODMAPs and other plans that we utilize and that we share through our practitioner training programs. For online FODMAPs sources, look at http://www.siboinfo.com (Siebecker). IFM has plans too. My best, Kara
This is a great case study! As a premed student/acupuncturist this is so great and I plan on doing functional med. on the other hand, One concern that has been felt by myself as a patient is the financial side. All the testungs and supplements are very costly for the average person. Do you think things will shift to the point where these dx tests are going to be covered my people’s ins and eventually easier for people to do a treatment plan such as this?
Anela, there are many tests that will effectively guide our approach to PCOS that we can obtain that are covered by insurance. Further, if someone doesn’t have insurance, there are companies that offer more affordable testing (standard Quest labs can be obtained through Doctor’s Choice, and Genova offers testing discounts matching a clinician’s discount to patients).
I agree with you- it’ll be GREAT DAY when we can get good coverage for a full FxMed approach. In the healthspan of an individual, the cost savings for the Fx approach is undeniable.
My niece has elevated Testosterone and insulin. She had a dermoid cyst removed. And is now on BC pills. She complains of constipation and chin hairs. She has been told that she doesn’t have PCOS so what does she have? I beg to differ. And what can she do if she’s seeing an FM MD?
Dear Marjorie, a Functional Medicine workup would be advisable here. Evidence of hormone dysregulation, even if she doesn’t have a full PCOS diagnosis. These imbalances are often very addressable through dietary, supplement, and lifestyle interventions. Our nutrition team does remote consultations if needed, or you can look for a local practitioner by searching on functionalmedicine.org. My best, DrKF
I loved this review. It helps me see how others work through symptoms and progress. I wonder if she adds sufficient salt to her diet. Dr DiNicolantonio strongly suggests salt is lost heavily during exercise. 1 gram for intense exercise. This is especially true for ketosis situations where sodium consumption is even higher. I seem to recall it affects the thyroid hormone production when sodium is low. Anyway just a thought 😉