Professional Documents
Culture Documents
Zeynep Uraz, ND
Table of Contents
Definition, Epidemiology, Etiology................................................................................2
PCOS....................................................................................................................................2
Epidemiology ,.....................................................................................................................2
Pathophysiology...........................................................................................................3
Clinical Presentation.....................................................................................................3
Common presenting signs and symptoms:...........................................................................3
Phenotypes..........................................................................................................................3
Diagnosis......................................................................................................................4
Long-term Health Outcomes........................................................................................7
Patient Monitoring:......................................................................................................7
Treatment....................................................................................................................8
Conventional Treatment......................................................................................................8
Treatment Goals/Approach.................................................................................................8
Note: The following lists contain therapies in order of clinical relevance (most important,
impactful therapies listed near the top of each category). Clinical importance is determined
by research where possible, and by clinical judgment and experience..................................9
Diet and Lifestyle Interventions...........................................................................................9
Exercise..................................................................................................................................9
Weight Loss............................................................................................................................9
Diet/Calorie Restriction/Low Glycemic Index/Load...............................................................9
Soy.......................................................................................................................................10
Flax Seed..............................................................................................................................11
Almonds and Walnuts..........................................................................................................11
Foods that may potentially increase Sex Hormone Binding Globulin (SHBG)......................12
Exposure to Endocrine Disrupting Chemicals.......................................................................12
Patient Education/Counseling............................................................................................12
Counseling............................................................................................................................12
Nutritional Supplements....................................................................................................12
**Myo-Inositol.....................................................................................................................12
**Calcium and Vitamin D.....................................................................................................13
**N-Acetyl Cysteine.............................................................................................................13
**Fish Oil..............................................................................................................................14
Chromium............................................................................................................................14
Botanical Medicine............................................................................................................16
Vitex.....................................................................................................................................16
Cimicifuga racemosa..........................................................................................................17
Tribulus................................................................................................................................17
Maitake ,..............................................................................................................................18
Spearmint (Mentha spicata)................................................................................................18
Traditional Chinese Medicine.............................................................................................18
Acupuncture......................................................................................................................20
Discussion topics:...............................................................................................................20
Background Reading
If you plan on becoming well-versed in PCOS, this is essential reading:
https://www.monash.edu/__data/assets/pdf_file/0004/1412644/PCOS_Evidence-
Based-Guidelines_20181009.pdf
PCOS
“A syndrome associated with a range of metabolic abnormalities which can lead
to long-term health problems
A multifactorial endocrine disorder
A constellation of signs and symptoms that present in a variable manner
Most commonly: hirsutism (90%), menstrual irregularity - with anovulation
(90%) and infertility (75%) 1
History: Used to be called Stein Leventhal syndrome. Named after two doctors
(in the 1920s) who reported the classic symptomatology in a group of women
who were obese, had amenorrhea, infertility, hirsutism.
Surgical exploration of these women showed enlarged ovaries (2-4x the normal
size), with tiny fluid filled cysts. After taking biopsies, they noted that some
women menstruated. One even became pregnant after many years of infertility
2
.
1
Hacker et al. Essentials of Obstetrics and Gynaecology, 4th Ed. 2004. Elsevier.
2
http://medind.nic.in/jaq/t10/i2/jaqt10i2p121.pdf
Epidemiology 3,4
Prevalence: 5-10% of reproductive age menstruators have PCOS
The most common endocrine disorder in menstruators of reproductive age
Most frequent cause of anovulatory infertility
Most often spans menarche to menopause, but can be diagnosed anytime in the
reproductive years
There is likely a genetic component, as there is an increased prevalence among
first-degree relatives of menstruators with PCOS (25-50%)
Pathophysiology
There is an overall “hormonal imbalance” in individuals with PCOS, but the underlying
cause or origin for this remains unknown.
Clinical Presentation
Diagnosis
European Society for Human Reproduction and Embryology (ESHRE) and
American Society for Reproductive Medicine (ASRM) 2003 consensus (known as
the Rotterdam criteria):
Diagnosis made with 2 of 3 criteria:
1. Oligo/anovulation
2. clinical and/or biochemical hyperandrogenism
3. Polycystic ovaries on transvaginal US where possible
5
http://journals.aace.com/doi/pd f/10.4158/EP15748.DSC
***The following conditions should be excluded in ALL with a suspected diagnosis of
PCOS: ***
Anti-mullerian hormone (AMH): in the near future, AMH will likely be a part of the
diagnostic work-up for PCOS. Currently, an elevated AMH level is suggestive of PCOS,
but there are no clearly defined cut off values.
Phenotypes
Due to the variety of clinical features of this syndrome, PCOS can be categorized into 4
“phenotypes”: 6
o Frank PCOS – all three clinical features (most common - 66%)
o Ovulatory PCOS – hyperandrogenism, PCO but regular menstrual cycles
(13%)
o Non PCO – PCOS – hyperandrogenism, oligomenorrhea, but normal
ovaries (11%)
o Mild or normoandrogenic PCOS – oligomenorrhea, PCO ovaries but
normal androgens (9%) – metabolic disturbances equal to controls in
this group
6
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126218/
Long-term Health Outcomes
Individuals with PCOS are at an increased risk of the following conditions:
Acne
Type II Diabetes mellitus
Obesity
Dyslipidemia
Endometrial hyperplasia and cancer ***
Infertility
Hypertension
Obstructive sleep apnea
Mood disorders
Gestational diabetes
Pregnancy induced hypertension
Autoimmune thyroid conditions
Elevated liver enzymes (30%)
Non-alcoholic liver disease
Better bone density (!!)
Cardiovascular disease ***
Patient Monitoring:
Endometrial hyperplasia and cancer***:
Those who experience extended periods of amenorrhea, especially in the presence of
adequate estrogen levels are at a higher risk for endometrial hyperplasia and cancer.
ESHRE and ASRM recommend induction of menses when there is an absence of
menses for longer than 3 months. The risk is particularly high in PCOS as estrogen is
unopposed for a prolonged period of time. Cyclic treatment with progestins or
combined oral contraceptives is recommended to induce endometrial shedding every 3-
4 months.
Urine LH strips:
- may not be accurate, as ongoing LH surge may yield false positive results
Treatment
Conventional Treatment
1. Hormonal Contraceptives (oral, patch, IUD or vaginal ring): First-line
management for menstrual abnormalities and hirsutism/acne.
2. Exercise: As a means to weight loss and to reduce cardiovascular risk factors and
risk of diabetes.
3. Weight Loss: Calorie-restriction diets, low simple-carbohydrate diets. Especially
in overweight individuals.
4. Metformin: Not used as first line treatment. Should be reserved for those with
T2DM who fail lifestyle modification, or in conjunction with Clomid to prevent
ovarian hyperstimulation syndrome (OHSS). Can also be used as second-line
therapy in individuals who do not tolerate hormonal contraceptives for
management of menstrual irregularity.
5. Clomiphine citrate (Clomid)/Letrozole: First-line treatment for ovulation
induction in infertility related to PCOS. Initial dosage is 50mg/day for five days
starting on days 3-5 of cycle.
Treatment Goals/Approach
As PCOS is a constellation of symptoms, each individual with this diagnosis should be
assessed and treated according to her individual presentation of sign, symptoms, serum
hormone levels and desire for fertility, as well as her own principles and preferences. All
individuals should be counseled about the increase risk of long-term health outcomes
and preventive measures should be discussed. There is a particular opportunity to
make a large impact on adolescents through the early adoption of positive lifestyle
modifications.
Note: The following lists contain therapies in order of clinical relevance (most
important, impactful therapies listed near the top of each category). Clinical
importance is determined by research where possible, and by clinical judgment
and experience.
Diet and Lifestyle Interventions
Exercise
Exercise is crucial for so many reasons, however, in those with PCOS, we see an increase
risk of cardiovascular disease, T2DM and psychological pathologies. Exercise may also
improve these long-term risks in these individuals.
7
https://www.ncbi.nlm.nih.gov/pubmed/20833639
What type of exercise would you recommend to your patients with PCOS?
Weight Loss
Approximately 50% of patients with PCOS are obese. Being overweight exerts and
additive effect on metabolic and hormonal imbalances of PCOS (cardiovascular risk,
oligomenorrhea, reduced insulin sensitivity, T2DM).
Individuals with PCOS often report that they find it very difficult to lose weight and very
easy to gain weight.
Individuals with PCOS who lose as little as 5-10% of their body weight report returning
to normal menstruation.
A combination of diet and exercise modifications has been shown to be the most
effective method of weight loss in folks with PCOS.
Please refer to comment on metformin above in the use of weight loss in PCOS.
This diet will serve to reduce long-term cardiovascular risk factors, reduce insulin
resistance, and potentially serum androgens and associated clinical signs. Can promote
weight loss and decrease abdominal obesity.
Soy
There are three small studies on the effects of soy/soy isoflavones on the metabolic
parameters of PCOS.
1. In this RCT 70 women with PCOS were allocated to two groups (50mg/day soy
isoflavones or placebo) for 12 weeks. Baseline evaluation of metabolic, endocrine,
inflammatory, and oxidative stress markers and then again at 12 weeks. After 12 weeks
of intervention, compared to the placebo group, soy isoflavone administration
significantly decreased circulating serum levels of insulin (-1.2 ± 4.0 vs +2.8 ± 4.7
μIU/mL; P < .001) and homeostasis model of assessment-estimated insulin resistance (-
0.3 ± 1.0 vs +0.6 ± 1.1; P < .001) and increased the quantitative insulin sensitivity check
index (+0.0009 ± 0.01 vs -0.01 ± 0.03; P = .01). Supplementation with soy isoflavones
resulted in significant reductions in free androgen index (-0.03 ± 0.04 vs +0.02 ± 0.03; P
< .001) and serum triglycerides (-13.3 ± 62.2 vs +10.3 ± 24.5 mg/dL; P = .04) compared to
the placebo group. There was a significant increase in plasma total glutathione (+96.0 ±
102.2 vs +22.7 ± 157.8 μmol/L; P = .04) and a significant decrease in malondialdehyde
levels (-0.7 ± 0.8 vs +0.8 ± 2.3 μmol/L; P = .001) by soy isoflavone intake compared with
the placebo group. We did not observe any significant effect of soy isoflavone intake on
other lipid profiles and inflammatory and oxidative stress markers. 9
2. Twelve Caucasian, obese women with hyperinsulinemia and dyslipidemia and PCOS.
Patients received 36 mg/d of genistein for 6 months. Ultrasonographic pelvic exams,
hormonal and lipid features, oral glucose tolerance test, and euglycemic
hyperinsulinemic clamp were performed at baseline and after 3 and 6 months of
treatment. Phytoestrogens supplementation significantly improved total cholesterol
levels, reducing low-density lipoprotein (LDL) cholesterol and resulting in a significant
decrease in the LDL-high-density lipoprotein ratio (LDL-HDL). Triglycerides showed a
trend toward decrease, whereas no changes were detected in very low-density
lipoprotein cholesterol plasma levels. Genistein treatment did not significantly affect
anthropometric features, the hormonal milieu, and menstrual cyclicity. No significant
changes occurred in glycoinsulinemic metabolism. 10
3. In this quasi-randomized trial, 146 subjects with PCOS were divided into two groups;
the experimental group who received Genistein (Bergamon, Italy) 18 mg twice a day
orally and the control group that received similar capsules with cellulose for 3 months.
Hormonal features and lipid profiles were measured before and after 3 months of
supplement therapy. After 3 months of supplement therapy there were no statistically
significant differences in high density lipoprotein cholesterol (HDL) and follicle
9
https://www.ncbi.nlm.nih.gov/pubmed/27490918
10
https://www.ncbi.nlm.nih.gov/pubmed/18166189
stimulating hormone (FSH) serum levels in Genistein and placebo group before and after
treatment; however serum levels of luteinizing hormone (LH), triglyceride (TG), low
density lipoprotein cholesterol (LDL), dehydroepiandrostrone sulfate (DHEAS) and
testosterone were significantly decreased after 3 months therapy in Genistein group. 11
Generally, soy phytoestrogens have a weak estrogenic effect in some parts of the body.
Early research shows that soy phytoestrogens (specifically genistein) may benefit lipid
parameter, decrease serum androgens, and may benefit glucose dysregulation.
Flax Seed
The effects of flax seed on PCOS are theoretical and there is one case study that
evaluates its use in PCOS.
This clinical case study describes the impact of flaxseed supplementation (30 g/day) on
hormonal levels in a 31-year old woman with PCOS. During a four-month period, the
patient consumed 83% of the flaxseed dose. Heights, weights, and fasting blood samples
taken at baseline and 4-month follow-up indicated the following values: BMI (36.0 vs.
35.7kg/m(2)); insulin (5.1 vs. 7.0 uIU/ml); total serum testosterone (150 ng/dl vs. 45
ng/dl); free serum testosterone (4.7 ng/dl vs. 0.5 ng/dl); and % free testosterone (3.1%
vs. 1.1%). The patient also reported a decrease in hirsutism at the completion of the
study period. The clinically-significant decrease in androgen levels with a concomitant
reduction in hirsutism reported in this case study demonstrates a need for further
research of flaxseed supplementation on hormonal levels and clinical symptoms
of PCOS. 13
11
https://www.ncbi.nlm.nih.gov/pubmed/22091248
12
https://www.ncbi.nlm.nih.gov/pubmed/10946884
13
https://www.ncbi.nlm.nih.gov/pubmed/19789727
At the beginning and at the end, anthropometric parameters, fasting lipids,
phospholipid-fatty acids, inflammatory markers, androgens, oral glucose tolerance tests
(OGTT) and frequently sampled intravenous-GTT were obtained.
Weight remained stable. Within group, walnuts increased the n-3/n-6 essential PUFA in
the diet and plasma phospholipids. Walnuts decreased low-density lipoprotein-
cholesterol by 6% from 3.76 ± 0.27 to 3.38 ± 0.22 mmol/l (P = 0.05) and apoprotein B by
11% from 0.72 ± 0.04 to 0.64 ± 0.05 g/l (P < 0.03). Although almonds also reduced low-
density lipoprotein-cholesterol by 10% and apoprotein B by 9%, these were not
significant. Walnuts increased insulin response during OGTT by 26% (P < 0.02).
Both walnuts and almonds increased adiponectin (walnuts from 9.5 ± 1.6 to 11.3 ± 1.8
μg per 100 ml, P = 0.0241; almonds from 10.1 ± 1.5 to 12.2 ± 1.4 μg/dl, P =
0.0262). Walnuts decreased HgBA1C from 5.7 ± 0.1 to 5.5 ± 0.1% (P = 0.0006) with
significant intergroup difference from almonds (P=0.0470). Walnuts increased sex
hormone-binding globulin from 38.3 ± 4.1 to 43.1 ± 4.3 nmol/l (P=0.0038)
and almonds reduced free androgen index from 2.6 ± 0.4 to 1.8 ± 0.3 (P = 0.0470). 14
Overall nut intake exerted positive effects on plasma lipids and androgens in women
with PCOS.
Foods that may potentially increase Sex Hormone Binding Globulin (SHBG)
Green tea
Flax seed
Nettle root
Soy
Walnuts
Patient Education/Counseling
What are the potential opportunities for patient education?
Counseling
- Often ignored/medicated until desire to conceive
- Can take a number of months to return to normal cycle
- Hirsutism can also take 3-6 months to respond to treatment
- Loss of feminine identity (low fertility, male pattern hair growth, obesity)
14
https://www.ncbi.nlm.nih.gov/pubmed/21157477
- Effects on mood, sexual function, quality of life
- Should be recognized early (menarche) and educated about long term health
outcomes
Nutritional Supplements
**Myo-Inositol
Restores ovulation and improves egg quality in women with PCOS or insulin resistance.
May reduce miscarriage risk associated with insulin resistance. Use with caution in
bipolar, or schizophrenia as can exacerbate manic episodes. Titrate dose up slowly as
can cause gas, bloating and diarrhea. The higher the concentration of myo-inositol
inside the follicle, the better the embryo quality (observational). Higher insulin levels
cause infertility by increasing T in the ovaries. Myo-inositol works by increasing insulin
sensitivity. Therefor only see improvements in women with insulin resistance and PCOS.
In women undergoing IVF, when inositol was given at the start of stimulating drugs,
myo-inositol was found to increase the proportion mature eggs retrieved and decrease
number of immature eggs. Fewer cancelled cycles because of overstimulation of ovaries.
But probably better to start myo-inositol sooner. Even in individuals with PCOS who are
not displaying poor insulin sensitivity, it is still effective as treatment (improving egg and
embryo quality during IVF). May also reduce the risk of gestational diabetes. D-chiro-
inositol may have a negative effect on egg quality. Women given this had fewer eggs
and fewer good quality embryos.
Some studies are now looking at the benefits of combining myo-inositol with d-chrio-
inositol in a 40:1 ratio.
Can also be combined with COQ10 to support egg quality.
Myo-inositol also has anxiolytic properties, especially in higher doses.
Dose – 2g bid (total 4g). Can increase to 8-12g if necessary.
15
http://www.ncbi.nlm.nih.gov/pubmed/25535503
- Co-supplementation of both (in Vit D def women with PCOS) led to decreased
serum insulin level and HOMA-IR, and serum TG, and VLDL 16 (compared to
supplementation with either one alone and placebo). Dose was 1000mg Ca and
50000IU/week vit D3 for 8 weeks.
- Also see other studies to support the use of this combination, especially in
vitamin D deficient women with PCOS17.
- Some studies show reductions in testosterone, androstenedione, and decrease
in BP.
**N-Acetyl Cysteine
Precursor to glutathione, acts as an antioxidant. Improves insulin sensitivity. Most
study trials are 1500-1800 mg/day. Most products come in 500mg/capsule dosing.
Various trials show18,19,20,21:
- improvement in menstrual regularity
- reduction in hyper-insulinemia
- reduction in hyperandrogenism
- embryo quality in IVF with ICSI
- can improve ovulation rates in individuals who are resistant to clomid (when
combined with clomid) (but perhaps not as high as with clomid combined with
metformin)
**Fish Oil
Can improve metabolic pathways in PCOS. Has been shown to improve insulin
sensitivity, hirsutism (F-G score), BMI, and HOMA levels decreased. May improve lipid
profile. May improve liver fat content and reduce triglycerides.
Dose- 1500mg (omega 3) - 4000mg 22.
Chromium
Although the exact mechanism of action of chromium is still unknown, chromium has
been shown to enhance the effects of insulin on target tissues. Supplementing
chromium with 1000mg of vitamin C has been shown to increase its absorption
(increased serum levels). The studies on chromium are mixed. Some studies show a
benefit to serum insulin and glucose levels and others do not. The different outcomes
could potentially be accounted for by nutritional status of chromium (only those who
are deficient benefit from supplementation).
16
http://www.ncbi.nlm.nih.gov/pubmed/25300649
17
http://www.ncbi.nlm.nih.gov/pubmed/22780885
18
https://www.ncbi.nlm.nih.gov/pubmed/21831508
19
https://www.ncbi.nlm.nih.gov/pubmed/12057717
20
https://www.ncbi.nlm.nih.gov/pubmed/26654154
21
https://www.ncbi.nlm.nih.gov/pubmed/20939675
22
https://www.ncbi.nlm.nih.gov/pubmed/21270384
A typical prenatal vitamin contains 100mcg/dose.
A few studies have been conducted specifically in women with PCOS. Some studies
show that supplementation with approximately 1000mcg of chromium picolinate
improve insulin sensitivity23,24,25,26.
Botanical Medicine
Vitex
- Lowers prolactin due to dopaminergic effects
- FSH – no change
- LH – lowered or no change
23
https://www.ncbi.nlm.nih.gov/pubmed/16730719
24
https://www.ncbi.nlm.nih.gov/pubmed/24639797
25
https://www.ncbi.nlm.nih.gov/pubmed/26663540
26
https://www.ncbi.nlm.nih.gov/pubmed/26613790
- Binds to ER-Beta
- Increased serum estradiol
- Increased serum progesterone
- Improved pregnancy rates
Cimicifuga racemosa
- Impacts of black cohosh on PCOS
- Binds with estrogen receptors in pituitary and decreases LH secretion
- Increases luteal progesterone secretion
- Improves endometrial thickness for infertile women with PCOS
- Lower LH for women with PCOS
- Improves LH:FSH ratio for women with PCOS
- Limits anti-estrogen effects when used with Clomiphene citrate for women with
PCOS
- 2014 RCT:
- Women <35 years of age presenting with PCOS and infertility
- 98 women received Clomiphene citrate (CC); 96 women received CC and
Cimicifuga racemosa
- Significant improvements were found in:
o Days to HCG injection (shorter time for follicular development)
o Endometrial thickness
o Serum levels of mid-luteal and midcycle estradiol
o Serum levels of mid-luteal progesterone
o Higher rates of pregnancy per cycle (17.2% for CC, 34.8% for CC+CR)
Tribulus
Impacts of Tribulus on PCOS
- Ovulation induction in polycystic ovaries
- No estrogenic effects
- Increased FSH in healthy women
- Equivalence for ovulation induction compared to CC for women with
oligo/anovular infertility
- In one study, suggested that use for 3 months may normalize ovulation and
result in pregnancy in women with endocrine infertility
- Standardized extract of 40% furostanol saponins
- Daily dose should be approximately 300-400mg/day from day 5 to ovulation
Maitake 27,28
- Maitake extract tablets containing 18mg of extract called SX-fraction (MSX) in
water soluble glycoprotein and 250mg of dried maitake mushroom powder.
Each patient given 3 tablets TID. 26 patients in maitake group.
- 31 patients in CC group – given 50 mg/day from days 5 to 9 of menses.
- Evaluated for ovulation with pelvic US. Ovulation rate for maitake was 76.9%
(20/26) and 93.5% (29/31) for CC.
- Combination group 7 of 7 patients who failed MSX monotherapy and 6 of 8 who
failed CC monotherapy demonstrated ovulation.
27
J Altern Complement Med. 2010 Dec;16(12):1295-9. doi: 10.1089/acm.2009.0696.
Epub 2010 Oct 29.
28
PMID: 21034160
29
https://www.ncbi.nlm.nih.gov/pubmed/19585478
30
https://www.ncbi.nlm.nih.gov/pubmed/17310494
accumulate as Dampness/Phlegm. This can cause ovarian cysts to form. The deficiency
of Kidney Yang itself causes amenorrhea or infertility. There may also be blood stasis.
The difference between PCOS and ovarian cysts is that in PCOS there is a congenital
deficiency of Kidney Yang.
Treatment includes tonify Kidney Yang and resolve Dampness/Phlegm at the same time.
Resolve blood stasis if also an issue.
Acupuncture
A recent Cochrane review showed that evidence quantity and quality is low and level of
effect is low31.
Best approach:
- address overall TCM picture (as above), while still doing local points to aid with
pelvic blood flow (CV3, CV4, Zigong)
- determine measurable outcomes to assess if treatment is having a positive
effect, and continue for a pre-determined amount of time.
Discussion topics:
When is conventional treatment warranted?
How would you approach the naturopathic treatment of a woman with PCOS?
Important Resources:
2018 International Guideline for Assessment and Management in PCOS.
https://www.monash.edu/__data/assets/pdf_file/0004/1412644/PCOS_Evidence-
Based-Guidelines_20181009.pdf
31
https://www.ncbi.nlm.nih.gov/pubmed/27136291