• Presented by Stacey Roberts BSPhysio, Herbalist, Naturopath

PCOS and Fertility •Module 6• Part 2 (ep 1)

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Copyright Optimal Health Strategies, LLC

Medical Disclaimer Module 6Stacey Roberts, Optimal Health Strategies, LLC, Sharkeyshealingcentre.com, Thebabymakernetwork.com and any associated websites or companies are not medical doctors. The information provided in this program is for educational purposes only and is not claiming to cure, diagnose or medically treat anyone. All medical issues should always be discussed and evaluated by your medical practitioner.

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Review• Discussed PCOS definition • Criteria for diagnosis and why the

confusion • Signs and Symptoms of PCOS • PCOM ultrasound • Phenotypes of PCOS: more studies are

using these phenotypes to see how each reacts to different drugs and or supplementation.

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Other Important Factors to Remember

• Obesity, insulin resistance, and hyperinsulinemia are commonly present in obese or non obese women with PCOS

• Approximately 40% to 50% of women with PCOS are overweight

• A history of weight gain frequently precedes the onset of clinical manifestations of this syndrome

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PCOS Causes• No agreement on what the cause is• Insulin resistance is a common denominator in many

women with PCOS• ________________ results from abnormalities at all levels

of the hypothalamic-pituitary-ovarian axis. The increased frequency and amplitude of LH pulses in PCOS seems to result from an increased frequency of hypothalamic gonadotropin-releasing hormone (GnRH) pulses. The increased LH secretion stimulates theca cells to increase production of androgens. The hyperandrogenic milieu alters the intrafollicular microenvironment, leading to aberrant folliculogenesis.

Endocrinology and Metabolism Clinics, 2011-12-01, Volume 40, Issue 4, Pages 865-894

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What Contributes to Androgen Excess?

• Hyperinsulinemia may affect the synthesis of steroids in the human ovary both directly and indirectly.

• Insulin receptors are present in the human ovary • In vitro studies have shown that, in the ovaries of

women with PCOS, insulin is capable of stimulating androgen production in the theca cells.

• In vivo, both acute and chronic hyperinsulinemia stimulate testosterone production in some studies, whereas suppressing insulin levels by any means uniformly decreases circulating androgen concentrations

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PCOS Cause• PCOM likely caused by pulsatile LH• Pulsatile LH created due to excess

androgens• Excess androgens correlated by poor

glucose metabolism and/or insulin resistance• Low progesterone will discuss later but can

be related to stress from the above and or thyroid issues.

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PCOS Causes: Clinical Observations

• “Mild” genetic predisposition “switched on” by poor lifestyle choices”

-improve lifestyle/eating plan and PCOM goes away and hormones normalize and pregnancy occurs.

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PCOS Causes: Clinical Observations• “Moderate” genetic predisposition switched on by underlying

thyroid issue causing poor glucose metabolism, exacerbated by poor lifestyle choices of food sensitivities such as gluten.

• “Moderate” genetic predisposition switched on by adrenal stress and poor lifestyle eating plan choices, creating inflammation and effecting thyroid function which in turn impacts glucose metabolism

- These patients improve with dietary changes and exercise but need support for adrenals and or thyroid and reprohormones for improved chance for pregnancy

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PCOS Causes: Clinical Observation• “Severe” or multifactorial genetic predisposition that

lifestyle/dietary changes, support of thyroid and adrenals, support of reproductive hormones, and overall improvement in glucose metabolism by bloods and tests doesn’t produce pregnancy:

• Either overlooked male fertility issue (if ovulation is regular)

• Patient compliance and amenorrhea persists, no weight loss, and/ no pregnancy: needs further assessment for SNP’s,

methylation cycle, etc.

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Takako Araki MD, et al Endocrinology and Metabolism Clinics, 2011-12-01, Volume 40, Issue 4, Pages 865-894

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Blood testsFirst line tests for PCOS• Free androgen index (FAI) (increased)• Total Testosterone and free testosterone

(increased)• Free testosterone (increased)• Androstenodione (increased)• DHEA-S (increased or low)• Sex Hormone Binding Globulin (decreased <60)Note: While on OCP androgen testing is not true test

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Blood tests

• Fasting insulin level (increased); • LH/follicle-stimulating hormone (FSH) ratio

(increased)• Glucose Tolerance Test (elevated)• HbA1c (increased)

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Blood Tests• Estradiol can be low or high• Progesterone (typicall low)• Tsh (often >2.0)• Ft4 (Normal or low)• Ft3 (Usually low or if normal ratio ft3 to Rt3 out of range)

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Blood Tests• Vitamin D (typically low)• Iron studies (with amenorrhea often normal but can be low, even with amenorrhea, if this is the case think thyroid or significant adrenal fatigue)

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Blood Tests• Triglycerides (If elevated sign of insulin resistance)• Fasting cholesterol (If elevated: eating plan and/or thyroid)

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Important Considerations Re Blood Tests

• Amount of issues via bloods doesn’t correlated with how well or poorly the patient is going to do

• With compliance most will respond extremely well and others will struggle

• Each person will have their own unique individual results, not everyone will have issues with each of the results discussed

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Review of Part 2 Episode 1• Underlying causes of PCOS• How insulin can impact androgen production• How the HPO axis can impact androgen

production• Blood tests and common results• Theory about underlying genetic

predisposition• Reintroduced thyroid and adrenal involvement

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Medical Intervention• Non fertility patients

OCP and other interventions• Great link to other medical interventions for PCOS: http://emedicine.medscape.com/article/ 273153-medication#1

• OCP works to decrease hyperandrogegism by suppressing LH and stimulating SHBG but obviously not a good choice for fertility patients

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Medical Intervention• Fertility intervention

• Clomid • Metformin, • Ovarian drilling (laser or diathermy)

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Clomiphene Citrate (Clomid)• Partially selective estrogen receptor

modulator• Anti-__________effect • Induces a change in the hypothalamus’

GnRH pulse frequency

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Clomid • Why use?• Considered safe• Effects on hypothalamus result in increased

FSH• Increased follicular development• Increased estrogen production

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Clomid• Why not?• Increases risk of multiple pregnancies (4-10%)• Obese women with PCOS are commonly resistant to

Clomid• Ovarian hyperstimulation syndrome (OHSS) may occur

(less risk than gonadotropins)• Significant side effects: moodiness, headaches, irritability,

bloating, hot flushes, night sweats, vaginal bleeding, sore breasts, nausea, vomiting and cyst formation.

• Possible increased risk of uterine cancer with higher doses and longer duration use

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Clomid• High ovulation rates 60-85% but low

successful pregnancy rates 30-40%• Could be caused by the _________

properties of Clomid• These properties can cause - poor thickening of the cervical mucus - poor thickening of the endometrium

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Clomid• 15-40 % of women clomiphene resistant• Obese women are often resistance and higher

doses are used

Brown J, Farquhar et al. Cochrane Database Syst Rev. 2009;(4):CD002249.

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Metformin• Insulin sensitizer• Decreases fasting insulin levels• Decreases hepatic gluconeogenesis• Correlated with decrease body weight

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Metformin• It’s impact on hyperandrogenism believed to

be associated with its reduction in hyperinsulinemia

• It inhibits IGF 1 signalling and IGFBP 1 production which increases SHBG levels

• Improved ovulation rates

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Metformin• Meta-analysis • Metformin alone

improves odds of ovulation in women with PCOS but does not improve rates of clinical pregnancy

Creanga A.A et al. Obstet Gynecol 2008; 111: pp. 959

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Metformin • Why?• Obese women especially seem to benefit

from 3 months' pretreatment with Metformin and its combination thereafter with routine ovulation induction in anovulatory infertility

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Metformin• Miscarriage rates were low and similar in the two

groups (Metformin 15.2% vs. placebo 17.9%,). • Metformin significantly improved PR and Live Birth

Rate (LBR) (vs. placebo) in the whole study population (PR: 53.6 vs. 40.4%,) LBR: 41.9 vs. 28.8%) and PR in obese women (49.0 vs. 31.4%), and nonobese (PR: 58.6 vs. 47.6%,; LBR: 46.7 vs. 34.5%,) and in obese women with regard to LBR (35.7 vs. 21.9%,).

• Cox regression analysis showed that Metformin plus standard infertility treatment increased the chance of pregnancy 1.6 times

J. Clin. Endocrinol. Metab. - May 1, 2012; 97 (5); 1492-500

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Metformin and Phenotypes• Why not?• Study failed to demonstrate a significant

benefit of Metformin therapy in different phenotypes of PCOS.

• “Still, it is possible that future studies with bigger sample sizes in all subtypes of PCOS can show the effectiveness of Metformin.” n = A174, B26, C50, D108

Hossenni, M.A., et al. Arch Gynecol Obstet (2013) 288: 1131. doi:10.1007/s00404-013-2800-5

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Metformin• Why not?• Significant depletion of_______ ___• Folate depletion• No improvement in pregnancy rates whether

used alone or in combo with Clomiphene

Pongchaidecha M, J Med Assoc Thai - July 1, 2004; 87 (7); 780-7Dimitrios Samaras M.D.,Nutrition, 2013-04-01, Volume 29, Issue 4, Pages 605-610

Tang T et al Cochrane Database Syst Rev - January 1, 2012; (5)

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Combination Therapy • Metformin and Clomid• Combination therapy (Clomid and

Metformin) improved ovulation and early pregnancy but NOT live births unless patient was previously Clomid resistant

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Rausch ME et al J Clin Endocrinol Metab 2009;94:3458

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Laparoscopic Ovarian Drilling (LOD)35

LOD• Why?• A total of 43 women underwent LOD during the study period. • 26 to 30 years and two-thirds were overweight or obese. • 72% of them had primary infertility. • Other factors which could have contributed to infertility such

as superficial endometriosis, septate uterus and unilateral tubal block were observed in 30.2% of the women, which were dealt with concomitantly.

• When we excluded the 14% who were lost to follow up, 23 of 43 (53.5%) women achieved pregnancy and almost 70% of them did so within the first 6 months

Yanamandra NK, Gundabattula SR - J Clin Diagn Res - February 1, 2015; 9 (2); QC01-3

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LOD• Overall ovulation rate was 82.61% after LOD. • Thirty-one out of 69 patients ovulated spontaneously

within first 6 weeks after LOD • 26 patients ovulated after getting treatment with CC in

addition to LOD. • Thirty-three (47.82%) patients conceived in their first year

after surgery. • About 54% of patients reported improvement in their

symptoms related to hyperandrogenism

Hameed N, Ali MA - J Ayub Med Coll Abbottabad - July 1, 2012; 24 (3-4); 90-2

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LODWhy not?• A lower number of retrieved oocytes, • Fewer available embryos• Lower number of cryopreserved embryos were observed

in among patients in the LOD-group compared with the other groups.

• No differences in birth rates following fresh embryo transfers were observed between the LOD-group, and the age-matched group and the no-LOD group .

• A higher adjusted odds ratio of cumulative pregnancy per initiated in vitro fertilization cycle was observed in the no-LOD group when compared with the LOD group.

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LOD• Why not?• LOD could compromise

cumulative ongoing pregnancy rates during subsequent in vitro fertilization.

• Could contribute to scarring and adhesions

Jiali Cai, et al International Journal of Gynecology & Obstetrics, Copyright © 2016 International Federation of Gynecology and Obstetrics

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Review Ep 2• Discussed medical interventions for PCOS• Clomiphene Citrate (Clomid)• Metformin • Ovarian Drilling• Pro’s and Con’s of each• Information to share with patients

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Medical/Naturopathic Complimentary Protocols

• Combination with Clomid• Black Cohosh• Co Q 10• L-Carnitine• N-Acetyl Cysteine (NAC) and Clomid• Myo Inositol and Clomid (discussed in next

section)

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Clomid and Black Cohosh• Black Cohosh and Clomid 120mg of Black Cohosh dry extract (days 1 to 12) plus 150mg of Clomid (days 3 to 7)

= Increase clinical pregnancy rate, increased serum progesterone, and endometrial thickness

Shahin AY et al Reprod Biomed Online. 2008 Apr;16(4):580-8 PMID 18413068

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Clomid and Black Cohosh versus Clomid and Estradiol (E2)

• 150 women with PCOS• All had PCOM• 3 Groups • G1:CC alone, • G2 CC/ E2, • G3 CC/ Black Cohosh

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Clomid and Black Cohosh versus Clomid and Estradiol (E2)

• Clomid 50mg every 8 hours days 3-5 plus Black Cohosh (20mg D 1-12)

• Results: Adding phytoestrogens to CC as an alternative to estradiol in women with PCOS have increased number of dominant follicles and improved endometrial thickness and pattern with improvement of both ovulation and pregnancy rates.

Uterus & Ovary 2015; 2: e904.2015 by Ahmed M Maged, et al.

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Black Cohosh• Parts Used: Root

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Black Cohosh• Actions:• Anti inflammatory• Diurectic• Spasmolytic• Antihypertensive• Decrease effect of excess androgens

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Black Cohosh• USES:• Interstitial cystis• Amenorrhea• Anxiety• Chronic pelvic pain• Dysfunction uterine bleeding (DUB)• Endometriosis• Hypertension

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Black Cohosh • USES:• Osteoporosis prevention• Musculoskeletal pain or spasms• PMS• Uterine fibroids• Vasomotor complaints of perimenopause or

menopause• Vaginal dryness and atrophy

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Black CohoshDosage:• Dry herb (root) 20-40mg twice per day• Tincture: .5ml per day

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Clomid with L Carnitine• Utilized with Clomiphene resistant women• 172 women CC resistant• G1: 250mg of CC days 3-7 and L-Carnitine

3g daily• G2: 250mg of CC plus placebo

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Clomid L-Carnitine• Group with L Carnitine • Improved quality of ovulation• Increased pregnancy rate• Acceptable patient tolerability• Improved lipid profile• Improve BMI

Isamail, A et al EurJour of Obst & Gyn and Repr Bio 2014-09-01, Volume 180, Pages 148-152

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L Carnitine• Synthesized by lysine and methionine• Transports fatty acids into the mitochondria• L- Carnitine biologically active form• D- Carnitine biologically inactive

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L- Carnitine• Actions• Plays a role in energy production• Decreases oxidative stress • Improves glucose metabolism• Stabilize mitochondrial membranes• Cytoprotective• Hyperinsulinemia and hyperandrogengism

related to lower levels of L-Carnitine

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L-Carnitine• Uses• Has also been related to increased sperm quality• Decreases ammonia (relevant from OATS test results)• Decreases exercise induced oxidative stress• Physical performance • In conjunction with prescription medicine: - Cardiovascular health - AIDS - Alzheimer’s disease

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L Carnitine• Dosage: 500mg to 4 g

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Linus Pauling Institute, Oregon State University

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Why Would L Carnitine Work With Clomid?

• Reduces Ammonia• Elevated Ammonia increases ROS• Ammonia is normally converted to urea by

the liver which is then eliminated in the urine

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Why Would L Carnitine Work With Clomid?

• Improves glucose metabolism

• Stabilize mitochondrial membranes

• Cytoprotective

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Co Enzyme Q 10 and Clomid• 110 women (153 cycles)• Clomid resistant women • Two groups:• G1 Clomid 150mg days 2-6, Co Q10 180mg

stay 2 until HCG injection• G2 Clomid 150mg day 2-5

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CoQ10 and Clomid• G1 CoQ10 and Clomid - Increased endometrial thickness - Increased ovulation 66% versus 16% G2 - E2 and progesterone significantly higher - Clinical pregnancy 37.3% versus 6.0% G2

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CoQ10 and Clomid

Follicles >14mm > 18mm

Endo thickness

E2 levels

Mid luteal P4

Ovulation per/Cy

Clinical preg

Abdelaziz El Refaeey et al Reproductive BioMedicine Online, 2014-07-01, Volume 29, Issue 1, Pages 119-124

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What Is A Co Enzyme• Co Enzyme Definition:• Substance that works with an enzyme to

initiate or assist in the function of an enzyme.

• B vitamins are also co enzymes that assist enzymes that breakdown fat, carbohydrates and proteins

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Co Enzyme Q10• Fat soluble “vitamin like” compound• Like Carnitine, needs the methylation

process to be synthesized, specifically SAMe

• Also referred to as Ubiquinone• Most common Coenzyme Q is mitochondrial

CoQ10• Found in all cell membranes

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CoQ10• Actions:• Antioxidant • Assists in the electron transport chain in a

series of redox reactions that are involved in the synthesis of ATP.

• Therefore it is required for cells to produce energy

• Boosts the immune system (immune cells are highly energy dependent)

Saini, Rajiv J Pharm Bioallied Sci. 2011 Jul-Sep; 3(3): 466–467 PMCID: PMC3178961

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CoQ10Uses• Cardiovascular disease• Parkinson’s• Radiation injury• Obesity (help prevent fatty liver)• AIDS• Gastric ulcers• Boosting physical performance

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CoQ10Uses• Allergies• Diabetes• Migraine• Ulcers• Headaches• Kidney failure• Anti-aging

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CoQ10 67

Co Q10• Dosage: Generally recommended • 20-90mg per day• Fertiity 300-600mg per day• I usually suggest less if taking _________

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Why Ubiquinol versus Co Enzyme Q10

• Some studies have shown Ubiquinol may be more absorbable

http://www.wholefoodsmagazine.com/news/supplier/news-international-coq10-conference/

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Why Ubiquinol versus CoQ10• If under <30 years old and healthy generally

ubiquinol is it believed that CoQ10 not needed due to optimal conversion of Coq10 to Ubiquinol

• Due to increasing arNOX enzyme activity appearing after 30.

• arNOX increases oxidative stress• CoQ10 inhibits this• Use of ubiquinol is more bioavailable

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Why Ubiquinol versus CoQ10• In some, genetic variations

don’t allow the conversion from CoQ10 to Ubiquinol (NQO1, or NAD[P]H: quinone reductase 1)

(http://www.drpasswater.com/nutrition_library/Q-10%20Basics.htm)

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Why Would CoQ10 Work With Clomid?

• Energy production

• Present in all cell membranes

• Antioxidant

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N Acetyl Cysteine (NAC) and Clomid

• NAC was associated with improved clinical pregnancy but there was limited evidence that NAC improved live birth rates alone or in combination with clomiphene.

D. Thakker, A. Raval, I. Patel and R. WaliaValue in Health, 2013-05-01, Volume 16, Issue 3, Pages A156-A157

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Naturopathic Options• Address potential insulin

resistance (IR), hyper insulinemia (HI), and or poor glucose metabolism (GM)

• Address hyperandrogenism (HA)

• Improve balance of reproductive hormones

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Addressing IR, HI and GM• N-Acetyl Cysteine• Myo inositol• Myo inositol and folic acid• Alpha Lipoic Acid• Chromium• Vitamin D• Cinnamon• Gymnena• Maitake mushroom

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NAC• Metformin and NAC appear to have

comparable effects on hyperandrogenism, hyperinsulinaemia and menstrual irregularity in women with PCOS.

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NAC vs Metformin• Non obese PCO• Metformin versus NAC• 12 weeks• Comparable results (Live birth rate not

tracked)• Metformin 500mg twice a day for 2 weeks

and increased to three times a day thereafter• Other group 600mg NAC, three times daily

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NAC vs Metformin• No change in PCOM (likely too short duration)• In NAC group significant change in ovulation and

ammenorrhea• Pregnancy rate with NAC 50% • Pregnancy rate Metformin 40%• NAC group more significant fasting blood sugar levels• No change in fasting insulin in Metformin but significant

decrease in NAC group• LH decreased in both but more significant in NAC• More significant decrease in TT but none in FT or SHBG• More significant improvement in IR in NAC group

Gayatri, Kar et al Indian Journal of Clinical Medicine 2010:1 7–13

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NAC• Actions: precursor to Glutathione

Lekha Saha et al J Pharmacol Pharmacother. 2013 Jul-Sep; 4(3): 187–191.

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NACUses• Reduces lead bioaccumulation• Aids in quitting smoking• Decease of acne• Decrease symptoms of marijuana addiction• Decrease symptoms of cocaine addiction• Improvement in insulin levels and insulin

sensitivity• Anti depressive

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NACWould use• If on Metformin long term and it seems to be

losing its effectiveness (as long as eating plan is optimized)

• If suspected of confirmed heavy metal toxicity• If addictive history (cocaine, marijuana, cigarettes• If mental health issue: depression, obsessive

compulsive disorder• If history of miscarriage

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NAC• Not found naturally in foods• Altered form of amino acid cysteine• Body converts NAC into cysteine and from

cysteine into glutathione (master antioxidant)

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Myo Inositol

• Structurally similar to glucose

• Present in cell membranes

• Rich in ovarian fluid and seminal fluid

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Myo Inositol Actions:• Insulin sensitizer• Precursor of inositol triphosphate (impacts/

regulates TSH, FSH and insulin)

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Myo Inositol (MI)• Improvement in oocyte and embryo quality• Treatment with MI on PCOS with oligo

ovulation/amenorrhea, high testosterone, hirsutism cases showed,

improved ovarian function, metabolic and hormonal parameters• The presence of high levels of MI can indicate the well being of the follicle

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Myo Inositol Uses• Effective in addressing • Insulin resistance• Hyperandrogenism• Oligo-amenorrhea• Metabolic syndrome• Panic disorder• Obsessive compulsive disorder• Bipolar depression• Improving thyroid function

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Myo Inositol Dosage:• 200-4000mg once a day

• 4g for improving TSH levels

• Powdered form or soft gelatin capsule• Soft gelatin capsule showed similar effects

compared with three times higher doses of MI

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCESVolume 4, Issue 06, 137-155, 2015

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Myo Inositol Followed by Clomid• After Myo-Inositol treatment, ovulation was present in

29 women (61.7%) and 18 (38.3%) were resistant. Of the ovulatory women, 11 became pregnant (37.9%). Of the 18 Myo-Inositol resistant patients after clomiphene treatment, 13 (72.2%) ovulated. Of the 13 ovulatory women, 6 (42.6%) became pregnant.

• Myo-Inositol treatment ameliorates insulin resistance and body weight, and improves ovarian activity in PCOS patients

• 25259724 (PubMed ID)

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Coming up…• Myo Inositol and Folic Acid• Alpha Lipoic Acid• Chromium• Vitamin D• Cinnamon• Gymnena• Maitake mushroom

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Putting It All Together • And wait there’s more…

• Clinical Applications and • Case Studies

• Thank you for your attention!!

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