Polycystic Ovarian Syndrome (PCOS) Treatment Protocol

Polycystic Ovarian Syndrome (PCOS) Treatment Protocol

Definition and Pathophysiology

Polycystic ovarian syndrome (PCOS), an endocrine disorder associated with hormonal and cardiometabolic complications, affecting up to 26% of women and those assigned female at birth globally.[1] For the large majority of PCOS patients, the core of their symptoms results from derangements in hyperandrogenism, insulin resistance and inflammation.[2]

Patient Signs and Symptoms

Common clinical signs and symptoms of PCOS include:

  • Enlarged ovaries, generally 2-3 times larger than normal, resulting from multiple cysts
  • Irregular menstrual cycles – i.e., oligomenorrhoea or amenorrhoea
  • Hirsuitism (espcially facial hair)
  • Central obesity – "apple-shaped" obesity centred around the lower half of the torso
  • Infertility, generally resulting from chronic anovulation (lack of ovulation)
  • Androgenic alopecia (male-pattern baldness)
  • Jaw-line acne, oily skin, seborrhoea
  • Acanthosis nigricans (associated with insulin resistance)
  • Sleep apnoea (especially if with metabolic syndrome)
  • Blood sugar dysregulation – e.g., hypoglycaemic episodes, diabetes, etc

Risk Factors

Major causative factors and risk factors that can contribute to the incidence of PCOS include:

  • Obesity
  • Genetics
  • Lifestyle
  • Diet
  • Neuroendocrine alterations (HPO-HPA-HPT axis)
  • Gut dysbiosis
  • Environmental pollutants.[3]

Screening and Investigations

The International Evidence-based Guideline for the assessment and management of PCOS 2023 indicates diagnosis of PCOS if positive for two out of three following signs:

  • Clinical and/or biochemical evidence of hyperandrogenism;
  • Evidence of oligo-anovulation; or
  • Transvaginal ultrasonographic evidence of a polycystic ovary OR elevated anti-mullerian hormone (AMH) levels.4

For further information on PCOS pathophysiology, risk factors, testing and treatment discussed by key opinion leaders, see on demand webinar Taking the Stress out of PCOS.

Test

Interpretation

Follicle Stimulating Hormone (FSH)[5]

Evaluate in early follicular phase, day 2 to 6 of menstrual cycle. Elevated FSH levels indicate poor follicle development and consequently, anovulatory cycles. Reduced levels of FSH may indicate hyperprolactinaemia.

LH:FSH ratio[5]

The ratio is usually close to 1:1, but if the LH is higher, it is one possible indication of PCOS. Evaluate LH:FSH ratio in early follicular phase between day 2 to 6 of menstrual cycle.

Anti-Mullerian Hormone (AMH)[4]

Can be used as an alternative to transvaginal ultrasound to support a diagnosis of PCOS if levels are elevated. However, it is not to be used as a single diagnostic test on its own.

Oestradiol (E2)[6]

Reduced levels may indicate ovarian abnormalities. Elevation in basal E2 may indicate diminished ovarian reserves secondary to increased early follicular FSH levels.

Serum Progesterone (P4)[6]

Reduced progesterone levels can indicate luteal phase defects and/or anovulatory cycles. Evaluate serum progesterone levels in mid-luteal phase (7 days prior to onset of menses).

Testosterone[4]

Recommended to use calculated free testosterone along with calculated free androgen index for superior specificity and sensitivity.

Oral Glucose Tolerance Test (OGTT)[4]

Oral glucose tolerance test is most accurate to assess glycemic status in PCOS irrespective of body mass index.

Oral Glucose Tolerance Test (OGTT) interpretation: blood glucose level (mmol/L)

Normal Values

Impaired glucose tolerance

Impaired fasting glycaemia

Diabetes mellitus

Fasting

<5.5

<5.5

5.5–6.9

≥7.0

2 hour

<7.8

7.8–11

<7.8

≥11.1

Treatment recommendations

Core Treatment

Attenuate androgen excess, promote insulin sensitivity and aromatase activity

Inositol, Peony & Liquorice to Clear Testosterone

Acute dose: 2 tablets twice daily Maintenance:2 tablets once daily

  • Peony and licorice shown to inhibit androgen and testosterone synthesis.[7,8] Inositol enhances insulin sensitivity whilst supporting FSH and aromatase activity.[9,10]

Promote healthy blood glucose metabolism and insulin signalling.

Magnesium & Inositol to Support Healthy Female Hormonal Balance & Vitality

Dose: 1 serve twice daily

  • Magnesium required for insulin synthesis and secretion.[11] Magnesium and chromium required for phosphorylation of insulin receptor required for insulin binding.[11,12] Myo-inositol and chromium required for intracellular insulin signalling and glucose metabolism.[9,12]

Resveratrol Age Well

Dose:1 tablet daily

  • Research shows quercetin, resveratrol and curcumin offer anti-oxidant and anti-inflammatory activity whilst supporting mitochondrial activity,13–18 thereby improving glycaemic control and cardiovascular health.[19,20]

Additional Recommendations

To support healthy blood glucose, carbohydrate metabolism and liver function

Indian Barberry and Milk Thistle For Blood Glucose Metabolism and Liver Function Support

Dose:1 tablet twice daily

A blend of berberine, milk thistle and chromium in combination with diet and lifestyle support can help rebalance these patterns of metabolic dysfunction and support PCOS management.[21–24]

To assist in weight loss if necessary The Shake It Practitioner Weight Management Program is a novel 3 phase program structure to:

  • Prevent metabolic adaptation
  • Reset the patient’s metabolic set point
  • Provide regular psychological breaks from active dieting in order to achieve sustained weight loss.

Support progesterone status and corpus luteum health present with lengthened cycles or infertility, also refer to the Amenorrhoea protocol

Vitex, Ginger & Withania to Increase Progesterone

Dose: 1 tablet daily

An herbal and nutritional blend designed to manage the symptoms and causes of progesterone deficiency, working in both the brain and the body to provide effective relief for PMS, painful periods, irregular cycles and infertility.25–27

Address gut dysbiosis associated with PCOS pathophysiology

Choose from Metagenics probiotic range

To support detoxification of environmental pollutants Metagenics Clinical Detoxification Programs designed to support gut health and address the primary source of toxicity in patients. These programs encourage elimination of and protection against these toxins. There are three programs available:

  • Health Reset
  • Gut Pathogen Elimination
  • Liver Chemical Clearance

Promote healthy vaginal ecosystem

Probiotics Lactobacillus rhamnosus (GR-1™) and Lactobacillus reuteri (RC-14™) with liquorice for women’s urogenital health

Dose:1 capsule daily

To promote a healthy vaginal ecosystem L. rhamnosus (GR-1™) and L. reuteri (RC-14™) help to restore lactobacilli levels.28 The addition of vitamin C and vitamin D can also help mitigate UTI symptoms,29,30 promoting local urogenital immune function. Adding further clinical benefits, a deglycyrrhizinated extract of liquorice root (GutGard® liquorice) supports a healthy vaginal mucosa.31

Promote healthy thyroid function

Lycium Hypothyroid support

Loading dose: 2 tablets twice daily with food until improvement, then maintenance dose: 1 tablet twice daily with food

Selenium, iodine, zinc and vitamin A all play important roles in thyroid hormone synthesis, metabolism or activity and optimal thyroid hormone production and receptor function.32–34 In Traditional Chinese medicine and Ayurvedic disciplines, Lycium barbarium is used for fatigue whilst Withania somnifera is an adaptogen and thyroid tonic.[35,36]

Diet and Lifestyle

  • Lower intake of refined carbohydrates including sugar, sweets, fruit juices, white breads, pasta and potatoes.
  • Regular aerobic exercise (moderate to vigorous) has been shown to improve insulin sensitivity in women with PCOS.
  • Manage chronic stress to reduce impact on hypothalamic-pituitary-ovarian (HPO) axis. Further, chronic stress increases HPA axis which further drives insulin secretion.[37]
  • Avoid environmental toxins (in food, skin care products, home products), shown to disrupt HPO axis along with glucose metabolism and insulin signalling.[38]

References

  1. KR N, R N. Hormones of HPG-axis and their Active Role during Chronic Stress and PCOS Induction: A Review. Int J Sci Basic Appl Res. Published online 2022.
  2. Armanini D, Boscaro M, Bordin L, Sabbadin C. Controversies in the Pathogenesis, Diagnosis and Treatment of PCOS: Focus on Insulin Resistance, Inflammation, and Hyperandrogenism. Int J Mol Sci. 2022;23(8):4110. doi:10.3390/ijms23084110
  3. Singh S, Pal N, Shubham S, et al. Polycystic Ovary Syndrome: Etiology, Current Management, and Future Therapeutics. J Clin Med. 2023;12(4):1454. doi:10.3390/jcm12041454
  4. Teede H. International Evidence-based Guideline for the assessment and management of polycystic ovary syndrome 2023. Eur J Endocrinology. 2023;189(2):G43-G64. doi:10.1093/ejendo/lvad096
  5. Saad AssocProfM. Female Reproductive Hormones and Fertility Testing. Australian Clinical Labs. https://www.clinicallabs.com.au/about-us/doctor-media-releases/female-reproductive-hormones-and-fertility-testing/
  6. Hunt S, Vollenhoven B. Assessment of female fertility in the general practice setting. AJGP. 2020;49(6):304-308. doi:10.31128/ajgp-01-20-5205
  7. Sakamoto K, Wakabayashi K.Inhibitory Effect of Glycyrrhetinic Acid on Testosterone Production in Rat Gonads. Endocrinol Japon. 1988;35(2):333-342. doi:10.1507/endocrj1954.35.333
  8. Ong M, Cheng J, Jin X, et al. Paeoniflorin extract reverses dexamethasone-induced testosterone over-secretion through downregulation of cytochrome P450 17A1 expression in primary murine theca cells. J Ethnopharmacol. 2019;229:97-103. doi:10.1016/j.jep.2018.09.006
  9. DiNicolantonio JJ, O’Keefe JH. Myo-inositol for insulin resistance, metabolic syndrome, polycystic ovary syndrome and gestational diabetes. Open Hear. 2022;9(1):e001989. doi:10.1136/openhrt-2022-001989
  10. Greff D, Juhász AE, Váncsa S, et al. Inositol is an effective and safe treatment in polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials. Reprod Biol Endocrinol. 2023;21(1):10. doi:10.1186/s12958-023-01055-z
  11. Melo SR de S, Santos LR dos, Soares T da C, et al. Participation of Magnesium in the Secretion and Signaling Pathways of Insulin: an Updated Review. Biol Trace Elem Res. 2022;200(8):3545-3553. doi:10.1007/s12011-021-02966-x
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  14. Davis JM, Murphy EA, Carmichael MD, Davis B. Quercetin increases brain and muscle mitochondrial biogenesis and exercise tolerance. Am J Physiology-regulatory Integr Comp Physiology. 2009;296(4):R1071-R1077. doi:10.1152/ajpregu.90925.2008
  15. Rastogi M, Ojha RP, Rajamanickam GV, Agrawal A, Aggarwal A, Dubey GP. Curcuminoids modulates oxidative damage and mitochondrial dysfunction in diabetic rat brain. Free Radic Res. 2008;42(11-12):999-1005. doi:10.1080/10715760802571988
  16. Boots AW, Haenen GRMM, Bast A. Health effects of quercetin: From antioxidant to nutraceutical. Eur J Pharmacol. 2008;585(2-3):325-337. doi:10.1016/j.ejphar.2008.03.008
  17. Chainani-Wu N. Safety and Anti-Inflammatory Activity of Curcumin: A Component of Tumeric (Curcuma longa). J Altern Complementary Medicine. 2003;9(1):161-168. doi:10.1089/107555303321223035
  18. de la Lastra CA, Villegas I. Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications. Biochem Soc Trans. 2007;35(5):1156-1160. doi:10.1042/bst0351156
  19. Kuroda M, Mimaki Y, Nishiyama T, et al. Hypoglycemic Effects of Turmeric (Curcuma longa L. Rhizomes) on Genetically Diabetic KK-Ay Mice. Biol Pharm Bull. 2005;28(5):937. doi:10.1248/bpb.28.937
  20. Hertog MGL, Feskens EJM, Kromhout D, et al. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet. 1993;342(8878):1007-1011. doi:10.1016/0140-6736(93)92876-u
  21. Orio F, Muscogiuri G, Palomba S, et al. Berberine improves reproductive features in obese Caucasian women with polycystic ovary syndrome independently of changes of insulin sensitivity. e-SPEN J. 2013;8(5):e200-e204. doi:10.1016/j.clnme.2013.07.002
  22. Amooee S, Parsanezhad ME, Shirazi MR, Alborzi S, Samsami A. Metformin versus chromium picolinate in clomiphene citrate-resistant patients with PCOs: A double-blind randomized clinical trial. Iran J Reprod Med. 2012;11(8):611-618.
  23. Farrokhian A, Mahmoodian M, Bahmani F, Amirani E, Shafabakhsh R, Asemi Z. The Influences of Chromium Supplementation on Metabolic Status in Patients with Type 2 Diabetes Mellitus and Coronary Heart Disease. Biol Trace Elem Res. 2020;194(2):313-320. doi:10.1007/s12011-019-01783-7
  24. Guarino G, Strollo F, Carbone L, et al. Bioimpedance analysis, metabolic effects and safety of the association Berberis aristata/Bilybum marianum: a 52-week double-blind, placebo-controlled study in obese patients with type 2 diabetes. J Biol Reg Homeos Ag. 2017;31(2):495-502.
  25. Azgomi RND, Zomorrodi A, Nazemyieh H, et al. Effects of Withania somnifera on Reproductive System: A Systematic Review of the Available Evidence. Biomed Res Int. 2018;2018:4076430. doi:10.1155/2018/4076430
  26. Fathizadeh S, Iran N and MDRC Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Amani R, et al. Comparison of serum zinc concentrations and body antioxidant status between young women with premenstrual syndrome and normal controls: A case-control study. Int J Reproductive Biomed. 2016;14(11):699-704. doi:10.29252/ijrm.14.11.699
  27. Hossein-Rashidi B, Nemati M. Effects of Vitex agnus-castus extract on the secretory function of pituitary-gonadal axis and pregnancy rate in patients with premature ovarian aging (POA). J Herb Med. 2017;10:24-30. doi:10.1016/j.hermed.2017.10.003
  28. Reid G, Charbonneau D, Erb J, et al. Oral use of Lactobacillus rhamnosus GR‐1 and L. fermentum RC‐14 significantly alters vaginal flora: randomized, placebo‐controlled trial in 64 healthy women. Fems Immunol Medical Microbiol. 2003;35(2):131-134. doi:10.1016/s0928-8244(02)00465-0
  29. Li D, Zhang T, Yang H, Yang W, Zhang C, Gao G. Effect of Vitamin D on the Proliferation and Barrier of Atrophic Vaginal Epithelial Cells. Molecules. 2023;28(18):6605. doi:10.3390/molecules28186605
  30. Yousefichaijan P, Goudarzi AA, Rezagholizamenjany M, et al. Efficacy of Ascorbic Acid Supplementation in Relief of Symptoms Due to Febrile Upper Urinary Tract Infection in Children, a Clinical Trial and Hospital Based Study. Archives Pediatric Infect Dis. 2018;In Press(In Press). doi:10.5812/pedinfect.57071
  31. Kapoor LD. Ayurvedic Medicinal Plants. In: CRC Handbook of Ayurvedic Medicinal Plants. CRC Press; 1990.
  32. Gerasimova LI, Denisov MS, Samoilova AV, Gunin AG, Denisova TG. Role of Iodine Deficiency in the Development of Menstrual Disorders in Young Females. Sovrem Teh v Med. 2016;8(4):104-107. doi:10.17691/stm2016.8.4.14
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  34. Morley JE, Melmed S, Reed A, et al. Effect of vitamin A on the hypothalamo-pituitary-thyroid axis. Am J Physiol-Endocrinol Metab. 1980;238(2):E174-E179. doi:10.1152/ajpendo.1980.238.2.e174
  35. Sharma AK, Basu I, Singh S. Efficacy and Safety of Ashwagandha Root Extract in Subclinical Hypothyroid Patients: A Double-Blind, Randomized Placebo-Controlled Trial. J Altern Complementary Medicine. 2018;24(3):243-248. doi:10.1089/acm.2017.0183
  36. Yao R, Heinrich M, Weckerle CS. The genus Lycium as food and medicine: A botanical, ethnobotanical and historical review. J Ethnopharmacol. 2018;212:50-66. doi:10.1016/j.jep.2017.10.010
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  38. Urbanetz LAML, Junior JMS, Maciel GAR, Simões R dos S, Baracat MCP, Baracat EC. Does bisphenol A (BPA) participates in the pathogenesis of Polycystic Ovary Syndrome (PCOS)? Clinics. 2023;78:100310. doi:10.1016/j.clinsp.2023.100310

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