Unived PCOS Management Plus

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women and a major cause of anovulatory infertility[1] Polycystic ovary syndrome (PCOS) is a complex heterogeneous disorder that has several aspects in terms of pathology such as metabolic, endocrine, reproductive, and psychological[2]. It is the most common endocrine diseases that affects 5 to 10% of women of adolescent and reproductive age[2].

There is increasing evidence to suggest that PCOS affects the whole life of a woman. It can begin in utero in genetically predisposed subjects, it manifests clinically at puberty, and continues during the reproductive years[1] .

Several studies suggest that insulin resistance and hyperandrogenism play a central role in the progression of PCOS pathophysiology. Therefore, common treatment strategies of PCOS are based on lifestyle modification, which include exercise, diet, and nutrient supplementation therapy[2].

The menstrual cycle is regulated by hormones. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are produced by the pituitary gland, promote ovulation and stimulate the ovaries to produce estrogen and progesterone. Estrogen and progesterone stimulate the uterus and breasts to prepare for possible fertilization. The menstrual cycle has three phases:

• Follicular (before release of the egg)
• Ovulatory (egg release)
• Luteal (after egg release)

In a Healthy Menstrual cycle, when the follicular phase begins, levels of estrogen and progesterone are low. As a result, the top layers of the thickened lining of the uterus (endometrium) break down and are shed, and menstrual bleeding occurs. About this time, the follicle-stimulating hormone level increases slightly, stimulating the development of several follicles in the ovaries. Each follicle contains an egg. Later in this phase, as the follicle-stimulating hormone level decreases, only one follicle continues to develop. This follicle produces estrogen.

The ovulatory phase begins with a surge in luteinizing hormone and follicle-stimulating hormone levels. Luteinizing hormone stimulates egg release (ovulation), which usually occurs 16 to 32 hours after the surge begins. The estrogen level decreases during the surge, and the progesterone level starts to increase.

During the luteal phase, luteinizing hormone and follicle-stimulating hormone levels decrease. The ruptured follicle closes after releasing the egg and forms a corpus luteum, which produces progesterone. During most of this phase, the estrogen level is high. Progesterone and estrogen cause the lining of the uterus to thicken more, to prepare for possible fertilization.

If the egg is not fertilized, the corpus luteum degenerates and no longer produces progesterone, the estrogen level decreases, the top layers of the lining break down and are shed, and menstrual bleeding occurs (the start of a new menstrual cycle).

In PCOS, the cycle is hindered right in the follicular phase. The follicle stimulating hormone increases for follicle maturation but;

1. With PCOS, LH levels are often high when the menstrual cycle starts. The levels of LH are also higher than FSH levels.
2. Because the LH levels are already quite high, there is no LH surge. Without this LH surge, ovulation does not occur, and periods are irregular.
3. Girls with PCOS may ovulate occasionally or not at all, so periods may be too close together, or more commonly too far apart. Some girls may not get a period at all.

A high percentage (55–75%) of women with PCOS have an elevated LH/FSH ratio presumably due to high levels of LH rather than reduced production of FSH. Higher LH further leads to excessive androgen production and the ovaries may develop numerous small collections of fluid (follicles) and fail to regularly release eggs. Inositol imbalance consisting of excess myo-inositol and deficient chiro-inositol is a measure of insulin resistance this is because of epimerase inactivity in PCOS. All this could be a result of many factors.

1. Menstrual disorder – oligomenorrhea or amenorrhea meaning irregular periods or no periods at all.
2. Reproductive concerns/Anovulatory cycles – The majority of women with PCOS have anovulation. With this comes infertility as well as problems of dysfunctional bleeding[3]. Perhaps the most frustrating reproductive concern for women with PCOS is pregnancy loss. The spontaneous abortion rate in PCOS is approximately one third of all pregnancies3.
3. Hirsutism – presence of terminal hair on the face and/or body in a masculine pattern. It is the most common symptom, found in about 60 % of women with PCOS1.
4. On diagnosis – presence of 12 or more follicles of diameter 2–9 mm or an ovarian volume of more than 10 mL in follicular phase1.
5. Obesity – not all women with PCOS are obese and not every obese woman has PCOS. But when present, obesity worsens the clinical presentation of PCOS increasing insulin resistance and resulting in a further elevation of ovarian and adrenal androgens and of unbound testosterone3.
6. Impaired glucose tolerance & diabetes – All women with PCOS are therefore at risk to develop impaired glucose tolerance and overt type 2 diabetes3. In a recent study, impaired glucose tolerance was found in 31% of women of reproductive age, with PCOS and diabetes in 7.5%3.
7. Acne
8. Alopecia – consists of progressive hair loss or thinning Hair loss in PCOS usually involves thinning at the vertex with maintenance of the frontal hairline1.

1. Altered secretion of GnRH and gonadotropins: GnRH produced by the Hypothalamus enters the anterior pituitary gland and cause it to produce two important hormone; FSH and LH. GnRH over stimulation causes, indeed, excessive LH production1.
2. Ovarian and extraovarian hyperandrogenism: Hyperandrogenemia is the most typical hormonal alteration of PCOS. Hyperandrogenism has a multifactorial origin attributed mostly to the ovaries with a substantial contribution from the adrenals and a minor contribution from fatty tissue. Aromatase is the enzyme that converts androgens into estrogens. It may be responsible for hyperandrogenism as Low aromatase activity has also been demonstrated in women with PCOS1.
3. Hyperinsulinemia and insulin resistance: Since many women with PCOS seem to have insulin resistance, compensatory hyperinsulinemia is thought to contribute to hyperandrogenism by direct stimulation of ovarian production of androgens and by inhibition of liver synthesis of SHGB that increases testosterone availability. Insulin also increases ACTH mediated adrenal androgen production1.

The action of insulin on the ovary uses the inositol glycan system as a signal mediator, a different mechanism from the system activated by phosphorylation of the receptor at tyrosine level in other tissues. An increase was observed in urinary clearance of inositol in some American and Greek women with PCOS. It reduces tissue availability of inositol. This mechanism could contribute to insulin resistance present in PCOS women1.

Briefly, insulin is considered as a key hormone for hyperandrogenism in the PCOS pathophysiology via two different pathways2:

• Insulin stimulates androgen production of theca cells with luteinizing hormone (LH) and elevated androgen production leads to hirsutism, acne, and anovulatory infertility.
• Hyperandrogenism associated function of insulin is inhibition of sex hormone-binding globulin (SHBG) synthesis in the liver.

1. Anti-Mullerian hormone (AMH): Women with PCOS have higher serum and Follicular Fluid concentrations of AMH compared to controls. This is closely correlated with greater development of antral follicles and arrest of follicular growth. High serum levels of AMH are directly correlated with an increase in testosterone and/or LH concentrations in women with PCOS, as well as with altered oocyte maturation and low embryo quality1.

1. Other factors like unhealthy diet or eating habits, inactive lifestyle, environmental factors or genetics can also contribute in the development of PCOS.

Although the etiopathogenesis of PCOS is still controversial, mentioned above are some hypotheses that have been proposed in the recent decades1.

Stages

According to the Rotterdam criteria, PCOS is confirmed by the existence of at least two out of three criteria

1. Hyperandrogenism,
2. Chronic anovulation,
3. Polycystic ovaries on ultrasound findings

Clinical Manifestation

The typical clinical indications of PCOS are: anovulatory cycles, ultrasonographic evidence of polycystic ovaries and hirsutism1. Many women are also overweight or obese and have an increased risk of developing metabolic syndromes in later life1. During pregnancy, there is a higher chance of miscarriage, gestational diabetes and hypertension1.

Unived’s PCOS products are for a woman trying to deal with daily struggles of  PCOS.

If you are someone who is looking for something that helps regularize your cycles and manage symptoms associated with PCOS, but at this age & stage in life you may not be very focused on trying to conceive, then we recommend our PCOS Management or our PCOS Management Plus product for you.

If you are someone who is looking for all of the above, but at this age & stage in life you are also trying to conceive, then we recommend our PCOS Fertility product for you.

Please study our PCOS Supplement Guide to determine which product is right for you. 

Please note, the PCOS Management product is formulated to address PCOS related imbalances, when these imbalances get addressed and your menstrual cycles resume, you do stand a chance to conceive. So, it is not that if you consume the PCOS Management product you will not have chances of conception.

The PCOS Fertility formulation is specifically formulated in a ratio that is clinically studied and has shown to deliver a higher chance of conception, while also addressing all the PCOS symptoms.

Therefore, if you are at the age & stage in life where you not only want to address the symptoms but also want to try and conceive in the coming months, then we recommend choosing the PCOS Fertility product. Otherwise, if your focus and desire is only symptom management then do opt for the PCOS Management product.

It is just that one formulation offers a higher chance of conception as compared to the other.

We hope the suggestions are clear. Please feel free to speak with us if you require further clarification.

Inositols

Two inositol isomers, Myo-Inositol (MI) and D-Chiro-Inositol (DCI) have been proven to be effective in PCOS treatment, by improving insulin resistance, serum androgen levels and many features of the metabolic syndrome[4].

The enzyme epimerase converts MI to DCI, maintaining a physiological ratio of 40:1, which varies from tissue to tissue. The conversion rate of MI to DCI ranges from 7% to about 9% in normal healthy females and is much lesser in women with PCOS due to insulin resistance in the systemic circulation. In the setting of epimerase deficiency, less MI can be converted to DCI, a state of relative DCI deficiency occurs, and insulin resistance is promoted. This, in turn, leads to the metabolic complications of hyperinsulinemia[5].

Therefore to summarize; in the serum,

In the ovary, MI and DCI have specific duties to perform. MI supports FSH signaling, whereas DCI is responsible for insulin-mediated testosterone synthesis. In the normal ovary, these activities proceed in balance, allowing the maintenance of normal hormonal levels and facilitating ovarian function. In the polycystic ovary, systemic insulin resistance (hyperinsulinemia) accentuates epimerase activity, thus creating a higher DCI-to-MI ratio. This promotes hyperandrogenism and reduces the efficiency of MI-mediated FSH signaling5.

Myo-inositols

• Myo-inositol administration improves reproductive axis functioning in PCOS patients reducing the hyperinsulinemic state that affects LH secretion[6].
• Consistent significant changes were observed in Group A (under MYO+folic acid administration) since several hormonal parameters changed during the treatment interval. Indeed mean plasma LH, PRL, T and insulin levels significantly decreased, as well as LH/FSH ratio, the index of insulin sensitivity glucose/insulin ratio and the HOMA index.
• Insulin response, evaluated thirty minutes following oral glucose load, was significantly reduced in group A patients as well as the AUC of insulin with respect to baseline conditions.
• Reduces LH/FSH ratio (40.05%)[7]
• Reduces total testosterone (6.84%) levels7
• Reduces HOMA Index (5.54%) i.e. reduces insulin resistance7.

Caronositol® D-Chiro-Inositol it is natural Plant-Based DCI from carob extract obtained by a patented process. It helps reduce hyperandrogenism and skin disorders in women suffering with PCOS. DCI helps PCOS affected women by regulating normal ovulation.

• DCI administration to PCOS patients is able to improve insulin sensitivity and to reduce serum free testosterone levels leading to normal cycle and ovulation4.
• Serum levels of DCI are reported to be lower in women with PCOS, both at baseline and after administration of glucose loads. DCI treatment has been found to reduce insulin levels, lipids, and blood pressure, in women with PCOS5.
• Administration of exogenous DCI may be a means of bypassing defective epimerase activity and achieving the downstream metabolic effects of insulin in DCI-deficieny tissues5.
• Reduces LH (0.88%) levels7
• Reduces Free testosterone (1.26%) levels7

Alpha Lipoic Acid (ALA) is a potent antioxidant and has been reported to improve glucose control in type 2 diabetes patients and in women with PCOS, to improve insulin sensitivity and reproductive and metabolic disorders4.

• Clinical and metabolic aspects of women on DCI and lipoic acid treatment (p<0.5) underwent improvement with respect to the Control Group4.
• 3% of women on treatment underwent a significant improvement of the HOMA-IR and 68.1% of insulin4.
• Improvement of the number of menses and of progesterone serum levels was reported by 68.6% (p<0.001) and 64.4% (p<0.001) for treated women, respectively4.
• Data confirmed that 2/3 of (p<0.001) women underwent ovulation4.
• 2% of women underwent a reduction of number of ovarian peripheral cysts4.
• A significant increase of HDL-C was demonstrated in the treatment group4.
• Such improved metabolic profile obtained with a short treatment can improve the clinical and reproductive aspect of women with PCOS and all the symptoms primarily related to hyperandrogenism, chronic anovulation and insulin resistance4.
• In a study, 68.6% of women on treatment obtained increased menses; this could be due to the associated antioxidant effect of lipoic acid to the DCI4.
• The administration of DCI plus ALA significantly changed LH, A, insulin and LDL plasma levels. Also, BMI and the HOMA index decreased significantly[8].
• Patients with no familial diabetes showed improvements only in plasma LH, insulin and A levels, as well as in the HOMA index8.
• The combined DCI+ALA regimen, at the low dosages was effective in improving both hormonal and metabolic parameters8.

Chromium Picolinate consists of trivalent chromium, an extremely safe and highly tolerable trace mineral which is present in normal diet and is combined with picolinate acid in order to enhance gut absorption. Chromium (Cr) is a safe and highly tolerable trace element provided by dietary intake and dietary supplementation, especially chromium picolinate. Cr is an essential element in glucose and insulin homeostasis[9].

• Previous study have reported that daily supplementation of Cr (200-1000 mcg) in form of Cr picolinate has resulted in decreased blood glucose levels9.
• Chromium picolinate, an over-the-counter product, improved insulin sensitivity at the insulin receptor level9^,[10] and effectively reduced insulin resistant and treated hyperinsulinemia as well as hyperandrogenemia but did not significantly affect the hormonal changes10, at the elevated level of intake, was devoid of adverse effects in human studies10.
• Chromium functions as a part of an auto amplification system for insulin Signaling and promotes enhancement of insulin sensitivity10
• In the patients who received chromium picolinate, Fasting Blood Sugar significantly decreased after 3 months of treatment (p=0.042)10.
• Cr supplementation reduced fasting insulin in subgroup of studies with>10 participants (effect size: -0.86 mIU/ml, 95% CI: -0.67, -0.17; p = 0.001) (I²= 63.7%, P= 0.06)6.
• The serum levels of fasting insulin significantly decreased leading to an increased insulin sensitivity as measured by QUICKI index (p=0.014)10.
• After 3 months of treatment by chromium picolinate, serum levels of testosterone decreased by 0.12. In the same way, the serum levels of free testosterone decreased by 0.2 in chromium9^,10.

Vitamin D3

Studies have suggested that vitamin D also plays a role in reproductive functions. Vitamin D receptors are expressed in the ovary and testis, suggesting that vitamin D is active in these organs. Vitamin D deficiency may be the missing link between insulin resistance and PCOS.

• Several studies indicated an association between low levels of serum 25-hydroxyvitamin D (25-OH-vitamin D) and manifestations of PCOS including insulin resistance, hyperandrogenism, and infertility[11].
• Anti-Mullerian hormone (AMH) inhibits the recruitment of primordial follicles, decreases the follicular sensitivity to FSH, and inhibits granulosa cell aromatase, leading to an increase in intrafollicular androgen levels. Treating PCOS women with vitamin D supplements normalized their serum AMH levels11.
• Vitamin D may activate the transcription of human insulin receptor gene as the promoter of this gene has a vitamin D responsive element (VDRE)11.
• Menstrual regularity was reported six months after the intervention in 58% of the patients in group I and 70% of the patients in Group II[12].
• As compared to group I, follicular response was relatively higher in group II three and six months after the treatment12.
• On the other hand, vitamin D deficiency causes insulin resistance and diabetes which induce hyperandrogenism followed by menstrual irregularity12.
• In a study, the regulation of menstrual dysfunction occurred in 70% of the subjects who had taken calcium & vitamin D and metformin12.
• A study showed menstrual regularity in 70% and follicular response in 28% of the patients who had taken calcium & vitamin D and metformin12.
• Vitamin D treatment has been shown to improve various clinical parameters in vitamin D-deficient women with PCOS including glucose intolerance, hypertension, and androgen levels12^,[13].

Folate

Unived’s PCOS formulation also includes L-5-methyltetrahydrofolate, which is the most biologically active form of the B9-vitamin, folic acid. Folate in this product supports MI functions and helps to reduce Homocysteine levels that may be elevated in PCOS

Calcium

The importance of calcium in the regulation of both meiotic and mitotic cell division cycles in mammalian oocytes has aroused considerable interest Because of the importance of calcium in both oocyte activation and maturation; abnormalities in calcium homeostasis may play a role in the pathogenesis of PCOS[14].

• Follicular response was relatively higher in supplemented group14
• The growth of follicles after treatment was significantly higher in supplemented group than in placebo14.
• Menstrual cycle irregularity improved significantly only in the supplementation group11.
• The combination of dietary calcium insufficiency and vitamin D deficiency may be largely responsible for the menstrual abnormalities associated with PCOS11.
• A significant decrease in LH levels was observed in the supplemented group11.
• A significant increase in FSH was observed in the supplemented group11.

Zinc

Zinc plays many important functions in the body. It has crucial role in regulating cell growth, hormone release, immunological response and reproductive health. In women with PCOS, zinc supplementation has shown a positive effect on parameters related to insulin resistance and lipid balance. Zinc deficiency in women could lead to conditions like impaired synthesis and /or secretion of FSH and LH hormones, abnormal ovarian development, disruption of menstrual cycle etc. Zinc is considered an anti-androgen by inhibiting 5α- reductase and thus decreasing the production of dihydrotestosterone [17]

Zinc supplementation seems to improve PCOS symptoms, particularly among women with dysregulated insulin resistance and lipid balance. In addition, reduced levels of zinc in PCOS are accompanied by impaired hormonal, lipid and glucose metabolism and increased concentrations of oxidative stress biomarkers.[17]

In a study on women with PCOS, decreased lipid peroxidation, indicated by lower malondialdehyde (MDA) concentrations, was observed following zinc supplementation.[17]

Diet and exercise are important parts of managing PCOS. Knowing the right foods to eat as well as the kinds of food to limit can improve the way you feel. Eating well, staying active, and maintaining a healthy weight (or losing even a small amount of weight if you’re overweight) can improve PCOS symptoms[15].

Exercise

It’s really important that girls with PCOS exercise, because exercise brings down insulin levels15,[16] and can help with weight loss. Exercise can be especially helpful in lowering insulin after a meal15^,16. So, if possible, go for a walk after you eat a large meal. Any increase in exercise helps, so find an activity, sport, or exercise that you enjoy. If you aren’t doing a lot of exercise now, start slowly, and build up to your fitness goal. If you only exercise once in a while, try to exercise more regularly. Work towards increasing your physical activity to at least 5 days a week for 60 minutes per day16.

A good fitness plan should include a balance of stretching, toning, and aerobic activities.

Weight Management Tips

• Choose nutritious, high–fiber carbohydrates instead of sugary or refined carbohydrates
• Balance carbohydrates with protein and healthy fats
• Limit your portions when you’re eating high–carbohydrate foods (especially ones that are low in fiber), and try to eat them with foods that contain protein.
• Eat small meals and healthy snacks throughout the day instead of large meals
• Exercise regularly to help manage insulin levels and your weight

References

[1] V. De Leo, et. al., “Genetic, hormonal and metabolic aspects of PCOS: an update”, De Leo et al. Reproductive Biology and Endocrinology (2016) 14:38

[2] Elif Günalan, et. al., “The effect of nutrient supplementation in the management of polycystic ovary syndrome-associated metabolic dysfunctions: A critical review”, the Turkish-German Gynecological Education and Research Foundation Assoc 2018; 19: 220-32

[3] Enrico Carmina And Rogerio A. Lobo,“Polycystic Ovary Syndrome (PCOS): Arguably the Most Common Endocrinopathy Is Associated with Significant Morbidity in Women”, The Journal of Clinical Endocrinology & Metabolism 1999 Vol. 84, No. 6

[4] Antonio Cianci, et. al., “D-chiro-Inositol and alpha lipoic acid treatment of metabolic and menses disorders in women with PCOS”, Gynecol Endocrinol, Early Online: 1–4 2015 Informa UK Ltd.

[5] Kalra, Bharti et al., “The inositols and polycystic ovary syndrome”, Indian journal of endocrinology and metabolism vol. 20,5 (2016): 720-724.

[6] Alessandro D. Genazzani, et. al., “Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome”, Gynecological Endocrinology, March 2008; 24(3): 139–144

[7] Alfonsa Pizzo, et. al., “Comparison between effects of myo-inositol and D-chiro-inositol on ovarian function and metabolic factors in women with PCOS”, Gynecol Endocrinol, 2014; 30(3): 205–208

[8] Alessandro D. Genazzani, et. al., “Modulatory role of D-chiro-inositol and alpha lipoic acid combination on hormonal and metabolic parameters of overweight/obese PCOS patients”, European Gynecology and Obstetrics. 2019; 1(1):29-33

[9] Siavash Fazelian, et. al., “Chromium supplementation and polycystic ovary syndrome: A systematic review and meta-analysis”, Journal of Trace Elements in Medicine and Biology 42 (2017) 92–96

[10] Sedigheh Amooee, et. al., “Metformin versus chromium picolinate in clomiphene citrate-resistant patients with PCOs: A double-blind randomized clinical trial”, Iran J Reprod Med Vol. 11. No. 8. pp: 611-618, August 2013

[11] Sally Kadoura et. al., “Effect of calcium and vitamin d supplements as an adjuvant therapy to metformin on menstrual cycle abnormalities, hormonal profile and IGF-1 system in polycystic ovary syndrome patients: a randomized, placebo-controlled clinical trial”, Hindawi, Advances in Pharmacological Sciences, Volume 2019, Article ID 9680390

[12] Raziah dehghani Firouzabadi et. al., “Therapeutic effects of calcium & vitamin D supplementation in women with PCOS”, Complementary Therapies in Clinical Practice 18 (2012) 85e88 2012 Elsevier Ltd.

[13] Mohamad Irani, et. al., “Vitamin D Supplementation Decreases TGF-β1 Bioavailability in PCOS: A Randomized Placebo-Controlled Trial”, J Clin Endocrinol Metab, November 2015, 100(11):4307–4314

[14] Batool Rashidi, et. al., “The effects of calcium-vitamin d and Metformin on polycystic ovary syndrome: A pilot study”, Taiwan J Obstet Gynecol • June 2009 • Vol 48 • No 2

[15] Phaedra Thomas RN, BSN, et. al., “PCOS Resources for a Healthier You” ©Center for Young Women’s Health | Boston Children’s Hospital

[16] Chris Kite, et. al., “Exercise, or exercise and diet for the management of polycystic ovary syndrome: a systematic review and meta-analysis”, Systematic Reviews (2019) 8:51

[17] Nasiadek, M., Stragierowicz, J., Klimczak, M., & Kilanowicz, A. (2020). The role of zinc in selected female reproductive system disorders. Nutrients, 12(8), 2464.