PCOS Fertility, 3.6:1 Ratio Myo-inositol D-Chiro-Inositol featuring Caronositol

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.

Main Symptoms

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 PCOS[1].
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 phase[1].
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 hairline[1].

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 production[1].
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 PCOS[1].
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 production[1].
   1. 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 women[1].Briefly, insulin is considered as a key hormone for hyperandrogenism in the PCOS pathophysiology via two different pathways:
      • 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.
4. 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 quality[1].
5. 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 decades[1].

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.

Factors that may be responsible for PCOS

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 production[1].
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 PCOS[1].
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 production[1].
   1. 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 women[1].Briefly, insulin is considered as a key hormone for hyperandrogenism in the PCOS pathophysiology via two different pathways:
      • 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.
4. 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 quality[1].
5. 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 decades[1].

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.

PCOS Fertility is a product that will help manage the symptoms of PCOS by lowering the many features of the metabolic syndrome and help restore the physiological balance of MI and DCI which are impaired and resulting in problems. Once the right balance is achieved in the systemic circulation and the ovaries, the chances of fertility are higher.

This product is especially designed based on research to help the women for whom PCOS is the reason of infertility. However, conception is a very sensitive topic and can be affected by various factors.

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 product for you.

If you are someone who is looking for all of the above, but is also trying to conceive, then we recommend our PCOS Fertility product for you.

Please note, the PCOS Fertility product is 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.

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 fair chance to conceive. So, it is not that if you consume the PCOS Management product you will not have chances of conception.

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

If you are someone who has tried our PCOS Management and PCOS Fertility products, and found that PCOS Fertility works better for you in terms of regularizing your cycles, despite the fact that you are not planning for conception, you may continue using this product for regular PCOS Management as well.

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[iv].

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[v].

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 signaling[v].

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[vii].

Exercise

It’s really important that girls with PCOS exercise, because exercise brings down insulin levels7,[viii] and can help with weight loss. Exercise can be especially helpful in lowering insulin after a meal8^,7. 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 day7^,[viii].

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

[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

[iii] 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

[iv] 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.

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

[vi] Nicolas Mendoza, et. al., “Comparison of the effect of two combinations of myo-inositol and D-chiro-inositol in women with polycystic ovary syndrome undergoing ICSI: a randomized controlled trial”, Gynecological Endocrinology, 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

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

[viii] 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