Recently there has been considerable interest in the use of myoinositol (M-inositol, M-IN) in the treatment of infertility for polycystic ovarian syndrome (PCOS) and IVF. Questions about inositol arise such as what is it, how does it work, and does the literature support the use inositol in the treatment of various aspects of infertility?
MEET MYOINOSITOL (M-IN)
What is myo-inositol? M-inositol is actually a sugar that is found in a number of human organs. M-IN has half the sweetness of table sugar (sucrose). The body can make M-IN from glucose, with the kidney making as much as two grams of M-IN a day. Other tissue can make M-IN, but the highest amount is found in the brain. M-IN was formerly thought to be vitamin B8, but since it is made in the body and is not an essential nutrient, it cannot be a vitamin.
What does it do? M-IN is involved in several molecular functions in the body. It is involved with neurotransmitters, as second messengers in various cells, and in the synthesis of some hormones. The body has two systems for coordinating the functions of the body: the nervous system and the hormonal system. The hormonal system regulates the normal functioning of the body. In order to regulate the various functions, there must be a message system which is how hormones work. Suppose the body wants to mature an egg to be released so that a person can achieve a pregnancy. The brain releases the hormone FSH which travels in the blood to the ovary where it attaches to the cells (granulosa) that surround an egg. The cells multiply and release estrogen which then travels back to the brain so that the brain knows the job it wants done is underway. Estrogen and FSH represent two broad categories of hormones. Estrogen is a steroid (like cholesterol) that can easily pass through the cell wall (it is mostly fat lipid) and goes to the nucleus of the cell where it attaches to the cell’s DNA. FSH, a protein that is not dissolvable in fat and thus cannot pass through the cell wall, attaches to the cell wall of the granulosa cell which causes a substance within the cell to set off several reactions that will cause release of hormones or stimulate the cell’s DNA. The substances that are created in the cell after the attachment of the FSH are called second messengers, with FSH being the primary messenger. Inositol functions as a second messenger in several cells. One type of second messenger is involved with insulin. Since insulin plays a central role in the pathology of PCOS, it seems reasonable to determine if M-IN could help in the treatment of PCOS. M-IN plays a role in other functions including structure of cells, intracellular calcium levels and gene expression. Perhaps, M-IN might be helpful in IVF to enhance proper function of the oocyte in the formation of embryos with the correct number of chromosomes.
A TOOL FOR TREATING PCOS?
Can M-IN help in the treatment of PCOS? PCOS is a complicated metabolic disease. People with PCOS are born with a set of genetic risk factors. These are, as yet unidentified, and while there is an increased risk for PCOS in families with a history of obesity and adult onset diabetes, many people with PCOS will not have a family history. Their genetic risk arises because that is how they, personally, were constructed. People who have the genetic risk factors can develop PCOS is certain things happen as they go through life. One such cause of PCOS is insulin resistance. For women with PCOS whose BMI is > 26-30, 95% will have insulin resistance. For women with PCOS and a BMI < 26, 75% will have insulin resistance. Thus, insulin resistance plays a large role in the development of PCOS in those people with the genetic risk factors. The way insulin resistance causes PCOS involves the regulation of glucose. Insulin resistance means that insulin is not as efficient as it should be in lowering blood sugar (glucose) levels so that a person with insulin resistance needs to release more insulin that those who do not have insulin resistance. The effect is that most young people with PCOS have normal blood sugar levels. However, this puts a strain on the pancreas, the organ responsible for making insulin, and like any machine, overworking the pancreas leads to early failure and the onset of diabetes as an adult. The ovary has receptors for insulin so insulin can influence the functioning of the ovary. Insulin causes the ovary to produce male hormones. Normal ovarian functioning requires the production of male hormones (androgens, testosterone) from cholesterol, but then the ovary converts the androgens to estrogen. The egg unit(follicle) primarily produces estrogen. Increased androgen levels retard or arrest the normal development of the egg unit. This leads to an ovary with an increase in the number of small eggs units (antral follicles) which gives rise to the term polycystic. A cyst is any fluid – filled space in the body and a developing egg unit creates a fluid- filled space (that black circle seen on ultrasound) and this can be called a cyst instead of a follicle. A more accurate name for PCOS would be poly-follicular syndrome. The increased insulin from people with insulin resistance causes the follicle to produce excess androgens which result in irregular cycles of no menses, and to the effects of androgen on the body such as acne and unwanted body hair. Therefore, if the insulin could be made more efficient, this should reduce the production of the male hormone and allow more normal functioning of the follicle. Medical intervention has been used to make the insulin more efficient. Metformin is the current medication of choice and it works by reducing the insulin secretion. However, M-IN is involved with how insulin tells the cells in the follicles to make androgens. Therefore, it makes sense to determine if using M-IN could work like metformin and reduce the levels of male hormone in the ovary. There is an overabundance of articles about this form of treatment. When there are numerous articles about a topic, physicians rely upon summary articles in the form of systemic reviews and meta- analysis to provide a more accurate summary of what the literature is suggesting. For a popular topic, there can be numerous meta- analysis which hopefully agree in general as to what the literature is suggesting. Pundar et al (2017 BMJ) published a meta- analysis evaluating what the literature had to say about the treatment of non-ovulating PCOS patients. The authors identified 107 potential useful articles, but after applying the criteria needed to answer the question, only 10 studies were used for the analysis. This loss of articles is typical of meta- analysis because so much of the medical literature is duplicated, not done well, not relevant or difficult to analyze. Nonetheless, the meta- analysis is a standardized way to obtain useful information from a sea of data. The summary from the meta- analysis was that inositol treatment significantly improved the ovulatory rate and frequency of menses when compared to placebo. The study did not look at pregnancy rates. Zheng et al (2017) evaluated M-IN treatment for patients undergoing IVF with a meta- analysis. This study identified 469 potential articles but after applying the criteria of the analysis, only seven trials were included. The authors reported that M-IN improved the clinical pregnancy rate. So, what to do? M-IN is a safe, over-the -counter substance that may help in the treatment of PCOS or in certain circumstances when patients are undergoing IVF. One treatment suggestion was to use M-IN at two grams twice a day. Metformin can be added to this regimen if deemed necessary. This combined with lifestyle changes such as a 10% loss of weight, a reduction in carbohydrate consumption, and an increased in daily mild exercise, can improve the chance of obtaining a successful pregnancy. When successful, the pregnancy usually occurs within the first six months of consciously trying to conceive. If after six months, there is no pregnancy then other treatments are available, such as letrozole and IVF. Overall, cumulative success rates of pregnancy for women with PCOS are extremely high given today’s knowledge about PCOS and the technology available.