Food for special medical purposes for the dietary management of women with autoimmune thyroiditis who want to conceive.

A-Bregenz, 27.04.2016 To Romanian authorities / to whom it may concern, Römerstrasse 2,, Austria, hereby informs. Fertilovit F THY Food for special medical purposes for the dietary management of women with autoimmune thyroiditis who want to conceive. What is Fertilovit F THY? Fertilovit F THY is a food for special medical purposes for the dietary management of women with autoimmune thyroiditis who want to conceive. Autoimmune thyroiditis and the desire for children Chronic autoimmune thyroiditis is an auto-immune disease of the thyroidea. It can occur in various forms. In Hashimoto s thyroiditis, the commonest form, the patient s body produces auto-antibodies directed against healthy thyroid cells, destroying them. As a consequence of this, thyroid hormone production decreases substantially (thyroid hypofunction or hypothyroidism). The rarer Graves disease, on the other hand, is associated with the production of antibodies directed against a signaling molecule on the thyroid cells surface. This causes the thyroid cell to produce an excessive amount of thyroid hormones (thyroid hyperfunction or hyperthyroidism). In the long run, however, many patients experience thyroid hypofunction as well. It is estimated that one in six women have a predisposition for autoimmune thyroiditis. However, it still is not clear which reasons and triggers are responsible for the onset of the disease. Scientific studies have found associations with a variety of factors, such as genetic factors, excess iodine exposure, changing levels of sexual hormones during pregnancy or menopause, smoking or radiation. Symptoms are divers and vary individually Thyroid hyperfunction is associated with symptoms such as sleeplessness, nervousness, hot flashes, rapid heartbeat and hair loss. Thyroid hypofunction on the other hand results in weight gain, fatigue and generally diminished performance, sensitivity to cold, diminished ability to concentrate and even depressive disorder. Women who wish to conceive suffer particularly from diminished sexual desire, impaired menstrual cycles, decreased fertility and increased risk of miscarriage. In these cases fertility treatment with thyroid hormones can help to achieve healthy pregnancy. The patient herself can support therapy as well by making healthy lifestyle choices and maintaining a healthy diet that takes into account some specifics of the disease. A diet low in iodine According to scientific studies excessive iodine exposure worsens the progress of the disease. A diet low in iodine on the other hand has been reported to result in an 55

improvement. Hence patients with autoimmune thyroiditis are recommended to abandon iodized table salt. Any dietary supplements should be free of iodine as well. Vitamins and minerals The importance of a sufficient supply with certain vitamins and minerals has long been acknowledged. Every gynecologist recommends taking folic acid, particularly because of its protective role in the early embryo s neurological development. More and more it becomes evident that other vitamins and minerals, too, can have a major impact on fertility. Scientific studies have shown that iron as well as B-vitamins are important for healthy conception. Selenium Soils in Europe are poor in selenium. Consequently plants grown in this soil and thus food produced there have a low selenium content. In addition to this autoimmune thyroiditis is associated with an increased selenium demand. Hence it can be difficult for patients to take up selenium in sufficient quantities. Oxidative stress Even though, as mentioned above, the reasons for the onset of the disease are not quite understood, recent research has revealed oxidative stress to be an important contributing factor. The term oxidative stress refers to the impairment of body cells by reactive oxygen species (ROS). Oxidative stress increases the immunological turmoil in the thyroid gland and many experts claim it to be responsible for a substantial part of the symptoms. Oocytes on the other hand are particularly susceptible to attacks by reactive oxygen species, too. Antioxidants Normally the ROS produced in the body are defanged by the body s own protective antioxidant system. However, if there are too many ROS or too few antioxidants, this delicate balance can collapse and body cells are damaged. Stress, smoking and poor eating habits can weaken the body s own antioxidant system. In these situations taking additional antioxidants can improve symptoms of autoimmune thyroiditis. Simultaneously oocytes are protected from the detrimental effects of oxidative stress, too. B-Vitamins Research has revealed that patients suffering from autoimmune thyroiditis also have an increased risk of having a vitamin B12 deficiency. Vitamin B12 is not only important for cell division, but together with folic acid and vitamin B6 - is also vitally needed for homocysteine metabolism. Therefore experts recommend that thyroiditis patients supplement B-vitamins. Administration form: Capsules Packaging sizes (Net quantity): 30 capsules (16.6 g) The composition of Fertilovit F THY accounts for the special requirements of women with autoimmune thyroiditis planning for conception. 55

Supplement facts: Daily dose (1 % NRV* capsule) Vitamin C 100 mg 125 Vitamin E 15 mg 125 Vitamin B1 4 mg 364 Vitamin B2 4.5 mg 321 Pantothenic acid 18 mg 300 Vitamin B6 5.4 mg 386 Vitamin B12 9 µg 360 Folic acid 800 µg 400 Vitamin D 5 µg 100 Niacin 17 mg 106 Biotin 180 µg 360 Zinc 2.25 mg 23 Magnesium 100 mg 26 Iron 7.5 mg 54 Selenium 100 µg 181 Coenzyme Q10 20 mg - *Percentage of Nutrition Reference Values (according to regulation 1169/2011/EU) Fertilovit F THY contains neither lactose, gluten, nor gelatin. Directions For best results, experts recommend to start taking a supplement about three months prior to conception. However, taking Fertilovit F THY can be started at any time. Take one capsule Fertilovit F THY daily. If you need to take thyroid hormones, please make sure not to take them at the same time as Fertilovit F THY, because the iron in the micronutrient preparation could bind to the hormones, compromising their effectiveness. Fertilovit F THY is a nutritionally incomplete food for special medical purposes. Some of its ingredients exceed defined maximum quantities. The product must be used under medical supervision. Do not exceed the recommended dosage. Fertilovit F THY cannot and must not replace a healthy lifestyle and a well-balanced diet. Please store out of reach of children. Scientifically Proven Effects of the Ingredients Vitamin C Vitamin C is a water soluble antioxidant and protects the body s cells as well as fat soluble vitamins like E from oxidative stress. Studies have revealed that oxidative stress worsens autoimmune thyroiditis and that patients benefit from taking antioxidants. Vitamin C is also important because it helps absorb iron. However, women should avoid high doses of vitamin C because it can dry up cervical fluid, preventing sperm from reaching the egg. This is why Fertilovit F THY features a relatively low dose of vitamin C. To make the most of its vitamin C content, it is released in a sustained manner, providing its positive effect for many hours. 55

Zinc Zinc is one of the essential trace minerals, which means that the body cannot produce it itself, but it has to be supplied via the diet. It has been found that zinc deficiencies are quite frequent even in western countries, which might be due to the fact that the body is not able to store zinc. Yet zinc plays a crucial role in the metabolism of carbohydrates, fats and proteins alike. In addition to that the immune and hormone systems as well as important antioxidative enzymes need zinc for their work. Furthermore it is crucial for the synthesis of the nucleic acids DNA and RNA, which are essential during cell division, tissue repair and embryo development. Last not least, zinc is needed for thyroid hormone metabolism. Vitamin E (D-alpha-tocopheryl acetate) Vitamins E s anti-oxidative properties promote oocyte health by effectively protecting these sensitive cells from the harmful impact of oxidative stress. Niacin Niacin belongs to the vitamins of the B-complex. It is present in every living cell and can be stored in the liver. It forms a vital building block of various coenzymes and is involved in key processes of metabolism. Additionally it has antioxidative properties. Vitamin B1 Thiamin or vitamin B1 is a water-soluble vitamin essential for the nervous system. Vitamin B2 Vitamin B2 or riboflavin has been called growth vitamin in colloquial language. It is an important precursor for coenzymes, thus playing a central role in metabolism. Vitamin B5 Vitamin B5 or pantothenic acid is necessary for the formation of coenzyme A. Coenzyme A plays a major role in the metabolism. It is involved in synthesis and breakdown of carbohydrates, fats and proteins and is crucial for the production of cholesterol. Cholesterol is needed for the synthesis of steroid hormones, many of which are essential for reproduction. Vitamin B6 Vitamin B6 has traditionally been used for easing the symptoms of premenstrual syndrome and menopause. Recent research has revealed its importance for reproductive wellness. This effect is mediated by vitamin B6 s involvement in the homocysteine pathway. Homocysteine is a potentially harmful amino acid and vitamin B6 is needed for its breakdown into other, harmless molecules. Vitamin B6 deficiency has been associated with hyperhomocysteinemia, which impairs fertility and placenta performance. Vitamin B12 Recent research has shown that vitamin B12 supplementation may promote fertility and decrease the risk for miscarriage. Like vitamin B6 it is needed for the degradation of homocysteine. A recent study from 2006 has shown that patients with autoimmune thyroiditis have an increased risk of vitamin B12 deficiency. 55

Vitamin D3 Among others vitamin D3 is important for the calcium and phosphate metabolism, thus being essential for bone growth. Furthermore it is needed for the development and performance of the nervous and muscle systems. Folic acid Folic acid is very delicate and easily destroyed during storage and cooking, which is why deficiencies are quite common even though fruit and vegetables are rich in folic acid. Folic acid deficiency has been associated with neurological disorders such as spina bifida (split spine). In addition to that it has antioxidative properties. Finally, folic acid is vital for the homocysteine pathway. Homocysteine is a potentially toxic amino acid, yet can be broken down into harmless molecules with the aid of folic acid, vitamin B6 and vitamin B12. A rise in homocysteine levels is known to be associated with infertility, impairment of placenta function and even increased risk of miscarriage. Biotin Biotin belongs to the vitamin B-complex. It is a constituent of enzymes and as such is involved in key pathways of the metabolism. It is known that it is also involved in the epigenetic regulation of gene function. Animal studies have found evidence that biotin deficiency is associated with a decline of fertility and an increase of malformation risk. Magnesium Magnesium deficiency is not uncommon during pregnancy. This is due to an increase in magnesium excretion on the one hand and elevated magnesium needs of the baby on the other hand. A first symptom of magnesium deficiency may be cramps in the calf, but may also involve muscular hyperexcitability of uterus muscle. Worst possible consequence of this is premature labour. Iron Iron, being a major constituent of hemoglobin, is considered essential as a blood building nutrient. It is also needed for normal hormone metabolism of the thyroid gland. Thyroid hypofunction, however, has frequently been found to be associated with reduced iron absorption, leading to an increased risk of iron deficiency. Women with iron deficiency have an elevated risk of impaired fertility. In addition to that experts recommend to check iron levels when planning for conception, because the need for iron rises considerably during pregnancy. Selenium Studies have shown that supplementing selenium can improve the symptoms of Hashimoto s thyroiditis. Two features of selenium seem to account for this: Firstly selenium is needed for the metabolism of thyroid hormones. Secondly selenium, having anti-oxidative properties, can counteract reactive oxygen species formed as a by-product of thyroid hormone synthesis. Contra-indications Women who have issues with your iron metabolism or have a known intolerance to any of the ingredients should not consume Fertilovit F THY. 55

Representative bibliography Fertilovit F THY - In an observational study, dietary supplementation with Fertilovit F THY improved blastocyst number and ongoing pregnancy rate of IVF (in vitro fertilization) patients with Hashimoto thyroiditis (Wogatzky et al 2013, attached). Vitamin C - Contributes to normal energy metabolism: EFSA 2009; 7(9):1226 ; 2010;8(10):1815 - Contributes to normal function of the immune system: EFSA 2009; 7(9):1226 ; 2010;8(10):1815 - Contributes to protecting cells from oxidative stress: EFSA 2009; 7(9):1226 ; 2010;8(10):1815 - Contributes to collagen formation - Vital for iron metabolism (transferrin -> ferritin) - Henmi et al showed 2003 in a controlled randomized study that women taking 750 mg ascorbic acid per day had higher progesterone levels and higher pregnancy rates - Antioxidants like vitamin C are particularly important for active and passive smokers (Alberg et al, 2002, Dietrich et al, 2003). - Women with total vitamin C intakes of <10th percentile preconceptionally have twice the risk of preterm delivery because of premature rupture of the membranes (Siega- Riz et al, 2003) - In patients with a luteal phase defect supplementation of vitamin C leads to higher pregnancy rates (Henmi et al, 2003) Vitamin E - Contributes to protecting cells from oxidative stress: EFSA 2010;8(10):1816 - particularly folic acid, vitamin B6, vitamin C, vitamin D, vitamin E, iodine, selenium, iron,... might have a positive impact on infertility treatment (Buhling and Graejecki, 2013) Vitamin D - vitamin D deficiency has been linked to infertility and pregnancy loss (Lerchbaum et al, 2012) - Contributes to normal function of the immune system: EFSA 2010; 8(2):1468 - Has a role in cell division: EFSA 2009; 7(9):1227 Vitamin B1 (Thiamine) - Contributes to normal energy metabolism: EFSA 2009; 7(9):1222 - Contributes to normal heart action: EFSA 2009; 7(9):1222 Vitamin B2 (Riboflavin) - Contributes to normal energy metabolism: EFSA 2010;8(10):1814 - Contributes to maintenance of normal red blood cells: EFSA 2010;8(10):1814 - Contributes to protecting cells from oxidative stress: EFSA 2010;8(10):1814 Vitamin B3 (Niacin) - Contributes to normal energy metabolism: EFSA 2009; 7(9):1224; 2010;8(10):1757 55

Vitamin B5 (Pantothenic acid) - Contributes to normal energy metabolism: EFSA 2009; 7(9):1218 - Contributes to normal synthesis and metabolism of steroid hormones, vitamin D and some neurotransmitters: EFSA 2009; 7(9):1218 Vitamin B6 (Pyridoxine) - Contributes to normal energy metabolism: EFSA 2010;8(10):1759 - Contributes to normal homocysteine metabolism: EFSA 2010;8(10):1759 - Contributes to normal red blood cell formation: EFSA 2009; 7(9):1225 - Contributes to normal function of the immune system: EFSA 2009; 7(9):1225 - Contributes to regulation of hormone action: EFSA 2009; 7(9):1225 - Used in traditional medicine for relief of premenstrual syndrome, menopausal symptomes and for fertility improvement. - Deficiency of vitamin B6 has been linked to decreased conception rates and an increased risk of early miscarriage (Ronnenberg et al, 2007) Biotin - Contributes to normal energy metabolism: EFSA 2009; 7(9):1209 - Folic acid - Contributes to growth of maternal tissue during pregnancy: EFSA 2009; 7(9):1213 - Contributes to normal blood formation: EFSA 2009; 7(9):1213 - Contributes to normal homocysteine metabolism: EFSA 2009; 7(9):1213 - Contributes to normal function of the immune system: EFSA 2009; 7(9):1213 - Has a role in cell division: EFSA : 2009; 7(9):1213 ; 2010;8(10):1760 - A diet high in synthetic folate may be associated with increased progesterone levels and lower risk of sporadic anovulation (Gaskins et al, 2012) - Important for healthy neural tube development - Supplementation during fertility treatment improves oocyte quality (Szymanski et al, 2003) Vitamin B12 (Cobalamin) - Contributes to normal energy metabolism: EFSA 2009; 7(9):1223 - Contributes to normal homocysteine metabolism: EFSA 2010;8(10):4114 - Contributes to normal formation of red blood cells: EFSA 2009; 7(9):1223 - Contributes to normal function of the immune system: EFSA 2009; 7(9):1223 - Has a role in cell division: EFSA 2009; 7(9):1223; 2010;8(10):1756 - Deficiencies are frequently found in vegetarians - In 2001, Bennet et al found that patients (n=14) with vitamin B12 deficiency often suffer from from subfertility and miscarriage. Supplementing the vitamin resulted in a rise in pregnancy rate and a fall in miscarriage rate - Molloy et al (2008) showed that low B12 levels in early pregnancy are linked to an increased risk of spina bifida (split spine) Zinc - Contributes to normal DNA-synthesis: EFSA 2010;8(10):1819 - Contributes to normal fertility and reproduction: EFSA 2009; 7(9):1229 - Contributes to normal function of the immune system: EFSA 2009; 7(9):1229 55

- Contributes to protecting cells from oxidative stress: EFSA 2009; 7(9):1229 - Has a role in cell division: EFSA 2009; 7(9):1229 Magnesium - Contributes to normal energy metabolism: EFSA 2009; 7(9):1216 - Has a role in cell division: EFSA 2009; 7(9):1216 - Pregnancy is associated with an increased risk for deficiency due to an increased demand and an increase of up to 25 % in excretion - Deficiency symptoms include muscular hyperexcitability, which in pregnancy might lead to premature labor - Therefore supplementation of magnesium is recommended from 16 gestational week - Dose is important: Studies show (e.g.fine et al, 1991) that only 35 % from 120 mg are resorbed by the body and when taking a higher dose of 360 mg this is even reduced to 18 % Iron - Contributes to normal energy metabolism: EFSA 2009; 7(9):1215; 2010;8(10):1740 - Contributes to normal to normal hemoglobin and red blood cell formation: EFSA 2009; 7(9):1215; 2010;8(10):1740 - Contributes to normal transport of oxygen in the human body: EFSA 2009; 7(9):1215; 2010;8(10):1740 - Contributes to normal function of the immune system: EFSA 2009; 7(9):1215 - Contributes to reduction of tiredness: EFSA 2010;8(10):1740 - Has a role in cell division: EFSA 2009; 7(9):1215 - Consumption of iron supplements and nonheme iron from other sources may decrease the risk of ovulatory infertility (Chavarro et al 2006) - During pregnancy demand doubles from 15 mg to 30 mg - Women with iron deficiency have decreased fertility (Rushton et al, 1991) Coenzyme Q10 - Antioxidant - Tissue concentration is 5 10 x higher than vitamin E (Bentinger et al, 2007) - Important for ATP-synthesis in the mitochondria (Mitchell, 1975, Santos-Ocana, 2002) - Effective ATP production is required for oocyte maturation and early stages of embryonic development (Jansen etal, 1998) - Tissue concentration of coenzyme Q10 declines with age (Pignatti et al, 1980) - When supplementing coenzyme Q10, the majority is detected in adrenal gland and ovary (Bentiger et al, 2008) Dr. Daniel Matthes, Regulatory Affairs 55