Patent Publication Number: US-2004058014-A1

Title: Pharmaceutical or dietetic preparation for improvement of fertility and sperm quality

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS  
     [0001] The present application is a continuation of Ser. No. 09/610,536, filed Jul. 7, 2000, the entire content of which is hereby incorporated by reference. 
    
    
     
       TECHNICAL FIELD OF THE INVENTION  
       [0002] The present invention relates to preparations and compositions for improving the fertility of, and/or for improving the quality of the semen produced by, male individuals of mammalian species, including but not limited to human beings.  
       [0003] More in particular, the invention concerns a pharmaceutical or dietetic preparation that after oral intake can increase fertility and improve sperm quality in male animals in general and men in particular.  
       [0004] The preparations and compositions of the invention can inter alia be used to prevent and/or treat, in male individuals of mammalian species including but not limited to human beings, low fertility, disorders in fertility and/or conditions of poor semen quality, including but not limited to phenomena such as low sperm count, aberrations in morphology of the sperm cells, low motility of the sperm cells, or generally low sperm quality.  
       [0005] In one aspect of particular interest, the preparations and compositions of the invention may be used to prevent and/or treat a condition known as male sub-fertility, by which herein is generally meant a failure to conceive after 1 year of unprotected intercourse with the same partner; and in particular with a sperm count of less than 20 million cells/ml and with more than 30% of sperm cells having normal morphology and more than 50% of sperm cells having normal motility.  
       [0006] In another aspect of particular interest, the preparations and compositions of the invention may be used to prevent and/or treat disorders of male fertility and/or conditions of poor semen quality—including but not limited to male subfertility—as may be caused by, and/or as may be associated with, drug therapy.  
       [0007] In yet another aspect of particular interest, the preparations and compositions of the invention are used in animal breeding, e.g. in breeding programs for livestock and other economically important animals, in horse breeding, in breeding of pets and/or in breeding of zoo animals.  
       [0008] Further aspects of the invention will become clear from the description given hereinbelow.  
       BACKGROUND OF THE INVENTION  
       [0009] Subfertility is a disorder in which a relatively low number of pregnancies (conceptions) result from a certain number of copulations. Subfertility is a major problem in society. More than 14% of the families in many countries of the Western hemisphere experience problems with fertility and it has been reported that this problem may increase in the near future when the decrease in sperm quality as observed in the last decades is extrapolated. Also in animal breeding subfertility has become a matter of concern. In intensive animal breeding programs, as e.g. applied in horse, cattle and pig breeding an increase of sperm counts has a clear economic advantage.  
       [0010] Subfertility problems have to be distinguished from erectile or libido disorders. To our knowledge no associations have been published between disorders with libido and subfertility.  
       [0011] Subfertility in males may result from genetic disorders, hypothalamic disorders, undescended testis, clinical disorders [cancer of testis, variocele], germ cell aplasia, medical treatment [irradiation, drug treatment e.g. with sulphasalazine, beta-blockers, anabolic steroids], malnutrition (deficiencies in energy/protein or specific nutrition such as food very rich in phytocomponents), diabetes and environmental factors. Male subfertility is generally associated with decreased semen quality, characterized by a diminished number of sperm cells per semen volume (sperm count) and/or an altered morphology and motility of the sperm cells.  
       [0012] Generally, it is an object of the invention to provide a preparation or composition for improving the fertility of, and/or for improving the quality of the semen produced by, a male individual of a mammalian species.  
       [0013] In the art, attempts have been made to improve fertility in animals via administration of dietetic preparations.  
       [0014] Landau B. et al., disclosed in  Experientia,  1978, 34(10), 1301-2, that administration of 10 mg folic acid over 30 days did not result in an increase in sperm counts and motility and DNA content of spermatozoa.  
       [0015] Bentivoglio et al. disclosed in  Fertil Steril  1993, 60(4), 698-701 titled “ Folinic Acid in the Treatment of Human Male Infertility”  that administration of 15 mg folinic acid per day during 3 months increases spermatozoa number and fertility in men suffering from round cell idiopathic syndrome. The authors do not refer to the potential effect of lower amounts of folinic acid or other folate sources nor to beneficial effects that could be obtained by administration of zinc.  
       [0016] Recommendations for folate are typically maximally 400 μg per daily dose except for pregnant women who have a history of neural tube defects in their offspring. Higher amounts can only be allowed when prescribed under medical supervision. It is desirable to decrease doses to avoid risks of underdiagnosing vitamin B12 deficiencies in persons suffering from pernicious anemia.  
       [0017] The use of a complex of zinc with an amino acid, in particular aspartate, or with orotate for improving libido has been reported in WO 00-011396. No effect on sperm quality is disclosed. Blesbois E. and Mauger I. have reported in  Br.Poult.Sci.  1989, 30 (3), 677-685 that a concentration of zinc above 3 μg per ml storage medium reduced the fertilizing ability of fowl seminal plasma. Sprenger et al, in  Contributions to Nephrology  (1984), 38, 103-28 disclosed the effect of zinc salts on sexual dysfunction. No reference is made to folic acid or sperm quality.  
       [0018] European patent application 0 194 710 discloses the use of a zinc salt of fructose-1,6 diphosphate for treatment of male infertility. Folic acid is not mentioned.  
       [0019] European patent application 0 534 033 discloses the use of an injected preparation of zinc gluconate to inhibit the generation, maturation, motility and viability of sperm. The teaching of this European application is therefore contrary to the teaching of the present application, in which zinc is used—in combination with folic acid—to increase the generation and/or the maturation and/or the viability of sperm cells. Also, according to the present application, oral administration is preferred.  
       [0020] Tikkiwal et al. disclose in  Ind. J. Physiol. Pharmac.,  Vol. 31, no. 1, January-March 1987, pages 30 ff., that after administration of 220 mg zinc sulphate to males that suffer from idiopathic oligospermia, sperm count and the number of spermatozoa having normal morphology and motility improved significantly. No reference is made to an additional effect that could be obtained by (co-) administering low doses of a source of folic acid.  
       [0021] Also, the amount of zinc sulfate administered according to Tikkiwal is very high, as administration of zinc salts is typically limited to amounts of maximally about 30 mg/day.  
       [0022] The research group of R. Steegers have reviewed published prior art literature in Wong, W. Y, et al,  Fertil. Steril.  73(3), 2000, pp 435-442) titled: “ Male factor subfertility: possible causes and the impact of nutritional factors”.    
       [0023] ZA-A 994697 describes a composition for treatment of erectile dysfunction and loss of libido that includes folic acid, zinc and vitamin B12. No suggestion is made in said application to employ a reduced folic acid.  
       [0024] U.S. Pat. No. 5,922,704 describes a formula that is provided in 5 tablets and 1 gel capsule, comprising a tablet containing 280-400 mcg folic acid and 50-200 mcg vitamin B12 and another tablet containing 12-18 mg zinc (citrate). Reduced forms of folic acid are nowhere mentioned in this patent.  
       SUMMARY OF THE INVENTION  
       [0025] It has now been found that the fertility of, and/or the quality of the semen produced by, a male individual of a mammalian species can be improved by administering to said male individual zinc, a relatively high dose of a reduced folic acid and vitamin B12 in the amounts indicated hereinbelow. The composition of the present invention contains a particularly high amount of folate. Because of this high folate content, the use of a reduced folate is beneficial since the metabolic capacity in that particular patient/animal may not be sufficient to maintain all folate in plasma in the biologically active reduced form.  
       [0026] In particular, it has been found that the administration of a combination of zinc, a reduced folic acid and vitamin B12 improves fertility in both subfertile individuals as well as fertile individuals. The improvement exceeds the effect on semen quality that is observed when each of these components is applied in isolation. Furthermore, the invention offers the advantage that it is not associated with potential side effects as might arise from the circulation of oxidized folates in blood in case an oxidized folate is employed. This means that with advantage, the invention may be used not only in fertile and sub-fertile individuals, but also in male individuals suspected to be subfertile and/or at risk of becoming subfertile—i.e. without the need for (prior) testing—or more generally by male individuals of couples that want to concieve a baby.  
       DETAILED DESCRIPTION OF THE INVENTION  
       [0027] Accordingly, in a first aspect, the invention relates to a preparation or composition for improving the fertility of, and/or for improving the quality of the semen produced by, a male individual of a mammalian species, said composition comprising:  
       [0028] a reduced folic acid in an amount of between 0.4 and 5.5 mg;  
       [0029] at least one source of zinc in an amount of between 13 and 25 mg;  
       [0030] vitamin B12 in an amount of more than 1 μg per 400 μg of the reduced folic acid.  
       [0031] and optionally:  
       [0032] one or more further components (i.e. as outlined below);  
       [0033] and/or optionally:  
       [0034] one or more carriers, excipients and/or adjuvants (i.e. as outlined below);  
       [0035] in particular in the amounts indicated hereinbelow.  
       [0036] Further aspects of the invention will become clear from the further description hereinbelow.  
       [0037] The preparations and/or compositions of the invention may in particular be preparations and/or compositions intended and/or suitable for oral administration to a male individual of a mammalian species, including but not limited to pharmaceutical and/or veterinary preparations or compositions, and/or food supplements, i.e. for human food or animal feed.  
       [0038] By “a reduced folic acid” is generally meant herein a compound that is suitable for administration, and in particular for oral aministration, to a male individual of a mammalian species; and that upon such administration provides and/or makes (biologically) available the reduced folic acid to said individual  
       [0039] Suitable examples of such reduced forms of folic acid include, but are not limited to, 7,8-dihydrofolic acids, 5,6,7,8-tetrahydrofolic acids, salts of these hydrofolic acids and esters of these hydrofolic acids. Preferably, the reduced folate comprises a substituent in the 5- and/or 10-position. The preferred substituents are methyl, formyl, methenyl and formimino radicals. Most preferably, the substituents are either methyl or formyl substituents.  
       [0040] In a particularly preferred embodiment the reduced folate is selected from the group consisting of (6S)-tetrahydrofolic acid, 5-methyl-(6S)-tetrahydrofolic acid, 5-formyl-(6S)-tetrahydrofolic acid, 10-formyl-(6R)-tetrahydrofolic acid, 5,10-methylene-(6R)-tetrahydrofolic acid, 5,10-methenyl-(6R)-tetrahydrofolic acid, 5-formimino-(6S)-tetrahydrofolic acid, salts of these tetrahydrofolates or esters of these tetrahydrofolates.  
       [0041] The present invention encompasses the use of salts of reduced folic acids wherein a carboxyl group is complexed with a cation, e.g. an (alkali) metal cation or an amine. Furthermore, the invention includes the use of esters of reduced folic acids, i.e. such folates wherein a carboxyl group has been esterified, preferably with an alcohol, an amino acid or a peptide. In another preferred embodiment the reduced folic acid employed in the present composition is the 1-isomer. In a particularly preferred embodiment of the invention the reduced folate in the present composition is selected from the group consisting of 5-formyl tetrahydrofolic acid (folinic acid), 5-methyl tetrahydrofolic acid; salts of these tetrahydrofolic acids, esters of these tetrahydrofolic acids and any suitable combination thereof.  
       [0042] The reduced folates may suitably be incorporated in the present composition in the form of (fresh) aqueous extracts from well known natural folate sources green leafy vegetables such as spinach, turnip tops, purslane, endive, beet leaves, green cabbage, broccoli and sprouts. In addition, also potato extracts and extracts from specific fruits like strawberries, raspberries and blackberries can be used. The extracts are manufactured by mixing the fresh clean and optionally roughly cut pant material with a predominantly aqueous solution and optionally an antioxidant like ascorbic acid, disrupting the cell structures of the plant by means of ultrasonic vibration or enzymatic processes, waiting 0.2-3 hours at a temperature between 1-40 degrees Celsius and optionally under non-aerobic conditions, filtering slurry and having the filtrate pass through a chromatographic column (e.g. anion exchanger or activated carbon) to purify and concentrate the folates and remove undesired components such as odors and colorants. It is particularly preferred to use the reduced monoglutamate form. Even more preferably folinic acid or 5-methyl tetrahydrofolate, especially 6S-5-methyl tetrahydrofolate are applied, in particular their monoglutamate forms.  
       [0043] By “a source of zinc” is generally meant herein a compound that is suitable for administration, and in particular for oral administration, to a male individual of a mammalian species; and that upon such administration provides and/or makes (biologically) available to said individual zinc, in particular in the form of Zn 2+  ions. Suitable examples of such “bioavailable” sources of zinc will be clear to the skilled person, for instance from the prior art mentioned above, and may for instance include bioavailable zinc salts, including but not limited to salts with inorganic anions such as chloride, carbonate and sulphate, but also zinc salts with organic anions such as lactate, gluconate, fructosephosphates, orotate, citrate, malate, pyruvate, etc. and complexes of zinc with an organic molecule such as an aminoacid, or bi- or tridentate compound; or any suitable combination thereof.  
       [0044] It is preferred to use a non-hygroscopic food-grade ingredient with good organoleptic properties such as zinc sulphate or zinc citrate.  
       [0045] The preparations and/or compositions may optionally contain one or more further components known per se, including but not limited to components which by themselves have some biological, pharmacological and/or veterinary activity, i.e. upon (oral) administration to a male individual of a mammalian species.  
       [0046] In particular, these one or more further components may be one or more compounds that are known per se to have, upon (oral) administration to a male individual of a mammalian species, a beneficial influence on the fertility and/or sperm quality of a male individual of a mammalian species; and/or may be one or more components that, upon (oral) administration to a male individual of a mammalian species, may further increase, enhance and/or facilitate the fertility- and/or semen quality-improving action of the combination of zinc, reduced folic acid and vitamin B12 according to the present invention.  
       [0047] The one or more further components used should most preferably be suitable for (oral) administration to a male individual of a mammalian species, and should also be compatible with the other constituents of the preparations and/or compositions of the invention, and in particular with the at least one source of zinc and the reduced folic acid used.  
       [0048] For instance, the further component(s) may be one or more compounds which support spermatogenesis or any part and/or pathway of spermatogenesis, such as the so-called “methylation pathway”. Some non-limiting example of such compounds include but are not limited to:  
       [0049] magnesium, i.e. in the form of a bioavailable source of magnesium such as a bioavailable magnesium salt, e.g. magnesium citrate;  
       [0050] one or more vitamins, and in particular vitamin B2;  
       [0051] a suitable source of methyl groups like methionine, serine, dimethylglycine, sarcosine, betaine and/or choline, the latter for instance in the form of phosphatidylcholine or a suitable source thereof such as lecithine;  
       [0052] a suitable methylation agent such as S-adenosyl methionine (SAM); and, if required,  
       [0053] a suitable source of glucose;  
       [0054] or any suitable combination thereof.  
       [0055] Such further components may also be one or more compounds which improve levels of (reduced) glutathione in the spermatozoa. Some non-limiting example of such compounds, include, but not are limited to vitamin B6, which may be present/administered in the form of a (stable) pyridoxine or as a derivative thereof, such as pyridoxal or pyridoxamine. Improvement of glutathione status in spermatozoa is important for improving sperm quality, including but not limited to increasing half-life, motility and/or the capacity to fertilize an egg-cell.  
       [0056] Other suitable components for use in the compositions and preparations of the invention are for instance mentioned in some of the prior art mentioned above, and in particular in WO 99-03365.  
       [0057] The compositions and preparations may also contain a suitable source of copper, and in particular Cu 2+ -ions, such as copper(II)sulphate, copper(II)carbonate or copper(II)citrate.  
       [0058] The preparations or compositions of the invention may be in any form suitable for administration, and in particular for oral administration, to a male individual of a mammalian species, including but not limited to a human being. As such, the compositions of the invention may for instance be in the form of:  
       [0059] a pharmaceutical composition suitable for (oral) administration, such as a tablet, powder, capsule, sachet, syrup, elixer; and/or  
       [0060] a veterinary composition suitable for (oral) administration to the intended mammal; and/or  
       [0061] an additive or supplement for human food or animal feed, such as a concentrate, powder, syrup or premix that is to be mixed with human food or animal feed; and/or  
       [0062] a food or food supplement, such as a bar, a fortified food product such as a cereal, sauce, dessert soup, etc; and/or an animal feed.  
       [0063] The formulation/preparation of such preparations or compositions may be carried out in a manner known per se, which will generally comprise combining the reduced folic acid, the at least one source of zinc, vitamin B12 and optionally the one or more further components with each other and optionally with one or more acceptable carriers, excipients, adjuvants; and/or a suitable food or food base, depending upon the intended final preparation or composition, as will be clear to the skilled person.  
       [0064] The preparation of the invention may also be suitably packaged. The packaging form that is selected depends on the application and form of the preparation and is the choice thereof is known in the art.  
       [0065] The preparations and compositions of the invention may generally be used to improve the fertility of, and/or to improve the quality of the semen produced by, a male individual of a mammalian species, e.g. to improve the chance of reproduction of said male individual and/or to improve the quality of the semen produced by said male individual.  
       [0066] For instance, the compositions and/or preparations of the invention may be administered to human beings; to economically important animals such as cattle, sheep, pigs and horses; to pets such as cats and dogs; to zoo animals and/or to any other desired mammal. More generally, and in addition, the compositions of the invention may also be used in male individuals of a non-mammalian, vertebrate species, such as species of birds, fowl (chicken), reptiles, and/or fish.  
       [0067] As such, the compositions of the invention may be administered to fertile male individuals, to sub-fertile male individuals, to male individuals which are suspected of being sub-fertile and/or to male individuals which are at (increased) risk of becoming sub-fertile, e.g. due to drug therapy, radiation therapy, disorders of the urogenital tract, and/or due to other factors, such as environmental factors and/or the further factors mentioned above.  
       [0068] For example, in fertile male individuals, increase of sperm counts in fertile male animals may be of interest to increase further the chance of fast reproduction, which can have an economical benefit in animal breeding, but also may have psychological and practical advantages in men.  
       [0069] Also, in fertile male individuals, the invention may be used to provide sperm of improved quality, e.g. for use in animal breeding programs; for use in insemination, IVF and other fertilization techniques; and/or when sperm is to be frozen and stored over longer periods of time.  
       [0070] In sub-fertile male individuals, the compositions of the invention may be used to treat said sub-fertility, i.e. again to enable or at least to improve the chances of successful fertilization.  
       [0071] In another advantageous application, the compositions and preparations of the invention may be administered to a male individual of a mammalian species, and in particular to a human, without it being known a priori whether said male individual is fertile or sub-fertile. For instance, in this application, the compositions of the invention may be administered to the male individual of a couple when fertilization is retarded, e.g. to obviate testing and/or as a first step before any further testing is carried out. This is important since sperm testing is expensive, places a burden on the individual involved, and because the specificity and sensitivity of testing systems vary, and because there may be fluctuations in sperm count and/or sperm quality.  
       [0072] The compositions of the invention may be also used (i.e. prophylactically) by male individuals of couples that are intending to have a baby, i.e. to increase the chances of fertilization and/or to counteract any problems with male fertility that may be present, again without the need of prior testing.  
       [0073] The compositions of the invention may also be used to prevent or counteract the effects on reproduction of fluctuations of sperm count or sperm quality over time.  
       [0074] In yet another important aspect, the compositions and/or preparations may be used prophylactically to prevent a decrease in fertility and/or to prevent a decrease in sperm quality in individuals at risk thereof, for instance in male individuals that are (to be) subjected to drug therapy, and in drug therapy, radiation therapy, individuals suffering from disorders of the urogenital tract, and/or other disorders that may effect fertility and/or sperm quality, such as those mentioned above.  
       [0075] Also, the compositions and/or preparations of the invention may for instance be used to improve fertility and/or to improve sperm quality caused by factors such as malnutrition, environmental factors, and/or exposure to harmful substances.  
       [0076] The invention will now be discussed in more detail below.  
       [0077] The invention concerns a pharmaceutical or dietetic preparation that after oral intake can increase fertility and improve sperm quality in male animals in general and men in particular.  
       [0078] The preparations can be in the form of a powder, a liquid, a bar, a fortified food product such as a cereal, a sauce, a dessert, a soup, etc. The preparation can be a supplement, concentrate, premix or a complete food.  
       [0079] The present invention (also) concerns a preparation to enhance male fertility through increasing the number of sperm cells with no visible and/or detectable aberrations in morphology and motility per semen volume.  
       [0080] In one aspect of the invention the preparations are meant to be used to prevent and treat subfertility in general in male subjects of animals, especially in men.  
       [0081] In another aspect of the invention the preparations can be used in association with drug therapy, radiation therapy, disorders in the urogenital tract and other causes of subfertility as mentioned above.  
       [0082] In a third aspect of the invention it is aimed to increase sperm counts in general. Increase of sperm counts in fertile male animals is of interest to increase further the chance of fast reproduction, which can have an economical benefit in animal breeding, but also may have psychological and practical advantages in men.  
       [0083] In a fourth aspect of the invention it is aimed to develop a preparation that is effective for both fertile and subfertile males at the same time. This is important in order to avoid extensive testing of sperm quality when fertilization is retarded. This is important since testing is expensive and specificity and sensitivity of testing systems vary, an the fluctuations in time of the sperm count and/or the sperm quality of an individual.  
       [0084] In this document animals are meant to be any (vertebrate) animal including but not limited to humans and/or (other) mammals.  
       [0085] Pharmaceutical preparations are meant to be any nutritional product suitable for oral administration. Such preparations can be in the form of a powder, a liquid, a bar, a fortified food product such as a cereal, sauce, dessert soup, etc. The preparation can be a supplement, concentrate, premix or a complete food.  
       [0086] The packaging form that is selected depends on the application and form of the preparation and is the choice thereof is known in the art.  
       [0087] In this document, subfertility in humans is defined as being a condition in which sperm count is less than 80 million sperm cells per millimeter semen. The product is also effective in subfertile men demonstrating less than 20 million sperm cells/ml semen (WHO classification), more in particular in subfertile men demonstrating less than 20 million sperm cells/ml and more than 30% sperm cells with normal morphology and more than 50% of sperm cells with normal motility.  
       [0088] The preparations according to the invention include reduced folate, zinc and vitamin B12. The inventors have investigated the relative effectiveness of the administration of 5 mg folic acid alone (as oxidised monoglutamate), 15 mg zinc alone (66 mg as zinc sulphate) and the combination of 5 mg folic acid and 15 mg zinc during three months in either fertile men and subfertile men in terms of sperm count versus the initial situation before the dosage regimen.  
               TABLE 1                          Percentage improvement of spermcount after administration       of active agents, compared to initial spermcount.                         Relative improvement after           administration during 5 months of                                 5 mg folate   15 mg zinc   5 mg folate and 15 mg zinc                                         Fertile men   0   +   +       Subfertile men   +++   ++   +++(+)                          
 
       [0089] It can be concluded that administration of the combination of zinc and folate (including reduced folate, which is the active metabolite of oxidized folate) produces a synergistic effect. Without wanting to be bound by theory it is thought that a proper functioning of methylation pathways for a long time, preferably more than 2 months, is essential for proper spermatogenesis. Up to now, no relationship is. found in the prior art between fertility and methylation processes or semen quality and metabolic capacity of methylation processes. In accordance with the present invention, the methylation process is supported by administration of vitamin B12.  
       [0090] As is disclosed in WO 99-03365 methylation pathways could be supported by administration of magnesium, vitamin B12 and a source of methyl groups like methionine or betaine and, if required, a source of glucose. Also the methylation agent S-adenosyl methionine could be used.  
       [0091] Methylation processes may further be supported by administration of vitamin B2.  
       [0092] It is claimed that above-mentioned components, especially magnesium and vitamin B12 improve fertility of male animals.  
       [0093] In the spermatozoa relatively high levels of reduced glutathione occur. By the inventors it is considered to be essential for survival of the cell during storage and during the time that sperm is underway to the egg cell that glutathione levels be high. WO 99-03365 discloses that administration of vitamin B6 may help. It is claimed that administration of more than 1 mg vitamin B6 per daily doses increases spermatozoa glutathione levels.  
       [0094] In a preferred embodiment vitamin B12 is included in the present composition in an amount of more than 2 μg per 400 ug folate. These amounts act synergistically in patients/animals suffering from malnutrition or urogenital infections or cancer.  
       [0095] In order to maintain the reduced form of folate during storage and passage through the first part of the intestinal tract, a type of product formulation and packaging is selected which ensures release of a high amount of reduced folic acid in the proximal part of the small intestine, e.g. an enteric coating of the active ingredients.  
       [0096] A further beneficial effect can be obtained by including magnesium in the preparation, for example in the form of magnesium citrate.  
       [0097] Magnesium should be administered in an amount of at least 0.7 mg per kilogram bodyweight per day.  
       [0098] In order to avoid imbalances with minerals also calcium should be included when magnesium is administered and in an amount of at least 2 mg calcium.  
       [0099] S-adenosyl methionine (SAM) can be administered in an amount of 0.1-5 g, preferably 0.2-1 g.  
       [0100] Vitamin B12 is preferably administered as cyanocobalamine but also other cobalamines can be used.  
       [0101] Vitamin B6 can be administered as the stable pyridoxine or as a derivative such as pyridoxal or pyridoxamine.  
       [0102] Betaine is considered to be an important source of methylgroups and therefore an important component for the improvement of semen quality of especially the group of males that experience an impaired folate metabolism or require a rapid restoration of sperm quality, so especially subfertile men. It supports the methylation pathways in a way that is independent from folate metabolism.  
       [0103] Betaine can be replaced by choline or a source thereof, such as phosphatidylcholine or sources thereof such as lecithin.  
       [0104] Betaine should be administered in an amount of 0.5-20 g, in particular 1-10 g. The amount of the precursors or other methyldonors to be incorporated in the present composition can be calculated by administering equimolar doses.  
       [0105] In addition to or instead of betaine and/or choline, also other methyldonors, particularly methionine, serine, dimethylglycine and/or sarcosine may be employed. In a particularly preferred embodiment the present composition contains a methyldonor selected from the group consisting of serine, dimethylglycine, sarcosine and combinations thereof.  
       [0106] Methionine is mandatory for those patients that suffer from subfertility due to malnutrition.  
       [0107] Methionine can be administered as free amino acid or as methionine-rich peptides or proteins, such as casein. The amount of methionine that is consumed per day should be 0.6-6 g and preferably 1.2-3 g.  
       [0108] In Table 2 are summarized some preferred compositions of the preparations.  
       [0109] Table 2: Compositions of the preparations according to the invention. Amounts are given per daily dose, either in one preparation or as a combination preparation.  
       [0110] Most preferred:  
       [0111] Folinic acid 0.4-5.5 mg; Zinc 13-25 mg; Vit B12 &gt;2 ug; Magnesium &gt;50 mg; Copper &gt;1 mg; Vit. B6 &gt;1 mg; Methionine equivalents &gt;0.3 mg; Betaine equivalents &gt;0.3 mg 
     
    
    
     EXAMPLES  
     Example 1 
     [0112]                               Packaged powder (10 g) to be reconstituted with water:                                                    Folinic acid   600   μg           Zinc sulphate   60   mg           Hydroxycobalamine   10   μg           Betaine   2   g                             Carrier (based on mixture of   Remainder           maltodextrins, moisture, colourant,           flavorings and gelatine)                        
     Example 2 
     [0113]                               Packaged powder (10 g) to be reconstituted with water:                                                    (6S)-5-methyltetrahydrofolate   1   mg           Hydroxycobalamine   8   μg           zinc citrate   80   mg           Dimethylglycine   1.8   g                             Carrier   Remainder                                    
     Example 3 
     [0114]                               Pudding of 100 g containing:                                            10   g   egg lecithin       3   g   milkproteins       1.5   g   lipids (triglycerides)       15   g   carbohydrates       1   g   gelatizing agent       5   g   fruits, flavourings and colorants       1000   mg   folinic acid       100   mg   zinc citrate       2   ug   cyanocobalamine       3   ug   hydroxycobalamine                     Remainder:   water