DD300071A5 - Composition for contraception in women - Google Patents

Abstract

The invention relates to a novel ovulation-inhibiting composition containing a preparation analogous to melatonin in combination with a progestogen and / or an estrogen. The preparation analogous to melatonin has the general formula with R1, R3 and R4H or alkyl which is optionally substituted by OH or alkoxy; andA OH or NHCR5 {Presence prevention; Contraception; inhibition of ovulation; Composition, pharmaceutical; progestin; estrogen; melatonin; Melatonin analogues; 5-hydroxytryptophol; 5-methoxytryptophol; N-acetylserotonin; 6-hydroxymelatonin; Kombinationspraeparat}

Description

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The invention relates to a composition for contraception in women based on an ovulation-inhibiting Preparations or a preparation combination. Research and development work on contraception in humans has so far been aimed at the penetration

of sperm by mechanical and chemical means, e.g. As vaginal foam, spiral, intrauterine pessary and condom, or to develop oral contraceptive containing one or more steroid hormones. High potency drugs have been developed in oral anticonceptives, and currently more than 50 million women use oral contraceptives across the board. Usually, oral contraceptives are a combination of estrogen and progestin (also known as progestin). In some forms of administration, usually as

Combined treatment is consistent throughout the period of administration daily Given dose of a cystrogen and a gestagen. In other forms, which are referred to as a follow-up treatment is

the administration of estrogen or progestogen or both in the course of the menstrual cycle increased or decreased. In some subsequent treatment variants there is a two-cap or two-phase control (see also, for example,

U.S. Patent 3,969,502). In others, there is a three-fold or three-phase combination of the components (see

for example, US Pat. Nos. 4,628,051 and 4,390,531). Also known is a third form in which one or more gestagens are administered during the menstrual cycle daily.

In the case of oral contraceptives, the hormones act both in the central nervous system and in the nervous system Tissues of the genitourinary system to inhibit reproductive function, they act mainly in the hypothalamus and in the Pituitary gland, around the middle of the menstrual cycle occurring release of luteinizing hormone (LH) and thus

to prevent the follicle jump. The basic concentration of LH and follicle stimulating hormone (FSH) as well as the

Plasma levels of estradiol and progesterone are suppressed among users of oral contraceptives. in the In principle, these contraceptives work to bring about changes in hormone levels

same with a pregnancy. This effect is dose-dependent. These conventional oral contraceptives will last for at least 21 days of a woman's menstrual cycle, in some cases even over the entire 28 to 30 days of the woman

Cycle, administered. Oral anticonceptives also have a direct impact on the genitourinary system. They change the structure and

Physicochemical composition of the endometrium and the consistency of the cervical mucus and thus change the

Capacity of the uterus for the egg. It has been proven that oral anticonceptives have other benefits besides preventing pregnancy. in the Compared to non-users, women who take oral contraceptives tend to be less inflammatory Pelvic diseases (PID), abdominal cavity pregnancies, endometrial carcinoma and benign breast disease. At the

Most striking, however, is that the common combined anticonceptive drugs also decrease the frequency of

Cause ovarian cancer. Oral contraceptives can also relieve the usual menstrual disorders

including menstrual abnormalities, premenstrual syndrome, excessive blood loss and convulsions.

However, the intake of conventional oral contraceptives is also accompanied by certain risks. It is believed

That risks, including an increased possibility of occurrence of venous thrombosis, ischemic

Heart disease, cerebrovascular diseases and hypertension belong, by and large, to the Estrogen component (especially ethinylestradiol or menstranol) in the pregnancy-preventing center

are. The risk of such symptoms has mainly been found in women over 30 years of age, especially smokers. Women taking estrogen may also experience other negative side effects such as Mogen-Üarm-

Be exposed to disturbances, immunity and weight gain. The negative concomitant symptoms or the use of estrogen-containing oral contraceptives

Associated with possible associated side effects, oral contraceptives have been developed that only one or more

Progestogens are included as active ingredient. However, these contraceptives have generally been less effective

proved to be those agents containing both estrogen and progestin. A common by-product in women taking contraceptives containing progestins is breakthrough bleeding during pregnancy

Menstrual cycle. Given the Nacnteile and negative side effects of conventional oral contraceptives is looking for new Contraceptives sought. Accordingly, it is the concern of the present invention, a

to develop a contraceptive method that is extremely effective, offers benefits and the negative effects of the present

avoids contraceptives in use.

According to the invention, a method is described which leads to contraception in women of childbearing age. there

a preparation analogous to Melatoni.i is administered in doses which cause a prevention of follicle jumping.

Optionally, the melatonin or the analogous preparation is administered together with a gestagen and / or an estrogen. The contraceptive agents according to this invention are preferably administered orally. The graphs in Figures IA-D show the concentration of various hormones in the blood of a woman

every day of her menstrual cycle, represented by the average of 5 cycles. The graphic representations

Pictures I! A-D. Ill A-u and, VA-D show the effects of the administration of Meiatomn on the concentration of each of these hormones during each vr .1 three menses.

Melatonin (N-acetyl-5-methoxyptryptamine) is a hormone synthesized and secreted by the ciliary gland.The exact function of dps hormone has not yet been definitively determined.Examinations have shown that melatonin injections in Syrian golden hamsters at certain times of the day have an inhibiting effect on the Development of the gonads, which had the weight of the testicles in the male and on the follicle jump in the female animals.Feminine rats sprayed with melatonin at certain times of the day also showed an inhibition of follicle jumping.Therefore, it has been shown that melatonin has a primary inhibitory effect However, a similar effect has not been seen in other melatonin-injected mammalian species, particularly the administration of melatonin to sheep (Kenneway, DJ, et al., J. Reproductive Fertility 73: 859 (1985)) and primates (Reppert, SM, et al., Endocr. 104: 295 [1979]) e direct change in their reproductive physiology.

Exogenous melatonin administration in humans has been associated with the hypothesis that an abnormal melatonin rhythm is associated with endogenous depression for pharmacokinetic purposes (Waldhauser, F., Neuroendocrnnology 39: 307,313 [1984]) as well as in association with the sleep-wake rhythm and investigated the occurrence of difficulties in the time change after flights through different time zones.

The present invention is based on the discovery that pharmacological dosages of melatonin daily administered to a woman selectively suppress the normal secretion of luteinizing hormone in the middle of the menstrual cycle so as to prevent the follicle jump. The present invention is directed to a method of effecting contraception in women of childbearing age through the daily administration of melatonin in dosages that prevent follicle jumping by suppressing and necessitating the release of the luteinizing hormone that occurs prior to the follicle jump is.

As used in this document, the term melatonin also includes analogs that exert an antiviral effect in women. Such analog preparations may have the following general formula:

which is characterized in that R ₁ , R ₃ and ι < _{4 are} each hydrogen or an alkyl group having 1 to about 4 carbon atoms, R _{2 is selected} from hydrogen, hydroxy or an alkoxy group having 1 to about 4 carbon atoms, and A is either - OH or 'NH-CR ₆ , where Ro is either hydrogen or an alkyl group having from 1 to about 4 carbon atoms

provided that when A is NH-CR ₆ , R ₁ and R _{3 are} both methyl and R _{2 is} hydrogen, both R ₃ and R ₄

are not hydrogen. Preferred compounds are those in which R _{2 is} hydrogen or methoxy, with hydrogen being preferred. Among the preparations included in this definition which are analogous to melatonin include N-acetylserotonin, N-acetyl, 5-hydroxy, 6-methoxytryptamine, 6-hydroxy-melatonin, 5-hydroxytryptophol and 5-methoxytryptophol, with N-acetylserotonin being preferred becomes.

The melatonin is administered daily in dosages sufficient to suppress the normal release of the luteinizing hormone in the user and thus to prevent the follicle jump. In general, the melatonin is administered in dosages ranging from 2 mg to about 1000 mg daily per 70 kg body weight of the woman receiving it. Preferably, about 30mg to about 500mg of melatonin are given daily.

The melatonin can be given every day during a woman's cycle. However, it has been found that the intake of melatonin over a period of only one to about 7 days in the cycle immediately preceding the usual woman's follicle jumping day is sufficient to achieve the contraceptive effect. Usually, on the 14th day of the cycle, or between about the 9th and 17th day of the cycle, a woman ovulates. This time administration mode is preferably used for melatonin administration. Which mode is chosen may have a repercussion on the daily dose of melatonin. The amount present in each daily dosage may also be varied according to the chosen method of administration.

The melatonin can be administered to women orally, parenterally or in the form of an implant. The most practical form of melatonin administration is oral administration, for example in the form of capsules, tablets, suspensions or solutions. Capsules and tablets are given preference. Capsules can be prepared by mixing the compound with a pharmaceutically acceptable carrier and filling gelatin capsules with this mixture according to conventional procedures. However, the melatonin may also be mixed with one or more lubricants such as stearic acid or magnesium stearate, aroma enhancing agents, dissolving ingredients including potato starch and alginic acid, binders such as gelatin and corn starch and / or basic tablet ingredients including lactose, corn starch and sucrose and then compressed into tablets become.

As an alternative to oral GaI ^% , melatonin can be administered parenterally or in the form of a solid implant. For parenteral administration, melatonin is provided in injectable dosages of a solution or suspension of the hormone in a physiologically acceptable diluent with a pharmaceutical carrier. The vehicle may contain water or an oil and optionally also a surfactant or other pharmaceutically acceptable additive. Suitable oils include those produced on an animal, vegetable, petroleum or synthetic basis oils such as peanut, soybean, corn, sesame, castor and mineral oil. The preferred liquid carrier substances include water, salt solutions, aqueous sugar solutions and glycols such as propylene glycol or polyethylene glycol. The melatonin can also be administered in the form of an implant. Diesss must be such that it continuously releases the melatonin over a certain period of time. The implant is made so that it is small

Cylinder can be compressed and introduced into a physiologically acceptable wrapping material such as a biodegradable or porous polymer in accordance with the usual implantation technique. Similarly, the melatonin may also be administered in the form of a vajina suppository or depot preparation which provides for the continuous release of melatonin. Melatonin can be mixed with a conventional suppository base, that is, with a physiologically acceptable material that melts at body temperature. In the present invention, melatonin is preferably administered in conjunction with a progestogen. The progestin is added to induce a cyclic bleeding similar to cyclical menstrual bleeding and to assure the beneficial effects associated with the administration of progestins in conventional oral contraceptives. Each yellow body hormone-active compound is suitable for use as a gestagen component in the present invention. The suitable progestagens include progesterone and its derivatives. The currently preferred progestogen is norethindrone (ie, 19-nor-17a-ethynyl-17β-hydroxy-4-androstene-3-ci) and norgestrel (13β-ethyl-17a-ethynyl-17β-hydroxygon-4-en-3-one ). Other progestins are chlormadinonoacetate C-chloro-n-hydroxy-pregna-α-diene-S, 20-dione acetate), norethyno-cel {17a-ethynyl-17-hydroxy-estr-5 (10) -en), medroxyprogesterone acetate (17a-citrate). Acetoxy-6a-methyl-pregn-4-ene-3,20-dione), megestrol acetate (17a-acetoxy-6-methyl-pregna-4, e-diene-3,20-dione), lynestrenol (17a-ethynyl) 17β-hydroxyestr- <J pn), quinone β-cyclopentyloxy-pregna-SiB-diene ^ O-one), norethindrone acetate (17β-acetoxy-17a-ethynyl-estr-4-en-3-one),>. ^: uiynediol acetate (3β, 17β-diazetoxy-17a-ethynyl-estr-4-ene), dimethisterone [17β-hydroxy-6α-methyl-17 (-1-propynyl-ar .. '. iost-4-en-3 on], desogestrel and levonorgestrel.

The diarrheal component of these contraceptives is generally administered in the range of 7.5 mg to about 2 OOOMg per day, but more preferably in the range of about 7.5 to about 600 mg daily. In most cases, the progestin is given in the range of about 7.5 μ to about 250 mg daily. The actual amount of progestogen contained in each daily dosage will depend on the specific progestogen chosen, its relative efficiency and the chosen method of administration. For example, a smaller amount of a more effective gestagen can give the same results as a larger amount of a less effective gestagen. As noted above, the amount of progestogen may vary depending on the mode of administration, with lower dosages usually being required for an implant or intravenous injection than for oral administration.

Various forms are suitable for administering a combination of melatonin and progestogen. For example, in a 28-day cycle, both melatonin and progestin can be administered for about 21 days, and thereafter, melatonin is given without progestogen for about 7 days. In a second form, melatonin and progestin are given for about 21 days, and then both are discontinued for about 7 days. If desired, melatonin and progestin may also be given daily throughout the menstrual cycle for a total of 28 days i. In a fourth proposed mode of administration, melatonin and progestin are administered in combination for about 13 days, usually from about day 5 to day 17 of a cycle, and thereafter, both melatonin and progestin are discontinued during the remaining days of the cycle.

However, melatonin and progestogen may also be co-administered during the follicular phase of a menstrual cycle in dosages of about 300 micrograms of progestogen and about 75 mg of melatonin over a period of about 10 or 11 days. Subsequently, a second combined melatonin and progestogen is administered during the following ten to eleven days - during the luteal phase of the cycle - for a total of about 21 days in dosages of about 750 micrograms of progestogen and about 75 mg of melatonin. In this mode, less progestagen dosage is given during the first half of the cycle because endogenous (low growth due to melatonin input) has produced an insufficient amount of estrogen and administering relatively high levels of progestogen may result in breakthrough bleeding. In the second half of the cycle, however, there is considerable estrogen production. Breakthrough bleeding can occur during this half of the cycle as estrogen production reaches its peak value and then decreases. An increase in progestin daily dosing during this portion of the cycle prevents this cause of breakthrough bleeding.

In another mode, the melatonin is administered for about 5 to 14 days; thereafter, either melatonin and progestin are combined or progestogen alone is given for about 7 to 14 days, so that the total is administered for a total of about 24 days, but preferably about 21 days. During the remaining 7 days of the cycle, neither melatonin nor gestayon is given. A seventh option is to take a placebo in the first 5 days, then melatonin for about 3 to 7 days, and then continue progestogen until the 21st day. Also in this case, no melatonin or gestagen will be given during the remaining 7 days of the cycle.

In another variant, progestin is given for about 21 to about 28 days. Melatonin is combined with progestin for about 1 to 13 days (preferably about 3 to 5 days) at midcycle (eg, during days 5-17 of the cycle), just prior to the day on which the user usually undergoes the follicle jump , If the progestin is given less than the full 28 days of the cycle, nothing is administered in the remaining days. As stated above, the 21 to 28 day daily dose of pure congestion-based contraceptives has not been very effective. The addition of melatonin compensates for the low effect of the administration of progestin alone.

In each of the above-mentioned modes of administration, on the days when both the administration of melatonin and gestagen occurs, the two active components are conveniently combined and administered together, although they may also be given separately.

In another variant of the invention, a small amount of estrogen may be added to each of the melatonin or melatonin gestagen administration forms set forth above. If desired, to prevent any unwanted follicle jumping that may occur when the melatonin is administered in the absence of an estrogen, the estrogen may be added to stabilize the melatonin. Any conventional estrogen can be used as a suitable component of the contraceptive compositions of the invention. The currently preferred estrogens are ethinyl estradiol, i. (17a-Ethynyl-3,17β-dihydroxy-estra-1,3,5 (10) -triene) and Mestranol (Ua-ethynyl-Nβ-hydroxy-S-methoxy-estra-l.s, dO) -triene). Other suitable estrogens are estradiol (3,17β-dihydroxy-estra-1,3,5 (10) -triene; i), estradici (3,16a, 17β-trihydroxyestra-1,3,5 (10) -triene) , Estrone (3, hydroxy-estra-1,3,5 (10) -trien-17-one), diethylstilbestrol, quinestradiol (3-cyclopentyloxy-16a, 17β-dihydroxy-estra-1,3,5 (10) - trien) and estrone sulfate. The estrogen may be administered daily for 21 days of the 28-day cycle in each of the administration modes described above, but the administration is preferred

the usual day of the Follikalsprungs. Generally the estrogen is in the range of about 2 vg 1 to about 00 micrograms per day is preferably administered between about 10 pg and about 50μς per day. As with progestogen, the actual amount of estrogen used in a daily dose will depend on the particular estrogen chosen for its relative potency. Ethinylestradiol, for example, has twice the biological potency as mestranol. In view of the unhealthy side effects of the estrogen, it is desirable to use only the minimum amount of estrogen needed to stabilize the melatonin. The estrogen may be combined with melatonin and / or progestogen in any of the above-suggested modes of administration. Another possibility is to give estrogen at the beginning of the menstrual cycle for about 5 to 13 days, and then for about 1 to 7 days (but preferably about 3 to 5 days) before the usual day of follicle jumping melatonin, followed by until 21.Day of drug administration a Gestager, administered.

A further mode of administration according to the invention is that melatonin can be administered as a "pill afterwards" - either alone or in combination with an estrogen or progestogen in this form, the melatonin is administered in daily doses of 100 mg to 100 mg 10000 mg, preferably as a dose of at least 2000 mg, given over a period of 1 to 5 days after sexual intercourse If the melatonin is given with a gestagen and / or an estrogen, the daily dosages for the administration of progestogens are usually between about 10 mg and 20mg and daily estrogen dosing in the range between about 2.5 and 25mg.

In the embodiment according to the invention, the anticonceptives are preferably administered orally, if possible in the form of pills or capsules. The pills or capsules may be packaged in any manner that ensures proper distribution and use. Preferably, this should be in the form of a pharmaceutical package in which the daily dosage units are arranged in a predetermined order so that the user has the right recipe at the appropriate time of the reproductive cycle. Suitable packages are the commercially available Blistei packs of synthetic material in which - depending on the selected mode of taking - 21 or 28 pills individually in wells (blisters) arranged in flexible plastic sheets sine. ¹ These blisters are closed by an overlying film of synthetic material, which can be pressed by pressure on one of the blisters and then releases a pill.

On the first day of taking, d. H. Generally, on the first day after the last menstrual period subsides, the first pill, whether it is an anticonceptive or a placebo, is taken and ingested. The next pills are then taken in the order given next and taken on the following days until the pack is empty. On the 7th day of the next cycle, a new pack will be started. Appropriate notes or instructions for use may be placed on the packaging so that the user is aware of the correct use of oral contraceptives.

The present invention will be further described and illustrated by the following examples, which are given for informational purposes and are not intended to be limiting.

Example I

The contraceptive effect of melatonin was studied using the example of a patient born on September 21, 1950, followed by the initials S.B. referred to as. Figures IA, IB, IC and ID show the concentration of luteinizing hormone (LH), follicle stimulating hormone (FSH) and progestin and estradiol in their blood on each day of the cycle, rounded to the average of 5 consecutive cycles , As shown in the figures, this patient had a normal LH release before ovulation and a normal peak of FSH with progestogen rise after ovulation. In the pictures, PHC means plasma hormone concentration. For each of the three cycles, the patient was intravenously administered 300 mg of melatonin in a physiological glucose saline from the 9th day of the cycle on six consecutive days. Figures Il A, Il B, MC and Il D show the effects of melatonin administration during the first cycle (January 1983). The pictures show an anovulatory cycle after the injections. Figures III A-IIID show the results of melatonin administration in the second cycle (May 1983) and Figures IVA-IVD show the results of melatonin administration in the third cycle (November 1984). These images also show an anovulatory cycle after melatonin injection.

The data shows three cycles in which the melatonin administration led to the suppression of the patient's normal release of LH before ovulation.

The figures also show that there was a marginal suppression of FSH and preovulatory estradiol and a significant reduction in progesterone levels. LH suppression is sufficient evidence that the patient did not experience a follicular leap in any of the three months in which melatonin was administered.

Example Il

The LH, FSH, progesterone and estradiol concentrations in a patient's plasma were measured daily over three menstrual cycles of the patient. The average concentration of each hormone was determined for each day of the cycle. The average concentration of the patient's LH peak was 295ng / ml, and the mean value of her FSH peak was 410ng / ml. Her average progesterone level at d6m peak of the luteal phase of her cycle was 14.5 ng / ml and the average concentration of her estradiol peak was 0.6 ng / ml. The patient's LH peak was observed on the 15th day of her cycle.

The patient was given 500mg of melatonin daily in a glucose saline intravenously during the 7th to 12th day of her cycle. The concentration of the four hormones in their plasma was measured as before during this cycle.

It was found that the melatonin dose had the following effects on the hormone concentration:

PHC peak LH110ng / ml FSH295ng / ml estradiol 0.4 ng / ml progesterone 0.3 ng / ml

The numbers show that the patient did not get ovulatory during this cycle; Investigations have shown that a peak value of LH concentration of at least 250ng / ml is required for a follicle jump.

Example III

For a woman with a 28-day menstrual cycle of 3-5 days of moderate menstrual bleeding (± 50 ml blood loss), 350 mg of melatonin in a glucose saline solution was injected intravenously on seven consecutive days from the 8th day of her cycle. From the 14th to the 28th day of her cycle, she was given 0.75 mg norethindrone as an oral dose daily. During her cycle, her daily blood glucose, FSH, progesterone and estradiol levels were measured. There was no ovulation during this cycle (the PHC peak of the LH was 115 ng / ml). The menstrual blood loss was minimal (± 15ml).

Example IV

A woman with a normal menstrual cycle of 30 days (follicle jump on the 12th day) was injected with 200 mg of melatonin daily in a glucose saline intravenously during the 7th to 10th day of her cycle. It did not ovulate during this cycle, although it was found that the LH-spiegeli was not uniformly suppressed in its blood, but was fluctuating at levels between 50 ng / ml and 180 ng / ml during the cycle , Your FSH PHC during this cycle was normal for her, her progesterone PHC was somewhat reduced, \ r \ d her estradiol PHC was normal throughout the cycle.

Example V

In an ongoing investigation, four women are taking melatonin in Torrn from gelatin capsules. The melatonin is administered in daily dosages between 30mg to 1000mg. From a preliminary evaluation, it can be seen that the melatonin from the gastrointestinal tract without adverse side effects (such as diarrhea or nausea) is satisfactorily absorbed.

Example Vl

A woman with a normal menstrual cycle of 30 days (follicle jump 6m 12th day) will receive a daily oral dose of a combination of 200mg N-acetylserotonine (5-hydroxy-N-acetyltryptamine) and 7.5% norethisterone from 7 to 30. Administered on the day of her cycle. It was found that this dosage effectively blocked ovulation, as well as the measurement of the LH and FSH concentration in their blood on each day ihros cycle.

Similar results are obtained when each 5-hydroxytryptophol, 5-methoxytryptophol, 6-hydroxymelatonin and N-acetyl, 5-hydroxy, 6-methoxytryptamine with norethisterone in cycle-appropriate dosages -above-administered.

Claims (22)

1. A composition for contraception b> i women, characterized in that it contains a preparation analogous to the melaionin in Kombii ut'jn with a progestogen and / or an estrogen. Composition according to Claim 1, characterized in that the preparation analogous to melatonin has the general formula: CH-CH-A wherein P ₁ R ₃ and R ₄ independently represent hydrogen or an alkyl group having 1 to about 4 carbon atoms, wherein R _{2 is} hydrogen, hydroxy or an alkoxy group having 1 to about 4 carbon atoms, and A is selected from hydroxy and NH-CR ₆ is, under O the proviso, when A is NH-CR ₅ , R _{2 is} hydrogen and R and R _{5 are} both methyl, both R ₃ and O
also R4 is not hydrogen. 3. Composition according to claim 2, characterized in that R _{2 is} hydrogen or methoxy. 4. The composition according to claim 3, characterized in that R _{2 is} hydrogen. 5. A composition according to claim 4, characterized in that A is -OH. Composition according to Claim 2, characterized in that the preparation analogous to melatonin is 5-hydroxytryptophol. 7. The composition according to claim 2, characterized in that the melatonin analogous preparation is 5-methoxytryptophol. Composition according to Claim 2, characterized in that A is -NH-CR ₅ . 9. A composition according to claim 8, characterized in that the melatonin analog preparation is N-acetylserotonin. Composition according to Claim 8, characterized in that the preparation analogous to melatonin is N-acetyl, 5-hydroxy, 6-methoxytryptamine. 11. The composition according to claim 8, characterized in that the melatonin analogous preparation is 6-hydroxymelatonin. The composition of claim 1 wherein the progestogen is selected from the group consisting of norethindrone, norgestrel, chlormadinone acetate, norethynodrel, medroxyprogesterone acetate, megestrol acetate, lynestrenol, quingestrone, norethindrone acetate, ethynodiol acetate, levenorgestrel, desogestral and dimethisterori. 13. The composition according to any one of claims 1 to 12, characterized in that about 2 to about 1000 mg per 70 kg body weight of the melatonin annogenous preparation are included. 14. The composition according to any one of claims 1 to 13, characterized in that the progestin is contained in an amount between about 7.5Mg and 2500pg per 7Ckg body weight. 15. A composition according to claim 1, characterized in that the estrogen is selected from the group consisting of ethinylestradiol, mestranol, estradiol, estrone, estriol, diethylstrilbestrol, quinestradiol and estrone sulfate. 16. The composition according to any one of claims 1 to 15, characterized in that the estrogen is contained in an amount of between about 2 pg and about 100 pg per 70 kg of body weight. 17. The composition according to any one of claims 1 to 16, characterized in that the dfim melatonin analogous preparation in an amount of about 30 to about 500mg is included. . 18. A composition according to any one of claims 1 to 17, characterized in that the gestagen is contained in an amount between about 7.5pg and 600 μg. 19. A composition according to claim 17, characterized in that the estrogen is contained in an amount of between about 10 and about 50pg. 20. Use of the composition according to one of claims 1 to 19, characterized in that it is used for contraception in women. 2 1. Use according to claim 20, characterized in that it is used for administration in oral form. 22. Use according to claim 20, characterized in that it is used for administration as an intravenous injection in a physiologically suitable carrier substance. 23. Use according to claim 20, characterized in that it is used for administration by implant.