PT94074A - METHOD OF CONDUCTING CONTRACEPTION AND PROCESS FOR THE PREPARATION OF COMPOSITIONS BASED ON A MELATONIN ANALYSIS USED IN THEM - Google Patents

Description

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This patent application is a continuation-in-part of U.S. Pat. with Serial Number 029 229 * presented on 23 March 1987, Scope of_Invent

This invention relates to a method of inhibiting ovulation in human females. More particularly, the invention relates to a method of inhibiting ovulation by administering an amount of melatonin or a melatonin analogue. Optionally, melatonin or melatonin analog is administered in combination with a progesterogenic and / or estrogenic agent.

BACKGROUND OF THE INVENTION Research and development in the field of contraception in humans has focused on the areas of physical and chemical barriers to the transport of semen, such as vaginal foams, diaphragms, intrauterine devices and condoms, and in the area of oral contraceptives containing one or more hormanas stereo-des ·. The oral contraceptives that have been developed are highly effective in preventing contraception, and today more than 50 million women worldwide use oral contraceptives.

Typically, the oral contraceptives take the form of a combination of an estrogen and a progesterogen (also known as progestin). In some of these regimens, a consistent dose of estrogen and

progesterogen throughout the administration period. In other regimens, referred to as sequential regimens, the amount of estrogen or progesterogen or both is increased or decreased during the menstrual cycle. Some sequential regimes provide double-stage or two-phase control. (See, for example, U.S. Pat. 3,969,502). Others prepare a combination of three component stages or tri-phasic. (See, for example, U.S. Patent 4,268,051; U.S. Patent 4,390,531). A third type of regimen is also known in which one or more progesterogens are administered daily throughout the menstrual cycle.

Hormones in oral contraceptives act not only within the central nervous system but also in tissues of the urogenital tract to inhibit reproductive function. The main sites of action are the hypothalamus and the pituitary to avoid the half-wave cycle of the luteinizing hormone (LH) and, consequently, to avoid ovulation. The baseline concentrations of LH and follicle stimulating hormone (FSH) and plasma levels of estradiol and progesterone are suppressed in users of oral contraceptives. In essence, these contraceptives work by causing changes in levels of hormones that mimic those caused by pregnancies. This effect depends on the dose. These conventional oral contraceptives are administered for a minimum of 21 days of a woman's cycle and in some cases during all 28-30 days of the cycle.

Oral contraceptives also have a direct effect on the urogenital tract. They alter the structure and physico-chemical composition of the endometrium and the consistency of the cervical mucosa, thereby altering the uterine capacity for implanting the egg. J t

Oral contraceptives have been shown to be beneficial in preventing pregnancy. Compared with non-users, women taking oral contraceptives have been shown to have a lower risk of pelvic inflammatory disease (PID), ectopic pregnancy , endometrial cancer, and benign breast disease. Significantly, current-type contraceptives are also responsible for reducing the incidence of ovarian cancer. Oral contraceptives may also provide relief from common menstrual disorders, including irregular menstrual bleeding, premenstrual tension, excess blood loss, and cramping. The use of oral contraceptives, however, is also accompanied by certain risks. These risks, which include a greater chance of suffering from venous thromboembolism, ischemic heart disease, cerebrovascular disease and hypertension, are believed to be largely due to the estrogen component (typically ethinyl estradiol or menstranol) in the counteroceptives. The risk of suffering from any of these conditions has been found to be confined mainly to women over the age of 35, especially women over 35 years of age and who smoke. Women who take estrogen may also experience other negative side effects, including gastrointestinal disturbances, nausea, and weight gain.

In an effort to avoid the negative side effects or possible side effects associated with the estrogen-containing oral contraceptives, oral contraceptives have been developed which contain one or more progesterogens as an active component. It has been found that these contraceptives, however, are less effective than those containing not only an estrogen but also a pregesterogen. A common side effect suffered by women who make progestin-only oral contraceptives is to stop the loss of blood during the menstrual cycle.

In view of the advantages and side effects are being an obiec-contracepoSo and avoid the currently negative of conventional oral contraceptives, sought new contraceptives. Accordingly, the present invention provides a method of which it is highly effective. adverse effects associated with the contraceptives used.

Summary of the Invention of giving

According to the present invention there is disclosed a method of effecting contraception in human females of childbearing age which comprises administering a melatonin analog in effective dosages to prevent ovulation. Optionally, melatonin or melatonin analog is administered in combination

In an embodiment with a preferred progesterogen and / or estrogen, the contraceptives of this oral dosage form. invention are administered in

Bcssa Description -

The graphs of Figures I-D show the concentration of various hormones in the woman's bloodstream for each day of her menstrual cycle, based on the average obtained over 5 cycles.

The graphs in Figures IIA-B, ΙΪΙΑ-D and IVA-B show the effects of melatonin on the concentration of each of these hormones during each of three menstrual cycles.

Detailed Description of the Invention Melatonin CN-acetyl-5-methoxytryptamine) is a hormone synthesized and secreted by the pineal gland. The exact role of the hormone has not been determined yet. Studies have shown that the introduction of melatonin into golden hamsters of Syria at certain specific times of the day has had an inhibitory effect on the development of gonads, testis weight in males and ovulation in females. Female ratasanas indected with melatonin at certain times of the day also showed an inhibition of ovulation. Accordingly, melatonin has been shown to have primarily an inhibitory effect on gonads in various species of rodents. However, a similar effect has not been found in other species of mammals indisting with melatonin. Specifically, administration of melatonin to sheep (Kenneway, DJ, et al., J. Renroductive, 73: 859 C19853) and primates (Reppert, S. M., et al., Endo.cr.in. 104: 295 [19793] did not result in a direct change in their reproductive physiology. The administration of melatonin in humans has been studied in conjunction with the hypothesis that an abnormal melatonin rhythm is associated with endogenous depression and with farrookinetic obJectti / Waldhauser, F., Neuroendocrinology. 39: 337, 313 C18843 and in connection with sleep-wake rhythms and the phenomenon of " iet-lag " (" jet lagging ") that follows airplane travel with a change of time zones.

The present invention is based on the discovery that pharmacological doses of melatonin given daily to a female selectively suppress the normal menstrual cycle of the luteinizing hormone cycle sufficient to prevent ovulation, the present invention is directed to a method of effecting the in a human female of childbearing age comprising daily administration to the female of melatonin in dosages effective to prevent ovulation by suppression of the luteinizing hormone wave occurring prior to and if required during ovulation.

Where used herein, the term melatonin also encompasses melatonin analogs which have an ovulation inhibitory effect when administered to human females. These melatonin analogs may have the general structure formula:

R, R, CH-CH-A H2

RIO was that

Eg and, are, in general, hydrogen or an alkyl group having 1 to 4 carbon atoms,

Eg is hydrogen, hydroxyl or an alkoxy group having 1 to 4 carbon atoms, and A is either -OH or NH-CQ-Rg, wherein Eg is either hydrogen or an alkyl group having 1 to 4 carbon atoms; carbon, with the proviso that Δ is NH-CO-R g, R 1 and R 2 are both methyl and E 2 is hydrogen, R 3 and E 4 are not both hydrogen.

Preferred compounds are those in which Kg is hydrogen or methoxy, those having hydrogen are most preferred. Melatonin analogs encompassed by this definition include N-acetylserotonin, N-acetyls 5-hydroxy, 6-methoxy-tryptamine, 6-hydroxymelatonin, 5-hydroxytryptophol and 5-methoxy-triptofol, with N-acetylserotonin being most preferred. Melatonin is administered daily in dosages sufficient to suppress the user's normal wave in the luteinizing hormone and thus prevent ovulation. Generally, melatonin is administered in amounts ranging from 2 mg to 1000 g per day per 70 kilograms of body weight of the woman receiving melatonin. Preferably, 3 mg to 50 g are administered daily. Melatonin can be administered every day during a woman's cycle. However, it has been found that the administration of melatonin for only a period of 1 to 7 days in the cycle immediately preceding the normal ovulation day of the woman is sufficient to achieve a contraceptive effect. Ovulation typically occurs on the fourteenth day of the cycle or alternatively between the ninth and seventeenth day of a woman's cycle. This regimen is preferred for the administration of melatonin. The type of regimen chosen may affect the amount of melatonin administered daily dosage can also daily. The amount given in each veriar with the chosen method of administration. melatonin can be administered to women either orally or parenterally, or in the form of an implant, administration is more convenient when the melatonin is in the oral dosage form. such as capsules. tablets, suspensions or solutions. Capsules or tablets are preferred.

The capsules may be prepared by mixing the compound with a pharmaceutically acceptable excipient and then filling the gelatin capsules with the mixture according to standard procedures.

Alternatively, melatonin may be mixed with one or more lubricants, such as stearic acid or magnesium stearate, aroma enhancers, disintegrating elements, including potato starch and alginic acid, binding agents such as gelatin and corn starch , and / or tablet bases which include lactose, corn starch and sucrose, and then subjected to pressure to obtain tablets.

As an alternative to oral administration, melatonin can be administered parenterally or in the form of a solid implant. For parenteral administration, melatonin is given in injectable doses of a solution or suspension of the hormone in a physiologically acceptable diluent with a pharmaceutical carrier. The carrier may contain water or an oil and, optionally, may also comprise a pharmaceutically acceptable surfactant or other adjuvant. Suitable oils include those of vegetable origin, of animal origin, those of petroleum or of synthetic origin, including peanut oil, soybean oil, corn oil, sesame oil, beaver and mineral. Preferred liquid carriers include water, saline, aqueous sugar solutions and glycols such as propylene glycol or polyethylene glycol. Melatonin may also be administered in the form of an implant which is formulated so as to provide a release sustained melatonin over time. To enhance the implant, melatonin can be compressed into small cylinders and placed into a physiologically acceptable wrapping material such as a porous or biodegradable polymer in accordance with conventional implant technology. Similarly, melatonin can be administered in the form of a vaginal depot or suppository, which can also produce a sustained release of melatonin. Melatonin can be mixed with a conventional suppository or reservoir base, i. and a physiologically acceptable material which can melt at body temperature. melatonin 0 progeste-corrientemen

In a preferred embodiment of this invention, it is administered in combination with a progesterogen. rogen is added to provide the benefits associated with the administration of progesterogens in conventional oral contraceptives. Any active progesterone-active compound is suitable for use as the progesterogen component in the present invention. Suitable progesterogens include progesterone and its derivatives.

The presently preferred progesterogens are norethindrone (ie, 19-nor-17β-ethynyl-17β-hydroxy-4-androsten-3-one) and norgestrel (13β-ethyl-17Î ± -ethynyl-17β-hydroxy- -en-3-one). Other progesterogens include chlormadinone acetate (β-chloro-17-hydroxypregna-4,6-diene-3,20-dione acetate), norethynodrel (17β-ethynyl-17S-hydroxy-estr-5 (105-ene) ), medroxyprogesterone acetate (17β-acetoxy-4-pregn-4-ene-3,20-dioxa), megestrol acetate (17β-acetoxy-6-methyl- 17-ethynyl-17β-hydroxy-estr-4-ene), quingestrone (3-cyclopentyloxy-pregna-3,5-diene-2-one), (17B-acetoxy-17β-ethynyl-estr-4-en-3Î ±) acetate, ethynodiol acetate (3B, 17S-diacetoxy-17Î ± -ethynyl-estr-4-ene), dimethylethrone [17β- 6-methyl-17- (1-propenyl) -androst-4-en-3-one] desogestrel and levonorgestrel. 11 -

The progesterone component of these contraceptives is generally administered in the range of from 0.5 to 2500æm per day, preferably in the range of from 7.5æg to 600æg per day. More preferably, the progesterogen is administered in a range of from 7æm , 5æg to 250μg per day. The actual amount of progesterogen given in each daily dosage will depend on the particular progesterogen chosen, its relative potency and the method of administration selected. For example, a minor amount of a more potent progesterogen may achieve the same results as a larger amount of a less potent progesterogen. As previously noted, the amount of progesterogen may also vary with the mode of administration at typically lower doses required for administration of an implant or intravenous injection than for oral administration. Various regimens are suitable for administering a combination of melatonin and a progesterogen. For example, assuming a 28-day cycle, not only melatonin but also the progesterogen may be administered for 21 days, followed by administration of melatonin without the progesterogen for 7 days.

One second administered for 7 days. melatonin and progesterone are 21 days and then both are rejected.

If desired, melatonin and progesterogen may alternatively be administered each day, continuously during the woman's cycle for a total of 28 days.

In a fourth melatonin and progesterogen regimen it is suggested, an administered combination of for days, typically from the day & without interruption until the 17th day of a woman's cycle, and then not only the melatonin but also the progesterogen are rejected for the remainder of their cycle.

An alternative regimen, a combination of melatonin and progesterogen is administered for 10 or onae days, during the follicular phase of a woman's cycle, in dosages of 300 micrograms progesterogen and 75 milligrams of melatonin. A second combination of melatonin and progesterogen is then administered over the next days or during the luteal phase of its cycle for a total of twenty-one days in dosages of 750 micrograms progesterogen and 75 milligrams of melatonin. In this regimen, a smaller progesterogen dosage during the first half of the woman's cycle is given because of an insufficient amount of estrogen (due to the slow follicular growth resulting from the administration of melatonin) and the administration of relatively elevated levels of a progesterogen can lead to bleeding. In the second half of the cycle, however, there has been a high level of estrogen production. Bleeding eruption may occur during this half of the cycle as a result of the peak estrogen production and subsequent withdrawal. Increasing the amount of progesterogen in each daily dose administered during this portion of the woman's cycle will prevent this cause of bleeding.

In another regimen, melatonin is administered for 5-14 days, followed by either a combination of melatonin and progesterogen or progesterogen alone for 7-14 days until a combined total of 24, preferably 21 days, is obtained. Neither melatonin nor progesterone is administered during the remaining 7 days of the cycle. 13

A seventh regimen comprises administering a placebo for the first 5 days and then administering melatonin for 3-7 days followed by administration of the progesterogen by the twenty-first day of the medication. Again, neither melatonin nor progesterone is administered during the remaining 7 days of the cycle.

In another regimen, a progesterogen is administered for 21 to 28 days. Melatonin is administered in combination with the progesterogen for 1-13 days (preferably up to 3-5 days) in the mid-cycle (e.g., 5-17 cycle days), just before the normal ovulation day of the carrier. If the progesterogen is administered for less days than the combined 28 days of the cycle, no medication is administered for the remaining days.

As previously noted, the 21-28 conventional daily doses of progestin-only contraceptives have not been very effective. The addition of melatonin overcomes the inefficacy of the administration of the progesterogen alone.

In any of the suggested regimens indicated above, the progesterogen are conveniently although they may be days in which they are not only melatonin but also administered, the two active components combined and administered together, be administered separately.

In an alternative embodiment of the present invention, a small amount of an estrogen may be added to any of the melatonin or melatonin-progesterogen regimens indicated above. Estrogen may be added, if appropriate. is desired to stabilize melatonin by preventing any ovulation which may possibly occur if melatonin is administered in the absence of an estrogen. 14 -

Any conventional estrogen may be employed as an appropriate component of the compositions of the present invention. Presently preferred estrogens are ethinyl estradiol Ci.e. 17β-ethynyl-3,17β-dihydroxy-estra-1,3,5 (10) -triene} and mestranol (17α-ethynyl-17β-hydroxy-3-methoxy- Other suitable estrogens include estradiol (3.17B-dihydroxy-estra-1,3,5 (10) -triene), estradiol (3,16a, 17β-trihydroxy-estra- 3,5 (18) -triene), estrone (3-hydroxy-estra-1,3,5 (10) -trien-17-one), diethylstilbestrol, kinestradiol (3-cyclopentyloxy-16α, 17β-di The estrogen can be administered daily for 21 days of the 28 days of the cycle in any of the aforementioned regimens, but preferably it is administered only before of the normal ovulation day. Estrogen is usually administered in the range of 2 mg to 100 mg daily, and preferably in a range of from 10 μg to 50 μg per day.

When in conjunction with the progesterogen, the actual amount of estrogen used in a daily dosage will depend on the particular estrogen chosen and its relative potency. Ethinyl estradiol, for example, has a dual biological potency of mestranol. Given the deleterious side effects of estrogen, it is desirable to use the estrogen necessary at < may be combined with the minimum amount of melatonin stabilization alone. The estrogen melatonin and / or melatonin-progesterogen in any of the regimens suggested above. an estrogen in the following (preferably ovulation, and in

In an alternate regimen, a woman is initiated onset for 5-13 days, given melatonin for 1-7 days for 3-5 days) before her normal day of 15, and a progesterogen is then administered until the twenty-first day of your medication.

In another embodiment of this invention, melatonin may be administered as a " hangover " pill either by itself or in combination with an estrogen and / or progesterogen. In such embodiment, melatonin is administered in daily doses from 100 mg to 10 000 mg, preferably a dose of at least 2000 mg. during a post-coital period of 1-5 days. If melatonin is administered in combination with a progesterogen and / or estrogen, the progesterogen is administered in a daily amount in the range of 10 mg to 2 mg, and the estrogen is administered in a daily amount ranging from 2.5 mg to 25 mg .

In one embodiment of this invention, the contraceptive compositions of this invention are administered in an oral dosage form, preferably in the form of pills or capsules. The pills or capsules may be packaged in any manner suitable for proper delivery and use. Preferably, they are packaged in the form of a pharmaceutical package or apparatus in which the daily unit dosage forms are provided or are arranged in a sequential and continuous order which will enable the woman to take the pills to take the correct formulation at the appropriate time of her reproductive cycle.

Suitable packagings or kits include conventional plastic bubble packs which contain individual bubbles for either 21 or 28 pills, depending on the regimen chosen, on a flexible plastic sheet. The bubbles are sealed by a plastic sheet that can break and release a pill when the bubble is compressed. On the first day of your medication, which is usually the first day after the end of last menstrual period, the first pill in the sequence containing the contraceptive or a placebo is removed from your individual groove and taken to the next pill in the sequence is taken the next day and so on until the dispenser is empty. A new dispenser is started on day 7 of your next cycle. Appropriate notes or instructions may be placed on the dispensing stool to guide or instruct the wearer in the correct use of oral contraceptives. The present invention is further described and illustrated by the following examples, which are given for informational purposes and should not be construed as limiting.

The contraceptive efficacy of melatonin has been studied in a patient, referred to herein by the initials SB, born 21 September 1850. Figures 1A, IB, IC and IB, respectively, show the concentrations in your blood of the hormone LH), follicle stimulating hormone (FSH), progesterone and estradiol for each day of their cycle, calculated as averages of 5 consecutive cycles. As if. shows in the figures, this patient had a normal pre-ovulatory LH onset and a peak FSH followed by an increase in post-ovulatory progesterone. In the figures, the FHC caption represents the hormone concentrate in the

Plasma.

During each of three cycles, the patient was administered 3.00 mg of melatonin in a physiological solution of glucose in saline from day 9 of its cycle for 8 consecutive days, Figures IIA, IIB, IIC and IIB show the effects of melatonin administration during the first cycle (January 1983). The figures show an anovulatory cycle following injections,

Figures IIIA-IId show the results of melatonin administration in the second cycle (May 1983) and Figures IVA-IYD show the results of melatonin administration in the third cycle (November 1984). These figures also show an anovulatory cycle following injections.

The data show three cycles in which the administration of melatonin resulted in the suppression of the patient's normal preovulatory LH wave. The data also illustrates that there was a marginal suppression of pre-ovulatory FSH and estradiol and a significant reduction in progesterone levels. LH suppression is a sufficient indication that the patient did not ovulate in any of the three months that melatonin was administered.

Example II

The concentrations of LH, FSH, progesterone and estradiol in a patient's plasma were measured daily over three of the patient's menstrual cycles. The mean concentration of each hormone was determined for each day of the cycle. The mean LH peak concentration of the patient was 295 ng / ml and the mean peak FSH level was 410 ng / ml. Their mean progesterone level at the peak of the luteal phase of their cycle was 14.5 ng / ml and the mean concentration of their estradiol peak was 0.8 ng / ml. The patient's LH peak occurred on the fifteenth day of her cycle.

The patient was given an intravenous injection of 500 mg of melatonin in a glucose salt solution on each of days 7 through 12 of its cycle. The concentrations of the four hormones in their plasma were measured during this cycle as before. The administration of melatonin has been shown to affect hormone concentrations as follows: PHC LH 110 ng / ml FSH 295 ng / ml estradiol 0.4 ng / ml progesterone 0.3 ng / ml.

These data indicate that the patient did not ovulate during this cycle; studies have shown that a peak LH concentration of at least 250 ng / ml is required for ovulation.

Example-UI A woman who had a normal 28-day menstrual cycle with 3-5 days of moderate menstrual bleeding (± 50 ml of blood loss) was given intravenous injections of 350 mg of melatonin in a saline solution was glucose for seven days consecutive days, starting on day 8 of your cycle.

On days 14-28 of his cycle he was administered orally 0.75 mg norethindrone per day. The concentrations of LH, FSH, progesterone and estradiol in your blood were measured daily throughout your cycle. Ila did not ovulate during this cycle (the LH PHC peak was 115 ng / ml). Had minimal menstrual blood loss (± 15 ml).

Example IV To a woman having a normal 30-day menstrual cycle (ovulation on the 12th day) intravenous injections of 200 mg of melatonin were given in a saline solution on glucose on each of days 7-10 of her cycle.

She did not ovulate during her cycle, although it was found that the level of LH in her blood was not uniformly suppressed but was rather erratic with levels between 50 ng / ml and 180 ng / ml during the cycle. Her FSH PHC during this cycle was normal for her, her progesterone PHC was decreased to some degree and her estradiol PHC during the cycle was normal.

In a continuous study, four women took melatonin. Dosed doses A preli evaluation in gelatin capsules, Δ melatonin was daily ranging from 30 mg to 1000 mg. showed a satisfactory uptake of melatonin from the gastrointestinal tract without negative side effects (such as diarrhea or nausea).

Example VI To a woman having a normal 30-day menstrual cycle (ovulation on the 12th day) oral doses of a combination of 200 mg of N-acetyl-serotonin (5-hydroxy-H-acetyltriphmine) and 7, 5æg norethisterone on each of 7-30 days of its cycle. The dosage was found to effectively block ovulation, as evidenced by measuring the concentration of LH and FSH in your blood on each day of your cycle. Similar results are obtained when each of 5-hydroxytryphofol, 5-methoxytryphofol, 6-hydroxymelatonin and N-acetyl, 5-hydroxy, 8-methoxytryptamine is administered with norethisterone at dosage levels and according to the cyclic schedule indicated above.

Claims (1)

Claims 1. A method of effecting the combination comprising administering, cyclically, a raeiatonine analogue, which has an ovulation inhibitory effect on human females, in a series of daily doses to a human female of childbearing age at dosage levels sufficient to prevent ovulation, the daily dosage level of melatonin analog being in the range of from about 2 mg to about 1000 mg per 70 kg body weight of the female. 2. A method according to claim 1, wherein the analog has the general structure formula wherein R4, R4 and each are hydrogen or an alkyl group having 1 to 4 carbon atoms, and hydrogen, hydroxy or an alkoxy group having 1 to 4 carbon atoms, , A is chosen from hydroxyl and NH-CH2-R1, However, if A is NH-CO-Rg, Rg is hydrogen and Rg are both methyl, R3 and are not both hydrogen. 3. A method according to claim 2, wherein R 2 is selected from hydrogen and methoxy. 4. A method according to claim 3, wherein R 1 is hydrogen. 5. A method according to claim 4, characterized in that A is -OH. 6a. 5. A method according to claim 5, wherein the analog is 5-hydroxytryptofol. The method of claim 5, wherein the analog is 5-methoxytryptofol. 8. A method according to claim 2, wherein A is -MH-CO-Rg. 9. A method according to claim 8, wherein the analog is N-acetylserotonin. The method of claim 8, wherein the analog is N-acetyl, 5-hydroxy, 6-methoxytryptamine. III. 6. A method according to claim 8, characterized in that the analogue is 6-hydroxymelatonin. 12. The method of claim 1 wherein the daily dosage level of the analogue is between of from about 30 mg to about 500 mg per 70 kg of body weight. 13. The method of claim 1 or 2 characterized in that a progesterogen is administered in combination with the melatonin analog. 14. The method of claim 13 wherein the melatonin analogue dosage level is from about 2 mg to about 1000 mg per 70 kg of body weight and the dosage level of the progesterogen is between about 7.5 Âμg to about 2500 Âμg per 70 kg of body weight on each day of administration. 15. A method according to claim 14 characterized in that the progesterogen dosage level is from about 7.5æg to about 800æg per 70kg of body weight on each day of administration. 18. A method according to claim 15 wherein the progesterogen is selected from the group consisting of norethindrone, norgestrel, chlordane-nona-acetate, norethynodrel, medroxyprogesterone acetate, megestrol acetate, lynestrenol, quingestrone, norethindrone acetate, ethynodiol acetate, levonorgestrel, desogestrel and dimethysteone. 17. A method according to claim 2 wherein an estrogen is administered in combination with the melatonin analog. A method according to claim 17 characterized in that the melatonin analogue dosage level is from about 2 mg to about 1000 mg per 70 kg body weight of the female and the estrogen dosage level is from about 2æg to about 100æg per 70 kg body weight on each day of administration. 19. The method of claim 18 characterized in that the melatonin analogue dosage level is from about 30 mg to about 500 mg per 70 kg of body weight and the estrogen dosage level is from about 10 μg to about 50 μg per 70 kg of body weight on each day of administration. 20ã. 6. A method according to claim 18 wherein a progesterogen is administered in combination with the melatonin analog and the estrogen. 2. A method according to claim 20 characterized in that the melatonin analogue dosage level is from about 2 mg to about 1000 mg per 70 kg body weight, the progesterogen dosage level is ranging from about 7.5 Mg to about 2500 Mg per 70 kg body weight and the estrogen dosage level is from about 2 Mg to about 100 Mg per 78 kg body weight on each day of administration . 22. The method of claim 17 or 28 wherein the estrogen is selected from the group consisting of ethinyl estradiol, mestranol, estradiol, estrone, estriol, diethylstilbestrol, kinestradiol and estrone sulfate. 23. The method of claim 1 wherein the method of administration is oral. 25. A method according to claim 1, characterized in that the method of administration is by intravenous injection into a physiologically suitable carrier. 25. The method of claim 1 wherein the method of administration is by implant. 26ã. A process for the preparation of a composition for effecting contraception in a human being of childbearing age characterized by comprising the contraceptively effective combination of a melatonin analog having inhibitory effects on ovulation in human and progesterogen females, the amounts of melatonin analog from 2mg to 1000mg per kg body weight and the progesterogen from 7.5pg to 2500μg per body weight. 27. A process for the preparation of a composition for effecting contraception in a human female of childbearing age characterized by comprising the contraceptively effective combination of a melatonin analog having inhibitory effects on ovulation in human and estrogen twins, quantids 28 to achieve pregnancy * by body weight. 2mg to 1000mg per kg of 100μg per body person. weight of the melatonin analogue of body and estrogen of 2. a. A process for the preparation of a composition for contraception in a human female of age characterized as comprising the contraceptive combination of a melatonin analog having inhibitory effects of ovulation in human females, a progesterogen and an estrogen, the amounts of the melatonin analog being from 2mg to 1000mg per kg body weight and the estrogen of 2mg to 10æg per person and the progesterogen from 7.5æg to 2500 μ. A process according to claim 26 or 28 characterized by: the progesterogen is selected from the group consisting of norethindrone, riorgestrel, chlormadinone acetate, norethynodrel, medroxyprogesterone acetate, megestrol acetate, lynestrenol, quingestrone, norethindrone acetate, ethynediol acetate, levonorgestrel, desogestrel and dimethisterone. 30. The process of claim 27 or 28, wherein the estrogen is selected from the group consisting of ethinyl estradiol, mestranol, estradiol, estrone, estriol, diethylstilbestrol, kinestradiol and estrone sulfate. 31. The process of claim 25, 26, 27, 28 or 29, wherein the analog has the general structure formula; R 2, wherein R 3 and R 4 individually are hydrogen or an alkyl group having 1 to 4 carbon atoms, H 2 is hydrogen, hydroxy or an alkoxy group having 1 to 4 carbon atoms; And A is selected from hydroxy and NH-CG-R 5, with the proviso, however, that if Δ is NH-CO-R 2, R 2 is hydrogen and R 2 and R 2 are both methyl, R 2 and R 3 are not both hydrogen. 32. The process of claim 31, wherein the melatonin analog is N-acetylserotonin. 33. A process for the preparation of the analogue according to claim 1, claim 32, 5-hydroxytryptophan. 34. A process characterized in that the analog according to melatonin is claim 32,5-methositript = ofol. 35. The process of claim 32, wherein the melatonin analog is 6-hydroxymelate-nma. 38. A process according to claim 31, characterized in that the analog of raelatonin is N-acetyl, 5-hydroxy-6-methoxytryptamine. Lisbon, May 17, 1880 Agent Oilcid & Industrial Prepifeasia RUA VICTOn CCHDGii 10-A, 1/1200 LfêSOá