WO2003041719A1

WO2003041719A1 - Method of contraception in mammalian females and pharmaceutical kit for use in such method

Info

Publication number: WO2003041719A1
Application number: PCT/NL2002/000740
Authority: WO
Inventors: Herman Jan Tijmen Coelingh-Bennink; Agatha Antonia Magdalena Van Beek
Original assignee: Pantarhei Bioscience B.V.
Priority date: 2001-11-15
Filing date: 2002-11-15
Publication date: 2003-05-22

Abstract

The present invention is concerned with a new method of contraception in mammalian females, said method comprising the administration to the female of dosage units containing at least two different steroids, including an androgen, in a therapeutically effective amount to inhibit ovulation, wherein the androgen is administered continuously during a period of at least 28 days, preferably of at least 60 days. Another aspect of the invention relates to a pharmaceutical kit for use in the contraceptive method described above, which kit comprises 10-28 oral dosage units containing estrogen, progestogen and androgen, and 3-18 dosage units containing estrogen, androgen and essentially no progestogen. Yet another aspect relates to a kit comprising at least 28 dosage units containing estrogen, progestogen and androgen.

Description

METHOD OF CONTRACEPTION IN MAMMALIAN FEMALES AND PHARMACEUTICAL KIT FOR USE IN SUCH METHOD

TECHNICAL FIELD OF THE INVENTION

The present invention is concerned with a new method of contraception in mammalian females. More particularly the present invention relates to a contraceptive method comprising the administration to a female of one or more dosage units containing a combination of steroids including at least an androgen, in a therapeutically effective amount to inhibit ovulation. Generally the inhibition of ovulation is achieved by suppressing the pituitary release of follicle stimulating hormone (FSH), which gonadotrophin stimulates the ovarian follicular development that precedes ovulation and/or by the prevention of the occurrence of a luteinising hormone (LH) surge that induces actual ovulation. The invention also relates to a pharmaceutical kit containing a plurality of oral dosage units for use in the aforementioned contraceptive method.

BACKGROUND OF THE INVENTION

Currently on the market there are a number of hormonal contraceptives for females which can be classified into two general types. The first are known as monophasic preparations. These contain a constant amount of an estrogen and a progestogen. Newer preparations known as bi- or triphasic preparations have varying levels of estrogen and progestogen; in most cases consisting of relatively constant levels of estrogen with a step- wise increase in progestogen throughout the cycle. This pattern of estrogen and progestogen administration results in a relatively dominant estrogenic formulation at the beginning of the package with increasing progestogenic activity toward the end of the package. Mono-, bi- and triphasic contraceptives are commonly referred to as combined contraceptives. Virtually all combined contraceptives have in common that they are based on a regimen which involves an administration-free interval of about 7 days whereby withdrawal bleeding, simulating the natural menses, occurs. Thus 21 day intervals of hormone administration alternate with 7 days during which no hormones are administered. As an alternative to the aforementioned combined contraceptive methods, the so called sequential method has been proposed. Typical of the sequential contraceptive method is that it comprises two consecutive phases, i.e. one phase during which estrogen and no progestogen is administered and another phase during which a combination of estrogen and progestogen is aolministered. The first sequential methods, like the aforementioned combined contraceptives, made use of an administration free interval of about 7 days. More recently, sequential methods have been proposed which do not include such an administration-free (or placebo) period, meaning that estrogen is administered throughout the full cycle and that progestogen is co-administered during only part of that cycle. WO 95/17895 (Ehrlich et al.) describes such an uninterrupted sequential method. These uninterrupted sequential contraceptive methods, which employ continuous estrogen administration, exhibit an optimum combination of contraceptive reliability and cycle control. The combination of a pause of 6-7 days during which significant follicular development occurs and the well documented bad compliance of many pill-users (30%-40% forget pills occasionally) cause an increased risk of escape ovulation especially if the pause is (unintentionally) extended. This results in "real life" pregnancy rates of 3-8% per year. By removing the pause and administering ovulation inhibiting steroids daily, the risk of escape ovulation is much lower.

Despite the aforementioned advantages, the (sequential) methods without pauses have found little application so far. This is mainly due to the fact that traditionally hormonal contraceptive methods have been designed to include regular administration free intervals, so as to have periods without exogenous steroids. Furthermore, it was generally believed that pauses were required to allow withdrawal bleeding. In addition, in sequential regimens there are concerns about the so called unopposed administration of estrogen, i.e. administration of estrogen without co-administered progestogen. Scientific data obtained in connection with hormone replacement therapies in menopausal and post-menopausal females show that long term unopposed estrogen administration may cause hyperplasia of the endometrium.

All the aforementioned contraceptive methods suffer from the drawback that a significant fraction of the users experience recurring mood disturbances during at least some part of the cycle. It is believed that these mood disturbances are associated with hypo- androgenicity, which results from the (cyclic) suppression of ovarian androgen (e.g. testosterone) production due to the hormonal contraceptive.

US 5,770,226 (Hughes et al.) describes oral contraceptives which comprise dosage units that contain a combination of estrogen, androgen and progestogen. The additional inclusion of an androgen is said to mitigate a decrease in bone accrual in younger users of oral contraceptives. The contraceptives disclosed make use of a 7 day placebo interval, followed . by 21 days, during which a combination of estrogen, androgen and progestogen is administered.

An important drawback of the contraceptive method described in US 5,770,226 is that fluctuations in blood serum androgen levels occur as a result of the recurring placebo interval. The lowering of the blood serum androgen levels during the placebo interval will have negative effects on mood, energy and well-being. Also low serum androgen levels have been shown to affect blood clotting properties in a negative way (i.e. increased clotting tendency). US 6,117,446 (Place) describes buccal dosage units that may be used in female hormone replacement therapy, in female contraception, to treat female sexual dysfunction, and to treat or prevent a variety of conditions and disorders which are responsive to the active agents contained therein. The examples of the US-application describe the use of buccal dosage units containing a combination of testosterone, progesterone and either estradiol or ethinyl estradiol in a method of hormone replacment and in the treatment of female sexual dysfunction. The buccal dosage units described in the US-application are not suitable for use in a method of female contraception as the bioavailability of bucally administered steroids, especially the bioavailablity of progesteron, is too low to inhibit ovulation during the complete menstrual cycle.

In view of the above there is a need for an effective contraceptive method that gives less rise to mood disturbances and venous thromboembolism (VTE) than observed with the aforementioned contraceptive methods.

SUMMARY OF THE INVENTION

It was found that the aforementioned objective is realised by a contraceptive method that employs the administration of at least two different steroids in a manner known per se to inhibit ovulation, which method additionally employs the continuous administration of an androgen during a prolonged period of time (i.e. 28 days or more). The continuous aoministration of the androgen helps to avoid androgen deficiency and/or the occurrence of fluctuations in serum androgen levels, both of which phenomena are often observed when steroids are administered in accordance with the regimens commonly used to inhibit ovulation. The fact that the present method maintains serum concentrations of androgens such as testosterone, dihydrotestosterone and dehydroepiandrosterone (a precursor of testosterone) at a constant physiological level, has a particularly advantageous effect on mood. Low serum androgen concentrations in females have been associated with feelings of discomfort. Also fluctuations in serum androgen concentrations are believed to affect mood. In the present method serum androgen concentrations are maintained at a fairly constant physiological level, which is sufficiently high to prevent mood changes and feelings of discomfort.

It was found that androgens affect blood clotting properties (haemostasis) by increasing anticoagulation and/or fibrinolysis. It is also known that estrogens influence blood coagulation in the sense that aαlministration of estrogens may stimulate blood coagulation. Thus, co-administration of estrogen and androgen may suitably be employed to prevent undesirable, i.e. potentially dangerous, changes in blood clotting properties. The beneficial effect on blood clotting properties is particularly pronounced in case the androgen is co- administered with ethinyl estradiol. The present method, when employing the combined administration of a progestogen and an androgen, is extremely effective in suppressing endometrial stimulation. This effect of androgen is particularly appreciated if the method additionally employs an estrogen, since estrogens are known to have an endometrial stimulating effect. Progestogens are known to suppress such endometerial stimulation. It was an unexpected discovery, however, that androgens may enhance this action.

Without wishing to be bound by theory, it is believed that the androgen may exert this effect through activation of androgen receptors. It is known that androgen receptors are present in endometrial tissue. Horie et al., "Immunohistochemical localisation of androgen receptor in the human endometrium, decidua, placenta and pathological conditions of the endometrium", Hum. Reprod. vol. 7, No. 10 (1992), pp. 1461-1466 report that although the proliferation and differentiation of endometrium are mediated mainly by estrogen and progesterone receptors, the androgen receptor may play a role in modulating these changes. It was also surprisingly found that the proliferative effect of estrogens on the endometrium in female contraceptive users may also be suppressed by co-administration of an androgen only, i.e. without progestogen. Such co-administration can be effective in suppressing the proliferative effect of estrogen in contraceptive regimens which use periods of estrogen only administration (e.g. a sequential method).

The present method also offers the advantage that the continuous co-administration of androgen in known contraceptive regimens produces less vaginal breakthrough spotting and bleeding.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, one aspect of the invention is concerned with a method of contraception in mammalian females, said method comprising the administration to the female of dosage units containing at least two different steroids, including an androgen, in a therapeutically effective amount to inhibit ovulation, wherein the androgen is administered continuously during a period of at least 28 days, preferably of at least 60 days.

The term "continuous" when used in relation to the administration of one or more active principles, means that said one or more active principles are administered at relatively regular intervals, with no (therapeutically) significant interruptions. Naturally, minor interruptions may occur that do not affect the overall effectiveness of the present method, and indeed such aberrations are encompassed by the present invention. In a preferred embodiment, and more arithmetically, an administration regimen is deemed to be continuous if the longest interval between 2 subsequent administrations is not more than 3.5 times as long as the average interval. Even more preferably said longest interval is not more than 2.5 times as long as the average interval.

Preferably, in the present method, androgen is co-administered in an amount which is therapeutically effective to suppress symptoms of hypoandrogenism. Preferably the androgen is administered in an amount sufficient to maintain the serum androgen concentration of the female mammal at a level equivalent to between 0.5 and 5.0, preferably between 0.7 and 4.0 and most preferably between 1.0 and 3.0 nanomoles testosterone per litre. Here the testosterone concentrations relate to the total testosterone present in the serum, i.e.including both free testosterone and bound testosterone. The present method preferably employs, in addition to the androgen, at least one estrogen and optionally at least one progestogen in a therapeutically effective amount to inhibit ovulation during a period of at least 28 days, preferably at least 60 days. Examples of such methods include the aforementioned combined and sequential contraceptive methods. Another preferred embodiment of the present invention is concerned with a contraceptive method that comprises the administration of dosage units containing at least one progestogen in a therapeutically effective amount to inhibit ovulation during a period of at least 28 days, preferably at least 60 days. Particularly preferred is a method which comprises uninterrupted administration of at least one progestogen. Throughout this document, by uninterrupted administration is meant that out of the sequence of dosage units that are being ^■ administered at regular (i.e. essentially constant) intervals, not more than 1 dosage unit is skipped. In case of e.g. an uninterrupted daily oral administration regimen this means that the maximum administration-free interval is 2 days. Particularly preferred are uninterrupted regimens wherein no skips occur at all.

The contraceptive method comprising uninterrupted administration of at least one progestogen encompasses a method that comprises the continuous combined administration of progestogen and androgen in an amount that is effective to inhibit ovulation. Said method also encompasses a contraceptive method which employs continuous uninterrupted administration of progestogen and at least one estrogen as described in WO 99/12531. In accordance with the present invention these so called continuous combined methods employ continuous co- administration of androgen, progestogen and optionally estrogen during a prolonged period of time (e.g. several months). In contrast to combined and sequential contraceptive methods, no regular menses occur as the continuous administration of progestogen in the indicated amounts induces amenorrhoea.

The term female, whenever referred to in here, relates to female mammals. Preferably the female mammal is a homo sapiens. For homo sapiens, females are usually biologically capable of child bearing between the age of 12 and 55.

The dosage units according to the invention may be administered orally, parenterally, transdermally, intravaginally or intranasally. Dosage units to be administered on a daily basis can suitably be selected from oral, transdermal and intravaginal dosage units. Methods for transdermal administration including the associated methods for manufacturing such systems are well known in the art. In this connection, reference may be made to U.S. Pat. Nos. 4,752,478, 4,685,911, 4,438,139 and 4,291,014, which are included herein by reference. Preferably, in the present method, the dosage units are administered orally, transdermally or intravaginally. In a particular preferred embodiment of the present method the dosage units are administered orally. In accordance with the method of the invention the dosage units may be administered at intervals which may range from 6 hours to 2 weeks. Preferably however, the dosage units are administered at least once daily as this helps to n inimise fluctuations in blood serum levels of the active principles.

The present contraceptive method encompasses three main embodiments, i.e.: i. a continuous combined method which comprises continuous co-administration of progestogen, androgen and optionally estrogen during a period of a least 28 days, preferably of at least 60 days. ii. an uninterrupted sequential method which comprises continuous co-administration of estrogen and androgen during a period of a least 28 days, preferably of at least 60 days, and co-administration of progestogen during at least a part of said period. iii. a method comprising continuous administration of androgen, intervals during which progestogen and optionally estrogen are co-administered, separated by estrogen and progestogen-free intervals of at least 2 days (e.g. an interrupted sequential method or a combined method).

In each of the aforementioned embodiments, preferably, the period during which estrogen, androgen and progestogen are co-administered spans at least 10 days. More preferably estrogen, androgen and progestogen are co-administered during a period of at least 14 days. In case the invention is practised as a combined or continuous combined method, the estrogen, androgen and progestogen are suitably co-administered during a period of at least 20 days. An important advantage of the present method resides in the fact that androgen levels are maintained at a stable physiological level. Preferably also serum estrogen levels are maintained at a relatively constant level through the continuous administration of an effective amount of estrogen during a period of at least 28 days, preferably of at least 60 days. The continuous co-administration of estrogen and androgen makes it possible to maintain even more stable serum androgen levels due to the resulting stabilisation of sex hormone binding globulin (SHBG), which protein binds (competitively) to both steroids. Androgens are known to decrease SHBG synthesis, whereas estrogens stimulate SHBG synthesis. Continuous co- administration of estrogen and androgen results in stable SHBG concentrations and avoids changes in the binding of free androgen. Continuous co-administration also prevents fluctuations in estrogen serum levels. Such fluctuations have been associated with sleep disturbances , headaches, breast tension, bloating, nausea, weight changes, emotional symptoms such as irritability and depression, vasomotor symptoms such as hot flushes and night sweats, and irregular bleeding and spotting. A preferred embodiment of the invention relates to a continuous combined method that comprises continuous co-administration during a period of at least 28 days, preferably of at least 60 days, of at least one estrogen, at least one progestogen and at least one androgen in an amount effective to inhibit ovulation. The main advantages of such a method reside in the prevention of withdrawal bleedings, a decrease of break through bleeding/spotting, less subjective complaints such as the symptoms caused by hormone fluctuations and a lower risk of VTE. It is also believed that the avoidance of chronic fluctuations in blood serum steroid levels may have a positive impact on the occurrence of premenstrual syndrome and the risk of breast cancer. In another preferred embodiment, the present invention relates to an uninterrupted sequential method consisting of two alternating consecutive phases, an estrogenic and a progestogenic phase, wherein during the estrogenic phase one or more dosage units are administered to provide a therapeutically effective amount of a combination of estrogen and androgen to inhibit ovulation and during the progestogenic phase one or more dosage units are administered to provide a combination of estrogen, progestogen and androgen in a therapeutically effective amount to inhibit ovulation and to transform the endometrium from a proliferative into a secretory state.

Typically, in a sequential method, dosage units containing an estrogen, an androgen and no progestogen are administered at least once daily during a period of 3-18 consecutive days, preferably during a period of 5-14 consecutive days. The advantages of the present invention are particularly appreciated in contraceptive methods wherein unopposed estrogen is administered during a significant part of the 4-weekly cycle. As mentioned herein before, it was found that in the absence of co-administered progestogen, an androgen can suitably be applied to reduce the proliferative effect of the estrogen. The present invention also encompasses a combined contraceptive method comprising the combined administration of estrogen, androgen and progestogen, wherein the method comprises an interval of at least 2 days during which no progestogen and no estrogen is administered and wherein the resulting decrease in serum progestogen and estrogen level induces menses. Examples of estrogens (synthetic and biogenic) which may suitably be used in the present invention include ethinyl estradiol, mestranol, quinestranol, estradiol, estrone, estran, estriol, estetrol, conjugated equine estrogens, precursors capable of liberating such an estrogen when used in the present method and mixtures thereof. Of these estrogens ethinyl estradiol is most widely used in oral contraceptives and it is also the estrogen which is most renowned for its proliferative effect on endometrium. In case of continuous co- ao'miriistration of estrogen and androgen it is feasible to at least periodically employ a biogenic estrogen instead of a synthetic estrogen. Hence, in a preferred embodiment of the invention, the present method comprises the administration of a biogenic estrogen, such as estradiol, during a period of at least 3 days, preferably of at least 5 days. Although it is feasible to co-administer a combination of a biogenic and a synthetic estrogen, it is preferred to administer only biogenic estrogen.

The estrogen containing dosage units employed in the present method preferably contain one or more estrogens in an amount which is equivalent to a daily oral dosage of 3-40 μg, preferably 10-30 μg ethinyl estradiol. The phrase "equivalent to a daily dosage" should not be interpreted restrictedly. For instance, the above mentioned requirement that the administration of the present medicament is to provide the equivalent of a daily dosage of 3- 40 μg ethinyl estradiol, encompasses a protocol wherein ethinyl estradiol is administered once a week, provided the weekly dosage is between 21 and 280 μg, i.e. such that the average daily dose is between 3 and 40 μg ethinyl estradiol. The androgen used in the present method is preferably selected from the group consisting of dehydroepiandrosterone (DHEA); DHEA-sulphate; testosterone; testosterone esters such as testosterone undecanoate , testosterone propionate, testosterone phenylpropionate, testosterone isohexanoate, testosterone enantate, testosterone bucanate, testosterone decanoate, testosterone buciclate; danazol; gestrinone; methyltestosterone; mesterolon; stanozolol; androstenedione; dihydrotestosterone; androstanediol; metenolon; fluoxymesterone; oxymesterone; methandrostenolol; 7α-methyl-19-nortestosterone (MENT); precursors capable of liberating these androgens when used in the present method and mixtures thereof. Most preferably the androgen is selected from the group consisting of DHEA, danazol, gestrinone, testosterone esters, androstenedione, precursors capable of liberating these androgens when used in the present method and mixtures thereof. Preferably the testosterone esters employed in the present method comprise an acyl group which comprises at least 6, more preferably from 8-20 and preferably 9-13 carbon atoms. Most preferably the androgens used in the present method are DHEA and/or testosterone undecanoate. These androgens offer the advantage that they can effectively be used in oral dosage units.

It is noted that, for instance, DHEA, testosterone undecanoate and androstenedione are precursors of testosterone and that said precursors per se exhibit virtually no affinity for androgen receptors in the female body. The effectiveness of the androgens within the method of the invention is determined by their functionally active form, which may well be different from the form in which they are administered.

In a preferred embodiment the androgen is provided in an amount equivalent to a daily oral dosage of 5 to 250 mg DHEA, which is equivalent to a daily oral dosage of 1 to 50 mg testosterone undecanoate. More preferably the androgen is provided in an amount which is equivalent to a daily oral dosage of 10-120 mg DHEA. Most preferably the androgen is administered in an amount which is equivalent to a daily oral dosage of 20-60 mg DHEA.

DHEA and its sulphate ester (DHEAS) are the major secretory products of the human adrenal gland and collectively circulate at levels far exceeding any other steroid in the body. DHEA is weakly active as a sex hormone but is a precursor for the androgen testosterone and for the estrogenic hormones estrone and estradiol. Once DHEA is released into the body from the adrenal gland it is partly converted into the sulphate ester DHEA-S by the liver. Many tissues are able to convert DHEAS back to DHEA, which in turn can act as a precursor for testosterone, estrone and estradiol. The liver and the kidney are the principal organs involved in clearing steroid hormones from the circulation. Hepatic metabolism accomplishes two functions for DHEA: a decrease in the biologic activity of the hormone, and an increase in its water solubility, because of conversion to the hydrophilic sulphate form that can be excreted in urine.

In order to obtain the desired impact from the present method it is advisable to administer the dosage units in an amount which leads to an increase in blood serum androgen level of no more than 5 nmole testosterone equivalent per litre, preferably less than 3 nmole testosterone equivalent per litre and most preferably less than 1.5 nmole testosterone equivalent per litre.

The progestogen contained in the kit of the invention is preferably selected from the group consisting of levonorgestrel, norgestimate, norethisterone, dydrogesterone, drospirenone, 3-beta-hydroxydesogestrel, 3-keto desogestrel (=etonogestrel), 17-deacetyl norgestimate, 19-norprogesterone, acetoxypregnenolone, allylestrenol, anagestone, chlormadinone, cyproterone, demegestone, desogestrel, dienogest, dihydrogesterone, dimethisterone, ethisterone, ethynodiol diacetate, flurogestone acetate, gastrinon, gestodene, gestrinone, hydroxymethylprogesterone, hydroxyprogesterone, lynestrenol (=lynoestrenol), medrogestone, medroxyprogesterone, megestrol, melengestrol, nomegestrol, norethindrone (=norethisterone), norethynodrel, norgestrel (includes d-norgestrel and dl norgestrel), norgestrienone, normethisterone, progesterone, quingestanol, (17alpha)-17-hydroxy-l 1- methylene-19-norpregna-4,15-diene-20-yn-3-one, tibolone, algestone acetophenide, nestorone, promegestone, trimegestone, 17-hydroxyprogesterone esters, 19-nor- 17hydroxyprogesterone, 17alpha-ethinyl-testosterone, 17alpha-ethinyl-19-nor-testosterone, d- 17beta-acetoxy- 13 beta-ethyl- 17alpha-ethinyl-gon-4-en-3 -one oxime and precursors of these compounds. Specific examples of progestogen precursors which may be employed in accordance with the present invention include: anagestone acetate, chlormadinone acetate, cyproterone , acetate, gestodene acetate, hydroxymethylprogesterone acetate, hydroxyprogesterone acetate, hydroxyprogesterone hexanoate, hydroxyprogesterone caproate, hydroxyprogesterone enanthate, medroxyprogesterone acetate, megestrol acetate, melengestrol acetate, nomegestrol acetate, norethindrone acetate, norethisterone acetate, norethisterone enanthate, quingestanol acetate, (17alpha)-17-hydroxy-l l-methylene-19-norpregna-4,15-diene-20-yn-3-one, tibolone, algestone acetophenide, nestorone, promegestone, 17-hydroxyprogesterone esters, 19-nor- 17hydroxyprogesterone esters, 17alpha-ethinyl-testosterone;

Progestogen containing dosage units employed in accordance with the present method, preferably contain progestogen in an amount which is equivalent to a daily oral dosage of 30- 750 μg, preferably of 75-150 μg levonorgestrel.

Throughout this document by precursors of an active ingredient are meant components capable of liberating the active ingredient when used in the present contraceptive method, particularly after administration e.g. as a result of metabolic conversion of the precursor substance. Particularly useful precursors of the hormones present in the kit according to the invention are substances that differ from these hormones in that the hydrogen in at least one of the hydroxyl groups in the hormone-molecule has been substituted by -CO-R, wherein R is a hydrocarbon radical comprising from 1-25 carbons.

It is to be understood that the present invention not only encompasses the use of estrogens, androgens and progestogens specifically mentioned in this application, but also metabolites of these hormones that display comparable functionality. In this context it is noted that, for instance, levonorgestrel is a metabolite of norgestimate and that estriol is a metabolite of 17beta-estradiol. Both these progestogens and estrogens have found application in contraceptive formulations and/or preparations for hormone replacement therapy. Another aspect of the invention relates to a pharmaceutical kit that can suitably be used in the sequential contraceptive method described above. The pharmaceutical kit for use in such a method comprises 10-28 oral dosage units containing estrogen in an amount which is equivalent to 3-40 μg ethinyl estradiol, progestogen in an amount which is equivalent to 30- 750 μg levonorgestrel and androgen in an amount which is equivalent to 5-250 mg dehydroepiandrosterone and 3-18 dosage units containing estrogen in an amount which is equivalent to 3-40 μg ethinyl estradiol, androgen in an amount which is equivalent to 5-250 mg dehydroepiandrosterone and essentially no progestogen. For most human females the natural interval between menses is somewhere between 20 and 35 days. To mimic the natural cyclic menses pattern, it is preferred that the aforementioned kit consists of 20 to 35 daily dosage units. Most preferably the kit consists of 28 daily dosage units.

Yet another aspect of the invention is concerned with a pharmaceutical kit that can suitably be used in the aforementioned continuous combined method. Such a kit typically comprises at least 28 oral dosage units containing estrogen in an amount which is equivalent to 3-40 μg ethinyl estradiol, progestogen in an amount which is equivalent to 30-750 μg levonorgestrel and androgen in an amount which is equivalent to 5-250 mg dehydroepiandrosterone. An advantage of such a kit is that all dosage units are identical, meaning that, unlike similar kits for use in sequential and combined contraceptive methods, the reliability of the method cannot be affected by administering the wrong dosage unit. The dosage units in the aforementioned kits preferably contain estrogen in an amount equivalent to 10-30 μg ethinyl estradiol and/or progestogen in an amount equivalent to 75-150 μg levonorgestrel and/or androgen in an amount equivalent to 10-120 mg dehydroepiandrosterone. Most preferably said dosage units contain one or more androgens in an amount equivalent to 20-60 mg dehydroepiandrosterone. The dosage units are preferably arranged in a fixed sequence corresponding to the intended order of administration, e.g. in a tablet strip. Preferably, dosage units to be used in different phases, e.g. estrogenic or progestogenic phase are easily distinguishable, e.g. because they are different in colour and/or shape. Data indications may be provided on the packaging. The packaging may be a tube or box or a strip. The box may be circular, square, or otherwise shaped with the dosage units being accommodated separately therein for ease of administration. Date indications may appear adjacent to each dosage unit corresponding with the days on which each dosage unit is to be taken. Some indication of the sequence in which the dosage units are to be taken preferably appears on the packaging regardless of its form. Generally speaking, the dosage units in the present kit are prepared according to conventionally known procedures in accordance with the method of administration. Thus, the active ingredients are prepared according to known methods in a pharmaceutically acceptable form for administration. These ingredients, in their required quantities are combined with the appropriate pharmaceutical carriers such as additives, vehicles and/or flavour ameliorating substances. These substances may be referred to as diluents, binders and lubricants. Gums, starches and sugars are also common terms. Typical of these types of substances or excipients are pharmaceutical grades of mannitol, lactose starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate and the like. The active ingredient(s) may comprise from about 0.01% by weight to about 99.99% by weight of the total formulation and the remainder comprises the pharmaceutically acceptable carrier. The percentage of active ingredient(s) may vary according to the delivery system or method of administration and is chosen in accordance with conventional methods known in the art.

Thus, the active ingredients are compounded with the chosen carrier and in for example the case of a tablet form, placed in a tablet moulding apparatus to form the tablets which are subsequently packaged in accordance with the chosen regimen.

The invention is further illustrated by means of the following examples.

EXAMPLES

Example 1

A clinical study is conducted in 200 healthy young women. Four groups of 50 women, who use a combined oral contraceptive containing 30 microgram ethinyl estradiol for at least 21 days before the start of the study, receive a daily oral dose of 20 microgram ethinyl estradiol and 100 microgram levonorgestrel, or 30 microgram ethinyl estradiol and 150 microgram levonorgestrel, either with or without 50 mg DHEA for 104 days (15 weeks) without pauses. Vaginal spotting and bleeding is scored daily by the participants in a diary and the effects on general well being are scored at baseline and at the end of the study on a psychometric rating scale. The psychometric rating scale used is especially suited for identifying differences in a population of healthy young women. The scale is a 24-item (placid, sleepy, jittery, intense, lacking confidence, energetic, sensitive, tired, well-balanced, at-rest, drowsy, fearful, lively, sickly, in a good mood, irritable, clutched-up, quiet, full-of- pep, optimistic, moody, active, tense, sad), 4-point (yes, definitely; yes, a bit; no, in fact not; no, definitely not) scale to be scored by the woman herself. In addition, endocrine measurements are performed in a subgroup of the participants (17β-estradiol, progesterone, total testosterone, LH, FSH and SHBG).

Ovulation inhibition is investigated by analysing pregnanediol samples twice a week during 4 weeks between week 7 and 14. In addition, endocrine measurements are performed in a subgroup of the participants (17β-estradiol, progesterone, total testosterone, LH, FSH and SHBG).

Consistent inhibition of ovulation is observed in all four groups. Results show that in the groups of women receiving DHEA less vaginal breakthrough spotting and bleeding is reported and generally better scores are obtained on items in the domain of energy (viz. tired, drowsy, energetic, placid and clutched-up) and less side effects occur than in those women not receiving it. In addition, in the participants receiving DHEA significantly higher testosterone levels are seen which are well within the physiological range.

Example 2

A clinical study is conducted in 100 healthy young women. Two groups of 50 women, who use a combined oral contraceptive containing 30 microgram ethinyl estradiol for at least 21 days before the start of the study, receive a daily oral dose of 3 mg 17β-estradiol and 1.5 mg norethisterone acetate either with or without 50 mg DHEA for 104 days (15 weeks) without pauses. Ovulation inhibition is investigated as described in Example 1. Vaginal spotting and bleeding is scored daily by the participants in a diary. The effects on general well being are scored at baseline and at the end of the study using the psychometric rating scale described in example 1. Again consistent inhibition of ovulation is observed in both groups. Furthermore results show that in the group of women receiving DHEA less vaginal breakthrough spotting . and bleeding is reported and generally better scores are seen on items in the domain of energy (viz. tired, drowsy, energetic, placid and clutched-up) and less side effects occur than in those women not receiving it. In addition, in the participants receiving DHEA significantly higher testosterone levels are seen which are well within the physiological range.

Example 3

In another study, 100 women are recruited (applying the criteria mentioned in

Example 1) who receive an oral dose of 20 mg dydrogesterone daily, without interruption for 104 days; 15 weeks), Of these 100 women, 50 receive an additional daily oral dose of 50 mg dehydroepiandrosterone, while 50 others do not.

Ovulation inhibition, vaginal spotting and bleeding are assessed using the methods described in Example 1. Also the effects on general well being are scored using the method described in example 1. Both groups showed consistent inhibition of ovulation throughout the period of 104 days.

Example 4

A clinical study is conducted in 40 healthy young women with regular cycles. Blood samples are taken for the state of the art haemostatic variables during the late follicular phase of the normal cycle and at the end of the luteal phase of that cycle. These two measurements serve as baseline control. Twenty women receive 30 microgram of ethinyl estradiol starting on Day 1 of the spontaneous menses, for 14 days (days 1-14). On day 12, 13 or 14, another blood sample is taken for haemostasis parameter testing. Subsequently the women receive 30 microgram ethinyl estradiol combined with 20 mg dydrogesterone on days 15-28. On day 26, 27 or 28 another blood sample is taken for haemostasis parameter testing. On day 29 the women continue with 30 microgram EE for 14 days again followed by the combination regimen. Total period of hormonal exposure will be 3x28 days. The comparator is a group of 20 women who continuously receive 50 mg of DHEA in addition to the regimens mentioned above.

Altogether samples are taken during the spontaneous cycle (2x baseline) at the end of the first period of EE administration and at the end of the first combined administration. Furthermore, samples are taken at similar timepoints during the last cycle of 28 days.

Results show that the addition of DHEA resulted in better anticoagulant and fibrinolytic activity when compared to the group of women not using the additional DHEA.

Consistent ovulation inhibition is observed in both groups. Furthermore, results show that in the group of women receiving DHEA less vaginal breakthrough spotting and bleeding is reported and generally better scores are seen on items in the domain of energy (viz. tired, drowsy, energetic, placid and clutched-up) than in those not receiving it. In addition, in the participants receiving DHEA significantly higher testosterone levels are seen which are well within the physiological range.

Example 5

A clinical study is conducted in 100 healthy young women. Fifty women receive the monophasic contraceptive pill containing 30 microgram EE plus 150 microgram desogestrel for 21 days, followed by a pause of 7 days. Another 50 women receive the same pill with the addition of 50 mg DHEA daily, continuing in the contraceptive pill pause of 7 days. Both regimens are followed for 112 days (16 weeks).

Example 6

In examples 1-5, data are obtained of altogether 270 women who received DHEA and 270 who did not. Results of the overall statistical analysis show that irrespective of the regimen of administration and hormonal contraceptive used, the addition of DHEA has significant positive effects on mood and on the bleeding pattern, when compared to non- administration of DHEA. In addition, in the participants receiving DHEA significantly higher testosterone levels are seen which are well within the physiological range. Example 7

The effects on endometrium of the progestogen levonorgestrel and the androgens DHEA and testosterone undecanoate are determined in rabbits according to the method of McPhail (Mc Phail M.K. "The assay of progestin" J Physiol (1934), 83, 145-156). Ten groups of each 5 rabbits are pretreated with daily oral dosages of 5 μg 17β-estradiol for 6 days.

After pretreatment, 8 groups receive one or two of the study compounds for 5 days. One group receives the positive control levonorgestrel at an oral dose of 0,8 μg per day for 5 days, and one group is used as the negative control. The following study compounds are given to the rabbits for 5 days: three groups receive DHEA, each group in a different dose (25 mg, 100 mg or 500 mg per day orally). Three other groups receive levonorgestrel (0.8 μg/day) together with DHEA in the aforementioned doses and two groups receive either testosterone undecanoate in an oral dose of 80 mg per day, or an infra muscular dose of 30 mg per day. Autopsy is performed after the treatment period and the uterus is weighed and histological sections are prepared from each uterine horn and these are microscopically evaluated according to the McPhail Index.

The pre-treatment phase induces proliferation of the endometrium. In the second phase, when the study compounds are administered, the degree of endometrial differentiation is investigated. More differentiation of the endometrium is observed when levonorgestrel and DHEA are given together compared to the groups only receiving levonorgestrel or DHEA. This differentiation is particularly pronounced in the group that has received the highest dosage of DHEA together with levonorgestrel. In the second phase, no further proliferation of the endometrium is observed in any of the treatment groups. In this setting it is presumed that the effect of the study compounds on the endometrial tissue is indicative of the effect on endometriotic tissue. This is a reasonable presumption because this latter tissue is essentially identical to endometrial tissue.

Claims

1. A kit comprising a plurality of hormone-containing dosage units for use in a method of contraception in mammalian females, said method comprising the administration to the female of dosage units containing at least two different steroids, including an androgen, in a therapeutically effective amount to inhibit ovulation, wherein the androgen is administered continuously during a period of at least 28 days, preferably of at least 60 days.

2. Kit according to claim 1, wherein the androgen is administered in an amount sufficient to maintain serum androgen concentration of the female mammal at a level equivalent to between 0.5 and 5.0, preferably between 0.7 and 4.0 and most preferably between 1.0 and 3.0 nanomoles testosterone per litre.

3. Kit according to claim 1 or 2, wherein the method comprises the administration of dosage units containing at least one estrogen and optionally at least one progestogen in a therapeutically effective amount to inhibit ovulation during a period of at least 28 days, preferably at least 60 days.

4. Kit according to claim 1 or 2, wherein the method comprises the administration of dosage units containing at least one progestogen in a therapeutically effective amount to inhibit ovulation during a period of at least 28 days, preferably at least 60 days.

5. Kit according to any one of claims 1-4, wherein the method comprises at least once daily administration of the dosage units.

6. Kit according to any one of claims 1-5, wherein the method comprises administration of dosage units containing an estrogen, an androgen and a progestogen, during a period of at least 10 consecutive days.

7. Kit according to any one of claims 1 -6, wherein the method comprises continuous administration of dosage units containing an estrogen, an androgen and a progestogen during a period of at least 28, preferably at least 60 days

8. Kit according to claim 6, wherein, following the combined administration of estrogen, androgen and progestogen, the method comprises an interval of at least 2 days during which no progestogen and no estrogen is admimstered and wherein the resulting decrease in serum progestogen and estrogen level induces menses.

9. Kit according to claim 6, wherein the method comprises continuous administration of estrogen during a period of at least 28 days, preferably at least 60 days, and wherein, following the combined administration of estrogen, androgen and progestogen, dosage units containing an estrogen, an androgen and no progestogen are administered during 3-18 consecutive days and the resulting decrease in serum progestogen level induces menses.

10. Kit according to any one of claims 1-9, wherein the dosage units are administered orally.

11. Kit according to any one of claims 1-10, wherein the estrogen containing dosage units contain one or more estrogens in an amount which is equivalent to a daily oral dosage of 3-40 μg, preferably of 10-30 μg ethinyl estradiol

12. Kit according to any one of claims 1-11, wherein the androgen containing dosage units contain one or more androgens in an amount which is equivalent to a daily oral dosage of 5- 250 mg, preferably of 10- 120 mg, more preferably of 20-60 mg dehydroepiandrosterone.

13. Kit according to any one of claims 1-12, wherein the progestogen-containing dosage units contain progestogen in an amount which is equivalent to a daily oral dosage of 30-750 μg, preferably of 75-150 μg levonorgestrel.

14. Kit according to any one of claims 1-13, wherein the androgen is selected from the group consisting of dehydroepiandrosterone, danazol, gestrinone, esters of testosterone and mixtures thereof.

15. A kit comprising a plurality of oral dosage units for use in a method of contraception, wherein the kit comprises 10-28 dosage units containing estrogen in an amount which is equivalent to 3-40 μg ethinyl estradiol, progestogen in an amount which is equivalent to 30- 750 μg levonorgestrel and androgen in an amount which is equivalent to 5-250 mg dehydroepiandrosterone and 3-18 dosage units containing estrogen in an amount which is equivalent to 3-40 μg ethinyl estradiol, androgen in an amount which is equivalent to 5-250 mg dehydroepiandrosterone and essentially no progestogen.

16. A kit comprising a plurality of oral dosage units for use in a method of contraception, wherein the kit comprises at least 28 dosage units containing estrogen in an amount which is equivalent to 3-40 μg ethinyl estradiol, progestogen in an amount which is equivalent to 30- ^■ 750 μg levonorgestrel and androgen in an amount which is equivalent to 5-250 mg dehydroepiandrosterone.