JPH0635388B2 - Pharmaceutical composition for the hormonal treatment of perimenopausal, menopausal and postmenopausal disorders - Google Patents

Description

The present invention relates to a pharmaceutical composition for the hormonal treatment of peri-menopausal, post-menopausal and post-menopausal disorders in women, which consists of selective volume units of progestogen and estrogen.

Peri-menopausal (ie, approximately 40 years and older), menopausal and post-menopausal women often experience a variety of symptoms and disorders due to estrogen deprivation resulting from ovarian failure. The duration of these disorders is very variable, with prominent flushing in some women and very mild in some women. Vaginal dryness is susceptible to mild infections and often causes discomfort during intercourse. This is also one of the symptoms directly linked to the lack of estrogen.

In the long run, the most detrimental health hazard during menopause is a loss of bone minerals (osteoporosis) that increases bone loss and increases the risk of fracture. For example, there is evidence that post-menopausal women have six times more fractures than men of the same age (Gilaway et al. Mayo Clinic Proceedings 54: 701-787, 197).
9th year, Garrawr et al, Mayo Clinic Proceedings, 5
4 , 701-707, 1979). This fracture has a high rate of complications in the elderly, significantly increasing the morbidity and morbidity, and of course increasing the risk of death.

Another serious health threat to menopause is the dramatic reduction in heart attack protection in young women up to the age of 60 compared to men of the same age. Around menopause (40 and 5
The rapid increase in mean serum control levels seen in the 0s is strongly associated with a rapid increase in deaths due to ischemic heart disease in older women. In the 80s and 90s,
Mortality from this ischemic heart disease is reduced to the same level as in males (RJ Habrik and PH Manigue Feinlaid NIH HB Publication 79-1610, 1979, US).
Department of H.E.W, Ha
vlik, RJ and Manning-Feinleid, PH1979, N
IH Publication No 79-1610, US Depart
ment of HEW).

In addition to the major physical problems described above, some women experience depression, insomnia and a variety of other symptoms ranging from nervousness to arthritis symptoms.

It is generally accepted that estrogen is the most effective agent for controlling or preventing flushing and vaginal atrophy during menopause. It is also effective in delaying or preventing the clinical appearance of osteoporosis. The appropriate dose is dl-
When combined with norgestrel (or levo-norgestrel), a favorable effect is also seen on blood lipids. However, there are also problems with estrogen therapy, which have been extensively studied and reported in the medical literature. Generally speaking, methods of administering estrogen include the use of estrogen alone and the addition of progestogen to estrogen.
Continuous small doses of estrogen alone are effective in controlling the above symptoms and associated problems in most patients. However, while the majority of women who continue to use low doses of estrogen do not bleed for months or years, this continued use causes "hidden endometrial thickening" (ie, no symptoms). There is a clear danger. Of course, this term refers to overstimulation of the inner surface of the uterus that can become precancerous, and is associated with the possibility of even such low-dose therapy actually causing cancer of the inner surface of the uterus (Gasberg et al., Opstrix and Guy. Necology, Vol. 17, 397-412, 1961, Gusb
erget al, Obstetrics and Gynaecology, 17 , 397
-412, 1961).

Estrogen alone may be given cyclically, usually for 21-25 days, with rest for 5-7 days. Again, low doses of estragen are needed to control the symptoms, and when used in this way, about 10
Only% experience abrupt bleeding during the actual dosing period. However, there is a relative risk of developing endometrial thickening and a risk of developing uterine cancer (Study on menopause: Levot of WBC Scientific Group, pp. 53-68, 1981, Resear.
ch on the Menopanse: Report of a WHO Scientific
Group, 53-68, 1981).

Addition of progestogen during the last 7-10 days of each estrogen administration cycle virtually eliminates the worry of developing endometrial hyperplasia, and the risk of developing endometrial carcinoma is Will probably fall below the rate of. However, rapid bleeding always occurs in this case, which is very unacceptable to most old women (Whitehead, American Journal of Obstetrics and Guinecology, Vol. 6, No. 6, 791-795, 1982). Year, Wh
itehead, Am.J. Obs / Gyn., 142 , 6, 791-79
5, 1982).

Another conventional method of administering estrogen is to administer a relatively small amount of estrogen for a 20-21 day cycle, such as a birth control pill, plus a strong progestogen in substantially the same amount for the same period. It is a formulation contained as described above. This method, of course, besides causing rapid bleeding with each cycle, can be used to increase the risk of arterial complications such as stroke or myocardial infarction in women over the age of 35-40 years. It cannot be done. The risk is particularly high if the person is a cigarette smoker (Blanket, American Journal of Opstetrics and Guynecology 142, No. 6 747-.
751, p. 1982, Plunkett, Am. J. Obs / Gyn.,
142 , 6, 747-751, 1982).

Therapies using only progestogen require relatively large doses to control hot flushes. Moreover, while progestogen alone is good at preventing osteoporosis, it does not prevent atrophy of the vaginal mucosa. However, when a large amount of progestogen is administered with a large amount of synthetic estrogen,
It promotes arteriosclerosis and induces changes in blood lipids associated with seizures and myocardial infarction in women taking oral contraceptives during the late reproductive period (Plunkett, Plunkett, supra).

The present invention provides a dose of levo-norgestrel of about 0.025 mg to about 0.05 mg and about 0.5 mg to about 0.75, respectively.
for the hormonal treatment of perimenopausal, postmenopausal and postmenopausal disorders in women comprising a dose unit of progestogen and estrogen with a pharmaceutically acceptable carrier equivalent to a dose of mg estradiol Pharmaceutical composition. The therapeutic regimen by administering this pharmaceutical composition is designed to avoid or minimize bleeding and prevent overstimulation of the inner surface of the uterus while favorably altering blood lipids.

The term "peri-menopause" refers to women who are approximately 40 years of age and older, who have not yet reached full menopause but who are experiencing symptoms associated with menopause.

The term "continuous" as used in this specification and in the claims, means "dosing" at least once a day.
Means times. Thus, for example, every other day, or once every three days, administration is not "continuous" in the present invention. However, it should be noted that it is “continuous” that the administration frequency is more than once a day, for example, 2 or 3 times a day without exceeding the prescribed dose.

The term “without interruption” means that there is no discontinuation of administration. Thus, “continuous and uninterrupted administration” of progestogen means administration of progestogen at least once a day, substantially permanently, or until the end of the entire treatment. In this sense, “periodic” administration means that there is discontinuation of administration, and thus, by definition, “without interruption” to periodic administration.
That is impossible.

The term "dosage" refers to the amount of estrogen or progestogen administered daily. Thus, for example, "consecutive administration" of a progestogen to a woman in a "dosage" of 75 μg means that
It may be administered as a 75 μg dose, or for example 2
Try to administer 5 μg in 3 divided doses, but the total daily dose should be 7
It means that 5 μg of progestogen is administered to the woman. The most conventional method of continuous administration of estrogen or progestogen is to administer the prescribed dosage as a single daily oral dose. Parenteral administration releases progestogen slowly and may replace the oral route.

Therefore, the method of treatment by administering the pharmaceutical composition of the present invention controls flushing of the face, restores the vaginal mucosa to a healthier state, and prevents demineralization of bones over a long period of administration. A method of treatment in which estrogen is administered so as to prevent lipid changes that are susceptible to cardiovascular disease, and this method achieves the purpose of providing a method that does not cause an increased risk of bleeding or endometrial carcinoma.

The actual unit dose will be selected according to known methods, eg according to the weight of the patient, the biological activity of the hormone, etc., in order to achieve the desired result with the minimum amount of hormone.
The following are based on daily doses, but the total sustained release with muscle depot or insertion is up to 100 mg estrogen, 500 mg progesterone.

Discontinuation of estrogen administration is necessary for perimenopausal women to maintain normal menses, and there are certain legislations for health considerations-especially overstimulation of the uterine surface that causes precancerous conditions. May be needed. If estrogen is not administered for a short period of time, the inner surface of the uterus will undergo carrion formation to avoid precancerous conditions. However, the inventors believe that even if estrogen is continuously administered, the presence of progestogen causes atrophy of the uterus that does not occur.

The important point for reference of the present invention is the prescribed administration method,
The estrogen is then to provide a means to administer to the woman an appropriate amount and dosage unit of progestogen and estrogen according to that which is cyclically administered. Such means take the form of composite packaging, which facilitates administration by a nurse or physician under appropriate circumstances, or more often self-administration by a woman.

This complex packaged product has a dosage unit of progestogen and estrogen sufficient for continuous administration of progestogen and estrogen for about 20 to 120 days, and further administration of estrogen is discontinued for about 3 days. Included in additional dose units of progestogen administered for 7 to 7 days.

The estrogens used in the present description are orally active and suitable for oral contraception and include estradiol, estradiol-17β, estradiol valerate, conjugated horse estrogen, piperazine estrone sulfate, estrone, estriol, estriol succiol. Natural estrogen such as nate and polyestriol phosphate or natural estrogen selected from synthetic estrogens such as ethinyl estradiol, quinestranol and mestranol are preferred.

Progestogen is also orally active and suitable for oral contraception, for example, dl-norgestrel, levo-norgestrel, norethindrone (norethisterone), norethindrone acetate, ethinodiol diacetate, medroxyprogesterone acetate, cyproterone acetate. Or it is norethinodren.

Tables 1A and 1B below show desirable unit doses, minimum unit doses, and maximum unit doses of estrogen and progestogen useful in the present invention. The amount is generally determined by the biological activity of the material purchased from the source supplied in micronized form.

Of the estrogens in Table 1A, the asterisk (*) marked estriol preparation is not recommended as much as estradiol or estrone because it is not effective on bone in postmenopausal women.
However, they can reach the object of the present invention in combination with natural or synthetic estrogens. Also, the following nonsteroidal estrogens, which are useful in the present invention, should be avoided in women who may not have fully reached menopause (may be pregnant). This form of estrogen is known to induce vaginal cancer and other abnormalities in offspring when administered during pregnancy.

Although chlormadinone acetate and megesterol are useful in the context of the present invention, these progestogens are presumed to be prone to breast cancer with no clinical evidence. Obviously these compounds are not recommended unless such questions have been proven unfounded.

The estrogen / progestogen complex may be administered parenterally by intubation or intramuscular injection. Generally speaking, the required daily dosage will be less than that for orally administered estrogen and progestogen. This is simply because the former is released directly into the bloodstream, so the activity of the same substance is stronger than when it is taken orally.

Estradiol, estradiol valerate and estradiol-17β are suitable for implantation, with maximum and minimum doses of 100 mg and 20 mg, preferably 100 mg. These amounts are suitable for low emission insertion tubes that are replaced every 3 to 12 months.

Suitable progestogens for intubation and intramuscular injection are shown in Table 1C.

dl- norgestrel, levonorgestrel (d-13β-
Ethyl-17α-ethynyl-17β-hydroxygon-4-en-3-one (common name), norethindrone (17-hydroxy-9-nor-17α-pregn-4)
-En-20-in-3-one trivial name), ethinodiol diacetate (19-nor-17α-pregan-4)
-En-20-yne-3β, the common name for 17-diol diacetate), norethindrone acetate and cyproterone acetate may also be administered by injection. It will be readily apparent to those skilled in the art that other synthetic progestogens that are orally active or effective for use in connection with contraception are also useful in the present invention.

Any of the useful estrogens and progestogens (especially those shown in the table above) may be combined in order to obtain estrogen / progestogen complexes within the scope of the present invention. A particularly preferred combination is one that includes estradiol or conjugated horse estrogen and norgestrel, norethindrone or medroxyprogesterone. Therefore, a particularly desirable combination is as follows.

Estradiol / Levo-Norgestrel Estradiol 17β / Levo-Norgestrel Estradiol Valerate / Levo-Norgestrel Conjugated Horse Estrogen / Levo-Norgestrel Estradiol / dl-Norgestrel Estradiol 17β / dl-Norestrel Estradiol Valerate / dl-Norgestrel Conjugated Horse Estrogen / dl-Norgestrel Estradiol / norethindrone (norethisterone) Estradiol 17β / norethindrone (norethisterone) Estradiol valerate / norethindrone (norethisterone) Conjugated horse estrogen / norethindrone (norethisterone) estradiol / norethindrone (norethisterone) norethisterone 17β / norethisterone (norethisterone) Terone) acetate estradiol valerate / norethindrone (norethisterone) acetate conjugated horse estrogen / norethindrone (norethisterone) acetate estradiol / medroxyprogesterone acetate estradiol 17β / mesoloxyprogesterone acetate estradiol valerate / medroxyprogesterone acetate conjugated horse estrogen / medroxydromester Lonacetate The maximum, minimum and desired dosages of each estrogen and progestogen in the above combinations are shown in the table.

The compositions of the invention are usually administered orally in admixture with a pharmaceutically acceptable inert carrier. Estrogen and progestogen may be formulated in any pharmaceutically acceptable inert (non-toxic) form. The package may be any convenient for actual distribution. For the preferred oral dosage form, the pharmaceutical carrier will typically be a conventional mannitol, lactose, starch, magnesium stearate, saccharin soda, talc, cellulose, glucose, sucrose, magnesium carbonate, or the like. Any of the carriers used can be used. The composition may be formulated as a solution, suspension, tablet, pill, capsule, powder, sustained release formulation and the like.

One of the features of the present invention is the use of a complex formulation package to administer progestogens continuously and without interruption and to cyclically administer estrogen.
The duration of the estrogen administration cycle is very variable,
20 to 120 days of continuous administration followed by about 3 to about 7 days of estrogen discontinuation (ie discontinuation). However, if estrogen is discontinued for more than 5 days, flushing is likely to recur in many patients.

The composite packaging preparation system may be packaged in conventional packaging equipment, such as continuous strips of daily doses or transparent foil packaging or means known in the art. When a complex package is used for cyclic administration of estrogen with progestogen, the package may contain, for example, one of up to 120 total combination drugs.
The daily dosage units are serially arranged and 3 to 7 progestogen dosage units are placed at the end of the combined drug daily dosage unit, which results in the progestogen being at the end of the series. Conveniently it is a transparent strip foil wrapping such as

The inventors have obtained from this steady-state administration clinical evidence that the amounts of estrogen and progestogen required to control hot flushes, vaginal symptoms and related subjective symptoms are very low.
Preliminary metabolic responses in sensitized patients showed desirable changes towards low blood lipid levels seen in young premenopausal women.

Example 1 Thirty women were tested in a randomized, double-up study crossover procedure based on a placebo, progestogen alone, estrogen alone and continuous uninterrupted progestogen / periodic estrogen dosing regimen. . As for the treatment, administration and combination of each hormone were as follows.

(1) Estrogen only for 2 months (2) Progestage only for 2 months (3) Combination therapy of (1) and (2) for 6 months After each period of hormone administration of this combination, placebo (hormone activity Substance) was administered for 1 month. Estrogen is micronized 17β-estradiol and the daily dose is 1 mg,
On the other hand, as progestogen, dl-norgestrel was administered at a dose of 75 μg.

Twenty-two of the thirty women who completed the study requested that the combination therapy be selected and continued from the responses in the 14-month observation. This indicates a high level of acceptance.

Reference example 2 In the observation continuation period (follow-up phase), 1
Seven (the uterus was not treated) completed a total of 125 menstrual cycles with combination therapy (dl-norgestrel was given continuously and uninterrupted with 17β-estradiol). No one has experienced “bleeding” that requires protection.
1.6% of the cycles are petechial hemorrhage that does not require protection, 98.
4% did not bleed at all.

The combination therapy was not associated with the fact of any endometrial thickening (overstimulation of the uterine surface). One patient who received estrogen alone (in a double-blind method) showed abnormal findings that were interpreted as showing precancerous changes as well as endometrial thickening after 2 months. Low dosage of progestogen (dl-
Norgestrel) was added for 2 weeks, and it was found that the endometrial membrane was completely atrophic again due to total expansion and curettage, and the above findings were completely recovered.

Levo-norgestrel may be used instead of dl-norgestrel. Since dl-norgestrel consists of equal amounts of dextrorotatory (inactive) and levorotatory (active) forms, half the amount of evoked
The same effect can be obtained using norgestrel. Therefore, if the dl-norgestrel in the above example is replaced with levo-norgestrel, the dosage of levo-norgestrel is 37.5 mg.

At least five young women who needed ovarian and uterine removal due to marked endometrial hyperplasia were also successfully treated with the above combination therapy. These women had little total removal of endometrial tissue. It is important to treat these patients with estrogen replacement therapy to prevent the early development of bone demineralization (osteoporosis), to prevent elevated cholesterol and triglycerides, and to control flushing and vaginal atrophy. When such patients are treated with estrogen alone, the painful symptoms often recur due to residual endometriosis restimulated by the administered estrogen. The combination therapy of the inventors, whether it is normally in the uterus or endometrial tissue in the pelvis, tends to promote atrophy of the inner surface of the uterus (endometrium), so these patients Tolerates this therapy well and does not recur or reactivate endometriosis. Moreover, continuous progestogen administration, even in small amounts, in combination with estrogen is sufficient to control the severe flushing experienced by such patients.

Thus, the present invention can control menopausal disorders, including hot flushes and vaginal atrophy, many subjective symptoms. In addition, it is considered that if both components of this combination therapy are given, it has the effect of delaying osteoborosis, and long-term treatment is effective in order to prevent this incapacitating disease.

Furthermore, the risk of developing endometrial (uterine) cancer from combination therapy is reduced to the normal frequency of expression in normal individuals, as opposed to the increased risk actually shown with estrogen alone. The inventors obtained evidence that this combination therapy would reduce the risk of pre-cancerous endometrial changes and the risk of developing endometrial cancer. Reducing bleeding or ecchymosis in patients receiving combination therapy is highly desirable, especially for older women, as compared to known therapies.

In accordance with one of the reference embodiments of the present invention, the instructions for use in a combination formulation packaging particularly suitable for cyclic administration of estrogen as well as continuous administration of progestogen are described below as reference examples.

About this tablet (the tablet packaged here) is used to cure menopausal symptoms. This should not be considered a contraceptive pill and may prevent pregnancy. Oral contraceptives should not be taken at the same time as this tablet. If contraception is needed, talk to your doctor about other physical methods of contraception.

If you are starting treatment for the first time, you may have milk sores, a mild upset, or occasional vaginal bleeding. This will settle in a short time.

Please consult your doctor if you have any unusual symptoms.

Take under the supervision of a doctor.

How to use this package Always take the first tablet on a day that is convenient for you to take the entire tablet, regardless of whether it is menstruating or not.

The last 7 different colored tablets should be taken after taking all other tablets.

Alternatively, the above instructions may be printed on a leaflet and the packaging may have the following instructions.

Please read the enclosed instruction leaflet carefully before beginning treatment. Ask your doctor if the instructions are difficult to understand.

Precautions To remove the tablet, press a suitable piece of clear plastic bulge with your thumb from above. Hold the card with your other finger around the aluminum foil and the tablet will come out easily between the fingers.

The figure shows a combined preparation package suitable for administration of tablets according to the above administration method. The blister package 10 (which may be folded along the line 10a) is sold in a protective sleeve 11, which is printed on the back with instructions for use and necessary for tablets as shown at 12. When the user removes it from the protective sleeve, the blister package contains as many tablets as the intended number of days for this packaging (120 days in this reference example). Each blister part may be numbered from 1 to 120 if desired, but it is important to clearly distinguish the last few blister containing progestogen-only tablets from the rest. . In this reference example, the part 13 containing the first 113 tablets (progestogen / estrogen combination) is light colored (eg white) and the last 7 parts 14 containing progestogen only tablets are dark color. (For example, red). By following the caveats on the sleeve and looking at the color of the blister package (“day number”, if any), the user can
You will be taking a combination tablet for one day and a progestogen tablet for the last seven days. Therefore, the cycle is repeated each time a new package is opened.

Although only a few embodiments and reference embodiments of the present invention have been illustrated in detail, those skilled in the art will appreciate many modifications to the examples without departing significantly from the novel teachings and advantages of the invention. It will be readily appreciated that is possible.

[Brief description of drawings]

1 and 2 show an example of a combined preparation package suitable for administration of tablets according to the present invention.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yale Earl Plunkett, Canada N6 H4 Sea 4, Ontario, London, Kingspark Crescent St 34 (72) Inventor Bernard M. Jay. Wolf Canada. N6 G1 R2, Ontario, London, Metamora Cretsent 17 (56) Reference US Patent 3733407 (US, A) US Patent 3639600 (US, A) US Patent 3957982 (US, A) Chem. Ab95 (19): 162809j Chem. Ab94 (25): 203125h Chem. Ab93 (5): 38140d Chem. Ab90 (3): 16877k Chem. Ab81 (23): 146137u Chem. Ab79 (8): 45822s Chem. Ab76 (25): 149417t

Claims (18)

[Claims] 1. A dose of levo-norgestrel of about 0.025 mg to about 0.05 mg and about 0.5 mg to about 0.1 mg each.
For the hormonal treatment of perimenopausal, postmenopausal and postmenopausal disorders in women comprising a dose unit of progestogen and estrogen with a pharmaceutically acceptable carrier equivalent to a dose of 75 mg estradiol Pharmaceutical composition. 2. The composition according to claim 1, wherein the estrogen is a synthetic estrogen. 3. A composition according to claim 2 wherein the synthetic estrogen is selected from the group consisting of ethinyl estradiol, mestranol and quinestranol. 4. A composition according to claim 1 wherein said estrogen is a natural estrogen. 5. The method according to claim 4, wherein the natural estrogen is selected from the group consisting of conjugated horse estrogen, estradiol, 17β-estradiol, estradiol valerate, estrone, piperazine estrone sulfate, estriol, estriol succinate and polyestrol phosphate. The composition according to the item. 6. The progestogen is levo-norgestrel, dl-norgestrel, norethindrone (norethisterone), norethindrone (norethisterone).
A patent claim selected from the group consisting of acetate, ethinodiol diacetate, didrogestone, medroxyprogesterone acetate, norethinodrel, allylestrenol, linoestrenol, quingestanol acetate, medrogestone, norgestrienone, dimethisterone, ethisterone and cyproterone acetate. A composition according to any one of claims 1 to 5. 7. For each of the highest and lowest dosage units as follows, the estrogen is in the following groups: The composition according to any one of claims 1 to 6, which is selected from the group consisting of: 8. The progestogens in the following groups for each of the highest and lowest dosage units as follows: The composition according to any one of claims 1 to 7, which is selected from the group consisting of: 9. For each dosage unit such as the following, the estrogen is in the following groups: 9. The composition according to claim 7, which is selected from the group consisting of: 10. For each dosage unit as described below, the progestogen is in the following groups: The composition according to claim 7, which is selected from the group consisting of: 11. The combination of the estrogen and the progestogen in the following: estradiol / levo-norgestrel, 17β-estradiol / levo-norgestrel, conjugated horse estrogen / levo-norgestrel, estradiol / dl-norgestrel, 17β-estradiol / dl. -Norgestrel, estradiol valerate / dl-norgestrel, conjugated horse estrogen / dl-norgestrel, estradiol / norethindrone (norethisterone), 17β-estradiol / norethindrone (norethisterone), estradiol valerate / norethisterone (norethisterone) / northederone (norethisterone) / conjugated horse , Estradiol / norethindrone (nor Tysterone) acetate, 17β-estradiol / norethindrone (norethisterone) acetate, estradiol valerate / norethindrone (norethisterone) acetate, conjugated horse estrogen / norethindrone (norethisterone) acetate, estradiol / medroxyprogesterone acetate, 17β-estradiol / medroxyprogesterone / destrodiol / medestrodiol The composition according to any one of claims 8 to 10, which is selected from valerate / medroxyprogesterone acetate and conjugated horse estrogen / medroxyprogesterone acetate. 12. The composition according to claim 11, wherein the estrogen is 17β-estradiol and the progestogen is dl or levo-norgestrel. 13. Between about 0.5 mg and about 0.75 mg of said 17
13. The composition of claim 12 in a dosage unit of β-estradiol and a dosage unit of between about 50 μg and 100 μg of dl-norgestrel. 14. A composition according to claim 13 in a dosage unit of about 75 μg of said dl-norgestrel. 15. A daily dose for oral administration of about 0.025 mg to about 0.05 mg levo-norgestrel, wherein the composition is in insertable or intramuscular injectable form,
The estradiol peripheries of women, in combination with a pharmaceutically acceptable carrier, in an amount sufficient to provide the woman with a dose of progestogen and estrogen corresponding to each of the daily doses of about 0.5 mg to 0.75 mg of estradiol. A pharmaceutical composition for the hormonal treatment of menopause, menopause and postmenopausal disorders. 16. A composition according to claim 15 wherein, in insertable form, the estrogen is selected from the group consisting of estradiol, 17β-estradiol and estradiol valerate. 17. In insertable form, the progestogen comprises levo-norgestrel, dl-norgestrel,
A composition according to claim 15 or 16 selected from the group consisting of norgestrienone and norethindrone acetate. 18. A composition according to claim 15 wherein, in injectable form, the progestogen is selected from the group consisting of medroxyprogesterone acetate, norethindrone enanthate, gestronol hexanoate and argestone acetophenide.