GB2091552A - Use of progesterone for the treatment of post-menopausal women - Google Patents

Abstract

A method of relieving post- menopausal symptoms involves administering dosages of up to 300 mg per day of natural progesterone. Preferably 100 mg per day of natural progesterone is administered during the mid-luteal phase of the ovarian cycle.

Description

SPECIFICATION Use of progesterone for the treatment of postmenopausal women The present invention relates to the use of natural progesterone in treatment of postmenopausal women.

Synthetic progestogens have been used with benefit in the management of dysfunctional uterine bleeding, endometrial hyperplasia and carcinoma, premenstrual tension and endometriosis. In addition, they have been combined with oestrogens in oral contraceptive preparations and in therapies for the treatment of menopausal symptoms.

These synthetic steroids possess chemical configurations based on either 1 9 or 21 carbon atoms. The structural differences lead to variations in biological effects. Certain progestogens possess androgenic effects while others have antiandrogenic and some even oestrogenic properties. Adverse reactions due to excessive androgenic or oestrogenic activity are well recognised.

To date, naturally occurring progesterone has rarely been used in clinical practice. Relatively large amounts -- 100 mg/day - have been administered orally to pregnant women with a history of habitual abortion and low pregnanediol levels. In 60% of pregnancies delivery of a viable baby was achieved, 300 mg daily have been shown to inhibit ovulation. In men, a smaller dosage - 100 mg -- produced a plasma surge lasting less than 6 hours. Until now, no information has been available on the pharmocodynamics of progesterone following oral administration to women.

Accordingly the present invention provides a method for the relief of post-menopausal symptoms which method comprises administering a dosage up to 300 mg per day of natural progesterone, preferably a maximum dosage of 200 mg per day and more preferably 100 mg per day during the mid-luteal phase of the ovarian cycle.

A past dosage may be administered once or more times daily up to the maximum desired. The dosage may be given in conjunction with a suitable pharmaceutical carrier to increase the bioavailability of the progesterone. A suitable carrier is cholesterol pivalete. In order to administer the dosage conveniently, the dosage may be made up in convenient units.

The following tests were carried out to determine the rate of progesterone absorption from the gastrointestinal tract and to determine the concentration in the peripheral circulation.

Five asymptomatic postmenopausal women volunteered to participate in the study. All were parous, had intact ovaries and had experienced a natural menopause between 2 and 8 years previously. Their ages ranged from 51 to 57 years and their weights from 61 to 92.4 kg. Four patients had never received any hormonal medication but the fifth had beeen prescribed an oestrogen/progestogen preparation to alleviate menopausal symptoms for 36 months. Therapy had been discontinued 1 2 months previously.

The study lasted 11 days. To obtain base-line values venepuncture was performed between 09.00 and 10.00 hours on days 1 and 2. For the next 5 consecutive days (Days 3 to 7) one progesterone capsule containing 100 mg pure steroid was administered orally at 08.00 hours.

On Day 7 venepuncture was performed at hourly intervals from 9.00 hours to 16.00 hours and again at 20.00 hours. Additional blood samples were taken at 08.00 hours on Days 8, 9, 10 and 1 - i.e. 24, 48, 72 and 96 hours after administration of the last capsule. Each 20 ml blood sample was collected into iithium heparin tubes, centrifuged immediately and the plasma stored at -200C.

The metabolism was studied by determining the conversion to pregnanediol-3e'-glucurnnide, 20a-dehydrnprogesternne and 17hydroxyprogesterone.

All steroid hormones were measured by radioimmunoassay. The method for progesterone was as described by Youssefnejadin et al, Journal of Steroid Biochemistry, 1972, 3, p893, except that a more specific antiserum to progesterone11 a-succinyl-bovine thyroglobulin was used, and this reduced the cross-reaction with 5a- dihydroprogesterone to less than 15%. 20adihydroprogesterone and 1 7-hydroxyprogesterone were measured by the methods of Florensa et al in Steroids, 1973, 22, p451-465, and Youssefnejadian et al in Steroids 1972, 20, p733-788, respectively.Pregnanediol 3a- glucuronide was measured in a 50 ,ul plasma aliquot by adapting the method for estimating the concentration of this metabolite in urine in Acta Endocrinologica, 1979, 90, p336. Oestradiol was assayed using the method of Emment et al in Acta Endrocrinologica 1972, 69, p567 except that a more specific antiserum to oestradiol-6carboxymethyl oxime-BSA was used and this reduced the cross-reaction with oestrone to less than 2%.

For each steroid the distribution of values was examined by calculating the arithmetic mean, geometric mean, median, degree of skewness and kurtosis. The results obtained between 09.00 hours and 16.00 hours on Day 7 were examined in a similar manner after adjusting the time relative to the peak value for progesterone. As all values approximated to a normal distribution the levels before and after ingestion of progesterone were compared using Student's 't' test.

The attached figures will further illustrate the present invention by way of example.

Figure 1 shows the concentration of plasma progesterone plotted against time.

Figure 2 shows the concentration of the various steroids in peripheral plasma before and after oral administration of progesterone.

The concentration of plasma progesterone in all samples from every patient is shown in Figure 1.

All pretreatment levels (Days 1 and 2) were within the postmenopausal range for our laboratory.

Inter-patient differences in absorption of progesterone are shown by the variation in time elapsed between administration of the last capsule and achievement of maximal plasma values. Thus, in 3 patients maximal levels were observed 1 hour after the last capsule had been taken. However, the other 2 patients demonstrated slower absorption and peak values were reached 3 hours later at 12.00 hours. Similar plasma patterns were observed for pregnanediol-3c'- glucuronide, 20cr-dihydroprogesterone and 17hydroxyprogesterone.

To establish the temporal relationship in plasma between progesterone and pregnanediol 3-glucuronide, 20-dihydroprogesterone, 17hydroxyprogesterone and oestradiol the Day 7 values obtained between 09.00 hours and 16.00 hours were all standardised using the maximal plasma concentration of progesterone as a reference point "P". The means of these results, the Day 1 and 2 base-line values and those obtained between 24 and 96 hours after last capsule administration on Days 8 to 11 are shown in Figure 2. All pretreatment values were within the postmenopausal range for our laboratory.

The plasma concentrations of progesterone, pregnanediol-3 a-glucuronide, 20- dihydroprogesterone and 1 7-hydroxyprogesterone reached a peak simultaneously. Progesterone concentrations fell most rapidly and 4 hours after maximal levels were observed approximated those for 20e'-dihydrnprngesternne. Thereafter, the levels of these two hormones declined in a similar manner, the concentrations of 20- dihydroprogesterone just exceeding those of the parent compound. The values for pregnanediol 3o'-glucurnnide on Days 7 to 11 greatly exceeded those of 20a-dihydroprogesterone and 17hydroxyprogesterone and the latter were least elevated. Oestradiol levels were not changed by administration of progesterone and remained within the pretreatment range.

For each hormone, the peak values obtained on Day 7 and the values observed 12, 24 and 96 hours after administration of the last progesterone capsule were compared with the pretreatment levels.

The concentrations of progesterone were significantly elevated when maximal (p < 0.0005) and 96 hours after therapy had been discontinued (p < 0.01). The levels of pregnanediol-3- glucuronide and 20a-dihydrnprogesternne were significantly elevated when maximal and for up to 24 hours after discontinuation of therapy (p < 0.0005). The concentration of 17hydroxyprogesterone was significantly elevated only when maximal (p < 0.0025) and had returned to the pretreatment range within 12 hours of last progesterone ingestion. There was no significant change in oestradiol levels during the study.

The preferred mass of progesterone administered, 100 mg daily, is approximately four times the mean daily production by the ovary during the mid-luteal phase of the ovarian cycle.

However, the peak progesterone concentrations are generally within the luteal phase range thus indicating that approximately 25% of the orally ingested progesterone appeared in peripheral plasma.

The absorption, further metabolism and clearance of oral progesterone are rapid. Within 4 hours of ingestion maximal plasma concentrations of progesterone had been achieved in all 5 paitents and peak levels of the parent steroid and its 3 major metabolites occurred simultaneously.

The elevation of plasma progesterone to levels within the mid-luteal phase range lasted approximately 6 hours although the values at both 24 and 96 hours after ingestion of the last capsule were still significantly elevated above the baseline.

Of the major metabolites the elevation in the concentrations of pregnanediol 3cz-glucuronide was greatest and most prolonged. The peak mean factorial increase was 20.9 and 24 hours after discontinuation of therapy was 1 0.3. The values for 1 7-hydroxyprogesterone were least elevated, the peak factorial increase being only 3.7 and within 12 hours of administration of the last capsule had returned to the pretreatment range.

20a-dihydroprogesterone, uniike the other 2 metabolites, is not only biologically effective in its own right but is also formed from progesterone in target tissues such as the endometrium. Therefore elevation in the plasma levels of this hormone are important in terms of biological activity. The plasma concentrations of progesterone and 20a- dihydroprogesterone appear to indicate that orally administered progesterone may affect target tissues. Plasma concentrations which are sustained within the luteal phase range for longer periods of time may be necessary to achieve the optimal therapeutic response. Logically, administering progesterone either twice daily or in combination with cholesterol pivalete which increases the bioavailability will produce this effect.

Progestins are prescribed primarily for their anti-oestrogenic effects. Physiologically progesterone is an oestrogen precursor and extensive conversion of administered progesterone to oestradiol would be undesirable.

The absence of any significant change in oestradiol values during administration of progesterone is thus reassuring. Clinically oral progesterone may be of value when synthetic progestogens are either contraindicated or have produced adverse reactions. No side-effects appeared in the above tests.

Claims (9)

1. A method of relieving post-menopausal symptoms which method comprises administering a dosage of up to 300 mg per day of natural progesterone.

2. A method as claimed in claim 1 wherein the dosage is up to 200 mg per day.

3. A method as claimed in claim 1 wherein the dosage is up to 100 mg per day.

4. A method as claimed in any one of the preceding claims wherein the natural progesterone is administered in conjunction with a suitable pharmaceutical carrier.

5. A method as claimed in claim 4 wherein the pharmaceutical carrier is cholesterol pivalate.

6. A method as claimed in claim 1, substantially as hereinbefore described.

7. A unit dosage of natural progesterone in conjunction with a suitable pharmaceutical carrier.

8. A unit dosage of natural progesterone in conjunction with cholesterol pivalate as a suitable pharmaceutical carrier.

9. A unit dosage of natural progesterone, substantially as hereinbefore described.