JPS5913731A - Birth control using gestogenic hormone releasing factor agonist - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The "natural" occurrence of a short or insufficient luteal phase of the menstrual cycle in humans [G. Nis Jones and V. Madrigal Castro, Fertil.

Steril, Volume 21, Page 1 (1970) *B.
M Sherman and H.S.G. Korenman, J.
CIin, gndocrinol, Metab,
Vol. 38, p. 89 (1974); T. Annus, I. E. Thompson and M. L. Timer, Qb.
stet, (jynecol, vol. 55, no. 705
Sada (1980)) and that in a colander [Lieu W. Wilkes, G. D. Holadien and T. J., CI in, Endocrinol
, Metab, f, vol. 45, p. 1261 (
1976); T.E. Nass, T.L. Dierschke, L.R. Clark, B.N. Mellor and K.K. Shiloh, "Ovarian follicles and the corpus luteum system", C.B. Channing, Lew Marsh and W Zadler, eds. (Plenum Publishing, New York, 1979), p. 519; G. Nis de Zerega and G. D. Horadien, Fertil.

5teril 0, Volume 35, Volume 4B90 (1981)
] is increasingly being recognized as a prominent cause of amnesia and recurrent early miscarriage. C Tsuda [Ryu L H
Horta, Liu G. Fernandez, L.B.
Punto and D. Cortex Gallegos, (Jbs
tet, Qynecol, vol. 49, p. 705 (
1977); G. Nis Deizerega and G. D. Horadien, ); ndocrinol, Itev
, vol. 2, p. 27 (1981)). The endometrium of women with such luteal phase defects is affected by estradiol (
It is known that as a result of the inhibition of secretion of E2) and progesterone, it develops inadequately both in terms of its morphology and function. In general, normal pre-reactions do not occur and normal egg implantation is therefore inhibited [D.
Earl Treadway, D. R. Mitschel and D. L. Moyer, AlT1. J, sbst
et, Qynecol, %117, No. 1031
(1973); D. L. Rosenfelt and C. R. Garcia, Fertil, 5teri.
1. Vol. 27, p. 1256 (1976); N. C. Wentz, supra, Vol. 66, p. 121 (1980)
).

In monkeys, it has been demonstrated that this type of luteal defect is the result of a deficiency of follicle-stimulating hormone (FSH), resulting in suboptimal holiculogenesis. However, in women, there is no direct proof that FSH deficiency during the early follicular phase of the menstrual cycle is causative for the consequences of luteal dysfunction following inhibition of follicular maturation.

Since dystonia is a major feature of luteinizing hormone dysfunction, pharmacologically induced luteal defects would be expected to provide significant "J" potential as a treatment for luteinizing hormone-releasing factor (LJ). Long-term infusion or long-lasting effect of (F) L It
1! ``Daily administration of the active agent is known to induce pituitary desensitization, resulting in decreased concentrations of circulating gonadotropins [C. Bergist, Nis. Liu, N. and L. Waid, J.;

Cl1n, Endoctinol, Metab, fruit 4
Volume 9, No. 472A (1979); D. Rabin and El W. Maccnail, Volume 51, No. 87.
Page 3 (1980); D. Henoku and R. Nis. Swerdlov, vol. 52 (1981 L. R. F. Kasper and Nis.
Ibid. Volume 56, No. 1056 Sada (1981)).

Now, according to the present invention, it has been found that administering an LktF agonist very early in the follicular phase causes insufficient folliculogenesis and subsequent luteal dysfunction.

As used herein, 1J) means luteinizing hormone, FSI-1 means follicle ψ1 hormone, E2 means estradiol, and P means progesterone. .

In short, the present invention is a novel fertility inhibitor consisting of an active agent of luteinizing hormone-releasing factor, which acts on the membranes of +E stereotypic women during menstruation.

Further, in detail 1, the present invention provides an effective amount of (D-Trp6.Pro
It includes a novel fertility suppressant consisting of I'JE t ) I, ) tF.

The aim of the present invention is to provide a new means of fertility control.

It is particularly important to note that the object of the present invention is to avoid the frequent use of drugs: 1. The objective is to provide an anti-fertility biomembrane.

These and other advantages of the present invention will become apparent from the detailed description below.

Five normal women (age 22~) with 28B menstrual cycle.
69 years old) was subjected to this test. In each specimen, luteinizing hormone (J, H), F S II, E2, and progesterone were determined daily to determine the comparison cycle and treatment cycle [Nis-Nis-C-Yen, O. Relena, Be Little and O-Hex
Pearlson, J., CI in, 11;n(lo-
crinol, MetaJ, Volume 28, No. 176”)
Sada (196B); Nis Nis See Yen, El Ni Lilena, O. H. Pearlsson and Hier Nis Little, vol. 30, p. 325 (1970);
D.C. Undergin, B.R. Twoper, B.L. Laslei and Hies Nis.C, (
, T-n, 5teroids Yang vol. 28, p. 179 (1976);
S.C., Am, J., (Jbstet, G.
ynecol.

Vol. 121, p. 495 (1975)]. The treatment cycle is
For the first 5 days after the onset of heavy menstruation, s o pg
[D −'l”rp' −Pro9NE t )−1
, ltF 9) 8 included subcutaneous administration. This long-acting LltF agonist has approximately 140 times the ability of natural decapeptide LRF in women.
F Song, H. LeBlanc and T.M. Schiller, Recent Prog, Norm, ) (e
s, vol. 31, p. 321 (1975)). [L)-1”rp6・Pro9NEt] used in this test
-LRF+! Synthesized and provided by W Peil and G. Rivier, Salk Institut, Giora, California. The use of a dose of 50 µg with active rate is pre-administration during the follicular phase of the menstrual cycle - response test [
R.F. Kasper, G.L.C/1n and H.N.C.Y., J., C11n.

Endocrinol, Meta3 Vol. 50, No. 179 Negative (1979)), where the maximal gonadotropin response and the small (pronounced L, both lasting 24 hours) - (upper row) This was achieved with only a 50μy dose.

Ltl' administered in this study was first administered to LH and F
It induced a transient increase in circulating concentrations of S H as well as gonadotropin-dependent secretion of ovaline. A low F level of FS) I then occurs, which is lower than that in the comparison cycle during the remainder of the follicular phase (P<0.1, i
(Fig. 1). Figure 1 shows 1.3 days after the onset of menstruation. Changes over time and quantitative changes in circulating concentrations of L HlF S H1E2 and progesterone (inside the hatched frame, upper left) during the menstrual cycle of four normal women treated with LTF active drugs (standard error above the mean) ) compared to previous comparison cycles. Data were centered around the mid-cycle gonadotropin peak (day zero). The onset of heavy menstruation occurred during the treatment cycle (within the solid box).
It occurred at 9H in the comparison cycle (within the dotted line frame), and occurred 14B after the mid-cycle surge. On the other hand, L
Administration of RF-driven rates did not produce appreciable changes in serum LH concentrations.

After an initial transient rise, serum E2 was not significantly affected until the last 4 days of the follicular phase, during which time E2 concentrations in the treatment cycle were found to be significantly lower than in the comparison cycle ( Pku01, analysis of changes). L
The hormonal changes induced by RF activation were associated with a 9-day delay in the onset of the mid-cycle gonadotropin surge, thus resulting in a long-lasting follicular phase (
Table 1).

The peak levels obtained for 1J11, FSH and I in the surge were significantly lower in the treatment cycle than in the comparison cycle (Po, o1, respectively).
, < 0.005 and (o, os) (Fig. 1)
.

Table 1 Comparison period and l, It ↓ Half mean difference (Semi-standard error) between the period with the main drug treatment and the circumference M length and length of the follicular phase and j + ￥ body phase in K. Administration of I, it F (6) drug resulted in short luteal phase in 4 subjects and incomplete luteal phase in 1 subject.

Treatment iK 2i2±1.2 9.2±0.2
5&4±(1,7 comparison 142±0.2
14.0±03 28.2±021 samples (second
The results for this specimen with an incomplete dorsal phase, as indicated by abnormally low levels of E2 and progesterone that precipitate a normal-length luteal phase, indicate an average shortening of the follicular phase. excluded in the analysis of persistence. Figure 2 is 1
LH,l! between the comparison cycle and the LRF active drug treatment IN cycle in human samples (Table 1)! ” shows the pattern of circulating concentrations of SH, W2 and progesterone (P). This specimen shows a long follicular phase (1
19 days instead of 4 days) and F at the time of the round 1 intermediate surge.
They showed decreased concentrations of S H and E2 and normal luteal phase length, but decreased I arch and progesterone levels during the entire luteal phase of the treatment cycle.

Data are mid-cycle gonadotropin surge (day zero)
(The solid line frame indicates the period of menstruation).

These follicular phase deviations appear to continue into the luteal phase.

)! Although the concentrations of LH and FSH during the systemic phase were similar to those in the comparison, a significant decrease in the accuracy of E2 and progesterone in the serum was observed during the treatment cycle. What is most important is the early loss of luteal function, evidenced by the decline in 1c2 and progesterone on days 8 and 9 after the gonadotropin surge, approximately 5 days before the luteal regression event in the comparison cycle. It corresponds to Therefore, the average luteal N' was shortened from 14.0 days to 92 days (Table 1 and Figure 1). In one specimen with a luteal phase of normal length in the treatment cycle (Fig. 2), the concentrations of E2 and progesterone were clearly lower than in the comparison cycle (incomplete luteal phase); It shows impaired steroidogenesis and luteal insufficiency.

Wound follicle 4Ii abnormalities common to treatment cycles in all specimens may be the cause of subsequent luteal dysfunction.

1. The mechanism explaining this sustained effect on whole ovarian cycles after early exposure to J(l' agonists is unclear. Unlike the effect of LkJ, F agonist rates in rats, L4F agonists in humans It probably does not act directly on the ovary, indicating the lack of effect of I on steroidogenesis in isolated human M granulosa cells and the lack of effect on It F agonism on corpus luteal cells in monkeys.
4E is revealed by the absence of Jtlli' or its main garden music combination [R.F. Kasper, G.F.
Eric Gin, Earl W Liver and Varnish
Nis See Yen, JI'r2rtii, 5ter
il (in press);
C.N.E.T., T.H.K.O. and N.V.Shari-1J, Cl1n, Endocri
nol, Metab, f, vol. 53, p. 215 (
1981)), FS) i minute that decline and therefore FS
Jl vs 1. An inappropriate ratio of H has a negative effect, It
This may result from initial hyperstimulation and subsequent gonadotropin "desensitization" due to F activation. This preferential decrease in FSH9 secretion can also be explained by the initial increase in IB, whose inhibitory effect is more potent on FSH than on L14.

In any case, this relative FSH reduction would result in a relative deficiency of FSH-dependent enzymes such as aromatase, which converts androgens to estrogens in granular gland cells. ,knee·
Petro and Sonny Kaiser, J.
, l;ndocrinol, Metab, Volume 28, Page 355 (196B); Rai Nis.
Moon, B.G. Tsang, C. Simpson and D.T. Armstrong, Volume 47, No. 265N (1978); , R.W. Lever and Niss Niss.Yen, l”l ifi vol. 49, 451
4 Tei (1979); G.B. Matsukunutty, Nie Marquis, C. DeGrazia, Earl Osatano/
and G. Sonny Ryan, Volume 51, No. 12.
86 pages (19ao)). 1 for granular gland #Ill cyst!
'Selective binding of SR not only results in FSH receptors and aromatase activity, but also induces LH receptors [Sonny Nis Richyard, "Development and Function of Ovarian Follicles", Eng. Parle Midgley and Dubsonny Knee Chorus 2~ (Lapen Publishing, New York, 197
9), No. 225]. Therefore, in the ovolateral phase)'
SR deficiency leads to a decrease in the number of J and H receptors for the luteal phase, resulting in a decrease in the luteotrophin activity of LH to the luteal cells. This interpretation suggests that human chorionic gonadotropin (t+ C
Consistent with the observation that treatment with (↑) fails to restore luteal function [Gi Nis Jones,
Nice Axel and Nie C. Wentz, Ol]S
te t, (j)'necol, vol. 44, p. 26 (1974); R. L. Stonfer and G. D. Horadien, J C11n, 1st ndocrinol.

Ivletab, Volume 51, No. 669 (1980
)).

Furthermore, low F HCq sensitivity of the corpus luteum^11 follicles in vitro was observed in monkeys with follicular phase F S H deficiency exposed to porcine follicular fluid.

L Hl! 'Although the main agonists are also effective luteolytic agents, the existence of a narrow range of maximum sensitivity during the capsule phase of the cycle precludes the practical use of these active drugs as evacuation agents.・F. Kasper and Hiece Nissian, 5C1enCe Volume 205, No. 408
Page (1979); N. Lemay, F. Laplier, N. Pelanger and Sonny B. Tinaud, Fert.
il, 5jeri1. Volume 32, page 646 (197
9); C.L. Sheehan, R.F. Kasbah and H.N.C. Ibid. (in press)]. The corpus luteum group did not occur with the administration method used by the applicant, and the second pregnancy was probably 1-2 days after the expected date of egg implantation) ii, + (
Early regression of the corpus luteum (8 to 9 days after the LH surge) [N.T. Hertig and Sonny Locke,
Am, J, (Jbstet, '(jynecol
, Vol. 4, p. 149 (1974); T. N. Cosaza, L. N. Lebesta, T. P. Goldstein and M. L. Timer, J. (I'l
in, P;ndo-crinol, Metab,
Volume 36, No. 622 Sada (197+); G.D. Brownstein, G.M. Prolin, Sonny Vuaikkaitis and G.T.-0S, Am1J,
(Jbstet, 1jynecol, vol. 115,
No. 447 (1973); C. Sonny Kat, M. L. Dufau and Sonny L. Guaitzkaitis, J., CI in, Endoctinol 1.
Metab.

Volume 40, page 537 (1975); D.R.
Mitschel, R.O.M. Nakamura, Sony M.
Barberia and F.H.7-Neycroft, #+
1. J, (Jbstet, Qynecol,
@ Vol. 118, No. 990 (1974)) and the resulting incomplete growth of the estrogen-progestin A+ sex glands in the uterus. The convenience of coordinating the administration of a li lt F active drug at the onset of menstruation is a major advantage for practical use against fertility control, and the convenience of administering only one li lt F active drug per month. Give possibilities.

The drug of the present invention is [D-tryptophan-6/proline-
9=ethylamide) L +t II''. The production of this drug is already in its quiver 1. This drug can be administered at doses 5-10 times higher than 50 μM per day. , this drug can give only 2 losses of 41 days counting from the onset of profuse menstruation. do.

There are various administration methods: subcutaneous route, Kaisatsu route,
The intravaginal route etc. fall within l)- of the present invention.

The drug can be administered as a solution in standard diluents or as an intranasal spray, or in other conventional forms.

Having thus described the invention in detail, it is intended that the invention be limited only by the scope of the claims that follow.

Male 1 figure shows Lll, FSH1E2 and glogesterone (
FIG. 2 is a graph showing changes over time and changes in the concentration of L H, F in different samples.
S H1E2 and glogesterone (P) 54 t
It is a graph which shows the pattern of I degree.

Name of agent: Motohiro Kurauchi - Akira Kurahashi (Procedure: November 1982) IB Commissioner of the Patent Office Kazuo Wakasugi Indication of 1981 Patent application 117th
059 Relationship with f'l among those making amendments Patent applicant's agent telephone number 273-6436 Same address Same as above 1'\ Name (7563) Patent attorney Kurahashi
FEI of notification of arrest order (= 1 January 26, 1981, 1. Roaring Light Tsurike was invented and the subject application of Sodeichi was invented t - Applicant's (1 1 □ 1 - next year) (Detailed explanation of the invention - Power of attorney and its translation)
1 copy each of drawings 1 copy ltn, 1: Contents of engraving of the drawings as shown in the attached sheet (no changes to the content)

Claims (1)

[Scope of Claims] (il) A fertility inhibitor consisting of a luteinizing hormone-releasing factor active drug administered during menstruation to women with normal cycles. (2) Administered primarily for 6 days from the start of multilobar menstruation. (3) The fertility inhibitor according to claim 1, which is administered by subcutaneous route. (3) The fertility inhibitor according to claim 1, which is administered by subcutaneous route. ``The fertility suppressant according to claim 1. (5) The fertility suppressant according to claim 1 which is administered by vaginal route. (6) The effective dose for suppressing fertility administered during menstruation in a woman with a normal cycle. (D-Trp'-Pro NE t ) LR
Fertility suppressant consisting of F. (Katana) The fertility suppressant according to claim 6, which is mainly administered for three days from the start of Tabazuki bond. (8) The fertility suppressant according to claim 1, which is administered by subcutaneous route. (9) The fertility suppressant according to claim 6, which is administered by the nasal route. OI The fertility suppressant according to claim 86, which is administered by the vaginal route.