US3795734A - Cyclic regimen of hormone administration for contraception - Google Patents

Cyclic regimen of hormone administration for contraception Download PDF

Info

Publication number
US3795734A
US3795734A US3795734DA US3795734A US 3795734 A US3795734 A US 3795734A US 3795734D A US3795734D A US 3795734DA US 3795734 A US3795734 A US 3795734A
Authority
US
Grant status
Grant
Patent type
Prior art keywords
progestin
day
estrogen
cycle
regimen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
Inventor
J Rochefort
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth LLC
Original Assignee
Wyeth LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Grant date

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/565Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/57Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane, progesterone
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S514/00Drug, bio-affecting and body treating compositions
    • Y10S514/841Contraceptive

Abstract

THE IS DISCLOSED HEREIN A METHOD OF ADMINISTERING HORMONES FOR PROVIDING CONTRACEPTION AND REGULATION OF THE MENSTRUAL CYCLE WHEREIN CONSECUTIVE DAILY DOSAGES OF A PROGESTIN ARE GIVEN DURING THE EARLY PHASE OF THE CYCLE, CONSECUTIVE DAILY DOSES OF AN ESTROGEN-PROGESTIN COMBINATION ARE GIVEN DURING THE MIDCYCLE AND CONSECUTIVE DAILY DOSAGES OF A PROGESTIN ARE GIVEN DURING THE FINAL PHASE OF THE CYCLE.

Description

United States Patent 3,795,734 CYCLIC REGIMEN F HORMONE ADMINISTRA- TION FOR CONTRACEPTION Joseph Guy Rochefort, St. Laurent, Quebec, Canada, as-

siguor to American Home Products Corporation, New York, N.Y. No Drawing. Filed Apr. 20, 1970, Ser. No. 30,302

- Int. Cl. A61k 17/06 US. Cl. 424-238 2 Claims ABSTRACT OF THE DISCLOSURE There is disclosed herein a method of administering hormones for providing contraception and regulation of the menstrual cycle wherein consecutive daily dosages of a progestin are given during the early [phase of the cycle, consecutive daily doses of an estrogen-progestin combination are given during the midcycle and consecutive daily dosages of a progestin are given during the final phase of the cycle.

BACKGROUND OF THE INVENTION Two therapeutic regimens are in general use for the present day estrogen-progestin contraceptives:

(1) Combinedthe estrogen and progestin are administered together Starting on day of the menstrual cycle. Day 1 is designated as the first day of menstrual bleeding. Medication is continued until day 25 or day 26. Normally menstruation occurs three to five days thereafter.

(2) Sequentialestrogen is administered alone from day 5, either for 15 or 11 days, a progestin is then added for another 5 to days, respectively, to induce withdrawal bleeding.

Notwithstanding the relative Wide acceptance of these regimens, adverse reactions are continually being reported for them in both the scientific literature and the lay press. A comprehensive report with leading references on the complications associated with these regimens can be found in the Second Report on Oral Contraceptives, Advisory Committee on Obstetrics and Gynecology, to the Food and Drug Administration, US. Govt. Printing Ofiice, Washington, DC, August 1, 1969.

In view of the recognized risks and side elfects of the present combined oral contraceptives, an intense effort has been mounted to develop contraceptives with reduced side effects while maintaining maximal efficacy. The most promising approaches in this direction include the use of progestin alone therapy by either oral administration, such as the continuous low dosage of a progestin regimen, or parenteral administration, such as depot injection or implantation of a progestin-filled silicone rubber implant, Second Report on Oral Contraceptives, cited above, pp. 16-17.

Side elfects associated with the estrogen-progestin regimens, such as nausea, weight gain, headaches and risk of thromboembolic problems, appear to be significantly reduced, rendering these progestin alone regimens better 3,795,734 Patented Mar. 5, 1974 irregular bleeding will make these progestin alone regimens unacceptable to most women, J. dA. Jefiery and A. I. Klopper, J. Reprod. Fert., Suppl, 4, 81 (1968) and Brit. Med. J., 4, 286 (1969).

-It is the object of this invention to disclose a new contraceptive regimen, which is effective, well-tolerated and substantially free from the side effects associated with either the currently available estrogen-progestin regimens or the newer progestin alone approaches.

SUMMARY OF THE INVENTION- The present invention relates to a new therapeutic regimen which provides contraception and regulation of the menstrual cycle.

More particularly, the regimen of this invention involves the administering of consecutive daily dosages of a progestin during the early phase of the cycle followed by consecutive daily dosages of an estrogen-progestin combination during the midcycle, followed by consecutive daily dosages of a progestin during the final phase of the cycle.

DETAILS OF THE INVENTION The intense effort to develop new techniques of contraception are attempts to escape from the multiple administrations of estrogen and combined estrogen-progestin and the side effects thereof, such as nausea, headache, weight .gain and increased risk of thromboembolic problems.

As noted above, even the most promising of the newer techniques, those involving progestin alone approaches have serious disadvantages of another kind, such as irregular bleeding and cycling.

Our present knowledge does not allow us to explain the reasons for these disadvantages. Clinical observations to date, however, point to the fact that the progestin alone regimens impede endometrial growth, J. Martinez- Manautou et al., Fertil. Steril., 17, 49 (1966) and references therein. A direct consequence of this impediment of growth, I believe, is the high incidences of breakthrough bleeding and irregular cycling.

I have now developed a reliable oral contraceptive regimen, comprising the administration of la progestin alone with a minimal supplemental estrogen reinforcement at a critical period of the menstrual cycle. The regimen is tolerated as well as the progestin alone regimens and overcomes the high incidences of breakthrough bleeding and irregular cycling. Indeed, an important aspect of this regimen is that it allows a normal or near normal endometrial morphology by supplying sufiicient estrogen at a critical period of the cycle, namely at the early part of the midcycle. By using this regimen with supplemental estrogen at this critical period, sufficient estrogen is available for development of a proliferative endometrium and subsequent support of the endometrium as it crosses from a proliferative phase to a secretory phase. Furthermore, since the present regimen allows an endometrial morphology similar to the natural, menstruation follows regularly after withdrawal of the medication in the final phase of the cycle.

Another important aspect of this invention is that only a minimal amount of estrogen is employed. Consequently, the side effects associated with the administration of large dosages of estrogens to women of child bearing age are avoided.

A preferred embodiment of the present invention is illustrated by the following regimen:

For the purpose of describing this embodiment a menstrual cycle of 28 days is assumed. The cycle is considered to be divided into four phases. Day 1 is the first day of menstrual bleeding of the first medicated cycle. In the first phase, days 1, 2, 3, and 4 are medication free. On

day 5, phase II begins. For' days 5 to inclusive, a pro- 11 to inclusive, medication is combined estrogen-progestin. On day 16, phase I V'begins. For days 16 to 26 in elusive, medication reverts to progestin alone. Phase I then begins anew with no medication for days 27, 28, 1, 2, 3 and 4 inclusive. (Alternatively, placebo treatment could be given during the phase I periods, to effect continuous pill-taking and by-pass possible patient failures.)

The actual duration of the various phases is not critical in that both days limiting their duration may be varied a day earlier or later. In other words, phase III may range from days 12 to 14 inclusive (three days) to days 10 to 16 inclusive (seven days).

The choice of suitable estrogens or progestins for use in this regimen also is not critical provided that they have proven therapeutic utility. Examples of suitable estrogens include 170a [3 furyl] estra-1,3,5(10),7-tetraene-3,17- diol S-acetate, ethynyl estradiol, mestranol and equilin sulfate. Examples of suitable progestins include medrogestone, ethisterone, norethindrone and clogestanone acetate. Examples of these and other suitable estrogens and progestins are described in the literature; for example, U. Banik 'et al., J. Reprod. FertiL, 18, 509 (1969), C. Dodds, Clin. Pharmacol. Therap., 10, 147 (1969) and E. Diczfalusy, Am. J. Obstet. Gynecol., 100, 136 (1968).

'Each of the aforenamed estrogen or progestin possesses its own particular degree of efiectiveness and has certain advantages over the others so that a particular estrogen or progestin to be used in a particular regimen of this invention will depend on the specific needs of the patient. Examples of daily dosages that may be used for this regimen are, for the estrogens, 0.01-0.1 mg./day/patient for 170: [3 furyl] estra-1,3,5(l0),7-tetraene-3,17diol and 0.1 to 0.5 mg./day 3-acetate, ethynyl estradiol, or mestranol; patient for equilin sulfate; and for the progestins mentioned above 0.5 to 3.0 mg./day/patient.

The above estrogens and progestins may be administered orally in solid dosage forms such as, for example, tablets, capsules, or the like. For those days when the regimen calls for administration of both estrogen and progestin tablets, capsules or the like may be formulated containing both those hormones. In tablet form the hormones are compounded with inert pharmaceutical carriers;

It is apparent that many variations may be'made in the" construction of the present embodiment of this invention without departing from the spirit of this invention. Such variations are intended to be included within the scope of this invention.

" I claim? 1. In a method of providing contraception and regulation of the menstrual cycle wherein estrogen and progestin hormones are administered to women during their menstrual cycle, the improvement which comprises: (a) administering orally, consecutive daily doses of a progestin in an oral daily dosage amount of 0.05

to 3.0 milligrams per day from the fifth day to the 26th day of said menstrual cycle after the first day of menstrual bleeding; and

(b) administering orally, consecutive daily doses of estrogen in an oral daily dosage amount of 0.01 to 0.10 milligram per day fona duration of three to seven. days within the tenth to-the 16th day of said menstrual cycle,

said specified dosages of estrogen and progestin being the only estrogens and progestins administered during said menstrual cycle.

2. In a method of providing contraception and regulation of the menstrual cycle wherein estrogen and progestin hormones are administered to women during their menstrual cycle, the improvement which comprises:

(a) administering orally, consecutive daily doses of progestin selected from the class consisting of medrogestone, e'thisterone, norethindrone and clogestanone acetate in an oral daily dosage amount of 0.5 to 3.0 milligrams per day from the fifth day to the 26th day of said menstrual cycle after the first day of menstrual bleeding; and

(b) administering orally, consecutive daily doses of estrogen selected from the class consisting of 17a- [3 furyl] estra 1,3,5 (10),7-tetraene-3,17-diol 3- acetate, ethynyl estradiol, mestranol and equilin sulfate in an oral daily dosage amount of 0.01 to 0.10 milligram per day for a duration of three to seven days within the tenth to the 16th day of said menstrual cycle,

said specified dosages of estrogen and progestin being the References Cited Physicians Desk Reference,- 22nd ed., published by Medical Economics, Inc, Oradell, N.J., 1967, pp. 1064- 1067.

RICHARD L.,HUFF, Primary Examiner US. Cl. X.R. 4424l, 242, 243

333 v UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent -a'mmvsu Dated March 5, 1 7? In nwfl Di. Rochefort It is certified that error appears in the above-identified patent and that said Letters 'Patent are hereby corrected as shown below:

The sentence starting at Column 3, line 32, should. readcorrectly as follows:

"Examples of dailyvdosages that may be used for this regimen are, for the estrogens, O-.Ol-O.l mg./da,y/patient for 17oL-[3-furyl1 -estra.-l,3,5,(10),7-tetraene-3,l7-dio1 3'- acetate, ethynyl estradiol, or mestranol; and. 0.1-0.5 mg./day/patient for equilin sulfate; and. for the progestins mentioned above, 0. 5 to 3.0 mg.,/d.ay pa.tient.

Signed and sealed this 17th day of September 1974.

(SEAL) Attest: V

McCOY M. GIBSON JR. o c. MARSHALL DANN o Attesting Officer 7 Commissioner of Patents

US3795734A 1970-04-20 1970-04-20 Cyclic regimen of hormone administration for contraception Expired - Lifetime US3795734A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US3030270 true 1970-04-20 1970-04-20

Publications (1)

Publication Number Publication Date
US3795734A true US3795734A (en) 1974-03-05

Family

ID=21853557

Family Applications (1)

Application Number Title Priority Date Filing Date
US3795734A Expired - Lifetime US3795734A (en) 1970-04-20 1970-04-20 Cyclic regimen of hormone administration for contraception

Country Status (1)

Country Link
US (1) US3795734A (en)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3892855A (en) * 1973-10-10 1975-07-01 Searle & Co Method for fertile breeding control in female bovine
US3939264A (en) * 1972-04-14 1976-02-17 Schering Aktiengesellschaft Method for contraception by the administration of sequential contraceptive preparations
US3957982A (en) * 1973-12-21 1976-05-18 Schering Aktiengesellschaft Method for contraception by the application of combination-type sequential preparations
US4018919A (en) * 1975-07-16 1977-04-19 Eli Lilly And Company Sequential contraceptive method using two types of progestational agents
US4143136A (en) * 1976-11-20 1979-03-06 Akzona Incorporated Method of contraception
DE3229612A1 (en) * 1981-08-10 1983-02-24 Syntex Inc pharmaceutical packaging
US4610687A (en) * 1984-08-06 1986-09-09 Board Of Trustees Operating Michigan State University Method for breeding control in female bovines
US5010070A (en) * 1987-06-15 1991-04-23 Warner-Lambert Company Graduated estrogen contraceptive
US5108995A (en) * 1987-09-24 1992-04-28 Jencap Research Ltd. Hormone preparation and method
US5276022A (en) * 1987-09-24 1994-01-04 Jencap Research Ltd. Hormone preparation and method
US20030207855A1 (en) * 2000-03-10 2003-11-06 Hill Edward N. Novel estrogenic compounds
US20040198670A1 (en) * 2003-04-04 2004-10-07 Hill Edward N. Novel estrogenic compounds
US20040259851A1 (en) * 2003-04-11 2004-12-23 Leonard Thomas W. Methods of administering estrogens and progestins
US6855703B1 (en) 2000-03-10 2005-02-15 Endeavor Pharmaceuticals Pharmaceutical compositions of conjugated estrogens and methods of analyzing mixtures containing estrogenic compounds
US20050038006A1 (en) * 1998-12-23 2005-02-17 Shangold Gary A. Triphasic oral contraceptive
US20060183724A1 (en) * 2005-02-03 2006-08-17 Diliberti Charles E Compositions of unconjugated estrogens and methods for their use
US20070111977A1 (en) * 2005-10-17 2007-05-17 Susan Zeun Combination preparation for oral contraception and oral therapy of dysfunctional uterine bleeding containing estradiol valerate and dienogest and method of using same
US20070142307A1 (en) * 2000-03-10 2007-06-21 Barr Laboratories, Inc. Novel estrogenic compounds
US20070259840A1 (en) * 2004-04-20 2007-11-08 Schering Ag Multi-Phase Contraceptive Preparation Based on a Natural Estrogen
US20080125401A1 (en) * 2006-10-20 2008-05-29 Susan Zeun Use of estradiol valerate or 17beta-estradiol in combination with dienogest for oral therapy to maintain and/or increase feminine libido
US20100234330A1 (en) * 2003-07-23 2010-09-16 Hill Edward N Novel Estrogenic Compounds

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3939264A (en) * 1972-04-14 1976-02-17 Schering Aktiengesellschaft Method for contraception by the administration of sequential contraceptive preparations
US3892855A (en) * 1973-10-10 1975-07-01 Searle & Co Method for fertile breeding control in female bovine
US3957982A (en) * 1973-12-21 1976-05-18 Schering Aktiengesellschaft Method for contraception by the application of combination-type sequential preparations
US4018919A (en) * 1975-07-16 1977-04-19 Eli Lilly And Company Sequential contraceptive method using two types of progestational agents
US4143136A (en) * 1976-11-20 1979-03-06 Akzona Incorporated Method of contraception
DE3229612A1 (en) * 1981-08-10 1983-02-24 Syntex Inc pharmaceutical packaging
US4610687A (en) * 1984-08-06 1986-09-09 Board Of Trustees Operating Michigan State University Method for breeding control in female bovines
US5010070A (en) * 1987-06-15 1991-04-23 Warner-Lambert Company Graduated estrogen contraceptive
US5108995A (en) * 1987-09-24 1992-04-28 Jencap Research Ltd. Hormone preparation and method
US5276022A (en) * 1987-09-24 1994-01-04 Jencap Research Ltd. Hormone preparation and method
US20050038006A1 (en) * 1998-12-23 2005-02-17 Shangold Gary A. Triphasic oral contraceptive
US20070142307A1 (en) * 2000-03-10 2007-06-21 Barr Laboratories, Inc. Novel estrogenic compounds
US20090105198A1 (en) * 2000-03-10 2009-04-23 Duramed Pharmaceuticals, Inc. Novel estrogenic compounds
US7459445B2 (en) 2000-03-10 2008-12-02 Duramed Pharmaceuticals, Inc. Estrogenic compounds and topical pharmaceutical formulations of the same
US6844334B2 (en) 2000-03-10 2005-01-18 Endeavor Pharmaceuticals (3) and (6) substitued estrogenic compounds
US6855703B1 (en) 2000-03-10 2005-02-15 Endeavor Pharmaceuticals Pharmaceutical compositions of conjugated estrogens and methods of analyzing mixtures containing estrogenic compounds
US20030207855A1 (en) * 2000-03-10 2003-11-06 Hill Edward N. Novel estrogenic compounds
US6660726B2 (en) 2000-03-10 2003-12-09 Endeavor Pharmaceuticals Estrogenic compounds, pharmaceutical compositions thereof, and methods of using same
US8227454B2 (en) 2000-03-10 2012-07-24 Duramed Pharmaceuticals, Inc. Estrogenic compounds, pharmaceutical compositions and formulations comprising the same
US7179799B2 (en) 2000-03-10 2007-02-20 Barr Laboratories, Inc. (3) and (6) substituted estrogenic compounds
US7749989B2 (en) 2000-03-10 2010-07-06 Duramed Pharmaceuticals, Inc. Estrogenic compounds, methods of using and methods of administering the same
US6992075B2 (en) 2003-04-04 2006-01-31 Barr Laboratories, Inc. C(14) estrogenic compounds
US20040198670A1 (en) * 2003-04-04 2004-10-07 Hill Edward N. Novel estrogenic compounds
US20040259851A1 (en) * 2003-04-11 2004-12-23 Leonard Thomas W. Methods of administering estrogens and progestins
US7989436B2 (en) 2003-07-23 2011-08-02 Duramed Pharmaceuticals, Inc. Estrogenic compounds and pharmaceutical formulations comprising the same
US20100234330A1 (en) * 2003-07-23 2010-09-16 Hill Edward N Novel Estrogenic Compounds
US8071577B2 (en) 2004-04-20 2011-12-06 Bayer Pharma Aktiengesellschaft Multi-phase contraceptive preparation based on a natural estrogen
US20070259840A1 (en) * 2004-04-20 2007-11-08 Schering Ag Multi-Phase Contraceptive Preparation Based on a Natural Estrogen
US20060183724A1 (en) * 2005-02-03 2006-08-17 Diliberti Charles E Compositions of unconjugated estrogens and methods for their use
US20070111977A1 (en) * 2005-10-17 2007-05-17 Susan Zeun Combination preparation for oral contraception and oral therapy of dysfunctional uterine bleeding containing estradiol valerate and dienogest and method of using same
US8153616B2 (en) 2005-10-17 2012-04-10 Bayer Pharma Aktiengesellschaft Combination preparation for oral contraception and oral therapy of dysfunctional uterine bleeding containing estradiol valerate and dienogest and method of using same
US20080125401A1 (en) * 2006-10-20 2008-05-29 Susan Zeun Use of estradiol valerate or 17beta-estradiol in combination with dienogest for oral therapy to maintain and/or increase feminine libido
US8349820B2 (en) 2006-10-20 2013-01-08 Bayer Pharma Aktiengesellschaft Use of estradiol valerate or 17β-estradiol in combination with dienogest for oral therapy to maintain and/or increase feminine libido

Similar Documents

Publication Publication Date Title
US3409721A (en) Oral dosage system effective to control the reproduction cycle
Croxatto et al. Fertility control in women with a progestogen released in microquantities from subcutaneous capsules
US5521166A (en) Antiprogestin cyclophasic hormonal regimen
Wallach et al. Prolonged estrogen therapy in postmenopausal women
US5543150A (en) Method of progesterone delivery and affect thereof
US3957982A (en) Method for contraception by the application of combination-type sequential preparations
Magos et al. Treatment of menstrual migraine by oestradiol implants.
US4425339A (en) Treatment of menopausal symptoms
US4628051A (en) Triphasic oral contraceptive
US4616006A (en) Triphasic oral contraceptive
US4390531A (en) Method of contraception using peak progestogen dosage
US3639600A (en) Process of establishing cyclicity in a human female
US4544554A (en) Triphasic oral contraceptive
US4921843A (en) Contraception system and method
US6451779B1 (en) Composition and method for contraception and treatment of tumors of the mammary glands
US5827843A (en) Preparation for substitution therapy, containing at least one progestogen and at least one estrogen
US4945103A (en) Method of treating pre-menstrual syndrome
US4530839A (en) Triphasic oral contraceptive
US4291028A (en) Follicular phase estrogen or progestin with physiologic estrogen/progestin luteal phase replacement drug delivery system
US6995149B1 (en) Contraceptive process and kit for female mammals, comprising a combination of gestagen and oestrogen
US7427609B2 (en) Treatment of conditions relating to hormone deficiencies by administration of progestins
US5583129A (en) Composition for contraception
US4855305A (en) Compositions and methods of effecting contraception utilizing melatonin
Zárate et al. Successful induction of ovulation with synthetic luteinizing hormone-releasing hormone in anovulatoy infertility.
US5418228A (en) Contraceptive regimen