INFERTILITY OR INCREASING FERTILITY
Technical Field The present invention relates to the use of an anti-inflammatory substance, corticosteroid hormone or acetylsalicylic acid for the manufacture of a medicament for use against infertility or for increasing fertility.
Background of the invention
Infertility is generally not considered as an illness. Infertility or subfertility is often a problem for people afflicted therewith. A common treatment of infertile women is IVF (in vitro fertilization) treatment. The basis of the IVF treatment is as follows: Stimulation of ovulation: Daily hormonal injections, ultrasound examinations and blood samples. Oocyte retrieval : Ultrasound guided ovarian punctures performed vaginally under local anesthesia. Preparation of spermatozoa: Swim-up, swim- down, sperm select or other methods to select the optimal population with the best progressive motility.
In vitro fertilization: Incubation of oocytes and the selected population of spermatozoa in a cell incubator. Direct microscopic inspection of cell division and selection of the most vital fertilized oocyte .
Embryo transfer: 2-3 fertilized oocytes with the best vitality is deposited in the uterine cavity for hopeful implantation in the endometrium.
IVF treatment is an expensive method that, for some couples, initiates complicated psychological side effects. The technical and artificial way of trying to
become pregnant has the disadvantage that the couple going through the treatment may experience adverse effects to their relationship because of the treatment process. After all the troublesome treatment, there is only an overall pregnancy rate of 25-30%, leaving those who did not succeed with a damaged relationship and still no child. The cost for complete IVF treatment is around 20,000-25,000 SEK per menstrual cycle.
In spite of several previous investigations, the reasons for infertility during endometriosis is not clear and neither is the lack of improved fertility rate after treatment. Particularly, the relationship is unclear between mild endometriosis and subfertility in the absence of pelvic adhesions. Increased numbers of leukocytes have been found in the peritoneal fluid (PF) in patients with endometrial peritoneal implants and has been considered as an ongoing sterile inflammation. The increased number of leukocytes contains in vivo primed macrophages secreting a macrophage derived growth factor (MDGF) that may explain the proliferation of the endometrial tissue. Other secretory products from the macrophages, growth factors such as TNF and interferon, exhibit gamete toxicity and may also have an adverse impact on the fertility process. Also, the cell-free peritoneal fluid is of importance in the reduced fecundity since it has been shown that it significantly reduces the ovum pick-up capacity of the fimbriae of the fallopian tubes. In peritoneal fluid from patients with endometriosis and unexplained infertility, respectively, a reduced progressive velocity of spermatozoa has been found. Even more interesting is the increased phagocytosis of spermatozoa that have been found during incubations for 24 hours in vitro with peritoneal fluid from patients with endometriosis. In that particular study, there were, however, several different sperm donors and,
therefore, immunological factors involved cannot be excluded.
Summary of the invention The present invention is an alternative method to the IVF treatment for fertilization of women. It has been found by in vitro studies that phagocytosis of spermatozoa is reduced by lidocaine and it is suggested that this effect of lidocaine is due to stabilization of the cell membrane by prohibiting the increase of Na+ permeability and by probably interfering with ATP in the cell membrane. The same effect could be expected for anti-inflammatory substances such as NSAID (non steroid anti -inflammatory drugs) , corticosteroid hormones, acetylsalicylic acid and other drugs with anti -inflammatory effect. The cost for enhancing fertility with anti-inflammatory drugs will be approximately 10% of the IVF treatment, e.g., 2,500 SEK per menstrual cycle. There is no technical fertilization process that can cause psychological side effects. This treatment can be tried in patients with endometriosis and/or slight mechanical cause of infertility. It can be carried out while waiting for IVF and does not affect the possibility of successful later IVF treatment. So far, no treatment of infertility with anti -inflammatory substances is reported in the literature.
Detailed description This invention refers to the use an anti -inflammatory substance, corticosteroid hormone or acetylsalicylic acid, for the manufacture of a medicament for reducing the sperm phagocytosis and thereby the use against infertility and for increasing fertility. The anti-inflammatory substance may be selected from any substance that has an anti-inflammatory effect. A membrane stabilizing and reduced effect on phagocytosis
of spermatozoa is expected of anti-inflammatory substances in the same way as for local anaesthetic substances. Examples of such substances are indomethacin, sulindac, diklofenac, ketorolak, piroxicam, aceklofenak, tenoxikam, meloxikam, ibuprofen, naproxen and ketoprofen. Other anti-inflammatory substances could also be used. The same effect could be expected for anti-inflammatory substances such as NSAID (non steroid anti-inflammatory drugs) , corticosteroid hormones, acetylsalicylic acid and other drugs with anti-inflammatory effect.
A suitable NSAID may be selected from the group of:
1. Indomethacin: [1- (4-chlorobenzoyl) -5-methoxy-2-methylindol-3-yl] acetic acid;
2. Sulindac:
(Z) [5-fluoro-2-methyl-l- {4- (methylsulphinyl) benzylidene] i nden-3-yl] acetic acid; 3. Diklofenac: [2- (2 , 6-Dichloroanilino) phenyl] acetic acid;
4. Ketorolak: (+) -5-Benzoyl-2 , 3-dihydro-lH-pyrrolizine-1-carboxylic acid with 2-amino-2- (hydroxymethyl) -1, 3-propanediol ; 5. Piroxicam:
4=Hydroxy-2 -methyl -N- (2-pyridyl) -2JJ-1, 2-benzothiazine-3-c arboxamide 1,1-dioxide;
6. Aceklofenak: [o- (2 , 6-Dichloroanilino) phenyl] acetate glycolic acid ester; 7. Tenoxikam:
(4 -Hydroxy-2 -methyl -N(pyrid-2 -yl ) 2N-thieno [2 , 3-e] 1,2 thiazine-3-carboxamide) 1, ldioxide;
8. Meloxikam.
9. Ibuprofen: (RF) -2- (4-isobutylphenyl) propionic acid; 10. Naproxen : (S) -2- (6-methoxy-naphth-2-yl) propionic acid; and
11. Ketoprofen: (RF) -2- (3-benzoylphenyl) propionic acid.
The corticosteroid hormone may be selected from any substance that has an steroid effect. Examples of such substances are :
1. Cortisonacetat : 17 , 21-dihydroxypregn-4-ene-3 , 11, 20-trione 21-acetate;
2. Hydrocortisone : llβ, 11 oi , 21-trihydroxypregn-4-ene-3 , 20-dione;
3. Betamethasone :
9-fluoro-llβ, 17c, 21-trihydroxy-16β-methylpregna-l, 4-diene -3, 20-dione;
4. Dexamethasone :
9 - f luoro- 1 lβB , 11 a , 21 - trihydroxy- 16o;-methylpregna- 1 , 4 -dien e-3 , 20-dione ;
5 . Methylprednisolone : llβ, 17 , 21 -trihydroxy- 6c methylpregna- l-4 -diene-3 , 20 -dione 21 - (hydrogenbutanedioate) ;
6. Prednisone:
17, 21-dihydroxy-pregna-l, 4-diene-3 ,11, 20-tione;
7. Prednisolone : llβ, 17,21-trihydroxypregna-1, 4-diene-3, 20-dione;
8. Triamcinolone : 9-fluoro-llβ, 21-dihydroxy-16o!, 17-isopropylidenedioxypregna-l,4-diene-3 , 20-dione; and
9. Deflazakort.
Other corticosteroid hormones could also be used. The same effect could be expected for anti-inflammatory substances such as NSAID (non steroid anti-inflammatory drugs) , corticosteroid hormones, acetylsalicylic acid and other drugs with anti-inflammatory effect. The acetylsalicylic acid may be selected from any substance that is analogue to acetylsalicylic acid and has similar anti-inflammatory effect. Examples of such substances are :
1. Acetylsalicylic acid (ASA) and derivatives of ASA: 2-acetoxybenzoic acid;
2. Salazopyrin:
3. Nabumeton :
4. Azapropazone;
5-Dimethylamino-9-methyl-2-propylpyrazolol [1, 2-a] [1, 2 , 4] b enzotriazine-1, 3 (2H) -dione;
5. Sodium Aurotiomalate : Gold Sodium Thiomalate, Sodium Aurothiosuccinate;
6. Auranofin: (1-Thio-β-D-glycopyranosato) (triethylphophine) gold; and
7. Penicillamine :
(S) -2-amino-3-mercapto-3-methylbutyric acid. Another feature of the present invention is a pharmaceutical composition comprising a pharmaceutically effective concentration of an anti-inflammatory substance, corticosteroid hormone or acetylsalicylic acid together with a pharmaceutically acceptable excipient. The composition is preferably administered in the peritoneal cavity, preferably by perturbation.
The active ingredient can be mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient, and in amounts suitable for use in the therapeutic methods described herein. In addition, if desired, the composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and the like, which enhance the effectiveness of the active ingredient.
The pharmaceutical composition of the present invention can include pharmaceutically acceptable salts of the components herein. Pharmaceutically acceptable salts include the acid addition salts that are formed with inorganic acid, such as, e.g., hydrochloric or phosphoric acids; or such organic acids as acetic, tartaric and mandelic acid.
Suitable physiologically tolerable carriers may include liquid carriers such as sterile aqueous solutions that contain no materials in addition to the active ingredients and water, or contain a buffer such as sodium phosphate at physiological pH value, physiological saline
or both, such as phosphate-buffered saline. Still further, aqueous carriers can contain more than one buffer salt, as well as salts such as sodium and potassium chlorides, dextrose, propylene glycol, polyethylene glycol and other solutes .
The composition may also comprise hyaluronan, which is a viscous substance, e.g., in gel formate. Hyaluronan may give a slow release of the active substance which is preferable as conception may take place up to 24 hours after ovulation and treatment according to the invention. Another advantage is that hyaluronan has the capacity and capability of selecting the most active spermatozoa.
The invention also embraces a process for treating infertility in a woman with a pharmaceutical composition according to the invention, characterized in that the pharmaceutical composition is inserted by perturbation.
The invention especially relates to a cosmetic or a non-therapeutic method against infertility or for increasing fertility wherein: a) ovulation is diagnosed, b) a treatment with an anti-inflammatory substance, corticosteroid hormone or acetylsalicylic acid is given when ovulation is expected according to step a) . The treatment is preferably done by perturbation. Preferably the steps are as follows: Spontaneous ovulation: primary treatment during normal menstrual cycle. Stimulation only in anovulatory patients and primary with Clomifen (tablets) which is easy and inexpensive. One blood sample is needed postovulatory to confirm that there has been an ovulation during the treated cycle.
LH (luteinizing hormone) test: The LH-surge 24-36 hours prior to ovulation is diagnosed by self test at home of urine sample.
Perturbation: When the LH-test is positive a perturbation treatment is given with, e.g., 10 ml of a
suitable concentration of the anti-inflammatory substance in physiological NaCl or Ringer-solution during a normal gynecological examination. There will be no need for anesthesia. Fertilization: No artificial treatment. The couple will try and achieve pregnancy by normal way by coitus at home after the perturbation treatment is given. As mentioned in the introduction, the fimbriae of the fallopian tubes are constantly moistured by peritoneal fluid which, in the case of patients with endometriosis, reduces the capacity of ovum pick-up. We have found that the leukocytes in the peritoneal fluid of patients with endometriosis are more potent in phagocytizing spermatozoa. Thus, women with endometriosis can have two factors contributing to their reduced fertility.
While the present invention has been described in accordance with preferred compositions and embodiments, it is to be understood that certain substitutions and alterations may be made thereto without departing from the spirit and scope of the following claims .