MXPA01011208A - Gonadotrophins - Google Patents

Abstract

The present invention relates to the use of gonadotrophins in the induction of folliculogenesis in anovulatory women. In particular, it relates to the use of LH (or an equivalent dosage of hCG) in the production of a medicament for inducing folliculogenesis in anovulatory women at a specified daily doses. In certain embodiments, LH may be used in conjunction with FSH.

Description

GONADOTROPINAS Description of the invention The present invention relates to the use of gonadotropins in the treatment of anovulatory women. In particular, this refers to the use of luteinizing hormone (LH) to promote follicle development, and especially paucifollicular and monofollicular development, when ovulation is induced in anovulatory women. Gonadotropins are widely used in clinical practice to treat women with anovulation WHO of group II and WHO of group I (Technical Report of the World Health Organization 514, (1973)). Conventionally, folliculogenesis is induced by the administration of hMG (human menopausal gonadotropin) or u-hFSH (human follicle stimulating hormone, urinary) at a dose of 75-150 IU / day. This dose is increased after a few days (usually five) by gradual moments of 75 IU. It is rare to exceed 450 IU / day. When there is at least one follicle having an average diameter of at least 18 mm and no more than two follicles having a mean diameter of at least 16 mm, a high dose (of 5000) is administered. Ul for example) of hCG (human chorionic gonadotropin) to induce ovulation. This "conventional protocol" has been used successfully for more than 20 years. This nonetheless carries some risks, mainly in patients with polycystic ovarian disease (PCOD). These risks include the onset of ovarian hyperstimulation syndrome (OHSS), and a relatively high incidence of multiple pregnancies (Schenker et al., Fertil, Steril, 35: 105-123 (1981)). Although most of the multiple pregnancies are twins, the induction of ovulation contributes to one third of high-ranking multiple births in the UK (Levene et al., Br. J. Obstet, Gynacol. 99: 607-613 (1992 )). Careful periodic verification during ultrasound treatment (US) and evaluation of serum estradiol (E2) have reduced other risks but have not been able to prevent them in all patients. These problems are directly related to the difficulty in obtaining the development of a simple dominant follicle that leads to non-physiological multifollicular development. During the last 10 years, a new protocol (the "chronic low dose protocol") has been designed and tested in order to reduce the additional incidence of complications of gonadotropin therapy (Seibel et al., Int. J. Férti 1, 29: 338-339 (1984), Buvat et al., Fertil, Steril., 52: 553-559 (1989), Hamilton-Fairley et al., Human Reprod. 6: 1095-1090 (1991); Sagle et al. , Fertil Steril, 55: 56-60 (1991), Shoham et al. Fertil, Steril., 55: 1051-1056 (1991), Meldrum, Steril. Steril., 55: 1039-1040 (1991)). This protocol starts with a low dose of FSH or hMG (75 IU / day) and no dose adjustment before 7 or preferably 14 days of treatment. If a dose adjustment is required, it is performed by gradual increments of only 37.1 IU. In addition, each subsequent increase can only be effected after seven days of treatment at a given dose. The concept of this chronic low dose protocol is to find the threshold amount of FSH, necessary to promote unifolliculogenesis. Encouraging results have been published, however, which show that this procedure reduces the average number of preovulatory follicles, the average preovulatory E2 level and the size of the ovary in the intermediate luteal phase.

However, despite the use of the chronic low dose protocol, some treatment cycles have yet to be canceled due to an over-response (for example, where there are more than 3 follicles with an average diameter of 16 mm or more). In addition, the proportion of multiple pregnancies, although clearly improved when compared to the conventional protocol, is still higher than in cycles of spontaneous conceptions, for example 5-10% in induced ovulation as opposed to 1.5% in spontaneous cycles. This is due to the fact that the development of a simple preovulatory follicle is obtained only in approximately two thirds to three quarters of the induced cycles and follicles having an average diameter of 15 mm or less are usually considered when evaluating the number of Pre-ovulatory follicles on the day of hCG administration (Buvat et al., Fertil. Steril., 52: 553-559 (1989); Hamilton-Fairley et al., Human Reprod 6: 1095-1099 (1991)). However, it is not clear whether follicles with an average diameter of 14 to 15 mm, or even less, on the day of administration of hCG, will ovulate and lead to the release of a fertilizable, healthy oocyte. Thus, it may be desirable to have improvements in the treatment of follicular development induced by FSH in which the rates or proportions of multiple pregnancies and cancellation of the cycle are reduced. The development of the antral follicle is induced by FSH. Continually throughout life and until menopause, some follicles enter a phase of development which is interrupted by regression and atresia before reaching the stage of complete maturity of the preovulatory state (Hillier, Hum. Reprod, 9 : 181-191 (1994)). During the development phase, any follicle could be rescued from the atresia, with the condition that it is exposed to a sufficient concentration of FSH. The level of FSH required to prevent atresia and promote the further development of a follicle is called the "FSH threshold" level (Brown, Aus NZJ Obsteet Gynecol., 18: 47-55 (1987). FSH threshold value varies with time and, at a given time point, follicles that are currently in a developmental phase have different threshold levels of FSH.This is the reason on which the "low" protocol is based chronic dose. "A progressive and cautious increase in the FSH dose is used to find the threshold level of a minimum number of follicles, and with the hope of achieving mono-ovulation.

It is known that luteinizing hormone (LH) also contributes to the dominance phenomenon of the follicle mono-ovulation. Of course, although some LH is essential for the synthesis of estrogen during folliculogenesis, there is evidence that excessive exposure to LH will trigger follicular atresia and suppress granular proliferation. The developing follicles thus appear to have finite requirements for stimulation by LH, beyond which normal follicular development ceases. This is the concept of "LH roof" (Hillier, Hum. Reprod; 9: 181-191 (1994)). It is believed that, at a given time point, follicles that are currently in a developmental phase have different LH ceiling levels. It is suggested that the more mature follicles are more resistant to the atretic action of LH than the less mature follicles. Two cases of WHO group I anovulation treated either by FSH alone or hMG using an adjustment protocol, have been reported (Glasier et al., Journal of Endocrinology, 119 A- 159 (1988)). The "FSH alone" cycle had a much larger number of mature follicles than the hMG cycle, possibly supporting a role of LH in the atresia of the secondary follicles. After this, two comparative studies were published. In a first crossover study in 10 hypogonadic hypogonadotropic women, a surprising difference was recorded in terms of preovulatory E2 levels, but follicular counts were not reported (Couzinet et al., "Clin Endocrinol, Metab, 66: 552-556. (1988).) A second cross-over study in 9 hypogonadal hypogonadotropic women, reported an average number of follicles that had an average diameter of more than 16 mm on the day of hCG administration of 2.0 (0.7 in cycles treated with hMG and of 1.2 in the cycles treated with FSH (Shoham et al., Fertil, Steril., 55: 1051-1056 (1991)) No information on the number of smaller follicles is available, more recently, the results of administering 150 IU of hFSH (human FHS) and 75 IU of r-hLH (recombinant human LH) to a single patient with immeasurably low concentrations of FSH, LH and estradiol have been published (Hall et al., The Lancet, 344 (891 8): 334-335 (1994)). The administration of r-hLH and hFSH caused E2 levels to be high, and the total number of follicles 10 mm or more in diameter was reduced, compared to the administration of hFSH alone. However, the number of large follicles remained high enough to suggest an unacceptably high proportion of multiple pregnancies. An additional study compared the effect of administering r-hLH (at a dose of either 300 IU / day or 750 IU / day) and r-hFSH to normal ovulatory women, after treatment with FSH to stimulate multiple follicular development before intrauterine implantation (Sullivan et al., Journal of Clinical Endocrinology and Me taboli sm, 84, 228-232, (1999) ) . The results indicate that serum E2 levels were elevated in those women who received LH, although no measurements of the number and size of the follicles were made and a multiple pregnancy occurred in the group that received 750 IU / day of LH. According to a first aspect of the present invention, there is provided the use of LH and / or a biologically active analogue thereof in the production of a medicament for inducing folliculogenesis in anovulatory women, at a daily dose in the range of 100 to 1500 Ul. As used herein, a "Ul ratio" is the ratio of the number of Ul of one component to the number of Ul of another component. It is well known that gonadotropins can now be expressed in (mass / μg) instead of biological Ul. In this case, a conversion factor has to be used to convert the new value to Ul. For convenience, references hereinafter in the present LH, FSH and hCG are intended to include the biologically active analogues thereof. The inventors have found that the administration of LH at a dose of 100 to 1500 IU / day can promote paucifollicular development, that is, it can reduce the number of preovulatory follicles per treatment cycle in patients suffering from follicular induction, in comparison to the cycles where LH is not administered at a dose of 100 to 1500 IU / day. The LH administered according to the invention can induce unifolliculogenesis, for example the development of a single preovulatory follicle. Doses in the range of 200 to 800 IU / day, more preferably 225 to 450 IU / day, have been found to be particularly effective. The reduction in multifollicular development can reduce the number of canceled cycles due to excessive follicular development, for example, it can reduce those cycles when there is an excessive number of follicles, making the process of induction of ovulation more efficient.

In addition, the incidence of multiple pregnancy and OHSS may also be reduced. The required daily dose can be administered as a single dose each day. In this way, the medicament can be packaged to provide only the daily dose of LH, for example in a multiple dose container such as a bottle. However, it is possible that LH can be administered on two or more occasions during the day - provided of course that the total LH administered during the day is equal to the daily dose - and the medicine packaged accordingly, for example in a multi-dose container. It is also possible that LH could be administered on alternating days or at even longer intervals. Such decisions will be made by the doctor administering the medication and will depend on parameters such as the patient's body mass index (BMI), medical history, the stage of follicular development when LH is received, metabolism, response to treatment , the half-life of the medication and so on. Folliculogenesis in general will be induced in anovulatory women by administration of FSH using the conventional protocol or the protocol low chronic dose described above, or an alternative protocol. LH must be administered at an appropriate stage of follicular development, for example the intermediate to delayed follicular phase. This stage can be decided by the doctor who administers the medication, and may depend on the regimen by which ovulation is induced. By way of example, it can be judged that the appropriate stage of follicular development has been achieved when at least one simple follicle reaches an average diameter of 8 mm, or when at least one follicle has an average diameter in the range of 10 to 15 mm. (preferably 11-14 mm), or when there are more than 3 follicles with a mean diameter in the range of 8 to 13 mm and no larger follicles. The administration of LH will generally cease when ovulation is induced by the administration of the high dose of hCG. Again, the synchronization of the administration of hCG to induce ovulation can be decided by the physician. For example, this can be when there is at least one follicle having a diameter of 18 mm or more, and no more than 3, preferably 2, follicles having a diameter of 11 mm or more.

LH can only be administered when the required stage of follicular development has been reached. In this case, the administration of FSH can be discontinued together or it can be continued at the same dose as described above, or at a lower or higher dose. It is preferred if the administration of FSH is continued but at a lower dose than that previously described, the dose being lower than that of LH. Alternatively, LH can be administered concomitantly with conventional or low-dose chronic protocols, for example before follicular development reaches an appropriate stage. When the required stage of follicular development has been achieved, the administration of FSH can be discontinued or continued as described above, or at a lower or higher dose, provided that the LH is administered at the appropriate dose. In a further alternative, the medicament can be formulated such that it can be used in a procedure that replaces conventional or low-dose chronic protocols. In this way, FSH and / or a biologically active analogue thereof can be used in the production of the medicament. In this embodiment, the Ul ratio of LS to FSH is preferably in the range of 1.5: 1 to 20: 1. More preferably, the ratio is in the range of 1.5: 1 to 10: 1. When the medicament is for administration after the appropriate stage of follicular development has been reached, the Ul ratio of LH: FSH can be about 10: 1. A particularly preferred daily dose for such a medicament is 375 IU of r-hLH and 37.5 IU of r-hFSH. According to a second aspect of the invention, the use of LH and FSH and / or the biologically active analogues thereof in the production of a medicament for the induction of folliculogenesis in women is provided at an Ul ratio of LH to FSH in the range of 1.5: 1 to 20 :1. The uses of the first and second aspects of the invention can be modified since LH is replaced by an equivalent dose of hCG, and / or a biologically active analogue thereof. As used herein, an "equivalent dose" of human chorionic gonadotropin (hCG) is calculated on the basis that an ul of hCG is equivalent to 5-7 IU of LH in the Van Hell bioassay of the pharmacopoeia (Van. Hell, H et al., Effects of preparations of human menopausal gonadotropin in different bioassay methods, Acta Endocrin; 47: 409-418, 1964). For convenience, references in the present to luteinizing hormone (LH) is intended to include hCG, with doses of LH that are intended to include the equivalent dose of hCG. According to a third aspect of the invention, a product containing LH is provided (or an equivalent dose of hCG) and FSH and / or biologically active analogs thereof, as a combined preparation for simultaneous, sequential or separate use in the induction of folliculogenesis in women, comprising the LH preparation (or an equivalent dose of hCG) and FSH and / or biologically active analogs thereof at an Ul ratio of LH (hCG) to FSH in the range of 1.5: 1 to 20: 1. According to the second and third aspects of the invention, LH or hCG and FSH can be administered to anovulatory women, preferably throughout the cycle until the induction of ovulation by the administration of the high dose of hCG. Alternatively, these can be administered after the follicular development has reached an appropriate stage. The invention also provides a method for the induction of folliculogenesis in anovulatory women, including the administration of luteinizing hormone and / or a biologically active analogue thereof, at a dose in the range of 100 to 1500 IU / day or a dose equivalent of human chorionic gonadotropin and / or a biologically active analogue thereof. LH, FSH and hCG can be obtained from natural sources, for example isolated from urine, pituitary, or placenta, or can be obtained using recombinant DNA technology (see WO85 / 01959 and Loumaye et al., Human Reprod, 11: 95-107, 1996). Biologically active analogs thereof include peptide analogs, non-peptide analogs and chimeras. It is preferred if human LH and FSH are used in the present invention. The compounds useful in the invention can be formulated for administration by any convenient route, often in association with a pharmaceutically and / or veterinarily acceptable carrier. It is preferred that the compounds be formulated for parenteral administration. It is preferred that LH and FSH (when present) are administered subcutaneously, preferably in the anterior abdominal wall.

Formulations for parenteral administration will usually be sterile. Pharmaceutical formulations adapted for parenteral administration include sterile aqueous and non-aqueous injection solutions, which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, which are also within the scope of the invention. The formulations can be presented in unit dose or multi-dose containers, for example sealed vials and flasks, and can be stored in a freeze-dried condition. (lyophilized) which requires only the addition of sterile liquid carrier, for example water for injections, immediately before use. Solutions and suspensions for extemporaneous injection can be prepared from sterile powders, granules and tablets. The formulations can be administered through a filled syringe, an autoinjector or a multiple dose autoinjector. Oral formulations and other oral formulations do not need to be sterile and can be presented in unit dose or multiple dose form. Oral formulations may be in the form of solids, such as powders, granules, tablets, capsules (e.g., soft or hard gelatin capsules) or pills, or liquids such as syrups or elixirs. The fillers and / or carriers may be present as appropriate, and those skilled in the pharmaceutical formulating art will be able to provide such additional or alternative excipients as may be necessary or desirable.; the flavoring agents are an example. Any formulation designed for oral administration can be formulated for enteric resistance, to aid distribution to the small intestine, by avoiding or mitigating any digestion of the compound or compounds, as they may occur in the stomach or proximal small intestine . The tablets or capsules can be coated with enteric layer, for example by conventional methods. Liquid formulations can be effectively made enterally resistant, by inclusion or by being co-administered with a suitable agent such as medium chain triglycerides. The different inorganic compositions of the oral compositions include rectal compositions, which may be in the form of a suppository. Suppositories will generally include a suppository base, such as cocoa butter. Again, particular formulations containing the active ingredient (s) may be routinely prepared by those skilled in the art of the pharmaceutical formulation. The preferred features of each aspect of the invention are as for each of the other aspects, mu ta ti s u tandi s. All patent and literature documents referred to throughout this specification are incorporated herein by reference to the fullest extent permitted by law. The invention will now be further described in the following non-limiting examples.

Example 1 The effect of LH was examined when administered after stimulation with FSH on WHO Group II anovulatory women, during a clinical study conducted according to the guidelines of the International Conference on Harmonization Good Clinical Practices (ICH GCP) (for its meaning in English). The patients had the following characteristics: Premenopausal; aged between 18 and 39; infertile due to ovulatory dysfunction; have had spontaneous menses, menstruations induced by clomiphene citrate therapy or removal of positive progestin-induced bleeding within the previous year; a body mass index of 35 or less (calculated as body weight in kg divided by (height x weight) in m2); euthyroid; no medical condition that may interfere with the absorption, distribution, metabolism or excretion of LH; no clinically systemic disease; no known allergy to gonadotropin preparations; no persistent ovarian cyst of 11 mm or larger or ovarian endometrioma (as determined by ultrasound); no previous or current hormone-dependent tumor; no clinically relevant reproductive tract disease; and no abuse of active substances. The patients underwent routine ovulation induction with FSH until there were 4 or more follicles in the range of 8 to 13 mm in diameter, there were no larger follicles and an endometrium of 8 mm or more in thickness. These were divided randomly into 3 groups in blind, one to receive a placebo, one to receive 225 IU / day of r-hLH and one to receive 450 IU / day of r-hLH. Table 1 below summarizes the respective groups of patients: Table 1 R-hLH (LHadi ®, Serono) was used in bottles containing 75 IU of r-hLH and 47.75 mg of sucrose, phosphate buffer and Tween 20 in a lyophilized form. LHadi is produced in Chinese hamster ovary cells engineered by genetic engineering (CHO) in which the genes encoding the alpha and beta chains of human LH have been introduced through recombinant technology. The specific activity of LHadi is approximately 15,000 Ul of LH / mg. For a dose of 225 IU, 3 bottles were used. One bottle was reconstituted in 1 ml of water and gently shaken, taking care to avoid contact with the rubber stopper. The whole of the resulting solution was aspirated and used for the reconstitution of the second bottle. After gentle agitation, all of the resulting solution was aspirated and used for the reconstitution of the third vial. After further mild agitation, the entire resulting solution was aspirated and immediately injected subcutaneously into the anterior abdominal wall using a new needle. For a 450 IU dose, two injections of 225 IU were made. The placebo was in bottles that resembled the vials of r-hLH but contained only sucrose, phosphate buffer, and Tween 20. Treatment with r-hLH / Placebo was continued for 7 days unless at least one follicle reached a mean diameter of at least 18 mm, and there were 3 or fewer follicles having an average diameter of 11 mm or greater. In this case, a single dose of 5000 IU u-hCG (Profasi®, Serono) was administered subcutaneously. Before and during treatment with r-hLH / placebo, ultrasound (US) was used at intervals of 1-2 days to measure the mean diameter of the follicles (determined as the average of the two longest perpendicular diameters) and thickness endometrial (evaluated as the distance from the hyperechoic interface of the endometrium and the myometrium to the opposite interface including the strongest intermediate line echo (endometrial interface)). All follicles with an average diameter of 11 mm or more were recorded. Before and each time an ultrasound scan was performed during treatment with r-hLH / placebo, a blood sample was taken and the resulting serum was analyzed for E2 (estradiol), P (progesterone), LH, FSH and androstenedione. E2 and P4 were analyzed using DPC Coat-a-count, solid-phase coated RIA, LH (serum and urine) and FSH were analyzed using MIACLONE IRMA, and androstenedione was analyzed using RIA's Diagnostic System Laboratories method . The results are summarized in Tables 2-4 and in Figure 1 of the accompanying drawings, which are a graph showing the size and number of the follicles on the day of hCG administration (or the last day of treatment in that hCG was not administered) for each of the patients. It can be observed that the administration of LH at 225 or 450 IU / day subsequent to treatment with FSH, resulted in a more marked follicular regression than in the administration of placebo, as was suggested by patients with complete follicular regression, a further number small follicles on the day of administration of hCG and a reduction in the average size of the follicle from 15 mm in the placebo group to 14 mm in the 225 IU group of r-hLH, and 13 mm in the group of 40 Ul de r-hLH. The efficacy of r-hLH in the promotion of mono-ovulation is illustrated by the appearance of a dominant follicle (as evidenced by the average size), the absence of follicular phase luteinization and a comparatively lower P4 level in the intermediate luteal phase.

Example 2 We examined the effect of LH and FSH administered during the late follicular phase on anovulatory women of Group I WHO during a clinical trial conducted according to the ICH GCP guidelines. The patients had the following characteristics: premenopausal: in ages between 18 and 39 years; a clinical history of hypogonadotropic hypogonadism; they have stopped treatment (if any) with pulsatile GnRH, therapeutic treatment with gonadotropins or estrogen-progesterone at least one month before the selection procedure; have had a negative challenge test with progesterone, performed during the selection period; had the following hormonal values in a fasting blood sample (between 7 and 9.30 AM) taken within 6 months before the treatment period: FSH: < 5 mUl / ml LH: < 1.2 mUl / ml thyroid stimulating hormone (TSH) < 6.5 μUl / ml Free T4: > 11 and < 24 pmol / l Testosterone: < 3.5 nmol / 1 Prolactin (PRL): < 520 mIU / 1; no clinically significant abnormal findings, within 6 months before the start of the study, in pretreatment hematology, in clinical chemistry and in urinalysis parameters or the results of lack of pathological significance of out-of-normal limits; have, in the file, if clinically indicated, a CT or MRI scan of the hypothalamic pituitary region to document the current putative tumor condition of the region; a body mass index between 18.4 (10th percentile for 18 years) and 31.4 (90th percentile for 38 years); no medical condition that may interfere with the absorption, distribution, metabolism or excretion of LH or FSH; no clinically systemic disease; no known allergy to gonadotropin preparations; no persistent ovarian cyst of 11 mm or larger or ovarian endometrioma (as determined by ultrasound); no previous or current hormone-dependent tumor; no clinically relevant reproductive tract disease; and no abuse of active substances. The study was divided into an open phase of a maximum of 28 days and a blind phase of a maximum of 7 days. In the open phase, all patients received 225 IU / day of r-hLH and 112.5 IU / day of r-hFSH. If there was no elevation in E2 levels or a sign of follicular development after 7 days, the dose of r-hFSH was elevated to 150 IU / day. After an additional 7 days, the dose of r-hFSH was elevated to 187.5 IU / day if there was no elevation in E2 levels or follicular development sign and after 7 additional days, the dose of r-hFSH was elevated to 262.5 Ul / day if there was no elevation in E2 levels or sign of follicular development. The dose of r-hLH remained constant throughout the open phase. When a patient had at least one follicle with a mean diameter in the range of 10 to 13 mm, she entered the blind phase. In this phase, patients were randomly divided into 3 groups in the blind, one to receive a placebo of LH, and continue the dose of r-hFSH received on the last day of the open phase, one to receive 225 IU / day of r - hLH and continue the dose of r-hFSH received on the last day of the open phase, and one to receive 225 IU / day of r-hLH and a placebo of FSH. Table 5 below summarizes the respective groups of patients.

Table 5 R-hFSH (Gonal-F®, Serono) was used in ampoules containing 75 IU of r-hFSH and 30 mg of sucrose and phosphate buffer in a lyophilized form, up to 3 of which were dissolved in 1 ml of water for injection. Adjustment of the ampoules containing only sucrose and phosphate buffer was provided for the FSH placebo.

R-hLH (LHadi ® serono) was given and administered as in example 1. The LH placebo was in bottles that fit the r-hLH bottles but contain only sucrose, phosphate buffer and Tween 20. All Injections were made subcutaneously in the anterior abdominal wall. The blind phase was continued for 7 days unless at least one follicle reached an average diameter of at least 18 mm and there were 2 or fewer follicles with an average diameter of 11 mm or greater. In this case, a single dose of 10000 Ul of u-hCG (Profasi ®, Serono) was administered subcutaneously. In the first, fifth and eighth days of the open phase, and at regular intervals (for example 1 to 2 days) during the blind phase, ultrasound was used to measure the average diameter of the follicles and the endometrial thickness. All follicles with an average diameter of 11 mm or larger were recorded. On the first day of the open phase, and at regular intervals (for example 1 to 2 days) during the blind phase, a blood sample was taken and the resulting serum was analyzed for E2, P4, LH, FSH and androstenedione as in Example 1 The results are summarized in Tables 6-9 and in Figure 2 of the accompanying drawings, which are a graph showing the size and number of follicles on the day of hCG administration (or the last day of treatment without hCG will be administered) for each of the patients. It can be seen that stopping FSH and administering r-hLH at 225 IU / day resulted in marked and excessive follicular regression. The efficacy of r-hLH in the promotion of mono-ovulation in the presence of FSH is illustrated by a reduction in the average number of follicles having a diameter of 14 mm or larger, an increase in the proportion of patients with only 1 or 2 follicles having a diameter of 14 mm or larger, the appearance of a dominant follicle (as evidenced by a mean follicle size of 12 mm, compared to 15 mm for the FSH / placebo group), and the absence of follicular phase luteinization.

Table 2 - Summary of data on the number and size of follicles and the cancellation of hCG The p values from the comparison with the placebo group (ANCOVA adjusted for the number of follicles in the baseline) p: pregnant patient Table 3 - Number of Patients with 0, 1, 2, 3 or > 3 Follicles on hCG Day or the Last Treatment Day if hCG was not Administered Contrast ** Total comparison: Jockheere-Terpstra test Comparison Comparison: Cochran-Armitage test for the trend Table 4 - Descriptive Statistics of Hormone Levels Measured to TI and on hCG Day or the Last Treatment Day if hCG was not administered Table 6- Summary of Data on Open and Blind Stimulation Phases, and Cancellation of hCG Table 7 - Summary of Data on the Number and Size of Follicles and the Cancellation of hCG The p-values adjusted to BMI: p-value of contrast with the previous treatment group * Gonal-F / r-hLH vs. Gonal-F '/ Placebo ** Gonal-F / placebo vs. r-hLH / Placebo *** r-hLH / placebo vs. Gonal-F / r-hLH p: pregnant patient Table 8 - Number of Patients with 0, 1, 2, 3 or > of 3 Follicles on the Day of hCG or the Last Day of Treatment if no hCG Contrast was Administered ** Full Comparison: Jonckheere-Terpstra Test Paired Comparison: Cochran-Armitage Test for the Trend Table 9 - Descriptive Statistics of the Hormone Levels Measured to TI and the Day of hCG or the Last Treatment Day if no hCG was administered

Claims (16)

1. The use of LH and / or a biologically active analogue thereof in the production of a medicament for the induction of folliculogenesis in anovulatory women, at a daily dose in the range of 100 to 1500 IU.

2. The use according to claim 1, wherein LH is r-hLH.

3. The use according to claim 1 or claim 2, wherein the daily dose is in the range of 200 to 800 IU.

4. The use according to claim 3, wherein the daily dose is in the range of 225 to 450 IU.

5. The use according to any preceding claim, wherein FSH and / or a biologically active analogue thereof is used in the production of the medicament.

6. The use in accordance with the claim 5, wherein the Ul ratio of LH to FSH is in the range of 1.5: 1 to 20: 1.

7. The use in accordance with the claim 6, where the ratio is in the range of 1.5: 1 to 10: 1.

8. The use of LH and FSH and / or a biologically active analogue thereof in the production of a medicament for the induction of folliculogenesis in women, at an Ul ratio of LH to FSH in the range of 1. 5: 1 to 20: 1.

9. The use in accordance with the claim 8, wherein the medicament is for inducing folliculogenesis in women at a daily dose of LH in the range of 100 to 1500 IU.

10. The use according to any preceding claim, modified in that LH and / or a biologically active analogue thereof is replaced by an equivalent dose of hCG and / or a biologically active analogue thereof.

11. The use according to any preceding claim, wherein the medicament is for the induction of paucifolliculogenesis or unifolliculogenesis in women.

12. A product containing LH (or an equivalent dose of hCG) and FSH and / or the biologically active analogues thereof as a combined preparation for simultaneous, sequential or separate use in the induction of folliculogenesis in women, the preparation comprises LH (or an equivalent dose of hCG) and FSH and / or the biologically active analogues thereof at an Ul ratio in the range of 1.5: 1 to 20: 1.

13. A product according to claim 12, wherein the ratio is in the range of 1.5: 1 to 20: 1.

14. A product according to claim 13, wherein the ratio is in the range of 1.5: 1 to 10: 1.

15. A product according to claim 12, 13 or 14, comprising 375 IU of r-hLH (or an equivalent dose of hCG) and 37.5 IU of r-hFSH

16. A product according to any of claims 12, 13 or 14, which is for the induction of paucifolliculogenesis or unifolliculogenesis in women.