Yoshinobu Ubukata

Treatment of uterine leiomyomata with a luteinizing hormonereleasing hormone agonist: the possibility of nonsurgical management in selected perimenopausal women

OBJECTIVE To evaluate the efficacy of luteinizing hormone-releasing hormone agonist (LH-RH-a) in the treatment of leiomyomata. DESIGN A retrospective randomized trial. SETTING Hospital department of obstetrics and gynecology. PATIENTS Twenty-five women, ages 36 to 54 years with symptomatic uterine leiomyomata, were divided into two groups according to the responsiveness to LH-RH-a: group A patients reached menopause after LH-RH-a, whereas resumption of menstruation occurred within 12 weeks after cessation of therapy in group B. INTERVENTIONS Luteinizing hormone-releasing hormone agonist was administered intranasally three times a day with 150 micrograms insufflation of one spray in each nostril (total dose: 900 micrograms/d). MAIN OUTCOME MEASURES Efficacies of treatment were assessed in terms of uterine volume, hemoglobin concentrations, serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), and bone density during and after treatment. RESULTS In both groups, hemoglobin concentrations increased significantly after 16 weeks of treatment. A significant reduction in uterine volume was observed in both groups. After completing therapy, there was no further significant change in uterine volume in group A, whereas uterine volume in group B returned to pretreatment values. Serum LH and FSH concentrations were suppressed during treatment, but those gonadotropins in group A increased significantly up to the menopausal levels after treatment. Serum E2 concentrations in both groups showed consistent suppression by the end of the first treatment cycle. After cessation of therapy, serum E2 levels on group A remained in the castrate range, whereas E2 in group B returned to pretreatment levels, concomitant with the return of normal ovulation. CONCLUSIONS Intranasal administration of LH-RH-a was successful in significantly decreasing uterine volume and increasing hemoglobin concentration in premenopausal women with leiomyomata.

A novel method of ovarian stimulation for in vitro fertilization: bromocriptine-rebound method

OBJECTIVE To examine whether a new method of ovarian stimulation, bromocriptine-rebound method, improves IVF outcomes compared with the conventional long protocol of GnRH agonist and hMG regimen. DESIGN A prospective clinical trial. SETTING In vitro fertilization program at a university hospital. PATIENTS Endocrine-normal ovulatory women less than 40 years of age, with normal male partners and previous failed IVF-ET using long protocol. INTERVENTIONS Patients were assigned to either bromocriptine-rebound method (group 1) or long protocol (group 2). The bromocriptine-rebound method was the same as the long protocol, except that bromocriptine was administered daily from day 4 of the preceding cycle until 7 days before hMG stimulation. MAIN OUTCOME MEASURES The number of cleaved and morphologically superior embryos, pregnancy rate per oocyte pick-up, and serum PRL concentrations during administrations of hMG. RESULTS Significantly more embryos were cleaved and had superior morphology in group 1 than group 2. Clinical and ongoing pregnancy rates per oocyte pick-up were significantly higher in group 1 (42% and 38%, respectively) than group 2 (24% and 21%, respectively). The mean PRL concentration was significantly higher in the group 1 than group 2. A significant correlation between the number of superior embryos and PRL concentrations was observed in group 1, but not in group 2. CONCLUSION The bromocriptine-rebound method enhanced embryonic development, resulting in an increased pregnancy rate compared with the long protocol.

Possible Contribution of Prolactin in the Process of Ovulation and Oocyte Maturation

The present study was undertaken to evaluate the effects of PRL in the process of ovulation and oocyte maturation. In the first experiment, using an in vitro perfused rabbit ovary model, the addition of PRL to the perfusate inhibited hCG-induced ovulation in a dose-related fashion, without any reduction in progesterone synthesis. In a subsequent experiment, PRL directly inhibited both the degeneration and decomposition of surface epithelial cells and the disruption of connective tissue at the apex of the follicle wall. Furthermore, PRL inhibited hCG-stimulated plasminogen activator (PA) activity in mature follicles in a dose-related fashion. In the final experiment, we demonstrated conditions in which rabbit oocytes matured in vitro acquire competence for early embryonic development. PRL, as well as gonadotropins and estradiol, was an important constituent in the process of oocyte maturation, promoting embryonic development. These results suggest that the preovulatory environment of PRL within the follicle may influence the process of ovulation and oocyte maturation.

Clinical experience in the induction of ovulation and pregnancy with pulsatile subcutaneous administration of human menopausal gonadotropin: a low incidence of multiple pregnancy.

The pulsatile subcutaneous administration of human menopausal gonadotropin (hMG) or follicle-stimulating hormone (FSH) was used for induction of ovulation in 26 patients with hypothalamic/pituitary amenorrhea or polycystic ovary syndrome (PCO). Ovulation was observed in 116 (90.6%) of 128 treatment cycles, and 15 (16 treatment cycles) of 26 patients became pregnant. All 14 fetuses, excluding two pregnancies interrupted spontaneously at weeks 6 and 9, were singleton conceptions. Ovarian hyperstimulation was observed in 15.6% of treatment cycles. Five patients with PCO who failed to conceive on the hMG regimen also received pulsatile FSH administration. Although ovulation rates in PCO patients did not differ significantly between the hMG (88.1%) and FSH (88.2%) regimens, a significant reduction in the average dose of FSH ( P

Gonadotropin-releasing hormone agonists induce meiotic maturation and degeneration of oocytes in the in vitro perfused rabbit ovary.

The present study was undertaken to assess the effects of gonadotropin-releasing hormone agonists (GnRH-a, buserelin and leuprolide acetate [LA]) on ovulation, oocyte maturation and degeneration, and steroid and prostaglandin production in the perfused rabbit ovary preparation. Ovulation did not occur in any of ovaries treated with buserelin or LA (10(2) to 10(4) ng/mL) in the absence of gonadotropin. Gonadotropin-releasing hormone agonists were associated with the resumption of meiosis in follicular oocytes in a dose-related manner. Furthermore, the addition of GnRH-a to the perfusate significantly increased the percentage of follicular oocytes that showed evidence of degeneration compared with contralateral untreated or human chorionic gonadotropin-treated controls. Prostaglandin E2 and prostaglandin F2 alpha production by the perfused rabbit ovaries were stimulated significantly by GnRH-a treatment. Exposure to GnRH-a failed to increase either progesterone or estradiol production by the perfused rabbit ovaries. These data demonstrate that GnRH-a act directly in the rabbit ovary to trigger meiotic maturation in oocytes within the follicles, concomitantly increasing oocyte degeneration.

Direct Ovarian Effect of Growth Hormone in the Rabbit

PROBLEM: This study was undertaken to assess whether growth hormone (GH) can stimulate follicle growth and ovarian steroidogenesis via putative GH receptors.

Induction of Ovulation with Pulsatile Subcutaneous Administration of Human Menopausal Gonadotropin in Patients with Polycystic Ovary Syndrome

The present study was undertaken to determine whether ovulation can be induced in patients with polycystic ovary syndrome (PCOS) by pulsatile subcutaneous administration of hMG after the pituitary secretion of LH and FSH was suppressed with a gonadotropin releasing hormone (GnRH) analogue. The results of the combined regimen cycles (group II) were compared with those of hMG (group I) or FSH (group III) pulsatile administration in the same PCOS patients. The ovulation rate (89.1% of 46 cycles) in group I was significantly greater (p less than 0.01) than that found in group II (65.9% of 41 cycles). In group III, ovulation occurred in 89.5% of the 19 treatment cycles. Ovarian hyperstimulation syndrome (OHSS) occurred in 28.3% of cycles in group I, 7.3% in group II, and 26.3% in group III, respectively. The incidence of OHSS in group II was significantly lower than that found in group I or III. The rates of pregnancy were 10.9% of cycles in group I, 4.9% in group II, and 21.1% in group III, respectively. All 10 fetuses were singleton conceptions, and the pregnancies continued successfully to term. The present data demonstrate that pulsatile subcutaneous administration of hMG or FSH is effective in the induction of successful ovulation and the establishment of singleton pregnancy in patients with PCOS.

TREATMENT OF POLYCYSTIC OVARIAN DISEASE BY INDUCING OVULATION WITH PULSATILE SUBCUTANEOUS ADMINISTRATION OF HUMAN MENOPAUSAL GONADOTROPHIN ASSOCIATED WITH LUTEINIZING HORMONE‐RELEASING HORMONE ANALOGUE

Treatment with a combination of luteinizing hormone‐releasing analogue (GnRHa, Buserelin) and pulsatile administration of hMG (Group I) were used to induce ovulation in nine patients with polycystic ovary syndrome (PCO). The same patients were also treated with pulsatile hMG administration alone (Group II). Ovulation was observed in all twelve treatment cycles in Group I, and there were two pregnancies. In Group II, ovulation occurred in 22 of 26 treatment cycles. Ovarian hyperstimulation occurred in one cycle of Group I and in 5 of 26 cycles of Group II. The total dose per cycle of hMG to induce ovulation in Group I was significantly lower than that needed when only pulsatile hMG administration was used. In response to Buserelin administration, the concentrations of serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) increased transiently and then declined to the normal range observed in the early follicular phase. The concentrations of FSH increased in response to hMG administration, resulting in a normal LH/FSH ratio. The present data demonstrated that pulsatile subcutaneous administration of hMG in addition to Buserelin was effective in inducing follicular maturation and ovulation in patients with PCO with a lower incidence of serious side‐effects.

An improvement in the embryo quality and pregnancy rate by the pulsatile administration of human menopausal gonadotropin in patients with previous unsuccessful in vitro fertilization attempts

OBJECTIVE To examine whether the pulsatile administration of hMG improves IVF outcomes in patients with previous unsuccessful attempts using IM injections of hMG. DESIGN A prospective randomized study. SETTING In vitro fertilization program at a university hospital. PATIENTS Eighty-eight endocrine-normal ovulatory women under 40 years of age, with normal male partners and a history of unsuccessful IVF treatment by the IM administration of hMG. INTERVENTIONS Patients were assigned randomly to receive either IM (bolus group) or pulsatile administration of hMG (pulsatile group) after pituitary desensitization by a GnRH agonist. MAIN OUTCOME MEASURES The proportion of retrieved oocytes with a polar body, the number of fertilized oocytes and embryos, the proportion of morphologically superior embryos, and the rate of pregnancy per initiated cycle were compared. RESULTS The proportion of retrieved oocytes with a polar body and the number of fertilized oocytes and embryos were similar in both groups. Significantly more embryos had superior morphology in the pulsatile group (77%) than the bolus group (52%). The rates of overall and clinical pregnancy per initiated cycle were significantly higher in the pulsatile group (39% and 30%, respectively, n = 44) than in the bolus group (18% and 11%, respectively, n = 44). CONCLUSION In women with failed IVF attempts using IM administration of hMG, the pulsatile administration of hMG produces superior embryos and, hence, a higher pregnancy rate.

Possible Involvement of Lipoxygenase Products in Human Corpora lutea

The present study was undertaken to determine the ability of cultured luteal cells from human corpora lutea to secrete progesterone (P4) and prostaglandins (PGs), and to assess the effects of the products of the lipoxygenase pathway on luteal P4 production. Luteal cells responded to human chorionic gonadotropin (hCG) with a significant increase (2- to 7-fold) in P4 production. Arachidonic acid significantly stimulated PGE2 synthesis by luteal cells in a dose-dependent manner. Both basal PGE2 production and the responsiveness to arachidonic acid were maintained for 8 days. In contrast, both PGF2 alpha and 6-keto-PGF1 alpha production abruptly declined as the culture proceeded. However, the addition of hCG did not further stimulate the accumulation of the 3 PGs assayed. In the subsequent experiment, 5-hydroxyeicosatetraenoic acid (5-HETE) and the reaction products of soybean lipoxidase of arachidonic acid (AA-LIP) were utilized for evaluating the involvement of the lipoxygenase pathway in luteolysis. The addition of 5-HETE dose-dependently inhibited P4 production by the cultured luteal cells. Although treatment with either arachidonic acid or lipoxidase alone had no effect on P4 production, AA-LIP significantly reduced P4 production in the presence or absence of hCG. These results suggest that the products of the lipoxygenase as well as of the cyclo-oxygenase pathway may be important in regulating the life span and function of human corpora lutea.