Direct effect of danazol on endometrial hyperplasia in adenomyotic women: treatment with danazol containing intrauterine device.

It is well known that danazol has a direct effect on endometriosis tissue and cell. We have been treating adenomyotic women with danazol containing intrauterine device (D-IUD) from June 1993 to August 2000 and significant decrease of dysmenorrhea and serum CA-125 levels were observed. Of fifty-nine adenomyotic women, eight women were also diagnosed by endometrial biopsy as endometrial hyperplasia and one woman was diagnosed as atypical endometrial hyperplasia. In these endometrial hyperplastic patients, endometrial tissues were obtained before insertion and at the time of removal or exchange of D-IUD and examined pathologically. In all of the 9 women, histopathological findings of endometrial hyperplasia disappeared after D-IUD treatment. In particular, in one patient, findings of atypical endometrial hyperplasia also disappeared after D-IUD treatment. She is now closely observed at our clinic using D-IUD. By these evidences, we postulate that D-IUD is one of the treatment choices of endometrial hyperplasia given exposure of the endometrium to such an extraordinary high concentration of danazol released by D-IUD and avoidance of adverse effects of oral danazol or general administration of GnRH and progesterone. In particular, in atypical endometrial hyperplasia case, its mechanisms might give great benefit to patient. However, mechanisms of direct effect of danazol on endometrial hyperplasia remain to be elucidated in the future study.

[A case of Borrmann type 4 colon cancer with a metastasis into hepatoma].

A rare case of a colon cancer with a hepatomatous metastasis is reported. A 79 year old female was admitted hospital in April, 1988 with liver cirrhosis. On death in November, 1988, an autopsy revealed a primary, linitis plastica type diffuse adenocarcinoma of the total colon with an extensive metastases into lungs, kidneys, liver, small intestine, bladder, spleen, the bone marrow, and the lymph nodes. In the cirrhotic liver two hepatomatous nodules were found. As a focus of one of these nodules, there was a metastatic linitis plastica lesion of the colon.

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 less than 0.05) was observed with pulsatile FSH administration. Furthermore, the number of patients who conceived during the FSH regimen was significantly greater than that found with hMG treatment. The present data demonstrate that pulsatile subcutaneous administration of hMG or FSH is effective in induction of successful ovulation and establishment of singleton pregnancy in patients with various types of anovulatory infertility.

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.

[Ovulation induction with a combination of LHRH analogue and hMG pulsatile subcutaneous administration in PCO patients].

The pulsatile subcutaneous administration of hMG (hMG therapy) and treatment with a combination of luteinizing hormone releasing hormone analogue (Buserelin) and hMG (combined therapy) were used to induce ovulation in 9 patients with polycystic ovary syndrome (PCO). Ovulation was observed in all twelve treatment cycles in the combined therapy, and two cases (delivery at term, and abortion) of pregnancy were confirmed. In the hMG therapy, ovulation occurred in 22 cycles of 26 treatment cycles. Ovarian hyperstimulation occurred in one cycle in the combined therapy and in 5 cycles (3 ovulated patients) in the 26 hMG therapy. The total dose per cycle of hMG required to induce ovulation in the combined therapy (1,700 +/- 203IU) was significantly lower than in the hMG therapy (2,344 +/- 223IU). In response to Buserelin administration, LH and FSH increased transiently and then declined to the normal range observed in the early follicular phase. The reduced LH level was sustained throughout the hMG administration. The concentration of FSH increased in response to hMG administration, resulting in a change in the LH/FSH ratio. The LH/FSH ratio in the combined therapy was significantly lower than in the hMG therapy. The present data demonstrated that pulsatile subcutaneous administration of hMG associated with Buserelin was effective in inducing ovulation in patients with PCO with a low incidence of serious side effects.

[A study on cellular interaction between theca and granulosa cells in estradiol biosynthesis by the human ovary].

Cellular interaction in estradiol biosynthesis by two types of cells in the ovary has been suggested by previous studies. To verify this, steroidogenesis by theca and granulosa cells, separated or combined, was investigated using a two cell combined monolayer culture method. Granulosa and theca cells were harvested from preovulatory follicles of women with normal menstrual cycles. RIA measurements of steroidogenesis revealed the following: 1) Estradiol (E2) production by the combined culture after 24 h and 48 h was significantly higher than the total for each separated culture. 2) delta 4-androstenedione (delta 4) production by the combined culture after 24 h was significantly lower than total delta 4 production by each separated culture. 3) E2 production by the combined culture revealed higher values than the delta 4-added granulosa cell culture after 24 h. These data suggest that cellular interaction is of a synergistic character and it may be attributed not only to aromatase substrate (delta 4), but also to some intercellular E2 stimulating factor.

Effects of luteinizing hormone and dibutyryl adenosine 3',5'-monophosphate in cultured granulosa cells from polycystic ovaries.

The present study was undertaken to assess the ability of granulosa cells from subjects with normal and polycystic ovaries (PCO) to secrete progesterone throughout a 10-day culture period. LH levels in serum and follicular fluid from PCO patients were significantly (P less than 0.001) higher than those in normal subjects. In the absence of LH, progesterone secretion by granulosa cells cultured from PCO follicles did not differ significantly from that of cells from normal early and midfollicular phase follicles. Granulosa cells cultured from follicles from normal subjects in the early and midfollicular phases responded to LH (100 ng/ml) with an 8- to 20-fold increase in progesterone production. In contrast, LH increased progesterone production to a much lesser extent (up to 4-fold) in cells from the ovaries of patients with PCO. Progesterone secretion by granulosa cells from normal ovaries in response to LH diminished as intrafollicular endogenous progesterone and LH levels increased. Cells from PCO follicles cultured with (Bu)2cAMP (100 micrograms/ml) secreted progesterone in quantities comparable to those secreted by (Bu)2cAMP-stimulated normal ovaries in the early and midfollicular phases. These data demonstrate the discrepancy between the ability of granulosa cells from PCO and normal follicles to secrete progesterone in response to stimulation by LH and (Bu)2cAMP. These results suggest that in women with PCO, the persistent elevation of follicular LH may lead to impaired progesterone production in response to exogenous LH.

[Induction of ovulation with subcutaneous pulsatile administration of human menopausal gonadotropin].

Induction of ovulation with subcutaneous pulsatile (every 90 min.) administration of HMG (Pergonal) 75 or 150 IU/day using a portable pump (Nipro SP-3I) was performed in 3 PCO patients (6 cycles), 4 first grade amenorrhea (Am-I) patients (7 cycles) and 4 Am-II patients (4 cycles). All patients ovulated except one cycle of Am-I patients and one PCO woman conceived. In regard to the duration of administration and the total dose of HMG until ovulation, the administration of 150 IU/day (M +/- SD=15.2 +/- 5.0 days, 2280 +/- 774 IU) is superior to 75 IU/day (39.5 +/- 11.4 days, 3900 +/- 1357 IU), and there was no significant difference between this method and the daily intramuscular injection of HMG. The group treated with HCG in the luteal phase revealed a longer luteal phase (14.0 +/- 2.3 days) than the nontreated group (12.6 +/- 1.5 days). Ovarian hyperstimulation was observed in one case and subsided spontaneously after admission. There were no other side effects. In conclusion, this method has the following advantages: A high ovulation rate, comparable with daily intramuscular administration. It is a less painful procedure than daily intramuscular injection. It is possible for the patient to lead normal life, insertion and removal being easily done by herself.