Toshihiro Aono

Congenital malformations of newborn infants after clomiphene-induced ovulation

The effect of clomiphene citrate (CC) on the incidence of congenital malformations in newborn infants was assessed from the outcome of 1034 pregnancies after CC-induced ovulation recorded at nine university hospitals in a 5-year period. Of these pregnancies, 14.2% ended in abortion, 0.5% in ectopic pregnancy, 0.1% in molar pregnancy, and 1.6% in stillbirth. In all, 935 infants were born, and 21 (2.3%) showed visible malformations. This incidence of malformations was not significantly different from that in 30,033 infants (1.7%) after spontaneous ovulation (spontaneous ovulation group), and the types of malformations after CC treatment were similar to e those in the spontaneous ovulation group. These data indicate that CC has no teratogenic effect.

Recovery of reproductive function in patients with anorexia nervosa: a 10-year follow-up study.

The recoveries of reproductive function and body weight of 21 patients with anorexia nervosa were studied in a 10-yr period from the time of their first presentation. The recovery rates of both menstruation and eating behavior were 81.0%, although at the end of the study period the rate of amenorrhea (19.0%) was still higher than that (6%) in women in the general population. The change of mean body weight in patients in whom regular menstruation was restored was not significantly different from that of patients in whom amenorrhea persisted. Of the patients, 16 married after treatment and 14 of these (87.5%) became pregnant after spontaneous (11 patients) or induced (3 patients) ovulation, and 12 delivered a baby. The present study suggests that resumption of regular menstruation may not depend only upon body weight gain, and that most patients may be able to have a child after appropriate treatments.

Effects of bromocriptine on prolactin-secreting pituitary adenomas. Mechanism of reduction in tumor size evaluated by light and electron microscopic, immunohistochemical, and morphometric analysis.

Prolactin‐secreting pituitary adenomas were studied to clarify the mechanism by which bromocriptine reduces tumor size. Patients examined consisted of three groups: Group I (four cases) received no medication, Group II (six cases) continued bromocriptine treatment (10 mg/day for 2 weeks) until the operation, and Group III (five cases) discontinued the treatment 1 week before the operation. Adenomas in Group II showed a variety of degenerative and necrotic changes of tumor cells in addition to marked decrease in volume of individual cell. Adenomas in Group III showed divergent structural changes. Irreversible changes seen in Group II became more pronounced with a marked increase in stromal tissue. Proliferative areas consisting of intermediate‐sized cells were found in the scarce stromal tissue. The findings seem to indicate that the reduction in size of prolactinomas by bromocriptine treatment results from the reduction in size of individual tumor cell as well as from cell loss secondary to necrosis.

Effect of sulpiride on poor puerperal lactation

Forty-two primiparous and 54 multiparous women with total yields of milk not exceeding 50 ml for the first 3 postpartum days were treated with 100 mg of oral sulpiride or placebo for 4 days from the third postpartum day. In the primiparous mothers, the mean daily yield of milk in the sulpiride group increased significantly (p less than 0.01) over that in the control group after the fourth postpartum day. Mean (+/- SE) total volumes of milk for the third to fifth postpartum days were 661.5 +/- 64.4 and 441.2 +/- 51.2 ml in the sulpiride and the control groups, respectively. However, in the multiparous mothers, no significant difference between the control and the sulpiride group was noted in total yield of milk, since a good increase in the secretion of milk was obtained without medication in these mothers. Determinations of daily serum levels of prolactin in 20 primiparous women revealed significantly higher concentrations in the sulpiride group. The ratio of primiparous mothers with complete breast-feeding 1 month after delivery was higher in the sulpiride group (55%) than in the control group (30%), whereas there was no difference between the control group and the sulpiride group of multiparous women. These data indicate that poor initiation of puerperal lactation in primiparous mothers can be effectively treated with oral sulpiride.

The diagnostic significance of LH-releasing hormone test in patients with amenorrhea

Abstract Serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) following intravenous injection of 100 μg of synthetic LH-releasing hormone (LH-RH) in 10 normal women in the follicular phase and in 80 amenorrheic women were determined by radioimmunoassay. The low or normal basal levels of LH and FSH with good response to LH-RH were observed in patients with galactorrhea, secondary amenorrhea responding to progestin with bleeding, and in some of the patients with anorexia nervosa. Low resting levels with little or no increase of LH and FSH following LH-RH were experienced in patients with Sheehans syndrome, postoperative patients with chromophobe pituitary adenoma, and in some of the patients with amenorrhea responding to progestin plus estrogen with bleeding. Elevated basal LH and FSH levels with further increase following LH-RH were seen in patients with Turners syndrome and in some of the patients with amenorrhea responding to progestin plus estrogen with bleeding. The three typical patterns stated above may indicate that the cause of anovulation lies in the hypothalamus, pituitary, or ovaries. It is concluded that the LH-RH test is useful in clarifying the pathophysiology of anovulatory conditions.

Improved method for determination of catecholamines in rat brain by isolation on boric acid gel and high-performance liquid chromatography with electrochemical detection

An improved sensitive, simple and time-saving method for determining catecholamine (CA) in rat brain is described. The method involves isolation on boric acid gel and high-performance liquid chromatography with electrochemical detection. Boric acid gel effectively adsorbs CA at weakly alkaline pH and the over-all recoveries of 5 ng and 10 ng samples of authentic norepinephrine (NE) and dopamine (DA) added to a homogenate of rat brain were 98.9 +/- 9.2% and 103.4 %/- 9.3% for NE and 96.2 +/- 4.6% and 99.4 +/- 4.8% for DA, respectively. Intra-assay variation was 5.3% (5 ng) and 3.0% (10 ng) for NE and 4.4% (5 ng) and 3.8% (10 ng) for DA. Inter-assay variation was 7.7% (1 ng) for NE and 5.0% (1 ng) for DA. With this analytical system, the lowest amount of NE or DA detectable was 40 pg. Application of this method to determination of the DA and NE contents of rat hypothalamus during estrous cycle revealed significant increases in the turnovers of both in the proestrus stage. This method should be useful for routine determination of plasma NE and DA because it is sensitive and inexpensive.

Response of pituitary LH and FSH to synthetic LH-releasing hormone in normal subjects and patients with Sheehan's syndrome.

Abstract Serum levels of LH and FSH were determined by radioimmunoassay in seven patients with Sheehans syndrome, eight women with normal menstrual cycles, and five normal men following intravenous injection of synthetic luteinizing hormone-releasing hormone (LH-RH) in a dose of 100 μg. The mean maximum increases of LH (M. ± S.E. mI.U./ml.) were in the following order: 279.4 ± 87.6 at the preovulatory phase, 69.2 ± 12.6 in normal males, 48.2 ± 3.5 at the midluteal phase, and 29.9 ± 4.9 at the early follicular phase. The response of serum levels of FSH was found to parallel the change in the levels of LH, but these changes were less pronounced. No response of LH and FSH to LH-RH was observed in five patients with Sheehans syndrome while the remaining two patients showed an increase of LH around normal lower limits. These findings seem to indicate that LH-RH test is useful for the evaluation of pituitary reserve function of gonadotropin secretion.

Effect of pituitary transplants on the LH-RH concentrations in the medial basal hypothalamus and hypophyseal portal blood

The effects of hyperprolactinemia on catecholamine turnover in the medial basal hypothalamus (MBH) and on the luteinizing hormone-releasing hormone (LH-RH) concentrations in MBH and hypophyseal portal blood were investigated in female Wistar rats. Chronic endogenous hyperprolactinemia was produced by implantation of anterior pituitary glands under the kidney capsule. Catecholamine turnover in the MBH was studied by inhibiting monoamine oxidase and then measuring the accumulation of catecholamines by high-performance liquid chromatography with electrochemical detection. Rats bearing pituitary transplants exhibited: (1) persistent vaginal diestrus within 3-6 days of the implantation; (2) increased serum concentrations of prolactin (PRL); (3) decreased serum concentrations of luteinizing hormone (LH); (4) increased pituitary concentrations of LH and follicle-stimulating hormone (FSH); (5) increased turnovers of dopamine in the MBH; and (6) decreased concentrations of LH-RH in the MBH and in plasma of hypophyseal portal blood. These findings suggest that chronic hyperprolactinemia may increase dopaminergic tone in the MBH that may inhibit LH-RH secretion from the MBH, and LH release from the pituitary. These processes may be responsible for disturbances of cyclic pituitary-ovarian activity.

Danazol binds to progesterone receptors and inhibits the growth of human endometrial cancer cells in vitro

Based on our recent findings that danazol, an isoxazol derivative of ethinyltestosterone, has a profound growth-inhibitory effect on an established human endometrial adenocarcinoma cell line, the effects of danazol on cancer cells from human endometrial adenocarcinomas obtained by hysterectomy were investigated in the present study. Of the 22 uterine adenocarcinomas, estrogen, progesterone, and androgen receptors were found in 12, 14, and 4 tumors, respectively. Competitive binding studies showed that danazol specifically binds to progesterone and androgen receptors but not to estrogen receptors. Of the five cancer cells from five patients succeeded in primary cell culture, a marked inhibition of cell growth was demonstrated by addition of danazol in two cancer cells having progesterone but not androgen receptors. However, danazol did not affect the growth of the remaining three cancer cells lacking progesterone receptors. These results strongly suggest that danazol has a significant growth-inhibitory effect on human endometrial adenocarcinoma cells, possibly through progesterone receptors in the cells.

Pregnancy Following 2-Bromo-α-Ergocryptine (CB-154)-Induced Ovulation in an Acromegalic Patient With Galactorrhea and Amenorrhea

An acromegalic patient with galactorrhea-amenorrhea who conceived following long-term 2-bromo-alpha-ergocryptine (CB-154) therapy is described. During CB-154 therapy, determinations of serum prolactin (PRL), luteinizing hormone (LH)-human chorionic gonadotropin, follicle-stimulating hormone a reduction in PRL level followed by an LH peak, a rise in basal body temperature and menstruation. The patient became pregnant during the next cycle, but therapeutic abortion was performed because of the active acromegaly. These results demonstrate that CB-154 can restore ovulatory function not only to the patient with a hypothalamic disorder but also to the acromegalic patient with an enlarged sella turcica.