Kiyohiko Yamada

A Comparative Study on Transforming Growth Factor-β and Activin A for Preantral Follicles from Adult, Immature, and Diethylstilbestrol-Primed Immature Mice

Both transformation growth factor-β (TGFβ) and activin belong to the TGFβ superfamily, and each receptor is structurally related. We have shown that the action of activin A on folliculogenesis is different in immature and adult mice, so it is of interest to study whether TGFβ has such an action on follicular development. The effect of TGFβ on folliculogenesis was studied in isolated preantral follicles from immature, adult, and diethylstilbestrol (DES)-primed immature mice and was compared with that of activin A. TGFβ caused a significant increase in follicular diameter and estradiol and immunoreactive inhibin secretion in adult mice in a dose-related manner, but did not affect the size of preantral follicles from immature mice. Activin A, on the other hand, caused a significant increase in the size of follicles from immature mice, but did not change the size of preantral follicles from adult mice. TGFβ enhanced the effect of FSH, whereas activin A completely blocked the action of FSH on preantral follicl...

Ovulation induction by step-down administration of purified urinary follicle-stimulating hormone in patients with polycystic ovarian syndrome

The step-down method can be an alternative method of ovulation induction in women with PCOS. This protocol can induce ovulation with a smaller dose of FSH and with lower incidence of excessive ovarian enlargement in comparison with the traditional fixed-dose administration method.

A comparative study of fixed-dose, step- down, and low-dose step-up regimens of human menopausal gonadotropin for patients with polycystic ovary syndrome

OBJECTIVE To compare the efficacy and safety of the fixed-dose, the step-down, and the low-dose step-up regimens of hMG for women with polycystic ovary syndrome (PCOS). DESIGN Prospective randomized study. SETTING Gunma University School of Medicine, Maebashi, Japan. PATIENT(S) Thirty-seven women with PCOS. INTERVENTION(S) The fixed-dose, the step-down. and the low-dose step-up regimens were administered. MAIN OUTCOME MEASURE(S) The number of growing follicles and serum hormone levels. RESULT(S) Serum FSH levels on the day of hCG administration were significantly higher in the fixed-dose regimen group than in the step-down and the low-dose step-up regimen groups, and the number of growing follicles (> or =11 mm) in the low-dose step-up regimen group was significantly smaller than in the fixed-dose regimen group. On the 7th day after hCG administration, the maximal diameter of the ovaries in the low-dose step-up regimen group was significantly smaller than in the fixed-dose and the step-down regimen groups, and the risk of excessive ovarian enlargement (> or =70 mm) was significantly lower in the low-dose step-up regimen group than in the fixed-dose regimen group. CONCLUSION The low-dose step-up regimen of hMG for patients with PCOS may be the safest protocol among the three stimulation regimens for reducing multiple follicular development.

In vitro fertilization of androgen sterilized mice

In order to explore the effect of neonatal androgen administration on oocyte quality, ovulation induction and in vitro fertilization (IVF) were performed in androgen-sterilized mice. Androgen sterilized mice were produced by the subcutaneous injection of testosterone propionate (TP) at 5 days of age and ovulation induction was performed by pregnant mares serum gonadotropin (PMSG)-human chorionic gonadotropin (hCG) treatment at 9 to 13 weeks old. The number of oocytes ovulated in TP-injected mice was 19.9 +/- 2.0 (Mean +/- SE) and was significantly less than that in normal mice (37.8 +/- 1.9; P < 0.01). The fertilization rate of oocytes retrieved from TP-treated mice (38.8%) was significantly lower than that from normal mice (60.3%; P < 0.01). These results indicate that neonatal androgen treatment has a detrimental effect on oocyte maturity.

Assessment of the implantation site by transvaginal ultrasonography

OBJECTIVE To investigate the implantation site in a singleton pregnancy. DESIGN Transvaginal ultrasonography (US) was performed at the mid or late follicular phase and/or at very early gestation before 6 weeks. SETTING, PATIENTS Ultrasound monitoring was performed on 21 women with spontaneous cycles or treated by administration of 2.5 mg/d bromocriptine mesylate (Parlodel; Sando Co., Tokyo, Japan) for occulted hyperprolactinemia at the Fertility Clinic of the Department of Obstetrics and Gynecology at Gunma University Hospital. MAIN OUTCOME MEASURES The site of the ovary with a growing follicle and/or a corpus luteum of pregnancy, and the location of a gestational sac in longitudinal and transverse views were observed. RESULTS When ovulation occurred in the right ovary, 12 of the 14 gestational sacs were located on the right wall, 1 on the midwall, and 1 on the left wall. Ovulation in the left ovary resulted in 5 gestational sacs located in the left wall and 2 on the midwall. That is, of 21 gestational sacs, 17 were located on the ipsilateral uterine wall to the ovulating ovary, 3 on the midwall, and only 1 on the contralateral. CONCLUSION Implantation occurs on the ipsilateral uterine wall to the ovulating ovary.

The role of endogenous gonadotropin release in the etiology of ovarian enlargement during purified urinary follicle-stimulating hormone therapy *

Patients with polycystic ovarian disease were grouped into three groups according to their maximum ovarian diameter (maxD) after ovulation induction by purified urinary follicle-stimulating hormone (FSH). Serum luteinizing hormone (LH) and FSH were measured daily by radioimmunoassay and size and number of follicles were assessed by ultrasonography. Follicle-stimulating hormone in group A (80 mm less than or equal to maxD) was significantly higher than those of group B (60 mm less than or equal to maxD less than 80 mm) and C (maxD less than 60 mm) for the last 4 days of the treatment. This FSH rise in group A was not accounted for by FSH accumulation by the study of pharmacodynamics, and so was thought to be of endogenous origin. Luteinizing hormone was also elevated 3 days before the administration of human chorionic gonadotropin (hCG) in both groups A and B. The number of follicles in group A at hCG administration was significantly greater than that of group C. Any significant differences were not found in either total amount of purified urinary FSH or in the basal FSH and the LH levels before treatment of the three groups. These results suggest that excessive ovarian enlargement during gonadotropin therapy is caused by multiple follicular development primarily stimulated by endogenous FSH. Endogenous LH release further enhances ovarian enlargement.

Prediction and prevention of ovarian hyperstimulation by monitoring endogenous luteinizing hormone release during purified follicle-stimulating hormone therapy*

Objective To elucidate whether early detection of premature luteinizing hormone (LH) release can be useful for prediction and prevention of ovarian hyperstimulation during purified follicle-stimulating hormone (FSH) therapy. Design Retrospective and prospective study. Patients Infertile women with polycystic ovarian syndrome. Main Outcome Measures Correlation between rate of endogenous LH release and incidence of excessive ovarian enlargement. In the prospective study, LH was measured by fluorometric enzyme immunoassay to obtain real-time concentration. Maximal ovarian diameter by ultrasonography. Results The rate of excessive ovarian enlargement (≥60mm) in cycles that were treated by a daily administration of purified FSH and accompanied by premature LH release was 83.3%. This rate was significantly higher than that in cycles without premature LH release (24.1%, P P Conclusion Early detection of premature LH release is useful for prediction of ovarian hyperstimulation. Ovarian hyperstimulation can be reduced by modulating the dose of FSH and the interval of administration in cycles with premature LH release.

Endometrial dating in the conception cycle

OBJECTIVE To investigate endometrial dating during the conception cycle. DESIGN Endometrial biopsies of the last half of the luteal phase of conception cycles were dated based on urinary luteinizing hormone (LH) surges. SETTING Endometrial samples were obtained from women attending the fertility clinic of the Department of Obstetrics and Gynecology at Gunma University Hospital. PATIENTS One hundred eighty-five women, of whom 15 (8.1%) conceived during this study. MAIN OUTCOME MEASURES Urinary LH surge, serum progesterone (P) levels, and endometrial dating. RESULTS All 10 women who conceived showed 2 or within 2 days in-phase endometrial biopsies on days 7 to 11 after the LH surge. In 4 of 5 women biopsied on day 12, an unequivocally delay in the stroma was found, i.e., a persistence of edema and poor development of predecidual reaction. Since serum P levels in conception cycles were significantly higher than in nonconception cycles on days 10, 11, and 12, we interpreted this delay in the stroma as a consequence of conception. CONCLUSION Endometrial specimens during the last half of the luteal phase of conception cycles are in-phase until day 12. On day 12, gestational hyperplasia causes apparent out-of-phase.

Association of immunoreactive-inhibin levels with luteal function.

To evaluate immunoreactive (IR) inhibin as a marker of corpus luteal function, 134 women with natural ovulatory cycles were studied. Serum IR-inhibin levels during the luteal phase were significantly lower in women with low progesterone (P4) levels (less than 10 ng/ml). Endometrial dating correlated more with serum P4 than IR-inhibin levels. All 14 conceiving cycles showed serum P4 levels greater than or equal to 10 ng/ml and IR-inhibin levels greater than or equal to 3.67 IU/ml during the midluteal phase. Furthermore, IR-inhibin levels in the early follicular phase seemed to be associated with lowered P4 levels in the ensuing luteal phase. These results suggest that IR inhibin may be closely related to corpus luteum function.

Ovarian follicular differentiation with prepubertal gonadotropin surges and gonadotropin priming in mice

Preantral follicles were mechanically isolated from the ovaries of 1.5 to 8 week old mice and cultured in vitro for 4 days in the presence or absence of either activin A or FSH. Plasma gonadotropin, estradiol and immunoreactive (IR) inhibin levels were measured. Cultured follicles showed stepwise changes in response to recombinant human (rh) FSH, with no response until 11 days, a gradual increase from 2 weeks, culminating in a strong response to rhFSH at 8 weeks. The response to activin A was vice versa. It enhanced the effect of rhFSH on preantral follicular growth of up to 4-week-old mice, but inhibited the effect of rhFSH in 8-week-old mice. The peak of the prepubertal gonadotropin surge was observed on day 11. Seven-day-old mice were treated with either luteinizing hormone releasing hormone (LHRH) or rhFSH or human chorionic gonadotropin (hCG) for 3 consecutive days from day 7, and follicles were collected on day 11. Those follicles showed enhanced response to rhFSH, no response to activin A, and an enhanced response to the combination of rhFSH and activin A, suggesting that the chronological changes in follicular response are a result of the prepubertal gonadotropin surge.