Outcomes of concurrent radiotherapy and weekly paclitaxel/carboplatin therapy in cervical cancer: a retrospective study.

PURPOSE OF INVESTIGATION: To determine if concurrent chemoradiotherapy (CCRT) with paclitaxel and carboplatin is effective, convenient, and tolerable for cervical cancer treatment. MATERIALS AND METHODS: The authors retrospectively reviewed the medical records of 49 patients. Primary outcomes included progression-free survival (PFS) and overall survival (OS). The Cox proportional hazards model was adjusted for all prognostic factors in the multivariable analysis. RESULTS: Over the median follow-up time of 32 months in a sample consisting of 87.8% (43/49) squamous cell carcinoma and 12.2% (6/49) adenocarcinoma, two-year PFS and OS rates were 67.2% and 80.9%, respectively. In univariate analyses, stage, histology, performance status, tumor size, and age were significant vari- ables for OS; only histology was significant in the multivariable analysis. Acute toxicity grade 3 or 4 neutropenia (85.7%), diarrhea (32.7%), and late toxicity grade 3 or 4 (12.2%) were detected. CONCLUSIONS: For cervical cancer treatment, CCRT with paclitaxel/car- boplatin is satisfactory.

Estradiol negative feedback regulates nocturnal luteinizing hormone and follicle-stimulating hormone secretion in prepubertal female rhesus monkeys.

In recent years, animal models of puberty in children have focused on factors responsible for the developmental increase in gonadotropin secretion independent of gonadal negative feedback. Although the testis may play little if any role in timing the initial increase in gonadotropin secretion in the male, the situation may be different for the female. The present study tested the hypothesis that removal of endogenous estradiol by ovariectomy would produce an immediate increase in nocturnal but not daytime LH and FSH concentrations, an effect reversed by estradiol replacement. Morning (1000 and 1030 h) and evening (2200 and 2230 h) concentrations of bioactive LH and, in selected samples, immunoreactive FSH were evaluated in young juvenile female rhesus monkeys (n = 7) before and after ovariectomy at 13 months of age. Evening but not morning concentrations of gonadotropins were significantly increased within 2 wk of ovariectomy, whereas estradiol replacement returned these to presurgical levels and to those observed in age-matched, gonadally intact females (n = 7). By 145 d after ovariectomy, or approximately 17 months of age, evening as well as morning concentrations of LH were significantly higher than concentrations seen immediately after surgery. Estradiol replacement at approximately 18 months of age suppressed both morning and evening LH but not to the degree seen during a similar treatment after ovariectomy. These data support the hypothesis that, for the female, the developmental rise in diurnal gonadotropin secretion is controlled by a gonad-independent mechanism as well as a gonadal negative feedback inhibition. The importance of gonadal restraint on gonadotropin secretion in young juvenile females is evident only in samples obtained during the evening. These data underscore the notion that, for the female puberty, onset, at least in terms of gonadotropin secretion, is a misnomer and that puberty reflects a progression in multiple control mechanisms that ultimately time the attainment of fertility.

Reduced growth hormone secretion prolongs puberty but does not delay the developmental increase in luteinizing hormone in the absence of gonadal negative feedback.

Previous studies have shown that the growth hormone (GH) axis is important for timing the later stages of puberty in female monkeys. However, it is not clear whether these growth-related signals are important for the initiation of puberty and early pubertal events. The present study, using female rhesus monkeys, used two approaches to answer this question. Experiment 1 tested the hypothesis that reduced GH secretion would blunt the rise in nocturnal LH secretion in young (17 mo; n = 7) but not older adolescent ovariectomized females (29 mo; n = 6). Reduced GH secretion was induced by treating females with the sustained release somatostatin analogue formulation, Sandostatin LAR (625 microg/kg). Morning (0900-0930 h) and evening (2200-2230 h) concentrations of bioactive LH were higher in older adolescent compared to young adolescent females. However, diurnal concentrations were not affected by the inhibition of GH secretion in either age group when compared to the placebo-treated, control condition. Experiment 2 tested the hypothesis that reduced GH secretion induced in young juvenile females would delay the initial increase in nocturnal LH secretion and subsequent early signs of puberty. In order to examine this hypothesis, puberty in control females (n = 7) was compared to those in which puberty had been experimentally arrested until a late adolescent age (29 mo) by the use of a depot GnRH analogue, Lupron (750 microg kg(-1) mo(-1); n = 7). Once the analogue treatment was discontinued, the progression of puberty was compared to a group treated in a similar fashion but made GH deficient by continuous treatment with Sandostatin LAR (n = 6). Puberty occurred as expected in control females with the initial rise in evening LH at 21 mo, menarche at 22 mo, and first ovulation at 30 mo. As expected, Lupron arrested reproductive maturation, but elevations in morning and evening LH and menarche occurred within 2 mo of the cessation of Lupron in both Lupron and Lupron-GH-suppressed females. In contrast, first ovulation was delayed significantly in the Lupron-GH-suppressed females (41 mo) compared to the Lupron-only females (36 mo). These data indicate that within this experimental model, reduced GH secretion does not perturb the early stages of puberty but supports previous observations that the GH axis is important for timing the later stages of puberty and attainment of fertility. Taken together, the data indicate that factors that reduce GH secretion may have a deleterious effect on the completion of puberty.

The amplitude of nocturnal melatonin concentrations is not decreased by oestradiol and does not alter reproductive function in adolescent or adult female rhesus monkeys.

Nocturnal concentrations of melatonin in serum decline significantly with advancing pubertal development in both children and non-human primates and elevated levels may be associated with anovulation in adults. Three studies, using female rhesus monkeys, were performed to determine whether (1) the decline in nocturnal melatonin concentrations in adolescents was due to maturational increases in serum oestradiol, (2) the experimental elevation in nocturnal melatonin would delay the normal progression of puberty in post-menarchial monkeys, and (3) the experimental elevation in nocturnal melatonin would disrupt normal ovulatory function in adults. In experiment 1, juvenile female rhesus monkeys, housed indoors in a fixed photoperiod (12 h light:12 h darkness), were assigned randomly to one of two treatment groups: ovariectomized with no replacement therapy (control; n = 4) or ovariectomized with oestradiol replacement therapy maintaining oestradiol at approximately 90 pmol/l (treated; n = 8). Twenty-four hour as well as daytime serum samples were collected from 19 to 35 months of age. Nocturnal melatonin concentrations declined significantly in all females with advancing chronological age and this change was unaffected by oestradiol treatment. The decline in nocturnal melatonin concentrations occurred, on average, 2.0 +/- 0.2 months after the initial rise in serum LH in control females and 6.0 +/- 0.8 months in treated females. Furthermore, this decline in night-time melatonin was not related to significant developmental changes in body weight. In experiment 2, control (n = 6) and melatonin-treated (treated; n = 6) adolescent female monkeys were studied from -30 to +105 days from menarche. Beginning at 45 days following menarche, treated females received 30 days of nocturnal melatonin infusion to elevate levels to prepubertal values. Developmental changes in perineal swelling and coloration as well as serum oestradiol and insulin-like growth factor-I (IGF-I) were compared with values observed during the 45-day pretreatment and 30-day post-treatment conditions as well as with those observed in control females. Despite a significant elevation in nightly melatonin levels for the 30-day period in treated females, developmental changes in oestradiol, IGF-I, and perineal coloration and swelling were not different compared with the control females. In experiment 3, adult females were given melatonin nightly beginning on the first day of menses following an ovulatory cycle and treatment was continued for 45 days or until the next menstruation occurred. Melatonin was elevated to supraphysiological levels every night throughout the treatment period.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of growth hormone on neonatal growth in nursing rhesus monkeys.

The effects of recombinant human GH treatment of either nursing mothers or their infants on neonatal growth in rhesus monkeys was determined. Growth rates of infants treated daily from birth with GH (INFGH; n = 9; 100 micrograms/kg, sc) were compared to those of infants given saline (INFc; n = 10), infants whose mothers received saline from the second trimester of pregnancy through 7 weeks postpartum (CON; n = 9), infants of mothers who received GH during pregnancy only from the second trimester to parturition (PRG; n = 8), infants of mothers who received GH during lactation only from parturition through 7 weeks postpartum (LAC; n = 9), and infants of mothers who received GH during the second trimester of pregnancy through 7 weeks postpartum (PRG/LAC; n = 8). Mothers receiving GH were given 250 micrograms/kg, sc, Monday, Wednesday, and Friday. Infants were allowed to nurse ad libitum. Although infant birth weights were similar among the six groups, body weights at 7 weeks of age were significantly greater in PRG/LAC infants (0.77 +/- 0.03 kg) compared to those in CON (0.66 +/- 0.02 kg), INFc (0.62 +/- 0.03 kg), LAC (0.62 +/- 0.04 kg), and INFGH infants (0.62 +/- 0.01 kg), with infants of PRG mothers intermediate (0.71 +/- 0.02 kg) between them. By 35 weeks of age, after infants had been weaned by their mothers, body weights were similar among all groups. Serum concentrations of insulin-like growth factor-I (IGF-I) rose significantly in all infants during the study period. Although IGF-I levels did not vary significantly among the treatment groups, average concentrations of IGF-I were significantly related to weight gains. Analyses of milk composition revealed that total protein, lactose, and IGF-I levels were similar among groups, whereas the percentage of fat in the milk was significantly higher in PRG/LAC mothers. Milk protein content was significantly related to weight gain. These data suggest that neonatal body weight gain can be accelerated in nursing infants whose mothers have received GH from at least the second trimester of pregnancy through the lactational interval. Since infants of mothers receiving GH during lactation only were not different from controls, the effect of GH in this treatment paradigm may be mammogenic rather than galactopoietic per se.

Evaluation of the SOS chromotest for the detection of antimutagens.

The SOS chromotest was applied for the detection of antimutagens. To raise SOS induction, the bacteria were treated with the mutagens, UV, 4-nitroquinoline N-oxide (4NQO), N-methyl-N'-nitro-N-nitroso-guanidine (MNNG), or benzo[a]pyrene (B[a]p). The inhibitory effects of L-ascorbic acid, glutathione, vanillin, 5-fluorouracil (5-FU), 5-chlorouracil (5-CU), cobaltous chloride, sodium selenite and sodium arsenite, which are known as antimutagens, were investigated with their addition either simultaneously or post treatment time. It became clear that the SOS chromotest was very useful for the detection of antimutagens.

Arrest of follicular development in a patient with 17 alpha-hydroxylase deficiency: folliculogenesis in association with a lack of estrogen synthesis in the ovaries.

The degree of follicular development was examined in a patient with 17 alpha-hydroxylase deficiency that accounted for impairment of estrogen and androgen biosynthesis. The ovarian content of P was markedly higher than those of any other steroids requiring 17 alpha-hydroxylation for synthesis. The morphologic analysis of the ovaries demonstrated that normal follicles could not develop to more than 2.2 mm in diameter, and most follicles with diameters of 1.0 mm or more yielded to atresia. It is known that estrogen and FSH act synergistically on the growth of the follicles. Our data suggest that the follicles can develop up to the size of 2.2 mm in diameter at most with the sole stimulation of gonadotropin.

[Follicular development in pregnancy and the polycystic ovarian syndrome].

In order to obtain some clues to the mechanism of follicular development, we studied sequential changes in circulatory hormone from spontaneous abortion up to the next ovulation in 11 women. In addition, morphological analysis of the follicles was performed in the ovarian tissue obtained from 4 pregnant women and another 4 women with polycystic ovarian syndrome (PCO). Blood was collected every 2-4 days and the serum samples were analyzed for HCG (LH), FSH, progesterone and estradiol by radioimmunoassay (RIA). Whole ovaries or the tissue obtained by ovarian wedge resection were sectioned serially at 2.5 micrometers. Every 13th slice was stained and examined under a light microscope. The present data were summarized as follows. A dominant follicle started to grow when LH.HCG levels declined to approximately 120 mIU l and FSH increased slightly. The largest nonatretic follicle seen in pregnancy or PCO was comparable with that seen in the late luteal phase of a normal cycle. The atretic rate of middle sized follicles (2.0 less than or equal to approximately less than 4.0 mm in diameter) was significantly higher in PCO than that seen in normal or pregnant women. These data indicate that the hormonal milieu of pregnancy or PCO does not interfere with the follicular development up to the stage of the largest nonatretic follicle seen in the late luteal phase of a normal cycle. This sized follicle grows to a dominant follicle within a short period under a minor stimulus by FSH.

Reevaluation of immunoreactive gonadotropin-releasing hormone (GnRH) levels in general circulation in women: changes in levels and episodic patterns before, during and after gonadotropin surges.

In order to reevaluate the earlier varying data regarding circulatory gonadotropin-releasing hormone (GnRH), we assayed extracted GnRH from the plasma frequently collected at mid-cycle in 11 women. For the analysis of episodic GnRH patterns and basal levels, blood samples were obtained at 6 h intervals for 72 h and at 15 min intervals for 2 h every 12 h throughout the experimental period. All blood samples were assayed for GnRH and selected samples for LH, FSH, estradiol and progesterone. For GnRH assay, 5 or 6 ml of blood was mixed with 60 mg of ethylenediaminetetraacetic acid, disodium salt, and 3 mg of phenylmethylsulfonyl floride immediately after blood collection. These enzyme inhibitors prevented the destruction of GnRH in the blood at room temperature for at least 4 h. Plasma GnRH was extracted through several steps including florisil absorption, acidic extraction and washing with organic solvent. Nonspecific immunoreactivity in the plasma was markedly decreased through this extraction process. Our assay values (approximate range, 0.1-2.0 pg/ml) of plasma GnRH in normal women corresponded to the low range of those obtained by others who used the alcohol extraction method. The basal levels of GnRH did not change significantly throughout 3 different periods, i.e., before, during and after the LH surges, and fluctuated between a small range of 0.11 and 1.44 pg/ml. Although the peak levels of GnRH observed in its episodic patterns did not change between the periods before and during the LH surges, they decreased significantly after the LH surge compared with those seen during the LH surges (0.93 +/- 0.07 vs 1.17 +/- 0.09 pg/ml, p less than 0.05). The present data demonstrate that immunoreactive GnRH in the extracted peripheral plasma does not change significantly in its mean, basal and peak levels during the periovulatory period except for a minor but significant decrease in the peak levels shortly after an LH surge.

Morphological and endocrinological studies on follicular development during the human menstrual cycle.

In order to clarify the morphological dynamics of follicular development and its correlation with ovarian endocrine activity, the present studies were performed in 45 regularly menstruating women who underwent gynecological surgery. Ovarian venous blood was collected from 35 women during the follicular phase. Thirteen of these 35 women were ovariectomized. In addition, 11 pairs of ovaries were obtained from women during the luteal phase. The ovaries were sectioned serially at 2.5 micron and every 13th stained slice was examined to assess the sizes and numbers of atretic and nonatretic follicles. The follicles were divided into five stages: 0.4 less than or equal to approximately less than 1.0 mm, 1.0 less than or equal to approximately less than 2.0 mm, 2.0 less than or equal to approximately less than 4.0 mm, 4.0 less than or equal to approximately less than 6.0 mm, and 6.0 mm less than or equal to approximately in follicular diameter. Estradiol concentrations in ovarian venous plasma were low on both sides on days 1 and 3 of the cycle, whereas a clear asymmetry was found on day 5 before morphological recognition of the dominant follicle. Thereafter, estradiol increased proportionally to the growth of the dominant follicle, followed by a sudden drop when ovulation was imminent. An asymmetrical rise of progesterone occurred on day 10 and later which was sustained up to ovulation. A dominant follicle was recognized in 8 of 11 women between days 6 and 14. All dominant follicles were invariably associated with higher estradiol concentrations in the ipsilateral ovarian blood. Seven of 8 dominant follicles were on the side contralateral to the preceding corpus luteum. The mean diameters of the largest nonatretic follicles were 5.4 +/- 0.3 (SE) mm during the luteal phase as a whole and 4.7 +/- 0.7 mm during the late luteal phase. The mean diameters of the largest nonatretic follicles were not significantly different between the groups with or without the corpus luteum in the luteal phase. In terms of number and atretic rate, follicles of less than 4.0 mm in diameter did not change throughout the cycle in the presence or absence of the corpus luteum. In contrast, cyclic changes of growth and atresia occurred in the larger antral follicles.(ABSTRACT TRUNCATED AT 400 WORDS)

Biphasic stimulatory effects of estrogen on gonadotropin surges induced by continuous administration of gonadotropin-releasing hormone in women.

The present experiments were performed to study the effects of preovulatory levels of estrogen on GnRH-induced gonadotropin release. Twelve female volunteers in various phases of the menstrual cycle received estradiol infusion for 66 h at a constant rate of 500 micrograms/24 h which is grossly equivalent to its production rate during the preovulatory follicular phase. In 8 of the women, GnRH was administered concomitantly from 6 h after the initiation of estradiol infusion. The administered doses of GnRH were 2.5 and 5 micrograms/h. Blood samples obtained throughout the infusion were analysed for LH, FSH, estradiol and progesterone. The sole administration of estradiol failed to induce the positive feedback effect on gonadotropin release within the experimental period in the early follicular phase (days 3-7) in 4 women. In 5 women treated during the follicular phase, remarkable LH releases were induced after a lag period by the infusion of both GnRH and estradiol. The induced LH surge formed a prolonged biphasic pattern. Although a similar pattern of FSH was observed in some cases, its response was minimal compared with that of LH. In 3 women during the luteal phase, however, a combined administration of estradiol and GnRH induced only a short term release of LH which was terminated in only 12 h. The present data indicate that 1) Preovulatory levels of estrogen affect the late part of the LH surge which is induced by constant administration of low doses of GnRH resulting in a prolonged biphasic release of LH, and 2) These effects of both hormones are not manifest in the presence of high levels of progesterone. These results indicate the possibility of a role of GnRH and estrogen in the mechanism of the prolonged elevation of a gonadotropin surge at mid-cycle.

Reduction in pituitary desensitization and prolongation of gonadotropin release by estrogen during continuous administration of gonadotropin-releasing hormone in women: its antagonism by progesterone.

The present study was designed to elucidate gonadal steroid influences on gonadotropin release and subsequent pituitary desensitization to GnRH. Sixteen women, 10 of whom were normal and 6 of whom had hypogonadism, were infused with GnRH at rates ranging from 0.313-10 micrograms/h via an indwelling iv catheter for 66 h. Blood samples obtained throughout the GnRH infusion were analyzed for LH, FSH, estradiol, and progesterone. A prompt and substantial release of gonadotropin occurred in women with ovarian failure or during the luteal phase in normal women compared with that during the follicular phase of the menstrual cycle. Thereafter, a gradual decrease in gonadotropin secretion occurred due to pituitary desensitization, which was slower in the follicular phase than in other groups. A dose-related increase in integrated LH release occurred during GnRH infusion, but this response tapered off with administration of large doses of GnRH to women with ovarian failure or during the luteal phase. In contrast, it increased linearly up to the maximum dose of GnRH in the follicular phase. These data suggest that 1) basal levels of estrogen suppress the early rapid release of gonadotropin in response to GnRH and reduce subsequent pituitary desensitization, resulting in the prolonged release of LH; 2) estrogen widens the range of dose-related increases in gonadotropin in response to GnRH; and 3) these effects of estrogen are antagonized by progesterone.

Follicular development and a single ovulation induced with pulsatile administration of Gn-RH in anovulatory women: studies of hormonal analysis and follicular sonometry.

The method of pulsatile administration of gonadotropin-releasing hormone (Gn-RH) has been proven as a useful means for induction of ovulation in anovulatory women. In our series of clinical trials, 23 out of 29 anovulatory patients ovulated with pulsatile administration of Gn-RH. Seven patients who ovulated volunteered for the present study with daily hormonal analysis and follicular sonometory . Two patients have oligomenorrhea, 3 patients secondary amenorrhea-1st grade (the sole administration of gestagen required for withdrawal bleeding) and the remaining 2 patients secondary amenorrhea-2nd grade (the combined administration of estrogen and gestagen required for withdrawal bleeding). A diagnosis of hyperprolactinemia was made for one patient with secondary amenorrhea-1st grade. Pulsatile administration of Gn-RH was performed by the use of a self-administered infuser . The infuser was connected to an i.v. indwelling catheter via a specially designed blood backflow eliminater . Five micrograms or less of Gn-RH was given every 2 hr from 07:00 to 23:00 hr daily. Five patients received HCG during the preovulatory period. In one patient, a short term treatment of HMG was added to Gn-RH treatment. Follicular sonometry revealed the development of a single dominant follicle which reached between 20 and 28 mm (23.7 +/- 0.12 mm, mean +/- S.E.) in diameter at the preovulatory period. Disappearance of a dominant follicle was recognized in the early luteal phase. Characteristic increases in estradiol were recognized concomitantly with the development of a dominant follicle. Progesterone levels after ovulation were within the limits of its normal "luteal phase" rise. The present data suggest that pulsatile administration of low dose Gn-RH with nocturnal interruption of treatment is effective for normal progress of follicular development in various types of anovulatory patients, culminating in single ovulation. This paper includes the discussion on our method which may be responsible for a high success rate of ovulation induction.

Hormonal profile after removal of the dominant follicle and corpus luteum in women.

The present experiments were performed to elucidate the mechanism of the selection and maturation of a dominant follicle in women. Eight normally menstruating women undergoing myonectomy or tubal surgery volunteered for the present study. In 3 patients who were operated on Day 9-11, a visual dominant follicle was removed. The other 5 patients underwent the removal of a newly developing corpus luteum on Day 15-21. After taking 3 or 4 preoperative blood samples in the morning after their hospitalization, blood was obtained at 3 or 6 h intervals for the first 36-45 h and at 1-3 day intervals thereafter for 21-34 days. Serum FSH, LH, estradiol and progesterone were measured by radioimmunoassay. Follicleectomy was followed by a sudden drop in estradiol and a minor increase in progesterone. FSH increased for a few days and then declined. There was a drastic, but short-term increase in LH following follicleectomy which was performed before a preovulatory gonadotropin surge. A LH surge occurred 10.7 +/- 1.2 days (mean +/- S.E.) after follicular ablation followed by a luteal phase. In contrast, there was no remarkable LH release in 4 out of 5 patients who underwent luteectomy. A slightly higher level of FSH was sustained for 2-7 postoperative days. "Luteal phase" rises in estradiol and progesterone terminated promptly following luteectomy. A LH surge was observed 14.2 +/- 1.7 days after surgery followed by a luteal phase. After either type of operation, a sustained increase in FSH was followed by a gradual increase in estradiol which preceded a gonadotropin surge. These hormonal sequences resemble those seen in the normal follicular phase. The present data demonstrated that follicleectomy and luteectomy bring on some characteristic hormonal changes which may exert stimulatory or suppressive effects on the selection and maturation of a dominant follicle after the removal of a main ovarian cyclic structure culminating in ovulation at a certain interval.

Novel action of a piperazine derivative on the end-plate of the frog.

The effects of a piperazine derivative, trimetazidine (1-(2, 3, 4-trimethoxybenzyl) piperazine dihydrochloride) on the frog end-plate membrane were studied. Action and resting membrane potentials and the input resistance of muscle fibers were not affected by trimetazidine (82-165 muM). Under these conditions, the frequency of the miniature endplate potentials was unchanged while its amplitude was slightly decreased. The amplitude of acetylcholine (ACh) potentials were markedly and reversibly decreased after application of trimetazine (82-165 muM). The dose response curve of the end-plate membrane to ACh showed a non-competitive type of blockade. Trimetazidine (165 muM) not only decreased the amplitude of the end-plate currents (EPC) recorded from the glycerinated muscles using a voltage clamp technique, but also drastically shortened its time course. Under these conditions, the falling phase of the EPC became completely voltage insensitive. The equilibrium potential for the EPC slightly shifted to a more negative value in the presence of trimetazine (165 muM). Coefficient of variation of EPC was increased by Trimetazidine (165 mum), indicating a decrease in the quantal content of the EPC. The rate of desensitization of the end-plate to ACh was facilitated and the rate of decrease in EPC amplitude during tetanic stimulation became voltage sensitive by the action of trimetazidine (133 muM). It is concluded that trimetazidine mainly acts on the postsynaptic membrane with a weak presynaptic action. The agent seems to block a step subsequent to the interaction of ACh with its receptor, which presumably involves changes in the ion conductance of the membrane and is responsible for the voltage sensitivity of the response.