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Biomedical subjects

I M Spitz

Publications and source records attributed to I M Spitz.

At least 19 recordsLinked to original sources
PubMed2003

Effects of levonorgestrel-releasing intra-uterine system on the expression of vascular endothelial growth factor and adrenomedullin in the endometrium in adenomyosis.

BACKGROUND: The levonorgestrel-releasing intra-uterine system (LNg-IUS) has been used to control menorrhagia, but irregular bleeding during the first 3 months of use was the most notable side effect. Endometrial angiogenesis is believed to be regulated by angiogenic factors. The study aim was to evaluate the effects of LNg-IUS on vascular endothelial growth factor (VEGF) and adrenomedullin (AM) expression in the endometrium. METHODS: VEGF and AM expression were analysed using the avidin-biotin immunoperoxidase method on endometrial curettage specimens from menorrhagic women associated with adenomyosis before and 3 months after LNg-IUS insertion. RESULTS: VEGF expression was abundant both in the endometrial glands and stroma before LNg-IUS insertion, but became scanty 3 months after insertion. No immunostaining for AM was noted in the endometrial glands and stroma before LNg-IUS insertion, whereas AM immunostaining became prominent in the endometrial glands and stroma 3 months after LNg-IUS use. CONCLUSIONS: This is the first study to demonstrate that LNg-IUS insertion results in decreased expression of VEGF and increased expression of AM in the endometrial glands and stroma after 3 months of use. The results obtained suggest that the increase in AM expression in the endometrium may be responsible for the frequent occurrence of irregular bleeding during the initial 3 months of LNg-IUS use.

Adrenomedullin↗
PubMed2003

Estradiol/progesterone-releasing vaginal rings for hormone replacement therapy in postmenopausal women.

In order to investigate whether vaginal rings delivering estradiol and progesterone could prevent endometrial hyperplasia and relieve climacteric symptoms, two variants of rings were used in 20 postmenopausal women with intact uteri for 4 months. One ring designated as PI-002 (n = 8) delivered in vitro estradiol 160 microg/day and progesterone 20 mg/day, while the other (PI-003; n = 12) delivered the same dosage of estradiol but only half the progesterone (10 mg/day). Serum estrone, estradiol and progesterone were measured at pretreatment, weekly for 4 weeks, and then monthly for 4 months. The incidence of hot flushes, frequency of night sweats, mood scores, vaginal discharge and bleeding profiles were recorded. Endometrial thickness was monitored by ultrasonography. The mean estrone level was 50 pg/ml for 16 weeks. The mean serum estradiol level was 75 pg/ml for the first 4 weeks and gradually decreased to 50 pg/ml at 16 weeks. The mean progesterone level with the PI-002 ring was 5 ng/ml for the first 4 weeks and decreased to 3.5 ng/ml at 16 weeks. With the PI-003 ring, the mean progesterone level was initially 3.5 ng/ml and then decreased to 2.5 ng/ml thereafter. Significant decreases in the incidence of hot flushes and night sweats as well as a striking improvement in mood scores were noted as early as 2 weeks after insertion. Three of the 20 women discontinued the treatment, owing to ring expulsion. Increased vaginal discharge was observed with both rings in the first 6 weeks. Vaginal bleeding was more frequently apparent among users of the PI-002 ring, although bleeding and spotting were confined to the first 6 weeks. Ultrasonographic monitoring of the endometrium constantly revealed a thickness of < 3 mm for both variants throughout use for 16 weeks. An estradiol/progesterone-releasing vaginal ring is a potential alternative to long-term hormone replacement therapy with minimum attention required. It provides effective protection against endometrial hyperplasia.

Administration, Intravaginal↗
PubMed2002

Serum inhibin B levels measured early during FSH administration for IVF may be of value in predicting the number of oocytes to be retrieved in normal and low responders.

BACKGROUND: In a previous study we have found that in normal ovulatory women, serum inhibin B levels on days 4-6 of FSH administration correlated with the number of oocytes retrieved. In the current study we examined the significance of earlier inhibin B measurements in predicting the oocyte number, in both normal and low responders. METHODS: Study A consisted of 19 patients undergoing their first IVF cycle (n = 10) or had a normal response ( vertical line 6 oocytes retrieved, n = 9), while study B consisted of 15 patients with a previous low ovarian response ( 16. Study B: oocyte number correlated significantly with inhibin B and inhibin A on all days of FSH treatment, even on day 2 (r = 0.90, P < 0.001 and r = 0.65, P < 0.05 for inhibin B and A respectively). No significant correlation was found with E(2) levels. In both studies, all patients with inhibin B >100 pg/ml on treatment day 2 had >6 oocytes. CONCLUSIONS: Our data suggest that serum inhibin B measured early during FSH stimulation may indicate whether sufficient oocytes will be retrieved, in both normal and low responders. Serum inhibin B measured during early FSH treatment may be of predictive value in monitoring ovarian stimulation treatment for IVF.

Adult↗
PubMed2001

Long-term mifepristone (RU486) therapy resulting in massive benign endometrial hyperplasia.

Mifepristone (RU486) is a potent antiprogestagen, and at high doses it also acts as an antiglucocorticoid drug. Mifepristone, administered as a single 600 mg dose, is commonly employed to induce medical abortion in conjunction with prostaglandins. The long-term safety profile of mifepristone, especially at high doses, is less well-established. Long-term mifepristone is considered efficacious in treating uterine myomas, endometriosis (25--100 mg/day), and possibly in inoperable meningiomas (200 mg/day), as well as inoperable Cushing's syndrome. Many animal studies document an antiproliferative effect (antioestrogenic), as do some reports in humans. However, there are also data to suggest that, as an antiprogestagen, mifepristone may promote an unopposed oestrogen milieu, and thus have a proliferative effect upon the endometrium. We hereby describe the first reported case of an adolescent female with Cushingoid features and morbid osteoporosis who was treated with mifepristone for its antiglucocorticoid effect (400 mg/day) in an attempt to prevent further bone loss. The patient's striae, weight gain, and buffalo hump markedly improved, and further bone loss was halted. However, with each of the two 6-month courses of mifepristone (9 months apart) she developed massive simple endometrial hyperplasia and a markedly enlarged uterus. This reversed to normal after cessation of mifepristone treatment. In conclusion, High doses of the antiprogestagen mifepristone over a prolonged period of time may promote an unopposed oestrogen milieu leading to endometrial hyperplasia. Therefore, interval pelvic imaging in women who receive long-term mifepristone may be prudent.

Adolescent↗
PubMed2001

Effects of the levonorgestrel-releasing intrauterine system on proliferation and apoptosis in the endometrium.

BACKGROUND: The levonorgestrel-releasing intrauterine system (LNg-IUS) has been shown to be effective in the management of menorrhagia. In order to evaluate the effects of LNg-IUS on endometrial proliferation and apoptosis, proliferating cell nuclear antigen (PCNA) expression, apoptosis, Fas and Bcl-2 protein expression in the endometrium were determined at the early proliferative phase of the menstrual cycle before and 3 months after LNg-IUS insertion. METHODS: PCNA, Fas and Bcl-2 protein expression were analysed using an avidin-biotin immunoperoxidase method. Apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick-end labelling (TUNEL) method. RESULTS: PCNA, immunolocalized both in the nuclei of endometrial glands and stroma was less abundant 3 months after insertion (P < 0.05). Bcl-2 protein, immunolocalized in the cytoplasm of endometrial glands but not in the stroma, became scanty 3 months after insertion. Fas antigen, immunolocalized only in endometrial glands before insertion, became prominent in both endometrial glands and stroma 3 months after insertion. The apoptosis-positive rate of the nuclei in both endometrial glands and stroma was significantly higher 3 months after insertion relative to that before insertion (P < 0.05). CONCLUSIONS: LNg-IUS resulted in a decrease in endometrial proliferation and an increase in apoptosis in endometrial glands and stroma. The increase in apoptosis associated with increased Fas antigen expression and decreased Bcl-2 protein expression in the endometrium may be one of the underlying molecular mechanisms by which LNg-IUS insertion causes the atrophic change of the endometrium.

Adult↗
PubMed2001

Follistatin and activin A serum concentrations in obese and non-obese patients with polycystic ovary syndrome.

BACKGROUND: Activin promotes ovarian follicular development, inhibits androgen production and increases FSH and insulin secretion. Follistatin, an activin-binding protein, neutralizes activin bioactivity. Therefore, a decrease in the ratio of activin/follistatin might encourage characteristic features of polycystic ovary syndrome (PCOS). We investigated whether women with PCOS showed disordered follistatin and/or activin serum concentrations. METHODS: The study group included 24 obese and 20 non-obese (body mass index vertical line and <27 kg/m2 respectively) clomiphene-failure PCOS patients. The control group included 16 obese and 46 non-obese patients with normal ovulatory cycles. Blood samples were obtained from the patients on day 3-5 of a progesterone-induced or spontaneous cycle and were assayed for LH, FSH, testosterone, 17-hydroxy-progesterone, androstenedione, follistatin, activin A, fasting glucose and insulin. RESULTS: Follistatin concentrations were comparable between obese and non-obese PCOS patients (mean +/- SE; 1171 +/- 103 and 1045 +/- 159 pg/ml respectively) and significantly higher than their respective controls (628 +/- 61 and 592 +/- 49 pg/ml, P < 0.0001 and P < 0.02 respectively). Activin A concentrations were comparable between the four groups (590 +/- 35, 513 +/- 74, 661 +/- 87 and 595 +/- 43 pg/ml in obese and non-obese PCOS and controls respectively). Stepwise regression analyses for relationships between follistatin or activin A levels and all other variables indicated that follistatin was significantly and independently positively affected by PCOS (P < 0.0001), age (P < 0.02), androstenedione (P < 0.03) and weight (P < 0.05). Activin A was significantly and independently negatively affected by PCOS (P < 0.003) and FSH (P < 0.03), and positively affected by weight (P < 0.009) and androstenedione (P < 0.02). CONCLUSIONS: Serum follistatin is increased in PCOS patients, regardless of obesity. PCOS is the most significant variable that relates to high follistatin and low activin A serum concentration. A high follistatin/activin ratio could well contribute to the pathophysiology of PCOS.

17-alpha-Hydroxyprogesterone↗
PubMed2000

An implant releasing the gonadotropin hormone-releasing hormone agonist histrelin maintains medical castration for up to 30 months in metastatic prostate cancer.

PURPOSE: The administration of gonadotropin hormone-releasing hormone agonists is well established for treating metastatic prostate cancer. In an ongoing study we evaluated the effect of a long acting implant that releases the gonadotropin hormone-releasing hormone agonist histrelin ([ImBzl]D-His6,Pro9-Net) in 15 patients with disseminated prostate cancer. MATERIALS AND METHODS: The 2.6 cm. implant releasing 60 microg. histrelin daily is inserted subcutaneously into the upper arm using local anesthesia. Of the patients 8 received 1 and the remainder received 2 implants. Treatment with the antiandrogen flutamide or cyproterone acetate began 2 weeks before implant insertion and continued for up to 12 weeks. Testosterone, luteinizing hormone (LH) and prostate specific antigen were determined monthly, and a metastatic evaluation was performed every 6 months. RESULTS: LH and testosterone increased after flutamide administration and decreased after implant insertion. By day 28 LH and testosterone were completely suppressed. LH and testosterone decreased immediately after cyproterone acetate administration. Prostate specific antigen began to decrease during antiandrogen therapy and decreased further after implant insertion. One patient requested implant removal after 1 year for personal reasons and 1 died of an unrelated cause 18 months after insertion. Escape was demonstrated in 4 cases at 5, 10, 12 and 19 months, although LH and testosterone remained suppressed. Duration of treatment in the remaining 9 patients was between 21 and 30 months. LH and testosterone remained completely suppressed and prostate specific antigen levels were in the normal range. The clinical and biochemical response was identical in those who received 1 or 2 implants. At 12 months 8 patients were challenged at intermittent intervals for up to 24 months with a bolus of 100 microg. gonadotropin hormone-releasing hormone followed by 2 weeks of flutamide. The response was compared with that in untreated controls recently diagnosed with prostate cancer. Unlike controls there was complete LH suppression in the 8 challenged patients. CONCLUSIONS: A histrelin implant suppresses LH and testosterone in prostate cancer for up to 30 months. This finding represents a significant improvement over existing preparations, which must be administered at 1 to 3-month intervals.

Aged↗
PubMed1999

Use of various ultrasonographic criteria to evaluate the efficacy of mifepristone and misoprostol for medical abortion.

OBJECTIVE: This study was undertaken to determine whether applying modern formulas for mean sac diameter and crown-rump length to data from the recently published US mifepristone-misoprostol abortion trial would result in differences in assigned gestational ages and a higher rate of complete abortion. STUDY DESIGN: Data from the US mifepristone-misoprostol trial were reanalyzed. The ultrasonographic findings at baseline examination of the 2121 participants were used to estimate gestational age according to criteria established by Rossavik et al for mean sac diameter and by Robinson and Fleming, Hadlock et al, and Goldstein and Wolfson for embryonic pole. The gestational ages as assigned by the different criteria were then compared and the treatment outcomes at various gestational ages were calculated for each of the dating criteria. These findings were compared with those reported in the original study. RESULTS: Fourteen percent of study subjects were assigned to the incorrect gestational age group according to the criteria used for the original report. Still, outcomes according to gestational age group were similar regardless of which ultrasonographic gestational age criteria were used and were comparable to those calculated in the original report. Overall efficacy for subjects at </=42 days' gestation was 95% to 96%, compared with 91% for subjects at between 43 and 49 days' gestation, when the various criteria were used. CONCLUSIONS: The results from the United States mifepristone-misoprostol abortion study were not altered by applying modern and appropriate ultrasonographic dating formulas. The rate of complete abortion was highest among subjects at </=42 days' gestation.

Abortifacient Agents↗
PubMed1998

Early pregnancy termination with mifepristone and misoprostol in the United States.

BACKGROUND: Mifepristone and a prostaglandin have been used successfully to terminate pregnancy in Europe and China. We report the results of a large U.S. study of mifepristone and misoprostol in women with pregnancies of up to nine weeks' duration. METHODS: We administered 600 mg of mifepristone and then 400 microg of misoprostol two days later to 2121 women seeking termination of their pregnancies at 17 centers. The women were observed for four hours after the administration of misoprostol and returned on day 15 for final assessment. RESULTS: Two thousand fifteen women completed the final assessment. Among them, pregnancy was terminated in 762 of the 827 women pregnant for < or =49 days (92 percent), 563 of the 678 women pregnant for 50 to 56 days (83 percent), and 395 of the 510 women pregnant for 57 to 63 days (77 percent) (P<0.001). Termination occurred within 4 hours after the administration of misoprostol in 49 percent of the women and within 24 hours in 75 percent. Failures, defined as cases requiring surgical intervention for medical reasons or because the patient requested it, the abortion was incomplete, or the pregnancy was ongoing, increased with increasing duration of pregnancy. The largest increase was in failures representing ongoing pregnancy, which increased from 1 percent in the < or =49-days group to 9 percent in the 57-to-63-days group (P<0.001). Abdominal pain, nausea, vomiting, diarrhea, and vaginal bleeding also increased with advancing gestational age. Two percent of the women in the < or =49-days group, as compared with 4 percent in each of the other two groups, were hospitalized, underwent surgical interventions, and received intravenous fluids (P=0.008). CONCLUSIONS: This mifepristone-misoprostol regimen is effective in terminating pregnancies, especially in women with pregnancies of 49 days' duration or less.

Abortifacient Agents, Nonsteroidal↗
PubMed1997

Alterations in the pituitary-thyroid and pituitary-adrenal axes--consequences of long-term mifepristone treatment.

The effects of short-term administration of the antiprogestin and antiglucocorticoid, mifepristone, have been well characterized. However, little is known about the effects of prolonged administration of mifepristone. We analyzed hormonal parameters in four female and three male patients with unresectable meningioma who were treated with mifepristone (200 mg/d) for 20 to 40 months. Serum samples were collected at monthly intervals approximately 24 hours following mifepristone ingestion. Serum thyrotropin (TSH), thyroxine (T4), free T4 (fT4), 3,5,3-triiodothyronine (T3), prolactin, and cortisol were analyzed by fluoroimmunoassay, and androstenedione by radioimmunoassay (RIA). Levels of mifepristone and its three most proximal metabolites were measured by high-performance liquid chromatography. TSH values increased significantly (P < .005, one-way ANOVA), with the most pronounced increase evident during the first 3 months of mifepristone treatment. Despite these changes, concentrations of TSH remained within the normal range throughout the treatment period. There were no significant changes in serum T4, fT4, T3 or prolactin; however, a transient decrease in serum T4 was noted at 2 to 3 months. Cortisol and androstenedione values increased significantly and in parallel (P < .05), suggesting an adrenal origin also for androstenedione. As during short-term administration, levels of mifepristone and its metabolites remained stable in the micromolar range. Individual levels of mifepristone were significantly correlated with those of TSH and cortisol. This suggests that the alterations in the pituitary-thyroid and -adrenal axes occurred in a concentration-dependent manner. It is concluded that long-term mifepristone treatment results in resetting of the pituitary-thyroid balance. As in the case with cortisol and androstenedione, it is likely that the alterations in serum TSH are due to the antiglucocorticoid properties of mifepristone. The clinical significance of these biochemical alterations in thyroid homeostasis remains to be determined. However, monitoring thyroid function during long-term mifepristone treatment appears to be warranted.

Administration, Oral↗
PubMed1996

Antiprogestins: mechanism of action and contraceptive potential.

Antiprogestins are characterized by substitutions at the 11 beta and 17 alpha positions of the steroid ring system and bind strongly to both progesterone and glucocorticoid receptors. Although they function predominantly as antiprogestins and antiglucocorticoids, on occasion they display progestin agonistic and even antiestrogenic properties. The most common clinical use of the antiprogestin mifepristone is to induce a medical abortion in the early stages of pregnancy. Progesterone maintains the endometrium, transforming it from a proliferative to a secretory state. It also facilitates the luteinizing hormone surge, which initiates ovulation. As a consequence, antiprogestins may also have contraceptive potential. Although antiprogestins do delay ovulation, this effect is inconsistent unless high doses are given, and under these circumstances, the antiprogestin effect is associated with unopposed estrogen action on the endometrium. Very low doses of antiprogestins do not affect hormonal secretion or ovulation or alter bleeding patterns, but they do have contraceptive potential by inducing profound alterations in endometrial morphology. Mifepristone is also a very effective and safe postcoital agent. This new class of pharmacological agents has numerous other gynecological and obstetrical indications, such as endometriosis, uterine myoma, and expulsion of the fetus in the case of fetal death in utero. Antiprogestins may also be used in the treatment of steroid-dependent tumors. There are also therapeutic implications consequent to their antiglucocorticoid properties.

Abortifacient Agents, Steroidal↗
PubMed1994

Effect of mifepristone on inhibition of ovulation and induction of luteolysis.

Mifepristone administration to women in the mid- or late follicular phase delays the luteinizing hormone (LH) surge and prolongs the follicular phase. Since the resumption of follicular growth commences following mifepristone cessation, the drug must be given either continuously or at repeated intervals in order to block ovulation. Using various regimens with or without exogenous progestins, ovulation was inhibited in the majority of subjects. However, this was not consistent and in several instances, LH surges and a rise in plasma progesterone were suggestive of ovulation and corpus luteum function. Therefore, mifepristone cannot be used as a contraceptive which will reliably inhibit ovulation. With low-dose mifepristone administration, alterations in endometrial morphology were characterized by a delay in maturation despite the presence of ovulation. This suggests that the endometrium displays a greater sensitivity to mifepristone than does the pituitary, a finding that may have important contraceptive implications. Late luteal-phase mifepristone administration to women who were not sexually active did not alter their menstrual rhythm, bleeding patterns or steroid and gonadotrophin concentrations. However, when used in unprotected women in the late luteal phase, mifepristone did not uniformly terminate all pregnancies. On the other hand, when used within 72 h of intercourse, mifepristone was as effective a post-coital agent as the standard high-dose oestrogen-progestin combination.

Abortion, Induced↗
PubMed1994

Effect of administration of a gonadotropin-releasing hormone (GnRH) antagonist (Nal-Glu) during the periovulatory period: the luteinizing hormone surge requires secretion of GnRH.

In primates, the LH surge that triggers ovulation is induced by an increase in circulating estradiol (E2) levels. Although several studies suggest that E2 acts on the pituitary, it is still not clear whether GnRH is involved. We investigated the role of GnRH during the periovulatory period in normal women by treating them with the GnRH antagonist Nal-Glu ([Ac-D2Nal1,D4-ClPhe2,D3Pal3,Arg5,DGlu6 (AA),DAla10] when E2 levels exceeded 550 pmol/L. In the first study (A), Nal-Glu was administered in five regimens (n = 4 in each group): a single sc injection of 10 mg (group 1), a single injection of 20 mg (group 2), and an injection of 10 mg, sc, on 2 (group 3), 3 (group 4), and 5 consecutive days (group 5). In the second study (B; n = 4), Nal-Glu (10 mg, sc, on 3 consecutive days) was coadministered with E2 benzoate (EB; 0.5 mg, im, every 12 h on 3 consecutive days). Controls (n = 4) were treated with EB alone at the same stage of the cycle. In the third study (C), three women received 10 mg/day Nal-Glu, sc, on 3 consecutive days together with pulsatile GnRH therapy (25 micrograms/pulse, one pulse every 90 min, sc, for 3 days); the first pulse was given 12 h after the first Nal-Glu injection. In study A, gonadotropin suppression resulted in a transient decline in E2 in groups 1 and 2. Relative to control cycles, the LH surge occurred with a delay of 24-48 h in group 1 and 24-120 h in group 2. In groups 3, 4, and 5, Nal-Glu administration resulted in the demise of the dominant follicle in half of the women in each group. The remaining women showed a profile similar to that of groups 1 and 2, i.e. a transient decline in E2 levels followed by a recovery, and a LH surge occurring 4 +/- 0.3 days after the last Nal-Glu injection. In study B, simultaneous administration of Nal-Glu and EB induced a rise in E2 levels from 951.3 +/- 79.6 to 4000.1 +/- 772.5 pmol/L 24 h after the beginning of treatment. Serum LH and FSH levels both decreased and remained low throughout Nal-Glu treatment. None of the women showed a LH rise in response to the EB injection. In controls, however, EB administration was followed by a significant gonadotropin discharge 48 h after the first EB injection.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗