Ovulation induction by human menopausal gonadotropin with ultrasonic monitoring of the ovarian follicles

One hundred sixteen cycles of human menopausal gonadotropin (hMG) treatment for ovulation induction were studied. The ovarian response to hMG treatment was monitored by the daily determination of serum estradiol (E2) or by daily serum E2 and repeated ultrasonic examination of the ovaries. There were more follicles 18 mm in diameter or larger at the time of human chorionic gonadotropin (hCG) administration in the pregnancy than in the non-pregnancy cycles, and in the hyperstimulated than in the nonhyperstimulated cycles. The ovulatory rate and the pregnancy rate per cycle did not improve with the use of ultrasound. The number of treatment cycles required to achieve pregnancy was less in patients who had ultrasonic examination of the ovarian follicles. These results suggest that ultrasonic examination of the ovarian follicle helps to reduce the number of hMG cycles required to achieve pregnancy. The development of multiple follicles results in more pregnancies. However, the use of ultrasound does not improve the pregnancy rate.     

Preovulatory follicular fluid steroid levels in stimulated and unstimulated cycles triggered with human chorionic gonadotropin

The purpose of this study was to analyze follicular fluid (FF) samples for steroid levels from stimulated and unstimulated cycles triggered with human chorionic gonadotropin (hCG) and to assess the influence of controlled ovarian hyperstimulation and luteinizing hormone/hCG on these levels. Spontaneous ovulatory cycles were monitored with serial ultrasound examinations, and hCG 10,000 IU was given when the lead follicle was mature. Fourteen FF samples yielding fertilizable oocytes were compared with 13 FF samples from controlled ovarian hyperstimulation cycles. Progesterone (P) was higher in controlled ovarian hyperstimulation than in unstimulated cycles (9.0 +/- 1.2 micrograms/mL versus 4.4 +/- 0.6 microgram/mL; mean +/- SEM), whereas estradiol (E2) was lower (0.8 +/- 0.1 microgram/mL versus 1.3 +/- 0.2 microgram/mL), resulting in a higher P:E2 ratio (15.5 +/- 3.3 versus 4.4 +/- 0.7). Androstenedione (A), testosterone (T), and T:E2 ratios were all higher in unstimulated than controlled ovarian hyperstimulation cycles. We conclude that controlled ovarian hyperstimulation is associated with increased FF P, decreased FF E2, T, and A levels, and decreased T:E2 ratios, suggesting altered steroidogenesis and enhanced follicular aromatase activity.     

Transvaginal ultrasound-guided follicular aspiration in the management of anovulatory infertility associated with polycystic ovaries.

STUDY OBJECTIVE: To investigate whether or not transvaginal ultrasound (US)-guided follicular aspiration can effectively induce ovulation and facilitate pregnancy in anovulatory patients with polycystic ovaries (PCO). DESIGN: Eight patients with polycystic ovarian disease (PCOD) and 10 patients with PCO were participants who failed to ovulate by the medical therapies. Most of persistent follicles were punctured, and their contents were thoroughly aspirated during the midluteal phase. The same ovarian stimulation regimen as used in the previous cycles were administered in the cycles after the aspiration. MAIN OUTCOME MEASURES: Evidence of ovulation and a subsequent pregnancy was ultrasonically monitored after the aspiration, and the responsiveness of pituitary gonadotropins to gonadotropin-releasing hormone was tested in these patients. RESULTS: The ovulation rates were 87.5% per patient, 52.6% per cycle monitored in PCOD patients and 100% per patient, 63.3% per cycle monitored in PCO patients, respectively. Half of the patients both with PCOD and PCO achieved pregnancy after the aspiration. A significant decrease (P less than 0.05) of the basal and peak levels of serum luteinizing hormone was observed after the aspiration. CONCLUSIONS: The US-guided follicular aspiration seems to be a new surgical method for treating anovulatory patients with PCO.     

Improved pregnancy rate with monitoring of gonadotropin therapy by three modalities

The frequency of complications during gonadotropin therapy was reduced after the introduction of rapid estrogen assays. However, pregnancy rates remained low especially in normoestrogenic women. One hundred forty-three infertile normoestrogenic women were treated with human menopausal gonadotropin-human chorionic gonadotropin for 661 cycles. Almost all cycles were ovulatory. Whereas 53.7% of the patients conceived when drug administration was monitored by cervical score and serum estradiol levels only, 72.1% became pregnant when treatment was monitored by these modalities and real-time ultrasonography of the ovaries (p less than 0.05). Mean serum estradiol levels were significantly higher when ultrasonography was used to monitor response, but complications such as multiple births and ovarian enlargement did not occur more often. The data suggest that "true" ovulation occurs more often when ovarian imaging is used to determine drug dosage. Because of the higher pregnancy rate achieved by combined clinical (cervical score), biochemical (serum estradiol), and sonographic methods of monitoring, this approach should replace less extensive techniques.     

Effect of 21-day and 24-day oral contraceptive regimens containing gestodene (60 microg) and ethinyl estradiol (15 microg) on ovarian activity.

OBJECTIVE: To compare ovulation inhibition and ovarian activity with 21-day and 24-day regimens of a low-dose combined oral contraceptive (COC) containing 60 microg of gestodene and 15 microg of ethinyl estradiol. DESIGN: Interventional observational study. SETTING: Reproductive medicine unit. PATIENT(S): Fifty-eight healthy volunteers aged 18-35 years. INTERVENTION(S): Ovarian activity was monitored every other day with the use of ultrasound to measure the diameters of follicle-like structures and blood samples to measure serum concentrations of 17beta-E2 and progesterone. Subjects were observed for five cycles: pretreatment and posttreatment control cycles and three cycles in which the COC was administered for either 21 or 24 days of each cycle. MAIN OUTCOME MEASURE(S): Occurrence of ovulation and evidence of ovarian activity. RESULT(S): The study was completed by 27 (90%) of the 30 subjects who received the 24-day regimen and by 24 (79%) of the 28 subjects who received the 21-day regimen. Ovulation was inhibited in all cycles in the 24-day group and in 74 of 75 cycles in the 21-day group. Luteinized unruptured follicles were seen in no cycles with the 24-day regimen and in 6 (8%) of 75 cycles with the 21-day regimen. Mean ovarian follicular development and serum 17beta-E2 and progesterone levels were lower in the 24-day group. CONCLUSION(S): The 24-day regimen is an innovative strategy for maintaining effective ovulation inhibition at ultra-low doses of contraceptive steroids.     

Safety and efficacy of lenalidomide (Revlimid) in recurrent ovarian and primary peritoneal carcinoma

OBJECTIVES: To conduct a phase I trial to determine the safety and toxicity profile of a novel immunomodulatory drug, lenalidomide, in recurrent ovarian and primary peritoneal cancer. The secondary objective is to evaluate the efficacy profile and quality of life (QOL) parameters in patients receiving this treatment. METHODS: Patients with recurrent ovarian or peritoneal cancer who received standard staging surgery and at least one prior platinum-based chemotherapy regimen were treated with single-agent oral lenalidomide 25 mg daily for 21 days of a 28-day cycle. Toxicities were monitored by patient report, physical exam, and laboratories. Response was assessed by imaging, physical exam, and CA-125. Therapy was discontinued with disease progression and/or unacceptable toxicity. RESULTS: 20 patients with recurrent ovarian or peritoneal cancer were enrolled and received 70 completed 28-day cycles and 10 partial cycles of lenalidomide therapy. The majority of adverse events were grades 1-2, including fatigue (25/80 cycles), nausea/vomiting (23/80), constipation (13/80), abdominal pain (17/80), rash (12/80), neutropenia (12/80), and anemia (12/80). Grade 3 toxicities occurred in 12 of 80 cycles (14%) and no grade IV toxicities were observed. Eleven patients completed > or = 2 cycles and were evaluable for response. Nine achieved stable disease (SD) of at least 3 months, with four patients maintaining SD for > 6 months. The mean time to progression was 5.8 months (range 2-12 months). CONCLUSION: Overall, oral lenalidomide was well tolerated and may have some activity as a single agent in this heavily pre-treated population. Further studies combining lenalidomide with cytotoxic treatments may be warranted in this disease setting.     

Ovarian hyperstimulation and follicular aspiration. Effect on ovulatory function.

The return of normal function of the reproductive axis immediately after hyperstimulation and follicular aspiration is of both physiologic and clinical interest. These cycles may be utilized for the replacement of cryopreserved embryos, for repeated ovarian stimulation or for any alternative treatment that relies upon normal ovulatory function. Thirty-five women were randomly assigned to be monitored in the first (n = 11), second (n = 13) or third (n = 11) menstrual cycle after in vitro fertilization (IVF). Five of 35 patients (14.3%) failed to ovulate, 2 in each of the first and second menstrual cycles and 1 in the third cycle after IVF. Six (20%) ovulatory cycles demonstrated luteal phase deficiencies. The defective luteal phases were evenly distributed between cycles immediately after IVF and those more remote in time from the procedure.     

Serum CA125 level modifications in women undergoing repeated IVF cycles

In the present paper, serum CA125 modifications in patients undergoing their first IVF cycle were compared with those of patients in their second attempt. A significant increase of this marker was detected in each group of patients at day 14 after embryo transfer. However, the level of CA125 monitored in the patients in their second attempt was significantly higher than that determined in patients undergoing their first ovarian stimulation. This condition does not influence either ovarian response or oocyte and embryo quality. Moreover similar IVF outcome was obtained. Therefore we propose that patients undergoing repeated assisted reproductive technology (ART) cycles may suffer from ovarian surface epithelial damage and/or altered cellular growth rate.     

Normal salivary progesterone levels throughout the ovarian cycle as determined by a direct enzyme immunoassay

This study, which is concerned with establishing clinically relevant corridors defining normal progesterone (P) levels in saliva, has addressed some of the shortcomings associated with previous equivalent studies (e.g., limited data, inadequately monitored ovulations, inadequately defined subjects). A sensitive, direct, microtiter plate, enzymeimmunoassay (EIA) for progesterone developed in the authors' unit, was used to determine daily salivary progesterone concentrations over 41 menstrual cycles in 41 women. Each woman was without associated factors known to affect ovarian function and each cycle included was judged to be (single) ovulatory by serial pelvic ultrasound examinations. Daily salivary progesterone levels from these cycles were statistically analyzed and corridors of progesterone concentrations associated with normal luteal function were established.     

Hormonal profile and endometrial morphology in letrozole-controlled ovarian hyperstimulation in ovulatory infertile patients

OBJECTIVE: To evaluate the clinical response and endometrial morphology during the implantation window on ovarian hyperstimulation with the aromatase inhibitor letrozole in infertile ovulatory women. DESIGN: Prospective trial in infertile patients. SETTING: Tertiary care hospital. PATIENT(S): Eight ovulatory infertile patient candidates for ovarian superovulation. INTERVENTION(S): Subjects were monitored in one control cycle. In the next cycle, they received letrozole 5.0 mg daily on days 3 through 7 after menses. MAIN OUTCOME MEASURE(S): Number of ovulatory follicles; dominant follicle diameter; endometrial thickness; hormonal profile of FSH, LH, E(2), A, T, and P; endometrial histological dating; and pinopode formation assessed by scanning electron microscopy. RESULT(S): Cycles stimulated with letrozole resulted in more ovulatory follicles than did natural cycles (mean +/- SD 2.0 +/- 0.9 vs. 1.0 +/- 0.0), which attained a greater preovulatory diameter (mean +/- SD 23.8 +/- 2.7 vs. 19.3 +/- 2.1 mm), with similar endometrial thickness at midcycle compared with spontaneous cycles. Endocrine profile of medicated cycles was characterized on day 7 by increased levels of LH (5.9 +/- 0.8 vs. 3.5 +/- 0.4 IU/mL), reduced E(2) (98.4 +/- 11.4 vs. 161.5 +/- 14.7 pmol/L), and elevated androgens. Preovulatory and midsecretory E(2) were similar to spontaneous cycle, and P levels during midluteal phase were significantly elevated (44.2 +/- 4.6 vs. 27.7 +/- 4.6 pmol/L). Endometrial morphology during the implantation window in letrozole-stimulated cycles was characterized by in-phase histological dating and pinopode expression on scanning electron microscopy. CONCLUSION(S): Letrozole induces moderate ovarian hyperstimulation in ovulatory infertile patients with E(2) levels similar to spontaneous cycles and higher midluteal P, leading to both a normal endometrial histology and development of pinopodes, considered to be relevant markers of endometrial receptivity.     

A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women

OBJECTIVE: To evaluate the ovarian follicular dynamics of cycle modification with the aromatase inhibitor letrozole compared with clomiphene citrate in normal ovulatory women. DESIGN: Randomized double-blind controlled trial. SETTING: Tertiary care hospital. PATIENT(S): Nineteen ovulatory female volunteers, ages 18-35 years. INTERVENTION(S): Subjects were monitored in one control cycle. Subjects then received either letrozole 2.5 mg daily or clomiphene citrate 50 mg daily on days 5-9 after menses. MAIN OUTCOME MEASURE(S): Number of mature follicles, endometrial thickness and endometrial pattern at ovulation, and follicular profiles of LH, FSH, and E(2). RESULT(S): The number of mature follicles at the LH surge in natural cycles was 1.0 with an exaggerated response seen for treatment both with clomiphene and letrozole. There was no difference in the endometrial thickness at midcycle during either the natural cycles or the medicated cycles. LH surges and spontaneous ovulation were documented in all natural and medicated cycles. When measured daily, follicular profiles of LH and FSH are similar between the groups in both the natural and medicated cycles. In the medicated cycles, clomiphene results in a significant increase in E(2) levels, while E(2) levels in letrozole-stimulated cycles appeared lower than in natural cycles. CONCLUSION(S): Transient inhibition of aromatase activity in the early follicular phase with the aromatase inhibitor letrozole results in stimulation of ovarian folliculogenesis similar to that seen with clomiphene citrate with no apparent adverse effect on endometrial thickness or pattern at midcycle.     

Monitoring of ovulation induction with HMG-HCG therapy by plasma estrogen and progesterone

Seventeen patients with anovulation or luteal deficiency were tested with HMG-HCG for 40 cycles. Follicular development was monitored daily by measurement of immunoreactive plasma estrogen. Ovulation was evaluated by determination of plasma progesterone. Ovulation was induced in 16 patients and 37 of 40 cycles (93%). Fourteen pregnancies occurred in 13 patients. Plasma estrogen measurements in ovulatory cycles at the time of HCG injection ranged from 315 to 1,482 pg/ml (mean 764 pg/ml). Mild hyperstimulation occurred in two cycles with preovulatory estrogen values of 720 pg/ml and 784 pg/ml. The highest preovulatory estrogen level which was followed by anovulation was 493 pg/ml. The preovulatory estrogen peak in one triplet pregnancy measured 1,356 pg/ml. Determinants of treatment failure included inadequate follicular stimulation, interruption of HMG therapy for more than 1 day, previous ovarian wedge resection, and congenital anomaly of the uterus. Increase in body weight required higher doses of drug therapy in one case. We conclude that optimal estrogen levels prior to HCG injection range from 500 to 700 pg/ml. The risks for ovarian hyperstimulation and multiple pregnancy may be reduced and ovulation accomplished by daily administration of HMG until the defined estrogen level is reached.     

Ultrasonic monitoring as a method of preventing risks of ovarian hyperstimulation during drug therapy

BACKGROUND AND AIMS: Ultrasonographic monitoring represents the most immediate method for an early confirmation of the onset of the worst complication of the pharmacological induction of ovulation: ovarian hyperstimulation. The aim of this study was to evaluate the incidence of this complication in a sample group of anovulatory patients receiving pharmacological treatment and undergoing repeated ultrasonographic monitoring. METHODS: The authors analysed the controls performed during 1996-1997 in which a total of 413 cycles were stimulated. The patients included in the study group (mean age 28.5 years) were treated using clomiphene, oestradiol, FSH, LH and GnRH, and in 5 cases stimulation was preceded by suppression of the menstrual cycle using tryptorelin. Each patient was monitored with 3 scans, except for those treated with tryptorelin or GnRH who were more closely monitored. RESULTS: In 413 patients included in this study the authors noted the onset of slight hyperstimulation in 6 cases (1.45%) which then resolved spontaneously without the need for hospitalisation. CONCLUSIONS: The authors affirm that ultrasonographic monitoring represents a valid means of controlling and preventing the risks of ovarian hyperstimulation.     

Follicular aspiration during the selection phase prevents severe ovarian hyperstimulation in patients with polycystic ovary syndrome who are undergoing in vitro fertilization

OBJECTIVE: The objective was to assess the effectiveness of follicular aspiration in the selection phase of infertile women with polycystic ovary syndrome (PCOS) under controlled ovarian hyperstimulation (COH). STUDY DESIGN: In group A, 13 infertile patients with PCOS failed at previous IVF or intracytoplasmic sperm injection (ICSI) treatment due to ovarian hyperstimulation syndrome (OHSS; a total of 13 cycles). In group B, new IVF cycles with ultrasound-guided transvaginal follicular aspirations during the selection phase (a total of 13 cycles) were conducted using the same patients. No more than ten follicles remained in bilateral ovaries. Parameters monitored included ovarian size, number of dominant follicles, estradiol (E2) level on the day of human chorionic gonadotrophin (HCG) injection, maturation of oocytes, fertilization rate, cleavage rate, embryo implantation rate, pregnancy rate, and level of serum hormone. RESULTS: In group B, the average number of follicles>or=12 mm and average serum E2 level were 15.5+/-4.0 and 9899+/-1430 pmol/l, respectively, which were significantly lower than 29.1+/-8.4 (P<0.001) and 15,544+/-1766 pmol/l (P<0.001) in group A. No cycles with moderate or severe OHSS occurred in group B, while nine out of 13 (69.2%) cycles did have this problem in group A. Oocyte maturation rate, fertilization rate and cleavage rate in group B were 80.7%, 76.9%, and 80.3%, respectively; and all of them are significantly higher than 56.4% (P<0.01), 58.7% (P<0.01), and 70.2% (P<0.02) respectively in group A. CONCLUSION: Follicular aspiration during the selection phase can prevent severe OHSS and reduce OHSS prevalence in patients with PCOS undergoing COH.     

Increasing the gonadotrophin dose in the course of an in vitro fertilization cycle does not rectify an initial poor response

OBJECTIVE: To evaluate the value of increasing the gonadotrophin dose after 5 days of controlled ovarian stimulation in IVF patients who show an initial poor response to stimulation. SUBJECTS AND METHODS: We identified all IVF cycles between January 1992 and March 1996 in which ovarian response after 5 days of controlled ovarian hyperstimulation (COH) with 225-300 IU per day of human menopausal gonadotrophins (hMG; Metrodin or Pergonal) was monitored by measurement of serum estradiol concentrations (n=596 patients). According to estradiol concentration, the daily dose of hMG was doubled or increased to 450 IU in 193 patients (group A) or maintained the same in 403 patients (group B). Further cycle monitoring was achieved using serial ultrasound and serum estradiol measurements. RESULTS: The two groups were age-matched. Group A patients experienced a higher cancellation rate despite having a higher mean number of hMG ampoules (59.5 versus 36.2) and a longer duration of stimulation (12.2 versus 10.8 days). They achieved lower levels of serum estradiol on days 9 and 10 of stimulation, produced a lower mean number of oocytes per retrieval (5.8 versus 8.9) and had a lower clinical pregnancy rate per cycle (8.3 versus 23.4%) compared to group B. All differences were statistically significant. CONCLUSION: The poor outcome of cycles with initial low response to COH appears not to be averted by doubling or increasing the hMG dose after 5 days of stimulation.     

应用hMG-hCG及人工授精治疗不育症

门诊应用hMG-hCG治疗下丘脑-垂体功能障碍引起的闭经、月经稀发和月经正常周期小卵泡不育患者28例38个周期,以B 超、宫颈评分作为主要监测手段,结合采用不同人工授精方法。结果28例38个周期均有排卵,20例妊娠,总妊娠率为71.43%,2例双胎,2例流产,流产率为10%(2/20)。3个治疗周期出现中度OHSS,发生率7.8%(3/38)。     

Induction of ovulation with clomiphene citrate in women with polycystic ovary syndrome: the difference between responders and nonresponders

To identify why some women with polycystic ovary syndrome (PCO) fail to respond to clomiphene citrate (CC), the authors have monitored the endocrine and ovarian response to CC 100 mg/day given for 5 days. Of 40 cycles studied in 27 women, 73% were ovulatory. In 8 of 9 anovulatory women, there was no follicular development despite a significant rise in serum gonadotrophin concentrations within 3 to 5 days of starting CC. There were no significant differences between the ovulatory and anovulatory groups in the peak response of either luteinizing hormone (LH) or follicle-stimulating hormone (FSH). The authors conclude that, in women with polycystic ovaries, the most common reason for the failure to ovulate is an absent ovarian response to an appropriate rise in serum FSH.     

Serum luteinizing hormone,follicle-stimulating hormone and oestradiol pattern in women undergoing pituitary suppression with different gonadotrophin-releasing hormone analogue protocols for assisted reproduction

Gonadotrophin-releasing hormone analogues (GnRH-a) are used widely in controlled ovarian stimulation (COS) cycles for assisted reproduction. At present, there is great debate about the influence of exogenous hormone activity on the hypothalamus–pituitary axis following pituitary desensitization. The objective of this comparative study was to investigate the pattern of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and oestradiol in women undergoing ovarian stimulation with different GnRH-a preparations. We retrospectively analysed 201 women, aged between 27 and 43 years, who were referred consecutively to our infertility clinic between January 2002 and January 2003. All women had no endocrinopathies or occult ovarian failure as assessed by day-3 hormone profile. Women were enrolled in one of the following COS protocols: depot triptorelin long protocol (n?=?38), buserelin long protocol (n?=?101) or buserelin short protocol (n?=?62). Recombinant FSH was used to induce ovulation. Treatment was monitored by transvaginal ultrasound scan and serum measurement of FSH, LH and oestradiol. Among the women initially included, 30 had cancelled cycles due to poor ovarian response. Serum LH levels were significantly higher in the short-protocol group compared with the long-protocol groups (p?<?0.001). The number of follicles, oocyte yield, number of grade-I embryos and fertilization rate were significantly lower in the short-protocol group than in the long-protocol groups. These findings showed that LH concentrations are significantly higher in women undergoing reversible medical hypophysectomy with a GnRH-a short protocol than in women treated with a long protocol. The hypothesis of an LH ceiling is confirmed.     

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 (greater than or equal to 60 mm) 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 less than 0.001). Interruption of FSH administration or alternate day FSH administration in cycles with premature LH release reduced the rate of ovarian enlargement to 45.5% (P less than 0.05). 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.     

促卵泡激素低剂量缓增方案治疗耐氯米芬多囊卵巢综合征？…

目的 评估促卵泡激素（ＦＳＨ）低剂量缓增方案治疗多囊卵巢综合征（ＰＣＯＳ）耐氯米芬（ＣＣ）无排卵不孕症的有效性和安全性。方法 对９例耐ＣＣ的ＰＣＯＳ不孕症患者,进行１０个周期低剂量ＦＳＨ缓增方案促排卵治疗,采用尿ＦＳＨ（Ｍｅｔｒｏｄｉｎ）或基因重组人ＦＳＨ（Ｇｏｎａｌ－Ｆ）治疗各５个周期。以阴道Ｂ超和血雌二醇（Ｅ２）水平作为监测卵泡发育的指标。结果 除１例因多卵泡发育、卵泡持续不长而中止外,余周期