Preliminary experince with a combination of clomiphene and variable dosages of menopausal gonadotropins for enhanced follicular recruitment

A combination of clomiphene citrate and human menopausal gonadotropin was employed for enhanced follicular recruitment in an in vitro fertilization program. All patients received 50 mg of clomiphene and 1 ampule of human menopausal gonadotropin daily from cycle day 5 through cycle day 9. Follicular monitoring was begun on day 10 using a combination of ultrasound measurement of follicular size and number and determination of peripheral estradiol levels. Based on the size and number of follicles, the peirpheral levels of estradiol, and the rate of follicular growth and increase in estradiol, human menopausal gonadotropin was continued at a dosage of 1 to 3 ampules/day through the day of human chorionic gonadotropin administration. Human chorionic gonadotropin was administered on the evening of the day the largest follicle reached or exceeded 20 mm in mean diameter if the estradiol levels had been rapidly rising or reaching a plateau and had exceeded a minimal level of 300 pg/ml. Using this protocol, 30 of 33 patients underwent laparoscopy, 29 patients had successful oocyte recovery, and 23 patients underwent embryo replacement, with the establishment of six clinical pregnancies.     

Human gonadotropin therapy. I. Serum estradiol and progesterone patterns during conceptual cycles

Hormone patterns during 43 conceptual cycles induced by human gonadotropins in 37 women with anovulatory infertility were analyzed. The treatment was monitored by daily determinations of estradiol (E2) in serum. The incidence of both multiple pregnancies and abortions during the gonadotropin therapy was high (30%). When the hormone patterns during the human menopausal gonadotropin-induced conceptual cycles were compared with spontaneous conceptual cycles, it became evident that the ovaries were hyperstimulated during the follicular and luteal phases of the induced cycle. The mean serum E2 level at induction of ovulation did not differ between treatment courses resulting in single or multiple pregnancies. The endogenous estrogen secretion at the initiation of treatment was lower in the multiple pregnancy group than in the single pregnancy group. The active phase, i.e., when the estrogens progressively increase during the late follicular phase of the induced cycle, was found to be prolonged in the multiple pregnancy group. The prolonged follicular stimulation by human menopausal gonadotropin might explain why multiple ovulations and pregnancies occur. Thus, both the duration of the active phase of follicular stimulation and the E2 level at the day of induction of ovulation by human chorionic gonadotropin should be determined for optimal monitoring of human gonadotropin therapy.     

Methods for monitoring follicle maturation decrease; the ovarian hyperstimulation syndrome during gonadotropin treatment

Therapy with human menopausal gonadotropin and human chorionic gonadotropin (hMG-hCG) has proved effective for induction of ovulation in patients with hypogonadotropic hypogonadism showing anovulation or sterility. However, two important complications, the ovarian hyperstimulation syndrome (OHSS) and multiple gestations, are observed in a few patients treated with these hormones. In the past, follicular maturation was evaluated by the cervical mucus score (CM) and serum estradiol level (E2). But recently, ultrasonographic monitoring (USG) and the measurement of urinary estrogen (E) with a commercial kit of sufficiently high sensitivity have been advocated for the prevention of these complications. In this study, we investigated the relationships between the monitoring methods during hMG-hCG treatment and the rates of the OHSS, ovulation, pregnancy and multiple pregnancy.     

Multiple pregnancies conceived with intrauterine insemination during superovulation: an evaluation of clinical characteristics and monitored parameters of conception cycles

The use of human menopausal gonadotropins to induce superovulation in conjunction with intrauterine insemination as treatment for infertility is associated with an increased incidence of multiple gestation. Identification of clinical characteristics and/or monitored parameters of the stimulation cycles highly associated with multiple gestation would enable cancellation of these cycles. We retrospectively evaluated the clinical profiles and conception cycle characteristics of 48 infertile women undergoing the induction of superovulation and intrauterine insemination. We compared 14 of these women who conceived multiple gestations (eight twins and six triplets) with 34 who conceived singleton gestations. We found no differences between the groups in age, parity, cause or duration of infertility, duration or amount of human menopausal gonadotropin administration, serum estradiol concentrations on the day of human chorionic gonadotropin injection, number of preovulatory-sized follicles, or number of motile sperm inseminated. We conclude that neither the patients' clinical characteristics nor the parameters evaluated in monitoring human menopausal gonadotropin cycles provide information helpful in predicting which superovulation cycles will result in multiple pregnancy.     

Gonadotropin induction of ovulation

Gonadotropins have been widely used worldwide for many years to induce ovulation. Three main exogenous gonadotropins are used for ovulation induction—follicle stimulating hormone (FSH), luteinising hormone (LH) and human chorionic gonadotropin (hCG). Currently, these gonadotropins are available in the urinary (with the exception of LH) and recombinant forms. FSH (± LH) is used to stimulate follicular development and hCG is used to trigger ovulation of the mature follicle(s). Indications for gonadotropin ovulation induction include hypogonadotrophic hypogonadism and clomifene-resistant normogonadotrophic anovulation. Gonadotropins are also used for controlled ovarian hyperstimulation in conjunction with intrauterine insemination in ovulatory women treated for unexplained or mild male factor infertility. Two main regimens of gonadotropin ovarian stimulation are used, namely step-up and the step-down protocols. The choice of gonadotropin preparation and treatment regimen depends on the underlying ovarian dysfunction. Strict monitoring of gonadotropin treatment with implementation of strict cancellation criteria are recommended to minimise the risks of ovarian hyperstimulation and multiple pregnancy.     

Correlation between plasma estradiol and estrone-3-glucuronide in urine during the monitoring of ovarian induction therapy

An improved radioimmunoassay was developed to determine estrone-3-glucuronide in daily urine. Resulting levels were compared with those of estradiol in plasma of 10 healthy women and 14 undergoing ovulation induction therapy with human menopausal gonadotropin and human chorionic gonadotropin. A highly significant correlation between plasma estradiol and urinary estrone-3-glucuronide in normal (r = .9209; P less than .01) and stimulated (r = .9229; P less than .01) women was demonstrated. These results proved that the pattern of excretion of estrone-3-glucuronide perfectly reflected the changes in plasmatic estradiol levels when monitoring ovarian induction and that estrone-3-glucuronide determinations can provide clinically useful information in human induction therapy.     

Spontaneous luteinizing hormone surge and cleavage of in vitro fertilized embryos

The importance of monitoring luteinizing hormone (LH) secretion during gonadotropin stimulation remains controversial. In the present study, the authors evaluated the occurrence of spontaneous LH surges in 170 cycles stimulated by clomiphene citrate and human menopausal gonadotropin, and correlated the success rate of embryo cleavage to the time interval between the occurrence of the LH surge peak value and the time of human chorionic gonadotropin (hCG) administration. LH was quantitated from urine by an avidin-biotin enzyme immunoassay. The results indicated that a spontaneous LH surge occurred in 18% of the cycles. The number of oocytes recovered was not affected by the occurrence of a spontaneous LH surge. In 12% of all cases, the spontaneous LH surge occurred less than 12 hours before the administration of hCG, and in these cases embryo cleavage was not reduced. In 6% of all cases, the spontaneous LH surge occurred over 12 hours before hCG administration, and in these cases embryo cleavage was reduced significantly.     

A comparison of leukocyte alkaline phosphatase and plasma estradiol measurements in the monitoring of clomiphene and gonadotropin therapy

Leukocyte alkaline phosphatase (LAP) and plasma estradiol (E2) were measured in 56 infertile women treated with clomiphene citrate and human chorionic gonadotropin (hCG) and in 21 infertile women treated with human menopausal gonadotropin (hMG) and hCG. Plasma LAP scores were found to correlate significantly with plasma E2 levels in both clomiphene- and hMG-stimulated patients, reflecting the depdence of LAP on the level of circulating plasma estrogens. However, the plasma LAP score failed to distinguish the difference between normal stimulated and hyperstimulated cycles following hMG administration. We conclude that plasma LAP measurements have little value in monitoring ovulation induction therapy.     

Gonadotropin-releasing hormone (GnRH) antibodies formation in hypogonadotropic azoospermic men treated with pulsatile GnRH--diagnosis and possible alternative treatment

Five hypogonadotropic azoospermic men received pulsatile, intravenous gonadotropin-releasing hormone (GnRH) treatment over prolonged period. In three patients, the spouses were successful in achieving five pregnancies, three of which generated five healthy newborns, one ended in a first-trimester abortion, and one is ongoing. In one patient, anti-GnRH antibodies were detected, secondary to initial response. This was associated with deterioration of gonadotropin levels and diminution in testosterone to pretreatment levels. The cross-reactivity of the antibodies with five GnRH agonistic analogs was examined. Possible treatment with pulsatile GnRH analogs in such patients is discussed. In light of the relatively long period of treatment needed to achieve spermatogenesis and fertility in patients with hypogonadotropic azoospermia, monitoring the appearance of GnRH antibodies seems appropriate to assess whether therapy should be concluded. The superiority of intravenous pulsatile GnRH treatment to subcutaneous GnRH treatment or to human menopausal gonadotropin (hMG)/human chorionic gonadotropin (hCG) treatment is discussed.     

Gestational trophoblastic disease and human chorionic gonadotropin measurement

Improved radioimmunometric assays for the glycoprotein human chorionic gonadotropin, its whole molecule and free beta and alpha subunits have improved the capability for trophoblast tumor detection and monitoring. New heights in survival rates have been reached with these improvements, particularly in high-risk disease.     

False-positive serum human chorionic gonadotropin results: causes,characteristics, and recognition

False-positive serum human chorionic gonadotropin results are estimated to occur in 1 in 10(3) to 1 in 10(4) tests. Most of these false-positive results are due to interference by non-human chorionic gonadotropin substances (especially human luteinizing hormone and anti-animal immunoglobulin antibodies) and the detection of pituitary human chorionic gonadotropin. The false-positive human chorionic gonadotropin measurements are characterized by serum levels that are generally <1000 mIU/mL, the absence of human chorionic gonadotropin in the urine, nonparallelism of the human chorionic gonadotropin levels in serial dilutions of the serum with the human chorionic gonadotropin standard, results that are not consistent with the clinical or operative findings, the absence of a substantial change in the serum levels over time or after therapy, and the finding of a negative result when an alternative type of human chorionic gonadotropin assay is used. An algorithm is presented to aid in the recognition of false-positive human chorionic gonadotropin results in patients.     

Ovarian hyperstimulation syndrome due to exogenous gonadotropin administration

During the last decade, 154 patients treated with human menopausal gonadotropin human chorionic gonadotropin developed hyperstimulation necessitating hospitalization in 201 cycles. Moderate ovarian hyperstimulation occurred in 116 of the patients and severe ovarian hyperstimulation in 34. Sixteen patients underwent operative procedures. Twelve patients underwent puncture of the pleura or abdomen to drain symptomatic hydrothorax or ascites, with clinical improvement of the symptoms in all of them. Three patients had coagulation abnormalities, and 1 patient had thromboembolic phenomena. Hyperstimulation seems to be associated with an increased pregnancy rate, since seventy-five pregnancies (35%) occurred in the study group. Appropriate monitoring can reduce the rate of OHSS but it should be kept in mind that death due to OHSS may occur.     

Urinary hormone levels at the time of ovulation and implantation

Daily early morning urine samples were collected from women receiving donor artificial insemination and were evaluated for estrone conjugates, pregnanediol-3-glucuronide, and human chorionic gonadotropin. All hormone concentrations in urine were indexed by creatinine levels and expressed as the concentration of hormone per milligram creatinine. Composite profiles of 23 women who conceived normal full-term pregnancies were compared with composite profiles obtained from 11 of the same women during nonconception cycles. The endocrine profiles of seven pregnancies that spontaneously aborted and two ectopic pregnancies were also evaluated retrospectively. The combined application of these three urinary hormone indices provides a practical approach for prospective monitoring of the major hormone dynamics during ovulation and implantation and during relatively infrequent events such as spontaneous abortion and ectopic pregnancy. The rise of estrone conjugates which precedes detectable increases of urinary human chorionic gonadotropin at the time of implantation appears to be an early indicator of implantation and may prove to be the best method for detection of occult pregnancy. This method is also suitable for monitoring early pregnancy when exogenous gonadotropins have been employed, as in embryo transfer following in vitro fertilization.     

The detection and measurement of oncodevelopmental proteins in gynecological malignant disease

Data from the literature and our own measurements with alpha-fetoprotein (AFP), carcinoembryonal antigen (CEA), alpha 2-pregnancy-associated globulin (alpha 2-PAG), human chorionic gonadotropin (HCG), human placental lactogen (HPL) and pregnancy-specific beta 1-glycoprotein (SP-1) are related to clinical data. Only AFP in endodermal tumors and HCG in germ cell carcinomas can be used for clinical monitoring.     

Treatment of cervical pregnancy with systemic methotrexate and KCI solution injection into the gestational sac--case report and review of literature

We report a case of a 6-week cervical pregnancy successfully treated with systemic methotrexate and gestational sac biopsy with 15%-calcium chloride solution injection. Serial monitoring of human chorionic gonadotropin levels, combined with ultrasound examinations, confirmed spontaneous miscarriage. Applied treatment allowed to avoid hysterectomy and preserve the patient's fertility.     

Prospective evaluation of maternal serum human chorionic gonadotropin levels in 3428 pregnancies.

As part of a multicenter prospective study, second-trimester human chorionic gonadotropin and alpha-fetoprotein concentrations were evaluated. Data included maternal age, human chorionic gonadotropin level, alpha-fetoprotein level, weight, race, and pregnancy outcome of 3428 pregnancies at between 15 and 20 weeks' gestation. The results of the study indicate that human chorionic gonadotropin levels decrease as maternal weight increases, that weight-adjusted human chorionic gonadotropin levels for Oriental and black women are higher than for white or Hispanic women, and that twin pregnancies have higher human chorionic gonadotropin levels than singleton pregnancies. Of 255 pregnancies that did not have normal outcomes, 54 (21.2%) had human chorionic gonadotropin levels greater than 2.0 multiples of the median and 26 (10.2%) had alpha-fetoprotein levels greater than 2.5 multiples of the median. Of 11 pregnancies with fetal aneuploidy, 6 (54.5%) had human chorionic gonadotropin levels greater than 2.0 multiples of the median. It is concluded that in human chorionic gonadotropin screening programs for fetal Down syndrome, weight and race adjustments are necessary for accurate risk assessment.     

Comparison of urinary hyperglycosylated human chorionic gonadotropin concentration with the serum triple screen for Down syndrome detection in high-risk pregnancies

OBJECTIVE: Both modest screening performance and declining patient and physician acceptance have stimulated interest in alternative markers to the triple screen for the detection of Down syndrome. Our purpose was to compare the concentration of a single urinary analyte, hyperglycosylated human chorionic gonadotropin, with the serum triple screen (alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol concentrations combined with age) for second-trimester Down syndrome detection. STUDY DESIGN: Urine and blood were obtained from pregnant women in the second trimester undergoing genetic amniocentesis. Urinary hyperglycosylated human chorionic gonadotropin concentration and serum triple-screen values were measured. Individuals undergoing amniocentesis because of abnormal triple-screen results were excluded. Individual Down syndrome risks on the basis of urinary hyperglycosylated human chorionic gonadotropin concentration plus maternal age and on the basis of the triple-screen results were calculated. For each algorithm the sensitivity and false-positive rate for Down syndrome detection at different risk thresholds were determined. From these values receiver operating characteristic curves were constructed, and the area under the curve was determined for each algorithm. Finally, the performance of a new combination in which urinary hyperglycosylated human chorionic gonadotropin concentration replaced serum human chorionic gonadotropin concentration in the triple screen was ascertained. RESULTS: We studied 24 pregnancies complicated by Down syndrome and 500 unaffected pregnancies between 14 and 22 weeks' gestation in a mostly white (93.5%) population undergoing amniocentesis primarily because of advanced maternal age. The sensitivity and false-positive rate for urinary hyperglycosylated human chorionic gonadotropin concentration were 75. 0% and 5.6%, respectively, whereas those for the triple screen were 75.0% and 33.2%, respectively. Urinary hyperglycosylated human chorionic gonadotropin concentration was superior to the triple screen (area under the curve, 0.9337 vs 0.7887; P =.02). The substitution of urinary hyperglycosylated human chorionic gonadotropin concentration for serum human chorionic gonadotropin concentration in the triple screen resulted in a 91.7% sensitivity at a 10.0% false-positive rate, versus a 54.2% sensitivity for the traditional triple screen at the same false-positive rate. CONCLUSION: The performance of urinary hyperglycosylated human chorionic gonadotropin concentration was statistically superior to that of the serum triple screen in a high-risk population. The use of urinary hyperglycosylated human chorionic gonadotropin concentration as an alternative test or substitution of this measurement for serum human chorionic gonadotropin concentration in the triple screen would improve diagnostic accuracy and address many current concerns related to the triple screen.     

Observations on the log human chorionic gonadotropin-time relationship in early pregnancy and its practical implications

In this study, we examined whether the doubling time of human chorionic gonadotropin is different at different stages of early pregnancy and whether the use of multiple nomograms for doubling time of human chorionic gonadotropin rather than a single critical value can improve the diagnosis of ectopic pregnancy. Forty-four women with intrauterine pregnancies who had abdominal pain and/or vaginal bleeding but who did not abort their pregnancies and 44 women with surgically proved ectopic pregnancies were studied. No difference was found in the doubling time of human chorionic gonadotropin when women were classified according to recently published criteria (Pittaway DE, Reish RL, Wentz AC. Doubling times of human chorionic gonadotropin increase in early viable intrauterine pregnancies. Am J Obstet gynecol 1985;152:299-302), and estimates of the doubling time of human chorionic gonadotropin were not influenced by the initial human chorionic gonadotropin values or the sampling interval used. In the human chorionic gonadotropin range of practical interest, multiple nomograms identified 26 of 33 (79%) women with ectopic pregnancy who had rising levels of human chorionic gonadotropin, whereas our previously reported criteria identified 28 of 37 (76%) cases. The false positive rate for each method was 9.7%. Seventeen (19%) of 88 patients could not be allotted to the human chorionic gonadotropin categories for which nomograms of the doubling time of human chorionic gonadotropin have been derived. We conclude that our previous recommendations for determining the rate of increase of human chorionic gonadotropin in serum from paired samples do not require revision at this time.     

Human menopausal gonadotropins: a justifiable therapy in ovulatory women with long-standing idiopathic infertility

Long-standing infertility of unknown etiology is currently an indication for in vitro fertilization. Because of the prolonged waiting time, expense, and operative risk, we have treated a group of women with empiric human menopausal gonadotropins/human chorionic gonadotropin before in vitro fertilization. A study group of 97 couples with well-documented, long-standing idiopathic infertility received up to four cycles of empiric human menopausal gonadotropin therapy before in vitro fertilization. This group was compared with a control group of 48 couples who did not receive human menopausal gonadotropin before in vitro fertilization. The 12 (12.4%) conceptions and eight (8.2%) term births resulting from empiric human menopausal gonadotropin therapy in the study group was significantly higher than the number of spontaneous conceptions and births (1%) in the study group (p less than 0.003) and was also greater than the spontaneous conception and birth rate (4%) in the control group (p less than 0.07). The conception rate with empiric human menopausal gonadotropin (12.4%) compared favorably with that after in vitro fertilization (7.9%) and 8 of 12 (66.7%) of empiric human menopausal gonadotropin conceptions resulted in term births, compared with two of seven (28.6%) of the in vitro fertilization conceptions. Preovulatory serum estradiol levels were similar for all study patients undergoing empiric human menopausal gonadotropin therapy, control patients undergoing in vitro fertilization, and patients receiving empiric human menopausal gonadotropin during conception cycles. It therefore appears appropriate to offer a 4-month trial of empiric human menopausal gonadotropin to that specific group of couples with long-standing idiopathic infertility.     

Plasma prorenin in first-trimester pregnancy: relationship to changes in human chorionic gonadotropin

Prorenin and human chorionic gonadotropin are both synthesized in chorionic cells. The relationship of changes in maternal plasma prorenin to changes in human chorionic gonadotropin were therefore evaluated during the first trimester. In samples submitted to the routine chemistry laboratory for detection of pregnancy a positive relationship was observed between prorenin and beta human chorionic gonadotropin during the 5 weeks following conception. Subsequently human chorionic gonadotropin continued to rise but prorenin had reached a plateau. Serial studies in one subject demonstrated that prorenin had increased to 65% of maximum by the thirteenth day following conception whereas human chorionic gonadotropin had risen to only 0.2% of maximum. By 3 to 5 days post partum, beta human chorionic gonadotropin had fallen by 98% but prorenin had fallen by only 50%. The early rise in prorenin following conception and the relatively slow fall post partum suggest that pregnancy-related changes in maternal plasma prorenin are of maternal, not fetal, origin.