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PubMed1996

The profound impact of patient age on pregnancy outcome after early detection of fetal cardiac activity.

OBJECTIVE: To evaluate the influence of maternal age on pregnancy loss rates after early documentation of fetal cardiac activity by transvaginal ultrasound (US) in previously infertile women. DESIGN: Retrospective, observational study. SETTING: Tertiary fertility center. PATIENTS: One hundred eighty-six previously infertile women 20 to 43 years of age undergoing ovulation induction. MAIN OUTCOME MEASURE: We analyzed 201 clinical pregnancies in which cardiac activity had been documented by transvaginal US 35 to 42 days after ovulation in a previously infertile population treated at a tertiary fertility center. Patient age, infertility diagnosis, ovulation induction protocol, and mode of insemination were analyzed by chi 2, Fisher's exact test and logistic regression analyses. RESULTS: A profound increase in spontaneous abortion rates occurred as a function of maternal age in this population (chi 2 for trend = 15.1). A spontaneous abortion rate of 2.1% was observed for maternal ages < or = 35 years but this rate increased to 16.1% for patients > or = 36 years (odds ratio, 8.72; 95 percent confidence interval 2.3 to 32.9). A fivefold increase in spontaneous abortion rate was observed in women > or = 40 years compared with women 31 to 35 years (3.8% versus 20.0%. Infertility diagnosis, mode of insemination, and ovulation induction protocol were not associated with an increased risk of spontaneous abortion. CONCLUSIONS: The incidence of pregnancy loss after confirmation of early fetal cardiac activity by transvaginal US is substantially greater in infertile patients than previously reported, when considered as a function of maternal age. In particular, patients > or = 36 years should be counseled that their risk of spontaneous abortion is significant even after fetal heart motion is present on transvaginal US. Cautious optimism and greater surveillance may be required during the first trimester of pregnancy in these women.

Abortion, Spontaneous↗
PubMed1999

Incorporation of a GnRH agonist, leuprolide acetate, into regimens with exogenous gonadotropins to produce ovarian stimulation and ovulation in the nonpregnant squirrel monkey.

This study was designed to measure the effects of variations in the length of pretreatment with a GnRH agonist, leuprolide acetate (LA), on subsequent follicular development and ovulation. The hypothesis was that the duration of LA suppression of pituitary function does not adversely affect ovarian response to standardized ovulation induction protocols in squirrel monkeys. The first phase determined the dose and duration of LA needed to achieve a hypogonadal state. One of two groups received daily subcutaneous injections of 50 microg of LA. The other received a single injection of 175 microg of a depot suspension of LA. Sera were assayed for estradiol (E2) and progesterone (P). E2 and P levels increased 2- to 5-fold with peak levels on days 4 and 7, respectively. Suppression of steroid levels took 10 to 15 days in the LA-treated group. Depot-LA did not effectively suppress steroid production. After suppression, females receiving daily LA received five daily injections of hMG to stimulate follicular development. E2 and P increased in these animals. These results suggest that cycling squirrel monkeys have P-secreting capacity throughout the cycle. This may explain how the squirrel monkey is able to accommodate both a short (4-5 day) luteal phase of their 9 day cycle and implantation from 5 to 7 days after ovulation. A second study compared exogenous follicle stimulating hormone (FSH) to endogenous gonadotropins released as a response to LA in ovulation induction. Steroid production and hCG-induced ovulation were assessed. LA treatment was compared to a standard ovulation induction protocol by using a randomized cross-over measures design. There were no differences in E2 and P levels in response to dosages of either LA or hMG. The ovulatory response following LA treatment was not significantly greater than that using FSH. The number of animals with unovulated, large follicles was greater on the FSH protocol (12/18) compared to the LA protocol (3/18). Thus, a single injection of a depot preparation of LA is sufficient to stimulate follicular development and ovulation when followed by an hCG injection. Based on this observation and the data on unovulated large follicles, it is suggested that the ovary responds more readily to endogenous gonadotropins released by LA than to exogenous FSH.

Animals↗
PubMed1991

Spontaneous pregnancies in two women with Laron-type dwarfism: are growth hormone and circulating insulin-like growth factor mandatory for induction of ovulation?

It has recently been claimed that growth hormone (GH) and insulin-like growth factors have a role in follicular development; different mechanisms of action have been proposed. Of late, many investigators have been led by these findings to use GH and growth hormone-releasing hormone (GHRH) for induction of ovulation, in combination with human menopausal gonadotrophins. It is, however, still doubtful whether or not growth hormones and/or insulin-like growth factors are mandatory for follicular development and fertility. In this study we describe two women with Laron-type dwarfism who lacked insulin-like growth factors and who had spontaneous pregnancies. We also discuss different natural defects in the production and metabolism of growth hormone and insulin-like growth factors in humans, and the fertility performance of the affected females. It is our assumption that GH and systemic insulin-like growth factors may modulate follicular development, but that they are not necessarily mandatory for ovarian follicular development.

Adult↗
PubMed1992

The effect of decrease in body temperature with Nembutal on meiosis and ovulation after induction by gonadotrophin-releasing hormone and luteinizing hormone in adult rats.

Sodium pentobarbital (Nembutal) is often used to block the pro-oestrous luteinizing hormone (LH) surge in rats. Nembutal is also known to lower body temperature. This study was designed to investigate whether Nembutal affected the time course of meiosis and timing of ovulation induced by exogenous hormones, and whether the possible effects of Nembutal on these processes were related to temperature. Gonadotrophin-releasing hormone (GnRH), the GnRH-analogue Ovalyse, or rat luteinizing hormone (LH) were administered to trigger resumption of meiosis and ovulation; Nembutal (35 mg kg-1 body weight) or saline was given 10 or 60 min later. Plasma profiles of LH were measured and Graafian follicles were studied histologically for meiotic progress and ovulation. Nembutal suppressed the spontaneous surge of LH at pro-oestrus and caused a long-lasting decrease in body temperature. If 1000 ng GnRH was given 2 h before the pro-oestrous LH surge, most of the oocytes had extruded a polar body 10 h later and most follicles had ovulated 14 h later. Nembutal given 1 h after GnRH delayed extrusion of the polar body and ovulation by about 2 h. Nembutal caused a similar delay in ovulation when it was administered after 100 ng of Ovalyse, and it also delayed meiosis when given after 1000 ng of LH. This effect of Nembutal was prevented if body temperature was maintained at 37 degrees C. The delaying effect of Nembutal on meiosis and ovulation induced by exogenous GnRH or LH is related to a long-lasting decrease in body temperature.

Animals↗
PubMed1987

Endocrine changes in the late-follicular and postovulatory intervals as determinants of the in vitro fertilization pregnancy rate.

This investigation examines the hormone pattern in in vitro fertilization (IVF) cycles from the time of human chorionic gonadotropin (hCG) administration through embryo transfer to ascertain whether the absolute levels or secretory patterns of the major reproductive hormones affect the IVF pregnancy rate. Thirty-one women who underwent IVF treatment were enrolled in the study. All patients received clomiphene citrate/human menopausal gonadotropin for ovulation induction. Significant elevations in serum estradiol (E2) levels in the pregnant group were found throughout the cycle interval studied. After hCG administration the serum hCG levels were not different between the groups. Significant elevations in serum progesterone (P) concentrations were found in the pregnant group from the day after laparoscopy through embryo transfer. Embryos obtained from the pregnant group appeared to be different in that the mean number of blastomeres per embryo transferred was significantly greater. Therefore for achievement of an IVF pregnancy the optimal hormone pattern employing combination ovulation induction in the ovulation to transfer interval is a relatively high E2 level in ovulation followed by a high P level at transfer and into the luteal phase. These elevated hormone levels do not depend on the response to exogenous hCG.

Adult↗
PubMed1997

[Ovarian hyperstimulation syndrome--a risk of treatment for infertility].

Ovarian hyperstimulation syndrome (OHSS), a potential life-threatening condition the causative factor of which is unknown, comprises a spectrum of clinical symptoms and laboratory signs. The main risk factors for the development of OHSS include inherent ovarian sensitivity to ovulation induction agents, the use of exogenous hCG (human chorionic gonadotrophin) for ovulation induction or luteal phase support, and endogenous hCG production in early pregnancy. Since assisted reproduction entails achieving a delicate balance between controlled ovarian stimulation and hyperstimulation, complete elimination of the risk of OHSS is unlikely. However, it seems possible to reduce the frequency of severe cases by observing strict rules for its prediction and prevention, allowing early diagnosis and active treatment of manifest OHSS by correction of fluid and electrolyte imbalance, and aspiration of ascitic fluid if necessary.

Ascitic Fluid↗
PubMed2000

Bleeding and spontaneous abortion after therapy for infertility.

OBJECTIVE: To determine the incidence of early-pregnancy bleeding and spontaneous abortion (SAB) after various treatments for infertility and to assess whether bleeding is predictive of SAB. DESIGN: An historic cohort study of women who conceived after various treatments. SETTING: Hospital-based private practice. PATIENT(S): We studied 418 patients in whom 500 consecutive clinical pregnancies occurred. INTERVENTION(S): Patients were grouped according to the method of conception: ovulation induction, IVF, and other. The latter category included interventions not requiring ovulation induction, such as surgery and insemination. A fourth group of subjects who conceived independently of treatment was used as the control. MAIN OUTCOME MEASURE(S): Bleeding and pregnancy outcome (SAB, ectopic pregnancy, or ongoing pregnancy). RESULT(S): Rates of SAB did not differ among the treatment groups. SAB occurred significantly more often after bleeding than when bleeding did not occur (30.8% versus 19.8%, respectively). Bleeding was predictive of SAB only in patients <35 years old (odds ratio 2.4). CONCLUSION(S): Infertile women who conceive after reproductive therapy are not at increased risk for SAB compared with women who conceive naturally. There appears to be no association between previous diagnosis or treatment and the occurrence of SAB in previously infertile women. Bleeding is associated with a twofold relative risk of SAB.

Abortion, Spontaneous↗
PubMed2004

Interleukin-18 levels correlate with severe ovarian hyperstimulation syndrome.

OBJECTIVE: To assess the involvement of interleukin-18 (IL-18) in the pathophysiology of severe ovarian hyperstimulation syndrome (OHSS), and study its use as a marker of disease and its correlation to capillary hyperpermeability. DESIGN: Prospective controlled study. SETTING: An IVF unit in a tertiary medical center. PATIENT(S): Twenty-four patients with OHSS in an IVF program, two control groups: group 1, 40 healthy age-matched women without ovulation-induction treatment; group 2, 19 women who received the same ovulation-induction regimen without experiencing OHSS. INTERVENTION(S): Blood samples were obtained at three times: during acute OHSS, on significant clinical improvement, after complete resolution. Ascitic and pleural fluids were obtained by therapeutic paracentesis. Serum, peritoneal, and pleural fluids were analyzed for IL-18 and IL-6, and blood for hematocrit, white blood cell count, and E(2) levels. MAIN OUTCOME MEASURE(S): Hematocrit white blood cell count, serum, peritoneal, pleural fluid levels of IL-18, IL-6, E(2) in severe OHSS. RESULT(S): Significantly higher IL-18 levels were detected in serum, peritoneal, and pleural fluids of patients with severe OHSS as compared with both control groups. Serum IL-18 dropped significantly on transition to the diuretic phase and resolution. A statistically significant correlation between serum IL-18 and hyperpermeability characteristics (white blood cell count, hematocrit), serum E(2), and IL-6 levels was recorded. CONCLUSION(S): This is the first study suggesting a role of IL-18 as a marker of OHSS, with correlation to capillary hyperpermeability parameters.

Biomarkers↗
PubMed1991

The value of menotrophin treatment for unexplained infertility prior to an in-vitro fertilization attempt.

This work was undertaken in order to evaluate retrospectively the relative efficacy of ovulation induction by menotrophins and that of in-vitro fertilization and embryo transfer (IVF-ET) in the treatment of unexplained infertility. These two treatments were compared between two groups of patients: 87 couples undergoing 446 cycles of ovulation induction by menotrophins (group A) and 72 couples undergoing 108 cycles of IVF-ET (group B). A total of 30 and 20 pregnancies were achieved in groups A and B for a rate of 34 and 28% per patient, respectively. A similar cumulative pregnancy rate (CPR) was achieved for three cycles of ovulation induction (23%) and one cycle of IVF-ET (22%). The cumulative live birth rate (CLBR) in group A was 22% after three cycles and exceeded that of one IVF-ET cycle (17%). It is concluded that menotrophin treatment in unexplained infertility is highly beneficial and should precede an IVF attempt.

Adult↗
PubMed1991

[Ovarian hyperstimulation syndrome].

The ovarian hyperstimulation syndrome is the most serious complication following ovulation induction. It is assuming greater clinical importance now that the indication for ovulation induction is no longer limited to anovulatory women but expands to other infertility problems. In its most severe manifestation the ovarian hyperstimulation syndrome consists of massive ovarian enlargement with multiple cysts, hemoconcentration, ascites, and pleural and pericardial effusion. There is no specific treatment and a reduction in the incidence of this iatrogenic syndrome can be achieved only by preventive measures.

Adult↗
PubMed1994

Follicular fluid contents of hyaluronic acid, follicle-stimulating hormone and steroids relative to the success of in vitro fertilization of human oocytes.

OBJECTIVES: To determine the concentrations of hyaluronic acid, FSH, P, and E2 in the follicular fluid (FF) obtained from IVF-ET patients and to assess the value of these measurements in predicting the outcome of fertilization. DESIGN: One hundred eleven samples were retrospectively analyzed for the hyaluronic acid and hormone contents. SETTING: University-based tertiary care center. PATIENTS: Preovulatory FF samples were collected from 67 women undergoing IVF-ET treatment because of tubal absence or obstruction. MAIN OUTCOME MEASURES: The FF hyaluronic acid and hormone concentrations were compared according to the type of ovulation induction, follicular development, and IVF outcome. RESULTS: According to the type of ovulation induction, a significantly lower hyaluronic acid concentration was found in FF harvested from the patients treated with GnRH agonist-hMG. No significant correlation was found between FF hyaluronic acid and either morphological maturity of the oocyte-cumulus complex or fertilizability of oocytes. The level of FSH was significantly higher in FF, yielding a mature oocyte-cumulus complex and from which the oocyte obtained successfully fertilized and cleaved. A significant increase in the E2 concentration was found in FF in which mature cumuli oophori were present. The levels of hyaluronic acid significantly correlated with FSH in FF. CONCLUSIONS: Expansion of the human oocyte-cumulus cell complex is an FSH-dependent phenomenon. The data are in agreement with the hypothesis that intrafollicular FSH plays an important role in the secretion of hyaluronic acid by granulosa cells and may act synergistically with E2 to enhance cytoplasmic maturation, resulting in successful fertilization.

Adult↗
PubMed1977

A direct radioimmunoassay for estriol-16-glucuronide in urine for monitoring pregnancy and induction of ovulation.

Antibodies to estriol-16alpha-[beta-D-glucuronide] were raised in sheep with the use of keyhold limpet hemocyanin and bovine serum albumin conjugates of estriol-16alpha-[beta-D-glucuronide]. A simple, rapid method is presented for direct radioimmunoassay of estriol-16alpha-[beta-D-glucuronide] in urine with dextran-coated charcoal used for separation of free from bound and deionized water used for dilutions. The method is thrifty in its use of reagents. The assay has been evaluated in the pregnancy range, and the sensitivity has been extended into the range necessary for monitoring induction of ovulation with Pergonal.

Animals↗
PubMed1989

Contraceptive potential of RU 486 by ovulation inhibition: I. Pituitary versus ovarian action with blockade of estrogen-induced endometrial proliferation.

In previous studies, RU 486 administration arrested spontaneous folliculogenesis. To investigate the central versus peripheral effects of RU 486 on the ovarian/menstrual cycle, including endometrial proliferation, RU 486 was administered daily (10 mg/kg/day, im) from menstrual cycle day 3 or 7 to day 25 in normal adult cynomolgus monkeys receiving hMG treatment (37.5 IU/day) from days 3-8 (n = 6). RU 486 administration with hMG/hCG therapy did not inhibit ovarian response, as evidenced by steroidogenesis and ovulation. Nine of 23 oocytes retrieved by lavage or follicular aspiration at laparotomy after ovulation induction were morphologically classified as mature preovulatory status. Whereas an endometrial biopsy performed on cycle day 25 in control monkeys revealed an in phase mature secretory endometrium, histologic sections from RU 486 plus hMG/hCG treated females uniformly demonstrated atrophic to weakly proliferative endometrium on cycle day 25, despite serum estradiol levels greater than 300 pg/ml. Three months after the initial 25-day study endometrial biopsies revealed persistent atrophic endometrium, even though repeated ovulation induction with hMG/hCG therapy elevated serum estrogen concentrations. The findings prevailed whether RU 486 treatment began on cycle day 3 or 7. The intermenstrual interval was significantly (P less than 0.01) lengthened by RU 486 treatments (28.5 +/- 2.0, control vs 131.3 +/- 11.5 days, RU 486). In summary, RU 486 consistently blocked ovulation unless hCG was provided and elicited a persistent retardation of early proliferative endometrium when administered daily beginning in early or mid-follicular phase. The normal mitogenic effects of elevated ovarian estrogen secretion on endometrial tissue were quelled, uniformly resulting in amenorrhea. The long-lasting action of RU 486, causing ovulation inhibition and atrophic endometrium, may be due to the depot effect of im injection. In addition, RU 486 did not prevent ovarian steroidogenesis, ovulation or oocyte maturation when an ovulation induction regimen of hMG/hCG was given. These findings show that RU 486 prevented ovulation by diminishing pituitary gonadotropin secretion, rather than by direct effects on ovarian folliculogenesis, and induced amenorrhea by inhibiting estrogen-induced endometrial proliferation.

Animals↗
PubMed1986

[Current developments in the study and management of unwanted childlessness].

After some introductory remarks on the investigation of the infertile couple in general, more specific new technologies in diagnosis and ways of treatment of infertility are discussed. In the infertile male with a varicocele the advantages of phlebography and embolisation over surgical ligation of the internal spermatic vein is presented. The value of the hamster ovum penetration test in order to evaluate the fertilizing capacity of spermatozoa is commented. A new method for diagnosis of immunologic infertility in men is briefly explained as well as the possibility for treatment of immunologic infertility by means of corticosteroids. In women the indications and disadvantages of LHRH ovulation induction are presented as well as the advantages of monitoring follicle growth during ovulation induction or stimulation by means of ultrasound. The major breakthrough in infertility therapy of course is in vitro fertilization (IVF): only a few indications other than tubal occlusion are commented and the impact and some future aspects of IVF for other medical disciplines are briefly discussed.

Adult↗
PubMed2006

Potential of aromatase inhibitors for ovulation and superovulation induction in infertile women.

For almost half a century, the first-line treatment for ovulation induction in cases of anovulation, unexplained infertility, or mild male factor has been clomifene (clomiphene citrate). Clomifene is an effective and safely used oral agent, but is known to have relatively common antiestrogenic endometrial and cervical mucous adverse effects that could prevent pregnancy in the face of successful ovulation. In addition, there is a significant risk of multiple pregnancies with clomifene compared with natural cycles. These drawbacks are mainly a result of the extended antiestrogenic effect of clomifene as a result of its accumulation in the body (clomifene isomers have a half-life of several days up to few weeks). Because of these problems, we proposed the concept of aromatase inhibition as a new method of ovulation induction that could avoid many of the adverse effects of clomifene. Over the last few years several published studies, both controlled and noncontrolled, compared clomifene and treatment with aromatase inhibitors (AIs), either alone or in combination with gonadotropins, for ovulation induction or augmentation. These studies found AIs as effective as clomifene in inducing ovulation, with the major advantage of absence of any antiestrogenic adverse effects. Several other major advantages of AIs include the lower serum estrogen production per developing follicle resulting in more physiological estrogen levels around the time of ovulation and good pregnancy rates with a lower incidence of multiple pregnancy than with clomifene. When combined with gonadotropins for assisted reproductive technologies, AIs reduce the dose of gonadotropins required for optimal follicle recruitment and improve the response to gonadotropin stimulation in poor responders. Such preliminary evidence suggests that AIs may replace clomifene in the future because of similar efficacy with a reduced adverse-effect profile. However, we believe that definitive studies in the form of randomised controlled trials comparing clomifene with AIs are needed.

Anovulation↗
PubMed1996

Evaluation and treatment of low responders.

Identification and treatment of low responders to ovulation induction is one of the most frustrating challenges in reproductive medicine. Because complex ovulation induction is required so frequently and is so expensive, efficient diagnosis of hyporesponders is critical. At present, the best techniques of evaluating ovarian reserve are basal follicle-stimulating hormone/Estradiol levels early in the proliferative phase and the clomiphene citrate challenge test. When poor responders are identified, strong consideration should be given to adjunctive approaches such as gonadotropin-releasing hormone analog and microdose flare or possibly, embryo hatching in those women undergoing in vitro fertilization.

Adult↗
PubMed2004

Should laparoscopy be a mandatory component of the infertility evaluation in infertile women with normal hysterosalpingogram or suspected unilateral distal tubal pathology?

OBJECTIVE: To assess the diagnostic benefit of laparoscopy in infertile women with normal hysterosalpingography (HSG) or suspected unilateral pathology on HSG. STUDY DESIGN: Charts of infertile women that underwent complete infertility evaluation between 1996 and 1998 were retrospectively reviewed. Eighty-six patients in whom both HSG and laparoscopy were performed were included in the study. HSG results were compared with laparoscopic findings and the suggested treatment based on HSG results was compared with the treatment plan based on laparoscopic findings. RESULTS: Among 63 patients with a normal HSG or suspected unilateral tubal pathology, who were assigned to ovulation induction and intrauterine insemination (IUI), 60 patients were found to have laparoscopic findings that did not necessitate any change in the original treatment plan. In three patients (4.8%), abnormalities discovered at laparoscopy were of such an extent that a change in the original treatment regimen and referral to in vitro fertilization (IVF) was needed. Among 23 patients with suspected bilateral tubal occlusion on HSG, 16 patients (69.6%) were found to have an abnormal laparoscopy with bilateral tubal adhesions, 6 patients (26%) had unilateral tubal adhesions, and 1 patient (4.3%) had pelvic adhesions with no obstruction. These latter findings led to changes in the original treatment plan of these seven patients from IVF to ovulation induction and IUI. CONCLUSIONS: Laparoscopy may be omitted in women with normal HSG or suspected unilateral distal tubal pathology on HSG, since it was not shown to change the original treatment plan indicated by HSG in 95% of the patients. However, laparoscopy should be recommended in cases with suspected bilateral tubal occlusion on HSG, since it altered the original treatment plan in 30% of the patients from IVF to induction of ovulation with IUI. The reassuring results found in the present study may be related to the low prevalence of pelvic inflammatory diseases and endometriosis in our population.

Adult↗