Optimal pregnancy outcome in a minimal-stimulation in vitro fertilization program.

OBJECTIVE: We sought to provide a cost-beneficial approach to in vitro fertilization for infertile patients who could not afford the standard treatment with in vitro fertilization and to determine the optimal level of minimal ovarian stimulation to achieve acceptable pregnancy rates. STUDY DESIGN: We performed a retrospective cohort study of 216 patients who underwent "minimal stimulation" in vitro fertilization between January 1994 and December 1998. During the first half of this study, various minimal ovarian stimulation protocols were performed in our private, free-standing center for in vitro fertilization. More recently, more ovarian stimulation, including a 4-day protocol featuring gonadotropin-releasing hormone agonist flare (ultrashort flare), was used. Clinical pregnancy outcome, multiple gestation, complications, and maternal age were compared between the first and second halves of this study. RESULTS: The average ages of patients in the first half (phase 1) and the second half (phase 2) were similar, 32.4 +/- 0.3 versus 32.6 +/- 0.3 years, respectively. An average of 3.5 oocytes per retrieval was obtained in phase 1 versus 5.9 oocytes in phase 2. Failure to retrieve oocytes occurred in 3% of all cases. The mean number of embryos transferred per patient was 2.0 in phase 1 versus 2.4 in phase 2. In phase 1, 16.1% of patients failed to have viable embryos for transfer, in comparison with 9.7% in phase 2. The overall clinical pregnancy rate per retrieval was 16.9% in phase 1 versus 36. 6% in phase 2. Multiple gestation occurred in 5.0% of clinical pregnancies in phase 1 but increased to 33% in phase 2, with 9 sets of twins and 6 sets of triplets. The implantation rate was 9.3% for phase 1 versus 23.3% for phase 2. The clinical pregnancy rates per retrieval for phase 2 patients were 41.6% in women < or =34 years old and 25.6% for those > or =35 years old. No case of ovarian hyperstimulation syndrome was noted. CONCLUSIONS: Minimal ovarian stimulation in the setting of in vitro fertilization offers a cost-beneficial alternative to standard treatment with in vitro fertilization in infertile patients who are <35 years old and in women <40 years old who have adequate oocyte reserve. More stimulation improves outcome. Minimalstimulation in vitro fertilization provides an alternative for those patients who cannot afford standard in vitro fertilization or who are concerned with exposure to high dosages of fertility medications.

Ovarian-pituitary hormone interactions during the perimenopause.

To describe the hormone changes that occur at the onset of the perimenopause, daily urine and random blood samples were collected from 5 peri-menopausal women for 3 or 4 consecutive cycles. Estrone conjugate and pregnanediol-3-glucoronide concentrations were determined for urine samples. Circulating luteinizing hormone, follicle stimulating hormone, progesterone, estradiol and estrone concentrations were determined in serum samples. Two of the 5 women experienced irregular menstrual intervals during the study period. One of these subjects experienced a prolonged intermenstrual interval. Three other women exhibited apparently regular ovulatory menstrual cycles. The prolonged intermenstrual interval of one women exhibiting irregular menstrual intervals was associated with low urinary estrogen levels in the early follicular phase of the affected cycle, followed by increased gonadotrophin levels and increased estrogen levels that rose to exceed normal cycle concentrations by 2- or 3-fold. Increased estrogen levels were followed by declining gonadotrophin levels, minimal progesterone production, and, ultimately, vaginal bleeding. These data suggest that there are some forms of menstrual variability at the time of the perimenopause associated with lowered early follicular phase estrogen levels. Reduced negative feedback and subsequently increased gonadotrophin levels may have stimulated estrogen production which may have suppressed gonadotrophin secretion and lowered estrogen excretion, resulting in the observed oscillations between episodes of hypo- and hyperestrogenism.

Cryopreserved zygotes and embryos and endocrinologic factors in the replacement cycle.

Several parameters relating to features of replacement cycles in 88 patients were found to influence implantation of cryopreserved zygotes and early cleaved embryos. Cryopreserved embryos were replaced in 47 patients with a natural cycle, resulting in 12 (25%) clinical pregnancies. Patients who had anovulation or irregular cycles received either 50 mg clomiphene citrate on days 5 to 9 or 100 mg on days 2 to 6; the incidence of clinical pregnancy was 7 of 23 (30%) and 2 of 18 (11%), respectively. Neither a rise in follicular phase estradiol (E2) nor absolute levels of E2 predicted implantation. The length of the follicular phase during the replacement cycle correlated well with previous menstrual cycles in 43 (54%) of the patients, and 16 (37%) of these patients became pregnant. The follicular phase was either longer or shorter than anticipated in 39 patients, and only 5 (13%) became pregnant: a detrimental effect was especially apparent when the follicular phase was shortened.

Cryopreservation of zygotes and early cleaved human embryos.

Zygotes and 2- to 5-cell human embryos were frozen in 1,2-propanediol and sucrose; results of the first 50 cycles (45 patients) are presented. A total of 41 zygotes (17 attempts at thawing) were thawed, resulting in six singleton clinical pregnancies (15% per embryo; 35% per cycle), of which three delivered, one aborted, and two are ongoing. Fifty-seven cleaved embryos were thawed in 33 other cycles, resulting in four singleton and one twin pregnancy (11% per embryo; 15% per cycle), of which four delivered and one is ongoing. Depending on the cell stage, 61% to 81% of embryos survived cryostorage, but 2-cell embryos did not implant. One fifth of cryoinjury was due to the formation of cracks in the zona pellucida. The incidence of implantation was not enhanced when more than one freeze/thawed embryo was replaced, most pregnancies being obtained from single embryo replacements. At least 8% more births are expected in addition to conventional in vitro fertilization methods when the current policy of replacing three fresh embryos and freezing the remainder using this technique is applied. This method will result in two to four times more pregnancies per spare embryo, compared with other cryopreservation methods using older embryos.

Bromocriptine therapy in normoprolactinemic women with unexplained infertility and galactorrhea.

Forty-three women with unexplained infertility and 16 women who ovulated with clomiphene citrate therapy, yet failed to conceive, were evaluated because of the presence of expressible galactorrhea and normal random prolactin levels. The overall mean duration of infertility for these women was 5.68 +/- 0.33 years (mean +/- standard error) and their mean age was 30.20 +/- 0.46 years. Fifty-two of these women had primary infertility. Three treatment protocols were evaluated. Twenty-five women with unexplained infertility (Group A) received low-dose bromocriptine (1.25 to 2.5 mg) at bedtime for the first 18 days of the cycle; 18 women with unexplained infertility (group B) received 100 mg of pyridoxine continuously; and 16 women receiving clomiphene citrate (group C) also received bromocriptine in a manner similar to that for group A. All subjects were followed for six treatment cycles or until pregnancy occurred. The estimated cumulative pregnancy rate after six treatment cycles was 65% for groups A and C, which is significantly higher than the 22% rate for group B (Lee-Desu statistic = 4.66, P = 0.03). Women treated with bromocriptine were 2.3 times more likely to conceive than women treated with pyridoxine. Furthermore, those infertile galactorrheic women whose random prolactin level was greater than or equal to 15 ng/ml were most likely to conceive. Expressible galactorrhea in women with unexplained infertility and high normal prolactin concentrations may serve as a clinical sign indicating those women who may benefit from low-dose bromocriptine treatment administered at bedtime.

Vasopressin levels during pregnancy and labor.

Baseline plasma vasopressin concentrations were measured in 10 healthy women during a normal menstrual cycle, 97 normal women during pregnancy and 43 pregnant women hospitalized during the third trimester because of pregnancy-induced hypertension (PIH). Plasma vasopressin levels were also measured in 44 normal pregnant women in early labor and in 30 parturients at delivery. The random plasma vasopressin concentrations did not vary significantly between the nonpregnant women during the follicular phase (2.3 +/- 0.2 microU/ml) and luteal phase (2.2 +/- 0.3 microU/ml) or during the third trimester in normal pregnant women (2.0 +/- 0.2 microU/ml) or those with PIH (2.0 +/- 0.1 microU/ml). There was a significant reduction (p less than 0.01) in plasma vasopressin levels in the pregnant women during the first trimester (1.5 +/- 0.1 microU/ml) and second trimester (1.5 +/- 0.1 microU/ml) as compared to levels in nonpregnant and pregnant women in the third trimester. The mean plasma vasopressin levels in the pregnant women complaining of nausea were similar to those in the pregnant women without nausea. Plasma vasopressin levels in women during labor did not increase significantly over third-trimester-pregnancy concentrations during the first stage of labor (1.9 +/- 0.1 microU/ml) or at delivery (1.8 +/- 0.1 microU/ml). These cross-sectional measurements of maternal plasma vasopressin levels do not support a role for vasopressin in the development of PIH or in the initiation or maintenance of labor.

Opioid peptides in pseudocyesis.

Five women with pseudocyesis were evaluated during a two-year period. A random, nontimed blood sample was obtained from each woman at the time of initial encounter that revealed a hormone pattern most consistent with polycystic ovarian disease; mean (+/- SE) concentration of luteinizing hormone (LH) was 14.2 +/- 2.1 mIU/mL, follicle-stimulating hormone (FSH) was 3.3 +/- 0.7 mIU/mL, prolactin (PRL) was 23.5 +/- 1.3 ng/mL, estrone was 74.7 +/- 15.0 pg/mL, and estradiol was 54.7 +/- 13.0 pg/mL. In four of these patients, serum progesterone concentration was elevated over expected follicular phase values. The opiate antagonist, naloxone, was administered to four women before disclosure of their diagnosis. Naloxone treatment failed to induce LH or PRL release. Because naloxone did not cause a change in hormone concentration, naloxone-sensitive opioid mechanisms are apparently not involved in this disorder. After resolution of pseudocyesis, naloxone-induced LH release was appropriate for the phase of the cycle in which the narcotic blocking agent was administered.

Comparison of dopamine agonists in the treatment of hyperprolactinemic syndromes: a multicenter study.

Thirty-one patients with hyperprolactinemia were admitted for protocol study. Twenty-one of these patients had no findings of prolactinoma by computerized axial tomography (CAT) scanning; 10 had documented tumor by CAT scan. The patients were assigned to either Parlodel or Pergolide treatment on the basis of random numbers tables. They were treated for 6 months continuously and followed during this time with radiologic survey, hormonal evaluation, and blood chemistry determinations. Patients in both groups showed a decrease in prolactin levels, whether they were treated with Parlodel or Pergolide. The response was similar whether patients had hyperplasia or pituitary tumors. Patients with pituitary tumors tended to have a diminution in the size of their lesions regardless of the dopamine agonist used. The types of side effects experienced by various groups were similar regardless of the treatment. It is concluded that both Pergolide and Parlodel are useful in the treatment of hyperprolactinemic syndromes, although neither one appears to be superior to the other.

Mechanism of arginine vasopressin release in the sheep fetus.

Maternal and fetal plasma concentrations of arginine vasopressin (AVP) during asphyxial and hypoxemic episodes were ascertained between 130 and 140 days of gestation in chronically catheterized sheep. During an acute asphyxial stress, i.e., decreased PaO2 and pHa and increased PaCO2, maternal AVP in plasma was unaltered, whereas fetal arterial plasma concentrations rose from 1.6-2.2 microunits/ml to 34-385 microunits/ml and were associated with massive expulsion of meconium into the amniotic fluid. Mild hypoxemia, induced while the mother breathed a gas mixture consisting of 85% nitrogen and 15% oxygen, did not affect either maternal or fetal plasma AVP concentrations. The use of 10% inspired oxygen resulted in 60% and 50% reductions in maternal and fetal PaO2, respectively (P less than 0.05). In this instance, the maternal plasma AVP levels were unchanged, whereas the fetal plasma AVP concentration rose from a mean of 2.61 +/- 0.14 (SE) to 10.2 +/- 2.59 microunits/ml (P less than 0.025) within 30 min. Expulsion of meconium into the amniotic fluid did not occur. No evidence or either fetal-maternal placental transfer or fetal-placental clearance of plasma AVP was obtained. Although hypoxemic stress resulted in an elevation of fetal plasma AVP concentration, it does not appear to be the sole factor responsible for AVP release during intrauterine stress. It is suggested that substantial elevations in fetal plasma AVP concentrations may play in integral role in the fetal expulsion of meconium into the amniotic fluid.

Testicular leydig cell hyperplasia as a cause of familial sexual precocity.

Testicular Leydig cell hyperplasia was observed in two brothers presenting with progressive sexual precocity at 2 yr of age. Virilization was shown to result from increased secretion rather than decreased clearance of gonadal testosterone. Testosterone hypersecretion appeared to be gonadotropin independent, as basal and gonadotropin-releasing hormone-induced serum LH concentrations were low by both RIA and bioassay. Adrenal steroidogenesis was demonstrated to be normal by ACTH stimulation, dexamethasone suppression, and split adrenal venous function tests. Testicular histology revealed immature reproductive structures in the 2 yr old, but advanced spermatogenesis in the 3 yr-old brother. The etiology of both Leydig cell hyperplasia and reproductive testicular maturation in the absence of significant gonadotropin secretion remains to be established.

Circulating gonadotropins, estrogens, and androgens in polycystic ovarian disease.

Serum gonadotropin, estrogen, and androgen levels were measured in samples obtained from 19 patients with polycystic ovarian disease (PCO) and from 10 normal women on day 2 to 4 of their menstrual cycles. In patients with PCO, the mean (plus or minus S.E.) concentration was significantly higher (P smaller than 0.001) than the concentrations found in the normal subjects for LH (35 plus or minus 4.6 vs. 12.7 plus or minus 2.6 m.I.U. per milliliter), but not for FSH (10.3 plus or minus 0.7 vs. 8.7 plus or minus 0.9 m.I.U. per milliliter). Estrone (E1) levels (92 plus or minus 4 vs. 52 plus or minus 5 pg. per milliliter) were also significantly higher (P smaller than 0.001), while estradiol (E2) concentrations (58 plus or minus 4 vs. 63 plus or minus 8 pg. per milliliter) were comparable. Testosterone (T) (468 plus or minus 41 vs. 325 plus or minus 34 pg. per milliliter, P smaller than 0.05), androstenedione (delta) (2,083 plus or minus 138 vs. 1,123 plus or minus 153 pg. per milliliter, P smaller than 0.001), and dehydroepiandrosterone sulfate (3.4 plus or minus 0.4 vs. 2.0 plus or minus 0.37 mug per milliliter, P smaller 0.02) were also significantly increased over the values in normal controls. The mean dehydroepiandrosterone (DHEA) was elevated in the patients with PCO (11.3 plus or minus 1.7 vs. 7.5 plus or minus 1.2 mug per milliliter), but was not significantly different. A positive correlation was found between LH levels and both E2 and E1 concentrations in the patients with PCO. These data show a distinct profile of gonadotropin, estrogen, and androgen levels in patients with PCO.