Evaluation of the mechanism for higher pregnancy rates in donor oocyte recipients by comparison of fresh with frozen embryo transfer pregnancy rates in a shared oocyte programme.

The objective of this study was to determine the mechanism for higher pregnancy rates in oocyte recipients by comparing the pregnancy rates following fresh and frozen embryo transfers in a shared oocyte programme. A prospective study was carried out of 135 matched pairs of donors and recipients who equally share the donors' pool of oocytes. Recipients were subclassified by ovarian function: 69 were in ovarian failure and 66 retained ovarian function. A total of 474 standard in-vitro fertilization cycles using the same ovarian stimulation protocol as the donors were also evaluated. The main outcome measures were the clinical pregnancy and implantation rates for donors and recipients following fresh and frozen embryo transfers. The clinical pregnancy rates per transfer for fresh embryo transfers were 17.5% for donors, 20.4% for recipients with ovarian function and 46.3% for recipients in ovarian failure (P < 0.05). The pregnancy rates for frozen embryo transfers were 15.3% for donors, 17.2% for recipients with ovarian function and 23.8% for recipients in ovarian failure (not significantly different). The implantation rates for fresh transfers were 7.5% for donors, 8.6% for recipients with ovarian function and 15.6% for recipients in ovarian failure (P < 0.05); for frozen cycles, the implantation rates were 5.1, 5.2 and 7.1% respectively (not significantly different). When classified by age and ovarian function, the clinical pregnancy rates per transfer for recipients with ovarian function were 14.0% for those aged > or = 40 and 22.2% for those aged < 40 years. For recipients in ovarian failure, the pregnancy rates were 33.3% for the older group of women and 39.4% for the younger group. A logistic regression analysis found that ovarian function was the only factor to have an independent effect on outcome. The demonstration of higher pregnancy and implantation rates in recipients versus donors following fresh embryo transfer, despite the use of a common pool of oocytes, strongly suggests that the well-known higher fecundity found in recipients is not predominantly related to the use of better quality oocytes. The demonstration of an implantation rate twice as high following fresh versus frozen embryo transfer in recipients with ovarian failure suggests that the frozen embryo is not as hardy as the fresh embryo. Thus, the fact that both the pregnancy and implantation rates in donors were the same with fresh versus frozen embryo transfer suggests that the ovarian stimulation regimen has a negative effect on outcome. However, the clear demonstration of higher pregnancy rates in recipients with ovarian failure compared with those with ovarian function suggests that, in addition, these higher rates may be linked to a superior uterine environment in patients with ovarian failure. Alternatively, the use of gonadotrophin-releasing hormone agonists may have a negative effect on implantation in patients with ovarian function.

A randomized comparison of the effect of two diuretics, a converting enzyme inhibitor, and a sympathomimetic amine on weight loss in diet-refractory patients.

We hypothesized that women refractory to dietary weight loss may have a type of idiopathic edema. In a study of 200 women, we compared four drugs, used previously for treating idiopathic edema, to determine their efficacy in causing weight reduction. After 6 months of treatment, the percentage of treated groups losing at least 10% of baseline weight was 6% for hydrochlorothiazide, 8% for spironolactone, 68% for dextroamphetamine sulfate, and 4% for captopril. The percentage losing >20% and >30% of baseline weight in the same treatment groups was 28% and 10% for dextroamphetamine therapy but 0% for the other three groups. Of the women who failed to lose weight with one of the nonamphetamine therapies during the first 6 months, 132 were then treated with dextroamphetamine; 68% lost =10% of their baseline weight, and 30% and 7% of patients lost =20% and =30%, respectively. With use of the classic definition of idiopathic orthostatic edema (urinary output of <55% of ingested water load in 4 hours), only 58 of the 200 study patients had this diagnosis; however, 144 patients excreted <75% of the load. Comparison of the efficacy of amphetamine therapy in patients with <75% versus =75% urinary excretion showed 120 of 131 (92%) lost =10% in the former category versus only 4 of 51 (8%) in the latter. Of the 58 patients who excreted <55% of the water load, 52 (90%) lost =10% of baseline weight with amphetamine therapy. The patients noted no effects of therapy on dietary consumption. The responsiveness of the patients to amphetamine therapy during the second 6-month period despite failing to lose weight with the three other therapies suggests that no inadvertent bias was present in the randomization process. Thus, the results suggest that some women who are recalcitrant to dietary weight loss may have a mild type of water retention that is refractory to diuretics but responsive to amphetamines.

Relationship of endometrial thickness and sonographic echo pattern to endometriosis in non-in vitro fertilization cycles.

The objective of this study was to investigate the effect of endometriosis on the proliferation of the endometrium as determined by sonographic measurements of endometrial thickness and echo pattern at peak follicular maturation. A prospective study of 60 infertility patients was conducted in which the endometrium was evaluated sonographically, both before and after laparoscopy. Prior to laparoscopy, the mean endometrial thickness was 10.5 +/- 1.9 mm in the group without endometriosis (n = 20) and 11.7 +/- 2.8 mm in the group with endometriosis (n = 40) (p > 0.05). Following the laparoscopy, there was no change in the mean thickness within each group. The incidence of an unfavorable echo pattern was negligible in both groups. Endometriosis does not cause a reduction in endometrial thickness, nor does it appear to influence the development of an unfavorable echo pattern at time of peak follicular maturation.

Pregnancy rates in donors versus recipients according to the serum progesterone level at the time of human chorionic gonadotropin in a shared oocyte program.

Previous data suggested a subtle increase in serum P at the time of hCG injection without LH surge reduces the PR of women having oocyte retrievals for IVF; this study compared PRs of recipients in a shared oocyte program according to the donors' pre-hCG P level. There was no difference in viable PRs between recipients and donors when P < or = 1 ng/mL. The PR was similar for recipients when donors' P was > 1 ng/mL (12.7%). Donors with P > 1 ng/mL had the lowest PR: 7.2%. The data suggest that the adverse effect of higher serum P without LH surge may be on the endometrium rather than the oocyte.

Effect of clomiphene citrate therapy on postcoital tests in successive treatment cycles including response to supplemental estrogen therapy.

Debate continues as to whether clomiphene citrate (CC) has an adverse effect on cervical mucus. Some researchers conclude that adverse effects maybe related to hormonal abnormalities, e.g., premature luteinization or improper timing. This study evaluated the initial and accumulative effects of CC on postcoital testing (PCT) and attempted to determine if supplemental estrogen (E) improves PCT and/or inhibits follicular maturation. The majority of patients taking CC had poor PCT tests even on the first treatment cycle. Good initial PCTs tended to remain so in subsequent cycles or at least to respond to subsequent supplemental E. Poor PCTs responding to E tended to continue to respond to the combination. PCTs not responding to E therapy continued this pattern in subsequent cycles. Supplemental E did not suppress follicular maturation.

The effect of the age of the recipients on pregnancy rates following donor-oocyte replacement.

PURPOSE: Besides waning ovarian function with advancing age, the question of a uterine senescence factor has been proposed as a cause of decreased fecundity. The replacement of oocytes from younger donors into older recipients allows further investigation into the aging endometrium. RESULTS: The pregnancy rate was considerably lower, 8.5% in recipients in ovarian failure who were > or = 40 years old (n = 23) compared to younger recipients, < 40 years of age (n = 55), who were also in ovarian failure, which would support the uterine senescence theory. CONCLUSION: The endometrial factor may be manifested by failure to generate a critical endometrial thickness of 10 mm by sonography in 61% of the older group, compared to only 29% of the younger group. Future studies should address methods of improving the endometrial thickness in the older group, to determine if improved pregnancy rates will occur and to evaluate whether increasing luteal support with extra progesterone may also improve pregnancy rates.

A conservative treatment protocol with human menopausal gonadotropins aimed at reducing multiple births.

In multicenter studies involving 3002 courses of human menopausal gonadotropins (hMG) therapy in 1286 patients, 20% of the patients who delivered had multiple gestations; 75% of these were twins and 25% were triplets or higher parity. Our stimulation regimen is very conservative in that we 1) try to allow a female with LPD and regular cycles but not reaching a mature follicle to first select her dominant follicle and wait until the serum E2 reaches approximately 100 pg/mL then add the hMG. With anovulatory women we frequently begin with only 75 IU hMG and gradually increase the hMG dosage. Using this approach we have usually attained at least a 70% pregnancy rate in six months. A study was performed to see if this conservative approach resulted in a decreased multiple birth rate percentage especially with triplets or more. The study was to evaluate the outcome of 241 consecutive pregnancies in which hMG was the sole therapy. There were 203 with one gestation and 38 with multiples. Twins--32; triplets--6. Thus 15% (38/241) had multiple births; six of 38 (15%) of the multiples had triplets or more. Though our multiple birth rate and especially higher parity rate appears to be lower than average no statistical difference was found. Thus even with conservative use of hMG multiple births cannot be easily avoided.

Influence of serum progesterone levels at the time of hCG on the release of ova during hMG cycles.

A study was designed to monitor release of ova by sonography in hMG-treated patients following hCG and to determine if failure to release ova correlates with critically low or high progesterone levels. This was a retrospective study of 292 consecutive patients treated with hMG. The requirement for treatment was that hCG be given when at least one follicle attained a 17-mm diameter with a serum estradiol level of at least 200 pg/mL per mature follicle. If the serum progesterone assay was greater than or equal to 1.8 ng/mL, then hCG would be given as long as there was at least one dominant follicle and a serum estradiol level greater than 200 pg/mL. The patients were divided into four groups for study based on the progesterone level at the time of hCG administration. There were no statistically significant differences in the ability to achieve ova release whether serum progesterone was very low or close to 2 ng/mL when hCG was given. The rise in the progesterone level prior to ovulation has been proposed to enhance egg release. However, the data presented herein do not support the necessity for a critical level of serum progesterone at the time of hCG injection in hMG-treated women.

Evaluation of sperm morphology using Kruger's strict criteria.

Prospective and retrospective studies were conducted to evaluate sperm morphology using strict criteria for predicting fertilization capacity in males. Severely impaired male fertility potential was measured by a result of less than or equal to 4% (denotes percentage sperm having normal morphology) and scores of greater than 14% indicated normal fertilization potential. There were no statistically significant differences found in pregnancy rates in partners of men with normal morphology of less than or equal to 4% vs. those with 14% or greater (chi 2 analysis): the prospective study showed a 41% pregnancy rate in less than or equal to 4% group vs. 29% rate in greater than 14% group (p = 0.44 NS); the retrospective analysis showed a 50% pregnancy rate in the group with less than or equal to 4% morphology scores vs. 67% in greater than 14% group (p = 0.45 NS). When only the men with normal motile density (greater than 10 x 10(6)/ml) were evaluated, a statistical difference was found in the retrospective study between the group with morphology results greater than 14% (93%) vs. the group less than or equal to 4% (40%). However, the 56% success rate in the men with less than 10 x 10(6)/ml sperm and normal morphology less than or equal to 4% reduces the significance of the diagnosis of sperm morphology using the new strict criteria.

Effect of antisperm antibodies on computerized semen analysis.

The effect of antisperm antibodies (ASA) in males was determined in 239 men by the use of a computerized semen analyzer (CASA). ASA was assessed using the direct immunobead test (IBT). Sperm variables for men with positive ASA were significantly lower than those with negative results in percentages of motility, velocity, and linearity.

Opposite responses to the addition of leuprolide acetate to human menopausal gonadotropin therapy in two perimenopausal women.

Leuprolide acetate was used to suppress the endogenous gonadotropins in order to prevent premature luteinization in two women under ovulation induction therapy. One patient had previously developed premature luteinization with clomiphene citrate, but consistently produced only one mature follicle with hMG therapy. However, when leuprolide acetate was started prior to hMG during an attempt for in vitro fertilization, it failed to stimulate even a mild rise in her serum estradiol. The other patient, who was not able to make a mature follicle with hMG alone because of premature luteinization, was enabled to make mature follicles with leuprolide therapy alone (without hMG). The exact mechanism for these totally different responses to leuprolide acetate in two perimenopausal women is not known.

An in vivo technique for screening immunologic factors in the etiology of the unexplained poor postcoital test.

A study was designed to determine the incidence and etiology of the unexplained poor postcoital test. An in vivo comparison of sperm penetration by husband's versus donor sperm in the wife's estrogen-stimulated mucus was performed. The 8 of 30 women showing improvement of husband's penetration in mucus (group 1) were treated with high-dose estrogen (HDE) and hMG, and 4/8 conceived. Anti-sperm antibodies (ASA) were insignificant in this group. In group 2, in which donor sperm penetrated but husband's sperm did not, 8 men of 17 were found to have an ASA level over 50% on the sperm surface; 6/8 treated with high-dose methylprednisolone (MP) had an improved postcoital test, and 5 achieved a pregnancy. Two patients with levels under 50% were still treated with MP, and one achieved a pregnancy. In five group-3 couples, positive ASA were found in the cervical mucus of two women; and one woman improved on the postcoital test and conceived following MP therapy. The 30 unexplained poor postcoital tests occurred in 5,000 couples evaluated. In general, those patients considered to have significant clinical antibody had levels over 50%. Because side effects of MP may be severe, and positive ASA may be found in normal donors, it is important to use a comparison penetration test to help determine if treatment with corticosteroids seems reasonable.

Pelvic sonography can predict ovum release in gonadotrophin-treated patients as determined by pregnancy rate.

Ultrasonographic monitoring of ovum release was performed in two consecutive cycles in each of 220 patients treated with gonadotrophin. Definite release occurred in 69% of cycles, indeterminate in 24% and non-release in 7%. Support for the accuracy of sonography in diagnosing the luteinized unruptured follicle (LUF) was demonstrated by a much higher pregnancy rate in those patients showing ovum release. There was a definite tendency for non-release to recur in the next cycle. Thus, the data support the routine use of sonography 2-3 days after human chorionic gonadotrophin (HCG) injection to monitor ovum release in gonadotrophin-treated patients (HMG).

Bromocriptine versus progesterone therapy for infertility related to luteal phase defects in hyperprolactinemic patients.

Several anecdotal reports suggested an association of luteal phase defects (LPD) and hyperprolactinemia. Some physicians treat LPD with ovulation-inducing drugs, whereas others recommend progesterone support of the luteal phase. A study was thus initiated to evaluate in cases of LPD associated with hyperprolactinemia which therapy would be more efficacious--bromocriptine or progesterone (P). LPD was divided into two types based on follicle dynamic studies: (1) LPD associated with immature follicles and (2) pure LPD when the follicle was mature. The objective was to determine if P or bromocriptine would be more effective depending on the type of LPD. Randomized therapy with either bromocriptine (BCT) or progesterone vaginal suppositories (PVS) was given to 60 patients with pure LPD (established by endometrial biopsy in the late luteal phase) and similarly randomized therapy was given to 40 women with LPD and immature follicles. The incidence of pregnancies during an 8-month treatment period was as follows: pure LPD--23 of 50 women (77%) treated by PVS versus 5 of 30 women (17%) treated by BCT; LPD associated with immature follicles--3 of 20 women (15%) treated by PVS versus 14 of 20 women (70%) treated by BCT. Those women failing to conceive were now given the alternate therapy for the next 8 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Empirical therapy of the male with clomiphene in couples with unexplained infertility.

Unexplained infertility may be secondary to a cryptic male or female factor. Although most often empirical therapy of the female partner may be attempted, clomiphene has been claimed, after uncontrolled studies, to improve fertility in men with subnormal spermograms. We chose to determine if clomiphene therapy of the male would improve fertility in couples with unexplained infertility despite normal-appearing semen parameters. One hundred husbands were randomized to treatment with clomiphene citrate, 25 mg daily for 25 days with 5 days' rest each month, if their social security numbers ended in an even number or ascorbic acid, 500 mg daily, if ending in an odd number. All female infertility factors had to be meticulously corrected for at least eight cycles for inclusion in the study, along with a minimum of 1 1/2 years' duration of infertility. Within 8 months, 29 of 50 couples (58%) with clomiphene therapy of the male achieved a pregnancy, but only 8 of 50 (16%) with ascorbic acid treatment of the male. There were no appreciable changes in sperm counts, motility, or morphology after either treatment, nor were there any significant differences in semen parameters in those conceiving versus those who did not. Further, improved fertility could not be accounted for by improvement in the hamster ova penetration test. Possibly, clomiphene improves some quality of the sperm that is defective but not measurable by standard androgenologic methods, or it improves some aspect of the seminal plasma. Perhaps, though, the results might be better explained on a psychogenic basis, i.e., clomiphene is a "better" placebo than ascorbic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Ovulation induction and pregnancy with an estrogen-gonadotropin stimulation technique in a menopausal woman with marked hypoplastic ovaries.

A case is described of a woman with ovarian failure and documented atrophic ovaries in whom ovulation was achieved with the use of high-dose estrogen and human menopausal gonadotropins. The proposed mechanism involves a reduction in the elevated gonadotropins, which restored an adequate number of receptors. Thus sensitivity to exogenous menotropins was reestablished.

Ovulation-inducing drugs versus progesterone therapy for infertility in patients with luteal phase defects.

The efficacy of ovulation-inducing drugs (OVI) for treating infertility related to luteal phase defects (LPD) was compared with the efficacy of progesterone vaginal suppositories (PVS). Patients were divided into two groups: (1) LPD secondary to immature follicles and (2) pure LPD, in which the follicle was mature. Twenty-four of 31 women (77%) with pure LPD conceived (one aborted) during the first 6 months, compared with only 3 of 27 (11%) treated with OVI--and 2 of 3 aborted. However, in women with LPD secondary to immature follicles, 14 of 20 (70%) treated with OVI and PVS conceived (and one aborted) compared with 7 of 10 conceiving (70%) with OVI only (four aborted), and 3 of 12 conceived (25%) with PVS only (none aborted). Thus, both PVS and OVI are effective in treating LPD; follicular maturation studies help determine the proper choice. PVS appears to decrease the risk of abortion in both categories.

Progesterone therapy to decrease first-trimester spontaneous abortions in previous aborters.

A study was designed to see if the use of prophylactic progesterone vaginal suppositories (PVS) reduced the risk of spontaneous abortions in women with a history of at least one spontaneous abortion. PVS was employed during the luteal phase to the end of the first trimester. The dosage was initially 50 mg/day, but was increased according to the endometrial biopsy and doubled as soon as pregnancy was established. Only 10 women (10%) aborted, and 8 of these 10 were successful in their next PVS-treated pregnancies. Overall there were 12 losses in 132 pregnancies (9%) in these PVS-treated patients. Forty-two percent of untreated controls aborted (10/24). The results suggest that PVS is effective in reducing the risk of spontaneous abortions in high-risk patients.

The efficacy of progesterone in achieving successful pregnancy: I. Prophylactic use during luteal phase in anovulatory women.

We have previously shown that prophylactic supplementation of progesterone beginning in the luteal phase of patients treated with human menopausal gonadotropins (hMG) could reduce the risk of spontaneous abortions. The present study was initiated with 100 patients to evaluate the efficacy of a new progesterone therapeutic regime in patients requiring either hMG or clomiphene citrate. A significantly decreased risk of spontaneous abortion (6% vs. 28%) was seen in 50 patients prophylactically treated with progesterone as compared with 50 control patients. The progesterone regimen was then tried on 566 consecutive patients who were treated and conceived with hMG or clomiphene citrate, and approximately the same risk (6.2% by 20 weeks) was found. This incidence of spontaneous abortion is even less than the accepted risk for the general population.

The efficacy of progesterone in achieving successful pregnancy: II. In women with pure luteal phase defects.

Controversy still exists as to the proper therapy of luteal phase defects. Some advocate using drugs to improve follicular dynamics, e.g., clomiphene citrate, while others treat luteal phase defects with progesterone. The possibility exists that in some cases the luteal phase defect is secondary to failure to produce a mature follicle, the better drug then being an ovulation-inducing drug, e.g., clomiphene. However, if the follicle is mature, then progesterone may be the best treatment. We defined mature follicle as one between 18 and 24 mm while the serum estradiol (E2) level is over 200 pg/mL. The efficacy of exclusive P therapy was evaluated in 50 women, all with a minimum of 1 1/2 years infertility and with no obvious fertility problems other than luteal phase defect. Seventy percent of the women conceived within 6 months. The abortion rate was 14.7%. The average period of infertility was 2.8 years in the 35 patients who conceived within 6 months. These data suggest that determining the degree of follicular maturation by serum E2 and pelvic sonography plus excluding the luteinized unruptured follicle syndrome by pelvic sonography helps determine the proper therapy for luteal phase defect.