Daniel Navot

Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment.

OBJECTIVEnTo overview the world literature on ovarian hyperstimulation syndrome (OHSS) and modes of prevention and treatment of OHSS.nnnSTUDY SELECTIONnAll the pertinent literature on OHSS, its prevention, and strategies for treatment were reviewed.nnnPREVENTIONnKey to prevention is proper identification of the population at risk, which includes women with either the hormonal or the morphological signs of polycystic ovarian disease, high serum estradiol (E2) before human chorionic gonadotropin (hCG) administration (E2 greater than 4,000 pg/mL), multiple follicular response (greater than 35), younger age, and lean habitus. When a high risk situation is recognized, ovulatory dose of hCG may be reduced, avoided (with cycle cancellation), or substituted by gonadotropin-releasing hormone or its agonist. Luteal support with hCG is to be bypassed. To minimize risk of OHSS, endogenous pregnancy-drived hCG may be eluded by judicious cryopreservation of all embryos. Last, follicular aspiration will allow higher levels of E2 and larger number of follicles to be matured with lesser risk of OHSS than conventional ovulation induction without follicular aspiration.nnnTREATMENTnIn-house for the severe and intensive care for the critical form. Meticulous fluid and electrolyte balance using both crystalloids and colloids (albumin) until hemoconcentration abates. Paracentesis is indicated for tight ascites, deteriorating kidney functions, and symptomatic relief. Diuretics may be prudently used once hemodilution is achieved. Dopamine drip may be used as a renal rescue, whereas heparin is indicated for thromboembolic phenomena and surgery reserved for abdominal catastrophies. Therapeutic interruption of an early gestation may be lifesaving when all other measures have failed.nnnCONCLUSIONSnAlthough severe and critical OHSS may not be completely avoided, early recognition of high-risk factors, judicious prevention schemes, and treatment strategies should reduce the complication and long-term sequelae of this iatrogenic syndrome.

Poor oocyte quality rather than implantation failure as a cause of age-related decline in female fertility.

Female fertility declines with advancing age. To establish whether this age-related reproductive failure results from diminished oocyte quality or uterine/endometrial inadequacy we investigated ovum donation in 35 infertile women, aged 40 years or older (mean 42.7 [SE 0.3]) who had failed at attempts at conception with their own (self) oocytes. Oocytes were donated by 29 young individuals (mean age 33.4 [0.7]) undergoing in-vitro fertilisation (IVF). 8 (5.3%) pregnancies were achieved in 150 cycles of ovulation induction with self-oocytes and 2 (3.3%) in 60 such cycles by in-vitro fertilisation (IVF), but none attained viability. By contrast in 50 cycles with donated oocytes 28 (56%) pregnancies and 15 (30%) deliveries were realised (p less than 0.005). The rate of implantation per embryo transferred was higher (14.7%) with donated oocytes than that with self-oocytes (3.3%) (p less than 0.01). To further elucidate the contribution of age to reproductive outcome, pregnancy results were compared between the young donors and older recipients. Both donors and recipients shared oocytes from the same induced cohort. Rates for clinical pregnancy and delivery did not differ between donors (33% and 23%) and recipients (40% and 30%). Our data suggest that the age-related decline in female fertility is attributable to oocyte quality and is correctable by ovum donation. The uterus can adequately sustain pregnancies even when reproductive potential is artificially prolonged into the late 40s.

Age-related decline in female fertility is not due to diminished capacity of the uterus to sustain embryo implantation*

OBJECTIVEnTo evaluate the contribution of the uterus to age-related reproductive failure in women.nnnPATIENTSnThirty-eight ovum donors (30.2 +/- 4.9 years [mean +/- SD]) donating oocytes throughout 102 ovum donations. Fifty-one cycles were documented in younger recipients (35.8 +/- 3.1 years) and 51 in older recipients (44.0 +/- 3.1 years). The study was prospectively designed; same-cohort oocytes obtained from one young donor during a specific cycle were evenly distributed between young and old ovum recipients. Use of oocytes from a single source and a unique ovulatory cohort provides strict control over oocyte quality. Uterine age is varied by design, according to the age of the recipient at the time of ET. The role of the aging uterus in the decline of female fertility can be thus isolated and scrutinized.nnnRESULTSnNo significant (NS) difference in the number of ova received (7.9 +/- 3.4 versus 7.0 +/- 3.5), ova fertilized (4.4 +/- 1.5 versus 4.5 +/- 2.3), or embryos transferred (4.1 +/- 1.5 versus 4.1 +/- 1.6) was observed between the < 40 and > or = 40 recipient age groups. A total of 23 pregnancies occurred among the 102 ETs (22.6%). Eleven clinical pregnancies (21.6%) resulting in 10 deliveries were observed in the < 40 recipient age group, and 12 clinical pregnancies (23.5%) leading to 10 deliveries occurred in the > or = 40 recipient age group (NS). The pregnancy loss rates were 9.1% (1 of 11) and 16.7% (2 of 12) for the two recipient age groups, respectively, (NS).nnnCONCLUSIONnThe capacity to conceive and to gestate a conception to term when oocyte quality is controlled appears to be independent of uterine aging through the fifth decade of life.

Premature luteinization in controlled ovarian hyperstimulation has no adverse effect on oocyte and embryo quality

OBJECTIVEnTo determine if premature luteinization has an adverse effect on oocyte and, hence, embryo quality.nnnDESIGNnRetrospective evaluation of anonymous ovum donors/oocyte recipients.nnnSETTINGnA large oocyte donation program.nnnPATIENTS, PARTICIPANTSnSixty-eight women undergoing controlled ovarian hyperstimulation (COH) as ovum donors were matched to 68 women with ovarian failure as ovum recipients who had endometrial maturation exogenously controlled by an identical hormone replacement protocol.nnnINTERVENTIONSnSerum was collected for E2 and P in donors and recipients.nnnMAIN OUTCOME MEASURESnThe incidence of premature luteinization was determined in donors. Cycle characteristics were compared between donors with and without premature luteinization, with emphasis on oocyte and embryo quality. Implantation rates per embryo and delivery rates per transfer were measured in recipients.nnnRESULTSnTwenty-one (31%) of the donors demonstrated premature luteinization. Serum P was higher on day before hCG, day of hCG, and day after hCG in women demonstrating premature luteinization. However, there were no differences between donor cycles with or without premature luteinization as determined by donor age, ampules of gonadotropins used, day of hCG administration, peak E2, total number of oocytes, and number of mature oocytes retrieved. Ovum recipients were of similar age and had similar E2 exposure (area under the E2 curve) before P administration. Similar fertilization rates, incidence of polyspermia, number of embryos transferred of similar embryo grade, and similar implantation rates and deliveries per transfer were observed in women receiving oocytes from donors with and without premature luteinization, respectively.nnnCONCLUSIONSnSimilar oocyte quality, fertilization, and polyspermia rates, embryo quality, implantation, and delivery rates suggest that any negative impact of premature luteinization on pregnancy rates in COH cycles from young women is not due to an adverse effect of PL on oocyte and hence embryo quality, but rather on the endometrial environment.

Ovarian hyperstimulation syndrome: A review of pathophysiology

Ovarian hyperstimulation syndrome (OHSS) remains the most serious complication of ovulation induction (OI). In its severest, critical form it is characterized by enormous, cystic ovarian enlargement with massive extravascular fluid shifts and secondary intravascular volume depletion (1,2). This acute fluid shift into third spaces, with accompanying electrolyte imbalance, and hemoconcentration is largely responsible for the serious morbidity (3-6) and occasional mortality (7,8) seen in OHSS. Although the pathophysiology of this syndrome has not been completely elucidated, the underlying mechanism responsible for the clinical manifestation of OHSS appears to be an increase in capillary permeability of mesothelial surfaces (9). Risk factors (10,11)for the OHSS include high serum estradiol (Ez) levels (2,12-14) and multiple immature and intermediate follicles (15-17). Patients with polycystic ovarian disease (PCO) are well-known to be predisposed to this syndrome (18-20). In addition, the OHSS is almost restricted to cycles with either exogenous or endogenous pregnancy-derived, human chorionic gonadotropin (hCG) stimulation (1,2,21,22). The events of OI leading up to the development of the OHSS, for the most part, represent an exaggeration of the normal process of follicular development and ovulation. Thus, a brief and selected review of the normal menstrual cycle is warranted before examining the phenomenon of OHSS.

The long-term predictive value of the zona-free hamster ova sperm penetration assay

Three hundred sixty-nine infertile couples were followed for 2 to 5 years in a study designed to determine the clinical long-term predictive value of the zona-free hamster ova sperm penetration assay (SPA). Semen analysis (SA), SPA, and a full infertility workup were done in all cases, and only couples in whom the female had no evident cause of infertility were included in the study. During the follow-up period, 106 couples (29%) achieved a pregnancy. Sixteen percent of 131 men who had an SPA of 0%, 23% of 120 men with 1% to 19%, and 48% of 118 men who had a penetration of greater than 19% impregnated their wives 2 to 5 years after the assays. Significant difference in fertility prognosis was found between those who had an SPA greater than 19% and those with an SPA less than 20% (48% versus 20%). Sperm penetration assay greater than 19% was predictive of higher pregnancy rates in both oligospermic (41% versus 17%) and unexplained infertile couples (52% versus 24%). The specificity and positive predictive values of the SPA were higher than those of the SA (77% versus 57% and 48% versus 37%). These findings emphasize the value and importance of the SPA in determining the long-term fertility potential of men.

The effect of female antisperm antibodies on in vitro fertilization, early embryonic development, and pregnancy outcome *

STUDY OBJECTIVEnTo evaluate the extent to which human in vitro fertilization-embryo transfer (IVF-ET) alleviates immunological infertility.nnnDESIGNnRetrospective.nnnSETTINGnIn vitro fertilization program.nnnPATIENTSnThirty-three patients with positive antisperm antibodies undergoing 50 cycles of IVF-ET in which maternal serum was replaced by 5 mg/mL of bovine serum albumin (BSA) comprised the study group. Seventy-one patients with tubal infertility served as controls. In 50 of these, medium was supplemented with 7.5% maternal serum, and 21 were assigned to BSA substitution.nnnRESULTSnPercentage of fertilization in the study group was significantly lower (41 +/- 31; mean +/- SD) than that of controls with maternal serum (77 +/- 15) and BSA (76 +/- 22). Early embryonic quality, as assessed by percentage of cleavage and morphological grading, was found to be inferior in patients with antisperm antibodies. The percentage of advanced embryos (greater than or equal to 4 blastomeres) at the time of transfer was 42 +/- 39 in the study group, compared with 65 +/- 23 and 75 +/- 35 for maternal serum and BSA controls, respectively. Percentage of morphologically favorable embryos (grades 1 and 2 in a 1 to 5 grading system) was 49 +/- 31 in the study group, compared with 78 +/- 35 and 74 +/- 23 for the controls. Percentage of clinical pregnancy was somewhat lower in the study group (12.5%) than in controls with either maternal serum (18%) or BSA (19%).nnnCONCLUSIONSnAntisperm antibodies may have an adverse effect on fertilization and early embryonic development. Female immunological infertility may not be completely alleviated by IVF-ET.

Progesterone/Estradiol Ratios Predict Outcome in In Vitro Fertilization

Despite increasing experience with in vitro fertilization (IVF), there are few endocrinological markers which can serve as a prospective predictor of IVF success. An initial investigation utilized periovulatory estradiol (E2) levels after administration of low dose human menopausal gonadotropin followed by a coasting period before giving human chorionic gonadotropin (hCG). The levels of estradiol studied were lower than those typically seen in many IVF programs today.1 Others have studied post-transfer progesterone/E2 ratios and suggested a predictive value.2 This report summarizes our efforts to further elucidate endocrinological markers that can be used to predict success or potential success in IVF.