Pharmacologic ovarian preservation in young women undergoing chemotherapy.

The prognosis of malignancies in young women undergoing chemotherapy has dramatically improved recently, and more attention is given to the long term quality of life, including fertility and reproductive function preservation. Some chemotherapeutic drugs are known to be associated with gonadal toxicity (cyclophosphamide, L-phenylanine mustard, busulfan and nitrogen mustard) and others have less or un-quantified effects (doxorubicin, bleomycin, vinca alkaloids, as vincristine and vinblastin, cisplatin, nitrosoureas, cytosine arabinoside). Women are in need to identify best options to minimize ovarian damage during chemotherapy through the administration of protective drugs, better choice of therapy and with advocating oncofertility preservation. We reviewed the possible options focusing on the most studied gonadotrophin-releasing hormone agonists (GnRH-a) and the psychologically promising oral contraceptives (OC). Controversy exist on the benefit of gonadotrophin releasing hormone agonist (GnRH-a) or combined oral contraceptive administered at time of cancer therapy in preventing premature ovarian failure in women and the available data from both human and animal studies have been mixed. The best way to preserve fertility and ovarian function in young women undergoing chemotherapy still remains to be determined. In the absence of a best approach, each case should be evaluated individually, considering patient's wishes and expectations, the type of chemotherapy, age, obstetric history, ovarian reserve (combining multiple indicators such as basal hormone profile, anti müllerian hormone -AMH- and antral follicle count), family history of premature ovarian failure. We present a review of the available evidence on the value of administering GnRH-a and OC use to minimize or prevent the effect of chemotherapy agents on reproductive function.

Assisted conception following radical trachelectomy.

BACKGROUND: Radical trachelectomy (RT) has been established as a valuable fertility-preserving treatment in women with early stage cervical cancer. A number of these women will require assisted conception which may bring certain challenges to those managing treatment. An awareness of those challenges is essential to maximize outcome in terms of live birth rates. METHODS: All women who had undergone assisted conception following RT were assessed with respect to treatment management and pregnancy outcome. RESULTS: Pregnancy rates were good, with nine pregnancies in seven women treated. Difficulties in treatment were essentially related to isthmic stenosis. There was a clear need for trial embryo transfer (ET) prior to treatment and dilatation of the isthmus where necessary. The premature delivery rate was high (75% at <37 weeks), highlighting the importance of single ET to avoid multiple pregnancy. CONCLUSIONS: Assisted conception following RT is associated with a good pregnancy rate, although there is a high miscarriage and premature delivery rate. Treatment outcome should be maximized by careful patient preparation in terms of assessing the need for isthmic dilatation, and ET should be performed by an experienced operator.

Relevance of basal serum FSH to IVF outcome varies with patient age.

Live birth rate (LBR), age and basal serum FSH values were analysed in 1589 women undergoing their first cycle of IVF. Four age groups (<30, 30-34, 35-38, 39-45 years) and three FSH groups (<5, 5-9.9, > or =10 IU/l) were established. Logistic regression analysis was used to determine the effect of age and FSH on live birth. A model to predict the probability of a live birth suggests that an additional 10 years of age reduces the odds for live birth (OR = 0.66, 95% CI 0.48-0.91); an increase of FSH by 5 IU/l reduces the probability of live birth (OR = 0.75, 95% CI 0.61-0.92); women > or =39 years have an additional reduction in probability of live birth (OR = 0.58, 95% CI 0.61-0.92). Analysis by age and FSH categories showed that pregnancy rate (PR) did not change significantly with rising FSH for women <35 years old. In cycles started with serum FSH <5 IU/l, increasing age did not effect PR and LBR. Cycles started with serum FSH > or =10 IU/l had a PR and LBR of 23.6 and 16.9% respectively. The clinical relevance of elevated FSH varies according to age; younger women with elevated FSH and older women with low FSH still have an acceptable LBR.

Characteristics of populations of granulosa cells from individual follicles in women undergoing 'coasting' during controlled ovarian stimulation (COS) for IVF.

BACKGROUND: The aim of this study was to evaluate the functional characteristics of granulosa cell populations of individual follicles of women undergoing controlled ovarian stimulation (COS) for IVF/ICSI in whom gonadotrophin had been withheld ('coasted') for the prevention of OHSS. METHODS: Follicular fluid and granulosa cells were isolated from 224 individual follicles in 41 women who had been coasted and from 257 individual follicles in 50 women who had a 'normal' response to COS. Cells were cultured at 10,000 cells per well, to evaluate progesterone secretion. Follicular fluid was assayed for progesterone and estradiol (E2). RESULTS: No significant differences were observed between the two groups with respect to granulosa cell number or follicular fluid progesterone and E2 and follicle size, the retrieval of an oocyte and the subsequent fertilization of the oocyte. However, the granulosa cells derived from the coasted group showed a higher rate of progesterone secretion per cell at 72 h which was sustained for longer. Differences were also seen at 72 and 120 h of culture with a loss of correlation between progesterone secretion and follicle diameter in the coasted group. CONCLUSIONS: Our findings suggest that coasting has an effect on the functional capacity of the granulosa cells and the duration of their function. It is likely that in women at risk of OHSS who are not coasted, the granulosa cells have the capacity to produce significantly more chemical mediators per cell and for a more prolonged period of time.

The effects of 'coasting' on follicular fluid concentrations of vascular endothelial growth factor in women at risk of developing ovarian hyperstimulation syndrome.

BACKGROUND: The aim of this study was to assess the effect of withholding gonadotrophins (coasting) during controlled ovarian stimulation (COS) on individual follicle concentrations of follicular fluid vascular endothelial growth factor (VEGF) in women at high risk of developing ovarian hyperstimulation syndrome (OHSS). METHODS: Twenty-two women who had been coasted and 26 optimally responding women (control group) undergoing COS for IVF were studied. At the time of oocyte retrieval, the follicular fluid from four to six individual follicles of different sizes was collected for VEGF analysis. RESULTS: A total of 118 follicles was analysed in the coasted group and 137 in the control group. A negative correlation was observed between the follicle size and VEGF concentration (r = -0.18, P = 0.03) in the control group, which was not seen in the coasted group. Similarly, the correlation between oestradiol (E(2)) and VEGF (r = 0.4, P < 0.0001) observed in the control group was not apparent in the coasted group. Significantly lower concentrations of VEGF were seen in the follicular fluid of the coasted patients. CONCLUSIONS: It is clear that there are differences in follicular fluid VEGF concentrations between the two groups. It is possible that coasting alters the capacity of the granulosa cells to produce VEGF and/or their response to hCG and in this way acts to reduce the severity and incidence of severe OHSS.

Excessive follicular response to controlled ovarian stimulation in a woman with menopausal FSH levels: case report.

A suspected poor responder to controlled ovarian stimulation (COS), with menopausal levels of follicular phase serum FSH, required coasting due to an excessive ovarian response. A 27 year old woman was referred to our Fertility Centre for ovum donation following repeated elevated, early follicular phase FSH levels (34.3, 27.1, 20.3 IU/l). Further investigations revealed the presence of antiovarian antibodies and a trial of COS, with the additional use of prednisolone, was proposed in view of her regular 28 day cycle. As 23 follicles were noted and an oestradiol level of 10,461 pmol/l following 7 days of stimulation with 450 IU of recombinant FSH per day, gonadotrophins were withheld for 9 days. Ten oocytes were retrieved and two grade I embryos were transferred. Pregnancy did not occur and she developed mild ovarian hyperstimulation syndrome. During a second cycle, multiple follicular development was again observed with an oestradiol level >13,200 pmol/l, despite a lower dose of gonadotrophin, and coasting was required for 4 days. Nineteen oocytes were collected, of which nine fertilized and cleaved. Two grade I embryos were replaced, leading to a singleton pregnancy. This patient subsequently had a vaginal delivery of a normal male baby at term. Young women with regular menstrual cycles and grossly elevated FSH levels may benefit from further investigation of autoantibodies and their ovarian response to exogenous gonadotrophins.

Clinical evaluation of three different gonadotrophin-releasing hormone analogues in an IVF programme: a prospective study.

The efficacy and safety of short acting buserelin and nafarelin intranasal spray were compared to long acting leuprorelin depot intramuscular or subcutaneous injection in this prospective study of 157 women undergoing controlled ovarian hyperstimulation (COH) for in-vitro fertilisation (IVF). Patients were allocated to three groups to receive buserelin 150 microg nasal spray three times daily (Group B), nafarelin nasal spray 400 microg twice daily (Group N), or leuprorelin depot 3.75 mg once by intramuscular or subcutaneous injection (Group L) for pituitary desensitisation prior to commencing COH with human menopausal gonadotrophins (hMG) according to the Centre's protocol. The mean (+/-S.D.) age (years) (32.6+/-3.8: Group B, 32.1+/-3.3: Group N versus 32.1+/-3.3: Group L); mean (+/-S.D.) total dosage of hMG (ampoules) (37.5+/-16.1: Group B, 39.8+/-14.2: Group N versus 41.9+/-12.6: Group L) and mean daily dosage of hMG (ampoules) (3.1: Group B, 2.8: Group N versus 3.0: Group L) seen were not statistically significantly different. The duration between starting the different gonadotrophin-releasing hormone (GnRHa) and the beginning of the next menstrual period was also not seen to be statistically significantly different between the three groups (Group B: 10+/-5.5, Group N: 9.1+/-4.1 versus Group L: 8.2+/-3, days). The number of abandoned cycles was higher in Group L (17% versus 11.8%: Group B and 11.3%: Group N) but this difference did not reach statistical significance. The clinical pregnancy rates per oocyte retrieval and per embryo transfer procedure were respectively, 31.1, 35% in Group B, 12.8, 14% in Group N versus 20.5, 23.7 in Group L and were not seen to be statistically significantly different even when ongoing pregnancy rates were compared. Apart from a statistically significantly greater incidence of allergic nasal reactions in the nafarelin group (P=0.001), all other side-effects were not shown to be statistically significantly different between the three groups. We conclude that a single dose of leuprorelin depot can be considered to be as an equally effective alternative to multiple doses of buserelin or nafarelin for pituitary desensitisation in women undergoing COH for IVF.

Value of measuring serum FSH in addition to serum estradiol in a coasting programme to prevent severe OHSS.

BACKGROUND: Withholding gonadotrophins (coasting) can reduce the risk of severe ovarian hyperstimulation syndrome (OHSS) in patients having assisted reproduction therapy. This requires daily serum estradiol (E(2)) measurements, which occasionally have been seen to decline suddenly and sharply. METHODS: To increase the sensitivity of the coasting programme we measured serum FSH in parallel with E(2) in patients at risk of developing OHSS. RESULTS: Out of a total of 1240 cycles, 106 were coasted and in 89 both serum E(2) and FSH were measured at least twice during the coasting period. One case of late severe OHSS was encountered in the study group. The serum FSH declined by a rate of 24.3 +/- 4.5% per day. Serum E(2) level reached a 'safe level' of <10,000 pmol/l when the serum FSH declined to 5 IU/l or less. CONCLUSION: The results from this study show that measuring serum E(2) and FSH can assist in predicting the point at which serum E(2) has declined to a level safe enough to administer the trigger HCG.

Prevention of severe ovarian hyperstimulation syndrome in IVF with or without ICSI and embryo transfer: a modified 'coasting' strategy based on ultrasound for identification of high-risk patients.

Ovarian hyperstimulation syndrome (OHSS) can be a severe and potentially life-threatening complication of ovarian stimulation for IVF. Coasting or withholding gonadotrophin stimulation relies on frequent estimation of serum oestradiol to identify patients at risk. A modified coasting protocol was developed in which identification of patients at risk of severe OHSS was based on ultrasound monitoring. Serum oestradiol concentrations were measured only in patients with >20 follicles on ultrasound (high risk). If serum oestradiol concentrations were <3000 pmol/l, the gonadotrophin dose was maintained; if concentrations were >/=3000 pmol/l but <13200 pmol/l and >/=25% of the follicles had a diameter of >/=13 mm, the gonadotrophin dose was halved; and if serum oestradiol concentrations were >/=13 200 pmol/l and >/=25% of the follicles had a diameter of >/=15 mm, patients were coasted. In the latter group, human chorionic gonadotrophin (HCG) 10000 IU was administered when at least three follicles had a diameter of >/=18 mm and serum oestradiol concentrations were <10000 pmol/l. Over a 10 month period, serum oestradiol concentrations were measured in 123 out of 580 cycles (24%) and in 50 cycles, gonadotrophins were withheld. Overall, moderate OHSS occurred in three patients (0.7%) and severe OHSS in one patient (0.2%). The pregnancy rates in the cycles where the gonadotrophin dose was reduced or withheld were 39.6 and 40% per cycle respectively; corresponding implantation rates were 30.7 and 25.6%. It is concluded that the modified coasting strategy is associated with a low risk of moderate and severe OHSS to a minimum without compromising pregnancy rates. Identification of patients at risk by ultrasound reduces the number of serum oestradiol measurements and thus inconvenience to patients as well as costs and workload.

Does laparoscopic ovarian diathermy affect the outcome of IVF-embryo transfer in women with polycystic ovarian syndrome? A retrospective comparative study.

Controlled ovarian stimulation for IVF and embryo transfer and outcome parameters were compared retrospectively in 31 women with clomiphene-resistant polycystic ovarian syndrome (PCOS). Of these women, 15 had previously undergone laparoscopic ovarian diathermy before IVF (group A, total 22 cycles) and 16 had not had surgical treatment (group B, total 24 cycles). No statistically significant differences were observed in the number of oocytes retrieved, although the number of embryos available for transfer was significantly higher in group B (7.1 +/- 3.8 versus 4.6 +/- 2.7, P < 0.01). The clinical pregnancy rate per embryo transfer appeared to be higher in group B (63.2 versus 41.2%), as did the miscarriage rate (66.7 versus 28.6%), giving an apparent improved ongoing pregnancy rate per embryo transfer in group A (29.4 versus 10.5%), but this was not statistically significantly different. The incidence of severe ovarian hyperstimulation syndrome (OHSS) was apparently higher in group B (4.2 versus 0%), but this difference was not statistically significant. No cases of severe OHSS were seen in group A. Ovarian diathermy does not appear to have a deleterious effect on controlled ovarian stimulation, and the outcome of IVF-embryo transfer may be beneficial in decreasing the risk of severe OHSS and improving the ongoing clinical pregnancy rate.

Does pretreatment with progestogen or oral contraceptive pills in low responders followed by the GnRHa flare protocol improve the outcome of IVF-ET?

PURPOSE: Women undergoing in vitro fertilization with low ovarian reserve and poor response to controlled ovarian hyperstimulation (COH) present a management dilemma. In a retrospective observational study, we compared the pretreatment use of the gestogen medroxyprogesterone acetate (10 mg twice daily from day 15 of the cycle for a minimum of 2 weeks) with an oral contraceptive pill (one tablet daily from day 4 of the cycle for a minimum of 3 weeks). METHODS: The criteria for inclusion in the study included one or more of the following: abandoned cycles due to poor response, fewer than four oocytes retrieved following a standard COH protocol, age > 39 years, and elevated basal serum follicle-stimulating hormone (FSH). Thirty-eight women received pretreatment with gestogen, and a similar number of women received pretreatment with the pill. The flare protocol was used in all treatment cycles combined with an individualized dose of human menopausal gonadotropin (hMG) (4-8 ampoules/day of 75 units FSH/ampoule) depending on previous response, age, and early follicular serum FSH level. Both groups were similar in mean age, duration of infertility, early follicular FSH levels, and the distribution of various aetiologies. RESULTS: Twenty-nine cycles were abandoned before oocyte retrieval, 15 (39.5%) in the pill group and 14 (36.8%) in the gestogen group, because of an inadequate ovarian response. The mean (+/- SD) number of ampoules (75 IU FSH/ampoule) of hMG used per cycle was similar in the pill and gestogen groups (59.7 +/- 19.3 vs. 70.2 +/- 29.4, respectively). There also was no difference seen in the numbers of oocytes retrieved (4.4 +/- 2.3 vs. 4.2 +/- 2.5), total number of embryos (2.5 +/- 2.4 vs. 2.2 +/- 1.1), or the number of embryos transferred (1.8 +/- 1.2 vs. 2.1 +/- 1.0) in the pill and gestogen groups, respectively. One pregnancy in each group resulted following embryo transfer in 22 women in the pill group and in 24 women in the gestogen group. CONCLUSIONS: We conclude that pre-IVF treatment with oral contraceptive pill or gestogen combined with the flare protocol in women at high risk of or with a history of poor ovarian response, as defined in this study, did not appear to result in an improvement in outcome of IVF-embryo transfer.

Superoxide dismutase activity in human follicular fluid after controlled ovarian hyperstimulation in women undergoing in vitro fertilization.

OBJECTIVE: To determine the activity of superoxide dismutase (SOD) and the total protein concentration in human preovulatory ovarian follicular fluid (FF) in relation to corresponding serum levels and the fertilization capacity of oocytes. DESIGN: Prospective, observational study. SETTING: Academic-based center for reproductive medicine. PATIENT(S): Twenty-eight female partners of infertile couples, 13 of whom were smokers, undergoing controlled ovarian hyperstimulation for IVF. INTERVENTION(S): Blood and follicular fluid samples were collected 34-36 hours after hCG administration. MAIN OUTCOME MEASURE(S): Levels of SOD activity and total protein concentrations. RESULT(S): Superoxide dismutase activity was present in all the FF studied and mean levels were statistically significantly higher than in serum. Total protein concentrations in serum were statistically significantly correlated with corresponding concentrations in FF. There was no difference in SOD activity between smokers and nonsmokers. Total protein concentrations in FF were marginally and statistically significantly lower in nonsmokers. Follicular fluid from patients whose oocytes did not become fertilized had a statistically significantly higher level of SOD activity than that from patients whose oocytes did become fertilized. CONCLUSION(S): Superoxide dismutase activity is present in FF and is higher than in serum. The degree of SOD activity is variable and seems to be inversely related to the fertilization of oocytes.

Effect of smoking on ovarian reserve and ovarian stimulation in in-vitro fertilization and embryo transfer.

The effect of cigarette smoking on ovarian reserve as measured by basal serum follicle stimulating hormone (FSH) concentrations, and by the response to a standard ovarian stimulation protocol, was examined retrospectively in 173 consecutive women (108 non-smokers and 65 smokers) undergoing in-vitro fertilization (IVF) and embryo transfer treatment. Women who smoked had a higher mean basal serum FSH concentration (P < or = 0.0001), in particular younger (<36 years) women, and required a statistically significantly higher mean dosage of gonadotrophins for ovarian stimulation than the non-smokers (48.1 +/- 15.6 versus 38.9 +/- 13.6 ampoules, 75 IU/ampoule; P < 0.0001). A lower mean number of oocytes was obtained in smokers than non-smokers (6.2 +/- 3.4 versus 11.1 +/- 6.3, oocytes P < or = 0.0001) and the rate of abandoned cycles (18.5 versus 8.5%) and total fertilization failure (18.5 versus 8.5%) was higher. The clinical pregnancy rate per cycle in smokers was 16.9% versus 21.3% in non-smokers but this was not statistically significant. In conclusion, cigarette smoking in women appears to significantly reduce their ovarian reserve and lead to poor response to ovarian stimulation at an earlier age.

Pinworms and postmenopausal bleeding.

The human pinworm Enterobius vermicularis is normally found within the human gastrointestinal tract. Pregnant females migrate out of their host's anus at night to lay their eggs perianally. As a consequence of this nocturnal migration some worms find their way into adjacent orifices, most commonly the female genitourinary tract, producing irritative symptoms such as vulvovaginitis. A case of pinworm infestation of the uterus presented as postmenopausal bleeding.

The obstetric outcome of in vitro fertilization and embryo transfer in women with congenital uterine malformation.

OBJECTIVE: Our purpose was to analyze 3 obstetric outcomes according to the various forms of congenital uterine malformation after in vitro fertilization and embryo transfer. STUDY DESIGN: We conducted a retrospective analysis of data from 24 patients with the following types of congenital uterine malformation: 6 unicomuate, 9 bicomuate, 5 septate, and 4 uterus didelphys. All patients underwent in vitro fertilization and embryo transfer at Boum Hall Clinic, a tertiary infertility referral center. RESULTS: Twenty-four patients conceived a total of 19 clinical pregnancies in 51 embryo transfer cycles. The clinical pregnancy rate was 19 of 51 (37.3%) per embryo transfer and 17 of 24 (70.8%) per patient. There were no significant differences in the clinical pregnancy rates when the various forms of uterine malformation were compared. There was a trend for the group with unicomuate uteri and uterus didelphys to have the highest rate of term delivery (6/9, 66.7%) and the lowest rate of first-trimester miscarriages (0/9, 0%) as compared with the group with septate and bicomuate uteri, in whom the term delivery rate was 1 of 10 (10%) and the spontaneous abortion rate was 3 of 10 (30%). The multiple pregnancy rate was 6 of 15 (40%) for women who had three embryos transferred, as compared with 0 in women who had two embryos or one embryo transferred. There was a high rate of preterm delivery (6/13, 46.2%) and cesarean section (10/13, 76.9%). CONCLUSION: In vitro fertilization and embryo transfer in women with congenital uterine malformation is associated with good pregnancy rates, and the patients should be counseled about the risks involved, in particular, the increased rate of preterm delivery and cesarean section.

Intracytoplasmic sperm injection improving embryo quality: comparison of the sibling oocytes of non-male-factor couples.

OBJECTIVE: Our objective was to investigate whether the quality of embryos developed after intracytoplasmic sperm injection (ICSI) is better than that of conventional IVF embryos. METHODS: Nine couples who previously achieved a normal rate of fertilization following IVF and four couples whose normal rate of fertilization was expected were involved in this study. The oocytes from those couples were randomly divided into two groups, group A by conventional insemination and group B by ICSI. The fertilization rate and quality of embryos were compared. RESULTS: Normal fertilization was achieved in 61% of the oocytes (83/136) after conventional insemination. In group B, 69% of the oocytes (99/144) achieved normal fertilization, although only 127 metaphase II oocytes were injected using the ICSI technique. More grade A embryos were obtained when the ICSI technique was used for fertilization than by conventional IVF (35.4 and 24.3%, respectively; P = 0.028). CONCLUSIONS: A similar fertilization rate can be achieved by ICSI in comparison with conventional IVF, when male factor is not involved. Embryos after ICSI have an improved quality.