Non-response to ovarian stimulation in normogonadotrophic, normogonadal women: a clinical sign of impending onset of ovarian failure pre- empting the rise in basal follicle stimulating hormone levels

The most important aspect of diminished ovarian reserve is the associated decline in reproductive potential. Assessment of ovarian reserve is mainly based on measurement of early follicular phase follicle stimulating hormone (FSH) concentration. The objective of this study was to report the identification of a group of 12 infertile women initially diagnosed as having unexplained or anovulatory infertility, who had a normal baseline hormonal profile and did not respond to repeated ovarian stimulation with gonadotrophins. All developed ovarian failure within a relatively short time span. Non-response to ovarian stimulation was defined by failure to achieve development of follicles >12 mm and failure to raise oestradiol concentration >350 pmol/l in two successive cycles of human menopausal gonadotrophin (HMG) doses of up to five ampoules per day for 5-8 days. Within a mean of 9 months following the failed attempts of ovarian stimulation the mean day 3 FSH concentrations rose from 5.4 +/- 2.7 IU/l to 53.5 +/- 19.7 IU/l. In these patients, day 3 FSH concentration failed to indicate the low ovarian reserve manifested only by lack of clinical response to treatment with gonadotrophins which was the first sign of impending ovarian failure. We conclude that women with normal early follicular phase serum FSH concentrations who do not respond to ovarian stimulation by HMG are at risk of developing ovarian failure within several months.      

Simultaneous evaluation of basal FSH and oestradiol response to GnRH analogue (F-G-test) allows effective drug regimen selection for IVF

To determine whether preliminary assessment of ovarian reserve by simultaneous evaluation of basal follicle-stimulating hormone (FSH) and oestradiol response to gonadotrophin releasing hormone (GnRH) analogue (F-G-test) can be used to tailor individually the drug regimen for ovarian stimulation, the in-vitro fertilization (IVF) results of 238 patients were retrospectively analysed. Sixty-two women with abnormal response to the test (DeltaE2 <180 pmol/l and/or FSH >9.5 mIU/ml) had commenced buserelin nasal spray in the mid-luteal phase and discontinued it on cycle day 1. Ovarian stimulation was started on cycle day 3 with 375 IU/day of gonadotrophin. Fifty-three patients completed the treatment cycle (group A). A total of 176 women with normal response to the test (DeltaE2 >180 pmol/l and FSH <9.5 mIU/ml) had continued the GnRH analogue throughout the stimulation cycle and a starting dose of 225 IU/day of gonadotrophin was used from cycle day 3. A total of 158 patients completed the treatment cycle (group B). Group A had significantly higher age (34.9 +/- 4.2 versus 33.2 +/- 4.2) (P < 0.05) and basal FSH (9.2 +/- 3.8 versus 7.0 +/- 2.2) (P < 0.05) and required a higher total dose of gonadotrophin. The numbers of oocytes retrieved and embryos transferred were significantly lower. However, fertilization, clinical pregnancies, and implantation rates were similar in both groups. It was concluded that simultaneous evaluation of basal FSH and oestradiol response to GnRH analogue can be useful in identifying subcategories of women with reduced ovarian reserve who may benefit from reduced GnRH analogue administration and a higher starting dose of gonadotrophin.     

Antral follicle count and FSH concentration after clomiphene citrate challenge test in the prediction of ovarian response during IVF treatment

BACKGROUND: We compared: (i) antral follicle count (AFC) in the early follicular phase, after the clomiphene citrate challenge test (CCCT) and before ovarian stimulation following pituitary down-regulation; and (ii) age of women, body mass index, basal and stimulated serum FSH concentrations and AFC in predicting the ovarian response of infertile women aged <40 years with basal FSH <10 IU/l on recruitment in their first IVF cycle. METHODS: Two months prior to the treatment cycle, AFC and basal FSH concentration were determined on day 2-3 of a spontaneous period and on day 10 after CCCT. All women received a standard stimulation regimen. Ovarian response was represented by the number of oocytes, serum estradiol, the duration and dosage of gonadotrophins. RESULTS: There was no significant difference between basal, stimulated and down-regulated AFC. AFC achieved the best predictive value in relation to the number of oocytes, followed by combined FSH concentration (sum of the two FSH concentrations) and age of women. Both basal AFC and combined FSH concentration were predictive factors of serum estradiol concentration, whereas stimulated FSH concentration was predictive of the total dosage of gonadotrophins. CONCLUSION: Combined FSH concentration after CCCT provides additional information in predicting ovarian response.     

The synergistic effects of clomiphene citrate and human menopausal gonadotrophin in the folliculogenesis of stimulated cycles as assessed by the gonadotrophin-releasing hormone antagonist Nal-Glu.

Clomiphene citrate (CC), alone or in combination with exogenous gonadotrophins, has been widely used in ovulation induction. CC promotes endogenous release of gonadotrophins, yet when used in combination with exogenous gonadotrophins, its contribution to folliculogenesis is difficult to assess. In order to determine the contribution of CC-induced endogenous gonadotrophin production to the overall ovarian stimulation in cycles treated with CC/human menopausal gonadotrophin (HMG), Nal-Glu, a gonadotrophin-releasing hormone (GnRH) antagonist was administered. Fertile women (n = 10) undergoing ovarian stimulation and oocyte aspiration for the sole purpose of gamete donation were studied. Five women received CC (100 mg daily for 5 days) in conjunction with pure follicle stimulating hormone (FSH) 150 IU daily. Five women received HMG alone. Nal-Glu (50 micrograms/kg/day) was administered intramuscularly to both groups when the leading follicles reached a mean diameter of 16 mm. Human chorionic gonadotrophin (HCG) 10,000 IU was given when the largest follicles reached a mean diameter of 20-22 mm. A significant fall in serum oestradiol levels was observed in women given CC/FSH (37.9 +/- 7.3%) within the first 24 h of Nal-Glu administration. Serum luteinizing hormone (LH) decreased greater than 20% within 24 h of Nal-Glu administration and remained low throughout the rest of the treatment. No decrease in oestradiol levels was noted in cycles receiving HMG alone. With supplemental FSH, falling oestradiol levels in CC/FSH cycles rebounded and continued to rise until the day after HCG administration. Despite a drop in oestradiol in CC/FSH cycles, the aspirated oocytes exhibited no untoward effects. The fertilization and cleavage rates were similar, and pregnancies occurred in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

High pregnancy rates and successful prevention of severe ovarian hyperstimulation syndrome by 'prolonged coasting' of very hyperstimulated patients: a multicentre study

In a multicentre trial, 65 in-vitro fertilization (IVF)-embryo transfer cycles were severely hyperstimulated. Instead of cancelling the cycle, gonadotrophins were withheld for a 'coasting period' until serum oestradiol concentrations had dropped below 10,000 pmol/l (mean 4.3 days), and then human chorionic gonadotrophin was administered. Four cycles were cancelled and there were 61 oocyte aspirations. A total of 103 fresh embryos was transferred to 53 patients, resulting in a pregnancy rate of 42% per started cycle (51% per embryo transfer), with an implantation rate of 31%. Only one patient developed severe ovarian hyperstimulation syndrome (OHSS). Four patients developed moderate OHSS. In all, two patients were hospitalized for OHSS. In order to optimize the coasting procedure, it seems important that each IVF centre identifies its appropriate cut-off limits for serum oestradiol concentrations and follicle size for initiating and ending of the coasting period. Correctly handled, it seems to be a major advance in the search for improved stimulation policies for high-responders.     

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.     

Ovarian stromal blood flow in the prediction of ovarian response during in vitro fertilization treatment

BACKGROUND: This study evaluated the role of ovarian stromal blood flow in the prediction of the ovarian response of infertile women by comparing age of women, body mass index (BMI), basal FSH concentration, antral follicle count (AFC) and ovarian stromal blood flow indices measured by power Doppler in two-dimensional ultrasound. Patients were aged <40 years with basal FSH <10 IU/l on recruitment for IVF treatment. METHODS: All received a standard regimen of ovarian stimulation in their first IVF cycle. AFC, pulsatility index, resistance index and peak systolic blood flow velocity of ovarian stromal vessels were determined on the second day of the treatment cycle prior to ovarian stimulation. Ovarian response was represented by the number of oocytes, serum oestradiol, and the duration and dosage of gonadotrophins. RESULTS: A total of 136 women were included in the analysis. Basal FSH concentration achieved the best predictive value in relation to the number of oocytes obtained, followed by AFC and BMI. AFC was the only predictive factor of serum oestradiol concentration on the day of HCG while BMI was predictive of the gonadotrophin dosage. CONCLUSION: Ovarian stromal blood flow indices measured by power Doppler ultrasound had no predictive value for the ovarian response.     

Elevated FSH concentrations in imminent ovarian failure are associated with higher FSH and LH pulse amplitude and response to GnRH

Imminent ovarian failure (IOF) in women is characterized by regular menstrual cycles and elevated early follicular phase FSH. This study explored underlying neuroendocrine causes of elevated FSH concentrations on day 3 of the menstrual cycle. The characteristics of episodic secretion of FSH and LH, the pituitary response to gonadotrophin-releasing hormone (GnRH), plasma oestradiol, and dimeric inhibin A and inhibin B on day 3 were compared in 13 women with elevated FSH concentrations (>10 IU/l) and 16 controls. FSH amplitudes were higher in the IOF group than in the controls (P < 0. 0001). The FSH pulse frequency did not differ between groups. The FSH response to GnRH was higher in the IOF patients than in the controls (P < 0.0001). Mean LH, LH amplitude and LH response to GnRH were higher in the IOF group, but LH pulse frequency did not differ between the groups. Concentrations of inhibin A and inhibin B were lower in the IOF group, while oestradiol showed no differences. We concluded that in women with IOF, the pituitary is more sensitive to GnRH. This leads to higher FSH and LH pulse amplitudes which underlie the elevated FSH concentrations in the early follicular phase.     

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.     

'Early coasting' in patients with polycystic ovarian syndrome is consistent with good clinical outcome

BACKGROUND: Coasting can be an effective strategy for the prevention of severe ovarian hyperstimulation syndrome (OHSS) during ovarian stimulation. However, OHSS may still occur in cases of excessive follicular response (i.e. >10 follicles/ovary and serum estradiol (E(2)) concentration >3000 pg/ml). Furthermore, prolonged coasting may result in a reduction of the oocyte retrieval rate and embryo quality. This pilot study investigates the potential of withholding gonadotrophins at an earlier stage, with the intention of minimizing these risks. METHODS: Gonadotrophin injections were withheld for a fixed period of 3 days once the leading follicle was 15 mm, whilst continuing pituitary down-regulation in 102 obese patients with polycystic ovarian syndrome (PCOS) in whom there was evidence of excessive ovarian follicular response (>10 follicles per ovary and serum E(2) >1500 but <3000 pg/ml). The events of ovarian stimulation, embryological and clinical outcomes were studied prospectively. RESULTS: The mean number of ampoules (75 IU per ampoule) of high purity (hp) FSH was 23.2. The mean serum E(2) level on coasting day 1 was 1943.7 and 2169.2 pg/ml on the day of HCG administration. Normal fertilization and cleavage rates were obtained despite early withdrawal of hpFSH in the obese PCOS patients, being 73.9 and 87.7% respectively. The clinical pregnancy rate was 45.1%. There were no cases of severe OHSS. Four patients suffered pregnancy-associated late-onset moderate OHSS. CONCLUSIONS: This pilot study suggests that withholding gonadotrophins at an earlier stage in patients with excessive ovarian follicular response at anticipated risk of developing severe OHSS in the course of ovarian stimulation is consistent with good embryological and clinical outcome in IVF and ICSI treatment cycles.     

Synchronization of endogenous and exogenous FSH stimuli in controlled ovarian hyperstimulation (COH)

We have previously observed that exogenous oestradiol can delay the intercycle increase in plasma follicle stimulating hormone (FSH). The increase in plasma FSH that follows discontinuation of exogenous oestradiol peaks after 3 days. We have now studied the possibility of using exogenous oestradiol to synchronize the increase in endogenous FSH with the onset of human menopausal gonadotrophin (HMG) treatment in controlled ovarian hyperstimulation (COH). A total of 30 women aged 35.1+/-6.3 years (mean+/-SD) undergoing ovarian stimulation received 2 mg of oestradiol valerate twice daily starting on day 25 of the previous menstrual cycle until the first Tuesday following menses. Ovarian stimulation was initiated 3 days later. On the last day of oestradiol treatment, plasma oestradiol, FSH and luteinizing hormone (LH) (mean+/-SEM) were 566+/-53 (pmol/l), 3.8+/-0.4 (IU/l) and 5.5+/- 0.8 (IU/l) respectively. After 3 days, the FSH and LH (mean+/-SEM) had increased to 6.7+/-0.7 and 6.9+/-0.7 (IU/l) respectively while oestradiol decreased to 251+/-29 (pmol/l). The mean number (+/-SEM) of HMG ampoules used was 25.1+/-2.7 and treatment lasted 11.3+/-0.9 days. Five women became pregnant for a pregnancy rate (ongoing) of 19 (15)%. If all women aged >40 years (six women who did not become pregnant) were excluded from analysis the pregnancy rate (ongoing) was 24 (19%). These results indicate that exogenous oestradiol can safely be used for the synchronization of endogenous and exogenous FSH stimuli in COH. This approach provides the practical advantage of permitting an advanced timing of the onset of COH treatments when gonadotrophin- releasing hormone (GnRH) agonists are not used, which improves treatment convenience for patients and team members alike. Further development of this model may enable control of the onset of natural cycles which may find practical applications for timing assisted reproductive techniques (intrauterine insemination or in-vitro fertilization) in the natural cycle.      

Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series

In patients with poor response to ovarian stimulation with gonadotrophins, growth hormone (GH) is sometimes used to increase paracrine insulin-like growth factor-1 (IGF-1) effect. We postulated that dehydroepiandrosterone (DHEA) administration to poor responders would augment gonado-trophin effect via a similar mechanism. Baseline ovarian stimulation response to a cycle with DHEA in five healthy non-smoking women <41 years old was compared with day 3 FSH <20 mIU/ml. All had documented poor response to vigorous gonadotrophin administration. After day 2 ultrasounds, DHEA-sulphate (DHEA-S), FSH, human chorionic gonadotrophin (HCG), and testosterone were measured, and the women were given 80 mg/day of oral micronized DHEA for 2 months. While still on DHEA, they underwent ovarian stimulation with FSH given i.m. twice a day, and HCG (10 000 IU) at follicular maturity, followed by intrauterine insemination. Cycle parameters assessed were peak oestradiol, and peak oestradiol/ampoule. The DHEA/ovarian stimulation cycles occurred between 4 and 24 months after the control cycles. After 2 months DHEA treatment, DHEA-S increased to 544 +/- 55 microg/dl, and testosterone increased to 67.3 +/- 6.1 ng/dl. All five subjects (six cycles; one subject had two DHEA cycles) had increased responsiveness; peak oestradiol concentrations increased from 266.3 +/- 69.4 pg/ml to 939.8 +/- 418.9 pg/ml. The oestradiol/ampoule ratio increased in all six cycles, by a mean of 2.94 +/- 0.50 fold (P = 0.012). One of the cycles resulted in a delivered twin pregnancy. In this small series, DHEA improved response to ovarian stimulation even after controlling for gonadotrophin dose. Supplemental DHEA treatment during ovarian stimulation may represent a novel way to maximize ovarian response.     

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.     

Studies on the influence of gonadotrophin levels in the early follicular phase on the ovarian response to stimulation

The gonadotrophic regulation of folliculogenesis has been extensively investigated but little attention has been paid to the influence of early follicular phase levels of endogenous FSH and the FSH/LH ratio when planning ovulation stimulation therapy for IVF. The influence of these factors was investigated in the three studies reported in this paper. A fixed schedule of ovulation stimulation therapy which employed standard treatment regimens, irrespective of the ovarian response, was used to eliminate variation due to treatment factors. Cycles were pretreated with an oestrogen-progestogen contraceptive pill or a progestogen (norethisterone). It was found that both oestrogen-progestogen and progestogen alone decreased the plasma FSH level, although the FSH/LH ratio was significantly reduced only by oestrogen-progestogens. In clinical IVF studies, oestrogen-progestogen pretreatment was associated with a significant reduction in the preovulatory concentration of oestradiol in plasma and the number of aspirated follicles, compared to norethisterone. The administration of FSH for 2 days following oestrogen-progestogen pretreatment and prior to the fixed schedule of ovulation stimulation normalized ovarian steroidogenesis and follicular development. Early follicular phase supplementation with FSH had no influence on progestogen pretreated cycles. The final experiment investigated the influence of FSH/LH levels in the early follicular phase on the outcome of ovarian stimulation. The preovulatory oestradiol concentration was reduced when baseline FSH/LH levels were low compared with when these values were high. Administration of FSH for 2 days in the early follicular phase improved the preovulatory level of oestradiol when baseline FSH/LH was low but had no effect when baseline FSH/LH levels were high.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endocrinology: Recombinant human follicle-stimulating hormone and ovarian response in gonadotrophin-deficient women

Seven women suffering from hypogonadism due to previous hypophysectomy,isolated gonadotrophin deficiency, or Kallman's syndrome [medianage 39 years (range 24–45)] volunteered to participatein a study to assess ovarian response following multiple-doseadministration of recombinant human follicle-stimulating hormone(rhFSH; Org 32489). Baseline serum FSH and luteinizing hormone(LH) concentrations were 0.25 (<0.05–1.15) IU/l and0.06 (<0.05–0.37) IU/l, respectively. Subjects receiveddaily i.m. injections of rhFSH for 3 weeks (week 1: 75 IU/day,week 2: 150 IU/day, week 3: 225 IU/day). Blood sampling andsonographic investigations were performed on alternate days.Steady-state FSH concentrations were reached 3–5 daysafter alterations of the doses administered. Maximum FSH concentrationswere between 7.1 and 11.8 IU/l, whereas serum LH concentrationsremained unchanged. Due to absent follicle development and lackof a rise in immunoreactive inhibin (INH) (response failurepossibly due to early ovarian failure or resistant ovary syndrome)in two subjects, analysis of ovarian response was restrictedto five volunteers. Serum androstenedione levels showed no significantchanges during rhFSH administration. Although serum immunoreactiveINH concentrations reached normal late follicular values [659(388–993) IU/l], serum oestradiol revealed only a minorincrease [77 (18–210) pmol/I]. Moreover, growth of (multiple)ovarian follicles was observed up to pre-ovulatory sizes (>15mm) in these patients. It may be concluded from the presentstudy that (i) rhFSH exhibits no intrinsic LH activity; (ii)rhFSH stimulation in hypogondotrophic women resulted in an immunoreactiveINH rise which was similar to that in normal women, whereasin contrast only a minor increase in oestradiol concentrationswas observed (suggesting normal granulosa cell function andlow availability of androgens as a substrate for aromatization);(iii) despite the minimal oestrogen increase, ovarian folliclesdeveloped normally to the pre-ovulatory stage.     

Induction of follicular growth and production of a normal hormonal milieu in spite of using a constant low dose of luteinizing hormone in women with hypogonadotrophic hypogonadism

This study was designed to examine ovarian performance, i.e.follicular growth, normal steroidogenesis and luteal phase function,following the administration of multiple increasing doses ofhuman follicle stimulating hormone (FSH) with a constant lowdose of luteinizing hormone (LH) in women with isolated hypogonadotrophichypogonadism. Human meno–pausal gonadotrophin (HMG) wasused in the first treatment cycle, starting with 150 IU of LHand 150 IU of FSH per day, for 7 days. The dose was increaseddaily with 75 IU of LH and 75 IU of FSH for another 7 days ifno response was detected by serial ultrasound measurements andserumoestradiol determinations. In the second treatment cycle,a constant dose of 75 IU of LH (using HMG) was administeredper day and up to 150 IU of FSH (using urofollitrophin) wassupplemented. If no response was detected after 7 days of treatment,the dose of FSH was increased. For the final stage of ovulationinduction, human chorionic gonadotrophin (HCG) was administeredin the presence of at least one follicle >17 mm in diameterbut with no more than three follicles >16mm in diameter.To verify the adequacy of the luteal phase, a pharmacokinetic/pharmacodynamicstudy of -HCG, oestradiol and progesterone was performed followingthe second treatment cycle only. Ovarian stimulation using aconstant dose of 75 IU of LH and increasing doses of FSH upto 225 IU, resulted in normal follicular growth and hormonalmilieu. Both women showed normal luteal phase oestradiol andprogesterone production and both women conceived following thesecond treatment cycle     

The effect of gonadotrophins with differing LH/FSH ratios on the secretion of the various species of inhibin in women receiving IVF

We have measured secretory patterns of inhibin A, B, total alpha inhibin, pro-alphaC inhibin and oestradiol in women following pituitary suppression who were randomised into two groups to receive either urinary gonadotrophin (25:75 IU/ampoule of luteinizing hormone (LH) and follicle stimulating hormone (FSH; Normegon; n = 11) or recombinant (r)FSH (75 IU/ampoule of FSH alone, n = 16). The women were of similar age (approximately 33 years) and length of infertility (approximately 4 years) and had a normal endocrine evaluation. Plasma FSH, LH, oestradiol, inhibin A, B, pro-alphaC and total alpha inhibin were measured by immunoassay prior to and following gonadotrophin stimulation. Immunoactive FSH, LH and oestradiol blood concentrations following pituitary down regulation were similar in the two groups being <2.0, <3.6 IU/l and <82 pmol/l respectively. The units of FSH given (2230 versus 2764 IU; Normegon versus rFSH), duration of treatment (9.1 versus 9.4 days) and number of follicles of > or =14mm on the day of human chorionic gonadotrophin (HCG) administration (17 versus 14) were also similar. Inhibin A or B concentrations rose similarly during Normegon or rFSH administration, peaking at days 9-11. Total alpha and pro-alphaC inhibin concentrations were lower (P < 0.05) in the rFSH group during days 10 and 11 of treatment being 18.9 +/- 15.9 ng/ml (Normegon) and 4.6 +/- 2.8 ng/ml (rFSH) for total alpha inhibin and 8.5 +/- 6.8 ng/ml (Normegon) and 2.8 +/- 1.6 ng/ml (rFSH) for pro-alphaC inhibin on day 10. Overall, higher total alpha inhibin concentrations were associated with more mature follicles and oocytes, greater fertilization rates and better quality embryos. We conclude that inhibin A and B secretion was similar in both groups and is primarily controlled by FSH, whereas total alpha inhibin and pro-alphaC increased preferentially in the Normegon group over the rFSH group, indicating that they are, in part, stimulated by LH.     

Doubling the human menopausal gonadotrophin dose in the course of an in-vitro fertilization treatment cycle in low responders: a randomized study

The effect of doubling the human menopausal gonadotrophin (HMG)dose in the same treatment cycle in which the ovarian responseafter 5 days of ovarian stimulation with 225 IU/day is ‘low’,has been evaluated in a prospective randomized study. Forty-sixpatients met the ultrasound and oestradiol criteria for enrolmentin the study, one patient participated twice. In 22 patientstreatment was continued with 225 IU HMG/day and in 25 patientsthe HMG dose was increased to 450 IU/day. No effect of doublingthe HMG dose was found on the length of the ovarian stimulation,peak oestradiol values, number of follicles 11 and 14 mm indiameter respectively on ultrasound on the day of HCG administration,number of cancelled cycles, number of oocytes at follicularpuncture and the number of patients with 3 oocytes at retrieval.It is concluded that doubling the HMG dose in the course ofan IVF treatment cycle is not effective in enhancing ovarianresponse in low responders. This is in accordance with currenttheories on follicular growth, which state that follicular recruitmentoccurs only in the late luteal and early follicular phase ofthe menstrual cycle.     

Lack of correlation between maximum early follicular phase serum follicle stimulating hormone concentrations and menstrual cycle characteristics in women under the age of 35 years

The gradual increase in follicle stimulating hormone (FSH) concentrations in women approaching menopause results from the depletion of the ovarian follicular pool, a process referred to as 'ovarian ageing'. This study investigates whether variable endogenous FSH concentrations, as have been observed in normo-ovulatory young women, are related to menstrual cycle characteristics, including predictors of ovarian ageing. Serum concentrations of immunoreactive FSH, oestradiol, and inhibin-A and inhibin-B were measured, and follicular growth was assessed by transvaginal ultrasound throughout the follicular phase in 39 healthy volunteers (20-35 years) with regular menstrual cycles. Median serum FSH concentration on cycle day 3 was 5.1 IU/l (range 3.6-11.2), and median maximum follicular phase FSH was 6.2 IU/l (range 4.3-11.2), observed on cycle day 6 (range 2-15). Maximum FSH concentrations were not correlated with age or cycle length, nor with maximum inhibin-B. The number of small (<10 mm) antral follicles on cycle day 3 was 11 (range 4-21) and was not correlated with age, nor with maximum FSH. Inhibin-A remained low until a significant rise on cycle day 9 (range 3-12), which was significantly correlated with the late follicular rise in oestradiol (r = 0.56, P = 0.01). These observations indicate a lack of correlation between maximum follicular phase serum FSH concentrations and parameters of ovarian ageing in women under the age of 35 years. In addition, FSH concentrations assessed on cycle day 3 represent an underestimation of maximum early follicular phase FSH. Distinct individual differences in intra-ovarian modification of FSH action, resulting in differences in the FSH threshold for stimulation of ovarian function, may be operative.      

Effects of exogenous LH administration during ovarian stimulation of pituitary down-regulated young oocyte donors on oocyte yield and developmental competence

BACKGROUND: The role of exogenous LH supplementation in ovarian stimulation is a matter of debate. Here we evaluate the impact of exogenous LH on oocyte yield and developmental competence in an oocyte donation programme. METHODS: Oocyte donors were randomized (computer-generated randomization list) to groups stimulated with FSH alone or with a combination of FSH and LH after pituitary down-regulation with a GnRH agonist administered in the mid-luteal phase. RESULTS: In donors with deep suppression of pituitary LH (<1 IU/l) before the beginning of ovarian stimulation, the inclusion of exogenous LH resulted in an increase in the number of mature oocytes and good-quality zygotes and embryos as well as higher implantation rates when compared with stimulation with FSH alone. In contrast, the inclusion of exogenous LH in the stimulation of donors with pre-stimulation serum LH of >or=1 IU/l impaired embryo morphology and lowered the implantation rate, although it increased the number of metaphase II oocytes. CONCLUSIONS: The inclusion of exogenous LH to the ovarian stimulation protocol can have beneficial or detrimental effects on oocyte yield and quality, depending on the level of endogenous LH. These data support the concept of a 'window' for LH requirement in ovarian stimulation.