Blunted LH surge after HCG administration in cycles superovulated for in-vitro fertilization

The preovulatory pattern of serum luteinizing hormone (LH) was investigated in cycles superovulated for in-vitro fertilization (IVF). The method used was immunoradiometric assay which shows no cross-reactivity with human chorionic gonadotrophin (HCG) at concentrations usually found after HCG administration. Of the 245 cycles stimulated by clomiphene citrate + human menopausal gonadotrophin, an endogenous LH surge was observed in 29.8% of the patients shortly prior to the HCG injection. In the post-HCG period, 49.4% of the cycles exhibited a blunted LH rise, whereas in the remaining 20.8% the LH level did not exceed twice the mean preovulatory value. According to the oestradiol-17 beta (E2) and progesterone concentrations, different hormonal patterns were found in patients with pre-HCG and post-HCG elevation of LH. However, the occurrence of a blunted LH surge following HCG administration cannot be attributed to different, HCG-induced secretory patterns of progesterone. There were no significant differences in clinical parameters, the pregnancy rate was slightly but not significantly higher (19.0%) in the post-HCG LH surge group than in the two other groups (13.7%). It is presumed that various factors may contribute to the suspension of preovulatory LH suppression. The possible beneficial influence of a post-HCG surge of LH requires further investigation.     

Delayed occurrence of an LH surge after HCG administration during ovarian stimulation with gonadotrophins: effect of LHRH treatment

Previous studies have shown the appearance of a spontaneous luteinizing hormone (LH) surge after human chorionic gonadotrophin (HCG) administration in human menopausal gonadotrophin (HMG)/HCG-stimulated menstrual cycles. In this report we investigated the effect of leuprolide acetate, a long-acting luteinizing hormone releasing hormone (LHRH) agonist, on the occurrence of these post-HCG rises in serum LH. Two groups of patients were included. Group 1: 10 patients receiving HCG as a part of an HMG/HCG protocol for induction of follicular development in an IVF/GIFT program and Group II: 10 patients treated as Group I, but receiving the LHRH agonist leuprolide acetate to inhibit gonadotrophin secretion prior to and during ovarian stimulation. In Group I, none of the patients showed a surge prior to HCG administration. However, an LH surge following HCG treatment was apparent in four patients (40%). Pregnant patients (2/10) had low mean levels (less than or equal to 2.5 mIU/ml LH) in the follicular phase and showed no LH surge after HCG. In Group II, baseline levels of serum LH were reduced significantly (mean, 1.4 +/- 0.1 mIU/ml; P less than 0.001) compared to Group I. No patient showed an LH surge either before or after HCG administration and the occurrence of pregnancy was higher (6/9 transfers) than in Group I. In spite of the differences in pregnancy rates, the combined therapy versus HMG therapy showed no significant difference in number of oocytes collected or serum oestradiol levels. This suggests that high levels of serum LH, whether prior to or after HCG administration, may have a detrimental effect on the establishment of pregnancy despite adequate follicular growth.(ABSTRACT TRUNCATED AT 250 WORDS)     

Accumulation of human chorionic gonadotrophin in the serum of patients during in-vitro fertilization treatment cycles with Pergonal

We examined the possible contribution of human chorionic gonadotrophin(HCG) in Pergonal to the serum luteinizing hormone (LH)-likebioactivity in 10 patients (median age32 years, range 28–38)with tubal infertility who were undergoing in-vitro fertilization(IVF), together with 19 controls (median age30 years, range21–43). IVF patients were treated with clomiphene (50mg twice daily) over days 2–6 and Pergonal (150 IU i.m.)daily from day 5 until at least day 10. Serum LH was measuredby fluoro-immunometric assay (I-LH) and in-vitro Leydig cellbioassay (B-LH). Serum HCG was measured by fluoro-immunometricassay. The data were analysed by paired two-tailed t-test, followinglogarithmic transformation. From days 1–5, there was anincrease in serum B-LH (mean, 95% confidence intervals givenin parentheses) from 8.3 (6.8, 10.2) IU/1 to 11.7 (9.8, 13.9)IU/1 [P= 0.004], and in serum I-LH from 4.5 (3.7, 5.4) IU/1to 5.4 (4.6, 6.3) IU/1 [P= 0.002]. From days 5–8, therewas a rise in B-LH to 16.6 (12.6, 21.9) IU/1 [P= 0.023]. Therise in I-LH to 6.3 (5.1, 7.8) IU/1 [P= 0.081] failed to reachsignificance. Furthermore, serum HCG was <<0.75 IU/1 untilafter Pergonal was administered on day 5, then rose to a plateauon day 8 at 1.2(0.8, 1.6) IU/1. Serum HCG in the controls remained<<0.75 IU/1 throughout. We conclude there is a disproportionateincrease in serum B-LH compared to I-LH from days 5–8,corresponding with a rise in serum HCG and the commencementof treatment with Pergonal. The HCG in Pergonal may be contributingto an undesirable rise in serum LH-like bioactivity, which mightreduce the success rate of IVF.     

Modulation of folliculogenesis and steroidogenesis in women by graded menotrophin administration

BACKGROUND: To test the effects of progressively decreasing dosages of exogenous LH we combined various amounts of HMG, containing FSH, LH and HCG, and highly purified (HP) FSH to treat 120 GnRH agonist-suppressed infertile female patients as candidates for controlled ovarian stimulation (COS). METHODS: Subjects were randomly assigned to four treatment groups that received the following daily i.m. gonadotrophin regimens: A, FSH 150 IU only; B, FSH 150 IU and LH activity 37.5 IU; C, FSH 150 IU and LH activity 75 IU; D, FSH 150 IU and LH activity 150 IU. FSH dose adjustments were allowed only after the 14th treatment day. Monitoring included transvaginal ultrasound at 2-day intervals and daily determinations of LH, FSH, estradiol (E(2)), progesterone, testosterone and HCG. RESULTS: Duration of COS was significantly shortened in patients receiving at least 75 IU daily of LH activity. Small (<10 mm diameter) pre-ovulatory ovarian follicle occurrence was inversely correlated with LH activity dose administered (r = -0.648, P < 0.0001) and serum HCG levels (r = -0.272, P < 0.01) but not to serum LH levels. Serum testosterone levels were positively correlated to the LH activity dose administered (r = 0.313, P < 0.001), while serum progesterone levels were positively correlated to the FSH dose administered (r = 0.447, P < 0.00001) but not to the LH activity dose administered. CONCLUSIONS: Firstly, HCG content considerably contributes to HMG activity; secondly, menotrophin LH activity content can reduce in a dose-dependent manner the occurrence of small pre-ovulatory follicles; and finally, contrary to common belief, enhanced FSH stimulation rather than LH activity appears to cause premature follicle luteinization during COS.     

Prolactin and gonadotrophin interactions on progesterone formation in cultured human granulosa cells

Human granulosa cells were isolated from preovulatory folliclesduring cycles stimulated with HMG-HCG or clomiphene-HMG-HCGor from unstimulated cycles. The cells were cultwed for 6–8days in medium M199 containing fetal calf serum under 5% CO₂in air. Highly purified human prolactin and human chorionicgonadotrophin were added alone or in combination to the cultures,and the content of steroids in the medium was measured everysecond day, utilizing conventional RIA techniques. In the presenceof HCG the formation of progesterone (P) increased 3–5-foldover the control level with maximal effect after 4 days. Incells derived from clomiphene-HMG-HCG stimulated cycles, prolactinper se did not influence basal P formation but reduced the stimulatoryeffect of HCG. This was only seen in granulosa cells from follicles< 20 mm in diameter. In experiments with Forskolin, an adenylatecyclase activator, P formation was stimulated and the stimulationwas counteracted by the concomitant presence of prolactin, indicatingthat prolactin did not interfere with the LH-HCG receptor. Incells from smaller follicles, or in cells from follicles aspiratedfrom the natural cycle prior to the endogenous LH peak, P formationwas stimulated by HCG but the addition of prolactin did notreduce this stimulatory effect. The results are discussed inrelation to earlier reports on prolactin effects in vitro bothon laboratory animals and human material.     

Recovery of corpus luteum function after prolonged deprivation from gonadotrophin stimulation

Three women with hypogonadotrophic hypogonadism, all desiringpregnancy, participated in a prospective open study attemptingto assess the ability of the human corpus luteum to recoverafter 7 days of deprivation from gonadotrophin stimulation.Follicular growth was induced by gonadotrophins. An endogenousluteinizing hormone (LH) surge was induced by the s.c. injectionof a gonadotrophin-releasing hormone agonist For luteal support,10 mg/day oral medroxyprogesterone acetate were given for 7days, after which a single i.m. injection of human chorionicgonadotrophin (HCG) was administered. Monitoring during thefollicular phase consisted of daily measurements of serum oestradiol,LH and follicle stimulating hormone (FSH) concentrations, andof follicular growth by trans-vaginal ultrasonography. Duringthe luteal phase, monitoring consisted of measurements of serumconcentrations of LH, FSH, oestradiol, progesterone, 17-hydroxy-progesteroneand -HCG. Ovulation and luteinization occurred in two patients,demonstrated by transient marked increases in serum progesteroneand 117-hydroxy-progesterone concentrations which decreasedto basal pre-ovulatory values and increased again followingthe administration of HCG 7 days later. In the third patient,ovulation and luteinization did not occur, and the subsequentadministration of HCG did not result in an increase in progesteroneconcentration. Of the two patients who ovulated, one conceivedand the second had a luteal phase of 15 days duration. Our preliminaryresults suggest that the human corpus luteum can be ’rescued‘and can function normally after 7 days of deprivation from gonadotrophinstimulation in patients with hypogonadotrophic hypogonadism.     

Is waiting for an endogenous luteinizing hormone surge and/or administration of human chorionic gonadotrophin of benefit in intrauterine insemination?

This retrospective study was undertaken to investigate the observation that the probability of pregnancy was higher with intrauterine insemination (IUI) when human chorionic gonadotrophin (HCG) was administered after the onset of the luteinizing hormone (LH) surge. A total of 219 patients who had 524 IUI cycles was included in this study. IUI cycles were divided into three groups: group 1, patients who had an endogenous LH surge but no HCG; group 2, patients given HCG after an endogenous LH surge was observed; and group 3, patients given HCG before an endogenous LH surge could be demonstrated. The overall clinical pregnancy rate was 16%. Forty-two (19.2%) patients had 91 cycles with their partner's semen, while 177 (80.8%) used donor semen in 433 cycles; clinical pregnancy rates were 12.1% and 16.9% respectively. There was no significant difference in pregnancy rate per cycle between patients in group 1 (12.7%) compared with those in groups 2 (15.6%) or 3 (20.5%). We could not establish any benefit in waiting for a spontaneous LH surge before administering HCG in the presence of a mature follicle(s) in this study. This strategy avoids further monitoring to detect the LH surge, allowing treatment to be planned for a time convenient to the patient.     

Endocrine responses to gonadotrophins after LHRH agonist administration on cycle days 1-4: prevention of premature luteinization

A treatment regime comprising an intranasally administered luteinizinghormone-releasing hormone (LHRH) agonist analogue (buserelin)on cycle days 1–4, followed by gonadotrophin administration[follicle stimulating hormone (FSH)/human menopausal gonadotrophin(HMG)] resulted in identical oestradiol (E₂) responses comparedwith the reference method using clomiphene citrate (CC) andgonadotrophins. Immediately after analogue administration (day4), buserelin-treated women showed short-lived elevations inserum LH and progesterone concentrations, but in the later follicularphase, the serum LH concentration was lowered compared withthe controls. None of the women treated with analogue displayedelevated serum LH or progesterone concentrations at the timeof injection of human chorionic gonadotrophin. In the earlyluteal phase, these women had higher serum levels of progesteroneand higher progesterone to E2 ratios than the controls, butthe length of the luteal phase was slightly shortened. Hence,in hyperstimulated cycles, 4-day treatment with buserelin causedprofound endocrinological changes: namely, short-term rescueof the corpus luteum, prevention of an endogenous LH rise andpremature luteinization and increased progesterone productionin the early luteal phase     

Endocrinology: Pre-ovulatory progesterone growth rate in patients treated with gonadotrophin-releasing hormone agonist and outcome of in-vitro fertilization

The present study was undertaken to assess whether the increasein serum progesterone concentration following the administrationof human chorionic gonadotrophin (HCG) may have predictive valueon the in-vitro fertilization (IVF) success rate. Progesteroneconcentration on the day of HCG administration and the increasein progesterone concentration on the following day were evaluatedin 140 consecutive patients undergoing IVF with embryo transfer.Stimulation protocol in all study patients entailed intranasaladministration of short-acting gonadotrophin-releasing hormoneagonist (GnRHa) buserelin and human menopausal gonadotrophin.A pregnancy rate of 37.2% was achieved when at least three embryoswere transferred. The only significant difference between conceptionand non-conception cycles was found in serum progesterone concentrationsafter HCG administration (P < 0.01), whereas the mean progesteroneconcentration on the day of HCG did not differ. No differencein other hormonal or cycle parameters was observed. The increasein progesterone concentration was significantly greater in thegroup of patients who achieved pregnancy than in the group whodid not (2.2 ± 0.2 versus 1.6 ± 0.1 ng/ml, respectively;P < 0.01). A critical breakpoint in serum progesterone wasarbitrarily determined at 1 ng/ml. An increase in progesteroneconcentration 1 ng/ml when three or more embryos were transferredwas associated with a positive predictive value for pregnancyof 40.4% (sensitivity of 94.7%), whereas a negative predictivevalue of 86.7% was obtained when this value was <1 ng/ml.These findings indicate that an adequate rise in serum progesteronefollowing HCG administration provides useful information aboutthe possible outcome of the treated cycle.     

Human prolactin release induced by follicle stimulating hormone, luteinizing hormone and human chorionic gonadotrophin

Plasma prolactin levels rise in stimulated cycles. To clarifythe effects of gonadotrophin on the lactotrophs, three studieswere performed. First, plasma concentrations of prolactin duringclomiphene citrate (CC)-human menopausal gonadotrophin (HMG)-humanchononic gonadotrophin (HCG) treatment of women enrolled forin-vitro fertilization (IYF) were compared with those duringHMG-HCG administration while under pituitary suppression witha gonadotrophin releasing hormone (GnRH) analogue (buserelin).Women suppressed with buserelin had higher basal levels of PRLin plasma (14.4 ± 4.3 nglml versus 6.9 ± 1.4 ng/ml,P<0.001). Only buserelin-suppressed women showed a significantrise in plasma prolactin before HCG administration, while bothpatient groups had marked prolactin peaks after HCG injection.This peak was higher in the buserelin group (71.9 ± 50.7ng/ml versus 52.6 ± 29.7 ng/ml). The second study showedthat plasma levels of prolactin of 6 post- menopausal womenwere significantly increased 48 h after an injection of 5000IU HCG, i.m. (24.9 ± 17.4 ng/ml versus 12.4 ±6.2 ng/ml P<0.05). Third, plasma prolactin was studied in5 women over 30 days after surgical castration. An upward trendwas observed similar to that of endogenous gonadotrophin, withthe change in prolactin values closely correlating with thechange in concentrations of follicule stimulating hormone (P<0.005).All these findings suggest that human gonadotrophins stimulatelactotrophs.     

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)     

Endocrinology: Luteal function following ovulation induction in polycystic ovary syndrome patients using exogenous gonadotrophins in combination with a gonadotrophin-releasing hormone agonist

The luteal phase was studied in 12 polycystic ovary syndrome(PCOS) patients following ovulation induction using exogenousgonadotrophins combined with a gonadotrophin-releasing hormoneagonist (GnRH-a). Human menopausal gonadotrophin (HMG) was precededby 3 weeks of treatment with GnRH-a (buserelin; 1200 µg/dayintra-nasally) and administered in a step-down dose regimenstarting with 225 IU/day i.m. GnRH-a was withheld the day beforeadministration of human chorionic gonadotrophin (HCG; 10 000IU i.m.). Blood sampling and ultrasound monitoring was performedevery 2–3 days until menses. The luteal phase was significantlyshorter in PCOS patients as compared to eight regularly cyclingcontrols: 8.8 (3.3–11.4) days [median(range)] versus 12.8(8.9–15.9) days (P = 0.01). Median peak values for progesteronedid not show significant differences comparing both groups:52.3 (17.1–510.3) nmol/l versus 43.0 (31.2–71.1)nmol/l, respectively (P = 0.8). The interval between the dayof the progesterone peak and return to baseline was significantlyshorter in the PCOS patients than in controls: 2.5 (0.3–4.9)days versus 4.2 (3.9–10.5) days (P < 0.005). Luteinizinghormone (LH) concentrations during the luteal phase as reflectedby area under the curve were significantly lower in PCOS ascompared to controls: 4.4 (1.6–21.0) IU/l x days and 49.0(27.8–79.6) IU/l x days, respectively (P < 0.001).In conclusion, patients with PCOS may suffer from insufficientluteal phases after ovulation induction using HMG/HCG in combinationwith a GnRH-a. The corpus luteum apparently lacks the supportof endogenous LH and may be stimulated only by the pre-ovulatoryinjection of HCG. Potential involvement of adjuvant GnRH-a medicationor HCG itself in luteal suppression of endogenous gonadotrophinsecretion, and the importance of luteal function for pregnancyrates following treatment, warrant further studies.     

Altered luteinizing hormone pulsatility in infertile patients with idiopathic oligoasthenozoospermia

In a previous study, we demonstrated that oligoasthenozoospermic(OAZ) patients had two types of testosterone response to humanchorionic gonadotrophin (HCG) administration: group 1 (OAZ-1)had an altered, monophasic (no first peak) response, and group2 (OAZ-2) had a normal biphasic response. The objective of thepresent work was to study the luteinizing hormone (LH) pulsatilityin OAZ-1 compared with both OAZ-2 and men of proven fertility(PF), in order partly to determine the possible aetiology ofthe blunted acute testosterone response to HCG in these patients.LH pulsatility was measured in 10 PF, 10 OAZ-1 and 10 OAZ-2patients, in blood samples taken every 5 min for 6 h in PF,and for 4 h in OAZ patients. LH values were determined by atime-resolved immunofluorometric assay. Frequency and amplitudeof the LH pulses were determined by a computer program. LH pulsefrequency, expressed as pulses/4 h, was significantly lowerin OAZ-1 (1.5 ± 0.97) than in PF (2.4 ± 0.63)and OAZ-2 (2.4 ± 0.84) patients. In six OAZ-1 and twoOAZ-2 patients, LH pulsatility was diminished, as they showedless than two pulses/4 h. No statistically significant differencesin LH pulse amplitude were found. These results, together witha higher number of OAZ-1 cases found with decreased LH pulsatility,suggest that, at least in a subset of these men, quantitativeand/or qualitative alterations of LH secretion might have occurred.     

Recombinant luteinizing hormone supplementation to recombinant follicle-stimulating hormone induced ovarian hyperstimulation in the GnRH-antagonist multiple-dose protocol

BACKGROUND: Suppression of endogenous LH production by mid-follicular phase GnRH-antagonist administration in controlled ovarian hyperstimulation protocol using recombinant (rec) FSH preparations void of LH activity may potentially affect ovarian response and the outcome of IVF treatment. The present study prospectively assessed the effect of using a combination of recFSH and recLH on ovarian stimulation parameters and treatment outcome in a fixed GnRH-antagonist multiple dose protocol. METHODS: 127 infertile patients with an indication for IVF or ICSI were recruited and randomized (using sealed envelopes) to receive a starting dose of either 150 IU recFSH (follitropin alpha) or 150 IU recFSH plus 75 IU recLH (lutropin alpha) for ovarian hyperstimulation. GnRH-antagonist (Cetrorelix) 0.25 mg was administered daily from stimulation day 6 onwards up to and including the day of the administration of recombinant HCG (chorion gonadotropin alpha). Gonadotropin dose adjustments were allowed from stimulation day 6 onwards, HCG was administered as soon as three follicles > or =18 mm were present. The primary outcome parameter was treatment duration until administration of HCG. RESULTS: Exogenous LH did not shorten the time necessary to reach ovulation induction criteria. Serum estradiol (E(2)) and LH levels were significantly higher on the day of HCG administration in the recLH-supplemented group (1924.7 +/- 1256.4 vs 1488.3 +/- 824.0 pg/ml, P < 0.03), and 2.1 +/- 1.4 vs 1.4 +/- 1.5 IU/l, P < 0.01, respectively). CONCLUSIONS: Except for higher E(2) and LH levels on the day of HCG administration, no positive trend in favour of additional LH was found as defined by treatment outcome parameters.     

Relationship of biochemical pregnancy to pre-ovulatory endometrial thickness and pattern in patients undergoing ovulation induction

In order to assess the relationship between pre-ovulatory endometrialthickness and pattern and biochemical pregnancy, the pregnancyoutcome was retrospectively analysed in 81 patients undergoingovulation induction evaluated by vaginal ultrasound on the dayof human chorionic gonadotrophin (HCG) administration or luteinizinghormone (LH) surge. Biochemical pregnancies occurred in 7/32(21.9%) pregnancies when endometrial thickness was <9 mm,compared to 0/49 when endometrial thickness was 9 mm on theday of HCG administration or LH surge (P < 0.0025). Clinicalabortions occurred in 5/32 (15.6%) pregnancies when endometrialthickness was 6–8 mm, compared to 6/49 (12.2%) when endometrialthickness was 6–8 mm (NS). Endometrial thickness was relatedto the cycle day of HCG or LH surge (r = 0.37, P < 0.001)but was unrelated to oestradiol level on the day of HCG administrationor LH surge (r = 0.12). Biochemical pregnancies were relatedto endometrial pattern (r = – 0.22, P = 0.02) but wereunrelated to maternal age or previous abortions. Clinical abortionswere related to age (r = 0.26, P = 0.01) and to previous abortion(r = 0.25, P = 0.013) but were unrelated to endometrial pattern.Neither biochemical pregnancy nor clinical abortion was relatedto oestradiol or LH levels on the day of HCG administrationor LH surge. These findings suggest that the majority of biochemicalpregnancies do not result from karyotypically abnormal embryos,as do clinical abortions.     

Multiple follicular development and ovarian steroidogenesis following subcutaneous administration of a highly purified urinary FSH preparation in pituitary desensitized women undergoing IVF: a multicentre European phase III study

A multicentre, multinational study was carried out between November1990 and February 1992 to assess the safety and efficacy ofa new highly purified urinary human follicle stimulating hormone(FSH; Metrodin HP®) which is practically devoid of luteinizinghormone (LH) activity. Metrodin HP was administered s.c. tostimulate multiple follicular development in women undergoingin-vitro fertilization (IVF) and embryo transfer. A total of139 women were recruited from 10 participatin centres. Of these,135 underwent pituitary desensitization with a long gonadotrophin-releasinghormone (GnRH) agonist protocol and following deter-minationof ovarlan inactivity (mean± SD of 12.9 ± 3.2days), Metrodin Hp s.c. stimulation was started; 122 patientswere fully eligible for efficacy analysios and 118 of these(97%) received up to 10 000 IU human chrionic gonadotrophin(HCG) to induce final folicular maturation and timed oocyterecovey. Mean plasma LH concentrations at the beginning of Metro-dinHP treaement were 1.6 ± 0.8 mIU/ml and by the day ofHCG administration were significantly (p<0.001) reduced (1.2±0.8mIU/ml). The mean plasma oestradiol and inhibin concentrationson the day of HCG were 6173±3567 pmol/l and 8.2 ±4.4IU/ml respectively. There was a positive correlation (r= 0.49,p<0.001) between individual oestradiol and inhibin concentrationson the day of HCG. In the 118 patients who received HCG, themean number of oocytes recovered was 8.4 ± 4.7 followingstimulation with 36 ± 10, 75 IU ampoules of MetrodinHP over 12.2±2.1 days. One-hundred-and-eight patients(89% of 122 eligible) ahd 5.3±3.3 oocyted fertilized,and 105 (86%) had 2.8±1.0 embryos transferred; 28 patients(23% perinitiated cycle) had a clinical pregnancy and subsequently18 of these (15% per initiated cycle) had a live birth. A totalof 135 patients who reveiced Metrodin HP were eligible for safetyanalysis. One patient did not receive HCG because of the riskof developing ovarian hyperstimulation syndrome (OHSS). Sevenpatients (5% of those who received HCG) developed OHSS, onesevere, five moderate and one mild case. Three OHSS patientswere pregnant and hospitalized. The patient with severe OHSSwas found to have an ectopic pregnancy. Local side effects werereported by 24 (18%) patients at the site of s.c injection.The most common compliant was brusing (48.5%). There was nodevelopment of antobodies to FSH. In conclusion Metrodln HP,a urinary gonadotrophin preparation in which>95% of the proteincontent is FSH, was effective in stimulating multiple folliculardevelopment and oestradol synthesis to a similar degree reportedfor other gonadotrophin preparations, even when endogenous LHsecretion was significantly reduced by a GnRH agonist. Thesedata support the concept that only very low concentrations ofLH are required in conjunction with FSH for the stimulationof follicular development and ovarian steroidogenesis. MetrodinHp was well tolerated locvally thus enabling convenient self-adminstrationwithout compromising safety or efficacy     

Complete and partial luteinized unruptured follicle syndrome after ovarian stimulation with clomiphene citrate/human menopausal gonadotrophin/human chorionic gonadotrophin

A total of 31 clomiphene citrate/human menopausal gonadotrophin(HMG)/human chorionic gonadotrophin (HCG)-stimulated cyclesin 28 patients were investigated to determine the fate of eachof the matured follicles. A standard stimulation regimen wasadhered to, and ultrasound as well as hormonal monitoring wasperformed. All follicles were measured by vaginal ultrasoundat –12, +35 and +45 h relative to HCG administration andat 7 days after HCG administration. Of the 220 follicles, 107(48.6%) ruptured. The number of ruptured follicles per cyclewas correlated with the mid-luteal progesterone concentration(r = 0.63, P = 0.0005). The probability of follicular rupturewas related to follicular diameter at 12 h before HCG administration;6% of follicles <12 mm in diameter ruptured compared with87% of follicles 18–19 mm. A complete luteinized unrupturedfollicle (LUF) syndrome was observed in six cycles (20%). Inthese cycles, follicular growth and oestradiol, progesterone,luteinizing hormone (LH) and follicle stimulating hormone (FSH)concentrations at 12 h before HCG administration were similarto those in cycles with follicular rupture. However, mid-lutealprogesterone concentrations were lower in complete LUF cycles(46.97 ± 8.95 nmol/1 versus 108.74 ± 12.27 nmol/1;P = 0.02). These data demonstrate that in stimulated cyclesmany follicles, usually the smaller ones, fail to rupture, evenafter HCG administration. Complete LUF syndrome, despite a strongexogenous ovulatory signal, and the absence of any differencein peri-ovulatory hormonal parameters, indicates that the defectcausing LUF resides in the follicle itself and/or hormonal changesduring the follicular phase.     

Triggering ovulation with endogenous luteinizing hormone may prevent the ovarian hyperstimulation syndrome

In a series of 126 therapeutic cycles in 48 patients with primary infertility and treated with HMG for anovulation or preparation to insemination, ovulation was triggered by endogenous LH instead of HCG when the patient was considered to be at high risk for ovarian hyperstimulation syndrome (OHS), (plasma oestradiol greater than 1200 pg/ml) and/or multiple pregnancy (greater than 3 follicles greater than 17 mm in diameter). The endogenous LH surge was provoked and maintained by intranasal buserelin 200 micrograms three times at 8-hourly intervals. In the 37 cycles with buserelin, no OHS occurred despite high preovulatory levels of oestradiol; a single twin pregnancy was recorded despite the presence of numerous mature preovulatory follicles. Conception results (21.6% pregnancy per therapeutic cycle) compared favourably with HCG administration (16.8%). It is concluded that, when ovulation must be triggered in a hazardous situation, the use of endogenous LH through the administration of a short-acting GnRH analogue prevents the complications of exaggerated follicular stimulation.     

Intrauterine insemination: effect of the temporal relationship between the luteinizing hormone surge, human chorionic gonadotrophin administration and insemination on pregnancy rates

The optimal time period for intrauterine insemination (IUI) in relation to either luteinizing hormone (LH) surge or human chorionic gonadotrophin (HCG) administration leading to the best pregnancy rates has not been determined. In this study, 856 consecutive human menopausal gonadotrophin (HMG)-stimulated and 49 natural unstimulated IUI cycles carried out at a reproductive medicine unit affiliated with a tertiary centre were analysed in a retrospective fashion. There were three scenarios in the temporal relationship of the LH surge, HCG administration and artificial insemination. These were (group A) subjects who had an endogenous LH surge but were not given HCG; (group B) subjects who were given HCG after an observed LH surge, and (group C) subjects who were given HCG before the LH surge. The overall pregnancy rate (PR) was 16% per cycle. The PR was 9% in group A, 20% in group B and 14% in group C. The PR in group B was significantly better than group C (P = 0.04). In group B, the longer the time interval between the LH surge and HCG administration, the better the PR up to 20 h (P = 0.025); the timing of IUI based on the LH surge was not critical to the achievement of pregnancy within 3 days. In group C, PR improved with the increasing interval between HCG and IUI from <28 h up to 60 h. We conclude that a better PR is achieved if a spontaneous LH surge occurs before HCG administration, especially where the administration of HCG is delayed 8-20 h after an observed LH surge; the timing of IUI based on the LH surge is not critical to the achievement of pregnancy within 3 days.      

EndocrinologyHormonal profile during the follicular phase in cycles stimulated with a combination of human menopausal gonadotrophin and gonadotrophin-releasing hormone antagonist (Cetrorelix)

A third-generation gonadotrophin-releasing hormone antagonist(Cetrorelix) was used during ovarian stimulation in 32 patientsundergoing assisted reproduction, in order to prevent the prematureluteinizing hormone (LH) surge. In all patients, ovarian stimulationwas carried out with two or three ampoules of human menopausalgonadotrophin (HMG), starting on day 2 of the menstrual cycle.In addition, 0.5 mg of Cetrorelix was administered daily fromday 6 of HMG treatment until the day of ovulation inductionby human chorionic gonadotrophin (HCG). A significant drop inplasma LH concentration was observed within a few hours of thefirst administration of Cetrorelix (P<0.005). Moreover, noLH surge was detected at any point in the treatment period inany of the 32 patients. A mean oestradiol concentration of 2122±935ng/1 was observed on the day of the HCG administration, indicatingnormal folliculogenesis. Like LH, progesterone concentrationalso dropped within a few hours of the first administrationof Cetrorelix (P< 0.005). A 0.5 mg daily dose of Cetrorelixprevented a premature LH surge in all the 32 patients treated.