Long-term follow-up of children born after inadvertent administration of a gonadotrophin-releasing hormone agonist in early pregnancy.

Our objective was to evaluate long-term outcome of children born after inadvertent administration of a gonadotrophin-releasing hormone agonist (GnRHa) in early pregnancy, compared to a control group of children born to matched women undergoing in-vitro fertilization and children born after spontaneous pregnancies. Six children from six pregnancies, exposed to a long-acting gonadotrophin agonist, comprised the study group and 20 children were included in the control groups. Pre-, peri- and postnatal data were collected and the children were followed and examined at a mean age of 7.8 +/- 2.0 years. All children underwent physical and neurological examination, and psychological tests. In the study group, one child was born with a major congenital malformation (cleft palate), and four children subsequently demonstrated neurodevelopmental abnormalities, including epileptic disorder (n = 1), attention deficit hyperactivity disorder (n = 3), motor difficulties (n = 3) and speech difficulties (n = 1). In the control groups, one child had attention deficit hyperactivity disorder. This observation of neurodevelopmental abnormalities in four of six children in the study group justifies the need for long-term follow-up of more children previously exposed to gonadotrophin-releasing hormone agonist.     

Favourable pregnancy outcome after administration of a long-acting gonadotrophin-releasing hormone agonist in the mid-luteal phase

Administration of a long-acting gonadotrophin-releasing hormone(GnRH) agonist in early pregnancy before implantation took placeis reported. Pregnancy outcome was favourable. The possibleluteolytic and teratogenic influences of GnRH agonists are discussed.     

Pregnancy outcome following exposure to gonadotrophin-releasing hormone analogue during early pregnancy: comparisons in patients with normal or elevated luteinizing hormone

The outcomes of established pregnancies following the treatmentof infertile women with pituitary down-regulation before andduring treatment with ovulation induction and either intrauterineinsemination or timed intercourse were reviewed. Once startedon gonadotrophin-releasing hormone analogue (GnRHa) treatment,the patients were maintained on GnRHa therapy throughout thefollowing luteal phase to facilitate the start of the next treatmentcycle if no pregnancy was established. This resulted in patientstaking GnRHa until a positive pregnancy test indicated cessationof the treatment. The aim of our study was to determine whetherexposure to GnRHa during early pregnancy constituted a risk.Patients who were diagnosed as having elevated follicular phaseluteinizing hormone (LH) concentrations during their investigationswere analysed as a separate cohort to assess whether this diagnosishad implications with respect to pregnancy outcome. Out of 226recorded clinical pregnancies, 173 were traced and the datacollated: 16 cases resulted in clinical abortions, two wereectopic pregnancies and 155 women had live births at variousages of gestation. There were three pregnancies which were complicatedby congenital abnormalities. Patients with elevated LH concentrationson examination showed a higher rate of total pregnancy lossthan those with normal LH concentrations, despite the fact thatthe LH was suppressed during the cycle in which they conceived.The results suggest that pregnancy outcome is not adverselyaffected by GnRHa administration during the luteal phase ofthe conception cycle, and that the group diagnosed as havingelevated LH concentrations may retain their propensity to higherrates of pregnancy loss even when their LH concentrations aresuppressed during treatment.     

Endocrinology: Outcome of inadvertent administration of a gonadotrophin-releasing hormone agonist (buserelin) in early pregnancy

All women undergoing pituitary down-regulation before plannedin-vitro fertilization (IVF) treatment in two IVF units werestudied to assess the risks of and to pregnancies occurringinadvertently when gonadotrophin-releasing hormone agonists(GnRHa) were used to achieve pituitary desensitization duringthe luteal phase prior to planned IVF treatment. In 2670 cycles,25 women conceived (0.9% of cycles). Of these, three resultedin pre-clinical abortions (12%) but there were no clinical abortions,and 22 have ended with live births at term of apparently normalinfants. Collation of these and other published data suggestthat pregnancy outcome is not adversely affected by GnRHa administrationin the luteal phase of the conception cycle.     

Impaired corpus luteum function and other undesired results of pregnancies associated with inadvertent administration of a long-acting agonist of gonadotrophin-releasing hormone.

Spontaneous pregnancies associated with inadvertent periconceptional administration of long-acting gonadotrophin releasing-hormone agonist (GnRHa), in in-vitro fertilization, occurred in 11 of 161 patients with non-tubal infertility. All these cases exhibited impaired function of the corpus luteum in terms of declining progesterone levels, despite rising levels of human chorionic gonadotrophin. The patients were categorized according to the timing of GnRHa administration: periovulatory (three cases), midluteal (five cases) and late luteal (three cases). Altogether, of the 11 pregnancies, seven ended with a normal livebirth, three with a preclinical gestation and one with a blighted ovum. It appears that spontaneous pregnancies associated with inadvertent administration of GnRHa are not rare. Awareness for early diagnosis and close hormonal monitoring are recommended for the assessment of corpus luteum function and adequate supplementation.     

Pregnancy outcome following early exposure to maternal luteinizing-hormone-releasing hormone agonist (buserelin)

A human pregnancy exposed to a luteinizing-hormone-releasing hormone agonist (buserelin) in its early stages is reported. The possible mechanisms leading to conception under this mode of treatment and its consequences are discussed.     

Inadvertent gonadotrophin-releasing hormone agonist (GnRHa) administration in the luteal phase may improve fecundity in in-vitro fertilization patients

Spontaneous pregnancies associated with inadvertent periconceptionaladministration of a gonadotrophin-releasing hormone agonist(GnRHa) oocur in 1% of in-vitro fertilization (IVF) cycles.The two main issues to be considered in these circumstancesare the luteolytic effect of the agonist and embyrotoxicity.In addition, some authors have suggested a higher incidenceof ectopic implantations. In view of these concerns, we reporton 15 patients who conceived during pituitary desensitizationwith a GnRHa in the luteal phase of the menstrual cycle, andreview the literature on the subject. A detailed analysis ofthe data available so far, which include 59 pregnancies exposedto GnRHa, shows that: (i) there is no clinical evidence forimpaired luteal function, and hormonal supplementation doesnot improve pregnancy outcome; (ii) with only two cases of reportedminor malformations among 37 deliveries, both having a geneticcomponent, there is no evidence of teratogenic effects; and(iii) ectopic implantations in these circumstances are relatedto tubal disease but not to the drug. Considering the long historyof infertility in these patients who had previously been treatedunsuccessfully by different therapeutic modalities, it is likelythat the occurrence of those pregnancies is not merely coincidentaland that GnRHa might have a positive role in fecundity. Theimproved fecundity may be explained by the mechanisms of luteinizinghormone action in the corpus luteum.     

Pregnancy and birth after high serum progesterone concentrations during the follicular phase in an in-vitro fertilization cycle with gonadotrophin-releasing hormone agonist suppression

This case illustrates the possibility of achieving a pregnancyand birth when elevated progesterone concentrations (>4 ng/ml)are present during the follicular phase (from 6 days beforehuman chorionic gonadotrophin injection) of a gonadotrophin-releasinghormone agonist/menotrophin cycle for in-vitro fertilization(IVF). The present patient underwent three IVF/embryo transfercycles in which progesterone concentrations were repeatedlyincreased from the mid-follicular phase onwards. A pregnancywas achieved after the first IVF attempt but ended in a miscarriagein the 19th week of gestation. During the second IVF attemptan endometrial biopsy taken on the day of oocyte retrieval revealedan endometrial advancement of 2 days. A successful pregnancyand birth was again achieved after the third IVF attempt althoughprogesterone concentrations were considerably increased from6 days before the ovulatory stimulus.     

Follicular and luteal phase characteristics following early cessation of gonadotrophin-releasing hormone agonist during ovarian stimulation for in-vitro fertilization

Gonadotrophin-releasing hormone agonists (GnRHa) are widely used in in-vitro fertilization (IVF) for the prevention of a premature rise in luteinizing hormone (LH) concentrations. However, the administration of GnRHa during the follicular phase may also impair subsequent luteal function due to retarded recovery of pituitary gonadotrophin secretion. Therefore, luteal supplementation is generally applied. The present study was designed to determine whether a premature LH surge would still be prevented after early cessation of GnRHa during ovarian stimulation and whether subsequent luteal phase LH production would be sufficient to support progesterone synthesis by the corpus luteum. Sixty patients were randomized for three groups: (i) A long GnRHa/human menopausal gonadotrophin (HMG) protocol with luteal support by repeated human chorionic gonadotrophin (HCG) (n = 20), (ii) early follicular phase cessation of GnRHa without luteal support (n = 20), and (iii) a long GnRHa protocol without luteal support (n = 20). Frequent ultrasound and blood sampling was performed during the entire IVF cycle. Forty normo-ovulatory women served as controls. No premature LH surges were found after early cessation of GnRHa. In this group, some pituitary recovery occurred during the late luteal phase, but this did not affect corpus luteum function. Progesterone concentrations were shown to be dependent on disappearance of the pre-ovulatory bolus of HCG. Pregnancies occurred in all three groups. In conclusion, early follicular phase cessation of GnRHa is still effective in the prevention of a premature rise in LH. Although some pituitary recovery was observed thereafter, corpus luteum function is still abnormal due to early luteolysis.     

Ovarian response and outcome of in-vitro fertilization in patients treated with gonadotrophin-releasing hormone analogues in different phases of the menstrual cycle

Gonadotrophin-releasing hormone analogues (GnRH-a) are currently used in combination with gonadotrophins in ovarian stimulation for in-vitro fertilization (IVF). The present study evaluates follicular recruitment and outcome of IVF in patients treated with GnRH-a, starting in different phases of the menstrual cycle. Ovarian quiescence was achieved by s.c. injection of a GnRH-a (600 micrograms/day). Three groups of patients were randomly established. Patients in group 1 (n = 14) started GnRH-a treatment 4-7 days after ovulation. Women in group 2 (n = 15) started GnRH-a 8-10 days after ovulation. Patients in group 3 (n = 15) began the analogue 1-3 days after the onset of menses. Multiple follicular development was achieved by a combination of pure follicle-stimulating hormone and human menopausal gonadotrophin. Oocyte collection was performed 35 h after administration of human chorionic gonadotrophin. Luteolysis was successfully induced in 15% of cases in group 1 and 40% in group 2. Ovarian arrest was achieved in a significantly (P less than 0.01) shorter period of time in group 3 in comparison to groups 1 and 2. There was no difference between groups in the dose of gonadotrophins necessary to reach an optimal response. Patients in group 1 showed a significant decrease (P less than 0.05) in the number and size of follicles developed in comparison to groups 2 and 3. Fertilization and cleavage rates were similar in all three groups. The pregnancy rate was 40% in group 3, while it decreased to 14.3 and 13.3% in groups 1 and 2, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endocrinology: Sequential gonadotrophin-releasing hormone agonist/ low-dose oral contraceptive treatment for leiomyomata uteri

On the basis that gonadotrophin-releasing hormone agonists (GnRHa)induce a significant but transient shrinkage of leiomyomas andthat oral contraceptive use may be associated with a decreasedrisk of fibroids, we tested the hypothesis that sequential GnRHa/low-doseoral contraceptive treatment could be a therapeutic alternativein perimenopausal women with uterine fibroids. Six premenopausalwomen with leiomyomata uteri were treated with D-tryptophan-6-luteinizinghormone-releasing hormone (D-Trp-6-LHRH) depot (Decapeptyl 3.75)for 6 months and demonstrated a significant reduction in meanuterine volume. A low-dose oral contraceptive containing 30µg of ethinyl oestradiol plus 150 µg of desogestrelwas given during the ensuing 12 months. When GnRHa therapy wasdiscontinued, there was a rapid regrowth of the uterine fibroidsand the uterine volume had reached, or even exceeded, pretreatmentvalues by the eighth to 12th month of contraceptive therapy.Sequential GnRHa/low-dose oral contraceptive treatment is nota useful tool for leiomyomata uteri.     

A comparison of three gonadotrophin-releasing hormone analogues in an in-vitro fertilization programme: a prospective randomized study

The use of gonadotrophin-releasing hormone analogues (GnRHa) has resulted in improved pregnancy rates in in-vitro fertilization (IVF) treatment cycles. Traditionally, short-acting analogues have been employed because of concerns over long-acting depot preparations causing profound suppression and luteal phase defects adversely affecting pregnancy and miscarriage rates. We randomized 60 IVF patients to receive a short-acting GnRHa, nafarelin or buserelin, or to receive a depot formulation, leuprorelin, all commenced in the early follicular phase and compared their effects on hormonal suppression and clinical outcome. We found that on day 15 of administration there was a significant difference in the suppression of oestradiol from initial concentrations, when patients on buserelin were compared with patients on nafarelin or leuprorelin (54 versus 72 and 65%; P < 0.05) and also in the number of patients satisfactorily suppressed, (80 versus 90 and 90%; P < 0.05), though there were no differences between the analogues by day 21. Similarly there was no difference in hormonal suppression during the stimulation phase or in implantation, pregnancy or miscarriage rates in comparing the three agonists. We conclude that with nafarelin and leuprorelin, stimulation with gonadotrophins may begin after 2 weeks of suppression and that long-acting GnRHa are as effective as short-acting analogues with no detrimental effects on the luteal phase.     

Short term pituitary desensitization: effects of different doses of the gonadotrophin-releasing hormone agonist triptorelin

Gonadotrophin-releasing hormone agonists (GnRHa) are used toprevent inadequate luteinizing hormone (LH) surges during ovarianstimulation in in-vitro fertilization (IVF). Dose studies foroptimal dose assessment are lacking and unfavourable effectsof the agonist on granulosa function and oocyte quality havebeen suggested. This double-blind randomized study was undertakento assess the effect of four different doses of triptorelinon the degree of desensitization of the pituitary, and the recoverytime of pituitary function after withdrawal of the agonist.Sixty-six regularly cycling women were allocated to a treatmentgroup (n = 32) and a control group (n = 34). To assess the degreeof pituitary desensitization and restoration in the treatmentgroup, gonadotrophin releasing hormone (GnRH) challenges (100µg, i.v.) were performed during treatment (day 17), and2, 4 and 6 days after discontinuation of treatment At the sametime blood samples for oestradiol and triptorelin concentrationswere drawn. In the control group a GnRH test was performed onday 2 of the menstrual cycle. Both pituitary desensitizationduring and pituitary recovery after agonist treatment, expressedas the LH response to exogenous GnRH, appeared to be dose dependentAs the use of reduced dosages still offers a considerable degreeof pituitary suppression, studies on dose adjustments in theuse of triptorelin in ovarian stimulation in IVF are warranted.     

Simplified ultralong protocol of gonadotrophin-releasing hormone agonist for ovulation induction with intrauterine insemination in patients with endometriosis

The present study was designed to assess the usefulness of thesimplified ultralong protocol of gonadotrophin-releasing hormoneagonist (GnRHa) for ovulation induction with intrauterine insemination(IUI) in patients with various stages of endometriosis. A prospectiverandomized trial was set up to compare the simplified ultralongprotocol (ULP) and the long protocol (LP) of GnRHa for ovulationinduction with IUI in patients with endometriosis. There wasno evidence of other factors in infertility in any patient Inthe ULP group (39 patients), 4 weeks after a single injectionof 3.75 mg Decapeptyl had been given, daily s.c administrationof 0.1 mg Decapeptyl was initiated and continued for at least2 weeks prior to ovarian stimulation. In the LP group (41 patients),daily s.c administration of 0.1 mg Decapeptyl was initiatedfrom the mid-luteal phase of the cycle preceding the stimulationcycle. After 14 days of administration, ovarian stimulationwas started if pituitary desensitization had been achieved.The amount of gonadotrophins required, number of days of gonadotrophinadministration, serum oestradiol response, and the number ofmature follicles were comparable in both groups. The clinicalpregnancy rate per cycle was significantly higher in the ULPgroup at 48.7% (19/39) compared with 26.8% (11/41) in the LPgroup. The miscarriage rates were 21.1% (4/19) in the ULP groupand 18.2% (2/11) in the LP group. In patients with stage I orII endometriosis, there was no significant difference betweenthe two groups with respect to Hinirnl pregnancy rate per cycle(47.4 versus 35.0%). In patients with stage III or IV endometriosis,the clinical pregnancy rate per cycle was significantly higherin the ULP group at 50.0% (10/20) compared with 19.0% (4/21)in the LP group. This study suggests that a simplified ULP ofGnRHa could give better chances of achieving pregnancy in endometriosispatients undergoing assisted reproductive technologies and thatthis protocol may be more useful in patients with an advancedstage of endometriosis.     

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.     

The influence of inadvertent intranasal buserelin administration in early pregnancy

Buserelin was inadvertently administered during 13 early pregnancies in 12 women with long-standing infertility, who had started the GnRH-agonist for gonadotrophin desensitization prior to ovarian stimulation for IVF. Six women delivered a healthy child and one pregnancy continues uneventfully. Three patients aborted before the sixth week and three women with tubal disease had an ectopic pregnancy. Corpus luteum function was normal in 11 of the 13 pregnancies. Although no evidence of embryotoxic effects of buserelin was observed, barrier contraceptive methods should be advised during the first days of its administration.     

Continuous administration of gonadotrophin-releasing hormone agonist during the luteal phase in IVF

BACKGROUND: It has been reported that ceasing the administration of gonadotrophin-releasing hormone (GnRH) agonist causes a profound suppression of circulating serum gonadotrophins. A comparative prospective and randomized study was conducted to investigate the effect of continuous administration of GnRH agonist during the luteal phase in an ovarian stimulation programme for IVF. METHODS: GnRH agonist was administered intranasally from the midluteal phase of the previous cycle, and pure FSH administration started on cycle day 7. In the continuous-long protocol (cL) group (n = 161 ), GnRH agonist administration was continued until 14 days after oocyte retrieval. In the long protocol (L) group (n = 158 ), GnRH agonist was administered until the day before human chorionic gonadotrophin (HCG) administration. RESULTS: The implantation rate and live birth rate per unit of transferred embryos were significantly higher in the cL group than the L group (P < 0.05 ). Serum LH and FSH concentrations on the day of, and 1 day after, HCG administration were significantly lower in the L group than the cL group (P < 0.01 ). CONCLUSIONS: Continuation of GnRH agonist administration during the luteal phase might facilitate implantation, and prevent the profound suppression of serum gonadotrophins.     

A protocol using a low dose of gonadotrophin-releasing hormone agonist might be the best protocol for patients with high follicle stimulating hormone concentrations on day 3

We studied 98 in-vitro fertilization (IVF) patients with a highbasal follicle stimulating hormone (FSH;>6.5 IU/I) concentrationon day 3 who were treated with a low dose gonadotrophin-releasinghormone agonist (GnRHa) protocol and who had received in theprevious 6 months a long protocol with GnRHa in a depot formula.The evaluation was made using the previous IVF cycle of thesame patient as a control. The mean ± SD age of the patientswas 34.1 ± 4.2 years. The use of a low dose agonist protocolended with significantly less ampoules (37.5 versus 46.1), ashorter duration of stimulation (10.7 versus 12.3 days), a higheroestradiol concentration on day 8 (1068 versus 495 pg/ml), ahigher number of mature oocytes (5.9 versus 4.4) and a highernumber of good quality embryos (3.3 versus 2.3). The cancellationrate was lower (11 versus 24%). A GnRHa low dose protocol maybe the protocol of choice for patients with high FSH concentrationson day 3. Larger randomized studies are needed to confirm thesedata.     

Endocrinology: Prevention of irreversible chemotherapy-induced ovarian damage in young women with lymphoma by a gonadotrophin-releasing hormone agonist in parallel to chemotherapy

To examine whether the concomitant administration of a gonadotrophin-releasinghormone agonist (GnRHa) during combination chemotherapy to youngwomen with lymphoma may facilitate preservation of gonadal function,a prospective clinical protocol was undertaken in 18 cyclingwomen with lymphoma, aged 15–40 years. Thirteen patientssuffered from Hodgkin disease (HD) and 5 from non-Hodgkin lymphoma.After informed consent a monthly injection of depot D-TRP⁶-GnRHawas administered for a maximum of 6 months starting prior tochemotherapy. Most of these patients (15/18) were treated withthe MOPP/ABV(D) combination chemotherapy followed by mantlefield irradiation in 10 patients. Hormonal profile [luteinizinghormone (LH), follicle stimulating hormone (FSH), oestradiol,testosterone, progesterone, insulin-like growth factor (IGF)-1,prolactin] was taken before the GnRHa/chemotherapy co-treatment,and monthly thereafter until resuming spontaneous ovulationand menses. This group of prospectivey treated lymphoma patientswas compared to a matched control group of 18 women (aged 17–40years) who have been treated with chemotherapy, mostly MOPP/ABV(14/18), with (11) or without (7) mantle field radiotherapy.Fourteen had Hodgkin's and four non-Hodgkin's lymphoma. Gonadalfunction was determined clinically, hormonally (LH, FSH, oestradiol,progesterone), and sono-graphically. Two of the patients ineach group died from refractory disease. Of the remaining 16patients, 15 (93.7%) resumed spontaneous ovulation and menseswithin 3–8 months of termination of the combined chemotherapy/GnRHaco-treatment. In contrast, only seven (39%) of the 18 similarlytreated patients in the control group (chemotherapy withoutGnRHa) resumed ovarian cyclic activity (regular menses). Theother 11 experienced premature ovarian failure (POF) (61%).Our preliminary data suggest a possible significant protectiveeffect of GnRHa co-treatment with chemotherapy from irreversibleovarian damage (POF).     

Andrology: Effectiveness of long-acting gonadotrophin-releasing hormone agonist treatment in combination with conventional therapy on testicular outcome in human orchitis/epididymo-orchitis

A group of 24 patients suffering from acute post-pubertal orchitis/epididymo-orchitiswere prospectively randomized to treatment over a total periodof 3 months with a combined conventional plus long-acting gonadotrophin-releasinghormone analogue (GnRHa) (leuprolide, 3.75 mg every 27 days)therapy (n = 13, group A) or conventional therapy alone (n =11, group B) respectively, in order to verify any differencesin clinical and sperm outcome during treatment and follow-up.Seven patients affected by uncomplicated mumps (group C), receivingGnRHa for 3 months, served as an additional control group. Combinedleuprolide plus conventional therapy provided better outcomesthan conventional therapy alone in terms of scrotal ultrasoundscans and serum antisperm antibodies (ASA) at time of presentationand monthly thereafter throughout the study: the most soliddata relate to testicular atrophy in three out of 11 patientsfrom group B and their sAb positivity persisting, as opposedto zero out of 13 in group A. Moreover, semen analyses performedat 3–6 months after therapy withdrawal revealed in groupsA and C mean total sperm counts and percentages of oval formssignificantly higher than those observed in group B. It is concludedthat GnRHa treatment is a promising pharmacological tool withno side-effects, effective in reducing testicular vascular leakagesin male orchitis.