Another look at co-treatment with growth hormone and human menopausal gonadotrophins in poor ovarian responders

The objective of this study was to evaluate whether a combinedhuman growth hormone (HGH) and human menopausal gonadotrophin(HMG) treatment can improve ovulation induction in poor ovarianresponders. Ten patients aged 28–43 years and requiring> 25 ampoules of HMG for ovulation were admitted to the study.Pituitary growth hormone reserve was evaluated by clonidinestimulation and insulin tolerance tests before commencementof treatment. The patients underwent one treatment cycle withD-tryptophan-6-luteinizing hormone-releasing hormone (D-Trp⁶-LHRH)and HMG and another cycle with D-Trp⁶-LHRH, HMG and HGH. SerumHGH, insulin-like growth factor (IGF)-I and oestradiol weremeasured throughout the two treatment cycles and follicularmaturation was assessed by ultrasonographic studies. All patientstested showed no elevation of their serum HGH concentrationduring a clonidine test, but showed an adequate response duringinsulin tolerance tests. No significant difference was foundin the number of HMG ampoules, duration of treatment, numberof leading follicles, and serum oestradiol concentration betweenthe two treatment cycles. Co-treatment with HGH and HMG didnot improve ovarian performance in poor ovarian responders.No correlation was found between the results of HGH pituitaryfunction tests and the ovarian response to gonadotrophins.     

Endocrinology: Development and applications of luteinizing hormone-releasing hormone antagonists in the treatment of infertility: an overview

Luteinizing hormone-releasing hormone (LHRH) plays a crucialrole in controlling the ovarian cycle in women. By modificationof the molecular structure of this decapeptide, analogues weresynthesized with agonistic or antagonistic effects on the gonadotrophiccells of the anterior pituitary gland. The agonists, after aninitial stimulatory effect (‘flare up’), lead todesensitization of the gonadotrophic cells and a reduction inthe number of LHRH receptors on the cell membrane (‘down-regulation’),while the antagonists produce an immediate effect by competitiveblockade of the LHRH receptors. After administration of LHRHantagonists, the serum levels of FSH and LH decrease withinhours. Nevertheless, the adenohypophysis maintains its responsivenessto an LHRH stimulus (‘pituitary response’) afterpretreatment with an antagonist. This different pharmacologicalmechanism of LHRH antagonists makes possible new approachesto ovarian stimulation and to the therapy of sex steroid dependentdiseases. The premature LH surge, the main cause of cancellationduring induction of superovulation in assisted reproductiontechnology (ART) programmes, can be abolished by short termapplication of an LHRH antagonist associated with a reducedhuman menopausal gonadotrophin (HMG) requirement for ovarianstimulation. A future approach to ART might be based on thecombination of pretreatment with an LHRH antagonist and ovulationinduction by native LHRH or an agonist. The severe side effectsencountered with early LHRH antagonists, such as anaphylactoidreactions due to histamine release, are almost completely eliminatedin modern antagonists, especially Cetrorelix which is presentlyused clinically in controlled phase II clinical studies.     

Results of JVF in the treatment of polycystic ovary disease

Sixteen patients with polycystlc ovanan syndrome (PCO) weretreated by in-vitro fertilization (IVF), 11 suffered from definitivetubal infertility and five had previously undergone multipleunsuccessful attempts at ovulation induction after conventionaltherapy. They were randomly allocated into two groups: A1 (sixpatients) treated with ‘pure FSH’ and A2 (10 patients)whose ovarian stimulation was performed by a combination ofLHRH agonist and pure FSH. More oocytes were recovered in groupA1 (7.5 ± 2.2) and group A2 (10.3 ± 5.8) thanin a control group (B) but this difference was not significant.There was no difference between groups A and B in the numberof immature oocytes, the oocyte fertilization rate (60%) andthe number of embryos replaced per patient (2.8). Four pregnancieswere achieved in the six patients in group A1, 5/9 in groupA2 and 3/6 in group B. One severe hyperstimulation was recordedin group Al but this patient developed a pregnancy which wasnormal at term. This small study suggests that IVF may be asolution to the treatment of PCO resistant to clomiphene citrateand HMG treatment and that the combination of pure FSH withan analogue of LHRH (in a short protocol of 15 days) does notseem to have an advantage over FSH stimulation alone and doesnot reduce the frequency of hyperstiinulation.     

Randomized controlled trial of follicle stimulating hormone versus human menopausal gonadotrophin in in-vitro fertilization*

The adverse effect of raised luteinizing hormone (LH) concentrationson reproductive outcome suggests that exogenous LH administrationfor ovarian stimulation may not be desirable. The aim of thisstudy was to compare the clinical pregnancy rates between folliclestimulating hormone (FSH) and human menopausal gonadotrophin(HMG) used in in-vitro fertilization (IVF) cycles. A total of232 infertile patients, with a mean duration of infertilityof 67.1 ± 32.9 months, were selected for IVF (femaleage <38 years, FSH <15 IU/1, and total motile sperm count>5x10⁶). A short (flare-up) protocol with daily leuprolideacetate was followed randomly from day 3 with FSH (n = 115)or human menopausal gonadotrophin (HMG; n = 117), at an initialdose of two ampoules per day. A maximum of three embryos wastransferred, and the luteal phase was supported with four dosesof HCG (2500 IU). No differences were observed between the twogroups in any of the cycle response variables except fertilizationrates per oocyte and per patient, both of which were significantlyhigher with FSH. Clinical pregnancy rates per cycle initiated,per oocyte retrieval and per embryo transfer were 19.1, 21.0and 22.7% respectively for FSH, and 12.0, 12.8 and 15.4% respectivelyfor HMG. Whilst these differences were not statistically significant,the results of this interim analysis suggest that HMG may beassociated with a lower clinical pregnancy rate than FSH.     

Pharmaco-dynamics of human menopausal gonadotrophin (HMG) and follicle-stimulating hormone (FSH). The importance of the FSH concentration in initiating follicular growth in polycystic ovary-like disease

Using a randomized double-blind cross-over design, the pharmaco-dynamicand pharmaco-kinetic properties of ‘pure’ follicle-stimulatinghormone (FSH) (Metrodin) and human menopausal gonadotrophin(HMG) (Pergonal) were studied in 24 women with polycystic ovary-likedisease (PCOD) during induction of ovulation. Fifty-six cycleswere stimulated with FSH and 60 cycles with HMG, according toa standard protocol. Gonadotrophins were administered i.v. ina pulsatile fashion using pulse frequencies of either 30 or120 min. The cycles stimulated with either 30 or 120 min pulseintervals showed no differences among themselves. During thestimulation phase, the FSH and HMG stimulated cycles showedequal and dose dependent FSH concentrations (mean ± SD).The luteinizing hormone (LH) concentrations (mean ± SD)were also equal but unchanged compared to the mean basal concentration.The LH, FSH, total urinary oestrogen excretion, and testosteroneprofiles (mean ± SD) obtained from cycle days –10to 0 as well as the pregnanediol profiles obtained from cycledays 0 to +14 showed no differences either. The occurrence ofan endogenous preovulatory LH surge was significantly more frequentin the cycles stimulated with a pulse interval of 30 min comparedto the cycles stimulated with a pulse interval of 120 min. Theaddition of LH as provided in HMG did not influence the FSHthreshold concentration above which initiation of folliculargrowth occurred, since no differences were found in the FSH‘stable’ concentrations between FSH and HMG stimulatedcycles. However, intra- and inter-individual variation in theFSH ‘stable’ concentration at which follicular growthwas initiated became obvious. It has been hypothesized thateither diminished circulating bioactive FSH or intrafollicularparacrine factors may influence the FSH threshold concentrationabove which the ovary responds with follicular growth.     

Miscarriage rates following in-vitro fertilization are increased in women with polycystic ovaries and reduced by pituitary desensitization with buserelin

To assess the risk of miscarriage after in-vitro fertilization(IVF) with respect to age, cause of infertility, ovarian morphologyand treatment regimen, a retrospective analysis was performedof the first 1060 pregnancies conceived between June 1984 andJuly 1990 as a result of 7623 IVF cycles. Superovulation inductionwas achieved with human menopausal gonadotrophin (HMG) and/orpurified follicle stimulating hormone (FSH) together with eitherclomiphene citrate or the gonadotrophin hormone-releasing hormone(GnRH) agonist buserelin, the latter either as a short ‘flare’regimen or as a ‘long’ regimen to induce pituitarydesensitization. There were 282 spontaneous abortions (26.6%)and 54 ectopic pregnancies (5.1%). The mean age of women withongoing pregnancies was 32.2 (SD 3.9) years compared with 33.2(SD 4.1) years in those who miscarried, which were significantlydifferent (P = 0.008). There was no relation between the miscarriagerate and the indication for IVF. The miscarriage rate was 23.6%in women with normal ovaries compared with 35.8% in those withpolycystic ovaries [P = 0.0038, 95% confidence interval (CI)4.68–23.10%]. There was no difference in the miscarriagerate between treatment with HMG or FSH. Women whose ovarieswere normal on ultrasound were just as likely to miscarry ifthey were treated with clomiphene or with the long buserelinprotocol. Those with polycystic ovaries, however, had a significantreduction in the rate of miscarriage when treated with the longbuserelin protocol, 20.3% (15/74), compared with clomiphenecitrate, 47.2% (51/108) (P = 0.0003, 95% CI 13.82–40.09%).     

Pituitary gonadotrophin secretory capacity during the luteal phase in superovulation using GnRH-agonists and HMG in a desensitization or flare-up protocol.

Pituitary gonadotrophin reserve and basal gonadotrophin secretion were tested during the luteal phase in women superovulated with buserelin/human menopausal gonadotrophin (HMG) in a desensitization (n = 17) or flare-up protocol (n = 7). In the desensitization protocol the luteinizing hormone-releasing hormone (LHRH) stimulated serum LH and follicle stimulating hormone (FSH) concentrations remained impaired at least until day 14 after arrest of the agonist. In the flare-up protocol basal and stimulated LH secretion was still abnormal on days 14 and 15 after human chorionic gonadotrophin (HCG) injection. Normal basal serum FSH concentrations were measured at the end of the luteal phase in the flare-up protocol, but the response of FSH to LHRH injection was still subnormal. We conclude that gonadotrophin function remained impaired until the end of the luteal phase after desensitization and flare-up GnRH-agonist and HMG stimulation protocols. Corpus luteum stimulation with exogenous HCG or substitution therapy using natural progesterone are required to prevent the possible negative effects resulting from pituitary dysfunction after GnRH-agonist treatment.     

Endocrinology: Ultrasonic control without hormone determination for ovulation induction in in-vitro fertilization/embryo transfer with gonadotrophin-releasing hormone analogue and human menopausal gonadotrophin

A total of 114 patients admitted to an in-vitro fertilization-embryotransfer programme for the first time, were randomly assignedto the study group or controls. Gonadotrophinreleasing hormoneanalogue (GnRHa) and human menopausal gonadotrophin (HMG) wereused for ovulation induction. The study patients were followedup merely by ultrasonography and the controls by ultrasonographyand serum determinations of oestradiol, progesterone and luteinizinghormone (LH). There was no significant difference in the durationand total amount of HMG used for ovulation induction (10.9 versus11.5 days and 34.8 versus 37.9 ampoules, respectively). Thenumber of oocytes retrieved (11.7 versus 13.4) and the numbersof embryos replaced (2.6 versus 2.8) and cryopreserved (1.9versus 3.3) were also similar. Pregnancy rates were similar.Pregnancy rate per ovum retrieval was 22.2 versus 25% and perembryo transfer 27.2 versus 26.5%. Oestradiol patterns werealso similar. The rate and severity of ovarian hyperstimulationsyndrome were virtually identical. We conclude that ‘ultrasound-only’monitoring of ovulation induction in IVF cycles treated by GnRHa-HMGin the long protocol is as effective and safe as the conventionalultrasound and hormone determination, but far simpler, swifterand more cost-effective     

Polycystic ovary syndrome: low-dose follicle stimulating hormone administration is a safe stimulation regimen even in previous hyper-responsive patients.

We studied 23 women with polycystic ovarian syndrome (PCOS), resistant to clomiphene citrate, who had a previous history of multifollicular ovarian development on gonadotrophin stimulation. Each woman had one cycle of gonadotrophin-stimulating hormone agonist/human menopausal gonadotrophin (GnRHa/HMG) stimulation and then one cycle of low-dose follicle stimulating hormone (FSH) stimulation. All GnRHa/HMG cycles were multifollicular. On the low-dose FSH protocol, 10 cycles were unifollicular, while two to three follicles were observed in nine cycles, and four cycles were multifollicular. The ovarian hyperstimulation syndrome ensued in one of the FSH cycles versus 13 of the GnRHa/HMG cycles. Despite decreasing luteinizing hormone (LH) levels and increasing FSH levels, androgen levels increased during stimulation on both protocols. There was one pregnancy in the GnRHa/HMG cycles versus six pregnancies following the FSH cycles. In conclusion, low-dose FSH administration seems a safe stimulation regimen with a satisfactory conception rate even in PCOS women with a previous record of multifollicular ovarian development.     

Infertility: Metastatic ovarian strumosis in an in-vitro fertilization patient

Malignant struma ovarii is a very rare tumour, with considerablecontroversy concerning the necessary histologic features formalignancy. Still more infrequent is the condition termed ‘metastaticovarian strumosis’ or simply ‘benign strumosis orstrumatosis’ and characterized by the presence of peritonealimplants of mature thyroid tissue occurring in struma ovarii.‘Strumosis’ should not be confused with malignancy.Presented is a case of ‘metastatic ovarian strumosis’in a 36-year-old woman with primary infertility who underwentthree in-vitro fertilization (IVF) cycles with ovarian stimulation.She received hormonal treatment for 6 months after her lastIVF because of ‘persistent enlarged ovarian follicles’which were in fact ‘thyroid follicles’.     

Ovarian stimulation with buserelin/HMG/HCG: prospective randomized study of short versus long protocol

The combined administration of the gonadotrophin-releasing hormone(GnRH) agonist buserelin and human menopausal gonadotrophin(HMG) was evaluated in 527 cycles (428 patients) of an assistedreproduction programme. All women were randomly allocated accordingto the ovulation induction protocol into two groups: group I(short protocol; 318 cycles) was given buserelin (1 mg/day)intranasally from cycle day 1 and HMG (2 ampoules/day) fromday 3 until human chorionic gonadotrophin (HCG) administration:group H (long protocol; 209 cycles) was given buserelin (1 mg/day)intranasally from cycle day 1 for at least 14 days and then2 ampoules HMG/day were added, increasing progressively accordingto the ovarian response. The number (mean ± SEM) of folliclesdeveloped was higher in group II than in group I (9.1 ±0.4 versus 7.7 ± 0.3, respectively; P < 0.05). Moreoocytes were retrieved in group II (8.4 ± 0.5) than ingroup I (6.5 ± 0.3) (P < 0.001), as well as more embryos(6.3 ± 0.5 and 4.0 ± 0.3, respectively; P <0.001). Moreover, in group II there was a better correlationbetween oestradiol and the total follicular volume (r = 0.5391)on cycle day 0 compared with group I (r = 0.458), while oestradiolvalues were similar between the two groups. No differences wereobserved in the cancellation rate, fertilization rate and maturityof the oocytes between the two groups. The pregnancy rate pertransfer was slightly better in group II (25.8%) than in groupI (19.4%), but this difference was not significant. More stimulationdays were needed in group II than in group I (11.8 ±0.2 and 10 ± 0.2, respectively) (P < 0.001) and moreHMG ampoules (37.7 ± 1.4 and 27.9 ± 0.1, respectively)(P < 0.001). In conclusion, the administration of the longprotocol is associated with a higher number of follicles developed,oocytes retrieved and embryos obtained, while it seems morepromising concerning the pregnancy rates. Nevertheless, treatmentwith this protocol increases the stimulation days and the numberof HMG ampoules administered and hence the cost.     

The in vitro cytokinesis-block micronucleus assay: a detailed description of an improved slide preparation technique for the automated detection of micronuclei in human lymphocytes

An improved slide preparation technique is described for theautomated detection of micronuclei in binucleate cytokinesis-blockedhuman lymphocytes. This automated system (Discovery Image Analyser,Becton-Dickinson Image Cytometry Systems, Leiden, The Netherlands)searches for the pattern of two touching nuclei in binucleatecells instead of the edges of the cytoplasm. For this purposeseveral ratios of the fixative mixture, methanol/acetic acid,were checked. After fixation with a ratio of 25:1, touchingnuclei were obtained in almost 100% of the binucleate cells.A hydrolysis treatment with 5 N HC1 before staining with Romanowsky-Giemsaresulted in binucleate cells with dark-stained nuclei and micronucleiand a vaguely stained cytoplasm. The high visual contrast betweencytoplasm and nuclear material obtained by this staining proceduremakes an accurate automated detection of micronulei feasible.Additionally, a 64 h culture time resulted in an optimal yieldof binucleate cells. The results of manual micronucleus scoringon slides prepared with the ‘manual protocol’ andwith the ‘automation protocol’ indicate no significantdifferences between both sets of data supporting the validityof the automation protocol. ³To whom correspondence should be addressed     

Ovarian response in repetitive cycles induced by menotrophin alone or combined with gonadotrophin releasing hormone analogue

The number of oocytes retrieved for in-vitro fertilization (IVF) has a major influence on the number of embryos developed and pregnancy success. This study was designed to investigate the ovarian response in the same patient under the same and different stimulation protocols. In group A, 19 patients underwent two consecutive cycles, both stimulated with human menopausal gonadotrophin (HMG). Group B comprised 27 patients who experienced two successive cycles treated with the combination of long-acting gonadotrophin releasing hormone analogue (GnRHa) and HMG. Group C included 27 patients whose first cycle was stimulated with HMG alone, and their second with a GnRHa/HMG combination. The mean number of HMG ampoules administered and the duration of treatment were similar in both cycles of group A and B patients while in group C, both the amount and duration of HMG administration were significantly higher and longer in the combined protocol compared to HMG alone. This study demonstrates an identical ovarian response using the same mode of stimulation in repeated cycles, and a significantly improved response with the GnRHa/HMG combination compared with HMG alone in the same patient.     

Relationship between the threshold of ovarian sensitivity to human menopausal gonadotrophin stimulation and in-vitro fertilization treatment outcome

In a retrospective study of 813 oocyte retrieval–embryotransfer cycles in women with normal follicle stimulating hormoneand luteinizing hormone concentrations, we sought to investigatethe relationship between the amount of human menopausal gonadotrophin(HMG) used for ovarian stimulation and treatment outcome. Patientswere divided into three groups: group A patients (495 cycles)required <40 ampoules of HMG and had a predicted probabilityfor pregnancy of 25% per embryo transfer; group B patients (165cycles) required 41–77 ampoules per cycle, with a predictedprobability rate for pregnancy of 5–25% per embryo transfer;and group C patients (153 cycles) required >77 ampoules ofHMG and the predicted probability for pregnancy was <5% perembryo transfer. Groups C and A differed significantly (P <0.005). The mean oestradiol concentration on the day of HCGadministration in group C was 6412 pmol/l, and the mean numberof eggs retrieved was seven. The highest success rates werefound when up to 2.5 ampoules of HMG were required for eachegg or 4.4 ampoules for each embryo. The lowest rates were obtainedwhen >4.8 ampoules of HMG were necessary for each oocyteor >9.6 ampoules for each embryo (P < 0.005). We identifieda group of infertile patients who required excessive amountsof HMG to achieve a fair degree of steroidogenesis, number ofeggs and number of embryos but who had very low pregnancy rates.Although all other relevant parameters were normal, this mayhighlight the beginning of ovarian–gamete insufficiencybefore the basic hormonal status is affected. In cases of repeatedfailure, oocyte donation should be considered.     

Endocrinology: Pure and highly purified follicle-stimulating hormone alone or in combination with human menopausal gonadotrophin for ovarian stimulation after pituitary suppression in in-vitro fertilization

The use of pure follicle stimulating hormone (pFSH) and highlypurified FSH (FSH-HP) versus the combinations pFSH/human menopausalgonadotrophin (HMG) and FSH-HP/HMG, respectively, was comparedfor stimulating follicular development after gonadotrophin-releasinghormone agonist (GnRHa) suppression in women undergoing in-vitrofertilization (TVF)—embryo transfer. Two consecutive prospective,randomized studies were carried out at the Assisted ReproductionUnit of the Hospital Clínic i Provincial in Barcelona,a tertiary care setting. Two groups of 188 (study 1) and 252(study 2) consecutive infertile patients respectively, scheduledfor IVF-embryo transfer were included. Pretreatment with leuprolideacetate (long protocol) was followed by gonadotrophin treatmentin all patients. In study 1, 92 patients received i.m. pFSHalone (group pFSH) and 96 were treated with the combinationof i.m. pFSH and i.m. HMG (group HMG-1). In study 2, 123 patientsreceived s.c. FSH-HP alone (group FSH-HP) and 129 patients weregiven the combination of s.c FSH-HP and i.m. HMG (group HMG-2).Main outcome measures included follicular development, oocyteretrieval, fertilized oocytes, duration and dose of gonadotrophintherapy, and clinical pregnancy. There were no significant differencesbetween pFSH and pFSH/HMG nor between FSH-HP and FSH-HP/HMGcycles with regard to the number of ampoules of medication used,day of human chorionic gonadotrophin (HCG) administration, meanpeak serum oestradiol concentrations, number of follicles punctured,and number of oocytes aspirated, embryos transferred, or pregnancies.We conclude that urinary FSH (either purified of highly purified)alone is as effective as the conventional combination of urinaryFSH/HMG for ovarian stimulation under pituitary suppressionin IVF cycles. Therefore, they can be used interchangeably inFVF programmes.     

Endocrinology: Follicular fluid insulin-like growth factor-I and insulin-like growth factor-II concentrations vary as a function of day 3 serum follicle stimulating hormone

We determined follicular fluid concentrations of insulin-likegrowth factor (IGF)-I, IGF-II and inhibin as a function of day3 serum follicle stimulating hormone (FSH) in 16 women undergoingfollicular fluid aspiration in preparation for in-vitro fertilizationand embryo transfer. Follicular fluid concentrations of IGF-Iand IGF-II were significantly less in the ‘low’FSH group as compared to the ‘high’ FSH group. Themean IGF-I concentration was 67.6 ng/ml [confidence intervals(CI) 51.6–92.5] in the ‘low’ FSH group comparedto 87.1 ng/ml (CI 72.8–104.2; P < 0.025) in the ‘high’FSH group. Mean IGF-II concentrations were 354.8 ng/ml (CI 297.8–422.9)in the ‘low’ FSH group compared to 489.8 ng/ml (CI384.6–624.5; P < 0.05) in the ‘high’ FSHgroup. Follicular fluid inhibin concentrations did not differbetween groups. These differences in follicular fluid IGF asa function of day 3 FSH may raise questions regarding the rolegrowth factors play in the physiological processes of the ageingfollicle.     

Endocrinology: Ovarian response in consecutive cycles of ovarian stimulation in normally ovulating women

Ovarian stimulation combined with intra-uterine insemination(IUI) is an effective treatment of non-tubal infertility butmost women undergo several cycles of treatment to achieve apregnancy. This prospective study was designed to assess theconsistency (or variation) of ovarian responses and the effectof various ovarian stimulation protocols on this consistencyin consecutive cycles of ovarian stimulation and IUI in womenwith non-ovulatory infertility. A total of 86 regularly menstruatingovulating patients each completed three to six cycles of ovarianstimulation and IUI (n = 347 cycles). Ovarian stimulation wasachieved by sequential clomiphene citrate/human menopausal gonadotrophin(HMG), HMG-only or combined gonadotrophin-releasing hormoneanalogue—HMG protocols in 33, 29 and 24 patients respectively,and each patient used the same protocol consistently throughoutthe study. Standard methods were used to monitor ovarian responseand to perform IUI. Using each patient as her own control, repeatedmeasurements analysis of variance revealed consistency of ovarianresponse in consecutive ovarian stimulation cycles, as shownby the number and mean diameter of maturing pre-ovulatory follicles,peak plasma oestradiol, duration of stimulation and mean HMGrequirements. This consistency existed using any of the ovarianstimulation protocols. We conclude that regularly menstruatingand ovulating women are likely to have similar ovarian responsesin consecutive cycles of ovarian stimulation and IUI if thesame ovarian stimulation protocol is used consistently. Thisis expected to reduce the frequency of treatment monitoringand clinic visits and to help schedule the timing of IUI.     

A randomized comparative study of highly purified follicle stimulating hormone and human menopausal gonadotrophin for ovarian hyperstimulation in an oocyte donation programme

A randomized comparative study of highly purified human follicle-stimulatinghormone (FSH-HP), administered s.c, and human menopausal gonadotrophin(HMG), administered i.m., was carried out in 41 volunteer oocytedonors. The response to ovarian hyperstimulation was similarin both groups. One cycle in both groups was cancelled. Thenumber of oocytes recovered was 16.0 ± 7.9 (mean ±SD) following stimulation with 32.8 ± 103 ampoules ofFSH-HP (n = 19) over 12.3 ± 1.7 days. Following stimulationwith 29.8 ± 10.6 ampoules of HMG over 11.5 ± 1.6days, the number of oocytes collected was 18.4 ± 12.7(n = 20). The oocyte recipients were allocated 9.2 ±3.6 oocytes in the FSH-HP group (n = 33) and 9.6 ± 4.6oocytes in the HMG group (n = 37). The fertilization rate (2PN/cell)was significantly higher in the HMG group (48%, 170/355) thanin the FSH-HP group (36%, 109/304) (P < 0.01). The numberof embryos transferred per recipient was 2.0 ± 0.4 inthe FSH-HP and 2.0 ± 03 in the HMG group. The pregnancyrate per embryo transfer was 25% in the FSH-HP (5/20) and 26%(8/31) in the HMG group. Fertile donors with body mass index£25 made up a poor responder group to s.c FSH-HP, possiblyindicating reduced absorption of the drug.     

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.     

Transfers of frozen-thawed human embryos in cycles stimulated by HMG

A total of 130 transfers of frozen-thawed (F-T) human embryos was carried out after moderate ovarian stimulation with human menopausal gonadotrophin (HMG). Embryos were replaced 3 days after the spontaneous luteinizing hormone (LH) surge or 4 days if ovulation was induced by human chorionic gonadotrophin (HCG). Embryos were thawed a few hours prior to transfer. One-hundred-and-twenty-three transfers were effective and 23 pregnancies were achieved. The rate of ongoing pregnancies per transfer was 17.9% (22/123). The survival rate of embryos originating from cycles stimulated by a combination of an LHRH analogue and HMG in a long protocol (LA-HMG protocol) was significantly lower when compared with the rate of embryos retrieved from clomiphene citrate-HMG (CC-HMG protocol) stimulated cycles (52 versus 67%, P less than 0.05). When fresh embryos originated from cycles stimulated with an LHRH analogue and HMG in a short protocol (SA-HMG protocol), the survival rate was not affected (59 versus 67%, NS). Although the difference was not significant, the ongoing pregnancy rate per transfer according to the three protocols from which the embryos originated seemed to be better with the SA-HMG protocol: 16% with the CC-HMG protocol, 14.5% with the LA-HMG protocol versus 27.6% with the SA-HMG protocol. The success rate was independent of the number of F-T transferred embryos if at least one embryo with 100% intact blastomeres was replaced.