The value of GnRH analogue therapy in IVF in women with unexplained infertility

Seventy-six women with unexplained infertility, undergoing in-vitro fertilization and embryo transfer (IVF-embryo transfer), were selected for three different ovulation induction protocols. In group I, induction of ovulation was performed with pure follicle-stimulating hormone/human menopausal gonadotrophin/human chorionic gonadotrophin (pFSH/HMG/HCG). Group II patients were given a combined therapy consisting of a gonadotrophin-releasing hormone (GnRH) analogue, decapeptyl (DTRP6) followed by pFSH/HMG/HCG. In group III, patients underwent two IVF-embryo transfer cycles, serving as their own controls. The initial cycle was induced with pFSH/HMG/HCG while the second was stimulated using decapeptyl/pFSH/HMG/HCG. Significantly higher rates of fertilization, cleavage and pregnancy (P less than 0.001, P less than 0.07, P less than 0.001, respectively) were achieved in group II patients to whom combined GnRH agonists and gonadotrophins were given. Furthermore, among group III patients, no pregnancies occurred during the initial IVF-embryo transfer cycles whereas a 23% pregnancy rate (P less than 0.001) was obtained after GnRH agonist therapy. Our results indicate that the combination of GnRH agonists and gonadotrophins is of value in cases of unexplained infertility. Further, larger studies must be performed before the true efficacy of this mode of therapy can be determined in women with unexplained infertility.     

Endocrinology: Induction of pre-ovulatory gonadotrophin surge with gonadotrophin-releasing hormone agonist compared to pre-ovulatory injection of human chorionic gonadotrophins for ovulation induction in intrauterine insemination treatment cycles

The clinical outcome of intrauterine insemination (IUI) treatmentcycles employing a gonadotrophin-releasing hormone agonist [GnRHa,triptorelin (Decapeptyl)] or human chorionic gonadotrophin (HCG)for ovulation induction was compared. A group of 48 patientspresenting with amenorrhoea, oligomenorrhoea or unexplainedinfertility were all treated with human menopausal gonadotrophins(HMG) from day 5 of the cycle, on an individualized schedule.They were then randomly divided into two groups to receive eithera single s.c. injection of 0.1 mg triptorelin or a single i.m.injection of 10 000 IU HCG after follicular maturation. IUIwas performed 24 and 48 h following the injection. A transitoryincrease in serum luteinizing hormone and follicle stimulatinghormone concentrations was achieved following injection of GnRHa.A total of 24 patients received 72 treatment cycles with GnRHa,producing 11 conceptions (15.3%) and two abortions (18.2%),resulting in a term pregnancy rate of 13.6%. There were fourcases of grade 3–4 ovarian hyperstimulation syndrome (OHSS),two of which were conception cycles. In all, 24 patients underwent68 cycles treated with HCG, producing 18 conceptions (26.5%)and six abortions (33.3%), resulting in a term pregnancy rateof 19.0%. There were eight cycles of grade 3–4 OHSS, twoof which were conception cycles. These results show that ans.c. injection of a relatively low dose of GnRHa can be as effectiveas HCG in producing pregnancy in IUI treatment cycles.     

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.     

Comparison of HMG/HCG superovulation for AID with or without superactive GnRH agonist

New methods of ovulation induction have been discovered andperfected in recent years. Among others, gonadotrophin-releasinghormone (GnRH) agonists are being used increasingly in the treatmentof ovulatory infertility. In a prospective study, 24 women undergoingartificial insemination with donor sperm (AID) and facing failureof treatment because of ovulation disorders, were treated withhuman menopausal gonadotrophin/human chorionic gonadotrophin(HMG/HCG) superovulation with or without pituitary densensitizationusing a superactive luteinizing hormone-releasing hormone (LHRH)agonist, buserelin (BUS), Suprefact (Hoechst, Frankfurt a/Main,FRG). In 86 cycles stimulated with HMG/HCG no pregnancy occurred,whereas 12 pregnancies occurred in the same group of patientsafter a total of 43 BUS/HMG/HCG stimulation cycles. SuperactiveLHRH agonists have a definite place in the treatment of AIDpatients presenting with refractory ovulation disorders and/orluteal insufficiency.     

Adjuvant growth hormone for induction of ovulation with gonadotrophin-releasing hormone agonist and gonadotrophins in polycystic ovary syndrome: a randomized, double-blind, placebo controlled trial

The objective of this study was to explore the effect of cotreatmentwith recombinant human growth hormone (GH), gonadotrophin-releasinghormone agonist (GnRHa) and human menopausal gonadotrophin (HMG)for induction of ovulation in women with clomiphene resistantpolycystic ovary syndrome (PCOS). It was designed as a randomized,double-blind, placebo controlled trial in which 30 women withanovulation associated with PCOS who were resistant to clomipheneall received DTRP6-LHRH (Decapeptyl microcapsules, 3.75 mg,i.m.) and, 2 weeks later, HMG in a standard, conventional, individuallyadjusted dose regimen until human chorionic gonadotrophin (HCG)and then luteal phase support could be given. From day 1 ofHMG therapy, patients were randomized to receive either humanGH (Norditropin, 12 IU/day, i.m., for 7 days) or placebo. Thenumber of ampoules, duration of treatment and daily effectivedose of HMG required to achieve ovulation, serum oestradiolconcentrations and number of follicles induced, ovulation andpregnancy rates, serum insulin and insulin-like growth factor-I(IGF-I) concentrations were measured. There were no significantdifferences between growth hormone and placebo groups in anyof the outcomes measured, other than a growth hormone inducedincrease in serum insulin and IGF-I levels. We conclude thatalthough GH kinetics are abnormal and GH pituitary reservesgenerally low in women with PCOS, adjuvant GH treatment to GnRHa/HMGdoes not influence follicular development or sensitivity inresponse to gonadotrophins and that it does not seem likelyto be of any potential clinical benefit for the treatment ofPCOS.     

A double-blind cross-over controlled study to evaluate the effect of human biosynthetic growth hormone on ovarian stimulation in previous poor responders to in-vitro fertilization

The effect of exogenous human biosynthetic growth hormone (HGH;12 IU/day; Norditropin, Novo-Nordisk) on the response to ovarianstimulation using a buserelin/human menopausal gonadotrophin(HMG) regimen was assessed in women who had previously showna ‘poor response’ in spite of increasing doses ofHMG. Forty patients were recruited into a prospective double-blindplacebo-controlled study. The serum follicle stimulating hormone(FSH) on day 2–5 of a menstrual cycle (< 10 IU/I) wasused to exclude any peri-menopausal candidates. The urinary24 h GH secretion was normal in all patients. Thirty-three patientscompleted the study with 21 patients having human chorionicgonadotrophin (HCG) in both arms, thus providing a completeset of placebo control data. Of these 21 patients, the administrationof HGH compared to the placebo cycle resulted in increased serumconcentrations of fasting insulin on the 8th (median 3.9 versus5.8 mU/I; P < 0.0005) and13th (median 4.4 versus 5.8 mU/I;P < 0.05) day of HMG in those cycles receiving HGH. After8 days of co-treatment with HGH the number of cohort follicles(14–16.9 mm) was significantly increased, but this changewas not sustained on the day of HCG administration. No statisticaldifference in the serum oestradiol on the 8th day of HMG orday of HCG, length of the follicular phase, total dose of HMGused, or the number of oocytes collected was seen between theplacebo or HGH cycles. This study demonstrates that HGH doesnot improve the ovarian response to ovulation induction in previouspoor responders.     

Human menopausal gonadotrophin increases pregnancy rate in comparison with clomiphene citrate during replacement cycles of frozen/thawed pronucleate ova

In a prospective randomized study, the effect of two ovulationinduction regimens on implantation rate of frozen/thawed pronucleateova was investigated. Patients received either human menopausalgonadotrophin (HMG) or clomiphene/HMG. Ovulation induction wasdone on an individual basis using ultrasound and plasma 17-oestradiolconcentrations. Ovulation was induced with human chorionic gonadotrophin(HCG) when the leading follicle reached a diameter of 18 mm.Pronucleate ova had been frozen using the slow-freezing methodof Lassalle et al. (1985) (Fertil. Steril., 44, 645–651)and were thawed in synchrony with the age of the endometrium.Both groups of patients were comparable for age, indicationfor in-vitro fertilization, pre-ovulatory 17-oestradiol concentration,number of large follicles and number and quality of embryostransferred. The only difference found was that HCG was administered1 day earlier in the HMG group compared to the clomiphene/HMGgroup (P< 0.01). Using univariate analysis, the pregnancyrate was higher in patients stimulated with HMG alone comparedto those stimulated with clomipheneöHMG (27 versus 15%respectively; P < 0.03), when HCG was administered laterin the menstrual cycle (P < 0.01) and when more and betterquality embryos were transferred (P < 0.01). Using multivariateregression analysis, the influence of the stimulation on pregnancyrate was even more pronounced (P < 0.01) when the day ofHCG administration and the number and quality embryos transferredwere taken into account. Therefore, we conclude that HMG aloneincreases pregnancy rate compared to clomiphene/HMG during replacementcycles of frozen/thawed pronucleate ova. These data suggestthat HMG results in a better endometrium receptivity for embryos.This could be important not only for embryo replacement cyclesbut also for ovulation induction in general.     

The effect of progesterone supplementation prior to the induction of ovulation in women treated for in-vitro fertilization

Thirty-one patients superovulated with clomiphene citrate (CC)and human menopausal gonadotrophin (HMG) were given a singleinjection of 25 mg progesterone (P group) 6 h prior to injectionof human chorionic gonadotrophin (HCG). Levels of urinary andplasma luteinizing hormone (LH) were significantly higher (P<0.001)immediately prior to HCG in the P group compared with thirty-onecontrol patients who had HCG on the same night. Plasma levelsof progesterone remained significantly elevated (P<0.02)for 80 h after injection in the P group, thereafter the levelwas similar to controls. The number of oocytes recovered, fertilizedand replaced per patient was identical in both groups. However,four control patients had no embryos replaced due to failedfertilization. It is concluded that (i) in the majority of Ppatients the timing of ovulation induction by HCG injectionwas appropriate as an LH surge was elicited thus reflectinga physiological stage of readiness, and (ii) elevated plasmaprogesterone levels around the time of oocyte recovery and inthe early luteal phase do not increase the likelihood of theestablishment of pregnancy in patients stimulated for in-vitrofertilization and embryo replacement (TVF/ER) with CC and HMG.     

Regulation of corpus luteum function

The effects have been studied of different ovulation inductionregimens [either domiphene citrate or buserelin in combinationwith human menopausal gonadotrophin (HMG)] on the circulatingconcentrations of progesterone, oestradiol, relaxin and humanchorionic gonadotrophin (HCG) during the first trimester ofpregnancy. Ovulation induction with clomiphene resulted in elevatedconcentrations of gonadotrophins in both phases of the cycle,while during ovulation induction with buserelin, gonadotrophinconcentrations were elevated in the follicular phase only. Theconcentrations of all corpus luteum products were greater inclomiphene pregnancies compared with spontaneous pregnancies,but only oestradiol and relaxin concentrations were greaterin clomiphene pregnancies compared with buserelin pregnancies.The concentrations of HCG were significantly reduced in clomiphenepregnancies compared to natural pregnancies. Relaxin concentrationswere significantly higher from 7 weeks gestation in buserelincompared with spontaneous pregnancies, while progesterone, oestradioland HCG concentrations were not consistently different. Consistentassociations were found between relaxin and HCG concentrationsin spontaneous pregnancies and between the concentrations ofrelaxin and both progesterone and oestradiol in pregnanciesachieved after ovulation induction. These data suggest that(i) given the similarity in the circulating concentrations ofHCG, the relatively lower circulating gonadotrophin concentrationsduring the luteal phase of the cycle of conception result inreduced circulating concentrations of oestradiol and relaxin;while in the case of relaxin this effect is partially reversible,there is no evidence that this is so for oestradiol; (ii) synthesisof progesterone in the corpus luteum is less affected by lowerconcentrations of gonadotrophins during the luteal phase; (iii)ovulation induction with clomiphene results in pregnancies withlower concentrations of HCG, suggesting that trophoblast functionmay be impaired; and (iv) corpus luteum function is linked withplacental steroidogenesis.     

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)     

Supplementary growth hormone treatment of women with poor ovarian response to exogenous gonadotrophins: changes in serum and follicular fluid insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3)

The effects of supplementary growth hormone (GH) treatment uponinsulin-like growth factor-1 (IGF-1), IGF binding protein-3(IGFBP-3) concentrations in serum and ovarian follicular fluidwere investigated in women undergoing buserelin human menopausalgonadotrophin (HMG) ovulation induction for in-vitro fertilization.Women (n = 40), aged 24–39 (mean 35 years), who showedpoor ovarian responses to HMG, were recruited and randomly dividedinto two groups. Each patient received two cycles of ovulationinduction, one with GH (12 IU/day x 12 days/HMG/buserelin) andanother with placebo/HMG. Serum IGF-1 increased substantiallyduring the GH treatment and remained significantly higher thanthe control 2 days after the last GH injection. Serum IGFBP-3fell steadily during the placebo/HMG treatment and to a nadiron the day of oocyte retrieval (P <0.05 compared to serumbefore any treatment). In contrast, IGFBP-3 was increased (P<0.01) during the GH administration and returned to the controllevel 2 days after GH injection. Serum oestradiol concentrationson the eighth day of HMG and the day of human chorionic gonadotrophin(HCG) were not significantly different between the two groups.Serum IGF-1 was highly correlated with IGFBP-3 before any treatment(r = 0.433, P < 0.001). This correlation disappeared afterbuserelin, placebo/HMG treatment in the control group, but itwas maintained during GH/HMG treatment (r = 0.343, P = 0.04).Follicular fluid concentrations of GH and IGF-1, not IGFBP-3or oestradiol, were significantly elevated in the GH-treatedwomen. Serum IGF-1 on the day of oocyte retrieval was highlycorrelated to the follicular fluid IGF-1 in both groups. Therelationships between the follicular fluid GH and IGF-1 werecompletely opposite in the two groups, being positive in thecontrol group and negative in the GH-treated group. In the controlgroup, significant correlations were found between follicularfluid concentrations of IGF-1 and IGFBP-3, and GH and IGFBP-3which were not found in the GH-treated group. There were nocorrelations found between follicular fluid concentrations ofGH or IGF-1 or IGFBP-3 and oestradiol. The results clearly demonstratethat the normal GH, IGF-1, IGFBP-3 relationships can be alteredby treatments which influence the ovarian—pituitary axis;the significance of such changes to ovulation remains to bediscovered.     

Endocrinology: Stimulation of ovarian adenylyl cyclase activity by gonadotrophins during the natural and gonadotrophin-induced cycles in the hamster

In this study we utilized the hamster ovary as a model to investigatethe effects of ovulation induction with gonadotrophin on theactivation of the signal transducer effector system, adenylylcyclase (AC). For this purpose, we prepared membrane particlesfrom the ovary and analysed both gonadotrophin-sensitive ACand non-receptor-mediated activation during a cycle in whichovulation and luteinization were achieved by pregnant mare’sserum gonadotrophin (PMSG)/human chorionic gonadotrophin (HCG)administration. Results were directly compared with AC activationin similarly prepared membranes obtained at different stagesof the natural unstimulated cycle. AC activity was quantifiedby the direct conversion of ATP substrate into cyclic adenosinemonophosphate (cAMP). Measurements of ovarian weights, serumoestradiol and progesterone concentrations provided a solidbase from which to evaluate the functional status of the ovaryat each time period during the natural and stimulated cycles.We found that ovarian membranes contain functional componentsof the AC system and demonstrated that AC is highly dependenton hormonal changes and the functional state of the ovary. Thus,during the natural cycle, ovarian AC showed relatively constantresponsiveness to follicle-stimulating hormone (FSH) throughoutthe cycle, whereas responsiveness to luteinizing hormone (LH)/HCGreached its peak during the luteal phase. On the other hand,during the stimulated cycle, sensitivity to FSH and LH/HCG variedconsiderably, being absent during the peri-ovulatory period.AC responsiveness to gonadotrophins was only regained 48 h afterovulation. Also during the peri-ovulatory period of the gonadotrophin-inducedcycle, stimulation of ovarian AC with non-hormonal activatorsdeclined. However, the rate of cAMP production in response tothese activators remained very high, indicating that despiterefractoriness to gonadotrophins, ovarian AC retained the capacityto generate cAMP at near maximal efficiency. Basal (non-stimulated)activity, guanine nucleotide activation, hormone responsivenessand stimulation by the non-hormonal activators NaF and forskolinwere all significantly increased in comparison with the naturalcycle. Basal activity alone was 7-fold higher than the activityobserved during the unstimulated cycle. These results suggestthat subsequent to exogenous gonadotrophin administration, thetransmembrane effector AC system must be primed for a higherlevel of activity in the ovarian tissue. This priming of theovarian AC system by exogenous gonadotrophin was also evidentwhen the enzyme was measured under conditions allowing maximalactivity, i.e. in the presence of a combination of NaF and forskolin.Maximal AC activity increased 4- to 5-fold compared with thenatural cycle. We conclude that gonadotrophin administrationinducing ovulation causes profound alterations in the expressionof AC in ovarian membranes. Gonadotrophin treatment increasedthe enzyme activity and induced a temporal desensitization toFSH and LH/HCG in the peri-ovulatory period of the stimulatedcycle. Because the gonadotrophin-sensitive AC system representsthe capacity of FSH and LH/HCG receptors to couple and elicita biological response, our results provide new insights intothe cellular mechanisms that regulate ovarian activity duringinduction of ovulation.     

Is continuation of a gonadotrophin-releasing hormone agonist (GnRHa) necessary for women at risk of developing the ovarian hyperstimulation syndrome?

A total of 28 women scheduled for in-vitro fertilization used buserelin and human menopausal gonadotrophin (HMG) for ovarian stimulation. One group (I) of 17 women was given human chorionic gonadotrophin (HCG 10,000 IU) to trigger ovulation, but the resulting embryos were electively cryopreserved because of the risk (serum oestradiol greater than or equal to 3500 pg/ml) of developing the ovarian hyperstimulation syndrome (OHSS). Six women continued the buserelin therapy in the luteal phase and eleven did not. In group II (n = 11), the HMG injections were discontinued because of an exaggerated ovarian response and the HCG was omitted. Six of these women continued the buserelin injections until the onset of menses and five did not. In both groups, the ovarian response to induction of ovulation (serum oestradiol concentrations and number of follicles) was similar for those who did or did not continue buserelin therapy. There was no difference in the rate of ovarian quiescence (weekly fall in serum oestradiol concentration following the stimulation) between those women who did or did not continue the buserelin therapy in either group. The serum luteinizing hormone concentrations remained low in all women in both groups. We conclude that the omission of buserelin therapy after discontinuing the HMG in women at risk of developing OHSS does not affect subsequent ovarian quiescence.     

Differential effects of gonadotrophin-releasing hormone agonists administered as desensitizing or flare protocols on hormonal function in the luteal phase of hyperstimulated cycles

The incorporation of gonadotrophin-releasing hormone agonist (GnRHa) in in-vitro fertilization (IVF) stimulation protocols has led to doubt about the quality of the subsequent luteal phase. The effects of two GnRHa stimulation protocols on luteal phase concentrations of oestradiol (E2), progesterone (P), luteinizing hormone (LH) and follicle stimulating hormone (FSH) were compared with the standard clomiphene stimulation regimen. Subjects receiving clomiphene with human menopausal gonadotrophin (HMG, n = 377) showed essentially similar luteal phase P concentrations to those receiving leuprolide acetate/HMG as a desensitization protocol. Subjects receiving concomitant leuprolide and HMG from day 2 to utilize the flare effect of the GnRHa exhibited significantly lower P levels in the luteal phase compared to clomiphene/HMG and leuprolide desensitization protocols despite the addition of HCG support. This occurred despite equivalent E2 concentrations at the time of ovulation and identical numbers of oocytes recovered. LH concentrations in non-conception cycles were suppressed for at least 14 days in the luteal phase in both GnRHa protocols compared to clomiphene stimulation. Differences were less obvious in cycles where conception occurred suggesting that implantation may proceed more favourably when the luteal endocrinology was optimal. It is concluded that flare methods of GnRHa hyperstimulation are associated with significantly different luteal phases compared with clomiphene or desensitization protocols. It is proposed that the use of the flare type of stimulation may significantly influence the response of the granulosa cells to LH or HCG via gonadotrophin receptors or through altered post-receptor function.     

Infertility: Is there a role for ovarian stimulation and intra-uterine insemination after age 40?

The objective of this study was to determine the conceptionrate in infertile couples in which the female partner was40years old and who had received ovarian stimulation treatmentand intra-uterine insemination (IUI). It was a retrospectivestudy of 77 patients who underwent a total of 210 treatmentcycles. Protocols for ovulation induction included clomiphenecitrate, human menopausal gonadotrophin (HMG) and clomiphenecitrate plus HMG. Patients were monitored using transvaginalultrasound, and two IUI were performed 24 and 48 h after thedetermination of urinary luteinizing hormone (LH) surge or humanchorionic gonadotrophin (HCG) injection. A total of 11 pregnancieswere reported, giving a pregnancy rate of 14% per patient and5% per cycle. Eight spontaneous abortions occurred, giving apregnancy wastage of 73%. In a previous comparative analysisof 543 patients <39 years old receiving IUI and identicalprotocols of ovarian stimulation, 141 pregnancies were achieved,giving a pregnancy rate of 21% per patient and 10% per cycle.The miscarriage rate in that group was 18%. This report comparesIUI results for women 40 years with those obtained previouslyfor younger women, and shows the very poor success rate in women>40 years of age. This information will be important in theproper counselling of this group of patients, as well as indicatingthat a prompt recommendation for assisted reproductive treatmentshould be made soon after the failure of a few attempted cyclesof ovarian stimulation treatment and IUI.     

Combined luteinizing hormone releasing hormone analogue and exogenous gonadotrophins for the treatment of infertility associated with polycystic ovaries

This study was designed to compare the results of treatment with, firstly, exogenous gonadotrophins, with (57 cycles) and without (65 cycles) pretreatment with a superactive analogue of luteinizing hormone releasing hormone (LHRH) and, secondly, pure follicle stimulating hormone (FSH) (50 cycles) with those of human menopausal gonadotrophin (HMG) (72 cycles) in 46 women with clomiphene-citrate-resistant anovulation associated with polycystic ovaries. Patients randomly allocated to the analogue group received buserelin (Suprefact, Hoechst, UK, Ltd, Hounslow, Middlesex), 800 micrograms/day by nasal insufflation and when hypogonadism was achieved, patients were again randomly allocated for ovarian stimulation with either FSH or HMG. Controls received FSH or HMG alone. Patients pretreated with the analogue had similar pregnancy and ovulation rates, needed larger doses and more days of gonadotrophin therapy and had more ovarian overstimulation than those receiving no pretreatment. The role of superactive LHRH analogues for induction of a single ovulation for in-vivo fertilization is thus uncertain. Pure FSH had no advantages over HMG, the LH content of HMG having no deleterious effect on the ovary.     

Sertoli-Leydig cell tumour in an infertile patient after stimulated ovulation

A 36 year-old infertile female developed a stage IV (FIGO) ovarian carcinoma consisting of a poorly differentiated Sertoli-Leydig cell tumour after receiving one course of ovulation induction with follicle stimulating hormone (FSH), human menopausal gonadotrophin (HMG) and human chorionic gonadotrophin (HCG) followed by gonadotrophin-releasing hormone analogue (GnRHa). The patient died of liver metastasis and hepatic failure 4 1/2 months after first diagnosis, despite aggressive treatment consisting of debulking surgery and aggressive adjuvant chemotherapy.      

Insulin-like growth factor binding proteins in serum and follicular fluid from women undergoing ovarian stimulation with and without growth hormone

The effects of supplementary growth hormone (GH) upon insulin-likegrowth factor binding proteins (IGFBP) in serum and ovarianfollicular fluid were investigated in women undergoing buserelin-humanmenopausal gonadotrophin (HMG) ovulation induction for in-vitrofertilization. IGFBPs were detected by Western ligand blotting(WLB) or radio-immunoassay (IGFBP-3) and were shown in the presentstudy to increase and decrease in patients with diseases ofGH excess or deficiency. In the women undergoing treatment forovulation induction, radioimmunoassay of IGFBP-3 gave resultswhich were consistent with the well-documented GH dependencyof this protein, increasing in the serum when GH was administeredat the same time as busereli-HMG. In contrast there were noconsistent patterns in the abundance of the IGFBPs in serumand follicular fluid examined by WLB whether or not the patientwas receiving GH, and the IGFBPs varied independently of theresult obtained by radioimmuno-assay. Other studies have shownthat during pregnancy a serum protease can dramatically decreasethe detection of the IGFBPs on the WLB. However, there was noevidence for a protease in the serum or follicular fluid fromthese non-pregnant women undergoing ovulation induction. Tissueavailability of IGFs is probably regulated by the BPs, so thatdata would suggest that in normal women, neither ovarian activitynor GH at pharmacological concentrations is the primary regulatorof the IGFBPs, which are likely to be regulated by some otherfactor(s), e.g. nutrition. These data may account for the lackof consistent clinical improvement in studies investigatingthe hypothesis that supplementary GH during ovulation inductionwith gonadotrophins would be beneficial.     

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.     

Beneficial effects of a 24 h delay in human chorionic gonadotrophin administration during in-vitro fertilization treatment cycles

We used a gonadotrophin-releasing hormone agonist (buserelin)and human menopausal gonadotrophin (HMG) for superovulationfor in-vitro fertilization (IVF) in 143 patients. The patientswere prospectively allocated to two balanced groups. In onegroup (47 patients) human chononic gonadotrophin (HCG) was givenwhen the three largest follicles were 17 mm ni diameter, withconsistent levels of plasma oestradiol (standard group). Inthe second group (96 patients), HCG injection was delayed by24 h (delayed group). In the delayed group of patients, proportionatelymore had clinical pregnancies (52.1% versus 34.0%). These resultssuggest that IVF patients will benefit from delayed administrationof HCG. The traditional criteria for HCG administration shouldbe changed when buserelin is used.