Endocrinology: Progesterone alone versus progesterone combined with HCG as luteal support in GnRHa/HMG induced IVF cycles: a randomized clinical trial

Two different regimens of luteal support in gonadotrophin hormone-releasinghormone (GnRH) analoguefhuman menopausal gonadotrophin (GnRHa/HMG)-inducedin-vitro fertilization cycles (IVF) were compared in a randomizedclinical trial. After embryo transfer, either vaginal progesteronealone was administered (n=89, P group), or a combination ofvaginal progesterone and human chorionic gonadotrophin (n=87,P/HCG group). The primary aim of this study was to assess theeffect of the different regimens of luteal support on the pregnancyrate. The secondary aim was to compare oestradiol and progesteroneconcentrations in the luteal phase between the two groups, andassess their effect on the pregnancy rate. A clinical pregnancyrate of 15% was found in the P/HCG group in comparison with26% in the P group (odds ratio 0.49; 99% confidence interval:0.18–1.3). The luteal serum oestradiol and progesteronevalues in the P/HCG group were significantly higher when comparedwith the P group on the 6th, 9th and 12th day after oocyte retrieval(Wilcoxon P<0.001). In accordance with the high oestradiolconcentrations, more cases of ovarian hyperstimulation syndrome(OHSS) were found in the P/HCG group. Oestradiol values on the9th day after oocyte retrieval, presumably the day of implantation,appeared to be higher in women who did not become clinicallypregnant. We conclude that vaginal progesterone alone providessufficient luteal support in GnRHa/HMG induced IVF cycles. Thecombination of vaginal progesterone and HCG as luteal supportleads to significant high luteal oestradiol and progesteroneconcentrations. But a high concentration of oestradiol seemsto have a deleterious effect on the implantation process, resultingin a low pregnancy rate.     

Physiology: Morphological characteristics of preimplantation stage endometrium in the rhesus monkey

The morphological characteristics of endometrium on day 6 afterovulation of conception (group 1) and non-fecund, menstrual(group 2) cycles have been studied in the rhesus monkey (n =30). A conception cycle was distinguished by the presence ofa developmentally normal, age—stage-synchronized embryo.Thus, 78% of the mated cycles (n = 18) yielding synchronousembryos (12 zona-encased and two zona-free blastocysts) wereused for this study. On day 6 after ovulation, no significantchanges in the serum concentrations of oestrogen and progesteronewere seen in conception cycles (n = 14) compared with the non-mated,normal ovulatory cycles (n = 12). Morphometric analyses revealedthat on day 6 of gestation (n = 8), endometrium differed fromthe corresponding non-mated luteal phase (n = 7) with significantincreases in epithelial mitosis (P < 0.01), height of glandularepithelium (P < 0.05), volume ratio of gland cell to gland(P < 0.03), degree of pseudostratification (P < 0.02),and higher frequency of supranuclear, adluminal accumulationof vacuoles in gland cells (P < 0.05). The degree of stromaloedema was higher (P < 0.02) in fecund cycles but there wasno change in venular diameter. In a separate set of experiments,estimates of tissue vascular response revealed a higher (P <0.02) endometrial extravascular albumin space on the same dayof gestation; there were no differences, however, in endometrialblood volume, or in the number of von Willebrand antigen-positivecapillaries and small vessels between the two groups (group1, n = 6; group 2, n = 5). The overall results of the presentstudy together with our earlier reports support the hypothesisthat differential changes occur in luteal phase endometriumfunctionalis in the presence of preimplantation stage blastocystin the rhesus monkey.     

Anti-nidatory effect of a single, early post-ovulatory administration of mifepristone (RU 486) in the rhesus monkey

The hypothesis that post-coital administration of mifepristone(RU 486) as a single dose in the early luteal phase can be aneffective anti-nidatory strategy was tested using the rhesusmonkey as the experimental model. Incidence of pregnancy, vaginalbleeding patterns, profiles of menstrual cyclicity and of serumlevels of progesterone and oestrogen were examined followingadministration of RU 486 as a single dose of 10 mg/kg and 2mg/kg body weight on the second day after ovulation. In controlmonkeys (group 1; n = 5) receiving the vehicle alone (benzylbenzoate: olive oil, 1: 4, v/v) there was a 60% pregnancy rate.Following s.c. administration of RU 486 at both doses, no pregnancywas recorded in a total of 33 treatment cycles in 12 monkeys.Five monkeys received RU 486 at 10 mg/kg s.c. (group 2) in threeconsecutive cycles. All animals had complete inhibition of implantation;in addition, the treatment cycle length was prolonged (P <0.001) due to an extension of the luteal phase. The subsequentfollicular phase was unaffected. Mild, premature vaginal bleedingduring the luteal phase was recorded in five treatment cycles,3–5 days after drug application. Though the serum profilesof progesterone and oestrogen in these monkeys showed markedindividual variations, there was a characteristic progesteronerebound about 18–20 days after drug administration. Monkeysin group 3 were given RU 486 at 2 mg/kg, s.c. either for threeconsecutive cycles (group 3a; n = 4) or for two consecutivecycles (group 3b; n = 3). Premature luteal phase vaginal bleedingoccurred only in four treatment cycles, within 2–6 dayspost-treatment. An increase in both the duration (P < 0.001)and degree (P < 0.001) of menstrual flow as compared withthe pre-treatment cycles was recorded in six treatment cyclesof three monkeys in group 3. These animals did not have prematureluteal phase vaginal bleeding. Collectively, 100% protectionagainst pregnancy with no change in the cycle length was obtainedin all seven monkeys in 18 treatment cycles. Analysis of pooleddata revealed that the subsequent follicular phase, as wellas the ovarian steroid hormone profiles of treatment cycleswere unaffected. Thus, a single application of RU 486 in theearly secretory phase appears to be a potential anti-implantationstrategy for intercepting pregnancy in the primate.     

Alternate day and daily administration of GnRH antagonist may prevent premature luteinization to a similar extent during FSH treatment

BACKGROUND: This randomized controlled trial was designed toevaluate whether a GnRH antagonist given every other day couldprevent premature luteinization in women undergoing IVF/ICSItreatment. METHODS: A total of 73 women receiving ovulationstimulation IVF cycles with recombinant FSH were allocated randomlyon cycle day 7 to GnRH antagonist ganirelix in multiple doses(0.25 mg each), either daily (n = 37 women, group 1) or everyother day (n = 36 women, group 2) until the day of HCG administration.RESULTS: Serum FSH, LH, estradiol and progesterone values showedsimilar trends in the two groups. During FSH stimulation, 13(35%) of the women in group 1 had premature LH rises (10 IU/l)of which eight (22%) were after the start of antagonist administration.In group 2 there were 14 (39%) LH rises during FSH stimulationof which 10 (28%) were after the start of antagonist administration.Luteinization (serum progesterone >2 ng/ml) occurred in onlyone woman in each group overall (3%). A significantly smallertotal dose of the antagonist was used in group 2 than in group1 (P < 0.001). The study did not have power to evaluate differencesin total dose of FSH, number of oocytes recovered and clinicalpregnancy rate, all of which appeared similar in the two groups.CONCLUSIONS: Whether alternate day is as effective as dailyadministration of ganirelix in preventing premature luteinizationshould be addressed in a non-inferiority trial powered to evaluatelive birth rate.     

Endocrinology: Low dose transdermal oestradiol suppresses gonadotrophin secretion in breast-feeding women

The object of the study was to investigate the effect on gonadotrophinsecretion of a small increase in oestradiol concentration. Atotal of 13 fully breast-feeding women (12 weeks post-partum)underwent serial blood sampling at 10 min intervals for 12 hon 2 different days; day 1 untreated and day 5 after 3 daysof treatment with transcutaneous oestradiol (100 µg/day).On both days bolus gonadotrophin-releasing hormone (GnRH; 10µg i.v.) was given after a 10 h baseline period. In sixof the subjects, a naloxone infusion was administered duringthe second study day. Application of transdermal oestradiolraised the oestradiol concentration within the normal follicularphase range. The mean luteinizing hormone (LH) concentrationon day 5 was found to be significantly lower than that on day1 (P < 0.05). The LH response to GnRH was, however, significantlyhigher on day 5 than day 1 (P < 0.001). The mean folliclestimulating hormone (FSH) concentration on day 5 was also significantlylower than that on day 1 (P < 0.01), while the peak concentrationafter GnRH was unchanged. When the opioid antagonist naloxonewas infused after oestradiol treatment, the subjects with lowpre-study oestradiol concentrations exhibited no effect on LHconcentration, while in the subjects with higher oestradiolconcentrations the LH concentration was increased. It was concludedthat the administration of small doses of oestradiol causeda significant fall in gonadotrophin concentration in breast-feedingwomen. This indicates a heightened sensitivity to the negativefeedback effect of oestradiol on GnRH release from the hypothalamus,since the pituitary response to GnRH was unaltered. Furtherstudies are required to investigate the possibility that thesedoses of oestrogen may have some clinical value in inhibitingovulation after delivery.     

Immunology: Serum markers of immune activation in women undergoing in-vitro fertilization and embryo transfer

We evaluated serum concentrations of two early and sensitivemarkers of immune activation, interleukin-2 receptor (sIL-2R)and intercellular adhesion molecule-1 (ICAM-1) in two age-matchedgroups of in-vitro fertilization (IVF)-embryo transfer women,group I (n = 26) without and group II (n = 40) with methylprednisolone(MPD) supplementation of the luteal phase, on the days of oocyteretrieval (sample A) and embryo transfer (B), and second (C)and 13th (D) days post-transfer and in 20 normally cycling women(controls) on the day of luteinizing hormone (LH) peak. No differencein the outcome of the IVF-embryo transfer was observed betweengroups I and II. In sample A, both immunomarker concentrationsshowed no significant difference between the two groups of IVFwomen, while they were significantly higher (P < 0.01) thanvalues in controls. In cycles in which conception occurred,significantly higher immunomarker concentrations were observedin sample A of both groups I and II compared with those in unsuccessfulcycles of the same group. A significant decrease of both sIL-2Rand ICAM-1 was noticed in sample B only in group II (P <0.0001 and P < 0.001 respectively; paired t-test) that continuedfurther in the late luteal phase only hi the case of conception,independently of MPD supplementation. These data suggest that(i) due to multiple ovulations, IVF-embryo transfer women showelevated concentrations of sIL-2R and ICAM-1 at oocyte retrieval;(ii) since, even at oocyte retrieval stage, high concentrationsof immunomarkers are associated with IVF-embryo transfer success,sEL-2R and ICAM-1 could be used as early indicators for conceptioncycles; (iii) transient suppression of T cell activity by MPDsupplementation following IVF-embryo transfer does not improvepregnancy rate.     

Endocrinology: Ovarian hyperstimulation syndrome: pre-ovulatory serum concentrations of interleukin-6, interleukin-1 receptor antagonist and tumour necrosis factor-{alpha} cannot predict its occurrence

The pathogenesis of the ovarian hyperstimulation syndrome (OHSS)is poorly understood. Since significant elevations in cytokinesare found in 01155, our objective was to conduct a prospectivecase-controlled study to assess if preovulatory cytokine serumconcentrations can predict its occurrence. The study group wasselected from in-vitro fertilization patients who subsequentlydeveloped severe OHSS, along with a matched group who did notdevelop this complication (n = 20), and a healthy normal controlgroup (n = 10). Interleukin-6 (IL-6), interleukin-1 receptorantagonist (IL-1RA) and tumour necrosis factor- (TNF) measurementswere performed with sensitive immune-assays and confirmed withbioassays. Serum IL-6 (mean concentration ± SEM: 4.38± 0.36 pg/ml), IL-1RA (829 ± 292 pg/ml) and TNF(15.5 ± 132 pg/ml) concentrations did not show differencesthroughout the normal menstrual cycle group. Cytokine variabilityand pre-ovulatory values were similar in OHSS compared to controlledovarian hyperstiinulation (COH) patients. However, average follicularphase serum 1L-6 concentrations were higher in OHSS (8.71 ±0.41 pg/ml) and COH (7.66 ± 0.38 pg/ml) patients thanin normally menstruating women (4.34 ± 0.99 pg/ml) (P< 0.0001). Pre-ovulatory serum 1L-6 concentrations were alsohigher in OHSS (9 ± 0.94 pg/ml) and COH (73 ±0.97 pg/ml) patients than in controls (4.57 ± 1.1 pg/ml)(P < 0.01 and P < 0.04 respectively). IL-1RA and TNF concentrationswere comparable in all the groups. This study suggests thatcytokine measurements cannot be used to predict the occurrenceof OHSS prior to the administration of human chorionic gonadotrophin.     

Endocrinology: Pre-ovulatory oxytocin administration promotes the onset of the luteinizing hormone surge in human females

Luteinizing hormone (LH) secretion during the ovulatory cycleis believed to be predominantly regulated by gonadotrophin-releasinghormone. Investigations in animals have strongly suggested thatoxytocin also participates in LH control and the physiologicalevents controlling LH surge initiation. In the human female,however, there has been no evidence supporting oxytocin's involvementin the processes leading to ovulation. In this study the effectof a preovulatory infusion of oxytocin on the onset of the LHsurge was investigated in women aged 20–35 years who hadnatural ovulatory menstrual cycles of lengths between 25–35days. Vaginal ultrasound scanning monitored follicular growthduring the late follicular phase. When a follicle >>14mm in diameter was observed each woman was randomized into oneof two groups. One group (n = 8) received an oxytocin infusionof 256 mlU/min for 2 h, the other group (n = 8) received normalsaline. The women who were administered oxytocin at this latefollicular stage had an earlier onset of the LH surge than thosewho had received saline (P < 0.01). The results indicatethat oxytocin promotes the onset of the LH surge in humans.     

Endocrinology: Comparison of gonadotrophin-releasing hormone analogues and human chorionic gonadotrophin for the induction of ovulation and prevention of ovarian hyperstimulation syndrome: a case-control study

Gonadotrophin-releasing hormone analogue (GnRHa) has been suggestedas an alternative to human chorionic gonadotrophin (HCG) fortriggering ovulation, while preventing ovarian hyperstimulationsyndrome (OHSS). Since a prospective, controlled study wouldbe unethical at this point, we used a retrospective, case-selfcontrol approach to compare GnRHa with HCG in that context.A group of 16 in-vitro fertilization (IVF) patients who hadsevere OHSS in previous cycles, in which HCG was given to triggerovulation, were studied in subsequent cycles in which GnRHawas used. Each GnRHa cycle (case) was compared to a previousHCG cycle that resulted in OHSS (self control). None of thesesubsequent cydes resulted in severe OHSS. The use of GnRHa didnot affect the number of oocytes retrieved or their quality.Serum oestradiol concentrations on the day of ovulation triggeringwere signilicantly (P<0.01) higher in the GnRHa cycles comparedto HCG cycles. Exogenous progesterone and oestra diol were effectivein maintaining relatively constant serum oestradiol and progesteroneserum concentrations during the luteal phase. Pregnancy rateper cycle was similar in the two groups. In conclusion, theuse of GnRHa to induce ovulation in IVF patients, who are athigh risk for developing OHSS, effectively eliminates this riskwithout affecting other parameters of the stimulation cycle.     

Endocrinology: High ovarian response in Yoruba African women during ovulation induction for assisted conception

Fertile Yoruba women from western Nigeria have a much higherincidence of naturally conceived multizygotic twin and tripletpregnancies than Caucasians. The objective of the present studywas to determine whether there are differences between infertileYoruba and Caucasian women in terms of ovarian response in stimulatedcycles for assisted conception. A total of 11 Yoruba women werescheduled for 14 in-vitro fertilization (IVF) and one gameteintra-Fallopian transfer (GIFT) cycles from 1990 to 1992. TheCaucasian group consisted of 209 women scheduled for 213 IVFand 22 GIFT cycles during the same period. Buserelin, 500 µgsubcutaneously daily, was started in the mid-luteal phase toachieve pituitary desensitization. Ovarian stimulation was withvariable amounts of menopausal gonadotrophins. Human chorionicgonadotrophin (HCG) was given to trigger the ovulatory process.The Yoruba and Caucasian groups were similar in age and bodyweight, but significantly more Yorubas (45 versus 11% P <0.005) had ultrasound features of polycystic ovary syndrome(PCOS). The serum oestradiol concentration (3024 versus 2058pg/ml; P < 0.05) and number of follicles >14 mm in diameter(15.5 versus 9.5; P < 0.05) on the day of HCG were higherin the Yoruba group. The ovarian hyperstimulation syndrome (OHSS)was also more prevalent in the Yoruba group (20 versus 5% P< 0.05). No difference was found in clinical pregnancy orembryo implantation rates. These results show a higher tendencytoward exaggerated ovarian response in infertile Yoruba thanCaucasian women, associated with a higher prevalence of PCOS.The risk of developing symptomatic OHSS is higher in Yorubawomen.     

Is endometrial development in the peri-implantation period influenced by high concentrations of luteinizing hormone in the follicular phase?

A retrospective study was designed to examine the relationshipbetween luteinizing hormone (LH) concentrations in the follicularphase and endometrial development in the luteal phase of naturaland artificial cycles. Two types of cycle were studied: naturalcycles (n = 51) in subjects with unexplained infertility weredivided into two subgroups, depending on whether LH measurementsin the late follicular phase were based on urine (n = 24) orplasma (n = 27) samples; and artificial cycles (n = 17), producedby the administration of a standard hormone replacement therapy,in two subgroups of women, those with premature ovarian failure(n = 10) in whom plasma LH concentrations were high, and thosewith unexplained infertility (n = 7) who had their hypothalamicpituitary — ovarian axis down-regulated and in whom plasmaLH concentrations were low. The correlation between plasma orurine concentrations of LH in the follicular phase and the resultsof endometrial biopsy obtained in the luteal phase was calculated.In natural cycles, LH concentrations were similar in those withnormal or retarded endometrium, and there was no significantcorrelation between high LH concentration and retarded endometrialdevelopment. In artificial cycles, endometrial development wasnot different between those with low LH concentrations (down-regulatedby Zoladex) and those with high LH concentrations (prematureovarian failure). Endometrial development in the peri-implantationperiod does not appear to be influenced by LH concentrationin the follicular phase. The reported association between highLH concentration and poor reproductive performance cannot thereforebe explained by abnormal implantation consequent upon retardedendometrial development.     

Endocrinology: A comparison of two starting doses of human menopausal gonadotrophin for follicle stimulation in unselected patients for in-vitro fertilization

Ovarian responses and embryology data were compared in patientsundergoing in-vitro fertilization following follicular stimulationusing long course gonadotrophin-releasing hormone (GnRH) analogue/humanmenopausal gonadotrophin (HMG) in which the initial daily dosewas two (150 IU) or three ampoules (225 IU) maintained for aminimum of 7 days. Group 1 (n = 31; centre A) patients weretreated with a starting dose of two ampoules, while group 2(n = 46; centre A) patients were treated chronologically immediatelybefore group 1 with a starting dose of three ampoules per day.Group 3 (n = 74; centre B) patients were treated with threeampoules per day simultaneously with group 1. There was no differencein the distributions of patient ages or reasons for treatmentbetween the three groups. Group 1 required longer treatmentbefore the plasma oestradiol attained 250 pg/ml than did boththe other groups (group 1, 9.0; group 2, 6.9; group 3, 6.7 days;P < 0.01), and this resulted in a longer follicular phasefor group 1 (mean: 14.5 days compared with 12.7 and 12.8 forgroups 2 and 3 respectively; P < 0.05). The numbers of follicles>16 mm in diameter at human chorionic gonadotrophin (HCG)administration and the numbers of eggs and embryos were allsignificantly lower (P < 0.04) in group 1, and cycle cancellationsdue to insufficient ovarian responses were higher (P < 0.02)in group 1. There was no difference in the numbers of ampoulesused, the oestradiol concentration at HCG, the fertilizationand pregnancy rates or the incidence of hyperstimulation syndromein the three groups. The lower starting dose, therefore, yieldedinferior responses without significant reduction in the HMGrequirement.     

Characteristics of urinary luteinizing hormone (LH) during the induction of LH surges of different magnitude in blood

Urinary luteinizing hormone (LH) testing has been proposed asa reliable method for the prediction of ovulation but its accuracyhas been challenged by some studies. To check how accuratelythe oscillations of urinary LH reflected the plasma changes,surges of LH of different magnitude and duration were artificiallyinduced in plasma and the hormone was measured simultaneouslyin urine. Post-menopausal women (n = 16) were stimulated during1 week with a combination of transdermal oestradiol (400 µg)and i.m. progesterone (25 mg on day 4, 50 mg on day 5) to obtainan LH discharge comparable with the pre-ovulatory LH peak. Ashort and moderate peak of LH was induced by the i.v. injectionof 100 µg gonadotrophin-releasing hormone (GnRH) in sixpre-menopausal women, whereas an LH discharge of higher amplitudeand longer duration was induced by a single dose of 0.3 mg s.c.buserelin. The total urine production of the day was fractionatedinto 8 h periods. LH was measured by a commercial radioimmunoassay.Unambiguous peaks of LH were detected in the urine of all thewomen stimulated with either oestradiol plus progesterone orbuserelin, but in only three out of the six women receivingGnRH. The urine LH reproduced the plasma changes of the hormonewith short delay since the peaks were mostly detected in thesame time fraction in which the serum discharge occurred.     

Endocrinology: Midluteal immunoreactive {alpha}-inhibin serum concentrations as markers of luteal phase deficiency

The present prospective clinical study was undertaken to determinethe usefulness of midluteal phase serum immunoreactive -inhibinconcentrations as markers of luteal phase deficiency and whetherthey are better indicators of biopsy confirmed luteal phasedefect than serum progesterone. Consecutive patients (n = 138)with regular menstrual cycles attending our Infertility Clinic(experimental group) and 15 fertile women who were requestingcontraception and had regular menstrual patterns (control group)were included. In all women (patients and controls), basal bodytemperature, midluteal serum concentrations of oestradiol, prolactin,progesterone and immunoreactive -inhibin, and premenstrual endometrialbiopsy were used in the same cycle to assess luteal function.Out-of-phase secretory endometria were detected in 15 of the138 patients. Thus, hormonal concentrations were compared betweenthe following three groups of women: group 1 (n = 15), infertilepatients with defective secretory endometria; group 2 (n = 123),infertile patients with normal secretory endometria; and controls(n = 15), fertile women with normal secretory endometria. Midlutealserum concentrations of progesterone, immunoreactive -inhibin,oestradiol, and prolactin of the two groups studied were similarto those of the control group of fertile women. Our resultsindicate that midluteal serum inhibin determination does notaccurately reflect histological maturation of the endo-metriumand it is not a better indicator of endometrial luteal phasedeficiency than midluteal serum progesterone concentration.     

Hormonal characteristics of follicular fluid from women receiving either GnRH agonist or hCG for ovulation induction

BACKGROUND: A recent prospective randomized study from our groupcompared GnRH agonist (0.5 mg buserelin) and hCG (10 000 IU)for triggering of ovulation following a flexible antagonistprotocol. The agonist group showed a poor reproductive outcomedespite luteal phase support with progesterone and estradiol(E₂). In the present prospective observational study, the healthstatus of follicles from the above study was monitored by analysingthe hormonal content of frozen/thawed follicular fluid samples.The aim was to test whether the poor reproductive outcome couldbe related to a defective pre-ovulatory follicular maturationresulting in oocytes with a compromised developmental competence.METHODS: Hormone concentrations were measured in two individualfollicular fluid samples from each of 32 women receiving buserelinand 37 receiving hCG, thus representing a subset of the folliclesretrieved. RESULTS: Follicular fluid levels of LH in the agonistgroup as compared with the hCG group was 11.1 ± 0.5 versus3.6 ± 0.3 IU/l (mean ± SEM; P < 0.001); FSH,6.3 ± 0.6 versus 3.3 ± 0.2 IU/l (P < 0.001);hCG, not determined versus 139±8 IU/l; E₂, 1.9 ±0.2 versus 1.8 ± 0.2 µmol/l (P > 0.10); progesterone,70 ± 4 versus 93 ± 6 µmol/l (P < 0.001);inhibin-A, 36.9 ± 3.1 versus 37.1 ± 2.5 ng/ml(P > 0.10) and inhibin-B, 35.6 ± 2.8 versus 40.1 ±3.1 ng/ml (P > 0.10). Thus, pronounced hormonal differencesexist in follicular fluid, and the collective concentrationof all three gonadotropins and the follicular fluid concentrationof progesterone were much higher in the group of women receivinghCG for ovulation induction. CONCLUSION: The study suggeststhat GnRH agonist results in proper pre-ovulatory follicularmaturation, but the ovulatory signal – probably in synergywith the resulting pituitary down-regulation – is toolow to support appropriate corpus luteum (CL) function.     

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

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

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.     

Decreased incidence of severe ovarian hyperstimulation syndrome in high risk in-vitro fertilization patients receiving intravenous albumin: a prospective study

The administration of human serum albumin has been reportedto prevent severe ovarian hyperstimulation syndrome (OHSS) inpatients considered at risk of developing OHSS while undergoingovarian stimulation protocols for in-vitro fertilization (IVF).This prospective, randomized study investigated the effectivenessof a single dose of human serum albumin (20 g) administeredi.v. immediately after oocyte retrieval. Women enrolled in theIVF programme were treated with the long gonadotrophin-releasinghormone agonist, triptorelin, and an individually-adjusted humanmenopausal gonadotrophin protocol. The criteria for inclusionin the study were young age, nonobesity, oestradiol concentration>9200 pmol/l on the day of human chorionic gonadotrophinadministration and >20 follicles >14 mm diameter as observedby transvaginal sonography. The treatment group (n = 22) receivedalbumin while the control group (n = 18) did not. Patients werefollowed-up using ultrasound every 3 days. There was a significantlyhigher number of severe OHSS cases in the control group (n =4) than in the treatment group (n = 0) (P = 0.035). Where thedata base was restricted to patients with an oestradiol concentration>15 000 pmol/l, the difference between control and treatmentgroups was highly significant (P = 0.008). These findings supportthe use of i.v. albumin in preventing severe OHSS during IVFtreatment.     

Atrial natriuretic peptide, oestradiol and progesterone in women undergoing spontaneous and gonadotrophin-stimulated ovulatory cycles

The objective of this study was to examine the relationshipbetween the concentrations of oestradiol and progesterone onthe one hand and atrial natriuretic peptide (ANP) concentrationson the other, during the follicular and luteal phases of spontaneousand gonadotrophin-stimulated ovulatory menstrual cycles. A totalof 27 ovulatory women undergoing either a spontaneous (n = 9)or a gonadotrophin-stimulated (n = 18) cycle were selected forinclusion in this study. In comparison with spontaneous cycles,gonadotrophin-stimulated cycles had increased peak follicularoestradiol (mean ± SE; 937 ± 150 versus 195 ±18 pg/ml; P < 0.05) and midluteal progesterone (mean ± SE; 44.0 ± 7.4 versus 14.1 ± 2.4 ng/ml; P <0.05) concentrations. There were no differences in the circulatingANP concentrations between the follicular and luteal phasesof the menstrual cycle. Despite the increased oestradiol andprogesterone concentrations following gonadotrophin stimulation,no difference in ANP concentrations was seen between stimulatedand spontaneous cycles. There was no correlation between circulatingconcentrations of oestradiol, progesterone (at physiologicaland supraphysiological concentrations) and ANP throughout themenstrual cycle.     

Total ovarian volume before human chorionic gonadotrophin administration for ovulation induction may predict the hyperstimulation syndrome

Total ovarian volumes were measured before the administrationof HCG in 42 women undergoing treatment for infertility by in-vitrofertilization (IVF) and embryo transfer and considered to havean exaggerated response to stimulation (>20 follicles). Sevenwomen who subsequently developed moderate or severe ovarianhyperstimulation syndrome (OHSS) (n = 7; group 1) were comparedwith 35 matched controls (five matched controls per case; n= 35; group 2) of similar age, number of follicles and durationof infertility who underwent follicular stimulation, oocyterecovery, in-vitro fertilization and embryo transfer duringthe same period but did not develop moderate or severe OHSS.The mean age, duration of infertility and total number of follicleswere similar but the mean total ovarian volume was significantlyhigher in the group of women who developed moderate or severeOHSS compared with controls (271.00 ± 87.00 versus 157.30± 54.20 ml; P < 0.01). We conclude that total ovarianvolume measured before HCG administration is higher in womenwho develop moderate or severe OHSS compared with controls andmay therefore be used as an additional parameter in the preventativestrategy for the ovarian hyperstimulation syndrome.