Cost-effectiveness analysis of different embryo transfer strategies in England.

OBJECTIVE: The objective of this study was to assess the cost-effectiveness of different embryo transfer strategies for a single cycle when two embryos are available, and taking the NHS cost perspective. DESIGN: Cost-effectiveness model. SETTING: Five in vitro fertilisation (IVF) centres in England between 2003/04 and 2004/05. POPULATION: Women with two embryos available for transfer in three age groups (<30, 30-35 and 36-39 years). METHODS: A decision analytic model was constructed using observational data collected from a sample of fertility centres in England. Costs and adverse outcomes are estimated up to 5 years after the birth. Incremental cost per live birth was calculated for different embryo transfer strategies and for three separate age groups: less than 30, 30-35 and 36-39 years. MAIN OUTCOME MEASURES: Premature birth, neonatal intensive care unit admissions and days, cerebral palsy and incremental cost-effectiveness ratios. RESULTS: Single fresh embryo transfer (SET) plus frozen single embryo transfer (fzSET) is the more costly in terms of IVF costs, but the lower rates of multiple births mean that in terms of total costs, it is less costly than double embryo transfer (DET). Adverse events increase when moving from SET to SET+fzSET to DET. The probability of SET+fzSET being cost-effective decreases with age. When SET is included in the analysis, SET+fzSET no longer becomes a cost-effective option at any threshold value for all age groups studied. CONCLUSIONS: The analyses show that the choice of embryo transfer strategy is a function of four factors: the age of the mother, the relevance of the SET option, the value placed on a live birth and the relative importance placed on adverse outcomes. For each patient group, the choice of strategy is a trade-off between the value placed on a live birth and cost.

The impact of luteal supplement on pregnancy outcome following stimulated IVF cycles.

This is a prospeve randomised study designed to clarify the impact of various luteal support regimes (HCG and progesterone) on progesterone profiles and pregnancy outcomes. This study involved subjects undergone down regulated. stimulated IVF cycles using various types of luteal support, namely: Cyclogest (n=35). Crinone gel (n=36), various doses of Utrogestan (n=55) and HCG (n=35). Various doses of Utrogestan (administered vaginally), Crinone gel (progesterone administered vaginally) and Cyclogest (progesterone administered rectally) supplementation induced similar end plasma progesterone concentrations ranging from 26 to 32 mmnl/l. These progesterone regimes produced no significant differences. Hence, the impact of exogenous proge,terone supplement was relatively trivial and did not 'stabilise' the sub-optimal luteal phase. In contrast, two small HCG injections during the early and mid-luteal phase possessed a much greater ability to 'stabilise' progesterone profiles. Despite this additional advantage, implantation and pregnancy rates with either HCG or progesterone supplements were similar. Although none of these forms of luteal support adequately 'normalised' luteal progesterone profiles, this did not appear to be detrimental to the process of implantation.

Differential responses to a simulated implantation signal at various stages of the luteal phase in women.

Human CG (hCG) was administered to three groups of four normally cycling women in the early luteal phase (LH +4 to +5, group I), the midluteal phase (LH +8 to +9, group II), and the late luteal phase (LH +11 to +12, group III). Two hundred and fifty IU hCG were given im followed in half of the subjects by 750 IU hCG 24 h later. Serial blood samples were then taken at 15- or 30-min intervals following either the first or second hCG injection and continued for 12 or 24 h. The samples were stored frozen at -20 C until assayed for LH, progesterone, estradiol, and hCG concentrations. Treatment with 250 IU hCG at each stage of the luteal phase did not result in any marked change in hormone concentrations. Further hCG administration (750 IU 24 h later) in both the early and the midluteal phases elicited a clear increase in progesterone concentrations. Further hCG treatment in the late luteal phase did not evoke any rise in progesterone levels. Further hCG administration in the midluteal phase resulted in a sharp decline in LH concentrations, brought about mainly by a decrease in LH pulse frequency, this response was not apparent at any other stage of the luteal phase. Despite the lack of any pulsatile steroidogenic stimulus at this time, progesterone was clearly secreted in a pulsatile manner. The decline in LH levels following hCG administration in the midluteal phase resembled that seen in spontaneous conception cycles following implantation. The restriction of this response to the time of normal implantation may suggest a role for the pituitary in the establishment of the "implantation window." The importance of this pituitary response and the mechanisms involved are currently unknown. Its absence in the early luteal phase would suggest that it cannot be directly attributed to either progesterone or hCG. It is possible that some other luteal factor may be responsible for the midluteal decline in LH concentrations.

Acute effects of progesterone and the antiprogestin RU 486 on gonadotropin secretion in the follicular phase of the menstrual cycle.

Considerable controversy still exists concerning the role of progesterone in the initiation of the midcycle gonadotropin surge in humans. We, therefore, carried out a prospective randomized study to determine the potential of progesterone to initiate a gonadotropin surge and the acute effects of a potent progesterone antagonist (RU 486) on follicular phase gonadotropin secretion in normal women. The women underwent frequent blood sampling for 4 in the midfollicular (day 6) or late follicular phase (day 10). They then received either progesterone (10 mg, im) or RU 486 (10 or 100 mg, orally), and blood sampling was continued for an additional 8 h. Four women received each of the drug regimens in the early follicular phase, and four received each regimen in the late follicular phase. Two additional women were studied as control subjects at each stage of the cycle. Progesterone administration in the mid- and late follicular phases resulted in an acute increase in plasma LH and FSH concentrations, and the increases correlated with the base line plasma estradiol concentrations (P less than 0.05). In contrast to progesterone, the women who received RU 486 in the mid- and late follicular phases had a reduction in plasma LH and FSH concentrations after drug administration. The response in the mid-follicular phase was considerably less than that in the late follicular phase, and the extent of the response correlated with the baseline plasma estradiol concentrations (P less than 0.005). The changes were similar in response to both RU 486 doses. We conclude that progesterone can initiate a gonadotropin surge in the late follicular phase of the menstrual cycle. The inhibitory effect of the progesterone antagonist RU 486 suggests that a positive feedback mechanism involving progesterone may be influential some time before the surge onset.

Inhibin concentrations throughout the menstrual cycles of normal, infertile, and older women compared with those during spontaneous conception cycles.

Plasma immunoreactive inhibin levels have been measured in a series of normal conception cycles (group I; n = 7), and the data compared to inhibin concentrations in normal menstrual cycles (group II; n = 8), in women with luteal phase defects (group III; n = 7), and in women in the perimenopausal period (group IV; n = 6). Daily plasma levels of LH, FSH, progesterone, estradiol, and inhibin were determined in each subject, and daily mean profiles for each hormone in each subject group were calculated and expressed as geometric means with 68% confidence limits. During the follicular and early luteal phases, inhibin concentrations in the normal nonpregnant group (group II) were significantly higher than those in the conception cycles of group I, but after implantation in the conception cycles, inhibin concentrations increased to levels in excess of those seen at any time in nonconception cycles (716-1352 U/L; P less than 0.02). The postimplantation rise in inhibin did not initially appear to follow the same pattern as progesterone. While progesterone concentrations rose within 24 h of the first detectable increase in hCG, inhibin levels did not increase until 3 days later, although after this point concentrations increased serially and in parallel with progesterone. LH and FSH concentrations were markedly suppressed after implantation. Follicular and early luteal inhibin concentrations in cycles with luteal phase defects were also higher than those in conception cycles, although this difference was only significant in the midfollicular phase. Follicular phase inhibin concentrations in cycles from older women (group IV) were lower than those in groups II and III, but were not distinguishable from those in the conception cycles. Estradiol concentrations in the same subjects were significantly lower during the early follicular phase, while follicular and luteal FSH concentrations were significantly higher than those during conception cycles. Finally, examination of the relationship between inhibin, FSH, and estradiol around menstruation in the older women revealed a far closer temporal association between FSH and estradiol than between FSH and inhibin. In conclusion, inhibin concentrations rise and fall throughout the human menstrual cycle in a manner that is similar to but at specific times significantly different from that of either of the ovarian steroids estradiol and progesterone. It is considered to be a peptide of granulosa cell origin and may be an indicator of the size of the follicular pool during the early stage of the cycle. However, although there is some degree of inverse correlation between profiles of inhibin and profiles of FSH, this relationship is not particularly clear.(ABSTRACT TRUNCATED AT 400 WORDS)

The temporal relationship between melatonin and prolactin in women.

The relationship between the concentrations of melatonin and prolactin (PRL) over 24 hours has been investigated. Two peaks in PRL concentrations were distinguished: an evening peak (at 8:00 P.M.) and a nocturnal peak (at 6:00 A.M.). Melatonin concentrations showed a single peak (at 2:00 A.M.). In both the follicular and luteal phases of the menstrual cycle, melatonin increased 2 to 3 hours after the evening increase in PRL and 4 hours before the nocturnal rise in PRL concentrations. Oral administration of melatonin stimulated PRL release. The PRL response varied with menstrual cycle stage being significantly greater in the ovulatory (P less than 0.001) and luteal (P less than 0.01) phases than in the follicular phase. The results suggest that melatonin may be involved in control of the nocturnal PRL increase.

Plasma concentrations of human chorionic gonadotropin from the time of implantation until the second week of pregnancy.

A systematic study of the daily concentrations of human chorionic gonadotropin (hCG) in maternal circulation following the time of probable implantation in 19 normal pregnancies was carried out. With the use of a specific antiserum to hCG beta-subunit, significant increases in circulating hCG were observed by day 8 following the luteinizing hormone (LH) peak in 5.3% of cycles. by day 9 in 15.8%, by day 10 in 53.2%, and by day 11 in 100% of the cycles resulting in a normal pregnancy. After an initial rapid rise, mean plasma concentrations rose exponentially, with a doubling time of 1.3 days, to reach concentrations between 50 and 250 IU/l at the time of the first missed period. The time of detection of hCG was in close agreement with the anticipated time for this event estimated from morphologic studies. In three abnormal pregnancies, all of which ended in spontaneous abortion, hCG concentrations became progressively more abnormal from within 2 to 5 days of the appearance of this hormone in maternal plasma. Despite this, actual abortion did not occur for several days, or in one case for several weeks, after the divergence of hCG concentration from the normal range.

Long-term follow-up of the apparently normal couple with a complaint of infertility.

Ninety-one couples with no obvious cause for their infertility were followed after periods of 1 to 17 years (96% were followed until they conceived or for more than 5 years). All of the couples had been fully investigated and no specific abnormality had been demonstrated. The majority of women (88%) had primary infertility of at least 2 years' duration, although a small number (12%) had had one or more first-trimester abortions and were thus classified as having secondary infertility. Cumulative conception rates (using life tables) at the end of 7 years were 36.2% for the primary infertility group and 78.8% for the women with secondary infertility. Of those couples achieving a first pregnancy and desiring a second, only 44.3% had conceived at the end of another 4-year period. These rates are markedly lower than the published conception rates of a normal population.

A comparison between two methods of chronological dating of human endometrial biopsies during the luteal phase, and their correlation with histologic dating.

This prospective study was performed on 61 infertile women to examine the correlation between histologic dating using the same criteria by two independent observers and chronological dating by two different methods: (1) determination of luteinizing hormone (LH) peak by daily LH assay, (2) calculation based on the onset of the next menstrual period (NMP). The correlation between histologic dating and chronological dating was found to be significantly better if the LH peak was used to determine the chronological date than if the NMP was used (r = 0.70 and 0.37, respectively).

A new method of histologic dating of human endometrium in the luteal phase.

Morphometric analysis was performed on 70 endometrial biopsy specimens collected from a population of fertile women. Of the 17 morphometric measurements that were performed on each endometrial biopsy, only 5 were required to achieve a highly significant correlation with chronologic dating based on luteinizing hormone surge (R = 0.99). The result of histologic dating, based on morphometric analysis of endometrial biopsies collected from a separate, unbiased population, correlated strongly and significantly with chronologic dating (r = 0.98, P less than 0.0001). The correlation was better than that achieved when histologic dating was performed according to the conventional dating criteria (r = 0.88, P less than 0.001).

The effects of progesterone receptor blockade in the luteal phase of normal fertile women.

The effects of a single, variable dose (5 to 200 mg) of RU38486 (RU486) (Roussel-Uclaf, Paris, France) in the first half of the luteal phase of the menstrual cycle were studied in 30 normal fertile volunteers. Quantitative histologic techniques were employed, and the results were compared with normal ranges derived from a separate, normal, fertile population. It was found that RU486 inhibited glandular secretory activity, accelerated degenerative changes, induced various vascular changes, increased stromal but not glandular mitotic activity, and did not affect the predecidual reaction. The superiority of morphometric analysis over traditional dating criteria was demonstrated in this study of endometrial responses to an exogenously administered agent. In addition, it was found that temperature drop occurred in 56%, menstrual induction in 43%, luteolysis in 24%, mood change in 23%, and thirst sensation in 3% of women studied. Both menstrual induction and changes in hypothalamic function after the administration of RU486 occurred independently of luteolysis and so were likely to be the direct result of progesterone receptor blockade in these organs. Menstrual induction was significantly related to the dose given and the day on which RU486 was administered. Mood change was significantly related to the day on which RU486 was given. Most of the effects of RU486 occurred around 48 hours after its administration.

PIP: The effects of a single, variable dose (5-200 mg) of RU38486 (RU486; Roussel-Uclaf, Paris, France) in the 1st 1/2 of the luteal phase of the menstrual cycle were studied in 30 normal fertile volunteers. Quantitative histologic techniques were employed, and the results were compared with normal ranges derived from a separate, normal, fertile population. It was found that RU486 inhibited glandular secretory activity, accelerated degenerative changes, induced various vascular changes, increased stromal but not glandular mitotic activity, and did not affect the predecidual reaction. The superiority of morphometric analysis over traditional dating criteria was demonstrated in this study of endometrial responses to an exogenously administered agent. In addition, it was found that temperature drop occurred in 56%, menstrual induction in 43%, luteolysis in 24%, mood change in 23%, and thirst sensation in 3% of the women studied. Both menstrual induction and changes in hypothalamic function after the administration of RU486 occurred independently of luteolysis and thus were likely to be the direct result of progesterone receptor blockade in these organs. Menstrual induction was significantly related to the dose given and the day on which RU486 was administered. Mood change was significantly related to the day on which RU486 was given. Most of its effects occurred around 48 hours after administration.

Chorionic gonadotropin concentration in early human pregnancy: comparison of specific and nonspecific assays.

Daily blood samples were collected during 10 menstrual cycles in which conception had occurred, and changes in circulating concentrations of human chorionic gonadotropin (hCG) were measured simultaneously in specific and nonspecific radioimmunoassays. The hCG concentration profiles were not identical, and the fundamental differences could not be related to differences in technique. Both specific and nonspecific parameters of hCG concentration rose exponentially for the first 2 to 3 weeks following first detection and were thus amenable to linear regression analysis. Doubling times were significantly different at 2.3 and 1.8 days, respectively. Extrapolation of the regression data gave a (theoretical) plasma concentration of 3 IU/liter at 9.5 days after the luteinizing hormone peak using the specific assay but at only 5.5 days using the nonspecific assay. This difference is sufficiently large to suggest the presence of other forms of hCG or its subunits about the time of implantation and during early pregnancy.

Human oviductal fluid prolongs sperm survival.

OBJECTIVE: To compare the effect of human oviductal fluid on sperm motility and hyperactivation during 9 hours' incubation in vitro with follicular fluid (FF) and medium controls. DESIGN: Fertile donor spermatozoa were allowed to penetrate human cervical mucus in vitro and then recovered and incubated in either 30% human oviductal fluid, 20% FF, or medium for up to 9 hours. Sperm motion characteristics were measured using a sperm motility analyzer. SETTING: The donor insemination program at the University Clinic within the Jessop Hospital for Women, Sheffield, United Kingdom. PATIENTS: All donors used in this study were involved in the donor insemination program. MAIN OUTCOME MEASURES: Sperm motility, hyperactivation, curvilinear velocity, progressive, lateral head displacement, and linearity were measured using a sperm motility analyzer. RESULTS: After 9 hours' incubation, spermatozoa in human oviductal fluid had a significantly higher percentage motility than sperm incubated in FF or the control medium. A more linear sperm motion was consistently observed in the spermatozoa incubated in human oviductal fluid: significantly different from FF and media at 3 hours and 6 hours. The effect of human oviductal fluid on maintaining sperm motility was not affected by the addition of P. CONCLUSION: Human oviductal fluid can maintain sperm motility in a mechanism that is not mediated by the low concentration of P. We suggest that human oviductal fluid is a favorable environment for sperm survival.

Round cells and sperm fertilizing capacity: the presence of immature germ cells but not seminal leukocytes are associated with reduced success of in vitro fertilization.

Fifty semen samples produced for IVF by patients diagnosed as having unexplained infertility were screened for leukocytes, leukocyte subsets, and immature germ cells using a mAB-based staining procedure. Nonfertilizing ejaculates were found to contain significantly larger numbers of immature germ cells, although no significant differences in leukocyte content were observed between groups. Neither sperm density or progressive motility were significantly different between fertilizing and nonfertilizing groups. We conclude that seminal leukocytes have little if any influence on the fertilizing capacity of the spermatozoa in patients undergoing IVF for unexplained infertility, but the presence of large numbers of germinal elements is associated with reduced fertilizing capacity and may be indicative of an immature sperm population.

The interaction of parameters of male and female fertility in couples with previously unexplained infertility.

A prospective study was undertaken of the relationship between semen variables, serial endocrine and follicular ultrasound measurements in one complete menstrual cycle, and the treatment-independent chance of conception for couples who were referred with unexplained infertility. For the 91 couples studied, the mean length of infertility was 70 months. A 100% follow-up rate was achieved. When a stepwise analysis was performed examining semen variables and ultrasonographic and endocrine variables, the mean ratio of salivary progesterone/plasma estradiol between days +1 and +3, with respect to the luteinizing hormone surge and the Grade 2 motile sperm density, were the only variables that achieved the 5% level of significance. There was a highly significant relationship between the product of these two variables and the chance of conception. This study clearly demonstrates an interaction between parameters of male and female fertility.

Are factors that influence oocyte fertilization also predictive? An assessment of 148 cycles of in vitro fertilization without gonadotropin stimulation.

Fertilization characteristics of 152 consecutively obtained oocytes in an in vitro fertilization (IVF) program employing only natural and clomiphene citrate-induced cycles were retrospectively analyzed. Fertilization occurred significantly more often (1) in women with tubal infertility, (2) in spontaneous cycles, and (3) in cases of secondary infertility. Grade I sperm motility from the original semen sample and the duration of infertility were also significant influencing factors. A similar sperm correlate was not identified on samples after sperm migration. Preovulatory follicular fluid steroids, progesterone (P), estradiol (E2), E2:P ratio, and luteinizing hormone (LH), as well as baseline plasma LH and the magnitude of the LH surge did not correlate with fertilization. However, when the identified factors were used to predict fertilization (discriminant analysis), only 58.3% of oocytes were correctly classified. This data supports the concept of performing IVF as a test in its own right.

Progressive changes in LH and FSH and LH: FSH ratio in women throughout reproductive life.

Gonadotropin secretion during the post-menopausal period is considerably higher than during the reproductive years. In this study, we present evidence that changes in the hypothalamic-pituitary-ovarian unit occur over a period of years before the onset of menstrual irregularity which heralds the menopause. FSH and LH were measured in blood samples taken on 6 days during the mid-follicular phase from 127 regularly cycling women aged between 23 and 49 yr. The women aged 23-30 yr were taken as the control group and the remainder were grouped in 2-yr age bands. A significant increase in FSH underwent a further increase in the oldest group (48-49 yr) in whom LH also became significantly elevated. The difference in the timing of the change in FSH and LH concentrations was related not only to chronological age but also to the number of years before the menopause. The increase in FSH occurred 5-6 yr pre-menopause, that in LH not until 3-4 yr before the cessation of menstruation. It is concluded that an early sign of the aging of the reproductive mechanism can be detected in women who are having normal ovulatory cycles. The regulation of FSH and LH secretion appears to be sufficiently independent to permit the observed differences in the age of onset of these premenopausal increases.

Why does RU486 fail to prevent implantation despite success in inducing menstruation?

The administration of RU38486 (RU486) in the luteal phase may induce menstruation, but it may not be associated with shedding of the functional layer of the endometrium. This provides an explanation why, in some cases of successful menstrual induction by RU486, pregnancy continues undisturbed. The ability of RU486 to interrupt a very early pregnancy is more likely to be related to its ability to cause shedding of the endometrium than its ability to induce menstruation.

PIP: To see why RU-486, given in luteal phase, induces menstruation but does not always prevent pregnancy, daily progesterone assays and 3 endometrial biopsies were taken from 2 volunteers who received a single dose. Progesterone was assayed by direct radioimmunoassay from saliva samples. The 1st subject was a 36-year old multipara who took a single oral dose of 150 mg RU-486 on Day 4 after the LH surge. She menstruated apparently normally 2 days later, and again 10 days after RU-486, at the expected time of menstruation. Her endometrial biopsy resembled secretory phase, and her progesterone profile did not indicate luteolysis. The 2nd volunteer was a 38-year old multipara. She took 75 mg RU-486 on Day 6 after her LH surge, and had apparently normal menses 2 days later. The endometrial histology was suggestive of menstruation, and the progesterone profile had fallen to baseline, indicating luteolysis. Menstruation did not recur at the normal time. In this woman who had complete shedding of the endometrium, RU-486 had been taken later in the luteal phase, and in a smaller dosage.

Effect of culture in vitro and organ culture on the dry mass of preimplantation mouse embryos.

The dry mass of mouse embryos cultured in vitro in medium alone or in an organ culture system were measured by means of the Vickers M86 scanning microinterferometer. The data were compared with previous data on the dry mass of preimplantation embryos in vivo. The metabolism of embryos cultured in vitro differs from that of fresh embryos. In cultured embryos, dry mass decreases throughout the 2-cell stage whereas the dry mass is increasing at this stage in vivo. Embryos in an organ culture system regain a dry mass profile, similar to that observed in vivo at the late cleavage stage. These results support the view that conditions for embryo metabolism are suboptimal in vitro and that, although the oviduct may confer some advantage on developing embryos in vitro, it is unable fully to support the pattern of metabolism, as assessed by dry mass, observed in vivo.

Prolactin concentrations during the normal menstrual cycle: rhythms within rhythms.

Prolactin concentrations were measured in frequent blood samples collected over a 2 h period randomly distributed during day and night, during the follicular and the luteal phases of the normal menstrual cycle in women. Episodic fluctuations in prolactin concentrations were observed throughout the 24 h period and the pattern of these fluctuations appeared to vary depending on the time, and sleep wake state. Thus a changing pattern of the 'primary pulse' of prolactin may be responsible for the time related and sleep related changes in prolactin during the 24 h period.