1 Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, 2 Department of Internal Medicine and 3 Center for Clinical Decision Sciences, Department of Public Health, Erasmus University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: follicle development/FSH/luteal phase/menstrual cycle/ovarian stimulation
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A brief but distinct elevation of FSH concentrations above the threshold in the early follicular phase does not affect dominant follicle development, although a transient increase in the number of small antral follicles could be observed (Schipper et al., 1998). On the contrary, a moderate but continued elevation of FSH concentrations during the mid to late follicular phase extending the FSH window does interfere with single dominant follicle selection and induces ongoing growth of multiple follicles (Schipper et al., 1998
). This confirms previous observations in the monkey showing that interference with decremental FSH can override the selection of a single dominant follicle (Zeleznik et al., 1985
).
It is known from ovarian stimulation for IVF or intrauterine insemination (IUI), that a marked and continued elevation of FSH during the entire follicular phase will induce growth of large numbers of dominant follicles of different size (Hillier et al., 1985). These stimulation protocols overrule single dominant follicle selection by extending the FSH window by serum FSH concentrations far above the threshold. Recently, serious concerns have been expressed concerning the stimulation of growth of large numbers of follicles for assisted reproduction (Edwards et al., 1996
; Fauser et al., 1999
). Considering the risks, side-effects and the high costs of ovarian hyperstimulation and multiple gestation, current approaches for ovarian stimulation regimens should be re-evaluated (Hughes et al., 1998
; de Jong et al., 2000a
; Macklon and Fauser, 2000
). Additional insight into the significance of the timing of initiation of exogenous FSH on follicle recruitment and selection may help to further develop and optimize milder ovarian stimulation protocols for assisted reproduction.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Inclusion criteria were: (i) age 1935 years; (ii) history of regular menstrual cycles (cycle lengths 2532 days) and no use of oral contraceptive pills or other medical or hormonal treatment for 3 months prior to study initiation; (iii) body mass index (BMI) 1927 kg/m2; (iv) midluteal progesterone concentrations, assessed 7 days before expected menses, >25 nmol/l; (v) no prior treatment for infertility; (vi) willingness to use contraceptive measures (intrauterine device, condoms or prior tubal ligation) or to refrain from intercourse during the study period. Detailed oral and written information concerning the importance of contraception was given before and during the study period.
All subjects were studied during a single menstrual cycle. At the onset of menses, subjects were assigned to one of three interventions using a computer-generated randomization schedule, assigned via numbered sealed envelopes. Group cycle day (CD) 3 received a daily fixed dose of 1 ampoule (75 IU) recombinant FSH (rFSH, Gonal-F®; Serono Benelux BV, The Hague, The Netherlands), starting on CD 3 until the administration of human chorionic gonadotrophin (HCG). Group CD 5 and group CD 7 received a similar daily dose rFSH, but started on CD 5 or CD 7 respectively. rFSH was administered s.c. by self-injection at 22.00 h. Participants were instructed by qualified nurses. As soon as the largest follicle reached a diameter of 18 mm, a single dose of 5000 IU HCG (Profasi®; Serono Benelux BV) was administered i.m. at 22.00 h to induce ovulation.
Monitoring consisted of transvaginal sonography (TVS) and blood sampling was performed between 8.00 and 10.00 h, every 2 days starting on CD 3. As soon as the largest dominant follicle reached a diameter of 15 mm, TVS and blood sampling were performed on a daily basis until the day of HCG. Finally, TVS and blood sampling were repeated on day HCG+2 and HCG+8. The day of initiation of the following menstrual period was recorded. TVS was performed by a single observer (F.H.), using a 6.5 MHz transvaginal transducer (EUB-420; Hitachi Medical Corp., Tokyo, Japan). Follicle diameter was calculated as the mean diameter (measured in two dimensions when <9 mm, and in three dimensions if at least one diameter was
9 mm) as published previously (Pache et al., 1990
; van Santbrink et al., 1995
).
Hormone assays
Blood samples were centrifuged within 2 h after withdrawal and stored at 20°C until assayed. Serum FSH, LH, and progesterone concentrations were measured by chemiluminescent immunoassay [Immulite, Diagnostic Products Corporation (DPC), Los Angeles, CA, USA] in single assays. Addition of various doses of rFSH to serum without FSH yielded a curve parallel to that of the standard. Recovery of rFSH was 55.5 ± 3.7% (SD, n = 4). Serum oestradiol concentrations were measured in duplicate using radioimmunoassay kits provided by DPC (Los Angeles, CA, USA), as described previously (Fauser et al., 1991). Dimeric inhibin A and inhibin B concentrations were also determined in duplicate using an immuno-enzymometric assay (Serotec, Oxford, UK), as described previously (Groome et al., 1996
). Intra- and inter-assay coefficients of variation were <5% and <7% for FSH, <5% and <6% for LH, <10% and <10% for progesterone, <5% and <7% for oestradiol, <8% and <15% for inhibin A and <8% and <14% for inhibin B respectively. All samples from one subject were run in the same assay.
Data analysis
Results are presented as the median and range. Comparisons of outcome measures between the three randomized groups were performed using the Kruskal-Wallis H-test for continuous data and using the 2-test for binary variables. Two group comparisons (between single and multiple dominant follicle selection) were performed using the Mann-Whitney U-test. Comparisons of means of values in time between two groups were performed using analysis of variance (ANOVA). Correlation coefficients given are Pearson's. P values are two-sided and 0.05 was considered the limit for statistical significance. A dominant follicle was defined as a follicle with a mean diameter of
10 mm (Pache et al., 1990
; van Santbrink et al., 1995
). A pre-ovulatory follicle was defined as a follicle with a mean diameter of
15 mm. This distinction seems clinically important, since not all follicles of
10 mm necessarily develop into pre-ovulatory follicles. Arbitrarily, progesterone concentration (day of HCG)
3.2 nmol/l (1.0 ng/ml) was considered as premature luteinization (Harada et al., 1995
; Ganirelix dose-finding study group, 1998
). The four subjects showing premature ovulation were not included in the analysis of hormone serum concentrations on the day of HCG. Data were analysed using the commercially available software package SPSS, Inc. (Chicago, IL, USA).
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
|
|
|
Midluteal serum hormone concentrations between women exhibiting single and multiple dominant follicle selection are presented in Table II. The differences in midluteal serum concentrations were more pronounced in single versus multiple pre-ovulatory follicle development [median FSH 2.6 IU/l (range 0.27.3) versus 0.7 IU/l (range 0.11.7), P < 0.001; median LH 4.1 IU/l (range 0.18.5) versus 0.4 IU/l (range 0.113.8), P = 0.006; median oestradiol 497 pmol/l (range 158969) versus 729 pmol/l (range 3232486), P = 0.001; median inhibin A 61 ng/l (range 9122) versus 91 ng/l (range 37205), P = 0.01]. Midluteal serum hormone concentrations between the three randomization groups were similar (data not shown).
Cycle characteristics
Reported previous cycle length of the subjects correlated positively with the cycle length in the intervention cycle (r = 0.44, P = 0.005; data not shown). The intervention cycle was shorter compared to the normal cycle length [median length 26 days (range 1733) versus 28 days (range 2533), P < 0.001]. Four subjects showed premature ovulation (follicle collapse before the dominant follicle reached a diameter of 18 mm) and did not receive HCG. The difference in the length of the intervention cycle and the normal cycle remained when corrected for subjects showing premature ovulation [median length 26 days (range 2133) versus 28 days (range 2531), P < 0.001].
The length of the follicular phase (from onset of menses until 2 days after HCG administration or until day of spontaneous ovulation) comparing the three groups, is presented in Table I. Within groups CD 3 and CD 5, no difference was seen in the length of the follicular phase comparing women with mono- or multifollicular growth [median follicular phase 13 (range 1214) versus 14.5 days (range 1219) in group CD 3 and 13 (range 1116) versus 16 days (range 1117) in group CD 5]. In group CD 7, the subjects exhibiting multifollicular growth had a significantly longer follicular phase [median follicular phase 15 days (range 1420) versus 12 days (range 914), P = 0.004]. In this group, the mean diameter of the lead follicle on the day of initiation of rFSH (CD 7) was significantly larger in the group showing monofollicular growth compared with the group with multifollicular growth [median size lead follicle 10.6 mm (range 8.117.6) versus 7.8 mm (7.28.8)].
The luteal phase (from 2 days after HCG administration or from the day of spontaneous ovulation until the start of the next menstrual period) in the subjects with multiple dominant follicle selection was significantly shorter compared with the subjects with single dominant follicle development (Table II P, = 0.002). Two subjects were excluded for calculation of the luteal phase length, since these subjects conceived during the intervention cycle.
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The present study shows that the administration of low doses of exogenous FSH starting on CD 3, 5 or as late as CD 7, can overrule single dominant follicle selection in the majority of women. In subjects who did not respond, the amount of exogenous FSH might have been insufficient to elevate the FSH concentration long enough above the FSH threshold for the remaining non-dominant follicles from the recruited cohort. A negative correlation was found between BMI and the number of dominant follicles developed. Lower bodyweight women received a higher FSH dose per kg. However, no correlation was found between BMI and FSH concentrations in the mid or late follicular phase (data not shown). Individual differences in metabolic clearance rate (Diczfalusy and Harlin, 1988) and distribution volume of FSH (Chong et al., 1986
; Mannaerts et al., 1993
), related to body weight may be involved. Moreover, the influence of weight on induction of ovulation for IVF has previously been stressed (Chong et al., 1986
; Lashen et al., 1999
). Women presenting with multiple dominant follicles exhibit higher mid to late follicular phase inhibin B concentrations and higher late follicular phase oestradiol and inhibin A concentrations. Serum FSH concentrations were not distinctly different, suggesting differential ovarian responsiveness to FSH being the predominant factor determining mono- or multifollicular response. On the other hand, an immunoassay was used to assess FSH concentrations (combining endogenous and exogenous FSH) and therefore differences in in-vivo bioactivity may not be disclosed (Mannaerts et al., 1991
; Rose and Gaines-Das, 1998
).
Surprisingly we did not find a significant difference in the number of women with irreversible single dominant follicle selection between the three groups. However, there was a tendency toward a lower percentage of women presenting with multiple dominant follicle development when FSH was initiated on CD 7 (36 versus 69 and 77%). A larger number of subjects is required to establish whether this tendency represents a true difference. There was a significant difference when CD 7 initiation was compared with the two other groups (CD 3 and CD 5) together (P = 0.02). The subjects who showed multiple dominant follicle selection after intervention in the mid to late follicular phase had a longer follicular phase and no signs of selection of the dominant follicle at the day of initiation of exogenous FSH. These results confirm the FSH window hypothesis: administration of low doses of exogenous FSH will induce multifollicular development, unless selection of the dominant follicle has occurred (defined as the appearance of a follicle 10 mm), coinciding with a rise in oestradiol and a decrease in FSH concentrations.
We observed a substantial number of subjects presenting with premature luteinization (a rise in serum progesterone concentration on or before the day of HCG administration, which was based on ultrasound criteria only) in all intervention cycles. The definition used for premature luteinization and the threshold concentrations used for progesterone rise differ from study to study. Threshold concentrations for a subtle rise in progesterone on the day of HCG differ between 0.5 ng/ml (1.59 nmol/l) (Schoolcraft et al., 1991) and 1.5 ng/ml (4.77 nmol/l) (Sengoku et al., 1994
). The occurrence of premature luteinization in our study was not dependent on the day of initiation of exogenous FSH, the occurrence of single or multiple dominant follicle selection or late follicular phase oestradiol concentrations (data not shown). The mechanism underlying a subtle progesterone rise during the late follicular phase after ovarian stimulation, the incidence and the implications for outcome of IUI or IVF are not yet clear. Some studies associate premature luteinization in IVF with poor oocyte quality, decreased fertilization rates, poor embryo quality and impaired implantation (Schoolcraft et al., 1991
; Silverberg et al., 1991
; Harada et al., 1995
), whereas other studies suggest no difference in pregnancy outcome (Edelstein et al., 1990
; Hofmann et al., 1996
; Ubaldi et al., 1996
). Studies regarding the effects of premature luteinization on clinical outcome in IUI are also contradictory (Sengoku et al., 1994
; Manzi et al., 1995
).
Although we found a correlation between the reported normal cycle length and the length in the intervention cycle, the intervention cycle was shorter. This phenomenon remained if we corrected for subjects showing a premature ovulation. There is no reason to believe that the administration of exogenous FSH will accelerate the growth of the lead follicle (Pache et al., 1990). However, the administration of HCG might shorten the follicular phase in some women since ovulation was triggered as soon as the lead follicle reached a diameter of 18 mm. In a spontaneous cycle, the median pre-ovulatory follicle size is 21 mm, with a range of 1830 mm (van Santbrink et al., 1995
). A decreased luteal phase length in the subjects presenting with multiple dominant follicle development may represent an additional explanation for the shorter intervention cycle.
The length of the luteal phase was significantly reduced in all the cycles with multiple dominant follicle development. A short luteal phase in cycles stimulated with gonadotrophins for IVF has previously been documented (Laatikainen et al., 1988; de Jong et al., 2000b
). However, it remains unclear if the reduction in luteal phase length is a consequence of gonadotrophin therapy, co-treatment with gonadotrophin-releasing hormone analogues, HCG or the follicle puncture procedure (Smitz et al., 1990
). In the current study, the short luteal phase was independent from the administration of HCG or the amount of exogenous FSH administered. Midluteal phase endocrine concentrations in intervention cycles presenting with single dominant follicle development were comparable with non-intervention cycles in normo-ovulatory women (Macklon and Fauser, 2000
). Although midluteal oestradiol and inhibin A concentrations were significantly higher in cycles with multiple follicle development, midluteal progesterone was similar. As midluteal gonadotrophin serum concentrations were significantly lower in cycles with multiple dominant follicle development, high oestradiol and inhibin A might trigger luteolysis through negative feedback mechanisms. In vitro, oestradiol was found to inhibit gonadotrophin-stimulated progesterone synthesis by luteal cells (Hahlin et al., 1986
). Other studies suggest a luteolytic action of oestrogens mediated via prostaglandins (Auletta et al., 1976
) or arachidonic acid (Fisch et al., 1994
). In cycles with multiple dominant follicle development, high initial progesterone production may fall rapidly during the luteal phase, which in turn reduces the length of the luteal phase.
In conclusion, our findings are supportive of the FSH window concept. Subtle interference with decremental FSH by low-dose exogenous FSH can induce multiple dominant follicle development. Provided that no dominant follicle selection has occurred, initiation of FSH administration as late as cycle day 7 is sufficient to interfere with single dominant follicle selection. Multiple follicle development per se induces changes in the length and endocrine profile of the luteal phase. This information seems relevant for the design of mild ovarian stimulation protocols for IUI or IVF.
![]() |
Acknowledgements |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Baird, D.T. (1987) A model for follicular selection and ovulation: lessons from superovulation. J. Steroid Biochem., 27, 1523.[ISI][Medline]
Brown, J.B. (1978) Pituitary control of ovarian function|concepts derived from gonadotrophin therapy. Aust. NZ J. Obstet. Gynaecol., 18, 4654.[Medline]
Chong, A.P., Rafael, R.W. and Forte, C.C. (1986) Influence of weight in the induction of ovulation with human menopausal gonadotropin and human chorionic gonadotropin. Fertil. Steril., 46, 599603.[ISI][Medline]
de Jong, D., Macklon, N.S. and Fauser, B.C. (2000a) A pilot study involving minimal ovarian stimulation for in vitro fertilization: extending the `follicle-stimulating hormone window' combined with the gonadotropin-releasing hormone antagonist cetrorelix. Fertil. Steril., 73, 10511054.[ISI][Medline]
de Jong, D., Macklon, N.S. and Fauser, B.C. (2000b) Minimal ovarian stimulation for IVF: extending the `follicle stimulating hormone window'. In Jansen, R. and Mortimer, D. (eds), Towards Reproductive Certainty. Parthenon Group, New York, pp. 195199.
Diczfalusy, E. and Harlin, J. (1988) Clinicalpharmacological studies on human menopausal gonadotrophin. Hum. Reprod., 3, 2127.[Abstract]
Edelstein, M.C., Seltman, H.J., Cox, B.J. et al. (1990) Progesterone levels on the day of human chorionic gonadotropin administration in cycles with gonadotropin-releasing hormone agonist suppression are not predictive of pregnancy outcome. Fertil. Steril., 54, 853857.[ISI][Medline]
Edwards, R.G., Lobo, R. and Bouchard, P. (1996) Time to revolutionize ovarian stimulation. Hum. Reprod., 11, 917919.[ISI][Medline]
Erickson, G.F. and Danforth, D.R. (1995) Ovarian control of follicle development. Am. J. Obstet. Gynecol., 172, 736747.[ISI][Medline]
Fauser, B.C. and Van Heusden, A.M. (1997) Manipulation of human ovarian function: physiological concepts and clinical consequences. Endocr. Rev., 18, 71106.
Fauser, B.C., Pache, T.D., Lamberts, S.W. et al. (1991) Serum bioactive and immunoreactive luteinizing hormone and follicle-stimulating hormone levels in women with cycle abnormalities, with or without polycystic ovarian disease. J. Clin. Endocrinol. Metab., 73, 811817.[Abstract]
Fauser, B.C., Donderwinkel, P. and Schoot, D.C. (1993) The step-down principle in gonadotrophin treatment and the role of GnRH analogues. Baillières Clin. Obstet. Gynaecol., 7, 309330.[ISI][Medline]
Fauser, B.C., Devroey, P., Yen, S.S. et al. (1999) Minimal ovarian stimulation for IVF: appraisal of potential benefits and drawbacks. Hum. Reprod., 14, 26812686.
Fisch, B., Rose, M.P., Elder, M.G. et al. (1994) Effects of oestrogen on progesterone synthesis and arachidonic acid metabolism in human luteal cells. Clin. Endocrinol., 40, 2132.[ISI][Medline]
Ganirelix dose-finding study group (1998) A double-blind, randomized, dose-finding study to assess the efficacy of the gonadotrophin-releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon). Hum. Reprod., 13, 30233031.[Abstract]
Goodman, A.L. and Hodgen, G.D. (1979) Between-ovary interaction in the regulation of follicle growth, corpus luteum function, and gonadotropin secretion in the primate ovarian cycle. I. Effects of follicle cautery and hemiovariectomy during the follicular phase in cynomolgus monkeys. Endocrinology, 104, 13041309.[ISI][Medline]
Groome, N.P., Illingworth, P.J., O'Brien, M. et al. (1996) Measurement of dimeric inhibin B throughout the human menstrual cycle. J. Clin. Endocrinol. Metab., 81, 14011405.[Abstract]
Hahlin, M., Bennegard, B. and Dennefors, B. (1986) Human luteolysis|interaction between HCG and oestradiol-17beta in an in-vitro model. Hum. Reprod., 1, 7579.[Abstract]
Hall, J.E., Schoenfeld, D.A., Martin, K.A. et al. (1992) Hypothalamic gonadotropin-releasing hormone secretion and follicle-stimulating hormone dynamics during the lutealfollicular transition. J. Clin. Endocrinol. Metab., 74, 600607.[Abstract]
Harada, T., Yoshida, S., Katagiri, C. et al. (1995) Reduced implantation rate associated with a subtle rise in serum progesterone concentration during the follicular phase of cycles stimulated with a combination of a gonadotrophin-releasing hormone agonist and gonadotrophin. Hum. Reprod., 10, 10601064.[Abstract]
Hillier, S.G., Afnan, A.M., Margara, R.A. et al. (1985) Superovulation strategy before in vitro fertilization. Clin. Obstet. Gynaecol., 12, 687723.[ISI][Medline]
Hodgen, G.D. (1982) The dominant ovarian follicle. Fertil. Steril., 38, 281300.[ISI][Medline]
Hofmann, G.E., Khoury, J., Johnson, C.A. et al. (1996) Premature luteinization during controlled ovarian hyperstimulation for in vitro fertilizationembryo transfer has no impact on pregnancy outcome. Fertil. Steril., 66, 980986.[ISI][Medline]
Hughes, E.G., Collins, J.A. and Gunby, J. (1998) A randomized controlled trial of three low-dose gonadotrophin protocols for unexplained infertility. Hum. Reprod., 13, 15271531.[Abstract]
Laatikainen, T., Kurunmaki, H. and Koskimies, A. (1988) A short luteal phase in cycles stimulated with clomiphene and human menopausal gonadotropin for in vitro fertilization. J. In Vitro Fertil. Embryo. Transfer, 5, 1417.[ISI][Medline]
Lashen, H., Ledger, W., Bernal, A.L. et al. (1999) Extremes of body mass do not adversely affect the outcome of superovulation and in-vitro fertilization. Hum. Reprod., 14, 712715.
Le Nestour, E., Marraoui, J., Lahlou, N. et al. (1993) Role of estradiol in the rise in follicle-stimulating hormone levels during the lutealfollicular transition. J. Clin. Endocrinol. Metab., 77, 439442.[Abstract]
Macklon, N.S. and Fauser, B.C. (2000) Regulation of follicle development during the normal menstrual cycle: Relevance for ovarian stimulation for IVF. Hum. Reprod. Update, 6, 307312.
Mannaerts, B., De Leeuw, R., Geelen, J. et al. (1991) Comparative in vitro and in vivo studies on the biological characteristics of recombinant human follicle-stimulating hormone. Endocrinology, 129, 26232630.[Abstract]
Mannaerts, B., Shoham, Z., Schoot, D. et al. (1993) Single-dose pharmacokinetics and pharmacodynamics of recombinant human follicle-stimulating hormone (Org 32489*) in gonadotropindeficient volunteers. Fertil. Steril, 59, 108114.[ISI][Medline]
Manzi, D.L., Dumez, S., Scott, L.B. et al. (1995) Selective use of leuprolide acetate in women undergoing superovulation with intrauterine insemination results in significant improvement in pregnancy outcome. Fertil. Steril, 63, 866873.[ISI][Medline]
Pache, T.D., Wladimiroff, J.W., de Jong, F.H. et al. (1990) Growth patterns of nondominant ovarian follicles during the normal menstrual cycle. Fertil. Steril., 54, 638642.[ISI][Medline]
Rose, M.P. and Gaines-Das, R.E. (1998) Characterisation, calibration and comparison by international collaborative study of international standards for the calibration of therapeutic preparations of FSH. J. Endocrinol., 158, 97114.
Roseff, S.J., Bangah, M.L., Kettel, L.M. et al. (1989) Dynamic changes in circulating inhibin levels during the lutealfollicular transition of the human menstrual cycle. J. Clin. Endocrinol. Metab., 69, 10331039.[Abstract]
Schipper, I., Hop, W.C. and Fauser, B.C. (1998) The follicle-stimulating hormone (FSH) threshold/window concept examined by different interventions with exogenous FSH during the follicular phase of the normal menstrual cycle: duration, rather than magnitude, of FSH increase affects follicle development. J. Clin. Endocrinol. Metab., 83, 12921298.
Schoemaker, J., van Weissenbruch, M.M., Scheele, F. et al. (1993) The FSH threshold concept in clinical ovulation induction. Baillières. Clin. Obstet. Gynaecol., 7, 297308.[ISI][Medline]
Schoolcraft, W., Sinton, E., Schlenker, T. et al. (1991) Lower pregnancy rate with premature luteinization during pituitary suppression with leuprolide acetate. Fertil. Steril., 55, 563566.[ISI][Medline]
Sengoku, K., Tamate, K., Takaoka, Y. et al. (1994) A randomized prospective study of gonadotrophin with or without gonadotrophin-releasing hormone agonist for treatment of unexplained infertility. Hum. Reprod., 9, 10431047.[Abstract]
Silverberg, K.M., Burns, W.N., Olive, D.L. et al. (1991) Serum progesterone levels predict success of in vitro fertilization/embryo transfer in patients stimulated with leuprolide acetate and human menopausal gonadotropins. J. Clin. Endocrinol. Metab., 73, 797803.[Abstract]
Smitz, J., Devroey, P., and Van Steirteghem, A.C. (1990) Endocrinology in luteal phase and implantation. Br. Med. Bull., 46, 709719.[Abstract]
Sullivan, M.W., Stewart-Akers, A., Krasnow, J.S. et al. (1999) Ovarian responses in women to recombinant follicle-stimulating hormone and luteinizing hormone (LH): a role for LH in the final stages of follicular maturation. J. Clin. Endocrinol. Metab., 84, 228232.
Ubaldi, F., Camus, M., Smitz, J. et al. (1996) Premature luteinization in in vitro fertilization cycles using gonadotropin-releasing hormone agonist (GnRH-a) and recombinant follicle-stimulating hormone (FSH) and GnRH-a and urinary FSH. Fertil. Steril., 66, 275280.[ISI][Medline]
van Santbrink, E.J., Hop, W.C., van Dessel, T.J. et al. (1995) Decremental follicle-stimulating hormone and dominant follicle development during the normal menstrual cycle. Fertil. Steril., 64, 3743.[ISI][Medline]
Zeleznik, A.J., Hutchison, J.S. and Schuler, H.M. (1985) Interference with the gonadotropinsuppressing actions of estradiol in macaques overrides the selection of a single preovulatory follicle. Endocrinology, 117, 991999.[Abstract]
Submitted on October 3, 2000; accepted on January 31, 2001.