| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Departments of Obstetrics, Gynecology, and Women’s Health, Albert Einstein College of Medicine and Beth Israel Medical Center, New York, New York 10461
Address all correspondence and requests for reprints to: Dr. Nanette Santoro, Department of Obstetrics, Gynecology and Women’s Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Mazer 325, Bronx, New York 10461. E-mail: glicktoro{at}aol.com.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
45 yr old). Women underwent serial transvaginal ultrasounds to follow follicular growth over 1 menstrual cycle. A subset of women (nine MRA and 19 ORA) had daily blood sampling. Scans were initiated within 1 wk of menses and were performed at least 3 times/wk until evidence of follicular collapse was observed. If there was no evidence of follicle growth beyond 10 mm by 20 d, observations (ultrasounds and blood sampling) were ended. Follicle growth was organized backward from maximum presumed preovulatory diameter. Hormones were standardized to d 0, the day when progesterone levels exceeded 2 ng/ml. Group comparisons were performed using ANOVA with Mann-Whitney post hoc testing and Kruskal-Wallis testing for integrated hormones. The main outcome measures were peak follicle diameter, follicle growth patterns, and circulating LH, FSH estradiol, progesterone, inhibin A, and inhibin B. Six of 34 ORA women never underwent serial ultrasound. An additional 5 ORA women failed to ovulate on the basis of daily blood sampling or had no evidence of follicle growth beyond 10 mm by 20 d. Two of 16 MRA women were excluded: 1 due to severely decreased ovarian reserve at screening and 1 due to failure of follicle growth by cycle d 20. Small follicle counts in the follicular phase of the cycle (beginning of cycle through d -4) were greater in MRA women compared with ORA women (4.7 ± 0.56 vs. 3.4 ± 0.34; P = 0.042). Among presumed ovulatory cycles, ORA women demonstrated considerably more variable follicle growth patterns, with larger initial follicle size, but a trend toward smaller peak follicle diameters (15.22 ± 0.95 vs. 17.85 ± 0.71 mm; P = 0.07). ORA women were twice as likely to have multiple follicles as younger women (odds ratio, 2.06; 95% confidence interval, 0.93–4.6), but this observed difference was not statistically significant (P = 0.083). Comparisons of LH, FSH, estradiol, and progesterone between ORA (n = 14) and MRA (n = 8) women indicated the expected increase in FSH secretion, most evident in the early follicular phase of the cycle. Estradiol and progesterone concentrations did not differ between these groups. Inhibin B was decreased in ORA women compared with MRA women (P = 0.030). Despite normal-appearing patterns of follicle growth, grossly abnormal hormonal patterns were observed in some of the ORA women’s cycles. Other cycles demonstrated a failure of folliculogenesis. These patterns are not observed in MRA women’s cycles. ORA women ovulated at a smaller mean follicle diameter and had larger initial follicle diameters than younger women. The overall follicle growth curves of the older women tended to be flatter than those of the younger women. Taken together, the data suggest that follicle growth begins earlier in the cycle of perimenopausal women, but growth progresses more slowly. Ovulation may occur at an earlier stage of growth in association with reproductive aging. |
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Some recent studies have described the ovarian morphology and patterns of follicle growth associated with reproductive aging. Ovarian volume has been reported to decrease with age in a population of 13,963 women undergoing ovarian cancer screening (4). The inclusion of women in the age group between 30–50 yr who were already naturally menopausal may have contributed disproportionately to these results, however, and the menopausal status of the younger women in this study is not provided. The number of antral follicles (i.e. >2 mm) in the ovaries has been reported to be significantly decreased in women over an age range of 22–42 yr old (5). These differences in follicle counts were independent of the stage of the menstrual cycle. Another study of 162 women that was confined to the early follicular phase alone (6) reported a mean yearly decline of antral follicle counts of about 5%, which increased to almost 12% after the age of 37 yr. Taken together, these data suggest that follicles in various stages of growth constitute the bulk of ovarian volume and that declining numbers of observable follicles occur concomitant with reproductive aging.
Others have observed the patterns of follicle growth in older reproductive aged (ORA) women, aged 40–45 yr, compared with younger women, aged 20–25 yr (7). In this study women were observed throughout a natural cycle. Follicle growth and collapse were similar between the younger and older women in this study.
We and others have previously reported deviations in reproductive hormone patterns associated with reproductive aging. Shortened follicular phases (7, 8, 9), elevated follicular phase estrogen (9, 10, 11), and decreased luteal phase progesterone (9, 12) have been reported. These data suggest that folliculogenesis in the face of a reduced follicle pool proceeds rapidly in ORA women. Moreover, the approximately 1.8-fold overall increase in whole cycle estrone conjugate excretion we have previously reported (9) in women in their late 40s and early 50s compared with women aged 19–38 yr led us to hypothesize that multiple folliculogenesis was a common phenomenon associated with reproductive aging. Thus, although the total follicle pool was reduced, there might be a dysregulation of monofolliculogenesis, such that rapid maturation of more than one follicle could occur. We further hypothesized that the growth rates of follicles of ORA women would be slower than those of younger women. We also hypothesized that endometrial morphology might be affected by either aging per se or hormonal alterations in the cycles of ORA women.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Forty-nine women were screened and scheduled to be studied. All studies were approved by the committee on clinical investigation at Albert Einstein College of Medicine and Montefiore Medical Center. All women provided informed consent before participation in the study. Perimenopausal women were required to meet the following criteria: onset of menarche aged 11–15 yr, normal TSH and PRL, no excessive exercise (>4 h/wk) or weight loss (>1 lb/wk), weight at least 90% normal for height (13), age 45 yr or older at the time of study, at least one menstrual period within the past 3 months before study, evidence of cycle irregularity (at least one skipped menses within the past year), and screening cycle d 2–5 FSH of 7.2 IU/liter or greater.
Controls
MRA controls were women aged 22–34 yr who met the first four criteria above as well as the following: regular menstrual cycles occurring every 25–35 d and screening cycle d 2–5 FSH less than 6.5 IU/liter, within 1 SD of our previously obtained normal MRA values (9).
Protocol
Women were asked to undergo transvaginal ultrasonography over the course of a single menstrual cycle. Ultrasonography was performed by a single observer (B.I.) using an ALOKA (Wallingford, CT) 625 scanner with a 5-MHz transvaginal probe. This model ultrasound has a resolving power of about 2 mm. All follicles seen in the ovary were measured in two dimensions, and the mean diameter was recorded along with a photograph of each measurement. No follicles were excluded from measurement, providing they could be seen. Reliability was checked every 6 months using a phantom. The mean coefficient of variation of three measures each of three different phantoms (mean phantom diameter, 0.8–1.5 cm) on three separate occasions was 3.1% (range, 2.5–3.9%). Participants were instructed to report to the research nurse during their menses after the screening tests were complete. All transvaginal ultrasounds were performed at the General Clinical Research Center of Albert Einstein College of Medicine. An initial ultrasound was scheduled within 7 d of menses. Scans were then usually performed at least three times a week (Mondays, Wednesdays, and Fridays) until evidence of follicular collapse or an increase in echogenicity of the large follicle was observed. These latter two findings were considered presumed evidence of luteinization, as has been reported by other similar studies (1, 2, 3, 4, 5).
Development of parameters of follicle growth
All visible follicles were measured at each ultrasound in each woman. For counts of follicles, measurements were divided into small and large classifications, based on a size of 10 mm or more as the cut-off for large. We calculated the total count of each class of follicles on each day for each of the participants. Multiple large follicles were derived as the percentage of participants with more than one follicle 10 mm or larger. Follicle diameters were calculated as the average of large and small follicle diameters on each day for each of the participants. For lead follicle diameter, the maximal follicle diameter was found on each day for each woman. These definitions provided us with a dataset comprised of summary measurements of large and small follicles for each participant on each day of observation.
Cycle measurements
We reconciled the different cycle day parameters among the participants by determining the midcycle day through inspection of the follicle growth curves and, when available, the endocrine data. The midcycle day for each participant was assigned a value of 0, and all other cycle days were numbered relative to midcycle. The reconciled cycle days were then grouped into phases. The days from the beginning of menses through d -4 were grouped as follicular. Days -3 through -2 were grouped as late follicular. Days -1 through 2 were grouped as midcycle. Days 3 through the end were grouped as luteal. In women who had hormonal assessments performed (n = 19 ORA and nine MRA women), the day of ovulation was assigned when progesterone levels exceeded 2 ng/ml (6.4 nmol/liter) within 3 d of an LH surge. This day was standardized to d 0, and the cycle was divided into a follicular phase (from the cycle start up to, but not including, d 0) and a luteal phase (d 0 up to subsequent menses). For the remaining women, who did not have blood sampling, the largest follicle diameter attained between cycle d 6 and 24 was considered the maximum preovulatory follicle, and the day on which this was achieved was considered d 0.
Hormonal sampling
In a subset of the women (19 ORA and nine MRA), daily blood samples were taken from the onset of 1 menstrual period to the next. These cycles were analyzed for LH, FSH, estradiol, progesterone, inhibin A, and inhibin B using previously reported assays (9, 10).
Endometrial thickness
Endometrial thickness was measured in a midsaggital plane. The thickest fundal echo was taken as a single measurement after scanning in three dimensions to rule out intrauterine lesions, such as myomas or polyps, that might falsely increase the echo (11).
Data analysis
Power. The present report is an interim analysis of a study that was designed to examine 50 perimenopausal women and 40 MRA women. Assumptions of multiple folliculogenesis ranged from a minimum of 30–50% in the ORA group and no more than 5% in the MRA women to achieve a power of between 84–88% with this final sample size. As the difference between the two groups in the rate of multiple folliculogenesis was much less than expected (less in the older women and more in the younger women), an interim analysis was performed to assist in the decision as to whether to complete the full sample.
Statistics. Descriptive statistics were calculated for grouped data. Maximum preovulatory follicle diameters and follicle counts for ORA women were compared with MRA women within each cycle phase using nested ANOVA. Nonparametric testing (Mann-Whitney U tests) were used to confirm significance testing if the data were not normally distributed. If the nonparametric testing confirmed the ANOVA, we reported only the parametric results. We compared multiple large follicle development between groups by creating a binary variable representing the presence of more than one follicle greater than or equal to 10 mm in diameter for each participant in each cycle phase. Binary logistic regression of multiple large follicle development was tested against reproductive status (ORA vs. MRA). The odds ratio for the presence of multiple follicle development was calculated for ORA vs. MRA women. Hormonal data were meaned and presented graphically standardized to d 0 ± SEM. Area under the curve (AUC) values were computed for the follicular and luteal phases of the cycle (15). The net change in AUC was defined as the total AUC minus the baseline AUC. The mean net change in AUC for each hormone was compared after log transformation using an analysis of covariance, adjusting for the baseline hormone level. Throughout Results, data are expressed as the mean ± SEM, except for integrated hormones, which are expressed as the mean with the 95% confidence interval in parentheses. SPSS software Base 10.0 (SPSS, Inc., Chicago, IL) was used for all statistical testing, and data were stored in a Microsoft Access database (Microsoft, Redmond, WA).
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
A total of 49 women underwent screening for these studies. One ORA participant developed vaginal hemorrhage secondary to a submucosal uterine myoma in between her screening tests and her study cycle and withdrew from the study. Another 5 ORA women never had another menstrual period or could not be successfully scheduled for a study cycle due to menstrual irregularity. One MRA participant was screened and found to have a baseline FSH of 36 mIU/ml. She went on to develop oligomenorrhea and a presumed diagnosis of premature ovarian failure was made.
Of the 42 women who completed the cycle of study, 5 of the ORA women and 1 MRA woman did not demonstrate a large follicle by cycle d 20 or did not ovulate on the basis of the hormone analysis. This left a sample size of 36 women, 14 MRA and 22 ORA, whose data are represented within the ovulatory cycles. Of these 36 women, eight MRA and 14 ORA women underwent both ultrasound and blood-sampling studies and had evidence of ovulatory cycles suitable for between-group comparisons.
Small follicle counts
Small follicles were counted and compared between both groups. At the time of the first ultrasound scan, the MRA women had a mean of 4.87 ± 0.57 small follicles present in their ovaries, whereas the ORA women had a mean of 4.11 ± 0.30 small follicles (P = 0.2). When examined throughout the cycle, follicle counts tended to be lower in the older women compared with the younger MRA control group, but this finding was not statistically significant at any one cycle stage (Fig. 1
). In the early and midfollicular phases (beginning of cycle through d -4), MRA women had higher small follicle counts (4.7 ± 0.56 follicles compared with 3.4 ± 0.34 follicles for ORA women; P = 0.042).
|
The overall patterns of the two groups diverged significantly, but in a complex way. In follicular phase scans encompassing the first several scans up to cycle d -4 (4 d before presumed ovulation), the mean diameter of the largest follicle was 11.38 ± 1.33 mm for the MRA women and 13.37 ± 2.29 mm for the ORA women (P = 0.036). The older women had a larger mean follicle diameter in the earlier stages of follicle growth. However, older women tended to have a smaller lead follicle on midcycle d 0 (15.22 ± 0.95 vs. 17.85 ± 0.70; P = 0.07). These data are depicted in Fig. 1
. When the midcycle phase of d -1 to 2 was isolated, and all scans were included (i.e. more than one per woman), the mean lead follicle diameter in the MRA women was 18.13 ± 0.86 vs. 14.7 ± 0.81 in the ORA women (P < 0.01; data not shown in Fig. 1).
Presence of multiple, large follicles
In 42% of the older women’s cycles, there was evidence of more than one follicle with a diameter of 10 mm or greater. The MRA women had more than one large follicle in only 26% of cycles. The ORA women in our study were twice as likely to have multiple follicles with a diameter of 10 mm or greater (odds ratio, 2.06; 85% confidence interval, 0.93–4.6). The percentage of cases with multiple follicles observed at the various cycle stages is shown by group in Fig. 1.
Hormonal patterns in ovulatory cycles
Analysis of LH, FSH, estradiol, progesterone, inhibin A, and inhibin B patterns are depicted in the ORA and MRA groups in Fig. 2. As expected, a highly significant increase in FSH was observed in ORA cycles: 127 (confidence interval, 88, 185) vs. 54 (confidence interval, 39, 74) in MRA women (P = 0.01). LH was also greater in ORA women (78; confidence interval, 61, 100) vs. MRA women (30; confidence interval, 11, 87; P = 0.026). Estradiol and progesterone did not differ significantly between groups. Inhibin B was significantly lower in the ORA women compared with the MRA women [1074 (confidence interval, 734, 1571) vs. 2116 (confidence interval, 1805, 2497); P = 0.030].
|
In 5 of the 19 hormonally documented cycles of ORA women, no evidence of luteal function was observed. In some of these cycles the growth of a large follicle was documented. An example of such a cycle is shown in Fig. 3. Despite a complete lack of progesterone production, there was ultrasound evidence of follicle growth and even presumed luteinization, and her menses occurred on d 30, at the end of the blood sampling.
|
We examined the endometrial thickness at each scan to determine whether older women would have altered endometrial thickness. As shown in Fig. 4, there was no difference between the two groups of women.
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Our data support previous observations that the follicular phase of the cycle in ORA women is accelerated (7, 8, 9). We found evidence of a relatively early appearance of a large follicle in the ORA women who had presumed ovulation. It is possible and has been suggested that follicle growth begins in the preceding luteal phase in older women.
We add to these previous observations new information that suggests that the progress of folliculogenesis is slower in ORA women. Although these women begin the cycle with a larger follicle, they tend to ovulate a smaller follicle compared with younger MRA women. These findings imply that there is impairment of the latter stages of antral follicle growth in older women. It has been demonstrated that growth factors such as IGF-II are reduced in the follicular fluid of ORA women (7, 18) and that circulating IGF-I is also reduced (19). The latter stages of folliculogenesis are more gonadotropin dependent, particularly LH dependent (20, 21), and it is possible that a deficit of these growth factors, which act in concert with gonadotropins to stimulate the follicle, plays a role in slowing follicular growth. Alternatively, the follicles of ORA women may be vascularly compromised and therefore less capable of receiving a circulating gonadotropin signal. Recent studies of follicular fluid have demonstrated increased vascular endothelial growth factor in follicles of older vs. younger women (18). This may be reflective of overall hypoxia within the follicle. Vascular endothelial growth factor appears to be a critical molecule involved in corpus luteum formation (22).
The smaller follicle size at ovulation in ORA women may be a manifestation of lesser follicle fitness in association with aging, but may also contribute to their reduced fertility and pregnancy wastage. Ovarian follicles that are immature may contain oocytes that lack nuclear maturity and have not completed the first meiotic division at the time of extrusion (23). These oocytes would be expected to be less likely to fertilize and may have greater potential for chromosomal errors. This is known to occur in reproductively aged women (24). If some of the age-related losses in reproductive function are due to a relative dysregulation of the processes of folliculogenesis and ovulation with age, then therapeutic interventions designed to treat these modifiable factors might have the potential to improve reproductive performance.
Similar to previous reports of the hormonal dynamics of ORA women’s cycles, we observed a large rise in FSH that was particularly pronounced in the early follicular phase of the cycle (7, 8, 9, 12, 25). Consistent with the idea that an early loss of inhibin is responsible for this FSH rise, we observed a decrement in inhibin B, but not inhibin A, in the older women’s cycles (15, 16). These data are consistent with previous work with regard to inhibin B; however, we and others have reported decreased inhibin A in the luteal phase of ORA women’s cycles (10, 25, 26, 27). The sample of women selected for this study may have been somewhat less reproductively aged than those in previous studies, and this may account for the variance of our findings with our own prior work and that of others. The menopause transition is probably a dynamic process that involves serial changes in hormones without obvious clinical signs or symptoms.
Further support for the idea that the women in this sample differed from other studies is the finding that serum estradiol was not elevated in this study. In a previous report from our group using daily urine samples, but no ultrasound or inhibin testing, we observed an almost 2-fold elevation in urinary estradiol metabolites in association with elevated FSH in ovulatory cycles of women of a similar age (9). The lack of agreement between the current report and our past study may reflect differences between the participants studied, differences between urinary excretion patterns of estrone conjugates and serum estradiol, or the fact that multiple ovulations were observed infrequently in the present study and may have occurred more commonly in the participants from the 1996 report. As parallel assessments of ovarian morphology were not performed in the previous study, it is not possible to fully explain the discrepancy.
Our frequent finding of aluteal cycles in a sizeable proportion of ORA women is not surprising, but has not been previously reported in a sample of women undergoing such intensive monitoring. This finding suggests that ovulation cannot be taken for granted in a cycle with apparent large follicle growth. All of these women had a normal intermenstrual interval in the cycle of study and had no clue that their cycle was grossly abnormal by the hormonal standards anticipated in MRA women. Therefore, this marked impairment in follicular function would have gone totally clinically unrecognized by both investigator and participant if blood samples had not been analyzed concomitantly. The silent nature of these anovulatory cycles and their relative frequency (6 of 20 cycles in which blood sampling and ultrasound measurements were both performed) imply that the absence of luteal function may be a more common event than previously believed, and that luteal failure may be an early sign of entry into the menopausal transition. Our ORA women were selected to meet the WHO 1996 definition of the early menopausal transition, as they had had some irregularity, but no prolonged amenorrhea. A large, multicenter study of 848 cycles (SWAN, the Study of Women’s Health Across the Nation) has recently reported that luteal function appears to be affected early in the menopause transition based upon daily sampling of women for an entire menstrual cycle (28). Frequent failure to form a functional corpus luteum may also help explain the relative infertility that accompanies reproductive aging. The lack of luteal function without premature menstruation may occur because the follicle fails to undergo some of the transformational molecular events associated with corpus luteum formation (29) yet continues to produce sufficient estradiol to maintain the endometrium. Bleeding then occurs on schedule for the woman because the follicle regresses at the expected time.
There were several limitations of our study. First, we did not perform serial blood sampling on every woman and cannot therefore assume that all cycles that appeared ovulatory by ultrasound were, in fact, associated with progesterone production. This might have resulted in a bias, as the aluteal cycles that may have occurred in the ORA women who did not have blood sampling may have had markedly abnormal patterns of follicular growth, whereas the luteal cycles corresponded more closely to the patterns of the younger women. However, our data do not confirm a bimodal distribution of follicle growth patterns, and the inclusion of all women into the database yielded results similar in nature to the inclusion of only women with documented hormones during their cycles of study. Second, we were unable to recruit a matched size control group of MRA women sufficient to rule out a type II error in some of our statistical comparisons. Our study may have lacked sufficient statistical power to make stronger comparisons. Finally, systematic differences in ultrasound image quality in either the MRA or ORA women could have introduced a bias into the results that would be undetected by our methods.
The only prior ultrasound study of follicle growth in ORA women is that by Klein et al. (7). These investigators did not find differences in the follicular growth patterns of the ORA women when they were compared with younger controls. These women also underwent induced ovulation at a specified peak follicle size. Women beyond age 45 yr or those with cycle irregularity were not studied, and the differences between our findings and those of Klein et al. may be because the women we studied were further along in the process of the menopausal transition.
In cycles without clear-cut evidence of ovulation and corpus luteum function, as shown in Fig. 5, a discrepancy was noted between estradiol secretion and lead follicle growth. A recent study reported by Baerwald et al. (30) examined the cycles of 63 MRA women and identified several waves of small follicle (<10 mm) growth within a 28-d cycle. These investigators conjectured that such small follicles might be capable of producing estradiol and may be responsible for the luteal phase rise in estradiol that accompanies progesterone. It may well be possible that an aggregation of smaller follicles that are capable of responding to FSH with aromatase expression and estradiol production led to the rise in estradiol noted in some of our anovulatory cycles. Thus, the hormonal activity of small follicles may be of physiological relevance.
Our findings confirm that small follicle counts are lower in ORA women. Our overall sample size is smaller than that in other reports, and the lower small follicle counts were not evident at every scan. It is likely that our sample size was insufficient to detect this difference consistently, as reported by several others (4, 5, 6). Follicle counts were also not a primary initial goal of this study, and there may therefore have been a systematic underestimation. Our ultrasound machine may also have lacked the sensitivity to detect very small follicles (2 mm), as this diameter is at the limit of the resolving power of the machine we used.
We did not observe a statistically significant difference in the proportion of women who had more than one large follicle at the time of ovulation in this sample. If ORA women do, in fact, have marked dysregulation of the process of folliculogenesis, one would expect that this event might be more likely. It appears that the usual mechanisms that operate in the cycles of MRA women to limit the numbers of larger (10 mm) follicles do not operate as effectively in older women. We speculate that the decreased follicle density of the aging ovary may be less effective in producing the paracrine factors necessary to control local follicle growth. It is also possible that the presence of these larger follicles provides supplemental estradiol to the cycle in both the follicular and luteal phases and thereby disrupts further the optimal reproductive milieu.
We also did not find any differences in endometrial thickness between younger and older women. It has been hypothesized that uterine factors play a significant role in the relative infertility that accompanies aging (31). If defects in uterine function are part of reproductive aging, they do not appear to be detectable using morphological studies of endometrial thickness or pattern.
In summary, we have demonstrated that women in the early stages of the menopausal transition have larger follicles at early stages of development, smaller follicles at the time of ovulation, and an overall slower follicle growth pattern than younger women. Ultrasound alone is insufficient to determine whether ovulation has occurred in an ORA woman.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Abbreviations: AUC, Area under the curve; MRA, midreproductive aged; ORA, older reproductive aged.
Received December 9, 2002.
Accepted July 2, 2003.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  K. A. O'Connor, R. J. Ferrell, E. Brindle, J. Shofer, D. J. Holman, R. C. Miller, D. E. Schechter, B. Singer, and M. Weinstein Total and Unopposed Estrogen Exposure across Stages of the Transition to Menopause Cancer Epidemiol. Biomarkers Prev., March 1, 2009; 18(3): 828 - 836. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Santoro, S. L. Crawford, W. L. Lasley, J. L. Luborsky, K. A. Matthews, D. McConnell, J. F. Randolph Jr., E. B. Gold, G. A. Greendale, S. G. Korenman, et al. Factors Related to Declining Luteal Function in Women during the Menopausal Transition J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1711 - 1721. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Niklaus, M. Aubuchon, G. Zapantis, P. Li, H. Qian, B. Isaac, M. Y. Kim, G. Adel, J. W. Pollard, and N. F. Santoro Assessment of the proliferative status of epithelial cell types in the endometrium of young and menopausal transition women Hum. Reprod., June 1, 2007; 22(6): 1778 - 1788. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Bristol-Gould, C. G. Hutten, C. Sturgis, S. M. Kilen, K. E. Mayo, and T. K. Woodruff The Development of a Mouse Model of Ovarian Endosalpingiosis Endocrinology, December 1, 2005; 146(12): 5228 - 5236. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. S. Malhi, G. P. Adams, and J. Singh Bovine Model for the Study of Reproductive Aging in Women: Follicular, Luteal, and Endocrine Characteristics Biol Reprod, July 1, 2005; 73(1): 45 - 53. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Miro and L.J. Aspinall The onset of the initial rise in follicle-stimulating hormone during the human menstrual cycle Hum. Reprod., January 1, 2005; 20(1): 96 - 100. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
