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Original Articles: Hormones and Reproductive Health |
Departments of Obstetrics and Gynecology (D.A.D., M.A.D., D.R.S., A.F., A.R.T.) and Biostatistics (T.G.L.), Mayo Clinic, Rochester, Minnesota 55905; and Medical Research Council, Human Reproductive Sciences Unit, University of Edinburgh (A.S.M.), Edinburgh, Scotland, United Kingdom EH3 9ET
Address all correspondence and requests for reprints to: Daniel A. Dumesic, M.D., Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota 55905. E-mail: ddumesic{at}mayo.edu
Abstract
Twenty-five normal ovulatory women underwent three-dimensional transvaginal ultrasonography and blood sampling before and after oral glucose tolerance testing to compare ovarian morphology and circulating hormone levels in the early follicular phase as predictors of the number of oocytes retrieved after gonadotropin stimulation for in vitro fertilization. Serum levels of gonadotropins, inhibins, testosterone, dehydroepiandrosterone sulfate, and estradiol as well as summed ovarian volume were unrelated to oocyte number. Antral follicle number and serum androstenedione level, however, positively correlated, whereas postoral glucose tolerance test (post-OGTT) insulin release negatively correlated, with total and mature oocyte numbers. Adjusting for age and body mass index by regression analysis, the serum androstenedione level significantly predicted mature, but not total, oocyte number. The relationships of antral follicle number and post-OGTT insulin release to total oocyte number were additive; each was significant after controlling for the other. In contrast, antral follicle number significantly correlated with mature oocyte number after controlling for post-OGTT insulin release, whereas post-OGTT insulin release was unrelated to mature oocyte number after controlling for antral follicle number. Therefore, early follicular phase antral follicle number positively correlates with total and mature oocyte numbers after gonadotropin stimulation for in vitro fertilization and is linked to androgen and insulin actions in predicting ovarian follicle recruitment by gonadotropins.
THERE IS NO consensus regarding the best predictor of ovarian follicle recruitment by gonadotropins for in vitro fertilization (IVF). For example, two-dimensional transvaginal sonography (TVUS) has been used to estimate the number of ovarian antral follicles and the size of the ovaries, both of which appear to positively correlate with the number of oocytes retrieved (1, 2, 3, 4). Antral follicle number and ovarian size also negatively correlate with the basal serum FSH level and the amount of gonadotropins required for IVF (1, 2, 3, 4). Such ovarian measurements by two-dimensional TVUS, however, are notoriously susceptible to evaluator error, which might be improved by three-dimensional imaging techniques that also store ovarian images for examination at a later time (5).
Predicting ovarian follicle recruitment by gonadotropins also can be based upon the principle that ovarian follicles secrete estradiol and inhibins, which, in turn, negatively feed back on FSH secretion. As the number of follicles diminishes, reduced granulosa cell inhibin production enhances FSH secretion, causing an increase in estradiol secretion as well. Consequently, basal serum FSH and estradiol levels in the early follicular phase (EFP) and FSH responsiveness to clomiphene citrate negatively correlate with ovarian follicle recruitment by gonadotropins and the number of oocytes retrieved (6, 7, 8, 9, 10, 11, 12, 13). These circulating hormone markers, however, do not assess the actions of other hormones (e.g. insulin, inhibins, and androgens) that also could influence ovarian follicle development.
Unfortunately, it is difficult to compare ovarian morphology and serum hormone markers as predictors of ovarian follicle recruitment for IVF because different patient populations have been investigated under various clinical circumstances. To determine which of these parameters is the most accurate under the same clinical circumstance, the present study compares ovarian morphology and serum hormone markers in the EFP as predictors of the number of oocytes retrieved from normal ovulatory women undergoing the same gonadotropin stimulation for IVF. Using three-dimensional TVUS and blood sampling before and after oral glucose tolerance testing (OGTT), ovarian antral follicle number in the EFP is better than summed ovarian volume or serum gonadotropin, estradiol, and inhibin determinations in predicting the number of oocytes retrieved after gonadotropin stimulation. In this role, it also shows that ovarian antral follicle number at this time is inextricably linked to androgen and insulin actions in estimating ovarian follicle recruitment by gonadotropins.
Materials and Methods
Experimental subjects
After approval was granted by the Mayo Institutional review board, 25 women [mean ± SD age, 30.8 ± 3.5 yr; mean body mass index (BMI), 24.1 ± 5.8 kg/m2] undergoing IVF with intracytoplasmic sperm injection for male infertility were recruited. All women gave signed informed consent before participating in the study. All women had regular menstrual cycles every 27–32 days, with ovulation confirmed by luteal phase progesterone levels over the preceding 2-month interval. There was no history of galactorrhea, hirsutism (defined by a modified Ferriman-Gallwey score >8) (14), or ovarian surgery, except for 1 woman who reported unilateral oophorectomy for a benign cystic teratoma. All women with hyperandrogenemia, hyperprolactinemia, or late-onset 21-hydroxylase deficiency, as shown by a basal serum 17-hydroxyprogesterone level above 2.0 ng/mL, were excluded. Twenty-three women were nonsmokers, and 3 women were smokers, all of whom smoked 10 or fewer cigarettes daily. Twenty-two women were lean, and 3 women were obese, as defined by a BMI greater than 28.5 kg/m2 (15).
TVUS and blood sampling
TVUS using a 4- to 8-mHz vaginal probe (HDI 5000, ATL Ultrasound, Inc., Bothell, WA) was performed on the fifth day after menses in the cycle immediately preceding IVF. Based upon manufacturing specifications, axial and lateral resolutions at a 2–4 cm depth were 1.0 and 1.8 mm, respectively. Summed ovarian volume, defined as the total volume of both ovaries, was calculated by 2-dimensional imaging using the formula for a prolate ellipsoid (0.5237 x D1 x D2 x D3, in which D1, D2, and D3 were the maximal longitudinal, anteroposterior, and transverse diameters, respectively). All sonographic images were immediately computerized and stored for later three-dimensional imaging. Antral follicle number, defined as the total follicle number (<10 mm in diameter) of both ovaries, was determined within 48 h by 1 investigator (D.A.D.) using 3-dimensional imaging of the stored ovarian images. Two patients had unilateral ovarian cysts measuring 11 and 19 mm in diameter, which were excluded from the antral follicle number, but not from the summed ovarian volume. Polycystic ovaries, as defined by more than 10 cysts in one ultrasonographic plane, each 2–8 mm in diameter, were not observed in any patient (16).
Blood sampling under fasting conditions and after OGTT was performed the next day (cycle day 6) because basal serum inhibin B levels at this time have been shown to correlate with the ovarian response to gonadotropin stimulation for IVF (17, 18). Blood samples were used to measure LH, FSH, total and free testosterone, androstenedione, dehydroepiandrosterone sulfate, PRL, 17-hydroxyprogesterone, estradiol, inhibin B, inhibin A, glucose, and insulin.
Summed ovarian volume, antral follicle number and serum estradiol, inhibin B, and inhibin A levels were determined again on the day of hCG administration after pituitary down-regulation and gonadotropin stimulation.
Serum FSH, LH, testosterone, dehydroepiandrosterone sulfate, and PRL were measured by chemiluminescent immunoassay; serum progesterone and insulin by immunoenzymatic assay; serum androstenedione, estradiol, and free testosterone by RIA; and serum glucose using hexokinase reagent from Roche Diagnostics (Sommerville, NJ) at the Immunochemical Core Laboratory of the Mayo General Clinical Research Center. The interassay coefficients of variation (CVs) were: FSH, 4.3%; LH, 5.5%; testosterone, 8.7%, dehydroepiandrosterone sulfate, 10.7%; estradiol, 11.6%; PRL, 9.4%; progesterone, 9.7%; insulin, 4.1%; androstenedione, 6.0%; free testosterone, 9.5%; and glucose, 3.2%. Serum 17-hydroxyprogesterone was determined by RIA at the Endocrine Laboratory of the Mayo Clinic. The interassay CV for 17-hydroxyprogesterone was 5.4%. The intraassay CVs were: FSH, 4.5%; LH, 4.0%; testosterone, 5.1%, dehydroepiandrosterone sulfate, 6.6%; estradiol, 9.8%; PRL, 3.3%; progesterone, 6.2%; insulin, 2.3%; androstenedione, 4.3%; free testosterone, 5.6%; glucose, 0.8%; and 17-hydroxyprogesterone, 7.2%. The laboratory of Dr. A. S. McNeilly was used to measure inhibin A and inhibin B by immunoenzymatic assay, as previously described (19, 20). The inter- and intraassay CVs for inhibin A and inhibin B were less than 10.0%.
Serum glucose and insulin levels before and after OGTT
Fasting and post-OGTT measurements of circulating glucose and insulin were performed by the nursing staff of the General Clinical Research Center at St. Mary’s Hospital (Rochester, MN). After the patient was admitted to the General Clinical Research Center on day 5 for an overnight stay, the age, height, and weight of the subject were recorded. Body mass index was calculated by established criteria [body weight (kilograms)/height (meters)2].
Each patient received a standardized mixed meal the evening before the study and ingested a 75-g glucose solution the next morning, as directed by a dietitian. Each patient then had blood drawn for serum glucose and insulin determinations at -30, -20, and -10 min and at time zero after a 12-h fasting state, followed by additional blood sampling at 30-min intervals during the next 6 h for a total of 12 additional blood drawings.
After completing the blood sampling and then eating breakfast, the patient was discharged from the General Clinical Research Center and instructed to begin GnRH analog therapy to induce pituitary down-regulation, starting on day 21 of the same cycle.
Gonadotropin stimulation for IVF
Gonadotropin stimulation for IVF was preceded by pituitary down-regulation with the GnRH analog, leuprolide acetate (Lupron, TAP Pharmaceuticals, Inc. Deerfield, IL), starting at a dose of 1.0 mg daily, injected sc into the thigh or arm. Once pituitary down-regulation occurred (e.g. no ovarian cysts larger than 18 mm in diameter, serum E2 <50 pg/mL), the dose of GnRH analog was decreased to 0.5 mg daily and then continued up to and including the day of hCG administration.
After adequate pituitary down-regulation, treatment with recombinant FSH (Gonal-F, Serono Laboratories, Inc., Norwell, MA) was administered sc at a starting dose of 225 IU daily for the first 5 treatment days. Thereafter, the daily dose of recombinant FSH was increased by 75–150 IU/day every 2–3 days or decreased at any time as necessary. Serial serum estradiol levels and two-dimensional TVUS determinations were performed until at least two dominant follicles reached more than 18 mm in diameter, and serum estradiol concentrations reached approximately 300 pg/mL/dominant follicle. Human CG (Profasi, Serono Laboratories, Inc.) then was administered at a dose of 10,000 IU, im, and oocyte retrieval was scheduled 36 h after hCG administration.
All oocytes were retrieved by one of three board-certified reproductive endocrinologists, according to standard procedures established by the Division of Reproductive Endocrinology at Mayo Clinic (Rochester, MN). The nuclear maturity of oocytes was assessed 3–3.5 h postretrieval using the hyaluronidase technique to remove cumulus cells from the oocyte immediately before intracytoplasmic sperm injection. Mature metaphase II oocytes were defined as possessing one polar body in the perivitelline space and no visible nuclear structure in the cytoplasm. Mature oocytes were subjected to intracytoplasmic sperm injection as previously described (21).
Statistical analysis
All hormonal measurements were expressed as the mean ± SD. The insulin response to oral glucose over 2- and 6-h time intervals was calculated by area under the curve estimation using the trapezoidal rule. Standard simple linear regression analysis methods (22) were used to estimate correlations, regression coefficients, and P values for pairs of variables. Sets of nested multiple regressions (22), adjusting for the known population confounders of age and BMI, were used to select EFP study variables that predict the total number of oocytes and the number of mature oocytes.
Results
Predictors of total and mature oocyte numbers
Table 1
lists ovarian morphological
characteristics and serum hormone levels in the EFP and on the day of
hCG administration. Antral follicles grew in number and size after
gonadotropin stimulation, causing an increase in summed ovarian volume
at the time of hCG administration. Serum estradiol, inhibin A, and
inhibin B levels increased as expected after gonadotropin stimulation.
On the day of hCG administration, antral follicle number, summed
ovarian volume, and serum levels of estradiol, inhibin A, and inhibin B
positively correlated with the numbers of total oocytes and mature
oocytes retrieved (Table 2).
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and Fig. 1, A and D). The serum androstenedione
level in the EFP also positively correlated with the number of total
oocytes (P = 0.04) and mature oocytes
(P = 0.02) retrieved (Table 2 and Fig. 1, B and E). The
fasting serum glucose to insulin ratio at this time was more
positively correlated with the total oocyte number (P =
0.007) than with the mature oocyte number (P = 0.07;
Table 2).
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and Fig. 1, C and F). The fasting serum insulin level at this
time was a poorer negative predictor of oocyte numbers (total oocytes,
P = 0.04; mature oocytes, P = 0.19).
During the EFP, summed ovarian volume; serum levels of LH, FSH, total
and free testosterone, dehydroepiandrosterone sulfate, estradiol,
inhibin B, and inhibin A; and fasting as well as post-OGTT serum
glucose release did not significantly correlate with the number of
total or mature oocytes retrieved. After adjusting for the confounding effects of age and BMI by multiple regression analysis, the serum androstenedione level in the EFP was not significantly related to total oocyte number (P = 0.06), but remained positively correlated with the number of mature oocytes retrieved (P = 0.04). Antral follicle number and post-OGTT insulin release in the EFP remained positively and negatively correlated, respectively, with the numbers of total oocytes (follicle number, P = 0.0001; 2 h post-OGTT insulin release, P = 0.001; 6 h post-OGTT insulin release, P = 0.006) and mature oocytes (follicle number, P = 0.001; 2 h post-OGTT insulin release, P = 0.001; 6 h post-OGTT insulin release, P = 0.01) retrieved. The relationships of antral follicle number and 6 h post-OGTT insulin release to total oocyte number were additive, each was significant after controlling for the effect of the other (antral follicle number, P = 0.0002; 2 h post-OGTT insulin release, P = 0.06; 6 h post-OGTT insulin release, P = 0.04). In contrast, the relationships of antral follicle number and post-OGTT insulin release to mature oocyte number were not additive. In this case, antral follicle number significantly correlated with mature oocyte number after controlling for post-OGTT insulin release (P = 0.008), whereas post-OGTT insulin release was not significantly related to mature oocyte number after controlling for antral follicle number (2 h, P = 0.16; 6 h, P = 0.09). Lastly, fasting insulin levels did not significantly correlate with total oocyte number (P = 0.10) or mature oocyte number (P = 0.31) after adjusting for age and BMI.
Correlations in the EFP between antral follicle number and other ovarian markers
Correlations in the EFP were determined between antral follicle
number and other possible markers of follicle recruitment by
gonadotropins (Table 3). Patient age,
BMI, and serum inhibin as well as gonadotropin levels were not
significantly related to antral follicle number. Summed ovarian volume,
serum androstenedione level, and the fasting serum glucose to insulin
ratio were significant positive correlates with EFP antral follicle
number (summed ovarian volume, P = 0.03; serum
androstenedione level, P = 0.02; fasting serum glucose
to insulin ratio, P = 0.03). Conversely, the serum
estradiol level and post-OGTT insulin release were significant negative
correlates with EFP antral follicle number (serum estradiol level,
P = 0.02; 2 h post-OGTT insulin release,
P = 0.01; 6 h post-OGTT insulin release,
P = 0.02).
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There is no consensus regarding the best predictor of ovarian follicle recruitment by gonadotropins for IVF, because ovarian morphology and serum hormone markers have been compared in different patient populations under various clinical circumstances. To determine which of these parameters is the most accurate under the same clinical circumstances, the present study compares ovarian morphology and serum hormone markers in the EFP as predictors of the number of oocytes retrieved from normal women undergoing the same gonadotropin stimulation for IVF. Its experimental design is simple, yet more precise than that of previous studies for several reasons. First, it incorporates three-dimensional TVUS with data storage, so that one investigator reviews a continuous sequence of stored ovarian images from each patient, eliminating observer variability in estimating antral follicle number at the time of scanning (5). Second, only nonhirsute, ovulatory women with normal ovarian morphology are enrolled in the study, removing the influences of hyperandrogenism and ovulatory disorders on follicle development. Third, each woman undergoes a single IVF cycle with intracytoplasmic sperm injection, so that oocyte maturity is based upon nuclear criteria without bias from patients undergoing multiple treatment cycles. Fourth, three-dimensional TVUS is performed during the same cycle of pituitary down-regulation to eliminate intercycle variability in follicle cohort size (23).
Under these experimental conditions, summed ovarian volume in the EFP does not correlate with oocyte number after gonadotropin stimulation for IVF, agreeing with the previous observation that mean ovarian size in the EFP does not predict the number of oocytes retrieved (17). After pituitary down-regulation, summed ovarian volume also does not correlate with the number of oocytes retrieved (3), although a mean ovarian volume of less than 3 cm3 under this circumstance can predict poor ovarian responsiveness to gonadotropins (4). Nevertheless, the summed ovarian volume in the luteal phase and the smallest ovarian volume after ovulation do predict both the serum estradiol response to gonadotropins, the number of oocytes obtained, and the number of embryos produced by IVF (24, 25). Although estimating ovarian volume by TVUS may occasionally be difficult (23), the ability of ovarian volume to predict follicle recruitment by gonadotropins probably depends more upon the hormonal milieu in which the ovaries are examined.
Our study confirms other reports that antral follicle number under basal conditions predicts follicle recruitment by gonadotropins and numbers of total and mature oocytes retrieved by IVF (1, 2, 3). It further demonstrates that antral follicle number in the EFP positively correlates with total and mature oocyte numbers, even after adjusting for the confounding effects of age and BMI. The fact that mean antral follicle number increased from 18 to 26 during gonadotropin stimulation raises the intriguing possibility that preantral follicles are recruited by FSH into the extant pool of antral follicles potentially responsive to gonadotropins. In this regard, preantral follicles in hypophysectomized or GnRH-antagonist treated juvenile rats undergo further development in response to FSH (26). Moreover, human primordial follicles in ovarian tissue transplanted to hypogonadal mice develop to the antral stages when exposed to FSH (27). It is tempting to speculate, therefore, that antral follicle number in the EFP, as detected by current sonographic techniques, underestimates follicle recruitment by gonadotropins, perhaps because a pool of undetectable preantral follicles also responds to FSH.
The use of serum FSH and estradiol determinations as predictors of ovarian reserve is based upon the principle that FSH secretion is under negative feedback inhibition by ovarian steroid and peptide hormones. Consequently, basal serum FSH and estradiol levels often correlate negatively with follicle recruitment by gonadotropins and numbers of oocytes retrieved by IVF because FSH hypersecretion (from diminished ovarian inhibin production) may cause a concomitant increase in ovarian estradiol secretion (6, 7, 8, 9, 17). In our study this phenomenon may be evidenced by the subtle, yet significant, negative correlation between antral follicle number and serum estradiol level in the EFP. Nevertheless, serum FSH and estradiol levels in the EFP do not predict follicle recruitment by gonadotropins in our patients, agreeing with some (24, 25), but not all, studies (2, 4). Our findings may represent the fact that elevated serum FSH levels predict diminished ovarian reserve, whereas normal serum FSH and estradiol levels do not (28). As the serum FSH levels of our patients are within the normal range, it is not surprising that serum FSH and estradiol measurements in our study are less sensitive than antral follicle number as predictors of follicle recruitment by gonadotropins. Whether FSH responsiveness to clomiphene citrate (10) compares to antral follicle number in detecting subtle abnormalities of follicle recruitment by gonadotropins remains to be determined.
Inhibins, consisting of an 
-subunit covalently joined to either a
ßB-subunit (inhibin B) or a ßA-subunit (inhibin A), may be
alternate markers of follicle recruitment by gonadotropins because
inhibin B and inhibin A are preferentially produced by small antral and
dominant follicles, respectively (29). Specifically, serum
inhibin B measurement may be more sensitive that serum estradiol
determination in detecting diminished ovarian reserve, as its
production diminishes before that of estradiol in IVF patients with
poor follicle recruitment by gonadotropins (30, 31, 32). Serum
inhibin B levels also positively correlate with the number of oocytes
retrieved after controlling for the confounding effects of FSH and
estradiol (33). In our study the serum levels of inhibin B
and to a lesser extent, inhibin A are strong positive predictors of the
number of oocytes retrieved only when measured after gonadotropin
stimulation. Although basal serum inhibin B levels may estimate ovarian
reserve to a limited degree (18, 33), our findings support
the observation that serum inhibin B (and, to a lesser extent, inhibin
A) levels during gonadotropin stimulation are better than basal
measurements in predicting the number of oocytes retrieved (32, 34). Taken together, ovarian inhibin production parallels the
degree of follicle recruitment during gonadotropin stimulation for IVF,
with serum inhibin B being better than serum inhibin A as a marker of
the number of oocytes retrieved.
Our study is the first to demonstrate in IVF patients that the serum androstenedione level in the EFP positively correlates with follicle recruitment by gonadotropins, as evidenced by the numbers of total and mature oocytes retrieved. Furthermore, it shows that the correlation between serum androstenedione level and mature oocyte number remains significant after adjusting for age and BMI, supporting the hypothesis that androgen stimulates follicle growth in the primate ovary. Administration of testosterone for 10 days to adult female rhesus monkeys increases the number of small ovarian follicles, from primary follicles to small antral follicles up to 1 mm in diameter (35). It also increases granulosa cell proliferation, as measured by the cell proliferation-specific antigen, Ki67, and decreases apoptotic cell death, as determined by in situ detection of DNA fragmentation (35). These testosterone actions on follicle growth and granulosa cell function are probably mediated through the androgen receptor, because similar testosterone and dihydrotestosterone treatment for 5 days in adult female rhesus monkeys induces comparable follicle growth, granulosa cell proliferation, and apoptotic cell death (35). In the same animal model, similar testosterone and dihydrotestosterone treatment for 5 days also stimulates comparable insulin-like growth factor I (IGF-I) and IGF-I receptor messenger ribonucleic acid expression in granulosa cells (36) and primordial follicle oocytes (37). These findings are consistent with in situ hybridization studies showing that androgen receptor messenger ribonucleic acid expression in granulosa cells of growing follicles is up-regulated by testosterone (38). Therefore, our study provides further evidence that androgens in primates play a physiological role in follicle growth and implicate hyperandrogenism as a cause of the enlarged polycystic ovaries in women with androgen excess.
The most intriguing aspect to our study of normal ovulatory women is that post-OGTT insulin release during the EFP is negatively correlated with the number of oocytes retrieved, even after adjusting for the effects of age, BMI, and EFP antral follicle number. It is possible that heavy women (presumably with increased post-OGTT insulin release) need more exogenous FSH because of their larger volume of distribution, consistent with our finding that BMI is positively correlated with gonadotropin dose (r = 0.55; P < 0.005). Heavy women also appear to exhibit low FSH and LH secretion (39), a phenomenon that also might explain why post-OGTT insulin release is inversely related to EFP antral follicle number and serum androstenedione level (r = -0.46; P < 0.025). Alternatively, increased post-OGTT insulin release may either directly or indirectly impair ovarian follicular development. For example, adiposity in IVF patients receiving gonadotropins is positively related to leptin production, perhaps of ovarian origin (40, 41). Excess intraovarian leptin production could inhibit gonadotropin-dependent follicle recruitment, as leptin abolishes the stimulatory effects of IGF-I on FSH-stimulated estradiol production and LH-stimulated androstenedione production in cultured human granulosa and thecal cells, respectively (42).
Therefore, ovarian antral follicle number in the EFP is better than summed ovarian volume or serum gonadotropin, estradiol, and inhibin determinations in predicting the numbers of total and mature oocytes retrieved after gonadotropin stimulation for IVF. In this role, antral follicle number also is inextricably linked to androgen and insulin actions in estimating ovarian follicle recruitment by exogenous gonadotropins.
Acknowledgments
As always, we are indebted to the outstanding contributions of Rebekah R. Herrmann, Research Study Coordinator, Mayo Clinic (Rochester, MN), for her recruitment of patients and preparation of the data.
Footnotes
1 This work was supported by Mayo Grant MO1-RR-00585 from the General
Clinical Research Centers, Division of Research Resources, and Serono
Pharmaceuticals. 
Received December 7, 2000.
Revised March 8, 2001.
Accepted March 20, 2001.
References
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