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Endocrine Care |
Reproductive Medicine Unit (C.B., F.M., S.V.) and Department of Obstetrics and Gynecology (C.F.), University of Bologna, 40138 Bologna, Italy; and Departments of Obstetrics and Gynecology (G.R., A.V.) and Pediatrics (L.I., S.B.), University of Modena, 41100 Modena, Italy
Address all correspondence and requests for reprints to: Cesare Battaglia, M.D., Reproductive Medicine Unit, University of Bologna, Via Massarenti, 13, 40138 Bologna, Italy. E-mail: . battaglia{at}med.unibo.it
Abstract
Twenty-seven girls with premature pubarche were studied by ultrasonographic and color Doppler analyses to determine the incidence of polycystic ovaries (PCO), to longitudinally assess their evolution, and to search for any hormonal correlation.
The girls were submitted to auxological, clinical, and hormonal evaluation, and 21-hydroxylase deficiency was ruled out by an ACTH test. Furthermore, the girls underwent ultrasonographic and color Doppler ovarian and uterine analyses.
Among girls with premature pubarche, the prevalence of PCO was 41%. Advanced skeletal maturation, tall stature, and increased hair distribution were constant in these patients. In patients with ultrasonographic and color Doppler evidence of PCO, the ovarian volume, the number of small-sized subcapsular follicles, the stromal echogenicity, and the ovarian stromal vascularization progressively increased during the study.
In the whole studied population, ovarian volume correlated with the number of small-sized follicles (r = 0.719; P < 0.0001). Furthermore, a slight and inverse correlation has been found between ovarian volume and ovarian stromal artery pulsatility index (r = -536; P = 0.048).
In conclusion, we affirm that PCO are greatly represented among girls with premature pubarche and progressively evolve.
IN GIRLS, PREMATURE pubarche or adrenarche is commonly defined as the appearance of pubic hair before 8 yr of age. Pubic hair is generally limited to labia majora, and thus it may not be diagnosed on casual examination. The clinical presentation may include axillary hair and adult apocrine secretion, advanced bone maturation, and increased growth velocity. Breast size is, in typical premature pubarche, at prepubertal level (1, 2).
The pathophysiological basis of premature pubarche is an early isolated maturation of the adrenal gland with increased adrenal androgen secretion for chronological age (CA) (compatible with Tanner stage II of pubertal development) (3, 4). The cause for this adrenal oversecretion is, at the moment, unclear. In addition, normal androgen levels have been found, suggesting an increased peripheral sensitivity to these hormones (5). Gonadotropins do not seem to play a role in the etiology of premature pubarche (6, 7).
Because in girls with typical premature pubarche, gonadarche (pubertal activation of gonadal function) is not anticipated (8), all pubertal events seem to occur normally, and final adult height is not influenced (9), an observational policy and a healthy therapeutic nihilism are generally adopted. Although these data appear reassuring, an increased incidence of hirsutism and polycystic ovary syndrome (PCOS) represent possible late sequelae of premature pubarche. In one series, 45% of postpubertal girls with a history of premature pubarche showed clinical and hormonal features consistent with PCOS (10). Hawkins et al. (11), searching among girls with premature pubarche for a typical hormonal pattern useful in predicting hirsutism and/or PCOS in the absence of evident clear-cut cases of adrenal hyperplasia, found no hormonal markers that can be used to distinguish those girls who are at risk for hirsutism and/or PCOS from those who are not.
Pelvic ultrasound (US) is a safe, accurate, and noninvasive method for examining uterine and ovarian size and appearance (12, 13). Its use in the evaluation of advanced puberty has been well established. Several investigators have documented increase in ovarian volume with age during childhood and increased number and size of ovarian follicles in the peripubertal age (14, 15). These US findings agree with those observed at postmortem (16).
Assessment of ovarian morphology by means of US is currently used as a substitute for histological examination in the diagnosis of polycystic ovaries (PCO). The US criteria established for diagnosis of PCO are an enlarged ovary and multiple small follicles scattered around an echogenic stroma. However, the number of small follicles necessary to establish the diagnosis of PCO has been reported to vary between more than 5 (17), more than 10 (18), and at least 15 (19). We recently refuted the necessity of establishing an exact number of microcysts to diagnose PCO (20). In fact, we observed that the number of subcortical small-sized follicles is related to the developmental stage of the syndrome; as the number of ovarian microcysts increases and ovarian volume enlarges, endocrine and clinical abnormalities become more remarkable.
Color Doppler facilitates the detection of small vessels in the utero-ovarian circulation and the measurement of impedance to flow in this vascular tree. A few years ago, we showed (21), and Zaidi (22) and Aleem (23) and colleagues successively confirmed, that in patients with PCOS significant vascular changes occur within the intraovarian vessels.
The aims of the present study among girls with premature pubarche were to determine by ultrasonographic and color Doppler analyses the incidence of PCO, to assess their evolution longitudinally, and to search for any correlation with specific hormonal parameters.
Subjects and Methods
Study population
The study protocol was in accordance with the Declaration of Helsinki II and was approved by the Hospital Research Review Committee. Between January and December 1997, 29 girls (age range, 6.2–7.8 yr) were referred to Modena Hospital Auxological and Pediatric Endocrine Clinic for the evaluation of premature pubic hair. By definition, pubic hair had developed before 8 yr of age. Girls participated in the study after informed consent from parents and an assent from minors were obtained.
On the basis of history, physical examination, basal ultrasonography, and laboratory data, we excluded from the study patients affected by chronic disease, Cushing’s syndrome, hyperprolactinemia, hypothyroidism and hyperthyroidism, sex steroid-secreting tumors, ovarian cysts (>10 mm in maximum diameter), multifollicular ovaries (more than five follicles with a maximum diameter >4 mm, a distribution evenly throughout the ovary, and no increase in stromal echodensity). Girls with gonadal puberty were not included in the study. The patients had not received hormonal therapy before the study.
The pubertal development in all girls was assessed by a single examiner (L.I.) according to the classification of Tanner (24, 25). Staging of the breast was as follows: stage I, preadolescent; stage II, elevation of breast and papilla as a small mound, enlargement of areola diameter; stage III, further enlargement of breast and areola with no separation of contours; stage IV, projection of areola and papilla to form a secondary mound above the level of the breast; and stage V, projection of a mature papilla, areola part of general breast contour. Staging for pubic hair was as follows: stage I, preadolescent; stage II, sparse, slightly pigmented, straight; stage III, darker, coarser, beginning to curl, increased amount; stage IV, adult in type, but less area covered; stage V, adult in quantity and type, distributed as an inverse triangle, spread to medial surface of thighs. In the presence of pubic hair, a breast stage II development was taken as a definite sign of gonadal puberty.
Standing height was measured using a Harpenden stadiometer (Holtain Ltd., Crymych, UK) to the nearest 0.1 cm; weight was measured on a digital scale with a precision of 0.1 kg (Seca 707, HH, Modena, Italy). The mean body mass index [BMI = weight (kg)/height2 (m2)] was calculated in all patients. Skeletal maturation was staged according to Greulich and Pyle (26). Hirsutism was evaluated according to the Ferriman and Gallwey method (27).
All of the girls were further submitted to basal hormonal assay, ovarian and uterine ultrasonographic, and color Doppler evaluation.
All examinations were performed at baseline, 12, and 24 months. ACTH test was done at the beginning of the study.
On the basis of ultrasonographic analysis, the patients were subdivided into girls presenting normal ovaries (group I, n = 17) and PCO-like ovaries (more than five small subcortical follicles, 2–10 mm in maximum diameter, increased ovarian volume, and increased ovarian stroma echogenicity) (group II, n = 12).
US and Doppler examination
Uterine and ovarian ultrasonographic examinations were performed with a 3.5-MHz convex transducer (AU4 Idea; ESAOTE, Milan, Italy). The US scans were performed transabdominally when the participants had a full bladder, obtained by voluntary urine retention and oral administration of fluids. Uterine and ovarian volume, endometrial thickness, and the number, diameter, and distribution of the follicles were recorded. Volumes were calculated by measuring length, width, and depth, assuming the forms to be ellipsoid, using the formula based on a prolate ellipsoid: V = 
/6 x D1 x D2 x D3, where D1, D2, and D3 are the maximal longitudinal, anteroposterior, and transverse diameters, respectively. The maximum diameter of each follicle was reported. The echogenicity of ovarian stroma [stromal score (SS)] was subjectively scored as 0 (normal), 1 (moderately increased), or 2 (markedly increased). No significant differences between left and right ovaries were observed, and therefore, the average value of both ovaries was used for statistical analysis. Midline endometrial echo was checked, and endometrial thickness was measured as the distance between the two internal sizes of the myometrium.
Doppler flow measurements of the uterine and intraovarian vessels were performed transabdominally with a 3.5-MHz color Doppler system (AU4 Idea color Doppler). All of the patients were in recumbent position and were evaluated between 0800 and 1100 h to exclude the effects of circadian rhythmicity on utero-ovarian blood flow (28). Furthermore, they rested in a waiting room for at least 15 min before being scanned to minimize external effects on pelvic blood flow (29). A 50-Hz filter was used to eliminate low-frequency signals originating from vessel wall movements. Color signals were sought in the ovarian stroma at the maximum distance from the surface of the ovary (21). The ovarian stroma was considered to be avascular if no blood vessels were demonstrated by color Doppler imaging. When several blood vessels were detected inside the ovarian stroma, only the one with the lowest downstream impedance was selected for Doppler measurements. Color flow images of the ascending branches of the uterine arteries were sampled laterally to the cervix in a longitudinal plane (21). The angle of insonation was always adjusted to obtain maximum color intensity. When good signals were obtained, blood flow velocity waveforms were recorded by placing the sample volume across the vessel and activating the pulsed Doppler mode. The pulsatility index (PI), defined as the difference between the peak systolic and end-diastolic flow divided by the mean maximum flow velocity, was calculated for the ovarian stromal and uterine arteries. For each examination, the mean value of three consecutive waveforms was obtained. No significant differences between the PI values of the left and right uterine arteries were observed, and therefore, the average value of both arteries was used. Similarly, the lowest PI values of the stromal arteries were not significantly different between the left and right ovaries, and the mean value was used. The correlation between PI and heart rate was not tested (20). US and color Doppler analyses were performed by a single examiner (C.B.).
Hormonal assay
Peripheral blood was obtained from all patients between 0800 and 1100 h, after an overnight fast, on the same day that US and Doppler examinations took place, and different hormonal parameters were analyzed. Plasma concentrations of LH, FSH, estradiol (E2), and testosterone (T) were determined by a RIA (RADIM; Pomezia, Italy) as previously described (30). Dehydroepiandrosterone sulfate (DHEAS), and 17-hydroxyprogesterone (17-OH-Pg) were determined by RIA using the Coat-A-Count kit (DPC; Los Angeles, CA). Androstenedione (A) was measured by RIA with the Quantitative Measurement of Androstenedione in Serum and Plasma kit (Diagnostic Systems Laboratories, Inc., Webster, TX). All hormone analyses were performed in duplicate. On the basis of two quality control samples, the average within-assay and between-assay coefficients of variation were 4.9 and 6.8% for LH, 4.8 and 7.1% for FSH, 3.9 and 7.5% for E2 and T, 6.4 and 8.7% for A, 5.1 and 7.7% for DHEAS, and 4.3 and 6.6% for 17-OH-Pg. The sensitivity of assay methods was: LH, 0.1 mIU/ml; FSH, 0.3 mIU/ml; E2, 37.6 pmol/liter; T, 0.35 pmol/ml; A, 0.35 nmol/liter; DHEAS, 0.27 µmol/liter; and 17-OH-Pg, 0.30 nmol/liter.
To exclude congenital adrenal hyperplasia and verify a possible exaggerated adrenal response, an ACTH stimulation test was performed with a single iv injection of 0.25 mg ACTH (Synachten; Novartis Farma, Origgio, Italy) (31). The patients did not receive an overnight dexamethasone suppression. All tests were performed between 0800 and 1100 h. Serum samples were drawn at -30, baseline, 60, and 120 min. All samples were stored at -20 C until they were assayed for A, 17-OHPg, and cortisol (F).
Statistical analysis
A statistical analysis (SPSS software; SPSS, Inc., Chicago, IL) was performed using the Mann-Whitney U test and one-way ANOVA. The relationship between the parameters analyzed was assessed using the stepwise linear regression method. A P value of 0.05 was considered as statistically significant. Data are presented as mean ± SD, unless otherwise indicated.
Results
Among girls affected by premature pubarche, the prevalence of ultrasonographic PCO-like ovaries was 12 of 29 (41%). Data on 27 patients were available for analysis because, in PCO-like group, two girls at the 12-month evaluation had developed a gonadal puberty (Tanner breast stage II-B2 at 8.6 and 8.8 yr, respectively) and were excluded from the study.
At the beginning of the study, the CA was similar in both the normal (7.1 ± 0.6 yr) and PCO-like (7.4 ± 0.5 yr) groups. Bone age (BA) was significantly higher in group II (8.8 ± 1.6 yr) than group I (7.8 ± 1.8 yr; P = 0.039). However, the differences were not significant at 12 and 24 months (Table 1
). The BA/CA ratio was greater than 1 at baseline, 12 and 24 months, but it was not significantly different among the two groups (Table 1). The BMI at baseline was at the upper limit of reference data for obesity (32). It smoothly but not significantly decreased during the study and was not significantly different among the two groups (Table 1). The basal height was between the 75th (122 cm) and 97th (133 cm) centile of Italian reference data (33) (group I, 126 ± 0.5 cm; group II, 130.6 ± 3.6 cm). The growth curve remained in the same centiles up to the end of the study (Table 1). No significant differences were registered between the two groups. None of the studied patients was hirsute (Ferriman-Gallwey >8), however, 6 of 10 of the PCO-like girls presented a slightly increased hair distribution on the distal portion of both arms and legs. Pubic hair was at stage II in 30% of PCO-like patients vs. 77% of non-PCO-like patients, and at stage III in 70% of PCO-like patients vs. 23% of non-PCO-like patients. Axillary hair was present in 3 of 17 girls in group I and 3 of 10 in group II.
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). No significant differences were evidenced between the two groups. Testosterone, 17-OH-Pg, and DHEAS plasma levels, although normal, were at the upper limit of the normal ranges (Table 2). At baseline and subsequent follow-up, values presented no significant differences among the PCO-like and non-PCO-like girls.
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. The 
D value (peak value at 60-min basal value) are illustrated in Table 3. No significant differences were noticed between the studied patients (34).
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). Endometrial echo was present in 5 of 27 (15%) cases, and thickness was always below 2 mm in maximum fundal diameter.
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). The number of small-sized follicles was, at baseline, statistically different among group I (0.92 ± 1.41) and group II (6.48 ± 1.57; P < 0.001) and significantly increased in the PCO-like group throughout the study (Fig. 1). The ovarian stroma was scored as normal (SS = 0) in 100% of girls of group I and did not change during the study. In group II, the ovarian stroma progressively became more echogenic (baseline, SS = 1:30%, SS = 2:70%; 12 months, SS = 1:10%, SS = 2:90%), presenting at 24 months a SS of 2 in all of the studied ovaries.
In all patients, compared with normal adults, we observed on Doppler analysis elevated resistances within the uterine arteries, and there were not significant differences between the groups either at the beginning or during the study (Fig. 2). In the group I patients, we failed by color flow mapping to identify any ovarian stromal artery and, consequently, spectral Doppler signals were not obtained at any stage of the study. On the contrary, in PCO-like girls, the intraovarian arteries were always identified: at least in one ovary in 100% of the cases, and bilaterally in 80, 80, and 100% of the cases at baseline, 12, and 24 months, respectively. In addition, the downstream impedance to flow progressively and significantly declined (Fig. 2).
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Discussion
Premature pubarche (clinical expression of premature adrenarche), in the absence of specific adrenal enzymatic defects, is slowly progressive, independent from gonadotropins, and is considered a benign phenomenon that, although it produces a transient acceleration in growth and bone maturation, has no negative effects on the beginning and progression of puberty and adult height in almost all affected girls (8, 9, 37).
The cause of premature pubarche is still unclear, however, it seems to be secondary to an early isolated adrenal activation (3, 4). Various theories have been advanced to explain this paraphysiological phenomenon. Oversecretion of a central androgen-stimulating proopiomelanocortin-derived hormone, alone or associated with ACTH, may be the primum movens of anticipated adrenarche (39). An accelerated development of the zona reticularis, the site of adrenal androgen production, with increased 17-hydroxylase and 17,20-lyase activity has also been considered (40, 41). Because the regulation of both of the above enzymes is coded by a single gene for cytochrome P450C17, Zhang et al. (42) postulated a posttransitional alteration of the cytochrome P450C17. Furthermore, it has been demonstrated that the 3ßb-hydroxy-steroid dehydrogenase shows a decreased efficiency in the zona reticularis leading to DHEAS rise and consequent increased peripheral conversion to more potent androgens (43, 44, 45, 46). In addition, overweight (47, 48) (our patients with premature pubarche showed a high BMI) or sudden weight gain (49) may be a trigger factor to the induction of adrenarche regardless of basal adrenal androgen secretion, CA, and developmental age. Ethnic origin, modified adrenal blood flow, and immunorelated adrenal stimulation have been considered as possible factors involved in an anticipated adrenarche (2).
In premature pubarche, generally, adrenal androgens (DHEAS, A, and T) are increased for CA but fall within the reference ranges for height age and pubertal stage of pubic hair (37, 50). However, sometimes plasma androgens falling in the normal ranges for CA suggest just an increased peripheral sensitivity to circulating androgens (5, 51). In the present study, circulating DHEAS values greater than 1.5 µmol/liter could represent a subtle index of an activated adrenarche in all girls (52, 53). Other hormonal values were at the normal to upper limit of the reference ranges for CA and did not significantly change during the 2-yr follow-up. Although the basal 17-OH-Pg plasma levels were more than 3.0 nmol/liter (>4 SD above the published normative data) (34), the ACTH-stimulated values were, in both groups, within the normal range for CA (34) excluding the late-onset congenital adrenal hyperplasia due to P450C21 deficiency. The diagnosis of late-onset congenital adrenal hyperplasia is clinically based on an excessive 17-OH-Pg increase (>45 nmol/liter) after an ACTH stimulation test. Values ranging between 35 and 45 nmol/liter are doubtfully considered, whereas values below 35 nmol/liter have never been associated with P450C21 deficiency (54, 55). The molecular analysis showed that no mutations of the CYP21 gene (the gene encoding for cytochrome P450C21) have been shown in those patients who presented a post-ACTH challenge test plasma 17-OH-Pg value greater than 35nmol/liter (56).
Previous studies suggested that premature pubarche is not associated with an anomalous pubertal development and final adult height. Ibanez et al. (9) recently showed in Spanish and Italian girls with premature adrenarche that growth velocity may be increased and an advanced BA and a tall stature are often seen as initial clinical findings. However, they underlined that the above findings rapidly wane during the first years of the follow-up and puberty normally develops, emphasizing the transient effects of premature adrenarche/pubarche on either growth or sexual maturity. Our present study confirmed the above growth patterns and showed that the onset of puberty (2 of 29; 7%) is not influenced by premature pubarche.
In the present study, in agreement with Wierman et al. (53), it was further shown that height is significantly correlated with BA and plasma DHEAS concentrations. This could reflect the role of adrenal androgens on growth spurt and skeletal maturation.
Although data on final height are reassuring, it is acknowledged that premature pubarche is associated with an increased peri- and postpubertal incidence of hirsutism and PCOS and that no biochemical marker has proven useful to distinguish girls who are at risk of hirsutism/PCOS from those who are not.
Ultrasonographic studies showed that PCO have an incidence of about 22–25% in healthy adult women (57, 58). Bridges et al. (35), studying ovarian morphology in childhood, found a prevalence of PCO of 6% at 6 yr. The incidence rises with age until puberty when it reaches the same values as those reported in adult women. However, Ibanez et al. (10) showed that 45% of postpubertal girls with a history of premature pubarche have clinical and hormonal features of PCOS. In the present study, the prevalence (41%) of PCO among girls with premature pubarche was consistent with the above findings.
It has been shown that anatomical structure of the pelvic organs could not be adequately assessed with a transabdominal approach in as many as 42% of cases (59) (i.e. obesity, limited resolution of low-frequency transducers, troublesome full bladder technique, and dilated bowel loops) (60) and that transvaginal US appears to provide a more accurate ovarian picture (61). Although we did not perform the transvaginal procedure in our patients, owing to their young age and virginal status, we visualized the uterine structures in 100%, both ovaries in 89%, and at least one ovary in 100% of cases. From this we derived that by using the transabdominal approach, the percentage of visualization of pelvic organs may be basically correlated with the operator’s skill and the quality of the ultrasonographic machine.
The ovaries of girls with premature adrenarche have been reported to be larger than would be expected for CA, indicating that premature adrenarche results in ovarian growth (35). In the present study, patients with a homogeneous echo-structure of the ovaries presented an ovarian volume comprised in the normal ranges of prepubertal stage. Furthermore, no significant ovarian growth was observed throughout the observational period. On the other hand, girls with PCO-like ovaries were characterized by increased ovarian volumes (similar to those of patients at Tanner stage II-B2), increased echogenic stroma, and higher number of subcortical small follicles. All of the above parameters evolved during the study, and the echogenic ovarian patterns resembled those observed in adult life. In addition, an inverse correlation between ovarian volume and ovarian stromal artery PI values was found.
At Doppler analysis, elevated resistances were observed at the level of uterine arteries throughout the study. This was associated with low E2 plasma levels. Estrogens are well known to enhance blood flow in many tissues and are inversely correlated with uterine artery PI values (21, 61, 62). Estrogen action seems modulated by a direct dilating effect on the smooth muscle cells in the media of vessel wall (63) or by a decreased function of periarterial sympathetic vasoconstrictor nerves (64). In addition, it has been shown recently (65) that the flow velocities in the uterine arteries increase from prepuberty to adulthood and that they are positively correlated with uterine size. This suggests that uterine flow resistances have an inverse relationship with internal genitalia growth and maturation. However, in the present study no significant differences were observed between the basal and 24-month PI values. In the PCO-like group, specific color Doppler changes in ovarian vascularization (high percentage of intraovarian vessels visualization and low PI values) occurred at the level of intraovarian arteries and progressively worsened up to the end of the study. We previously reported that this typical vascular modification intervenes in adult PCOS, that color Doppler analysis has a high diagnostic value, and that elevated LH plasma levels may be responsible for increased stromal vascularization (21). Our present data do not seem to confirm the prominent role of high circulating LH values in the determinism of intraovarian Doppler flow modification in PCOS; gonadotropins were in the prepubertal range, were not different among girls, and did not change throughout the study. Alternative mechanisms must be sought to explain increased ovarian vascularization (66, 67, 68, 69, 70, 71, 72, 73, 74).
In the present study, although none of the studied girls showed an evidence of hirsutism (Ferriman-Gallwey score >8), the patients with a PCO-like ovarian appearance demonstrated a slight increased hair distribution of the distal portion of both arms and legs. This disagrees with previous findings and may be correlated with a nonspecific ethnic peripheral increased sensitivity to circulating androgens or with a precocious sign of developing hirsutism.
Uterine volume, as elsewhere demonstrated, resulted in our own normal range/height age; endometrial echo was present in 15% of the cases, and thickness was always below 2 mm in maximum fundal diameter. These findings express a low estrogen stimulation because an increased estrogen secretion causes an increase in uterine size, a change to the adult heart-shaped configuration, and development of a midline endometrial echo. The circulating estrogen concentrations did not differ among groups, did not change during the study, and were associated with relatively high and stable downstream resistances at level of uterine arteries. In disagreement with Mosfeldt Laursen et al. (65), uterine artery flow velocity was found in 100% of prepubertal population, and measurable diastolic flow was found in 74% of the cases. We think that the technique standardization and the repetition in 1 wk of Doppler analysis may also provide good diagnostic results in prepubertal girls.
In conclusion, we affirm that PCO are highly represented among girls with premature pubarche, that PCO are present since childhood, and that it is possible to perform ultrasonographic and color Doppler since childhood. On the basis of our data, we believe that Doppler analysis could be a useful and easy method to diagnose PCO. In addition, considering that PCOS may be a progressive syndrome up to the time of menopause with esthetical, reproductive, biohumoral, and cardiovascular consequences, we suggest that an early diagnosis and an early therapeutic intervention could be necessary to ameliorate fertility and prevent the long-term sequelae.
Footnotes
Abbreviations: A, Androstenedione; BA, bone age; BMI, body mass index; CA, chronological age; DHEAS, dehydroepiandrosterone sulfate; E2, estradiol; F, cortisol; 17-OH-Pg, 17-hydroxyprogesterone; PCO, polycystic ovaries; PCOS, polycystic ovary syndrome; PI, pulsatility index; SS, stromal score; T, testosterone; US, ultrasound.
Received March 26, 2001.
Accepted March 14, 2002.
References
1-adrenergic receptors in altering uterine blood flow during the estrous cycle of gilts. Am J Obstet Gynecol 150:480–484[Medline]
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