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. 2007 Dec 18;93(3):951–958. doi: 10.1210/jc.2007-1322

Pituitary and/or Peripheral Estrogen-Receptor α Regulates Follicle-Stimulating Hormone Secretion, Whereas Central Estrogenic Pathways Direct Growth Hormone and Prolactin Secretion in Postmenopausal Women

Mihaela Cosma 1, Joy Bailey 1, John M Miles 1, Cyril Y Bowers 1, Johannes D Veldhuis 1
PMCID: PMC2266945  PMID: 18089703

Abstract

Background: Estradiol (E2) stimulates GH and prolactin secretion and suppresses FSH secretion in postmenopausal women. Whether central nervous system (CNS) or pituitary mechanisms (or both) mediate such actions is not known.

Objective: Our objective was to distinguish between hypothalamic and pituitary or peripheral (hepatic) actions of E2.

Setting: This study was performed in an academic medical center.

Design: This was a double-blind, prospectively randomized, placebo (Pl)-controlled study.

Methods: The capability of a selective, noncompetitive, non-CNS permeant estrogen receptor (ER)-α antagonist, fulvestrant (FUL) to antagonize the effects of transdermal E2 and Pl on GH, prolactin, and FSH secretion was assessed in 43 women (ages 50–80 yr) in a four parallel-cohort study. Each woman received four secretagogue infusions to stimulate GH secretion. IGF-I and its binding proteins were measured secondarily.

Results: Administration of Pl/E2 increased GH and prolactin concentrations by 100%, and suppressed FSH concentrations by more than 50% (each P ≤ 0.004 compared with Pl/Pl). Treatment with FUL/E2 compared with Pl/E2 partially relieved estrogen’s inhibition of FSH secretion (P = 0.041), without altering E2’s stimulation of prolactin secretion. ANOVA further revealed that: 1) estrogen milieu (P = 0.014) and secretagogue type (P < 0.001) each determined GH concentrations; 2) FUL/Pl suppressed IGF-I concentrations (P < 0.001); 3) FUL abrogated estrogen’s elevation of IGF binding protein-1 concentrations (P < 0.001); and 4) FUL did not oppose estrogen’s suppression of IGF binding protein-3 concentrations (P < 0.001).

Summary and Conclusions: Responses to a non-CNS permeant ERα antagonist indicate that E2 inhibits FSH secretion in part via pituitary/peripheral ERα, drives prolactin output via nonpituitary/nonperipheral-ERα effects, and directs GH secretion and IGF-I-binding proteins by complex mechanisms.

In postmenopausal women given the nonbrain-permeant estrogen receptor antagonist fulvestrant, estrogen inhibits FSH secretion via pituitary and peripheral estrogen receptor alpha (ERα), stimulates prolactin and GH via nonpituitary and nonperipheral-ERα effects, and drives IGF-I-binding proteins by complex mechanisms.

Aging is accompanied by declining concentrations of GH, IGF-I, and gonadal sex steroids (1,2). Hyposomatotropism and hypogonadism are in turn associated with visceral adiposity, sarcopenia, osteopenia, glucose intolerance, decreased aerobic capacity, and possibly, impaired psychosocial function (3,4). Cross-sectional studies suggest that menopausal estradiol (E2) depletion may contribute to hyposomatotropism (5,6), and interventional experiments demonstrate that estrogen supplementation can stimulate GH secretion (7,8,9).

GH secretion is under the control of multiple peptidyl signals, including GHRH and somatostatin released by hypothalamic neurons, the GH-releasing peptide (GHRP), ghrelin, produced in the stomach, hypothalamus, and pituitary gland, and circulating GH and IGF-I, which feed back negatively on the hypothalamo-pituitary unit (10,11,12,13,14,15). Clinical studies indicate that E2 regulates hypothalamo-pituitary responses to each of these peptides (16,17,18,19,20). However, whether estrogen drives GH secretion predominantly via hypothalamic or pituitary actions remains unknown (2,10,21,22). Indeed, whether E2 influences the production of other human hypophyseal hormones principally by effects on the brain or pituitary has not been elucidated.

The present study attempts to distinguish central nervous system (CNS) (hypothalamic) and pituitary effects of E2 in postmenopausal women by administering E2 in the presence or absence of fulvestrant (FUL) (ICI 182,780), a highly specific nonbrain-permeant estrogen receptor (ER) antagonist (23,24). The drug is a systemically active 7α-alkylsulfinyl analog of E2, which binds ERα, thereby preventing receptor dimerization, forcing receptor degradation, and inhibiting gene transcription (25,26). In breast cancer, FUL decreases ERα protein and inhibits cellular replication without exerting intrinsic estrogen-agonist activity (23). An important mechanistic property of this antiestrogen is that it does not cross the blood-brain barrier. In particular, peripheral administration of FUL, unlike tamoxifen, does not antagonize the E2-induced prolactin surge, brain progesterone-receptor expression, or radiolabeled E2 binding in the hypothalamus of the rat (23,24), and does not induce hot flushes in women.

ERα is expressed in normal human pituitary cells producing GH (2.3%), FSH (70%), and prolactin (50%) (27,28). ERβ is present in normal pituitary cells, the majority of pituitary tumors, and coexpressed with ERα in prolactinomas and gonadotrope tumors (29,30). We could find no direct experimental evidence for ERβ effects on human pituitary hormone secretion in vivo, but ERβ induces progesterone-receptor immunoreactivity in rat gonadotrope cells in vitro and antagonizes ERα effects on stress-induced ACTH secretion in the rat in vivo (31,32). Both ER subtypes also exist in the hypothalamus (33). In the arcuate nucleus, the majority of GHRH neurons express ERα and GnRH neurons ERβ, whereas few (<5%) somatostatin neurons have either ERα or ERβ (34,35). Accordingly, estrogens could act on both the pituitary gland and the brain. Which action predominates in the human is not known.

To assess the importance of pituitary vis-à-vis CNS mechanisms in mediating estrogen actions, we developed a novel investigative paradigm comprising: 1) transdermal delivery of placebo (Pl) or E2 in postmenopausal women to mimic the young-adult estrogen milieu, and 2) concomitant administration of Pl or FUL to distinguish between central-neural (FUL resistant) and pituitary or hepatic (FUL accessible) loci of E2 action. GH secretion was the primary endpoint, and FSH and prolactin responses were secondary outcomes.

Subjects and Methods

Subjects

Healthy postmenopausal women provided written informed consent approved by the Mayo Institutional Review Board. Inclusion criteria were stable body mass index (BMI) less than or equal to 30 kg/m2, no night-shift work, unremarkable medical history, physical examination, and renal screening, and hepatic, endocrine, metabolic, and hematological function. Exclusion criteria included any sex hormone replacement 4 wk before participation, vascular or gallbladder disease, breast or endometrial cancer, anemia, psychiatric illness, alcohol abuse, and use of neuroactive medications. Menopausal status was confirmed by concentrations of FSH more than 50 IU/liter, LH more than 20 IU/liter, and E2 less than 35 pg/ml (<120 pmol/liter).

Protocol design

This was a prospectively randomized, Pl-controlled, double-blind, parallel cohort design (Fig. 1). Randomization was by a randomized-number table to Pl/Pl, Pl/E2, FUL/Pl, and FUL/E2 administration. A total of 43 women were randomly assigned to receive double Pl [Pl/Pl (n = 10)], Pl/E2 (n = 10), FUL/Pl (n = 12), and FUL/E2 (n = 11). Median (range) age and BMI were 61 yr (50–80) and 25 kg/m2 (18–30), respectively. Before E2 and Pl replacement, a baseline outpatient screening blood sample was obtained (Table 1 data). Thereafter, eligible subjects received three consecutive weekly im injections of Pl or FUL (250 mg) under an investigator-initiated Food and Drug Administration new drug number (Fig. 1). The antiestrogen is approved for single monthly injections of 250 mg for the therapy of breast cancer (26). The higher schedule and dose were selected to allow the maximal clinically safe blockade of ERs during E2 administration. Beginning 1 wk after the second FUL injection, transdermal Pl or E2 supplementation was begun daily for 18 d (Fig. 1). Doses were 0.05 mg daily for 4 d, 0.10 mg for 4 d, 0.15 mg for 4 d, and then 0.20 mg for 7 d to mimic the normal menstrual cycle pattern in young women (36). Oral micronized progesterone of 100 mg was prescribed for 12 d beginning on the last day of the study.

Figure 1.

Figure 1

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Schema of volunteer recruitment and protocol randomization with time line of procedures followed in 43 postmenopausal women (Subjects and Methods). **, Continuous infusion.

Table 1.

Baseline hormone concentrations

Hormone Pl/Pl (n = 10) Pl/E2 (n = 10) FUL/Pl (n = 12) FUL/E2 (n = 11)
Age (yr) 63 ± 1.8 65 ± 2.2 62 ± 2.7 60 ± 1.7
BMI (kg/m2) 26 ± 0.8 25 ± 1.1 24 ± 0.8 25 ± 1.0
FSH (IU/liter) 79 ± 6.0 85 ± 8.2 73 ± 4.2 75 ± 6.2
LH (IU/liter) 34 ± 2.6 37 ± 4.4 34 ± 2.2 36 ± 3.8
Prolactin (μg/liter) 8.6 ± 1.2 7.2 ± 0.8 7.8 ± 1.2 8.8 ± 0.4
IGF-I (μg/liter) 121 ± 12.1 103 ± 5.5 95 ± 6.4 117 ± 10
SHBG (nmol/liter) 53 ± 6.7 48 ± 5.0 62 ± 7.7 62 ± 11
IGFBP-1 (μg/liter) 39 ± 6.7 34 ± 5.5 43 ± 10 31 ± 4.3
IGFBP-3 (μg/liter) 4360 ± 345 4020 ± 339 3860 ± 280 4410 ± 274
Testosterone (ng/dl)a 20 ± 2.2 14 ± 4.2 21 ± 2.1 18 ± 1.5
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No significant differences among groups were detected by one-way ANOVA. Data are the mean ± sem before any intervention, including Pl, FUL, or E2 administration. 

a

Multiply by 0.0347 to convert to nmol/liter. 

Outpatient sampling paradigm

Serum was collected at 0800 h every fourth outpatient day and on the last day of the entire study to assay E2, testosterone, LH, FSH, SHBG, prolactin, IGF-I, and IGF binding protein (IGFBP)-1 and IGFBP-3.

Each volunteer was admitted to the Clinical Research Unit on four separate evenings once before each infusion study to allow overnight adaptation. Sleep was deferred until 2200 h. To obviate food-related confounds, subjects ate a standard meal at 2000 h, and then fasted until 1400 h the next day. At 0700 h two iv catheters were inserted into contralateral forearm veins. Between 0800 and 1400 h, plasma was collected every 10 min to assay GH.

Inpatient secretagogue infusions

Infusion studies were performed in randomized order during any four of the last 5 d of the Pl and E2 (highest dose) supplementation schedule. The four iv infusion paradigms were: 1) saline continuously at 50 ml/h, from 0800–1400 h; 2) saline (0800–1000 h), followed by GHRH and GHRP-2 infused constantly from 1000–1400 h (both at a rate of 1 μg/kg·h); 3) saline (0800–1000 h), l-arginine (30 g iv over 30 min, from 0930–1000 h), and GHRH (1 μg/kg bolus iv) at 1000 h; and 4) saline/l-arginine infusion as in the third paradigm, followed by GHRP-2 (3 μg/kg bolus iv) at 1000 h. The combined-peptide infusion permits indirect appraisal of potential estrogenic modulation of somatostatin outflow (37). The two interventions, which are preceded by l-arginine and followed by a maximally stimulatory peptide dose, are designed a priori to identify possible evidence of estrogen-dependent effects on endogenous ghrelin and GHRH-sensitive pathways, respectively (36,38,39,40). Constant infusion of GHRH/GHRP-2 permits evaluation of somatostatin restraint, as verified in model simulations (38,39). Thus, this intervention allows one to compare how the four estrogen milieus influence somatostatin outflow. The comparison is not among secretagogues, but among estrogen milieus.

Hormone assays

Plasma GH concentrations were measured in duplicate by automated ultrasensitive double-monoclonal immunoenzymatic, magnetic particle-capture chemiluminescence assay using 22-kDa recombinant human GH as standard (Sanofi Diagnostics Pasteur Access, Chaska, MN), as described recently (36,40). Details of the LH, FSH, E2, and testosterone assays were reported earlier (36,40).

Total IGF-I concentrations were measured by immunoradiometric assay after extraction (Diagnostic Systems Laboratories, Webster, TX). Interassay coefficients of variation (CVs) were 9% at 64 μg/liter and 6.2% at 157 μg/liter. Intraassay CVs were 3.4, 55.4, and 1.5% at 9.4, 55.4, and 264 μg/liter, respectively. IGFBP-1 and IGFBP-3 concentrations were measured by two-site immunoradiometric assay (Diagnostic Systems Laboratories), with interassay CVs of 3.5% at 5.16 μg/liter and 3.6% at 142 μg/liter, and intraassay CVs of 5.2% at 5.23 μg/liter and 2.7% at 144.6 μg/liter (IGFBP-1), and interassay CVs 1.9% at 7690 μg/liter and 0.6% at 803 μg/liter, and intraassay CVs 1.8% at 8272 μg/liter and 3.9% at 735 μg/liter (IGFBP-3).

Statistical comparisons

Baseline (preintervention) characteristics in the four study groups were evaluated by one-way ANOVA. Post hoc comparisons of means were made using Tukey’s honestly significantly different (HSD) criterion (41). Significance was construed at experiment-wise P < 0.05. Time-dependent effects of E2 and/or FUL on outpatient fasting hormone measurements were analyzed using two-way ANOVA in a repeated-measures design (42). The model examined the individual and interactive effects of time (four factors) and drug (four other factors, Pl, FUL, and/or E2). Logarithmic transformation was first applied to limit the dispersion of residual variance. Data obtained in the Clinical Research Unit after the highest dose of E2 or Pl, were also analyzed by two-way ANOVA to compare peak and incremental GH-concentration responses to peptide infusions, wherein four types of secretagogues replaced the four time factors. The same statistical structure was applied to evaluate the incremental effects of Pl or FUL on GH, IGF-I, IGFBP-1, and IGFBP-3 concentrations. Incremental responses were assessed to minimize variability due to larger interindividual variations in starting measurements.

Statistical power analysis performed a priori assumed a 2.1-fold stimulatory effect of E2 over Pl on mean fasting baseline GH concentrations [obtained from earlier aggregate data (n = 73 subjects)], and postulated 33% inhibition of the E2 effect by coadministration of FUL. Assuming nominal mean fasting GH concentrations of 0.24 ± 0.08 (sd) μg/liter in postmenopausal women (n = 52), E2 would be expected to elevate GH concentrations to 0.48 ± 0.17 μg/liter. A 33% decline would then represent a decrement of 0.16 μg/liter. By an unpaired one-tailed t test, the latter decrease could be detected with 90% power at P < 0.05 if a total of 20 subjects were studied.

Results

All women completed each phase of the study. No data were excluded from analyses. One subject developed itching at the FUL injection site, and several reported local tenderness. Peptide infusions were associated with brief sensation of warmth and flushing, mild nausea, headache, or metallic taste in several volunteers.

Preinterventional (baseline) data

Table 1 summarizes mean age, BMI, and baseline hormone concentrations obtained before Pl, E2, or FUL administration in the four study groups. There were no differences in these variables at study outset. E2 concentrations were 11 ± 1.6 pg/ml at baseline in the double-Pl group. Values increased significantly and comparably in response to successive 4 d outpatient increments in the E2 dose (P < 0.001) (Fig. 2). Maximal E2 concentrations (pg/ml) approximated those of the normal late-follicular phase whether or not FUL was administered concomitantly (152 ± 15 and 137 ± 15 in Pl/E2 and FUL/E2, respectively; P = 0.16).

Figure 2.

Figure 2

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E2 concentrations monitored every 4 d during outpatient escalation of the transdermal E2 dose. Data are the mean ± sem in which N indicates group size. FUL had no effect on E2 profiles. Multiply E2 concentration by 3.67 to convert pg/ml to pmol/liter. none, Absence of any E2 patch; Pl, inactive vehicle for FUL.

GH responses

One-way ANOVA revealed a significant overall drug (E2 or FUL) treatment effect on mean fasting GH concentrations obtained on the day of saline infusion (d 14–18 of Pl or E2 exposure; P = 0.004; Fig. 3). Post hoc analysis using the Tukey HSD criterion showed that GH concentrations were 2- and 2.6-fold higher in the Pl/E2 (P = 0.047) and FUL/E2 (P = 0.017) groups, respectively, than in the Pl/Pl cohort. GH concentrations did not differ between Pl/E2 and FUL/E2 or between FUL/Pl and Pl/Pl (both P > 0.50).

Figure 3.

Figure 3

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Effects of Pl/Pl, Pl/E2, FUL/Pl, and FUL/E2 on secretagogue-induced increments in GH concentrations in postmenopausal women. Data are the mean ± sem. Columns surmounted by different (unshared) alphabetical superscripts have significantly different means as tested by Tukey’s HSD test (e.g. A differs from B, but not from AB).

Two-way ANOVA was applied to test the impact of the estrogen/antiestrogen milieu on secretagogue-stimulated peak GH concentrations. First, this analysis revealed a significant overall drug-treatment effect independently of secretagogue type (P = 0.022) (Table 2). Post hoc analysis of this effect disclosed greater peak GH concentrations in women receiving FUL/E2 than Pl/Pl (P = 0.014). Responses to Pl/E2 and FUL/Pl (both P > 0.30) were numerically intermediate, viz., not significantly different from those to either Pl/Pl or FUL/E2. Second, there was a significant overall secretagogue effect independently of the estrogen milieu (P < 0.001) (Table 2). This was attributed to higher peak GH concentrations after infusion of l-Arg/GHRP-2 than each of l-Arg/GHRH (P = 0.039), GHRH/GHRP-2 (P = 0.002), or saline (P < 0.001). Third, there was no significant interaction between drug and secretagogue type (P = 0.19).

Table 2.

GH concentrations in postmenopausal women

Absolute peak concentrations (μg/liter)
Pl/Pl (n = 10)
Pl/E2 (n = 10)
FUL/Pl (n = 12)
FUL/E2 (n = 11)
P value
60 ± 8.2A
66 ± 6.7A,B
73 ± 9.1A,B
83 ± 13B
0.022
Saline/saline
GHRH/GHRP-2
l-arginine/GHRH
l-arginine/GHRP-2
P value
1.2 ± 0.31A 45 ± 3.1B 52 ± 4.9B 91 ± 9.2C P <0.001
Peak GH increments (μg/liter over saline)
GHRH/GHRP-2 l-arginine/GHRH l-arginine/GHRP-2 P value
Pl/Pl (n = 10) 40 ± 5.5A 47 ± 5.0A,B 76 ± 15B 0.031
Pl/E2 (n = 10) 39 ± 4.8A 46 ± 7.0A 95 ± 8.9B 0.002
FUL/Pl (n = 12) 60 ± 11AB 48 ± 4.2A 94 ± 13B 0.010
FUL/E2 (n = 11) 45 ± 8.7A 66 ± 11AB 112 ± 20B 0.014
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Data are the mean ± sem. 

Means with different (unshared) alphabetical superscripts differ significantly. Thus, A differs from B as well as C, but neither A nor B differs from AB. 

GH responses to secretagogues were also evaluated as increments over the 2-h mean preinjection GH concentration in the same subject on the same day (Table 2). The incremental response to l-Arg/GHRP-2 exceeded that to: 1) GHRH/GHRP-2 in the Pl/Pl (P = 0.031) and Pl/E2 groups (P = 0.001); 2) l-Arg/GHRH in the Pl/FUL group (P = 0.010); and 3) GHRH/GHRP-2 in the FUL/E2 cohort (P = 0.014).

LH, FSH, and prolactin

Fasting gonadotropin and prolactin concentrations measured at the end of study (last day of peptide infusions) are given in Table 3. FSH concentrations were significantly lower and prolactin concentrations significantly higher in the Pl/E2 and FUL/E2 groups than in the Pl/Pl or FUL/Pl groups (both P < 0.001). LH concentrations (P = 0.08) did not differ among the four estrogen treatment groups. Because of prominent intersubject variability, ANOVA was also applied to intraindividual changes (increments) in FSH (P < 0.001), LH (P = 0.042), prolactin (P < 0.001), and SHBG (P = 0.002) concentrations from baseline (Fig. 4). Post hoc analysis disclosed that FUL partially muted E2’s inhibition of FSH secretion (P = 0.024) without altering E2’s stimulation of prolactin secretion. The effects of FUL/E2 on (incremental) SHBG and (decremental) LH concentrations did not differ from those due to E2 or FUL individually.

Table 3.

Hormone concentrations at the end of study

Hormone Pl/Pl (n = 10) Pl/E2 (n = 10) FUL/Pl (n = 12) FUL/E2 (n = 11) P valuea
FSH (IU/liter) 70 ± 6.8A 24 ± 3.1B 64 ± 5.9A 38 ± 6.0C <0.001
LH (IU/liter) 22 ± 2.5 17 ± 2.8 25 ± 1.9 18 ± 2.1 0.08
Prolactin (μg/liter) 5.6 ± 0.5A 14.4 ± 2.7B 6.6 ± 1.0A 14.5 ± 1.2B <0.001
E2 (pg/ml) 10.6 ± 1.6A 152 ± 15B 10.4 ± 1.1A 136 ± 15B <0.001
SHBG (nmol/liter) 56 ± 6.9 66 ± 5.5 64 ± 9.0 71 ± 9.5 0.74
Testosterone (ng/dl) 17 ± 2.4 13 ± 2.3 18 ± 1.6 17 ± 2.3 0.19
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Data are the mean ± sem. Means with different alphabetical characters differ significantly by Tukey’s HSD post hoc test. To convert E2 and testosterone to Systeme International units, multiply by 3.67 and 0.0347, respectively. 

a

P values were assessed by one-way ANOVA. 

Figure 4.

Figure 4

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Absolute decrements in FSH and LH (top panel) and increments in prolactin and SHBG (bottom panel) concentrations compared with baseline (no drug or hormone exposure). Treatment was with E2, Pl, and/or FUL. Data are the mean ± sem. P values denote overall interventional effects assessed by one-way ANOVA. Uppercase letters apply to FSH and prolactin data, and lowercase to LH and SHBG data. Means with no shared alphabetical superscripts differ significantly by the post hoc Tukey HSD test (e.g. A differs from B or C, but not from AB).

IGF-I, IGFBP-1, IGFBP-3

There was no effect of Pl vs. FUL before E2 or Pl was initiated (P = 0.81). Successive comparisons of IGF-I, IGFBP-1, and IGFBP-3 concentrations measured every 4 d with individual baseline values are given in Fig. 5. Two-way ANOVA of these differences revealed significant effects of treatment, but not a treatment-by-time interaction (P = 0.37). Primary treatment effects were P = 0.009 (IGF-I), P < 0.001 (IGFBP-1), and P < 0.001 (IGFBP-3). Post hoc analysis showed that FUL/Pl lowered IGF-I concentrations compared with Pl/Pl (P = 0.001) and Pl/E2 (P = 0.015), but not FUL/E2 (P = 0.096). Pl/E2 elevated IGFBP-1 concentrations compared with the other three interventions (each P ≤ 0.035). Pl/E2 decreased IGFBP-3 concentrations compared with Pl/Pl (P < 0.001) and FUL/Pl (P = 0.014). Finally, FUL alone increased IGFBP-1 (P = 0.002) and decreased IGFBP-3 (P = 0.009), and with E2 opposed the effect of E2 on IGFBP-1 (P = 0.005), but not on IGFBP-3 (P = 0.094).

Figure 5.

Figure 5

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Incremental or decremental changes in fasting concentrations of IGF-I (A), IGFBP-1 (B), and IGFBP-3 (C) during outpatient escalation of transdermal E2 doses, and administration of Pl and/or FUL. The overall P value is based upon two-way ANOVA. Significant contrasts are denoted by different (unshared) alphabetical superscripts at the end of each row (e.g. B differs from A and C, but not from BC). Data are the mean ± sem. Increments were calculated as the difference between the concentration on the indicated day and that on the first day of Pl or E2 administration.

Discussion

The salient outcomes of the present investigation in postmenopausal women are that a highly specific ERα antagonist that does not traverse the blood-brain barrier: 1) does not decrease GH secretion whether or not it is combined with E2, 2) partially opposes E2’s suppression of FSH concentrations, and 3) does not attenuate E2’s stimulation of prolactin secretion (Fig. 6). The antiestrogen when given alone reduced fasting IGF-I and IGFBP-3 concentrations, elevated IGFBP-1 concentrations, and had no effect on unstimulated GH, FSH, prolactin, LH, SHBG, E2, or testosterone concentrations. FUL alone lowered IGF-I concentrations, mimicking the outcome of ERα knockout in adult female mice (43). Thus, low endogenous E2 concentrations in postmenopausal women acting via ERα appear to maintain IGF-I availability. The collective data indicate that E2 suppresses FSH secretion in part via a direct ERα-mediated effect on the pituitary gland; augments fasting GH and prolactin secretion principally via CNS actions, which are not inhibitable by a peripheral antiestrogen; regulates IGFBP-1 availability partially by peripheral ERα mechanisms; and directs IGFBP-3 production via unknown non-ERα pathways.

Figure 6.

Figure 6

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Model of proposed sites of action of E2 and FUL on GH, FSH, and prolactin secretion inferred from the assumption that FUL does not cross the blood-brain barrier. Estrogen’s stimulation of both GH and prolactin secretion includes CNS (FUL resistant) pathways, whereas its inhibition of FSH secretion includes both brain and pituitary (FUL antagonized) mechanisms.

The transdermal E2 supplementation regimen implemented here doubled fasting GH concentrations, as reported earlier (36). FUL, a non-CNS-permeant drug, did not impede or enhance this effect. This outcome points strongly away from ERα pituitary/peripheral and toward central actions of E2 given that a priori estimates of statistical power predicted a greater than 90% probability of detecting at least 33% inhibition by FUL of ERα-dependent stimulation of GH secretion (see Subjects and Methods). In mechanistic clinical studies, E2 supplementation augments GHRH potency, blunts inhibition by somatostatin, potentiates stimulation by synthetic GHRP, and amplifies GH release evoked by somatostatin withdrawal (16,17,18,44). Although the definitive in vivo mechanisms are not known, E2-stimulated CNS sites include GHRH neurons that express ERα and hypothalamic cells expressing IGF-I receptors, GHRP receptors, and the IGF-I gene; conversely, E2-inhibited CNS loci include GH and somatostatin receptors (45,46,47,48,49). Whereas ERβ has not been established directly as a clinical mediator of any in vivo pituitary effects, somatotrope cells contain both ERα and ERβ (27,28,34). In various animal species, E2 can augment pituitary IGFBP-2 concentrations, IGF-I binding sites, and somatostatin receptor subtype 2, and repress somatostatin receptor subtype 5 and GHRH receptors (50,51,52,53). Depending upon dose, estrogens are able to inhibit, not affect, or stimulate GH synthesis and secretion by pituitary cells in vitro (54,55,56,57). In the accompanying analyses, antagonizing the ERα pathway sufficiently to impede the inhibitory effect of E2 on FSH secretion by almost 50% had no detectable effect on GH secretion before or after infusion of three mechanistically distinct types of GH secretagogues (Subjects and Methods). We interpret this outcome to indicate that estrogen’s 2-fold stimulation of GH secretion when FUL is present is not mediated via pituitary ERα pathways, but rather requires CNS mechanisms or far less well-studied peripheral or pituitary ERβ (or other) pathways.

Exogenous estrogen elevates IGFBP-1 but suppresses IGFBP-3 and acid-labile subunit concentrations in a dose-dependent manner (58,59,60). If ERα were required to maintain physiological concentrations of IGFBP-1 or IGFBP-3 as we postulate for IGF-I, then administration of FUL should inhibit E2’s induction of IGFBP-1 and suppression of IGFBP-3. Because this prediction was true for IGFBP-1 but not IGFBP-3, we believe that peripheral ERα is not the exclusive regulator of IGFBP-3. Whether ERβ is such a countervailing mediator is not known.

Studies in animal models indicate that estrogens inhibit gonadotropin and stimulate prolactin secretion via ERα (61,62,63), which is localized in lactotropes and GnRH-stimulatory kisspeptin neurons (64). Concentrations of FSH and LH increase and those of prolactin decrease in gonadectomized wild-type and ERα knockout mice, and are normalized by E2 administration in wild-type but not ERβ knockout animals (63,65). Although the endocrine effects of FUL are reversed by selective ERα agonists in animals (66), in the present clinical study, estrogenic suppression of FSH secretion was not totally overcome by the ERα antagonist. This may be due to an inadequate dose of FUL, or involvement of CNS pathways or pituitary/peripheral ERβ. Because depletion of ERα can augment ERβ, which opposes the effects of ERα on certain gene promoters (67,68,69), further investigations should appraise whether ERβ controls pituitary-hormone secretion.

FUL inhibits E2-stimulated lactotrope proliferation in vitro (66) but does not block suckling- or E2-evoked prolactin secretion in the rat in vivo (24). The topographical restriction of FUL action to outside the CNS is not shared by another antiestrogen (tamoxifen), which is able to antagonize brain actions of E2 (24,66,70). Accordingly, earlier laboratory outcomes and current clinical data together argue that estrogen stimulates prolactin secretion primarily by CNS mechanisms that do not involve peripheral ERα.

In conclusion, in healthy postmenopausal women, E2’s suppression of FSH secretion in part involves pituitary ERα, whereas estrogenic stimulation of prolactin and GH secretion entails principally nonperipheral ERα (putatively CNS) mechanisms. Estrogenic effects on IGF-I and IGFBPs are more complex with evidence of ERα dependence (IGF-I and IGFBP-1) and independence (IGFBP-3).

Acknowledgments

We thank Kay Nevinger for support of manuscript preparation, Ashley Bryant for data analysis and graphics, the Mayo Immunochemical Laboratory for assay assistance, and the Mayo research nursing staff for implementing the protocol.

Footnotes

This work was supported in part via the Center for Translational Science Activities Grant no. 1 UL 1 RR024150 to the Mayo Clinic and Foundation from the National Center for Research Resources (Rockville, MD), and Grants R01 NIA AG029362, R21 DK072095, DK063609, RR019991 from the National Institutes of Health (Bethesda, MD).

Disclosure Statement: The authors have nothing to declare.

First Published Online December 18, 2007

Abbreviations: BMI, Body mass index; CNS, central nervous system; CV, coefficient of variation; E2, estradiol; ER, estrogen receptor; FUL, fulvestrant; GHRP, GH-releasing peptide; HSD, honestly significantly different; IGFBP, IGF binding protein; Pl, placebo.

References

  1. Finkelstein JW, Roffwarg HP, Boyar RM, Kream J, Hellman L 1972 Age-related change in the twenty-four-hour spontaneous secretion of growth hormone. J Clin Endocrinol Metab 35:665–670 [DOI] [PubMed] [Google Scholar]
  2. Giustina A, Veldhuis JD 1998 Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev 19:717–797 [DOI] [PubMed] [Google Scholar]
  3. Corpas E, Harman SM, Blackman MR 1993 Human growth hormone and human aging. Endocr Rev 14:20–39 [DOI] [PubMed] [Google Scholar]
  4. Cuneo RC, Salomon F, McGauley GA, Sönksen PH 1992 The growth hormone deficiency syndrome in adults. Clin Endocrinol (Oxf) 37:387–397 [DOI] [PubMed] [Google Scholar]
  5. Ho KKY, Evans WS, Blizzard RM, Veldhuis JD, Merriam GR, Samojlik E, Furlanetto R, Rogol AD, Kaiser DL, Thorner MO 1987 Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. J Clin Endocrinol Metab 64:51–58 [DOI] [PubMed] [Google Scholar]
  6. Lieman HJ, Adel TE, Forst C, von Hagen S, Santoro N 2001 Effects of aging and estradiol supplementation on GH axis dynamics in women. J Clin Endocrinol Metab 86:3918–3923 [DOI] [PubMed] [Google Scholar]
  7. Frantz AG, Rabkin MT 1965 Effects of estrogen and sex difference on secretion of human growth hormone. J Clin Endocrinol Metab 25:1470–1480 [DOI] [PubMed] [Google Scholar]
  8. Mauras N, Rogol AD, Veldhuis JD 1990 Increased hGH production rate after low-dose estrogen therapy in prepubertal girls with Turner’s syndrome. Pediatr Res 28:626–630 [DOI] [PubMed] [Google Scholar]
  9. Shah N, Evans WS, Veldhuis JD 1999 Actions of estrogen on the pulsatile, nyctohemeral, and entropic modes of growth hormone secretion. Am J Physiol 276(5 Pt 2):R1351–R1358 [DOI] [PubMed] [Google Scholar]
  10. Veldhuis JD, Roemmich JN, Richmond EJ, Bowers CY 2006 Somatotropic and gonadotropic axes linkages in infancy, childhood, and the puberty-adult transition. Endocr Rev 27:101–140 [DOI] [PubMed] [Google Scholar]
  11. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K 1999 Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656–660 [DOI] [PubMed] [Google Scholar]
  12. Shuto Y, Shibasaki T, Otagiri A, Kuriyama H, Ohata H, Tamura H, Kamegai J, Sugihara H, Oikawa S, Wakabayashi I 2002 Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity. J Clin Invest 109:1429–1436 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Low MJ, Otero-Corchon V, Parlow AF, Ramirez JL, Kumar U, Patel YC, Rubinstein M 2001 Somatostatin is required for masculinization of growth hormone-regulated hepatic gene expression but not of somatic growth. J Clin Invest 107:1571–1580 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Roelfsema F, Biermasz NR, Veldman RG, Veldhuis JD, Frolich M, Stokvis-Brantsma WH, Wit JM 2000 Growth hormone (GH) secretion in patients with an inactivating defect of the GH-releasing hormone (GHRH) receptor is pulsatile: evidence for a role for non-GHRH inputs into the generation of GH pulses. J Clin Endocrinol Metab 86:2459–2464 [DOI] [PubMed] [Google Scholar]
  15. Pantel J, Legendre M, Cabrol S, Hilal L, Hajaji Y, Morisset S, Nivot S, Vie-Luton MP, Grouselle D, de Kerdanet M, Kadiri A, Epelbaum J, Le Bouc Y, Amselem S 2006 Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J Clin Invest 116:760–768 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Anderson SM, Shah N, Evans WS, Patrie JT, Bowers CY, Veldhuis JD 2001 Short-term estradiol supplementation augments growth hormone (GH) secretory responsiveness to dose-varying GH-releasing peptide infusions in healthy postmenopausal women. J Clin Endocrinol Metab 86:551–560 [DOI] [PubMed] [Google Scholar]
  17. Bray MJ, Vick TM, Shah N, Anderson SM, Rice LW, Iranmanesh A, Evans WS, Veldhuis JD 2001 Short-term estradiol replacement in postmenopausal women selectively mutes somatostatin’s dose-dependent inhibition of fasting growth hormone secretion. J Clin Endocrinol Metab 86:3143–3149 [DOI] [PubMed] [Google Scholar]
  18. Veldhuis JD, Anderson SM, Patrie JT, Bowers CY 2004 Estradiol supplementation in postmenopausal women doubles rebound-like release of growth hormone (GH) triggered by sequential infusion and withdrawal of somatostatin: evidence that estrogen facilitates endogenous GH-releasing hormone drive. J Clin Endocrinol Metab 89:121–127 [DOI] [PubMed] [Google Scholar]
  19. Veldhuis JD, Anderson SM, Kok P, Iranmanesh A, Frystyk J, Orskov H, Keenan DM 2004 Estradiol supplementation modulates growth hormone (GH) secretory-burst waveform and recombinant human insulin-like growth factor-I-enforced suppression of endogenously driven GH release in postmenopausal women. J Clin Endocrinol Metab 89:1312–1318 [DOI] [PubMed] [Google Scholar]
  20. Anderson SM, Wideman L, Patrie JT, Weltman A, Bowers CY, Veldhuis JD 2001 E2 supplementation selectively relieves GH’s autonegative feedback on GH-releasing peptide-2-stimulated GH secretion. J Clin Endocrinol Metab 86:5904–5911 [DOI] [PubMed] [Google Scholar]
  21. Yamamoto K, Taylor LM, Cole FE 1970 Synthesis and release of GH and prolactin from the rat anterior pituitary in vitro as functions of age and sex. Endocrinology 87:20–26 [DOI] [PubMed] [Google Scholar]
  22. Haug E, Gautvik KM 1978 Effects of sex steroids on growth hormone production in cultured rat pituitary cells. Acta Endocrinol (Copenh) 87:40–54 [DOI] [PubMed] [Google Scholar]
  23. Wade GN, Blaustein JD, Gray JM, Meredith JM 1993 ICI 182,780: a pure antiestrogen that affects behaviors and energy balance in rats without acting in the brain. Am J Physiol 265(6 Pt 2):R1392–R1398 [DOI] [PubMed] [Google Scholar]
  24. Yin P, Kawashima K, Arita J 2002 Direct actions of estradiol on the anterior pituitary gland are required for hypothalamus-dependent lactotrope proliferation and secretory surges of luteinizing hormone but not of prolactin in female rats. Neuroendocrinology 75:392–401 [DOI] [PubMed] [Google Scholar]
  25. Fawell SE, White R, Hoare S, Sydenham M, Page M, Parker MG 1990 Inhibition of estrogen receptor-DNA binding by the “pure” antiestrogen ICI 164,384 appears to be mediated by impaired receptor dimerization. Proc Natl Acad Sci USA 87:6883–6887 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. McKeage K, Curran MP, Plosker GL 2004 Fulvestrant: a review of its use in hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Drugs 64:633–648 [DOI] [PubMed] [Google Scholar]
  27. Friend KE, Chiou YK, Lopes MB, Laws Jr ER, Hughes KM, Shupnik MA 1994 Estrogen receptor expression in human pituitary: correlation with immunohistochemistry in normal tissue, and immunohistochemistry and morphology in macroadenomas. J Clin Endocrinol Metab 78:1497–1504 [DOI] [PubMed] [Google Scholar]
  28. Zafar M, Ezzat S, Ramyar L, Pan N, Smyth HS, Asa SL 1995 Cell-specific expression of estrogen receptor in the human pituitary and its adenomas. J Clin Endocrinol Metab 80:3621–3627 [DOI] [PubMed] [Google Scholar]
  29. Shupnik MA, Pitt LK, Soh AY, Anderson A, Lopes MB, Laws Jr ER 1998 Selective expression of estrogen receptor α and β isoforms in human pituitary tumors. J Clin Endocrinol Metab 83:3965–3972 [DOI] [PubMed] [Google Scholar]
  30. Chaidarun SS, Swearingen B, Alexander JM 1998 Differential expression of estrogen receptor-β (ER β) in human pituitary tumors: functional interactions with ER α and a tumor-specific splice variant. J Clin Endocrinol Metab 83:3308–3315 [DOI] [PubMed] [Google Scholar]
  31. Sanchez-Criado JE, Martin De Las Mulas J, Bellido C, Tena-Sempere M, Aguilar R, Blanco A 2004 Biological role of pituitary estrogen receptors ERalpha and ERbeta on progesterone receptor expression and action and on gonadotropin and prolactin secretion in the rat. Neuroendocrinology 79:247–258 [DOI] [PubMed] [Google Scholar]
  32. Lund TD, Hinds LR, Handa RJ 2006 The androgen 5α-dihydrotestosterone and its metabolite 5β-androstan-3β, 17β-diol inhibit the hypothalamo-pituitary-adrenal response to stress by acting through estrogen receptor β-expressing neurons in the hypothalamus. J Neurosci 26:1448–1456 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Osterlund MK, Gustafsson JA, Keller E, Hurd YL 2000 Estrogen receptor β (ERβ) messenger ribonucleic acid (mRNA) expression within the human forebrain: distinct distribution pattern to ERα mRNA. J Clin Endocrinol Metab 85:3840–3846 [DOI] [PubMed] [Google Scholar]
  34. Shimizu T, Kamegai J, Tamura H, Ishii S, Sugihara H, Oikawa S 2005 The estrogen receptor (ER) α, but not ER β, gene is expressed in hypothalamic growth hormone-releasing hormone neurons of the adult female rat. Neurosci Res 52:121–125 [DOI] [PubMed] [Google Scholar]
  35. Hrabovszky E, Shughrue PJ, Merchenthaler I, Hajszan T, Carpenter CD, Liposits Z, Petersen SL 2000 Detection of estrogen receptor-β messenger ribonucleic acid and 125I-estrogen binding sites in luteinizing hormone-releasing hormone neurons of the rat brain. Endocrinology 141:3506–3509 [DOI] [PubMed] [Google Scholar]
  36. Erickson D, Keenan DM, Mielke K, Bradford K, Bowers CY, Miles JM, Veldhuis JD 2004 Dual secretagogue drive of burst-like growth hormone secretion in postmenopausal compared with premenopausal women studied under an experimental estradiol clamp. J Clin Endocrinol Metab 89:4746–4754 [DOI] [PubMed] [Google Scholar]
  37. Veldhuis JD, Evans WS, Bowers CY 2002 Impact of estradiol supplementation on dual peptidyl drive of growth-hormone secretion in postmenopausal women. J Clin Endocrinol Metab 87:859–866 [DOI] [PubMed] [Google Scholar]
  38. Farhy LS, Veldhuis JD 2005 Deterministic construct of amplifying actions of ghrelin on pulsatile growth hormone secretion. Am J Physiol Regul Integr Comp 288:R1649–R1663 [DOI] [PubMed] [Google Scholar]
  39. Farhy LS, Bowers CY, Veldhuis JD 2007 Model-projected mechanistic bases for sex differences in growth-hormone regulation in humans. Am J Physiol Regul Integr Comp Physiol 292:R1577–R1593 [DOI] [PubMed] [Google Scholar]
  40. Erickson D, Keenan DM, Farhy LS, Mielke K, Bowers CY, Veldhuis JD 2005 Determinants of dual secretagogue drive of burst-like GH secretion in premenopausal women studied under a selective estradiol clamp. J Clin Endocrinol Metab 90:1741–1751 [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Fisher LD, van Belle G 1996 Descriptive statistics. In: Biostatistics: a methodology for the health sciences. New York: John Wiley, Sons; 58–74 [Google Scholar]
  42. Zar JH 1996 Biostatistical analysis. 3rd ed. Upper Saddle River, NJ: Prentice Hall [Google Scholar]
  43. Vidal O, Lindberg M, Savendahl L, Lubahn DB, Ritzen EM, Gustafsson JA, Ohlsson C 1999 Disproportional body growth in female estrogen receptor-alpha-inactivated mice. Biochem Biophys Res Comm 265:569–571 [DOI] [PubMed] [Google Scholar]
  44. Veldhuis JD, Evans WS, Bowers CY 2003 Estradiol supplementation enhances submaximal feed-forward drive of growth hormone (GH) secretion by recombinant human GH-releasing hormone-1,44-amide in a putatively somatostatin-withdrawn milieu. J Clin Endocrinol Metab 88:5484–5489 [DOI] [PubMed] [Google Scholar]
  45. Duenas M, Luquin S, Chowen JA, Torres-Aleman I, Naftolin F, Garcia-Segura LM 1994 Gonadal hormone regulation of insulin-like growth factor-I-like immunoreactivity in hypothalamic astroglia of developing and adult rats. Neuroendocrinology 59:528–538 [DOI] [PubMed] [Google Scholar]
  46. Cardona-Gomez GP, Chowen JA, Garcia-Segura LM 2000 Estradiol and progesterone regulate the expression of insulin-like growth factor-I receptor and insulin-like growth factor binding protein-2 in the hypothalamus of adult female rats. J Neurobiol 43:269–281 [DOI] [PubMed] [Google Scholar]
  47. Slama A, Videau C, Kordon C, Epelbaum J 1992 Estradiol regulation of somatostatin receptors in the arcuate nucleus of the female rat. Neuroendocrinology 56:240–245 [DOI] [PubMed] [Google Scholar]
  48. Lam KS, Lee MF, Tam SP, Srivastava G 1996 Gene expression of the receptor for growth-hormone-releasing hormone is physiologically regulated by glucocorticoids and estrogen. Neuroendocrinology 63:475–480 [DOI] [PubMed] [Google Scholar]
  49. Bennett PA, Levy A, Carmignac DF, Robinson IC, Lightman SL 1996 Differential regulation of the growth hormone receptor gene: effects of dexamethasone and estradiol. Endocrinology 137:3891–3896 [DOI] [PubMed] [Google Scholar]
  50. Yan M, Jones ME, Hernandez M, Liu D, Simpson ER, Chen CH 2004 Functional modification of pituitary somatotropes in the aromatase knockout mouse and the effect of estrogen replacement. Endocrinology 145:604–612 [DOI] [PubMed] [Google Scholar]
  51. Clapper JA, Snyder JL, Roberts AJ, Hamernik DL, Moss GE 1998 Estradiol increases relative amounts of insulin-like growth factor binding protein (IGFBP)-3 in serum and expression of IGFBP-2 in anterior pituitaries of ewes. Biol Reprod 59:124–130 [DOI] [PubMed] [Google Scholar]
  52. Kimura N, Tomizawa S, Arai KN, Kimura N 1998 Chronic treatment with estrogen up-regulates expression of sst2 messenger ribonucleic acid (mRNA) but down-regulates expression of sst5 mRNA in rat pituitaries. Endocrinology 139:1573–1580 [DOI] [PubMed] [Google Scholar]
  53. Michels KM, Lee WH, Seltzer A, Saavedra JM, Bondy CA 1993 Up-regulation of pituitary [125I]insulin-like growth factor-I (IGF-I) binding and IGF binding protein-2 and IGF-I gene expression by estrogen. Endocrinology 132:23–29 [DOI] [PubMed] [Google Scholar]
  54. Simard J, Hubert JF, Hosseinzadeh T, Labrie F 1986 Stimulation of growth hormone release and synthesis by estrogens in rat anterior pituitary cells in culture. Endocrinology 119:2004–2011 [DOI] [PubMed] [Google Scholar]
  55. Horvath JE, Schally AV 1994 Reciprocal changes in prolactin and growth hormone secretion in vitro after in vivo estrogen treatment. Acta Biol Hung 45:249–262 [PubMed] [Google Scholar]
  56. Jin L, Song J, Lloyd RV 1989 Estrogen stimulates both prolactin and growth hormone mRNAs expression in the MtT/F4 transplantable pituitary tumor. Proc Soc Exp Biol Med 192:225–229 [DOI] [PubMed] [Google Scholar]
  57. Childs GV, Iruthayanathan M, Akhter N, Unabia G, Whitehead-Johnson B 2005 Bipotential effects of estrogen on growth hormone synthesis and storage in vitro. Endocrinology 146:1780–1788 [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Helle SI, Omsjo IH, Hughes SC, Botta L, Huls G, Holly JM, Lonning PE 1996 Effects of oral and transdermal oestrogen replacement therapy on plasma levels of insulin-like growth factors and IGF binding proteins 1 and 3: a cross-over study. Clin Endocrinol (Oxf) 45:727–732 [DOI] [PubMed] [Google Scholar]
  59. Campagnoli C, Biglia N, Altare F, Lanza MG, Lesca L, Cantamessa C, Peris C, Fiorucci GC, Sismondi P 1993 Differential effects of oral conjugated estrogens and transdermal estradiol on insulin-like growth factor I, growth hormone and sex hormone binding globulin serum levels. Gynecol Endocrinol 7:251–258 [DOI] [PubMed] [Google Scholar]
  60. Duenas M, Torres-Aleman I, Naftolin F, Garcia-Segura LM 1996 Interaction of insulin-like growth factor-I and estradiol signaling pathways on hypothalamic neuronal differentiation. Neuroscience 74:531–539 [DOI] [PubMed] [Google Scholar]
  61. Couse JF, Yates MM, Walker VR, Korach KS 2003 Characterization of the hypothalamic-pituitary-gonadal axis in estrogen receptor (ER) null mice reveals hypergonadism and endocrine sex reversal in females lacking ERα but not ERβ. Mol Endocrinol 17:1039–1053 [DOI] [PubMed] [Google Scholar]
  62. Scully KM, Gleiberman AS, Lindzey J, Lubahn DB, Korach KS, Rosenfeld MG 1997 Role of estrogen receptor-α in the anterior pituitary gland. Mol Endocrinol 11:674–681 [DOI] [PubMed] [Google Scholar]
  63. Wersinger SR, Haisenleder DJ, Lubahn DB, Rissman EF 1999 Steroid feedback on gonadotropin release and pituitary gonadotropin subunit mRNA in mice lacking a functional estrogen receptor α. Endocrine 11:137–143 [DOI] [PubMed] [Google Scholar]
  64. Franceschini I, Lomet D, Cateau M, Delsol G, Tillet Y, Caraty A 2006 Kisspeptin immunoreactive cells of the ovine preoptic area and arcuate nucleus co-express estrogen receptor α. Neurosci Lett 401:225–230 [DOI] [PubMed] [Google Scholar]
  65. Dorling AA, Todman MG, Korach KS, Herbison AE 2003 Critical role for estrogen receptor α in negative feedback regulation of gonadotropin-releasing hormone mRNA expression in the female mouse. Neuroendocrinology 78:204–209 [DOI] [PubMed] [Google Scholar]
  66. Kansra S, Yamagata S, Sneade L, Foster L, Ben-Jonathan N 2005 Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release. Mol Cell Endocrinol 239:27–36 [DOI] [PubMed] [Google Scholar]
  67. Matthews J, Gustafsson JA 2003 Estrogen signaling: a subtle balance between ER α and ER β. Mol Interv 3:281–292 [DOI] [PubMed] [Google Scholar]
  68. Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J, Kushner PJ, Scanlan TS 1997 Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science 277:1508–1510 [DOI] [PubMed] [Google Scholar]
  69. Montanaro D, Maggiolini M, Recchia AG, Sirianni R, Aquila S, Barzon L, Fallo F, Ando S, Pezzi V 2005 Antiestrogens upregulate estrogen receptor β expression and inhibit adrenocortical H295R cell proliferation. J Mol Endocrinol 35:245–256 [DOI] [PubMed] [Google Scholar]
  70. Donath J, Nishino Y 1998 Effects of partial versus pure antiestrogens on ovulation and the pituitary-ovarian axis in the rat. J Steroid Biochem Mol Biol 66:247–254 [DOI] [PubMed] [Google Scholar]

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