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Original Studies |
Reproductive Endocrinology Center, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California (V.L.B., J.S., R.B.J.), San Francisco, California 94143; Eli Lilly Co. (M.D., S.P., S.A.), Indianapolis, Indiana 46285; Diagnostic Cytology Laboratories (M.G.), Indianapolis, Indiana 46268
Address all correspondence and requests for reprints to: Robert B. Jaffe, M.D., Reproductive Endocrinology Center, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California 94143-0556.
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Abstract |
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This study has demonstrated that 1) raloxifene does not prevent ovulation in women with normal menstrual cycles; 2) ovarian estrogen production will continue, and in some cases increase, in response to raloxifene; and 3) antiestrogenic effects of raloxifene on the endometrium are subtle in the endocrine milieu of normal to high circulating estradiol concentrations.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A compound with estrogen antagonistic activity on the endometrium, but estrogen agonistic activity with respect to bone and circulating lipoproteins, potentially will be useful for postmenopausal women who cannot or choose not to take estrogen therapy. Given this profile, raloxifene or a similar compound could also be useful for the treatment of estrogen-responsive disorders, such as endometriosis and uterine leiomyomata, which occur in reproductive-aged women. Preliminary laboratory studies support the concept that raloxifene may be useful for the treatment of leiomyomata; raloxifene inhibited proliferation of rat leiomyoma cells in culture (6) and produced regression of abdominal wall leiomyomata in guinea pigs (7).
Before proceeding to clinical trials in women with these gynecological disorders, it is essential to obtain data concerning the effect of raloxifene in normal women of reproductive age. Because human studies of raloxifene to date have been performed only in postmenopausal women (3, 5) or in men (8), little is known about its effect on ovulatory function, circulating gonadotropin and ovarian steroid levels, or the endometrium in the presence of circulating estradiol (E2) levels typical of women of reproductive age. Therefore, we undertook the first study of raloxifene in healthy women of reproductive age to determine its reproductive hormonal and in vivo endometrial effects.
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Subjects and Methods |
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Healthy women with regular ovulatory menstrual cycles, aged 21–45 yr, were invited to participate. All participants were within 25% of ideal body weight and had not used any hormonal medications for at least 3 months before the study. All women agreed to use barrier contraception during treatment and for 3 months after completion of raloxifene administration. Women with symptomatic endometriosis or symptomatic uterine leiomyomata were excluded. The project was approved by the committee on human research, University of California-San Francisco, and informed consent was obtained from each volunteer.
Clinical protocols
There were two parts to this study, which were conducted concurrently. The purpose of part I was to determine the effects of a 5-day course of raloxifene when administered in selected phases of the menstrual cycle. The purpose of part II was to determine the effect of daily raloxifene administration beginning on cycle day 2 or 3.
Part I: 5-day raloxifene administration in follicular, periovulatory, or luteal phase
In the control cycle before treatment with raloxifene, blood samples were obtained, and a limited pelvic vaginal sonogram (General Electric Advantage 3200 with a 7.0-mHz vaginal probe, Milwaukee, WI) was performed daily during a 7- to 10-day period surrounding the anticipated time of ovulation and every other day throughout the remainder of the cycle. The sonogram consisted of an evaluation of ovarian follicles and an assessment of endometrial thickness and pattern (presence or absence of a triple line). The triple line pattern is thought to represent the normal pattern expected during the periovulatory period. Its presence appears to correlate with higher pregnancy rates, as noted during fertility treatment (9). Monitoring during the treatment cycle was the same as that in the control cycle, with the addition of daily visits during raloxifene administration. During the treatment cycle, 12 women, aged 21–45 yr, received raloxifene (400 mg, orally) on 5 consecutive days at one of three times in the menstrual cycle: the midfollicular phase (n = 4), the periovulatory phase (n = 4), or the luteal phase (n = 4). The midfollicular phase group received raloxifene after sonographic documentation of an emerging dominant follicle with a maximum diameter of 10–12 mm. The periovulatory group began raloxifene 1–2 days before the anticipated LH surge, based upon the previous cycle and size of the dominant follicle. The luteal phase group began raloxifene approximately 3 days after ovulation.
Part II: 28-day raloxifene administration beginning on cycle day 3
A total of 19 women, aged 21–45 yr, received raloxifene daily for 4 weeks beginning on day 2 or 3 of the menstrual cycle. Using a double blind, randomized study design, half of the women received raloxifene (100 mg daily), and half received (200 mg daily).
A screening visit was performed on day 10 of the cycle before treatment, and ovulation was documented by serum progesterone (P) 7 days after a positive urinary LH (ClearPlan Easy, Unipath, Bedford, UK). On day 2 or 3 of the subsequent menstrual cycle, the volunteers began raloxifene treatment after sonographic confirmation that no persistent ovarian cysts 10 mm or larger were present. Volunteers were seen on day 10, daily around the time of ovulation, once in the midluteal phase, and at the conclusion of 28 days of raloxifene administration. Cervical mucus was examined on day 10 of the pretreatment cycle and at three times during treatment (day 10, periovulatory phase, and midluteal phase). Mucus was scored according to the following scale: amount (none = 0, minimal = 1, moderate = 2, copious = 3), spinnbarkeit (0 cm = 0, 1–2 cm = 1, 3–6 cm = 2, 7–10 cm = 3), and ferning (negative = 0, positive = 2). Endometrial biopsies and vaginal cytology also were performed at the screening visit, on day 10 of the treatment cycle, and in the midluteal phase.
Serum assays for parts I and II
Blood samples were centrifuged, and serum was stored at -20 C until assayed. RIA was used to quantify FSH (Diagnostic Products Corp., Los Angeles, CA) and LH, the latter according to the method of Midgely and Jaffe (10). FSH and LH values are expressed in terms of the Second International Reference Preparation for human menopausal gonadotropin. Serum hCG was determined every 2 weeks using an immunoradiometric assay (MAIAclone, Biodata Diagnostics, Rome, Italy) with a lower limit of detection of 2 mIU/mL (Second International Standard). PRL was determined by immunoradiometric assay (MAIAclone, Biodata Diagnostics). RIA was used to quantify concentrations of E2 (Pantex, Santa Monica, CA), P (Coat-a-Count Progesterone, Diagnostic Products Corp., Los Angeles, CA), testosterone, androstenedione, estrone (E1) (11), and dehydroepiandrosterone sulfate (12). For each of the gonadotropin and steroid assays, all samples for an individual volunteer were assayed on the same day. All RIAs were performed in duplicate, and values were averaged. Intra- and interassay variability for peptides were both 5% or less. For steroids, intraassay variability was 10% or less, and interassay variability was 15% or less.
Sex hormone-binding globulin (SHBG) was quantified by a binding capacity assay using tritiated testosterone (Endocrine Sciences, Calabasas,CA). Cortisol was measured by a fluorescence polarization assay (TDx assay, Abbott Laboratories, Abbott Park, IL).
Endometrial histology and vaginal cytology in part II
Endometrial biopsies were performed using a Pipelle biopsy instrument (Unimar, Wilton, CT) and placed in neutral buffered formalin for transport to the central laboratory (Diagnostic Cytology Laboratories, Indianapolis, IN). After routine hematoxylin and eosin staining, two pathologists blinded to treatment assessed each biopsy. Eighteen luteal phase biopsies from laboratory archives were added to the study biopsies to blind the pathologists to the presence or absence of raloxifene treatment in the secretory phase.
Detailed morphometric assessment, including measurement of number of glands, number of glandular mitoses, number of stromal mitoses, and calculation of glandular mitotic rate (gland mitoses per number of glands), was performed. For each of the morphometric measurements, 10 high power fields (x400) were reviewed, and an average value per high power field was calculated.
Isolated gland cell death may be seen when a replicating stimulus is withdrawn or rapidly blocked (13). Because blockage of E2 action by raloxifene potentially could result in isolated gland cell death, this feature was examined by light microscopy. A semiquantitative scale was used: 0 = less than 0.5 necrotic figures/10 high power fields, 1 = 0.5–1.4 necrotic figures/10 high power fields, and 2 = 1.5–2.4 necrotic figures/10 high power fields.
For secretory phase biopsies, the postovulatory day of the glands and stroma was individually determined using the criteria of Noyes et al. (14) and Buckley and Fox (15). Secretory biopsies were considered to suggest abnormal endometrial development based on either of two criteria: a disparity of greater than 2 days between pathological dating and the day of ovulation or a disparity of greater than 2 days between the dating of the glands and the stroma (gland-stromal dysynchrony). Postovulatory day 1 was defined as the first day follicular collapse was noted by ultrasound.
Vaginal cytology was obtained by lightly scraping the vaginal sidewalls. Direct smears were fixed immediately by alcohol pump spray and subsequently stained by a modified Papanicolaou method. Cytotechnologists blinded to treatment classified the cells as parabasal, intermediate, or superficial, and Meisel’s maturation value was calculated.
Posttreatment monitoring
Return of ovulation in the cycle after treatment in both parts of the study was assessed by serum P measured 1 week after a positive result from the urinary LH testing.
Statistical analyses
The area under the curve (AUC) was calculated using the trapezoidal rule. The AUC values were calculated for four time periods: the first to fifth doses (in part I of the study only), the first half of the cycle, the second half of the cycle (part I only), and over the entire cycle. The first half of the cycle was defined as day 1 through the day before the serum LH peak, and the second half was defined as the day of the LH peak to the end of the cycle. The date of the LH surge was used to align control and treatment cycles.
For part I, to assess both overall treatment and phase-specific effects, data were analyzed using a repeated measures procedure with an unstructured or a compound-symmetry variance-covariance matrix, whichever provided the best fit. Initially, a term for phase by treatment interaction was included and tested for significance at the 0.10 level. If it was not significant for a particular variable, it was deleted from the model. Otherwise, treatment comparisons among follicular, periovulatory, and luteal phases were performed.
Several comparisons were made for part II. To assess the effect of treatment vs. no treatment, data for the volunteers who received either 100 or 200 mg raloxifene daily were compared with data from the control cycles for the 12 volunteers who participated in part I. Original data or square root transformations were analyzed using one-way ANOVA with only treatment and not phase in the model. To compare the 100 vs. 200 mg doses of raloxifene, data were analyzed using a one-way ANOVA. For variables for which data were available for both pretreatment and treatment cycles in part II, paired t tests were performed to assess the effect of treatment vs. no treatment. For follicular phase endometrial biopsies, control and treatment cycle morphometric data were compared using the Wilcoxon sign rank test.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The mean age was 33.1 yr for part I, 32.7 yr for the 100 mg group, part II, and 33.7 yr for the 200 mg group, part II (P = 0.804, NS). There was also no significant difference in age among the three treatment groups in part I. There was no significant difference in body mass index, gravidity, or parity among the three treatment groups in part I, the 100 vs. 200 mg groups in part II, nor the volunteers in part I vs. those in part II.
Part I
Pituitary gonadotropins and cycle characteristics. The general
patterns of LH and FSH throughout the cycle were unaffected by
raloxifene administration in any phase of the cycle. In Fig. 1
, the general FSH pattern of a
representative volunteer is shown for a control cycle and a raloxifene
cycle. All women had a spontaneous LH surge in both treatment and
control cycles. There was no change in the day of the LH surge or the
length of the cycle with raloxifene administration. The LH AUC for the
entire cycle and for the first and second halves of the cycle did not
change with raloxifene. Administration of raloxifene in the
periovulatory phase decreased the LH AUC for the period of 5 days when
raloxifene was administered by 23% (Table 1; P < 0.01). The FSH
AUC for the entire cycle and for the 5-day period when raloxifene was
administered was 15–20% higher with raloxifene treatment in any phase
(Table 1; P 
0.03). With respect to FSH AUC for the
first half of the cycle, there was a trend towards an increase with
follicular phase treatment (26% increase in mean FSH AUC;
P = NS), but no statistically significant change with
treatment in any phase. The mean FSH AUC for the second half of the
cycle did not change with follicular phase treatment, but was 60%
higher if treatment was received in the periovulatory phase and 37%
higher if raloxifene was received in the luteal phase compared with
that in control cycles (Table 1; P < 0.001).
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, the general
E2 pattern of a representative volunteer is shown
for a control cycle and a raloxifene cycle. All women ovulated in both
control and treatment cycles, as assessed by follicular development and
collapse on serial sonograms and serum P levels greater than 10 ng/mL
in the luteal phase. Although a normal general pattern of
E2 was present, with periovulatory and midluteal
increases, maximum E2 concentrations,
E2 AUC for the entire cycle, and
E2 AUC for the first half of the cycle were
increased 86%, 57%, and 62%, respectively, with follicular phase
treatment compared to those during control cycles (P <
0.01). Administration of raloxifene in the periovulatory or luteal
phases did not appear to change maximum E2 levels
or E2 AUC for the entire cycle or the first half
of the cycle. The E2 AUC for the second half of
the cycle was 31% higher than that in control cycles when data from
all 12 volunteers were pooled, but the increase did not reach
statistical significance for treatment in a particular phase
(P < 0.01). Raloxifene administration in any phase did
not affect the E2 AUC for the 5 days during the
period of raloxifene administration. There was no statistically
significant effect of treatment on maximum P or P AUC for the entire
cycle. The increase in E2 with raloxifene treatment could not be accounted for by an increase in the number of dominant follicles, as all but one volunteer developed a single dominant follicle with raloxifene treatment. One volunteer who received raloxifene in the follicular phase developed two dominant follicles. Although the maximum size of the domi-nant follicle was somewhat larger with raloxifene treatment in the follicular phase (mean, 26.0 vs. 22.5 mm; P = NS), there was no difference in the maximum size of the dominant follicle with periovulatory or luteal phase raloxifene administration. The maximum E2 level correlated with the maximum size of the dominant follicle (r = 0.83; P = 0.002) for treatment cycles.
The PRL AUC for the entire cycle was not affected by raloxifene, but
the PRL AUC was 10–35% lower during the 5-day period of raloxifene
administration regardless of which phase in the cycle raloxifene was
given (P < 0.005; Table 1).
Sonographic appearance of the endometrium. There was a nonsignificant trend toward a decrease in maximum endometrial thickness between the 12 treatment compared with the 12 control cycles. In the follicular, periovulatory, and luteal phase groups, the mean maximal endometrial thicknesses in control vs. treatment cycles were 14.2 vs. 13.5, 12.5 vs. 12.2, and 12.8 vs. 11.2 mm, respectively (P = 0.14). All but one volunteer developed a triple line endometrial pattern with raloxifene (compared with all volunteers developing a triple line in their control cycles). The woman who never developed a triple line pattern received raloxifene during the periovulatory period.
Part II
Pituitary gonadotropins and cycle characteristics. General
patterns of FSH and LH were unaffected by daily raloxifene treatment
(Fig. 2). All women had a spontaneous LH
surge. There was no difference in cycle length when comparing each
woman with her own pretreatment cycle. Raloxifene did not alter the day
of the urinary LH surge when comparing each woman with her own
pretreatment and posttreatment cycles.
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Follicular development, ovarian and adrenal steroids, and PRL.
All women ovulated, as assessed by development and collapse of a
dominant follicle and serum P levels of 10 ng/mL or more. The major
significant effect of raloxifene was to increase serum
E2 concentrations (Fig. 2). The mean maximum
E2 was 60% higher with treatment compared with
that in the control group (P = 0.056). The mean
E2 AUC for the entire cycle was 25% higher with
raloxifene (100 mg; P = 0.12) and 43% higher with
raloxifene (200 mg; P < 0.02) compared with the mean
for the control group (Table 2). The
E2 AUC for the first half of the cycle was 75%
higher with raloxifene (100 mg) and 84% higher for raloxifene (200 mg)
compared with the control value (P < 0.01). The
E2 AUC for the second half of the cycle was not
significantly different from the control value for either dose. No
significant differences in maximum P were observed among 100 and 200 mg
raloxifene and controls.
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E1 levels were higher on day 10 of the treatment cycle compared with those during each woman’s pretreatment cycle (P < 0.05). Comparing treatment to pretreatment values, the mean E1 levels were 74 vs. 58 pg/mL (100 mg group) and 103 vs. 62 pg/mL (200 mg group). Mean E1 levels at the time of the LH peak (216 vs. 141 pg/mL) and mean E1 levels for the cycle (124 vs. 96 pg/mL) were significantly higher with 200 mg compared with 100 mg raloxifene (P < 0.04).
Serum levels of androgens during the cycle were similar to those described previously (16). Androgen levels at the time of the LH peak and mean androgen levels for the cycle did not differ statistically between the 100- and 200-mg doses. There was a slight increase in the random cortisol levels with raloxifene treatment (P = 0.03). Comparing treatment to pretreatment cycles, mean random cortisol levels were 13.7 vs. 11.8 (100 mg group) and 14.3 vs. 9.6 (200 mg group). PRL concentrations remained within the normal range for our laboratory.
Sonographic appearance of the endometrium. There was a nonsignificant decrease in the mean maximum endometrial thickness with raloxifene treatment. Mean ± SD values for part I controls, 100 mg, and 200 mg groups were 13.2 ± 2.0, 11.1 ± 2.9, and 11.3 ± 2.6 mm, respectively. Whereas a triple line pattern was noted in all 12 control cycles, 5 patients who received raloxifene in part II never developed a triple line pattern.
Endometrial biopsy. Complete data were available for nine women who received 100 mg raloxifene and for seven women who received 200 mg raloxifene. Comparing pretreatment vs. treatment proliferative biopsies, the number of gland mitoses was lower in the cycle in which raloxifene was received (P = 0.05). There was no significant difference between the pretreatment and the treatment proliferative phase biopsies with respect to gland number or stromal mitoses. The number of cells demonstrating isolated gland cell death was higher with raloxifene treatment (P = 0.05). There was no difference in any of the parameters between the two doses of raloxifene for follicular or secretory phase biopsies.
In five secretory phase biopsies obtained during raloxifene administration, the glandular development lagged behind the stromal development by more than 2 days (gland-stromal dysynchrony). In four cases (all with gland-stromal dysynchrony), the endometrial dating of the glands was more than 2 days out of phase with the date of ovulation. In addition to these five cases, one biopsy demonstrated evidence of menstrual breakdown on postovulatory day 12, suggesting a short luteal phase.
Vaginal cytology. The Meisel’s maturation value was significantly lower during the follicular phase with raloxifene treatment compared to the value in the pretreatment cycle (median, 44.0 vs. 51.0; P = 0.006), with no difference between doses of raloxifene. In the luteal phase, the median maturation value was 54.5 for both 100- and 200-mg doses of raloxifene, a value that remained within the normal range.
Cervical mucus scoring. There was a trend toward lower day 10 cervical mucus scores with raloxifene treatment. The mean ± SD day 10 cervical mucus scores in pretreatment vs. treatment cycles were 3.3 ± 1.4 vs. 2.3 ± 0.95 for the 100 mg group (P = 0.05) and 4.4 ± 1.7 vs. 3.7 ± 2.1 for the 200 mg group (P = NS). The expected increase in cervical mucus during the periovulatory period did not occur with raloxifene treatment. The mean cervical mucus scores ± SD in the periovulatory and luteal phase of the treatment cycles were 3.5 ± 1.5 and 2.2 ± 1.1 for the 100 mg group and 4.1 ± 1.9 and 2.4 ± 0.88 for the 200 mg group.
SHBG levels. SHBG was significantly higher with raloxifene treatment compared with values in the pretreatment cycle (P < 0.01). Mean SHBG ± SD levels in pretreatment vs. treatment cycles were 1.49 ± 0.60 vs. 1.84 ± 0.88 for the 100 mg group and 1.16 ± 0.43 vs. 1.57 ± 0.94 for the 200 mg group. All SHBG levels remained within the normal range.
Safety of raloxifene in reproductive-age women: parts I and II. Raloxifene was well tolerated at all doses. In the cycle following raloxifene administration, all volunteers had ovulatory P values. One volunteer reported possible hot flashes. No volunteers reported symptoms of genito-urinary atrophy.
One pregnancy occurred during periovulatory treatment with raloxifene (part I). Data from this cycle were not included in the analysis. This pregnancy ended in a spontaneous abortion with menses delayed by 3–4 days and no tissue passed for analysis. It is unclear whether this event was related to raloxifene, as this pregnancy occurred in a 44-yr-old woman who would be expected to have a high spontaneous abortion rate.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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E2 levels were elevated in women who received raloxifene for 5 days beginning in the follicular phase and in women who received raloxifene for 4 weeks continuously beginning in the follicular phase. These findings are similar to those seen with a 5-day course of clomiphene (17) and with a short course of tamoxifen or continuous tamoxifen in premenopausal women (18). Raloxifene was noted to either elevate FSH levels or to leave FSH levels unchanged. Both of these findings are suggestive of antiestrogenic activity at the level of the hypothalamus and/or pituitary, because the elevation of E2 noted with raloxifene would be expected to suppress gonadotropin levels, rather than resulting in an elevation or no change. It is possible that raloxifene has a different effect on gonadotropins when E2 levels are low, similar to the effect of tamoxifen, which partially decreases gonadotropins in postmenopausal women (20), but not in premenopausal women. Another finding suggestive of estrogen antagonism at the level of the hypothalamus and/or pituitary was that PRL levels were decreased during the 5-day period of raloxifene administration in part 1 despite elevation of E2 levels, which would be expected to increase PRL.
Elevation of gonadotropin levels is the mechanism most commonly invoked to explain the elevation of E2 seen with clomiphene and in some, but not all, studies of tamoxifen in women of reproductive age (see Ref. 17 for review). Because raloxifene elevated FSH levels in some women, it is tempting to attribute the increase in E2 with raloxifene administration to elevated FSH production. However, significant elevations in the FSH AUC were not uniformly seen in all treatment groups with elevated E2 in this study. Thus, the mechanism by which raloxifene elevates E2 levels may not simply be via elevation of gonadotropins, but may involve other mechanisms, e.g. a direct effect on the ovary. Adashi (21) previously proposed that clomiphene may act directly on the ovary as well as on the pituitary or hypothalamus. A follow-up study with a larger sample size may clarify the mechanism by which raloxifene elevates E2 levels.
No clear effect of a 5-day course of raloxifene on the sonographic appearance of endometrial development was noted. With continuous raloxifene administration for 28 days, there was a nonsignificant trend toward thinner endometrium and impairment of normal triple line development. Clomiphene also has been noted to decrease endometrial thickness in some (22, 23), but not all (24), studies.
Previous studies in rats have demonstrated that raloxifene antagonizes the action of estrogen and produces a minimal stimulatory effect on the endometrium (25). In postmenopausal women, raloxifene does not stimulate endometrial development and, in fact, may inhibit endometrial proliferation noted in the presence of low levels of endogenous estrogen (5). In the endocrine milieu of normal to high circulating E2 levels present in the current study, subtle morphological changes that could be due to an antiestrogenic action of raloxifene were noted in follicular and luteal phase endometrial biopsies. However, this study did not definitively demonstrate estrogen antagonistic activity on the endometrium, possibly due to small sample size, the absence of luteal phase endometrial biopsies in the pretreatment cycle, and/or the techniques of biopsy analysis that were employed. It is possible that the estrogen antagonistic effect of raloxifene noted in menopausal women is blunted by high circulating E2 concentrations in women of reproductive age.
The follicular phase Meisel’s maturation value decreased with raloxifene administration, suggesting a blocking of the estrogen effect on vaginal epithelial maturation. Cervical mucus production appears to decrease with raloxifene treatment, an antiestrogenic activity also noted in some women who received clomiphene (17, 26).
Raloxifene elevated SHBG levels, an hepatic estrogen-like action also seen with clomiphene (27) and tamoxifen (20, 28). In postmenopausal women, raloxifene elevates SHBG, coricosteroid-binding globulin (CBG), and thyroid-binding globulin (data on file, Eli Lilly Co.), lending support to the idea that a direct hepatic effect, rather than a secondary effect due to elevation of E2 levels, was responsible for the elevation of SHBG noted in the current study. Although random cortisol levels were elevated slightly in this study, CBG was not measured, and it is likely that this elevation of cortisol is due to stimulation of hepatic CBG production, with no increase in bioavailable cortisol.
This study has demonstrated that in reproductive-aged women, ovarian estrogen production will continue and in some cases increase in response to raloxifene. Any anti-estrogenic effect that raloxifene may have on the endometrium is probably blunted in the face of normal to high circulating E2 concentrations in vivo. Under the conditions and in the doses examined in this study, raloxifene did not demonstrate the characteristics needed for treating estrogen-responsive disorders such as endometriosis in reproductive-aged women.
In summary, in reproductive-aged women, raloxifene appears to have estrogen agonistic activity on hepatic SHBG synthesis, estrogen antagonistic activity on the hypothalamic-pituitary axis that does not prevent ovulation, and possibly estrogen antagonistic activity on the endometrium that is subtle in the endocrine milieu of normal to high circulating E2 concentrations.
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Acknowledgments |
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Footnotes |
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Received May 23, 1997.
Revised August 29, 1997.
Accepted September 5, 1997.
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References |
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R. T. Chlebowski, D. E. Collyar, M. R. Somerfield, and D. G. Pfister American Society of Clinical Oncology Technology Assessment on Breast Cancer Risk Reduction Strategies: Tamoxifen and Raloxifene J. Clin. Oncol., June 1, 1999; 17(6): 1939 - 1939. [Abstract] [Full Text] [PDF]
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Y. Sadovsky and S. Adler Editorial: Selective Modulation of Estrogen Receptor Action J. Clin. Endocrinol. Metab., January 1, 1998; 83(1): 3 - 5. [Full Text]
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