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1.
B L Cohen  M Katz 《Contraception》1979,20(5):475-487
A study was performed to further evaluate pituitary-ovarian function in women receiving an oral contraceptive preparation. Basal hormone levels (follicle stimulating hormone, luteinizing hormone, estradiol and prolactin) and gonadotropic response to gonadotropic releasing hormone were studied in 12 healthy, regularly ovulating women in the early follicular and mid-luteal phases of their menstrual cycle (non-treatment control period). These same women were then given NORDETTE (ethinyl estradiol 30 microgram +d-Norgestrel 150 microgram) cyclically for 3 months. In the third month of treatment, the tests were repeated on day 21, i.e. after 21 active pills, and on day 28, i.e. after 21 active and 7 inactive tablets. On active preparation, basal luteinizing hormone, follicle stimulating hormone and estradiol and gonadotropin response to gonadotropin releasing hormone were significantly suppressed. However, by day 28 (after completion of the inactive tablets), basal gonadotropin and estradiol concentrations and the gonadotropic response to gonadotropic releasing hormone were not significantly different to their pretreatment levels. No consistent change in prolactin concentration occurred as a result of oral contraceptive therapy. These results indicate that the 'active' component of even a relatively low-dose pill causes considerable suppression of pituitary-ovarian function but that after 7 days of placebo, pituitary function and basal estradiol secretion have virtually returned to normal.  相似文献   

2.
Serum gonadotropin and progesterone levels were studied in longterm (>18 months) patients receiving oral contraceptives containing either 1.0 mg or 0.5 mg norethindrone in combination with 35 μg of ethinyl estradiol. In ten patients treated with 1.0 mg norethindrone and 35 μg ethinyl estradiol, no mid-cycle surges of LH were noted and LH levels never exceeded 225 ng/ml. FSH levels were generally elevated during the first half of the cycle. Serum progesterone concentrations in these patients and in fourteen additional women whose blood was sampled intermittently were generally less than 1 ng/ml, and no characteristic luteal phase elevation of this hormone was detected. Of six patients treated with 0.5 mg norethindrone and 35 μg ethinyl estradiol, five clearly had no mid-cycle surge of LH, and levels of this hormone never exceeded 250 ng/ml. The concentrations of FSH and progesterone in these patients and serum progesterone levels in two additional women whose blood was sampled intermittently were similar to those found in patients treated with 1 mg norethindrone and 35 μ ethinyl estradiol. In the sixth patient, hormonal levels did not follow the same pattern, but they were not characteristic of ovulation. It is concluded that there is no evidence of cyclic fluctuations in FSH, LH and progesterone characteristic of ovulation in patients treated longer than eighteen months with either 1.0 mg or 0.5 mg norethindrone in combination with 35 μg ethinyl estradiol.  相似文献   

3.
The effects of d-norgestrel (40 mg), contained in a single dimethylp olysiloxane rod implanted subcutaneously in the gluteal region, were studied in 4 women. The rods were left in place for 93-128 days. Based on the pattern of plasma progesterone levels; all of the subjects appeared to ovulate. However, the inhibition of the positive feedback effects of natural estrogens indicated that ovulation was suppressed. There was no increase in plasma progesterone concentrations over the 3-4 month treatment period. Plasma estradiol concentrations fluctuated irregularly and showed surges characteristic of the midcycle peak. Plasma gonadotropin levels fluctuated periodically, though midcycle peaks of luteinizing hormone (LH) and follicle stimulating hormone (FSH) did not occur. FSH and LH concentrations were low when estradiol concentrations were high, and vice versa. Plasma concentrations of the hormone were similar to those found during the 1st 6-8 hours after ingestion of low-dose d-norgestrel. All the subjects had unpredictable bleeding patterns during treatment.  相似文献   

4.
Peripheral plasma levels of d-norgestrel were determined by radioimmunoassay in five women after oral administration of 30, 250 and 1000 μg d-norgestrel. Peak levels of d-norgestrel in plasma were mostly seen within 2 hours after intake of the pills. The peak concentrations found were 0.9–2.0 ng/ml, 3.3–5.1 ng/ml and 14.0–23 ng/ml, respectively, for the three doses administered. The plasma concentrations of d-norgestrel 24 hours after ingestion of the pills were 0.05–0.14 ng/ml, 0.3–0.7 ng/ml and 1.8–5.2 ng/ml, respectively.The plasma half-life of d-norgestrel for the period 8–24 hours following the tablet intake was around 13 hours but varied considerably among the participants. For the period 24–72 hours the corresponding half-life was around 21 hours.During 3 weeks treatment with combined oral contraceptives containing d-norgestrel and ethinyl estradiol, increasing d-norgestrel levels in plasma were found in most of the subjects. Patients on low dose gestagen pills (30 μg d-norgestrel) showed constant plasma levels of d-norgestrel throughout a treatment period of 3 weeks.The results obtained in this study suggest that the gradual increase of the d-norgestrel levels found in plasma when d-norgestrel is given in combination with ethinyl estradiol might be due to increased levels of sex hormone binding globulin, the carrier protein for d-norgestrel, rather than to accumulation caused by a long biological half-life.  相似文献   

5.
The effects of two different doses of a contraceptive ethinyl estradiol/ D-norgestrel combination (30 μg ethinyl estradiol + 150 μg D-norgestrel, SH 7.1155, Microgynon vs. 50 μg ethinyl estradiol + 250 μg D-norgestrel, Neogynon) upon parameters of reproductive function (karyopyknotic index, cervical function, Spinnbarkeit, crystallization of cervical mucus, serum levels of 17β-estradiol, progesterone and LH, respectively) were investigated in each of three women, who exhibited regular biphasic cycles prior to the study. The series of tests covered one control cycle before treatment, one treatment cycle and one control cycle after therapy, respectively. Parameters were checked daily from the eighth day of the cycle. The results suggest that the combined preparation containing the lower doses of active ingredients inhibits ovulation in the same way as the higher-dosed preparation already in the first cycle of administration. This data is consistent with clinical trials, which indicate a Pearl Index range for Microgynon of 0.12 –0.2.  相似文献   

6.
The effect of deliberate omission of a phased formulation pill, Trinordiol (ethinyl estradiol 30 micrograms + levonorgestrel 50 micrograms: 6 tablets; ethinyl estradiol 40 micrograms + levonorgestrel 75 micrograms: 5 tablets; ethinyl estradiol 30 micrograms + levonorgestrel 125 micrograms: 10 tablets) or a low-dose, combined, oral contraceptive pill, Microgynon (ethinyl estradiol 30 micrograms + levonorgestrel 150 micrograms: 21 tablets) on the hypothalamo-pituitary-ovarian axis were studied. Thirty-six women were recruited to the study and divided equally between the two types of pill. Medication was begun on the 8th pill-free day of the cycle and continued for 7 days (Group 1), 14 days (Group 2) or 21 days (Group 3). Levels of FSH, LH, estradiol (E2) and progesterone (P) were measured in plasma on alternate days during the final week of pill therapy, and daily for the 7 days after stopping the pill. For the first 2 weeks of pill therapy, follicular activity, as judged by plasma levels of E2, was greater in women taking Trinordiol than in those taking Microgynon, but was similar in both groups by the third week of pill treatment. Five women taking Trinordiol (2 in Group 1 and 3 in Group 2) had plasma levels of E2 in excess of 500 pmol/l whilst taking the pills, and only 1 patient achieved this degree of follicular activity after stopping the tablets. One woman who had taken 7 days of Trinordiol (Group 1) showed a rise of plasma levels of P to 6.8 nmol/l, but luteinization did not occur in any of the remaining 35 women who took Trinordiol or Microgynon. These findings suggest that follicular activity is less completely suppressed by Trinordiol than Microgynon, at least in the first 2 weeks of pill therapy, but that normal ovulation is still a rare event in the week after cessation of either of these pills, even if only 7 days of medication have been taken.  相似文献   

7.
The concentrations of plasma LH, FSH, estradiol, and progesterone, as well as urinary LH, were measured during the last treatment cycle and during the recovery cycle in women who, immediately after abortion, had started microdose combined oral contraceptives containing 30 μg of ethinylestradiol and 150 μg of d-norgestrel.During the treatment, cyclic variations were found in LH, FSH, and estradiol concentrations. FSH levels were highest during the first treatment week as well as the treatment-free week. LH concentrations were highest during the first treatment week. Estradiol concentrations showed a significant increase during the treatment-free week and during the first treatment week suggesting a follicle stimulation.The recovery of ovulation occurred rapidly, in a great majority of the subjects, after discontinuation of the treatment. The first midcycle LH peak was observed thirteen days after the intake of the last pill, and 50% of the subjects had ovulated within 22 days. In 91% of the subjects, plasma progesterone concentration during the luteal phase was higher than 5 ng/ml.  相似文献   

8.
Plasma levels of ethinyl estradiol were measured by radioimmunoassay in five women after oral administration of 30μg and of 50μg of ethinyl estradiol. Peak levels of ethinyl estradiol were mostly observed within two hours after the tablet intake. The peak concentrations found were 50–90 pg and 95–135 pg for the two doses administered. Twenty-four hours after the administration of the tablets, the plasma concentration of ethinyl estradiol did not exceed the plasma blank values (25 pg/ml) in most women.  相似文献   

9.
目的研究慢性砷暴露对雌性大鼠的内分泌干扰作用。方法 50只4周龄雌性Wistar大鼠随机分成对照组(饮用去离子水)及砷暴露组(饮用砷含量分别为0.05、0.1、0.2和0.4μg/ml水),32周后采用放射免疫法测定血清雌二醇(E2)、孕酮(P)、黄体生成素(LH)、卵泡刺激素(FSH)、促性腺激素释放激素(GnRH)、垂体泌乳素(PRL)和皮质醇(Cort)含量。结果与对照组相比,各浓度砷暴露组E2和P含量均有升高趋势,LH水平有降低趋势,但差异均无显著性(P>0.05);FSH和PRL水平在低砷暴露组有升高趋势,而高砷暴露则有降低趋势(P>0.05);GnRH和Cort含量升高,且0.4μg/ml暴露组大鼠GnRH明显升高(P<0.05),0.1、0.4μg/ml组大鼠Cort升高明显(P<0.05)。结论慢性砷暴露可干扰雌性大鼠体内上述激素的水平。  相似文献   

10.

Objective

The objective was to investigate changes in luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2) and progesterone (P) during the hormone-free interval (HFI) of 6 combined oral contraceptives (COCs).

Design

Blood samples were obtained from 62 women.

Results

When COCs were grouped by ethinyl estradiol (EE) dose, there was a significant positive mean slope for LH and FSH during the HFI for the 30- and 35 mcg-EE doses, whereas 20 showed a gradual nonsignificant slope. All E2 slopes were significant. P remained suppressed with all doses.

Conclusion

A more rapid rebound of gonadotropin levels is found with higher doses of EE during the HFI.

Implications

This study showed a more rapid rebound of pituitary hormone levels among women using higher-EE-dosage formulations, which was demonstrated by the statistically significant slope for mean LH and FSH from day 1 to day 7 of the HFI. The degree of suppression did not vary across progestin generations. It remains to be established whether women who experience side effects during their HFI may benefit from using a COC with a lower EE dose to minimize changes in endogenous pituitary hormone levels.  相似文献   

11.
OBJECTIVE: Our objective was to test the hypothesis that shortening the hormone-free interval (HFI) between cycles of 21 days of oral contraceptives (OCs) reduces pituitary secretion of gonadotropins and ovarian production of estradiol and inhibin-B. DESIGN: We used a prospective trial design comparing the standard 7-day HFI and shortened HFI during cycles, with an OC containing 0.03 mg of ethinyl estradiol and 3 mg of drospirenone. METHODS: Twelve current OC users initially utilized an OC in the standard fashion, with 21 days of active pills and a 7-day HFI, followed by 21 days of active pills with randomization to either a 3-day or a 4-day HFI. Nine daily blood samples were obtained for the measurement of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol and inhibin-B, beginning with active pill 21 days before each HFI of the two cycles. Analysis of variance was used to compare hormones for 9 days bracketing the standard 7-day HFI and to compare, within individuals, the 7-day HFI and the subsequent shortened HFI. RESULTS: During the 7-day HFI, all four hormones significantly (p>.001) increased from baseline. FSH increased beginning on HFI Day 4, inhibin-B increased beginning on HFI Day 5, and LH and estradiol increased beginning on HFI Day 6. Subjects randomized to the 3-day or the 4-day HFI did not differ with regard to age and body size (p=.88) or initial hormone level (p=.67). Greater pituitary and ovarian suppression was seen with the shortened HFI for all four hormones (p<.001). Hormone levels in the 7 days after the last active pill of the second cycle did not differ (p>.4) between the 3-day and the 4-day HFI groups. CONCLUSIONS: Shortening the HFI from 7 days to 3 or 4 days blunts increases in the pituitary-ovarian axis during cycles of OC use.  相似文献   

12.

Background

The study was conducted to examine the impact of oral contraceptives (OCs) on serum antimullerian hormone (AMH) levels by obesity status in reproductive-age women.

Study Design

Ovulatory women, ages 18-35 years, of normal (<25 kg/m2; n=10) and obese (>30 kg/m2; n=10) body mass index (BMI) received a low-dose OC (20 mcg ethinyl estradiol/100 mcg levonorgestrel) for two cycles. Serum samples obtained at several time points during active pill use and hormone-free intervals were analyzed for AMH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol and inhibin B.

Results

AMH levels did not differ by OC cycle day in either BMI group. On average, AMH levels were 34% lower in the obese group (2.9±2.1 vs. 4.4±1.8 ng/mL, p<.05). Modeling to determine differences in AMH throughout the cycle based on obesity status demonstrated significantly lower levels (p<.05), whereas serum AMH, FSH, LH, estradiol and inhibin B levels revealed no correlations when all time points were included.

Conclusions

In reproductive-age women, serum AMH levels do not appear to fluctuate during OC use, but AMH levels are significantly lower in obese women. Lower levels do not appear to be due to differences in gonadotropin levels or ovarian activity.  相似文献   

13.
The mechanism of action of various oral contraceptives has not yet been satisfactorily resolved, as to how gonadotropins affect ovarian function. Alterations of the pulsatile release of LH might be a common denominator. As methodological difficulties for the evaluation of LH pulse pattern with low basal levels exist, we elected to determine the area under the curve (AUC) for LH and FSH for 6 hours before and during treatment with oral contraceptives. LH and FSH were determined every 15 min for 6 hours on day 4 and day 20 of a control cycle and a treatment cycle in 22 women with ovulatory cycles. They received either a combined preparation containing 150 micrograms desogestrel and 30 micrograms ethinyl estradiol, a sequential preparation containing 50 micrograms of ethinyl estradiol and 125 g of desogestrel or only 125 micrograms desogestrel. There was no difference between the sum of LH pulses on day 4 and day 20 of the control cycle. The AUC for FSH was lower on day 20. When the combined preparation was taken, FSH was suppressed on day 4, and FSH and LH on day 20 of treatment. The degree of suppression was even more pronounced when the sequential OC was taken. Ethinyl estradiol alone was as effective as the combination with desogestrel. Desogestrel alone inhibited ovulation without affecting serum LH and FSH in a comparable manner, suggesting a direct effect on the ovary. The determination of the AUC seems to be a sensitive tool for the evaluation of OC-induced changes in gonadotropin output.  相似文献   

14.
Menstrual events among users of contraceptive vaginal rings (CVRs), releasing levonorgestrel and estradiol, were studied in comparison with a combined oral contraceptive, Nordette,1 in multicentered trials. CVRs were made with outside diameters of 50 and 58 mm and released about 250 μg and 290 μg of levonorgestrel and 150 μg and 180 μg of estradiol per day, respectively. The CVRs were used continuously for 3 weeks and then removed for 1 week. Both the CVRs and Nordette were perceived to reduce menstrual flow and days of menstrual bleeding. Twenty to 25% of CVR users perceived increased inter menstrual bleeding or spotting. Diaries indicate, however, that on average, CVR users experienced about 1 day per month of bleeding or spotting with the ring in place. CVRs and Nordette produced approximately the same total number of bleeding and spotting days during 6 cycles of use, 27–29, but the small (50-mm OD) ring was associated with somewhat more spotting. This ring was also associated with somewhat more prolonged bleeding and spotting runs and with more prolonged nonbleeding intervals than reported by users of the larger (58-mm OD) ring or of Nordette. Differences among regimens, however, tended to be small even when statistically significant. Evidence from menstrual diaries indicates that these CVRs, and in particular the 58-mm ring, provide control over the menstrual cycle comparable to that of Nordette.  相似文献   

15.
BackgroundMifepristone alone or in combination with ethinyl estradiol (EE) can effectively stop an episode of uterine bleeding in women using the etonogestrel-releasing contraceptive implant, Implanon® but could impair contraceptive efficacy.AimTo examine the effects of administration of mifepristone alone or with EE on ovarian function and cervical mucus consistency in women using Implanon.Study DesignWomen using Implanon were randomized to mifepristone 25 mg twice daily on day 1 plus placebo 1 daily for 4 days or plus EE 20 mcg daily for days 2–5. Measurements of serum estradiol (E2), progesterone (P4), luteinizing hormone (LH), follicle-stimulating hormone (FSH), cervical mucus examination and maximal follicle size (by vaginal ultrasound) were carried out at various times.ResultsFollowing mifepristone intake, there was a dramatic increase in E2 levels ranging from 543 to 1183 pmol/L (p=.000), which was not correlated with maximal follicle size or preceded by LH or FSH increase. The increase in E2 triggered an LH increase resulting in development of a luteinized follicle in four women with no evidence of ovulation. One of these women had estradiol and progesterone levels suggestive of ovulation, but no corpus luteum was seen. Almost all women had very low mucus scores, which did not correlate with E2 levels.DiscussionDespite a transient increase in E2 levels after mifepristone, there was no evidence of subsequent ovulation irrespective of whether they also received EE. The mechanism by which mifepristone in the presence of etonogestrel results in a rapid increase in E2 levels remains unclear and could not be related to any significant changes in FSH, LH, ovarian follicle dynamics or subsequent possible ovulation.ConclusionPregnancy is very unlikely to occur if mifepristone and EE are given during use of Implanon to stop an episode of bleeding.  相似文献   

16.
《Contraception》2012,85(6):600-608
BackgroundMifepristone alone or in combination with ethinyl estradiol (EE) can effectively stop an episode of uterine bleeding in women using the etonogestrel-releasing contraceptive implant, Implanon® but could impair contraceptive efficacy.AimTo examine the effects of administration of mifepristone alone or with EE on ovarian function and cervical mucus consistency in women using Implanon.Study DesignWomen using Implanon were randomized to mifepristone 25 mg twice daily on day 1 plus placebo 1 daily for 4 days or plus EE 20 mcg daily for days 2–5. Measurements of serum estradiol (E2), progesterone (P4), luteinizing hormone (LH), follicle-stimulating hormone (FSH), cervical mucus examination and maximal follicle size (by vaginal ultrasound) were carried out at various times.ResultsFollowing mifepristone intake, there was a dramatic increase in E2 levels ranging from 543 to 1183 pmol/L (p=.000), which was not correlated with maximal follicle size or preceded by LH or FSH increase. The increase in E2 triggered an LH increase resulting in development of a luteinized follicle in four women with no evidence of ovulation. One of these women had estradiol and progesterone levels suggestive of ovulation, but no corpus luteum was seen. Almost all women had very low mucus scores, which did not correlate with E2 levels.DiscussionDespite a transient increase in E2 levels after mifepristone, there was no evidence of subsequent ovulation irrespective of whether they also received EE. The mechanism by which mifepristone in the presence of etonogestrel results in a rapid increase in E2 levels remains unclear and could not be related to any significant changes in FSH, LH, ovarian follicle dynamics or subsequent possible ovulation.ConclusionPregnancy is very unlikely to occur if mifepristone and EE are given during use of Implanon to stop an episode of bleeding.  相似文献   

17.
The peripheral plasma levels of immunoreactive follicle-stimulating hormone (hFSH) and luteinizing hormone (hLH) were measured daily in 43 normally menstruating women during a pretreatment (control) cycle and during the second month of daily administration of the 300 μg norethisterone (NET) minipill. In addition, the levels of biologically active LH were also determined in 29 of the 43 subjects.

As described in detail in the first paper of these series (1), the 43 women studied exhibited four distinctly different types of ovarian reaction to NET, as indicated by the daily estradiol and progesterone levels. Seven women (16 %) showed neither follicular, nor luteal activity (group A), 10 women (23 %) exhibited a cyclic follicular activity, but no luteal function (group B), 9 women (21 %) had normal follicular function, but insufficient luteal activity (group C), and 17 women (40 %) had estradiol and progesterone levels undistinguishable from those seen in a normal ovulatory cycle (group D).

Administration of the NET minipill did not influence the mean FSH lvel of cycle days 1–6, or those of 3 to 7 days before the LH peak; it slightly decreased the mean luteal phase FSH level in group C, but no in group D, and markedly suppressed the FSH peak value in all groups. There was no difference in this respect between women exhibiting different types of ovarian reaction. Similar to its effect on FSH, the administration of NET did not diminish the mean LH levels of days 1–6, those of 3 to 7 days before the LH peak, or of the luteal phase, but greatly suppressed the LH peak. Again, there was no difference in LH levels during NET administration among women showing different types of ovarian response to the drug. On the other hand, significant differences were found in the LH levels of the pretreatment (control) cycles of the various groups. The mean levels of LH both during days 1–6 and during the luteal phase of the pretreatment cycles were significantly lower in women in whom the minipill subsequently abolished all lutaeal activity (groups A+B) than in women exhibiting different degrees of luteal function (groups C+D). Hence the NET minipill will preferentially inhibit ovulation in women exhibiting relatively low tonic LH-levels in untreated cycles.

The results of the daily LH bioassays were in good agreement with those of the radioimmunoassays.

In the majority of women who exhibited normal (“ovulatory”) estradiol and progesterone profiles during NET administration, the preovulatory FSH, and especially LH peaks were below the lower limit of normal values, and in several instances, normal estradiol and progesterone profiles were found in the virtual absence of any FSH and LH surge.

It is concluded that ovarian suppression by the NET minipill is unrelated to the degree of inhibition of FSH and LH secretion as far as this is reflected by their peripheral levels measured daily.  相似文献   


18.
19.
Endocrine-disrupting chemicals can influence the hypothalamus-pituitary-gonad axis and possibly affect reproduction in vertebrates. We analyzed the effect of 30-day endosulfan (ES) exposure in sexually undifferentiated larvae of the cichlid fish Cichlasoma dimerus. The number, area, mean cytoplasmic and nuclear diameter, and mean cytoplasmic optical density of gonadotropin-releasing hormone (GnRH) I, II, and III immunoreactive (ir-) neurons and β follicle-stimulating hormone (βFSH) ir-cells were measured. Animals exposed to the highest ES concentration (0.1?μg/l) showed a decrease in GnRH I nucleus/cytoplasm area ratio upon exposure. Nuclear area and mean nuclear diameter of βFSH ir-cells was higher in ES treated fish. βFSH nucleus/cytoplasm area ratio was high in exposed animals, and animals exposed to 0.1?μg/l ES showed smaller mean cytoplasmic optical density. These findings suggest that ES affects GnRH I and βFSH protein synthesis/release. However, these responses seem to be insufficient to affect gonadal differentiation at this stage of development.  相似文献   

20.
目的观察去氧孕烯炔雌醇与地屈孕酮对青春期排卵障碍性异常子宫出血(AUB-O)的疗效。方法回顾性分析丽水市人民医院妇产科2017年1月至2019年9月治疗的青春期AUB-O患者113例临床资料,患者根据治疗方案不同分为去氧孕烯炔雌醇组(58例)和地屈孕酮组(55例),观察两组患者治疗效果。结果去氧孕烯炔雌醇组患者血量减少1/2时间、完全血止时间均显著短于地屈孕酮组(t值分别为3.568、3.125,均P<0.05)。两组患者调整月经周期第一疗程月经正常率比较差异均无统计学意义(χ^2=2.562,P>0.05),去氧孕烯炔雌醇组调整月经周期第二疗程和第三疗程月经正常率均显著低于地屈孕酮组(χ^2值分别为6.444、6.482,均P<0.05)。两组患者人工周期治疗后血清FSH、LH水平与治疗前比较均有所下降,但治疗前后血清FSH、LH、E2水平比较差异均无统计学意义(t值0.132~1.135,均P>0.05)。结论去氧孕烯炔雌醇治疗青春期AUB-O止血时间短,但地屈孕酮不影响青春期生殖轴调控,月经规律和排卵恢复优于去氧孕烯炔雌醇,临床应用时应根据患者具体情况而定。  相似文献   

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