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Sequential clomiphene citrate and human menopausal gonadotrophin for ovulation induction: comparison to clomiphene citrate alone and human menopausal gonadotrophin alone.

The need for frequent injections and monitoring, the possibility of multiple gestations, and the higher cost compared to clomiphene citrate, prevents many clinicians from using human menopausal gonadotrophin (HMG) for ovulation induction. A sequential medication regimen, in which HMG is taken after clomiphene, overcomes these problems. We retrospectively compared per cycle fecundity and birth rates in 119 cycles of clomiphene-HMG, 524 cycles of clomiphene alone, 57 cycles of HMG alone, and 79 cycles of concurrent HMG and clomiphene in patients receiving intra-uterine insemination (IUI), who were free of endometriosis or tubal disease. Per cycle fecundity for clomiphene-HMG was 22% [95% confidence interval (CI) 12-34%], double that of clomiphene alone (11%) (95% CI 8-14%) (P < 0.01), and equal to HMG alone (18%) (95% CI 7-29%) or HMG and clomiphene together (19%) (95% CI 10-28%). The multiple birth rate for clomiphene-HMG (7/21) equalled that for HMG alone (3/12) and HMG and clomiphene together (3/8). The average number of ampoules of HMG required [follicle stimulating hormone (FSH) 75 mIU, luteinizing hormone (LH) 75 mIU] was decreased by 65% from 24.5 +/- 1.0 for HMG or HMG and clomiphene together to 8.6 +/- 0.3 for clomiphene-HMG (P < 0.001). Per cycle fecundity was identical when one, two or three ampoules of HMG per day were administered after clomiphene. We conclude that ovulation induction with sequential clomiphene-HMG results in fecundity double that of clomiphene alone and equal to HMG alone or concurrent with clomiphene, thereby reducing the requirement for HMG.

Clomiphene

Clomiphene and dexamethasone in women unresponsive to clomiphene alone.

Twelve oligomenorrhic women with polycystic ovary syndrome (PCO) in whom clomiphene (250 mg daily for 5 days) and 10,000 IU human chorionic gonadotropin had failed to induce ovulation were treated with clomiphene and dexamethasone. Eight of the 12 women underwent complete hormonal assessment during treatment. Six of the 12 ovulated and 1 conceived. Serum total and unbound estradiol and testosterone (T), serum dehydroepiandrosterone sulfate (DHEA-S), sex hormone binding-globulin binding capacity (SHBG-BC), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin (PRL) were measured during clomiphene and dexamethasone therapy. SHBG-BC increased in response to clomiphene whether or not ovulation occurred. After treatment with clomiphene and dexamethasone there was a significant decrease in serum T, unbound T, and DHEA-S 2 weeks after dexamethasone administration, but there were no change in LH, FSH, or PRL. In patients who ovulated after clomiphene and dexamethasone, T and unbound T increased again after clomiphene was begun despite the continuation of dexamethasone. The women who ovulated after clomiphene and dexamethasone treatment had significantly higher pretreatment levels of DHEA-S than those who did not ovulate. Clomiphene and dexamethasone treatment may be beneficial to women who have elevated levels of DHEAS and who fail to ovulate with maximum doses of clomiphene.

Anovulation

Comparison between clomiphene plus pulsatile human menopausal gonadotrophin and clomiphene plus pulsatile follicle stimulating hormone in induction of multiple follicular development in women.

Eighteen normally cycling women with tubal infertility undergoing in-vitro fertilization and embryo transfer were treated with clomiphene only (nine cycles), clomiphene plus human menopausal gonadotrophin (HMG) (18 cycles) and clomiphene plus follicle-stimulating hormone (FSH) (12 cycles). Clomiphene was given from day 2 to 6 (150 mg daily). HMG and FSH were injected s.c. in a pulsatile manner via a pump (28 IU every 3 h). Plasma FSH and oestradiol levels and the number of follicles greater than or equal to 16 mm in diameter were similar in the clomiphene/HMG and the clomiphene/FSH cycles, but significantly higher than in the clomiphene-only cycles. In contrast, luteinizing hormone and progesterone levels during the treatment did not differ significantly among the three regimens. Twelve of the 18 women were treated with clomiphene/HMG in one cycle and clomiphene/FSH in another and eight of them with clomiphene only in a third cycle (a total of 32 cycles). In the clomiphene/HMG cycle seven of these 12 women (58%) had plasma FSH levels during treatment similar to those in the clomiphene/FSH cycle and six of them (86%) had the same number of follicles in both cycles. A significant, but not very strong correlation was found between FSH treatment levels and the number of follicles greater than or equal to 16 mm when all 32 cycles were combined (r = 0.40). It is suggested that pulsatile HMG and FSH in combination with clomiphene are in general equally effective in inducing multiple follicular development in normal women. However, individual responses show great variability.

Clomiphene

[Combined clomiphene-dexamethasone therapy in cases with resistance to clomiphene (author's transl)].

Combined clomiphene-dexamethasone treatment was applied to 13 patients with clomiphene-resistant anovulation which had been caused by androgenic hyperactivity of ovarian or adrenal origin. The women, following induced withdrawal bleeding, received 200 mg/die clomiphene over five days, from the fifth through the ninth days of their cycles, plus 2 mg/die dexamethasone over ten days, from the fifth to 14th days of cycle, after they had failed to conceive in response to clomiphene alone administered in rising doses up to 200 mg/die. Nine pregnancies were successfully induced by that treatment. Two of them ended in abortion and one in premature twin delivery. Combined clomiphene-dexamethasone treatment is recommended for clomiphene-resistant cases with ovarian or adrenal hyperandrogenism, particularly for patients with polycystic ovaries (Stein-Leventhal syndrome).

Adrenocortical Hyperfunction

Induction of ovulation with clomiphene and estradiol benzoate in anovulatory women refractory to clomiphene alone.

Twenty-two infertile and clomiphene-nonresponding patients received a course of clomiphene, 100 mg/day for 5 days, followed 7 days later by an intramuscular injection of 1 mg of estradiol benzoate. The diagnosis of idiopathic chronic anovulation had been established. None of these patients had galactorrhea, hirsutism, or ovarian enlargement. Thirteen of the twenty-two women had surges of both luteinizing hormone and follicle-stimulating hormone after the estradiol injection; the peak gonadotropin levels occurred within 72 hours of the injection. These 13 patients ovulated and pregnancy ensued in 10 of them. The estradiol benzoate injection also elicited a significant increase in serum prolactin levels- This enhanced prolactin release had no apparent effect on the gonadotropin surge. These results suggest that the association of clomiphene and estradiol benzoate potentiates the action of clomiphene and may prove useful in clomiphene nonresponders.

Adult

Clomiphene-dexamethasone treatment of clomiphene-resistant women with and without the polycystic ovary syndrome.

We used clomiphene and dexamethasone in 40 infertile women to treat chronic anovulation resistant to the use of clomiphene alone. Eighteen (45%) of the women had the polycystic ovary (PCO) syndrome; the remaining 22 (55%) had clomiphene-resistant anovulation from idiopathic causes. Both groups of women were similar in regard to age, parity, duration of infertility and absence of other causes of infertility besides chronic anovulation. Ovulation could be induced in approximately 90% of the women in each group. Altogether, 19 of 36 women (52.8%) conceived without any side effects or complications. The cumulative probability of conception at nine months of treatment was 87.5% in PCO patients and 46% in the non-PCO group. Clomiphene plus dexamethasone was highly effective in the treatment of clomiphene-resistant anovulation associated with infertility in women with and without the PCO syndrome.

Adult

Metabolism of clomiphene in the rat. Estrogen receptor affinity and antiestrogenic activity of clomiphene metabolites.

Incubation of the nonsteroidal antiestrogen clomiphene with rat liver microsomes resulted in the formation of the 4-hydroxy-, N-desethyl-, and N-oxide metabolites, in qualitative contrast to results previously obtained analogously with rabbit microsomes, with which only the first two metabolites were detected. Metabolites were characterized by thin-layer chromatography in comparison with synthetic standards. They were similarly compared using low resolution electron ionization mass spectrometry, except for the N-oxide which was best characterized by fast atom bombardment mass spectrometry. Oral administration of clomiphene resulted in no detectable urinary elimination of the drug or its metabolites; 4-hydroxyclomiphene was the sole detectable elimination product in fecal extracts. The relative uterine cytosol estrogen receptor binding affinities, at 4 degrees, of 4-hydroxyclomiphene and the E-isomers of clomiphene, desethylclomiphene, and clomiphene N-oxide were, in turn, 331, 0.71, 0.62, and 0.88 (estradiol = 100). In the 3-day immature rat uterotropic assay, 4-hydroxyclomiphene had no significant uterotropic effect at doses up to 50 micrograms/day, but substantially inhibited that of estradiol (0.5 micrograms/day) at doses of 2 micrograms/day.

Animals

Successful induction of ovulation in normogonadotrophic clomiphene resistant anovulatory women by combined naltrexone and clomiphene citrate treatment.

Patients suffering from normogonadotrophic anovulation and infertility are initially treated with clomiphene citrate. Those who do not respond to clomiphene citrate usually receive gonadotrophin treatment which is labour-intensive, expensive, and associated with an increased risk of multiple pregnancies and ovarian hyperstimulation syndrome. We treated 22 patients with clomiphene resistant normogonadotrophic anovulation with naltrexone (an opioid receptor blocker) alone or naltrexone in combination with an antioestrogen. In 19 patients ovulation and resumption of a regular menstrual cycle was achieved and in 12 out of 19 a singleton pregnancy was observed. In conclusion, ovulation can be induced successfully using naltrexone alone or naltrexone in combination with an anti-oestrogen in clomiphene citrate resistant anovulatory patients. Compared to gonadotrophin induction of ovulation, this method is safe, simple and inexpensive.

Administration, Oral

Clomiphene test and clomiphene therapy in idiopathic male infertility.

Clomiphene citrate, 50 mg/day, was administered to 105 patients with idiopathic azoospermia or oligoasthenospermia. Plasma FSH, LH, testosterone, and in a few cases estradiol were evaluated on day 0 and day 15 of therapy. Twelve other patients with no treatment were assayed in the same way. Statistical analysis demonstrated that, as a group, the infertile male population responds normally to clomiphene administration. On the other hand, three types of individual responses were recorded: complete positive response, dissociated positive response, and negative response. Sixty-nine patients were randomly selected for clomiphene therapy, 50 mg/day for 100 days; however, of 54 who completed the treatment schedule, only 11 showed elevated sperm counts. A study of correlations between hormonal and semen responses to clomiphene indicates that a complete or dissociated endocrine response is not an accurate predictor of possible semen amelioration on long-term therapy; on the other hand, sperm characteristics did not improve in those patients who did not demonstrate a positive hormonal response, mainly testosterone, on the 15th day of therapy.

Adult

Menometrorrhagia of the puberty: therapy with Clomiphene (Clomiphene and puberal menometrorrhagia).

The authors administrated the Clomiphene, in different doses, to 8 patients among 27 observed. These patients were checked for a long time by basal body temperature and in some cases, measuring total urinary estrogens and pregnandioluria. The therapy was administrated in 38 cicles of the 163 cicles observed. This drug got evident results on flux duration, less significant results on the cicle length. The Clomiphene produced ovulatory cicles in 58 per cent of the cases, against 7 per cent of spontaneous ovulatory cicles of the same patients. The drug effect is better in the cases with normo or moderate hypo or hyper estrogenism, not so good in the cases with a remarcable hypoestrogenism. The therapy with Clomiphene did not produce any inconvenient. The results got were put in comparison with those of the other drug (Ciclophenile) and the superiority of Clomiphene was confirmed.

Adolescent

Induction of ovulation by combined clomiphene citrate and dexamethasone treatment in clomiphene citrate nonresponders.

Fifteen anovulatory, oligomenorrheic, hyperandrogenic and normoprolactinemic women who failed to respond to prolonged clomiphene citrate (CC) treatment, were subsequently treated with CC and small doses of dexamethasone (Dex). Twelve (80%) of the patients ovulated according to BBT and progesterone values, and 7 (49%) conceived during 3--6 treatment cycles. Five of these pregnancies terminated in live, single, full term deliveries, one set of twins and one first trimester abortion. It is concluded that a regimen of combined CC and a small dose of Dex may be offered to CC nonresponders as an effective alternative to Menotropins--HCG treatment.

Adult

Comparison of human menopausal gonadotropin, clomiphene citrate, and combined human menopausal gonadotropin-clomiphene citrate stimulation protocols for in vitro fertilization.

Human menopausal gonadotropins (hMG) and clomiphene citrate (CC), either alone or in combination, are frequently used for in vitro fertilization (IVF) in an attempt to maximize the number of oocytes recovered and the number of embryos transferred. However, direct comparison of the relative efficacy of these protocols in the same institution has been limited. To evaluate this question, the authors examined the outcome of 304 consecutive women attempting IVF. One hundred eighty-one women received hMG, 42 received CC, and 81 received combination hMG/CC. The percentages of women undergoing laparoscopy were not different among the groups (69%, 71%, and 74%, respectively), nor were the rates of oocyte recovery (94%, 100%, and 100%). However, the percentage of women achieving oocyte fertilization (77%, 83%, and 93%) and embryo transfer (73%, 83%, and 90%) were significantly greater among those who had received hMG/CC stimulation. A comparison of hMG/CC with hMG and CC cycles revealed a statistically significant increase in the total number of developing follicles (4.5 +/- 0.3, 3.3 +/- 0.2, and 3.1 +/- 0.3, respectively; P = 0.0137), total oocytes recovered (4.1 +/- 0.3, 3.2 +/- 0.2, and 2.5 +/- 0.2; P = 0.0011), and embryos transferred (2.2 +/- 0.2, 1.4 +/- 0.2, and 1.4 +/- 0.2; P = 0.0013). However, there was no significant difference in the occurrence of ongoing pregnancies. Thus, in terms of the per-patient number of follicles, oocytes, and embryo transfers, combined hMG/CC stimulation appears to be superior to either hMG or CC alone. However, to date the combined regimen has not improved pregnancy rates.

Clomiphene

Menotropins alone are superior to a clomiphene citrate and menotropin combination for superovulation induction among clomiphene citrate failures.

OBJECTIVE: To examine the difference in efficacy between two protocols of superovulation induction with IUI among infertile couples. DESIGN: A prospective randomized trial. SETTING: Normal human volunteers in an infertility clinic. PATIENTS: Consecutively treated patients attending our infertility clinic for superovulation induction with IUI who had been unsuccessfully treated by clomiphene citrate (CC). INTERVENTIONS: Infertile couples were randomized to undergo one of two controlled ovarian hyperstimulation protocols. Group A patients received daily hMG beginning on cycle day 3, whereas group B patients were administered CC days 3 through 7, followed by hMG from day 7 onward. Randomization was performed using a random numbers table. In both groups, ovulation was triggered by 5,000 IU hCG and IUI was performed by 36 hours. MAIN OUTCOME MEASURES: Studied cycle performance parameters included peak E2, number of dominant and intermediate-sized follicles recruited, endometrial thickness and pattern, and frequency of monitoring. RESULTS: Data analysis demonstrated no significant difference between the two groups with respect to patient age, parity, weight, indication for superovulation and IUI, number of dominant follicles recruited, peak E2, or mean number of total motile sperm inseminated. Endometrial thickness and pattern differed between treatments, however, with group A demonstrating relatively thicker and proportionately more trilaminar patterns than group B. Group A had significantly more serum E2 measurements, as well as transvaginal sonograms performed, when compared with group B. Pregnancy rates for groups A and B were 0.192 and 0.091, respectively. Of 25 pregnancies in group A, 7 (0.28) were multiples, whereas there were no multiple gestations in group B. CONCLUSION: For patients undergoing superovulation with IUI, a menotropin-alone protocol yields significantly higher pregnancy rates than one using a combination of menotropin with CC. These differences could not be explained by patient characteristics. Among cycle performance parameters, endometrial thickness and pattern differed significantly between the two groups.

Adult

[Combined therapy with bromocriptine, clomiphene and gonadotropin for polycystic ovary syndrome patients failing to respond to clomiphene alone].

The purpose of this study is to investigate the ovulatory effect of the combined therapy with bromocriptine (Brc), clomiphene (Cl) and HMG. We investigated 25 patients with polycystic ovary syndrome (PCOS) who had anovulatory normoprolactinemia and failed to respond to Cl therapy alone. The results were as follows: 1) The ovulation rate with Method I(Brc/Cl) was 64.0% (16/25) in 25 cases, and 59.8% in 122 cycles. 2) Resting levels of serum dehydroepiandrosterone sulfate in the effective group with Method I were significantly lower than those in the non-effective group. 3) With Method I, serum prolactin (PRL), LH and testosterone were significantly decreased, while estradiol and progesterone concentrations were significantly increased in the effective group. However, there were no significant changes in the hormone levels except PRL in the non-effective group. 4) Out of the 9 nonrespondent Method I cases, 5 additional cases ovulated with both Method II(Brc/Cl+ a small dose of HMG) and Method III(Brc/Cl+ an increased dose of HMG-HCG). The total ovulatory rate was 84.0% (21/25) in 25 cases and 59.4% (85/143) in 143 cycles. 5) The total pregnancy rate was 43.8% (7/16). Six cases were normal pregnancies, one case was a twin pregnancy and there was no case of abortion. Our results suggested that the combined therapy with Brc, Cl and HMG had almost the same therapeutic effect as the HMG-HCG therapy in severe cases of PCOS.

Adolescent

[Combined therapy of bromocriptine, clomiphene citrate and HMG in normoprolactinemic amenorrhea patients who fail to respond to bromocriptine-clomiphene citrate therapy].

The purpose of this study is to investigate the ovulatory effect of the following three methods on 40 patients with normoprolactinemic amenorrhea patients who failed to respond to clomiphene citrate (Cl) alone. Method I is the combined therapy with bromocriptine and Cl (Brc/Cl). Method II is the combined therapy with Brc/Cl and an additional small amount of HMG (less than or equal to 300 IU). Method III is the combined therapy with Brc/Cl and an increased amount of HMG (less than or equal to 1,200 IU) and HCG. The ovulation rate of method I was 57.5% (23/40) in 40 cases, and 55.6% (99/178) in 178 cycles. The pregnancy rate for this method was 23.8% (5/21). Out of the 12 nonrespondent method I cases, 5 additional cases were ovulated by method II and 3 cases were ovulated by method III. The total pregnancy rate was 42.9% (9/21) with these three methods. Seven cases were normal pregnancies, one case was a twin pregnancy and 1 case was an abortion. No other side effects were found in this study. From these results, the combined therapy with Brc/Cl or Brc/Cl + HMG had almost the same ovulatory rate as the HMG-HCG therapy, and fewer side effects.

Adolescent

[The combined effect of bromocriptine and clomiphene citrate on normoprolactinemic anovulation; the lack of effectiveness of clomiphene citrate treatment alone].

The purpose of this study is to investigate the combined effect of bromocriptine and clomiphene citrate (Cl) treatment on 35 patients with normoprolactinemic amenorrhea who failed to respond to Cl alone. Ovulation was restored by this treatment in 20 of these patients (57.1%), and the pregnancy rate was 26.7%. This treatment was effective in 11 of 15 women with polycystic ovary like syndrome (73.3%). Resting levels of prolactin, estradiol and testosterone in the effective group were significantly higher than those in the non-effective group. As a result of the treatment, the prolactin and LH levels were significantly decreased, and estradiol and progesterone levels were significantly increased in the effective group. Before the treatment, the responsiveness of LH to LHRH in the effective group was significantly higher, but the responsiveness of prolactin to TRH in this group was not significantly higher than that in the non-effective group. After the treatment, the LH-releasing response following a premarin injection in the effective group was significantly higher than that in the non-effective group. The present results indicate that the therapeutic effect of this treatment may be primarily due to the restoration and improvement of the impaired hypothalamo-pituitary system without the suppression of pituitary prolactin secretion.

Adolescent

Comparative trial of clomiphene citrate/human menopausal gonadotropin and the contraceptive pill, followed by clomiphene citrate/human menopausal gonadotropin, in a gamete intrafallopian transfer program.

PURPOSE: It may sometimes be necessary to regulate cycles in assisted reproduction. Cycles can be regulated with gonadotropin releasing hormone (GnRHa) agonist but other methods can also be used. The aim of this study was to compare the pregnancy rate in a gamete intrafallopian transfer (GIFT) program in patients receiving a contraceptive pill/Clomid/human menopausal gonadotropin (hMG) regimen (study group), with the standard Clomid/hMG regime (control group). Fifty one patients in the study group were carefully matched for patient age, infertility diagnosis (female), semen parameters, number of follicles, and number of oocytes transferred into consideration with a control group. RESULTS: The overall pregnancy rate was 21.6% (11/51) in the study group and 47% (24/51) in the control group (P = 0.01). However, the ongoing pregnancy rate in the two groups did not differ significantly, 11.8% (6/51) vs 27.5% (14/51) (P = 0.08). In the study group, 7.8% of patients had to be seen over a weekend, compared to 13.7% in the control group (not significant). CONCLUSION: From the findings we conclude that, although this method of controlling cycles can be useful in selected patients, it is not the ultimate method.

Adult