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PubMed1975

Assessment of the therapeutic effect of epimestrol and epimestrol associated with clomiphene in female sterility.

In 24 women with disturbances of ovulation treated for sterility with Epimestrol, ovulation was achieved in 3 patients but none of these became pregnant after therapy. Since it has been suggested that the association of Clomiphene with a weak estrogen might improve the pregnancy rate, we decided to administer Clomiphene associated with Epimestrol. Using this combined therapy in 58 patients, 32 out of the 58 women ovulated and 17 conceived. The overall rate of pregnancy using the combined therapy was no better than that obtained when Clomiphene alone is administered. From this study it is concluded that: (1) Epimestrol is not an effective method for the induction of ovulation, and (2) addition of Epimestrol to Clomiphene is of no clinical benefit.

Clomiphene↗
PubMed1983

Effects of clomiphene administration on ovarian function as measured by estradiol and ultrasound.

The growth and rupture of the graafian follicle were studied in 23 women during 40 cycles (20 spontaneous, 20 clomiphene-induced) by the estimation of plasma estradiol levels and ultrasound scan. The mean preovulatory estradiol peak level was 415 pg/ml in spontaneous cycles and 626 pg/ml after clomiphene administration when one follicle was present. Ultrasonic examination revealed the presence of more than one developing follicle in one of 20 spontaneous cycles, and in 11 of 20 cycles after clomiphene treatment. The determination of follicle size and number by ultrasound scan during ovulation induction by the routinely used starting dosage of clomiphene has revealed a previously unrecognized incidence of ovarian overstimulation, and may allow the rationalization of ovulation induction regimens.

Clomiphene↗
PubMed1980

LH patterns during clomiphene-induced menstrual cycles.

A total of 409 sterility patients with amenorrhea classified as group II according to the WHO rating scheme were treated with a daily dose of 100 mg of Clomiphene daily for five days in 452 cycles. In addition, 300 infertile subjects with spontaneous cycles (375), but with slight irregularities in the lengths of cycles were included in this investigation as control group. Daily LH serum levels were monitored by rapid solid-phase coated tube RIA. 61.87% of LH single peaks, 28.53% of plateau peaks and 0.53% of double peaks were registered in spontaneous cycles. Similarly, 60.28% single peaks, 23.67% plateau peaks and 0.66% double peaks were registered in Clomiphene-induced cycles. Highest rate of LH plateau and single peaks were found 4 to 6 days and 5 to 7 days, resp., after the end of Clomiphene therapy. No LH peaks were found in 9.07% of spontaneous cycles and in 15.39% of Clomiphene-induced cycles. Data combine to suggest that timing of ovulation by a rapid LH radioimmunoassay is a valuable aid in consulting infertile couples. Failures of patients to conceive must be due to causes other than incorrect timing of ovulation.

Clomiphene↗
PubMed1982

Cooperativity pattern in the interaction of the antiestrogen drug clomiphene with the Muscarinic receptors.

The possible interaction between the muscarinic receptors and the antiestrogenic drug clomiphene citrate was investigated in competition experiments using the highly specific tritiated antagonist N-methyl-4-piperidyl benzilate (4-NMPB) in various regions of rat brain. It was found that clomiphene can displace muscarinic antagonists from their receptor-ligand complexes. Binding analyses as well as determinations of the kinetics of dissociation of [3H]4-NMPB-receptor complexes indicate the binding of more than one molecule of clomiphene in a positively cooperative pattern. These findings suggest that the nonsteroidal antiestrogenic drugs, e.g., clomiphene, might exert their effects not only through the specific estrogen receptor but also in conjunction with the muscarinic system.

Allosteric Regulation↗
PubMed1978

Circulating pituitary-gonadal hormones in clomiphene-induced cycles.

Plasma follicle stimulating hormone (FSH) and luteinizing hormone (LH), prolactin (PRL), estradiol (E2), progesterone (P), testosterone (T), and dihydrotestosterone (DHT) were measured by radioimmunoassay in 7 patients who had ovulation induction with clomiphene citrate and human chorionic gonadotropin. Six of the 7 patients ovulated. There was higher increase in FSH than LH in 3 patients who also showed a midcycle FSH and LH peak. Plasma PRL was initially elevated in 2 patients, remained normal (less than 25 ng/ml) throughout the cycle in one patient, and showed an increase in the late luteal phase in 3 patients. Plasma E2 showed a good response at the end of clomiphene intake, with a subsequent preovulatory surge. Plasma P increased to more than 25 ng/ml in patients who ovulated and reached higher levels than in normal ovulatory cycles. Plasma T increased and decreased in a similar pattern to plasma E2 and was higher with clomiphene therapy than in the normal menstrual cycle. Plasma DHT remained similar to concentrations found in normal menstrual cycles. The findings are discussed in relation to the effect of clomiphene and these hormones on the pituitary-ovarian axis, ovulation rate, and conception rate.

Chorionic Gonadotropin↗
PubMed1976

Human pituitary gonadotrophin index. II LHRH test and clomiphene response before and after LHRH stimulation.

To monitor the effect of LHRH treatment on hypothalamo-pituitary-gonadal function, women with functional amenorrhoea were investigated by standardized LHRH and repeated clomiphene tests before and after LHRH therapy. The actual pituitary gonadotrophin reserve was defined by a Human Pituitary Gonadotrophin Index (HPGI). Clomiphene response served as hypothalamic function test, plasma oestradiol and progesterone concentrations were measured for assessment of the gonadal function. LHRH treatment as performed in this study did not change basal gonadotrophin levels or the pituitary responsiveness in our standardized LHRH test. Plasma oestradiol concentrations remained unaltered at the lower limit of the early follicular phase values of a normal menstrual cycle. The inability to respond to clomiphene was changed to clomiphene responsiveness during therapy in eighteen out of twenty-nine women with anovulation. The majority of the responders had HPG-Indices of R2. Patients with hyperprolactinaemic anovulation did not convert. The possibility of an ultrashort feedback action of LHRH on its own production in the human is discussed.

Adult↗
PubMed1976

The relationship between the pituitary response to luteinizing hormone-releasing hormone and the ovulatory response to clomiphene citrate.

Luteinizing hormone-releasing hormone (LH-RH), at a dose level of 10 mug, was administered intravenously to 31 patients, 9 with oligomenorrhea and 22 with secondary amenorrhea. A serum luteinizing hormone level higher than 45 mIU/ml at 30 or 45 minutes after injection was considered to be a "positive response" to LH-RH. All 9 patients in the oligomenorrheic group and 11 of the 22 patients with secondary amenorrhea had a "positive" response. The patients were then treated with increasing doses of clomiphene citrate until an ovulatory dose was reached. Eight of the nine patients with oligomenorrhea ovulated with doses of up to 150 mg of clomiphene daily for 5 days. Of the 11 patients in the group with secondary amenorrhea who had a "positive" response to LH-RH, 7 ovulated at a dose of 150 mg (or less) of clomiphene citrate, while only 1 of the 11 patients with a "negative" response ovulated while receiving a similar dosage of clomiphene. These results suggest that a simplified LH-RH test might be of value in selecting the level of therapy for ovulation induction.

Adult↗
PubMed1995

Clomiphene-induced quintuplets with a failed attempt at delayed-interval delivery.

Clomiphene citrate is widely used for ovulation induction. It is associated with a 6 to 17% incidence of multiple gestation. We report on a 27-year-old para 0010 patient who, after an initial evaluation for secondary infertility of 2 years' duration, was deemed to have oligo-ovulation. She conceived during the second cycle of clomiphene citrate administration. An early obstetric sonogram identified five fetuses with cardiac activity. The patient experienced preterm premature rupture of the membranes at 19 weeks gestation. A delayed-interval delivery was attempted, but all five fetuses were born over a period of 15 days. No maternal complications occurred. Multiple pregnancies of high order are commonly associated with human menopausal gonadotropins but rarely with clomiphene citrate. This is the seventh reported case of quintuplets related to clomiphene citrate, and possibly the first on whom no other fertility-enhancing medication was utilized. In this case, attempted delayed-interval delivery was not successful.

Adult↗
PubMed1996

Metabolic parameters that predict response to clomiphene citrate in obese oligo-ovulatory women.

OBJECTIVE: To determine whether the presence of insulin resistance in obese subjects would adversely affect the rate of ovulation induction by clomiphene citrate. RESULTS: Fasting hyperinsulinemia was associated with the failure to ovulate in response to clomiphene. In addition, other parameters found to correlate with insulin resistance and clomiphene citrate non-response were elevations of total and free testosterone and lower serum sex hormone-binding globulin. CONCLUSIONS: The existence of the presence of endocrine abnormalities associated with hyperinsulinemia and insulin resistance may serve as clinical indicators to help predict which obese patients are likely to respond to clomiphene citrate therapy.

Adult↗
PubMedDate not supplied

Effect of two anti-estrogens, clomiphene citrate and tamoxifen, on cervical mucus and sperm-cervical mucus interaction.

OBJECTIVE: To compare the effect of two ovulation-inducing agents, clomiphene citrate and tamoxifen, on cervical mucus and sperm-cervical mucus interaction. SUBJECTS AND SETTING: Forty couples with unexplained infertility attending infertility clinic. METHODS: Cervical mucus scoring and postcoital test done using the Moghissi system in a spontaneous cycle (control cycle) and with clomiphene citrate or tamoxifen (study cycles). RESULTS: Clomiphene citrate significantly decreased cervical mucus production, whereas tamoxifen significantly improved the total score. CONCLUSION: Tamoxifen is a better drug than clomiphene for ovulation induction in women with poor cervical mucus quality.

Adult↗
PubMed1997

Histopathological changes in the uterus of rats treated neonatally with clomiphene citrate.

Clomiphene citrate has estrogenic and teratogenic effects on the developing rat and human fetal genital tract. Clomiphene citrate was given subcutaneously to newly born rats by daily injections of 100 micrograms/kg and changes caused by clomiphene in female rats were investigated at 28 and 35 days. Depending upon the effect of clomiphene citrate, histopathological changes such as the observation of polygonal shaped nodular cells in the uterus epithelium and presence of erythrocytes in free nature in the stroma were considered as important findings.

Animals↗
PubMed1976

[Further reproduction after clomiphene-induced pregnancy (author's transl)].

The study of menstrual pattern and further pregnancy after clomiphene-induced pregnancy showed a comparatively high rate of improved menstrual pattern and of spontaneous conception. 12 of 29 women, who concluded a clomiphene-induced pregnancy more than 2 years ago, showed an improvement of menstrual pattern. Spontaneous conception occurred in 16 of the 29 women, in 2 cases once more. It is remarkable, that 7 of these 16 women conceived spontaneously without any improvement of menstrual pattern following the clomiphene-induced pregnancy. It is therefore difficult, to advise patients and to make a prognosis concerning further fertility. It is not possible to say, that spontaneous conception can be excluded respectively that it will occur. In case of desire for pregnancy another induction of ovulation is indicated, on the contrary contraceptive questions are to be discussed.

Clomiphene↗
PubMed1980

Combined use of clomiphene and intranasal luteinizing hormone-releasing hormone for induction of ovulation in chronically anovulatory women.

Combined therapy with clomiphene and intranasal luteinizing hormone-releasing hormone (LHRH) was used to induce ovulation in eight chronically anovulatory patients under treatment for infertility. Clomiphene, 100 mg daily, was given from the 5th to the 9th day of the cycle. Synthetic LHRH was administered intranasally in different dosages from day 11 to day 14, in an attempt to induce late follicular development and ovulation. Five of the eight patients ovulated, and three conceived. The success achieved with combined clomiphene and intranasal LHRH administration suggests a therapeutic potential in the management of anovulatory infertility.

Administration, Intranasal↗
PubMed2000

Ovulation induction with urinary follicle stimulating hormone versus human menopausal gonadotropin for clomiphene-resistant polycystic ovary syndrome.

BACKGROUND: The risks of multiple pregnancy and ovarian hyperstimulation syndrome (OHSS) are increased in women with clomiphene resistance WHO group 2 dysfunction undergoing ovulation induction as well as the risk of spontaneous abortion if conception takes place. Semi-purified preparations of FSH have been developed in an effort to reduce the impact of exogenous LH, relatively high levels of which are present in human menopausal gonadotropin (hMG). Ovulation induction in women with clomiphene resistant WHO group 2 dysfunction who often have clinical features of polycystic ovarian syndrome (PCOS), is a major challenge. The risks of multiple pregnancy and ovarian hyperstimulation syndrome (OHSS) are increased in this population. There also appears to be an increased risk of spontaneous abortion in those who conceive, perhaps associated with elevated LH levels. Semi-purified preparations of FSH have been developed in an effort to reduce the impact of exogenous LH, relatively high levels of which are present in human menopausal gonadotrophins. OBJECTIVES: To determine the effectiveness of daily FSH versus daily hMG in women with clomiphene-resistant polycystic ovary syndrome (PCOS), in terms of rates of pregnancy and moderate to severe ovarian hyperstimulation syndrome (OHSS). SEARCH STRATEGY: The Cochrane Subfertility Review Group specialised register of controlled trials was searched. SELECTION CRITERIA: All RCTs relevant to the clinical question were selected. DATA COLLECTION AND ANALYSIS: A diverse search strategy was employed, including hand-search of 43 core journals from 1966 to the present, bibliographies of relevant trials, MEDLINE database, abstracts from North American and European meetings and contact with authors of relevant papers. Relevant data were extracted independently by two reviewers using the standardized data extraction sheet. Validity was assessed in terms of method of randomisation, completeness of follow-up, presence or absence of crossover and co-intervention. DATA SYNTHESIS: 2x2 tables were generated for all relevant outcomes. Odds ratios were generated using the Peto modified Mantel-Haenszel technique. Statistical heterogeneity was assessed using x2. MAIN RESULTS: No significant benefit was demonstrated from semi-purified FSH versus hMG in terms of pregnancy rate: common odds ratio per patient 0.66 (95% CI 0.35-1.24) and per cycle 0.89 (95% CI 0.51-1.53). FSH appeared to be associated with a reduction in moderate to severe OHSS: common odds ratios 0.2 (95% CI 0.09-0.46). REVIEWER'S CONCLUSIONS: In women with PCOS, no significant difference could be demonstrated between FSH and hMG, in terms of pregnancy rate. However, given similar cost, potential advantages in terms of purity and a possible reduction in OHSS risk, highly purified or recombinant FSH are likely to be widely adopted in the future. Further research should consider live birth as a primary clinical outcome, given concerns over the association between high androgen and LH levels with spontaneous abortion risk.

Clomiphene↗
PubMed1984

Effects of the anti-oestrogens, clomiphene and tamoxifen, on the cervical factor in female infertility.

The anti-oestrogens clomiphene and tamoxifen are successful therapeutic agents in the induction of ovulation but the associated pregnancy rates are low. One cause for this may be a direct anti-oestrogenic effect on cervical mucus, reducing its sperm penetrability. This potentially adverse effect has been shown to occur with clomiphene. In this study the effects of clomiphene and tamoxifen on the cervical factor are compared in women who were anovulatory or had defective ovulation. Forty fully investigated infertile women were randomly allocated to different treatment sequences after being observed for three control cycles. A double-blind placebo technique was used with four different treatment regimes. Serial serum progesterone and oestradiol were assayed. Cervical mucus from the periovulatory phase was assessed by means of the cervical score and in vitro sperm penetration tests. Both these anti-oestrogens can affect cervical mucus but their effect seems to be related more to the end-organ sensitivity of the individual than to a specific action of the drug per se.

Cervix Mucus↗
PubMed1985

The antiestrogenic effect of clomiphene on perineal tumescence of the baboon in an in vitro fertilization program.

In a nonhuman primate in vitro fertilization program clomiphene citrate was used to superovulate the chacma baboon Papio ursinus. The antiestrogenic effect of clomiphene citrate was demonstrated locally on the perineal tumescence. In comparing the result of 50 spontaneous cycles and 18 clomiphene citrate-stimulated cycles, there was a statistical significant influence on cycle length and duration and degree of perineal swelling. This inhibitory effect on perineal tumescence of the baboon is another example of a local antiestrogenic effect of this drug. Furthermore, it nullified an important clinical parameter of ensuing ovulation.

Animals↗
PubMed1985

Implantation, abortion, and birth after in vitro fertilization using the natural menstrual cycle or follicular stimulation with clomiphene citrate and human menopausal gonadotropin.

The incidence of pregnancy and abortion was analyzed in 1679 patients having embryos replaced after oocyte recovery and in vitro fertilization in order to alleviate their infertility. In these patients, 364 pregnancies were achieved and 108 abortions occurred. Patients were treated either on their natural cycle, having a spontaneous luteinizing hormone (LH) surge to induce ovulation, or after ovarian stimulation using clomiphene citrate alone or in combination with human menopausal gonadotropin (hMG). The data were assessed in relation to the numbers of embryos replaced, the follicular stimulation and ovulation induction regime used, the dose of gonadotropins and the dose of antiestrogens, and the age of the patient. The most successful treatment for the number of live births per laparoscopy was the use of clomiphene citrate in combination with human menopausal gonadotropin followed by human chorionic gonadotropin (hCG) to induce follicular maturation and ovulation. This treatment produced a significantly higher (P less than 0.001) number of patients with multiple embryos (86.5%). There was no significant effect on pregnancy or abortion with a low (less than 400-mg) or high (greater than or equal to 400-mg) dose of clomiphene. The total dose of gonadotropins used did not influence the incidence of pregnancy or abortion. The use of hCG with hMG induced a significant (P less than 0.01) positive effect on the incidence of pregnancy. The incidence of pregnancy showed a progressive decline with increasing age but there was a highly significant (P less than 0.01) increase in the incidence of abortion with increasing age. With increasing numbers of embryos replaced, up to three, the incidence of deliveries increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Abortion, Spontaneous↗
PubMed1985

Follicular-phase response in two clomiphene-human menopausal gonadotropin regimes for an in vitro fertilization program.

Two clomiphene-human menopausal gonadotropin regimes were assessed for our in vitro fertilization and embryo replacement (IVF and ER) program since September 1983. Clomiphene, 50 mg bd, was taken from day 2 for 5 days. Human menopausal gonadotropin (hMG) was given from day 6; for the first regime, 75 IU/day was given for the first 3 days, and for the second, 150 IU/day. The subsequent dosages were dependent on the estradiol response. There were 9 cases for the first regime and 10 cases for the second. The mean number of hMG ampoules given was 16.5 and 19.25, respectively. The number of follicles seen on ultrasound was 3.0 +/- 0.5 and 3.4 +/- 1.2 (mean +/- SD), respectively. There was no statistical difference in the estradiol response up to the day of laparoscopic ova recovery for the two regimes. However, a spontaneous luteinizing hormone (LH) surge was observed in 4 of 9 cases in the first group and 6 of 10 cases in the second group. When a comparison was made between cases that had a spontaneous LH surge and cases that were given human chorionic gonadotropin (hCG), there was a higher estradiol level on the day of the laparoscopy in the hCG group with the lower hMG regime (P less than 0.05). There were no other differences. Our small series shows a 52.6% incidence of spontaneous LH surge with clomiphene-hMG. Hence such stimulated regimes can result in a high proportion of spontaneous LH surges; this may be an index of satisfactory endocrinological control in spite of an increase in the number of follicles.

Clomiphene↗