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PubMed1998

Contralateral ovulation shortens follicular phase length and favours pre-embryo development during ovarian stimulation with clomiphene citrate.

The present study was undertaken to evaluate whether the site of ovulation affects the following follicular phase length and pre-embryo development during infertility treatment with ovarian stimulation using clomiphene citrate. A total of 363 cycles in 97 patients undergoing infertility treatment (182 intrauterine insemination (IUI) cycles in 60 patients and 181 in-vitro fertilization (IVF) cycles in 52 patients) were studied. The cycles were divided into two main groups: preceding unilateral ovulation (PUO) and preceding bilateral ovulation (PBO). In the PUO group, the cycles were subdivided into contralateral ovulation, bilateral ovulation and ipsilateral ovulation. In IVF cycles alone, bilateral ovulations were further divided into bilateral ovulation-contralateral side and bilateral ovulation, ipsilateral side. Contralateral ovulations were seen in 134 of 240 cycles (56%), excluding bilateral ovulation and PBO. The follicular phase length in contralateral ovulation (16.2 +/- 2.6 days, mean +/- SD) was significantly (P < 0.05) shorter than that of ipsilateral ovulation (16.9 +/- 2.8). There were no significant differences of follicular phase length among contralateral ovulation, bilateral ovulation and PBO. Of IVF cycles including contralateral ovulation-ipsilateral ovulation and bilateral ovulation a total of 107 preovulatory follicles was assessed in the contralateral side (contralateral ovulation + bilateral ovulation-contralateral side) and 97 in the ipsilateral side (ipsilateral ovulation + bilateral ovulation, ipsilateral side). The oocyte retrieval rate (88%), fertilization rate (84%), cleavage rate (95%), embryo transfer rate (70%) of contralateral follicles were higher than those of ipsilateral follicles (71, 62, 86, 38% respectively) and those of PBO (76, 62, 87, 41% respectively). The total pregnancy rate of both IUI and IVF did not differ among contralateral ovulation (15%), ipsilateral ovulation (8%), bilateral ovulation (11%) and PBO (10%). The results confirm and extend our previous findings in natural cycles, suggesting that local ovarian factors, e.g. from corpus luteum, affect the health of preovulatory follicle and the enclosed oocyte in the same ovary (ipsilateral) negatively. Contralateral selection of preovulatory follicles in the succeeding cycle shortens the follicular phase length and favours pre-embryo development. The chance of conceiving during ovarian stimulation with clomiphene citrate may thus be affected by the site of ovulation in the previous cycle.

Adult↗
PubMed2001

Clomiphene citrate does not affect the secretion of alpha3, alphaV and beta1 integrin molecules during the implantation window in patients with unexplained infertility.

BACKGROUND: The expression of integrin molecules on the endometrium suggests that certain integrins may participate in the cascade of molecular events leading to successful implantation. A prospective, controlled study was carried out to investigate the effect of clomiphene citrate (CC) on secretions of beta1, alpha3 and alphaV integrin molecules in the endometrium of patients with unexplained infertility during the implantation window. METHODS: A total of 40 endometrial samples was evaluated in both spontaneous (n = 13) and ensuing clomiphene-treated cycles (100 mg on days 5-9) and also from fertile women serving as controls (n = 14) during postovulatory 7th or 8th day of menstrual cycle. A semiquantitative grading system (H-score) was used to compare the immunohistochemical staining intensities. Endometrial thickness and serum oestradiol and progesterone concentrations were also measured on the day of sampling. RESULTS: Staining of alpha(v) but not beta1 and alpha3 integrins was significantly less intense in infertile cases than fertile control cases (1.42 +/- 0.12 versus 2.21 +/- 0.13 respectively, P = 0.012) and this was not restored to normal concentrations with treatment. CONCLUSIONS: Our study indicated that cc treatment significantly decreased the endometrial thickness and increased oestradiol and progesterone concentrations. However, secretion of alpha(v), beta1 and alpha3 integrin molecules, which might play a role in implantation, was not affected.

Antigens, CD↗
PubMed2001

Effects of metformin on ovulation rate, hormonal and metabolic profiles in women with clomiphene-resistant polycystic ovaries: a randomized, double-blinded placebo-controlled trial.

BACKGROUND: Metformin, an insulin-sensitizing agent, has been used successfully as the first-line drug to induce ovulation in women with polycystic ovary syndrome. There are, however, very few studies evaluating metformin treatment in women with clomiphene citrate (CC)-resistant polycystic ovaries (PCO). METHODS: Twenty infertile Chinese women aged <40 years, who had ultrasound features of PCO and remained anovulatory on CC, were randomized by computer using the sealed envelope method to receive placebo or metformin 500 mg three times a day for 3 months. Hormonal and metabolic profiles were determined before the therapy and were repeated after 3 months for women who failed to become pregnant within this period. Clomiphene was then added for one cycle to those women who did not ovulate after taking placebo or metformin alone. RESULTS: The median ovulation rate in the placebo group was 0% (range: 0--50%) after placebo only and 6.9% (range: 0--50%) after placebo and CC, whereas the corresponding rates in the metformin group were 0% (range: 0--22%) and 0% (range: 0--22%) respectively. There was no improvement in the ovulation rate despite a significant reduction of body mass index, serum testosterone and fasting leptin concentrations in the metformin group. CONCLUSIONS: Metformin treatment may result in successful ovulation only in certain subgroups of these women.

Adult↗
PubMed2002

Co-administration of metformin during rFSH treatment in patients with clomiphene citrate-resistant polycystic ovarian syndrome: a prospective randomized trial.

BACKGROUND: This study aims to evaluate the impact of metformin on ovarian response when co-administered during recombinant (r)FSH using the low-dose step-up protocol in clomiphene citrate-resistant polycystic ovarian syndrome (PCOS) patients with normal glucose tolerance. METHODS AND RESULTS: Thirty-two patients were randomized to metformin (n = 16) and placebo (n = 16) groups. Hormonal assessment, a 75 g oral glucose tolerance test (OGTT) and a frequently sampled i.v. glucose tolerance test (FSIGTT) were performed before and after oral administration of metformin (850 mg twice daily) or placebo for 6 weeks. Recombinant FSH treatment was undertaken, thereafter, in women who did not ovulate on metformin (n = 10) or placebo (n = 15). There was no significant change in all insulin sensitivity indices in both groups. The only change noted was a decline in mean serum free testosterone concentration in the metformin group (P = 0.049). One patient on placebo and six patients on metformin ovulated spontaneously (P < 0.05). All parameters of ovarian response were comparable between the two groups during rFSH treatment. Combining the 6 week placebo or metformin-only period with a single rFSH treatment cycle, the overall ovulation rates were 75 and 94% in the placebo and metformin groups respectively (P > 0.05). The respective figures for pregnancy were 6.3 and 31.3% (P > 0.05). CONCLUSIONS: Metformin may restore ovulation with no improvement on insulin resistance in clomiphene citrate-resistant PCOS patients with normal glucose tolerance, but has no significant effect on ovarian response during rFSH treatment.

Adult↗
PubMed2002

Female sex selection using clomiphene citrate and albumin separation of human sperm.

BACKGROUND: This study was undertaken to assess whether the use of clomiphene citrate in conjunction with albumin-separated sperm would alter the sex ratio (expressed as the proportion of males) towards females and, if so, whether this skewing was due solely to the induction of ovulation. METHODS: The sex ratios of 184 single and 42 twin births at five assisted reproduction biology clinics were determined. The normal approximation to the binomial distribution was used to determine significant differences between these sex ratios and the established sex ratios for single, twin and combined (single and twin) non- and ovulation-induced births. RESULTS: The non-ovulation-induced sex ratios for singletons (51.4%) and twins (50.2%) were greater than the treatment singleton (27.7%; P < 0.001) and twin (33.3%; P < 0.01) sex ratios respectively. Correspondingly, the non-induced sex ratio for combined births (51.4%) was greater than the treatment sex ratio (28.8%; P < 0.001). The previously established induced singleton and twin sex ratios (48.1%) were lower than the non-induced sex ratio (51.4%), but higher than the treatment singleton (27.7%; P < 0.001) or twin (33.3%; P < 0.03) sex ratios. The ovulation-induced combined ratio (48.1%) was less than the non-induced combined (51.4%) sex ratio, although greater than the treatment combined sex ratio (28.8%; P < 0.001). CONCLUSION: Clomiphene citrate in conjunction with albumin-separated sperm decreased the sex ratio; a reduction that was not exclusively due to induction of ovulation.

Cell Separation↗
PubMed1995

Corpus luteum function and pregnancy rates with clomiphene citrate therapy: comparison of human chorionic gonadotrophin-induced versus spontaneous ovulation.

A total of 508 clomiphene citrate cycles with intra-uterine insemination (IUI) performed in 233 consecutive patients were studied. In 247 cycles insemination was performed 36-38 h after human chorionic gonadotrophin (HCG)-triggered ovulation; in the remaining 261 cycles IUI was performed 18-20 h after urinary luteinizing hormone (LH) kit detection of a spontaneous LH surge. Corpus luteum function, as determined by luteal phase length and mid-luteal progesterone concentrations, together with pregnancy rates were analysed. There was no difference in luteal phase parameters between spontaneous and HCG-triggered cycles when adjusting for patient age. Furthermore, the pregnancy rates did not differ between the HCG and LH kit groups, even after adjusting for patient age and number of motile spermatozoa inseminated. Additionally, the large numbers of cycles analysed provided sufficient power to detect increases in clinical pregnancy rates in spontaneous ovulatory cycles and HCG-induced ovulation of 10.1 and 2.4% respectively, using the customary significance level (alpha-type error) of 0.05. These findings indicate that pregnancy rates and corpus luteum function in carefully monitored clomiphene citrate/IUI cycles do not differ between HCG-triggered and spontaneous ovulatory cycles.

Adult↗
PubMed1987

Response to clomiphene citrate in the polycystic ovarian syndrome according to different LH/FSH ratios.

Twenty-nine clomiphene tests were carried out, 19 on subjects with polycystic ovarian syndrome (PCO) who did not wish to conceive and 10 on women with correct ovarian function (control women). The intention was to determine if the response of the hypothalamic-pituitary-ovary axis varies according to different LH/FSH ratios. The results indicate that with repeated LH/FSH ratios of less than 3, the positive and negative feedback systems are preserved in most subjects, but when the ratio is higher than 3, both systems are significantly altered (P less than 0.01). In the control group, both systems were preserved in all subjects. In another group composed of 26 infertile patients with PCO, the rate of ovulation and pregnancy after administration of clomiphene citrate (CC) was correlated according to different LH/FSH ratios. A significant (P less than 0.0001) reduction in the rate of ovulation and a lesser reduction in pregnancy was found with increasing LH/FSH ratios. In conclusion we suggest that the LH/FSH ratio is a good marker of this syndrome, and can be used to give a prognosis on the severity of the syndrome, as well as the ovulatory capacity of the subject after administration of CC.

Adult↗
PubMed1990

Sonographic determination of a possible adverse effect of clomiphene citrate on endometrial growth.

We recently demonstrated, using transvaginal sonography, that conception cycles in in-vitro fertilization (IVF) are associated with a significantly thicker endometrium at midcycle than non-conception cycles, suggesting that endometrial growth may influence implantation. In the present study, to examine whether the type of stimulation protocol affects endometrial development, we compared the sonographic appearance of the endometrium in 22 patients randomized to receive clomiphene citrate and human menopausal gonadotrophin (CC/HMG) and in 19 who received HMG alone. A significantly thicker endometrium was observed in the HMG patients compared to the CC/HMG group (P less than 0.005) throughout the follicular phase of the cycle, although serum concentrations of oestradiol (E2) did not differ in the two groups. Twenty-three patients (13 in the HMG group and 10 in the CC/HMG group) had previous IVF cycles with CC/HMG stimulation in which endometrial thickness was measured. A thin endometrium recurred with subsequent CC/HMG cycles while increased growth occurred with HMG only compared to previous CC/HMG cycles. Therefore, ultrasound examination of the endometrium in this study demonstrated that CC results in a thinner endometrium than HMG alone. We believe these findings may be of importance in improving pregnancy rates in IVF and possibly in other infertility therapy which involves the use of clomiphene citrate.

Clomiphene↗
PubMed1991

Use of the hormonal response to clomiphene citrate as an endocrinological indicator of ovarian ageing.

We compared the gonadotrophin and oestradiol responses to clomiphene citrate (CC) in women aged 18-25 versus 35-40 years. Despite similar baseline hormone concentrations and the attainment of similar concentrations of the E and Z isomers of clomiphene, higher follicle stimulating hormone (FSH) concentrations were observed in the older women, possibly indicative of their ageing ovaries. Furthermore, diminished oestradiol responses occurred in a subgroup of women showing FSH hyper-responsiveness to CC. These preliminary results support the concept that the hormonal response to CC may be an indicator of approaching perimenopause.

Adolescent↗
PubMed1980

Clomiphene-citrate-induced hydatidiform mole.

The reported incidence of molar pregnancies induced by clomiphene citrate is 1:659. Only nine cases, including this one, were found in an extensive search of the literature. Several questions are raised regarding the true incidence of molar pregnancy in clomiphene-induced pregnancies. Evaluation of the induced pregnancy with diagnostic ultrasound is urged.

Adult↗
PubMed1992

Multiple primary melanomas in a patient with familial-type DNS during clomiphene-induced pregnancy.

A 35-year old woman developed six primary cutaneous melanomas during her third pregnancy. She had received clomiphene treatment for nearly 2 years previously. She developed two more primary melanomas 15 and 21 months after giving birth. All melanomas were histologically associated with preexisting dysplastic naevi. The patient showed the characteristic phenotype of the dysplastic naevus syndrome; a cousin and an aunt were treated for malignant melanoma and the patient's brother had histologically confirmed dysplastic naevi. The course of her first two pregnancies was not complicated by the development of melanomas. We suggest that clomiphene may have played a role in the activation or progression of these 'precursor lesions' into malignant melanoma.

Adult↗
PubMed1978

Oestrogen amplification of LH-RH response in the polycystic ovary syndrome and response to clomiphene.

An LH-RH test was performed before and 44 and 92 h after treatment with 2.5 mg oestradiol benzoate in 17 patients with a diagnosis of polycystic ovarian (PCO) disease. The responses were compared with the same tests performed on ten normal subjects during the early follicular phase of their menstrual cycles (days 4--6). Patients were divided into two groups on the basis of their LH responses to LH-RH. In Group A (seven patients) the response at 92 h was greater than at 44 h as in the normal subjects, but in Group B (ten patients) the response at 44 h was greater than at 92 h. Basal serum hormone values were similar in the two groups except for androgens and oestrone, which were significantly (P less than 0.01) higher in Group B patients. There was a negative correlation between the basal androgen and oestrone concentrations and the LH and FSH amplifications at 92 h in all PCO patients. The ratios of the basal concentrations of LH to FSH and the ratios of the highest levels of each achieved during the basal LH-RH test, were significantly higher in the two groups of patients when compared to controls (P less than 0.01). The test is of value in predicting the subsequent responsiveness to clomiphene. All patients in Group A showed evidence of ovulation following treatment with 100 mg clomiphene for 5 days, but only one of Group B responded in this way.

Adult↗
PubMed1981

Clomiphene citrate administration to normogonadotropic subfertile men: blood hormone changes and activation of acid phosphatase in seminal fluid.

Clomiphene citrate was administered as a 50 mg oral daily dose to 44 normogonadotrophic (serum FSH 2-10 mIU/ml) subfertile men for 3 months. The treatment resulted in significant increases in FSH and LH concentrations, whereas prolactin remained unchanged. Serum testosterone and oestradiol both increased highly significantly. The increased testosterone levels suggest that the elevated LH levels had not led to "down regulation" of Leydig cell LH/hCG receptors, neither had the greatly increased estradiol led to depletion of these receptors. This is suggested to be a result of the blocking of testicular oestradiol receptors by the estrogen antagonist, clomiphene. Sperm count increased highly unchanged. The spermatic fluid concentrations of zinc and magnesium ions were also increased, whereas fructose remained unchanged. The katalytic activity of acid phosphatase in spermatic fluid increased highly significantly, whereas the concentration of the main prostate-specific acid phosphatase, as measured by a specific radioimmunological method, remained unchanged. Therefore, the increased Zn and Mg ion concentrations may be responsible for activation of acid phosphatase (s) in semen, or the treatment led to increased secretion of other prostatic acid phosphatase(s) than the main enzyme. However, it is clear that the secretion of the main prostatic acid phosphatase into semen is under different control than that of Zn++ and Mg++.

Acid Phosphatase↗
PubMed1981

Effect of clomiphene treatment on the human testicular response to a single dose of hCG.

The effect of antioestrogen treatment on the human testicular response to hCG was investigated in 17 adult men to further clarify the role of endogenous oestradiol in the regulation of testicular steroidogenesis. Clomiphene citrate was administered in 2 different modes. Group 1 (n = 8) was treated for 6 days (100 mg of the antioestrogen once a day) and a single dose of hCG (5000 IU im) was given at the beginning of the experiment. In group 2 (n = 9), the treatment was started 7 days prior to the hCG injection and was continued for additional 6 days. In both groups peripheral blood samples were collected up to 6 days after hCG, and the sera were analysed for FSH, prolactin and 8 steroids. In group 1, the steroidogenic response was identical to that found previously in untreated men. In group 2, the 7-day treatment with clomiphene citrate led to elevated serum concentrations of LH, FSH, pregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, testosterone, 5 alpha-dihydrotestosterone and oestradiol. When compared with these elevated values, the response of serum 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione and testosterone to hCG were diminished. The ratios of the steroid concentrations support previous reports that hCG-induced inhibition of 17-hydroxylase, 17--20 desmolase and 3 beta-hydroxysteroid dehydrogenase-delta 4-5 isomerase is decreased during antioestrogen administration. This further substantiates the idea of a central role for endogenous testicular oestradiol in the mediation of steroidogenic lesions following acute large doses of hCG.

Adult↗
PubMed1979

Histochemical studies of testicular delta5-3beta-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase after chronic indomethacin administration in rats pretreated with clomiphene-citrate.

Histochemical studies of testicular delta5-3beta-Hydroxysteroid Dehydrogenase and 17beta-Hydroxysteroid Dehydrogenase in sexually immature rats treated chronically with simultaneous Indomethacin and Clomiphene revealed greater inhibition in the enzyme activities when compared to Clomiphene treated animals alone. This suggests prostaglandin-inhibitors may be directly inhibitory to NAD-requiring enzymes involved in testicular steroid biosynthesis.

17-Hydroxysteroid Dehydrogenases↗
PubMed2006

Role of aromatase inhibitor in ovulation induction in patients with poor response to clomiphene citrate.

AIM: To examine the efficacy of aromatase inhibitor in the induction of ovulation. METHODS: This prospective clinical trial in patients with infertility and poor response to clomiphene citrate (CC) was undertaken in a tertiary referral infertility clinic. Thirty-five infertile patients, who were treated by clomiphene citrate for several cycles and referred to the infertility clinic, were the target population. Initially, the response of CC was assessed by same dose of CC that the patient had in her last cycle. The patients who did not respond adequately were treated by aromatase inhibitor 2.5-5 mg/day from day 3-7 of the menstrual cycle. The main outcome measures were the number of mature follicles, ovulation rate, endometrial thickness and pregnancy rate. RESULTS: Twenty-seven (90%) patients developed mature follicles by day 12. The majority (77.77%) developed single follicle. Except for one cycle of one patient, the follicles of all patients were ruptured in all cycles and seven (25.94%) got pregnant. CONCLUSION: The aromatase inhibitor letrozole is effective for ovulation induction in anovulatory infertility in patients that failed to ovulate by CC.

Adult↗
PubMed1982

Randomised trial of clomiphene citrate treatment and vitamin C for male infertility.

A prospective randomised trial was carried out to assess the effect of 6 months' treatment with either clomiphene citrate or vitamin C in 179 men complaining of infertile marriage. There was no significant difference in the wife's pregnancy rates between the 2 treatment groups. In order to detect a subgroup that might respond to clomiphene the results were analysed according to pre-treatment FSH and sperm density, with allowance being made for the result of the wife's tests, but still there was no significant difference in treatment response Vitamin C would seem a preferable and cheaper alternative treatment for male infertility.

Ascorbic Acid↗
PubMed1975

Infertility in women with apparently ovulatory cycles. II. The effects of clomiphene treatment on the profiles of gonadotrophin and sex steroid hormones in peripheral plasma.

Six infertile patients had been studied previously (Dodson et al., 1975b) and were shown to produce inefficient corpora lutea which appeared to be predetermined by ovulation of "poorly grown" follicles. In a second cycle these infertile patients were treated with 50 mg of clomiphene per day for five days. The resulting plasma sex steroid and gonadotrophin profiles were compared with those found before treatment and with the profiles in normal patients (Dodson et al., 1975a). Treatment with clomiphene appeared to produce increased follicular growth and more active corpora lutea.

Clomiphene↗