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Preovulatory luteinization during induction of follicular maturation with menotrophin and menotrophin--clomiphene combination.

Late follicular phase levels of 17 beta-oestradiol (E2) and progesterone (P) in serum were studied during the induction of follicular maturation with human menopausal gonadotrophin (HMG) (n = 23) and HMG-clomiphene citrate (CC) (n = 18). For each patient one hormonal profile was studied between 6 days to 2 h before administration of human chorionic gonadotrophin (HCG). Ultrasonographic follicular measurement at the time of evaluation demonstrated preovoulatory ovarian follicles of various number and size in all patients studied. Sixteen endometrial biopsies were performed at the time of evaluation (eight for each subgroup), before HCG administration. Mean late follicular phase levels of E2 did not differ significantly between the two groups (436 +/- 348 and 475 +/- 267 pg/ml for the HMG and HMG-CC groups respectively). The mean progesterone levels in the HMG-CC group (1.233 +/- 0.67 ng/ml) was significantly higher than that for the HMG group of (0.86 +/- 0.55 ng/ml, P less than or equal to 0.04). The mean time interval between ovulation and HCG administration for the two groups was 2.5 and 2.4 days for the HMG and HMG-CC groups, respectively. In all eight biopsies taken from the HMG group, various stages of endometrial proliferation were demonstrated. Premature glandular secretory transformation and oedematous stroma were observed in three out of eight biopsy specimens obtained from the HMG-CC group. Taken together, these results demonstrate that subtle or full premature luteinization in the late follicular phase occurs more frequently with the use of HMG-CC for induction of follicular maturation.

Adult↗

Establishing pregnancies after follicular stimulation for IVF with clomiphene citrate and human menopausal gonadotrophin only.

Data are presented on establishing pregnancies by IVF during 1987 using only clomiphene citrate and human menopausal gonadotrophin for follicular stimulation. Of the 562 patients undergoing follicular stimulation, 80% reached oocyte recovery and 70% had at least one conceptus replaced. Patients having one or more (up to a maximum of four) conceptuses replaced demonstrated a significant increase in the establishment of pregnancies from one to two (14-29%: P = 0.035) and from two to three conceptuses (29-42%: P = 0.037). There was a significant decline in pregnancies when four conceptuses were replaced compared with three (P = 0.004). The data were also analysed according to the cause of infertility, specifically tubal, endometriosis, unexplained infertility and male factors only. After the replacement of conceptuses, the incidence of implantation and abortion was not significantly different. The incidence of pregnancy declined significantly after 35 years (26%) compared with women under 31 years (43%; P = 0.043). Of 129 women having three conceptuses replaced, in those greater than 35 years (63 patients) 23 (37%) became pregnant whereas in those less than 31 years (65 patients), 34 (52%; P = 0.05) became pregnant. Twenty-two per cent of stimulated cycles resulted in an endogenous LH surge and the incidence of patients having three conceptuses replaced in this group was lower than those in the HCG group (P = 0.007). Fertilization per oocyte was also significantly reduced (P less than 0.001) in patients with an LH surge. In total, 2824 oocytes were recovered and 57% fertilized with 54% of patients having three conceptuses replaced.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Pure FSH for ovulation induction in patients with polycystic ovary syndrome and resistant to clomiphene citrate therapy.

Twenty-nine infertile women with polycystic ovary disease which was resistant to therapy with clomiphene citrate underwent a combined treatment for follicle recruitment consisting of pure FSH during the first days of the cycle and HMG during the last days of the follicular phase. Sixty cycles were stimulated of which 83% were ovulatory. Eighteen pregnancies were achieved (36% of cycles, 62% of patients). The multiple pregnancy rate was 39%. Twelve cycles (20%) showed the ovarian hyperstimulation syndrome (OHS) although seven of these resulted in full term deliveries. There were no miscarriages among the patients studied.

Adult↗

The effects of clomiphene citrate upon ovulation and endocrinology when administered to patients with unexplained infertility.

Twenty-four couples with unexplained infertility were studied in a spontaneous cycle followed by a clomiphene citrate (CC) cycle (150 mg, days 5-9). All spontaneous cycles were ovulatory, as defined by follicular collapse determined by transvaginal sonography. In CC cycles, 6/24 (25%) cycles demonstrated luteinized unruptured follicles (LUF). In 2/6 LUF cycles there was no apparent luteinizing hormone (LH) surge. LUF cycles had significantly elevated LH levels in the follicular phase compared to ovulatory CC cycles. There was no apparent difference in serum oestradiol. In CC cycles multifollicular development occurred in 87.5% of cycles, with significantly elevated serum oestradiol. Luteinizing hormone and follicle-stimulating hormone were elevated in the follicular phase compared to spontaneous cycles. This study suggests a high incidence of LUF when CC is administered to ovulatory patients, and its use in patients with ovulatory infertility is questioned.

Clomiphene↗

Effect of clomiphene citrate on the synthesis and release of the human beta-lactoglobulin homologue, pregnancy associated endometrial alpha 2-globulin, by the uterine endometrium.

As an extension to a previous study to examine the effects of clomiphene citrate (CC) on human chorionic gonadotrophin/luteinizing hormone (LH) receptors in human corpora lutea, we sought to determine the effect of CC on the synthesis of the beta-lactoglobulin homologue, pregnancy associated endometrial alpha 2-globulin (alpha 2-PEG) by the luteal phase human endometrium. Seventeen normally-cycling women aged 25.9 +/- 2.1 years (mean +/- SE), undergoing elective tubal ligation, were divided into four groups consisting of controls (n = 2) and three treatment groups. Each of the treatment groups (n = 5/group) was treated with either 50 mg (group 1), 100 mg (group 2) or 150 mg (group 3) of CC daily on days 5 to 9 of the cycle. Portions of endometrial tissue were obtained by curettage 7 to 9 days following the urinary LH surge and were either fixed for histological analyses or cultured in vitro in the presence of [35S]methionine. Tissue media (TCM) that were analysed by two-dimensional gel electrophoresis followed by fluorography indicated that the synthesis of alpha 2-PEG was most markedly reduced in groups 2 and 3. Densitometric scans of TCM Western blots and radioimmunoassay (RIA) of TCM showed that the overall synthesis of alpha 2-PEG decreased from 5.8 +/- 1.9 arbitrary units (AU) and 371.2 +/- 239.3 ng/ml in group 1 to 3.1 +/- 0.8 AU and 69.4 +/- 24.9 ng/ml, and 2.7 +/- 1.1 AU and 52.4 +/- 19.8 ng/ml in groups 2 and 3 respectively. On cycle days 20-22, control values were 5.8 AU and 498.1 ng/ml respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

The synergistic effects of clomiphene citrate and human menopausal gonadotrophin in the folliculogenesis of stimulated cycles as assessed by the gonadotrophin-releasing hormone antagonist Nal-Glu.

Clomiphene citrate (CC), alone or in combination with exogenous gonadotrophins, has been widely used in ovulation induction. CC promotes endogenous release of gonadotrophins, yet when used in combination with exogenous gonadotrophins, its contribution to folliculogenesis is difficult to assess. In order to determine the contribution of CC-induced endogenous gonadotrophin production to the overall ovarian stimulation in cycles treated with CC/human menopausal gonadotrophin (HMG), Nal-Glu, a gonadotrophin-releasing hormone (GnRH) antagonist was administered. Fertile women (n = 10) undergoing ovarian stimulation and oocyte aspiration for the sole purpose of gamete donation were studied. Five women received CC (100 mg daily for 5 days) in conjunction with pure follicle stimulating hormone (FSH) 150 IU daily. Five women received HMG alone. Nal-Glu (50 micrograms/kg/day) was administered intramuscularly to both groups when the leading follicles reached a mean diameter of 16 mm. Human chorionic gonadotrophin (HCG) 10,000 IU was given when the largest follicles reached a mean diameter of 20-22 mm. A significant fall in serum oestradiol levels was observed in women given CC/FSH (37.9 +/- 7.3%) within the first 24 h of Nal-Glu administration. Serum luteinizing hormone (LH) decreased greater than 20% within 24 h of Nal-Glu administration and remained low throughout the rest of the treatment. No decrease in oestradiol levels was noted in cycles receiving HMG alone. With supplemental FSH, falling oestradiol levels in CC/FSH cycles rebounded and continued to rise until the day after HCG administration. Despite a drop in oestradiol in CC/FSH cycles, the aspirated oocytes exhibited no untoward effects. The fertilization and cleavage rates were similar, and pregnancies occurred in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Clomiphene↗

Reproductive performance of patients treated with clomiphene citrate.

From 1967-1980, 488 infertile women underwent induction of ovulation with clomiphene citrate at the University of Virginia Hospital. Conception occurred during treatment cycles in 209 women (group 1), but 279 women (group 2) failed to conceive. The outcome of pregnancy was defined in group 1, and the pregnancies that occurred in both groups after treatment was discontinued were analyzed. Early pregnancy wastage (spontaneous abortion and ectopic pregnancy) in these groups was compared with the accepted incidence in the general population. Although the rates of adverse pregnancy outcome were higher in our study populations, there was no statistical difference when compared to the general population.

Abortion, Incomplete↗

Body fat patterning in polycystic ovary syndrome women as a predictor of the response to clomiphene.

BACKGROUND: To investigate the difference in the response to clomiphene citrate (CC) based on body fat distribution in women with polycystic ovary syndrome (PCOS). METHODS: Ninety anovulatory PCOS women were divided into two subgroups based on treatment response: women who ovulated with CC (CC responders, n = 49) and those who did not ovulate with CC (CC nonresponders, n = 41). Baseline characteristics included age, age at menarche, height, weight and body mass index [BMI; weight/(height)2]. Percentage of body fat, body fat mass and the ratio of trunk fat to leg fat mass amount (trunk-leg fat ratio) were measured by dual-energy X-ray absorptiometry (DEXA). RESULTS: Age, age at menarche and height did not differ between the two groups. However, trunk-leg fat ratio in CC responders (0.9 +/- 0.4) was significantly lower than that in CC nonresponders (1.3 +/- 0.4) (p < 0.001). Percentage of body fat, body fat mass and BMI were also lower in CC responders (p < 0.01). On multiple regression analysis, however, trunk-leg fat ratio proved to be a superior predictor of CC responder to percentage of body fat, BMI or body fat mass (standardized regression coefficient > or = 0.510; t-values > or = 3.432; p < 0.001). CONCLUSIONS: Response to CC in anovulatory PCOS women differs with body fat distribution.

Adipose Tissue↗

Factors associated with pregnancy or miscarriage after clomiphene therapy in WHO group II anovulatory women.

OBJECTIVES: The present study was designed to determine whether clinical and endocrine characteristics assessed on initial screening of normogonadotropic oligo/amenorrhoeic infertile patients could predict ovulation and then conception and successful live birth or miscarriage. STUDY DESIGN: Retrospective cohort study SETTING: Outpatient clinic. POPULATION: Eighty-two consecutive women receiving clomiphene citrate (CC) therapy from 1993 to 1998. RESULTS: A cumulative conception rate of 67% was reached after six or more CC-induced cycles. Patients with failure of ovulation after a full course of CC had more severe oligomenorrhoea (p < 0.001) and greater BMI (p < 0.05) at initial screening. There was no relationship with levels of LH or androgens. In contrast, among women who ovulated in response to CC, conception was associated with less frequent periods, and higher basal levels of LH, free testosterone and androstenedione. Conceptions with subsequent miscarriage were associated with intermediate levels of LH and numbers of spontaneous periods between non-conception and live births. CONCLUSIONS: These observations are consistent with the hypothesis that failure of ovulation after CC is related to different factors (overweight and severe oligomenorrhoea) from those that predispose to non-conception (low basal LH and androgen levels and mild oligomenorrhoea).

Abortion, Spontaneous↗

Hormonal profiles following clomiphene citrate therapy in conception and nonconception cycles.

The hormonal profiles following clomiphene citrate (CC) administration during a single cycle were compared in infertile women who conceived and in those who did not. Of 41 treated patients, ovulation was assumed to have occurred in 28 and was confirmed by clinical pregnancy in five. In the 28 women who presumably ovulated, two distinct patterns of hormonal secretion were observed. A normal response was exhibited by 17 patients (including the five who became pregnant). The other 11 patients exhibited an abnormal response, characterized by significantly higher luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratios than in the normal response group from day 9 until the occurrence of the LH peak (days 9 and 10, P less than 0.05; days 11 and 12, P less than 0.001), and significantly higher oestradiol (E2) levels throughout the cycle (P less than 0.01). In addition, in comparison with the normal response group their LH levels during the follicular phase were significantly higher (P less than 0.05) but their LH peaks at ovulation were significantly lower (P less than 0.02). Moreover, their progesterone levels, in contrast to those in the normal response group, began to increase prior to the LH peak and remained high during the early and mid-luteal phases. None of the women who exhibited this abnormal gonadotrophin response to CC therapy achieved a clinical pregnancy. Exposure to high LH levels in the follicular phase following CC therapy seems to reduce the rate of fertilization and/or to contribute to early embryonic loss.

Clomiphene↗

Effects of clomiphene and raloxifene on gonadotrophin secretion in postmenopausal women: evidence of nongenomic action.

OBJECTIVE: To evaluate the effect of raloxifene (R) and clomiphene (Cl) on FSH and LH secretion in postmenopausal women. DESIGN: Postmenopausal volunteer women participated in two experimental (Exp) procedures. In Group 1, the women received R (180 mg/day orally) for 30 days plus oestradiol (E2) through skin patches (100 microg/24 h) from days 21 to 30 (R-Exp). After a month's break the same women received Cl (150 mg/day orally) for 30 days plus E2 as above (Cl-Exp). In Group 2, the women received E2 for 30 days plus R from days 21 to 30 (R-Exp) and after a month's break they received E2 for 30 days plus Cl from days 21 to 30 (Cl-Exp). Daily doses were as in Group 1. A GnRH test (100 microg intravenously) was performed in all women on days 0, 10, 20 and 30 of each experiment. PATIENTS: Sixteen healthy postmenopausal women were divided into two groups (eight women in each group). MEASUREMENTS: The area under the curve (AUC) of DeltaFSH and DeltaLH response to GnRH (net increase above the basal value) was calculated. RESULTS: In Group 1, basal levels of FSH and LH did not change significantly during the R-Exp, while they decreased significantly in the Cl-Exp (P < 0.001). The addition of E2 did not have any effect. The AUC of LH response to GnRH increased significantly in the R-Exp (P < 0.05) and that of FSH in the Cl-Exp (P < 0.05). In Group 2, basal levels of FSH and LH declined significantly during treatment with E2 in both the R-Exp (P < 0.01) and the Cl-Exp (P < 0.001). However, the addition of Cl (for 10 days) interrupted this decrease, while the addition of R stimulated FSH levels significantly (P < 0.05). E2 suppressed significantly the AUC of LH in both experiments (P < 0.05). The addition of Cl did not affect the AUC in response to GnRH, while the addition of R increased the AUC of both LH and FSH (P < 0.05). CONCLUSIONS: These results demonstrate for the first time that in contrast to Cl, R does not exert oestrogenic effects on basal gonadotrophin secretion. Although the antioestrogenic action of these drugs was evident only after pretreatment with E2, both R and Cl stimulated GnRH-induced gonadotrophin secretion in oestrogen-deprived women. It is hypothesized that these two compounds sensitize the pituitary to GnRH through mechanisms not involving the oestrogen receptor complex (nongenomic).

Area Under Curve↗

Metformin administration and laparoscopic ovarian drilling improve ovarian response to clomiphene citrate (CC) in oligo-anovulatory CC-resistant women with polycystic ovary syndrome.

OBJECTIVE: To compare the efficacy of clomiphene citrate (CC) administration for ovulation induction in CC-resistant oligo-ovulatory women with polycystic ovary syndrome (PCOS) after metformin treatment or laparoscopic ovarian drilling (LOD). Design Prospective controlled study. PATIENTS: Twenty-eight overweight oligo-amenorrhoeic women with PCOS who were still anovulatory after metformin administration (group A, n = 8) or LOD (group B, n = 20). METHODS: Treatment with CC 150 mg/day for 5 days from the third to the seventh day of a progesterone-induced uterine bleeding for 6 months. MEASUREMENTS: The ovulation, pregnancy, abortion and live-birth rates were evaluated in each group. RESULTS: The subjects of groups A and B were studied for a total of 36 and 74 cycles, respectively. At the end of the study, no differences in ovulation [11/36 (30.6%) vs. 23/74 (31.1%); P = 0.96], pregnancy [6/36 (16.7%) vs. 12/74 (16.2%); P = 0.95], abortion [2/6 (33.3%) vs. 5/12 (41.7%); P = 1.00] and the live-birth [4/6 (66.7%) vs. 7/12 (58.3%); P = 1.00] rates were observed between groups A and B. CONCLUSION: Metformin administration as well as LOD improves the effectiveness of CC for ovulation induction in overweight infertile CC-resistant women with PCOS.

Adult↗

The effect of clomiphene citrate on sex hormone binding globulin in normospermic and oligozoospermic men.

The effect of clomiphene citrate (CG) on sex hormone binding globulin (SHBG) was studied in 10 oligozoospermic patients with varicocele and 6 normospermic men. Plasma SHBG, testosterone (T), oestradiol (E2), FSH, LH, Prolactin (Prl), thyroxine (T4) and 17-OH-progesterone (17-OH-P) were determined before and during medication. SHBG concentration rose from 38.1 +/- 18.3 to 54.3 +/- 16.0 nmol/l (P less than 0.01), while T and E2 showed significant increases from 31.2 +/- 10.8 nmol/l and 24.6 +/- 5.4 pg/ml to 52.0 +/- 3.6 and 43.3 +/- 14.9, respectively in the oligozoospermic patients, with similar rises noted in the normospermic men. FSH, LH and 17-OH-P were markedly elevated while on CC, but Prl and T4 remained unchanged. The findings of this study indicated the CC causes an increase of SHBG concentration, which is probably related to the rise of E2 concentration. This SHBG change, combined with the intrinsic oestrogenic activity of CC might be one of the factors responsible, through a decrease of free T and a T to E2 imbalance, for the lack of significant effect on parameters of seminal quality in so treated patients.

Clomiphene↗

Haemorrhage into the anterior pituitary during pregnancy after induction of ovulation with clomiphene.

A 34-year-old woman with secondary amenorrhoea and primary infertility became pregnant after treatment with clomiphene. She developed pre-eclampsia. Visual symptoms were experienced due to rapid enlargement of the anterior pituitary gland. The patient was delivered by Caesarean section. At subsequent craniotomy the patient was found to have haemorrhage into the pituitary gland, but histological examination of the pituitary tissue which was removed revealed no tumour tissue. One year after delivery the patient was still amenorrhoeic and had galactorrhoea with hyperprolactinaemia indicating that she probably had a small pituitary adenoma which was incompletely removed during neurosurgery.

Adult↗

Induction of ovulation with clomiphene and human chorionic gonadotrophin in women with hyperprolactinaemic amenorrhoea.

Seventeen women complaining of infertility (one with primary amenorrhoea, 14 with secondary amenorrhoea, and two with oligomenorrhoea) all had hyperprolactinaemia and were treated with clomiphene citrate and human chorionic gonadotrophin (HCG), and plasma oestradiol, FSH and LH levels were measured. Although adequate pre-ovulatory oestradiol levels were present, the surge of LH was absent until the injection of HCG after which all patients ovulated. There were 12 pregnancies in 9 patients resulting in 10 full-term livebirths, one premature livebirth and one continuing pregnancy. The relevance of these findings to the possible role of prolactin in amenorrhoea is discussed.

Adult↗

Influence of laparoscopic follicular aspiration under general anaesthesia on corpus luteum progesterone secretion in normal and clomiphene-stimulated cycles.

In 32 patients with unstimulated normal cycles and 24 with cycles stimulated with clomiphene and human chorionic gonadotrophin (hCG) all visible follicles were punctured laparoscopically under general anaesthesia for the purpose of in vitro fertilization. In unstimulated cycles the time of surgery was between 24 and 32 h after the first luteinizing hormone (LH) increase in the urine; in the cycles stimulated with hCG (5000 i.u.) laparoscopy was between 35 and 37 h after injection. Blood samples for progesterone determination were taken about 7 days later. Progesterone levels were compared with those in a control group not subjected to surgery, in which the progesterone levels were determined 7 days after the LH increase. There was no statistically significant difference in the progesterone levels in the unstimulated subjects after laparoscopy compared with those in the control subjects but progesterone levels in the stimulated subjects were significantly higher (p less than 0.01). Durations of the luteal phases showed no significant differences thus laparoscopy under general anaesthesia does not impair luteal function.

Adult↗