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Endometrial thickness cannot predict ongoing pregnancy achievement in cycles stimulated with clomiphene citrate for intrauterine insemination.

To date, limited data exist concerning the relation between endometrial thickness on the day of human chorionic gonadotrohin (HCG) administration and ongoing pregnancy achievement in cycles stimulated with clomiphene citrate for intrauterine insemination (IUI). In a prospective study, 168 couples were stimulated with clomiphene citrate from day 3 to day 7 of the cycle and endometrial thickness was assessed by ultrasound three times on the day of ovulation triggering. Ovulation was induced with HCG as soon as >/=1 follicle of >/=17 mm was present at ultrasound independently of endometrial thickness. IUI was performed 36 h after HCG administration. The main outcome measure was ongoing pregnancy. No difference was observed in endometrial thickness between patients who did or did not achieve an ongoing pregnancy (7.6 +/- 0.3 versus 7.6 +/- 0.2 respectively; P = 0.7). No discriminative ability of endometrial thickness on the achievement of ongoing pregnancy could be shown by receiver operating characteristic (ROC) curve analysis (area under the ROC curve 0.51, 95% CI: 0.44-0.59). In conclusion, endometrial thickness cannot predict ongoing pregnancy achievement in IUI cycles stimulated with clomiphene citrate.

Adult↗

Clomiphene increases free testosterone levels in men with both secondary hypogonadism and erectile dysfunction: who does and does not benefit?

Secondary hypogonadism is more common than primary gonadal failure and is seen in chronic and acute illnesses. Although testosterone has a role in erections, its importance in erectile dysfunction (ED) has been controversial. Hypogonadism produced by functional suppression of pituitary gonadotropins has been shown to correct with clomiphene citrate, but with a modest effect on sexual function. We wondered if longer treatment would produce improved results. A total of 178 men with secondary hypogonadism and ED received clomiphene citrate for 4 months. Sexual function improved in 75%, with no change in 25%, while significant increases in luteinizing hormone (P<0.001) and free testosterone (P<0.001) occurred in all patients. Multivariable analysis showed that responses decreased significantly with aging (P<0.05). Decreased responses also occurred in men with diabetes, hypertension, coronary artery disease, and multiple medication use. Since these conditions are more prevalent with aging, chronic disease may be a more important determinant of sexual dysfunction. Men with anxiety-related disorders responded better to normalization of testosterone. Assessment of androgen status should be accomplished in all men with ED. For those with lower than normal age-matched levels of testosterone treatment directed at normalizing testosterone with clomiphene citrate is a viable alternative to giving androgen supplements.

Aging↗

Clomiphene citrate versus varicocelectomy in treatment of subclinical varicocele: a prospective randomized study.

BACKGROUND: The purpose of the study was to compare the effect of varicocelectomy with that of clomiphene citrate on seminal improvement and pregnancy rates in patients with subclinical varicocele. METHODS: A total of 42 infertile men with left subclinical varicocele were randomized to group I (21 patients, surgery) and group II (21 patients, medical therapy). The patients in group I were treated with varicocelectomy and those in group II with clomiphene citrate, 50 mg/day, orally. Sperm parameters (sperm density, motility and morphology) were recorded before and 6 months after beginning the treatment and pregnancy rates were estimated. In statistical analysis, paired and independent-samples t-tests, Kaplan-Meier and Log rank tests and Fisher's exact test were used. RESULTS: Mean +/- SD age of the series was 32.7 +/- 6.1 years, that of group I was 32.2 +/- 5.5 years and that of group II was 33.1 +/- 6.7 years (P = 0.680). All seminal parameters increased after both surgical and medical treatment, but only increases in sperm density and motility following varicocelectomy were statistically significant. Changes in seminal parameters between groups I and II were statistically insignificant. Pregnancy was seen in two cases in group I and in one in group II (P = 0.500). The cumulative pregnancy rates were 12.5% in group I and 6.7% in group II (P = 0.589). CONCLUSIONS: Clomiphene citrate did not increase sperm density and motility as effectively as subclinical varicocelectomy, but there was no statistically significant difference between surgical and medical therapy methods in terms of seminal improvement and pregnancy rate.

Adult↗

Blood flow changes in the ovarian and uterine arteries in women with polycystic ovary syndrome who respond to clomiphene citrate: correlation with serum hormone concentrations.

OBJECTIVE: Our purpose was to study the hemodynamic changes in the uterine and intraovarian vessels in women with polycystic ovary syndrome (PCOS) and to relate the vascular changes to hormonal indices. METHODS: Six women with a history of previous anovulatory cycles and/or oligomenorrhea and/or elevated serum luteinizing hormone concentrations in addition to polycystic ovaries underwent induction of ovulation with clomiphene citrate. Serial transvaginal ultrasonography was performed on menstrual cycle day 2, daily from the estimated day of ovulation minus 6, 6-hourly from the estimated day of ovulation minus 2 or when the mean follicular diameter was greater than 16 mm (whichever was earlier) until 6 h after follicular rupture, and once 7 days after follicular rupture. At each scan, uterine and intraovarian blood flow was assessed by transvaginal color Doppler ultrasound, and serum concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol and progesterone were assessed by fluoroimmunoassay. RESULTS: All six women demonstrated ultrasonographic features of ovulation. Follicular peak systolic blood flow velocity (Vmax) and ovarian stromal Vmax in the dominant ovary increased during the follicular phase of the menstrual cycle and reached a peak at 36 and 42 h after the onset of the LH surge of 30.7 +/- 4.6 cm/s and 37.0 +/- 3.9 cm/s, respectively. There was no significant change in the ovarian stromal Vmax of the non-dominant ovary. There was no significant change in the pulsatility index (PI) in either the follicular or the ovarian stromal vessels during the menstrual cycle. The changes in follicular Vmax correlated significantly with changes in serum concentrations of FSH, LH and progesterone. Uterine artery time-averaged maximum velocity (TAMX) declined to its lowest levels at LH surge minus 6 days, and thereafter increased. In contrast, the PI increased during the follicular phase of the cycle, reaching a peak at LH surge minus 4 days, and thereafter declined. The changes in uterine artery PI correlated inversely with serum estradiol and serum progesterone concentrations. CONCLUSIONS: Women with PCOS have significant differences in intraovarian and uterine artery hemodynamics, both at the baseline ultrasound scan and during the clomiphene-induced menstrual cycle, compared with women with normal ovaries. The intraovarian and uterine artery vascular differences are likely to be due to a primary disorder within the polycystic ovary and their different hormonal status. Clomiphene citrate may have an effect on uterine artery blood flow.

Adult↗

Effect of dexamethsone on luteinizing hormone and follicle stimulating hormone responses to LHRH and to clomiphene in the follicular phase of women with normal menstrual cycles.

In an attempt to elucidate the mechanism of suppressive action of glucocorticoids on the hypothalamo-pituitary-ovarian axis, we studied the effects of short-term high dose dexamethasone administration of the LH and FSH responses to LHRH and to clomiphene in healthy women with normal menstrual cycles. Seven women, 21--35 years of age, received 100 micrograms of LHRH i.v. on day 6 of two consecutive menstrual cycles, once with and once without pre-treatment with dexamethasone 2 mg orally every 6 hrs. on days 2 through 5 of the menstrual cycle. Seven other women (ages 21--35 years) received clomiphene citrate 100 mg on days 2 through 5 of their menstrual cycle, once with and once without simultaneous administration of dexamethasone 2 mg orally every 6 h. The administration of dexamethasone suppressed baseline serum levels of LH and FSH and blunted LH and FSH response to both LHRH and clomiphene. The results indicate that short-term administration of pharmacological doses of glucocorticoids suppress the secretion of LH and FSH by a direct effect on the anterior pituitary and possibly by an effect at the hypothalamic level with inhibition of the release of LHRH.

Adult↗

Evaluation of the antilipolytic action of clomiphene in vitro.

Clomiphene (10(-3) - 10(-2) M) in a dose-dependent manner inhibited the lypolytic response of isolated rat epididymal adipose tissue and fat cells to epinephrine, ACTH, and dibutyryl-cyclic AMP. Furthermore, it reduced the non-hormonally stimulated activity of a crude preparation of lipase from epididymal adipose tissue. The accumulation of cyclic AMP produced by epinephrine in fat cells was not prevented by clomiphene at a concentration causing antilipolytic activity. It is concluded from these results that clomiphene unlike most other antilipolytic drugs exerts its antilipolytic effect by an inhibition of the lipase rather than by inhibition of adenylcyclase.

Adipose Tissue↗

Naloxone fails to increase LH levels in clomiphene treated men.

The gonadotrophin response to the opiate antagonist naloxone administered per infusion has been investigated before and after 5 days of clomiphene treatment in 5 male subjects. Before clomiphene treatment, naloxone caused a significant increase in LH levels, however, after clomiphene, naloxone failed to induce the same effect. An important role for gonadal steroids on the opiatergic inhibitory tone of LH secretion in man is suggested.

Adult↗

A cost comparison of infertility treatment for clomiphene resistant polycystic ovary syndrome.

BACKGROUND: The study compares treatment outcome and costs of ovulation induction cycles and in vitro fertilization cycles in infertile women with clomiphene resistant polycystic ovary syndrome. METHODS: Twenty-eight infertile women with clomiphene resistant polycystic ovary syndrome referred to a university clinic were prospectively randomized to ovulation induction or in vitro fertilization. Forty-one ovulation induction cycles and thirty in vitro fertilization cycles were performed. Mann-Whitney U-test was used for between group comparisons and frequencies were compared with Fisher's exact test. RESULTS: More pregnancies per completed cycle were noted in the in vitro fertilization group than in the ovulation induction group. Drug costs were not much higher in the in vitro fertilization group but treatment costs were higher due to the additional costs of ovum pick up and embryo transfer. The cost per pregnancy was about twice as high in the ovulation induction group as in the in vitro fertilization group. The cost per term pregnancy including delivery was 1.6 times higher in the ovulation induction group. CONCLUSION: For a group of obese women with clomiphene resistant polycystic ovary syndrome, in vitro fertilization seems a cost-effective treatment.

Clomiphene↗

A documented clomiphene-induced follicular development in pregnancy.

A case of clomiphene-induced follicular growth in pregnancy is presented in a 34-year-old woman with ectopic pregnancy treated at a university teaching hospital. Following administration of clomiphene citrate in pregnancy, follicular growth to 18 mm mean diameter was noted. It is concluded that clomiphene citrate can induce follicular growth and maturation in pregnancy, possibly by reversing pregnancy-induced pituitary suppression.

Adult↗

Use of cetrorelix in combination with clomiphene citrate and gonadotrophins: a suitable approach to 'friendly IVF'?

BACKGROUND: With the recently introduced GnRH antagonists, soft stimulation protocols on the basis of clomiphene pretreatment should be possible as the pituitary remains fully sensitive at the beginning of the cycle. METHODS: A prospective trial was carried out on 107 patients undergoing IVF treatment using the multiple dose GnRH antagonist protocol (cetrorelix), clomiphene citrate, and either HMG (n = 54) or recombinant FSH (rFSH) (n = 53). Different stimulation protocols were used to find the most appropriate one for clinical application. RESULTS: Both treatment groups, HMG and rFSH, yielded comparable results concerning gonadotrophin dose, stimulation days and pregnancy rate. A mean number of 6.34 +/- 4.4 metaphase II oocytes was retrieved and a mean number of 2.45 +/- 0.65 embryos was transferred. However, the overall rate of premature LH surges was 21.5% (defined as measurement of LH >10 IU/l and progesterone >1 ng/ml) which is unacceptable for clinical practice. CONCLUSIONS: Increasing the daily cetrorelix dose from 0.25 to 0.5 mg might decrease the number of premature LH surges. Soft stimulation protocols with clomiphene should be used cautiously.

Adult↗

An economic comparison of a laparoscopic electrocautery strategy and ovulation induction with recombinant FSH in women with clomiphene citrate-resistant polycystic ovary syndrome.

BACKGROUND: Recombinant FSH (rFSH) is the current standard treatment for ovulation induction in women with polycystic ovary syndrome (PCOS) that do not respond to clomiphene citrate. Ovulation induction with rFSH is known to be costly due to the necessity of daily injections and intensive monitoring. An alternative strategy, starting with electrocautery of the ovaries, may be a less costly option. METHODS: An economic evaluation was set up alongside a multicentre randomized clinical trial comparing laparoscopic electrocautery of the ovaries, followed by clomiphene citrate and rFSH when anovulation persisted, and treatment with rFSH in 168 women with clomiphene citrate-resistant PCOS. Data on resources used for treatment and productivity loss were collected prospectively up to an eventual ongoing pregnancy with a time horizon of 12 months. RESULTS: At 12 months the ongoing pregnancy rates were 67% for both the electrocautery strategy and rFSH treatment. Mean total costs per woman were 5308 euros for the electrocautery strategy and 5925 euros for treatment with rFSH, resulting in a mean difference of 617 (95% CI: -382 euros to 1614 euros). CONCLUSIONS: The total treatment costs up to an ongoing pregnancy are comparable for rFSH treatment and an alternative strategy starting with electrocautery. Due to a lower number of multiple pregnancies, the electrocautery strategy can be expected to result in lower total costs when costs of the delivery are included.

Adult↗

Effects of clomiphene citrate stimulation on endometrial structure in infertile women.

Investigations into the effect of clomiphene citrate stimulation on endometrial differentiation were retrospectively performed in the mid-luteal phase on 21 patients undergoing ovulation induction prior to artificial insemination. A high incidence of irregular endometrial development was seen using morphological and morphometric criteria; in addition, increasing stromal oedema after clomiphene citrate treatment was observed. Measurable differences in glandular development (i.e. numbers of glands and glandular epithelial height) were found in early luteal phase biopsies (LH+2/+6) from patients treated with clomiphene citrate and normal fertile controls. Impaired endometrial development in the early luteal phase, which is a sensitive interval in preparation for implantation, might lead to an effective asynchrony between embryonic and uterine development and unfavourably influence the outcome of implantation.

Adult↗

Gonadotrophin-releasing hormone agonist compared with human chorionic gonadotrophin for ovulation induction after clomiphene citrate treatment.

The objective of this study was to compare hormonal response, luteal phase adequacy and pregnancy and abortion rates in patients randomized to receive human chorionic gonadotrophin (HCG) or gonadotrophin-releasing hormone agonist (GnRHa) during ovulation cycles stimulated by clomiphene citrate. Anovulatory patients received either one s.c. dose of tryptorelin (0.1 mg; n = 104) or one i.m. dose of HCG (10,000 IU; n = 106) after clomiphene citrate stimulation had induced enlarged ovarian follicles (> 17 mm in diameter). A short-lived, transitory increase in serum luteinizing hormone (98 +/- 9 IU/l) and follicle-stimulating hormone (30 +/- 5 IU/l) concentrations was measured at 12 h following the injection of GnRHa, and these concentrations returned to baseline levels by 36 h post-injection. Midluteal progesterone concentrations were similar in both groups (> 10 ng/ml), and the mean luteal phase duration was also not significantly different (13 days). There were no significant differences in the mean number of pregnancies (12.0 versus 12.6% per cycle) and the abortion rate (18.2 versus 12.5%) between the GnRHa- and HCG-treated groups respectively. There were no complications related to treatment in either group. The results show that a relatively low dose of GnRHa can be used in place of HCG to induce ovulation in clomiphene citrate-treated patients.

Abortion, Spontaneous↗

Prospective randomized study of clomiphene citrate and gonadotrophins versus goserelin and gonadotrophins for follicular stimulation in assisted reproduction.

We performed a prospective randomized study of goserelin, a long-acting gonadotrophin-releasing hormone agonist (GnRHa) and human menopausal gonadotrophin (HMG) versus clomiphene citrate and HMG for follicular stimulation in assisted reproduction to investigate whether the use of this GnRHa provides a clear advantage in terms of pregnancy per treatment cycle in unselected patients, who entered a first trial of assisted reproduction. From a retrospective analysis comparing the two stimulation protocols, a relative increase of the pregnancy rate per cycle of 50% was anticipated. To detect this difference with a power of 90%, 300 patients had to be included. The main prognostic factors affecting the outcome of assisted reproduction were equally divided among the two groups by a minimization procedure. The pregnancy rates per cycle were significantly better in the goserelin/HMG group than in the clomiphene citrate/HMG group, both for all procedures of assisted reproduction combined (36.8 versus 24.5%; P < 0.02) and for the main procedure of in-vitro fertilization (IVF) (37.0 versus 23.5%; P < 0.02). Differences in pregnancy rates per oocyte retrieval and per embryo transfer were less pronounced (37.8 versus 30.8%; P = 0.40 and 44.4 versus 36.8%; not significant). On the other hand, stimulation with goserelin/HMG was associated with a higher number of ampoules of HMG (44.9 versus 9.9; P < 0.0001), a longer duration of stimulation (11.2 versus 8.7 days; P < 0.0001) and an incidence of ovarian stimulation of 4.5% (7/154) versus 0% in the clomiphene citrate/HMG group. Goserelin was well tolerated and proved to be very reliable as an adjunct of follicular stimulation in assisted reproduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

The choice of treatment for anovulation associated with polycystic ovary syndrome following failure to conceive with clomiphene.

The choice of treatment for clomiphene-resistant anovulation associated with polycystic ovary syndrome (PCOS) is presently arbitrary and selection criteria are not available. A total of 144 women with anovulatory infertility associated with PCOS who failed to conceive on clomiphene were treated with either pure follicle stimulating hormone (FSH) (n = 29), or human menopausal gonadotrophin (HMG) (n = 60), or gonadotrophin-releasing hormone analogue (GnRHa) and HMG (n = 55). Analysis of 306 treatment cycles and 53 pregnancies revealed a cumulative conception rate at 4 months of 23% with FSH, 47% with HMG and 69% with GnRHa + HMG. The miscarriage rate was highest in the HMG group (44%) and consequently the cumulative live birth rate was superior when GnRHa was used in combination with HMG. There were no significant differences in the basal clinical and endocrinological features of those who conceived compared with those who did not, either in the whole group, or in the individual treatment groups. Thus, the choice of treatment for clomiphene-resistant women with PCOS cannot be guided by the basal clinical or endocrinological features of this heterogeneous syndrome with the present state or knowledge.

Adult↗

Clomiphene's effect on endometrium in infertility.

Secretory-phase endometrium from patients receiving clomiphene has an identifiable, distinctive character. We reviewed 710 endometrial biopsies from 566 infertility patients, including 108 from 79 patients receiving clomiphene. Endometrial glands in biopsies from clomiphene-treated patients were straight, narrow, and less tortuous than normal. Gland-to-stroma ratio was decreased. In the early secretory phase, glands had crisp subnuclear vacuoles and distinct glandular lumenal borders. Secretions were scant throughout the secretory phase, with few apical snouts. Lumenal secretions appeared inspissated and hyaline-like. Late secretory epithelium was generally low cuboidal and rarely showed hypersecretory change. Stromal predecidualization in the late phase showed progression, but in some cases decidual cells were smaller than usual. All of these features are consistent with a hypoestrogenic effect.

Biopsy↗

Bromocriptine treatment of women with clomiphene-resistant polycystic ovary syndrome.

Twenty-three patients with polycystic ovary syndrome and anovulatory infertility have been treated with bromocriptine. All had previously failed to respond to clomiphene. Twenty had normal serum prolactin concentrations and, of these, four (20%) developed regular ovulatory cycles. All three women with moderate hyperprolactinaemia ovulated regularly on bromocriptine so that, overall, seven of 23(30%) responded, which was a significantly higher proportion than that observed during a control period of no treatment. A further eight women ovulated at least once during the study period but these occasional ovulations were no more common during bromocriptine than with either clomiphene or no treatment. No suppression of LH was noted except during the luteal phase of ovulatory cycles and there was no change in the pattern of pulsatile release of LH. Testosterone and androstenedione concentrations remained elevated and unchanged. We conclude that bromocriptine may be expected to induce ovulation in hyperprolactinaemic women with polycystic ovary syndrome but that there is no clear indication for its use in clomiphene-resistant patients with normal serum prolactin concentrations.

Adult↗

Hypothalamic function in women with secondary hypogonadism and unresponsive to clomiphene therapy.

Seven women with secondary hypogonadism who had been previously unresponsive to two 5-d courses of clomiphene citrate, were treated with clomiphene citrate 100 mg daily for 10 d. LH and FSH concentrations were measured in serum collected at 15-min intervals for 5 h before and on the 10th day of treatment and oestradiol was measured in the first two samples on each day. Four women responded with an increase in the amplitude of LH pulses and in mean LH values and in three there was a marked increase in serum oestradiol concentrations. Three women who showed no gonadotrophin response were subsequently unresponsive to pulsatile LHRH therapy. These preliminary data are consistent with the hypothesis that hypothalamic hypogonadotrophism may result from hypersensitivity of the hypothalamus to oestrogen negative feedback and that the hypothalamic potential for secretion of LHRH is unimpaired. Prolonged treatment with clomiphene may provide a simple test of hypothalamic function in women with normal pituitary function.

Adult↗