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The role of chronic anovulation in the polycystic ovary syndrome: normalization of sex-hormone-binding globulin levels after clomiphene-induced ovulation.

A group of anovulatory patients with polycystic ovaries (PCO) was given clomiphene citrate and compared with three control groups: normal women having spontaneous, ovulatory cycles, patients with PCO having spontaneous, regular, ovulatory cycles, and anovulatory patients without PCO. Comparisons were made at precise points of the menstrual cycle (taking the day of ovulation as day 0), using ultrasound estimates of mean follicular diameter, uterine volume, and endometrial thickness, and biochemical measurements of LH, FSH, oestradiol (E2), testosterone (T), progesterone (P) and sex-hormone-binding globulin (SHBG). Before clomiphene treatment, the anovulatory patients with PCO had significantly lower levels of SHBG and higher follicular phase concentrations of LH than all three control groups. After two cycles of clomiphene-induced ovulation, the serum LH concentration fell significantly and levels of SHBG increased significantly to levels similar to those found in spontaneously ovulating women with normal ovaries. It is likely that the loss of the usual considerable rise in E2 in both the follicular and luteal phases of ovulatory cycles is the main reason for the low SHBG found in the PCO syndrome. The loss of the normal P-induced gonadotrophin suppression may be a factor in allowing LH levels to rise.

Adolescent↗

Effect of clomiphene citrate on testicular steroid metabolism in man.

Administration of clomiphene citrate to males with normal peripheral testosterone levels increased the serum levels of FSH, LH, testosterone and low polar oestrogens and also the urinary excretion of LH, low polar oestrogens, dehydroepiandrosterone, androsterone and aetiocholanolone. No significant change was noted for the urinary excretion of 17-oxogenic steroids. Addition of clomiphene citrate (10(-4) to 2 X 10(-3) M) to incubations of [7-3H, 21-14C] progesterone with human testicular biopsy specimens in vitro caused a slight inhibition in the formation of 17 alpha-hydroxyprogesterone and a slightly increased formation of 20 alpha-hydroxy-4-pregnen-3-one but no measurable changes in the C19 steroid formation. The results support the hypothesis that there is selective action of clomiphene citrate upon the adrenal C19 steroid biosynthesis in the human male, combined with an indirect effect upon the testes via the hypothalamic-pituitary system. A direct effect on the gonadal steroidogenesis can, however, not be ruled out.

Adult↗

The effect of clomiphene citrate and its Zu or En isomers on the reproductive system of the immature male rat.

The effect of clomiphene citrate (CC) and of its Zuclomiphene (ZuC) and Enclomiphene (EnC) isomers on the reproductive organs of immature male rats under different experimental conditions is reported. CC, ZuC, and EnC were administered daily to groups of either intact or castrated rats between the age of 21-44 d. This led to inhibition of weight increase of testis and accessory glands in the intact group. Spermatogenesis was arrested at the stage of primary spermatocyte following CC and ZuC treatment, and at the stage of young spermatids by EnC treatment. In the castrated group clomiphenes significantly stimulated weight increase of seminal vesicles (SV) compared with castrated control animals, but the former group were unable to achieve organ weight gain comparable to that in normal controls. Administration of human Chorionic Gonadotropin (hCG) together with CC or each of its isomers to intact animals, abolished the drug effect on spermatogenesis and on reproductive organ growth. Administration of CC, ZuC, and EnC together with testosterone to castrated animals, abolished the drug effect on growth inhibition of accessory glands. In intact treated rats LH and testosterone secretion were suppressed by all forms of clomiphenes. In the castrated group ZuC proved to be the most potent inhibitor of LH secretion. Therefore, it is inferred that ZuC and EnC have different potencies as far as their biological activity in the immature male rat is expressed.

Animals↗

Actions of the anti-oestrogen agent clomiphene on outward K+ currents in rat ventricular myocytes.

1. The effects of clomiphene (CLM) on cardiac outward K+ current components from rat isolated ventricular myocytes were investigated using the whole-cell patch-clamp technique. Clomiphene (10 micromol/L) significantly inhibited both peak (Ipeak) and end-pulse (Ilate) outward currents (elicited by a 500 msec voltage step from -40 to +50 mV in the presence of K+-containing intracellular and extracellular solutions) by approximately 37% (n = 6; P < 0.01) and 49% (n = 6; P < 0.01), respectively. In contrast, CLM had no effect on outward currents when K+-free solutions were used. 2. A double-pulse protocol and Boltzmann fitting were used to separate individual K+ current components on the basis of their voltage-dependent inactivation properties. At potentials positive to -80 mV, two inactivating transient outward components (Ito) and (IKx) and a non-inactivating steady state component (Iss) could be distinguished. 3. Clomiphene inhibited both Ito and Iss. The maximal block of Ito and Iss induced by CLM (100 micromol/L) was approximately 61% (n = 5) and 43% (n = 5) with IC50 values of 1.54 +/- 0.39 and 2.2 +/- 0.4 micromol/L, respectively. In contrast, the peak magnitude of IKx was unaltered by CLM, although its time-course of inactivation was accelerated. 4. Further experiments whereby myocytes were superfused with the vasoactive peptide endothelin (ET)-1 (20 nmol/L) revealed that CLM (10 micro mol/L) completely abolished the ET-1-sensitive component of Iss. 5. Our findings demonstrate, for the first time, the effects of CLM on distinct cardiac K+ current components and show that CLM modulates the voltage-gated K+ current components Ito and IKx and inhibits the steady state outward current Iss in rat ventricular myocytes.

Algorithms↗

Plasma oestradiol and progesterone estimation for the monitoring of induction of ovulation with clomiphene and chorionic gonadotrophin.

Two hundred and thirty-five courses of treatment with clomiphene and human chorionic gonadotrophin (HCG) were administered for the induction of ovulation in 75 infertile women (three with primary amenorrhoea, 45 with secondary amenorrhoea and 27 with oligomenorrhoea) of whom 61 had previously been unsuccessfully treated with clomiphene alone. The treatment was monitored by plasma oestradiol estimations on day 15 and day 22 in 103 cycles and by plasma progesterone estimations on day 22 in all 235 cycles. Injections of HCG were given on day 15 and 22. Twenty patients failed to respond to treatment (43 courses). The remaining 55 patients showed no response in 32 courses, deficient responses in 55 cycles and adequate responses in 105 cycles (plasma progesterone level exceeding 10 ng per ml on day 22). The mean values (+/- SD) of plasma oestradiol on day 15, reflecting follicular development, were: 73 +/- 30 pg per ml for cycles with no response; 255 +/- 182 for deficient cycles and 366 +/- 226 pg per ml for adequate cycles. There was a positive correlation (r = 0-57) between day 15 plasma oestradiol and day 22 plasma progesterone values. Increased clomiphene dosage resulted in higher plasma oestradiol and progesterone levels. Thirty-nine pregnancies occurred in 34 out of 55 patients capable of response (62 per cent). The plasma progesterone levels during conception cycles were higher than those in non-conception cycles in the same patients. Monitoring of induction of ovulation by plasma hormone estimations allows detection and correction of inadequate response.

Amenorrhea↗

An hypothesis for high multiple pregnancies after clomiphene.

A triplet and a quadruplet pregnancy following induction of ovulation with clomiphene are described; in each patient secondary amenorrhoea followed oral contraceptive use and several anovulatory or inadequate menstrual cycles had occurred on initial clomiphene therapy. Conception occurred in the first cycle after increasing drug dosage or the addition of human chorionic gonadotrophin (HCG) to the treatment regimen. We suggest, in explanation of these pregnancies, that repeated suboptimal stimulation of the ovaries as a result of clomiphene therapy develops several follicles to a critical stage; a subsequent greater ovulatory stimulus allows for synchronous development of several large follicles and multiple ovulation.

Adult↗

Clomiphene citrate and ovarian resistance.

An uncommon association between clomiphene citrate and the development of ovarian resistance to gonadotrophins is described. We advise against the use of clomiphene in the rare patient with the resistant ovary syndrome, and advise caution in any patient who exhibits a decreasing oestrogen response to clomiphene ovulation induction.

Adult↗

Clomiphene citrate and pregnancy outcome.

Data from Australia and elsewhere have shown consistently that adverse perinatal outcomes such as preterm birth and perinatal mortality are more common in pregnancies resulting from assisted conception with IVF and GIFT than normally conceived pregnancies. Factors that may contribute to the excess of poor outcomes include maternal factors, the assisted conception procedures themselves and possibly the influence of drugs used to induce superovulation. This review examines the medical literature describing pregnancies following ovulation induction with one of the drugs used to induce superovulation, clomiphene citrate, and compares their outcomes with Australian IVF and GIFT pregnancy outcomes. The review shows that whilst some studies have suggested higher rates of ectopic pregnancy, spontaneous abortion and congenital malformations in clomiphene citrate induced pregnancies, the findings are inconsistent and the data are flawed. There are only very poor data available on the incidence of preterm birth. Multiple pregnancy is a well-recognized adverse outcome of clomiphene citrate induced pregnancies. Attempts to improve perinatal outcomes of pregnancies following assisted conception will be helped by a better understanding of the relative contributions of maternal and treatment factors and further studies of pregnancy outcome after ovulation induction are needed.

Abortion, Spontaneous↗

Clomiphene-induced mood swings.

A study of couples' perceptions of infertility treatment with clomiphene (clomiphene citrate) revealed mood swings in 9 out of 14 women using the drug. This paper describes the mood swings and the responses of women and their spouses. Three phases of mood swing response emerged from the data: lacking awareness of the relation of the mood swings to the drug; gaining awareness of that relation; and managing the mood swings. The results of the study provide important information for nurses counseling couples who are experiencing clomiphene-induced mood swings.

Adaptation, Psychological↗

Clomiphene citrate effects on testosterone/estrogen ratio in male hypogonadism.

AIM: Symptomatic late-onset hypogonadism is associated not only with a decline in serum testosterone, but also with a rise in serum estradiol. These endocrine changes negatively affect libido, sexual function, mood, behavior, lean body mass, and bone density. Currently, the most common treatment is exogenous testosterone therapy. This treatment can be associated with skin irritation, gynecomastia, nipple tenderness, testicular atrophy, and decline in sperm counts. In this study we investigated the efficacy of clomiphene citrate in the treatment of hypogonadism with the objectives of raising endogenous serum testosterone (T) and improving the testosterone/estrogen (T/E) ratio. METHODS: Our cohort consisted of 36 Caucasian men with hypogonadism defined as serum testosterone level less than 300 ng/dL. Each patient was treated with a daily dose of 25 mg clomiphene citrate and followed prospectively. Analysis of baseline and follow-up serum levels of testosterone and estradiol levels were performed. RESULTS: The mean age was 39 years, and the mean pretreatment testosterone and estrogen levels were 247.6 +/- 39.8 ng/dL and 32.3 +/- 10.9, respectively. By the first follow-up visit (4-6 weeks), the mean testosterone level rose to 610.0 +/- 178.6 ng/dL (P < 0.00001). Moreover, the T/E ratio improved from 8.7 to 14.2 (P < 0.001). There were no side effects reported by the patients. CONCLUSIONS: Low dose clomiphene citrate is effective in elevating serum testosterone levels and improving the testosterone/estradiol ratio in men with hypogonadism. This therapy represents an alternative to testosterone therapy by stimulating the endogenous androgen production pathway.

Adult↗

Clomiphene citrate alters surface ultrastructure of uterine luminal epithelial cells.

Scanning electron microscopy was used to evaluate the uterine luminal epithelium from ovariectomized rats treated with a single minimal physiological dose of clomiphene citrate, oestradiol-17 beta or progesterone. It was found that clomiphene treatment produced some ultrastructural surface features which were similar to those seen with both oestrogen and progesterone treatment, but in addition it produced features unique to clomiphene treatment.

Animals↗

Clomiphene and tamoxifen inhibit progesterone synthesis in granulosa cells: comparison with estradiol.

The actions of clomiphene, tamoxifen, and 17 beta-estradiol were studied in an isolated avian granulosa cell system during short term incubations. A dose-dependent inhibition of ovine LH-enhanced progesterone production was observed for all three compounds, with an IC50 of 3 X 10(-6) M and maximal inhibition (95%) at 5 X 10(-5) M. A similar inhibition was found when cells were stimulated by either 8-bromo-cAMP or forskolin. Neither clomiphene nor tamoxifen had an inhibitory effect on the conversion of pregnenolone to progesterone, a step that was blocked by 17 beta-estradiol and isoxazole , a known inhibitor of 3 beta-hydroxysteroid dehydrogenase. On the other hand, cells exposed to clomiphene failed to use [6-3H]25-hydroxycholesterol, while estradiol significantly increased the conversion of labeled substrate to pregnenolone at the expense of progesterone (30% vs. 7% of the total radioactivity). By comparison, in control cells, progesterone represented the major metabolite with 36% of the total radioactivity; pregnenolone had only 2.8%. The results demonstrate that these triphenylethylene compounds, which are used clinically as antiestrogens, inhibit steroidogenesis at a step before pregnenolone formation, probably at the site of the cholesterol side-chain cleavage enzyme complex, while 17 beta-estradiol inhibits 3 beta-hydroxysteroid dehydrogenase.

1-Methyl-3-isobutylxanthine↗

Response to LH-RH and clomiphene citrate in two women with the Prader-Labhart-Willi syndrome.

Two women with the Prader-Labhart-Willi syndrome are presented. The gonadotropin response to LH-RH administration was studied prior to, immediately following, and 6 months after a 6-week trial of clomiphene citrate, 200 mg per day for 21 days in divided doses, followed by 100 mg for 21 days in divided doses, followed by 100 mg per day for 14 days in divided doses, and followed by 50 mg per day in a single dose for an additional 14 days. During therapy, the basal gonadotropin and estradiol concentrations rose from prepubertal levels to those of mature women in midmenstrual cycle. However, 6 months after cessation of treatment, the basal gondadotropin and estradiol levels had returned to the prepubertal range. The initial response to LH-RH in the 2 patients differed in that one was clearly prepubertal and the other indistinguishable from the broad range of the adult normal response. The LY and FSH responses to LH-RH administration was greater after 6 weeks of clomiphene citrate therapy than they were either before (both patients) or 6 months after treatment (1 patient). We conclude that there is heterogeneity in the response to LH-RH administration in the Prader-Labhart-Willi Syndrome, just as there is in other syndromes of hypogonadotropic hypogonadism. A normal adult response of gonadotropins to the administration of LH-RH was acheived during clomiphene citrate therapy.

Adult↗

Comparison of short and long-term treatment with synthetic LH-releasing hormone and clomiphene citrate in male hypothalamic hypogonadism.

The effects of short and long-term treatment with clomiphene citrate and with synthetic LH-releasing hormone (LHRH) on gonadotropin release were studied in 5 male patients with hypothalamic hypogonadism. Neither short-term treatment with clomiphene citrate (50 mg or 200 mg daily for 4 days) nor long-term treatment (25 mg or 100 mg for 30-62 days) was effective in increasing serum LH and FSH in any patients. On the other hand, 5 cases showed slight or no rise in LH after administration of a single dose of 100 mug LH-releasing hormone (LHRH) and higher rises after administration of 400 mug. Four cases who were given 200 mug LHRH daily for 3 weeks showed an increasing response of serum LH and reached maximal LH levels at 2 weeks, followed by no further increase. In two of the four cases serum LH level reached normal adult male ranges. There was no increase of serum testosterone during LHRH treatment. These results suggest that long-term treatment with synthetic LHRH may be effective for gonadotropin restoration in some patients with hypothalamic hypogonadism in which long-term treatment of clomiphene citrate was shown to be ineffective.

Adult↗

Restoration of plasma testosterone levels in uremic men with clomiphene citrate.

Five men with chronic renal failure and symptoms suggestive to androgen deficiency were treated with clomiphene citrate (Clomid) at a dose of 100 mg/day for a period of 5 to 12 months. The treatment resulted uniformly in increased libido, sexual potency, and a general sense of well-being. Circulating testosterone rose from mean basal value of 223 +/- 164 to 879 +/- 171 ng/dl (SD), representing a mean increment of 290%. Mean serum lutenizing hormone (LH) and follicle-stimulating hormone (FSH) values before treatment were 76 +/- 40 and 143 +/- 85 ng/ml (SD). During treatment, both LH and FSH increased dramatically to 518 +/- 302 and 787 +/- 291 ng/ml (SD), respectively. Both serum gonadotropin values are expressed as ng/ml of LER 907. The effect of clomiphene on spermatogenesis in these subjects was inconclusive as either improvement or deterioration occured. In these five patients, serum prolactin was not related in any way to testicular function as its values were consistently in the normal range throughout the entire study period. Serum total estrogen, however, was elevated in all; the significance of this high circulating estrogen in relation to gonadal dysfunction in uremia is not clear at the present time. However, we found that normalization of circulating androgen was beneficial to our patients and that long-term clomiphene treatment achieved this goal by increasing pituitary gonadotropin secretion and secondarily stimulating testicular hormonogenesis.

Clomiphene↗

Differential response of serum LH in hypogonadotropic hypogonadism and delayed puberty to LH-RH stimulation before and after clomiphene citrate administration.

The differential diagnosis between hypogonadotropic hypogonadism and delayed puberty is facilitated by comparing the response of gonadotropins to LH-RH stimulation before and after administration of clomiphene citrate 200 mg daily during 7 days. Premedication of clomiphene citrate depresses peak values of LH and FSH on LH-RH in delayed puberty. In hypogonadotropic hypogonadism clomiphene citrate raises LH-RH induced peak LH while FSH does not change.

Adolescent↗

Dual effect of clomiphene citrate on pituitary gonadotropin secretion in postmenopausal women.

Fifteen postmenopusal women were given 25 mg, 50 mg of clomiphene citrate daily by mouth for 3 consecutive days. Significant (p less than 0.01)decrease of serum LH (73%, 65%) and FSH (76%, 76%) resulted after administration of 25 mg and 50 mg clomiphene citrate respectively. The suppressive effect was sustained for at least 4 days after cessation of this drug. On other hand decreased LH and FSH levels after administration of ethinyl estradiol increased again by simultaneous administration of clomiphene citrate. These results suggest deficient subjects but anti-estrogenic effects are evident when serum estrogen levels are restored in subjects with estrogen deficiency.

Aged↗

Rise in dehydroepiandrosterone and oestrogens during clomiphene administration in normal men.

Serum concentrations of LH, FSH and testosterone, and urinary excretion of individual 17-ketosteroids, oestrogenic substances and free cortisol was investigated in 12 normal men after a daily administration of 50 mg clomiphene citrate for 14 days. A significant increase in the serum concentrations of LH, FSH and testosterone was seen after 8 days with a further increase when measured a week later. The percentual increase in urinary excretion of oestrogens and dehydroepiandrosterone was of the same order as the increase in serum testosterone concentrations whereas the increase in androsterone and a aetiocholanolone was significantly lower. The excretion of free cortisol was unaltered. The study that measurements of oestrogens in the urine might be used as a parameter of the stimulatory effect of clomiphene on the hypothalamic - pituitary - gonadal axis in man. In addition, of the results support the hypothesis of an independent effect of clomiphene on adrenal steroidogenesis, not related to the production of glucocorticoids.

17-Ketosteroids↗