Clomiphene Citrate: Further Observations on its Use in Induction of Ovulation in the Human and on its Mode of Action

Roy, Somnath; Greenblatt, Robert B.; Mahesh, Virendra B.; Jungck, Edwin C.

doi:10.1016/s0015-0282(16)35041-5

Cited by 144 publications

(25 citation statements)

References 11 publications

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“…Clomiphene has since been shown to decrease plasma testosterone in prepubertal boys (19) and to suppress plasma gonadotropins in adult males with "hypogonadotropic eunuchoidism" (20). The unexpected finding of gonadotropin 'suppression in contrast to the stimulatory response elicited in adults given clomiphene citrate (21)(22)(23)(24), was attributed to the intrinsic estrogenic properties of clomiphene citrate (25). The current results with ethinyl estradiol, a potent semisynthetic estrogen, support this interpretation.…”

Section: Discussionsupporting

confidence: 55%

Suppression of Urinary and Plasma Follicle-Stimulating Hormone by Exogenous Estrogens in Prepubertal and Pubertal Children

Kelch¹,

Kaplan²,

Grumbach³

1973

J. Clin. Invest.

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A B S T R A C T Clomiphene citrate, an "anti-estrogen" with mild estrogenic properties, inhibits rather than stimulates gonadotropin excretion in prepubertal and early pubertal children. These and other data suggest that the sensitivity of the hypothalamic-pituitary "gonadostat" decreases at the onset of puberty. To test this hypothesis further, the daily excretion of urinary folliclestimulating hormone (FSH) and luteinizing hormone (LH) was determined in 19 children (5 "short normals" and 14 with isolated human growth hormone (HGH) deficiency) who were given ethinyl estradiol (EE) 1.4-14.7 Ag/m2 per day (2-10 Ag/day) for 4 to 7 days. In addition, plasma and urinary gonadotropins and plasma estrogens were serially determined in two prepubertal females( with isolated HGH deficiency) given two injections (24 h apart) of estradiol benzoate, 10 isg/kg.FSH and LH concentrations in plasma and kaolin-acetone urinary concentrates and plasma 173-estradiol (E2) and estrone (El) were measured by radioimmunoassays. 2-3 Ag/m2 per day of EE significantly suppressed urinary FSH (and LH when detected in the control period) in two out of six prepubertal children, while all doses > 5 ,ug/m2 per day suppressed urinary gonadotropins to undetectable levels in eight prepubertal subjects. In early to midpubertal subjects, 2-10 Ag/m2 per day of EE produced a slight suppression of urinary FSH, but failed to suppress to undetectable levels. gonadotropins remained suppressed for the duration of the study (3 days). Plasma E2 and Ei rose from prepubertal values to peak concentrations of 150 to 250 pg/ml (E2), and 50 and 100 pg/ml (Ei) at approximately 36 h. We conclude that the hypothalamic-pituitary-gonadal axis is operative in the prepubertal child and that the sensitivity of the hypothalamic-pituitary center(s) which control the secretion of FSH and LH decreases at the onset of puberty in man. INTRODUCTIONMounting evidence suggests that the gonads in the prepubertal human being are not quiescent and, in fact, play a significant role in regulating the release of gonadotropins (1-4). Previous reports from this laboratory (5, 6) demonstrated that clomiphene citrate, an "anti-estrogen" with mild estrogenic properties, suppresses the excretion of urinary follicle-stimulating hormone (FSH) in prepubertal children. As little as 1 mg/m2 per day of oral clomiphene citrate decreases

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Section: Discussionsupporting

confidence: 55%

Suppression of Urinary and Plasma Follicle-Stimulating Hormone by Exogenous Estrogens in Prepubertal and Pubertal Children

Kelch¹,

Kaplan²,

Grumbach³

1973

J. Clin. Invest.

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“…Dickey (1965) and Sexena et al(1968) reported that FSH was gradually increased with treatment of clomiphene in the cases of sucessful induction of ovulation. When Roy, Greenblatt (1963) and Riley, Evans (1964) administered clomiphene to anovulatory patients, they reported that an increase in pituitary secretion was discernible. also studied the variation in LH secretion when clomiphene was administered to anovulatory patients, and reported the relation between the initial peak, ovulatory peak and ovulation.…”

Section: Resultsmentioning

confidence: 99%

Effects of Cyclophenyl and Clomiphene on Excretion of Urinary LH

et al. 1973

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SynopsisFluctuations in the urinary LH levels were determined by radioimmunoassay during treatment with cyclophenyl (F6066) and clomiphene in healthy subjects and women with various anovulatory conditions in order to elucidate the effect of these compounds on the hypothalamico-pituitary center. Except Sheenhan's syndrome, Chiari-Frommel syndrome and a few cases of amenorrheic patients where the cause of the disorder was located in hypothalamico-pituitary axis, an increase of LH was observed in all cases. The available evidence suggest that these compounds stimulate the hypothalamico-pituitary regulatory centers and release LH. One of the prime objectives of an ovulation inducer is to stimulate the production of gonadotropins in the pituitary.

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“…Clomiphene citrate (CC) is a triphenylethylene deriv ative that has been used for years to induce ovulation in women [1,2]. However, despite its widespread use there is much confusion as to its exact mode of action.…”

Section: Introductionmentioning

confidence: 99%

Comparison of the Long-Term Effects of Estrogen and Clomiphene Citrate on Pituitary and Uterine Function in Ovariectomized Rats

Brown

Byrd²,

Mitchell³

et al. 1991

Gynecol Obstet Invest

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The effects of estradiol-17Β (E₂) and clomiphene citrate (CC) on pituitary-uterine function in ovariectomized (OVX) rats were compared in two experiments. In experiment 1 CC completely blocked E₂ stimulation of uterine weight when administered concurrently for 10 and 30 days. In experiment 2, content of total (occupied and unoccupied) uterine nuclear estrogen receptors was increased by E₂, but not by CC, compared to OVX controls. Only a fraction of the nuclear receptors was occupied in E₂-treated rats, whereas all of these receptor sites were occupied in CC-treated rats. In addition, uterine cytoplasmic estrogen receptors were increased by E₂ and diminished by CC treatment. Both E₂ and CC were effective in preventing the postovariectomy rise in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH), although LH was always inhibited to a greater extent than FSH. After 30 days of treatment, pituitary gonadotropins were also substantially reduced by E₂ and CC, suggesting that long-term treatment decreased both pituitary synthesis and release. An increase in pituitary weight observed in E₂-treated rats only was due largely to the stimulation of lactotropes, as serum prolactin was increased. In summary, although CC and E₂ similarly depressed pituitary gonadotropin secretion, they exhibited marked differences in the stimulation and occupancy of uterine estrogen receptors and the stimulation of pituitary prolactin secretion.

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Clomiphene Citrate: Further Observations on its Use in Induction of Ovulation in the Human and on its Mode of Action

Cited by 144 publications

References 11 publications

Suppression of Urinary and Plasma Follicle-Stimulating Hormone by Exogenous Estrogens in Prepubertal and Pubertal Children

Suppression of Urinary and Plasma Follicle-Stimulating Hormone by Exogenous Estrogens in Prepubertal and Pubertal Children

Effects of Cyclophenyl and Clomiphene on Excretion of Urinary LH

Comparison of the Long-Term Effects of Estrogen and Clomiphene Citrate on Pituitary and Uterine Function in Ovariectomized Rats

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