Direct evidence of estrogen modulation of pituitary sensitivity to luteinizing hormone-releasing factor during the menstrual cycle.

Wang, C. F.; Yen, S. S. C.

doi:10.1172/jci107913

Cited by 43 publications

(18 citation statements)

References 21 publications

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“…6). This contrasts with the observation that clomiphene blocked the enhanced gonadotropin responses to GnRH that occur during those phases of the menstrual cycle characterized by higher circulating estrogen concentrations (30). These disparate effects of tamoxifen on basal and GnRH-stimulated gonadotropin secretion are not readily explainable, but reinforce the impression that the actions of estrogen antagonists may vary among themselves and in different tissues.…”

Section: Methodsmentioning

confidence: 67%

“…Estrogens have been shown to either increase or decrease the gonadotropin response to GnRH depending on dose and duration of administration (28)(29)(30). Other studies have shown the gonadotropin responses to GnRH were diminished by infusions of 17,8-estradiol that increased circulating E2 concentrations to levels comparable to those obtained during tamoxifen treatment (27,29).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Endocrine Consequences of Continuous Antiestrogen Therapy with Tamoxifen in Premenopausal Women

Sherman¹,

Chapler²,

Crickard³

et al. 1979

J. Clin. Invest.

147

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A B S T R A C T Daily administration of estrogen antagonists to premenopausal women has been incorporated into the adjuvant treatment ofbreast cancer. We have studied the changes in reproductive hormones, pituitary responses to hypothalamic-releasing hormones, and endometrial histology during treatment with the antiestrogen tamoxifen in five healthy, premenopausal women. These studies were carried out during one menstrual cycle before and during two cycles ofantiestrogen treatment. All subjects continued to have regular menses with biphasic basal body temperature records. During treatment, estradiol (E2) levels were increased but followed the usual pattern reflecting follicular maturation and corpus luteum formation. The mean E2 concentration at the midcycle peak and during the luteal phase was twice that observed during the non-treatment cycle. By contrast, the concentrations and secretory patterns of luteinizing hormone and follicle-stimulating hormone were not greatly changed, and the gonadotropin responses to gonadotropin-releasing hormone were not suppressed.Endometrial biopsies obtained during the follicular phase of control and tamoxifen treatment cycles showed no differences whereas biopsies obtained during the luteal phase of tamoxifen cycles uniformly showed a lack of changes attributed to progesterone action with no progression of histologic changes beyond those expected on day 7-8 of the luteal phase.These observations are consistent with maturation of multiple ovarian follicles, a surprising finding considering the normal gonadotropin concentrations. The retarded development of the endometrium in the presence of supranormal serum E2 and progesterone concentrations is a morphologic demonstration of the antiprogestational effect of antiestrogens. The lack of gonadotropin suppression in the presence of hyper-

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Section: Methodsmentioning

confidence: 67%

Section: Methodsmentioning

confidence: 99%

Endocrine Consequences of Continuous Antiestrogen Therapy with Tamoxifen in Premenopausal Women

Sherman¹,

Chapler²,

Crickard³

et al. 1979

J. Clin. Invest.

147

View full text Add to dashboard Cite

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“…The involvement of a hypothalamic site has been suggested by Levine et al (1985), who, by measuring hypothalamic LHRH using the technique of push-pull perfusion, showed evidence of increased LHRH output, albeit of variable magnitude and at lower levels than might be expected from the duration of the LH surge. The rising concentrations of oestradiol during the follicular phase, or following the administration of oestradiol benzoate, result in an increase in the numbers of pituitary LHRH receptors (Adams et al, 1981) and an increase in gonadotroph responsiveness (Ferin et al, 1974b;Wang & Yen, 1975;Hoffe/ al, 1977), and these changes are thought to be due in part to direct actions of oestrogen on the pituitary gonadotroph.…”

Section: Resultsmentioning

confidence: 99%

Blockade of the oestrogen-induced LH surge in the ovariectomized common marmoset (Callithrix jacchus) by an LHRH antagonist

O’Byrne

Lunn²,

Fraser³

1989

Reproduction

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Summary. Six long-term ovariectomized adult marmoset monkeys were treated at 0 h with 35 \g=m\g oestradiol benzoate s.c. to induce an LH surge. They were also treated with detirelix (an LHRH antagonist) at 0 h, 12 h and 24 h (Exp. 1), or at 0 h and 24 h (Exp. 2) at a dose of 300 \g=m\g/kgs.c., or received the detirelix vehicle alone at 0 h, 12h and 24 h (Exp. 3). All animals received the three treatments, with at least 4 weeks between experiments. Blood samples were collected at 0 h and at 6\p=n-\12h intervals for 72 h after oestradiol for the determination of plasma LH by bioassay. In control animals, oestrogen treatment resulted in a decline in plasma LH from 30\m=.\0 \ m=+-\ 5\m=.\8at 0 h to 12\m=.\8 \ m=+-\ 2\m=.\6 ng/ml at 6 h (negative feedback), followed by a positive feedback surge, reaching a maximum of 148\m=.\0\m=+-\ 34\m=.\6ng/ml at 24h. Values then declined to pretreatment levels by 56h. In contrast, antagonist-treated animals showed complete abolition of the expected increase at 24 h, the low levels of the negative feedback phase being maintained for 36\p=n-\72h.These results show that hypothalamic LHRH release is essential during the oestrogen-induced LH surge, and that a direct oestrogen-induced component at the pituitary level is not expressed in the absence of LHRH in the marmoset.

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“…A marked increase in pituitary responsivenessto a fixed dose ofexogenous GnRH has been demonstrated at the midcycle surge in normal women (31). The mechanisms responsible for this increase in pituitary sensitivity to GnRH at the midcycle have not been completely elucidated but may be due to an increase in receptor number orto post-receptor effects on the gonadotrope (23).…”

Section: Discussionmentioning

confidence: 99%

Decreased release of gonadotropin-releasing hormone during the preovulatory midcycle luteinizing hormone surge in normal women.

Hall

Taylor²,

Rivier³

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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To investigate the contribution of hypothalamic gonadotropin-releasing hormone (GnRH) secretion to the midcyde gonadotropin surge in the human, the response of luteniZing hormone (LH) to competitive GnRH receptor blockade achieved by administration of a range of doses of a pure GnRH antagonist was used to provide a semiquantitative estimate of endogenous GnRH secretion. The LH response to 5, 15, 50, and 150 iag/kg s.c. of the NAL-GLU GnRH antagonist ',D-4CIPhe2,D-Pal3,Arg5,D-4-p-methoxybenzoyl-2-aminobutyric acid'6,D-Ala1O'GnRH, where 2Nal is 2-naphthylalanine, 4CIPhe is 4-chlorophenylalanine, and 3Pal is 3-pyridylabnine) was measured in normal women in the early and late follicular phases of the menstrual cycle, at the time of the midcycle LH surge and in the early luteal phase. LH decreased in a dose-response fashion after administration of the GnRH antagonist in aUi cycle phases (P < 0.0001 Direct measurements of GnRH in pituitary portal blood indicate that a surge of GnRH secretion is generally associated with spontaneous and sex steroid-induced gonadotropin surges in sheep (4-6). GnRH levels also appear to increase at the time of the proestrus surge in rats (7) and rhesus monkeys (8, 9). These direct techniques of accessing information regarding the hypothalamic component of the preovulatory surge are clearly not feasible in the human and measurements of GnRH in the peripheral circulation do not accurately reflect hypothalamic GnRH secretion ifat all (10). Therefore, an understanding of the physiology of GnRH secretion and pituitary responsiveness to this releasing hormone in the human can only be achieved by combining a number of indirect approaches. Monitoring of pulsatile LH secretion can provide insight into the frequency of GnRH secretory episodes (11) but does not permit estimates to be made ofthe amount of GnRH secreted. The dose of exogenous pulsatile GnRH required to mimic normal menstrual cycles and a normal midcycle surge in GnRH-deficient women (3) has been determined empirically, by comparison with "target"or reference ranges derived from studies in normal women, but does not provide information about potential changes in the actual quantity of endogenous GnRH secreted under various physiologic conditions in the intact human.A competitive receptor antagonist can be used to assess the relative amount of an unmeasurable endogenous ligand by determining the susceptibility of a marker of its action to specific blockade. This principle derives from quantitative theories of drug action (12) and has proven extremely useful in determination of opioid tone using the opiate receptor blocker, naloxone (13,14). We have applied an analogous approach to the assessment of the overall amount of GnRH secreted by using a GnRH antagonist that competitively blocks the GnRH receptor and LH secretion as the marker of GnRH action. The underlying assumption is that the amount ofGnRH present at a given time is directly proportional to the dose of GnRH antagonist required to inhibit LH secretion. 2Nal is 2-napht...

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Direct evidence of estrogen modulation of pituitary sensitivity to luteinizing hormone-releasing factor during the menstrual cycle.

Cited by 43 publications

References 21 publications

Endocrine Consequences of Continuous Antiestrogen Therapy with Tamoxifen in Premenopausal Women

Endocrine Consequences of Continuous Antiestrogen Therapy with Tamoxifen in Premenopausal Women

Blockade of the oestrogen-induced LH surge in the ovariectomized common marmoset (Callithrix jacchus) by an LHRH antagonist

Decreased release of gonadotropin-releasing hormone during the preovulatory midcycle luteinizing hormone surge in normal women.

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