[Pulsatile therapy of hypothalamic amenorrhea with gonadotropin releasing hormone].
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Publications and source records attributed to L Wildt.
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The physiological and pathophysiological basis of hypothalamic amenorrhoea are reviewed as well as the clinical results of chronic intermittent (pulsatile) administration of Gn-RH in the treatment of infertility. Hypothalamic amenorrhoea is considered to be the result of a deficient hypothalamic secretion of Gn-RH. By pulsatile administration of Gn-RH, which is a pre-requisite of normal pituitary gonadotrophic function, deficient endogenous Gn-RH is replaced. If an adequate dose of Gn-RH is provided, which takes into account the degree of impairment of hypothalamic function in the individual case, follicular maturation, ovulation and corpus luteum formation are achieved in nearly every treatment cycle. Although dependent also on factors other than the treated dysfunction, a high conception rate is achieved.
The effects of danazol on pulsatile luteinizing hormone (LH) release, basal LH and follicle-stimulating hormone serum levels, gonadotropin release induced by estradiol (E2) and gonadotropin-releasing hormone were examined in five eugonadal women. Danazol administration resulted in a significant suppression of follicle-stimulating hormone serum levels. LH concentrations and LH pulse frequency appeared to be reduced, but these changes did not reach statistical significance. The pituitary response to exogenous gonadotropin-releasing hormone was not altered. The stimulatory effect of E2 on LH secretion was completely abolished in one subject, severely diminished in three subjects, and unchanged in one subject. In addition, the time course of this response was altered. Serum prolactin concentrations were lowered, whereas basal E2 and progesterone levels did not seem to be affected.
The physiological and pathophysiological basis of hypothalamic amenorrhoea are reviewed as well as the clinical results of chronic intermittent (pulsatile) administration of Gn-RH in the treatment of infertility. Hypothalamic amenorrhoea is considered to be the result of a deficient hypothalamic secretion of Gn-RH. By pulsatile administration of Gn-RH, which is a pre-requisite of normal pituitary gonadotrophic function, deficient endogenous Gn-RH is replaced. If an adequate dose of Gn-RH is provided, which takes into account the degree of impairment of hypothalamic function in the individual case, follicular maturation, ovulation and corpus luteum formation are achieved in nearly every treatment cycle. Although dependent also on factors other than the treated dysfunction, a high conception rate is achieved.
In this review an account is made on the physiological and pathophysiological basis as well as on the clinical results of chronic-intermittent (pulsatile) administration of Gn-RH in the treatment of infertility in hypothalamic amenorrhea. Hypothalamic amenorrhea is considered to be the result of a deficient hypothalamic secretion of Gn-RH, which is a prerequisite of normal pituitary gonadotropic function, deficient endogenous Gn-RH is replaced. An adequate dose of Gn-RH provided, which takes into account the degree of impairment of hypothalamic function in the individual case, follicular maturation, ovulation and corpus luteum formation are achieved in nearly every treatment cycle. The conception rate, which is, in addition to the treated dysfunction, also dependent upon other factors, is remarkably high as well.
The temporal relationship between cessation of GnRH delivery to the pituitary gland and the loss of responsiveness to the stimulatory action of estradiol (E2) was examined in 4 ovariectomized rhesus monkeys whose endogenous GnRH production had been abolished by hypothalamic lesions. Gonadotropin secretion was re-established by the intermittent administration of GnRH. The GnRH-replacement regimen was then discontinued and estradiol benzoate (EB) injected 24, 48, 72 and 96 hours later. Unambiguous gonadotropin discharges were induced when EB was administered 24 or 48 hours after discontinuation of GnRH replacement. We conclude that E2 can initiate gonadotropin discharges in the absence of circulating GnRH. E2 may, therefore, be viewed as a gonadotropin releasing hormone.
In adult ovariectomized rhesus monkeys bearing hypothalamic lesions which reduced circulating LH and FSH to undetectable levels, sustained elevated gonadotropin concentrations were reestablished by the intermittent administration of gonadotropin-releasing hormone (GnRH) at the rate of 1 microgram/min for 6 min once every hour. The effects of varying either the frequency or the amplitude of these GnRH pulses on gonadotropin secretion were examined in such animals. Increasing the frequency of GnRH administration from the physiological one pulse per h to two, three, or five pulses h while maintaining a constant infusion rate and pulse duration resulted in gradual declines in plasma gonadotropin concentrations. These declines were most profound at the highest frequencies and the consequence of reduced pituitary responses to individual GnRH pulses. Decreasing the frequency of GnRH pulses from one per h to one every 3 h led to variable declines in plasma LH levels, but circulating FSH invariably rose. Reducing the GnRH infusion rate from 1 to 0.1 mg/min while maintaining constant frequency and pulse duration resulted in abrupt declines in plasma LH and FSH to immeasurable levels, although pulsatile increments in circulating GnRH concentrations without a concomitant reduction in plasma LH concentrations, which remained unchanged. An infusion rate of 0.5 microgram/min resulted in unstable plasma LH and FSH levels. These results demonstrate that changes in the frequency or amplitude of hypophysiotropic stimulation have profound effects on plasma gonadotropin levels as well as on FSH to LH ratios in the circulation. The physiological implications of these observations are discussed.
The site of action of progesterone (P) in the blockade of estradiol-induced gonadotropin discharges was examined in rhesus monkeys bearing hypothalamic lesions which abolish endogenous GnRH production. Normal ovulatory menstrual cycles were re-established in these animals by the pulsatile, hourly administration of GnRH. In the follicular phase of these induced menstrual cycles, P-containing Silastic capsules were implanted sc yielding luteal phase plasma P concentrations which normally block estradiol-induced gonadotropin surges. P failed to block estradiol-induced surges in lesioned animals on GnRH replacement. In such animals, however, P advanced the initiation of these surges. While estradiol acts on the pituitary to cause gonadotropin discharges, P appears to block this effect by acting on the central nervous system. On the other hand, the results also suggest that the site of facilitatory action of P on gonadotropin release is at the level of the pituitary gland.
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In rhesus monkeys with hypothalamic lesions (which appear to abolish the endogenous production of gonadotropin-releasing hormone), normal ovulatory mestrual cycles were reestablished by an unvarying, long-term replacement regimen consisting of one intravenous pulse of synthetic gonadotropic-releasing hormone per hour. This finding is in accord with the hypothesis that the pattern of pituitary gonadotropin secretion throughout the menstrual cycle (basal secretion interrupted, once every 28 days on the average, by a preovulatory surge) is not directed by alterations in hypothalamic gonadotropin-releasing hormone secretion but by the ebb and flow of ovarian estrogens acting directly on the pituitary gland.
Normal ovulatory menstrual cycles were initiated in prepubertal female rhesus monkeys by the infusion of gonadotropin-releasing hormone for 6 minutes once every hou;. When this regimen was discontinued, the animals promptly reverted to an immature state. These findings permit the conclusion that neither adenohypophysial nor ovarian competence is limiting in the initiation of puberty and suggest that this process depends on the maturation of the neuroendocrine control system that directs the pulsatile secretion of gonadotropin-releasing hormone from the hypothalamus.
The characteristics of the early stages of ovarian follicular maturation were investigated in rhesus monkeys during the luteal phase of the menstrual cycle using a novel procedure to supply low levels (10 microCi) of [3H]thymidine directly to ovaries in vivo. With this labeling procedure, plasma levels of [3H]thymidine did not exceed 8 cpm/microliters and labeled ovarian cells were readily identifiable by autoradiography. Results from four animals studied during the luteal phase of the cycle indicated that all sizes of preantral follicles contained granulosa cells that incorporated [3H]thymidine. There was a progressive increase in the percentage of labeled follicles in direct relationship to follicular size; 10% of the single granulosa cell layer follicles were labeled and the labeling frequency increased to greater than 60% in the large (> 6 granulosa cell layer) preantral follicles. The labeling frequency of all size classifications of preantral follicles during the luteal phase of the menstrual cycle was similar to that of an animal which was studied during the follicular phase of the menstrual cycle. The results suggest that growth of ovarian follicles to the preantral stage occurs during the luteal phase of the menstrual cycle in rhesus monkeys, and thus the cessation of preovulatory folliculogenesis during the luteal phase of the cycle is not due to a defect of growing preantral follicles.
In previous studies it could be demonstrated that in severe hypothalamic amenorrhea, which is associated with absent or deficient hypothalamic secretion of Gn-RH, ovarian function could be restored by chronic intermittent (pulsatile) administration of Gn-RH. In order to apply chronic intermittent administration of Gn-RH as a new mode of treatment of infertility in hypothalamic amenorrhea on an outpatient basis a portable device ("Zyklomat") was constructed consisting of a peristaltic pump, a computerized timing device and a Gn-RH containing bag, which delivers 50 microliters of a Gn-RH containing solution once every 90 minutes via an i.v. catheter into the circulation. It is the purpose of this communication to present this new method of treatment and the successful induction of the first two pregnancies with this method in two patients with severe hypothalamic amenorrhea.
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