Inhibition of gonadotropin-releasing hormone receptors in rat anterior pituitary monolayer cell cultures by danazol

To study possible cellular antigonadotropic effects of danazol, monolayer cultures of anterior pituitary cells from immature female rats were treated with danazol. Measurements of luteinizing hormone release in response to 10(-8) mol/L gonadotropin-releasing hormone challenge and iodine 125-labeled gonadotropin-releasing hormone binding activity were done after exposure to increasing concentrations of danazol and for increasing lengths of time. It was found that luteinizing hormone secreted by pituitary cells in response to gonadotropin-releasing hormone was inhibited after danazol treatment in a dose- and time-dependent manner when compared to controls. Also, a 45% decrease in gonadotropin-releasing hormone receptor binding capacity was observed in pituitary cells cultured in the presence of increasing concentrations of danazol in the range of 10(-8) to 10(-4) mol/L when compared to controls. Furthermore, exposure to danazol for 25 to 96 hours caused a marked decrease in gonadotropin-releasing hormone binding activity (p less than 0.005). Under these experimental conditions danazol treatment decreased the pituitary receptors for gonadotropin-releasing hormone in a dose- and time-dependent manner. Scatchard analysis of saturation curves for the binding of gonadotropin-releasing hormone to cellular gonadotropin-releasing hormone receptors indicated that the observed decrease in gonadotropin-releasing hormone binding in the danazol-treated group was due to a change in the number of gonadotropin-releasing hormone binding sites rather than a change in the affinity. It is therefore concluded that the antigonadotropic activity of danazol appears to be related to a decrease in gonadotropin-releasing hormone receptors in the pituitary.     

Adrenal function during chronic danazol administration.

Ten healthy female volunteers received Danazol, 400 mg twice daily for 90 days. Adrenal function testing then showed a normal capacity of the gland to respond to stimulation with synthetic adrenocorticotrophic hormone, and a lack of suppression of central areas controlling adrenal function by a normal response to the metyrapone challenge.     

The effect of danazol on pulsatile gonadotropin secretion in women with endometriosis

OBJECTIVE: To determine whether the effect of danazol on gonadotropin pulsatility was due to a direct effect of the drug or the suppression in the estradiol (E2) levels. DESIGN: Prospective analysis of serial blood samples at 10-minute intervals for 5 hours on days 3, 4, or 5 of the control cycle and 2 months after the start of danazol treatment. SETTING: Tertiary institutional outpatient care. PATIENTS, PARTICIPANTS: Six eugonadal women with minimal endometriosis. INTERVENTIONS: Oral administration of danazol, 200 mg three times daily. MAIN OUTCOME MEASURES: Gonadotropin mean levels, pulse frequency, and amplitude. RESULTS: The mean level of E2 was the same in the control cycle as that during danazol treatment (170 pmol/L). Danazol administration resulted in a 16% increase in the mean luteinizing hormone (LH) pulse amplitude (95% confidence interval [CI] 6% to 26%, P less than 0.01), associated with a 20% decrease in LH pulse frequency (95% CI -71% to +31%, P = 0.37). There was a nonsignificant increase in follicle-stimulating hormone (FSH) pulse amplitude (2%, 95% CI -9% to +14%, P = 0.68) and in FSH pulse frequency (27%, 95% CI -4% to +58%, P = 0.08). The 22% decrease in the mean LH level (95% CI -85% to +12%, P = 0.13) and the 20% decrease in the mean FSH level (95% CI -53% to +37%, P = 0.33) were also not significant. CONCLUSIONS: The increase in LH pulse amplitude represents a direct effect of danazol on the hypothalamic-pituitary axis.     

Physiological significance of the self-priming effect of LH-RH on the anterior pituitary glands

To investigate the intracellular mechanisms of the self-priming effect of LH-RH on the anterior pituitary gland, the responses of pituitary and serum gonadotropins to two administrations of this decapeptide at a 60 min, interval were studied in male rats. A clearly recognized self-priming effect in male rats was significantly suppressed by the administration of RNA synthesis inhibitor. Although the pituitary LH content decreased significantly after the first administration, the content increased to the control level immediately before the second administration. This recovery was prevented by the administration of RNA synthesis inhibitor. In spite of the large second response, the rate of the second LH depletion was low. The number of secretory granules in gonadotrophs showed similar changes to the pituitary LH content. The dilatation of the Golgi apparatus was observable at 60 min. after the first administration. These results of rat experiments indicate that the second response includes the newly synthesized gonadotropins, and a clinical LH-RH two step test could be employed to evaluate both pituitary gonadotropin synthesizing and secreting functions.     

Post-traumatic anterior and posterior pituitary dysfunction.

BACKGROUND AND PURPOSE: The recognition of hypopituitarism after head trauma is important because related neurobehavioral problems can be alleviated by hormone replacement. This study investigated the clinical presentations and imaging findings of patients with hypopituitarism developing after head trauma. METHODS: We retrospectively reviewed the medical records of patients with hypopituitarism from 1982 through 2002. Data on disease history and hormone deficiencies of patients with hypopituitarism which developed after head trauma were analyzed. RESULTS: Eighteen patients with hypopituitarism or diabetes insipidus (DI) due to head trauma, including 11 men and 7 women, were identified. Head trauma thus accounted for the etiology in 2.8% of all 635 patients with a diagnosis of hypopituitarism during the study period. The major cause of head trauma was road accident (n = 11, 61%). Ten of the patients (56%) had lost consciousness after the head injury. The duration from head trauma to the onset of symptoms of hypopituitarism ranged from < 1 month to 15 years. Sex hormone (61%) and growth hormone (56%) were the most common hormone deficiencies, followed by corticotropin deficiency (39%) and thyrotropin deficiency (22.2%). DI developed in 9 patients (50%) and 5 of these patients had only DI without anterior hypopituitarism. Routine skull radiograph did not show abnormal signs. Among the 10 patients with magnetic resonance imaging of the pituitary gland, a small or atrophic anterior lobe was seen in patients with anterior hypopituitarism. Loss of bright signal intensity from the pituitary posterior lobe on T1-weighted magnetic resonance imaging was seen in all 3 patients with DI. An ectopic posterior lobe could be seen in 2 patients with hypopituitarism without DI. CONCLUSIONS: Identification of head trauma as the etiology of hypopituitarism may be overlooked if there is a long delay in onset after trauma. DI is a common early complication. Since anterior hypopituitarism can develop decades after the episode of head trauma, monitoring for endocrine dysfunction during follow-up of these patients is important.     

The effects of fetal exposure to danazol.

OBJECTIVE: To assess the consequences of exposure to danazol in utero. Additionally, by assessing the risk, to facilitate the counselling of pregnant women inadvertently exposed to danazol in early pregnancy. DESIGN: Retrospective review of reported case histories. SUBJECTS: 129 women exposed to danazol during pregnancy were identified from individual case reports, data from the Australian Drug Reactions Advisory Committee and the United States Food and Drug Administration and from the reports of danazol exposure made directly to the manufacturers. MAIN OUTCOME MEASURES: Teratogenic effects of fetal exposure to danazol in relation to dosage and duration of exposure. RESULTS: Of the 129 reported pregnancies, 12 miscarried and 23 were aborted. Of the 94 completed pregnancies, 37 resulted in the birth of normal males, 34 in non-virilized females and 23 in virilized females. Virilization occurred in a proportion of female fetuses with a pattern of cliteromegaly, fused labia and urogenital sinus formation. Surgery to the genital tract was usually, but not always, required in childhood. The abnormality has not been reported where danazol therapy had been discontinued before the 8th week of pregnancy. Although more common in the higher dosages, virilization was reported in one case with a 200 mg daily dosage. CONCLUSIONS: Danazol should remain contraindicated in pregnancy and clinicians should give careful contraceptive advice to patients commencing or continuing danazol therapy. Nonetheless it is possible to be cautiously optimistic about the outcome of danazol-exposed pregnancies, particularly if treatment is discontinued before 8 completed weeks gestation.     

The effect of lisuride hydrogen maleate on anterior pituitary hormones, oestradiol and cortisol in normal and hyperprolactinaemic women

The effects of single oral doses of 0.1 mg lisuride hydrogen maleate (lisuride), a semisynthetic ergot derivative given at 09.00 h, on the serum levels of prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), thyroid-stimulating hormone (TSH), oestradiol and cortisol were studied in six normally cycling women and six patients with hyperprolactinaemic amenorrhoea. The same subjects received placebo and the results were compared with those of lisuride. Within 1 h after oral administration of lisuride, PRL levels decreased significantly (P less than 0.05) and reached the lowest level at 4 h after ingestion and stayed low until 8 h in both normal women and hyperprolactinaemic patients. LH levels slightly but not significantly decreased after lisuride administration in hyperprolactinaemic patients. Serum cortisol levels increased at 13.00 h, probably due to the effect of meal. No significant differences between the lisuride group and placebo group were observed in GH, TSH, FSH and oestradiol levels. These results suggest that lisuride acts as a long-acting prolactin suppressor and that it has little effects on the secretion of other pituitary hormones. Therefore, this drug could be useful for treatment of hyperprolactinaemic patients.     

The effect of methadone on fetal brain function.

The effect of methadone on fetal brain function in terms of the electroencephalogram (EEG) was studied in eight short-term fetal sheep experiments by single injections of 5 to 20 mg. of methadone into the fetal circulation. Plasma methadeone concentrations (determined by radioimmunoassay) greater than 0.065 mg. per cent were associated with an immediate brief decrease in carotid blood flow, a rapid decrease in frequency and amplitude in the EEG that occasionally became isoelectric but recovered, and immediate and relatively prolonged bradycardia. Similar cardiovascular observations were obtained with plasma methadone concentrations less than 0.065 mg. per cent, but the EEG changes were either minimal or not observed. These results indicate that uptake of methadone by the fetal brain is rapid and that electrical activity and heart rate are affected.     

The effect of contraceptive steroids on hypothalamic-pituitary function.

A study was performed to obtain additional information about the effects of oral contraceptives on pituitary function. A sequential pituitary stimulation test (SST) was used to study normal control women who then received either a combination pill with 50 mug of ethinyl estradiol or an injectable or oral progestin for three weeks, after which the test was repeated. The same test was also performed on five long-term oral contraceptive users. The SST consists of measurement of growth hormone (GH), thyroid-stimulating hormone (TSH), prolactin (PRL), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) at frequent intervals after stimulation by hypoglycemia, thyrotropin-releasing hormone, and gonadotropin-releasing hormone. GH and TSH release following stimulation were unaffected by the use of contraceptive steroids, while PRL release was increased by both the combination pill and the progestin alone. LH and FSH release was decreased in the three short-term and most of the long-term users of the combination pills but was not decreased in two of the long-term users as well as in those receiving the progestin alone. These results indicate that the combination oral contraceptives have a direct effect upon the pituitary gland, causing an increase in prolactin release and a decrease in gonadotropin release. This effect varies among individuals receiving the same formulation and may be related to the development of syndrome of postpill amenorrhea-galactorrhea.     

The acute effect of hysterectomy on ovarian function.

The acute effect of abdominal and vaginal hysterectomy on the ovarian production of estradiol-17-beta (E2) and progesterone (P) was studied in a group of patients undergoing hysterectomy for various gynecologic indications. Plasma levels of steroids as well as gonadotropins (FSH and LH) were measured by RIA. There was a significant but transient drop of plasma E2 during the follicular phase and of plasma E2 and P during the luteal phase, following hysterectomy. No significant variations in the steroid plasma levels were found in a control group of patients undergoing laparoscopy for diagnostic purposes. No changes were noted in either group in the plasma levels of gonadotropins. The changes seen appear to be related to the surgical manipulation in the ovarian region rather than to the type of hysterectomy performed or the stress of surgery.     

The effect of combination chemotherapy on ovarian, hypothalamic and pituitary function in patients with breast cancer

Treatment of breast cancer by combination therapy induced luteal insufficiency, anovulatory cycles and sometimes hypergonadotropic amenorrhea in premenopausal women with previously normal mentrual cycles and ovarian function. In chemotherapy induced amenorrhea 17 beta-estradiol levels were those found in ovarectomised or postmenopausal women. Chemotherapy affected the ovary itself and not the hypothalamus or pituitary, the negative feedback mechanisms remaining intact. The ovary of perimenopausal patients was much more sensitive to cytotoxic drugs; following a short time chemotherapy hypergonadotropic amenorrhea invariably developed and the ovary seemed to be again the prime site of action. Postmenopausal patients continued to have physiologically high LH and FSH plasma concentrations and low plasma levels of prolactin and 17 beta-estradiol under cytotoxic treatment.     

Fertility in the rhesus monkey following long-term inhibition of ovarian function with danazol.

Danazol was previously reported to be an oral contraceptive in the rhesus monkey at doses of 200 and 400 mg/monkey/day for 90 days. The drug is now shown to be an effective long-term inhibitor of ovarian function in the monkey. In the final 3 months of a 27-month period of treatment at a dose of 400 mg/monkey/day, the drug continued to be an effective oral contraceptive. During the 27-month treatment period, three of seven monkeys were amenorrheic and the remaining had only 16 of the 109 expected menstrual cycles. Following the discontinuation of medication, all seven monkeys conceived within 2 to 6 weeks. One monkey aborted early in pregnancy and the remaining six delivered normal, healthy infants at term. Therefore, following the discontinuation of long-term treatment with danazol in the monkey, there was rapid and complete return of normal ovarian function.     

The "treatment" of unexplained infertility with danazol.

In order to investigate the possible stimulating effect of danazol on fertility, a randomized clinical trial was performed on 40 women with unexplained infertility. Of these 40 women, 21 received 200 mg of danazol daily for 100 days and 19 received a placebo treatment during the same period. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, estrone, estradiol, progesterone, and testosterone were followed before, during, and after treatment. Danazol administration induced anovulation in all women, with prompt resumption of normal ovulatory function after discontinuation of the drug. No influence was seen on serum LH, FSH, and testosterone levels, but serum estrone, estradiol, and progesterone levels decreased significantly during treatment. Serum prolactin levels also decreased, but not significantly. No pregnancies occurred in the placebo group during a 6-month follow-up period. In the danazol group, five pregnancies occurred, of which two were ectopic and three went to term. The difference in pregnancy rate between both groups was statistically significant (P less than 0.05).