J. H. Liu

Characteristics of menopausal women seeking assistance

Using a questionnaire approach, we have determined the demographic, social, and clinical characteristics of the first 100 participants attending our menopause clinic. Of the respondents, 79% reported onset of significant physical symptoms and 63% significant emotional symptoms during the menopause. Among the participants, 65% had varying degrees of depression as determined by the Zung self-rating depression scale. This seemed to be more prevalent in patients with previous pelvic operations. Only half the women were on a regimen of estrogen replacement therapy, and most were receiving estrogen in an unopposed fashion. In our menopause clinic, more than half the women were over their ideal body weight, which is in contrast to the popular misconception that only thin women develop menopausal symptoms. Data from our patients suggest the need for multidisciplinary menopause clinics to adequately address the physical and emotional problems of menopausal women.

Endocrine responses to long-term administration of the antiprogesterone RU486 in patients with pelvic endometriosis

OBJECTIVE To examine endocrine and clinical responses to long-term administration of RU486 in patients with endometriosis. DESIGN Prospective open trial. SETTING Faculty practice of the authors. PATIENTS, PARTICIPANTS Six normally cycling women with endometriosis were recruited. INTERVENTIONS Subjects received RU486 100 mg/d for 3 months. MAIN OUTCOME MEASURE(S) Hormonal changes during RU486 were compared with control data obtained in the preceding cycle during the early follicular phase. Clinical responses were determined by patient assessment and second-look laparoscopy. RESULTS All women became amenorrheic, and daily urinary levels of ovarian steroid metabolites remained acyclic. Mean luteinizing hormone (LH) (P less than 0.02) and LH pulse amplitude (P less than 0.05) were increased without changes in LH pulse frequency. An antiglucocorticoid effect was demonstrated by an increase in serum cortisol (P less than 0.01) and adrenocorticotropic hormone (P less than 0.05) levels. Treatment resulted in an improvement in pelvic pain in all subjects without significant change in the extent of disease as evaluated by follow-up laparoscopy. CONCLUSIONS Daily administration of RU486 results in acyclic ovarian function and improvement in the subjective painful symptoms of endometriosis.

INTRINSIC PULSATILITY OF ACTH RELEASE FROM THE HUMAN PITUITARY IN VITRO

An in‐vitro perifusion system was used to investigate spontaneous ACTH release from human fetal (21–23 weeks gestation) and adult pituitaries. The pattern of ACTH release from fetal pituitaries (n= 7) exhibited a remarkable pulsatile character with a mean (± SEM) pulse interval of 11.3 ± 0.8 min. The mean pulse amplitude was 49.7 ± 6.3 pg, with a nadir to peak increment of 90.7 ± 10.4%. The mean ACTH release rate was 87.2±13.3 pg/2 min. Addition of the calcium chelator EGTA (4 nM) to the perifusion medium induced a significant (p±0.01) decrease in both ACTH release rate (from 102.0 ± 8.5 to 52.0 ± 9.9 pg/2 min) and ACTH pulse amplitude (from 57.7 ± 2.8 to 31.3 ± 4.6 pg) (n= 3). Administration of either 2 nM corticotrophin releasing factor (CRF) or 56 mM KCl induced 10‐ and 2‐fold increases in ACTH secretion, respectively (n= 2). Quarters of adult human pituitaries (n– 6) also secreted ACTH in a pulsatile fashion, with a pulse interval of 14.8±1.7 min, pulse amplitude of 86.7± 10.0 pg, nadir to peak increment of 84.5 ± 9.8%, and overall release rate of 167.2 ± 8.8 pg/2 min. These studies demonstrate that ACTH release from the isolated human pituitary in vitro is characterized by high frequency/low amplitude pulses, independent of hypothalamic stimulation. Accordingly, this spontaneous calcium‐dependent pulsatile ACTH release apparently reflects the activity of an intrinsic intrapituitary pulse‐generating mechanism.

Intrinsic pulsatility of luteinizing hormone release from the human pituitary in vitro

An in vitro perifusion system was used to investigate the spontaneous luteinizing hormone (LH) release from 10 human fetal (21–23 weeks of gestation) and 1 adult female pituitaries. The pattern of LH

Neurosecretion of Human Hypothalamic Immunoreactive β-Endorphin: In vitro Regulation by Dopamine

An in vitro perifusion system was used to investigate immunoreactive beta-endorphin (beta-END-I) release from adult human hypothalami in response to dopamine (DA) and the DA receptor antagonist haloperidol (HAL). Administration of a 1 microM pulse of DA consistently elicited a mean (+/- SE) 88 +/- 9% increase (p less than 0.05, n = 5) in beta-END-I release, whereas 1 microM HAL had no effect. Administration of 1 microM DA during three perifusions in which 1 microM HAL was added to the medium failed to alter basal beta-END-I release. In contrast, DA did evoke an acute 230 +/- 31% increase (p less than 0.05) in beta-END-I release during three matching perifusions with medium containing the alpha-adrenergic antagonist phentolamine. These studies demonstrate that DA can stimulate in vitro release of beta-END-I from the adult human hypothalamus by a DA receptor mediated mechanism.

Role of oxytocin in the modulation of ACTH release in women.

To determine if oxytocin (OT) may have a modulatory role on corticotropin-releasing factor (CRF) and vasopressin (AVP) mediated ACTH-cortisol release in women, serial experiments were performed in which saline, OT, AVP and CRF were administered singly or in combinations. OT administration (2 IU intravenous bolus followed by 111 mIU/min infusion for 3 h) maintained a circulating concentration of 7.7 X 10(-8) M and did not significantly influence basal, AVP or CRF-induced ACTH-cortisol release. In contrast, OT inhibited significantly the potentiating effect of AVP on CRF-stimulated ACTH-cortisol release. These findings suggest that OT and AVP may modulate, in a reciprocal fashion, the CRF-mediated ACTH release and support the contention that OT may be involved in the neuroendocrine response to stress in women.

Pharmacodynamics of the antiprogesterone RU486 in women after oral administration

The pharmacokinetic characteristics of RU486 and its acute effects on anterior pituitary hormone secretion after oral administration were examined in six normal women. Serum RU486 concentrations were determined by a radioimmunoassay. The absorption of RU486 was rapid with peak serum levels reached approximately 90 minutes after a single oral dose (4 mg/kg). The disappearance of RU486 and its metabolites conformed to a noncompartmental model with a mean apparent half-life of 53.7 +/- 6.9 hours. The mean apparent volume of distribution and clearance rate were 1.47 +/- 0.25 l/kg and 1.04 +/- 0.09 1/hour, respectively. In comparison with a control group of normal women (n = 9), there were significant elevations in transverse mean cortisol levels in the RU486 group (P less than 0.01). However, mean adrenocorticotropic hormone (ACTH) levels and the diurnal pattern of ACTH and cortisol secretion were not changed. RU486 induced a mild prolactin (PRL) elevation (P less than 0.01), whereas thyroid-stimulating hormone (TSH) and luteinizing hormone (LH) levels were not altered. In view of the relatively slow clearance rate for RU486 and its metabolites, our findings suggest that the pharmacologic action of RU486 is prolonged after a single oral dose.

Pituitary responses to synthetic corticotropin-releasing hormone: Absence of modulato effects by estrogen and progestin

To determine if the activity of the adrenocorticotropic hormonal-adrenal axis is modulated in part by estrogens and progestins, we have compared pituitary and adrenal responses to corticotrophin-releasing hormone in normal women during the early follicular, late follicular, and midluteal phases of the menstrual cycle and in four women undergoing ovariectomy who received estradiol (E2) implants alone or in combination with oral medroxyprogesterone acetate administration. Basal adrenocorticotropic hormone and cortisol levels (9:00 AM) and responses to ovine CRH were unaffected by variations in E2 and progesterone during each phase of the menstrual cycle. In women undergoing ovariectomy who received E2 replacement therapy, basal concentrations of adrenocorticotropic hormone and cortisol (9:00 AM) and the responses to human corticotrophin-releasing hormone were not altered by administration of E2 alone or E2 with medroxyprogesterone acetate. Under these experimental conditions, our findings suggest that physiologic changes in E2 and progesterone levels during the menstrual cycle and replacement doses of estrogen and progestin commonly used clinically do not significantly influence basal adrenocorticotropic hormone and cortisol levels or responsiveness to corticotrophin-releasing hormone.

Effects of the antiprogesterone RU486 in the early follicular phase of the menstrual cycle

To investigate the role of progesterone (P) in the early follicular phase, the antiprogesterone effect of RU486 was examined in five normally cycling women monitored by daily hormonal levels during three consecutive cycles (control, treatment, and recovery). In addition, luteinizing hormone (LH) pulse characteristics were assessed by frequent blood sampling (10 minutes for 10 hours) on day 3 of the control and the corresponding day of treatment cycles. Administration of RU486 (3 mg/kg, orally) for the first 3 days of the menstrual cycle did not significantly alter the length of the follicular phase (13.4 +/- 1.7 to 15.2 +/- 1.3 days), the LH surge, or the luteal phase length (12.2 +/- 0.5 to 12.6 +/- 0.7 days). The intermenstrual length of the treatment cycle (29.8 +/- 1.9 days) did not differ from the control (27.6 +/- 1.8 days) or recovery cycles (29.6 +/- 2.5 days). Integrated secretion of P and estradiol (E2) did not vary during the luteal phase of the control, treatment, or recovery cycles. During RU486 treatment, LH pulse frequency, pulse amplitude, and mean LH were not altered. Whereas mean E2 levels were significantly decreased from 150.5 +/- 15.1 to 110.1 +/- 7.0 pmol/L, follicle-stimulating hormone, P, adrenocorticotropin hormone, and cortisol were not significantly altered. Thus, in spite of the transient decrement in E2 secretion during RU486 treatment, the integrity of the ovulatory menstrual cycle was maintained. We conclude that administration of the antiprogesterone RU486 at the dose used during the first 3 days of the follicular phase does not perturb menstrual cyclicity.

HUMAN FETAL HYPOTHALAMIC GnRH NEUROSECRETION: DOPAMINERGIC REGULATION IN VITRO

An in‐vitro perifusion system was used to investigate GnRH release from fetal (21–23 weeks gestation) human hypothalami in response to dopamine (DA) and the DA receptor antagonist haloperidol. Administration of 1 μmol/l DA during five perifusions in which 1 μmol/l haloperidol was added to the medium failed to alter basal GnRH release. In contrast DA evoked a rapid and sustained 95·8 ± 20·3% increase (P > 0·01) in GnRH release during five matching perifusions with medium containing the α‐adrenergic antagonist phentolamine. While exposure to 0·01 μmol/l DA failed to alter basal GnRH release during three perifusions, 0·1 μmol/l DA elicited a 145·7 ± 65·2% increase (P > 0·05) in GnRH release in three matching perifusions, indicating a dose‐dependent effect. These studies demonstrate that DA can stimulate in‐vitro release of GnRH from the mid‐gestation fetal human hypothalamus by a DA receptor mediated mechanism.