Pulsatile administration of gonadotropin-releasing hormone for induction of ovulation.

Chronic pulsatile administration of gonadotropin-releasing hormone (GnRH) was used to induce ovulation in 12 women with various ovulatory disorders. In the first group of eight patients with normal to low baseline levels of gonadotropin, seven responded favorably to the treatment. Follicular maturation was observed in 57% of the treated cycles, and normal ovulatory cycles were induced in 24% of the patients. Two patients became pregnant. The intravenous route of administration was more effective than the subcutaneous one, possibly in response to the GnRH profile after each pulse. (The amplitude of GnRH peaks after an intravenous pulse was four times that seen after a subcutaneous one.) In contrast, follicular maturation and ovulation could not be induced in four women of a second group of patients with normal baseline levels of follicle-stimulating hormone but with high and frequent pulses of luteinizing hormone. The conclusion reached was that pulsatile administration of GnRH can be a new therapeutic tool in the treatment of ovulatory disorders in women who have an insufficient endogenous release of GnRH.

Effects and site of action of morphine on gonadotropin secretion in the female rhesus monkey.

The effects of morphine on gonadotropin secretion, and the site of its action, were tested in female rhesus monkeys. In Exp 1, morphine sulfate (3, 6, or 9 mg iv) was injected into ovariectomized monkeys, and its effects on tonic (pulsatile) LH and FSH secretion were examined. Administration of morphine (9 mg) resulted in a significant decrease in circulating LH and FSH, which lasted for 4-5 h. Exp 2 was performed to evaluate the site of action of morphine, whether hypophyseal or suprahypophyseal. The effects of morphine (6, 9, or 12 mg) on the LH response to GnRH pulses were evaluated in stalk-sectioned monkeys, in which gonadotropin secretion had been restored by long term pulsatile infusion of GnRH. LH responses to GnRH were not significantly altered by morphine. Exp 3 was performed to determine the effects of morphine on the estrogen-induced LH surge. Estradiol benzoate (330 micrograms in oil) was administered on days 2-5 of the menstrual cycle to nine animals. Four of these also were injected with 9 mg morphine at 5-h intervals for 40 h. Four of the five control and three of the four morphine-treated monkeys showed similar LH surges. The results demonstrate that, in the monkey, opiates inhibit tonic (pulsatile) gonadotropin secretion, most probably by acting at a suprahypophyseal site. In contrast, morphine does not alter the estradiol-induced LH surge, a result that differs from that seen in lower species and that may be related to differences in estradiol positive feedback characteristics.

Vasopressin secretion induced by hypoxia in sheep: developmental changes and relationship to beta-endorphin release.

To investigate the developmental changes in the secretion of vasopressin and the potential role of beta-endorphin as a stimulus to the release of vasopressin, the concentrations of these peptides were measured in fetal, newborn, and adult sheep after episodes of induced hypoxia. The studies confirm that hypoxia is a potent stimulus to the release of both vasopressin and beta-endorphin in the fetal animal. In both the newborn lamb and the ewe, more profound hypoxia is necessary for a similar release. In the fetus, the release of both vasopressin and beta-endorphin after hypoxia increased with gestational maturation. A comparison of control concentrations of both peptides, the discordance of release in the newborn lamb, and the absence of a change in concentrations of vasopressin with infusion of beta-endorphin implies that these hormones are released in parallel but independently during hypoxic stress.

Multiple gestations: management of pregnancy and delivery.

The antenatal management and outcome of 31 higher-order multiple gestations, 24 triplets, six quadruplets, and one set of quintuplets were analyzed. Bedrest was advised as soon as the diagnosis was made; hospitalization along with the administration of betamethasone and phenobarbital was begun during the second trimester. Caesarian section was performed on 13 women (42%). The overall mortality rate was 14.8%; excluding neonates less than 28 weeks of age, however, it became 7.5%. The primary cause of death was respiratory distress syndrome.

The use of human menopausal and chorionic gonadotropins for induction of ovulation. Sixteen years' experience at the Sloane Hospital for Women.

Gonadotropin therapy for anovulation is highly successful: 58.6% of treated patients conceive. Better results are achieved in patients with galactorrhea-amenorrhea (77.1%) and hypogonadotropic hypogonadism (63.3%) than in patients with normal gonadotropin levels (45.4%). The spontaneous abortion rate (27.5%) is somewhat higher than that in spontaneous pregnancies. The multiple pregnancy rate is 31% and was slightly lower in cycles with preovulatory estrogen levels in the physiologic range. In patients treated with human menopausal and chorionic gonadotropins for 7 to 9 days per cycle, the multiple pregnancy rate is considerably less (12.9%) than in patients with longer treatment. The efficacy of treatment does not diminish with repeat-treatment cycles.

Clinical course and outcome of pregnancy in twenty-five patients with pituitary microadenomas.

Twenty-five patients, aged 23-39, with amenorrhea of 18 to 168 months' duration, galactorrhea, hyperprolactinemia (prolactin levels of 45 to 370 ng/ml), and radiologic evidence of a pituitary microadenoma, were treated with bromocriptine or lergotrile, 7.5 mg daily for 2 to 16 weeks until conception occurred. All conceived and were delivered of infants. Follow-up during pregnancy included frequent office visits and monthly visual field examinations from the sixth month until delivery. All the pregnancies resulted in single infants and uneventful and no neurological or visual symptoms developed. All infants born were normal. Twelve patients breast-fed while the others did not by choice. Menstrual function resumed in two patients after delivery and one of them subsequently conceived spontaneously. We believe that the presence of a pituitary microadenoma without neurological or visual symptoms should not be a contraindication to ovulation induction and pregnancy. Most of such pregnancies are uneventful. If symptoms arise during pregnancy, they can be treated medically or, in extreme emergencies, surgically.

Arginine vasopressin during gestation and parturition in sheep fetus.

The possible correlation between plasma arginine vasopressin (AVP) concentration and the processes leading to parturition was assessed in 11 chronically catheterized pregnant ewes. Samples of blood withdrawn intermittently during a 20-day period preceding labor and during parturition were analyzed for AVP by a specific radioimmunoassay, as well as for pH, PaCO2 and PaO2. Fetal AVP was 1.74 +/- 1.55 pg/ml and maternal AVP 1.47 +/- 0.74 pg/ml (mean +/- SD). No preparturient rise in fetal vasopressin was noted, but levels increased progressively during labor to reach peak levels in cord blood (range 7.5--8,000 pg/ml). There was no consistent rise in maternal vasopressin during the same interval. A relationship between prolonged antepartum intrauterine asphyxia and increases in fetal vasopressin was noted. It is concluded that the markedly elevated levels of vasopressin observed in cord blood are the result of intrapartum 'stress', but are not related to the initiation of parturition.

Estrogen-induced gonadotropin surges in female rhesus monkeys after pituitary stalk section.

In order to investigate the primary site of action of estradiol, whether pituitary or hypothalamic, gonadotropin responses to estrogen were studied in female rhesus monkeys before and immediately after pituitary stalk section. The estrogen challenge, consisting of either an injection of estradio benzoate (400 microgram) or an implant of three silastic capsules containing 17 beta-estradiol, was initiated on days 2--5 of the menstrual cycle. The estrogen was given not later than 8 h after stalk section. Estrogens induced LH surges in all five animals before and after stalk section. FSH increases were observed in four of five intact and three of four stalk-sectioned animals. Mean FSH and LH levels in three stalk-sectioned animals treated with oil alone did not differ significantly from preinjection controls. These experiments suggest that the locus of estrogens on gonadotropin release in the rhesus monkey may well reside within the pituitary gland itself.

Anorexia nervosa and the hypothalamus.

A new name, "puberal starvation-amenorrhea", is proposed as more descriptive of the syndrome and less committal concerning its etiology. Though the etiology remains uncertain, a growing body of evidence--deranged hormonal secretory patterns, deficient thermal and water regulation, and other physiologic abnormalities--indicates that a specific hypothalamic dysfunction is responsible for this bizarre, sometimes lethal disease.

Gonadotropin, estrogen and progesterone response to long term gonadotropin-releasing hormone infusion at various stages of the menstrual cycle.

PIP: 6 normally menstruating women, aged 22-27, were given constant infusions of 12.5-25 mcg/hour gonadotropin releasing hormone (GnRH) for 24 hours during 10 cycles. 4 were infused in the early follicular, 3 in the late follicular, and 3 in the luteal phase. Frequent blood samples were assayed for luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, progesterone, and GnRH. The increase in gonadotropin and patterns of response varied in the different stages of the cycle. Quantitatively the response was minimal in the early follicular phase, maximal at midcycle, and moderate in midluteal phase. In the latter 2 phases most of the gonadotropins were released during the first 8 hours of infusion. The ratio of the LH-FSH areas under the curves favored FSH in the early follicular phase and LH at midcycle and luteal phase. In all the cycles there was an initial increase in both gonadotropins which lasted 6-8 hours after which the levels declined but nevertheless remained above baseline as long as the infusion was continued. Plasma GnRH measured during 6 infusions was undetectable prior to the starting and after discontinuation of the infusion, but during infusion fluctuations were considerable ranging from 150 to 500 pg/ml. These studies bring additional evidence to the possible existence of 2 gonadotropin pools in the human pituitary and point to the complexity of the response mechanism to GnRH stimulation and its relation to ovarian secretion.^ieng

Pregnancy in patients with pituitary tumors.

Thirteen patients with pituitary tumors had a total of seventeen pregnancies. Nine of these patients were treated prior to conception (four by radiation therapy, four by hypophysectomy, and one with lergotrile); four patients received no treatment. The untreated group had a total of six pregnancies, two of which were complicated by visual symptoms which regressed spontaneously after delivery. One of the hypophysectomized patients developed diabetes insipidus at 34 weeks' gestation which resolved spontaneously after delivery. Of the four irradiated patients, one had a child with Down's syndrome and another had a child with multiple congenital anomalies who died. The clinical course and various modes of treatment of these patients are discussed and the pertinent literature is reviewed.

Obstetric complications after treatment of intrauterine synechiae (Asherman's syndrome).

This review comprises 36 patients who were treated for Asherman's syndrome from 1968 to 1974 at the Sloane Hospital for Women. Of the 18 patients who later conceived only 6 had uncomplicated term deliveries. Four had premature deliveries resulting in neonatal death. Three had placenta accreta and postpartum hemorrhage, necessitating a cesarean hysterectomy in 1. Two patients required cesarean section for complications due to the syndrome, 2 had spontaneous abortion, and 1 had a cervical pregnancy requiring total hysterectomy. Only 10 babies survived. The incidence and severity of complications in conceptions following treatment for Asherman's syndrome is high, and the obstetrician must be prepared to manage them.

Neurohormonal control of gonadotropic secretion in primates.

With immunohistochemical techniques, products from both the parvicellular system (such as Gn-RH) and from the magnocellular system (vasopressin, oxytocin, and neurophysins) have been shown to be present in the neurons ending around the hypothalamopituitary portal capillary system. A neurosurgical technique for prolonged collection of pituitary stalk blood has been developed. Gn-RH, vasopressin, and neurophysins have been found in large amounts in pituitary stalk blood. Gn-RH levels were found to vary in a pulsatile fashion, thereby providing direct evidence for hypothalamic modulation of the discharge of LH by the pituitary. The finding of large amounts of estrogen-neurophysin in portal vein blood adds further evidence to the hypothesis that "estrogen" neurophysin may play a role in the control by the hypothalamus over the secretion of gonadotropins.

Immunoreactive gonadotropin-releasing hormone (Gn-RH) during maturation in the rat: Ontogeny of regional hypothalamic differences.

The developmental appearance of immunoreactive gonandotropin releasing hormone (Gn-RH) was measured by radioimmunoassay in male and female rats from the 12th day of gestation to adulthood. Gn-RH content of the whole hypothalamus of both sexes increased from birth to 21 days of age. By the 28th day, Gn-RH content in females had approximately reached adult levels, while that in males continued to increase. Adult male rats exhibited significantly higher levels than adult females. The ontogeny of the regional differences previously observed in cycling female rats (4) was also studied. Regional analysis of Gn-RH development was characterized in the anterior hypothalamus by the rapid attainment of adult levels by day 7. In striking contrast, in the mid-hypothalamic region, Gn-RH content increased gradually, rising dramatically just prior to vaginal opening. The developmental pattern of Gn-RH content is consistent with the maturation of those hypothalamic structures concerned with synthesis, transport and storage of Gn-RH. The regional patterns observed may thus represent sequential maturation of the neural pathways involved.

The significance of weight loss in the evaluation of pituitary response to LH-RH in women with secondary amenorrhea.

Sixteen women with amenorrhea occurring in the setting of severe self-imposed weight loss and 18 women with secondary amenorrhea due to other causes were given LH-RH (luteinizing hormone-releasing hormone). Women with weight loss were found to be unresponsive to LH-RH when severely underweight. FSH responsiveness returned in a linear fashion as weight gain occurred and was not related to estrogen levels. LH responsiveness also returned with weight gain although the relationship was not linear but exponential and a sudden increase in responsiveness occurred at 15% below ideal weight. No relationship to estrogen levels could be found. Women who experienced amenorrhea in a setting other than weight loss did not demonstrate responsiveness to LH-RH which could be correlated with body mass, even when underweight. Women who experienced amenorrhea with weight loss had a consistently lower LH response to LH-RH than the second group and their LH response was always lower than the FSH response. On the other hand, a variety of patterns was found in women with amenorrhea due to other causes.