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.

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.

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.

Neural control of gonadotropin secretion in primates.

In the rhesus monkey, there is abundant evidence to indicate that ovarian secretions, mainly estradiol-17beta, control "tonic" as well as "cyclic" secretion of gonadotropins during the menstrual cycle. This mechanism of control ensures coordination of ovarian morphology and anterior pituitary secretory patterns. The primary site of action of estradiol in controlling both "tonic" and "cyclic" secretion of gonadotropins has been circumscribed to the medial basal hypothalamic-pituitary unit. A modulatory role in "cyclic" secretion by neural structures situated within the anterior hypothalamic-preoptic area or by efferent fibers in passage through this region also has been postulated. However, the accrued evidence indicates that in the primate, contrary to the rodent, the role of these rostral neural structures is not essential for menstrual cyclicity. Strong evidence also indicates that the isolated pituitary gland can respond to estrogen signals as well. Secretion of gonadotropin-releasing hormone, the hypothalamic decapeptide, into the long portal vessels is, however, essential to maintain function of the gonadotroph. Further, pulsatile release of luteinizing hormone is distinctly under the control of a similarly paced hypothalamic clock.

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.

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.

Ovarian modulation of immunoreactive gonadotropins-releasing hormone (Gn-RH) in the rat brain: evidence for a differential effect on the anterior and mid-hypothalamus.

Gonadotropins-releasing hormone (Gn-RH) in selected regions of the female rat brain was measured by radioimmunoassay. Detectable immunoreactive Gn-RH was found in the anterior hypothalamic-septal region and in the mid-hypothalamic (arcuate-median eminence) region. Gn-RH was several times higher in the middle region than in the anterior region. Gn-RH was undetectable in the posterior hypothalamic region, frontal cerebral cortex and pineal glands, as well as in random blood samples, and low to undetectable in anterior pituitary glands. Gn-RH activity varied during the estrous cycle and after castration. In the mid-hypothalamic region, Gn-RH content was lowest throughout diestrus and in late morning and early afternoon of proestrus, and highest early in the morning of proestrus and during estrus. A significant decrease at mid-day was only found on the day of proestrus, a few hours prior to the critical period for LH release. In the anterior hypothalamic region, low Gn-RH activity was found from 1200 h of estrus to 1200 h of diestrus-2. A comparatively higher activity was seen at 1700 h of diestrus-2 and also from 1400 h of proestrus to 0800 h of estrus. Twenty-one days after ovariectomy, Gn-RH in the mid-hypothalamic region was significantly lower than the lowest values seen during the estrous cycle, while Gn-RH in the anterior hypothalamic region remained between low and high values seen during the cycle, being significantly higher than the low values. The changes observed during the estrous cycle and after castration suggest that gonadal steroids play a direct role in the control of hypothalamic Gn-RH. These data also demonstrate that Gn-RH varies in a different way in the anterior and mid-hypothalamic regions.