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Inappropriate lactation and idiopathic hyperprolactinemia are frequently associated with amenorrhea. In these individuals, peripheral levels of follicle-stimulating hormone (hFSH) are usually normal, and luteinizing hormone (hLH) levels are often found in the low-normal range. The present study was undertaken to evaluate the functional capacity of the pituitary by the response of hFSH and hLH to synthetic gonadotropin-releasing hormone (Gn-RH). Six women with amenorrhea, inappropriate breast secretion, and idiopathic hyperprolactinemia (prolactin levels ranged from 45 to 355 ng/ml) were given 100 mug of Gn-RH intramuscularly. Serum hFSH and hLH levels were assessed in samples obtained at 15-minute intervals over the next 2-hour period. Initial hFSH levels were normal in all women, with a mean of 242 +/- 72 ng/ml. The absolute increase after Gn-RH administration averaged 486 +/- 193 ng/ml. Serum hLH was below normal in three of the six women, and normal in the remaining three women initially. The absolute increase averaged 1308 +/- 315 ng/ml. The greatest percentage increase in hLH was found in the women with the subnormal basal titers. In these women, hLH rose from a mean of 22 ng/ml to a mean of 1092 ng/ml. These data demonstate an exaggerated increase in hFSH and hLH levels after exogenous Gn-RH administration. This suggests that the amenorrhea associated with elevated serum prolactin levels is principally of hypothalamic origin.

In conclusion, although there are changes in the hypothalamic pituitary axis in terms of release of FSH and LH resulting in anovulation in women on oral contraceptives, the evidence to date does not support a cause and effect phenomenon. On the basis of both epidemiologic as well as biochemical studies, the etiology of secondary amenorrhea is diverse. This serves only to indicate that amenorrhea is a symptom, not a diagnosis. It appears at the present time that amenorrhea following the use of oral contraceptives should indicate only the preceding temporal use of exogenous steroids without implication as to a cause of the amenorrhea. Investigation should be aimed at determining the underlying cause of the amenorrhea.

Pituitary luteinizing hormone secretory dynamics (pulse frequency and amplitude) were evaluated in eight normal women administered clomiphene citrate or placebo. After 5 days of treatment clomiphene citrate was found to increase mean luteinizing hormone secretion by increasing the amount of pituitary luteinizing hormone released per pulse. No change in pituitary luteinizing hormone interpulse interval was found in the follicular phase of the cycle, although a faster pulse frequency in the luteal phase was found after clomiphene citrate when compared with placebo. No differences were found in the luteal phase (pulse frequency, amplitude, and mean luteinizing hormone level) after clomiphene citrate versus placebo in the volunteers. These data suggest that the principal mechanism of action of clomiphene citrate is an increase in the concentration of hypothalamic gonadotropin releasing hormone into the hypothalamic-pituitary portal circulation, with a resultant increase in pituitary luteinizing hormone secretion.

Previous observations by other workers indicating suppression of serum prolactin (hPRL) by water loading could not be confirmed. Sequential testing using an acute water load in patients with various clinical diagnoses did not aid conclusively in differentiating functional hyperlactinemic states from pituitary adenoma. It was of interest that the acute ingestion of water resulted in a triphasic response in serum hPRL levels. The response to breast stimulation was more marked in patients with excessive breast hypertrophy and galactorrhea. This was in contrast to patients with hypo- or hyperthyroidism, anorexia nervosa, and our normal subjects. In response to breast stimulation, there was no difference among the normal group, women with functional hyperlactinemia, and patients with proven pituitary adenoma. When they were compared with other patient groups in this study, marked responsiveness was found in patients with amenorrhea and galactorrhea, amenorrhea with elevated hPRL levels without galactorrhea, breast hypertrophy, and adrenal overactivity in response to these two stimuli. The physiologic mechanisms resulting in the increase in serum hPRL levels seen in these patients remain unclear at the present time.

Thirty-eight women with pelvic endometriosis diagnosed by laparotomy or laparoscopy were enrolled in a double-blind study utilizing danazol. Danazol was administered for 6 months in four doses schedules: 600, 400, 200, and 100 mg/day. At the completion of 6 months of therapy, repeat laparoscopy was performed and 71% of the women were found to have improvement of pelvic endometriosis. Minimal and moderate pelvic endometriosis appeared to respond well to doses of danazol of less than 400 mg/day, whereas severe endometriosis appeared to be best treated with danazol doses of greater than 400 mg/day. Symptomatic relief of pain, dysmenorrhea, and dyspareunia occurred in 89% of the women. The over-all pregnancy rate in women attempting conception was 28% (8 of 28). Fifty-four per cent of the women had recurrence of symptoms within 1 year of discontinuation of danazol.

Pituitary luteinizing hormone (LH) pulse frequency and amplitude were assessed as an indirect indicator of hypothalamic luteinizing hormone-releasing hormone (LH-RH) release in women with evidence of ovarian failure. Exogenous LH-RH (20 micrograms) was administered intravenously every 2 hours for 48 hours to determine the effect on pituitary LH release and the hypothalamic pulse generator for LH-RH secretion. This study design was used to investigate the possibility of an ultrashort negative feedback of LH-RH upon the synthesis and release of endogenous LH-RH. A wide range of LH pulse frequencies (8 to 28 pulses/24 hours) was present in these women. There was no discernible inhibition of hypothalamic LH-RH pulse frequency during or following exogenous LH-RH administration. Mean peripheral LH levels were significantly increased during exogenous LH-RH administration (P = 0.0038), reflecting both an increased baseline and an augmented pituitary LH response to the exogenous LH-RH. There were no differences found in LH pulse amplitude before and after LH-RH treatment. These data indicate that pituitary LH secretion in women with ovarian failure can be further stimulated by exogenous LH-RH. However, there was no evidence for inhibition of either pituitary LH secretion or hypothalamic LH-RH release using this administration schedule of exogenous LH-RH.

A patient with 46,XY karyotype and 17 alpha-hydroxylase deficiency is reported who illustrates marked virilization of the external genitalia. Marked phallic development and almost complete labioscrotal fusion with no development of a utriculovaginal pouch were noted. Because the perineum was essentially similar to that seen in male-to-female transsexuals, vaginal construction required the McIndoe procedure. Hence, although some patients with 17 alpha-hydroxylase deficiency have minimal virilization of the external genitalia, this patient's history indicates the operative management necessary in the opposite extreme, when patients show complete masculinization. Hormonal evaluation after gonadectomy revealed the enzyme deficiency based on abnormalities of steroid secretion by the adrenal cortex.

A case is presented and 11 others are reviewed in which symptomatic pituitary tumor enlargement occurred during pregnancies that resulted from induced ovulation. The syndrome is usually characterized by headache and visual disturbances with bitemporal visual field abnormalities, but may present with ocular muscle palsies. The cases are divided into two groups. The patients in one group had a shorter duration of amenorrhea (3.8 years), developed symptoms before the 14th week of pregnancy, and were usually treated by tumor removal. Patients in the second group had a longer period of amenorrhea (10.2 years), developed symptoms after the 24th week of pregnancy, and their symptoms regressed with delivery of the infant. Tumor removal or termination of the pregnancy both resulted in resolution of symptoms. All pregnancies resulted in normal infants. This series provides guidelines for management of future cases.

The principal physiologic effect of PRL in human females is the initiation of lactation. The cellular events leading to actual secretion of breast milk are reasonably well defined in the experimental animal. Other than the direct effects on breast tissue in pregnancy, prolactin's role at puberty, during the menstrual cycle, and in pregnancy is poorly defined at present. Although there are large quantities of PRL in amniotic fluid the physiologic role is unknown. There is evidence for an osmoregulatory role of PRL in the amniotic fluid, and a very questionable role for PRL in fetal lung maturation. Overall, much more investigation is warranted to define more clearly the effects of PRL in reproductive physiology.

Adenomatous tissue was obtained from 10 women with evidence of prolactin-secreting pituitary adenoma at the time of transsphenoidal removal of the tumor. Tissue levels of prolactin (hPRL) were estimated after extraction and were compared to preoperative peripheral serum levels of hPRL. No correlation was found between the tissue and serum concentrations of hPRL, although high levels of hPRL were found in the tissue extracts. Electron microscopy confirmed active secretion of the individual cells, and the ultrastructural findings were compatible with prolactin-secreting adenomas. Associated with the active secretion was extensive exocytosis of the secretory granules away from the capillary wall. These findings suggest that, although active secretion of hPRL is occurring, large amounts of secreted hPRL are not available for immediate uptake into the capillary plexus; thus a slow absorption of hPRL could be taking place from the adenomatous tissue. These data could explain the failure of provocative tests of hPRL stimulation and inhibition to unequivocally characterize an adenoma in an individual with elevated serum levels of hPRL.

Evaluation of the roles of prolactin and placental lactogen in pregnancy in primates has revealed mammotropic, fetal osmoregulatory, metabolic, and steroidogenic roles, which appear to protect the uterine contents during late pregnancy and prepare the fetus for the changes in nutrition at the time of delivery.

The present study was designed to investigate the efficacy of bromocriptine in reducing serum prolactin (PRL) levels and in decreasing the size of PRL-secreting microadenomas. Bromocriptine, 5.0 mg, was administered daily for 2 years of 17 women who had galactorrhea, hyperprolactinemia, and hypocycloidal polytomographic evidence suggestive of a pituitary microadenoma. Serum PRL levels were normalized in 16 of 17 women during therapy. Associated with this was resumption of regular menses in 15 of 16 women with menstrual dysfunction and cessation of galactorrhea in 16 of the 17 women. Improvement in the roentgenographic appearance of the sella turcica occurred in two women. No progression in tumor size was found during the course of therapy. Side effects attributed to bromocriptine were minimal, transient, and usually well tolerated. These data suggest that bromocriptine is an appropriate therapeutic modality for PRL-secreting pituitary microadenomas.

Prospective evaluation of 155 couples with two or more consecutive pregnancy losses disclosed uterine morphologic abnormalities in 27%, chromosomal abnormalities in 21 individuals (7.7%, or 15.4% of the couples), and at least one abnormal diagnostic test suggestive of a cause for recurrent pregnancy losses in 106 (68%). A positive test for antinuclear antibody was found in 7.5% of the women, whereas the expected rate in a population of this age is less than 2%. Cervical cultures for Ureaplasma urealyticum (T-strain mycoplasma) were positive in 48% of the women, and 28% of these women had a genetic or uterine abnormality to explain their pregnancy losses. Thyroid function profiles and cervical cultures for Mycoplasma hominis provided no significant information in the evaluation in these couples. With the exception of women with a positive antinuclear antibody, the overall prognosis for later pregnancies was quite good whether the diagnostic evaluation of the couple was normal (77% subsequent live births) or abnormal (71% subsequent live births). The significance of the positive antinuclear antibody in these women is unclear, but further studies and long-term evaluation are necessary to determine the relationship between recurrent pregnancy losses and later development of collagen-vascular diseases.