Oscar A. Kletzky

Longitudinal evaluation of patients with untreated prolactin-secreting pituitary adenomas

A group of 43 patients with galactorrhea, hyperprolactinemia, and radiographic evidence of pituitary adenomas were followed from 3 to 20 years. Initial polytomography and computerized tomographic (CT) scans revealed no evidence of extrasellar extension. Serum levels of prolactin (PRL) were measured at 6 month intervals, and visual fields were assessed annually. Polytomograms and CT scans were repeated every 9 to 36 months. During the period of follow-up, CT scans (but not polytomograms) indicated tumor enlargement in two patients, both of whom underwent selective transsphenoidal removal of the tumor. Polytomograms and CT scans did not show any change in the other 41 patients, and three of them have resumed normal menses, are no longer lactating, and have normal PRL levels. The initial results of this ongoing study indicate that most patients with small pituitary adenomas can be followed with annual CT scans with or without medical therapy, and that surgical treatment should be reserved for those patients with large tumors, those with visual-field loss, and those who show signs of enlargement of the tumor.

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.

Prolactin modulation of dehydroepiandrosterone sulfate secretion

To clarify the controversy about the effect of prolactin (PRL) on dehydroepiandrosterone sulfate (DHEA-S), this study was undertaken to investigate the effects of alterations in plasma PRL on plasma DHEA-S concentrations in hyperprolactinemic women, as well as in normal male subjects. DHEA-S was measured in a group of 21 women with hyperprolactinemia, galactorrhea, and amenorrhea (PRL:257 +/- 89 ng/ml; mean +/- SEM). In these women, mean plasma concentrations of DHEA-S (2.54 +/- 0.2 microgram/ml) were significantly higher (p < 0.005) than those in 41 normal control women (1.78 z microgram/ml) and those in a group of 11 amenorrheic patients (1.77 +/- 0.2 microgram/ml). Eight women with hyperprolactinemia were given 5 mg of bromocriptine each day for 4 consecutive weeks. Within 1 week of medication, PRL levels fell by 60% (p < 0.05). To test whether lowering normal plasma levels of PRL would affect plasma concentrations of DHEA-S, five normal male subjects received a 48-hour infusion of dopamine at an average rate of 6 microgram/kg/min. Plasma levels of PRL fell by 60% (p < 0.01) after 8 hours of infusion, and DHEA-S decreased by 27% by 16 hours (p < 0.05). These data suggest that PRL modulates the secretion of DHEA-S: an increase in plasma levels of PRL is correlated with elevated concentrations of DHEA-S, whereas a decrease in PRL is followed by a fall in DHEA-S.

Monitoring techniques to predict and detect ovulation

This study was designed to evaluate the accuracy of various methods in predicting and detecting ovulation in 14 spontaneous and 17 clomiphene citrate (CC)-induced cycles. From cycle day 11 all subjects (n = 27) were followed with daily transvaginal ultrasound; rapid measurement of serum luteinizing hormone (LH) and estradiol (E2); determination of urinary LH with First Response (Tambrands Inc., Palmer, MA) and Ovustick (Monoclonal Antibodies, Inc., Mountain View, CA) kits; and recording of basal body temperature (BBT). The results demonstrated that transvaginal ultrasound detected ovulation in all cycles. Mean daily serum LH levels were similar in both groups, and peak values of 40 mIU/ml or greater preceded the day of ovulation in all cycles. Serum E2 peak was significantly greater in CC cycles (961 +/- 96 versus 463 +/- 39 pg/ml) (P less than 0.01) and preceded the LH peak in 97% of the cycles. First Response and Ovustick predicted ovulation in 53.3% and 87.5% of the cycles, respectively (P less than 0.01). BBT nadir predicted the day of ovulation in only 10% of cycles. In conclusion, this study revealed that transvaginal ultrasound is an excellent method for detection of ovulation and that Ovustick is a very useful method for prediction of the day of ovulation.

Elevated bioactive luteinizing hormone in women with the polycystic ovary syndrome

Serum measurements of bioactive (bio) luteinizing hormone (LH), immunoreactive (i) LH, iLH/follicle-stimulating hormone (FSH) ratios, serum androgens and estradiol (E2) were determined in 20 women with the clinical diagnosis of the polycystic ovary syndrome (PCO), and compared with the levels of 10 women with chronic anovulation (CA) and 10 control subjects in the early follicular phase. Women with CA and control subjects had similar levels of E2, androgens, bioLH, iLH, and iLH/FSH ratios. Fourteen of 20 women with PCO had levels of iLH exceeding 3 standard deviations (SD) of the levels of control women (21 mIU/ml), and 13 of 20 had iLH/FSH ratios above 3.2 (3 SD of control levels). Nineteen of 20 women, however, had bioLH levels above 70 mIU/ml (3 SD of control levels). Mean levels for bioLH were 131 +/- 18 in PCO, 39 +/- 3 in control subjects, and 40 +/- 3 in women with CA. The ratio of bioLH/iLH was 3.5 +/- 0.4 in control subjects and 3.2 +/- 0.3 in women with CA but significantly elevated in PCO (4.6 +/- 0.4, P less than 0.05). There was, however, a significant positive correlation between bioLH and iLH values in PCO (r = 0.64, P less than 0.01). A significant correlation was found between bioLH and serum testosterone as well as between bioLH and serum dehydroepiandrosterone sulfate (DHEA-S) (P less than 0.05), although no correlation was found between iLH and serum DHEA-S. Weight and obesity also did not correlate with either iLH or bioLH in women with PCO and CA. These data suggest that bioLH may be an important hormonal marker in the clinical diagnosis of PCO.

Natural History of Microprolactinomas: Six-Year Follow-up

A 6-year follow-up of patients harboring microprolactinomas suggests that few patients (3 of 27) demonstrate significant growth of their tumor during this time. The major hazard for such patients who are not treated seems to be their risk for the development of premature osteoporosis in the face of sustained hyperprolactinemia. The risks of this complication may exceed the risks of early surgical intervention in selected patients. This short term risk of tumor growth (about 10%) must be weighed in the decision about therapeutic endeavors.

Correlation of ultrasonic measurement of ovarian follicle size and serum estradiol levels in ovulatory patients following clomiphene citrate for in vitro fertilization

Ovarian follicle development was investigated in 38 normally cycling women who received clomiphene citrate, 150 mg per day for 5 days, to maximize follicular development. Ultrasonic determination of follicle growth was performed on a daily basis with a real-time sector scanner and correlated with daily concentrations of estradiol (E2) in the peripheral serum as measured by rapid radioimmunoassay. Human Chorionic gonadotropin was given to induce ovulation, and the day of injection was considered day 0. Mean concentrations of E2 reached a maximum of 1,150 +/- 65 pg/ml on day 0. Mean diameter of the dominant follicle increased to 22.1 +/- 0.4 on day 0. When peripheral concentrations of E2 were correlated with diameter and total follicular volume it was found that plasma E2 levels varied, depending on the number of follicles seen on ultrasound examination, with a mean E2 value of 459 +/- 18.9 pg/ml per follicle per day. Multiple growth of follicles occur with artificial induction of ovulation; therefore, the use of ultrasound is an important parameter to assess follicular maturation and the timing of ovulation more precisely.

Log normal distribution of gonadotropins and ovarian steroid values in the normal menstrual cycle

In the statistical analysis of the values of luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone obtained from normal menstrual cycles, a depature from normality was noted. Chi square, W test, and linear transformation were used to check the normality of the distributions. The results of this investigation showed that the distributions were not normal (Gaussian) but log-normal. By plotting the probit of the percentages of cumulative frequency on a log scale (probit-log), linearity of the data was obtained. This resulted in direct graphical estimations of values with a useful clinical range, which included the mean and the 95 per cent confidence interval.

Serum prolactin patterns in early human gestation.

The relation between levels of human prolactin (HPRL), other protein hromones, and estradiol in serum immediately prior to and for the first weeks after conception was determined. HPRL was measured by radioimmunoassay in serum samples obtained daily from these women during the menstrual cycle in which conception took place and for several weeks therafter. It was found that the concentration of HPRL initally increased above nonpregnant levels 32 to 36 days after the luteinizing hormone (LH) peak. The patterns of estradiol and HPRL were similar in early gestation, while there was no similarity between the patterns of HPRL and human placental lactogen. These results are in aggreement with other studies showing that high levels of estrogen influence HPRL secretion in the human subject.

Disappearance of human chorionic gonadotropin and resumption of ovulation following abortion

The disappearance of human chorionic gonadotropin (hCG) and resumption of pituitary ovarian function was investigated in 13 patients following first- and second-trimester abortions. First-trimester abortion patients (with suction curettage) had a mean time of 37.5 +/- 6.4 days for the clearance of hCG to a level of 2 mlU/ml. Second trimester abortions (with prostaglandin) had a mean time of 27.4 +/- 4.8 days. Patients undergoing second-trimester hysterectomy had a mean disappearance time of 39.7 +/- 5.3 days and only 12 days if the hysterectomy was initiated with ligation of the uterine and ovarian vessels. No significant difference in clearance time was found when it was compared on the basis of the baseline hCG levels. Based on a concomitant luteinizing hormone (LH) and follicle-stimulating hormone (FSH) peak, nine of 12 patients resumed normal pituitary function. These LH and FSH peaks were seen even though the serum hCG levels were as high as 35 mlU/ml. Based on serum progesterone levels of greater than 3 ng/ml, all these nine patients ovulated as early as 21 days after abortion. In view of these results, the clearance of hCG after pregnancy termination depends mainly upon the type of procedure used. Moreover, in view of the early time of ovulatory recovery, contraception should be instituted within the first 2 weeks following pregnancy termination.