Ten-year follow-up of patients with secondary amenorrhea and normal prolactin.

A group of 46 patients with secondary amenorrhea without galactorrhea or hyperprolactinemia were studied retrospectively after being clinically categorized into four groups with the use of progesterone-induced uterine bleeding and measurement of serum gonadotropins and prolactin levels. The ability to have regular spontaneous menstrual cycles and to conceive was assessed after a follow-up period of 10 years. Patients who had been classified as having hypothalamic pituitary "failure" (hypoestrogenic amenorrhea) with low levels of circulating estradiol had a greater rate of recovery of spontaneous ovulation and menses when compared with patients who had been classified as having only hypothalamic pituitary dysfunction (euestrogenic amenorrhea). The patients with diagnosis of hyperandrogenic chronic anovulation or polycystic ovary syndrome generally required clomiphene citrate for induction of ovulation and almost all the patients with premature ovarian failure (hypergonadotropic amenorrhea) remained estrogen-deficient and unable to ovulate. Hyperprolactinemia or an identifiable pituitary adenoma has not developed in any of the patients to date.

Early detection of pregnancy with transvaginal ultrasound.

The gestational age and the serum human chorionic gonadotropin (hCG) at which an intrauterine pregnancy can be detected using transvaginal ultrasonography (TVU) is not known. In this study, ten pregnant women were serially scanned with TVU from the time of initial positive pregnancy test, to determine when an intrauterine sac greater than 2 mm, fetal pole greater than 2 mm, and fetal heart motion could be detected. A gestational sac was seen 34.8 +/- 2.2 days from the last menstrual period (LMP), at which time the hCG was 1398 +/- 155 mIU/ml of the International Reference Preparations (IRP) or 914 +/- 106 mIU/ml of the Second International Standard (second IS). A fetal pole was seen 40.3 +/- 3.4 days from the LMP when the hCG was 5113 +/- 298 mIU/ml of the IRP or 3783 +/- 683 mIU/ml of the second IS. Fetal heart motion was detected 46.9 +/- 6.0 days from the LMP when the hCG was 17,208 +/- 3772 mIU/ml of the IRP or 13178 +/- 2898 mIU/ml of the second IS. From these results, it can be concluded that transvaginal ultrasonography can detect an intrauterine gestation earlier than what has been previously reported with transabdominal ultrasonography.

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.

Management of patients with hyperprolactinemia and normal or abnormal tomograms.

Forty women with hyperprolactinemia with and without radiologic evidence of prolactin-secreting pituitary adenoma were prospectively treated with bromocriptine. On the basis of tomographic studies, the patients were divided into either a microadenoma group (N = 19) or no adenoma group (N = 21). Both groups had similar distributions as to obstetric history, menstrual abnormalities, levels of baseline serum luteinizing hormone, follicle-stimulating hormone, and thyrotropin. Patients in the adenoma group had significantly higher (p less than 0.001) baseline serum prolactin levels (173 +/- 4.4 ng/ml) than those of patients without adenoma (61.1 +/- 4.5 ng/ml). Patients without an adenoma required significantly less bromocriptine (5 to 7.5 mg) (p less than 0.005) to normalize serum prolactin or establish a pregnancy than did those who had an adenoma (5 to 20 mg). Similarly, patients with adenoma resumed ovulatory cycles (8.7 +/- 1.2 versus 5.7 +/- 0.06 weeks), had their galactorrhea disappear (11.3 +/- 2.1 versus 5.6 +/- 1.1 weeks), and become pregnant (16.2 +/- 2.5 versus 9.8 +/- 1.5 weeks) in a significantly longer time (p less than 0.01) than did those who had no adenomas. There was no significant difference in the pregnancy rate between the groups, and the overall rate was 86% of 28 patients desiring pregnancy. No complications were observed during pregnancy. The conclusion is that both patients with and those without radiologic evidence of a prolactin-secreting pituitary adenoma can be safely treated with bromocriptine. In addition, the resumption of ovulatory cycles is more important than the absolute normalization of serum prolactin.

An extended regimen of clomiphene citrate in women unresponsive to standard therapy.

An extended regimen of clomiphene consisting of 250 mg of clomiphene for 8 days followed by the administration of 10,000 IU of human chorionic gonadotropin (hCG) 6 days later was administered to 13 oligomenorrheic women who had previously failed to ovulate when treated with 250 mg of clomiphene for 5 days and hCG. Eight of these 13 women ovulated. Their postovulatory mean progesterone (P) level 7 days after hCG was 16 +/- 2 ng/ml. Three pregnancies occurred during 25 treatment cycles. Posttreatment estrogen levels were higher when women were treated for 8 days than for 5 days. Women ovulating after 8 days of treatment had increased concentrations of luteinizing hormone (LH) and testosterone (T) prior to hCG administration and higher pretreatment levels of estrogen and T, compared with women who did not ovulate. Changes in the timing of hCG administration may induce ovulation in some women who fail to ovulate when hCG is given on day 14. Because this 8-day regimen of clomiphene and hCG was successful in more than 50% of women failing to ovulate after 5 days, this regimen should be used prior to human menopausal gonadotropin (hMG) therapy.

The effect of gonadotropin-releasing hormone on ovarian estradiol secretion.

The present study was undertaken to determine if more than one dose of GnRh is necessary to induce luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion that is sufficient to cause a significant increase in circulating estradiol (E2) levels. Thirty-four women were studied. Of these, eight control women were studied in the early follicular phase (baseline E2, 48 +/- 4.5 pg/ml); eight patients had secondary amenorrhea caused by hypothalamic dysfunction (baseline E2, 52.0 +/- pg/ml), seven had secondary amenorrhea caused by hypothalamic pituitary failure (baseline E2, 21 +/- 2.5 pg/ml), and 11 women had amenorrhea, galactorrhea, and hyperprolactinemia (baseline E2, 16.5 +/- 3 pg/ml and baseline prolactin, 443 +/- 98 ng/ml). An initial intravenous bolus of 150 microgram of gonadotropin-releasing hormone was followed 2 hours later by a smaller dose of 50 microgram. Thirty minutes following the first and second doses of GnRH, plasma LH and FSH increased significantly in all subjects. The initial increase of LH and FSH did not result in an increase in the plasmma E2 levels in any of the subjects. However, following the second gonadotropin peak, a significant increase in plasma E2 values was observed at 4 hours in all subjects (P less than 0.01). It can be concluded that (1) GnRH can be used to induce ovarian stimulation in normal women as well as in amenorrheic patients with low or normal baseline E2 levels as long as a sequential increase in LH and FSH can be elicited and (2) hyperprolactinemia does not interfere with ovarian E2 synthesis.

Clinical and laboratory evaluation of patients with primary amenorrhea.

Sixty-two patients with primary amenorrhea were retrospectively categorized into 4 groups: 1) breast development absent and uterus present (29 patients), 2) breast development present and uterus absent (9 patients), 3) both breast development and uterus absent (2 patients), and 4) both breast development and uterus present (22 patients). Patients in category 1 were diagnosed as having hypogonadotropic hypogonadism (low or normal follicle-stimulating hormone [FSH]) or gonadal dysgenesis (elevated FSH). Patients in category 2 were diagnosed as having congenital absence of the uterus (female range testosterone [T] or testicular feminization [male range T]). In the 2 patients in category 3, a 46,XY karyotype occurred with an enzyme defect (17,20 desmolase) in 1 and the other had agonadism. In category 4, 5 patients with elevated prolactin and a pituitary adenoma were identified. The remaining 17 patients were divided into 2 groups based on progesterone withdrawal bleeding. Patients who had withdrawal bleeding and had elevated luteinizing hormone level were diagnosed as having polycystic ovaries and patients with normal gonadotropins as having hypothalamic dysfunction. Patients who did not bleed were diagnosed as having hypothalamic failure (normal or low FSH) or primary ovarian failure (elevated FSH). This study demonstrates that it is possible to classify patients with primary amenorrhea into 4 useful diagnostic categories based on physical examination and a minimal laboratory investigation.

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.

Comparison of serum prolactin, plain radiography, and hypocycloidal tomography of the sella turcica in patients with galactorrhea.

Hypocycloidal tomography of the sella turcica is being used with increasing frequency in patients with galactorrhea in order to establish the diagnosis of pituitary adenoma. In 201 patients with galactorrhea, serum prolactin (PRL) levels were correlated with anteroposterior (AP)--lateral plain radiographs and hypocycloidal tomography of the sella turcica. Plain films were normal in 167 and abnormal in 34 patients. Of the 167 patients with normal AP-lateral plain films, 80 had normal tomograms and normal serum prolactin levels while 80 patients had normal tomograms and elevated serum PRL levels (21 to 256 ng/ml). The remaining seven of the 167 patients had normal plain films with abnormal tomograms and elevated serum PRL levels (28 to 176 ng/ml). All patients with abnormal plain radiographs had abnormal tomograms and had either elevated or normal serum PRL levels. In view of these findings, sella tomography is only necessary in patients with normal plain radiographs and elevated serum PRL levels.

Galactorrhea and pituitary tumors in postpill and non-postpill secondary amenorrhea.

One hundred sixty-seven women with secondary amenorrhea were observed from six months to four years. In 66 patients, the amenorrhea followed the discontinuation of oral contraceptives (postpill) while in the remaining 101 the amenorrhea was not temporally pill related (non-postpill). Galactorrhea was present in 43 (65%) of those with postpill amenorrhea and in 32 (32%) of those with non-postpill amenorrhea (p less than 0.001). Tomography of the sella turcica was performed in the 75 women with galactorrhea and in the 35 without galactorrhea who did not have withdrawal uterine bleeding following progesterone administration and who had low or normal serum follicle-stimulating hormone levels (hypothalamic-pituitary failure). Forty of the 75 patients with amenorrhea and galactorrhea had radiographic evidence of a pituitary tumor whereas only eight of 35 patients with hypothalamic-pituitary failure without galactorrhea had an abnormal sella turcica (p less than 0.01). The incidence of radiographic abnormalities in those with galactorrhea was similar in both the postpill and non-postpill groups.

Ovulation induction in amenorrheic women.

Seventy-six patients with primary or secondary amenorrhea who wished to conceive were treated with clomiphene citrate, 2-Br-alpha-ergocryptine, and/or human menopausal gonadotropins (hMG). Of these 71 patients who received clomiphene citrate, 39 (55%) ovulated. Of these 71 patients, 52 had withdrawal uterine bleeding following IM progesterone, and 38 (73%) ovulated; only 1 of the 19 who did not bleed ovulated (P less than 0.001). Ovulation occurred in the former group of patients whether or not they had galactorrhea. Of the 32 patients who failed to ovulate despite treatment with the maximal dose of clomiphene, 250 mg/day for 5 days, 26 received hMG-hCG. All 26 ovulated and 15 conceived. All 8 patients with amenorrhea-galactorrhea who were treated either primarily or secondarily with bromergocryptine ovulated, and 4 conceived. Therefore, the drug of choice for ovulation induction in amenorrheic patients depends on 1) the presence of withdrawal bleeding after progesterone and 2) the presence of galactorrhea. In all patients with progesterone withdrawal bleeding with or without galactorrhea, the initial treatment of choice is clomiphene citrate. In the absence of withdrawal bleeding, hMG should be administered if galactorrhea is absent, and bromergocryptine should be administered if galactorrhea is present.

The significance of galactorrhea in patients with normal menses, oligomenorrhea, and secondary amenorrhea.

Thyroid-stimulating hormone and prolactin (PRL) were measured in a group of 149 women with galactorrhea. Three of these patients were found to have primary hypothyroidism. In the remaining 146 patients, the PRL assay was correlated with the menstrual history and the results of hypocycloidal polytomography. Sixty-two per cent of these patients had hyperprolactinemia and 35 per cent had abnormal tomograms. Nine patients with abnormal x-rays had normal prolactin levels. None of the patients with normal menses and normal PRL was found to have an abnormal x-ray. Fourteen of the 15 patients with PRL levels greater than 200 ng. per milliliter had abnormal tomograms. Almost 70 per cent of patients with secondary amenorrhea and low estrogen status had abnormal x-rays. In patients with oligomenorrhea and secondary amenorrhea with normal estrogen status, it was not possible to differentiate between patients with normal or abnormal tomograms based on the level of serum PRL. Polytomography remains the single most important diagnostic test in establishing the presence of a pituitary tumor.

PIP: Thyroid-stimulating hormone and prolactin (PRL) were measured in 149 women with galactorrhea; 3 were found to have primary hypothyroidism. In the remaining 146, the PRL assay was correlated with menstrual history and results of hypocycloidal polytomography. 14 of 15 patients with PRL levels greater than 200ng/ml had abnormal tomograms. Almost 70% of patients with secondary amenorrhea and low estrogen status had abnormal X-rays. Differentiation among patients with normal or abnormal tomograms based on serum PRL level in patients with oligomenorrhea and secondary amenorrhea with normal estrogen status was not possible. A medical panel discussion of the study's design and results focuses on high level radiation exposure during diagnosis and the relationship of oral contraceptive (OC) use to galactorrhea, including temporal correlation between time of ingestion and onset of symptoms. Galactorrhea has been associated with prior use of OCs, but this study gives no data due to the lack of reliable OC-use history by many of the patients. Thyroid surgery is recommended for women wishing fertility because pregnancy could stimulate tumor growth and cause sudden blindness.

An in vivo system in man for quantitation of estrogenicity. I. Physiologic changes in binding capacity of serum corticosteroid-binding globulin.

A modified method of measuring the binding capacity of corticosteroid-binding globulin (CBG-BC) in serum using 3H-cortisol saturation-charcoal adsorption is described. Forty serum samples per day can be assayed in duplicate, each sample with a heated nonspecific binding blank (60 degrees C.). The interassay coefficient of variation is less than 6 per cent. All age groups of men and women had similar levels of CBG-BC, except postmenopausal women, whose levels were higher (15.9 +/- 0.2 vs. 18.7 +/- 0.8 microgram per 100 ml., mean +/- standard error of the mean, respectively; z = -3.51, p less than 0.001). The variance of serum levels of CBG-BC throughout the menstrual cycle in five women was small (coefficient of variation = 13 per cent) and showed no relationship to the marked and cyclic changes in estradiol levels (coefficient of variation = 73 per cent). In pregnancy the levels of CBG-BC increased linearly after estradiol levels exceeded 1,300 pg. per milliliter and after estrone levels exceeded 500 pg. per milliliter (r = 0.88, p less than 0.001; and r = 0.85, p less than 0.001, logarithmic regression analysis). The findings of this study indicate that serum levels of CBG-BC are relatively constant in men and menstruating women. In pregnancy after a high threshold of endogenous estrogen is reached, CBG-BC increases in a direct dose-response manner as levels of estradiol increase further.

The cervical factor in infertility: diagnosis and treatment.

One hundred and fourteen women with an abnormal fractional postcoital test (PCT) and no other demonstrable cause of female infertility were included in this study. By utilizing the results of the postcoital test, it was possible to divide the patients into three major groups: (1) those with anatomical cervical defect, (2) those with abnormal cervical mucus, and (3) those with an abnormal PCT and normal cervical mucus. In the latter group the abnormality was due to either an abnormal male factor or an undetermined factor. The treatment used in all cases was either steroidal (diethylstibestrol) or mechanical (cervical cup insemination). In 53 of the patients there was an improvement in the PCT as a direct result of therapy. Twenty-three of these patients became pregnant--a pregnancy rate of 43%. Of the entire group of 110 patients (excluding 4 patients whose husbands had azoospermia), only 21% became pregnant. Of the 57 patients who failed to respond to therapy, 41 have been followed for 1 year, and only 2 pregnancies have been noted without therapy. No correlation was found between an abnormal PCT and the immunologic factor.