CV 205-502 treatment of hyperprolactinemia.

CV 205-502 is a nonergot oral dopamine agonist with specific D2 activity, which has a prolonged suppressive effect on serum PRL and may have fewer side-effects than other dopamine agonists. We treated 26 hyperprolactinemic women with this compound given as a single bedtime (hs) dose for up to 12 weeks. All had gonadal dysfunction, either amenorrhea or oligomenorrhea, and 15 had galactorrhea. The initial and subsequent doses were administered in a randomized fashion; the initial dose ranged from 0.01-0.05 mg, and the dose at 12 weeks ranged from 0.03-0.09 mg. The women were evaluated every 2 weeks, and the dose was increased by 0.02 mg every 4 weeks if the serum PRL level was greater than 20 micrograms/L. Of the 26 women initially enrolled, 24 completed 12 weeks of therapy, and 2 discontinued therapy because of side-effects. Thirteen women (54%) had return of menses, and 12 (80%) had either a decrease in or disappearance of galactorrhea. Serum PRL concentrations decreased to a variable degree in all patients; 13 (54%) achieved a normal serum PRL level (less than or equal to 20 micrograms/L). The mean (+/- SE) pretreatment serum PRL concentration was 129 +/- 34, and it was 29.9 +/- 5.9 micrograms/L after 12 weeks of treatment (P = 0.005). The mean (+/- SE) percent reduction in serum PRL was 66.5 +/- 5.0% (median, 78.0%). A dose response was not demonstrated (r = -0.08; P = 0.70) among the 6 dose groups during the last 4 weeks of therapy. In 5 women, serum PRL levels, measured frequently for 24 h after treatment remained low. Side-effects after the initiation of therapy included nausea, headache, and morning fatigue in 10 women. These symptoms caused 2 women to discontinue therapy; they subsided in the other women. An optimal dose was not determined and will probably need to be determined by titration in each patient. CV 205-502, given once daily, appears to be a safe and effective alternative to other dopamine agonists in the treatment of hyperprolactinemia.

Bromocriptine as primary therapy for prolactin-secreting macroadenomas: results of a prospective multicenter study.

To assess the effectiveness of bromocriptine in reducing the size of PRL-secreting macroadenomas with extrasellar extension, we conducted a prospective multicenter trial in patients without prior radiotherapy, applying a standard protocol of treatment and tumor size evaluation. Basal serum PRL levels [1441 +/- 417 (+/- SEM) ng/ml for women; 3451 +/- 1111 ng/ml for men] fell in all patients and to 11% or less of basal values in all patients but 1. Normal PRL levels were reached in 18 of the 27 patients. In 13 patients (46%), tumor size was reduced by greater than 50%, in 5 patients (18%) by about 50%, and in 9 patients (36%) by approximately 10-25%. The extent of tumor size reduction did not correlate with basal PRL, nadir PRL, percent fall in PRL, or whether PRL levels reached normal. However, a reduction in PRL levels always preceded any detectable change in tumor size. In 19 patients, reduction in tumor size was evident by 6 weeks, but in the other 8, such reduction was not noted until the 6 month evaluation. In the 4 patients in whom bromocriptine was discontinued at the end of 1 yr, tumor reexpansion occurred in 3. Visual fields improved in 9 of the 10 patients in whom they were abnormal. Because of the excellent results found in most of the patients in this series, we suggest that therapy with bromocriptine should be considered as initial management for patients with PRL-secreting macroadenomas.

Hyperprolactinemia. Evaluation and management.

Hyperprolactinemic syndromes are a diverse group of disorders that present in widely different age groups. They are common disorders in both men and women and require management over a lifetime. The past 20 years have greatly increased our knowledge about these disorders and simplified their management. Yet, we have made little progress in understanding the origin and dynamics of pituitary tumors and their natural histories, and as yet we have been unable to develop effective tumoricidal therapy or medication that corrects, at the central axis level, neurotransmitter disorders that may produce hyperprolactinemia. Perhaps these issues will be the subject of such reviews in the future.

Secretory immune system of the female reproductive tract: I. Immunoglobulin and secretory component-containing cells.

We have investigated tissues from the female reproductive tract to determine whether the distribution of cells involved in the formation of secretory immunoglobulin A (IgA) molecules is analogous to that described for intestines, bronchus, and mammary and salivary glands. Fresh tissues from fallopian tube, ovary, uterus, and vagina were obtained, and sections were stained with fluorochrome-labeled polyclonal or monoclonal antibodies specific for IgG, IgA, IgA1, and IgA2 subclasses; IgM; secretory component; and J chain. Subepithelial plasma cells were identified in each specimen of fallopian tube, endocervix, ectocervix, and vagina. Approximately two-thirds of the immunoglobulin-positive cells contained IgA and J chain, indicating that they produced polymeric IgA. In comparison to tissues such as spleen and bone marrow, where IgA1-positive cells are produced, we found a high proportion of IgA2-positive cells in fallopian tube, cervix, and vagina. Epithelial cells in fallopian tube and endocervix contained secretory component. These data indicate that secretory IgA, which provides the first line of defense against invading pathogens, is produced locally in tissues of the female reproductive tract.

Long-term monolayer culture of human anterior pituitary cells: functional validation of a method.

This study demonstrates the response of human pituitary cell monolayers to a wide variety of hormonal stimuli. Appropriate release of luteinizing hormone (LH) and prolactin (PRL) was used as a verification of cell function. Cells that had been in culture for 20 days, with no hormonal additions, were exposed to LH-releasing hormone (LH-RH) continuously for 14 days. This resulted in an immediate fivefold increase in secretion of LH followed by a depression in LH production over the remaining 10-day period. After an 8-day period without hormonal additions, the same cultures again demonstrated a threefold increase in response to retreatment with LH-RH. In two similar studies, cells that had been in culture for 28 and 31 days were treated with bromocriptine, pergolide, dopamine, or thyrotropin-releasing factor (TRF). TRF elicited an increase of PRL in the medium by nearly double the control values. The addition of dopamine, pergolide, or bromocriptine resulted in a depression of PRL during the treatment period. This study has shown that human pituitary cells maintained in long-term monolayer culture respond predictably to a wide range of hormonal stimuli.

Hormonal treatment of functional ovarian cysts: a randomized, prospective study.

Estrogen (E)/progestin therapy for functional ovarian cysts is widely used in clinical practice, but the efficacy of this treatment has not been determined in controlled trials. In this study, we examined the effect of E/progestin administration in a group of infertility patients enrolled in a program of ovulation induction who had cysts identified by transvaginal sonography. Patients were randomized to receive either norethindrone 1 mg/mestranol 0.05 mg/d (group A, n = 24) or no treatment (group B, n = 24) for up to 6 weeks. Patients were re-evaluated by sonography at 3, 6, and 9 weeks after entry into the protocol. The ages, mean cyst diameters, and proportions of patients having received gonadotropins in the previous menstrual cycle were not significantly different among the two groups. All patients who had a sonographic abnormality persisting for 9 weeks were surgically explored and found to have pathological cysts. The rate of disappearance of functional ovarian cysts was not affected by E/progestin treatment.

Evaluation of Delestrogen and Parlodel as a luteolytic agent in humans.

Ten women ages 22 to 39 years were treated with a single injection of Delestrogen on day 19 of the menstrual cycle and increasing doses of Parlodel on days 19 to 23. This treatment resulted in a shortening of the luteal phase and a decrease in the production of progesterone and had no effect on serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), or prolactin levels. Side effects reported with this therapy included lethargy, dizziness, nausea, vomiting, hot flashes, depression, and nasal congestion. These preliminary clinical data suggest a combination of estrogen and bromocriptine regimen is luteolytic and may be useful as an interceptive abortifacient preparation in the human being.

Effect of estrogen/progestin administration on the ovarian response to gonadotropins: a randomized, prospective study.

The findings of our study indicate that women pretreated with E/progestin demonstrate increased gonadotropin requirements when undergoing ovulation induction. Whether this treatment has a significant effect on the outcome of ovulation induction in patients receiving gonadotropins remains to be established.

A one-year experience with a capitated health care plan for infertility.

OBJECTIVE: To report on a one-year experience participating in a capitated healthcare plan for infertility. DESIGN: Prospective study. SETTING: University population. PATIENT(S): Reproductive-age women 15 to 50 years. INTERVENTION(S): The first-generation Lewin infertility algorithm and CATHI software were used to negotiate infertility services under a capitated arrangement for $0.50 per member per month. The following reports our experience for the fiscal year 1997. MAIN OUTCOME MEASURE(S): Infertility services rendered, pregnancy rate, cost of services, collection rates. RESULT(S): Five thousand forty-six women representing 39,689 member months generated 39 new and 198 return visits. Thirty-two percent of the patients required three visits or less; six patients generated 22% of the visits. Fifty-one percent listed infertility as one of their chief complaints; 31% had mixed diagnoses. Eight (7.6%) patients required surgery, 11 (10.5%) patients underwent either IVF or GIFT cycles. Total charges submitted were $176,636; the amount assigned to specialty care was $135,277, and to IVF/GIFT, $33,433. Total capitated payments, including copayments, was $126,256 under the reproductive medicine agreement and $32,891 under the infertility rider. This resulted in a 71% gross collections rate. CONCLUSION(S): This study indicates that entering into a capitated health care plan to provide an infertility benefit can produce a successful result.

Detection of antigalactosyltransferase antibodies in plasma from patients with antisperm antibodies.

Sperm-associated galactosyltransferase has been implicated as a macromolecule involved in sperm to egg binding interactions during fertilization. An analysis of human plasma from 18 patients with antibodies to sperm antigens detected antigalactosyltransferase antibodies when compared with 10 control patients. These plasma antibodies were all able to immunoprecipitate enzyme activity from a preparation of human milk galactosyltransferase but varied in their ability to detect the protein by Western blot analyses. These results confirm the antigenic presence of galactosyltransferase in human sperm.

Identification of early pregnancy landmarks by transvaginal sonography: analysis by logistic regression.

OBJECTIVE: To assess the feasibility of logistic regression analysis for determining the gestational ages at which detection of early pregnancy landmarks first can be observed. DESIGN: Retrospective analysis. SETTING: University-based tertiary care clinic. PATIENT(S): Eighty-two women with viable singleton pregnancies in whom ovulation had been achieved by an injection of hCG. INTERVENTION(S): Two hundred fifteen transvaginal sonographic scans. MAIN OUTCOME MEASURE(S): Logistic regression was used to estimate the probability of detection of sonographic findings as a function of gestational age. RESULT(S): We found that the likelihood of visualization of a gestational sac or fetal heart motion could be represented accurately by logistic equations. Gestational age at which there was 95% probability of visualization was 35.5 days for the gestational sac and 44.5 days for fetal cardiac activity. The probability of detecting fetal cardiac activity was 95% when the mean gestational sac diameter was 1.6 cm and was 99% at 1.9 cm. CONCLUSION(S): The sonographic appearances of developmental landmarks in early pregnancy occurs within well-defined gestational time periods, and the probabilities for visualization can be closely approximated using a logistic model. Our results suggest that the number of sonographic examinations required to document infertility treatment success can be minimized by surveillance at standardized gestational ages.

Peripheral progesterone (P) levels and endometrial response to various dosages of vaginally administered P in estrogen-primed women.

OBJECTIVE: To compare the pharmacokinetics and pharmacodynamics of 100 mg/d, 200 mg/d, and 400 mg/d (200 mg two times per day) of P administered vaginally for 14 days to estrogen-primed postmenopausal women. DESIGN: Randomized, open-label, three-way crossover study. SETTING: Two university-based investigative sites. PATIENT(S): Twenty healthy postmenopausal women with histologically normal endometria. INTERVENTION(S): Oral 17 beta-E2 was given each day of a 28-day cycle; a P vaginal suppository was inserted daily according to the randomization schedule during days 15-28 of each cycle; blood samples were collected; an endometrial biopsy was obtained on day 25; and patients were crossed over to the next treatment cycle after a washout period of at least 30 days. MAIN OUTCOME MEASURE(S): Mean P blood levels, endometrial dating/conversion. RESULT(S): There was good vaginal absorption of P for all dosages. Endometrial conversion occurred in all 200- and 400-mg/d P-dosed cycles, whereas the 100-mg/d dosage failed to convert primed endometria consistently. There also was a significantly increased tendency for earlier bleeding and spotting with the 100-mg/d dosage. CONCLUSION(S): Both the 200- and 400-mg/d dosage regimens consistently convert an estrogen-primed endometrium, and yield appropriate endometrial dating and bleeding patterns. However, the 400-mg/d dosage attains the highest sustained blood levels and may be the best dosage regimen for further study.

The effect of routine breast examination on serum prolactin levels.

OBJECTIVE: To evaluate the effect of a routine breast examination on serum PRL levels. DESIGN: Prospective clinical study. SETTING: University-based reproductive endocrinology unit. PATIENTS: Eleven nonlactating, euprolactinemic women of reproductive age with a history of regular menstrual cycles and currently taking no medications. INTERVENTIONS: Breast examination using standard technique. MAIN OUTCOME MEASURE: Changes in serum PRL levels after breast examination. RESULTS: Baseline PRL levels ranged from 3.64 to 19.23 ng/mL (mean 7.17 ng/mL; conversion factor to SI unit, 1.00). There were no significant increases in PRL levels after breast examination, with mean PRL levels after 15, 30, and 45 minutes of 6.59, 6.84, and 6.45 ng/mL, respectively. CONCLUSION: Routine breast examination does not alter acutely serum PRL levels in normal women.

Secretory immune system of the female reproductive tract. II. Local immune system in normal and infected fallopian tube.

The existence of a secretory immune system in the female genital tract has been demonstrated by the predominance of immunoglobulin (Ig)A-producing plasma cells in human fallopian tube, uterine cervix, and vagina. Epithelium lining fallopian tubes expresses a receptor for IgA, secretory component (SC), and thus resembles other secretory tissues such as intestine, mammary, lacrimal, and salivary glands. The present study extends the characterization of the local immune system in the fallopian tube and assesses its response to infection. We examined normal and infected fallopian tubes from surgical specimens, obtained at tubal ligation and abdominal hysterectomy, for the presence of Ig-producing cells, T cells, and natural killer cells. All tubular segments contained a predominance of IgA plasma cells in the subepithelial lamina propria. The epithelial cells were strongly positive for SC. Luminal contents stained positively for IgA, SC, and J chain, suggesting that this material contained secretory IgA. Submucosal plasma cells of IgM and IgG classes were less frequent than IgA. T cells were present in numbers approximately twofold greater than plasma cells in normal fallopian tubes. T-suppressor (CD8+) cells, which may function in the induction of immune tolerance, were present in the intraepithelial spaces. Infected segments of fallopian tubes demonstrated six- to tenfold increased numbers of plasma cells of all classes. These data suggest that a local immune system is functioning in the human fallopian tube and may provide a first line of defense against tubal infection and the prevention of tubal factor infertility.

In vitro and in vivo evaluation of latex condoms using a two-phase nonoxynol 9 system.

In vitro studies were carried out that indicated that a lubricant system consisting of 0.45 +/- 0.1 ml of silicon fluid containing 6.6% +/- 0.5% by volume of nonoxynol 9 and a spermicidal cream consisting of 0.45 +/- 0.1 ml made up of 63.4% polyethylene glycol 400 and 30.0% polyethylene glycol 3350 containing 6.6% +/- 0.5% nonoxynol 9 was effective in reducing sperm motility and viability. This system was tested in vivo with the use of simulated rupture techniques and was found to be equally as effective. Double-blind preference studies were carried out in vivo which showed that the condom system is convenient and comfortable to use, nonirritating to the vagina or urethral mucosa, and esthetically pleasing to the young, reproductive-age population.

Performance anxiety during infertility treatment: effect on semen quality.

The requirement to obtain a semen sample at a specific time for an infertility treatment procedure has potential to produce considerable performance anxiety. This study was designed to evaluate the semen quality of men participating in infertility treatments associated with heightened performance anxiety. The most recent pretreatment semen analysis and the infertility treatment semen analysis, as well as the first and last procedure semen analyses, were compared using paired t-tests for 77 patients undergoing assisted reproductive technology procedures and 121 patients undergoing intrauterine insemination. No significant differences were noted in either of these groups of patients. However, in men with total motile sperm counts of less than 40 million, semen parameters improved significantly in the procedure semen analyses. Thus, participation in infertility treatments associated with performance anxiety does not appear to be detrimental to semen quality, and in certain groups of patients semen quality may improve.

Regulation of human prolactin secretion by gonadotropin-releasing hormone in vitro.

The regulation of human prolactin (PRL) secretion by gonadotropin-releasing hormone (GnRH) was evaluated with human pituitary monolayer cell cultures. Synthetic GnRH stimulated PRL secretion when exposed to cells in an estrogen-depleted environment. This response was inhibited by pretreatment of the cells with 17 beta-estradiol (E2). A 10(-5) M GnRH antagonist inhibited luteinizing hormone (LH) but not PRL secretion when cells were maintained in an estrogen-depleted environment. However, the GnRH antagonist inhibited basal PRL secretion when cells were maintained in medium containing 10(-8) M E2. The 10(-5) M GnRH antagonist, when coincubated with 10(-5) M GnRH inhibited the release of PRL in an estrogen-depleted environment. However, coincubation of the 10(-5) M GnRH antagonist with 10(-5) M thyrotropin-releasing hormone (TRH) failed to inhibit PRL secretion. Incubation of 10(-8) M TRH and 10(-8) M GnRH produced a synergistic release of PRL in an estrogen-depleted environment. These observations led us to conclude that GnRH stimulates PRL secretion by direct action on human pituitary cells and that GnRH acts either via the gonadotrope or through receptors on the galactotrope other than that acted upon by TRH to release PRL.

Assessment of pituitary function in patients with serum prolactin levels greater than 100 ng/ml.

Twelve women with galactorrhea-amenorrhea and prolactin levels greater than 100 ng/ml were evaluated with dynamic pituitary challenge testing. Forty-two per cent of the patients had positive findings on polytomography and subsequent surgical confirmation of a pituitary tumor. Patients with tumors had a delayed elevation of growth hormone (GH) and cortisol following induction of insulin hypoglycemia. Patients had increased thyroid-stimulating hormone levels after injection of thyrotropin-releasing factor, but showed blunting of prolactin secretion. Patients with tumors had decreased basal levels of GH and showed a blunted response to luteinizing hormone-releasing hormone (LRF) stimulation. These patients had normal elevations of follicle-stimulating hormone after LRF challenge. Patients with tumors showed a delay in elevation of GH levels following l-dopa treatment. They also failed to show prolactin suppression following this treatment. There are consistently predictive changes that occur in pituitary functions in the presence of a pituitary tumor. However, absolute prolactin levels and sellar polytomography are more reliable in diagnosing the presence of a pituitary tumor in the patient with galactorrhea-amenorrhea.

Comparison between 1-hour and 24-hour follow-up radiographs in hysterosalpingography using oil based contrast media.

A comparison was made between oil-contrast hysterosalpingogram (HSG) with 1-hour follow-up radiograph and the traditional 24-hour follow-up radiograph with respect to detection of tubal patency and pelvic adhesive disease. The results on either modality were assessed by subsequent laparoscopy. The 1-hour HSG was comparable to the 24-hour HSG in defining tubal patency. Even though it was inferior to the 24-hour HSG with respect to identifying pelvic adhesions, it may serve as an adequate substitute to the above since the sensitivity of the HSG in identifying adhesions is low and has little influence on the clinical decision process in the evaluation of infertility.

Comparison of dopamine agonists in the treatment of hyperprolactinemic syndromes: a multicenter study.

Thirty-one patients with hyperprolactinemia were admitted for protocol study. Twenty-one of these patients had no findings of prolactinoma by computerized axial tomography (CAT) scanning; 10 had documented tumor by CAT scan. The patients were assigned to either Parlodel or Pergolide treatment on the basis of random numbers tables. They were treated for 6 months continuously and followed during this time with radiologic survey, hormonal evaluation, and blood chemistry determinations. Patients in both groups showed a decrease in prolactin levels, whether they were treated with Parlodel or Pergolide. The response was similar whether patients had hyperplasia or pituitary tumors. Patients with pituitary tumors tended to have a diminution in the size of their lesions regardless of the dopamine agonist used. The types of side effects experienced by various groups were similar regardless of the treatment. It is concluded that both Pergolide and Parlodel are useful in the treatment of hyperprolactinemic syndromes, although neither one appears to be superior to the other.