PROLACTIN AND REPRODUCTION

Transcription

1 FERTILITY AND STERILITY Copyright" 1981 The American Fertility Society Vol. 35, No.3, Man:h 1981 Printed in U.SA. PROLACTIN AND REPRODUCTION ROGER J. PEPPERELL, M.B.,B.S., M.G.O., M.D.(MoN.), F.R.A.C.P., F;R.C.O.G., F.AuST.C.O.G. Department of Obstetrics and Gynaecology, University of Melbourne, Royal Women's Hospital, Melbourne, Victoria, Australia The almost simultaneous development of assays to measure serum prolactin and the release of a drug which suppresses prolactin secretion have resulted in an avalanche of publications concerning the effect of prolactin antagonists in patients with elevated prolactin levels. At the Royal Women's Hospital, Melbourne, we have treated 260 infertile patients with bromocriptine, and the effectiveness of this agent in these patients is shown in Table 1. When the serum prolactin levels were normal, the pregnancy rate was approximately the same as that seen with placebo therapy (Table 2). However, when the prolactin level was high, especially if a disorder of ovulation was also present, the pregnancy rate was markedly improved. Seven basic questions need to be asked by the clinician who is treating infertile couples. Which patients should have their serum prolactin levels determined? What other investigations are required in patients who are shown to have elevated prolactin levels? What is the most appropriate way to induce ovulation in hyperprolactinemic patients? When a satisfactory response to treatment with bromocriptine does not occur, what further investigations and treatment are required? Once pregnancy is achieved, are the problems over? Are there indications for treatment with bromocriptine other than disorders of ovulation associated with elevated prolactin levels? What is the appropriate treatment for patients with elevated prolactin levels who do not wish to conceive? WHICH PATIENTS SHOULD HAVE THEIR SERUM PROLACTIN LEVELS DETERMINED? Unless the serum prolactin level is markedly elevated (more than 5 times the upper limit of the normal range), the investigation should be repeatedon at least two more occasions before labeling the patient with the diagnosis of "hyperprolac- tinemia." It should be remembered that prolactin levels tend to be higher in the afternoon than in During the 2 years 1975 to 1977, 682 patients attending the Endocrine Clinic of the Royal Women's Hospital had their serum prolactin 267 levels determined. None of the 38 patients with primary amenorrhea had elevated prolactin levels; however, 22.8% of the 270 patients with secondary amenorrhea of more than 6 months' duration and 7.6% of the 304 patients with oligomenorrhea (cycles occurring every 6 weeks to 6 months) had elevated prolactin levels.! Only 1 of 40 patients (2.5%) with unexplained infertility and only 1 of 30 oligospermic men (3.3%) had mildly elevated prolactin levels. The incidence of hyperprolactinemia in our anovulatory population is almost identical with that in Germany as reported by Wolf et al. 2 and similar figures are probably applicable for most Caucasian countries. Less than half of our patients and the patients of Wolf et al. 2 had galactorrhea on clinical examination, even when this examination was repeated when the elevated prolactin level was known to be present. There is no doubt that women with disorders of ovulation should have their serum prolactin levels determined, as this evaluation enables theclinician to choose the most appropriate therapy for ovulation induction. However, the diagnosis of hyperprolactinemia among patients with unexplained infertility and among men with semen abnormalities appears to be infrequent. WHAT OTHER INVESTIGATIONS. ARE REQUIRED IN PATIENTS WHO ARE SHOWN TO HAVE ELEVATED PROLACTIN LEVELS?

2 268 PEPPERELL March 1981 TABLE 1. Effectiveness of Bromocriptine as a ~Fertility Pill" No. No. Pregnancy treated pregnant rate Ovulatory cycles, nor % mal prolactin Ovulatory cycles, high % prolactin Anovulatory, normal, % prolactin Anovulatory, high 83 61a 73.5%a prolactin Total a 30.8%a aeighteen patients have had two pregnancies each. the morning and' are elevated by sleep, exertion, emotional stress, breast manipulation, and a number of drugs. The first visit to a gynecologist is often a stressful experience and an inappropriate time for obtaining a blood sample for measurement of prolactin. The ingestion of drugs, particularly the tranquilizers of the phenothiazine group, may also cause prolactin levels to be elevated; all such agents should be discontinued, if possible, before the serum prolactin level is measured. There are many other causes ofhyperprolactinemia, but the common ones-and those the clinician must exclude-are the presence of a pituitary tumor, primary hypothyroidism, and renal failure. Primary hypothyroidism is easily excluded by measurement of serum levels of thyroxine, triiodothyronine resin uptake (T 3 RU), and thyroidstimulating hormone (TSH), and renal failure resulting in elevation of serum prolactin levels rarely occurs before the serum creatinine level reaches 0.20 mmolelliter. Exclusion of a pituitary tumor does pose problems, however. For many years the only radiographic means available routinely to the clinician wishing to. assess the pituitary fossae were plain coned films of the region. This procedure enabled assessment of the fossa in both anteroposterior and lateral projections, was easy to perform, subjected the patient to minimal irradiation, and could be repeated frequently. It did not enable recognition of all small tumors, as many of these were not included in the projection plane used. Pituitary polytomography (1 to2 mm) largely overcame this problem and enabled recognition of small "microadenomas" in peripheral parts of the pituitary gland, since these caused blistering or erosion of the lamina dura in that region. However, poly tomography results in significantly more irradiation to the lens (probably about 12 rads during the procedure) and thus cannot be repeated on a yearly or bi-yearly basis. Unfortunately, polytomography does not clearly demonstrate suprasellar extension of a tumor, which is best seen during pneumoencephalography. Because of the need for hospitalization and the side effects of pneumoencephalography, this procedure has largely been replaced by computerized axial tomography (CAT), which results in only 0.5-rad radiation to the lens and is able to recognize suprasellar extension greater than 3 mm. The recent reports of high false-positive and false-negative polytomographic studies have cast serious doubts on the usefulness of the procedure in the assessment of pituitary microadenomas. Newton et al. 3 studied 100 randomly selected sphenoid bones, resected at the time of autopsy, from patients with no known history of pituitary disease. The fixed sections were subjected to 1- mm hypocycloidal tomography and then examined histologically. Fourteen tumors were identified histologically but only six of these were visible radiologically (false-negative rate of 57%). In 86 patients no tumor was identifiable histologically but 8 had abnormal tomograms (false-positi ve rate of 9%). Wortzman et al.,4 in studying 120 similar specimens, identified histologically 32 tumors with a size range up to 6 mm. Only 6 of these were recognizable radiologically (false-negative rate of 81 %), although 20 of the 88 patients without tumors had abnormal tomograms and had been diagnosed as having microadenomas (false-positive rate of 23%). However, it seems likely that the most recent generation of CAT scanners may overcome this problem and enable accurate localization and measurement of tumors both within the pituitary fossa and in the suprasella,r region. TABLE 2. Spontaneous Pregnancy Rates in Infertile Subjects! Number and proportion of patients Secondary amenorrhea Oligomenorrhea Patients No. pregnant Pregnancy rate Patients No. pregnant Pregnancy rate Evans (1975) Pepperell (1978) % 7.8% % 14.1%

3 Vol. 35, No.3 PROLACTIN AND REPRODUCTION 269 It is our practice to obtain plain coned films of the pituitary fossa in all patients with elevated prolactin levels, but to proceed to polytomography and CAT only when such patients require treatment for infertility or when the plain films indicate that a macroadenoma is present. Although the results of the investigations rarely make any difference to the treatment program, unless the tumor is large we prefer to proceed with treatment and subsequent monitoring during a pregnancy if we know exactly what is going on within the pituitary fossa at that time. When a large pituitary tumor is diagnosed, especially if there is suprasellar extension greater than 5 mm, it has been usual to remove the tumor surgically and to administer postoperative x-ray therapy. These procedures rarely normalize serum prolactin levels, and bromocriptine and/or gonadotropins are usually required in subsequent attempts to induce ovulation. The total number of patients requiring surgery is small. Since 1974 only 4 of 450 hyperprolactinemic subjects evaluated at the Royal Women's Hospital have undergone surgical excision of a tumor and/or radiotherapy to the pituitary fossa. In addition to the radiologic asssessment of the pituitary fossa, it is also essential to chart the visual fields accurately (using Bjerrum or Goldmann screens) so that a suprasellar tumor of significant size can be excluded. Recently, Marrs et al. 5 have suggested that it may be possible to identify those patients with high prolactin levels who have adenomas by studying the prolactin response to an injection of thyrotropin-releasing hormone (TRH). In their study all patients subsequently proven histologically to have an adenoma had a flat response when given TRH, whereas the responses in nine patients with equivocal sellar tomograms ranged from a normal response (two patients), a blunted response (three patients), to a flat response similar to that seen in the group with adenomas (four patients). WHAT IS THE MOST APPROPRIATE WAY TO INDUCE OVULATION IN HYPERPROLACTINEMIC PATIENTS? Prior to the development of assays to measure serum prolactin, most anovulatory subjects were treated with clomiphene citrate and, if this was unsuccessful, progressed to treatment with gonadotropin. Blood samples from many such patients were in storage in 1975 when the prolactin assay was developed at the Royal Women's Hospital. The subsequent measurment of prolactin in these samples showed that most patients with elevated prolactin levels failed to ovulate, or did so irregularly, when given clomiphene citrate, whereas approximately 32% of patients with normal prolactin levels responded satisfactorily to treatment with this agent (Fig. 1). The subsequent administration of bromocriptine to patients with elevated prolactin levels has indicated that prolactin antagonists are the drugs of choice for such patients, and clomiphene citrate is now rarely used. When our treatment program with bromocriptine commenced in 1975, the drug was administered, with meals, in a dosage of 1.25 mg twice daily for 1 week, then 2.5 mg twice daily for 8 weeks, then 5.0 mg twice daily for 4 weeks, then 5.0 mg three times daily for 4 weeks. During the treatment program, serum samples were collected at weekly intervals for the measurement of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin levels; weekly urine specimens were collected for the measurement of Regular oyulatlon o ~ o o (,0 0 0 Variable response No oyulatlon o FIG. 1. Predictive value of serum prolactin levels in determining response to treatment with clomiphene citrate. The horizontal lines and boxes represent means and standard error of the mean, respectively , Upper limit of the normal range; 0 indicates values of patients who conceived following treatment with clomiphene citrate.

4 270 PEPPERELL 5 -c:t ;;;; 4 DOl -= 41 GO -=...&:I 3 cd DOl.. N l1li III ~! l1li 41 -= ; I:>.;: 1:><0> l1li41 DOI- ~ 20 iii... : ~ 10 PIEB. TlST. I I POSITIVI ~ DOl -= 0 ;:... ; <0> c:t,,,, c:t! 0.. ~"L.I S IS FIG. 2. Weekly.serum prolactin and urinary estrogen and pregnanediol values during treatment with bromocriptine. The initial response was ovulation with deficient corpus luteum function, but normal ovulation occurred in the next cycle without an increase in the dose of bromocriptine administered. estrogen and pregnanediol excretion; and bromocriptine therapy was continued until a positive pregnancy test was obtained, usually 10 days after the missed menstrual period (Fig. 2). This treatment program was followed for the first 25 patients but has since been modified as the number of serum and urine specimens was found to be excessive. However, the program did enable close monitoring of the exact response of the ovaries and pituitary, and much was learned about the physiology of the menstrual cycle in patients with elevated prolactin levels. No ovarian response was seen until the serum prolactin level was suppressed to normal, and the initial ovarian response in two-thirds of the patients was that of follicular maturation only, or ovulation but deficient corpus luteum function. 6 Follicular maturation only was defined as an increase in urinary estrogen excretion to above 10 j.1g/24 hours without an increase in pregnanediol levels; deficient corpus luteum function was de- March 1981 fined as estrogen values rising above 15 j.1g/24 hours with an increase in pregnanediol values which did not reach 2 mg/24 hours; normal ovulation was defined as an estrogen excretion in excess of 15 j.1g/24 hours with an increase in pregnanediol values to above 2 mg/24 hours. 7 When the initial ovarian response was not that of normal ovulation, an improved response was seen if the dose of bromocriptine was increased, but some patients spontaneously showed an improved ovarian response even when the dose ofbromocriptine was kept constant. It is now our practice to administer bromocriptine in a dosage of 1.25 mg twice daily for 1 week and then to increase the dose to 2.5 mg twice daily thereafter. Further dose increases are instituted only ifthere is no ovarian response or if the ovarian response shows follicular maturation only or deficient corpus luteum function, or if the serum prolactin level is not suppressed to the normal range. Blood and urine specimens are thus collected at monthly intervals, timed for the midluteal phase (Fig. 3). Only 14% of the 83 hyperprolactinemic patients required treatment with bromocriptine in a dosage in excess of 10 mg/day, and the mean number of ovulatory cycles prior to conception was 1.9. WHEN A SATISFACTORY RESPONSE TO TREATMENT WITH BROMOCRIPTINE DOES NOT OCCUR, WHAT FURTHER INVESTIGATION AND TREATMENT ARE REQUIRED? Although the vast majority of patients ovulate during treatment with bromocriptine alone, some remain anovulatory even when large doses ofbromocriptine are administered. In our own series of 83 hyperprolactinemic anovulatory patients, 75 ovulated during treatment with bromocriptine alone, 2 others ovulated when bromocriptine plus thyroxine and/or clomiphene citrate were given, and only 6 remained anovulatory (7%). Two of the six anovulatory patients were subsequently shown to be perimenopausal, one had an obvious macroadenoma of the pituitary gland, and another was subsequently shown to have a meningioma compressing the pituitary stalk; the reason for the failed response to treatment in the remaining two patients is unknown. When the serum prolactin level cannot be suppressed to normal, the possibility of a previously unrecognized pituitary tumor must be considered. If such a tumor cannot be identified, the dose of bromocriptine should be progressively increased to 40 mg/day. In a study in which serum prolactin levels in such a patient were determined at hourly

5 Vol. 35, No.3 PROLACTIN AND REPRODUCTION 271! i ';: u o ~ III 60 _ 50 E 40 0; ~10'0 ca ~7-5 a» 50() E... 2'5 Positive Pregnancy Test 9 7 * ro n ~ Duration of Treatment [weeks] FIG. 3. Weekly serum prolactin and urinary estrogen and pregnanediol values during treatment with bromocriptine. No response occurred until the dose of bromocriptine was increased to 10 mg/day. Asterisks indicate the appropriate timing of urine and blood collections. intervals for 6 hours after the administration oflo mg, 15 mg, and 20 mg ofbromocriptine, no shortterm suppression of prolactin levels was seen. 6 We have thus limited the dose of bromocriptine to 40 mg/day. However, we have administered thyroxine in addition to bromocriptine, and have achieved a better response with this therapy. It has been well documented that the TSH response following the intravenous injection oftrh in hyperprolactinemic patients resembles that seen in patients with primary hypothyroidism. Although none of our patients had biochemical evidence of hypothyroidism as assessed by serum thyroxine, T aru, or TSH levels, two patients who failed to respond to treatment with bromocriptine alone were treated with thyroxine in addition. One patient had had very irregular responses during treatment with bromocriptine alone but conceived following the addition of thyroxine, and the other showed the first episode of ovarian activity 4 weeks after commencement of thyroxine (Fig. 4). The latter patient subsequently ovulated when clomiphene citrate was also added to the regimen and conceived during the second cycle of treatment with this agent. She subsequently returned to the clinic requesting another pregnancy and again failed to have any ovarian response when given bromocriptine alone in a dosage of 30 mg/day, achieved follicular maturation only when given thyroxine in addition (0.1 mg/day), but again ovulated and conceived when clomiphene citrate was also given. Although it is well known that the administration of thyroxine will result in sup. pression of serum TRH and TSH levels and that when TRH is given intravenously prolactin levels increase, the mode of action of thyroxine in the two patients described above is unclear. Each patient had normal serum TSH levels, and the administration of thyroxine had little or no effect on the serum prolactin levels, which remained just above the upper limit of the normal range. When the serum prolactin level is suppressed well into the normal range during treatment with bromocriptine but ovulation does not occur, it is now our practice to administer clomiphene citrate in addition. The rational basis for this treatment is the postulate of a dual disorder of hypothalamic function resulting in the disorder of ovulation. However, it must be remembered that anovulatory patients may have elevated FSH and LH levels if they are entering a phase of ovarian resistance or failure. The two perimenopausal patients in our series had elevated levels of both FSH and LH for 3 to 4 weeks of every 6 to 8 weeks, both when their serum prolactin levels were elevated and when they were suppressed during treatment with bromocriptine. Both patients were under 35 years of age and have not ovulated, in spite of continuing treatment with bromocriptine, for more than 12 months. ONCE PREGNANCY IS ACHIEVED, ARE THE PROBLEMS OVER? As indicated earlier, it has been our policy to cease bromocriptine therapy as soon as a pregnancy test is found to be positive. This policy has meant that the medication is stopped at a gestation of approximately 5% weeks, and there is an immediate increase in serum prolactin levels to values significantly higher than those found at the same stage of pregnancy in patients who have not had hyperprolactinemia prior to conception. A significant reduction in progesterone levels, whether measured in the serum or as pregnanediol in the urine, is seen at 8 to 14 weeks of gestation but has not been associated with an increased incidenc~ of abortion in spite of the fact that supplemental progesterone therapy has not been given. 8 In our

6 272 PEPPERELL own series of 98 pregnancies following treatment with bromocriptine, the first-trimester abortion rate was 7.1 %, and five of the seven abortions were known to be associated with a blighted ovum. There was also one midtrimester abortion due to cervical incompetence, one perinatal death due to antepartum hemorrhage at 27 weeks' gestation, and one congenital. abnormality (a small facial nevus). In addition to the problems of disordered corpus luteum function, abortion, and the possible teratogenic effects of bromocriptine, the clinician must also be concerned with the possibility of expansion of a pituitary tumor during a bromocriptineinduced pregnancy. Recently Kelly et al.,9 in a summary of the world literature on pregnancies in women with hyperprolactinemia, reported a 19% incidence of tumor expansion during pregnancy when the presence of a tumor had been established prior to conception. Where there was no evidence of tumor prior to the pregnancy, there were no reported cases of tumors discovered during the pregnancy. There are now many reports of the effectiveness of bromocriptine in reducing tumor growth, and it would seem appropriate to administer this agent during pregnancy when a tumor is known to be present prior to conception. The lack of teratogenic effects of this agent in more than 1000 pregnancies reported to the company producing bromocriptine (Sandoz) has made clinicians less reluctant to continue its administration during the pregnancy. In an attempt to prevent tumor growth during pregnancy, Thorner and Besser lo have given megavoltage radiotherapy (4500 rads). prior to inducing ovulation in patients with pituitary macroadenomas. This therapy no longer seems appropriate. Persistent headache or the development oftemporal visual field abnormalities is suggestive of tumor expansion during the pregnancy. It is imperative that the physician be alert to these symptoms as blindness may result if the expansion is ignored and chiasmal compression continues. Visual fields should be assessed every 3 months during pregnancy in patients with normal fossae on radiologic examination but more frequently when a microadenoma or macroadenoma is known to be present. When tumor expansion does occur during pregnancy, four modes of treatment are available and all appear to be equally effective. Surgical decompression can be performed, although the area is more vascular during pregnancyll; delivery can be induced, and is the treatment of. choice when the gestation exceeds 34 weeks l2 ; March 1981 treatment with bromocriptine can be reintroduced,13 the dose being that which restores the serum prolactin level to the normal nonpregnant range; or treatment with dexamethasone can be given to reduce edema of the tumor and surrounding structures.14 If surgical decompression is not employed, the clinician must continue to assess the visual fields regularly to ensure that reduction in tumor size is occurring. In our own series of 83 hyperprolactinemic patients, of whom 61 conceived on 79 occasions, only 2 have required bromocriptine therapy during pregnancy. In each of these patients a pituitary microadenoma had been diagnosed radiologically prior to the pregnancy and each was recommenced on bromocriptine during the third trimester of the pregnancy. One subject was asymptomatic but developed a temporal visual field abnormality in one eye; the other patient had persistent headaches during the third trimester of pregnancy but no change in the visual fields or in the radiologic appearance of the fossa. On each occasion, treatment with bromocriptine caused resolution of the problem and the pregnancy then progressed uneventfully. Neither of these subjects has shown deterioration of the visual fields or expansion of the fossa radiologically since completion of the pregnancy, and the follow-up interval for each is now in excess of 12 months. The remaining 59 patients, of whom 6 had radiologic abnormalities of their fossae prior to pregnancy, showed no evidence of "tumor expansion" and were not given bromocriptine during their pregnancies. With the exception of the two patients who were given bromocriptine during the latter stages of pregnancy, all of the other patients were allowed to breast-feed if they so desired. Virtually all of these patients successfully established breastfeeding while they were in the hospital, and many continued breast-feeding for 6 to 12 months. ARE THERE INDICATIONS FOR TREATMENT WITH BROMOCRIPTINE OTHER THAN HYPERPROLACTINEMIC ANOVULATION? Four other indications for treatment with bromocriptine have been evaluated in our clinic: normoprolactinemic anovulation, corpus luteum dysfunction, unexplained ovulatory infertility, and disorders of spermatogenesis. As indicated earlier, bromocriptine appears to be oflittle value in patients with normoprolactinemic anovulation or unexplained ovulatory infertility, as the response rate is no better than that seen with placebo. In our clinic, disorders of corpus luteum

7 Vol. 35, No.3 PROLACTIN AND REPRODUCTION 273 function are uncommon except in patients receiving treatment with clomiphene citrate or those being treated with bromocriptine. In the latter patients increasing the dose ofbromocriptine commonly resolves the disorder; in patients being treated with clomiphene, increasing the dose of clomiphene citrate usually also has the desired effect. We have not identified patients with evidence of corpus luteum dysfunction and elevated serum prolactin levels; at the present time we believe that such patients must be quite rare. We have treated 30 men with disorders of spermatogenesis in an attempt to evaluate the usefulness of bromocriptine.15 Six of these men had severe oligospermia (sperm count less than 5 million/mi), 12 had mild to moderate oligospermia (sperm count 5 to 20 million/mi), and 12 patients had isolated low spermatozoal motility. Serum FSH, LH, and prolactin levels of all patients were determined monthly for 3 months prior to treatment with bromocriptine, for the 4 months during the treatment program, and for 3 months after treatment. Each man also underwent semen analyses during the 10-month period. Although four pregnancies occurred, no changes were seen in the husbands' seminal profiles, and the responses were similar to those seen with placebo. The only significant changes which occurred during therapy were suppression of prolactin levels, mild increases in semen volume (approximately 0.5 mi), and mild decreases in blood pressure (systolic 11 mm Hg, diastolic 7 mm Hg). WHAT IS THE APPROPRIATE TREATMENT FOR PATIENTS WITH ELEVATED PROLACTIN LEVELS WHO DO NOT WISH TO CONCEIVE? Although surgical removal of pituitary tumors with suprasellar extension remains the treatment of choice in most clinics, there is considerable debate about the need for surgery when there is no suprasellar extension oftumor. Complete surgical excision with normalization of serum prolactin levels and restoration of ovarian function is unusual when the tumor is more than 1 cm in diameter, but can be achieved in approximately 70% of patients with microadenomas (less than 1 cm in diameter).16 In competent hands, surgery results in few complications, but leakage of cerebrospinal fluid, meningitis, and temporary hypopituitarism remain the major ones. Unfortunately, little is known of the natural history of small pituitary tumors, particularly those classified as microadenomas. The diagnosis of microadenomas has been made possible byrel- WEEIS OF TRE ATIIE NT FIG. 4. Serum prolactin and urinary estrogen and pregnanediol values during treatment with bromocriptine, thyroxine, and clomiphene citrate in a dose of 100 mg/day for 5 days (C 100). The dose of thyroxine was reduced from 0.2 to 0.1 mg/day because of clinical toxicity with the higher dose. atively recent advances in radiologic techniques, and most patients have not been followed untreated for more than 5 years. The discovery of microadenomas in 15% to 25% of asymptomatic patients at postmortem examination 3, 4 suggests that these tumors may not increase in size and that conservative treatment is appropriate. In Melbourne we have recently established a "prolactinoma register" so that all patients with elevated prolactin levels can be followed in a predetermined manner for at least the next 5 years. Patients with a grade 0, grade I, or grade II prolactinoma 17 will be allocated no treatment at all if they desire this, bromocriptine if they request treatment for galactorrhea or amenorrhea, or bromocriptine or placebo if they are prepared to enter a single-blind trial with these agents. The dose of bromocriptine administered will be that which suppresses the prolactin level to below the mean of the normal range. Irrespective of the treatment given, measurement of serum prolactin levels, assessment of the visual fields, and coned-view radiography of pituitary fossae will be carried out yearly; CAT scans will be repeated every 2 years for patients with grade 0 and grade I tumors, but yearly for those with grade II lesions. Because the number of patients with grade III or grade IV prolactinomas is sma1l17 and such patients are currently treated by surgery and/or radiotherapy, a trial of bromocriptine has not been instituted, although these patients are being registered and any treatment given is documented in detail. The main problem the clinician has in managing these patients is providing appropriate contraceptive advice. Although elevated prolactin levels are commonly associated with disorders of

8 274 PEPPERELL ovulation and infertility, it cannot be assumed that the patients do not require contraception. Of our 61 hyperprolactinemic patients who achieved 1 or more pregnancies during treatment with bromocriptine, 4 later conceived spontaneously while their prolactin levels were still moderately elevated. For patients not receiving treatment with bromocriptine we are thus recommending barrier methods of contraception (diaphragm, sheath) or the progestogen"only pill; the vaginal dryness which accompanies the low estrogen levels can usually be overcome by education in coital technique or by the use of lubricants. Estrogencontainingoral contraceptives or vaginal estrogen creams are contraindicated because of evidence that the increased estrogen levels of pregnancy may be responsible for increased tumor growth during pregnancy. When bromocriptine is being administered to relieve symptoms, or in a trial situation, contraception with an intrauterine device is advisable since, when the prolactin level has been suppressed to normal, these patients usually have normal fertility. CONCLUSIONS The measurement of serum prolactin levels in infertile patients and the administration ofbromocriptine to patients with elevated prolactin levels have revolutionized the treatment of infertility during the 1970s. Unless there are unusual circumstances, this drug should be administered only to anovulatory subjects shown to have elevated prolactin levels, as the pregnancy rate in normoprolactinemic subjects is approximately the same as that achieved with placebo therapy. Every attempt should be made to rule out the presence of a pituitary tumor before pregnancy is attempted, but, even when such a tumor is identified, surgical excision prior to bromocriptine therapy is often unnecessary. When treatment with bromocriptine fails to. result in restoration of ovulation, the perimenopausai state should.be excluded and consideration given to administering thyroxine and/or clomiphene citrate in addition to bromocriptine. REFERENCES March Pepperell RJ: Prolactin suppression in the treatment offemale infertility. Med J Aust [Suppl] 3:20, Wolf AS, Musch K, Lauritzen C: Hyperprolactinemia in anovulatory women. Incidence and endocrine features. J Endocrinol Invest 2:5, Newton TH, Turski P, Horton B: Anatomic correlation with complex motion tomography in 100 normal sphenoid specimens. Presented at the Eighteenth Annual Meeting of the American Society of Neuroradiology, Los Angeles, March Wortzman G, Holgate RC, Rewcastle NB, Burrow GN: Abnormal sellas and pituitary adenomas in 120 postmortem sphenoid specimens. Presented at the Eighteenth Annual Meeting of the American Society of Neuroradiology, Los Angeles, March Marrs RP, Bertolli SJ, Kletzky OA: The use of thyrotropinreleasing hormone in distinguishing prolactin-secreting pituitary adenoma. Presented at the Thirty-Sixth Annual Meeting of The American Fertility. Society, Houston, March Pepperell RJ, McBain JC, Healy DL: Ovulation induction with bromocriptine in patients with hyperprolactinemia. Aust NZ J Obstet GynaecoI17:181, Pepperell &1, Brown JB, Evans JH, Rennie GC, Burger HG: The investigation of ovarian function by measurement of urinary oestrogen:and pregnanediol excretion. Br J.Obstet Gynaecol 82:321, Pepperell RJ, McBain JC, Winstone SM, Smith MA, Brown JB: Corpus luteum function in early pregnancy following ovulation induction with bromocriptine. Br J Obstet Gynaecol 84:898, ; Kelly WF; Doyle FH, Mashiter K, Banks LM, Gordon H: Pregnancies in women with hyperprolactinemia: clinical course and obstetric complications of 41 pregnancies in 27 women. Br J Obstet Gynaecol 86:698, Thorner MO, Besser GM: Bromocriptine treatment ochyperprolactinaemic hypogonadism. Acta Endocrinol [Suppl 216] (Kbh) 88:131, GemzellC: Induction of ovulation in infertile women with pituitary tumors. Am J Obstet Gynecol 121:311, Corbey RS, Cruysberg JRM, Rolland R: Visual abnormalities in a pregnancy following bromocriptine medication. Obstet Gynecol [Suppl] 50:69, Bergh T, Nillius SJ, Wide L: Clinical course and outcome of pregnancies in amenorrhoeic women with hyperprolactinaemia and pituitary. tumours. Br Med J 1:875, Jewelewicz R, Zimmerman EA, Carmel PW: Conservative management oca pituitary tumor during pregnancy following induction of ovulation with gonadotropins. Fertil Steril 28:35, Baker HWG, Pepperell RJ: Lack of effect ofbromocriptine on semen quality in men with normal or slightly elevated prolactin levels.aust NZ J Obstet GynaecoI20:158, Kramer RS: Prolactin-producing pituitary tumors: surgical therapy. Clin Obstet Gynecol 23:425, Vezina JL: Progress in Prolactin Physiology and Pathology; Edited by C Robyn, M Marter. Amsterdam, North Holland Elsevier, 1978 Received August 15, Reprint requests: RogerJ. Pepperell, M.B., B.S., Department of Obstetrics and Gynaecology, University of Melbourne, Royal Women's Hospital, Melbourne, Victoria, Australia.