W. R. Butt

An abnormality of oestrogen feedback in amenorrhoea-galactorrhoea.

Fourteen patients with amenorrhoea and hyperprolactin-anemia but no evidence of pituitary tumours were each given an intramuscular injection of 1 mg oestradiol benzoate. Thirteen patients failed to release luteinizing hormone in response to the oestrogen. This hypothalamic abnormality may help to explain the menstrual disturbances in subjects with hyperprolactinaemia.

CLINICAL TRIAL OF HUMAN GONADOTROPHINS

INTRODUCTION MANY attempts have been made to induce ovulation in women with amenorrhoea using gonadotrophins from different sources, but it is generally believed that only the gonadotrophins from primates are satisfactory for this purpose. The best source of human follicle stimulating hormone is from pituitary glands obtained at autopsy but the material is not available in sufficient quantities for extended clinical trials. Another source is from the urine of postmenopausal women but supplies are very limited and the material is much less potent. Successful use of human pituitary gonadotrophin resulting in pregnancy has been reported by Gemzell, Diczfalusy and Tillinger (1960) and Gemzell (1962) but multiple ovulation resulting in the birth of more than one baby has been noted. The purpose of this study was to compare the effectiveness of pituitary and urinary follicle stimulating hormone of various degrees of purity, given in combination with chorionic gonadotrophin, to patients with idiopathic secondary amenorrhoea. A series of experiments of factorial design were used to establish the optimum conditions for their administration with the ultimate objective of ovulation and pregnancy. MATERIALS AND METHODS The Patients The patients selected had complained of infertility associated with secondary amenorrhoea of unknown aetiology of at least three years’ duration. They were chosen because they were considered to be sufficiently intelligent, co-operative and willing to undertake a series of trials with human gonadotrophins. They had no other complaints and their excretion of urinary gonadotrophins was in the lower half of the normal range on at least three occasions. They were coded alphabetically in the order in which they volunteered for treatment, with the intention that if one gave up for any reason whatever, she would be replaced by the patient having the next letter. They were admitted to the ward for clinical investigation which included a pelvic examination under anaesthesia, uterine curettage, tuba1 insufflation and culdoscopy. All other investigations including the chromosomal pattern of buccal or vaginal smears gave normal results. The husbands’ semen specimens were also normal. Table I shows that all patients had small uteri and the endometrium, when obtainable, was scanty and inactive. Culdoscopy revealed small ovaries with glistening white capsules and ’

A clinical trial using danazol for the treatment of premenstrual tension

Summary. Forty women with premenstrual tension received either placebo, 100, 200 or 400 mg danazol daily for 3 months in a pilot study arranged as a double‐blind trial. Thirteen patients withdrew by the third month usually because they complained of no improvement. They had significantly higher pretrial symptom scores than those who continued. In patients treated with danazol, symptom scores for breast pain during the second and third months and for irritability, anxiety and lethargy during the third month were significantly (P<0.05) lower than scores in those given placebo. Most symptoms improved on placebo in the first month but by the third month only three remained improved. In contrast eight symptoms were improved on 200 mg danazol by the third month. By the end of the trial more than 75% of patients who were still taking danazol were essentially free of breast pain, lethargy, anxiety and increased appetite, but results for other common symptoms were no better than with placebo.

Hormonal studies in women with premenstrual tension

Summary. Serum hormone concentrations were determined at intervals during the last 17 days of the menstrual cycle in 35 patients with premenstrual tension (PMT) and 11 control subjects without symptoms. The maximum mean concentration of oestradiol occurred 17 days before menstruation in the patients and 14 days before in the controls. The maximum concentrations of progesterone were similar in the two groups but the mean concentrations rose carlier in the cycle in the patients with PMT. These results suggested that the patients tended to ovulate earlier in the cycle than the controls and on the basis of the ovulatory surge in gonadotrophins two groups could be identified, group A who showed signs of ovulation 14 days or less before menstruation (17 patients, 9 controls) and group B who ovulated more than 14 days before menstruation (18 patients, 2 controls). There were no significant differences between the groups in prolactin, thyroid stimulating hormone or testosterone levels, but cortisol concentrations were uniformly higher in both groups of patients compared with those in the controls. Follicular growth was assessed with ultrasound in 18 patients and 16 control subjects. Mean follicular diameters were significantly lower in the patients than in the control group at the time of ovulation. Oestradiol determinations done at the same time correlated with the diameters and were also significantly lower in the patient group. The results suggest that ovulation tends to occur prematurely in women with PMT.

TREATMENT OF HYPERPROLACTINAEMIA WITH PERGOLIDE MESYLATE: ACUTE EFFECTS AND PRELIMINARY EVALUATION OF LONG-TERM TREATMENT

The acute and long-term effects of oral pergolide mesylate, a new potent, long-acting dopamine agonist, were investigated in 10 hyperprolactinaemic patients. After a single 50 micrograms dose of pergolide mesylate, serum prolactin concentrations fell steadily to reach a mean minimum value at 6 h of 20% of baseline values; this degree of suppression was maintained throughout the 24 h study period. In one patient serum prolactin was measured for 2 days after a single dose and remained suppressed for 45 h. There were no acute changes in the serum concentration of luteinising hormone, follicle-stimulating hormone and growth hormone. Preliminary evaluation of longer term treatment with pergolide indicates that this drug at a once-daily dose of 50-150 micrograms is a safe, well tolerated, and effective new treatment for hyperprolactinaemia.

PULSATILE ADMINISTRATION OF GnRH FOR THE TREATMENT OF HYPOGONADOTROPHIC HYPOGONADISM

Fourteen patients, aged 22‐35 years, complaining of infertility and failing to ovulate on clomiphene, were treated with GnRH administered in pulses at 90 min intervals. Four patients received a total of eight courses of GnRH given subcutaneously and 13 were given a total of 20 months of treatment with GnRH given intravenously. Serum concentrations of immunoreactive GnRH were measured in six patients before administration of the drug and at regular intervals for 60 min after subcutaneous and intravenous injections of 5, 10 and 20 μg GnRH. Maximum concentrations of GnRH were reached by 5‐10 min after subcutaneous injections and within 2 min after intravenous injections. The peak concentrations were 3.6‐6.3 times and the sums of increments were 2.0‐3.9 times greater following intravenous injections than after subcutaneous injections. Subcutaneous treatments extended for 15‐29 days with doses of 5‐20 μg per pulse. Only one patient ovulated as judged by the luteal phase progesterone and ultrasonic scanning of the follicle. Intravenous treatments were from 12‐22 days with doses of 10 μg per pulse and 16 treatments out of 20 were ovulatory with four pregnancies. HCG (5000 i.u.) was given when ultrasonic scanning indicated adequate follicular growth, but in eight of the cycles, including three of the pregnancies, the follicle had ruptured before HCG was given. Pulsatile administration of GnRH proved to be an effective treatment for infertility in hypogonadotrophic hypogonadism. Possible reasons for the better results by intravenous rather than subcutaneous injections are discussed.

ACTH FUNCTION IN WOMEN WITH THE POLYCYSTIC OVARIAN SYNDROME

Serum androgen levels, including dehydroepiandrosterone sulphate (DHAS) which is thought to be solely of adrenal origin, are elevated in women with the polycystic ovarian syndrome. We have investigated the possibility that this may be due to a mild form of congenital adrenal hyperplasia by measuring basal and stimulated levels of ACTH in women with this condition and have compared them to levels in normal women. We found no difference in the diurnal rhythm of ACTH between patients and normal subjects nor any difference in stimulated levels achieved after a single‐dose oral metyrapone test. Thus there is no evidence from this study to support the idea that these patients might have congenital adrenal hyperplasia. There are two alternative hypotheses to explain the elevated DHAS levels. They may be associated with the high oestrogen levels, which interfere with the enzyme 3β‐hydroxysteroid dehydrogenase, or there may be alteration of the factors controlling adrenal androgen secretion.

Effectiveness of pergolide mesylate in long term treatment of hyperprolactinaemia.

Twenty five patients with hyperprolactinaemia were treated with pergolide mesylate, a new dopamine receptor agonist. Twenty three received treatment for six to 20 months, and in all serum prolactin concentrations were considerably reduced. In most patients prolactin concentrations were maintained in the normal range by a low, once daily dose of pergolide and reversal of associated reproductive disorders was observed. Tumour volume as assessed by computed tomography decreased considerably during treatment in three out of four patients with a pituitary tumour. The drug was well tolerated. Side effects were similar to those of bromocriptine, but four out of eight patients who had been forced to stop taking bromocriptine because of untoward effects were subsequently able to tolerate treatment with pergolide. Pergolide mesylate promises to be a useful addition to the currently available long acting dopamine agonists in the management of hyperprolactinaemia.

ADRENAL FUNCTION IN SUBGROUPS OF THE PCO SYNDROME ASSESSED BY A LONG ACTH TEST

Fifteen patients with the polycystic ovarian (PCO) syndrome were classified into Group A (n= 6) and Group B (n= 9) based on their LH responses to LHRH before and at 44 and 92h after administration of oestradiol benzoate. Adrenal function in both groups was assessed by comparing the hormone responses to ACTH (0.5mg twice daily for 4 days) with those obtained in nine normally ovulating women during the early follicular phase of their cycles. In Group A patients there was no significant difference from normals in the serum concentration of dehydroepiandrosterone sulphate (DHAS), 17α‐hydroxy‐progesterone (17‐OHP) or androgens (testosterone and dihydrotestosterone). In contrast, the serum concentrations in Group B were significantly higher (P<0.01) for each of these steroids before ACTH, and remained higher at 2 and 4 days for DHAS, but not for the other two steroids. The concentration of oestrone was significantly higher (P<0.05) in Group B patients before, and 2 days after, ACTH, while in Group A patients higher concentrations (P<0.02) were found only after 2 days. The concentrations of oestradiol, on the other hand, were not different from normal in either group before ACTH and became lower than normal in both groups at 2 days and remained lower at 4 days in Group B. The concentration of cortisol was within the normal range throughout in Group A, but was lower than normal after 4 days in Group B patients (P<0.05). The ratios between the sums of concentrations of DHAS to cortisol on days 2 and 4 (P<0.001) or 17‐OHP to cortisol (P<0.05) were elevated in Group B compared with normal subjects. LH, FSH and prolactin values were normal throughout in Group A, but in Group B patients the mean value for LH was significantly elevated before ACTH and at 4 days after ACTH (P<0.02).

The oestrogen provocation test: a method of assessing the hypothalamic-pituitary axis in patients with amenorrhoea.

The oestrogen feedback and gonadotrophin release in ten amenorrhoeic women were investigated, using intramuscular injection of 1 mg oestradiol benzoate. Serial estimations of serum oestradiol and gonadotrophins (LH and FSH) were made over a period of 72 h following the injection. Five patients demonstrated positive feedback release of LH to the oestrogen stimulus with elevated levels of LH significantly above baseline (P<0.001), which occurred between 48 and 72 h after the injection. Two of the five patients also demonstrated elevated FSH levels accompanying these LH peaks. The hypothalamic‐pituitary axis was postulated to be intact in these five patients, and all ovulated on clomiphene.