R. Logan Edwards

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.

LAPAROSCOPIC STERILIZATION AND FOLLOW-UP HYSTEROSALPINGOGRAM

Over a period of three years 910 patients have been subjected to laparoscopic sterilization of which 443 have had a follow‐up hysterosalpingogram. The results are discussed.

Review of 59 patients with hypergonadotrophic amenorrhoea

Summary. Fifty‐nine patients presented with elevated concentrations of gonadotrophins and secondary amenorrhoea before the age of 35 years. Fifty‐three underwent laparoscopic examination and primordial follicles were observed in 16. Two others had follicles as they later became pregnant and a third showed biochemical evidence of spontaneous ovulation. There were streak ovaries in 12, two with follicles and three others with chromosomal abnormalities, two being 47XXX and one XO/XX. Two other patients had only one ovary each but no follicles. Chromosomal abnormalities were detected in two further patients one being XO/XX and the other a recombinant. Six patients became pregnant, two of them twice, resulting in four term deliveries and four spontaneous abortions. Three other patients showed biochemical evidence of ovulation; one spontaneously, one after oestrogen therapy and the third after treatment with gonadotrophin releasing hormone analogue.

Luteinizing hormone releasing hormone analogue in treatment of hypergonadotrophic amenorrhoea

Summary. The effect of a luteinizing hormone releasing hormone analogue (HOE 766) was studied in four patients with hypergonadotrophic amenorrhoea (resistant ovary syndrome). After an initial phase of stimulation, there was a uniform and sustained suppression of gonadotrophin concentrations in all the patients during the 20–24 days of treatment, presumably due to down‐regulation of the pituitary receptors. One patient ovulated after stopping treatment.

BASAL SERUM PROLACTIN VALUES AND RESPONSES TO THE ADMINISTRATION OF THYROTROPHIN RELEASING HORMONE (TRH) IN WOMEN WITH AMENORRHOEA

Basal prolactin concentrations were measured in 77 patients presenting with amenorrhoea; 17 per cent were found to have hyperprolactinaemia. The release of prolactin in response to a standard dose of thyrotrophin releasing hormone for amenorrhoeic subjects with normal basal levels of prolactin was within the normal range. However, patients with hyperprolactinaemic amenorrhoea and no evidence of pituitary tumour were found to have a blunted response.

SEX HORMONE LEVELS AND GONADOTROPHIN RELEASE IN PREMATURE OVARIAN FAILURE

Premature ovarian failure was studied in ten women under the age of 30; eight had an ovarian biopsy and five of these showed primordial follicles. Plasma levels of oestradiol and progesterone were similar to the follicular phase of a normal menetrual cycle, but in eight patients cervical smears showed a cornification index of less than one per cent. Levels of both androgens and of sex hormone binding globulin capacity were generally normal. Administration of LH‐RH caused a release of FSH which was similar to post menopausal women and higher than normally menstruating women, and a release of LH which was higher than both. Two patients were treated with exogenous gonadotrophins without effect.

ENDOCRINE STUDIES IN POST‐MENOPAUSAL WOMEN WITH OVARIAN TUMOURS

An endocrine assessment was made in 78 post‐menopausal women.