G. I. M. Swyer

PLASMA CORTISOL AND ADRENOCORTICOTROPHIC HORMONE IN NORMAL MEN AND NON‐PREGNANT WOMEN, NORMAL PREGNANT WOMEN AND WOMEN WITH PRE‐ECLAMPSIA

Determinations of plasma cortisol and adrenocorticotrophic hormone (ACTH) have been made in normal men and non‐pregnant women, in normal pregnant women and women with pre‐eclampsia, in maternal and cord blood during normal vaginal delivery and during delivery by Caesarean section. The findings in normal individuals, including the demonstration of diurnal variations, are in agreement with those of other workers, thus validating the methodology used. In pregnancy the plasma cortisol is raised and ACTH lowered so that, in comparison with non‐pregnant individuals, the ACTH/cortisol ratio is greatly reduced. In pre‐eclamptic pregnancies, on the other hand, the plasma cortisol tends to be lower and the ACTH much higher than in normal pregnancies, so that the ACTH/cortisol ratio is similar to that found in non‐pregnant individuals. This rise in ACTH/cortisol ratio may occur in pregnant women before the development of oedema, proteinuria and hypertension. It appears that in pregnancy adrenocortical responsiveness to ACTH is enhanced while in pre‐eclampsia the ability to secrete cortisol is relatively impaired, leading to increased ACTH secretion and this, by stimulating an increased output of aldosterone and possibly other salt‐retaining steroids, may partly be responsible for the manifestations of pre‐eclampsia. The concentration of cortisol in cord blood is lower than that in maternal blood at the time of delivery and both these concentrations are lower during delivery by Caesarean section than during normal vaginal delivery. On the other hand, although during delivery the ACTH levels in cord blood and maternal blood are greatly elevated, the difference between them is not significant, suggesting that the maternal adrenal cortex is more responsive to ACTH stimulation than the fetal adrenal cortex.

Plasma testosterone and testosterone binding affinities in men with impotence, oligospermia, azoospermia, and hypogonadism.

Mean plasma testosterone levels (± S.D.), using Sephadex LH-20 and competitive protein binding, were 629 ± 160 ng/100 ml for a group of 27 normal adult men, 650 ± 205 ng/100 ml for 27 impotent men with normal secondary sex characteristics, 644 ± 178 ng/100 ml for 20 men with oligospermia, and 563 ± 125 ng/100 ml for 16 azoospermic men. None of these values differ significantly. For 21 men with clinical evidence of hypogonadism the mean plasma testosterone (± S.D.), at 177 ± 122 ng/100 ml, differed significantly (P < 0·001) from that of the normal men. The mean testosterone binding affinities (as measured by the reciprocal of the quantity of plasma needed to bind 50% of 3H-testosterone tracer) were similar for normal, impotent, and oligospermic men. Though lower for azoospermic men the difference was not significant (P >0·1). For 12 of the 16 hypogonadal males the testosterone binding affinity was normal, but raised binding affinities, similar to those found in normal adult females or prepubertal boys (about twice normal adult male levels), were found in four cases of delayed puberty. These findings help to explain why androgen therapy is usually useless in the treatment of impotence.

Induction of Ovulation in Women with Hyperprolactinemic Amenorrhea Using Clomiphene and Human Chorionic Gonadotropin or Bromocriptine

Clomiphene citrate (Clomid), when given alone, is generally considered ineffective in inducing ovulation in women with hyperprolactinemia. This study reports the treatment of 29 infertile women with hyperprolactinemic amenorrhea. Twenty-one patients (eighteen of whom had previously had no ovulation response to Clomid alone) were treated with a combined regimen of Clomid (100 to 200 mg/day for 5 days) and two injections of 5000 IU of human chorionic gonadotropin (HCG), the first 8 to 10 days after Clomid withdrawal and a second injection 1 week later. Basal body temperature charts, conception, and/or plasma progesterone measurements showed that 19 patients ovulated (90%). There were 17 pregnancies in 12 of 21 patients (57% pregnancy rate) with 15 single live births and two abortions. When bromocriptine (Parlodel) became available, a total of 22 patients (including 14 patients previously treated with Clomid/HCG, six of them successfully) with amenorrhea associated with hyperprolactinemia were treated with this drug with dosages varying from 2.5 mg to 15 mg/day. Ovulation was confirmed in 20 patients (90%). There were 17 pregnancies in 15 patients (68% pregnancy rate) with 15 single live births and two first-trimester abortions. In all, 21 of 29 patients (73%) achieved one or more pregnancies resulting in live births with one or both of the above treatments. It is concluded that a combined Clomid/HCG regimen can often be used as an effective alternative to bromocriptine therapy in the treatment of infertility associated with hyperprolactinemic amenorrhea.

Plasma oestradiol and progesterone estimation for the monitoring of induction of ovulation with clomiphene and chorionic gonadotrophin.

Two hundred and thirty‐five courses of treatment with clomiphene and human chorionic gonadotrophin (HCG) were administered for the induction of ovulation in 75 infertile women (three with primary amenorrhoea, 45 with secondary amenorrhoea and 27 with oligomenorrhoea) of whom 61 had previously been unsuccessfully treated with clomiphene alone. The treatment was monitored by plasma oestradiol estimations on day 15 and day 22 in 103 cycles and by plasma progesterone estimations on day 22 in all 235 cycles. Injections of HCG were given on days 15 and 22. Twenty patients failed to respond to treatment (43 courses). The remaining 55 patients showed no response in 32 courses, deficient responses in 55 cycles and adequate responses in 105 cycles (plasma progesterone level exceeding 10 ng per ml on day 22). The mean values (±D) of plasma oestradiol on day 15, reflecting follicular development, were: 73±30 pg per ml for cycles with no response; 255±182 for deficient cycles and 366±226 pg per ml for adequate cycles. There was a positive correlation (r =0±57) between day 15 plasma oestradiol and day 22 plasma progesterone values. Increased clomiphene dosage resulted in higher plasma oestradiol and progesterone levels. Thirty‐nine pregnancies occurred in 34 out of 55 patients capable of response (62 per cent). The plasma progesterone levels during conception cycles were higher than those in non‐conception cycles in the same patients. Monitoring of induction of ovulation by plasma hormone estimations allows detection and correction of inadequate response.

PLASMA TESTOSTERONE AND ANDROSTENEDIONE LEVELS DURING MONITORED INDUCTION OF OVULATION IN INFERTILE WOMEN WITH ‘SIMPLE’ AMENORRHOEA AND WITH THE POLYCYSTIC OVARY SYNDROME

Twenty‐seven infertile patients with ‘simple’ amenorrhoea‐oligomenorrhoea and eighteen with the polycystic ovary (PCO) syndrome were treated for induction of ovulation with clomiphene, human menopausal gonadotrophin and human chorionic gonadotrophin. The treatment was monitored by plasma oestradiol, testosterone, andfostenedione and progesterone estimation. Women with PCO had significantly higher plasma androgen levels than women with ‘simple’ amenorrhoea (P < 0.01 to P < 0.001) both before treatment and during induction of ovulation. When ovulation was induced the pregnancy rate for women with the PCO syndrome with elevated androgens was 21% while for those with uncomplicated amenorrhoea it was 75%. It is concluded that high levels of circulating androgens might be a factor preventing conception in some patients in whom ovulation is apparently successfully induced.

INDUCTION OF OVULATION WITH CLOMIPHENE AND HUMAN CHORIONIC GONADOTROPHIN IN WOMEN WITH HYPERPROLACTINAEMIC AMENORRHOEA

Seventeen women complaining of infertility (one with primary amenorrhoea, 14 with secondary amenorrhoea, and two with oligomenorrhoea) all had hyper‐prolactinaemia and were treated with clomiphene citrate and human chorionic onadotrophin (HCG), and plasma oestradiol, FSH and LH levels were measured. Although adequate pre‐ovulatory oestradiol levels were present, the surge of LH was absent until the injection of HCG after which all patients ovulated. There were 12 pregnancies in 9 patients resulting in 10 full‐term livebirths, one premature livebirth and one continuing pregnancy. The relevance of these findings to the possible role of prolactin in amenorrhoea is discussed.

THE MONITORING OF GONADOTROPHIN THERAPY BY PLASMA OESTRADIOL AND PROGESTERONE DETERMINATIONS

Plasma oestradiol and progesterone determinations by competitive protein binding techniques were introduced as a means of monitoring treatment with human gonadotrophins of 32 infertile women with amenorrhoea or severe oligomenorrhoea. Human menopausal gonadotrophin (HMG) was administered on days 1, 3 and 5. Human chorionic gonadotrophin (HCG) was injected on day 8 if the response to HMG stimulation was adequate but not excessive, a second dose being given seven days later.

PROLACTIN AND LUTEAL INSUFFICIENCY

The relationship between mid‐luteal plasma levels of progesterone and prolactin was studied in 75 women with regular menstrual cycles. Eighteen women had normal prolactin (mean 260 ± 51.7 mU/l) and normal progesterone levels (mean 67 ± 21.3 nmol/l). Thirty‐nine women had elevated prolactin levels (mean 850 ± 503 mU/l); progesterone levels were normal in all cases (mean 61 ± 22.3nmol/l). Eighteen women had evidence of luteal deficiency (mean progesterone 15.3 ± 7.7 nmol/l); prolactin levels were normal in all cases (mean 243 106 mU/l). There was no correlation between plasma prolactin and progesterone levels.

PROGESTATIONAL AGENTS AND DISTURBANCES OF PREGNANCY

THE use of hormones, including oestrogens and thyroid hormone as well as progestagens, in disturbances of pregnancy, though now of many years’ standing, is still the subject of controversy. Though their use is widespread it is still largely empirical and has not been established on a scientific basis. The main reason for this is that disturbances of pregnancy during the early months may arise from many causes and hormone deficiency, in the presence of which alone hormone therapy could be expected to prove efficacious, is by no means the only, or indeed the most common, of these causes. Only on the assumption that hormone therapy can do no harm, even if it cannot do good except when hormone deficiency exists, could the widepsread empirical use of hormones in the treatment of threatened and habitual abortion be justified. In fact there are no good reasons for making such an assumption and several cogent ones for taking the opposite view. We do not propose to discuss the requirements which would have to be satisfied in order that an entirely valid trial of the clinical efficacy of hormone therapy of one kind or another in the treatment of pregnancy disturbances could be carried out. Suffice it to say they would be stringent, difficult to meet by any single investigator, and have not yet been met in any published study. If we confine ourselves to progestagen therapy for progesterone deficiency, there is at the outset the problem of demonstrating the presence of such a deficiency, since it follows from what has already been said that only patients with progesterone deficiency ought to be included in a trial of the value of progestagen therapy. This problem is not solved satisfactorily by measurements of pregnanediol excretion, or the examination of vaginal smears or of cervical mucus for ferning. Pregnanediol excretion, as a measure of progesterone production, is subject to a number of qualifying factors on the theoretical side and to severe limitations on the practical side. The time taken to collect a 24-hour urine aliquot and to carry out the determination by a reliable method virtually rules out its use in cases of threatened abortion. Though the vaginal smear shows characteristic appearances in pregnancy, and a low pyknotic index (below 20 per cent) is typical, no one has yet demonstrated convincingly that the pyknotic index is related reciprocally to progesterone production or has shown in what way it is affected by the concomitant oestrogen level. The ferning of cervical mucus, an oestrogen induced phenomenon, though inhibited by progesterone, is undoubtedly an even less precise indication of progesterone deficiency in pregnancy than elevation of the pyknotic index. From several points of view, therefore, we are not well equipped to make precise studies of the value of progestagen therapy in threatened and habitual abortion. The foregoing remarks are made in extenuation of our failure in this paper to contribute basically to the establishment of the value of progestagen therapy. The approach we have adopted to the treatment of our patients has had perforce to have been a somewhat pragmatic one, based on a number of assumptions. The first has been that the pyknotic index does, indeed, offer a useful guide to the progesterone level, a value above 20 per cent being regarded as indicative of progesterone deficiency, particularly when rising ; and second, that a progestagen which lowers a raised pyknotic index in pregnancy is likely to be beneficial. We have considered that the urinary excretion of human chorionic gonadotrophin (HCG) reflects the activity of the trophoblast so that a low and falling HCG excretion implies a dying embryo; we have reason to believe that the

Plasma Testosterone Using Sephadex LH-20 and Saturation Analysis by Competitive Protein Binding

A method Tor measuring plasma testosterone using separation on short columns of Sephadex LH-20 and competitive protein binding is described. This is more reliable and practicable than methods using paper or thin layer chromatography separation and Sephadex LH-20 can be re-used after washing.