D. R. London

The hypothalamo-pituitary-adrenal axis across the normal menstrual cycle and in polycystic ovary syndrome.

OBJECTIVE We explored the hypothesis that activation of the hypothalamo‐pituitary‐adrenal axis is involved in the pathogenesis of hyperandrogenism in the polycystic ovary syndrome.

SEX HORMONE LEVELS AND GONADOTROPHIN RELEASE IN THE POLYCYSTIC OVARY SYNDROME

The response to synthetic luteinizing hormone‐releasing hormone was studied in eighteen patients with the polycystic ovary syndrome. The release of follicle‐stimulating hormone was similar to that found in normal women. The mean response of luteinizing hormone was similar to that found in the luteal phase, but significantly greater (P<0.02) than that found in the early follicular phase of the normal menstrual cycle. Basal serum levels of FSH and LH, estimated in twenty‐five patients, were similar to those found in normal subjects. The sex hormone binding globulin capacity was reduced in twenty‐four of them. Basal serum testosterone levels were elevated in twelve of twenty‐two patients and the mean level was significantly greater (P<0.01) than the mean level of normal women. Basal serum androstenedione levels were elevated in nine of twenty‐two patients and the mean level was also significantly greater (P<0.02) than normal. There was a highly significant negative correlation (r=−0.86; P<0.001) between basal testosterone and LH levels. These data suggest that the pituitary gland of patients with the polycystic ovary syndrome contains adequate amounts of LH but that the ovulatory surge of LH which occurs in normal women is inhibited by testosterone acting on either the pituitary or, more probably, on the hypothalamus.

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.

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).

ANDROGEN AND CORTISOL RESPONSES TO ACTH STIMULATION IN WOMEN WITH HYPERPROLACTINAEMIA

Basal serum concentrations of androgens (testosterone and dihydrotestosterone) and dehydroepiandrosterone sulphate (DHAS) were measured in 7 normal and in 14 anovulatory women with raised serum prolactin. No patient had detectable skull x‐ray abnormalities. The mean DHAS, but not the androgens, were significantly higher in the women with hyperprolactinaemia (p < 0.01) and in 7 of the 14 the values were above the normal range which is 2.9–11.2 μmol/l. The 7 normal subjects and 9 of the women with hyperprolactinaemia were given ACTH (0.5 mg twice daily for four days). Cortisol and androgen concentrations in response to ACTH were not significantly different in the two groups, but the levels of DHAS (p < 0.001) were significantly higher over the four days in patients with hyperprolactinaemia. The concentrations of DHAS in these women were significantly higher by two days and continued to rise on day four of the test, but the concentration of androgens was greatest at two days as in the normal group.

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.

AN ACTH‐SECRETING PITUITARY TUMOUR ARISING IN A PATIENT WITH CONGENITAL ADRENAL HYPERPLASIA

The case reported is of a 46‐year‐old woman who had congenital adrenal hyperplasia due to a 21‐hydroxylase deficiency, and in whom there was the development of an ACTH secreting pituitary tumour. The patient was untreated with glucocorticoids until the age of 32 years when she presented with infertility. She next presented with amenorrhoea at the age of 44 years when she was found to have an enlarged pituitary fossa. Despite treatment with bromocriptine and adequate doses of dexamethasone, the tumour enlarged and required operative treatment 1 year later. Before and after operation, plasma ACTH levels were between 300 and 400 ng/1, immunocytochemistry showed staining for ACTH and other structurally related pro‐opiocortin peptides but for no other hormones, and the tumour secreted large amounts of ACTH in vitro. The report of this case is to our knowledge the first account of a feedback tumour in congenital adrenal hyperplasia and provides yet another reason why patients with this condition should be treated, and good control achieved.

THE EFFECT OF OESTROGEN PRETREATMENT ON SUBSEQUENT RESPONSE TO LUTEINIZING HORMONE RELEASING HORMONE IN NORMAL WOMEN

Twenty‐two normal, regularly menstruating female subjects had an LHRH test performed before and after pretreatment with 0.5 mg, 1 mg or 2.5 mg of oestradiol benzoate during the follicular phase of their menstrual cycles (days 4–8). Two further women acted as controls and received no oestrogen; they showed identical responses for both LH and FSH release when LHRH tests were performed at intervals of 48 h. Oestrogen pretreatment induced a biphasic effect upon subsequent LHRH response. Four subjects retested 20 h after 0.5 mg oestradiol benzoate showed either no change or a slight suppression of LH and FSH release. Fifteen of the eighteen women pretreated with oestradiol benzoate and retested 44 h later showed significantly increased LH release and fourteen significantly increased FSH release when compared to their control responses. The responses appeared to be dose related with a positive correlation between sum of LH increments and basal oestradiol levels (r= 0.61; P<0.001) and a similar correlation (r= 0.67; P<0.001) between sum of FSH increments and basal oestradiol levels. The physiological significance of this biphasic action of oestrogen upon pituitary sensitivity is discussed in relation to the control of the menstrual cycle.

Modification by sex steroids of LHRH response in the polycystic ovary syndrome.

Exogenously administered oestradiol or progesterone was found to induce augmentation of LH and FSH release in response to LHRH administration in patients with the polycystic ovary (PCO) syndrome. The effect of oestradiol upon LH release in the patients was significantly less than the augmented release induced in normal women (P < 0.02). In contrast, progesterone induced a significantly greater LH release in PCO patients than normal women studied during the early follicular phase (P < 0.001) but less than that in normal women studied during the mid‐follicular phase of the cycle (P < 0.01). The effects on FSH release in the PCO patients were less marked but similar to those in normal women with comparable basal steroid levels.

Effects of long term dexamethasone treatment in adult patients with congenital adrenal hyperplasia.

We have followed nine adult patients with congenital adrenal hyperplasia (CAH) for between 7‐77 months on dexamethasone (DXM) 0.5 mg mane and 0.25 mg nocte, reducing to 0.5 mg mane. Twenty‐four hour profiles of ACTH, 17‐hydroxyprogesterone (17OHP), and androstenedione were performed; the areas under the curves (AUC) and the heights of the morning peaks were used to assess biochemical control. Comparisons were made between treatment before DXM (pre‐DXM), 0.75 mg for 2 weeks (DXM‐ST), 0.75 mg for at least 3 months (DXM‐LT), and 0.5 mg for at least 3 months (DXM‐0.5). None of the three males suffered any significant side‐effects. All women had menstrual disturbance but in three ovulation was induced. One female developed Cushings syndrome and two developed hirsutism which resolved on stopping DXM. Overall there was no significant difference between DXM‐ST and DXM‐LT (mean AUCs for ACTH: DXM‐ST 660, DXM‐LT 383, for 170HP: DXM‐ST 1177, DXM‐LT 587, for androstenedione DXM‐ST 232, DXM‐LT 121). Reduction of the dose from 0‐75 mg to 0‐5 mg led to significant deterioration in control (Mean AUCs for ACTH DXM‐0 5,1123 (P < 0‐02), for 170HP DXM‐0‐5, 2068 (P < 0‐002), for androstenedione DXM‐05, 213 (P < 0‐5). We conclude that DXM is a satisfactory regime but the dose must be adjusted for each patient.