Howard S. Jacobs

MULTIFOLLICULAR OVARIES: CLINICAL AND ENDOCRINE FEATURES AND RESPONSE TO PULSATILE GONADOTROPIN RELEASING HORMONE

By means of pelvic ultrasonography, a multifollicular ovarian appearance was observed in women with weight-loss-related amenorrhoea. Multifollicular ovaries (MFO) are normal in size or slightly enlarged and filled by six or more cysts 4-10 mm in diameter; in contrast to women with polycystic ovaries (PCO), stroma is not increased. Unlike PCO patients, women with MFO were not hirsute and serum concentrations of luteinising hormone and follicle stimulating hormone were normal and decreased, respectively. The uterus was small indicating oestrogen deficiency. In MFO, treatment with gonadotropin releasing hormone (LHRH) induced ovulation in 83% of cycles and there were seven pregnancies in 8 women; in PCO, only 40% of cycles were ovulatory and there were eleven pregnancies (8 women) but six of these aborted. In MFO ovarian morphology reverted to normal in ovulatory cycles, whereas in PCO the polycystic pattern persisted despite the presence of a dominant follicle. MFO may represent a normal ovarian response to weight-related hypothalamic disturbance of gonadotropin control.

Cardiovascular disease in women with polycystic ovary syndrome at long‐term follow‐up: a retrospective cohort study

Polycystic ovary syndrome (PCOS) is associated with higher prevalence of cardiovascular risk factors but the relative prevalence of cardiovascular disease in women with PCOS has not previously been reported. We have compared cardiovascular mortality and morbidity in middle‐aged women previously diagnosed with PCOS and age‐matched control women.

Mortality of Women with Polycystic Ovary Syndrome at Long-term Follow-up

Metabolic disturbances associated with insulin resistance are present in most women with polycystic ovary syndrome. This has led to suggestions that women with polycystic ovary syndrome may be at increased risk of cardiovascular disease in later life. We undertook a long-term follow-up study to test whether cardiovascular mortality is increased in these women. A total of 786 women diagnosed with polycystic ovary syndrome in the United Kingdom between 1930 and 1979 were traced from hospital records and followed for an average of 30 years. Standardized mortality ratios (SMRs) were calculated to compare the death rates of these women with national rates. The SMR for all causes was 0.90 (95% CI, 0.69-1.17), based on 59 deaths. There were 15 deaths from circulatory disease, yielding an SMR of 0.83 (95% CI, 0.46-1.37). Of these 15 deaths, 13 were from ischemic heart disease (SMR 1.40; 95% CI, 0.75-2.40) and two were from other circulatory disease (SMR 0.23; 95% CI, 0.03-0.85). There were six deaths from diabetes mellitus as underlying or contributory cause, compared with 1.7 expected (odds ratio 3.6; 95% CI, 1.5-8.4). Breast cancer was the commonest cause of death (SMR 1.48 based on 13 deaths; 95% CI, 0.79-2.54). We conclude that women with polycystic ovary syndrome do not have markedly higher than average mortality from circulatory disease, even though the condition is strongly associated with diabetes, lipid abnormalities, and other cardiovascular risk factors. The characteristic endocrine profile of women with polycystic ovary syndrome may protect against circulatory disease in this condition.

HETEROGENEITY OF THE POLYCYSTIC OVARY SYNDROME: CLINICAL, ENDOCRINE AND ULTRASOUND FEATURES IN 556 PATIENTS

This paper reports an analysis of the clinical, endocrine and ultrasound data within a population of 556 patients with ultrasound‐diagnosed polycystic ovaries. Compared with those not so affected, hirsutism was associated with a higher mean serum testosterone concentration, infertility was associated with higher mean gonadotrophin concentrations, obesity was associated with a higher mean serum testosterone concentration, hyperprolactinaemia was associated with a lower mean serum testosterone concentration and smaller ovaries, alopecia was associated with lower mean serum LH and testosterone concentrations, and acanthosis nigricans was associated with obesity and a raised mean serum testosterone concentration. The heterogeneity illustrates the limitations in the use of specific clinical or endocrine criteria as requirements for the diagnosis of the polycystic ovary syndrome.

Influence of serum luteinising hormone concentrations on ovulation, conception, and early pregnancy loss in polycystic ovary syndrome.

Women with the polycystic ovary syndrome do not respond well to treatment with luteinising hormone releasing hormone. To determine whether this might be due to an underlying endocrine disturbance basal concentrations of luteinising hormone were measured in 54 infertile women treated with pulsatile luteinising hormone releasing hormone and concentrations at the time of maximum follicular growth were measured in 23 of the patients. Forty one patients ovulated. Forty one patients ovulated and 27 conceived, but nine pregnancies terminated within four weeks after ovulation. Basal luteinising hormone concentrations were significantly lower in those who conceived (12.4 (range 1.3-29.0) IU/l) than in those who did not (19.0 (3.5-50.0) IU/l) and in those whose pregnancy progressed (9.6 (1.3-29.0) IU/l) than in those with early loss of pregnancy (17.9 (7.0-29.0) IU/l). Concentrations at the time of maximum follicular growth were significantly lower in women who ovulated (9.4 (2.9-35.4) IU/l) than in those who did not (29.0 (7.0-50.0) IU/l) and in those who conceived (6.2 (2.9-8.5) IU/l) than in those who did not (17.9 (4.0-50.0) IU/l). These results indicate that high concentrations of luteinising hormone during the follicular phase in women with polycystic ovaries have a deleterious effect on rates of conception and may be a causal factor in early pregnancy loss.

Hypersecretion of luteinising hormone, infertility, and miscarriage

The relation between prepregnancy follicular-phase serum luteinising hormone (LH) concentrations and outcome of pregnancy was investigated prospectively in 193 women with regular spontaneous menstrual cycles. The group included 26 nulliparous and 167 multiparous women with various obstetric histories. Of the 147 women with LH concentrations of less than 10 IU/l (normal LH group) 130 (88%) conceived, whereas only 31 (67%) of the 46 women with LH values of 10 IU/l or more (high LH group) did so. In the high LH group, 20 (65%) of the pregnancies ended in miscarriage, whereas only 15 (12%) of pregnancies in the normal LH group did so. The adverse effect of a high prepregnancy LH concentration on fertility and outcome of pregnancy was seen in primigravidae, women with previously successful pregnancies, and women with a history of recurrent miscarriage. These data indicate an important role for hypersecretion of LH before conception in miscarriage. This finding offers the possibility of a simple predictive test for women before pregnancy, and could also be used to identify patients with an endocrine abnormality that can be remedied.

GROWTH HORMONE FACILITATES OVULATION INDUCTION BY GONADOTROPHINS

The addition of biosynthetic human growth hormone (GH) to treatment with human menopausal gonadotrophin (hMG) significantly augmented the ovarian response in four patients treated for in‐vivo and three patients treated for in‐vitro fertilization who had previously been resistant to hMG. The amount, duration of treatment and daily effective dose of hMG were all reduced by growth hormone. This action of growth hormone offers a new approach to ovulation induction.

Diagnosis, prevention and management of ovarian hyperstimulation syndrome

The overall incidence of clinically important (moderate to severe) OHSS ranges from 1% to 10% of IVF cycles, but only a small proportion (0.5% to 2%) of the cases are severe. In extreme but rare cases, secondary complications such as deep vein thrombosis, respiratory distress and acute hepato-renal failure may occur. The main risk factors are the presence of polycystic ovaries, high ovarian response to superovulation therapy, the use of hCG to trigger the ovulatory process or for luteal phase support, and the endogenous production of hCG by an early pregnancy. The pathogenesis of OHSS is unknown, although the predominant biochemical mediator is thought to be the renin-angiotensin system. Ovarian stimulation should always be carefully monitored to identify those women at risk. In IVF cycles, the hCG injection should be withheld if the risk is judged to be too great. Some women will benefit from a policy of proceeding to collect oocytes, but electively cryopreserving any resulting embryos, thus allowing the ovarian stimulation cycle not to be wasted. The administration of albumin at the time of oocyte collection will reduce the chance of severe OHSS occurring. If a decision is made to proceed with oocyte recovery and embryo transfer, it may be advisable to give 5000 IU of hCG, rather than 10,000 IU, as the ovulatory trigger. Progesterone, and not hCG, should be given in the luteal phase. Women developing mild or moderate OHSS should be kept under outpatient surveillance to detect the minority that may progress to severe OHSS. Those with severe OHSS should be hospitalised for fluid and electrolyte management. Paracentesis under ultrasound guidance is recommended where there are tense ascites, but further surgical intervention should rarely be undertaken and only when there is good clinical evidence of ovarian torsion or haemorrhage.

Laparoscopic ovarian diathermy in the management of anovulatory infertility in women with polycystic ovaries: endocrine changes and clinical outcome

Twenty-one nulliparous oligomenorrheic women with polycystic ovaries, complaining of infertility (mean duration 6 years) refractory to medical treatment, underwent laparoscopic ovarian diathermy. Eleven had adhesions and/or endometriosis. Regular ovulatory cycles ensued in 17 women (81%). In 9 responders there was a transient rise in mean follicle-stimulating hormone from 5.0 +/- 0.4 (standard error of the mean [SEM]) to 6.7 +/- 0.5 mIU/mL on postoperative day 1 and a fall in testosterone from 2.6 +/- 0.2 to 1.9 +/- 0.2 nmol/L by day 8. Luteinizing hormone fell from 19 +/- 1.2 to 10.4 +/- 1.2 mIU/mL by the follicular phase of the next cycle. Eleven women have conceived 13 pregnancies; 3 miscarried, 7 were delivered at term and 3 are ongoing. Ovarian diathermy is a useful option in women with polycystic ovaries complaining of refractory anovulatory infertility.

HYPERPROLACTINAEMIA AND IMPOTENCE

Clinical, laboratory and radiological findings were evaluated in twenty‐nine men who had raised serum prolactin concentrations and pituitary tumours. Twenty‐one had functionless pituitary tumours (‘prolactinomas’) and eight had acromegaly. Suprasellar extension was detected in twenty of the twenty‐six men who had lumbar airencephalography. Three patients were studied before, sixteen before and after and ten only after pituitary ablative therapy.