The ability of prolactin to change the sensitivity of the pituitary of the lactating rat to luteinising hormone releasing hormonein vitro

The ability of prolactin to influence the responsiveness of the lactating rat pituitary to luteinising hormone releasing hormone has been examinedin vitro. The pituitary responsivenessin vivo to luteinising hormone releasing hormone decreased as a function of increase in the lactational stimulus. Prolactin inhibited the spontaneousin vitro release of luteinising hormone and follicle stimulating hormone to a small extent, from the pituitary of lactating rats with the suckling stimulus. However, it significantly inhibited the release of these two hormones from luteinising hormone releasing hormone-stimulated pituitaries. The responsiveness of pituitaries of rats deprived of their litter 24 h earlier, to luteinising hormone releasing hormone was also inhibited by prolactin, although minimal. It was concluded that prolactin could be influencing the functioning of the pituitary of the lactating rat by (a) partially suppressing the spontaneous release of gonadotropin and (b) inhibiting the responsiveness of the pituitary to luteinising hormone releasing hormone.     

Loss of pulsatile luteinising hormone secretion in men with chronic renal failure.

In an attempt to determine the nature of hypothalamic and pituitary dysfunction in renal failure the secretory patterns of luteinising hormone were measured in men with end stage renal disease and compared with those in healthy controls and renal transplant recipients of similar age distribution. Mean luteinising hormone and oestradiol concentrations were significantly higher and the number of luteinising hormone secretory pulses was significantly lower in uraemic men compared with controls. Plasma testosterone and oestradiol concentrations were significantly lower in renal transplant recipients than normal men, but there were no significant differences in mean gonadotropin concentrations or the number of pulses of luteinising hormone between the two groups. As pulses of luteinising hormone are thought to reflect episodic gonadotropin releasing hormone from the hypothalamus these data suggest that uraemia interferes with central mechanisms controlling synchronised release of gonadotropin releasing hormone. This defect appears to be reversible after successful transplantation.     

Is changing hypothalamic activity important for control of ovulation?

The activity of the hypothalamic gonadotrophin releasing hormone pulse generator in women with regular ovulatory and anovulatory menstrual cycles was assessed to see whether changes therein are important determinants of normal and impaired ovarian function. Endogenous gonadotrophin releasing hormone secretion was inferred by measurement of the pituitary luteinising hormone response by characterisation of pulsatile luteinising hormone release over eight hours on three occasions during the course of follicular development and once during the luteal stage of the same cycles. In 13 ovulatory cycles (serum progesterone concentration greater than 25 nmol/l) confirmed by ovarian ultrasonography a pronounced variability in luteinising hormone pulse patterns among subjects was compatible with ovulation. In the luteal stage of ovulatory cycles the luteinising hormone interpeak interval (85 min, range 42-125) was significantly longer than that during the early follicular (64 min, 40-103), mid-follicular (62 min, 37-107), and late follicular (59 min, 39-80) stages of the same cycles. Thus in ovulatory cycles no increase in frequency of the gonadotrophin releasing hormone pulse generator was detected during follicular development, though this activity decreased in the luteal stage. In five late follicular stage studies in which part of the preovulatory luteinising hormone surge was captured no change in pulse frequency of luteinising hormone was detected compared with the mid-follicular stage of the same cycles or when compared with the late follicular stage of other cycles when no luteinising hormone surge was captured. Though mean luteinising hormone concentrations in luteinising hormone surge series (36 IU/l) were high, the amplitude of luteinising hormone pulses (165%) was only slightly greater than during non-surge late follicular stage studies (145%). Hence no change in hypothalamic gonadotrophin releasing hormone activity is required to generate the preovulatory discharge of luteinising hormone in man, which occurs as a result of the sensitising action of rising oestradiol concentrations on pituitary responsiveness to the same hypothalamic input signal. Luteinising hormone pulse frequency, peak amplitude, and mean serum luteinising hormone concentrations in seven anovulatory cycles (progesterone concentration less than 10 nmol/l) were not different from those at comparable stages of ovulatory cycles. These data suggest that the primary abnormality in this group of regularly menstruating anovulatory women lies in the ovary rather than in the hypothalamic control of the anterior pituitary.     

Mechanisms leading to hypogonadism in men with burns injuries.

A profound and persistent depression of serum testosterone concentrations was found in 19 men with burns injuries. This could not be explained by changes in sex hormone binding globulin capacity, hyperprolactinaemia, classical primary testicular failure, or a hypogonadotrophic state. Pulsatile release of luteinising hormone was found in control subjects but was absent or diminished in burnt patients with low serum testosterone concentrations. In addition, these patients showed reduced biological activity of luteinising hormone as measured by bioassay even though normal concentrations of luteinising hormone were detected by radioimmunoassay. The temporary hypogonadism after burns injury and possibly in other clinical states may be related to hypothalamic dysfunction, which leads to abnormal generation of luteinising hormone releasing hormone and non-pulsatile secretion of luteinising hormone of reduced biological activity.     

Long term treatment with luteinising hormone releasing hormone agonists and maintenance of serum testosterone to castration concentrations.

Serum concentrations of luteinising hormone and testosterone were measured by radioimmunoassay one, two, four, seven, and 24 hours after the subcutaneous administration of 500 micrograms of the luteinising hormone releasing hormone agonist [D-Trp6, des-Gly-NH2(10)] LHRH ethylamide or [D-Ser(TBU)6, des-Gly-NH2(10)]LHRH ethylamide in patients who had previously received daily treatment with these peptides for 0, 1, 6, 12, 18, and 24 months. No increase in the serum concentrations of luteinising hormone or testosterone were detected at any time between one and 24 months'' treatment. The data show that daily subcutaneous administration of the two luteinising hormone releasing hormone agonists used at the appropriate dose can maintain concentrations of serum androgens equivalent to those after castration during long term treatment.     

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.     

Does suppressing luteinising hormone secretion reduce the miscarriage rate? Results of a randomised controlled trial.

OBJECTIVE--To determine whether prepregnancy pituitary suppression of luteinising hormone secretion with a luteinising hormone releasing hormone analogue improves the outcome of pregnancy in ovulatory women with a history of recurrent miscarriage, polycystic ovaries, and hypersecretion of luteinising hormone. DESIGN--Randomised controlled trial. SETTING--Specialist recurrent miscarriage clinic. SUBJECTS--106 women with a history of three or more consecutive first trimester miscarriages, polycystic ovaries, and hypersecretion of luteinising hormone. INTERVENTIONS--Women were randomised before conception to receive pituitary suppression with a luteinising hormone releasing hormone analogue followed by low dose ovulation induction and luteal phase progesterone (group 1) or were allowed to ovulate spontaneously and then given luteal phase progesterone alone or luteal phase placebo alone (group 2). No drugs were prescribed in pregnancy. MAIN OUTCOME MEASURES--Conception and live birth rates over six cycles. RESULTS--Conception rates in the pituitary suppression and luteal phase support groups were 80% (40/50 women) and 82% (46/56) respectively (NS). Live birth rates were 65% (26/40) and 76% (35/46) respectively (NS). In the luteal phase support group there was no difference in the outcome of pregnancy between women given progesterone and those given placebo pessaries. Live birth rates from an intention to treat analysis were 52% (26/50 pregnancies) in the group given pituitary suppression and 63% (35/56) in the controls (NS). CONCLUSIONS--Prepregnancy suppression of high luteinising hormone concentrations in ovulatory women with recurrent miscarriage and hypersecretion of luteinising hormone does not improve the outcome of pregnancy. The outcome of pregnancy without pituitary suppression is excellent.     

One hundred pregnancies after treatment with pulsatile luteinising hormone releasing hormone to induce ovulation.

OBJECTIVE--To review treatment with pulsatile luteinising hormone releasing hormone in infertile women who do not ovulate and are resistant to clomiphene after 100 pregnancies achieved with this treatment. DESIGN--Retrospective analysis of 146 courses of treatment over 434 cycles. SETTING--Infertility clinic. PATIENTS--118 Women whose failure to ovulate was due to idiopathic hypogonadotrophic hypogonadism (n = 39), amenorrhoea related to low weight (n = 17), organic pituitary disease (n = 15), or polycystic ovaries (n = 47). INTERVENTIONS--Dose of 15 micrograms luteinising hormone releasing hormone/pulse subcutaneously every 90 minutes given with a miniaturised pump throughout cycle monitored by ultrasound. Women with hypogonadotrophic hypogonadism had 48 courses, women with amenorrhoea related to low weight 23, women with organic pituitary disease 18, and women with polycystic ovaries 57. END POINT--Follow up of 100 pregnancies achieved in 77 women during six years after introducing treatment. MEASUREMENTS and main results--One hundred pregnancies (seven multiple, 28 miscarriages). Cumulative rates of pregnancy were 93-100% at six months in women with idiopathic hypogonadotrophic hypogonadism, amenorrhoea related to low weight, and organic pituitary disease. In women with polycystic ovaries (cumulative rate of pregnancy 74%) adverse prognostic factors were obesity, hyperandrogenism, and high luteinising hormone concentrations, which were also associated with a high rate of early pregnancy loss. CONCLUSIONS--Treatment with pulsatile luteinising hormone releasing hormone is safe, simple, and effective, and the preferred method of inducing ovulation in appropriately selected patients. Compared with exogenous gonadotrophin treatment there is little need for monitoring, no danger of hyperstimulation, and a low rate of multiple pregnancies.     

Induction of ovulation with pulsatile luteinising hormone releasing hormone.

Ovulation was successfully induced with luteinising hormone releasing hormone in 28 women with hypothalamic amenorrhoea who had failed to respond to treatment with clomiphene. Luteinising hormone releasing hormone was administered in a pulsatile manner with miniaturised automatic infusion systems. The rate of ovarian follicular maturation, as monitored by serial pelvic ultrasonography, was similar to that observed in spontaneous cycles. Endocrine assessment by serial measurement of gonadotrophin, oestradiol, and progesterone concentrations showed hormone concentrations to be within the normal range. Intravenous treatment was required in only two patients, the remainder responding satisfactorily to subcutaneous infusion. All patients conceived within six cycles of treatment, and only one multiple pregnancy occurred.     

Long term effects of cyclophosphamide on testicular function.

Thirty men treated in childhood with cyclophosphamide for a mean of 280 days were assessed at a mean of 12.8 years after treatment for hormone concentrations and spermatogenesis. Four were azoospermic, nine oligospermic, and 17 normospermic. There was a significant inverse correlation of sperm density with cyclophosphamide dosage and duration of treatment. After a further mean follow up of 7.2 years three patients who were previously oligospermic and one who was azoospermic had normal sperm counts. All patients had normal sexual characteristics and libido. Serum androgen and prolactin concentrations did not differ significantly between patients and controls. Raised basal and stimulated follicle stimulating hormone concentrations were in keeping with impaired spermatogenesis. All patients had significantly raised luteinising hormone responses on stimulation with luteinising hormone releasing hormone. The results suggest compensated Leydig cell failure, and patients with this condition require long term evaluation of testicular function. Potential recovery of spermatogenesis with time requires appropriate counselling and contraceptive advice.     

Luteinising hormone,follicle stimulating hormone and gonadotropin releasing hormone immunoreactivity in two insects: Locusta migratoria migratoroides R&F and Sarcophaga bullata (Parker)

Summary

Materials immunologically related to luteinising hormone (LH), follicle stimulating hormone (FSH) and the gonadotropin releasing hormone (GnRH) were localised in cerebral tissue of Locusta migratoria and Sarcophaga bullata by means of the peroxidase-antiperoxidase method. Several polyclonal and a monoclonal antisera were used. From the third larval instar a positive reaction was observed in cells located in several parts of the brain. Each antiserum reacted with a constant number of well defined cells and nerve fibers. No differences between sexes were observed.     

Hypogonadism in chronic liver disease: impaired release of luteinising hormone.

Alcohol abuse leads to impotence, infertility, and feminisation. Patients with chronic alcoholism may have impaired hypothalamic-pituitary function. The release of luteinising hormone was investigated in men with alcoholic cirrhosis with and without hypogonadism and controls. Blood was sampled every 15 minutes for six or eight hours and luteinising hormone concentrations measured by radioimmunoassay. Data were analysed by iterative computerised analysis and spectral analysis to assess pulsatile release and the length of the cycle, respectively. Pulsatile release of luteinising hormone was shown in all the control subjects; in the men with alcoholic liver disease it was normal in those with subclinical primary testicular failure but absent or grossly attenuated in those with overt combined central and primary gonadal failure. The impaired release of luteinising hormone in the men with overt gonadal failure might be due to a hypothalamic defect.     

Intranasal treatment with luteinising hormone releasing hormone agonist in women with endometriosis.

An agonist analogue of luteinising hormone releasing hormone (buserelin) was successfully used to treat women with endometriosis. A dose of 200 micrograms administered intranasally thrice daily was found to be effective in five patients, in whom the endometriotic lesions resolved after six months'' treatment. Failure occurred in a sixth patient, who received only 400 micrograms once daily. Anovulation was induced in all subjects together with suppression of menstruation after the first month of treatment. Symptoms of abdominal pain, dysmenorrhoea, and dyspareunia were relieved during treatment, and one previously infertile patient conceived within two months of stopping treatment. No side effects were reported with this dosage, and the results suggest a new form of treatment for patients with endometriosis.     

Influence of peptides on 3H-dopamine release from superfused rat striatal slices

The effects of nine neuropeptides on the uptake and release of ³H-dopamine (DA) were studied in slices of rat striatum. Superfusion of preloaded slices at room temperature gave a steady release of ³H-DA after 30 min. Repetitive depolarisation with 20 mM K⁺ evoked pronounced, calcium-dependent releases of ³H-DA which declined exponentially. Substance P (SP), neurotensin and somatostatin all actively released ³H-DA, whilst cholecystokinin octapeptide (CCK), luteinising hormone releasing hormone (LHRH), thyrotrophin releasing hormone (TRH), adrenocorticotrophin (ACTH), vasopressin and oxytocin were without effect on spontaneous ³H-DA efflux. The effects of the peptides on K⁺-induced ³H-DA overflow were more varied; neurotensin, TRH and ACTH had no effect, whereas CCK, somatostatin and LHRH potentiated and SP, vasopressin and oxytocin attenuated ³H-DA release. None of the peptides altered the uptake of ³H-DA at the concentrations which modified its release (0.1–10 μM). It is suggested that modulating DA release may be fundamental to the central actions of these substances in the intact animal.     

Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism.

Polycystic ovaries were defined with ultrasound imaging in a series of 173 women who presented to a gynaecological endocrine clinic with anovulation or hirsutism. Polycystic ovaries were found in 26% of women with amenorrhoea, 87% with oligomenorrhoea, and 92% with idiopathic hirsutism--that is, hirsutism but with regular menstrual cycles. Fewer than half the anovulatory patients with polycystic ovaries were hirsute, but in 93% of cases there was at least one endocrine abnormality to support the diagnosis of polycystic ovaries--that is, raised serum concentrations of luteinising hormone, raised luteinising hormone: follicle stimulating hormone ratio, or raised serum concentrations of testosterone or androstenedione. This study shows that polycystic ovaries, as defined by pelvic ultrasound, are very common in anovulatory women (57% of cases) and are not necessarily associated with hirsutism or a raised serum luteinising hormone concentration. Most women with hirsutism and regular menses have polycystic ovaries so that the term "idiopathic" hirsutism no longer seems appropriate.     

Preliminary report on use of depot formulation of LHRH analogue ICI 118630 (Zoladex) in patients with prostatic cancer.

A study was conducted of the response of the pituitary-testicular axis to two different methods of administration of the luteinising hormone releasing hormone (LHRH) analogue ICI 118630 (Zoladex) in patients with prostatic cancer. The analogue was given by continuous infusion to four previously untreated patients with prostatic cancer for 60 days (group 1). Subsequently a further four patients were given a depot formulation of the same analogue by subcutaneous injection once every 28 days (group 2). Both methods of administration produced similar, successful suppression of luteinising hormone (LH) associated with a reduction of testosterone to castrate concentrations. The median basal testosterone concentrations before treatment in groups 1 and 2 were 20.6 and 14.1 nmol/l (5.94 and 4.07 ng/ml) respectively; these were reduced to 1.4 and 1.1 nmol/l (0.40 and 0.32 ng/ml) within four weeks of the start of treatment. The median basal LH concentration in groups 1 and 2 were 7.9 and 16.6 IU/1 respectively, which were suppressed to 2.6 and 2.4 IU/1 by four weeks. The suppression of LH and testosterone was maintained with continuous subcutaneous infusion for up to 60 days in group 1, and by subsequent injections of the depot every 28 days in group 2. The use of depot preparation of an LHRH analogue to suppress gonadotrophin and sex hormone secretion offers the convenience of once monthly injections when LHRH analogues are required for the long term treatment of elderly patients with prostatic cancer and children with precocious puberty.     

Reproductive potential and endocrinological responses of sheep kept under controlled lighting. III. Prolactin and pituitary responsiveness to gonadotrophin releasing hormone in the post partum period

Five ewes of each of four breed types (pure Merino and crosses with Dorset Horn, South Suffolk and Border Leicester) were kept on a 6-monthly light-cycle in each of two light controlled rooms in an attempt to breed them twice in one calendar year. Four and 17 days following parturition they were treated with gonadotrophin releasing hormone (GnRH) (75, 150, 300 μg) and the pattern of release of luteinising hormone (LH) was studied and compared with that obtained in ‘normal’ cyclic ewes. Weekly plasma prolactin levels were determined at weeks 1–5. Overall, mean and peak levels of LH in the post-partum ewes were only one half those of cyclic ewes. The mean level ran from 8.4 ng/ml at day 4 to 18.2 ng/ml at day 17. This compared with 25.3 ng/ml for cyclic ewes. There was a significant effect of breed type, Merino and Dorset Horn × ewes releasing more LH than did South Suffolk × and Border Leicester × ewes. There were no significant effects of breed or week of sampling on plasma prolactin.None of the observed differences in pattern of release of LH could be related to the observed breed-type differences in fertility and it appears that factors other than endocrinological - e.g. uterine involution - may be involved in the ability to conceive of ewes in which oestrus and ovulation have been induced shortly after parturition.     

Antidiuretic function in Sheehan's syndrome.

Twenty patients with postpartum hypopituitarism underwent a dehydration test followed by the administration of synthetic arginine-vasopressin (DDAVP; desmopressin). Panhypopituitarism was confirmed by hormonal assays in the basal state and after stimulation with combined luteinising hormone releasing hormone-thyrotrophin releasing hormone-insulin. All the patients were given replacement therapy with hydrocortisone and thyroid hormones. Results were compared with those in 12 normal women. Urinary concentrating ability was diminished in the patients as compared with the controls (maximum urine osmolality 688 (SEM 23) mmol (mosmol)/kg in the patients v 967 (SEM 29) mmol/kg in the controls). Also the change in urine osmolality after administration of desmopressin was greater in the patients (+9.55 (SEM 1.98)% in the patients v 2.49 (SEM 0.96)% in the controls). Partial diabetes insipidus is apparently common in Sheehan''s syndrome. This association should be borne in mind when managing these patients, especially those in acute failure.     

Sodium valproate-induced menstrual disturbance in young women

Two young girls with epilepsy presented with menstrual disturbances whilst on treatment with sodium valproate. On withdrawing valproate therapy, period cyclicity returned to normal in both individuals. An exaggerated luteinising hormone response to parenterally administered gonadotropin-releasing hormone was present in both subjects. The temporal relationship between normalisatin of periods and stopping the sodium valproate suggests that this drug may possibly affect the control of the menstrual cycle through a GABAergic mechanism.     

Functional studies after storage at - 190 degrees C of isolated and cultivated pituitary cells from pig and rat

For the first time, it is shown here that enzymatically dispersed pituitary cells of animals survive freezing and storage at -190 degrees C in liquid nitrogen. Frozen/thawed pituitary cells from both rat and pig are able to form monolayer aggregates in culture, and to produce hormones similar to that observed with unfrozen cells. The production of both basal and LHRH (luteinising hormone releasing-hormone)-induced bioassayable LH (luteinising hormone) were measured before and after cry-opreservation. Though after cryopreservation the number of cells was reduced by about 50%, a highly significant amount of both basal and LHRH stimulation-induced release of LH was measured in cultures from frozen/thawed pituitary cells from both species.