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.     

Influence of testosterone and/or luteinizing hormone releasing hormone analogue on precocious sexual development in the juvenile rainbow trout

The influence of testosterone, luteinizing hormone releasing hormone (LHRH) agonist and combinations of these hormones on gonadotropic hormone (GtH) levels in the sexually immature trout was investigated. Both the steroid and releasing hormone preparations, testosterone in Silastic capsules and cholesterol-pelleted LHRH-A, were formulated for sustained release and long-term biological action following a single hormone implantation. Marked increases in pituitary GtH followed testosterone and/or testosterone and LHRH analogue treatment combined, but the low pituitary GtH level in controls remained unchanged after LHRH analogue administration alone. Plasma GtH titers increased with time after testosterone treatment, indicating a positive steroid feedback effect by androgen on GtH in the juvenile rainbow trout. When combined with testosterone treatment, LHRH analogue augmented plasma GtH levels compared to fish receiving testosterone treatment alone. In males the elevated plasma GtH levels were associated with testes stimulation and onset of spermatogenesis; in females, however, no significant stimulation of the ovaries was observed. It can be concluded from these studies that the testosterone stimulus is sufficient to induce onset of sexual development in immature males but not females. Whereas LHRH analogue releases GtH from the testosterone-primed trout pituitary, LHRH treatment alone under these conditions fails to stimulate the juvenile trout reproductive system.     

Studies of pituitary-adrenal-testis interaction in sheep. II. The effects of repeated injections of adrenocorticotrophic hormone outside the breeding season

The administration of 0.5 mg of long-acting adrenocorticotrophic hormone (ACTH, Synacthen-Depot) twice daily for 5.5 d to four rams outside the breeding season caused marked rises in plasma cortisol without any evidence of adrenal depletion. This treatment also caused marked rises in basal plasma follicle stimulating hormone (FSH) concentrations which remained high even after cessation of treatment. Plasma FSH responses to 5 ug of gonadotrophin releasing hormone (GnRH) were consistently observed and ACTH treatment increased the FSH response to GnRH. In contrast, spontaneous fluctuations in the plasma luteinizing hormone (LH) and testosterone concentrations were abolished by ACTH treatment. The quantity of testosterone released after GnRH (estimated by the maximum values reached and by the area under the response curve) was also suppressed while that of LH was only slightly lower. A comparison of the results of this experiment with those obtained in rams during the breeding season showed that the effects of ACTH on LH and testosterone were more marked during the breeding season. In contrast, the effect of ACTH on FSH is to increase the latter during the nonbreeding season, whereas no effect was observed during the breeding season.     

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.     

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.     

Studies of pituitary-adrenal-testis interaction in sheep. I. The effects of repeated injections of adrenocorticotrophic hormone during the breeding season

The administration of 0.5 mg of long-acting adrenocorticotrophic hormone (ACTH, Synacthen-Depot) twice daily for 5.5 d to four adult rams during the breeding season had no consistent effect on plasma follicle stimulating hormone (FSH) concentrations. In contrast, it suppressed both plasma luteinizing hormone (LH) and testosterone concentrations. The responses to injections of 5 ug of gonadotrophin releasing hormone (GnRH), as measured by maximum concentrations reached and areas under the response curves, were also suppressed. These findings suggest that ACTH exerts its suppressive efects on LH at the pituitary level.     

Effect of heat stress on plasma concentrations of prolactin and luteinizing hormone in ewes.

Basal concentrations of prolactin but not luteinizing hormone were elevated in ewes by 8--10 h of heat stress given daily during the first 11 days of their oestrous cycle. However, the prolactin and luteinizing hormone responses to thyrotrophin releasing hormone and gonadotrophin releasing hormone were unaffected.     

Alteration in the normal pattern of serum testosterone and 5α-androstane-3α,17β-diol in the immature male rat following chronic treatment with luteinizing hormone releasing hormone or luteinizing hormone

A major component of sexual maturation in the male rat is a progressive decline in serum concentrations of 5α-androstane-3α,17β-diol (3α-diol) and a concomitant increase in testicular testosterone biosynthesis and secretion. Chronic administration of synthetic luteinizing hormone releasing hormone (LHRH) or luteinizing hormone (LH)/human chorionic gonadotropin (hCG) to immature male rats has been shown to result in a delay in sexual maturation as evidenced by decreased sex accessory gland weights and altered testicular testosterone production. We have examined the postulate that such treatments may either reverse or retard the normal developmental pattern of serum testosterone and 3α-diol concentrations. Chronic $\text{in vivo}$ treatment of 28 day old immature male rats for 2 weeks with daily injections of either 0.5 μg of LHRH, 1.0 μg of LHRH, or 30 μg of LH was found to result in significant reductions in weights of the seminal vesicles and ventral prostate glands and diminutions in serum testosterone concentrations. Serum content of 3α-diol was either unchanged or slightly elevated in the LHRH treated animals and increased significantly in the LH treated animals. These data suggest that either a reversal of or retardation in the normal developmental pattern of serum testosterone and 3α-diol content has been achieved in the immature male rat by chronic LHRH or LH treatment.     

Effect of recombinant human erythropoietin on anterior pituitary function in patients on chronic hemodialysis.

In 7 patients with end stage renal failure, anterior pituitary function was tested by simultaneous application of maximally effective doses of the hypothalamic releasing peptides, corticotropin-releasing hormone, growth hormone-releasing hormone, thyrotropin-releasing hormone and gonadotropin-releasing hormone, and compared to 8 normal controls. In addition to the pituitary hormones, plasma cortisol, thyroxine and testosterone concentrations were measured. To test for possible effects of treatment with recombinant human erythropoietin (rhu-EPO), all patients with chronic renal failure were studied again after partial correction of anemia by treatment with erythropoietin. Before initiation of rhu-EPO treatment, plasma concentrations of follicle-stimulating hormone were significantly elevated and the thyroid-stimulating hormone and prolactin responses to thyrotropin-releasing hormone blunted when compared to normal controls. Treatment with rhu-EPO induced a significant increase in plasma ACTH and follicle-stimulating hormone concentrations. All other pituitary functions remained unchanged. Thus, the general improvement in well-being, working capacity and sexual activity cannot be attributed to hormonal changes.     

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.     

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.     

Luteinizing Hormone and Follicle Stimulating Hormone-Releasing Hormone Test in Patients with Hypothalamic Pituitary-Gonadal Dysfunction

A standard intravenous 100 μg luteinizing hormone/follicle stimulating hormone-releasing hormone (LH/FSH-RH) test was used to assess the pituitary gonadotrophin responses in 155 patients with a variety of diseases of the hypothalamic-pituitary-gonadal axis. In all but nine patients there was an increase in circulating levels of either LH or FSH in response to the releasing hormone though 137 (88%) were clinically hypogonadal. It was not possible with this test to distinguish between hypothalamic and pituitary causes of hypogonadotrophic hypogonadism, since a variety of LH and FSH responses emerged within the disease groups. However, primary gonadal failure characteristically resulted in exaggerated gonadotrophin response. The potential therapeutic use of the gonadotrophin releasing decapeptide is suggested in certain patients with hypogonadotrophic hypogonadism.     

Effect of gonadotropin releasing hormone on ventral prostate of rat

Testosterone induced increase in ornithine decarboxylase (ODC) activity was inhibited by simultaneous treatment with gonadotropin releasing hormone (GnRH) and its analogue in the ventral prostate of rat. Inhibition of 3H-uridine, 3H-phenylalanine and 3H-leucine incorporation into TCA precipitable material was also inhibited by GnRH in the dihydrotestosterone (DHT) treated animals. These studies further confirm that GnRH acts directly on ventral prostate and causes inhibitory effects.     

Hormonal responses to gonadotrophin releasing hormone during testicular development in male African green monkeys

Reproductive development in male African green monkeys was characterized by evaluating both luteinizing hormone (LH) and testosterone (T) before and after gonadotrophin releasing hormone (GnRH) stimulation in relation to the physical maturation of the testis. There were LH responses to GnRH at all ages studied, but the failure of some animals to respond at earlier ages suggested developmental changes in the responsiveness of the pituitary. The T secretion developed progressively but did not reach adultlike characteristics until approximately 44 months of age, at which time sperm could be demonstrated in ejaculated semen.     

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.     

Effects of chronic treatment with a GnRH agonist on oestrous behaviour and on the secretion of LH and progesterone in the ewe

A study was carried out to investigate a novel approach to oestrus synchronization in the ewe by treatment with a gonadotrophin releasing hormone (GnRH) agonist. Groups of ewes were initially treated on Day 2, 10 or 14 of the oestrous cycle with 10 mug GnRH analogue (D-Ser(Bu(t)) 6 des Gly GnRH ethylamide) per ewe per day for 14 days. Behavioural oestrus was inhibited during GnRH agonist treatment and recurred from 8 to 38 days after the treatment in an unsynchronized manner. Luteal activity during treatment was not impaired but reduced progesterone concentrations occurred in cycles after the treatment. The rhythm of ovarian function, generally characterized by prolonged follicular development, was impaired. During the treatment and subsequent recovery period, integrity of pituitary function was examined by measuring luteinizing hormone (LH) after GnRH agonist was injected, and after stimulation test doses of 150 ng natural GnRH were administered. During treatment there was, with time, a decline in pituitary response to the agonist which suggested that pituitary release of LH was exhausted. After the 14-day treatment the stimulation test with GnRH revealed a gradual return to normal responsiveness although this was not complete three weeks after the treatment when compared to control ewes. This lowered pituitary activity could cause the impaired ovarian function.     

Gonadal function in young adults after surgical treatment of cryptorchidism.

In a follow-up study of 48 young men who had been surgically treated for cryptorchidism before puberty testicular function was assessed by examining the genitalia, testicular volume, secondary sex characteristics, semen, plasma luteinising hormone (LH) and follicle-stimulating hormone (FSH) concentrations after luteinising hormone-releasing hormone stimulation, and plasma testosterone concentrations. Clinical androgen effects were normal. The mean testicular volume of both testes was in the low normal range in those who had had unilateral cryptorchidism and below normal in those who had had bilateral cryptorchidism. Of 37 patients whose sperm counts were recorded (14 bilateral) six showed azoospermia (all bilateral), five had severe oligospermia (four bilateral), and 10 had moderate oligospermia (one bilateral). In nearly all those who had had bilateral cryptorchidism and most of those who had had unilateral cryptorchidism plasma gonadotrophin levels were increased. Four cases of possible partial LH deficiency were identified. Plasma testosterone concentrations were normal in all except two patients.     

Role of gonadal negative feedback on the gonadotrophin responses to gonadotrophin-releasing hormone (GnRH) in ram lambs from two lines of sheep selected for their luteinizing hormone response to GnRH.

Divergent selection has resulted in two lines of lambs (high and low) that have a 5-fold difference in their ability to release luteinizing hormone (LH) in response to 5 micrograms of gonadotrophin-releasing hormone (GnRH). Baseline gonadotrophin concentrations, the gonadotrophin responses to a GnRH challenge and the concentrations of testosterone and oestradiol were compared in lambs which were castrated at birth and intact lambs from both selection lines at 2, 6, 10 and 20 weeks of age. The pattern of LH and follicle-stimulating hormone (FSH) secretion was similar in the two lines, but differed between the intact and the castrated lambs. Basal LH and FSH secretion were significantly higher in the castrates than in the intact lambs from both selection lines. The high-line lambs had significantly higher basal FSH concentrations at all ages tested and significantly higher basal LH concentrations during the early postnatal period. The magnitude of the gonadotrophin responses to GnRH differed significantly between the intact and the castrated lambs within each line, the amount of gonadotrophins secreted by the castrated lambs being significantly greater. The removal of gonadal negative feedback by castration did not alter the between-line difference in either LH or the FSH response to the GnRH challenge. Throughout the experimental period, the concentration of testosterone in the intact lambs was significantly greater than in the castrated lambs in both selection lines, but no significant difference was seen in the concentrations of oestradiol. No significant between-line differences were found in the peripheral concentrations of testosterone or oestradiol in the intact lambs from the two selection lines. Therefore, despite similar amounts of gonadal negative feedback in the selection lines, there were significant between-line differences in basal gonadotrophin concentrations, at 2 and 6 weeks of age, and in the LH and FSH responses to an exogenous GnRH challenge, at all ages tested. Removal of gonadal negative feedback did not affect the magnitude of the between-line difference in the response of the lines to GnRH stimulation. The results indicate that the effects of selection on gonadotrophin secretion are primarily at the level of the hypothalamo-pituitary complex.     

Hormonal therapy for prostate cancer

Updates on hormonal therapy in the treatment of prostate cancer are presented. The most common therapy is to reduce testosterone to castrate levels. A dosage of 1 mg diethylstilbestrol daily prolonged survival in patients with advanced prostate cancer. The leuteinizing hormone-releasing hormone agonists have essentially replaced surgical orchiectomy in the vast majority of clinical settings; however, a major problem with the leuteinizing hormone- releasing hormone agonists has been the surge and flare of testosterone levels. If hormonal therapy is initiated early, the risk of major complications is significantly decreased. Combined androgen blockade is better than monotherapy, although there is only a small clinical benefit. When androgen deprivation is used for a short time and the normal androgen milieu is re-established, the side effects and toxicity of androgen deprivation are decreased. The major complications of androgen deprivation include hot flushes, reduction of bone mineral density, osteoporosis, and anemia. Intermittent androgen blockade might have the same benefits of total androgen suppression with fewer side effects, increased duration of androgen dependence, and less cost. The 10 steps to take when advising patients about initiation of androgen deprivation therapy are reviewed.     

Therapeutic significance and the mechanism of action of the LH-RH agonist ICI 118630 in breast and prostate cancer

The influence of the LH-RH agonist ICI 118630 on circulating levels of the pituitary gonadotrophins LH and FSH and the gonadal steroids oestradiol, progesterone, 17-hydroxyprogesterone and testosterone has been studied in phase I clinical trials of the drug in patients with advanced breast or prostate cancer. ICI 118630 initially stimulated plasma levels of LH and FSH. On continued treatment however, the drug reversed this response and produced a rapid decline in plasma testosterone and progesterone in male and female patients respectively. Plasma oestradiol concentrations equivalent to those seen in oophorectomised or postmenopausal women were eventually produced in all 5 female patients treated with ICI 118630. In one patient however persistent follicular activity occurred until her third menstrual cycle. No appreciable side effects of the drug were observed. These data indicate that ICI 118630 initiates a castration-like endocrine response and has potential in the treatment of hormone dependent tumours of the breast and prostate.