Abnormal twenty-four hour pattern of pulsatile luteinizing hormone secretion and the response to naloxone in women with hyperprolactinaemic amenorrhoea

OBJECTIVE Hyperprolactinaemic amenorrhoea is associated with disturbances of pulsatile gonadotrophin secretion. The underlying mechanism remains unclear and the aim of this study was to investigate the 24-hour secretory pattern of gonadotrophins in women with hyperprolactinaemic amenorrhoea. The effect of opioid blockade using naloxone infusion on LH secretory pattern was also studied. DESIGN The secretory patterns of LH, FSH, PRL and their responses to naloxone infusion were studied by serial blood samples collected at 10-minute intervals for 24 hours. On the following day, naloxone was infused at a dose of 1 6 mg per hour for 4 hours. PATIENTS Eight women with hyperprolactinaemic amenorrhoea, two women hyperprolactinaemic but with normal ovarian cycles, and nine control subjects in the early follicular phase of menstrual cycle. MEASUREMENTS Concentrations of LH, FSH and PRL were measured in plasma samples obtained at 10-minute intervals for 24 hours. In one woman, concentrations of urinary oestrone glucuronide were measured daily during treatment with pulsatile GnRH. RESULTS The number of LH pulses per 24 hours was significantly fewer in women with hyperprolactinaemic amenorrhoea than in those with hyperprolactinaemia with normal cycles or control subjects (mean ± SEM 4.5 ± 2.4 vs 13.5 ± 2.5 vs 17 3±0 8, P<0 001). The magnitude of each episode of secretion was significantly higher in the hyperprolactinaemic amenorrhoeic women (P<005) so the overall mean concentrations of LH throughout the 24-hour period was similar in the three groups (5 2±1 1, 4.8±0 8 and 5.2 ±0.4 U/I respectively). In women with hyperprolactinaemic amenorrhoea there was no significant change in the pattern of LH secretion during sleep in contrast to the control women in whom there was a slowing in the LH pulse frequency during the night. There was no significant change in the mean concentrations of LH, FSH and PRL during the naloxone infusion. There were also no significant changes in the LH pulse frequency in response to naloxone infusion when compared with an equivalent period of time in the previous 24 hours. In one hyperprolactinaemic amenorrhoeic woman, follicular development, ovulation and pregnancy were induced when gonadotrophin releasing hormone (GnRH) was infused in a pulsatile manner at a dose of 5 μg every 90 minutes. CONCLUSIONS The suppression of normal ovarian cycles in women with hyperprolactinaemic amenorrhoea is due to a significant reduction in frequency of LH (GnRH) secretion which is not due to an increase in hypothalamic opioid activity. As normal ovarian cycles can occur or be induced by exogenous GnRH in hyperprolactinaemia, it is unlikely that a high level of prolactin by itself inhibits follicular development and ovulation.     

DOPAMINERGIC CONTROL OF GONADOTROPHIN SECRETION IN NORMAL WOMEN AND IN PATIENTS WITH PATHOLOGICAL HYPERPROLACTINAEMIA

The role of dopaminergic mechanisms in the control of gonadotrophin secretion in normal and hyperprolactinaemic subjects is controversial. Whilst bromocriptine, a potent dopamine agonist, has been used to restore normal gonadotrophin secretion in subjects with pathological hyperprolactinaemia (PHP), dopamine and dopamine agonists have been reported to suppress basal and stimulated gonadotrophin release. We therefore investigated the importance of dopaminergic control of gonadotrophin secretion by studying LH, FSH and PRL responses in normal and PHP subjects to central dopamine synthesis inhibition using monoiodotyrosine (MIT) and to a 4 h dopamine infusion designed to elevate peripheral plasma dopamine concentration to levels reported for pituitary portal plasma (1-6 ng/ml). MIT administration resulted in a significant release of PRL (peak increment 520 +/- 84% above basal) but not of LH or FSH in normal subjects. In PHP subjects there was a blunted PRL response (peak 13.3 +/- 3.5%) to MIT administration and significant LH (P less than 0.05) but not FSH release. Dopamine infusion (0.5 microgram/kg/min) resulted in suppression of PRL (min 19 +/- 3% of basal) but not of LH or FSH. A rebound of PRL (peak 188 +/- 68% of basal) but not LH or FSH occurred on cessation of dopamine. There was an apparent rise in LH (P less than 0.02 vs. normals) but not FSH in PHP patients during dopamine infusion. Plateau dopamine levels achieved during the infusion were 2.9 +/- 0.3 ng/ml and 5.9 +/- 0.8 ng/ml in normal and PHP subjects respectively. The responses to MIT show that dopamine functions as an inhibitor of PRL but not of LH or FSH in normal subjects. In PHP patients the responses suggest increased dopaminergic inhibition of LH release but loss of inhibitory control of PRL release. Physiological concentrations of plasma dopamine do not significantly inhibit LH or FSH release in normal subjects but paradoxically results in an apparent release of LH in PHP patients. We conclude that dopamine mechanisms do not play a significant role in modulating gonadotrophin release in normal subjects. In PHP patients, PRL feedback results in increased hypothalamic dopamine activity which in turn inhibits LH release. We conclude that the inhibitory action of dopamine on PRL release restores LH secretion by removing central dopaminergic inhibition through hypothalamic feedback of PRL.     

THE INFLUENCE OF EXOGENOUS OESTRADIOL BENZOATE ON THE PITUITARY RESPONSIVENESS TO LHRH DURING THE PUERPERIUM IN WOMEN

The FSH and LH response to 25 μg LHRH was measured in lactating women and the results compared to a similar group in whom lactation was suppressed by administration of bromocriptine shortly after delivery. The response was also measured in both groups after “challenge” with oestradiol benzoate. In lactating women the FSH response to LHRH was diminished following the oestradiol challenge, as compared with that in unchallenged women. At the same time the LH responses were low in both circumstances, indicating a negative feedback effect of oestradiol. However, the oestradiol challenge resulted in a significantly increased response of FSH and LH to LHRH in bromocriptine-treated puerperal women, i.e. a positive feedback effect of oestradiol. We concluded that this and previous experiments favour the hypothesis that the lactational amenorrhoea during hyperprolactinaemia is caused by hypothalamic changes due to a predominance of the negative feedback system.     

OPIATE MEDIATION OF AMENORRHOEA IN HYPERPROLACTINAEMIA AND IN WEIGHT-LOSS RELATED AMENORRHOEA

Endogenous opiates are involved in the control of pituitary gonadotrophin and PRL secretion, and possibly of food intake. Both hyperprolactinaemia and weight loss (especially in anorexia nervosa) are frequently associated with amenorrhoea and an absence of gonadotrophin pulsatility. Since it has been suggested that increased endogenous opiate tone may operate in both conditions, we infused high-doses of naloxone into twelve patients with amenorrhoea of whom five had hyperprolactinaemia and seven had weight-loss related amenorrhoea. Eleven of the twelve patients had low levels of oestradiol (less than 50 pmol/l). Naloxone induced a marked rise in both LH and FSH levels in all of the five hyperprolactinaemic patients. In contrast, the patients with weight-loss amenorrhoea responded to naloxone with only a small or no rise in gonadotrophins. There was no consistent change in PRL in either group of patients. It is concluded that in hyperprolactinaemia, but not weight-loss amenorrhoea, there is an important endogenous opiate-mediated tonic inhibition of secretion of hypothalamic gonadotrophin releasing hormone.     

Growth hormone treatment affects plasma LH pulsatile release in women with secondary amenorrhoea

OBJECTIVE Since growth hormone (GH) is administered as a co-gonadotrophic factor in ovulation induction, this study aimed to assess the action of GH on the episodic pulsatile release of LH and FSH in amenorrhoeic patients. PATIENTS AND DESIGN Nineteen patients affected by hypothalamic amenorrhoea were enrolled for this study: group A, 9 patients with normal gonadotrophins; group B, 10 patients with low gonadotrophins. Both groups were studied during GH infusion (0015 IU/min for 4 hours) and after 7 days of GH administration (0 1 IU/kg/day). Patients underwent a 4-hour pulsatility study, with blood sampling every 10 minutes. A standard GnRH test (10 μ g i.v. bolus) was performed immediately after the pulsatility evaluation. MEASUREMENTS LH and FSH were assayed with an IFMA method; oestradiol and IGF-I were assayed by RIA and IRMA, respectively. PULSE DETECTION Time series were analysed with Detect program. RESULTS All patients showed similar LH and FSH pulsatile characteristics both under baseline conditions and during GH infusion. After 7 days of GH administration, episodic FSH release showed no change in either group. On the contrary, LH pulse frequency (mean ± SE) significantly increased in group A (4 0±0 2 peaks/4h, P&kt;0 05), while putse amplitude (baseline, 3.9± 0 6 IU/I; after 7 days, 2.9±0.3 IU/I, P<0 05), and integrated LH plasma concentrations (baseline, 7.6 ±1–1 IU/I; after 7 days, 5±0 8 IU/I, P<0 05) were significantly decreased. No significant changes were observed for LH pulse frequency, amplitude or integrated LH plasma concentrations in hypogonado-trophinaemic patients (group B). Plasma oestradiol levels were significantly increased only in group A (baseline, 154 18±23 8 pmoI/I; after 7 days, 380 3±110 1 pmoI/I, P < 005), while IGF-I levels were significantly increased in both groups after 7 days of GH administration (P<0 05). No significant differences were observed in the gonadotropin responses to GnRH test before and after GH administration. CONCLUSIONS The present study showed that the administration of GH in amenorrhoeic patients determines the significant changes in episodic LH release in those subjects with normal LH plasma levels and suggests that the action of GH may be dependent upon the ovarian-pituitary feedback action.     

PULSATILE GONADOTROPHIN SECRETION IN HYPERPROLACTINAEMIC AMENORRHOEA AND THE RESPONSE TO BROMOCRIPTINE THERAPY

Serum gonadotrophin concentrations were measured every 15 min for 8 h in six patients before and at weekly intervals during initiation of bromocriptine treatment of hyperprolactinaemic amenorrhoea. Before treatment mean gonadotrophin levels were similar to those found in the normal follicular phase, but LH secretion was characterized by infrequent pulses of large amplitude. In three subjects the patterns of LH pulsatility and serum oestradiol levels returned to normal within 7 days of starting bromocriptine. The other three subjects responded with an increase in the frequency of LH pulses and mean LH levels, but little rise in oestradiol. Thus some hyperprolactinaemic subjects have a defect in the ovarian response to endogenous gonadotrophin stimulation, which may persist for a few weeks after return of prolactin levels to normal. The restoration of a normal rate of LH pulsatility with bromocriptine can occur without any change in serum oestradiol concentration.     

OESTROGEN MODULATION OF GONADOTROPHIN AND PROLACTIN RELEASE IN WOMEN WITH ANOVULATION AND THEIR RESPONSES TO CLOMIPHENE

An LHRH test was performed before and at both 44 and 92 h after the administration of 2.5 mg oestradiol benzoate in eleven patients with hyperprolactinaemia, eight with idiopathic secondary amenorrhoea and seven with oligomenorrhoea. The basal serum hormone concentrations and the responses to LHRH were compared with the same tests performed on ten normal subjects during the early follicular phase of their menstrual cycles (days 4--6). Mean basal concentrations of oestradiol in each group of patients and oestrone in those with hyperprolactinaemia were significantly lower than in the normal subjects. The mean concentration of prolactin in women with secondary amenorrhoea remained lower than in the normal women throught the tests (P less than 0.05). The LH and FSH responses to LHRH before oestrogen in patients with hyperprolactinaemia and of FSH in those with secondary amenorrhoea, were greater than in the normal subjects (P less than 0.001). After oestrogen treatment the responses were similar in all groups except in those with oligomenorrhoea where LH and FSH responses at 44 h (P less than 0.05 and P less than 0.01 respectively) and LH responses at 92 h (P less than 0.01) were lower than in normal controls. The responses at 92 h in all groups were greater than at 44 h (amplification) but the amplification at 92 h and at 44 h compared to the pre-treatment responses, tended to be lower in each group of patients compared to the normal controls. In the hyperprolactinaemic group of patients there was a negative correlation between the basal prolactin concentration and the gonadotrophin amplifications at 92 h (P less than 0.01), and a positive correlation between the basal oestrone levels and the amplifications at 92 h (P less than 0.01). The results of the oestrogen amplification test in eleven of the non-hyperprolactinaemic anovular patients were compared with the ovulatory response to 100 mg clomiphene given for 5 days. Six showed a normal oestrogen amplification and they all ovulated. Two patients failed to show greater amplification at 92 than at 44 h and required human chorionic gonadotrophin (HCG) as well as clomiphene to ovulate. The other three showed a diminished LH amplification at 92 h; they required 200 mg clomiphene and showed a prolonged follicular phase. The responses of the hyperprolactinaemic patients to clomiphene were poor and there was a negative correlation between prolactin concentration and oestrogen production (P less than 0.01). All ten hyperprolactinaemic patients treated with bromocriptine ovulated and eight conceived. The oestrogen amplification test appears to have some value in predicting the subsequent response to clomiphene in non-hyperprolactinaemic anovular women.     

Luteinizing hormone regulation by sex steroids in men with germinal and Leydig cell tumours

OBJECTIVE We examined the gonadotrophin secretion in patients with increased plasma concentrations of testosterone and oestradiol due to hCG-producing tumours. DESIGN Comparison of plasma gonadotrophin concentrations before and after stimulation by GnRH, in eight men with hCG-producing tumours resulting in Increased testosterone and oestradiol plasma levels, and In 29 men with Leydig cell tumours resulting in increased oestradiol and normal to low testosterone plasma levels. PATIENTS Eight men with hCG-producing tumours (six with testicular tumours, two with extratesticular tumours), 29 men with Leydig cell tumours and 15 normal men. The six men with germinal cell tumours of the testis were studied before and after unilateral orchidectomy. MEASUREMENTS Plasma concentrations of hCG, testosterone and oestradiol were measured before and after intramuscular injection of hCG. LH and FSH were measured before and after intravenous Injection of 100 μg GnRH. RESULTS Plasma LH and FSH concentrations were low In patients with germ cell tumours, who exhibited increased plasma testosterone and oestradiol concentrations, and were normal in patients with Leydig cell tumours, in whom oestradiol only was increased. Plasma LH and FSH were normalized in the five patients with successful (e.g. normal hCG, testosterone and oestradiol) unilateral orchldectomy. Basal plasma testosterone concentrations correlated positively (P <001) with plasma oestradiol concentrations in patients with germ cell tumours and negatively (P <0 01) in patients with Leydig cell tumours. CONCLUSIONS In patients with hCG-secreting germ cell tumours complete suppression of plasma LH and FSH with increased plasma concentrations of both testosterone and oestradiol are often discovered. No such gonadotrophin suppression is found In patients with Leydig cell tumours, but the negative correlation observed between plasma testosterone and oestradiol in these patients suggests a weak negative feedback effect of oestradiol on LH secretion, which cannot be demonstrated by basal LH measurements in plasma.     

Effect of oestrogen treatment on gonadotroph function in adult male rats

The effect of oestradiol-17 beta on the hypothalamo-pituitary axis of intact adult male rats was studied. A single injection of oestradiol did not change the serum LH response to gonadotrophin-releasing hormone (GnRH) 48 h or 7 days after the injection, while administration of oestrogen over 66 days suppressed basal serum LH to less than 3.1 micrograms/l and did not enhance the LH response to GnRH at any time. Treatment of ovariectomized rats with oestradiol capsules, however, enhanced the LH response to GnRH on days 3 and 14 of the treatment as compared with the control group (P less than 0.02 and P less than 0.05 respectively). Long-term treatment with oestradiol suppressed intrapituitary LH and FSH contents as well as pituitary GnRH receptors (P less than 0.0004, P less than 0.005 and P less than 0.001 respectively), whereas serum and intrapituitary prolactin levels were increased. To exclude the possible lactin levels were increased. To exclude the possible inhibitory effect of hyperprolactinaemia on LH were treated with bromocriptine. This prevented the rise in serum prolactin, but failed to enhance the LH response to GnRH. Neither short- nor long-term treatment with oestradiol given under conditions shown to be effective in female animals stimulated the hypothalamo-pituitary-gonadotrophin axis in adult male rats.     

Regulation by oestradiol of serum levels of LH and FSH and pituitary levels of gonadotrophin-releasing hormone receptors after ovariectomy in the rat

We studied cyclic and ovariectomized, oestradiol treated rats to investigate whether oestradiol concentrations before ovariectomy determine the dynamics of the rises in serum levels of LH and FSH, and in pituitary gonadotrophin-releasing hormone (GnRH) receptors after ovariectomy. In cyclic rats, ovariectomy on metoestrus (oestradiol = 44 pmol/l), but not at midnight of dioestrus (oestradiol = 254 pmol/l) was followed by a rise in GnRH receptors 40 h later. Randomly cyclic females were ovariectomized under ether anaesthesia and treated with s.c. oestradiol implants for 2 days to provide serum levels spanning the physiological range. Exposure to lower oestradiol concentrations (48 or 74 pmol/l) resulted in significant rises in levels of LH and FSH, and in GnRH receptors earlier than exposure to higher (148 or 309 pmol/l) oestradiol levels (2 compared with 4 days). GnRH given for 24 h after removal of the implant was unable to induce a rise in GnRH receptors in any group, while LH and FSH responses to GnRH were proportional to the pretreatment levels of oestradiol. This suggests that the concentration of oestradiol before ovariectomy determines the subsequent dynamics of LH and FSH and of GnRH receptors through actions at the hypothalamic and pituitary level.     

ENDORPHINS AND THE REGULATION OF THE HUMAN MENSTRUAL CYCLE

In order to assess a possible influence of endogenous opioids upon gonadotrophin secretion in women, we examined the effects of i.v. administration of 10 mg naloxone, a specific opiate antagonist, in ten normal menstruating women, in thirteen women with amenorrhoea and/or hyperprolactinaemia and in two women with putative deficiency of gonadotrophin-releasing hormone (GnRH). In thirteen subjects, a saline vehicle control study (randomized order of administration) was also performed. In the normal women, naloxone failed to elicit changes in serum gonadotrophin levels when administered during the early follicular phase of the menstrual cycle. However, significant increments of LH were observed from 30 to 165 min following naloxone administration during the late follicular phase. Similar LH responses occurred in the amenorrhoeic and hyperprolactinaemic women. There was a tendency towards a concomitant increment in FSH levels, which reached statistical significance variably from 60 to 105 min post-naloxone. The LH response to naloxone in individual subjects showed a significant (P > 0·01) quadratic (U-shaped) relationship to the log basal oestradiol concentration. No response to naloxone was observed in the two patients with GnRH deficiency despite a brisk response to an exogenous GnRH bolus. Taken together, these data suggest that central nervous system inhibitory opioid pathways may be involved in the regulation of LH secretion in normal women and that excessive production of endogenous opioids may play a role in the pathophysiology of some amenorrhoeic conditions.     

Evidence for an altered luteinizing hormone sensitivity to naloxone in pathological hyperprolactinaemia

OBJECTIVE The underlying mechanisms involved in the pathogenesis of amenorrhoea in hyperprolactlnaemic states still remain unclear. Conflicting information exists on the role of endogenous opiates on gonadotrophin disturbances in this pathological condition. In this study we have undertaken a detailed investigation of LH and PRL secretion before and during administration of naloxone, an opioid receptor blocker, in hyperprolactinaemic women with or without ovarian function In order to assess the role of ovarian steroids upon naloxone induced LH and PRL release. DESIGN Five anovulatory and SIX ovulatory subjects with hyperprolactinaemia were studied before and during naloxone infusion. Five normo-prolactinaemic ovulatory subjects were included as controls. All ovulatory subjects were studled during the luteal phase of a menstrual cycle. Blood was sampled every 10–20 minutes over a 16-hour period on two alternate days. On study day 1 (control day), subjects received two sets of saline Infusion every 6 hours and one saline bolus at the beginning of the seventh hour; on study day 3 (naloxone day), they received a saline infusion during the first 6 hours, an Intravenous bolus of naloxone (20 mg) at the beginning of the seventh hour and then a continuous naloxone Infusion (1.6 mg/hour) during the ensuing 6 hours. Pituitary LH responsiveness and reserve were assessed on both study days by the subsequent administration of 5 and 95 μg of GnRH 4 hours before the completion of each sampling period. MEASUREMENTS Serum concentrations of LH, PRL, oestradiol and progesterone were determined by radio immunoassay. LH and PRL pulse detection and characteristics were analysed by the Cluster program. RESULTS Serum PRL levels In hyperprolactinaemic anovulatory and ovuiatory subjects were significantly elevated above the normal range. Oestradiol and progesterone serum levels during the luteal phase in women with hyperprolactinaemia and regular menses were similar to those in control ovulatory subjects. Mean LH concentrations Increased during naloxone Infusion (P < 0.05) in ovulatory hyperprolactinaemla and controls, whereas PRL Increased (P < 0.05) only In the group of control subjects. LH pulse amplitude and pulse interval were increased by naloxone (P < 0.05) in all the ovulatory subjects, with no significant changes in anovulatory hyperprolactinaemic women. PRL pulse characteristics were modified significantly by naloxone only In the control group. On day 1, GnRH administration Increased LH in all groups, whereas a consistently lower pituitary LH response was observed after naloxone (day 3). Serum PRL levels significantly increased after GnRH administration on day 1 only in normal women, whilst on day 3 this GnRH-dependent PRL releasing effect was significantly attenuated. CONCLUSIONS The absence of stimulatory effects of naloxone on LH in anovulatory hyperprolactinaemia implies that endogenous opiates do not play a significant role In the mechanisms governing hypothalamic amenorrhoea in this syndrome. The results in subjects with ovulatory hyperprolactinaemia suggest the existence of an active role of ovarian steroids on naloxone Induced LH release. These data, along with those previously reported in normal women throughout the menstrual cycle, are consistent with the concept that sex steroid hormones contribute to the underlying mechanisms Involved in the opioiderglc control of LH and PRL release. Whether PRL by itself or through other non-opioid neuroendocrine pathways alters the hypothalamic-gonadotroph unit still requires further investigation.     

EFFECT OF BROMOCRIPTINE ON LH PULSATILITY IN THE POLYCYSTIC OVARY SYNDROME

The effects were studied of bromocriptine, 10 mg daily for 1 year, on luteinizing hormone (LH) pulse characteristics in patients with classical polycystic ovarian syndrome (PCOS). All patients were hirsute, had been oligomenorrhoeic since menarche, had LH: FSH ratios of greater than 3:1, and either elevated serum testosterone (T) or dehydroepiandrosterone sulphate (DHAS) concentrations. In 10 subjects who completed the study menstrual frequency increased from an average of 3.6 to 8 per year but few of the cycles were ovulatory. Mean (SE) serum testosterone fell from 4.4 (0.5) nmol/l pretreatment to 2.8 (0.3) nmol/l (P less than 0.01) and DHAS from 7.9 (1.1) mumol/l to 5.4 (1.1) mumol/l (P less than 0.05). Serum delta 4 androstenedione and oestradiol did not change with bromocriptine treatment. Mean serum LH fell from 17.4 (2.4) IU/l to 11.2 (1.8) IU/l (P less than 0.03) after 12 months of bromocriptine. No pattern of LH pulsatility specific to PCOS was detected during 10 min sampling for an 8 h period prior to dopamine agonist treatment. LH interpeak interval (58 (5.2) min) and peak amplitude (156 (7.2%) of mean nadir) in untreated PCOS were similar to that of the mid-follicular stage of ovulatory cycles, and bromocriptine for 1 year did not alter these variables. We conclude that while bromocriptine reduces serum androgen levels and increases menstrual frequency it has no effect centrally to modify hypothalamic GnRH secretion. The reduction in LH levels by bromocriptine may be the result of diminished gonadotroph sensitivity to GnRH or reduced pituitary stores of LH available for release. Despite the return towards normal of various hormonal characteristics of PCOS, bromocriptine has little place in the management of this condition.     

Hypogonadism, galactorrhoea and hyper-prolactinaemia: Evaluation of pituitary gonadotrophins reserve before and under bromocriptine.

Twenty patients with hypogonadism (19 women with amenorrhoea and 1 man with impotence and infertility), galactorrhoea and hyper-prolactinaemia (range: 36 to 344 ng/ml) were studied. The radiological study of the sella turcica, including in all cases hypocycloidal tomograms, allowed classification of the patients into 3 groups: group I (n = 4) had a grossly enlarged sella turcica, group II (n = 12) had localized alterations indicating the probable existence of a prolactin-secreting microadenoma ("microdeformation") while group III patients presented no radiological abnormality. Before treatment, all the patients were submitted to a complete evaluation of the function of their anterior pituitary, including the LH and FSH responses to iv administration of Gn-RH. All the group I patients had low basal LH levels and a blunted response to Gn-RH. The basal LH and in response to Gn-RH were normal in most of the group II patients and in all of the group III patients. An exaggerated FSH response to Gn-RH was observed in 6/12 patients with microdeformation (group II) but not in groups I and III patients. A low LH and a blunted LH response to Gn-RH is highly suggestive of the existence of a pituitary prolactin-secreting adenoma in case of amenorrhoea and hyper-prolactinaemia patients; a normal response does not however rule out such a diagnosis. The reasons for a exaggerated FSH response to Gn-RH in patients with suspected prolactin-secreting microadenoma remain to be investigated though this pattern can also occur in other cases of amenorrhoea. Hence the Gn-RH test might contribute to the assessment of the hypothalamo-pituitary axis of patients with hyper-prolactinaemia. Six patients treated for 4 months with bromocriptine (CB-154) were submitted to re-evaluation of their pituitary gonadotrophins reserve. All the women experienced restoration of menses with 39 days of treatment and the male patient regained potency. It was observed that bromocriptine treatment and subsequent normalized prolactin levels in the 4 group II women tested were associated with normalization of their previously exaggerated FSH response to Gn-RH; LH responses were also diminished in these cases. These data are compatible with the hypothesis that hyper-prolactinaemia per se could interfere with the endogenous secretion of Gn-RH at the hypothalamic level. In one patient with grossly enlarged sella turcica and a previous lack of an LH and FSH response to Gn-RH, bromocriptine treatment restored a normal gonadotrophins response, confirming that, in this case, the alteration of this response was indeed due to a prolonged lack of endogenous Gn-RH secretion.     

Pituitary-ovarian response to the gonadotrophin-releasing hormone-agonist test in anovulatory patients with polycystic ovary syndrome: predictive role of ovarian stroma

Objective To evaluate the influence of ovarian stroma on basal and poststimulus androgen secretion in patients affected by secondary amenorrhoea and polycystic ovaries (PCO) at ultrasound (US). Design Prospective study. Patients Fifty‐one patients with PCO selected from a group of 72 normal weight women aged 20–25 years affected by secondary amenorrhoea and 10 normal ovulatory controls. Methods All subjects underwent US to evaluate volume, area, stromal area and stromal/total area ratio of both ovaries. Plasma levels of gonadotrophins, oestradiol (E2) and androgens were measured before and 24 h after GnRH‐a injection. 60 min after stimulus LH and FSH were also assayed. Results Thirty patients had increased ovarian stroma (IS) and 21 patients normal ovarian stroma (NS). Significantly higher LH levels characterized the IS group, both basally and after GnRH‐a stimulation compared with NS and controls (P < 0·01). Baseline levels of androstenedione, testosterone and 17‐OHprogesterone (17‐OHP) were significantly higher in IS group. Moreover, 17‐OHP hyper‐response to GnRH‐a was demonstrated in IS group in comparison to NS and control groups (P < 0·005). Conclusions Stroma evaluation may be of use in discriminating between different pathogenic factors in secondary amenorrhoea. This criterion may be applied to support the correct diagnosis of polycystic ovary syndrome (PCOS). Indeed, in line with the most recently proposed guidelines, patients affected by multifollicular ovaries could be classified as PCOS. The possibility of taking into account more than one US criterion or of carefully reanalysing the significance of increased stroma volume should be considered.     

Acute effects of L-dopa and bromocriptine on serum PRL, LH and FSH levels in patients with hyperprolactinemic and normoprolactinemic polycystic ovary syndrome

We have investigated the importance of the dopaminergic control of gonadotropin secretion by studying LH, FSH and PRL responses to L-dopa and bromocriptine in patients with polycystic ovary syndrome (PCOS). Both L-dopa and bromocriptine administration were followed by a statistically significant decrease in LH in the hyperprolactinemic PCO patients (compared to the normoprolactinemic subgroup - p less than 0.01 and control group - p less than 0.05); the decline was proportional to the basal level of LH. A significant positive correlation between basal LH levels and maximum net decrease of LH was observed after administration of both agents (p less than 0.01). Although both subgroups of PCO patients showed a similar decrease in PRL levels it was statistically significant only in the normoprolactinemic patients (p less than 0.01). Prolactin sensitivity to the inhibitory effect of bromocriptine and L-dopa showed a significant correlation with the basal PRL level (p less than 0.01). The response of serum FSH was variable and not significant. These results suggest that a reduction of an inhibitory influence of hypothalamic dopamine might be a cause of inappropriately elevated LH and PRL levels found in patients with polycystic ovary syndrome and hyperprolactinemia.     

EFFECTS OF SULPIRIDE INDUCED HYPERPROLACTINAEMIA IN PATIENTS WITH TURNER''S SYNDROME

In order to evaluate the interference of prolactin (PRL) on some aspects of pituitary-gonadal derangement observed in patients with hyperprolactinaemic amenorrhoea (HA), a GnRH stimulation test (100 micrograms i.v.) was performed on twenty-one patients with hyperprolactinaemia without evidence of pituitary tumour and in nine subjects with Turner's syndrome (TS) before and after sulpiride administration (200 mg/day orally, for 3 months). In patients with HA an enhanced response of gonadotrophins to GnRH was observed. In patients with TS a further increase of the gonadotrophin hyper-responsiveness to the releasing hormone occurred when hyperprolactinaemia was induced by chronic sulpiride administration. Since, in these patients, appreciable ovarian steroidogenesis is lacking, a direct effect of the increased plasma PRL at the hypothalamo-pituitary level is likely. In hyperprolactinaemic amenorrhoea pituitary hyper-responsiveness may not be due to PRL effects on ovarian steroidogenesis.     

Catecholamines and pituitary function. IV. Effects of low-dose dopamine infusion and long-term bromocriptine treatment on the abnormal thyrotroph (TSH) dynamics in patients with pathological hyperprolactinaemia

In order to gain further insight into the role of dopamine (DA) in the control of TSH release and to investigate whether an increased or defective DA inhibition on pituitary thyrotrophs may be considered responsible for the abnormal TSH dynamics in pathological hyperprolactinaemia, we examined the effect of low-dose DA infusion on TRH stimulated TSH secretion in normally cycling women and in patients with pathological hyperprolactinaemia. The effect of long-term bromocriptine therapy on TSH dynamics was also evaluated in a selected group of hyperprolactinaemic women. Fifty-two hyperprolactinaemic patients with no other signs of pituitary or thyroid dysfunction had significantly higher mean TSH serum concentrations and mean TSH peak values after TRH administration than 75 healthy controls. Furthermore, the TSH rises induced by the DA-synthesis inhibitor alpha-methyl-p-tyrosine (AMPT, 500 mg orally) were enhanced in both prolactinoma and 'idiopathic hyperprolactinaemia' patients as compared with controls. There was a positive correlation between the TRH- and AMPT-induced TSH rises in the hyperprolactinaemic group. Low-dose DA infusion (0.1 microgram/kg X min) reduced TSH response to TRH in both regularly cycling women and patients with hyperprolactinaemic amenorrhoea. Longterm bromocriptine therapy (2.5 mg tid over 60-150 days) not only normalized serum Prl levels, but also reduced the TSH response to TRH in 7 hyperprolactinaemic women who had presented exaggerated TSH responses to the basal TRH test.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypogonadism in congenital adrenal hypoplasia: evidence for a hypothalamic origin

Two unrelated boys with congenital adrenal hypoplasia were followed from birth for 20 yr. In spite of continuous treatment with hydrocortisone and fluorocortisone both patients had delayed growth and bone maturation since early childhood and failure of spontaneous puberty. Tests of the hypothalamic-pituitary function showed low basal plasma LH and FSH levels and blunted LH and FSH responses to standard GnRH tests and increased basal and TRH-stimulated PRL levels. Low dose pulsatile GnRH administration for 26 h, mimicking presumed physiological GnRH secretion, induced a continuing rise of plasma FSH in both patients and a slight increase of plasma LH and testosterone in one patient. These results indicate a hypothalamic origin of the gonadotropin deficiency with possible prenatal onset, since both patients had cryptorchidism during infancy. Hypogonadism in patients with adrenal hypoplasia may result from deficient steroid secretion of the hypoplastic fetal adrenals.     

Endocrine effects of GnRH analogue with low-dose hormone replacement therapy in women with endometriosis

OBJECTIVE GnRH analogues are being used Increasingly for a number of oestrogen dependent conditions In women. The resultant profound hypo-oestrogenism is a disadvantage, however, but the preservation of pituitary sensitivity to negative feedback by oestradiol is not well defined. We have determined the effect on gonadotrophins and Inhibin of GnRH analogue plus low-dose continuous combined hormone replacement therapy In comparison with GnRH analogue therapy alone. DESIGN Randomized controlled trial. PATIENTS Fifty premenopausal women with endometriosis randomized to treatment with goserelin alone (Group 1) or goserelin plus 17βoestradiol and medroxyprogesterone acetate (Group 2). MEASUREMENTS FSH, LH, oestradiol, oestrone, Inhibin before and during treatment. RESULTS Oestradiol and oestrone were suppressed in both groups, but Group 2 had significantly higher oestradiol during the hormone replacement therapy period. LH was suppressed in both groups. In Group 1, FSH levels recovered during treatment but, in contrast, in Group 2, FSH levels remained suppressed throughout treatment. Inhibin was significantly lower in Group 2, but not In Group 1, during treatment compared to pretreatment. CONCLUSIONS Pituitary secretion of FSH appears to remain responsive to feedback control by oestradiol during GnRH analogue therapy and Is Incompletely suppressed, unlike LH which remains completely suppressed. The possible mechanisms for this are discussed.