The effect of sequential administration of octreotide alone and octreotide/growth hormone simultaneously on buserelin stimulated ovarian steroid secretion in women with polycystic ovary syndrome.

OBJECTIVE: GH increases oestradiol secretion and promotes oocyte development in women with polycystic ovary syndrome (PCOS). However, there are no data on ovarian androgen production after GH treatment. We have therefore assessed the effect of sequential treatment with a long-acting somatostatin analogue (octreotide) alone and octreotide/GH simultaneously on ovarian steroid levels in PCOS and non-PCOS normal women. PATIENTS: Twenty-six PCOS and 12 non-PCOS women, aged 18-35 years, were studied. Ten of the PCOS and six of the non-PCOS women received sequential treatment with octreotide alone and followed by octreotide + GH together, while another eight PCOS and six non-PCOS women received saline instead of octreotide-octreotide + GH. The remaining eight PCOS women received GH alone. DESIGN: The octreotide-octreotide + GH and saline studies lasted 12 days, the GH alone 7 days. Octreotide (100 micrograms, s.c., t.d.s.) was given from the 2nd to the 10th and octreotide + GH (4 IU, s.c. at 2300h) from the 7th to the 10th day of the study. The GH alone treatment was given from the 2nd to the 5th day. On the 1st day, two tests were performed: (1) an oral glucose tolerance test (OGTT, 75 g, orally) at 0830h and (2) a buserelin (long-acting GnRH agonist) test (100 micrograms, s.c.) at the end of the OGTT. Both tests were repeated on the 6th and 11th days in the octreotide-octreotide + GH or on the 6th day only in the GH alone study. MEASUREMENTS: Blood glucose, insulin (IRI), C-peptide and IGF-I (at time 0 only) were measured before glucose administration and at 30-minute intervals for 3 hours and LH, FSH, delta 4-androstenedione (delta 4A), testosterone (TT), free testosterone (FT) and oestradiol (E2) before buserelin and at 1,2,6,10,14 and 18 hours. RESULTS: Octreotide alone significantly reduced the basal IGF-I stimulated LH and both basal and stimulated IRI, delta 4A, TT, FT and E2 levels in all PCOS women tested. Both octreotide + GH and GH alone increased significantly the basal IGF-I and both basal and stimulated IRI and E2 levels in all PCOS women, while the basal and stimulated LH, delta 4A, TT and FT levels were completely unaffected. In contrast, octreotide-octreotide + GH treatment did not modify either basal or stimulated gonadotrophin or ovarian steroid levels in non-PCOS women. No changes in either basal or stimulated hormone levels were observed in those PCOS women who received saline. Although both basal and stimulated levels of all ovarian androgens were significantly reduced by octreotide-octreotide + GH treatment in PCOS women, they still remained significantly higher than in the non-PCOS women. CONCLUSIONS: The data show that (1) octreotide is a potent inhibitor of ovarian steroid secretion, (2) GH increases oestradiol secretion, possibly by stimulating ovarian aromatase activity, and (3) the combined treatment with octreotide and GH significantly improves ovarlan function in women with PCOS and may thus have important clinical implications for the management of infertile women with this syndrome.

Ovarian function in women with non-insulin dependent diabetes mellitus.

OBJECTIVE: Although insulin has been shown to stimulate ovarian steroidogenesis and hyperinsulinaemia has been implicated in the raised androgen levels found in diseases associated with significant insulin resistance, ovarian function has not been studied so far in women with NIDDM. We have assessed ovarian function in women with NIDDM at the early (hyperinsulinaemic) and late (relative insulinopaenic) stages of evolution of the disease after strong stimulation with buserelin, a long-acting GnRH analogue. Significant differences in ovarian function would be expected, depending on the stage of evolution of NIDDM. DESIGN: Following an overnight fast, a standard OGTT (75 g, orally) was performed (0830 h) in all diabetic and control women. Blood samples were obtained for blood glucose, insulin and C-peptide measurements before and at 30-minute intervals for 2 hours. On the termination of the OGTT, a buserelin test (100 micrograms, s.c.) was performed (1030 h) and blood samples were obtained for FSH, LH, delta 4-androstenedione, total testosterone, free testosterone and oestradiol measurements before and then at 4-hour intervals for 20 hours. SUBJECTS: Thirty-one women with NIDDM (13 hyperinsulinaemic and 18 with relative insulinopaenia), 12 obese and 11 normally menstruating non-obese, non-diabetic women, aged 29-39 years, were studied. RESULTS: The integrated response (AUC) of oestradiol to buserelin was found to be normal in hyperinsulinaemic NIDDM and obese non-diabetic women in the face of an increased free testosterone response, while in relatively insulinopaenic NIDDM women the oestradiol response was significantly reduced in the face of a normal free testosterone response. CONCLUSIONS: The results suggest that in women with NIDDM the ovaries have a reduced ability to convert androgen to oestrogen, probably due to a reduction of ovarian aromatase activity. As oestrogens protect against atherogenesis, it is speculated that the relative inability of the ovaries to produce oestradiol in NIDDM women with relative insulinopaenia might be involved in the development of the macroangiopathy, which often complicates this disease.

Dysfunction of the growth hormone/insulin-like growth factor-I axis in women with polycystic ovarian syndrome.

OBJECTIVE: Although a defect in GH regulation has been suggested in women with polycystic ovarian syndrome (PCOS), the data are limited and mechanism obscure. We have assessed the function of the GH/IGF-I axis in women with PCOS by measuring basal IGF-I levels and the ability of the pituitary to secrete GH following dopamine and GHRH. DESIGN: For each woman the complete study lasted 3 days. On the 1st and 2nd days, saline (0.9%, 5 ml/h for 3 h) and dopamine (4 micrograms/kg/min for 3 h) infusion tests were performed, respectively, in all PCOS and control women. Blood samples for GH measurement were obtained before and at 20-minute intervals for 3 hours. On the 3rd day a GHRH test (100 micrograms, i.v. bolus) was performed in 9 of the women with PCOS and in 9 controls. Blood samples for GH measurements were obtained before and at 20-minute intervals for 3 hours. Basal IGF-I levels were measured in the basal blood samples from the saline infusion test in all patients studied. SUBJECTS: Thirteen women with PCOS and 11 normally menstruating women (control group), aged 18-35 years, were studied. All women with PCOS had hirsutism and oligomenorrhoea since menarche, elevated serum values of at least one ovarian androgen and the typical ultrasound appearance of PCOS. RESULTS: Growth hormone releasing hormone (GHRH) induced a significant increase in GH secretion in both control and PCOS groups. However, the GH response to GHRH was found to be significantly lower in women with PCOS. The 3-hour infusion of dopamine induced a significant increase in GH levels only in the control group, while it failed to stimulate GH release in the women with PCOS. Although both dopamine and GHRH failed to induce a normal GH response in women with PCOS, their IGF-I levels did not differ significantly from those observed in control women. CONCLUSIONS: The diminished GH responses to both GHRH and dopamine in women with PCOS, in the presence of normal circulating IGF-I levels, suggests a dysregulation in GH secretion. Although the data are suggestive of a hypothalamic defect, further studies are required to clarify the underlying mechanism and the role, if any, of GH in the pathogenesis of polycyctic ovarian syndrome.

The interaction of growth hormone releasing hormone with other hypothalamic hormones on the release of anterior pituitary hormones.

To determine whether the 29 amino-acid fragment of growth hormone releasing hormone (GHRH) can be combined with other hypothalamic releasing hormones in a single test of anterior pituitary reserve, the responses of anterior pituitary hormones to combinations of an i.v. bolus of GHRH(1-29)NH2 or saline with an i.v. bolus of either LH releasing hormone (LHRH) plus TRH, ovine CRH(oCRH) or saline were studied. Each infusion of GHRH(1-29)NH2 resulted in a rapid increment of the plasma GH value. Infusion of GHRH(1-29)NH2 also caused a small and transient rise in plasma PRL, but no change in the integrated PRL response. The combination of GHRH(1-29)NH2 with LHRH plus TRH caused a larger increment of peak and integrated plasma TSH levels than LHRH plus TRH alone. GHRH(1-29)NH2 did not affect the release of other anterior pituitary hormones after infusion with oCRH or LHRH plus TRH. Because of the finding of potentiation of the TSH-releasing activity of LHRH plus TRH by GHRH(1-29)NH2, the study was extended to the investigation of TSH release after infusion of TRH in combination with either GHRH(1-29)NH2 or GHRH(1-40). In this study the combination of TRH with both GHRH preparations also caused a larger increment of the peak and integrated plasma TSH levels than TRH alone. It is concluded that GHRH(1-29)NH2 possesses moderate PRL-releasing activity apart from GH-releasing activity. In addition, GHRH potentiates the TSH-releasing activity of TRH.(ABSTRACT TRUNCATED AT 250 WORDS)

A sensitive and specific immunoradiometric assay (IRMA) for human thyroid stimulating hormone.

A liquid phase "two-site" immunoradiometric assay (IRMA) specific for human thyroid stimulating hormone (hTSH) is described. The assay is based on the simultaneous addition of affinity purified sheep anti hTSH IgG-I 125 and rabbit anti hTSH antiserum to standards and unknowns followed by 4h incubation at room temperature. The separation of free labelled sheep IgG-I125 from that bound to hTSH is achieved by the addition of sheep anti-rabbit IgG Fc fragment antiserum. The radiolabelled sheep anti-hTSH IgG-I 125 was pretreated with solid phase urinary postmenopausal gonadotropins to remove cross reaction with FSH and LH. The assay is specific for hTSH and no cross reaction with the other anterior pituitary glycoproteins or protein hormones has been found. In addition it is characterized by a wide operating range, rapid equilibration of reactants and high sensitivity (0.02 microU/ml). The precision of dose estimates was less than 10% between 0.25-2.5 microU/ml and less than 2.5% over the range 2.5-60 microU/ml.

The sulpiride test in panhypopituitarism.

The results obtained with a new test of prolactin (PRL) release in six panhypopituitary patients as compared to fourteen normal subjects (eight females and six males) are presented. The test consists of the i.m. administration of 100 mg of sulpiride and the measurement of plasma PRL by a double antibody radioimmunoassay techniques at--15, 0, 15, 30, 45, 60, 75, 90, 105 and 120 min. Mean baseline PRL values were not significantly different in the three groups. After sulpiride a 800-4200% increment of prolactin over control values was noted in the females and 1200-3500% increment in the males. The peak values were obtained at 15 or 30 min (6030+/-670 mu/l +/-SEM in the females and 5550+/-870 mu/l in the males). The mean values were not significantly different in the two sexes until the sixtieth minute but were significantly higher (P less than 0.05) in the female thereafter. In the hypopituitary patients a complete failure of response was noted. These results show that the sulpiride test possesses a considerable potential as a screening procedure in the diagnosis of pituitary insufficiency.

Assessment of prolactin release in pituitary dwarfism with the sulpiride test.

We report here the results obtained with a new test of prolactin (PRL) release in six normal pre-pubertal boys, eleven children with short stature of non-pituitary origin and in thirteen pituitary dwarfs. The test consists of the administration of 100 mg of sulpiride i.m. and the measurement of PRL in serum samples up to 120 min after injection. Baseline PRL concentrations were not clearly different in the three groups. After sulpiride a marked increase (3--10 times over control values) in PRL was noted in all normal and short children without pituitary disease. A complete failure of response was observed in ten of the thirteen pituitary dwarfs. It is concluded that sulpiride has considerable potential in the differential diagnosis of children with stunted growth.