RESUMEN
Recent improvements to measure ultrasonic sound velocities of liquids under extreme conditions are described. Principle and feasibility of picosecond acoustics in liquids embedded in a diamond anvils cell are given. To illustrate the capability of these advances in the sound velocity measurement technique, original high pressure and high temperature results on the sound velocity of liquid mercury up to 5 GPa and 575 K are given. This high pressure technique will certainly be useful in several fundamental and applied problems in physics and many other fields such as geophysics, nonlinear acoustics, underwater sound, petrology or physical acoustics.
RESUMEN
X-ray absorption and Raman spectroscopies are complementary in the sense that both give very precise information about the local structure of a sample, both are not restricted to crystalline materials, and in both cases the volumes of the material probed are similar. The X-ray technique has the advantage of being element- and orbital-selective, and sensitive to orientational effects owing to polarization selection rules. In many cases, however, its analysis can present some ambiguity. Combining the two techniques on a micrometer scale could therefore be a very powerful method structurally. In this paper the experimental set-up developed at the LUCIA beamline and its application to a natural mineral are described.
RESUMEN
It is currently believed that the postmenopausal ovary remains a gonadotropin-driven, androgen-producing gland. However, the adrenal contribution to circulating androgen levels may explain some conflicting results previously reported. In addition, the steroidogenic potential and gonadotropin responsiveness of the postmenopausal ovary have not been recently reassessed. Plasma T, bioavailable T, free T, androstenedione (Adione), and dehydroepiandrosterone sulfate levels were measured in postmenopausal or ovariectomized women with complete adrenal insufficiency, compared with women with intact adrenals. A stimulation human chorionic gonadotropin test (on d 0, 3, and 6) was performed in postmenopausal women with adrenal insufficiency. Dexamethasone was administered for 4 d in postmenopausal women with intact adrenals. Intraovarian T and androstenedione were also measured in homogenates of ovarian tissue from postmenopausal women. Immunocytochemistry was performed on postmenopausal ovaries and premenopausal controls to detect the presence of steroidogenic enzymes (P-450 aromatase, P-450 SCC, 3beta HSD, and P-450 C17) and gonadotropin receptors. Plasma androgen levels were below or close to the limit of the assay in all women with adrenal insufficiency. They were similar in postmenopausal and oophorectomized women with normal adrenals. No hormonal changes were observed after human chorionic gonadotropin injections in women with adrenal insufficiency. In contrast, a dramatic decrease of all steroids was observed after dexamethasone administration in postmenopausal women with intact adrenals. Intraovarian T and androstenedione levels were negligible in postmenopausal ovarian tissue. P-450 aromatase was absent from the 17 ovaries studied, and the enzymes for androgen biosynthesis were either absent (n = 13) or present in very low amounts (n = 4). In all the postmenopausal ovaries, FSH and LH receptors were completely absent. In the absence of adrenal steroids, postmenopausal women have no circulating androgens. This result is consistent with the immunocytochemical studies showing the almost constantly absent steroidogenic enzymes and LH receptors in the postmenopausal ovary. Thus, the climacteric ovary is not a critical source of androgens. The arrest of androgen secretion after menopause may impact significantly on women's health.
Asunto(s)
Andrógenos/biosíntesis , Ovario/metabolismo , Posmenopausia/metabolismo , Glándulas Suprarrenales/metabolismo , Anciano , Aromatasa/metabolismo , Deshidroepiandrosterona/sangre , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Ovario/química , Receptores de HFE/análisis , Receptores de HL/análisis , Testosterona/análisisRESUMEN
UNLABELLED: Experimental data suggest that FSH-stimulated Sertoli cells can enhance LH-induced Leydig cell testosterone (T) production. The function of Leydig and Sertoli cells can be selectively studied by using recombinant human LH (rhLH) and recombinant human FSH (rhFSH) in patients with complete gonadotropin deficiency. The aim of the present study was to assess the secretion of testicular T, estradiol (E2), and inhibin B and the physiological relevance of the Sertoli-Leydig cell interaction in man. For that purpose, six patients with acquired complete hypogonadotropic hypogonadism received the following treatments for three periods of 1 month in a random order: 1) rhLH, 900 IU/day sc; 2) rhFSH, 150 IU/day sc; and 3) combined rhLH/rhFSH treatments. Each treatment period was separated by a washout period of 15 days. Plasma LH, FSH, T, E2, and inhibin B were measured before and every 10 days during each treatment. During rhLH administration, mean plasma LH levels rose significantly from 0.4 +/- 0.2 IU/L to 11.7 +/- 1.2 IU/L (P < 0.01) and plasma FSH levels did not change. rhFSH administration induced a significant increase in plasma FSH levels (from 0.5 +/- 0.4 to 12.1 +/- 1.4 IU/L; P < 0.01), whereas mean plasma LH levels remained low. Mean plasma E2 levels were unchanged during rhFSH treatment, but they increased significantly during rhLH from 22 +/- 4 to 54 +/- 8 pmol/L (P < 0.01) and during rhLH plus rhFSH administration. rhFSH treatment induced a sustained elevation of mean plasma inhibin B levels from 58 +/- 13 to 175 +/- 25 pg/mL (P < 0.01), similar to the increase occurring during rhFSH plus rhLH administration. In contrast, mean plasma inhibin B levels did not increase during rhLH administration. Finally, a similar and significant increase in mean plasma T levels occurred during both rhLH and rhLH plus rhFSH treatment from 0.9 +/- 0.3 to 5.4 +/- 0.7 nmol/L (P < 0.01) and from 1.0 +/- 0.4 to 6.0 +/- 0.9 nmol/L (P < 0.01), respectively. In contrast, during rhFSH treatment mean plasma T levels remained unchanged when compared with baseline. IN CONCLUSION: 1) the increase of plasma E2 induced by rhLH and the absence of effect of rhFSH confirm that Leydig cells are the major site of testicular E2 production in man; 2) the secretion of inhibin B is increased by rhFSH and not by rhLH, and, thus, Sertoli cells seem to be the main source of inhibin B production; and 3) the increase of plasma T induced by rhLH is not enhanced by rhFSH. These results suggest that the stimulatory effect of FSH on Leydig cell steroidogenesis by a Sertoli cell paracrine factor does not seem to play a major physiologic role in man.
Asunto(s)
Hormona Folículo Estimulante/uso terapéutico , Gonadotropinas/deficiencia , Hipogonadismo/tratamiento farmacológico , Hipogonadismo/metabolismo , Células Intersticiales del Testículo/metabolismo , Hormona Luteinizante/uso terapéutico , Células de Sertoli/metabolismo , Adulto , Estradiol/sangre , Hormona Folículo Estimulante/sangre , Humanos , Inhibinas/sangre , Células Intersticiales del Testículo/efectos de los fármacos , Células Intersticiales del Testículo/patología , Hormona Luteinizante/sangre , Masculino , Proteínas Recombinantes/uso terapéutico , Células de Sertoli/efectos de los fármacos , Células de Sertoli/patología , Testosterona/sangre , Factores de TiempoRESUMEN
Little is known about the physiological secretion of the free beta-subunit of LH (LHbeta). The aim of this study was to compare in women the secretion of LHbeta, using sensitive and specific two-site immunoassays, with dimeric LH and the free common alpha-subunit (FAS). The LHbeta assay does not recognize the dimeric LH and cross-reacts only with free hCG beta-subunit (CGbeta). Thus, all of the plasma samples were also tested with a highly specific immunoradiometric assay for free CGbeta. Molar concentrations (i.e. picomoles per L) were used to compare the plasma levels of LH and its free subunits. Plasma LH, LHbeta, FAS, and CGbeta levels were measured in five normally cycling women during the early follicular phase and the ovulatory peak of LH. The pulsatile profiles of LH, LHbeta, FAS, and CGbeta were studied in five postmenopausal women before and 21 days after injection of a depot preparation of the GnRH agonist D-Trp6 (3.75 mg, im) and in five women with functional hypothalamic amenorrhea (FHA), i.e. low plasma LH levels, during pulsatile GnRH administration (20 microg/pulse, 90 min, sc). Afterward, one of the patients with FHA received a single sc injection of 1350 U recombinant human LH, and plasma LH, LHbeta, FAS, and CGbeta levels were measured and compared with the high plasma levels of one postmenopausal woman. In cycling women, basal plasma LHbeta and CGbeta levels were below the detection limit of the assays (1.34 and 0.65 pmol/L, respectively), and plasma FAS levels were 13.60 +/- 0.13 pmol/L. During the LH surge, there was a parallel increase in LH, LHbeta, and FAS. Plasma CGbeta levels remained undetectable. In normal postmenopausal women, basal plasma dimeric LH, LHbeta, and FAS levels were increased in parallel, and their pulsatile profiles were similar, without measurable plasma CGbeta levels. After D-Trp6 administration, plasma LH and LHbeta levels were completely suppressed, whereas plasma FAS levels increased, and plasma CGbeta remained below 0.65 pmol/L. In FHA women, basal plasma levels of LH and FAS were low, without detectable LHbeta and CGbeta levels. During pulsatile GnRH administration, LHbeta became detectable, and pulses were synchronous with those of LH and FAS. The secretion of LH and LHbeta was almost equimolar. Plasma CGbeta levels remained undetectable. In the patient with FHA, administration of recombinant human LH increased only plasma LH levels, whereas plasma LHbeta and FAS levels remained very low. In conclusion, when the production of dimeric LH increases, a concomitant, parallel, and almost equimolar hypersecretion of uncombined and biologically inactive LHbeta occurs. Like the alpha-subunit, LHbeta may be secreted in the dissociated free form. This can lead to pitfalls during clinical investigations if assays of free CGbeta display some cross-reaction with free LHbeta.
Asunto(s)
Amenorrea/sangre , Hormona Luteinizante/sangre , Ciclo Menstrual/sangre , Posmenopausia/sangre , Adulto , Gonadotropina Coriónica Humana de Subunidad beta/sangre , Reacciones Cruzadas , Dimerización , Femenino , Humanos , Hormona Luteinizante/metabolismo , Persona de Mediana Edad , Periodicidad , Premenopausia , Sensibilidad y EspecificidadRESUMEN
We have previously shown in postmenopausal women that a 19-nor-progesterone derivative, nomegestrol acetate (NOMA) had a strong antigonadotropic activity and that this effect was not mediated via the androgen receptor. The aim of the present study was to further assess the action of this progestin on gonadotropin secretion in women. To demonstrate at which level of the hypothalamo-pituitary-ovarian axis the gonadotropin inhibition was exerted, 10 normally cycling (NC) women, 3 women with a gonadotropin-independent ovarian function [McCune-Albright (MCA) syndrome], and 5 women with functional hypothalamic amenorrhea (FHA) participated in the study. NC women were treated orally with 5 mg NOMA for 21 days, after one control cycle. Plasma estradiol (E2) and progesterone, LH, and FSH levels were measured during each cycle. A frequent sampling study (every 10 min for 4 h), followed by a classic GnRH test (100 microg, i.v.), was performed on day 11. Women with MCA were studied before, during NOMA, and after long-acting GnRH agonist administration. In women with FHA, pulsatile GnRH (20 microg s.c., every 90 min) was given for two cycles with or without NOMA (5 mg for 21 days). In all NC women, ovulation was suppressed by NOMA. Mean plasma LH levels, LH pulse frequency, and the LH response to exogenous GnRH were significantly decreased. In MCA, neither NOMA nor GnRH agonist modified multiple ovarian cysts on ultrasound or plasma E2, levels which remained elevated, ruling out a direct ovarian effect. In FHA, pulsatile GnRH administration recreated a normal ovulatory menstrual cycle. Addition of NOMA prevented the increase of plasma E2, decreased the amplitude of LH pulses, and prevented ovulation. In view of this unexpected action of NOMA at the pituitary level, seven samples of normal human female pituitaries were tested for the presence of progesterone receptor (PR) using a double labeling immunocytochemical technique. The presence of PR was detected in the seven human pituitary tissues. In addition, PR was found to be expressed only in gonadotroph cells. In conclusion, NOMA, a 19-nor-P derivative, has a potent antigonadotropic activity exerted at the hypothalamic level, inhibiting ovulation in NC women. In women with FHA, NOMA decreased the gonadotropin stimulation induced by pulsatile GnRH administration. According to the presence of PR in gonadotroph cells of normal human pituitaries, 19-nor-progesterone derivatives may also act on the gonadotropin secretion at the pituitary level.
Asunto(s)
Hormona Folículo Estimulante/sangre , Hipotálamo/efectos de los fármacos , Hormona Luteinizante/sangre , Megestrol , Norpregnadienos/farmacología , Hipófisis/efectos de los fármacos , Congéneres de la Progesterona/farmacología , Adolescente , Adulto , Amenorrea/fisiopatología , Estradiol/sangre , Femenino , Displasia Fibrosa Poliostótica/fisiopatología , Hormona Liberadora de Gonadotropina/administración & dosificación , Humanos , Hipotálamo/fisiopatología , Ovario/fisiopatología , Periodicidad , Hipófisis/fisiopatología , Progesterona/sangre , Receptores de Progesterona/análisisRESUMEN
Antimullerian hormone (AMH) is produced by immature Sertoli cells until pubertal maturation. At puberty, elevation of serum testosterone correlates with a decrease in serum AMH. To further investigate the hormonal control of AMH secretion, serum AMH levels were measured in 20 normal men (20-60 yr), in 12 patients (19-30 yr) with congenital hypogonadotropic hypogonadism (CHH), and in 18 patients (19-65 yr) with acquired hypogonadotropic hypogonadism (AHH) either untreated or during testosterone or human chorionic gonadotropin (hCG) therapy. Mean serum AMH levels in normal adult men were low (20+/-4.9 pmol/L). In untreated CHH patients, mean serum AMH levels were significantly higher than in normal men (292+/-86 pmol/L, P < 0.001) and were similar to those previously reported in prepubertal boys. In men with AHH, mean serum AMH levels were also significantly increased (107+/-50 pmol/L; P < 0.01) when compared with healthy men but were less than in men with CHH. In addition, in 10 patients treated for prostate cancer, a modest but significant increase of serum AMH (from 11.4 +/-5.7 pmol/L to 49+/-9.9 pmol/L; P < 0.01) was observed 12 months after suppression of the gonadal axis with the GnRH agonist Triptorelin (3.75 mg IM once a month). Plasma testosterone (T) and serum AMH levels were measured at baseline and at 3 and 6 months in 10 HH patients (6 CHH and 4 AHH) treated with hCG (1500 IU/twice weekly for 6 months) and in 8 HH (4 CHH and 4 AHH) patients treated with T (T enanthate 250 mg/3 weeks for 6 months). hCG treatment induced an increase of plasma T (from 1.0+/-0.7 to 11+/-2.4 and 19+/-4.8 nmol/L, at 3 and 6 months respectively) associated with a dramatic decrease of serum AMH (from 314+/-93 to 56+/-30 and 17+/-4.3 pmol/L). The similar increase in plasma T levels (from 1.4+/-1.0 to 15.6+/-4.2 and 23+/-6.2 ng/mL) obtained with exogenous T induced a lesser decrease of serum AMH (from 221+/-107 pmol/L to 114+/-50 and 66+/-17 pmol/L, at 3 and 6 months respectively). In conclusion, high plasma AMH levels in CHH patients are related to the absence of pubertal maturation of Sertoli cells. The high AMH levels in AHH and its increase after Triptorelin-induced gonadotropin deficiency suggest that the suppression of AMH is a reversible phenomenon. Finally, the inhibition of AMH production by Sertoli cells is induced by intratesticular T.
Asunto(s)
Glicoproteínas , Gonadotropinas/deficiencia , Inhibidores de Crecimiento/sangre , Hipogonadismo/sangre , Hormonas Testiculares/sangre , Adulto , Anciano , Hormona Antimülleriana , Gonadotropina Coriónica/farmacología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Testosterona/sangreRESUMEN
OBJECTIVE: Functional hypothalamic amenorrhoea (FHA) is a consequence of low dietary intake as observed in two major pathophysiological conditions, anorexia nervosa and/or intensive physical exercise. The aim of the present study was to assess in women with FHA and normal body mass index (BMI) and apparently normal daily activities, the degree of impairment of GnRH secretion, its nutritional origin and its reversibility. PATIENTS: Twelve women (22-35 years) with FHA not related with exercise and 12 age and BMI matched menstruating controls (NC) were studied. Six women with congenital hypothalamic hypogonadism (CHH), representative of complete gonadotrophin deficiency, were also enrolled for comparison. DESIGN: Plasma oestradiol (E2) and androstenedione (A) levels were measured and the pulsatile profile of LH was studied. A GnRH agonist test, using 100 micrograms S/C of DTrp6 GnRH (Triptorelin) was performed (sampling every 2 h for 24 h). Dietary intake, body composition and nutritional markers (FT3, ferritin, retinol binding protein (RBP), SHBG, IGF-1 and leptin) were measured. All the women with FHA were advised to normalize their diet during four months. The same studies were performed if nutritional markers and body composition were normalized. RESULTS: In FHA, mean plasma E2 and A levels were low. LH pulse frequency and amplitude were significantly reduced compared to NC (P < 0.005). FSH/LH ratio increased rapidly after triptorelin with a significant increase in plasma E2 levels between 18 and 24 h. In contrast, no response to triptorelin was observed in women with CHH. The fat body mass was lower and the lean body mass higher in FHA than in NC. Marked differences in nutritional intake were identified, with altered dietary composition. FHA consumed significantly less fat (P < 0.001) and less carbohydrate (P = NS) than the BMI-matched controls. Mean plasma levels of SHBG were increased whereas mean plasma levels of FT3, ferritin, RBP, IGF-1, and leptin were significantly decreased. Only three patients with FHA kept a balanced diet and improved their body composition after 4 months. LH pulsatile profile and response to triptorelin challenge were normalized in these patients. CONCLUSION: Mild dieting, close to normal but prolonged and characterized by an important fat restriction, is able to interfere with gonadotrophin secretion. Assessment of nutritional markers allows recognition of mild nutritional insufficiency as a common cause of FHAs. The gonadotrophin deficiency is partial and may be reversible after improvement of nutritional intake and body composition.
Asunto(s)
Amenorrea/etiología , Hormona Liberadora de Gonadotropina/metabolismo , Enfermedades Hipotalámicas/etiología , Trastornos Nutricionales/complicaciones , Adulto , Amenorrea/dietoterapia , Amenorrea/fisiopatología , Androstenodiona/sangre , Composición Corporal , Estradiol/sangre , Femenino , Hormona Liberadora de Gonadotropina/análogos & derivados , Humanos , Hipogonadismo/sangre , Hipogonadismo/fisiopatología , Enfermedades Hipotalámicas/dietoterapia , Enfermedades Hipotalámicas/fisiopatología , Hormona Luteinizante/sangre , Hormona Luteinizante/metabolismo , Trastornos Nutricionales/dietoterapia , Trastornos Nutricionales/fisiopatología , Estadísticas no Paramétricas , Pamoato de TriptorelinaRESUMEN
The physiological importance and therapeutical interest of dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are still controversial. Panhypopituitarism is characterized by the absence of secretion of adrenal and gonadal steroids and thus the production of their metabolites. The conversion of DHEA given orally into delta 5 derivatives, androgens, androgen metabolites, and estrogens was studied in ten patients with complete panhypopituitarism. Sex steroid therapy was withdrawn for at least 2 months. Each patient received, at 1-month intervals and in a random order, two single oral doses of DHEA (50 mg and 200 mg) and placebo. During each treatment, urine samples were collected for 24 h, and blood samples were drawn at hourly intervals for 8 h. In patients with pituitary deficiency, plasma DHEA and DHEAS were not detectable and increased, with the 50 mg dose, up to levels observed in young adults. The administration of 200 mg of DHEA induced an increase of both steroids to supraphysiological plasma levels. A small increase of delta 5-androstenediol was observed. In contrast, the increase of plasma delta 4-androstenedione was important and dose dependent. DHEA was also converted into the potent sex steroid testosterone (T). The administration of a 50 mg dose of DHEA restored plasma T to levels similar to those observed in young women. The 200 mg dose induced an important increase of plasma T, slightly below the levels observed in normal men. The increase of plasma dihydrotestosterone levels was small at both doses of DHEA, in contrast with the large conversion of DHEA into androsterone glucuronide and androstanediol glucuronide. Finally, DHEA administration induced a significant and dose dependent increase of plasma estrogens and particularly of estradiol. In conclusion, this short term study demonstrates that: 1) panhypopituitarism is a model of interest to study the metabolism of DHEA; 2) in the absence of pituitary hormones and of adrenal and gonadal steroids, DHEA given orally is mainly converted into delta 4 derivatives, which in turn are strongly metabolized into 5 alpha-3keto-reduced steroids; 3) a significant increase of sex active hormones was observed in plasma after 200 and even 50 mg of DHEA. Thus, biotransformation of DHEA into potent androgens and estrogens may explain several of the reported beneficial actions of this steroid in aging people.
Asunto(s)
Deshidroepiandrosterona/metabolismo , Hipopituitarismo/metabolismo , Modelos Biológicos , Adulto , Anciano , Androstano-3,17-diol/sangre , Androstenodiol/sangre , Androstenodiona/sangre , Androsterona/análogos & derivados , Androsterona/sangre , Deshidroepiandrosterona/sangre , Sulfato de Deshidroepiandrosterona/sangre , Dihidrotestosterona/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Placebos , Testosterona/sangreRESUMEN
Most clinically nonfunctioning pituitary adenomas (NFPA) are found to be gonadotropinomas when assessed by immunocytochemistry. However, they are rarely associated with increased basal plasma levels of FSH, LH and/or alpha-subunit. It has been claimed that the paradoxical free LHbeta response to TRH may be a useful clinical tool for determining the gonadotropic nature of NFPA. We used a very specific and sensitive immunoradiometric assay (IRMA) for free LHbeta measurement and another specific IRMA to check the absence of free CGbeta, to study normal subjects and 26 patients with NFPA. Basal plasma levels of LHbeta were undetectable in normal men and premenopausal women in the early follicular phase. In contrast, normal postmenopausal women had increased basal plasma LHbeta, parallel to dimeric LH and alpha-subunit levels. In healthy subjects, stimulation with GnRH elicited an increase in LHbeta while TRH was ineffective. In patients with NFPA, LHbeta hypersecretion was found basally and/or after stimulation with TRH in 3 of 16 men, 3 of 5 premenopausal women, and 1 of 5 postmenopausal women, i.e. 7 of 26 patients (26%). In 3 of these 7 cases, alpha-subunit and/or FSH levels were also increased. The LHbeta measurement was thus truly informative on the gonadotropic nature of NFPA in only 4 out of 26 cases (15%). In addition, increased LHbeta levels and/or a positive response of free LHbeta to TRH was observed in 3 patients with pure prolactinomas but in no patients with GH-secreting adenomas. Thus, using this very sensitive and specific IRMA, free LHbeta measurement is rarely helpful for determining the gonadotropic nature of NFPA.
Asunto(s)
Adenoma/sangre , Hormona Luteinizante/sangre , Neoplasias Hipofisarias/sangre , Acromegalia/sangre , Adulto , Gonadotropina Coriónica Humana de Subunidad beta/sangre , Femenino , Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina/farmacología , Humanos , Ensayo Inmunorradiométrico , Masculino , Persona de Mediana Edad , Posmenopausia , Prolactinoma/sangre , Valores de Referencia , Hormona Liberadora de Tirotropina/farmacologíaRESUMEN
To further study the mechanism of the antigonadotropic activity of progestins, the effects of a 19-nortestosterone derivative, norethisterone acetate (NETA), and a 19-norprogesterone derivative, nomegestrol acetate (NOMA), were compared. The aim was to assess whether their action is exerted via the androgen receptor. Ten healthy postmenopausal women were treated for five monthly periods of 24 days separated by 10 days in a randomized cross-over design. Transdermal estradiol, Estraderm TTS (25 micrograms; one patch every 3 days), was given from days 1-24 during the five periods. On the last 12 days, of each estradiol treatment, they all received a placebo, NOMA (5 mg/day), NOMA in association with the nonsteroidal antiandrogen, flutamide (FLU; 250 mg, twice a day), NETA (10 mg/day), or NETA plus FLU. On the other hand, three castrated patients with complete androgen insensitivity (CAI) received NOMA and NETA for two periods of 12 days separated by 3 weeks. In postmenopausal women, the effects of NOMA and NETA on metabolic parameters were studied. Only NETA decreased high density lipoprotein cholesterol. Plasma LH, FSH, and estradiol were measured during each treatment period. A significant decrease in mean plasma LH and FSH levels and their responses to exogenous GnRH was observed with NOMA and NETA treatments compared to placebo (P < 0.001). The pulsatile frequency, but not the amplitude, of LH was significantly decreased during both treatments. Interestingly, the effects of both progestins on gonadotropins were not antagonized by FLU administration. In the patients with CAI, the pulsatile study of gonadotropins was performed before and on day 12 of NOMA and NETA treatments. As in postmenopausal women, both progestins induced similar decreases in LH and FSH. In conclusion, a 19-nortestosterone derivative, NETA, and a 19-norprogesterone derivative, NOMA, have similar antigonadotropic activities. This effect, not antagonized by FLU and observed in patients with CAI, is not mediated via the androgen receptor. The absence of deleterious effects of 19-norprogesterone derivatives on metabolic parameters should favor the therapeutic use of these compounds.
Asunto(s)
Gonadotropinas/antagonistas & inhibidores , Megestrol , Noretindrona/análogos & derivados , Norpregnadienos/farmacología , Congéneres de la Progesterona/farmacología , Receptores Androgénicos/efectos de los fármacos , HDL-Colesterol/sangre , Estudios Cruzados , Femenino , Hormona Folículo Estimulante/sangre , Humanos , Hormona Luteinizante/sangre , Persona de Mediana Edad , Noretindrona/farmacología , Acetato de Noretindrona , Posmenopausia/sangreAsunto(s)
Neoplasias de la Corteza Suprarrenal/enzimología , Aromatasa/metabolismo , Neoplasias de la Corteza Suprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/cirugía , Adrenalectomía , Adulto , Aromatasa/genética , Northern Blotting , Estradiol/sangre , Estrona/sangre , Expresión Génica , Humanos , Masculino , Reacción en Cadena de la Polimerasa , ARN Mensajero/análisis , Tomografía Computarizada por Rayos XRESUMEN
In functional hypothalamic amenorrhea (HA), it has been reported that administration of opioid receptor antagonists restores gonadotropin secretion and ovarian function. However, endogenous opioids may modulate gonadotropin secretion only in the presence of ovarian steroids. To further study these conflicting results, a group of nine women with secondary functional HA who wished to become pregnant were studied. The opiate antagonist naltrexone (Nal; 100 mg/day) was administered for two 30-day periods, starting on either day 22 (Nal 1) of a well characterized replacement regimen with estradiol (E2) and progesterone (P), or on day 22 (Nal 2) of the luteal phase induced by exogenous pulsatile GnRH administration (10 micrograms/pulse, iv, every 90 min). Plasma LH and FSH were measured every 10 min for 8 h before treatment and on day 12 of each treatment period (Nal 1, pulsatile GnRH, and Nal 2). Ovulation was monitored during each treatment. Plasma E2 levels were measured on days 12 and 22, and P levels on day 22 of each treatment. During exogenous E2 and P administration, plasma steroid levels reached luteal phase levels. However, during Nal 1, plasma E2 levels fell to prestudy levels and remained low. No follicular growth occurred, and the pulsatile study showed pretreatment frequency, amplitude, and mean plasma levels of LH. On day 12 of pulsatile GnRH administration, plasma E2 levels increased, and LH and FSH pulses followed each GnRH pulse during the frequent sampling study. Ovulation occurred in all women during pulsatile GnRH treatment. During Nal 2 treatment, plasma E2 levels returned to prestudy levels without follicular growth, and the pulsatile study was similar to those prior treatment and during Nal 1 administration. In conclusion, Nal, started during priming either with exogenous E2 and P treatment or gonadotropin stimulation induced by pulsatile GnRH administration, was unable when continued alone to initiate or maintain gonadotropin secretion in women with HA. Thus, the exclusive role of opioids in HA and the effect of Nal even in the presence of ovarian steroids are questionable.
Asunto(s)
Amenorrea/fisiopatología , Estradiol/uso terapéutico , Terapia de Reemplazo de Estrógeno , Hormona Liberadora de Gonadotropina/uso terapéutico , Hipotálamo/fisiopatología , Naltrexona/uso terapéutico , Inducción de la Ovulación , Progesterona/uso terapéutico , Adulto , Amenorrea/sangre , Esquema de Medicación , Femenino , Hormona Folículo Estimulante/sangre , Hormona Folículo Estimulante/metabolismo , Hormona Liberadora de Gonadotropina/administración & dosificación , Hormona Liberadora de Gonadotropina/farmacología , Humanos , Hormona Luteinizante/sangre , Hormona Luteinizante/metabolismo , Embarazo , Estadísticas no ParamétricasRESUMEN
Polyglandular syndromes have been described for many years but only one case of panhypopituitarism with adrenal and thyroid insufficiencies has been documented. We present a 69-year-old woman with the initial diagnosis of idiopathic primary hypopituitarism. An associated primary adrenal disease was suspected on low plasma aldosterone and increased plasma renin values during unjustified withdrawal of treatment. The complete absence of cortisol response to long-term ACTH administration confirmed the diagnosis. In addition, primary hypothyroidism was demonstrated by the absence of radioiodine uptake by the thyroid gland and the inability to increase T4 secretion after repeated TSH injections. The pattern of hypopituitarism and the coexistence of both adrenal and thyroid deficiencies provide strong evidence for the diagnosis of autoimmune polyglandular syndrome with hypophysitis.
Asunto(s)
Glándulas Suprarrenales/fisiopatología , Hipopituitarismo/fisiopatología , Poliendocrinopatías Autoinmunes/diagnóstico , Glándula Tiroides/fisiopatología , Pruebas de Función de la Corteza Suprarrenal , Femenino , Humanos , Persona de Mediana Edad , Pruebas de Función Hipofisaria , Poliendocrinopatías Autoinmunes/fisiopatología , Sistema Renina-Angiotensina/fisiología , Pruebas de Función de la TiroidesRESUMEN
There is little information about the plasma concentrations of 3 beta-hydroxy-delta 5-steroids (delta 5-steroids) in untreated patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. To further study the delta 5 pathway, we measured plasma levels of delta 5- and delta 4-steroids in 21 adult patients with different degrees of 21-hydroxylase deficiency (11 salt-wasters, 5 simple virilizers, and 5 patients with the nonclassical form of the disease). In all patients, investigations were performed after withdrawal of steroid treatment for at least 10 days. In addition, catheterization of gonadal and adrenal veins was performed in two salt-wasting male patients displaying bilateral testicular tumors to study adrenal secretion of delta 5- and delta 4-steroids. In one of them, surgical resection of the intratesticular adrenal rests gave the opportunity to measure 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) activity. In all untreated patients, an increase in plasma delta 4-steroids was observed. In contrast, although plasma levels of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) were not significantly modified in simple virilizers, a paradoxical decrease in all delta 5-steroids was observed in salt-wasters. Catheterization of the adrenal veins confirmed the decrease in delta 5-steroids, particularly DHEA and DHEAS. The androstenedione/DHEA ratio was increased in all patients proportionally to the severity of the disease, suggesting an increase in adrenal 3 beta HSD. In vitro analysis of 3 beta HSD activity showed a 4-fold increase in intratesticular adrenal tissue compared to that in normal adrenals. A positive correlation between the androstenedione/DHEA ratio and plasma ACTH levels was observed, suggesting a long term stimulatory effect of ACTH on 3 beta HSD. Angiotensin-II could have an additive effect on ACTH-induced 3 beta HSD activity.
Asunto(s)
Hiperplasia Suprarrenal Congénita/sangre , Hiperplasia Suprarrenal Congénita/etiología , Hidroxiesteroides/sangre , Pregnenos/sangre , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/fisiología , Adulto , Deshidroepiandrosterona/análogos & derivados , Deshidroepiandrosterona/sangre , Sulfato de Deshidroepiandrosterona , Femenino , Humanos , Masculino , Complejos Multienzimáticos/metabolismo , Progesterona Reductasa/metabolismo , Radioinmunoensayo , Renina/sangre , Índice de Severidad de la Enfermedad , Esteroide 21-Hidroxilasa/sangre , Esteroide Isomerasas/metabolismoRESUMEN
In men with hypogonadotropic hypogonadism, prolonged treatment with LH and FSH induces spermatogenesis. To compare the respective role of exogenous testosterone and intratesticular testosterone on the induction and maintenance of spermatogenesis, 10 men with hypogonadotropic hypogonadism and without history of cryptorchidism were studied. They were treated with human gonadotropins (hMG; 150 IU FSH and LH and 1500 IU hCG, im, three times weekly) or pure FSH (150 IU, im, three times a week) and testosterone (T: 250 mg, im, once a week). Five men were treated first with hMG-hCG and then with pure FSH plus T. The other five men started with pure FSH plus T. Each treatment period lasted 24 months. In all men, hMG-hCG induced spermatogenesis after 24 months, with normal motility and quality. The combination of pure FSH and T was not able to induce spermatogenesis after 24 months. In addition, sperm count dropped dramatically to 0.3 +/- 0.1 x 10(6)/mL within 3 months and to 0 after 6 months when pure FSH and T followed [corrected] hMG-hCG. Plasma T levels were increased by both treatments, but significantly more after pure FSH and T (35.3 +/- 5.2 nmol/L) than after hMG-hCG (20.4 +/- 5.2 nmol/L; P < 0.05). Plasma estradiol levels after treatment with pure FSH and T were also increased, but the difference from those obtained during hMG-hCG treatment was not significant. In conclusion, in men with complete gonadotropin deficiency, FSH and exogenous T are not able to induce spermatogenesis. Furthermore, spermatogenesis induced by LH plus FSH (hMG-hCG) cannot be maintained when exogenous T replaced LH in the regimen. Thus, exogenous T is unable to replace LH (and intratesticular T) to induce spermatogenesis. These data are noteworthy in the prospect of male contraception after a complete blockade of gonadotropin activity.
Asunto(s)
Hormona Folículo Estimulante/farmacología , Hipogonadismo/tratamiento farmacológico , Espermatogénesis/efectos de los fármacos , Testosterona/farmacología , Adulto , Gonadotropina Coriónica/administración & dosificación , Quimioterapia Combinada , Hormona Folículo Estimulante/administración & dosificación , Humanos , Hipogonadismo/fisiopatología , Masculino , Menotropinas/administración & dosificación , Testosterona/administración & dosificaciónRESUMEN
Ovarian steroids exert feedback effects at the level of both the hypothalamus and anterior pituitary to regulate the secretion of gonadotrophins. Oestradiol decreases the activity of mRNA encoding the alpha and beta subunits of gonadotrophins. In the late follicular phase, oestradiol exerts a positive feedback control over pituitary luteinizing hormone (LH) release and a negative control over follicle stimulating hormone (FSH). Oestradiol also induces a pre-ovulatory increase of gonadotrophin releasing hormone (GnRH) secretion which is continuous rather than episodic. Such a GnRH rise may not be required to produce the LH surge. Progesterone exerts its major effect at the hypothalamic level and decreases GnRH pulse frequency by inducing the release of beta-endorphin. However, the hypothalamus is not the exclusive target of progesterone action, for its facilitatory action on gonadotrophin release may be at the level of the pituitary gland. This positive feedback effect was studied in women with hypothalamic gonadotrophin deficiency treated with pulsatile GnRH. In physiological doses, progesterone had a stimulatory effect on LH secretion at the pituitary level. Finally, regarding the effect of androgens upon gonadotrophin secretion, the administration of a non-steroidal pure anti-androgen (Flutamide) for 12 months in 10 normally cycling women did not change significantly the mean levels, frequency, or amplitude of LH pulses or the LH and FSH responsiveness to GnRH. Androgens (apart from their aromatization to oestrogens) do not directly play a physiological role in gonadotrophin regulation in normal women.
Asunto(s)
Andrógenos/farmacología , Estradiol/farmacología , Hormona Folículo Estimulante/metabolismo , Hormona Luteinizante/metabolismo , Progesterona/farmacología , Animales , Retroalimentación , Femenino , Humanos , MasculinoRESUMEN
OBJECTIVES: We assessed in women the effects of androgen suppression on gonadotrophin secretion and the therapeutic efficacy of the pure anti-androgen flutamide (2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide). DESIGN AND SUBJECTS: Ten women, aged 28-35 years, using an intrauterine device for contraception, were selected for this study. All women had idiopathic hirsutism with or without acne and seborrhoea. Flutamide was administered orally in a dose of 250 mg twice daily for 1 year. Basal body temperature was recorded and pelvic ultrasonography performed before and every 3 months during treatment. LH pulse frequency and amplitude (Cluster analysis) and basal and GnRH-stimulated plasma LH and FSH levels were determined on day 5 of the cycle prior to flutamide treatment, and after 6 and 12 months of therapy. Plasma total testosterone (T), non-SHBG bound T, androstenedione (A), dehydroepiandrosterone sulphate (DHEAS), androstanediol glucuronide (3 alpha-diol G) and sex hormone binding globulin (SHBG) levels were measured before and every 3 months during therapy, on day 5 of the cycle. Plasma oestradiol and progesterone levels were determined on day 22 of the studied cycles. RESULTS: Disappearance of acne and seborrhoea occurred after 2 months with a marked improvement of hirsutism at 6 months. At 12 months, hirsutism had disappeared with a Ferriman and Gallwey score < 7. No adverse side-effects, apart from transient diarrhoea in two patients, were reported with this flutamide dose. None of the patients had any disturbance of menstrual cycles which remained ovulatory. The pure anti-androgen flutamide induced no significant change in LH pulsatile profile, nor in LH and FSH responsiveness to GnRH. Plasma concentrations of steroids were not altered. Plasma SHBG and 3 alpha-diol G levels did not change during flutamide treatment. CONCLUSION: Flutamide, which interacts only with the androgen receptor, is effective for hirsutism, acne and seborrhoea, and does not disturb menstrual cyclicity or ovulation. It may represent a treatment of choice for essential hirsutism in women using safe contraceptive methods.
Asunto(s)
Andrógenos/sangre , Flutamida/uso terapéutico , Gonadotropinas Hipofisarias/sangre , Hirsutismo/tratamiento farmacológico , Acné Vulgar/tratamiento farmacológico , Adulto , Dermatitis Seborreica/tratamiento farmacológico , Femenino , Hormona Folículo Estimulante/sangre , Hirsutismo/sangre , Humanos , Dispositivos Intrauterinos , Hormona Luteinizante/sangre , Ciclo Menstrual/sangreRESUMEN
Plasma bioactive (B) and immunoreactive (I) FSH and LH were measured every 10 min for 8 h in the same postmenopausal women in a three-phase study: 1) during normal pulsatile gonadotropin secretion (basal study; n = 8), 2) 8 h after a single injection of a GnRH antagonist (5 mg Nal-Glu, sc; n = 5), and 3) 21 days after a GnRH agonist injection (D-Trp6, 3.75 mg depot preparation, im; n = 7). I-FSH and I-LH were measured by monoclonal antibody immunoradiometric assays. B-FSH and B-LH were measured in selected samples with the immature rat granulosa cell and mouse interstitial cell assays, respectively. Significant pulsatility of B- and I-FSH and LH was demonstrated in the basal samples, but only the B/I ratio of LH was slightly elevated within the secretion peaks. After GnRH antagonist treatment, I-FSH decreased from a mean pretreatment level of 55.7 +/- 7.8 IU/L by 26% (P less than 0.001), and B-FSH from 313.8 +/- 61.9 IU/L by 44% (P less than 0.01). The B/I ratio decreased from 6.4 +/- 1.7 to 4.5 +/- 1.0 (P less than 0.05). After agonist treatment, the I- and B-FSH levels decreased by 92% and 83% (P less than 0.0001), respectively, but the B/I ratio increased to 17.3 +/- 4.7 (P less than 0.05). The concentrations of I- and B-LH decreased by 75% and 80%, respectively (P less than 0.001), after antagonist treatment. After agonist treatment, I-LH decreased by 92%, and B-LH by 93% (P less than 0.0001). No changes in the B/I ratios of LH were found after either treatment. In conclusion, no changes were found in the quality of circulating LH during the treatments, whereas the antagonist treatment decreased and the agonist treatment increased the B/I ratio of FSH. These findings provide further evidence that the qualitative responses of FSH and LH to treatment with the same GnRH analog are different, and that the suppressive mechanisms of GnRH antagonist and agonist action on gonadotropin secretion are different.
Asunto(s)
Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Hormona Luteinizante/sangre , Menopausia , Adulto , Bioensayo , Femenino , Hormona Liberadora de Gonadotropina/fisiología , Humanos , Ensayo Inmunorradiométrico , Persona de Mediana Edad , Concentración OsmolarRESUMEN
OBJECTIVE: The present study was designed to determine the incidence of 3 beta-hydroxysteroid dehydrogenase deficiency (3 beta-HSD) in adult women with hyperandrogenism. DESIGN AND PATIENTS: In 78 hirsute patients and 30 normal women in the same age range, an ACTH stimulation test was performed on day 5 of the cycle by administration of a single bolus of 0.25 mg ACTH-(1-24) at 0800 h. MEASUREMENTS: The following steroids were measured before, 30 and 60 minutes after ACTH injection: delta 5-pregnenolone (delta 5-P), 17-hydroxy-delta 5-pregnenolone (17-OH delta 5-P), dehydroepiandrosterone (DHEA), delta 5-androstenediol, progesterone (P), 17-hydroxyprogesterone (17-OHP), androstenedione (A), testosterone (T) and cortisol. RESULTS: Maximum ACTH-stimulated values of delta 5-steroids were in excess of the 90% confidence limits of the control group in 19 hirsute women. Ten patients had an isolated increase in delta 5-P, 17-OH delta 5-P, DHEA or delta 5-androstenediol. Nine patients had an increase in two delta 5 steroids and none had increased values of three or four delta 5 steroids. The ratios of 17-OH delta 5-P to 17-OHP, DHEA to A, delta 5-P to P and delta 5-androstenediol to T were increased in 5, 1, 1 and 1 patients respectively. No patient had elevated values of more than one ratio. CONCLUSIONS: Using stringent diagnostic criteria, partial 3 beta-HSD deficiency was excluded in all 78 patients and therefore appears to be a rare disorder.