Characterization of endocrine features and genotype-phenotypes correlations in blepharophimosis-ptosis-epicanthus inversus syndrome type 1.

OBJECTIVE: Blepharophimosis syndrome (BPES) is an autosomal dominant genetic condition resulting from heterozygous mutations in the FOXL2 gene and clinically characterized by an eyelid malformation associated (type I) or not (type II) with premature ovarian failure. The distinction between the two forms is critical for female patients, as it may allow to predict fertility and to plan an appropriate therapy. Identifying an underlying causative mutation is not always predictive of the clinical type of BPES since genotype-phenotype correlations are not yet fully delineated. Here, we describe the clinical and hormonal phenotypes of three female patients with BPES type 1 from two novel families, correlate their phenotypes with identified mutations, and investigate the effects of hormone replacement therapy (HRT). METHODS: Clinical, biochemical, and genetic evaluation were undertaken in all the patients and genotype-phenotype correlation was analyzed. The effects of substitutive hormonal therapy on secondary sexual characteristics development and induction of menarche were evaluated. RESULTS: All patients presented with primary amenorrhea or other signs of ovarian dysfunction. Two distinct mutations, a missense p.H104R change and an in-frame p.A222_A231dup10 duplication in the FOXL2 gene were identified. Observed phenotypes were not in accordance with the prediction based on the current genotype-phenotype correlations. HRT significantly improved secondary sexual characteristics development, as well as the induction of menarche. CONCLUSIONS: This study highlights the importance of early recognition of BPES and emphasizes the need of personalized therapy and follow-up in female patients carrying distinct FOXL2 mutations.

The facilitative effects of heart-rate feedback in the emotional processing of claustrophobic fear.

This study examines predictions derived from Foa and Kozak's theory of emotional processing. We hypothesized that the provision of heart-rate feedback would facilitate emotional processing through a fuller activation of the participant's fear structure, and by focusing participants' attention on information that is incompatible with the fear structure, i.e., the interoceptive pattern of habituation. Nonclinical students (N = 54) showing marked claustrophobic fear received 30 min of self-directed exposure to a claustrophobic chamber. Three exposure conditions (heart-rate feedback, paced-tone control, and exposure only control) were examined across six 5-min exposure trials. Participants receiving heart-rate feedback displayed greater between-trial habituation across treatment trials and lower levels of fear at post-treatment. Treatment process findings failed to support the fear activation hypothesis. Implications of the findings for theories of fear reduction are discussed.

Nasal spray administration of bromocriptine: pharmacology and effect on serum prolactin level in puerperal women.

This study was aimed at investigating the absorption of nasally administered bromocriptine and its effect on serum prolactin level. Fifteen physiologically hyperprolactinemia women who had asked to discontinue breast feeding received a single nasal spray administration of 0.8 mg bromocriptine. Serum prolactin levels were measured by radioimmunoassay at 30 and 15 min before drug administration, at the time of administration and at 15, 30, 60, 120, 240, 480 and 720 min after administration; bromocriptine was radioimmunoassayed in only five of the patients from time 0 to 720 min after administration. Serum bromocriptine levels increased rapidly after administration, reached a maximum at 120 min and thereafter declined slowly over the subsequent 10 h. As the bromocriptine level increased there was a decline in the serum prolactin level. The first significant decline in serum prolactin level compared with the baseline level occurred at 30 min after administration and the level continued to decrease significantly until time 120 min. Four hours after administration the mean serum prolactin level was within the normal assay range. The maximum decline in serum prolactin level was reached at 720 min after administration. Correlation analysis between serum bromocriptine and prolactin concentrations yielded a significant negative value between times 0 and 120 min after administration. There was no significant change in mean orthostatic systolic or diastolic blood pressure or in mean heart rate. Only one patient complained of headache and dizziness; another experienced mild transient nausea, and none had vomiting. Ten patients (66.67%) reported light endonasal burning and an unpleasant taste which subsided after a few minutes; no patient showed nasal irritation at nasal examination. In conclusion, nasal administration of 0.8 mg bromocriptine was effective in reducing the serum prolactin level for more than 12 h after administration without inducing significant side-effects.

Nasal spray bromocriptine: effects on serum prolactin in puerperal women.

BACKGROUND: The objective of this study was to investigate the effectiveness of a single nasal spray administration of 0.8 mg bromocriptine in reducing PRL serum levels. METHODS: Eighteen physiologically hyperprolactemic women in the early days of puerperium were randomized to receive nasal bromocriptine or placebo; PRL serum levels were measured by RIA at 45, 30 and 15 minutes before the administration and after the following times: 15, 30, 45, 60, 120, 180, 240, 300, and 480 minutes. RESULTS: After the administration of bromocriptine serum levels of PRL decreased rapidly; the reduction was statistically significant after 45 minutes. Four hours after the administration mean serum levels of PRL resulted in the normal range (< 20 micrograms/l); at the eighth hour the PRL levels were still normal. No one patient complained of any local or systemic side-effects. CONCLUSION: Nasal route seems to be an effective and probably safe administration route for bromocriptine.

Nasal spray vs oral administration of bromocriptine: pharmacology and effect on serum prolactin in puerperal women.

The oral administration of bromocriptine induces a variety of side-effects in about 50-70% of patients, the most common being nausea and vomiting, probably related to the local gastrointestinal effect of the drug. Nasal administration makes it possible to avoid intestinal and liver metabolism. This study compared the serum concentrations of bromocriptine and prolactin (PRL) in twenty puerperal women who had asked to discontinue breast feeding and were randomized to receive a single oral (2.5 mg) or nasal spray dose (0.8 mg) of bromocriptine. Serum bromocriptine and PRL concentrations were measured at various times before and after drug administration. At 15 min, the circulating concentrations of bromocriptine were about eight times higher after nasal than after oral administration; peak serum concentration (CMax) was reached respectively 45 min and 60 min after administration, and was about three times higher after nasal administration (314 +/- 102 pg/ml vs 112.30 +/- 34.47 pg/ml). The reduction in serum PRL concentrations was also more rapid in the nasally-treated group reaching the normal assay range of < 20 micrograms/l within two as against five hours post-administration. Four orally-treated patients complained of nausea; in the nasally-treated group, six patients reported only a mild endonasal burning that disappeared within a few minutes of administration. Our results suggest that the nasal administration of bromocriptine may lead to a reduction in the required overall dose and fewer gastrointestinal side-effects, and may therefore improve therapy compliance.

Pharmacokinetics and endometrial effects of the vaginal administration of micronized progesterone in an oil-based solution to postmenopausal women.

OBJECTIVE: To study the pharmacokinetics of the transvaginal absorption of 100 mg micronized P from an oil-based solution in postmenopausal women before and after the estrogenization of the vaginal mucosa and to evaluate the endometrial effects of 10 days of once daily P vaginal administration. DESIGN: Prospective clinical trial. SETTING: University Medical School. PATIENTS: Nine postmenopausal women undergoing hormone replacement therapy. INTERVENTIONS: A micronized P (100 mg) oil-based solution currently available on the market for IM use was administered vaginally by means of a Teflon cannula without the aid of a speculum. Subsequently, the women received 4 weeks 0.1 mg/d transdermal E2 treatment combined on the last 10 days with the once daily vaginal administration of P in the same way as before. MAIN OUTCOME MEASURES: At the first (before estrogen) and second (during estrogen therapy) P administrations, P serum levels were measured at time 0, and then after 15, 30, 45, 60, 120, 240, 480, and 1440 minutes. Endometrial samples were collected at the end of treatment. RESULTS: After the first administration, a mean Cmax of 5.40 +/- 0.92 ng/mL (mean +/- SD) was reached at a Tmax of 45 minutes (range 30 to 480 minutes). The serum concentrations returned to their initial values after 24 hours. The second P administration reached a mean Cmax of 5.30 +/- 1.04 ng/mL at a Tmax of 60 minutes (range 30 to 240 minutes); after 24 hours, the serum P levels still were significantly higher than at baseline and at the same time after the first administration. None of the women complained of significant vaginal losses. No signs of vaginal phlogosis or irritation were observed. In all subjects, histologic evaluation showed clear endometrial secretory changes. CONCLUSIONS: The daily vaginal administration of one vial of micronized P for 10 days allowed useful serum P levels to be reached, especially after estrogen therapy, and induced clear secretory changes in the endometrium.

Administration of unmodified progesterone by nasal spray in fertile women.

A 11.20-mg dose of progesterone was administered by nasal spray to five healthy fertile women in the follicular phase of the menstrual cycle. Serial blood samples were collected and Cmax (the maximum progesterone concentration reached), Tmax (the time at which Cmax was reached) and the area under the curve (AUC), with the time limits of 0 and 720 min, were calculated. Serum progesterone levels were assayed by means of a non-extraction [125I]radioimmunoassay. The mean Cmax was 4.50 +/- 2.31 ng/ml at a Tmax of 30 min; levels returned to baseline after 720 min. The mean AUC value was 1180.50 +/- 613.90 ng.h/ml. The progesterone administered by nasal spray in fertile women was effective in reaching physiological progesterone levels. Even if a nasal first-pass metabolic effect is taken into account, this route allows progesterone to avoid liver first-pass metabolism and its metabolic consequences.

[Transvaginal absorption of an oleic solution of progesterone (Gestone) in fertile women]. / Assorbimento per via vaginale di una soluzione oleosa di progesterone (Gestone) in donne in età fertile.

Transvaginal absorption of a progesterone (P) oleic formulation, commercially available for intramuscular administration (Gestone, Amsa, Rome), has been investigated in five fertile women in the follicular phase. The contents of a vial, corresponding to P 100 mg, was administered intravaginally by a syringe connected to an atraumatic cannula inserted in the vagina. While administering and for a further 10 minutes the woman remained in the recumbent position. Blood samples for P assay were drawn at the following times: 0, 15, 30, 45, 60, 120, 240, 360, 480 and 1440 minutes. Mean CMax was 5.08 +/- 1.66 ng/ml, and the difference between baseline and CMax values was statistically significant (p < 0.01). TMax resulted as 60 minutes (range 45-240 minutes). Mean serum levels lowered subsequently but resulted as still significantly higher than baseline (p < 0.05) after 1440 minutes. Mean AUC 0-1440 value was 4236.75 ng h/ml. Any local or systemic side-effects were noted. No evidence of vaginal irritation was observed in any women. On the basis of the present data it is possible to suggest that a twice daily administration schedule could ensure suitable P serum levels in fertile women.

Responsabilidade do fator hemodinâmico na gênese da síndrome do túnel do carpo nos pacientes hemodialisados / Haemodynamic factor responsibility in the genesis of the carpal tunnel syndrome in haemodialyzed patients

A patologia esquelética representa uma complicaçäo importante no paciente dialisado a longo prazo, sendo numerosas as síndromes clínico-radiológicas de osteoartropatia com ela relacionadas. Entre essas, a síndrome de túnel do carpo é, sem dúvida, a mais importante e frequente. Muitos fatores säo mencionados como responsáveis na gênese da CTS no paciente dialisado crônico. Tendo presente o problema etiopatogênico, até hoje discutido, e considerando alguns dados clínicos verificados em 80 pacientes tratados na Divisäo de Cirurgia Plástica, iniciou-se um estudo com a finalidade de evidenciar o possível papel patogênico do fator hemodinâmico na gênese da síndrome do túnel do carpo no paciente hemodialisado. Os autores, com base nos resultados de um estudo retrospectivo, realizaram um estudo controlado, evidenciando o papel do fator hemodinâmico na gênese da síndrome do túnel do carpo no paciente hemodialisado. Os autores, com base nos resultados de um estudo retrospectivo, realizaram um estudo controlado, evidenciando o papel do fator hemodinâmico sobre os agentes etiológicos, no sentido de facilitar a determinaçäo da síndrome do túnel do carpo

Extensäo profilática da ligamentotomia ao membro contralateral nos pacientes hemodialisados afetados por síndrome do túnel do carpo / Prophilactic extension of ligamentotomy of the contralateral member in hemodialysed patients affected by the carpal tunnel syndrome

Dentro do contexto das patologias esqueléticas observadas com frequência no paciente dialisado, a síndrome do túnel do carpo ocupa os primeiros lugares na taxa de incidência. Embora seja relatada com percentagens diversas por vários autores, geralmente a mesma aparece de 5 a 8 anos após a hemodiálise, com um percentual de 50 por cento após 15 anos e de 100 por cento após 20 anos. Os A.A., examinando os dados relevados pela casuística própria e aqueles relatados na literatura, voltaram sua atençäo para a maior incidência das síndromes monolaterais do lado do acesso vascular e para a precocidade do aparecimento das mesmas. Com base nessas premissas, formularam a hipótese da possibilidade de uma intervençäo profilática ou de um rígido follow-up a nível do membro contralateral nos pacientes submetidos a ligamentotomia do membro sede do acesso vascular, visto que a intervençäo eletiva de ligamentotomia, mesmo sendo resolutiva para a sintomatologia álgica, näo permite a recuperaçäo morfo-funcional do nervo mediano

Nasal spray administration of unmodified progesterone: evaluation of progesterone serum levels with three different radioimmunoassay techniques.

A 11.20 mg dose of progesterone was administered by nasal spray (NS) to six healthy postmenopausal women. Serial blood samples were collected and plasma progesterone was assayed by radioimmunoassay (RIA) according to three different procedures. In the first, RIA was carried out directly on plasma aliquot (Method A), in the second after diethyl ether extraction (Method B) and the third, after diethyl ether extraction and Celite column chromatography (Method C). The mean serum peak level (CMax) calculated with Method A (2.87 +/- 1.14 ng/ml) was higher than that obtained with both Method B (2.24 +/- 0.76 ng/ml) and C (1.58 +/- 0.76 ng/ml; P < 0.05); similarly the area under the curve (AUC) measured with Method A (695.79 +/- 348.24 ng h/ml) was higher than that obtained with both Method B (390.12 +/- 95.16 ng h/ml) and C (243.71 +/- 82.97 ng h/ml; P < 0.02). On the other hand, progesterone serum levels measured with Method C peaked earlier than those observed with Methods B and A (21.67 +/- 19.40, 25.83 +/- 18.55 and 35 +/- 20.70 min, respectively). These data are consistent with the high specificity of Method C for progesterone whereas the other methods could overestimate the progesterone serum levels probably measuring also progesterone metabolites particularly 5 alpha- and 5 beta-dihydroprogesterone. This study confirmed the rapid absorption of progesterone across the nasal mucosa avoiding the first-pass liver metabolism; however, a 'first-pass effect' of the nasal mucosa should be taken into consideration when progesterone is delivered by the nasal route because probably a significant portion of progestational effects are due to its active metabolites.

Effects of the repetitive administration of progesterone by nasal spray in postmenopausal women.

OBJECTIVE: To study the effects of 10 days of nasal spray P treatment on P serum levels and the endometrium. DESIGN: Prospective. SETTING: University Medical School. PATIENTS: Eight postmenopausal women received oral conjugated estrogens at a daily dose of 0.625 mg for 4 weeks immediately before vaginal surgery for prolapse. For the first 9 of the last 10 days the patients also received a nasal spray dosage of 11.2 mg P three times a day; on the 10th day they received only one dose. MAIN OUTCOME MEASURES: Blood samples were taken at 8:00 A.M. on treatment days 1, 3, 5, 7, 10, and 11 to follow P serum concentration levels. Endometrial samples for histologic examination were collected before P administration and immediately after surgery to evaluate the end-organ effect. RESULTS: Mean P serum levels increased sixfold after 9 days of nasal spray P administration [from 0.612 +/- 0.280 ng/mL (1.958 +/- 0.896 nmol/L) to 3.925 +/- 1.553 ng/mL (12.560 +/- 4.970 nmol/L)] and declined thereafter, returning to the before treatment levels 24 hours after the last administration. In all subjects, the first histologic evaluation showed proliferative endometrium; the second showed clear secretive changes. CONCLUSIONS: Repetitive nasal spray P administration for 10 days in postmenopausal women led to increasing P serum levels and, when the estrogen stimulation was adequate, to secretory changes in the endometrium (end-organ effect).

Effects of progesterone administered by nasal spray on the human postmenopausal endometrium.

The aim of the study was to assess the effectiveness of progesterone (P) administered by nasal spray (NS) in inducing secretory changes within estrogen and non-estrogen primed postmenopausal endometrium. Ten healthy post-menopausal women before vaginal hysterectomy for prolapse were randomly treated by either oral estrogens for 3-4 weeks combined for the last 5-7 days with nasally administered P at the daily dose of 34 mg, or by only P for 6 days. Endometrial samples were taken before P administration and 8 h after the last dose. In the group not treated with estrogens, P did not induce significant secretory changes in any case except one which showed a proliferative endometrial pattern at the first evaluation. In the group treated with estrogens, in all the cases after P administration clear secretory changes (abundant vacuoles, endoluminal secretion) occurred. It is possible to conclude that P administered by NS exerts an end-organ effect within the endometrium of postmenopausal women pretreated with estrogens.

Hysteroscopy for diagnosis and treatment of endometrial adenocarcinoma precursors. A review of literature.

The guidelines for early detection of adenocarcinoma and its precursors are controversial. Ultrasound, due to its non invasive nature, could represent a useful technique for screening patients at risk but its specificity is low. Endometrial cytology, especially by using new device, is an effective, easy, and inexpensive method for screening asymptomatic women; however, cytologic investigation shows some limits due to the scarce desquamation of endometrial cells and to the difficulty in diagnosing hyperplasia. Blind biopsy can miss the pathology in cases of focal lesions. Dilatation and curettage gives, in most cases, a certain histologic diagnosis but, requiring anesthesia and hospitalization, is not suitable for mass screening; moreover, in cases of focal lesions its sensitivity is low. Microhysteroscopy allows an atraumatic and direct investigation of the uterine cavity and could be used as a routine basis in patients with risk factors for endometrial pathology and signs of hyperestrogenism. In symptomatic patients its employment must be considered necessary for a correct and modern management of these patients. Operative hysteroscopy represents a promising way for treating hyperplastic endometrial lesions without signs of atypia, but its value in comparison with hysterectomy must be confirmed; when atypia is found, hysterectomy is the treatment of choice.