A review of treatment response in type 2 diabetes: assessing the role of patient heterogeneity.

The response to treatment for type 2 diabetes typically varies among individuals within a study population. This variation is known as heterogeneity of treatment response. We conducted a comprehensive literature review to identify factors that account for heterogeneity of treatment response in patients treated for type 2 diabetes. Three databases (PubMed, EMBASE and Cochrane Library) were searched for articles published in the last 10 years describing investigations of factors associated with treatment response and outcomes among people with type 2 diabetes receiving pharmacological treatment. Of the 43 articles extracted and summarized, 35 (81%) discussed clinical factors, 31 (72%) described sociodemographic factors and 17 (40%) reported on comorbidity or behavioural factors. Clinical factors identified included baseline glycated hemoglobin A1c or fasting plasma glucose (FPG) levels, insulin response or sensitivity, C-peptide, body composition, adipose tissue proteins, lipid profile, plasma albumin levels and duration of disease or insulin treatment. Other factors identified included age, sex, race, socioeconomic status and comorbidities. This review identified the following research gaps: use of multiple definitions for response, few patient-reported measures and lack of evidence regarding whether factors were associated with treatment response for only specific medications or across pharmacological therapies. Furthermore, identification of factors associated with type 2 diabetes treatment response was generally a secondary objective in the research reviewed. Understanding which patient subgroups are more likely to respond to treatment and identifying factors associated with response may result in targeted treatment decisions and alter the interpretation of efficacy or effectiveness of results. In conclusion, accounting for these factors in clinical trials and when making clinical treatment decisions may improve therapy selection and individual patient outcomes.

Minimally invasive ablation of a toxic thyroid nodule by high-intensity focused ultrasound.

HIFU is used in the treatment of cancer (prostate, breast) and uterine fibroma but not yet in TNs. This case report describes the first successful ablation of a toxic TN with HIFU. TSH and radioiodine scan normalization were achieved without complications and maintained for 18 months. HIFU treatment is a minimally invasive technique that may be an effective safe alternative to radioiodine or surgery in patients with toxic TNs.

Expression of metalloproteinases and their inhibitors in blood vessels in human endometrium.

Matrix metalloproteinases (MMPs) are zinc-requiring enzymes that can degrade components of the extracellular matrix and that are implicated in tissue remodeling. Their role in the onset of menstruation in vivo has been proven; however, the expression and functions of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in vascular structures are poorly understood. We determined by immunocytochemistry, using characterized monoclonal antibodies, the distribution of MMPs and of their inhibitors TIMP-1 and TIMP-2 in the endometrium during the menstrual cycle. MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 had differing distributions and patterns of expression. In addition to the localization of MMP-9 in the epithelium and of MMP-2, MMP-3, and MMP-1 in the stromal tissue, these MMPs were detected in the vascular structures. MMP-2 (72-kDa gelatinase) and tissue inhibitors TIMP-1 and TIMP-2 were detectable in vessels throughout the cycle. In contrast, MMP-3 (stromelysin-1) was detected only in late-secretory and menstrual endometrial vessels, while MMP-9 (92-kDa gelatinase) was detected in spiral arteries during the secretory phase and in vascular structures during the midfollicular and menstrual phases. The expression of MMP-2 and MMP-9 in endometrial vessels during the proliferative and secretory periods suggests their relationship to vascular growth and angiogenesis. The pronounced expression of MMP-3 (stromelysin-1) in the vessels situated in the superficial endometrial layer during menses suggests that this metalloproteinase initiates damage in the vascular wall during menstrual breakdown. The finding of an intense expression of TIMP-1 and TIMP-2 in the vessels delineating necrotic from non-necrotic areas during menses also suggests that they could limit tissue damage, allowing regeneration of the endometrium after menses. These data indicate that, in addition to expression in epithelial cells and stromal tissue, MMPs are expressed in endometrial vascular cells in a cycle-specific pattern, consistent with regulation by steroid hormones and with specific roles in the vascular remodeling processes occurring in the endometrium during the cycle.

Main inhibitor of follicle stimulating hormone in the luteal-follicular transition: inhibin A, oestradiol, or inhibin B?

The roles of oestradiol, inhibin A and inhibin B in the luteal-follicular transition were assessed by means of specific assays. Six premenopausal women were studied during a control and then a cycle treated with percutaneous oestradiol 0.1 mg/day from day 10 after the luteinizing hormone (LH) surge until day 4 of the following cycle. Inhibin A concentrations decreased similarly in control and treated cycles from day -5 to day 2, then increased in control cycle to 23.3 +/- 3.4 pg/ml on day 10 (mean +/- SEM). They remained low until day 5 in treated cycles and were lower than controls on day 10 (P < 0.01). Follicle stimulating hormone (FSH) concentrations increased on day 1 in controls and on day 5 in treated cycles when oestradiol concentration fell abruptly. Inhibin B concentrations remained low until day 1 in controls and day 4 in treated cycles. In both, inhibin B concentrations increased 1 day after FSH, peaking at 160 pg/ml. FSH concentrations began to plateau when inhibin B concentrations were >100 pg/ml and oestradiol concentrations below 200 pmol/l. These data suggest that inhibin A is not responsible for FSH suppression in the luteal phase and that the negative control of FSH shifts from oestradiol in the luteal phase to inhibin B in the mid-follicular phase.

Human estrogen sulfotransferase (hEST1) activities and its mRNA in various breast cancer cell lines. Effect of the progestin, promegestone (R-5020).

Using reverse transcriptase-polymerase chain reaction amplification it was possible to detect the presence of type 1 human estrogen sulfotransferase (hEST1) mRNA in the hormone-dependent: MCF-7 and T-47D, and hormone-independent: MDA-MB-231 and MDA-MB-468, human breast cancer cells. The expression of this mRNA is significantly higher in the MDA-MB-468 cells and a correlation of this mRNA expression with the enzymatic activity was observed. The progestin promegestone (R-5020) at a low concentration (5 x 10(-7) M) can significantly increase the estrogen sulfotransferase activity and its mRNA in the hormone-dependent MCF-7 and T-47D cells. As estrogen sulfates are biologically inactive, the stimulatory effect on sulfotransferase by promegestone may open attractive possibilities in the control of estradiol in human breast cancer.

Silent necrosis of a pituitary corticotroph adenoma revealed by timely magnetic resonance imaging: a cause of spontaneous remission of Cushing's disease.

Spontaneous necrosis of a corticotroph adenoma is rare and is a very unlikely way of curing Cushing's disease. We report hereafter a case where magnetic resonance imaging of the pituitary provided clear evidence of the event. Successive and timely pituitary magnetic resonance imaging in this patient showed first a typical microadenoma as a well-limited mass with a low signal intensity before the necrosis, then a bright signal before gadolinium injection in the T1-weighted image at the time of the event and, finally, the aspect of an empty sella turcica with a small arachnoidocele 1 year later. The necrosis of a corticotroph adenoma is more frequent in macro- than in microadenomas, and is usually heralded by headache and visual disturbances. In this case, pituitary necrosis was entirely asymptomatic, and cured the patient as well as the surgeon's knife would have. Nevertheless, this exceptional occurrence does not rule out the possibility of a recurrence.

The combination of gonadotrophin-releasing hormone (GnRH) antagonist and pulsatile GnRH normalizes luteinizing hormone secretion in polycystic ovarian disease but fails to induce follicular maturation.

To evaluate the role of altered luteinizing hormone (LH) release in the mechanism of polycystic ovarian disease (PCOD) anovulation, we have co-administered a gonadotrophin-releasing hormone (GnRH) antagonist and pulsatile GnRH therapy to two clomiphene citrate-resistant PCOD patients. The aim was to correct their inappropriate gonadotrophin secretion. Nal-Glu was administered s.c. every 72 h to both subjects for 3 weeks. On day 7 after commencing the study, intravenous pulsatile GnRH therapy was initiated (10 micrograms/pulse) every 90 min for 15 days to both subjects. In one subject, Nal-Glu treatment was continued and the GnRH dose was increased to 20 micrograms/pulse for 10 additional days. Prior to Nal-Glu, mean serum LH levels were 10.4 +/- 1.6 and 9.3 +/- 1.3 mIU/ml (mean +/- SEM) and mean interpulse intervals were 67.1 and 60 min in patients 1 and 2, respectively. Mean serum FSH levels were 4.9 +/- 0.4 and 4.2 +/- 0.2 mIU/ml for patients 1 and 2, respectively. LH pulsatility was abolished following Nal-Glu, mean serum LH decreased to 1.1 +/- 0.1 and 1.3 +/- 0.5 mIU/ml and mean FSH to 1.8 +/- 0.1 and 2 +/- 0.1 mIU/ml in the two subjects. On the 4th day of the combined therapy, mean serum LH increased to 5.4 +/- 1.3 and 3.9 +/- 0.9 mIU/ml with a mean interpulse interval of 72 and 80 min, respectively. Mean FSH levels increased to 3 +/- 0.1 and 2.8 +/- 0.1 mIU/ml, respectively and to 5.5 +/- 0.2 mIU/ml after the GnRH dose was increased in patient 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of estradiol in the rise in follicle-stimulating hormone levels during the luteal-follicular transition.

Follicular recruitment takes place under FSH stimulation at the end of the luteal phase and the beginning of the subsequent follicular phase, the so-called luteal-follicular transition (LFT). Inhibin, a known suppressor of FSH, has been implicated in the onset of the rise in FSH levels, as the fall in its immunoreactive plasma levels after the demise of the corpus luteum has been shown to correlate negatively with the increase in FSH. To analyze the role of estradiol (E2), another inhibitor of FSH secretion in the LFT, we designed an experimental paradigm to dissociate the physiological falls in inhibin and E2. This was achieved by extending the duration of luteal plasma E2 levels with transdermal E2 treatment. Untreated ovulatory cycles in seven healthy female volunteers, aged 28-38 yr, were compared with E2-treated cycles in the same subjects, with treatment starting on the 10th day after the LH surge and continuing through the 4th day of the following menses [either 0.2 mg (n = 6; G1) or 0.1 mg (n = 6; G2) E2 daily]. Blood samples were obtained daily from the LH surge until the 11th day of the next cycle. Immunoreactive plasma inhibin levels reached a nadir on day 2 of menses regardless of whether women received E2. Plasma E2 (mean +/- SEM) levels remained within the normal luteal range (220 +/- 51 to 635 +/- 279 pmol/L) until the end of the treatment period in G2 (range, 253 +/- 40 to 382 +/- 62 pmol/L), but not in G1 (range, 598 +/- 195 to 1835 +/- 1259 pmol/L). However, the onset of the FSH rise was clearly delayed, from a mean of 2 days before menstruation in the controls to day 4 of the cycle in G1 and G2. Peak plasma FSH levels were attained within 6 days in the controls and within 2 or 3 days in both treatment periods. Our data suggest that it is the decrease in plasma E2 rather than inhibin that is the triggering signal for the LFT rise in plasma FSH. The exact roles of inhibin and other gonadal proteins (e.g. activins) in follicular recruitment remain to be determined.

Inhibin and follicle-stimulating hormone levels in gonadotroph adenomas: evidence of a positive correlation with tumour volume in men.

OBJECTIVE: Gonadotroph adenomas are generally revealed by symptoms of mass effect at the stage of macroadenoma. Most of them hypersecrete FSH and/or gonadotrophin subunits. Rarely they hypersecrete LH, which could induce endocrinological symptoms. As the glycoprotein inhibin is secreted by the gonads under FSH control, we have evaluated whether high immunoreactive inhibin (iINH) levels correlated with FSH hypersecretion and whether iINH and FSH levels were related to tumour volume in subjects with gonadotroph adenomas. PATIENTS: Forty-five patients (30 men, 15 women) were retrospectively selected on the basis of immunostaining technique using specific antibodies raised against FSH-beta, LH-beta and glycoprotein alpha-subunit. MEASUREMENTS: Immunoreactive inhibin (iINH) was measured by radioimmunoassay using antiserum 1989 raised to bovine inhibin. Tumour volume index was the product in cm3 of length, width and height of the adenoma as assessed by computerized tomography. RESULTS: In men (age 21-61 years), iINH levels were positively correlated with FSH levels (Spearman's r = 0.67, P < 0.001), and both iINH and FSH levels were significantly correlated with tumour volume index (Spearman's r = 0.38, P < 0.05 and r = 0.39, P < 0.05 respectively). In the subgroup of men with normal FSH levels (n = 17), the correlation of FSH with tumour volume index was high: Spearman's r = 0.56, P < 0.05. In the post-menopausal women (n = 8, age > 55 years), iINH levels were undetectable or below the follicular phase range regardless of FSH values. In the premenopausal women (n = 7, age 22-49 years, follicular phase or amenorrhoea) iINH levels were above follicular phase range in three women including one who had very high FSH levels. CONCLUSIONS: These data show that in men with gonadotroph adenoma FSH levels are related to tumour mass and suggest that a significant part of circulating FSH in patients with normal FSH levels arises from the tumour. The significant correlation between iINH and FSH levels demonstrates that tumoral FSH is bioactive and that high iINH levels do not exert any feedback control on tumoral FSH secretion. Therefore the coexistence of high FSH levels with high iINH levels is strongly suggestive of a gonadotroph adenoma. Gonadotroph adenomas seem to represent a unique model of long-term FSH stimulation of inhibin-producing cells, in some way analogous to that created by repetitive administration of exogenous FSH.