Individual effect of E2 and dydrogesterone on insulin sensitivity in post-menopausal women.

The aim of this study was to evaluate the impact of a three-month continuous administration of oral E2, alone, or combined with 2 different dosages of dydrogesterone, on the glucose tolerance and insulin sensitivity in postmenopausal women. In a prospective placebo-controlled study, 43 normal weight and normoinsulinemic women were randomized to receive either 2 mg of oral 17beta E2 daily (group A), or 2 mg E2 daily plus 5 mg daily oral dydrogesterone, from day 14 to 28, in a sequentially combined regimen (group B), or 2 mg of E2 and 10 mg dydrogesterone in the same sequentially combined regimen (group C) or placebo for 12 weeks. An OGTT and a euglycemic hyperinsulinemic clamp were performed before and after treatment. Serum glucose and insulin concentrations were measured both in fasting conditions and after OGTT. C-peptide pancreatic secretion was tested only in fasting conditions. Total body glucose utilization (M), for insulin sensitivity evaluation, was determined in each subject. Postmenopausal women treated with unopposed 17beta E2 (group A) showed a slight but statistically significant decrease of insulin sensitivity (p<0.05). A more marked deterioration of the same parameter was observed in the 2 groups treated with E2 plus dydrogesterone (group B and group C: p<0.01). Post hoc testing for the percent change from baseline indicated that group A significantly differed from group C (p<0.05) and all treated groups significantly differed from the placebo group (p<0.01). Finally, after treatment in group C, a significant reduction of insulin and an increase of glucose responses to OGTT (p<0.01) were observed. These results indicate that, in a short-term period, the use of 17beta E2 and overall 17beta E2 plus dydrogesterone, even with the reduction of insulin plasma levels, might cause a decrease in insulin sensitivity in normal weight and normoinsulinemic post-menopausal women.

Fertility outcome: long-term results after laparoscopic myomectomy.

From 1991 to 1998, 29 patients desiring a pregnancy underwent laparoscopic myomectomy for symptomatic myomas measuring 5.4 +/- 3.6 cm (mean +/- SD) (median 5; range 1-9). The overall rate of intrauterine pregnancy was 65.5% (19 pregnancies; two patients had two pregnancies each). Results were analyzed in relation to different preoperative clinical conditions. Out of nine patients with other infertility factors associated with uterine myomas, three (33.3%) became pregnant; out of 10 infertile patients with no other associated infertility factors, seven (70%) became pregnant; out of 10 patients to whom myomectomy was performed for the rapid growth of the tumor or for myoma encroaching on the cavity, nine (90%) had a pregnancy. Nine patients (73.4%) had a Cesarean section (one twice), four (26.6%) had spontaneous vaginal delivery, one patient had a serious placental failure at the 28th week, and four patients (19%) miscarried. Two pregnancies are still in progress (one in a patient with previous miscarriage). Out of 21 pregnancies, the viable term delivery rate was 57.14%. No uterine ruptures were observed. The pregnancy rate after laparoscopic myomectomy was similar to that reported in other studies after laparotomic myomectomy. It is concluded that laparoscopic myomectomy is a reliable procedure even in the presence of multiple or enlarged myomas. Moreover, our pregnancy rate and pregnancy outcome seem to indicate that both desire for pregnancy and infertility prior to surgery should not be exclusion criteria for the laparoscopic approach.

Long-term results of laparoscopic myomectomy: recurrence rate in comparison with abdominal myomectomy.

Laparoscopic myomectomy is still a debated procedure and there are conflicting opinions regarding the recurrence rate. Laparoscopic myomectomy may present a higher risk of recurrence compared with abdominal myomectomy. The aim of this investigation was to analyse the recurrence rate of myomas after surgery. From January 1991 to June 1998, 165 myomectomies were performed for symptomatic myomas measuring at least 3 cm in diameter and numbering seven or less per patient. During the first 3 years of this survey, 81 patients were randomized for abdominal or laparoscopic myomectomy. Transvaginal ultrasound examination was performed within 15-30 days of surgery and every 6 months for a post-operative period of 40 months. The two groups had similar pre-operative clinical features and the number and volume of myomas did not differ between the two groups. At the end of the study the group of abdominal myomectomies showed nine recurrences (23%) against 11 (27%) of the laparoscopic group. In order to evaluate the recurrence rate in relation to several risk factors, laparoscopic myomectomies were performed from 1991 in 84 patients who agreed to follow-up (and were not in the randomized group). Of these, 78 patients were evaluated with transvaginal ultrasound for a mean interval of 26 months and 17 (21.78%) recurrences were found. Most recurrences (75%) were seen at ultrasound between 10 and 30 months after surgery. The patient's age, pre- and post-operative gravidity and parity had no influence on recurrence. Neither the number of myomas removed nor the depth of penetration or size were positively associated with the risk of recurrence. However, an associated risk factor was pre-operative gonadotrophin-releasing hormone agonist treatment (P < 0.02). None of the women with recurrence required additional surgery. We conclude that laparoscopic myomectomy is a reliable procedure. The recurrence rate is similar to that seen after abdominal myomectomy.

Effect of feeding on growth hormone response to growth hormone-releasing hormone in polycystic ovarian syndrome: relation with body weight and hyperinsulinism.

The plasma growth hormone (GH) response to direct stimulation with growth hormone-releasing hormone (GHRH) before and after a standard meal was investigated in 14 polycystic ovarian syndrome (PCOS) subjects. Data were compared with those obtained from 14 healthy normovulatory matched patients. All women underwent an oral glucose tolerance test (OGTT) (75 g) and basal plasma hormone concentrations were evaluated. On a different day all subjects had a GHRH test (50 microg GHRH) both before and after lunch randomly. In obese PCOS subjects the GH response to GHRH was blunted after a meal, while in obese control patients there was an enhanced response of GH to GHRH after a meal. Normal control subjects showed an inhibition of the GH response after feeding and lean PCOS subjects showed a trend toward an augmented GHRH related secretion after a meal significantly higher than normal controls (P < 0.05) but not significantly higher than the pre-prandial response. In conclusion, the data indicate in PCOS a derangement of GH secretion related to food ingestion; in particular obese PCOS patients did not exhibit any change of GH response after a meal compared with the paradoxical response observed in obese controls. Several other factors beyond body mass index and hyperinsulinism could be involved in these pathophysiological events.

Differential effect of transdermal estrogen plus progestagen replacement therapy on insulin metabolism in postmenopausal women: relation to their insulinemic secretion.

OBJECTIVE: To evaluate the impact on glucose and insulin metabolism of transdermal estrogen patches before and after the addition of cyclic dydrogesterone in postmenopausal women. DESIGN: We studied 21 postmenopausal women seeking treatment for symptomatic menopause. All patients received transdermal 50 micrograms/day estradiol for 24 weeks. After 12 weeks of treatment, 10 mg/day dydrogesterone were added. METHODS: During both regimens, insulin and C-peptide plasma concentrations were evaluated after an oral glucose tolerance test (OGTT); insulin sensitivity was evaluated by a hyperinsulinemic euglycemic clamp technique. Insulin and C-peptide response to OGTT were expressed as area under the curve (AUC) and as incremental AUC; insulin sensitivity was expressed as mg/kg body weight. Fractional hepatic insulin extraction (FHIE) was estimated by the difference between the incremental AUC of the C-peptide and insulin divided by the incremental AUC of the C-peptide. Plasma hormone and lipid concentrations were assessed at baseline and at 12 and 24 weeks of treatment. RESULTS: Nine patients proved to be hyperinsulinemic and 12 were normoinsulinemic. Transdermal estrogen treatment significantly decreased the insulin AUC (P < 0.05) and the insulin incremental AUC in hyperinsulinemic patients; addition of dydrogesterone further decreased both the AUC and incremental AUC of insulin. Estrogen alone and combined with dydrogesterone evoked a significant increase in C-peptide AUC in hyperinsulinemic (79.2%) and normoinsulinemic (113%) patients. The treatment increased the values for FHIE and insulin sensitivity in all patients (P < 0.04) and in the hyperinsulinemic group (P < 0.01), whereas it did not affect such parameters in normoinsulinemic patients. CONCLUSIONS: Transdermal estrogen substitution alone and combined with cyclical dydrogesterone may ameliorate hyperinsulinemia in a selected population of postmenopausal women.

Growth hormone administration normalizes the ovarian responsiveness to follicle-stimulating-hormone in the early stages of the follicular maturation in women with Down syndrome.

To investigate the sensitivity of ovary to follicle-stimulating hormone (FSH) during the early follicular phase of the human menstrual cycle in patients with Down Syndrome (DS) six postmenarchal patients with Down Syndrome and twelve normoovulatory women were studied. Randomly, DS patients were submitted in two consecutive cycles to a treatment with GH (0.1 IU/Kg i.m.) or saline for 3 days. Pure FSH (75 IU) was given i.v. at day 3 and plasma levels of LH, FSH, E2, Testosterone, DHEAS, Androstenedione, GH and IGF-I were assayed in samples collected for a period of 26 h after the injection. Data were compared with those obtained from controls receiving pure FSH or saline. In control patients FSH injection increased E2 stimulated area under curve (AUC). This value was significantly greater than that found in DS patients, who exhibited an E2-stimulated AUC superimposable to saline treated controls. In DS GH plasma concentrations were significantly lower than in control group (p < 0.05). The treatment with GH is able to normalize the ovarian response to FSH in DS patients at levels similar to those found in FSH treated controls. Moreover in GH treated cycles, both GH and IGF-I plasma concentrations were higher at time of FSH injection with respect to those found in the cycles where saline was given. These results indicate that the ovarian sensitivity to FSH in patients with DS is blunted. Lower GH plasma levels found in this group may in part account for this biological feature, since GH treatment is able to restore the ovarian response, probably via an increase of IGF-I plasma concentrations.

Endocrino-metabolic features in women with polycystic ovary syndrome during pregnancy.

To elucidate the mechanism of metabolic adaptation of women with polycystic ovary syndrome (PCOS) during pregnancy, the endocrino-metabolic features of a group of PCOS patients with or without gestational diabetes were studied longitudinally during the three trimesters of gestation. Oral glucose tolerance test (OGTT, 100 g) and hyperinsulinaemic-euglycaemic clamp were performed throughout the study. Plasma concentrations of insulin and glucose were determined by radioimmunoassay and glucose oxidase technique, respectively. Five of 13 PCOS patients developed gestational diabetes (GD) at the third trimester (PCOS-GD), while the other eight patients did not develop any alteration of glucose metabolism (PCOS-nGD). Both fasting glucose and insulin plasma concentrations did not change significantly during pregnancy and no difference was seen between the two groups. On the contrary PCOS-GD group early exhibited higher values of area under the curve (AUC) for glucose and insulin response to OGTT with respect to those found in PCOS-nGD group. This difference was already significant in the first gestational trimester. Moreover insulin sensitivity value (M) was significantly lower in the first trimester of gestation in PCOS-GD as compared with that found in PCOS-nGD group. However, as gestation proceeded, M value decreased in PCOS-nDG group and the difference from PCOS patients developing gestational diabetes was not sustained into the second and third trimesters. Both groups had similar body mass index values and AUC insulin increase from first to third trimester of gestation. It is concluded that early alteration of insulin sensitivity and secretion constitute specific risk factors in PCOS patients for the development of abnormalities of glucose tolerance.

Growth hormone enhances estradiol production follicle-stimulating hormone-induced in the early stage of the follicular maturation.

OBJECTIVE: To investigate the ability of GH to increase the steroidogenic response of the ovary to FSH in the early stage of human follicle development in vivo. DESIGN: Ovarian sensitivity to FSH and/or GH during the early follicular phase of the human menstrual cycle was evaluated in a prospective study. SETTING: Normal human volunteers in the Department of Obstetrics and Gynecology, Università Cattolica Sacro Cuore. PATIENT(S): Twenty-four normal patients with normo-ovulatory cycles and tubal factor infertility. INTERVENTION(S): Pure urinary FSH (75 IU) or saline were injected IV in the early follicular phase with or without a pretreatment with human GH (0.1 IU/kg IM for 3 days). MAIN OUTCOME MEASURE(S): Plasma levels of LH, FSH, E2, and T in samples collected for a period of 26 hours after saline or FSH IV injection. RESULT(S): Follicle-stimulating hormone injection increased E2 and E2:T stimulated area under the curve (AUC) with respect to saline administration. Moreover, the E2 secretion was increased significantly in the group treated with GH plus FSH as compared with that found in the group receiving FSH alone. Growth hormone itself was unable to increase any steroidogenic response by ovary in terms of both E2 and E2:T AUC values. CONCLUSION(S): The results of present study demonstrate in vivo a synergistic effect of GH on the FSH-induced follicular steroidogenesis, suggesting a potential relevance of GH in the reproductive biology.