The pathogenesis of polycystic ovary syndrome: lessons from ovarian stimulation studies

In polycystic ovary syndrome (PCOS) the ovary produces markedly increased amounts of both androgens and estrogens in response to gonadotropin stimulation. Distinctive responses of 17-hydroxyprogesterone and androstenedione to ovarian stimulation testing suggest that ovarian hyperandrogenism is a result of dysregulation of theca cell androgen production which is intrinsic to the ovary. The occurrence of hyperestrogenism together with hyperandrogenism in PCOS suggests that whatever the abnormality of local regulatory factors of steroidogenesis, it affects granulosa as well as theca cells. Dysregulation is often associated with an increase in the number of follicles which evade atresia and reach the 2-8 mm stage of development. Autocrine/paracrine factors, especially those which are FSH-dependent, likely play an important role in the pathogenesis of the ovarian abnormality. Both LH and insulin hypersecretion probably play a secondary role in PCOS by amplifying the preexisting ovarian dysregulation. Because FSH secretion is under tight long-loop negative-feedback control and LH is not, hyperandrogenism is the primary clinical manifestation of dysregulation of steroid production in PCOS. However, anovulation in PCOS is most likely a result of excessive estrogen and inhibin production by multiple, small follicles which inhibit FSH secretory dynamics sufficiently to prevent selection of a dominant follicle.     

Late endocrine effects of ovarian electrocautery in women with polycystic ovary syndrome

Intravenous (i.v.) bolus injection of calcitonin gene-related peptide (CGRP) caused a depressor response, which was significantly larger in 12-week-old spontaneously hypertensive rats (SHR) than in Wistar-Kyoto rats (WKY). CGRP also caused decreases in carotid and hindquarter vascular resistance, the magnitude of which was larger in the carotid than the hindquarter. In both regions, the vasodilator response to CGRP was significantly larger in SHR than WKY. Plasma CGRP level was significantly lower in SHR than WKY. These results suggest that depressor and vasodilator responses to CGRP are enhanced in SHR and that decreased plasma CGRP level in SHR may contribute to the enhanced responses.     

Involvement of ovarian steroids in the opioid-mediated reduction of insulin secretion in hyperinsulinemic patients with polycystic ovary syndrome

To evaluate the possible involvement of ovarian steroids on the opioid-mediated disorders of insulin in patients affected by polycystic ovary syndrome (PCOS), we studied 40 PCOS women. All patients underwent an oral glucose tolerance test (OGTT; 75 g) and basal hormone assay; based on the insulin response to OGTT, 26 women were classified as hyperinsulinemic and continued the study protocol. Patients were randomly divided into three groups characterized by different treatments: group A (nine patients) was treated with GnRH analog (one ampule every 28 days for 2 months), group B (eight patients) was treated with naltrexone (an oral opioid antagonist, 50 mg/day, orally) for 8 weeks, and group C (nine patients) was treated with GnRH analog plus naltrexone for 2 months. After continuation of treatment, all patients repeated the basal study in a second hospitalization. Naltrexone treatment significantly reduced the insulin response to OGTT, whereas GnRH analogue administration did not significantly change the insulin secretion after the glucose load. The GnRH analog/ naltrexone cotreatment was not able to influence the insulin secretory pattern; in fact, the insulin area under the curve was superimposable before and after therapy. These data could lead to the hypothesis that the opioidergic regulation of insulin secretion requires a normal steroidogenic pattern, thus suggesting that ovarian steroids modulate opioid activity also at peripheric districts.     

Role of GnRH drive in the pathophysiology of polycystic ovary syndrome

Polycystic ovary syndrome may result from multiple mechanisms, but full expression of the PCO syndrome with hyperandrogenic anovulation depends upon sustained LH drive and relative FSH deficiency. We have described possible intrinsic and extrinsic factors capable of modifying the hypothalamic-pituitary-ovarian axis. Available evidence suggests the presence of an intrinsic alteration in GnRH-LH drive. The long-term natural history of HAA is variable and depends on several factors including obesity, aberrations in insulin action, intrinsic ovarian function, and end-organ responsiveness to androgens. Figure 1 presents a conceptualization of the pathogenesis of PCOS diagramming the multiple modulators of its expression. Long-term suppression of androgens when fertility is not desired should modify the full expression of the PCO syndrome. It is important to appreciate that therapy with oral contraceptive agents has few drawbacks and many immediate and potential long-term benefits for women with HAA. This therapy may be of greatest benefit when started in adolescence prior to the progression of obesity, hirsutism, and thecal-stromal hyperplasia. Women with HAA represent a large subgroup of patients who require individualization of their health care with sensitivity to issues surrounding anovulation, obesity, hirsutism, and infertility.     

Endometrioid carcinoma of the ovary: a retrospective analysis of 106 cases

138 surgical institutions in Germany retrospectively answered a questionnaire on available energy sources, techniques of preparation and complications due to the use of electric current in laparoscopic surgery. The median experience in this field of surgery was 6 years. For common laparoscopic operations the majority of surgeons use electrosurgery; only 8% never do so. Except in appendectomy, monopolar cautery is preferred for all operations. Other energy devices are of minor importance. The overall number of operations reported was nearly 138,000. The rate of complications due to the use of electric current was 0.1%. This figure is accounted for in equal part by intra- and postoperative burns. The complication rate is at the lower end of the range known from the literature. Even though the retrospective nature of this analysis may hide a certain number of injuries electric, current plays a minor role for complications in laparoscopic surgery.     

Rare manifestations of the ovarian hyperstimulation syndrome: a report of two cases

Eosinophilic ulcer of the oral mucosa (EUOM) is an uncommon lesion that usually affects the tongue. The lesion is benign and self-limiting, develops rapidly and usually disappears after several weeks without treatment. Microscopically, it contains a diffuse polymorphous cell infiltrate composed mainly of eosinophils. The cause of EUOM is unknown, but the condition has been attributed to trauma. We now describe a case of EUOM on the lateral surface of the tongue with recurrence on its dorsal surface 3 years later. The occurrence of multiple lesions, whether at the same time or subsequently as reported here, makes a purely traumatic origin rather unlikely and suggests that there may be a predisposition of some patients to develop EUOM. Eosinophilic ulcer of the oral mucosa (EUOM) is an uncommon lesion that is very rarely reported in the dermatological literature. It usually affects the tongue and presents clinically as an ulcer with elevated and indurated borders. Recognition is important because it often mimicks tongue cancer; however, the lesion is benign and self-limiting, develops rapidly and usually disappears after several weeks without treatment. Usually the ulcer occurs in a single episode, but the possibility of recurrence at other sites has been poorly emphasized.     

Adrenal androgen excess in the polycystic ovary syndrome: sensitivity and responsivity of the hypothalamic-pituitary-adrenal axis

Over 50% of patients with the polycystic ovary syndrome (PCOS) demonstrate excess levels of adrenal androgens (AAs), particularly dehydroepiandrosterone sulfate (DHS). Nonetheless, the mechanism for the AA excess remains unclear. It has been noted that in PCOS the pituitary and ovarian responses to their respective trophic factors (i.e. GnRH and LH, respectively) are exaggerated. Similarly, we have postulated that excess AAs in PCOS arises from dysfunction of the hypothalamic-pituitary-adrenal axis, due to 1) exaggerated pituitary secretion of ACTH in response to hypothalamic CRH, 2) excess sensitivity/responsivity of AAs to ACTH stimulation, or 3) both. To test this hypothesis we studied 12 PCOS patients with AA excess (HI-DHS; DHS, > 8.1 mumol/L or 3000 ng/mL), 12 PCOS patients without AA excess (LO-DHS; DHS, < 7.5 mumol/L or 2750 ng/mL), and 11 controls (normal subjects). Each subject underwent an acute 90-min ovine CRH stimulation test (1 microgram/kg) and an 8-h incremental i.v. stimulation with ACTH-(1-24) at doses ranging from 20-2880 ng/1.5 m2.h) with a final bolus of 0.25 mg. All patient groups had similar mean body mass indexes and ages, and both tests were performed in the morning during the follicular phase (days 3-10) of the same menstrual cycle, separated by 48-96 h. During the acute ovine CRH stimulation test, no significant differences in the net maximal response (i.e. change from baseline to peak level) for ACTH, dehydroepiandrosterone (DHA), androstenedione (A4), or cortisol (F) or for the DHA/ACTH, A4/ACTH, or F/ACTH ratios was observed. Nonetheless, the net response of DHA/F and the areas under the curve (AUCs) for DHA and DHA/F indicated a greater response for HI-DHS vs. LO-DHS or normal subjects. The AUC for A4 and A4/F and the delta A4/delta F ratio (delta = net maximum change) indicated that HI-DHS and LO-DHS had similar responses, which were greater than that of the normal subjects, although the difference between LO-DHS patients and normal subjects reached significance only for the AUC of the A4 response. No difference in the sensitivity (i.e. threshold or minimal stimulatory dose) to ACTH was noted between the groups for any of the steroids measured. Nonetheless, the average dose of ACTH-(1-24) required for a threshold response was higher for DHA than for F and A4 in all groups. No difference in mean responsivity (slope of response to incremental ACTH stimulation) was observed for DHA and F between study groups, whereas the responsivity of A4 was higher in HI-DHS patients than in normal or LO-DHS women. The net maximal and the overall (i.e. AUC) responses of DHA were greater for HI-DHS than for normal or LO-DHS women. The response of A4 and the delta A4/delta F ratio were greater for HI-DHS patients than for LO-DHS patients or normal subjects. Alternatively, HI-DHS and LO-DHS patients had similar overall responses (i.e. AUC) for A4 or A4/F, although both were greater than those of normal subjects. The relative differences in response to incremental ACTH stimulation between steroids was consistent for all subject groups studied, i.e. A4 > F or DHA. In conclusion, our data suggest that AA excess in PCOS patients is related to an exaggerated secretory response of the adrenal cortex for DHA and A4, but not to an altered pituitary responsivity to CRH or to increased sensitivity of these AAs to ACTH stimulation. Whether the increased responsivity to ACTH for these steroids is secondary to increased zonae reticularis mass or to differences in P450c17 alpha activity, particularly of the delta 4 pathway, remains to be determined.     

Febrile morbidity in severe and critical ovarian hyperstimulation syndrome: a multicentre study

The objective of this study was to define the incidence of febrile morbidity and its causes in severe and critical ovarian hyperstimulation syndrome (OHSS). For this purpose, we reviewed the medical records of all OHSS patients hospitalized in 16 out of 19 tertiary medical centres in Israel between January 1987 and December 1996. Febrile morbidity was defined as at least one episode of temperature rise above 38 degrees C lasting > or =24 h. A total of 2902 patients (3305 hospitalizations) with OHSS was identified, of whom 196 had severe, and 13 critical, OHSS. Among the 209 patients investigated the incidence of febrile morbidity was 82.3%, of which 20.5% was attributed to urinary tract infection, 3.8% to pneumonia, 3.3% to upper respiratory tract infection, 2.0% to intravenous line phlebitis, 1.0% to cellulitis at an abdominal puncture site, 1.0% to postoperative wound infections and 0.5 % to gluteal abscess at the site of progesterone injection. Non-typical organisms were frequently isolated, such as Pseudomonas, Proteus, Klebsiella and Enterobacter species. No infectious aetiology was found in 105 patients (50.2%). Hypoglobulinaemia was recorded in most patients, while ascitic and pleural fluids aspirated from these patients contained high globulin concentrations. We conclude that infection-related febrile morbidity in severe and critical OHSS is high, and may be attributed to some degree of immunodeficiency associated with loss of plasma globulins to the third space. However, non-infection-related febrile morbidity is even higher and may be attributed to endogenous pyrogenic mechanisms.     

Impaired adipocyte lipolysis in nonobese women with the polycystic ovary syndrome: a possible link to insulin resistance?

The polycystic ovary syndrome (PCOS) is the most common hyperandrogenic disorder among women and is characterized by metabolic and cardiovascular aberrations similar to those seen in the so-called insulin resistance syndrome. The regulation of lipolysis was investigated in isolated abdominal sc adipocytes from 10 nonobese women with PCOS and in 11 age- and body mass index-matched healthy women. Eight PCOS women were reinvestigated after 3 months of treatment with combined oral contraceptives containing ethinyl estradiol and norethisterone, which normalized hyperandrogenicity. The PCOS women showed a marked resistance to the lipolytic effect of noradrenaline due to defects at two different levels in the lipolytic cascade: first, a 7-fold reduction in sensitivity to the beta 2-selective agonist terbutaline (P < 0.005), which could be ascribed to a 50% lower beta 2-adrenoceptor density (P < 0.02) as determined with radioligand binding; there was no difference with regard to dobutamine (beta 1) or clonidine (alpha 2-sensitivity) or beta 1-adrenoceptor density; second, the maximum lipolytic response was also 35% lower (P < 0.02) in the PCOS women compared to that in the healthy women. This was seen with all beta-adrenergic agonists and the postreceptor-acting agents forskolin (activating adenylyl cyclase) and dibutyryl cAMP (activating protein kinase). Neither beta 2-adrenoceptor sensitivity or density nor the reduced lipolytic responsiveness was restored by 3 months of oral contraceptives treatment. The results indicate the existence of a marked impairment of catecholamine-induced lipolysis in nonobese PCOS women displaying early features of the insulin resistance syndrome due to multiple lipolysis defects as a lower beta 2-adrenoceptor density and reduced function of the protein kinase, hormone-sensitive lipase complex. These lipolysis defects are identical to those observed in the insulin resistance (metabolic) syndrome and could be a primary pathogenic mechanism for the development of these disorders.     

Computed imaging-assisted stereotactic brain biopsy: a risk analysis of 225 consecutive cases

BACKGROUND: Treatment strategies for intracranial mass lesions are most effective when based upon histopathological diagnoses. Image-guided stereotaxy has provided the means to sample tissue from small or deeply seated intraparenchymal lesions with a relatively high degree of safety and accuracy. Although procedural complications are infrequent, devastating neurological sequelae may result from hemorrhage or direct trauma. This study was undertaken to identify factors that may confer an increased risk of morbidity from stereotactic brain biopsy. METHODS: Two hundred twenty-five consecutive computer-assisted stereotactic brain biopsy procedures were reviewed. Patient age averaged 47.4 years (range, 3-84 years); gender ratio was approximately 2:1 (male:female). Pre-existing medical conditions were identified in nearly half of the cohort. 61.3% of biopsied lesions were lobar; the remainder (38.7%) were "deep-seated" (thalamus, basal ganglia, pineal, hypothalamus, cerebellum, brainstem). Glial tumors accounted for the majority (44.4%) of biopsied lesions; metastases (12.9%) and lymphoma (11.6%) were also relatively common. Demographical, anatomical, surgical, and histological data were compiled and putative risk factors for morbidity identified. These variables were then subjected to univariate and logistic regression analyses to determine their significance as independent predictors of operative risk. RESULTS: Twelve patients suffered complications as a consequence of the biopsy procedure (eight from hemorrhage, four from direct trauma). Major morbidity (hemiparesis, aphasia, obtundation) occurred in eight patients (3.6%). Three patients (1.3%) suffered minor morbidity (transient, mild neurological deficits). One operative fatality occurred (0.4%). An increased risk of morbidity was associated with the preoperative use of antiplatelet agents, chronic corticosteroids, deep-seated lesions, malignant gliomas, and a greater number of biopsy attempts (p < 0.05). Factors not conferring increased morbidity included gender, age, pre-existing illness, extracranial malignancy, cardiac disease, hypertension, diabetes, HIV status, and instrument used to procure the specimen. CONCLUSIONS: Complications arising from stereotactic brain biopsy are infrequent but can be disastrous. Operative risk is a function of several independent variables, including lesion properties (location, histology), preoperative pharmacological therapy (corticosteroids, antiplatelet agents), and operative technique. This analysis suggests that the morbidity of stereotactic brain biopsy may be minimized by risk factor modification.     

Pure immature teratoma of the ovary: analysis of 22 cases

Between 1970 and 1991, 22 patients with pure immature teratoma were treated at the Center of Oncology in Krakow. Sixteen (72.7%) patients had stage I, four (18.2%) stage II, and two (9.1%) stage III of disease, nine (40.9%) patients had grade 1, 11 (50%) grade 2, and two (9.1%) grade 3 tumors. Eight stage Ia, grade 1 patients were treated with surgery only, the remaining 14 (63.6%) received postoperative chemotherapy. Five-year NED (no evidence of disease) survival was achieved in 81.8% of patients. Out of 16 stage I patients, 15 (93.8%) survived 5-year NED, out of six stage II and III, three (50%) patients only survived this period. We cured all grade 1 patients, and 81.8% (9/11) grade 2; two grade 3 patients died because of tumors. We also cured all six stage Ia patients, treated with unilateral salpingo-oophorectomy (with or without chemotherapy), and all eight stage Ia grade 1 patients treated with surgery only.     

Laparoscopic resection of ovarian benign cystic teratomas: experience with 84 cases

Laparoscopic treatment of benign cystic teratoma of the ovary has been recommended following the study of relatively small numbers of patients. We reviewed our experience with a prospective ongoing protocol for the treatment of benign ovarian teratomas, between January 1990 and December 1996. Sonography established the diagnosis, and biochemical markers were used to screen for possible malignancy. Surgery consisted of resecting the cyst and conserving the ovary if appropriate. The resected cyst was aspirated of its contents following insertion into an EndoCatch bag. Removal was accomplished via the narrowest incision possible by pulling the bag's margins through the incision and grasping the solid parts with conventional surgical instruments. The diameter of the cysts ranged from 2 to 15 cm. Cystectomy was performed in 47, and oophorectomy in 37, patients. Spillage occurred in 11 cases, but none developed peritonitis or fever. The mean duration of post-operative stay was 0.9 days (range 0.5-2). We conclude that laparoscopic resection of benign teratomas of the ovary is safe, well tolerated, and shortens hospital stay.     

The effect of a pure antiandrogen receptor blocker, flutamide, on the lipid profile in the polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting women of reproductive age; it is associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. This study was designed to assess the long term effects of a pure androgen receptor blocker, flutamide, on the lipid profile in women with PCOS and to examine the possible mechanisms by which androgens may exert their influence. Seventeen women with PCOS (10 obese and 7 lean) were studied. All subjects received a 12-week course of oral flutamide (500 mg/day). The baseline and posttreatment evaluations included lipid profile, androgen levels, insulin sensitivity, and serum catecholamine determinations. The primary outcome was the change in the ratio of low density lipoproteins (LDL) to high density lipoproteins (HDL). Treatment with flutamide was associated with a significant decrease in the LDL/HDL ratio by 23% (P = 0.005), in total cholesterol by 18% (P < 0.0001), in LDL by 13% (P = 0.002), and in triglycerides by 23% (P = 0.002). Flutamide treatment was also associated with a trend toward an increase in HDL (by 14%; P = 0.14). The effects on lipid profile were found regardless of obesity and were not associated with a change in weight. Furthermore, actions of flutamide on lipid metabolism were not associated with significant changes in circulating adrenaline or noradrenaline, glucose metabolism, or insulin sensitivity. This report has demonstrated for the first time that treatment with the pure antiandrogen, flutamide, may improve the lipid profile and that this effect may be due to direct inhibition of androgenic actions.     

Injury of the popliteal artery & the popliteal branches: analysis of 31 consecutive cases

In complex traumas of lower limbs it is fundamental the reducing of the time of ischemia to reduce the number of failures in repairing surgery and the percentage of the demolishing of necessity surgery. The experience of the authors is based on 31 complex traumas of lower limbs with distal vascular injuries to Hunter's canal, which were associated to bone, nervous and muscular lesions. In total we are treated 37 vascular injuries by interposition of venous autografts in 37 cases, lateral pacth in one case ant suture T-T in two cases. The protection of the reconstructed vases, in case of a concomitant loss of substance, was entrused to microvascular flaps for 7 times latissimus dorsi, iliac crest and fascio-cutaneous for 5 times posterior reversed with distal baset and for three times antero-lateral, which in three cases of them needed successively a dermoepidermic grafts. The bone injuries, which were treated by external fixation, intramedullary nailing, plate and screws, just in two cases became worse in pseudoarthroses and just in one in osteomyelitis. The reparation of nervous injuries had bad results just in two cases. The percentage of saving of the limb it was about 83.9%.