Frequency and severity of vasomotor symptoms among peri- and postmenopausal women in the United States.

OBJECTIVE: To describe characteristics of vasomotor symptoms, specifically daily frequency and severity, among women 40-65 years old in the United States (US). DESIGN: A survey was completed by a nationally representative sample of 4402 US women aged 40-65 years old. A questionnaire focusing on menopausal symptoms was administered online in April 2005. RESULTS: The prevalence of vasomotor symptoms was 79% in peri- and 65% in postmenopausal women. Women with daily vasomotor symptoms had an average of 2.5 very mild/mild, 2.6 moderate, 2.5 severe, and 1.4 very severe daytime hot flushes in a typical day. Women with night sweats every night had an average of 2.4 moderate, 3.2 severe, and 2.7 very severe night sweats in a typical night. Overall, 9% of peri- and 7% of postmenopausal women reported 7+ moderate to very severe vasomotor symptoms in a typical day. Although some women reported that symptoms were worse in the evening and in the summer, many women reported they were consistent, both throughout the day and throughout the seasons of the year. CONCLUSIONS: The Menopause Epidemiology Study builds upon existing literature by providing data on daily frequency and severity of vasomotor symptoms. There are many women with frequent and severe vasomotor symptoms who may benefit from treatment.

Thromboembolic complications after inferior petrosal sinus sampling in patients with cushing's syndrome.

OBJECTIVE: To heighten the awareness of treating physicians of the potential for serious and fatal thromboembolic complications after inferior petrosal sinus sampling in patients with Cushing's syndrome. METHODS: We retrospectively reviewed inpatient and outpatient medical records for a 12-year period to identify patients with Cushing's syndrome who had thromboembolic complications after inferior petrosal sinus sampling at a single institution. Case reports of affected patients are presented. RESULTS: Of 34 patients with corticotropin-dependent Cushing's syndrome who underwent inferior petrosal sinus sampling, 2 had deep venous thrombosis. One of these patients succumbed to pulmonary thromboembolism. CONCLUSION: Serious and potentially fatal thromboembolic disorders may complicate inferior petrosal sinus sampling. Prospective studies should be undertaken to determine the true incidence of deep venous thrombosis after this procedure in patients with Cushing's syndrome.

Serum androgens: associations with prostate cancer risk and hair patterning.

Cancer of the prostate is the leading cancer among American men, yet few risk factors have been established. Hair growth and development are influenced by androgens, and it has long been suspected that prostate cancer also is responsive to these hormones. A blinded, case-control study was undertaken to determine if hair patterning is associated with risk of prostate cancer, as well as specific hormonal profiles. The study accrued 315 male subjects who were stratified with regard to age, race, and case-control status (159 prostate cancer cases/156 controls). Hair-patterning classification and serum levels of total and free testosterone (T), sex hormone binding globulin, and dihydrotestosterone (DHT) were performed. Data indicate that hair patterning did not differ between prostate cancer cases and controls; however, significant hormonal differences were detected between the two groups. Free T was greater among cases than in controls (16.4 +/- 6.1 vs. 14.9 +/- 4.8 pg/ml, P = 0.02). Conversely, DHT-related ratios were greater among controls (P = 0.03 for DHT/T and P = 0.01 for DHT/free T). Several strong associations also were found between hormone levels and hair patterning. Men with vertex and frontal baldness had higher levels of free T (16.5 +/- 5.5 and 16.2 +/- 8.0 pg/ml, respectively) when compared to men with either little or no hair loss (14.8 +/- 4.7 pg/ml) (P = 0.01). Data suggest that increased levels of free T may be a risk factor for prostatic carcinoma. In addition, although no differences in hair patterning were detected between cases and controls within this older population, further research (i.e., prospective trials or case-control studies among younger men) may be necessary to determine if hair patterning serves as a viable biomarker for this disease, especially given the strong association between free T levels and baldness.

History and physical examination.

In summary, the history and physical examination provide a valuable overview of a patient's condition and clues as to the causes. Typically, the most important features are evidence of gynecomastia, completeness of genital development and virilization, testicular size and consistency, and condition of the prostate gland. Preliminary laboratory evaluation is usually done at the conclusion of the initial evaluation and generally includes a total or free testosterone level, a semen analysis, urinalysis, and screening profiles for blood count, liver and renal function, and serum electrolytes. A more detailed hormonal evaluation would include gonadotropins, luteinizing hormone and follicle-stimulating hormone, prolactin, estradiol, and possibly thyroid studies. With this information complete, the astute clinician can develop a working diagnosis and plan for further evaluation or referral to a specialist.

Endogenous opioids and hypogonadism in human obesity.

Massively obese males often show symptoms of hypogonadism, but the mechanism for this is unclear. Increased endogenous opioid inhibition of the hypothalamic GnRH pulse generator resulting in insufficient stimulation of the pituitary gonadotroph has been proposed as a possible mechanism. If this hypothesis is correct, obese males should be more sensitive to the LH-elevating effects of the opiate antagonist, naloxone, than men of normal weight and gonadal status. This study investigated the etiology of obesity-related hypogonadism by examining luteinizing hormone (LH) and follicle stimulating hormone (FSH) responses to gonadotropin-releasing hormone (GnRH) and to infusions of saline or naloxone. Subjects were five obese (201 +/- 14% IBW) and five normal weight (control) (97 +/- 4% IBW) males. Before treatment, obese males had significantly (p < 0.05) lower testosterone levels than control subjects (307 +/- 72 vs. 597 +/- 49 ng/dl), whereas estradiol, androstenedione, and dehydroepiandrosterone levels were not different between the two groups. Both groups showed equivalent elevations in LH (fourfold to sixfold) in response to GnRH stimulation, but obese patients had significantly lower basal (p < 0.05) and GnRH-stimulated (p < 0.01) FSH levels. Infusions of naloxone (but not saline) led to significant (p < 0.01) increases in LH above preinfusion baseline levels (20.5 +/- 2.8% in obese and 28.6 +/- 6.3% in controls). In control subjects, integrated LH levels during naloxone infusion were not significantly elevated above those found during saline infusion, while obese subjects exhibited a 43% augmentation of integrated LH (31.0 +/- 5.3 ng/ml during naloxone vs. 21.7 +/- 1.8 ng/ml during saline, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Transsphenoidal adenomectomy for growth hormone-secreting pituitary adenomas in acromegaly: outcome analysis and determinants of failure.

The results of transsphenoidal adenomectomy for growth hormone (GH)-secreting pituitary adenomas in acromegaly performed over a 17-year period were analyzed retrospectively to determine which preoperative factors significantly influenced the long-term surgical outcome. These variables were then used to develop a logistic regression model to determine the probability of surgical failure. The series consisted of 103 patients. Long-term follow-up study (mean duration 102 +/- 64 months) was performed to derive outcome analysis and determinants of failure. Surgical control was defined as a long-term postoperative serum basal GH level of less than 5 micrograms/liter, a long-term postoperative serum somatomedin C (SM-C) level of less than 2.2 U/ml, and a favorable clinical response. Eighteen (17.5%) patients did not meet these criteria. The overall control rate by the GH criteria was 81.3% and by the SM-C criteria 76.2%. By multivariate logistic regression analysis, tumor stage was the strongest predictor of outcome (p < 0.05). The preoperative GH level, tumor grade, and preoperative SM-C level were significant univariate predictors (p < 0.05). There were statistically significant differences in mean preoperative GH and SM-C levels (p < 0.05, t-test) and tumor stage (p < 0.05, chi-squared test) between patients whose acromegaly was controlled by surgery and those whose acromegaly was not. Furthermore, estimates were derived of the probability of surgical failure based on preoperative GH level, preoperative SM-C level, and tumor grade and stage. The authors believe these findings will enhance clinical decision-making for neurosurgeons considering transsphenoidal microsurgery in patients with acromegaly.

Androgen UDP-glucuronyl transferase activity is found primarily in liver in the rat.

UDP-glucuronyl transferase (UDPGT) activity was determined for androgens in tissue minces and microsomal fractions from the liver and extrahepatic tissues (kidney, skin, prostate, and preputial glands) of the male rat. Liver microsomes showed the highest UDPGT activity with each of the androgens tested (Vmax = 7, 3, and 10 nmol/minute/mg protein for testosterone, androsterone, and androstanediol, respectively). UDPGT activity (Vmax) for androstanediol in the liver was 10(2)-fold higher than in the kidney and 10(3)-fold higher than in the skin and prostate. UDPGT activity for androgens was not detected in microsomes from preputial glands. Furthermore, no body site distribution was found for androgen UDPGT activity in skin microsomes. The Michaelis-Menten constant (Km) for UDPGT in liver microsomes was 20.4, 12.2, and 2.2 microM, respectively, for testosterone, androstanediol, and androsterone. Kidney microsomes showed a Km of 19.4 and 26.9 microM, respectively, for androstanediol and androsterone. The Km for testosterone was very high in the kidney (138 microM), suggesting that it was a poor substrate. In microsomes from the skin and prostate, the Km was very high (range 43-162 microM) for all three androgen substrates, suggesting that these androgens were not the preferred substrates for UDPGT in these tissues. These results indicate that the liver was the main site of androgen UDPGT activity and the skin and prostate formed little, if any, androgen glucuronides. These results suggest that androstanediol glucuronide was formed primarily in the liver and may not be a reliable marker of peripheral androgen metabolism.

Fatal disseminated Conidiobolus coronatus infection in a renal transplant patient.

A case of fatal disseminated fungal infection due to Conidiobolus coronatus in a patient with a renal transplant is described. This organism, known to cause localized infections in otherwise healthy individuals in the tropics, is now recognized as a cause of fatal infection in immunosuppressed hosts. Histologically, localized infections are characterized by lack of vessel invasion and the presence of an eosinophilic sleeve around fungal elements, called the Splendore-Hoeppli phenomenon. The histologic findings in the present case were more typical of mucormycosis, and the correct diagnosis was established only after the organism was isolated and identified in culture.

Paradoxical response of plasma lipoprotein(a) in patients undergoing cardiopulmonary bypass.

Plasma lipid, lipoprotein and apolipoprotein levels are known to decrease after major surgery. Coronary artery bypass surgery additionally involves use of extracorporeal circulation by use of a cardiopulmonary bypass pump, which necessitates hemodilution due to saline dextrose infusion to prime the pump. To investigate changes in lipids, lipoproteins and apolipoproteins as well as changes in C-reactive protein and albumin we conducted a study on 22 patients undergoing cardiac surgery involving cardiopulmonary bypass. Timed arterial blood samples were taken before, during and after cardiopulmonary bypass. At the onset and during cardiopulmonary bypass a rapid and significant fall was observed in all lipids and lipoproteins except lipoprotein(a) with recovery to near basal levels by 72 h for cholesterol, triglycerides, high density lipoprotein cholesterol and albumin, while apolipoproteins AI and B remained below basal levels during the postoperative period up to 72 h. In contrast, lipoprotein(a) levels increased at the onset, doubled during cardiopulmonary bypass and remained elevated postoperatively. On the other hand, C-reactive protein levels fell at the onset and during cardiopulmonary bypass but they became markedly elevated postoperatively. When results were corrected for hemodilution, the response patterns remained unchanged. As lipoprotein(a) is both atherogenic and thrombogenic, its elevation during cardiopulmonary bypass may be clinically important.

Effects of insulin on renal sodium excretion.

The ability of insulin to decrease urinary sodium excretion has been recognized for more than 30 years. While most investigators agree that this occurs predominantly through increased tubular sodium reabsorption, the nephron segments at which insulin exerts this effect in vivo remain controversial. Additionally, little information is available in mammalian systems on the mechanism of the insulin response or its relation to other hormonal systems important in the regulation of tubular sodium transport. Data from amphibian transporting epithelia suggest a potential for interactions between insulin and several other peptide hormones in the regulation of sodium transport. The following discussion attempts to review our knowledge of the effects of insulin on renal sodium reabsorption and describes new data suggesting that insulin's antinatriuretic response is dependent on antidiuretic hormone but independent of the angiotensin and prostaglandin systems.

Changes in endocrine function after adrenal medullary transplantation to the central nervous system.

Ten patients were studied before and after autologous adrenal medullary transplantation to the central nervous system for Parkinson's disease to determine if the presence of new catecholamine-producing tissue near the hypothalamus would alter hypothalamic or pituitary function, mineralocorticoid levels, or catecholamine production. No clinically apparent ill effects occurred. Changes in endocrine function were largely short-term and transient: at 7-10 days after surgery, urinary catecholamine levels were significantly increased, PRL levels were significantly elevated despite markedly increased serum dopamine levels, and gonadal steroid levels (estradiol and testosterone) were significantly lower despite unchanged basal and stimulated levels of gonadotropins. Dehydroepiandrosterone sulfate was significantly reduced at 7-10 days after surgery and remained low at 3-6 months. Other changes at 3-6 months after surgery included increased stimulated corticotropin levels and reduced serum aldosterone response to upright posture. The changes at 7-10 days were probably due to stress or unilateral adrenalectomy or both; the changes at 3-6 months were likely due to unilateral adrenalectomy. We conclude that unilateral adrenalectomy and autologous adrenal medullary transplantation to the central nervous system does not produce clinically important changes in endocrine function; however, possible adverse consequences of long-term reduction of dehydroepiandrosterone sulfate levels cannot be excluded.

Parallel assays of beta-endorphin and ACTH in Cushing's patients undergoing petrosal sinus sampling.

This study explores the possibility of improving endocrinologic testing during petrosal sinus catheterization by determining both beta-endorphin and corticotropin (ACTH). We studied 14 patients with Cushing's disease, two with adrenal tumor, and three with ectopic tumors secreting ACTH. In patients with Cushing's disease, beta-endorphin concentrations paralleled those of ACTH in all basal plasma samples collected either from petrosal sinuses or peripheral veins. Individual responses of beta-endorphin and ACTH to corticotropin releasing hormone (CRH) were closely related to the presence of a corticotroph adenoma. In such patients, a consistently higher concentration of beta-endorphin over ACTH was observed in all samples collected either from petrosal sinuses or peripheral veins; the ratios were unchanged after the administration of CRH. In patients with ectopic ACTH secretion, the mean ratio of beta-endorphin over ACTH (with both values expressed in pmol/L) was significantly higher (3.5) than that of patients with Cushing's disease (2.9) or Cushing's syndrome due to adrenal tumor (2.7).

Steroidogenic enzyme activities, morphology, and receptor studies of a testicular adrenal rest in a patient with congenital adrenal hyperplasia.

Steroid-secreting tumors of the testis have generally been considered to be of Leydig cell origin. Testicular tumors in patients with congenital adrenal hyperplasia have been thought to be adrenal rests, but no conclusive evidence supporting the hypothesis has been presented. We report a morphological and biochemical analysis of a patient with 21-hydroxylase deficiency who developed bilateral nodular hyperplasia of steroid-secreting tissue within the testis, despite suppression therapy with both exogenous glucocorticoids and testosterone. The tissue was formed of confluent nodules of homogenous cells. Electron microscopy showed the cells to have abundant smooth endoplasmic reticulum, well developed Golgi apparatus, and mitochondria with predominantly tubular cristae, features characteristic of steroid-secreting cells of adrenocortical origin. Crystals of Reinke were not observed. Functional studies in vivo showed a marked response to ACTH infusion, with 17-hydroxyprogesterone rising from 56 to 13,500 ng/mL, cortisol from less than 2 to 19 micrograms/dL, and testosterone from 369 to 629 ng/dL, with an attendant increase in testicular size and pain over 48 h. Receptor studies in vitro revealed no gonadotropin receptors, but abundant angiotensin-II receptors. Enzyme activity analysis in vitro showed undetectable 21-hydroxylase activity and an enzyme profile consistent with adrenocortical cells rather than Leydig cells. Based on these morphological and biochemical findings, we conclude that the nodular steroidogenic tissue that replaced this patient's testes was of adrenal origin. The study documents for the first time the development of adrenocortical tumors from adrenal rest tissue within the testis.

Cushing's disease: results of transsphenoidal microsurgery with emphasis on surgical failures.

From 1977 to 1988, 56 patients with a preoperative diagnosis of Cushing's disease were treated by transsphenoidal microsurgical exploration of the pituitary gland. In 42 patients, a discrete tumor was found and a selective adenomectomy was performed. Total hypophysectomy was performed in nine patients. In an attempt to preserve pituitary function, a technique of subtotal hypophysectomy was utilized in the remaining five patients. Regular and adequate follow-up results were obtained in 53 patients. A sustained remission was obtained in 45 of these 53 patients for a remission rate of 84.9%. Eight patients were classified as therapeutic failures. The causes for failure included: 1) invasive tumor; 2) hyperplasia mistaken for an adenoma; 3) a presumed ectopic source of adrenocorticotropic hormone; 4) misdiagnosis; 5) atypical tumor; and 6) recurrence of disease after remission. In cases of therapeutic failure, the original diagnosis of Cushing's disease must be reevaluated and treatment continued until sustained remission is achieved. Necessary measures to help avoid surgical failures and an approach for further diagnostic and therapeutic maneuvers in these cases are discussed.

Sex steroids and bone density in premenopausal and perimenopausal women.

Bone density begins to decline in women before menopause, and the degree of bone loss is variable. We performed a cross-sectional analysis on the entry data of a 5-yr prospective study of risk factors for osteoporosis to determine the correlation of bone density with serum sex steroid concentrations and body weight. We studied 292 healthy white women, aged 35-50 yr, who were menstruating regularly or had had menses in the past 12 months. Blood samples were drawn in the early follicular phase for estradiol (E2), testosterone (T), dehydroepiandrosterone sulfate, and sex hormone-binding globulin (SHBG). Free levels of E2 (FE2) and T (FT) were calculated based on total T and E2, SHBG, and albumin levels. Women were classified as premenopausal (FSH, less than 12 U/L) and perimenopausal (FSH greater than or equal to 12 U/L; n = 46; 16%). Bone density was measured by dual photon absorptiometry of the lumbar spine (L2-L4) and hip and by single photon absorptiometry of the wrist. Perimenopausal women were older than premenopausal women (45.5 +/- 3.5 and 41.0 +/- 3.9 yr, respectively), but did not differ in height or weight. While bone density did not correlate with age in each group, perimenopausal women had significantly lower bone density at the L2-L4 and femoral neck (L2-L4, 1.18 +/- 0.14 in perimenopausal and 1.24 +/- 0.12 g/cm2 in premenopausal women; femur, 0.84 +/- 0.11 in perimenopausal and 0.90 +/- 0.11 g/cm2 in premenopausal women; P less than 0.005). Body weight showed the strongest positive correlation with bone density. Log FT, percent FT, and FE2 percent correlated positively with bone density, even after controlling for weight. Log SHBG was negatively correlated with bone density in premenopausal women at the hip and wrist after controlling for weight. FSH was inversely correlated with bone density, and E2 and T were lower in perimenopausal than premenopausal women. These data suggest that women who are still menstruating may have relative deficiencies in both E2 and T, with reduced bone densities as a consequence.

Reversible impairment of gonadotropin secretion in critical illness. Observations in postmenopausal women.

Gonadotropin levels were measured in 65 postmenopausal women admitted to the intensive care unit. Sixteen patients (25%) were hypogonadotropic as measured by luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels of 5 IU/L or less, and only 20 patients (31%) were found to have gonadotropin levels within the expected postmenopausal range (greater than or equal to 30 IU/L). No significant differences in prolactin or free thyroxine levels were found, but the cortisol level was higher and the total thyroxine level lower in the hypogonadotropic group. The patients in the hypogonadotropic group also seemed more seriously ill, with a longer duration of hospitalization, an increased total number of days in the intensive care unit, an increased number of days in the intensive care unit before gonadotropin sampling, a higher incidence of parenteral hyperalimentation, lower serum albumin levels, and higher mortality. Stimulation of the gonadotropin-releasing hormone performed on 10 patients showed a blunted response in patients with baseline LH and FSH levels of 10 IU/L or less. Of 10 patients followed up sequentially, 6 showed a rise in gonadotropin levels that paralleled recovery, 1 died with low gonadotropin levels, and 3 continued to have low gonadotropin levels 17, 34, and 82 days, respectively, after initial screening. Critically ill postmenopausal women may exhibit a marked fall in gonadotropin, LH, and FSH levels. This disease in gonadotropin levels in response to illness is reversible and results from pituitary unresponsiveness to gonadorelin hydrochloride.

Treatment of men with idiopathic oligozoospermic infertility using the aromatase inhibitor, testolactone. Results of a double-blinded, randomized, placebo-controlled trial with crossover.

The hypothesis that increased estradiol production may be the cause of impaired spermatogenesis in infertile men with idiopathic oligozoospermia was tested by administering the aromatase inhibitor, testolactone, and by assessing its effects on sperm output and fertility. Our study was a randomized, placebo-controlled double-blind crossover trial. Subjects (n = 25) with infertility due to unexplained oligozoospermia were given testolactone (2 g/day) or placebo for 8 months followed by crossover to the other treatment for an additional 8 months. Total estradiol and testosterone levels during testolactone exposure did not change from basal and placebo values. However, sex hormone-binding globulin binding capacity consistently decreased (30%, p less than 0.01) and free testosterone levels increased (36%, p less than 0.01). Free estradiol values increased but not significantly. Additionally, LH and FSH serum levels increased by 15% and 20%, respectively (p less than 0.05), and 17 alpha-hydroxyprogesterone values increased by 90% (p less than 0.05) during drug administration. Sperm output and semen quality remained unchanged during either testolactone or placebo treatment, and no pregnancies occurred during the 16-month study. These data suggest that chronic administration of testolactone at this dose fails to maintain aromatase inhibition despite depression of 17,20-desmolase activity with elevated 17 alpha-hydroxyprogesterone and depressed SHBG binding capacity with elevation of free testosterone. Testolactone is not efficacious in the treatment of idiopathic oligozoospermic infertility.

A low sperm concentration does not preclude fertility in men with isolated hypogonadotropic hypogonadism after gonadotropin therapy.

In order to define the minimal number of sperm needed for conception, we studied semen characteristics of men with isolated hypogonadotropic hypogonadism (IHH) who became sperm-positive during gonadotropin therapy. Twenty-two of 24 men (92%) proved fertile, initiating a total of 40 pregnancies. The mean (+/- standard error of the mean) sperm concentration at the time of conception was 16.7 +/- 4.0 X 10(6)/ml. However, 71% of pregnancies were conceived when the mean sperm concentration was less than 20 X 10(6)/ml; in 16%, the mean sperm concentration was less than 1 X 10(6)/ml. Mean total sperm count correlated highly with sperm concentration (r = 0.67, P less than 0.001). We conclude that men with IHH can initiate conception even when their sperm concentration is well below the conventional lower limit of 20 X 10(6)/ml.