Reproductive endocrine issues in men with sickle cell anemia.

In patients with sickle cell anemia, the sickling of red blood cells is known to cause end-organ damage by infarction. In some men who are affected by sickle cell anemia, the obstruction of venous outflow of the penis causes priapism, which could lead to erectile dysfunction. There is also evidence that the disease is linked to other reproductive issues in men-specifically delayed puberty, low testosterone, and sperm abnormalities-although the causes of these problems are less clear. Treatment of sickle cell anemia can have effects on the reproductive system as well. This review summarizes the findings from various publications pertaining to reproductive endocrinology, along with their conclusions and discrepancies.

Circulating divalent cations in asymptomatic ovarian hyperstimulation and in vitro fertilization patients.

It is known that ovarian hyperstimulation and in vitro fertilization are accompanied by a steady increase in circulating estrogen and progesterone far beyond what is normal for young women. We have recently demonstrated that the biologically active fractions of calcium and magnesium in blood are altered depending on when in the menstrual phase a blood sample is drawn in normal cycling women. The serum ionized Ca/Mg ratio is also altered in accordance with the menstrual cycles. This suggests that the sex steroid hormones may modulate serum levels of ionized Mg and the ionized Ca/Mg ratio. We therefore studied the relationships between sex steroid hormones and the concentrations of ionized magnesium and calcium in the blood of hyperstimulated patients. We were able to demonstrate that with each increment in estrogen, a decrease in ionized Mg occurred, and as the progesterone rose in the blood, the ionized Ca/Mg ratio increased. Our results support the idea that serum estrogen and progesterone levels in women modulate the blood levels of circulating ionized Mg and the serum ionized Ca/Mg ratio.

Divalent cations in women with PCOS: implications for cardiovascular disease.

Polycystic ovary syndrome (PCOS) patients are known to have a high incidence of insulin resistance and glucose intolerance and tend to be at eventual high risk of hypertension, diabetes mellitus and cardiovascular disease. It has been repeatedly shown that a low serum ionized magnesium (Mg2+) and a high ionized calcium to magnesium (Ca2+/Mg2+) ratio is often associated with insulin resistance, cardiovascular problems, diabetes mellitus and hypertension. We were therefore interested in assessing the serum divalent cation profile of PCOS patients compared with that of normal women of similar age. We found significantly lower serum Mg2+ and total magnesium and a significantly higher serum Ca2+/Mg2+ ratio in the PCOS patients compared with the controls. No correlation was found, however, between the serum concentrations of steroid hormones (estrogen, progesterone and testosterone), or any of the cations in the PCOS patients or the controls.

Do heavier women benefit from a higher dose of leuprolide acetate for suppression of serum estradiol?

OBJECTIVE: To determine if heavier women benefit from a higher dose of the gonadotropin-releasing hormone analogue leuprolide acetate (LA) depot in terms of suppression of serum estradiol. METHODS: This was a retrospective analysis of the effect of LA depot 3.75 mg and 7.5 mg on serum estradiol from a multicenter, double-blind, parallel-group, 12-week study of women with anemia due to bleeding from uterine leiomyomata. Serum estradiol levels were obtained at baseline and at week 12. Patients were divided into weight quartiles according to their baseline weight in kilograms: 46-<64, 64-<72, 72-<89, 89-159 (pounds-102-<140, 140-<159, 159-<196, 196-350). RESULTS: At baseline there was no statistically significant difference in estradiol level between groups as a whole or within weight quartiles. Within each group there was no relationship between weight and baseline estradiol. At week 12, whereas estradiol levels were significantly greater in the heavier patients in each of the groups (LA 3.75 mg, p = 0.044; LA 7.5 mg, p = 0.002), there was no significant difference in estradiol between groups as a whole or within any of the weight quartiles. Moreover, at week 12 there was no significant difference between groups in the percentage of patients with estradiol suppressed to the menopausal range. CONCLUSION: Heavier women do not benefit from a higher dose of LA depot (7.5 vs. 3.75 mg) for suppression of serum levels of estradiol.

Serum ionized magnesium and calcium and sex hormones in healthy young men: importance of serum progesterone level.

OBJECTIVE: To determine the serum concentrations of the sex hormones with respect to the concentrations of the biologically active fractions of magnesium (Mg) and calcium (Ca) in healthy young men and to compare them with those in young and older women. DESIGN: Controlled clinical study. SETTING: An academic research environment. PATIENT(S): Twenty-five healthy young male volunteers. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Concentrations of the sex steroid hormones testosterone, estrogen, and progesterone, and levels of ionized Ca (Ca2+) and Mg (Mg2+) were measured in the serum of healthy young men. These levels were compared with those in young women at different phases of the menstrual cycle and with those in older women. RESULT(S): The Mg2+ and total Mg concentrations in young men were not different from those during the follicular phase in young women or from the mean concentrations in menopausal women. The Ca2+ levels in young men were similar to the levels in young women during the follicular phase but significantly lower than the levels in older women. The Mg2+ concentration in the young men was directly and significantly related to the progesterone level, and the Ca2+/Mg2+ ratio was inversely related to the progesterone level. CONCLUSION(S): Progesterone may be a more important steroid hormone in men than previously believed.

Hormonal treatment of bilateral proximal tubal obstruction.

OBJECTIVE: To see whether medical suppressive treatment might be considered in the treatment of a subgroup of patients. with proximal tubal obstruction (PTO), one of the major causes for infertility, often due to endometriosis of the tubouterine junction and therefore primarily treated by operative procedures. METHODS: 23 infertile patients with bilateral PTO were treated with hormonal suppression therapy with GnRH agonists, norethindrone acetate, or danazol for at least 3 months. The average age of the patients and duration of infertility were (mean + SD) 32.4 +/- 4.8 and 3.9 +/- 2.2, respectively. Bilateral PTO was diagnosed by both hysterosalpingography and laparoscopy. RESULTS: Fifteen of the 23 patients (65%) were diagnosed as having pelvic endometriosis prior to treatment. Following the treatment, 16 of the 23 patients (69.6%) were shown to have have at least one patent fallopian tube, and 9 patients conceived (39.1%). No patient became pregnant in the absence of one patent tube after treatment. CONCLUSION: Hormonal suppressive therapy can be an alternative treatment in patients with bilateral PTO for a period as short as 3 months before any invasive procedure.

Serum ionized magnesium and calcium in women after menopause: inverse relation of estrogen with ionized magnesium.

OBJECTIVE: To study the serum concentrations of the sex steroid hormones and free divalent cations Mg2+ and Ca2+ in healthy women at or past menopause and to compare them with the serum concentrations of healthy, cycling women of child-bearing age at different stages of the menstrual cycle. DESIGN: Controlled clinical study. SETTING: An academic medical center. PATIENT(S): Women of varying age and duration of menopause, and healthy, cycling women. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum levels of the sex steroids (estrogen, progesterone, and testosterone) and of Ca2+ and Mg2+ were measured in menopausal and postmenopausal women, and in healthy, cycling women at five different stages of the menstrual cycle. RESULT(S): The Mg2+ and total Mg levels of the postmenopausal women were inversely related to the serum level of estrogen and were similar to the levels present during the early follicular phase of healthy women of child-bearing age. The Ca2+ level was unrelated to the sex steroid hormones present, but it was increased compared with that of younger women in both the follicular phase and the luteal phase. CONCLUSION(S): Serum levels of Mg2+ and total Mg were inversely correlated with the estrogen concentration in menopausal women. Serum levels of Ca2+ were significantly elevated in menopausal women compared with younger women, but the ratio of Ca2+ to Mg2+, a measure of cardiovascular problems, was not elevated in the postmenopausal women.

Placental 11 beta-hydroxysteroid dehydrogenase activity in normotensive and pre-eclamptic pregnancies.

Apparent mineralocorticoid excess and licorice induced hypertension, both hypertensive disorders, have been attributed to a defect in the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), which interconverts cortisol to cortisone. Therefore, we undertook this study to determine the role of human placental 11 beta-HSD activity in preeclampsia, which is a hypertensive disorder in pregnancy. 11 beta-HSD activities were determined in placentas of 17 normotensive and 11 preeclamptic patients matched for gestational age at 34-42 weeks. Cortisol levels in umbilical venous and arterial sera were also determined for both groups. Statistical analysis was performed using Student's t-test, significance at p < 0.05. 11 beta-dehydrogenase (oxidation activity of 11 beta-HSD) activity was significantly lower in placentas of preeclamptic compared to normotensive patients (0.19 +/- 0.09 vs. 0.26 +/- 0.08 mmoles/min/placenta, p = 0.02). Cortisol level in umbilical cord blood was significantly higher in the preeclamptic group (14.99 +/- 14.08 vs. 6.71 +/- 3.69 g/dL, p = 0.02). The decreased 11 beta-HSD activity is accompanied by an expected increase in umbilical cord blood cortisol level and decrease in fetal weight. This enzyme may play an important role in influencing fetal growth.

Endometriosis with massive ascites.

We present 4 cases of endometriosis complicated by massive ascites from our institution and a review of 27 cases from the literature. In most of these patients, the presence of ascites with its related symptoms in association with pelvic masses suggested a neoplastic disease. However, a large proportion of these women had also classical manifestations of endometriosis, e.g., dysmenorrhea, cul-de-sac nodularities, and exacerbation of ascites and other symptoms during the menses. The response to hormonal therapy including GnRH agonists was often unsatisfactory. Repeat recurrences and severe complications required multiple laparotomies and thoracotomies for associated pleural and pulmonary involvement.

Effect of norethindrone acetate in the treatment of symptomatic endometriosis.

OBJECTIVE: The purpose of the study was to evaluate the efficacy of norethindrone acetate (NA) treatment in 52 women with dysmenorrhea, dyspareunia, noncyclic pelvic pain who had a diagnosis of endometriosis by laparoscopy. RESULTS: Dysmenorrhea and noncyclic pelvic pain were relieved in 48/52 (92.3%) and 25/28 (89.2%) of patients, respectively. Overall pain relief was obtained in 49/52 (94.2%) of patients. Breakthrough bleeding, of variable severity, was the most common side effect experienced by 30 patients (57.6%); however, only 4 patients (7.7%) dropped out for this side effect. One other patient dropped out for severe breast tenderness, and three for noncyclic pelvic pain. In general, treatment was successful in 44/52 (84.5%) of patients with the above symptoms. CONCLUSION: NA seems to be a cost-effective alternative with relatively mild side effects in the treatment of symptomatic endometriosis.

Presence of 11 beta-hydroxysteroid dehydrogenase in human semen: evidence of correlation with semen characteristics.

11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), the enzyme that catalyzes the conversion of biologically active glucocorticoids to their inactive metabolites, was shown to be located exclusively in Leydig cells of the rat testis, and its appearance was associated with the developmental rise in testosterone. Thus, 11 beta-HSD was suggested to play an important role in maintaining steroidogenesis by inactivating excess cortisol that inhibits testosterone production. Whether equivalent protection from glucocorticoids excess is necessary for spermatogenesis is not known, and we have, accordingly, investigated the 11 beta-HSD activity in ejaculated human semen. Both 11 beta-dehydrogenase (11 beta-DH) and 11 beta-oxoreductase (11-OR) activities of 11 beta-HSD were measurable in semen, although seminal plasma was devoid of 11 beta-HSD activity. Azoospermic specimens were associated with low 11 beta-dehydrogenase activity, indicating the presence of enzyme activity in cells other than spermatozoa. Pure spermatozoa separated on percoll gradient could oxidize corticosterone in the presence of NAD or NADP. Significantly higher 11 beta-DH activity is associated with semen specimens with low sperm count (p < .05) and higher level of morphologically abnormal spermatozoa (p < .05). The presence of 11 beta-HSD in human semen and its association with sperm characteristics thus suggests functional role for glucocorticoid exclusion in the sperm maturation process.

11 beta-Hydroxysteroid dehydrogenase enzyme activity in granulosa cells derived from ovarian follicles of in vitro fertilization patients.

11 beta-Hydroxysteroid dehydrogenase (HSD) activity was measured in freshly frozen granulosa cells isolated from follicles of twenty-one infertility patients undergoing in vitro fertilization-embryo transfer (IVF-ET). A total of 213 follicles were analyzed for 11 beta-HSD activity. Both nicotinamide-adenine dinucleotide (NAD) and nicotinamide-adenine dinucleotide phosphate (NADP) dependent 11 beta-dehydrogenase activities were measured in granulosa cells. The activity in reductive direction (11-oxoreductase activity) was not measurable either with NADH or NADPH as cofactors. NAD- and NADP-dependent dehydrogenase activities are in comparable levels at 100 nmol/l and 1 mumol/l corticosteroid concentrations. For comparing enzyme activities of individual follicles, significant enzyme activity was considered to be a level of > 2 nmol/l/min/mg. 41.3% of the follicles demonstrated enzyme activity, 58.7% did not. The mean 11 beta-dehydrogenase (11 beta-DH) activity was calculated for each patient. Those patients with levels > 2 nmol/l/min/mg were considered enzyme positive; those with mean levels < 2 nmol/l/min/mg were considered negative. No significant association was noted between follicle size, oocyte maturity or fertilization rates and 11 beta-DH activity. This study noted the presence of 11 beta-DH activity in granulosa cells, however, no association with oocyte maturity and fertilization was found.

Variations in human placental 11 beta-dehydrogenase and 11-oxoreductase activities of 11 beta-hydroxysteroid dehydrogenase enzyme during pregnancy.

Human placental 11 beta-hydroxysteroid dehydrogenase enzyme has an important role in controlling glucocorticoids reaching the fetus. Excess glucocorticoids impair fetal growth. Recent investigations show that the placenta is rich in NAD- and NADP-dependent 11 beta-hydroxysteroid dehydrogenase activity. Elucidation of the activities of both these isoforms is necessary to understand placental glucocorticoid metabolism. Hence we determined both NAD- and NADP-dependent 11 beta-hydroxysteroid dehydrogenase activities throughout pregnancy. 11 beta-dehydrogenase (oxidative) and 11-oxoreductase (reductive) activities of 11 beta-hydroxysteroid dehydrogenase were determined in 16 first-trimester (9-12 weeks) and 14 second-trimester (13-22 weeks) and 17 term (38-42 weeks) placentae. Both NAD- and NADP-dependent activities increased with pregnancy. The second-trimester NAD-dependent activity was higher than the first-trimester activity (p = 0.02). At term this activity was higher than during the second (p = 0.05) and first (p = 0.0002) trimesters. A similar increase was obtained with NADP isoform except that the difference between first and second trimesters was not significantly different at p = 0.05. The NADH-dependent 11-oxoreductase activity was also detected throughout the pregnancy. However, the activity at term was significantly higher than during the second (p = 0.005) and first (p = 0.001) trimesters. This increase may result in a concomitant increase of cortisol reaching fetus, thus helping fetal lung maturation.

Menstrual function in human immunodeficiency virus-infected women without acquired immunodeficiency syndrome.

To assess whether HIV infection is associated with menstrual abnormalities in HIV-infected women without AIDS, we evaluated 248 premenopausal HIV-infected women without AIDS and 82 HIV-negative women. Detailed medical, drug use, and menstrual histories (using menstrual calendars) were obtained. Complete physical and pelvic examinations and CD4 counts were performed. HIV-infected women were more likely to experience intervals > 6 weeks without menstrual bleeding [8 vs. 0%, odds ratio (OR) = 10.8, 95% confidence interval (CI) 1.8-1,000) and amenorrhea > 3 months (5 vs. 0%, OR = 7.1, 95% CI 1.1-1,000) (after adjustment for drug use, age, and race). Premenstrual breast swelling (p = 0.01), tenderness (p = 0.01), and dysmenorrhea (p = 0.04) were less common in HIV-infected women. There were no differences in intermenstrual bleeding or irregular menstrual cycles. Among HIV-infected women, only a past history of substance abuse was significantly associated with menstrual irregularities in a logistic regression model adjusting for age, current and past drug use, alcohol use, cigarette smoking, CD4 count, and category B conditions [1993 Centers for Disease Control (CDC) classification system]. The increase in amenorrhea (> 3 months) and in menstrual cycle intervals > 6 weeks and the lower rates of premenstrual breast symptoms in HIV-positive women suggest the possibility of disturbances in menstrual function that do not appear to be attributable to clinically apparent secondary complications of HIV. Changes in menstrual function were also significantly associated with a past history of, but not current, substance abuse, suggesting the possibility that socioeconomic factors rather than biologic effects of drugs may be responsible.

GnRH agonist and iron versus placebo and iron in the anemic patient before surgery for leiomyomas: a randomized controlled trial. Leuprolide Acetate Study Group.

OBJECTIVE: To determine the effectiveness of leuprolide acetate depot plus iron compared with iron alone in the preoperative treatment of anemia due to prolonged or excessive bleeding associated with uterine leiomyomas. METHODS: This was a phase III, stratified, randomized, double-blind, placebo-controlled, parallel-group, 12-week multicenter study. Enrolled patients had hemoglobin levels of 10.2 g/dL or less and/or hematocrit values of 30% or less. Patients were entered into one of two strata based on their pre-study hematocrit level: stratum A, hematocrit less than or equal to 28%, and stratum B, hematocrit greater than 28%. Patients within each stratum were randomized to one of three treatment arms: leuprolide acetate depot 7.5 mg, leuprolide acetate depot 3.75 mg, or placebo. All patients received iron orally. Response was defined as a hemoglobin level of 12 g/dL or more and a hematocrit value of 36% or greater. RESULTS: Three hundred nine patients were entered into the study, of whom 265 were evaluated. Using our response criteria, a significantly greater number of patients in both leuprolide acetate groups (combined strata) responded to therapy than did those in the placebo group: 74% in each leuprolide acetate group versus 46% in the placebo group (P < .001). Gonadotropin-releasing hormone agonist-treated patients had a significant reduction in uterine and myoma volume when compared with the placebo group (P < .01). Hot flashes and vaginitis were reported significantly more often (P < .001) in the leuprolide acetate-treated groups than in the placebo group. CONCLUSION: Both dosages of GnRH agonist plus iron were more effective than iron alone in treating the anemia of patients with uterine leiomyomas, in reducing uterine-myoma volume, and in alleviating bleeding and other leiomyoma-related symptoms.

Characterization of 11 beta-hydroxysteroid dehydrogenase of human placenta: evidence for the existence of two species of 11 beta-hydroxysteroid dehydrogenase.

The enzyme, 11 beta-hydroxysteroid dehydrogenase converts the active glucocorticoids cortisol and corticosterone to their inactive 11-oxo metabolites cortisone and dehydrocorticosterone, respectively. The properties of the human placental 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) were studied. The enzyme was active in the oxidative and reductive directions. pH optimum for 11 beta-dehydrogenase activity was in the range of 7-10 and for 11-oxoreductase it was in the range of 5.5-6.0. The crude placental homogenate was unstable. Reductase activity was more labile than dehydrogenase activity. Removal of cytosol enabled the enzyme to retain activity. 11 beta-HSD a membrane bound enzyme was distributed in all particulate subcellular fractions. Addition of detergent released latent activity of 11 beta-dehydrogenase and inactivated 11-reductase activity. Both corticosterone and cortisol were substrates for the enzyme. The Km value with corticosterone as substrate was much lower than with cortisol. The Km values with cortisone and dehydrocorticosterone were similar.

Circadian, ultradian, and episodic gonadotropin and prolactin secretion in human pseudocyesis.

Six women with pseudocyesis were studied by 15-min blood sampling for 12 to 24 h to determine their gonadotropin and PRL secretory profiles aiming to clarify the endocrine alterations in this form of hypothalamic amenorrhea. Clinical and biochemical evidence of hyperandrogenism was found in 4 patients. Persistent hyperprolactinemia was present only in one patient. Significant circadian and ultradian periodicities were identified by time series analysis in the 12-24 h profiles of FSH, LH and PRL secretion. Pulse analysis by the Van Cauter (UL-TRA.JN) method revealed a 24-h mean LH interpulse interval of 91 +/- 21 min with a mean LH amplitude of 5.4 +/- 0.8 IU/l. There was a significantly lower pulse frequency at night than during the daytime. The mean 24-h PRL interpulse interval and pulse amplitude were 134 +/- 22 min and 9.2 +/- 1.8 IU/l, respectively. Both FSH and LH mean levels were higher during the daytime than at night, while the reverse was true for PRL values. Decreased LH pulse frequency and amplitude emerged as the most distinctive findings. Antecedent hypothalamic-pituitary aberrations due to other endocrinopathies and the timing of the hormonal assessment (e.g. recovery phase) may explain, at least in part, the reported heterogeneity of neuroendocrinologic findings in pseudocyesis.

Diagnosis of stress-related hyperprolactinemia. Evaluation of the hyperprolactinemia rest test.

It remains controversial whether two or three random estimations of prolactin (PRL) concentration obviate the need for special testing to rule out stress-related hyperprolactinemia. In order to clarify this issue, we measured PRL, cortisol, and growth hormone (GH) in serial blood samples obtained under resting conditions (HPR test) in 70 women who had had high PRL levels in two or more random blood samples. Twenty out of 70 women were found to have stress-related hyperprolactinemia, and 11 of the 20 would have been misdiagnosed by using only three random samples. Cortisol levels from the HPR test indicated stress-related pituitary adrenal reactivity in all groups, including the idiopathic (N = 30) and prolactinoma (N = 20) groups. However, PRL secretion in response to stress--a downward trend as a function of time--was evident only in the stress-related hyperprolactinemia group. These results suggest that a limited HPR test (ie, serial PRL determinations at 0, 30, and 60 min) is a valuable and simple measure to identify stress-related hyperprolactinemia in order to avoid diagnostic pitfalls and unnecessary treatment.