Receiving Replacement Therapy Research Articles

Eye movement disorders in vitamin B12 deficiency: two new cases and a review of the literature

Eye movement disorders are rarely reported in vitamin B12 deficiency. We describe two cases with eye movement disorder and vitamin B12 deficiency; one with bilateral internuclear ophthalmoplegia and the other with downbeat nystagmus. Both of the patients received replacement therapy but their eye movement disorders did not respond to treatment. We also review the nine previously reported cases.

Abnormalities in Bone Mineral Density Distribution and Bone Scintigraphy in Patients With Childhood Onset Hypopituitarism

The aim of our study was to evaluate the effects of long-life severe growth hormone deficiency on bone mineral density (BMD) and bone scintigraphy in adult patients with childhood onset (CO) hypopituitarism never treated with growth hormone. Our studies included 22 adult patients with CO hypopituitarism never treated with growth hormone (13 males and 9 females, aged 25–66 yr). The patients received replacement therapy with thyroxine, sex steroid hormones, and patients with secondary adrenocortical deficiency, hydrocortisone, but none of the patients had ever received GH treatment. In 22 patients, the total body with regional distribution of BMD, the lumbar spine L2–L4, and radial (33% site) BMD were determined by dual energy X-ray absorptiometry (DXA). In addition, 12 patients had the femoral neck BMD examined. In 10 cases, bone scintigraphy using 99-technetium labeled methylene diphosphonate was performed. Our studies revealed abnormalities, not yet described, in the regional distribution of BMD and bone scintigraphy in adults with CO hypopituitarism never treated with GH. In all patients, the results obtained from the total body showed definite disproportion in the regional distribution of BMD with a significantly advanced bone mineral deficit in the legs and a moderate deficit in the arms and total body. Local BMD measured at the radial (33% site) and lumbar spine L2–L4 revealed also a more pronounced bone mineral deficit in the cortical bone (33% distal radius) than in the trabecular bone (spine L2–L4). Bone scintigraphy showed a decrease in tracer accumulation in the shafts of the long bones but normal uptake in the spine, ribs, sternum, skull, and periarticular areas, indicating suppressed skeletal metabolism of cortical bone. Our studies indicate that long-life growth hormone deficiency leads to deficient and abnormal distribution of bone mineralization, a more pronounced deficit of BMD at the cortical bone, mainly expressed in the shafts of the long bones of the legs and arms, and moderately reduced BMD at the trabecular bone. Bone scans displaying low diphosphonates uptake in the shafts of the long bones point to greatly suppressed skeletal metabolism of the cortical bone in the patients with CO hypopituitarism never treated with GH.

Extractions dentaires chez l’enfant présentant une maladie hémorragique constitutionnelle : protocole thérapeutique et résultats

We report the results of our 10-year experience with a protocol of local hemostasis specifically elaborated for children with congenital bleeding disorders. Sixty-four dental extractions procedures were performed in 37 children. Local hemostasis was achieved with the CO2 laser at the site of extraction previously filled with regenerated oxidized cellulose. The site of extraction was then protected with thermomolded splint. The replacement therapy (hemostasis factor concentrates, platelet concentrates) was coordinated by the hematologist and restricted as much as possible. 160 decidual teeth and 23 permanent teeth were extracted. None of the children with minor bleeding deficiency received replacement therapy. Ten post-operative bleedings were recorded but none was considered severe. This protocol characterized by the use of CO2 laser for the hemostasis gave satisfaction in children. The rare and minor post-operative bleedings could be explained by multiple extractions, local infection and/or children's anxiety. This strategy requires a close cooperation between the stomatologist and the hematologist in order to determine the optimal therapeutic management.

Mechanisms of action of immune tolerance induction against factor VIII in patients with congenital haemophilia A and factor VIII inhibitors

In its most severe form, haemophilia A is a life-threatening haemorrhagic bleeding disorder that is caused by mutations in the factor VIII (FVIII) gene. About 25% of patients who receive replacement therapy with intravenous FVIII products develop neutralising antibodies (FVIII inhibitors) that inhibit the function of substituted FVIII. Long-term application of high or low doses of FVIII has evolved as an effective strategy for eradicating antibodies and inducing long-lasting immune tolerance. Despite clinical experience with the therapy, little is known about the immunological mechanisms that cause the down modulation of FVIII-specific immune responses or the induction of long-lasting immune tolerance against FVIII. This review summarises current knowledge of the immunological mechanisms that might be involved in the induction of immune tolerance against FVIII in patients with haemophilia A who have FVIII inhibitors. In addition to data from patients with haemophilia A, data from patients who have had organ transplants or have immune-related disorders, such as autoimmune diseases, are considered as well as data from animal models.

Recommended dose for repair of serum vitamin A levels in patients with HIV infection/AIDS may be insufficient because of high urinary losses

Objective Retinol deficiency is quite frequent in the population of human immunodeficiency virus (HIV)-infected individuals. Serum retinol levels of less than 1.05 μmol/L determine a 3.5 to five times higher death risk. However, studies evaluating the efficacy of retinol supplementation in HIV-seropositive individuals have reported conflicting results. The World Health Organization recommends the treatment of vitamin A deficiency in seropositive individuals in the same manner as for seronegative individuals, but clinical studies proving the efficacy of this scheme are lacking. The proposal of the present study was to assess the efficacy of supplementation with high retinol doses in HIV-infected patients with vitamin A deficiency. Methods Twenty-five adult HIV-seropositive individuals were monitored over a period of 9 months, with determination of serum and urinary retinol every 3 months. The subjects received retinol palmitate doses ranging from 300,000 IU to 600,000 IU. Patients whose retinol levels were higher than 1.60 μmol/L were only observed. Results Eighteen patients received supplementation during clinical monitoring. The dose of 600,000 IU induced a significant mean increase in serum levels of 0.47 μmol/L ( P = 0.049) within a period of three months. Those who received 300,000 IU presented a mean increase of 0.29 μmol/L. In contrast, the patients who did not receive replacement therapy presented a significant decrease ( P = 0.017) in serum retinol levels, with initial and final values of 1.77 μmol/L and 1.55 μmol/L. The individuals with the worst response to supplementation presented a higher urinary loss of retinol at the beginning of the study. Even with a mean retinol supplementation of 771,428 IU during the study period, six patients had marginal serum retinol levels at the end of the study. Conclusion We conclude that, in view of the high urinary loss of this nutrient, there is the need to redefine the ideal dose for the treatment of HIV-infected individuals.

High-dose factor VIII inhibits factor VIII–specific memory B cells in hemophilia A with factor VIII inhibitors

AbstractHemophilia A in its severe form is a life-threatening hemorrhagic disease that is caused by mutations in the factor VIII (FVIII) gene (symbol F8). About 25% of patients who receive replacement therapy develop neutralizing antibodies that inhibit the function of substituted FVIII. Long-term application of high doses of FVIII has evolved as an effective therapy to eradicate the antibodies and to induce long-lasting immune tolerance. Little is known, however, about the immunologic mechanisms that cause the down-modulation of anti-FVIII antibodies by high doses of FVIII. We report that high doses of FVIII inhibit the restimulation of FVIII-specific memory B cells and their differentiation into antibody-secreting plasma cells in vitro and in vivo in a murine model of hemophilia A. The inhibition of memory B-cell responses is irreversible and not mediated by FVIII-specific T cells. Furthermore, it seems to involve the activation of caspases. We conclude that the inhibition of FVIII-specific memory B cells might be an early event in the down-modulation of anti-FVIII antibodies in patients with hemophilia A who receive high doses of FVIII.

Hypopituitarism and anemia: Effect of replacement therapy with hydrocortisone and/or levothyroxine

Although common, anemia associated with hypopituitarism has received little attention. We conducted a retrospective study to elucidate the effect of replacement therapy with hydrocortisone and/or levothyroxine on the decreased hemoglobin (Hb) level. A total of 68 patients who had been suffering from anterior pituitary deficiencies for more than 12 months were studied. The Hb level was significantly lower in patients with hypopituitarism (p=0.0012). Decreased Hb level (<12.0 g/dl) was observed in 22 patients (32.4%). It was related to hypocortisolism (regression weights=0.39), hypothyroidism (0.37), GHD (0.32) and hypogonadism in men (0.17). Among 68 patients, 30 patients had been receiving replacement therapy for at least 12 months. Hydrocortisone and levothyroxine increased the Hb level in 20 patients whose data were available before the replacement (p=0.0002). However, the Hb level was still lower in 30 patients receiving the replacement (p=0.0001). In 13 patients (8 men) with decreased Hb level (<12.0 g/dl) despite the replacement, GH and testosterone were deficient in 12 (92.3%) and 8 (100%) patients, respectively. In conclusion, replacement therapy with hydrocortisone and/or levothyroxine is effective in most patients but is not sufficient, at least in some patients, to improve the decreased Hb level. These results suggest that additional replacement therapy, i.e. with GH and/or androgen, is necessary to obtain further improvement.

Lack of bleeding in patients with severe factor VII deficiency

Factor VII deficiency, although rare, is now recognized as the most common autosomal recessive inherited factor deficiency. It is usually considered to be associated with bleeding only in the severely affected subject and heterozygotes (>10%) are not considered at risk. The general recommendation for surgery is to achieve a FVII level in excess of 15% (0.15 1U/mL). We present three cases of severe factor VII deficiency, each of whom appeared hemostatically competent based on clinical history. Subject 1 is a 33 year-old African-American female with a baseline FVII of <1%, who had a fractured tibia requiring open reduction with internal fixation without any FVII replacement and subsequently underwent successful laparoscopic knee surgery with a factor VII level measured at 6%. Subject 2 is a 58 year-old African-American female with a factor VII level of 9% who underwent an elective left total hip replacement without any factor replacement and had no excessive bleeding, but who sustained a pulmonary embolism postoperatively. Subject 3 is a 19-year-old African-American male with a baseline FVII of 1% with a history of active participation in football without noticeable injury and who underwent an emergent appendectomy without bleeding. These three cases represent individuals with the severe form of FVII deficiency who did not exhibit excessive bleeding when challenged with surgical procedures. The clinical history would appear the most valuable tool in predicting the likelihood of bleeding in these patients, and we suggest that the presumption that all patients with severe FVII deficiency should receive replacement therapy before surgical procedures may not be valid in all cases.

Emphysema in ??1-Antitrypsin Deficiency

Severe α1-antitrypsin (AAT) deficiency is an inherited disorder that leads to the development of emphysema in smokers at a relatively young age; most are disabled in their forties. Emphysema is caused by the protease-antiprotease imbalance when smoking-induced release of neutrophil elastase in the lung is inadequately inhibited by the deficient levels of AAT, the major inhibitor of neutrophil elastase. This protease-antiprotease imbalance leads to proteolytic damage to lung connective tissue (primarily elastic fibers), and the development of panacinar emphysema. AAT replacement therapy, most often applied by weekly intravenous infusions of AAT purified from human plasma, has been used to partially correct the biochemical defect and raise the serum AAT level above a theoretically protective threshold level of 0.8 g/L. A randomized controlled clinical trial was not considered feasible when purified antitrypsin was released for clinical use. However, AAT replacement therapy has not yet been proven to be clinically effective in reducing the progression of disease in AAT-deficient patients. There was a suggestion of a slower progression of emphysema by computed tomography (CT) scan in a small randomized trial. Two nonrandomized studies comparing AAT-deficient patients already receiving replacement therapy with those not receiving it, and a retrospective study evaluating a decline in FEV1 before and after replacement therapy, suggested a possible benefit for selected patients. Because of the lack of definitive proof of the clinical effectiveness of AAT replacement therapy and its cost, we recommend reserving AAT replacement therapy for deficient patients with impaired FEV1 (35–65% of predicted value), who have quit smoking and are on optimal medical therapy but continue to show a rapid decline in FEV1 after a period of observation of at least 18 months. A randomized placebo-controlled trial using CT scan as the primary outcome measure is required. Screening for AAT deficiency is recommended in patients with chronic irreversible airflow obstruction with atypical features such as early onset of disease or disability in their forties or fifties, or positive family history, and in immediate family members of patients with AAT deficiency.

Traumatic Brain Injury and Hypopituitarism

Results of recent and ongoing studies have made it clear that brain injuries like Traumatic Brian Injury (TBI) pose substantial risk to pituitary function, perhaps even greater risk than previously believed. Patients with TBI should be screened both prospectively and retrospectively for isolated, multiple and even total pituitary deficits. It is well known that, patients with “classical” hypopituitarism (due to primary hypothalamic-pituitary pathologies) do benefit from hormonal replacement therapy. It has been suggested that patients with TBI-induced hypopituitarism may benefit with appropriate hormonal replacement receiving replacement therapy such as anti-diuretic hormone (ADH), glucocorticoid and thyroid hormones when needed. Gonadal and recombinant human Growth Hormone (rhGH) replacement therapy should also be introduced if there are deficiencies demonstrated and even reconfirmed in a second step. The signs and symptoms of post-TBI hypopituitarism may be masked by what has been assumed to be merely the post-traumatic syndrome. By increasing awareness among physicians of the risks of brain injuries–induced endocrinopathies and the need for appropriate endocrinological testing, it may be possible to improve the quality of life and enhance the rehabilitation prospects for these patients. In most instances, these patients are first seen and treated by trauma surgeons and neurosurgeons, and subsequently by rehabilitation physicians; they must be knowledgeable about the risks of hypopituitarism so that they can determine which patients are candidates for screening for hypopituitarism. In addition, endocrinologists and internists must be educated about TBI-induced hypopituitarism and encouraged to actively share their expertise with other physicians.

Women With Primary Antibody Deficiencies Requiring IgG Replacement Therapy: Their Perception of Prenatal Care During Pregnancy

To investigate how a group of women with primary antibody deficiencies (PAD) and receiving replacement therapy with IgG experienced the care they received in their prenatal clinics in relation to PAD and IgG therapy. An exploratory study using a written questionnaire. The study originates from an immunodeficiency unit but evaluates care experienced at prenatal clinics. Nine women (25-43 years) attending an immunodeficiency unit and who fulfilled inclusion criteria for simultaneously having PAD, replacement IgG therapy, and full-term pregnancy (the latter within the past 5 years). Women's perception of the response of midwives and physicians at their prenatal clinics to their PAD and IgG therapy during pregnancy. Women perceived that the obstetricians and the midwives had insufficient knowledge about PAD and IgG replacement therapy. Two women reported that their IgG therapy during pregnancy had been questioned. All nine women felt marginalized and unheard by staff regarding their PAD and need for IgG therapy. However, the women were satisfied with the checkups regarding the pregnancy as such. This study is the first attempt to investigate the prenatal experience of women with PAD (Search of PubMed, 1980 to present, including search terms primary immunodeficiency, pregnancy, and prenatal care). This study demonstrates that increased knowledge about PAD and IgG replacement therapy among midwives and physicians working in prenatal care clinics is needed. This can prevent misleading advice that puts the health of the mother and her fetus at risk. Sensitizing staff about this special group of women can create conditions in which women feel respected, heard, and satisfied with their prenatal care.

Growth hormone (GH) replacement therapy in GH-deficient women during pregnancy.

The present recommendation is to discontinue GH replacement therapy in hypopituitary women, as they become pregnant. We report our experience of managing GH deficiency with GH replacement therapy in pregnant hypopituitary women. Eight hypopituitary women, median age 30.5 years (range 20-39 years), were followed prospectively during 12 distinct pregnancies. Six women were receiving replacement therapy for other pituitary hormone deficiencies and five pregnancies were achieved with ovulation induction therapy. GH replacement therapy was maintained at the same pregestational dose during the first trimester, with a gradual decrease of the dose during the second trimester and discontinuing the treatment at the beginning of the third trimester. Serum IGF-1 levels were measured in four selected pregnancies at three different points, one in each trimester of gestation. Seven pregnancies resulted in normal vaginal deliveries and five had programmed Caesarian sections. The median gestation age at time of delivery was 40 weeks (range 33-42 weeks). Newborns had a median birthweight SD score of -0.37 (range -1.93 to 1.21) and a median birthlength SD score of 0.07 (range -2.73 to 1.53). No congenital malformations were observed. Three women were able to breastfeed their babies. Before gestation, the median daily dose of GH was 0.5 mg (range 0.3-0.8 mg) and the median serum IGF-1 was 37.5 nmol/l (range 7.6-54.5 nmol/l). IGF-1 levels were fairly constant in the first and second trimesters of gestation, showing an increment during the last trimester, when GH treatment was discontinued. The GH replacement regimen presented for pregnant women with GH deficiency was safe. No major side-effects and no negative influences on maternal and fetal outcome were observed.

Does growth retardation indicate suboptimal clinical care in children with chronic renal disease and those undergoing dialysis?

Growth failure is an important problem for children with end-stage renal disease (ESRD). Patients receiving replacement therapy for longstanding renal failure since childhood are likely to report dissatisfaction with certain aspects of their lives, especially with final adult height. Additionally, recent data suggest that growth failure in children with ESRD is associated with adverse clinical outcomes, including more frequent hospitalizations, and increased mortality. Although poor growth is unlikely to be the cause of this increased morbidity, growth failure may be a marker for a group of patients at high risk of adverse events. In this review, the authors describe the prevalence of growth retardation in children in the US with chronic renal disease, and present recent data on morbidity associated with growth failure. After reviewing published reports documenting available strategies to optimize growth, the authors conclude that despite vigilance and aggressive clinical management, a subset of children with long-term renal insufficiency and ESRD may still have poor linear growth. A discussion of "optimal care" leads one to consider evidence of current variability in the management of growth retardation in ESRD, and the strengths and limitations of developing practice guidelines to optimize growth in this population.

Embryotoxic effects adjacent and opposite to the early regressing bovine corpus luteum

Early luteal regression in cattle has an embryotoxic effect that is not overcome by replacement with progesterone, but is prevented by removal of the regressing CL. Two experiments were designed to test the null hypothesis that the luteal component of the embryotoxic effect is delivered by a systemic pathway. Beef heifers and cows (n=39) received two good quality embryos, one placed into each uterine horn on Day 6 or 7 of the estrous cycle. Treated animals (n =20) received 15 mg of PGF 2α three times per day from Day 7 (n=11; Experiment 1) or 5 (n=9; Experiment 2) through 8; controls (n=19) received saline. Progestogen replacement therapy (12 mg flurogestone acetate daily, sc) was provided from Day 6 (Experiment 1) or 4 (Experiment 2) until ultrasonographic diagnosis of embryo survival on Day 35 after estrus. The effects of treatment, location of the embryo and location by treatment interaction on embryo survival were tested by Chi square. In Experiment 1, there was no significant difference in embryo survival rate between PGF 2α-treated and control recipients. In Experiment 2, only 6 of 18 embryos survived to Day 35 when transferred to animals treated with PGF 2α compared to 12 of 18 in control animals (P< 0.05). The survival of embryos did not differ with location (adjacent or opposite to the regressing CL) or location by treatment interaction. Thus no evidence was obtained to support a local effect of the regressing CL. The embryo mortality associated with luteolytic doses of PGF 2α in cows receiving replacement therapy with progestogen probably involves compounds that either act systemically or are transported via the uterine lumen to the uterine horn contralateral to the regressing CL.

Epidemiological survey of the orthopaedic status of severe haemophilia A and B patients in France. The French Study Group. secretariat.haemophiles@cch.ap-hop-paris.fr.

One hundred and 16 patients contributed to an analysis of the impact of the consequences of severe haemophilia A or B (factor levels < 2%) on orthopaedic status, resources consumed in relation to this status and resultant cost, and quality of life as perceived by the patient, using the MOS 36-Item-Short-Form Health Survey (SF-36). This French cross-sectional study involved outpatients regularly attending a haemophilia treatment centre. Data were collected retrospectively over a period of 1 year by the physician of the haemophilia treatment centre. Patients had a mean age of 23, and consisted of 50% students, 25% salaried workers, 17.2% with no professional activity and 7.8% physically impaired; 82.8% of them had type A haemophilia. Mean pain score was 2.5 per patient for the six main joints; 7.7 for the clinical score and 18.8 for the radiological score, with a mean number of bleeds of 16.3 per year per patient. During the year prior to inclusion, and because of their orthopaedic status, 22.4% of patients were hospitalized, 76.7% attended for an outpatient visit and 76.7% required at least one special investigation; 97.4% received replacement therapy, 41.4% required treatment for joint pain and 42.2% orthopaedic equipment. The less affected dimensions were the physical function (76.8 +/- 22. 2) and the social relations (76.1 +/- 23.1). Least good quality of life scores concerned the pain (60.2 +/- 25.2), perception of general health (59.3 +/- 23.1) and vitality (57.8 +/- 19.5) dimensions. The age was a discriminant criterion since quality of life was better in patients of the 18-23 age group for five dimensions. Mean annual treatment costs of a patient with severe haemophilia were determined as 425 762 French francs ($73 029). Loss of production was estimated at a mean of 4609 French francs ($791) per active patient over the course of the year. Results showed indirect evidence of the usefulness of early home treatment.

Quality of self-care in patients on replacement therapy with hydrocortisone.

To assess the quality of self-care in patients receiving replacement therapy with hydrocortisone for primary or secondary adrenal insufficiency. A questionnaire-based survey. The outpatient Clinic of Endocrinology at the University Hospital in Herlev, Denmark. Ninety-seven patients identified from the case reports of the clinic. All patients had received repeated oral information about hydrocortisone treatment and dose adjustments. Eighty-four (87%) patients completed the questionnaire. Ability to act appropriately in case of physical stress, possession of a 'Steroid warning card', number and nature of episodes of physical stress during the past year and self-experienced level of information was recorded. Thirty-nine (46%) of the patients were not sufficiently skilled in coping with physical stress. This was more prominent in the elderly patients. Seventeen (20%) did not possess a 'steroid warning card'. Thirty-seven (44%) had experienced at least one febrile episode and 24 (29%) had been admitted to hospital during the past year. Fifty (60%) felt themselves to be well informed, but this did not correlate with the ability to act appropriately. The study shows the need for continuous education of patients with adrenal insufficiency. Oral instructions should be supplemented with written information or a more detailed and structured education.

Is the measurement of serum testosterone routinely indicated in men with erectile dysfunction?

To investigate the usefulness of serum testosterone levels as a relevant or useful indicator of sexual potency in men attending an erectile dysfunction clinic. Ninety consecutive men attending the erectile dysfunction clinic completed a sexual-activity questionnaire, and underwent a focused physical examination and questioning about their medical history. The serum testosterone level was measured in all patients and the results analysed in relation to the patient's age. Patients with low serum testosterone levels commenced replacement therapy comprising three intramuscular injections of testosterone (Sustanontrade mark, Organon, The Netherlands) 250 mg every third week. Potency status and serum testosterone were reassessed after 3 months' treatment. Of the 90 men, 28 (31%) were aged < 50 years whilst 62 (69%) were >/=50 years old. Nineteen (21%) patients overall had low testosterone levels; four of these were < 50 and 15 were >/=50 years old. Five of 90 patients had a decreased libido; two of these also had low testosterone levels and all were < 50 years old. Testosterone levels returned to normal in all patients who received replacement therapy but potency returned in only two (10%); both were in the older group. Measuring testosterone was not helpful in assessing potency or libido and low serum levels were not related to age. Correcting low testosterone did not improve either impotence or libido.

Clinical utility of adrenal ultrasonography in the diagnosis of congenital adrenal hyperplasia

Rapid, accurate diagnosis of congenital adrenal hyperplasia (CAH) is essential in the neonate with ambiguous genitalia, life-threatening salt loss, or both. We aimed to determine the accuracy of adrenal ultrasonography in the diagnosis of CAH in a retrospective analysis of 52 children with ambiguous genitalia or salt-losing crises. Adrenal ultrasounds were interpreted as follows: “normal” if the adrenals were normal in size (adrenal limb width <4 mm), had a smooth surface, and a central echogenic stripe with a hypoechoic rim, and “abnormal” if they were increased in size (limb width >4 mm), had a lobulated or cerebriform surface, or showed abnormal echogenicity. Group 1 consisted of 25 neonates and infants with CAH; group 2, 19 children with conditions other than CAH; and group 3, 8 with treated CAH: 7 receiving replacement therapy and 1 whose mother received glucocorticoids during pregnancy. In all children in groups 2 and 3, adrenal ultrasounds were read as normal. In group 1 adrenal ultrasonography was normal in 2 (8%) and abnormal in 23 (92%). Thus adrenal ultrasonography has a sensitivity of 92% and a specificity of 100% for diagnosing CAH. Adrenal ultrasonography is a highly sensitive and specific adjunct in the diagnosis of CAH. The presence of enlarged, lobulated adrenals with stippled echogenicity is invariably associated with CAH. (J Pediatr 1999;135:71-5.)

Age-related differences in corticosterone secretion in female rats

The effects of age on steroidogenesis in rat zona fasciculata-reticularis (ZFR) cells were studied. Young, adult, and middle-aged rats were ovariectomized (Ovx) and received replacement therapy with oil or estradiol benzoate ([EB] 25 μg/mL/kg). Rat ZFR cells were incubated with corticotropin (ACTH), prolactin (PRL), or forskolin at 37°C for 1 hour. The effects of age on the activity of steroidogenic enzymes of ZFR cells were measured by the amount of intermediate steroidal products separated by thin-layer chromatography. Plasma levels were higher for PRL (54% to 254%) and corticosterone (179% to 257%) in middle-aged versus young rats. In oil-treated Ovx rats, basal and ACTH-stimulated corticosterone release by ZFR cells were also greater in middle-aged compared with young rats. Replacement with EB in Ovx rats increased the ACTH-stimulated release of corticosterone. Administration of ovine PRL in vitro resulted in a dose-dependent increase of corticosterone production. In oil-treated middle-aged rats, ovine PRL-stimulated corticosterone release was higher than in young rats. Forskolin-induced production of cyclic adenosine 3′,5′-monophosphate (cAMP) was greater in middle-aged versus young rats and correlated with the increase of corticosterone production. The activity of steroidogenic enzymes in rat ZFR cells was unchanged by age. These results suggest that the age-related increase of corticosterone production in female rats is associated with the stimulatory effect of PRL on ZFR cells and is due in part to an increase of cAMP generation.

Two-Year Prospective and Comparative Study on the Effects of Tibolone on Lipid Pattern, Behavior of Apolipoproteins AI and B

To investigate long-term lipid and lipoprotein changes in postmenopausal women treated with tibolone in a prospective study using appropriate control groups. Seventy-six of 105 postmenopausal women initially selected for this study completed the 2-year follow-up. Patients were allocated into three groups. The first received 2.5 mg/day tibolone continuously (n = 27; group T), the second received 0.625 mg/day conjugated equine estrogen plus 2.5 mg/day of medroxyprogesterone (group E-P) continuously (n = 25), and a third group contained an additional 24 women who did not receive replacement therapy; these constituted the untreated control group (group C). Plasma lipids and lipoproteins were determined in all patients before joining the study and also at 12 and 24 months after being included. Women treated with tibolone experienced the greatest decreases in cholesterol, both total and high density lipoprotein (HDL), and triglycerides (TG), whereas the highest increase in HDL was observed in the group E-P. A decrease in low density lipoprotein levels was detected in both therapy groups, whereas a significant increase was observed in the control group. TG were increased after E-P therapy. In all the groups, apolipoprotein AI showed parallel trends to HDL and apolipoprotein B to low density lipoprotein. Both therapy groups, tibolone and E-P, induced changes in levels of plasma lipids, lipoproteins and apolipoproteins. Long-term tibolone treatment is associated with a marked and significant decrease in HDL apolipoprotein AI and TG, an effect that defines the major difference with standard HRT. Clearly, further studies are necessary to establish the definite risk/benefit ratio of tibolone with respect to its overall effect on lipid metabolism.