Timo Laatikainen

Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy

Background Reproductive endocrine disorders are more common among women with epilepsy than among normal women. These disorders have been attributed to epilepsy itself, but could be related to antiepileptic-drug therapy. Methods We studied 238 women with epilepsy who were seen regularly at the Outpatient Department of the University Hospital, Oulu, Finland. Their mean age was 33 years (range, 18 to 45), and the mean duration of therapy was 9 years (range, 0 to 31). Twenty-nine (12 percent) were treated with valproate, 120 (50 percent) with carbamazepine, 12 (5 percent) with valproate and carbamazepine, and 62 (26 percent) with other medications; 15 (6 percent) were untreated. Vaginal ultrasonography was performed to determine ovarian size, and serum sex-hormone concentrations were measured in 41 women with epilepsy and menstrual disturbances, 57 women with epilepsy and regular menstrual cycles, and 51 normal women. Results Menstrual disturbances were present in 13 of the women receiving valproate alone (45...

Intrauterine 10μg and 20μg levonorgestrel systems in postmenopausal women receiving oral oestrogen replacement therapy: clinical, endometrial and metabolic response

Objective The clinical and endometrial efficacy and lipid response of two different doses of intrauterine levonorgestrel were assessed in comparison with sequential oral medroxyprogesterone acetate in postmenopausal women receiving continuous oral E2‐valerate.

CORTICOTROPIN-RELEASING HORMONE IN MATERNAL AND CORD PLASMA IN PRE-ECLAMPSIA

The concentration of corticotropin-releasing hormone (CRH) in maternal plasma increases greatly during the last trimester of normal pregnancy. This CRH has been proposed to originate from the placenta. We studied plasma immunoreactive CRH in 46 uncomplicated pregnancies, in 10 pregnant women with chronic hypertension, in 17 women with pregnancy-induced hypertension (PIH) and in 24 women with pre-eclampsia, and correlated it to the levels of corticotropin (ACTH) and cortisol. CRH levels were greatly increased in women with pre-eclampsia, less significantly in women with PIH, while no change was found in pregnant women with chronic hypertension. ACTH levels also were increased in pregnancies with pre-eclampsia or PIH and there was a positive correlation between CRH and ACTH levels. CRH levels in cord venous plasma were significantly increased in pregnancies with pre-eclampsia but cortisol did not show any significant increase. These findings suggest that placental release of CRH into the maternal and fetal circulation is increased in pre-eclampsia.

β-Endorphin and corticotropin release is dependent on a threshold intensity of running exercise in male endurance athletes

Relationship between the intensity of running exercise on a treadmill and the changes in the concentrations of beta-endorphin + beta-lipotropin (beta-E + beta-LPH) and adrenocorticotropic hormone (ACTH) in plasma were studied in 10 experienced male endurance athletes. At random order, the subjects run on a treadmill six exercises which required on an average (mean +/- S.E.) 50 +/- 0.8%, 58 +/- 0.8%, 69 +/- 1.1%, 80 +/- 0.7%, 92 +/- 1.0% and 98 +/- 0.5% of their maximal oxygen consumption. Plasma levels of beta-E + beta-LPH and ACTH did not show any significant changes during the 50-80%-tests. During the 92% test, the mean levels (+/- S.E.) of beta-E + beta-LPH and ACTH increased significantly (p less than 0.001), from 3.0 +/- 0.4 to 8.0 +/- 1.2 pmol/l and from 3.1 +/- 0.5 to 8.9 +/- 1.3 pmol/l, respectively, and during the 98% test, from 3.7 +/- 0.6 pmol/l to 20.4 +/- 1.5 pmol/l, and from 3.6 +/- 0.6 to 21.8 +/- 1.5 pmol/l, respectively. Increases in the plasma levels of beta-E + beta-LPH and ACTH were always accompanied by an increase in the blood lactate level. We conclude that intensive running with an anaerobic response causes an increase in the concentrations of beta-endorphin and ACTH in plasma in endurance athletes, whereas slight aerobic exercise did not elicit any response.

Oral contraceptives increase insulin-like growth factor binding protein-1 concentration in women with polycystic ovarian disease*

UNLABELLEDnInsulin-like growth factor-I (IGF-I) stimulates ovarian androgen production. Insulin-like growth factor binding protein-1 (IGFBP-1) inhibits IGF actions in vitro.nnnOBJECTIVEnTo investigate the effect of oral contraceptive (OC) pills, given for 3 months, on serum gonadotropin, androgen, IGF-I, and IGFBP-1 concentrations, and glucose tolerance in seven women with polycystic ovarian disease (PCOD) and in five healthy control subjects.nnnPATIENTSnSeven women with PCOD and five healthy control subjects.nnnINTERVENTIONSnAn oral glucose tolerance test (OGTT) was performed before and after treatment with OC.nnnRESULTSnAfter treatment with OC, serum luteinizing hormone, androstenedione, and free testosterone levels decreased, and sex hormone-binding globulin concentration increased in the women with PCOD as well as in the control subjects. The cumulative response of serum insulin to OGTT was larger in the women with PCOD than in the control subjects both before and after treatment. Serum IGF-I concentration, which was unchanged during OGTT, decreased from basal level of 326 +/- 70 micrograms/L to 199 +/- 28 micrograms/L after treatment with OC in the women with PCOD, whereas no change was found in the control subjects (from 235 +/- 11 micrograms/L to 226 +/- 11 micrograms/L). Treatment with OC caused an increase of the mean basal IGFBP-1 concentration from 24 +/- 7 micrograms/L to 73 +/- 14 micrograms/L in the women with PCOD. This increase was constant during the OGTT. In the control subjects, treatment with OC did not result in any significant change in IGFBP-1 concentrations (from 44 +/- 11 micrograms/L to 61 +/- 9 micrograms/L).nnnCONCLUSIONnThe combination of decreased total IGF-I concentration and increased IGFBP-1 concentration induced by OC may decrease ovarian androgen production in PCOD.

Midtrimester N-terminal Proatrial Natriuretic Peptide, Free Beta hCG, and Alpha-fetoprotein in Predicting Preeclampsia

Objective To determine whether maternal midtrimester serum N-terminal peptide of proatrial natriuretic peptide, free beta subunit of human chorionic gonadotropin (hCGβ), or alpha-fetoprotein (AFP) levels can predict preeclampsia. Methods A population-based cohort included 1037 nulliparous women, of whom 637 (61%) participated in a maternal serum Down syndrome screening program. Measurements of hCGβ, AFP, and N-terminal peptide of proatrial natriuretic peptide were made from maternal serum collected at 15-19 weeks gestation. Sensitivity, specificity, and predictive values were calculated for elevated AFP (at least 2.0 multiples of the median [MoM]) and hCGβ (at least 2.0 MoM) values. Results No difference was found in the concentrations of the N-terminal peptide of proatrial natriuretic peptide among the 30 women in whom preeclampsia developed later (median 270 [range 142-604] pmol/L) compared with 536 women who remained normotensive (274 [51-2626] pmol/L). The sensitivity and specificity of elevated AFP in predicting preeclampsia were 3% and 98% and those of elevated hCGβ were 20% and 84%, respectively. When a stepwise multiple logistic regression model was used, only mean arterial pressure was an independent risk factor in predicting preeclampsia. Conclusion Determinations of the proposed new marker N-terminal peptide of proatrial natriuretic peptide, as well as serum hCGβ or AFP, are not helpful in predicting preeclampsia.

Plasma insulin-like growth factor I and its binding proteins 1 and 3 in postmenopausal patients with breast cancer receiving long term tamoxifen.

Background. Insulin‐like growth factor I (IGF‐I) is a potent mitogen for breast cancer cells. The majority of IGF‐I in plasma is bound to IGF binding proteins (IGFBPs), which modulate the biologic effects of IGF‐I.

On the association between valproate and polycystic ovary syndrome: A response and an alternative view

In their article in this issue of Epilepsia, Genton et al. (1) raise the important issue of an association of polycystic ovary syndrome (PCOS) with epilepsy and antiepileptic drugs (AEDs). They review the relevant literature extensively, but in our view, their presentation and interpretation of much of the existing data is biased and potentially misleading. We fully agree with Genton et al. (1) that the issue of epilepsy-related reproductive endocrine disorders has been controversial (2–9). There are definitely data suggesting that epilepsy per se can be associated with development of reproductive endocrine disorders (2–4). However, there are also many studies suggesting that the role that AEDs play in the development of these disorders may be more important than the role of epilepsy itself (5–18). Many of the effects of AEDs on reproductive endocrine function have been confirmed in animal models (16,18). Genton and his colleagues are highly critical of studies by our group (1). In our view, their criticism is unfounded and is based mainly on incorrect interpretations of the studies (6,12–14,17,19). Other related studies are also incompletely presented (8,9), and experimental animal data (16,18,20–22) are completely missing from their review. Our group of investigators have studied the endocrine effects of AEDs since the mid-1980s. Indeed, we have published the only long-term prospective studies on the reproductive and other endocrine effects of AEDs. Isojärvi et al. reported 1and 5-year follow-up data in men and women who were given carbamazepine (CBZ) (5,7,11,23–26). Inexplicably, however, Genton et al. (1) did not include these prospective studies in their review of the endocrine effects of AEDs, even though they stress the importance of baseline measurements. The major criticism that Genton et al. (1) raised against our studies is that they are retrospective and, therefore, biased with regard to patient selection. This is not the case. The studies were not retrospective, and, therefore, patient selection could not have been biased by data collected retrospectively (6,12,14). The methods and patient populations are carefully described in each of our articles. Genton and colleagues also criticize us for arguing that lamotrigine (LTG) is preferable to valproate (VPA) in young women with epilepsy, and even that use of VPA is contraindicated in this group. We never drew conclusions. In all of our articles, we have emphasized that while the findings raise concern, the benefits of VPA treatment must be weighed against possible risks (6,12, 13,17). We believe that this should always be the practice when treating patients: the choice of any treatment should be based on a risk–benefit assessment. We have not advised physicians to replace VPA with LTG. Rather, we have merely stated that alternative treatments should be considered if VPA-related endocrine or metabolic problems are identified. In our article on obesity, hyperinsulinemia, and hyperandrogenism in women with epilepsy treated with VPA, we indicated that other effective medications, such as CBZ and oxcarbazepine (OCBZ), may be preferred in treating partial seizures in young women (12). In treating women with primary generalized epilepsies, LTG may be a reasonable alternative to VPA in some patients (13). Genton et al. (1) extensively reviewed the literature related to PCOS and its pathogenesis. This is important. However, it is hardly relevant when trying to understand VPA-related endocrine problems. Many studies have shown that use of VPA is associated with endocrine changes that include polycystic ovaries (PCOs), hyperandrogenism, and menstrual disorders (6,8,9,12,18). In the studies by Isoja ̈rvi et al., these changes have not been defined as PCOS, because as a drug-related condition it may be different from the spontaneous form of PCOS. Accepted November 22, 2000. Address correspondence and reprint requests to Dr. J. I. T. Isoja ̈rvi at Department of Neurology, University of Oulu, FIN-90220 Oulu, Finland. E-mail: jouko.isojarvi@oulu.fi Epilepsia,42(3):305–310, 2001 Blackwell Science, Inc.

Response of plasma endorphins to running exercises in male and female endurance athletes.

We studied the responses of plasma concentrations of beta-endorphin, beta-lipotropin, and corticotropin to an exhaustive graded treadmill exercise, to an anaerobic treadmill exercise, and to a sub-maximal outdoor running exercise in 5 male and in 5 female endurance athletes. During the graded treadmill exercise, the mean plasma level (+/- SE) of beta-endorphin in men rose from 1.2 +/- 0.1 to 8.1 +/- 0.7 pmol.l-1, beta-lipotropin rose from 1.6 +/- 0.5 to 7.4 +/- 1.4 pmol.l-1, and corticotropin rose from 4.9 +/- 1.0 to 31 +/- 3.3 pmol.l-1. In women, the mean level of beta-endorphin rose from 1.2 +/- 0.2 to 8.2 +/- 1.8 pmol.l-1, beta-lipotropin rose from 1.4 +/- 0.1 to 8.1 +/- 2.0 pmol.l-1, and corticotropin rose from 3.3 +/- 0.4 to 28 +/- 7.9 pmol.l-1. Concentrations of endorphins and corticotropin increased significantly also during the anaerobic exercise test. In response to sub-maximal running exercise, no significant change was found. These results showed a relationship between the intensity of exercise and the secretion of pro-opiomelanocortin-related peptides, and there were no differences between the groups of trained men and women.

Serum levels of insulin-like growth factor binding protein-1 and ovulatory responses to clomiphene citrate in women with polycystic ovarian disease.

Objective To study the serum levels of insulin, insulin-like growth factor I (IGF-I), and insulin-like growth factor binding protein-1 (IGFBP-1) in relation to clomiphene citrate (CC) responsiveness in women with polycystic ovarian disease (PCOD). Design Prospective. Patients, setting Twenty-three women with PCOD admitted consecutively to the University Infertility Clinic, a tertiary referral center. Interventions Blood samples were taken at fasting state and during oral glucose tolerance test (OGTT) for the determination of insulin, IGF-I, and IGFBP-1. A dose of 50 to 200xa0mg/d CC was given for ovulation induction. Results With CC treatment, ovulation was achieved in 13 of 23 PCOD patients. The IGFBP-1 concentration was lower in CC nonresponders than in CC responders (20.5xa0±xa04.0xa0ng/mL versus 41.0xa0±xa08.5xa0ng/mL) (Pxa0 Conclusion In lean PCOD patients, low serum IGFBP-1 concentration is related to CC unresponsiveness by a mechanism unrelated to insulin.