A. R. Genazzani

Characteristics of headache at menopause: A clinico-epidemiologic study

The prevalence and characteristics of primary headaches in a large sample of postmenopausal women were investigated. Seventy-six out of 556 women (13.7%) were affected by headache of either the migraine or tension type. In 82% of cases onset had preceded the menopause. The postmenopausal course of headaches with a premenopausal onset differed according to type of headache and type of menopause. Indeed, while migraine improved in almost two-thirds of cases, tension-type headache worsened or did not change in 70% of cases. However, in women who had undergone surgical ovariectomy, the natural course of migraine was worse than in those who had a physiological menopause (P = 0.003). Among the symptoms covered by the Kuppermann Index, only anxiety and insomnia were correlated with headache. The favourable course of migraine in the postmenopausal period can be attributed primarily to the absence of variations in sex hormone levels although psychological factors also seem to play a fundamental role.

Effects of Org OD 14 on pituitary and peripheral β-endorphin in castrated rats and post-menopausal women

The aim of the first part of this study was to evaluate the effects of a new synthetic steroid (7 alpha,17 alpha)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one (Org OD 14), on anterior pituitary (AP) and neurointermediate pituitary lobe (NIL) contents and on circulating levels of beta-endorphin (beta-EP) in rats. Three weeks after ovariectomy, groups of 9 rats were treated with either Org OD 14 (2 or 10 micrograms/day/rat for 14 days) or a placebo. In addition, 2 groups of ovariectomized rats were also treated with oestradiol benzoate (EB) (2 or 10 micrograms/day/rat for 14 days) to compare the effectiveness of the new steroid with that of a classical oestrogenic substance. beta-Ep concentrations were measured in plasma and in AP and NIL extracts by means of double-antibody radioimmunoassay (RIA), employing a specific anti-camel beta-EP (C-terminal fragment). Both doses of Org OD 14 induced a significant dose-related increase in plasma and pituitary lobe beta-EP concentrations as compared with the results on placebo treatment. By comparison, EB was active only at a dose of 10 micrograms/day. Despite the common stimulatory effects of EB and Org OD 14 on pituitary beta-EP, these findings suggest that the two steroids have different modes of action. The second part of the study investigated the changes in beta-EP and beta-lipotrophin (beta-LPH) plasma levels in a group of post-menopausal women treated for 6 months with Org OD 14 (2.5 mg/day) in comparison with the levels in a placebo-treated group. The clinical efficacy of Org OD 14 treatment in post-menopausal symptoms was confirmed, as well as its lack of or only transient effect on plasma lipids and lipoproteins. beta-EP and beta-LPH plasma levels were significantly higher in the Org OD 14-treated group than in the placebo group as from the second month until the end of the observation period.

A comparative, randomized study of three different progesterone support of the luteal phase following IVF/ET program

The use of luteal phase support has been demonstrated in patients undergoing IVF/ET in cycles stimulated after pituitary desensitization with gonadotrophin releasing hormone agonists. However, it is still not clear which is the most suitable kind of supplementation. This study was designed to compare the absorption and the efficacy of three different luteal support. We randomly administered progesterone i.m. (50 mg/day), human chorionic gonadotrophin (hCG) (2000 IU every three days), progesterone vaginal cream (100 mg/day) or nothing (controls) to 176 women treated for assisted procreation. We were not able to show any statistical differences for the percentage of pregnancy rate between groups. The serum progestrerone (P) and 17-ß-estradiol (E2) and E2/P ratio levels of the luteal phase were compared with the control not supplemented group. All the treatments were able to increase significantly the luteal P values versus controls (p<0.01). Moreover, vaginal cream and natural P im significantly decreased E2/P ratio (p<0.05). Serum P levels were more steady with P vaginal cream than im injection. Vaginal cream for better bioavailability and acceptance appear the most suitable and comfortable method for luteal phase support.

Long-term low-dose dehydroepiandrosterone replacement therapy in aging males with partial androgen deficiency.

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) age-related withdrawal is very likely to be involved in the aging process and the onset of age-related diseases, giving rise to the question of whether preventing or compensating the decline of these steroids may have endocrine and clinical benefits. The aim of the present trial was to evaluate the endocrine, neuroendocrine and clinical consequences of a long-term (1 year), low-dose (25u2009mg/day) replacement therapy in a group of aging men who presented the clinical characteristics of partial androgen deficiency (PADAM). Circulating DHEA, DHEAS, androstenedione, total testosterone and free testosterone, dihydrotestosterone (DHT), progesterone, 17-hydroxyprogesterone, allopregnanolone, estrone, estradiol, sex hormone binding globulin (SHBG), cortisol, follicle stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels were evaluated monthly to assess the endocrine effects of the therapy, while β-endorphin values were used as a marker of the neuroendocrine effects. A Kupperman questionnaire was performed to evaluate the subjective symptoms before and after treatment. The results showed a great modification of the endocrine profile; with the exception of cortisol levels, which remained unchanged, DHEA, DHEAS, androstenedione, total and free testosterone, DHT, progesterone, 17-hydroxyprogesterone, estrone, estradiol, GH, IGF-1 and β-endorphin levels increased significantly with respect to baseline values, while FSH, LH and SHBG levels showed a significant decrease. The Kupperman score indicated a progressive improvement in mood, fatigue and joint pain. In conclusion, the present study demonstrates that 25u2009mg/day of DHEA is able to cause significant changes in the hormonal profile and clinical symptoms and can counteract the age-related decline of endocrine and neuroendocrine functions. Restoring DHEA levels to young adult values seems to benefit the age-related decline in physiological functions but, however promising, placebo-controlled trials are required to confirm these preliminary results.

The association of menstrual migraine with the premenstrual syndrome

To investigate the comorbidity of premenstrual syndrome (PMS) and menstrual migraine, the Menstrual Distress Questionnaire (MDQ) was prospectively administered for two consecutive menstrual cycles to 22 patients with menstrual migraine, 12 cases with migraine without aura and 15 patients with PMS. MDQ scores varied throughout the menstrual cycle in each patient group, the wider changes being shown by patients with PMS. Fourteen menstrual migraine patients and 4 migraine without aura patients achieved diagnostic criteria for PMS over two menstrual cycles. In these patients MDQ scores did not differ from PMS sufferers at any stage of the menstrual cycle. The premenstrual increase of each cluster of PMS symptoms was identical in menstrual migraine and PMS subjects with the exception of negative affect. We suggest that PMS symptoms should be taken into account in the IHS diagnostic criteria for menstrual migraine.

Progesterone and progestins modulate beta-endorphin concentrations in the hypothalamus and in the pituitary of castrated female rats.

Hypothalamic and pituitary beta-endorphin (B-EP) concentrations are modified by ovariectomy and estrogen treatments, supporting a direct interaction between this peptidergic system and gonadal steroids. Because the use of progestins is becoming even more diffuse in clinical practice, we evaluated the effect of progesterone and of the synthetic progestins medroxyprogesterone acetate (MPA), norethisterone acetate (NET) and desogestrel on the concentration of B-EP in the medial-basal hypothalamus and the anterior and neurointermediate pituitary lobes in ovariectomized rats (OVX), treated or untreated with estradiol benzoate (EB). B-EP concentrations were significantly increased by desogestrel in the anterior lobe and by progesterone, desogestrel and medroxyprogesterone acetate in the neurointermediate lobe. Progesterone and progestins significantly reduced B-EP increase induced by estradiol benzoate in the anterior lobe. Estradiol benzoate treatment did not modify the effect of progesterone and desogestrel on B-EP in the neuro-intermediate pituitary lobe. Norethisterone acetate and progesterone increased B-EP concentrations in the medial-basal hypothalamus, while the other steroids were inactive. In contrast, in the hypothalamus all progestins attenuated the increase of B-EP induced by estradiol benzoate (p less than 0.01). These data indicate that progesterone and progestins modulate the hypothalamic and pituitary B-EP concentrations in concert with estrogens. The capacity of progestins to modify the hypothalamic contents of B-EP may represent one of the mechanisms of action of these steroids in influencing brain function.

The concomitant release of androstenedione with Cortisol and luteinizing hormone pulsatile releases distinguishes adrenal from ovarian hyperandrogenism

Androstenedione secretory characteristics and its possible temporal correlation with luteinizing hormone (LH) and/or cortisol, intended as the markers of, respectively, ovarian stimulation and adrenal secretion, were evaluated in 24 patients affected by clinical hyperandrogenism. A pulsatility test was carried out for 8 h, with sampling every 10 min, and LH, cortisol and androstenedione profiles were determined by radioimmunoassay. Time series were analyzed with the computer program DETECT and with a program for specific concordance estimation. A distinct episodic release of LH, cortisol and androstenedione was observed in all patients (6.9 +/- 0.8, 5.2 +/- 0.6 and 5.5 +/- 1 peaks/8 h, respectively). When specific concordance was tested between LH and androstenedione, and between cortisol and androstenedione, two distinct groups of patients could be identified. Group A (n = 13) showed a significant specific concordance (SC) index only for LH and androstenedione while group B (n = 11) showed a significant SC also for cortisol and androstenedione, thus demonstrating a consistent adrenal participation in the androstenedione secretion in these patients. In addition, specific differences were observed on androstenedione secretory profiles of group B which showed a significant (p < 0.05) decrease of androstenedione plasma concentrations emulating cortisol behavior. No such observation was noted in group A, whose androstenedione plasma levels did not show any reduction. In conclusion, our data support the use of circulating androstenedione, LH and cortisol plasma levels and copulsatile assessment to distinguish the presence of two populations of hyperandrogenic patients: one whose hyperandrostenedionemia is mainly due to ovarian secretion (group A) and one which showed a hyperactivation of the adrenal gland (group B).(ABSTRACT TRUNCATED AT 250 WORDS)

Disadaptive disorders in women: allopregnanolone, a sensitive steroid

Allopregnanolone, a neurosteroid acting as a potent anxiolytic agonist of the γ-aminobutyric acid A receptor, has been shown in animal models to modify its concentrations at central and peripheral levels according to the estrous cycle. Moreover, it modulates behavioral and biochemical responses to acute and chronic stress, anxiety, depression, aggressiveness, convulsions, anesthesia, sleep, memory, pain and feeding. These observations suggest that fluctuations of allopregnanolone might be involved in the development, course and prognosis of some mental disorders in humans. This has been hypothesized for depressive disorders, premenstrual dysphoria, anorexia and bulimia nervosa and Alzheimers disease, where increased, decreased or dysregulated secretion of the main neurosteroids and their metabolites has been observed. Women show a marked gender-related sensitivity to disadaptive disorders. In addition to the well-studied role of sex steroids in modulating mood and behavior, a putative involvement of neurosteroid fluctuations, and in particular of allopregnanolone, has recently been hypothesized. In fact, several paraphysiological events and various disadaptive disorders in women are associated with modifications of circulating levels of this neurosteroid that might associated with a certain vulnerability to an altered adaptation to stressful life events.

Absent or reversed end-diastolic flow in umbilical artery and severe intrauterine growth retardation: An ominous association

Uteroplacental insufficiency is a major cause of perinatal mortality and postnatal morbidity. Doppler velocimetry has been used to assess well‐being of the fetus for several years. In the present study we evaluated the perinatal outcome of growth retarded fetuses with presence or absence of diastolic flow in umbilical artery at Doppler analysis. Forty‐six pregnant women with intra‐uterine‐growth‐retardation were studied. Ultrasound assessment of amniotic fluid was performed on alternate days until parturition. A weekly ultrasound measurement of fetal abdominal circumference was done. Doppler analysis of fetal/maternal circulation was performed upon arrival of the patient in hospital and thereafter on alternate days until delivery. Fetal blood was sampled by cordocentesis for immediate blood‐gas analysis. In the group (/i = 26) with absent or reversed diastolic flow in the umbilical artery, we observed a correspondingly worse blood‐gas analysis; a reduced time interposed between the diagnosis and the delivery; a reduced birth weight associated with an increased fetal risk and with a perinatal mortality approaching 60%. Our data suggest that absent or reversed diastolic flow in umbilical artery of growth‐retarded fetuses, associated with alterations in other vessels, are ominous signs of serious fetal compromise.

Naproxen Sodium in the Treatment of Premenstrual Symptoms

The prostaglandin system is thought to play a role in the etiology of the premenstrual syndrome. Many authors describe that prostaglandins are involved in both central and peripheral symptoms. To test this hypothesis, we studied the effects of naproxen sodium treatment (550 mg twice daily, from day -7, in relation to next menses, to the 4th day of the cycle) in 34 patients suffering from premenstrual syndrome. Six cases dropped out. Fourteen women were given placebo for the first three cycles of the trial, followed by active drug. The other 14 patients were given naproxen sodium, beginning from the first cycle. In order to evaluate premenstrual symptoms, the Moos menstrual distress questionnaire was prospectively applied during the 2-month run-in period and at the 3rd and 6th cycles of treatment. During our double-blind naproxen sodium study, both menstrual and premenstrual pain decreased during active drug treatment, while placebo was ineffective. We also obtained a significant improvement of premenstrual behavioral changes which is probably related to the relief of painful symptomatology. In conclusion, this study indicates that naproxen sodium is a useful and safe drug in the treatment of premenstrual and menstrual pain related symptoms.