C. Nappi

Serum leptin levels in postmenopausal women: effects of transdermal hormone replacement therapy.

Objective: To evaluate serum leptin levels in postmenopausal women who are receiving hormone replacement therapy (HRT) and postmenopausal women who are not receiving HRT with similar body mass index (BMI) to determine whether estrogens exert effects on leptin secretion. Design: Cross‐sectional, prospective study comparing serum leptin levels in premenopausal women, postmenopausal women who were not receiving HRT (group A), and postmenopausal women who were receiving HRT (group B). Results: Serum leptin levels were significantly higher in group A in comparison to group B and control women (15.82 ± 6.6 ng/ml, 8.14 ± 4.17 ng/ml, and 10.12 ± 5.48 ng/ml, respectively; p < 0.05). Total fat mass (FM) was found to be significantly higher in untreated postmenopausal women in comparison to the other two groups (22.66 ± 2.79 kg vs. 19.14 ± 3.39 kg vs. 18.98 ± 3.82 kg; p < 0.05). No significant difference was observed in weight, height, BMI, blood pressure, or glucose levels among the three groups. A linear correlation between BMI and serum leptin levels as well as between total FM and serum leptin levels was observed in all groups. No correlation was found between serum leptin levels and months from menopause and months of HRT. Conclusions: Our results show that serum leptin is increased in untreated postmenopausal women, possibly as a consequence of the increase in FM, and that HRT reduces serum leptin levels to premenopausal values. These data need further investigation by a broader longitudinal study. (Menopause 2000;7:36‐41.

Effects of sex steroid hormones and menopause on serum leptin concentrations

Leptin is a protein secreted by adipocytes; its circulating levels are correlated to fat mass and it acts on the hypothalamic centers regulating body weight. Leptin may also play an important role in regulating reproductive function. Indeed, ob/ob mice, lacking leptin due to a genetic mutation, are obese and infertile; administration of recombinant leptin to these animals reduces body weight and restores fertility. A sexual dimorphism in serum leptin levels has also been observed, with higher concentrations in women. Studies in vitro seem to indicate that estrogens stimulate leptin secretion, while in vivo studies are extremely discordant. In humans, several studies showed increased, unmodified and decreased leptin levels after the menopause. Furthermore, hormonal replacement therapy (HRT) after the menopause was reported to result in unmodified, increased or decreased leptin levels. It is likely that the effects of postmenopausal hypoestrogenism on leptin levels are masked by the postmenopausal changes in body composition. Indeed, after menopause, there is an increase in body weight, body mass index (BMI) and fat mass with a centralization of fat distribution. Administration of HRT may stop these changes and even restore a premenopausal pattern, leading then to decreased leptin levels.

Reduced fertility and neuroendocrine dysfunction in women with epilepsy.

A reduction of fertility in women with epilepsy has been reported since 1950 and is confirmed in recent epidemiological studies. This phenomenon has usually been attributed to the increase of medical and socioeconomic problems in these patients or to hyposexuality, which has been consistently observed in epileptic subjects. Recently, a higher occurrence of reproductive endocrine diseases has been reported in epileptic women and proposed as an important cause of reduced fertility. In particular, polycystic ovary syndrome and hypothalamic ovarian failure have been reported in epileptic women with increased frequency compared to the general population. Moreover, an abnormal pattern of luteinizing hormone (LH) pulsatility has been observed in normally cycling, drug-free epileptic women. We suggest that epilepsy may interfere with the functional activity of the gonadotropin releasing hormone (GnRH) pulse generator. It is possible that paroxysmal discharges spreading within the hypothalamus might affect the regularity of the GnRH pulse generator; alternatively, a neurotransmitter dysfunction might at the same time be responsible both for the lowering of the seizure threshold and for the dysfunction of GnRH secretion. The consequent alteration of LH pulsatility might in the long run, under the effect of additional factors, give rise to a clinical reproductive endocrine disorder.

Endometrial hyperplasia: efficacy of a new treatment with a vaginal cream containing natural micronized progesterone.

Seventy-eight premenopausal women affected by benign endometrial hyperplasia (60 simple and 18 complex) were treated from the 10th to the 25th day of the menstrual cycle with a vaginal cream containing 100 mg of natural micronized progesterone in polyethylene glycol base. The treatment lasted 3 months in 58 patients and 6 in the other 16 patients. Four patients were lost from the study. We observed a total of 67 complete regressions (90.5%) of which 58 (78.3%) occurred in the first 3 months and 9 (11.5%) after 6 months of treatment. Simple hyperplasia showed a significantly higher response to treatment in comparison with the complex type (P < 0.001). The most frequent endometrial pattern detected in the patients in whom hyperplasia regressed was of a secretive type. Recurrence of hyperplasia occurred in 1 out of 58 (1.72%) patients at the 3rd month and in 3 out of 49 (6.1%) patients at the 6th month after treatment. There were no significant differences between the two hystological groups in the percentage of recurrence. During treatment we observed a significant reduction of the amount, duration and frequency of the menstrual bleeding. Minimal side-effects were observed. In conclusion, for its effectiveness and safety, vaginal administration of natural micronized progesterone seems to be an interesting approach to benign endometrial hyperplasia, particularly indicated in women also affected by metabolic disorders.

Effects of bilateral ovariectomy and postoperative hormonal replacement therapy with 17beta-estradiol or raloxifene on serum leptin levels.

Objective To verify the effects of hypoestrogenism and replacement therapy on body mass index (BMI) and leptin in ovariectomized women. Design We conducted a longitudinal study on 56 women undergoing abdominal bilateral ovariectomy divided into three groups: 19 untreated controls, 18 scheduled to receive 17&bgr;-estradiol, and 19 on raloxifene starting 15 days after surgery. Height, weight, and BMI were recorded on the day of surgery, 5 and 15 days later, and then after 6 months. Leptin and estradiol concentrations were determined by radioimmunoassay on the day of surgery, days 1, 5, and 15, and 6 months after. Results Leptin levels rose significantly on the day after surgery [median (range): 18.2 (9.8–25.0), 12.5 (9.1–20.9), and 20.5 (12.9–24.5);P < 0.01 v basal] and returned to values similar to baseline on day 5 in all groups. Six months later, controls showed significantly higher leptin levels in comparison with both treated women and basal values [median (range): 19.7 (10.4–22.8), 11.0 (7.6–16.9), and 13.5 (9.1–14.8) ng/ml;P < 0.01). Estradiol levels decreased in all groups, reaching statistical significance 5 days after surgery (P < 0.01 v basal). A significant rise was observed 6 months after surgery in women treated with estrogens (P < 0.01). Six months after surgery, BMI increased in untreated controls in comparison with treated women and baseline, although not significantly. Conclusions The absence of modifications in leptin on days 5 and 15 after ovariectomy suggests that, in humans, estrogens may not exert an important effect on leptin secretion. After 6 months, replacement therapy maintained leptin levels and BMI was unmodified, whereas untreated controls showed a significant increase in leptin and a trend toward higher BMI, suggesting that replacement therapy may prevent changes in fat distribution and in leptin levels.

Relationship between cerebrospinal fluid β-endorphin and plasma pituitary-gonadal hormone levels in women

Brain β-endorphin (β-EP) plays an important role in regulating the hypothalamus-pituitary-gonadal axis activity. Cerebrospinal fluid (CSF) β-EP levels seem to reflect the central rather than pituitary secretion. With the aim to correlate the changes of plasma estradiol (E2), progesterone, luteinizing hormone (LH) and follicle-stimulating hormone with brain β-EP, CSF levels of β-EP were measured in 15 normally cycling and 15 postmenopausal women. CSF β-EP levels in post-menopausal women were lower than in fertile women. A positive correlation between plasma E2 and CSF β-EP level was found in all women. In fertile women CSF β-EP levels were inversely correlated to plasma gonadotropin levels. These results showed that CSF β-EP levels differ between fertile and postmenopausal women and are correlated with plasma LH and E2, suggesting a strong linkage between central β-EP levels and pituitary-gonadal axis hormones.

Hormonal treatments modulate pulsatile plasma growth hormone, gonadotrophin and osteocalcin levels in postmenopausal women

Oestrogen plays a role in modulating growth hormone (GH), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and osteocalcin secretion in women. Indeed, the postmenopausal period is characterized by changes in plasma GH, LH, FSH and osteocalcin levels. The aim of the present study was to investigate the changes in the secretory patterns of these hormones in postmenopausal women under different therapeutic regimens. A total of 20 subjects took part in the study. They were subdivided into four groups comprising 5 untreated postmenopausal women (time since menopause 1-5 years), 5 postmenopausal women receiving steroid hormone replacement therapy, 5 postmenopausal women receiving salmon calcitonin and 5 fertile women with regular menstrual cycles. Blood samples were collected every 15 min for 4 h and hormone levels were measured by radioimmunoassay. Plasma GH levels fell in the postmenopausal women, but were restored under oestrogen-progestogen treatment. The pulsatile patterns of plasma LH and FSH did not show significant differences in the treated and untreated women. Plasma osteocalcin levels showed episodic fluctuations and mean levels decreased under steroid hormone or calcitonin treatment. No significant correlation was observed between plasma GH and osteocalcin or gonadotrophin levels or body mass index.

Double-blind controlled trial of progesterone vaginal cream treatment for cyclical mastodynia in women with benign breast disease

The clinical effectiveness and safety of vaginal micronized progesterone treatment in mastodynia were evaluated in a double-blind placebo controlled study. Eighty regularly menstruating worn-’ en affected by severe cyclical mastodynia were randomly assigned to two groups of 40 patients. One group was treated for 6 cycles from the 19th to the 25th day of the cycle with 4 g of vaginal cream containing 2.5% natural progesterone. The other group was similarly treated with placebo. The treatment was preceded by a control cycle. All patients reported every day their breast pain on a 100 mm visual linear analogue scale (VAS). The response of breast tenderness and nodularity to treatment was assessed by clinical examination. Vaginal progesterone resulted significantly more efficacious than placebo in reducing mean ratings of breast pain on VAS and mean scores of breast tenderness to touch. Success of treatment, defined as reduction greater than 50% of basal mean score of breast pain on VAS, was achieved in the 64.9% of patients treated with progesterone and in the 22.2% of patients receiving placebo (p<0.01). Conversely, at the end of treatment, the improvement in breast nodularity showed a not statistically significant difference between the two groups. No major side-effects were detected.

Positive response to compound CV 205-502 in hyperprolactinemic patients resistant to or intolerant of bromocriptine

The clinical effects of CV 205-502, a potent and non-ergot-derived dopamine agonist, were investigated in 24 selected patients with hyperprolactinemia previously treated with standard oral bromocriptine, the slow-release oral form of bromocriptine (BRC-SRO) and/or the long-acting injectable form of bromocriptine (BRC-LAR); 14 were chosen because of their resistance to treatment and ten because they were intolerant of the different forms of bromocriptine. A macroprolactinoma was present in seven patients and a microprolactinoma in ten, whereas seven had no radiological images of a pituitary tumor and were classified as having non-tumoral hyperprolactinemia. All the 24 patients were treated with CV 205-502 at a daily dose of 0.075-0.6 mg for 3-12 months. All the patients had gonadal dysfunction and galactorrhea. Basal serum prolactin values ranged from 70 to 1677 ng/ml. CV 205-502 was effective in 11 of the 14 patients resistant bromocriptine, BRC-SRO and BRC-LAR; serum prolactin levels became normal within 6 months and a tumor shrinkage was obtained in five of the seven macroprolactinomas. In general, the drug was effective and well tolerated. Only three patients (two resistant and one intolerant) manifested nausea, vomiting and postural hypotension. In conclusion, this study shows that CV 205-502 is effective in bromocriptine-resistant hyperprolactinemic patients. Furthermore, CV 205-502 has insignificant and tolerable side-effects in patients intolerant of bromocriptine. CV 205-502 can, therefore, be considered a useful and effective drug, and an interesting therapeutic alternative to the ergot-derived dopamine-agonist drugs in use today.

Review of the safety efficacy and patient acceptability of the combined dienogest/estradiol valerate contraceptive pill.

The aim of this review is to define the role of the combined dienogest (DNG)/estradiol valerate (E2V) contraceptive pill, in terms of biochemistry, metabolic and pharmacological effects and clinical application as well. E2V is the esterified form of 17β-estradiol (E2), while dienogest is a fourth-generation progestin with a partial antiandrogenic effect. The cycle stability is achieved with 2 to 3 mg DNG, supporting contraceptive efficacy. In this new oral contraceptive, E2V is combined with DNG in a four-phasic dose regimen (the first two tablets contain 3 mg E2V; the next five tablets include 2 mg E2V + 2 mg DNG, followed by 17 tablets with 2 mg E2V + 3 mg DNG; followed by two tablets with 1 mg E2V only, and finally two placebo tablets). Duration and intensity of scheduled withdrawal bleeding are lower with this contraceptive pill, whereas the incidence and the intensity of intra-cyclic bleeding are similar to the other oral contraceptive. With this new pill the levels of high density lipoprotein increased, while the levels of prothrombin fragment 1 + 2 and D-dimer remained relatively unchanged; the levels of sex hormone binding globulin, cortisol binding globulin, thyroxine binding globulin increased. The most frequently reported adverse events are: breast pain, headache, acne, alopecia, migraine, increase of bodyweight. The satisfaction rate is about 79.4%.