Current concepts in aesthetic endocrinology.

The extragenital effects of ovarian steroids are relevant to the metabolism of skin and hair, the changes in body composition and the alterations of the subcutaneous fat distribution throughout life. When ovarian steroids become deficient or are produced in excess, different problems may arise in these tissues and some of these problems, i.e., obesity and cellulite, display gender-specific components. Therefore, a new field in endocrine research known as aesthetic endocrinology is gaining more interest. Because sex steroids are small molecules they can be transported into the skin by topical application when properly formulated. This possibility is used in aesthetic endocrinology in order to achieve local effects but to avoid systemic reactions. After reviewing the current data it collectively seems legitimate to recommend estrogens, either orally or topically, in order to counteract the aging of the skin after menopause. Although a reconstitution of juvenile skin cannot be achieved through this method, a slowing in the skin aging process seems a reasonable expectation. In contrast, the successful treatment of hair loss in women is only confirmed for the application of the non-hormonal compound minoxidil. Apart from the difficult problem of hirsutism, acne and changes in body composition offer promising therapeutical options for endocrinological methods.

Tissue specificity: the clinical importance of steroid metabolites in hormone replacement therapy.

Metabolic activations or inactivations of estrogens, progesterone and androgens are important steps towards the understanding of the physiological and the pathological effects of these hormones in the female organism. Analysis of the tissue specific metabolic pathways of sex steroids will result in a better understanding of successful hormone replacement therapy on the one hand and of the occurrence of steroid hormone related side effects on the other hand. In this contribution we analyse the different mechanisms involved in the synthesis of tissue specific metabolites and discuss the therapeutical importance of these metabolites in hormone replacement therapy.

Melatonin in postmenopausal females.

There is little information about the interaction between melatonin, sexual steroids and neuroendocrine system in postmenopausal females, even if former research showed that melatonin is clearly involved in human physiology and pathophysiology. We evaluated the overnight urinary excretion of 6-sulfatoxymelatonin (6-SMT) using a radioimmunoassay in 60 postmenopausal women. The group has been divided into patients with insomnia (10), hyperprolactinemia (7), depression (9), obesity (7) and controls (27). Compared to controls 6-SMT values were significantly higher in depressive females. Patients with hyperprolactinemia showed a trend toward a significantly elevated average nocturnal melatonin concentration. Melatonin levels were significantly lower in patients with insomnia and obese postmenopausal females than in controls. Since previous studies described lower melatonin levels in postmenopausal than in premenopausal women, the indication of melatonin therapy, especially for sleep disorders in this collective, can be handled more generously. Melatonin should be prescribed restrictively in patients with depression and in those with hyperprolactinemia. The role of melatonin in obese females remains unclear.

Endocrinological disorders. Focusing on melatonin's interactions.

BACKGROUND: The interaction of melatonin to sterility and anovulation as well as related hormonal disorders has not been sufficiently examined yet. We set out to investigate the interaction between melatonin and hyperprolactinemia, hyperandrogenemia, hypothyreosis and obesity in premenopausal females. METHODS: We evaluated the overnight urinary excretion of 6-sulfatoxymelatonin (6-SMT) in a group of 155 women using a radioimmunoassay. RESULTS: Melatonin levels in patients with hyperprolactinemia and hyperandrogenemia with normal body mass index are significantly higher compared to matched controls. Obese females without hormonal disorders showed statistically lower 6-sulfatoxymelatonin levels and in hypothyreotic females we found no difference in 6-sulfatoxymelatonin levels compared to controls. CONCLUSION: Melatonin plays an important role in patients with hormonal disorders such as hyperprolactinemia and hyperandrogenemia. Melatonin should be prescribed restrictively in all sterile patients. In patients with untreated hypothyreosis or obesity, melatonin seems to play a minor part; in those with hyperprolactinemia and hyperandrogenemia additionally to standard sterility treatment light therapy may improve the outcome.

Effects of tibolone on auditory brainstem responses in postmenopausal women--a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To investigate the influence of tibolone, a synthetic steroid, in modifying auditory brainstem response (ABR) in postmenopausal women. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Outpatient menopausal clinic in a university hospital. PATIENT(S): Twenty-four healthy postmenopausal women. INTERVENTION(S): Administration of either tibolone or placebo for 12 weeks; evaluation of ABR and hormone levels before and after treatment. MAIN OUTCOME MEASURE(S): Changes in auditory brainstem response latencies. RESULT(S): Comparison of the ABR latency data from the two treatment groups showed a significant decrease in wave II, III, and V peak latencies in women receiving tibolone. No significant differences in pretreatment and posttreatment circulating hormone concentrations were observed between the tibolone and placebo group. Furthermore, there was no significant increase in hormone levels in either of the groups at 12 weeks. CONCLUSION(S): Our findings show an improvement in auditory function via brainstem auditory neural pathways sensitive to tibolone in postmenopausal women. Tibolone may offer new therapeutic strategies in otologic disorders.

Expression of inducible nitric oxide synthase in human breast cancer depends on tumor grade.

Expression of inducible nitric oxide synthase (iNOS) by tumor cells has been suggested to abrogate metastasis in several tumor models, whereas constitutive NOS expression correlated positively with tumor grade in human breast carcinoma. Whether or not expression of one of the various NOS isoforms could predict the prognosis of breast cancer, however, has not been established. In the present report we investigated the cellular distribution of NOS isoforms in a series of benign and malignant breast tumors and in normal breast tissue. Immunohistochemistry revealed that in samples of benign disease the number of iNOS+ epithelial cells or total epithelial cells was 69+/-16% (n = 50). In samples of grade II invasive ductal breast carcinomas the number of iNOS+ tumor cells or total tumor cells was 62+/-20% (n = 40), compared to 12+/-9% (n = 40) in samples of grade III carcinomas (P<0.0001). iNOS protein was also identifiable in most of the epithelial cells of normal breast tissue (n = 4). In contrast, eNOS protein was restricted to vascular endothelial cells in all of the specimens studied. Since the presence of tumor cell iNOS protein is inversely related to the tumor's metastatic potential, we conclude that endogenous tumor cell mediated iNOS expression might have an inhibitory effect on the metastatic process in breast cancer.

Computerized assessment of facial hair growth.

OBJECTIVE: To evaluate a computer-assisted technique for objective and sensitive monitoring of facial hair growth. DESIGN: Prospective study. SETTING: Department of Gynecological Endocrinology and Reproductive Medicine and Clinic for Ear, Nose, and Throat, General Hospital, University of Vienna, Vienna, Austria. PATIENT(S): Four men, three hirsute women, and three nonhirsute women. INTERVENTION(S): Using video equipment and computer software, we were able to document, analyze, and store data regarding hair growth in specific areas of interest. For digital image analysis, we used the Digi Trace System (Olympus, Vienna, Austria; Imatec, Munich, Germany). MAIN OUTCOME MEASURE(S): Hair growth within 20 days in well-defined regions of interest on the faces of hirsute and nonhirsute women and of men. RESULT(S): Hair growth on day 21 was significantly different between hirsute and nonhirsute women as well as in men. The scores for individual hair growth between day 0 and day 21 also were significantly different in hirsute women and in men. No statistically significant difference in hair growth was found within the group of nonhirsute women. CONCLUSION(S): With digital image analysis, facial hair growth, especially in hirsute women, can be calculated in a sensitive and objective manner.

Trends in the prescription of psychotropic drugs and hormone substitutes in Austria.

INTRODUCTION: Psychological instability as a result of changing hormone levels are commonly observed during menopause. We examined the question whether the prescription of psychotropic drugs is related to age or gender and whether the increase in the prescription rate of hormone substitutes has an impact on this phenomenon. METHODS: Age and gender-specific prescription rates of psychotropic drugs and hormone substitutes were examined in a retrospective study using data of the European Pharmaceutical Market Research Association of Austria. The relevant Austrian figures were established on the basis of representative samples. RESULTS: There are no gender-specific differences in terms of prescription frequency up to the age of 45 years. After the age of 45, there is a significant increase in the prescription of psychotropic drugs for women. When comparing the years 1991 and 1996, we find a reduction in the number of prescriptions of psychotropic drugs and an increase in the prescription rate of hormone replacement drugs. DISCUSSION: An increase in the prescription rate of hormone substitutes may contribute to the psychological stabilisation of menopausal women and thereby reduce the need for psychotropic drugs.

Gender-specific medicine: the new profile of gynecology.

The science of gynecology is undergoing a change and is swiftly turning into a holistic discipline, i.e. gender-specific medicine. The rationale for this is that the hormones of the ovary not only are responsible for reproduction but also perform a number of extragenital functions that extend far into other disciplines, giving rise to a different frequency of diseases in women than in men. For example, females are five times more likely to be affected by rheumatoid arthritis than males, the same also holding true for autoaggressive conditions. This phenomenon may be accounted for by the fact that physiological auto-aggression is involved in the reproductive process. Similarly, there is a difference between women and men with regard to the sicca phenomenon, or to such disorders as connective tissue weakness, cellulite, venous conditions or hypercholesterolemia. A cause-related treatment of such problems is now available through specific endocrine therapy. That is why gynecologists in future will increasingly have to adopt an interdisciplinary approach.

Endometrial cancer after combined hormone replacement therapy.

OBJECTIVE: It has been suggested that exposure to relatively high levels of unopposed estrogen is a risk factor for endometrial cancer. Combined therapy of estrogen with cyclic progestagen was therefore highly recommended for menopausal women with an intact uterus. METHODS: The cases of two postmenopausal women who developed endometrial cancer after taking continuous sequential HRT for 15 months are reported. Both were without bleeding for more than 2 years and presented with a normal vaginal ultrasound. They had severe menopausal symptoms and asked for HRT. RESULTS: After 15 months irregular bleeding occurred and a hysterectomy was performed. The pathohistological finding in both cases was endometrial cancer. As we measured the serum estradiol levels 4 h after tablet ingestion supraphysiologic values ranging between 418 and 442 pg/ml were found. CONCLUSION: Our report strengthens the evidence that supraphysiologic estradiol levels despite combination with cyclic progestagen therapy, increase the risk of endometrial cancer.

Non-invasive detection of alterations of the carotid artery in pregnant women with high-frequency ultrasound.

OBJECTIVE: To compare the thickness of the layers of the carotid artery wall in pregnant and fertile non-pregnant women. DESIGN: Prospective cross-sectional study. SUBJECTS: Fifty-one pregnant women at a mean gestational age of 38.9 weeks and 64 fertile non-pregnant women were examined at a University hospital. METHODS: The three layers (adventitia, media, intima) of the superficial wall of the left common carotid artery were identified and measured with high-resolution ultrasound (22.5 MHz). RESULTS: Pregnant women had a thinner intima layer (0.25 +/- 0.07/0.29 +/- 0.08 mm) and a thicker media layer (0.31 +/- 0.08/0.27 +/- 0.09 mm) compared with controls. A statistically significantly higher intima/media ratio was calculated for the pregnant women (1.14 +/- 0.03), compared with the non-pregnant women (0.88 +/- 0.04). CONCLUSION: There are differences in the thickness of the histological layers of the carotid artery wall in pregnant compared with non-pregnant women. This is likely to be due to the effect of different estradiol levels in these two groups.

Dehydroepiandrosterone in the treatment of erectile dysfunction: a prospective, double-blind, randomized, placebo-controlled study.

OBJECTIVES: In 1994, the Massachusetts Male Aging Study presented an inverse correlation of the serum levels of dehydroepiandrosterone (DHEA) and the incidence of erectile dysfunction (ED). We evaluated the efficacy of DHEA replacement in the treatment of ED in a prospective, double-blind, randomized, placebo-controlled study. METHODS: The inclusion criteria included ED, normal physical and neurologic examinations, serum levels of testosterone, dihydrotestosterone, prolactin, and prostate-specific antigen (PSA) within the normal range, and a serum DHEA sulfate level below 1.5 micromol/L. Also all patients had a full erection after a pharmacologic erection test with 10O microg prostaglandin E1; pharmacocavernosography showed no visualization in corporeal venous structures. Forty patients from our impotence clinic were recruited and randomly divided into two groups of 20 patients each. Group 1 was treated with an oral dose of 50 mg DHEA and group 2 with a placebo one time a day for 6 months. The International Index of Erectile Function (IIEF), a 15-item questionnaire, was used to rate the success of this therapy. RESULTS: Therapy response was defined as the ability to achieve or maintain an erection sufficient for satisfactory sexual performance according to the National Institutes of Health Consensus Development Panel on Impotence. DHEA treatment was associated with higher mean scores for all five domains of the IIEF. There was no impact of DHEA treatment on the mean serum levels of PSA, prolactin, testosterone, the mean prostate volume, and the mean postvoid residual urine volume. CONCLUSIONS: Our results suggest that oral DHEA treatment may be of benefit in the treatment of ED. Although our patient data base is too small to do relevant statistical analysis, we believe that our data show a biologically obvious trend that justifies further extended studies.

Progesterone and neurology.

Neurological diseases are frequently observed in perimenopausal women and can be characterized by their gender-specific occurrence. These observations raise the question whether sex steroids are also involved in neurological diseases. Epidemiological data have shown that in Austria in 1993, the prescription rate of psychotropics, hypnotics, and analeptics for women aged 50-55 years increased over 300% compared to other age groups. In males of the same age, an increase of the prescription rate was not observed. Molecular pharmacology research over the last ten years has shown that sex steroids may interact with the central nervous system via GABA receptors as well as with the peripheral nervous system. These observations confirm the epidemiological finding that neurological and psychological functions may also be directly influenced by sex steroids and their metabolites.

Conjugated estrogens--the natural SERMs.

Tissue selective and metabolite replacement therapy may become a new aspect in hormone replacement therapy (HRT). In addition to the naturally secreted hormones, there are also the later formed metabolites that exert a characteristic pharmacological profile. This mechanism is well known in thyroid replacement therapy, when triiodothyronine, the metabolite of thyroxine, is added to substitution therapy. The same is true for testosterone replacement therapy, when dihydrotestosterone is used for replacement. Also in menopausal HRT these aspects will gain tremendous importance. Progesterone metabolites have a strong clinical potency as neurosteroids, and estradiol metabolites are important factors in angiogenesis and angiostasis. Conjugated estrogens consist of different metabolites such as 16-hydroxy-equilin, which has no angiogenetic effect compared with 16-hydroxy-estrone. Estrone sulfate, the main component in conjugated estrogens, can be activated into estrone and 17 beta-estradiol in a tissue specific manner. This aspect will become of interest in clinical practice with HRT.

The effect of hormone replacement therapy on carotid arteries: measurement with a high frequency ultrasound system.

OBJECTIVE: To evaluate the effect of hormone replacement therapy (HRT) on carotid arteries in postmenopausal women with a high frequency ultrasound system. METHODS: In a clinical cross-sectional study carotid artery layers were measured in 82 postmenopausal women receiving a sequential regimen of HRT (oestradiol valerate 2 mg and dydrogesterone 10 mg) and in 70 postmenopausal women without HRT. Measurements of the left carotid artery layers (externa, media, intima) were taken with a single mechanically activated 22.5-MHz transducer with an effective band width of 8 MHz. RESULTS: A statistically significant increase in thickness of the media layer of the carotid artery was observed in the HRT group (0.34 +/- 0.06 mm) as compared to the untreated group (0.27 +/- 0.03 mm). The media/intima ratio of the treated group was statistically significantly higher than that of the untreated group (P < 0.05). The mean strength of the carotid wall was 0.70 +/- 0.17 mm in the 70 postmenopausal women without HRT and 0.76 +/- 0.24 mm in the 82 patients undergoing HRT. CONCLUSION: HRT has a morphological effect on the carotid arteries in postmenopausal women. These findings support a cardioprotective effect, especially in terms of prevention of atherosclerosis. This effect can be measured non-invasively by high frequency ultrasound.

Effect of percutaneous androgen replacement therapy on body composition and body weight in postmenopausal women.

OBJECTIVES: This study was carried out to assess the effect of topical androgen replacement therapy on body weight, body composition and fat distribution in postmenopausal women. METHODS: 39 healthy postmenopausal women (51.4 +/- 2.24 years), with increasing body weight, were prospectively studied for 6 months. Body composition (fat mass, kg, %) was measured by means of dual-energy X-ray absorptiometry (DXA). Hormonal and lipid parameters were also measured. Subjects were divided into two groups. An androgen gel (group A) or placebo gel (group P) was topically administered to the abdominal and gluteo-femoral regions. DXA was performed before commencement of topical treatment and after 6 months. RESULTS: A highly significant total body weight reduction was found in group A (68.0 +/- 13.1 to 65.4 +/- 11.8 kg). Abdominal fat (37.3 +/- 11.2 to 35.1 +/- 9.7%), gluteo-femoral fat (46.3 +/- 6.6 to 45.4 +/- 7.7%), total body fat (38.2 +/- 7.9 to 36.1 +/- 8.6%) and BMI (24.8 +/- 4.3 to 23.7 +/- 3.8) were also found to have decreased significantly in this group. No significant reduction in body weight (kg) and body fat (%) could be measured in the placebo group. No influence on lipid parameters was found although total testosterone increased significantly in group A (0.29 +/- 0.24 to 0.72 +/- 0.17 ng/ml). CONCLUSIONS: Topically applied androgen is capable of reducing abdominal fat accumulations as well as total body weight in postmenopausal women with unexplained weight gain. In contrast to systemic androgen application, topical administration has no effect on the lipid profile. Gluteal fat, however, is less effectively influenced by androgens.

[Thymopentin in alopecia areata]. / Thymopentin bei Alopecia areata.

Alopecia areata is a common cause of hair loss which leads to localized bald areas predominantly on the scalp. Etiological factors are not clear yet, but it is generally considered as a consequence of an autoimmune process. Histological findings revealed perifollicular infiltration of T-cells and antigen-presenting cells. Autoreactive T-cells are reported to amplify this abnormality by interacting with follicular epithelium. There is no effective treatment available at the moment. We report on a 53-year old climacteric woman who developed a bald lesion on her scalp spontaneously in november 1995. Alopecia areata was documented before and after therapy. Treatment with thymopentin 50 mg subcutaneously was offered successfully for 10 weeks, while continuing hormone replacement therapy. Other therapeutical strategies did not proof to be successful before.

Topical cyproterone acetate treatment in women with acne: a placebo-controlled trial.

OBJECTIVE: To evaluate the clinical and hormonal response of topically applied cyproterone acetate, oral cyproterone acetate, and placebo lotion in women with acne. DESIGN: Placebo-controlled, randomized study. SETTING: Patients were recruited from the Institute of Endocrine Cosmetics, Vienna, Austria. PATIENTS: Forty women with acne. INTERVENTIONS: Treatment with oral medication consisting of 0.035 mg of ethinyl estradiol and 2 mg of cyproterone acetate (n=12), 20 mg of topical cyproterone acetate lotion (n=12), and placebo lotion (n=16) was offered. Patients were assessed monthly for 3 months. MAIN OUTCOME MEASURES: Clinical grading according to acne severity and lesion counts as well as determinations of serum cyproterone acetate concentrations. RESULTS: After 3 months of therapy with topical cyproterone acetate, the decrease of mean facial acne grade from 1.57 to 0.67 was significantly better (P<.05) compared with placebo (which showed a change from 1.57 to 1.25), but not compared with oral medication (1.56 to 0.75) (P>.05). Lesion counts also decreased from 35.9 to 9.1 in the topical cyproterone acetate group compared with oral medication (45.4 to 15.5) (P>.05) and placebo (38.2 to 23.1) (P<.05). After topical cyproterone acetate treatment, serum cyproterone acetate concentrations were 10 times lower than those found after oral cyproterone acetate intake. CONCLUSIONS: The therapeutic effect of topically applied cyproterone acetate for acne treatment was clearly demonstrated. Topically applied sexual steroids in combination with liposomes are as effective as oral antiandrogen medication in acne treatment, while reducing the risk of adverse effects and avoiding high serum cyproterone acetate concentrations.