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Androgenic
alopecia. Alopecia Androgénica. ************************************
EDITORIAL ENGLISH:
I found 43
references that illustrate us very well this topic that never left of
being of interest for all.
OBSERVATIONS: Results of histological and scalp skin 5 alpha-dihydrotestosterone formation analyses and comparison of growth pattern of kinky hair in the affected areas with that of healthy hair were similar to those found in androgenetic alopecia. CONCLUSIONS: No
data are available
to confirm the presence of a sole entity, even if our arguments support our
hypothesis. The
confirmation of this tendency warrants further investigation.
Observations of patients with
disorders of androgen metabolism or function have determined the basic
physiology involved in
regulation of hair growth by androgens at selective body sites. More
recently, in vitro studies of
scalp skin and hair follicles have begun to define specific alterations in
androgen metabolism at the
local level that may play a key role in pathogenesis. The prominent role of
5-reductase in these
studies suggests that inhibitors of this enzyme may provide new therapeutic
opportunities for patients
with androgenetic alopecia. The effect of finasteride
develops above all at the level of
type II 5 alpha-reductase. Recent studies have evaluated the effect of
finasteride in patients of both
sexes with hirsutism and androgenetic alopecia. In women with various forms
of hyperandrogenism,
the use of the drug at the doses commonly used for the treatment of benign
prostatic hyperplasia
seems to have induced a significant reduction in the degree of hirsutism.
Furthermore, both in
animals and men with alopecia, the drug seems to have led to an increase in
the number and an
improvement in the shape of the follicles in the anagen phase, and a
simultaneous decrease of
dehydrotestosterone at the level of the scalp. This study represents a
review of the main results
obtained over the last two years and reports the prospects which the use of
finasteride may have in
this context. DESIGN: Prospective study in various groups of women and men. SETTING: Reproductive Endocrine Clinic at our university medical center. PATIENTS: Ten normal ovulatory female controls and 50 hyperandrogenic women divided on the basis of hirsutism and alopecia as follows: [1] 8 hirsute women with androgenic alopecia; [2] 12 nonhirsute women with androgenic alopecia; [3] 18 hirsute women without androgenic alopecia; and [4] 12 nonhirsute women without androgenic alopecia. Ten normal men and 10 young premature balding men matched for age and weight also were compared. I NTERVENTION: Blood was obtained from all subjects. MAIN OUTCOME MEASURE: Comparison of blood hormone levels in the various groups. RESULTS: Serum T, androstenedione, and DHEAS were similarly elevated in hyperandrogenic women with and without alopecia, compared with controls. The female groups were then divided on the basis of hirsutism. Hirsute groups with and without alopecia had similarly elevated levels of unconjugated 3 alpha-androstanediol, 3 alpha-androstanediol glucuronide, 3 alpha-androstanediol sulfate, androsterone glucuronide, and androsterone sulfate compared with controls. In the nonhirsute groups, androgenic alopecia patients were compared with hyperandrogenic females and cycling controls. The androgenic alopecia patients had elevated levels of 3 alpha androstanediol (0.75 +/- 0.12 versus 0.46 +/- 0.1 and 0.41 +/- 0.1 nmol/L), 3 alpha-androstanediol sulfate (200 +/- 31 versus 79.6 +/- 6 and 67.0 +/- 4.0 nmol/L), elevated ratios of 3 alpha-androstanediol sulfate:3 alpha-androstanediol (267 +/- 49 versus 170 +/- 20 and 164 +/- 49 nmol/L), elevated ratios of 3 alpha-androstanediol sulfate:3 alpha-androstanediol glucuronide (32.2 +/- 6 versus 10.8 +/- 1 and 10.0 +/- 1) and lower ratios of 3 alpha-androstanediol glucuronide:3 alpha-androstanediol glucuronide (8.3 +/- 1.8 versus 17 +/- 1.7 and 15.2 +/- 1.6 nmol/L). I n men the premature balding group had lower levels of 3 alpha-androstanediol glucuronide compared with the male controls (29.8 +/- 4.4 versus 15.2 +/- 1.6 nmol/L). Also, the ratio of 3 alpha-androstanediol glucuronide:3 alpha-androstanediol was significantly decreased, whereas the ratio of 3 alpha-androstanediol sulfate:3 alpha-androstanediol glucuronide was elevated. CONCLUSIONS: These data provided evidence confirming that enhanced 5 alpha-reductase activity occurs in androgenic alopecia but also suggests that a disorder of androgen conjugation, favoring sulfurylation over glucuronidation, may be a characteristic feature of scalp hair loss. ====================================================================== were investigated. Hormone levels were compared with those of 58 age-matched male and 45 female controls. In 38 of the 46 female AH patients, hypophyseal function was moreover evaluated by the 'TRH test', which detects slight, secondary hypothyroidism and/or hyperprolactinemia. Our findings showed a significant elevation of F in both male and female AH patients compared to controls, pointing to the suprarenes as a contributing factor in AH. This is confirmed by the observation of exacerbated AH in periods of increased stress. Concerning specifically male androgens, a significant elevation of androstenedione was noted. The mainly peripheral activity of this hormone and elevated E2 levels in males stress the importance of androgen metabolism especially at the peripheral level. Additional TRH
tests in females
demonstrated significant hypophyseal hypothyroidism. Multilayered
interaction between thyroid
hormones and androgens may contribute to the development of AH in
hyperthyroid patients.
Another significant finding was elevated PRL after TRH stimulation. Thus,
the androgen-stimulating
effect of PRL may also play a role in female AH. Our findings show
multilayered hormonal
influences in AH. Broad-range hormone determination demonstrated a
differentiated hormonal
situation in this disorder. ====================================================================== For example, an
increase in the anagen rate does not always reflect a lengthening of the
anagen stage, but may also
be due to shortened hair cycles. Accordingly, drug effects on hair growth
should be investigated by
methods that analyse the cell cycle kinetics. For this approach
DNA-flowcytometry of the outer
root sheath in plucked anagen hairs and of complete anagen hair bulbs taken
by micropreparative
techniques from scalp biopsies offers a reproducible method for quick and
reliable evaluation of hair
growth. Estrogen receptor positivity in the dermal papilla was found in only two of 13 cases of alopecia areata, and in one case of androgenic alopecia. Six of 13 cases of alopecia areata demonstrated focal reactivity with the progesterone marker in a similar location, while only three cases of androgenic alopecia showed positivity with this antibody. Examination of the perifollicular fibroblasts for the ER marker showed positivity in one of 13 cases of alopecia areata and in one case of androgenic alopecia. Two cases of alopecia areata revealed focal staining in this location for the PR marker, while the androgenic alopecia cases failed to stain. These results indicate that estrogen and progesterone receptor expression is not significantly increased or decreased in the pilosebaceous units or surrounding mesenchymal cells in androgenic alopecia vs. alopecia areata. Therefore, an indirectly mediated process of estrogen/progesterone control on hair growth and development must be presumed for cases of androgenic alopecia. ====================================================================== A subgroup, those traditionally labeled as having polycystic ovary syndrome (PCOS), additionally have anovulation, as well as menstrual abnormalities and, often, obesity. Although women with androgenic disorders usually present themselves for help with the skin or menstrual changes, there are other important implications regarding their health. Women with PCOS have varying degrees of insulin resistance, and an increased incidence of Type II diabetes mellitus, as well as unfavorable lipid patterns. The presence of these risk factors is suggested by upper segment obesity, darkening of the skin, and the other skin changes that make up acanthosis nigricans. Diagnosis involves measurement of circulating androgens (of which free testosterone is most important), together with prolactin and FSH when menstrual dysfunction is present. Many women with androgenic skin changes have normal serum androgen levels, suggesting increased end organ sensitivity to androgens. Others have hyperandrogenism (of ovarian or adrenal origin). Treatment is usually successful in controlling acne, reducing hirsutism and stabilizing, or partially reversing, androgenic alopecia. Pharmacological approaches involve suppressing androgen levels, for example, the use of an appropriate oral contraceptive, or antagonizing androgen action with several medications that have this activity. Unfortunately, most women with androgenic disorders are frustrated in their efforts to obtain medical help. Understanding androgenic disorders will enable the physician to significantly help the majority of women with these conditions. ====================================================================== DESIGN: A prospective study of women attending a joint skin/endocrine clinic complaining of these problems. PATIENTS: Three hundred and fifty consecutive women with hirsutism and/or androgenic alopecia were assessed. MEASUREMENTS: Baseline endocrine screens were conducted on two occasions and included measurement of serum testosterone, androstenedione, dehydroepiandrosterone sulphate, sex hormone binding globulin, LH, FSH, 17-hydroxyprogesterone and PRL. The ovaries were visualized by high-resolution pelvic ultrasound scanning. RESULTS: Eight women were identified with relevant endocrine disorders; of these, one was acromegalic and one had a microprolactinoma--in both cases the association may have been fortuitous. Three had clear-cut 21-hydroxylase deficiency, one a rare hepatic enzyme deficiency (11-reductase), one a virilizing adrenal carcinoma and one a Leydig cell tumour. The latter six cases all had persistently elevated levels of serum testosterone ( 5 nmol/l). In all, 13 women had baseline testosterone levels in excess of 5 nmol/l. Polycystic ovaries were present in 81% of the cases who had erratic cycles and 52% of those with regular cycles; PCO were present in two of the women with 21-hydroxylase deficiency and in the woman with 11-oxoreductase deficiency. The Leydig cell tumour (1.2 cm diameter) was not detected on ultrasound or CT scan. CONCLUSIONS: For the
exclusion of
enzyme deficiencies and virilizing tumours clinical assessment and a single
serum testosterone
measurement will suffice. Abstract BACKGROUND: The pathogenesis of androgenic alopecia is not fully understood. A microbial-driven inflammatory reaction abutting on the hair follicles might participate in the hair status anomaly. OBJECTIVE: The aim of our study was to determine if ketoconazole (KCZ) which is active against the scalp microflora and shows some intrinsic anti-inflammatory activity might improve alopecia. METHOD: The effect of 2% KCZ shampoo was compared to that of an unmedicated shampoo used in combination with or without 2% minoxidil therapy. RESULTS: Hair density and size and proportion of anagen follicles were improved almost similarly by both KCZ and minoxidil regimens. The sebum casual level appeared to be decreased by KCZ. CONCLUSION: Comparative
data suggest
that there may be a significant action of KCZ upon the course of
androgenic alopecia and
that Malassezia spp. may play a role in the inflammatory reaction. The
clinical significance of
the results awaits further controlled study in a larger group of
subjects. Abstract Background: Male baldness develops because of an increased duration of the lag phase. Objective and Methods: To assess if this occurs also in balding women we studied 2 women with Ludwig type I-II patterned baldness for 2 years with monthly phototrichograms. Hairs were identified as thick anagen hairs, thin anagen hairs and telogen hairs. Results and Conclusions: Most of the hairs followed the expected development,
namely they remained
thick anagen hairs or they became thick from thin anagen, telogen from
thick anagen or thin
anagen from telogen hairs. Other hairs, though, became thin from thick
anagen or telogen
from thin anagen or thick anagen from telogen hairs. Still others did
not regrow immediately
after being in the telogen phase, leaving an empty space. Some empty
spaces were not
refilled for a long time. As in men, in balding women tiny bald spots
develop corresponding to
telogen hairs not replaced in due time. Abstract In this study, 12 women and 12 men, ages 18-33 y, with androgenetic alopecia were selected for biopsies from frontal and occipital scalp sites. The androgen receptor, type I and II 5alpha-reductase, cytochrome P-450-aromatase enzyme were measured and analyzed in hair follicles from these scalp biopsies. Findings revealed that both women and men have higher levels of receptors and 5alpha-reductase type I and II in frontal hair follices than in occipital follicles, whereas higher levels of aromatase were found in their occipital follicles. There are marked quantitative differences in levels of androgen receptors and the three enzymes, which we find to be primarily in the outer root sheath of the hair follicles in the two genders. Androgen receptor content in female frontal hair follicles was approximately 40% lower than in male frontal hair follicle. Cytochrome
P-450-aromatase content in
women's frontal hair follicles was six times greater than in frontal
hair follicles in men. Frontal
hair follicles in women had 3 and 3.5 times less 5alpha-reductase type
I and II, respectively,
than frontal hair follicles in men. These differences in levels of
androgen receptor and
steroid-converting enzymes may account for the different clinical
presentations of
androgenetic alopecia in women and men. Abstract This paper summarizes all postmarketing safety surveillance data collected by Solvay Pharmaceuticals, Inc. (Marietta, Georgia), between 1989 and 1996 for Estratest and Estratest HS (half-strength). These oral esterified estrogens--methyltestosterone combination products have been marketed in the United States since 1964 for the treatment of moderate-to-severe vasomotor symptoms associated with menopause in patients whose symptoms have not been relieved by estrogens alone. Between 1989 and 1996, more than 1 million woman-years of exposure occurred. The safety profile contained in this paper is based on a cumulative total of 568 individual cases comprising 863 adverse events (AEs). The proportions of AEs associated with the use of Estratest (575 events; 66.6%) and Estratest HS (288 events; 33.4%) were commensurate with the proportions of individual reports of adverse experiences for the two formulations (369 reports [65.0%] and 199 reports [35.0%], respectively). The rank order and percentage of types of AEs reported were also similar. The cumulative volume of reports was relatively low given the extent of exposure. Despite the limitations inherent in spontaneous postmarketing surveillance, the safety profile derived from this assessment does not indicate a significant safety concern with Estratest or Estratest HS. No deaths were reported, and no adverse findings indicative of the need for more comprehensive surveillance or concern on the part of the medical community or consumers were observed. Reports of cancer, cardiovascular disease, thromboembolic phenomena, and hepatic dysfunction were few and were assessed as not related to treatment with Estratest or Estratest HS; reports of drug overdose, drug-drug interaction, and birth defects were rare (4 of 863 events; 0.5%). The most commonly reported
AEs were those
known to be associated with estrogen therapy (weight gain, headache,
nausea, and
vasodilatation) and androgen treatment (alopecia, acne, and
hirsutism). Twenty-three
(4.0%) of the 568 cases reported had at least one event that was
regarded as serious, and
53 (6.1%) of the total 863 AEs were regarded as serious. The findings
indicate that Estratest
and Estratest HS are safe when used as directed and that the marginal
increase in risk
associated with androgen coadministration can be managed with
appropriate patient
selection and monitoring, as stated in the package insert for these
compounds. Abstract Androgens can gradually transform large scalp hair follicles to smaller vellus ones, causing balding. The mechanisms involved are unclear, although androgens are believed to act on the epithelial hair follicle via the mesenchyme-derived dermal papilla. This study investigates whether the levels and type of androgen receptors in primary lines of cultured dermal papilla cells derived from balding scalp hair follicles differ from those of follicles from non-balding scalp. Androgen receptor content was measured by saturation analysis using the non-metabolisable androgen, [3H]mibolerone (0.05-10 nM) in a 9-10 point assay. Pubic dermal fibroblasts and Shionogi cells were examined as positive controls. Repetitive assays of Shionogi cells showed good precision in the levels of androgen receptor content (coefficient of variation = 3.7%). Specific, high affinity, low capacity androgen receptors were detected in dermal papilla cells from both balding and non-balding follicles. Balding cells contained significantly (P < 0.01) greater levels of androgen receptors (Bmax = 0.06 +/- 0.01 fmol/10(4) cells (mean +/- S.E.M.)) than those from non-balding scalp (0.04 +/- 0.001). Competition studies with a range of steroids showed no differences in
receptor binding
specificity in the two cell types. The higher levels of androgen
receptors in cells from balding
scalp hair follicles with similar properties to those from non-balding
scalp concur with the
expectations from their in vivo responses to androgens. This supports
the hypothesis that
androgens act via the dermal papilla and suggests that cultured dermal
papilla cells may offer
a model system for studying androgen action in androgenetic alopecia. Abstract Male pattern baldness is a common, androgen-dependent skin problem in adult men which is not well understood, although androgens are believed to act on the hair follicle via the mesenchyme-derived dermal papilla situated in the middle of the hair follicle bulb. Since dermal papilla cells retain specific characteristics in culture, such as hair-growth promoting ability and appropriate features of the mechanism of androgen action, dermal papilla cells from follicles undergoing androgen-stimulated miniaturization may provide a useful in vitro model system. Therefore, dermal papilla cells have been derived from intermediate follicles from balding and nearly clinically normal sites of men with androgenetic alopecia. Balding dermal papillae were much smaller than non-balding ones and grew much less well under normal growth conditions. Supplementing the medium with human serum, rather than fetal calf serum, increased both the yield of established cultures and the number and health of the dermal papilla cells produced. Non-balding cells also grew faster in human serum. Balding cells retained the normal fibroblastic shape and aggregative behaviour of dermal papilla cells, but always grew less well than non-balding cells. Nearly clinically
normal dermal papillae
were similar, or slightly smaller, in size to non-balding ones, but
their growth resembled
balding cells. Since balding dermal papilla cells can be cultured,
though with much greater
difficulty than nonbalding ones, and exhibit differing growth
characteristics to non-balding
cells, they merit further investigation which may increase our
understanding of, and ability to
control, androgenetic alopecia. Abstract In order to define the respective involvement of steroidogenesis enzymes subtypes in the control of hair follicle homeostasis, we evaluated, by semiquantitative RT/PCR, the expression levels of mRNAs coding for 17 beta-hydroxysteroid dehydrogenase type 1 and type 2, 3 beta-hydroxysteroid dehydrogenase, Cyt.P450-aromatase, steroid 5 alpha-reductase type 1 and type 2 and 11 beta-hydroxysteroid dehydrogenase. These assays were performed for several components of the pilosebaceous unit (PSU); fresh plucked anagen hairs, sebaceous glands and primary culture of dermal papilla, as well as other tissues involved in an active steroid metabolism (human testis, liver, placenta, prostate, ovary, uterus and adrenals) as controls. We found that plucked hair (i.e. mainly keratinocytes from the inner and outer root sheaths) expressed: (1) very high levels of 17 beta-hydroxysteroid dehydrogenase type 2 corresponding to levels found in liver and placenta; (2) high levels of steroid 5-alpha-reductase type 1 corresponding to levels found in testis, liver and ovary, and moderate levels of 17 beta-hydroxysteroid dehydrogenase type 1, which corresponded to the expression in testis, prostate and uterus. In contrast, Cyt.P450-aromatase, 3 beta-hydroxysteroid dehydrogenase and steroid 5 alpha-reductase type 2 were poorly expressed in the pilosebaceous unit as compared with other tissues. Interestingly, expression patterns of these enzymes in primary cultures of dermal papilla were distinctive since 5 alpha-reductase type 1 and 11 beta-hydroxysteroid dehydrogenase were the only mRNA detected. Taken together, these results suggest that not only
sebaceous gland but also outer
root sheath keratinocytes may contribute, through the activity of the
steroid 5 alpha-reductase
type 1, to the pathogenesis of androgen-dependent alopecia. Abstract Hirsutism, acne and androgenic alopecia represent, in females, some of the manifestations of the clinical spectrum of hyperandrogenism. These pictures represent not only cosmetic damage, but also a source of remarkable psychological distress. Often hirsutism is regarded as presumptive evidence of a lack of femininity. The major diagnostic concern is to exclude an ovarian or adrenal androgen-secreting tumor, a congenital hyperplasia or polycystic ovary disease. Ethnic background should be taken into account together with the progression of the symptoms. Following the etiology, surgery and exogenous glucocorticoids or inhibition of gonadotropin secretion have to be carefully chosen in the management of different kinds of hyperandrogenism. Several pharmacologic agents have recently shown the ability to block the androgen receptors at target organ sites, thus allowing a specific antiandrogenic treatment. In some cases cosmetic measures could be of great value. Obesity
accompanied by
hyperinsulinemia can represent the main cause of ovary androgen
hypersecretion; therefore
a reduced body weight and muscle activity represent the basis of any
treatment. Some other
drugs, such as long-acting analogs of somatostatin, could be
considered among possible
drugs for the future. The aim of this article is to provide an
appraisal of what is presently
known about the regulation of hair growth, the various causes of
excessive androgen
secretion and the current methods to solve, safely, this important
feminine clinical problem. Abstract OBJECTIVES: Both benign prostatic hyperplasia (BPH) and male pattern baldness (androgenic alopecia) share the pathogenesis of an androgen-dependent disorder and afflict a large population of elderly men with chronobiologic progress. However, it is unclear whether these diseases are related epidemiologically. We evaluated the association of frequency and severity of male pattern baldness between patients with BPH and a control group. METHODS: A total of 225 patients with BPH (mean age 69.3 +/- 6.5 years) and 1 60 controls (mean age 68.5 +/- 6.4 years), all over 60 years of age, were included in this study. The estimation of baldness severity was based on Norwood's classification (grade I to VII). The International Prostate Symptom Score (IPSS) and genetic tendency for baldness were also evaluated. The difference between IPSS and grade of baldness between the two groups was analyzed by the Mann-Whitney test and the frequency of inherited baldness was compared by the chi-square test. Correlation between severity of baldness and IPSS in each group was estimated by Spearman's rank correlation method. RESULTS: The patients with BPH had an apparently higher grade of male pattern baldness in comparison with that of controls (median value of grade IV versus III, P <0.001). The proportion of men with male pattern baldness of grade IV or higher in the BPH group was significantly larger than that of controls (53.8% versus 36.9%, P <0.01). There was a greater frequency of inherited baldness in the BPH group than in the controls (31.6% versus 12.5%, P <0.001). No significant correlation was noted between baldness severity and IPSS in either group. CONCLUSIONS: This study demonstrates a strong association of BPH with
male pattern
baldness. Abstract Today there are new classes of hair growth promotors with proven
efficacy. This article
reviews the current state of the art agents for treatment of two of
the most common forms of
hair loss encountered in clinical practice, androgenetic alopecia and
alopecia areata. Current
therapeutic strategies are based on recent advances in the
understanding of disordered hair
growth. Practical treatment protocols are presented. Abstract Androgenic disorders have many negative physical effects. These effects may be caused by excess androgen (exogenous or endogenous) or by end-organ sensitivity to normal levels of androgens. Historically, androgenic progestins in oral contraceptives have also been associated with some of these negative effects. The most apparent signs of androgen excess are the external manifestations, including oily skin, acne, hirsutism, android obesity, and androgenic alopecia. Of equal concern are the potential metabolic disturbances associated with hyperandrogenicity. Unfavorable lipid profiles and increased incidence of diabetes and hypertension are very real threats to long-term health. In oral contraceptive users, external manifestations of androgenicity often lead to poor compliance, decreased efficacy, and discontinuation of oral contraceptive use, especially in the younger patient. With the
introduction of the newer oral contraceptive formulations containing
less androgenic
progestins (norgestimate, desogestrel, gestodene), androgen-related
effects have been
reduced and better compliance is anticipated.
Language Abstract Five women affected by androgenetic alopecia developed severe
hypertrichosis of the face
and limbs after 2-3 months of treatment with 5% topical minoxidil.
Minoxidil was
discontinued and in all patients the hypertrichosis disappeared from
the face and arms after
1-3 months, and from legs after 4-5 months. Systemic absorption of
minoxidil, and a high
sensitivity to minoxidil of the follicular apparatus in these areas,
is hypothesized. Abstract The hair follicle dermal papilla which controls hair growth, is characterized in the anagen phase by a highly developed vascular network. We have demonstrated in a previous study that the expression of an angiogenic growth factor called vascular endothelial growth factor (VEGF) mRNA varied during the hair cycle. VEGF mRNA is strongly expressed in dermal papilla cells (DPC) in the anagen phase, but during the catagen and telogen phases. VEGF mRNA is less strongly expressed. This involvement of VEGF during the hair cycle allowed us to determine whether VEGF mRNA expression by DPC was regulated by minoxidil. In addition, the effect of minoxidil on VEGF protein synthesis in both cell extracts and DPC-conditioned medium, was investigated immunoenzymatically. Both VEGF mRNA and protein were significantly elevated in treated DPC compared with controls. DPC incubated with increasing minoxidil concentrations (0.2, 2, 6, 12 and 24 mumol/L) induced a dose-dependent expression of VEGF mRNA. Quantification of transcripts showed that DPC stimulated with 24 mumol/L minoxidil express six times more VEGF mRNA than controls. Similarly, VEGF protein production increases in cell extracts and conditioned media following minoxidil stimulation. These studies strongly support the likely
involvement of minoxidil in
the development of dermal papilla vascularization via a stimulation of
VEGF expression, and
support the hypothesis that minoxidil has a physiological role in
maintaining a good
vascularization of hair follicles in androgenetic alopecia. Abstract Minoxidil is the most used drug with proved effects in the treatment of androgenetic alopecia (AGA), but little is known about its pharmacological activity and target cells in hair follicles. As AGA is characterized by follicle atrophy, accelerated hair cycles and hair fiber thinning, we postulated that keratinocyte proliferation/differentiation is affected and we tested Minoxidil's effects on those parameters. Normal human keratinocytes (NHK) of follicular or epidermal origin were cultured in the presence of Minoxidil (0, 0.1, 1, 10, 100, 1,000 microM) during 5-8 days in various media (high-/low-calcium content, with or without serum). Proliferation was assessed by mitochondrial dehydrogenase activity (XTT), BrdU incorporation, lysosome numeration (neutral red incorporation) and total protein dosage. Drug-induced cytotoxicity was measured by lactate dehydrogenase release in culture supernatant, and pro-differentiating effects were evaluated by relative involucrin expression (ELISA dosage). On this basis, we showed that Minoxidil had biphasic
effects on the
proliferation and differentiation of NHK: Minoxidil stimulated NHK
proliferation at
micromolar doses, while antiproliferative, pro-differentiative and
partially cytotoxic effects
were observed with millimolar concentrations. We can hypothesize that
Minoxidil
hypertrichotic activity in vivo is possibly mediated by the
maintenance of proliferative
potential in follicular keratinocytes precociously committed to
differentiation. Abstract Alopecia is a common side effect in patients managed on the mood stabilizers lithium, valproate, and carbamazepine. Clinicians may be reluctant to discontinue medications in patients suffering from hair loss if the mood stabilizer is otherwise efficacious. Therefore it is important to be familiar with the epidemiology, diagnosis, and management of alopecia. A single representative case is provided to illustrate briefly the common presentation of a patient with mood stabilizer-induced alopecia. A literature search was conducted to provide the basis for discussion of diagnosis, the association of mood stabilizers with alopecia, and some management options of this side effect. The diagnosis of alopecia requires an understanding of normal hair growth and is best made following a careful history, an examination, and the maintenance of a high level of suspicion. Alopecia occurs in about 10%
of persons managed
on lithium, up to 12% of persons on valproate, and less than 6% of
individuals on
carbamazepine. Management of alopecia includes reassurance, hair care
techniques, trace
mineral supplementation, treatment with minoxidil, and hair
replacement pieces. Alopecia
due to mood stabilizer drugs can be potentially identified and managed
without medication
discontinuation. ====================================================================== Abstract Hyperandrogenism in women refers to both excess androgen production and clinical manifestations of androgen excess. Clinical evaluation of women with hyperandrogenism is complex. The synthesis and release of androgenic steroid in women are normal part of adrenal and ovarian steroidogenesis. One of the classic questions concerning androgenic disorders concerns the source of circulating androgens. Relative roles of adrenal and ovary vary greatly, both can be involved. The use of gonadal or adrenal steroid administration can sometimes be used to distinguish the source of androgen excess. In many cases of hyperandrogenism no laboratory diagnosis of adrenal and ovarian androgen overproduction can be made. These patients may have increased androgen sensitivity due to increased enzyme 5 alpha-reductase activity in the skin. To be active in the skin, testosterone (T) must be converted to dihydrotestosterone (DHT) by the 5 alpha-reductase. The increase in DHT production is a localized phenomenon and there is no generalized increase in enzyme activity in women with hyperandrogenism. DHT is rapidly converted to other steroid metabolites including androsteron, androstanediol and their glucuronide and sulfate conjugates. Although once thought to be specific for skin conversion of T to DTH these androgen conjugates reflect adrenal steroid production and metabolism. Antiandrogens (androgen receptor blockers) are the most effective therapeutic modalities of cutaneous hyperandrogenism. Clinical trials are in progress to determine efficacy of finasteride
for the treatment of
hirsutism and androgenetic alopecia. Finasteride is the first
available medication of a new
class of drugs that is an competitive inhibitor of 5 alpha-reductase
and therefore should be
beneficial for medical treatment of cutaneous hyperandrogenism. Abstract 5 alpha-Reductase, the enzyme system that metabolizes testosterone into dihydrotestosterone, occurs in two isoforms. The type 1 isozyme is composed of 259 amino acids, has an optimal pH of 6-9 and represents the 'cutaneous type'; it is located mainly in sebocytes but also in epidermal and follicular keratinocytes, dermal papilla cells and sweat glands as well as in fibroblasts from genital and non-genital skin. The type 2 isozyme is composed of 254 amino acids, has an optimal pH of about 5.5 and is located mainly in the epididymis, seminal vesicles, prostate and fetal genital skin as well as in the inner root sheath of the hair follicle and in fibroblasts from normal adult genital skin. The genes encoding type 1 and type 2 isozymes are found in chromosomes 5p and 2p, respectively, and each consists of 5 exons and 4 introns. During the last decade, several steroid analogues and non-steroid agents have been developed to interfere with 5 alpha-reductase activity. Finasteride, which
has a higher affinity for the type 2 isozyme, is the first 5
alpha-reductase antagonist clinically
introduced for treatment of benign prostate hyperplasia. The clinical
evaluation of finasteride
or other 5 alpha-reductase inhibitors in the field of dermatology has
been very limited; in
particular, those that selectively bind to type 1 isozyme (e.g.
MK-386, LY191704) may be
regarded as candidates for treatment of androgen-dependent skin
disorders such as
seborrhoea, acne, hirsutism and/or androgenetic alopecia. Abstract Finasteride is the first of a new class of 5 alpha-reductase inhibitors which allows selective androgen deprivation affecting dihydrotestosterone (DHT) levels in target organs such as the prostate and scalp hair without effecting circulating levels of testosterone thus preserving the desired androgen mediated effects on muscle strength, bone density and sexual function. Finasteride has been demonstrated to produce significant effects in
men with an enlarged
prostate gland. The long-term data now emerging suggests that
progression of benign
prostatic hyperplasia (BPH) may be arrested providing additional long
term benefits.
Experimental uses in prostate cancer prevention and male pattern
baldness offer new and
exciting possibilities for this class of compounds. Abstract Steroid 5alpha-reductase is a system of two isozymes (5alphaR-1 and 5alphaR-2) which catalyzes the NADPH-dependent reduction of testosterone to dihydrotestosterone in many androgen sensitive tissues and which is related to several human endocrine diseases such as benign prostatic hyperplasia (BPH), prostatic cancer, acne, alopecia, pattern baldness in men and hirsutism in women. T he discovery of new potent and selective 5alphaR inhibitors is thus of great interest for pharmaceutical treatment of these diseases. The synthesis of a novel class of inhibitors for human 5alphaR-1 and 5alphaR-2, having the 19-nor-10-azasteroid skeleton, is described. The inhibitory potency of the 19-nor-10-azasteroids was determined in homogenates of human hypertrophic prostates toward 5alphaR-2 and in DU-145 human prostatic adenocarcinoma cells toward 5alphaR-1, in comparison with finasteride (IC50 = 3 nM for 5alphaR-2 and approximately 42 nM for 5alphaR-1), a drug which is currently used for BPH treatment. The inhibition potency was dependent on the type of substituent at position 17 and on the presence and position of the unsaturation in the A and C rings. delta9(11)-19-Nor-10-azaandrost-4-ene-3,17-dione (or 10-azaestra-4,9(11)-diene-3,17-dione) (4a) and 19-nor-10-azaandrost-4-ene-3,17-dione (5) were weak inhibitors of 5alphaR-2 (IC50 = 4.6 and 4.4 microM, respectively) but more potent inhibitors of 5alphaR-1 (IC50 = 263 and 299 nM, respectively), whereas 19-nor-10-aza-5alpha-androstane-3,17-dione (7) was inactive for both the isoenzymes. The
best result was achieved with the 9:1 mixture of delta9(11)- and
delta8(9)-17beta-(N-tert-butylcarbamoyl)-19-nor-10-aza-4-
androsten-3-one (10a,b)
which was a good inhibitor of 5alphaR-1 and 5alphaR-2 (IC50 = 127 and
122 nM,
respectively), with a potency very close to that of finasteride. The
results of ab initio
calculations suggest that the inhibition potency of
19-nor-10-azasteroids could be directly
related to the nucleophilicity of the carbonyl group in the 3-position. Abstract Genetic predisposition and androgen dependence are important characteristics of the common patterned loss of scalp hair known as male pattern baldness. The involvement of the 5alpha-reductase enzyme in male pattern baldness has been postulated due to its role in the metabolism of testosterone to dihydrotestosterone. There are two known isozymes of 5alpha-reductase. Type I has been predominantly localized to the skin and scalp. Type II, also present on the scalp, is the target of finasteride, a promising treatment for male pattern baldness. We conducted genetic association studies of the 5alpha-reductase enzyme genes (SRD5A1 on chromosome 5 and SRD5A2 on chromosome 2) using dimorphic intragenic restriction fragment length polymorphisms. From a population survey of 828 healthy families comprising 3000 individuals, we identified 58 young bald men (aged 18-30 y) and 114 older nonbald men (aged 50-70 y) for a case control comparison. No significant differences were found between cases and controls in allele, genotype, or haplotype frequencies for restriction fragment length polymorphisms of either gene. These findings suggest that the genes encoding the two 5alpha-reductase isoenzymes are not associated with male pattern baldness. Finally,
no clear inheritance pattern of male pattern baldness was observed.
The relatively strong
concordance for baldness between fathers and sons in this study was
not consistent with a
simple Mendelian autosomal dominant inheritance. A polygenic etiology
should be
considered. Abstract The effects of spironolactone (5% SYC-201G, a preparation developed for clinical use in acne vulgaris by Searle Yakuhin K.K.), which is known to have antiandrogenic effects by competitively inhibiting dihydrotestosterone at androgen receptor sites, was topically applied to the androgen stimulated sebaceous glands of adult female golden hamsters. Androgen stimulation, induced by intramuscular injection of testosterone propionate (TP) every other day over a two week period, resulted in a 2.5 to 2.7 time increase in the size of the sebaceous glands of the hamster pinna. Once-daily treatment with 5%
SYC-201G or
matching placebo was applied to androgen-stimulated hamsters on one
pinna only during the
same period as TP injection. Comparison between the treated and
untreated sides revealed a
significant suppression in the sebaceous gland size (p < 0.05) by 5%
SYC-201G; no such
effect was observed with placebo. The difference in the suppression
rate of the sebaceous
gland size between 5% SYC-201G (23%) and matching placebo (-4.7%) was
significant (p < 0.01). Abstract To investigate the varying response of the pilosebaceous unit to androgens functional studies were performed on the effects of testosterone and 5 alpha-dihydrotestosterone on cultured human sebocytes derived from different skin regions. In addition, the effect of spironolactone on the proliferation of androgen-stimulated human sebocytes derived from facial skin was evaluated. Testosterone (10(-11) to 10(-5) M), 5 alpha-dihydrotestosterone (10(-11) to 10(-5) M) and spironolactone (10(-12) to 10(-7) M) were added for 10 days as single substances or in combinations to human sebocytes in secondary culture maintained in a serum-free medium. Cell proliferation was assessed using a fluorometric assay. Intracellular lipids were extracted from sebocytes treated with androgens (10(-7) M) for 10 days after confluency. Testosterone inhibited the proliferation of sebocytes derived from the legs with a 50%-inhibitory concentration at 10(-5) M and induced a 50% decrease of intracellular lipids. In contrast, 5 alpha-dihydrotestosterone stimulated the activity of leg sebocytes with a 50% increase of proliferation at 10(-5) M, and a 175% increase of intracellular lipids. On the other hand, the proliferation of facial sebocytes was significantly stimulated by testosterone with a 50%-stimulatory concentration at 10(-6) to 10(-5) M and mostly by 5 alpha-dihydrotestosterone with a 50% enhancement at 10(-8) to 10(-7) M. Spironolactone inhibited the proliferation of facial sebocytes in a dose-dependent manner with a 25%-inhibitory concentration at 10(-9) M. Simultaneous
treatment of facial sebocytes
with spironolactone and testosterone or 5 alpha-dihydrotestosterone
resulted in decreased
proliferation when compared to the growth obtained under androgens
alone.(ABSTRACT
TRUNCATED AT 250 WORDS) Abstract Increased bone mineral density (BMD) has been reported in young women
with androgen
excess. To determine whether antiandrogen treatment in young women
with androgen
excess reduces BMD in these patients, the authors measured BMD before
and a year after
the beginning of antiandrogen therapy with spironolactone and
linestrenol in 17 consecutive
androgenized patients (median age 22 years). After a year's treatment
BMD declined in 15
out of 17 patients, the mean decrease--0.032 g/cm2 (95% CI of the
difference
0.016-0.048)--being highly significant (p < 0.001). Androstenedione
decrease was the only
hormonal variable significantly correlating with BMD decrease (r =
0.5; p = 0.037) according
to simple linear regression. A decrease of BMD might become a key
factor in deciding about
the duration of antiandrogen treatment with spironolactone in functional
hyperandrogenemia. Abstract The effect of cyproterone acetate (CPA) and spironolactone (SPL) on the serum androgen concentrations of premenopausal women with symptoms of hyperandrogenism were investigated in a total of 39 women. The observation period was 12 months. CPA was administered according to the Hammerstein regimen: cyproterone acetate (CPA) [Androcur] 100 mg/die 5.-14. day of the cycle; ethinylestradiol (EE) [Progynon C]: 40 mg/die 5.-25. day of the cycle; Spironolactone (SPL) was given in a dosage of 100 mg/die from day 1.-21. of the cycle. During the therapy with CPA a significant decrease of total testosterone (61%), free testosterone (78%), LH (48%) and 17 alpha-Hydroxyprogesterone (72%) was observed; during the medication with spironolacton only a significant decrease of 5 alpha-dihydrotestosterone (81%), which could not be seen during CPA use, was observed. Serum concentrations of total testosterone, free testosterone, LH and 17 alpha-Hydroxyprogesterone remained unchanged. DHA and DHAS did not change during neither medication. Since peripheral androgens were not suppressed by
SPL the positive
therapeutical effect of SPL can be explained by the antiandrogenic
effect at the level of the
receptor. A disadvantage of spironolacton is the lack of contraceptive
efficacy. In cases
where contraindication for oral contraceptives are present SPL can be
considered as a good
alternative to CPA. The suppressive effect of CPA/EE on total
testosterone, LH addition to
the antivulatory effect makes it the preferable medication for
hyperandrogenemic patients with
polycystic changes of the ovaries (PCOD). Abstract To assess whether androgen excess per se might impair insulin action, insulin sensitivity was measured by a two-step (20 and 80 mU/m2.min) hyperinsulinemic euglycemic clamp combined with indirect calorimetry and tracer glucose infusion in 43 women (13 obese and 30 nonobese) with normal glucose tolerance and clinical evidence of increased androgen action (hirsutism and/or polycystic ovary syndrome) as well as 12 age- and body mass index-matched healthy controls. Hyperandrogenic women were studied basally and after 3-4 months of antiandrogen treatment with 3 different drugs: spironolactone (n = 23), flutamide (n = 10), or the GnRH agonist buserelin (n = 10). Six women given spironolactone were also reexamined after 1 yr of therapy. At baseline, insulin-mediated glucose uptake was lower in hyperandrogenic women than in controls (by ANOVA, F = 14.3; P < 0.001). Insulin resistance was observed in both ovarian and nonovarian hyperandrogenism, as distinguished by acute GnRH agonist testing. After antiandrogen therapy, insulin action on glucose metabolism significantly increased for both the patients as a whole (F = 7.4; P < 0.01) and each treatment group separately. However, insulin action remained lower than in controls and showed no further improvement in patients reevaluated after I yr of treatment. Increases in both oxidative and nonoxidative glucose metabolism accounted for the improvement in substrate disposal induced by antiandrogen drugs. The increase in the effectiveness of insulin was greater in the lean subjects, whereas the change was small and not statistically significant in the obese women. Response to treatment was more pronounced in women with nonovarian hyperandrogenism, particularly at the low insulin infusion rate. Endogenous glucose production in hyperandrogenic patients was similar
to that in healthy
women and was unaffected by therapy. In conclusion, antiandrogen
treatment partially
reversed the peripheral insulin resistance associated with
hyperandrogenism regardless of
which antiandrogen was used. These data strongly suggest that in
women, androgen excess
per se contributes to impairment of insulin action. Abstract The effects of topically applied spironolactone on the sebum secretion
rates (SSR) of young
adults were investigated. SSR was expressed as the ratio of wax
esters/[cholesterol+cholesterol esters] (WE/[C+CE]) and the amount of
sebaceous lipids
(squalene, triacylglycerol and wax esters). Topical spironolactone 5%
gel applied to the
right cheeks of the subjects produced a significant reduction in the
SSR at 12 weeks (4
weeks after termination of application), but not at 8 weeks (the end
of treatment). Untreated
"control" areas (the left cheeks of the subjects) showed no
significant change during the study.
None of the subjects experienced skin rash or signs of local
irritation. This results suggests
that topical spironolactone may be effective in the treatment of acne
patients with high SSR. Abstract Various substances of steroidal or nonsteroidal structure may serve as an alternative for the antiandrogenic treatment of acne. Compounds with antiandrogenic properties like cimetidine or ketoconazole are rarely administered for acne due to their weak effects. In contrast, spironolactone is an effective antiandrogen that shows good treatment effects in hirsutism and acne. Side effects occur frequently and are dose dependent. Isotretinoin--the most effective agent in acne therapy--has been under discussion for additional antiandrogenic properties for years. At present there is additional evidence for the antiandrogenic effects of isotretinoin. Regarding substances acting on both levels, androgen
receptor binding and 5
alpha-reductase inhibition, the question is raised whether the term
'antiandrogen' should be
amplified by including the 5 alpha-reductase inhibitors. This would
pay tribute to the
biological aspect of antiandrogenicity that takes into account not
only the mode of action but
also the effects of the substance. Under this aspect type 1 5
alpha-reductase inhibitors may
gain attention in the future. Abstract Although treatment of intact adult male rats with the pure antiandrogen flutamide or a luteinizing hormone-releasing hormone (LHRH) agonist alone leads to partial inhibition of ventral prostate weight, maximal inhibition is achieved by combination of the two drugs. Potentializing effects of the two compounds were observed even on prostatic ornithine decarboxylase activity. Because LHRH agonists are widely used to achieve medical castration in men treated for prostate cancer, it is of interest to observe that in the dog, known for being the best model for studies of the action of LHRH agonists, flutamide does not interfere with the potent desensitizing action of the LHRH agonist on pituitary LH secretion, thus supporting the combined use of flutamide with an LHRH agonist for maximal androgen blockade without loss of efficiency of the LHRH agonist. Because prostate cancer is known to show a high degree of heterogeneity of its sensitivity to androgens, we analyzed the effect of combined antiandrogen therapy on parameters more sensitive to androgens than ventral prostatic weight itself. In agreement with its pure antiandrogenic characteristics, flutamide alone has no stimulatory effect on the intraprostatic level of mRNA encoding the C1 or C3 component of prostatic binding protein (PBP), whereas cyproterone acetate (CPA), megestrol acetate (MEG), and, especially, medroxyprogesterone acetate (MPA) markedly stimulate PBP-C1 and PBP-C3 mRNA levels, an effect reversed by flutamide, thus further supporting the intrinsic androgenic activity of all these steroidal derivatives. Similar androgenic effects of the steroidal derivatives were observed on prostatic ornithine decarboxylase activity. Androgen-sensitive Shionogi tumor cells were then used to assess the antiandrogenic/androgenic properties of flutamide and the above-indicated steroidal derivatives. MPA, MEG, CPA as well as spironolactone-stimulated cell proliferation under both in vivo and in vitro conditions, thus illustrating the intrinsic androgenic activity of all these compounds. Flutamide was inactive by itself and reversed the stimulatory effect of all other compounds, thus indicating its pure antiandrogenic activity. Although castration reduces
intraprostatic dihydrotestosterone (DHT) to undetectable levels in the
rat and guinea pig, the
concentration remains at about 50% of the value found in intact men
after castration, thus
indicating an important contribution of the adrenals to DHT in the
human prostate, a finding
that requires the addition of an antiandrogen to block the action of
this important amount of
DHT remaining after castration. Abstract Drospirenone (ZK 30595; 6 beta, 7 beta, 15 beta, 16 beta-dimethylen-3-oxo-17 alpha-pregn-4-ene-21, 17-carbolactone) is a novel progestogen under clinical development. Drospirenone is characterized by an innovative pharmacodynamic profile which is very closely related to that of progesterone. Potential applications include oral contraception, hormone replacement therapy and treatment of hormonal disorders. The pharmacological properties of drospirenone were investigated in vitro by receptor binding and transactivation experiments and in vivo in appropriate animal models. In qualitative agreement with progesterone, the compound binds strongly to the progesterone and the mineralocorticoid receptor and with lower affinity to androgen and glucocorticoid receptors. There is no detectable binding to the estrogen receptor. Steroid hormone agonistic and antagonistic activities of progesterone and drospirenone were compared in transactivation experiments. Individual steroid hormone receptors were artificially expressed together with a reporter gene in appropriate cell lines. Both hormones were unable to induce any androgen receptor-mediated agonistic activity. Rather, both progesterone and drospirenone distinctly antagonized androgen-stimulated transcriptional activation. Likewise, both compounds only very weakly activated the mineralocorticoid receptor but showed potent aldosterone antagonistic activity. Drospirenone did not induce glucocorticoid receptor-driven transactivation. Progesterone was a weak agonist in this respect. Drospirenone exerts potent progestogenic and antigonadotropic activity which was studied in various animal species. It efficiently promotes the maintenance of pregnancy in ovariectomized rats, inhibits ovulation in rats and mice and stimulates endometrial transformation in the rabbit. Furthermore, drospirenone shows potent antigonadotropic, i.e., testosterone-lowering activity in male cynomolgus monkeys. The progestogenic potency of drospirenone was found to be in the range of that of norethisterone acetate. The majority of clinically used progestogens are androgenic. Drospirenone, like progesterone, has no androgenic but rather an antiandrogenic effect. This property was demonstrated in castrated, testosterone propionate substituted male rats by a dose-dependent inhibition of accessory sex organ growth (seminal vesicles, prostate). In this model, the potency of drospirenone was about a third that of cyproterone acetate. Drospirenone, like progesterone, shows antimineralocorticoid activity, which causes moderately increased sodium and water excretion. This is an outstanding characteristic which has not been described for any other synthetic progestogen before. Drospirenone is eight to ten times more effective in this respect than spironolactone. The natriuretic effect was demonstrable for at least three weeks upon daily treatment of rats with a dose of 10 mg/animal. Drospirenone is devoid of any estrogenic, glucocorticoid or antiglucocorticoid activity. In summary, drospirenone, like progesterone, combines potent progestogenic with antimineralocorticoid and antiandrogenic activity in a similar dose range. ====================================================================== |
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Produced by Dr. José Lapenta R.
Dermatologist
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