Strategic approach of hyperandrogenism in women

Based on the results of the laboratory screening of 35 hirsute patients, a strategic approach of hyperandrogenism is proposed. The determination of plasma concentration of total testosterone (T), androstenedione (A) and dehydroepiandrosterone sulfate (DHEAS) appeared to be the basic investigation before to further explore the adrenal (ACTH test) and/or ovarian (gonadotropin measurements) androgen secretion. Together with the clinical findings, plasma T, A and DHEAS levels generally bring evidence of androgen-secreting tumors or polycystic ovaries, or suggest the possibility of adrenal hyperplasia. In the other cases, only the determination of plasma unbound T level is useful for demonstrating the hyperandrogenism. Finally in patients with 'so-called' idiopathic hirsutism, while evidence of excessive androgen production can be obtained by the laboratory screening, the origin of this hyperandrogenism remains uncertain in most cases.     

Exploration of hirsutism: elements for a strategy

50 women complaining of hirsutism were investigated in order to establish an optimal strategy for hirsutism exploration. Basal hormonal evaluations were of great value, especially serum testosterone and, to a lesser degree, DHA-S and LH. LH response to LHRH stimulation appeared of little diagnostic value. ACTH stimulation tests may be useful in detecting enzyme deficiencies in patients with normal basal values. The origin of hyperandrogenism can hardly be detected by the inhibition tests. However, these tests allow to determine whether the androgen secretion is still under ACTH and/or LH control.     

Prevalence of polycystic ovary syndrome in girls aged 14-18 years in Isfahan, Iran

OBJECTIVE: To determine the prevalence of clinical polycystic ovary syndrome (PCOS) in 14- to 18-year-old high school girls in Isfahan, Iran. METHODS: In this cross-sectional study, 1,000 high school girls (14-18 years old) were selected by multi-stage random sampling from different high schools in Isfahan. Following physical examination, a single physician recorded the presence of hirsutism, severe acne, androgenic alopecia, menstrual dysfunction and obesity using a validated questionnaire. Clinical PCOS was diagnosed if menstrual dysfunction and clinical hyperandrogenism were detected. RESULTS: Clinical PCOS was present in 30 (3%), hirsutism in 60 (6%), menstrual dysfunction in 74 (7.4%) and severe acne in 47 (4.7%) of the population studied. CONCLUSION: The prevalence of clinical PCOS in our study population was similar to those of other studies; however, the prevalence could have been higher with hormonal assessment.     

Impact of electro-acupuncture and physical exercise on hyperandrogenism and oligo/amenorrhea in women with polycystic ovary syndrome: a randomized controlled trial

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is characterized by hyperandrogenism, oligo/amenorrhea, and polycystic ovaries. We aimed to determine whether low-frequency electro-acupuncture (EA) would decrease hyperandrogenism and improve oligo/amenorrhea more effectively than physical exercise or no intervention. We randomized 84 women with PCOS, aged 18-37 yr, to 16 wk of low-frequency EA, physical exercise, or no intervention. The primary outcome measure changes in the concentration of total testosterone (T) at week 16 determined by gas and liquid chromatography-mass spectrometry was analyzed by intention to treat. Secondary outcome measures were changes in menstrual frequency; concentrations of androgens, estrogens, androgen precursors, and glucuronidated androgen metabolites; and acne and hirsutism. Outcomes were assessed at baseline, after 16 wk of intervention, and after a 16-wk follow-up. After 16 wk of intervention, circulating T decreased by -25%, androsterone glucuronide by -30%, and androstane-3α,17β-diol-3-glucuronide by -28% in the EA group (P = 0.038, 0.030, and 0.047, respectively vs. exercise); menstrual frequency increased to 0.69/month from 0.28 at baseline in the EA group (P = 0.018 vs. exercise). After the 16-wk follow-up, the acne score decreased by -32% in the EA group (P = 0.006 vs. exercise). Both EA and exercise improved menstrual frequency and decreased the levels of several sex steroids at week 16 and at the 16-wk follow-up compared with no intervention. Low-frequency EA and physical exercise improved hyperandrogenism and menstrual frequency more effectively than no intervention in women with PCOS. Low-frequency EA was superior to physical exercise and may be useful for treating hyperandrogenism and oligo/amenorrhea.     

Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism.

Polycystic ovaries were defined with ultrasound imaging in a series of 173 women who presented to a gynaecological endocrine clinic with anovulation or hirsutism. Polycystic ovaries were found in 26% of women with amenorrhoea, 87% with oligomenorrhoea, and 92% with idiopathic hirsutism--that is, hirsutism but with regular menstrual cycles. Fewer than half the anovulatory patients with polycystic ovaries were hirsute, but in 93% of cases there was at least one endocrine abnormality to support the diagnosis of polycystic ovaries--that is, raised serum concentrations of luteinising hormone, raised luteinising hormone: follicle stimulating hormone ratio, or raised serum concentrations of testosterone or androstenedione. This study shows that polycystic ovaries, as defined by pelvic ultrasound, are very common in anovulatory women (57% of cases) and are not necessarily associated with hirsutism or a raised serum luteinising hormone concentration. Most women with hirsutism and regular menses have polycystic ovaries so that the term "idiopathic" hirsutism no longer seems appropriate.     

Management of hyperandrogenism in adolescent girls.

Hyperandrogenism in adolescent girls can be a troubling problem because of the difficulty in establishing a diagnosis and in prescribing appropriate therapy. Androgen excess in adolescent patients encompasses a spectrum of clinical presentations, including acne, hirsutism, oligomenorrhea, amenorrhea, virilism, and ovarian cysts. Androgen excess is a clinical and chemical feature of idiopathic hirsutism, late-onset forms of congenital adrenal hyperplasia, and polycystic ovarian disease; in some cases, functional hyperandrogenism is discussed. We recommend screening for hyperandrogenism by measuring blood levels of testosterone, dehydroepiandrosterone sulfate, and delta 4-androstenedione, while others propose a first dexamethasone suppression test for evaluation of free testosterone, dehydroepiandrosterone sulfate, and cortisol. Treatment will be chosen according to particular symptoms such as acne, hirsutism, obesity, or oligomenorrhea.     

Lactation, nutrition and fertility and the secretion of prolactin and gonadotrophins in Mopan Mayan women.

The effect of lactation on menstrual cycles, ovulation and conception was studied in a group of non-contracepting Amerindian Mopan Mayan women. Anthropological observations of relevant events were made over a 21-month period. Blood samples were assayed to determine the plasma concentrations of prolactin, luteinising hormone, follicle stimulating hormone, human chorionic gonadotrophin, placental lactogen, oestrogen, progesterone and cortisol. The data show that: frequent and prolonged breast-feeding was associated with a marked increase in plasma prolactin concentrations to levels similar to those in lactating Gaing but higher than those in lactating Scottish women; ovulatory menstrual cycles and pregnancy occurred during frequent lactation; in lactating menstruating women there was an inverse correlation between fat weight and months post-partum. These data suggest that other factors as well as suckling account for the effects of lactation on fecundity.     

Hyperandrogenism in a Postmenopausal Woman: Diagnostic and Therapeutic Challenges

ObjectiveTo describe a postmenopausal woman with severe hyperandrogenism who responded dramatically to a gonadotropin-releasing hormone (GnRH) agonist.MethodsDetailed clinical and laboratory findings are presented, and the pertinent literature is reviewed.ResultsA 53-year-old postmenopausal woman with end-stage renal disease, who had undergone kidney transplantation, was referred because of high serum testosterone levels. She presented with worsening acne and hirsutism for the previous 2 years. Her medications included prednisone (7.5 mg every other day). On examination, mild facial acne and hirsutism but no virilizing features were noted. Laboratory results showed generous postmenopausal gonadotropin levels and markedly elevated total and free testosterone levels, which failed to suppress with a 2-day low-dose dexamethasone test. Transvaginal ultrasonography and a computed tomographic scan failed to identify an ovarian or adrenal abnormality. Administration of a GnRH agonist (Depo-Lupron) resulted in a dramatic decline in follicle-stimulating hormone, luteinizing hormone, and testosterone levels after 1 month, which persisted during the course of 11 months of therapy. The source of marked hyperandrogenism in postmenopausal women represents a diagnostic challenge. The absence of a tumor on diagnostic imaging and the inability to perform catheterization studies confound the problem. Androgen levels did not suppress with glucocorticoids. We reasoned that a clear response to a GnRH agonist would indicate a nontumorous ovarian source of hyperandrogenism. Regrettably, the literature has described cases of ovarian tumors and, rarely, adrenal adenomas that are responsive to gonadotropins.ConclusionThe striking improvement in a postmenopausal woman with severe hyperandrogenism by means of GnRH agonist therapy demonstrates its potential use in poor surgical candidates without necessarily delineating the source of androgen excess. (Endocr Pract. 2011;17:e21-e25)     

High incidence of hyperandrogenism-related clinical signs in patients with multiple sclerosis

A mild prevalence of multiple sclerosis (MS) is present in females (2:1). To elucidate the pathogenetic role of sex steroids on the disease, we studied 76 women affected by MS, compared to 50 healthy women (mean age +/- SD, 34.9 +/- 0.9 vs. 33.4 +/- 1.7 years). The menarche was at mean age of 12.3 +/- 0.2 vs. 12.4 +/- 0.2. Interval between menses was 28.0 +/- 0.3 vs 27.8 +/- 0.3 days, with duration of menstrual flow of 5.0 +/- 0.2 vs. 5.0 +/- 0.2 days. Oligo- or amenorrhea was present in 20% of patients and in 16% of controls. Oral contraceptives were assumed by 21% of patients and 34% of controls (n.s.). Premenstrual symptoms were found in 43% of patients and in 46% of controls (n.s.). The incidence of hyperandrogenism (greasy skin, acne and hirsutism), evaluated by a specific questionnaire, was higher and statistically significant in MS patients than in controls (28% vs. 10%, p<0.05). Further studies, including a complete clinical and laboratory evaluation of gonadal function, are necessary in order to clarify whether hyperandrogenism may influence MS disease activity.     

Testicular responsiveness to hCG of the ovine fetus in the last third of gestation

The in vivo and in vitro testicular responsiveness to hCG of hemicastrated lamb fetuses 95-99, 110-118 and 130-141 days of gestational age was studied. Basal plasma testosterone (T) levels were similar at all ages (less than 0.25 ng/ml), while the mean testicular concentrations of dehydroepiandrosterone sulfate (DHA-S), 17 alpha-hydroxyprogesterone (17-OHP) and T were higher in 95- to 99-day-fold fetuses. Plasma T levels and the concentration of T, DHA-S, 17-OHP, androstenedione (A) and cyclic adenosine 3'5'-monophosphate (cAMP) were increased by hCG in the hemicastrated animal at all ages. cAMP and T production by enriched preparations of dispersed interstitial cells from control testes was increased by hCG in all groups. In fetuses pretreated with hCG in vivo the addition of hCG in vitro failed to modify cAMP and T production. 100 micrograms of LHRH to a 130-day-old fetus increased plasma LH and T levels. From these experiments, it is suggested that the low plasma LH and T levels found throughout the last trimester of fetal life reflect a relative lack of endogenous LHRH synthesis and/or release, rather than reduced testicular steroidogenic capacity.     

The SAHA syndrome

The presence of seborrhoea, acne, hirsutism and alopecia in women has first been summarized as SAHA syndrome in 1982 and can be associated with polycystic ovary syndrome, cystic mastitis, obesity and infertility. In 1994, the association of these androgen-dependent cutaneous signs, was classified according to their etiology into four types: (1) idiopathic, (2) ovarian, (3) adrenal, and (4) hyperprolactinemic SAHA. The HAIRAN syndrome has been currently described as a fifth variant with polyendocrinopathy. The SAHA syndrome generally occurs in young to middle-aged women and involves either the presence of elevated blood levels of androgens or increased androgen-driven peripheral response with normal circulating androgen levels. Peripheral metabolism of androgens takes place in various areas within the pilosebaceous unit, as indicated by local differences in the activities of aromatase, 5alpha-reductase as well as of the presence of the androgen receptors. In cases of SAHA syndrome, careful diagnostic and clinical evaluation has to be performed in order to identify the cause for peripheral hyperandrogenism and to exclude androgen-producing tumors. Treatment will target the etiology, whereas the management in idiopathic cases will aim to improve the clinical features of SAHA.     

Endocrine characteristics of polycystic ovary syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is probably the most prevalent endocrinopathy in women and the most common cause of anovulatory infertility. Patients with PCOS have clinical and biochemical features consistent with the ultrasound diagnosis and they are likely to face the problems of hyperandrogenism, subfertility and recurrent miscarriage. The aim of the present review is to summarize our present knowledge on the hormonal background of this very prevalent syndrome and to give some clinical examples how the present knowledge can be applied to treat PCOS patients according to their current problem, such as menstrual cycle disorder, hirsutism, infertility or to prevent late consequences as diabetes mellitus. The etiology and pathogenesis of PCOS is still a matter of controversies, but it is apparent that inappropriate gonadotropin secretion, obesity, hyperinsulinism and insulin resistance are the major determining factors in the development of ovarian hyperandrogenism an chronic anovulation. Reversal of insulin resistance in PCOS constitutes the fundamental goal in the management of hyperandrogenic anovulatory infertility and in the prevention of long-term consequences. The value of the insulin sensitizer metformin therapy awaits further evaluation and it should be integrated in the spectrum of therapeutical options that include the discussed surgical methods and GnRH analogues as well.     

Menstrual disorders in adolescence: pathophysiology and treatment.

Menstrual problems including amenorrhea, oligomenorrhea, irregular cycles, abnormal uterine bleeding or dysmenorrhea represent 50% of adolescents' gynecologic complaints. Irregular and anovulatory cycles are common during the first postmenarcheal years and may reflect a normal transient step of ovarian hyperandrogenism, but they may also result from hormonal abnormalities affecting the adrenals, the ovaries or the pituitary. Amenorrhea may be a sign of late puberty or of a problem affecting the hypothalamus, the pituitary or the ovaries. Evaluation includes a complete physical examination, basal hormonal determinations of the hypothalamic-pituitary-ovarian function, of the thyroid, of the androgens and of the nutritional and growth parameters. This first evaluation must be completed by a karyotype analysis in case of primary amenorrhea or by the measurements of free testosterone, androstanediol glucuronide and testosterone glucuronide in case of hirsutism, and may be followed by X-rays, echography or dynamic tests depending on the first results. Therapy will always be directed towards the etiology of the disease. Abnormal uterine bleeding is generally the result of anovulatory cycles and responds to hormonal therapy, but a systemic illness, a local pathology or a complicated pregnancy must always be excluded. In case of dysmenorrhea, endometriosis must be excluded. Simple dysmenorrhea is generally suppressed by antiprostaglandins.     

Antiandrogens: clinical applications

Antiandrogens, preventing androgen action at target tissue level, are used in the treatment of various androgen-dependent diseases. Pharmacologically these substances have either a steroidal structure, like cyproterone acetate (CPA) and spironolactone (SPL), or a non-steroidal structure, like flutamide (FLU). In women with hyperandrogenism (PCO syndrome, idiopathic hirsutism, acne), clinical benefit may be obtained with CPA, which also displays a progestational activity and an antigonadotropic effect. CPA (25-50 mg/day) is used in combination with ethinyl-estradiol (EE) (20-30 micrograms/day) in reversed sequential regimen. SPL, less effective than CPA may be employed in moderate hirsutism and acne at dosages of 100-200 mg/day. During SPL treatment menstrual irregularities are frequent: in this case an association with oral contraceptives is indicated. SPL + bromocriptine (2.5-5 mg/day) has been experienced with success in PCO syndrome. The pure antiandrogen FLU, inducing progressive increase in LH and testosterone secretion, may be used only in combination with oral contraceptives. In men antiandrogens have been tested in BPH and prostatic carcinoma. In BPH the decrease in nuclear receptors and DHT nuclear content during CPA or FLU may represent the rational base of the medical treatment. An improvement in urinary obstructive manifestation has been observed with CPA alone or associated with tamoxifen (100 mg + 100 mg day). In advanced prostatic carcinoma antiandrogens represent a good alternative to estrogen therapy with less side effects and in combination with surgical or medical castration (LH-RH analogues) achieve a complete androgen blockade. An increase in the percentage of remissions and survival has been reported.     

Effects of dihydrotestosterone treatment on adrenal gland function and morphology in adult female guinea-pigs

The effect of chronic treatment of female guinea-pigs with dihydrotestosterone (DHT) on growth and function of the adrenal gland and, in particular, on the reticular zone is described. Two groups of 6 young adult, female guinea-pigs were treated with DHT (1 mg/kg dissolved in peanut oil and injected s.c.) for 30 and 60 days. Two other groups of animals, treated only with oil, were used as controls. At the end of treatment, animals were killed and adrenal glands were quickly removed. Plasma levels of pregnenolone, dehydroepiandrosterone (DHA) and its sulfate (DHA-S), 17 alpha-hydroxyprogesterone, androstenedione, testosterone, estradiol, 11-deoxycortisol, androstenedione, DHT and 3 alpha-androstanediol were determined by R.I.A. following celite microcolumn chromatography. Animals treated for 30 days showed only elevated DHT and 3 alpha-androstanediol plasma levels, whereas animals treated for 60 days also showed increased values of pregnenolone (251 +/- 62 vs 193 +/- 51 ng/dl; P less than 0.05), DHA-S (12,046 +/- 4110 vs 2780 +/- 888 ng/dl; P less than 0.001) and slightly increased values of DHA (110 +/- 31 vs 86.5 +/- 55.4). In the 30-day-treated animals no histological changes were observed, but in the 60-day-treated group the total size as well as cell volumes of the zona reticularis were significantly increased. Normal estrous cycles were observed in the 30-day-treated animals whereas the 60-day-treated animals showed a progressive acyclicity during the second month of treatment. These results indicate that in guinea-pigs, prolonged treatment with DHT induces a growth of the zona reticularis of the adrenal gland associated with increased levels of 5-ene steroids, particularly DHA-S. The mechanisms inducing these modifications are probably mediated by a DHT effect at the hypothalamic-pituitary level. A direct effect of DHT on the zona reticularis, however, cannot be excluded.     

Hirsutism: Diagnosis and management

Background:Hirsutism is defined as excess hair growth in androgen-dependent areas of the body in women.Objective: This article provides an updated review of hirsutism, focusing on the etiologies, clinical features, approach to diagnostic evaluation, and treatment options.Methods: The PubMed database was searched for English-language articles published from 1981 to the present, using the terms hirsutism, polycystic ovarian syndrome, congenital adrenal hyperplasia, hirsutism diagnosis, and hirsutism treatment. Reference lists from review articles on hirsutism during this time period were also examined.Results: While there are many causes of hirsutism, the majority of patients have a benign process that may be idiopathic. In some circumstances, hirsutism is a sign of functional ovarian hyperandrogenism or congenital adrenal hyperplasia. Even more rarely, it is the presenting sign of an internal malignancy.Conclusions: Hirsutism clinically presents in women as excessive hair growth in androgen-dependent areas. It is a particularly important diagnosis to make, because it often significantly affects a woman's perception of her femininity and less commonly can be a sign of an underlying malignancy or a cutaneous manifestation of a condition with significant cardiovascular or other morbidity. A variety of treatments exist to help minimize the appearance of unwanted hair.     

Effects of DHA-S on placental 3 beta-hydroxysteroid dehydrogenase activity, progesterone and 20 alpha-dihydroprogesterone concentrations in placenta and serum

To study the effects of dehydroepiandrosterone sulfate (DHA-S) on placental steroid metabolism and maternal steroidal profiles at term, the following in vivo and in vitro experiments were performed. Two hundred mg of DHA-S was given to five pregnant women 30 minutes prior to delivery. After delivery, the placenta was collected and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) and sulfatase activity was determined by measuring the rate of conversion of pregnenolone to progesterone and DHA-S to DHA. The amount of C21-delta 4-steroid in the placental tissue was measured by gas chromatography mass spectrometry (GC-MS) and compared with the control groups. The maternal serum concentration of several steroids was also measured by GC-MS before and after the administration of DHA-S. 3 beta-HSD activity in the placentae from the mothers who received DHA-S before delivery was significantly lower than in the controls. On the other hand, no significant change was observed in the activity of sulfatase. The serum concentration of progesterone (P) and 20 alpha-dihydro-P (20-P) before DHA-S loading decreased following the administration whereas estradiol (E), DHA, and androstenedione (A) levels increased. To study the direct effect of DHA-S and its related steroids on placental 3 beta-HSD activity, placental tissue samples were incubated with pregnenolone in vitro. Several other steroids were added simultaneously into the medium. It was observed that placental 3 beta-HSD activity was directly inhibited by DHA-S. These results indicate that DHA-S inhibits 3 beta-HSD activity in the placenta and subsequently causes a reduction in P and 20-P.     

Association of Angiotensin-Converting Enzyme gene polymorphism in Pakistani women with the atypical steroidogenesis in Polycystic ovarian syndrome: A case-control study

BackgroundPolymorphism in the angiotensin-converting enzyme gene (ACE) is responsible for elevated ACE concentrations in plasma. High ACE levels induce insulin resistance and hyperandrogenism, which are the main attributes of polycystic ovary syndrome (PCOS). Therefore, it was hypothesized that I/D polymorphism plays a role in the pathogenesis of PCOS.ObjectiveA case-control study was designed to investigate the association of I/D polymorphism of the ACE gene with PCOS in Pakistani women of reproductive age.MethodsACE I/D polymorphism was assessed in 252 women of age group 16–40 years. For genotypic analysis, PCR amplification of genomic DNA was carried out. Statistical analysis was performed to interpret the results using SPSS software.ResultsOur study showed that PCOS women were more likely to have a high body mass index and waist circumferences. Most PCOS patients had menstrual irregularities 99.3%, hirsutism 75.2% and cysts in ovaries 66.6%, along with other hyperandrogenic conditions (P-value = 0.001). The genotypic and allelic frequencies were significantly different between patients and controls. There was a significant association of three genotypes with the ratio of LH: FSH among PCOS patients (P = 0.05). Anthropometric characters, comorbidities, clinical symptoms, and PCOS conditions showed no statistical significance with ACE polymorphism.ConclusionsACE I/D polymorphism was not found associated with clinical conditions of PCOS in women of reproductive age. However, it was associated with atypical steroidogenesis. So, it indicates that ACE I/D polymorphism aggravates the pathogenesis of PCOS.     

Neuroendocrine changes in the aging reproductive axis of female rhesus macaques (Macaca mulatta)

Femalerhesus macaques show monthly menstrual cycles and eventually enter menopause at approximately 25 yr of age. To help identify early biomarkers of menopause in this nonhuman primate, we monitored reproductive hormones longitudinally from aged female macaques during the transitions from premenopause to perimenopause and postmenopause and found that, indeed, elevated plasma FSH was a better predictive factor of menopause onset than age. In a second experiment, we compared reproductive hormone profiles of young adult macaques (8-10 yr old) with those of regularly cycling old macaques (approximately 24 yr old). Indwelling vascular catheters were used for remote blood collection for at least 100 consecutive days, thereby covering three complete menstrual cycles in each macaque. Plasma levels of estradiol, progesterone, LH, FSH, follicular phase inhibin B, and anti-müllerian hormone (AMH) were determined during each menstrual cycle and were averaged for each animal; group mean differences were analyzed using one-way ANOVA. Old premenopausal macaques showed regular menstrual cycles that were qualitatively indistinguishable from those of young macaques; peak plasma levels of estradiol, progesterone, and LH were not significantly different. In marked contrast, peak plasma FSH concentrations were significantly higher, while inhibin B and AMH levels were generally lower, in the old premenopausal macaques compared with those in the young macaques. These data provide further evidence that rhesus macaques serve as an excellent model to study underlying mechanisms of human menopause. Furthermore, the data suggest that an age-related change in FSH, inhibin B, and AMH secretion may be the first endocrine manifestation of the transition into perimenopause, potentially having value in predicting the onset of the perimenopausal transition.