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Francis De Zegher - One of the best experts on this subject based on the ideXlab platform.
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high neutrophil count in girls and women with hyperinsulinaemic Hyperandrogenism normalization with metformin and flutamide overcomes the aggravation by oral contraception
Human Reproduction, 2005Co-Authors: Lourdes Ibanez, Angela Ferrer, Adriana Maria Jaramillo, Francis De ZegherAbstract:BACKGROUND: The endocrine hallmark of polycystic ovary syndrome (PCOS) is hyperinsulinaemic Hyperandrogenism; another facet of PCOS is low-grade inflammation. METHODS: In adolescents and young women with hyperinsulinaemic Hyperandrogenism (n = 118; mean age 16 years, body mass index 22 kg/m 2 ), we analysed whether the PCOS-associated rise in leukocyte count is already detectable at young age and, if so, whether such elevation is lowered by metformin, flutamide-metformin, oral contraception (OC), or their combination. RESULTS: Leukocyte count ( × 1000/mm 3 ) in patients was high versus controls (7.5 ± 0.1 versus 6.4 ± 0.1; P< 0.001) due to a rise in neutrophils (4.2 ± 0.1 versus 3.0 ± 0.1; P < 0.001). Randomized studies at mean ages of 12.5 years (n = 24) and 15.2 years (n = 33) demonstrated normalizing effects of metformin (850mg/day; P< 0.001) and, respectively, metformin plus flutamide (62.5mg/day) on neutrophil counts; in young women (18.3 years; n = 41), the neutrophil count rose further on OC monotherapy (P = 0.003), but normalized on the same OC plus flutamide-metformin (P < 0.001 versus OC alone). CONCLUSIONS: (i) A high leukocyte count is already present in girls with hyperinsulinaemic Hyperandrogenism, and this is due to a raised neutrophil count; (ii) this hyperneutrophilia is attenuated by metformin or flutamide-metformin, and is amplified by OC monotherapy; (iii) if these treatments are combined, the normalizing effect of flutamide-metformin overcomes the OC effect on neutrophil count.
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low dose flutamide metformin therapy reverses insulin resistance and reduces fat mass in nonobese adolescents with ovarian Hyperandrogenism
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Lourdes Ibanez, Angela Ferrer, David B Dunger, R Amin, Francis De ZegherAbstract:Ovarian Hyperandrogenism is a common disorder often presenting post menarche with anovulatory oligomenorrhea and signs of androgen excess. Associated hyperinsulinemic insulin resistance, dyslipidemia, and central fat excess herald long-term disease risk. Combined antiandrogen (flutamide 250 mg/d) and insulin-sensitizing (metformin) therapy has beneficial effects, in particular on dyslipidemia and androgen excess in young women. We studied the effects of low-dose flutamide-metformin combination on metabolic variables and body composition in adolescent girls with ovarian Hyperandrogenism. Thirty teenage girls (age range, 13.6–18.6 yr) with hyperinsulinemic Hyperandrogenism participated in a 12-month pilot study with a 3-month off-treatment phase and a 9-month treatment phase (randomized sequence) on combined flutamide (125 mg/d) and metformin (1275 mg/d). Body composition was assessed by dual-energy x-ray absorptiometry; endocrine-metabolic state and ovulation rate were screened every 3 months. Insulin sens...
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additive effects of insulin sensitizing and anti androgen treatment in young nonobese women with hyperinsulinism Hyperandrogenism dyslipidemia and anovulation
The Journal of Clinical Endocrinology and Metabolism, 2002Co-Authors: Lourdes Ibanez, Carme Valls, Angela Ferrer, David B Dunger, Francis De ZegherAbstract:The endocrine-metabolic hallmarks of polycystic ovary syndrome are hyperinsulinism, Hyperandrogenism, dyslipidemia, and anovulation. We hypothesized that dyslipidemia and anovulation in nonobese women with polycystic ovary syndrome are essentially secondary to the concerted effects of Hyperandrogenism and insulin resistance. We tested this hypothesis by comparing the efficacy of anti-androgen (flutamide) or insulin-sensitizing (metformin) monotherapy to that of combined therapy in normalizing the endocrine-metabolic and anovulatory status of nonobese, young women with hyperinsulinemic Hyperandrogenism. Thirty-one young women (mean age, 18.7 yr; body mass index, 21.9 kg/m2; hirsutism score, 16; monthly ovulation rate monitored by weekly serum progesterone, 10%) were randomly assigned to receive once daily flutamide (250 mg; n = 10), metformin (1275 mg; n = 8), or combined flutamide- metformin therapy (n = 13) for 9 months. At baseline, there were no endocrine-metabolic differences among treatment groups. C...
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sensitization to insulin induces ovulation in nonobese adolescents with anovulatory Hyperandrogenism
Obstetrical & Gynecological Survey, 2002Co-Authors: Lourdes Ibanez, Maria Victoria Marcos, Carme Valls, Angela Ferrer, Francisco Rodriguezhierro, Francis De ZegherAbstract:Even nonobese girls with precocious pubarche may develop a variant of polycystic ovary syndrome (PCOS) characterized by hyperinsulinism, Hyperandrogenism, abnormal lipids, and persistent anovulation. Insulin-sensitizing treatment has limited hyperinsulinism and Hyperandrogenism and restored eumenorrhea in women with PCOS. Extrapolating from observations in obese women with PCOS who receive an insulin-sensitizing agent such as metformin or troglitazone and become more likely to ovulate, this study examined the effects of metformin in 18 nonobese adolescent girls with a mean age of 16½ years who were 3 to 7 years past menarche. All were anovulatory and met clinical and hormonal criteria for ovarian Hyperandrogenism. The participants also had a history of precocious pubarche caused by exaggerated adrenarche. All the girls were hyperinsulinemic but had normal glucose tolerance. Anovulation was confirmed twice by obtaining four consecutive serum progesterone levels below 4 ng/ml at 1-week intervals. Metformin was given for 6 months in a daily dose of 1275 mg. Hirsutism scores decreased with metformin therapy, as did levels of fasting serum insulin, luteinizing hormone, total testosterone, androstenedione, dehydroepiandrosterone sulfate, and the free androgen index. Serum levels of sex hormone-binding globulin increased at the same time, and the lipid profiles became less atherogenic. There were no changes in body mass index, fasting glycemia, or serum levels of estradiol or follicle-stimulating hormone. All but 2 of the 18 girls reported regular menses within 4 months of the start of metformin therapy and, after 6 months, all were eumenorrheic. Ovulation induction failed in 4 of the 18 girls (Fig. 1), including the 2 with the most severe Hyperandrogenism. Abdominal discomfort in 4 girls resolved spontaneously within 2 weeks. Metformin treatment tends to normalize endocrine-metabolic function in nonobese adolescent girls with anovulatory Hyperandrogenism and induces ovulation in many of them.
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sensitization to insulin induces ovulation in nonobese adolescents with anovulatory Hyperandrogenism
The Journal of Clinical Endocrinology and Metabolism, 2001Co-Authors: Lourdes Ibanez, Maria Victoria Marcos, Carme Valls, Angela Ferrer, Francisco Rodriguezhierro, Francis De ZegherAbstract:In nonobese girls with an adolescent variant of polycystic ovary syndrome, insulin-sensitizing treatment reduces hyperinsulinism, dyslipidemia, and Hyperandrogenism and restores eumenorrhea; however, the effect on anovulation is unknown. We assessed whether metformin treatment is capable of inducing ovulation in nonobese adolescents with anovulatory Hyperandrogenism after precocious pubarche. The study population consisted of 18 adolescents (mean age, 16 yr; body mass index, 21.4 kg/m2; 3–7 yr beyond menarche) with hyperinsulinemic Hyperandrogenism. All girls received metformin for 6 months in a daily dose of 1275 mg. Before inclusion, persistent anovulation was documented by weekly serum progesterone measurements less than 4 ng/ml (months −3 and −1); the ovulation rate was assessed similarly after 2, 4 and 6 months on metformin; a premenstrual progesterone level greater than 8 ng/ml was used as ovulation marker. Regular menses were reported by 16 of 18 girls within 4 months on metformin, and all girls we...
Lourdes Ibanez - One of the best experts on this subject based on the ideXlab platform.
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high neutrophil count in girls and women with hyperinsulinaemic Hyperandrogenism normalization with metformin and flutamide overcomes the aggravation by oral contraception
Human Reproduction, 2005Co-Authors: Lourdes Ibanez, Angela Ferrer, Adriana Maria Jaramillo, Francis De ZegherAbstract:BACKGROUND: The endocrine hallmark of polycystic ovary syndrome (PCOS) is hyperinsulinaemic Hyperandrogenism; another facet of PCOS is low-grade inflammation. METHODS: In adolescents and young women with hyperinsulinaemic Hyperandrogenism (n = 118; mean age 16 years, body mass index 22 kg/m 2 ), we analysed whether the PCOS-associated rise in leukocyte count is already detectable at young age and, if so, whether such elevation is lowered by metformin, flutamide-metformin, oral contraception (OC), or their combination. RESULTS: Leukocyte count ( × 1000/mm 3 ) in patients was high versus controls (7.5 ± 0.1 versus 6.4 ± 0.1; P< 0.001) due to a rise in neutrophils (4.2 ± 0.1 versus 3.0 ± 0.1; P < 0.001). Randomized studies at mean ages of 12.5 years (n = 24) and 15.2 years (n = 33) demonstrated normalizing effects of metformin (850mg/day; P< 0.001) and, respectively, metformin plus flutamide (62.5mg/day) on neutrophil counts; in young women (18.3 years; n = 41), the neutrophil count rose further on OC monotherapy (P = 0.003), but normalized on the same OC plus flutamide-metformin (P < 0.001 versus OC alone). CONCLUSIONS: (i) A high leukocyte count is already present in girls with hyperinsulinaemic Hyperandrogenism, and this is due to a raised neutrophil count; (ii) this hyperneutrophilia is attenuated by metformin or flutamide-metformin, and is amplified by OC monotherapy; (iii) if these treatments are combined, the normalizing effect of flutamide-metformin overcomes the OC effect on neutrophil count.
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low dose flutamide metformin therapy reverses insulin resistance and reduces fat mass in nonobese adolescents with ovarian Hyperandrogenism
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Lourdes Ibanez, Angela Ferrer, David B Dunger, R Amin, Francis De ZegherAbstract:Ovarian Hyperandrogenism is a common disorder often presenting post menarche with anovulatory oligomenorrhea and signs of androgen excess. Associated hyperinsulinemic insulin resistance, dyslipidemia, and central fat excess herald long-term disease risk. Combined antiandrogen (flutamide 250 mg/d) and insulin-sensitizing (metformin) therapy has beneficial effects, in particular on dyslipidemia and androgen excess in young women. We studied the effects of low-dose flutamide-metformin combination on metabolic variables and body composition in adolescent girls with ovarian Hyperandrogenism. Thirty teenage girls (age range, 13.6–18.6 yr) with hyperinsulinemic Hyperandrogenism participated in a 12-month pilot study with a 3-month off-treatment phase and a 9-month treatment phase (randomized sequence) on combined flutamide (125 mg/d) and metformin (1275 mg/d). Body composition was assessed by dual-energy x-ray absorptiometry; endocrine-metabolic state and ovulation rate were screened every 3 months. Insulin sens...
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additive effects of insulin sensitizing and anti androgen treatment in young nonobese women with hyperinsulinism Hyperandrogenism dyslipidemia and anovulation
The Journal of Clinical Endocrinology and Metabolism, 2002Co-Authors: Lourdes Ibanez, Carme Valls, Angela Ferrer, David B Dunger, Francis De ZegherAbstract:The endocrine-metabolic hallmarks of polycystic ovary syndrome are hyperinsulinism, Hyperandrogenism, dyslipidemia, and anovulation. We hypothesized that dyslipidemia and anovulation in nonobese women with polycystic ovary syndrome are essentially secondary to the concerted effects of Hyperandrogenism and insulin resistance. We tested this hypothesis by comparing the efficacy of anti-androgen (flutamide) or insulin-sensitizing (metformin) monotherapy to that of combined therapy in normalizing the endocrine-metabolic and anovulatory status of nonobese, young women with hyperinsulinemic Hyperandrogenism. Thirty-one young women (mean age, 18.7 yr; body mass index, 21.9 kg/m2; hirsutism score, 16; monthly ovulation rate monitored by weekly serum progesterone, 10%) were randomly assigned to receive once daily flutamide (250 mg; n = 10), metformin (1275 mg; n = 8), or combined flutamide- metformin therapy (n = 13) for 9 months. At baseline, there were no endocrine-metabolic differences among treatment groups. C...
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sensitization to insulin induces ovulation in nonobese adolescents with anovulatory Hyperandrogenism
Obstetrical & Gynecological Survey, 2002Co-Authors: Lourdes Ibanez, Maria Victoria Marcos, Carme Valls, Angela Ferrer, Francisco Rodriguezhierro, Francis De ZegherAbstract:Even nonobese girls with precocious pubarche may develop a variant of polycystic ovary syndrome (PCOS) characterized by hyperinsulinism, Hyperandrogenism, abnormal lipids, and persistent anovulation. Insulin-sensitizing treatment has limited hyperinsulinism and Hyperandrogenism and restored eumenorrhea in women with PCOS. Extrapolating from observations in obese women with PCOS who receive an insulin-sensitizing agent such as metformin or troglitazone and become more likely to ovulate, this study examined the effects of metformin in 18 nonobese adolescent girls with a mean age of 16½ years who were 3 to 7 years past menarche. All were anovulatory and met clinical and hormonal criteria for ovarian Hyperandrogenism. The participants also had a history of precocious pubarche caused by exaggerated adrenarche. All the girls were hyperinsulinemic but had normal glucose tolerance. Anovulation was confirmed twice by obtaining four consecutive serum progesterone levels below 4 ng/ml at 1-week intervals. Metformin was given for 6 months in a daily dose of 1275 mg. Hirsutism scores decreased with metformin therapy, as did levels of fasting serum insulin, luteinizing hormone, total testosterone, androstenedione, dehydroepiandrosterone sulfate, and the free androgen index. Serum levels of sex hormone-binding globulin increased at the same time, and the lipid profiles became less atherogenic. There were no changes in body mass index, fasting glycemia, or serum levels of estradiol or follicle-stimulating hormone. All but 2 of the 18 girls reported regular menses within 4 months of the start of metformin therapy and, after 6 months, all were eumenorrheic. Ovulation induction failed in 4 of the 18 girls (Fig. 1), including the 2 with the most severe Hyperandrogenism. Abdominal discomfort in 4 girls resolved spontaneously within 2 weeks. Metformin treatment tends to normalize endocrine-metabolic function in nonobese adolescent girls with anovulatory Hyperandrogenism and induces ovulation in many of them.
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sensitization to insulin induces ovulation in nonobese adolescents with anovulatory Hyperandrogenism
The Journal of Clinical Endocrinology and Metabolism, 2001Co-Authors: Lourdes Ibanez, Maria Victoria Marcos, Carme Valls, Angela Ferrer, Francisco Rodriguezhierro, Francis De ZegherAbstract:In nonobese girls with an adolescent variant of polycystic ovary syndrome, insulin-sensitizing treatment reduces hyperinsulinism, dyslipidemia, and Hyperandrogenism and restores eumenorrhea; however, the effect on anovulation is unknown. We assessed whether metformin treatment is capable of inducing ovulation in nonobese adolescents with anovulatory Hyperandrogenism after precocious pubarche. The study population consisted of 18 adolescents (mean age, 16 yr; body mass index, 21.4 kg/m2; 3–7 yr beyond menarche) with hyperinsulinemic Hyperandrogenism. All girls received metformin for 6 months in a daily dose of 1275 mg. Before inclusion, persistent anovulation was documented by weekly serum progesterone measurements less than 4 ng/ml (months −3 and −1); the ovulation rate was assessed similarly after 2, 4 and 6 months on metformin; a premenstrual progesterone level greater than 8 ng/ml was used as ovulation marker. Regular menses were reported by 16 of 18 girls within 4 months on metformin, and all girls we...
Geoffrey L. Hammond - One of the best experts on this subject based on the ideXlab platform.
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Human sex hormone-binding globulin variants associated with Hyperandrogenism and ovarian dysfunction
Journal of Clinical Investigation, 2002Co-Authors: Kevin N. Hogeveen, Michel Pugeat, Patrice Cousin, Didier Dewailly, Benoît Soudan, Geoffrey L. HammondAbstract:The access of testosterone and estradiol to target tissues is regulated by sex hormone-binding globulin (SHBG) in human blood. Serum SHBG levels are low in patients with Hyperandrogenism, especially in association with polycystic ovarian syndrome (PCOS) and in individuals at risk for diabetes and heart disease. Here, we identify SHBG coding region variations from a compound heterozygous patient who presented with severe Hyperandrogenism during pregnancy. Serum SHBG levels in this patient measured 2 years after her pregnancy were exceptionally low, and her non-protein-bound testosterone concentrations greatly exceeded the normal reference range. A single-nucleotide polymorphism within the proband's maternally derived SHBG allele encodes a missense mutation, P156L, which allows for normal steroid ligand binding but causes abnormal glycosylation and inefficient secretion of SHBG. This polymorphism was identified in four other patients with either PCOS, ioiopathic hirsutism, or ovarian failure. The proband's paternal SHBG allele carries a single-nucleotide deletion within exon 8, producing a reading-frame shift within the codon for E326 and a premature termination codon. CHO cells transfected with a SHBG cDNA carrying this mutation fail to secrete the predicted truncated form of SHBG. To our knowledge, these are the first examples of human SHBG variants linked to Hyperandrogenism and ovarian dysfunction.
Ricardo Azziz - One of the best experts on this subject based on the ideXlab platform.
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prospective association of polycystic ovary syndrome with coronary artery calcification and carotid intima media thickness the coronary artery risk development in young adults women s study
Arteriosclerosis Thrombosis and Vascular Biology, 2014Co-Authors: Ronit Calderonmargalit, David S Siscovick, Sharon Stein Merkin, Erica Wang, Martha L Daviglus, Pamela J Schreiner, Barbara Sternfeld, Dale O Williams, Cora E Lewis, Ricardo AzzizAbstract:Objective—To study the independent associations of polycystic ovary syndrome (PCOS), and its 2 components, Hyperandrogenism and anovulation, with coronary artery calcification (CAC) and carotid artery intima-media thickness (IMT). Approach and Results—At the year 20 of the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based multicenter cohort of young adults, women (mean age, 45 years) with information on menses and hirsutism in their twenties were assessed for CAC (n=982) and IMT (n=988). We defined PCOS as women who had both irregular menses and Hyperandrogenism (n=55); isolated oligomenorrhea (n=103) as women who only had irregular menses; and isolated Hyperandrogenism (n=156) as women who had either hirsutism or increased testosterone levels. Logistic regressions and general linear models were used to estimate the associations between components of PCOS and subclinical CVD. The prevalence of CAC was 10.3% overall. Women with PCOS had a multivariable adjusted odds ratio ...
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Differential Diagnosis and Evaluation of Hyperandrogenism
2003Co-Authors: Ricardo AzzizAbstract:Androgen excess or Hyperandrogenism is one of the most common reproductive endocrinologic defects in women, affecting 5–10% of the reproductive-aged female population. The most common cause of Hyperandrogenism is the polycystic ovary syndrome (PCOS), with nonclassic adrenal hyperplasia (NCAH), androgen-secreting tumors, and androgenic drug intake being much less frequent. Hyperandrogenism, the endocrine disorder, should be distinguished from dermatological disorders such as hirsutism, although there is significant overlap. Hirsutism affects approx 6–7% of reproductive-aged women in the United States, and is a common manifestation of androgen excess (Table 1). Nonetheless, Hyperandrogenism may present without obvious peripheral manifestations, as in the PCOS patient of Asian extraction with little or absent hirsutism. Alternatively, not all hirsute patients have evidence of detectable androgen excess or endocrine imbalance, as in patients with “idiopathic hirsutism.” Finally, androgen excess can also be suspected in those women with other peripheral hyper-androgenic signs, including acne, excessive oiliness or seborrhea, and alopecia. Here, we briefly review the differential diagnosis of androgen excess and denote the diagnostic scheme used for the evaluation of these patients.
Robert L. Barbieri - One of the best experts on this subject based on the ideXlab platform.
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induction of ovulation in infertile women with Hyperandrogenism and insulin resistance
American Journal of Obstetrics and Gynecology, 2000Co-Authors: Robert L. BarbieriAbstract:The polycystic ovary syndrome is a common cause of anovulatory infertility. Women with severe insulin resistance are a unique subset of polycystic ovary syndrome. The syndrome of Hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN syndrome) is one presentation of the insulin-resistant subset of polycystic ovary syndrome. Insulin resistance and Hyperandrogenism are caused by genetic and environmental factors. In women with anovulatory infertility caused by Hyperandrogenism and insulin resistance, clomiphene citrate treatment often fails to result in pregnancy. For these women, weight loss and insulin sensitizers can be effective methods of inducing ovulation and pregnancy and may reduce the number of clomiphene-resistant women with polycystic ovary syndrome who are treated with gonadotropins, ovarian surgery, or in vitro fertilization-embryo transfer.
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Hyperandrogenism, insulin resistance and acanthosis nigricans. 10 years of progress.
Journal of Reproductive Medicine, 1994Co-Authors: Robert L. BarbieriAbstract:Polycystic ovary disease is a heterogeneous endocrinopathy with many interacting causal factors. One potential such factor is chronic hyperinsulinemia. Multiple, independent lines of evidence support the contention that chronic hyperinsulinemia causes ovarian Hyperandrogenism. This evidence includes: (1) mutations in the insulin receptor gene that cause severe hyperinsulinemia appear to be associated with ovarian Hyperandrogenism, (2) insulin stimulates ovarian thecal and stromal androgen secretion in vitro, and (3) in some experimental models, manipulation of circulating insulin concentrations results in changes in circulating androgens. Although the association between hyperinsulinemia and Hyperandrogenism remains to be fully explained at the molecular level, chronic hyperinsulinemia appears to be an important cause of Hyperandrogenism.
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Hyperandrogenism: new insights into etiology, diagnosis, and therapy
Current Opinion in Obstetrics & Gynecology, 1992Co-Authors: Robert L. BarbieriAbstract:Mutations in the genes for the insulin receptor, 21-hydroxylase, 11 beta-hydroxylase, and 3 beta-hydroxysteroid dehydrogenase isomerase enzymes are associated with Hyperandrogenism. These genetic causes of Hyperandrogenism account for less than 10% of all cases. A major goal of future research will be to identify other genetic causes of Hyperandrogenism. Evidence continues to accumulate that luteinizing hormone, insulin-like growth factor I, and insulin are major factors regulating ovarian androgen production. Optimal therapy for Hyperandrogenism probably includes simultaneous suppression of androgen production and blockade of androgen action.
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Hyperandrogenism: new insights into diagnosis and therapy
Current Opinion in Obstetrics & Gynecology, 1991Co-Authors: Robert L. BarbieriAbstract:Many different disease processes can result in a phenotype of hirsutism, anovulation, and oligomenorrhea or amenorrhea. An important goal of reproductive endocrinologists is to identify specific genetic diseases that can produce the hyperandrogenic phenotype. Two genetic disorders that can result in the hyperandrogenic phenotype are 1) mutations in the 21-hydroxylase gene (adrenal hyperplasia), and 2) mutations in the insulin receptor gene (the syndrome of Hyperandrogenism-insulin resistance and acanthosis nigricans). The identification of these two genetic causes of Hyperandrogenism provides the opportunity to investigate new approaches to prenatal diagnosis and therapy, genetic analysis of pedigrees, and innovative forms of therapy.