leuprolide and Hyperandrogenism

Hirsutism is the excessive growth of terminal hair in a typical male pattern in a female. It is often a sign of excessive androgen levels. Although many conditions can lead to hirsutism, polycystic ovary syndrome and idiopathic hyperandrogenism account for more than 85% of cases. Less common causes include idiopathic hirsutism, nonclassic congenital adrenal hyperplasia, androgen-secreting tumors, medications, hyperprolactinemia, thyroid disorders, and Cushing syndrome. Women with an abnormal hirsutism score based on the Ferriman-Gallwey scoring system should be evaluated for elevated androgen levels. Women with rapid onset of hirsutism over a few months or signs of virilization are at high risk of having an androgen-secreting tumor. Hirsutism may be treated with pharmacologic agents and/or hair removal. Recommended pharmacologic therapies include combined oral contraceptives, finasteride, spironolactone, and topical eflornithine. Because of the length of the hair growth cycle, therapies should be tried for at least six months before switching treatments. Hair removal methods such as shaving, waxing, and plucking may be effective, but their effects are temporary. Photoepilation and electrolysis are somewhat effective for long-term hair removal but are expensive.

Topics: Adrenal Hyperplasia, Congenital; Androgen Antagonists; Antineoplastic Agents, Hormonal; Contraceptives, Oral, Hormonal; Cushing Syndrome; Drug-Related Side Effects and Adverse Reactions; Eflornithine; Female; Glucocorticoids; Gonadotropin-Releasing Hormone; Hair Removal; Hirsutism; Humans; Hyperandrogenism; Hyperprolactinemia; Leuprolide; Mineralocorticoid Receptor Antagonists; Neoplasms; Ornithine Decarboxylase Inhibitors; Polycystic Ovary Syndrome; Spironolactone; Thyroid Diseases

In women with PCOS (polycystic ovary syndrome), hyperinsulinaemia stimulates ovarian cytochrome P450c17α activity that, in turn, stimulates ovarian androgen production. Our objective was to compare whether timed caloric intake differentially influences insulin resistance and hyperandrogenism in lean PCOS women. A total of 60 lean PCOS women [BMI (body mass index), 23.7±0.2 kg/m²] were randomized into two isocaloric (~1800 kcal; where 1 kcal≈4.184 J) maintenance diets with different meal timing distribution: a BF (breakfast diet) (980 kcal breakfast, 640 kcal lunch and 190 kcal dinner) or a D (dinner diet) group (190 kcal breakfast, 640 kcal lunch and 980 kcal dinner) for 90 days. In the BF group, a significant decrease was observed in both AUC(glucose) (glucose area under the curve) and AUC(insulin) (insulin area under the curve) by 7 and 54% respectively. In the BF group, free testosterone decreased by 50% and SHBG (sex hormone-binding globulin) increased by 105%. GnRH (gonadotropin-releasing hormone)-stimulated peak serum 17OHP (17α-hydroxyprogesterone) decreased by 39%. No change in these parameters was observed in the D group. In addition, women in the BF group had an increased ovulation rate. In lean PCOS women, a high caloric intake at breakfast with reduced intake at dinner results in improved insulin sensitivity indices and reduced cytochrome P450c17α activity, which ameliorates hyperandrogenism and improves ovulation rate. Meal timing and distribution should be considered as a therapeutic option for women with PCOS.

Topics: Adult; Blood Glucose; Breakfast; Energy Intake; Female; Humans; Hyperandrogenism; Insulin; Insulin Resistance; Leuprolide; Meals; Polycystic Ovary Syndrome; Sex Hormone-Binding Globulin; Steroid 17-alpha-Hydroxylase; Testosterone; Thinness; Time Factors

Topics: Body Height; Body Mass Index; Child; Female; Gonadotropin-Releasing Hormone; Hormones; Humans; Hyperandrogenism; Hyperinsulinism; Infant, Low Birth Weight; Infant, Newborn; Infant, Small for Gestational Age; Leuprolide; Menarche; Menstrual Cycle; Pelvis; Ultrasonography

Women with polycystic ovary syndrome (PCOS) have chronic anovulation and hyperandrogenism and frequently have abnormalities in their lipid profiles and insulin/insulin-like growth factor axis that increase their lifetime risk for cardiovascular disease. Normal ovulatory women may have polycystic ovaries on ultrasonography and yet lack the clinical features of PCOS. To further explore whether ovulatory women without clinical/biochemical hyperandrogenism but with polycystic appearing ovaries (ov-PAO) have subclinical features of PCOS, we prospectively characterized 26 ov-PAO women and matched them by age and body mass index to 25 ovulatory women with normal appearing ovaries (ov-NAO) and to 22 women with PCOS. After an overnight fast, all women had baseline endocrine and metabolic assessments. In addition, a subset of each group of women underwent GnRH-agonist (leuprolide acetate 1 mg s.c.) testing, ACTH stimulation, and an insulin tolerance test (ITT). At baseline, ov-PAO and ov-NAO women had similar endocrine profiles (LH, LH:FSH, androstenedione, and DHEAS). Compared with ov-NAO, 31% of ov-PAO women had reduced glucose responses after insulin (K(itt)), suggesting mild insulin resistance, and 35% had high density lipoprotein levels below 35 mg/dL, a level considered to represent significant cardiovascular risk. After GnRH-agonist, ov-PAO women had response patterns in LH, total testosterone, and 17-hydroxyprogesterone (17-OHP) that were intermediate between ov-NAO and women with PCOS. Ovarian responses were above the normal range in 30-40% of women with ov-PAO. In ov-PAO, peak responses of LH after leuprolide correlated with triglyceride levels (P < 0.05) and peak responses of 17-OHP correlated inversely with Kitt values (P < 0.05). No significant differences were noted with ACTH testing. In conclusion, occult biochemical ovarian hyperandrogenism may be uncovered using GnRH-agonist in ovulatory women with ov-PAO, while adrenal responses remain normal. Subtle metabolic abnormalities may also be prevalent.

Topics: Adrenocorticotropic Hormone; Adult; Antineoplastic Agents, Hormonal; Body Mass Index; Female; Glucose Clamp Technique; Gonadotropin-Releasing Hormone; Hormones; Humans; Hyperandrogenism; Insulin Resistance; Leuprolide; Lipids; Ovary; Ovulation; Pituitary Gland; Polycystic Ovary Syndrome; Prospective Studies; Stimulation, Chemical

To test the hypothesis that in women with polycystic ovary syndrome (PCOS), adrenal cytochrome P450c 17alpha activity is different after physiologic vs. pharmacologic ACTH stimulation and that ovarian activity promotes adrenal hyperactivity that is different after physiologic vs. pharmacologic ACTH stimulation.. Prospective controlled pilot study.. Reproductive endocrinology unit of an academic medical center.. Six women with PCOS who had adrenal hyperandrogenism were compared with four women with normal ovulation.. Adrenal dynamic blood sampling was performed before and after 6 months of GnRH agonist administration.. Comparison of physiologic and pharmacologic ACTH-stimulated levels of progesterone, 17-hydroxyprogesterone, and androgens before and after ovarian steroid modulation.. In women with PCOS, exaggerated responses of androstenedione and 11beta-hydroxyandrostenedione as well as elevated ratios of 17-hydroxyprogesterone to progesterone and of androstenedione to 17-hydroxyprogesterone after physiologic ACTH stimulation did not persist after GnRH-agonist administration. Three of the six women with PCOS had an increased response of androstenedione and a ratio of androstenedione to 17-hydroxyprogesterone that were >2 SD above the mean of those in the women with normal ovulation after pharmacologic ACTH stimulation; this finding persisted after GnRH-agonist administration.. In women with PCOS, increases in adrenal androgen sensitivity after physiologic ACTH stimulation reflected in both arms of cytochrome P450c 17alpha activity may be influenced by ovarian activity. However, 17,20-lyase hyperactivity in a subset after pharmacologic ACTH stimulation may be an intrinsic adrenal disorder.

Topics: Adrenocorticotropic Hormone; Adult; Cosyntropin; Female; Gonadotropin-Releasing Hormone; Hormones; Humans; Hyperandrogenism; Leuprolide; Ovary; Pilot Projects; Polycystic Ovary Syndrome; Steroid 17-alpha-Hydroxylase

CRH is an adrenal androgen secretagogue in men and has been proposed as a candidate regulator of adrenarche. CRH also affects androgen production by theca cells and may be involved in the pathogenesis of ovarian hyperandrogenism (OH). Precocious pubarche (PP) in girls can precede adolescent OH, a condition characterized by a high ovarian 17-hydroxyprogesterone (17-OHP) response 24 h after GnRH agonist challenge. In adolescent girls with a history of PP, we assessed the early androgen response to CRH, as well as the CRH effect on the late ovarian response to GnRH agonist. Within a randomized cross-over design, saline or CRH (human CRH 1 microg/kg x h in saline) was infused over 3-h (1100-1400 h) into 12 adolescent girls (age 17+/-2 yr; body mass index 21.4+/-0.9 Kg/m2) who had been pretreated with dexamethasone (1 mg at 0 h) and GnRH agonist (leuprolide acetate 500 microg sc at 0800 h = time 0). All adolescents had hirsutism, irregular menses, hyperandrogenemia, and hyperinsulinemia after PP. Serum LH, FSH, androstenedione, dehydroepiandrosterone (DHEA), and DHEA-sulfate (DHEAS) were measured at time 0, 3, 6, and 24 h, and ACTH and 17-OHP were measured at time 0, 6, and 24 h. ACTH concentrations at the end of saline or CRH infusions were less than 45 pg/mL; neither saline nor CRH infusions evoked early changes in 17-OHP levels. Within 3 h of CRH infusion, DHEAS increased by 46%, on average; androstenedione increased 2.5-fold and DHEA increased 5-fold duringCRH infusion (all P < 0.0001 compared with saline). There was no detectable CRH effect on the responses of LH, FSH, DHEA, DHEAS, 17-OHP, androstenedione, testosterone, and estradiol 24 h after GnRH agonist administration; five of 12 girls had elevated 17-OHP responses suggestive of OH. In conclusion, CRH was found to be a potent adrenal androgen secretagogue in adolescent girls with hyperandrogenism after PP. In this study, CRH failed to detectably affect the ovarian androgen response to gonadotropins.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Androgens; Body Mass Index; Corticotropin-Releasing Hormone; Cross-Over Studies; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Dexamethasone; Female; Follicle Stimulating Hormone; Glucocorticoids; Humans; Hyperandrogenism; Leuprolide; Luteinizing Hormone; Puberty, Precocious

Insulin resistance and increased ovarian cytochrome P450c17 alpha activity are both features of the polycystic ovary syndrome. P450c17 alpha, which is involved in androgen biosynthesis, has both 17 alpha-hydroxylase and 17,20-lyase activities. Increased activity of this enzyme results in exaggerated conversion of progesterone to 17 alpha-hydroxyprogesterone in response to stimulation by gonadotrophin. We hypothesized that hyperinsulinemia stimulates ovarian P450c17 alpha activity.. We measured fasting serum steroid concentrations and the response of serum 17 alpha-hydroxyprogesterone to leuprolide, a gonadotrophin-releasing hormone agonist, and performed oral glucose-tolerance tests before and after oral administration of either metformin (500 mg three times daily) or placebo for four to eight weeks in 24 obese women with the polycystic ovary syndrome.. In the 11 women given metformin, the mean (+/- SE) area under the serum insulin curve after oral glucose administration decreased from 9303 +/- 1603 to 4982 +/- 911 microU per milliliter per minute (56 +/- 10 to 30 +/- 6 nmol per liter per minute) (P = 0.004). This decrease was associated with a reduction in the basal serum 17 alpha-hydroxyprogesterone concentration from 135 +/- 21 to 66 +/- 7 ng per deciliter (4.1 +/- 0.6 to 2.0 +/- 0.2 nmol per liter) (P = 0.01) and a reduction in the leuprolide-stimulated peak serum 17 alpha-hydroxyprogesterone concentration from 455 +/- 54 to 281 +/- 52 ng per deciliter (13.7 +/- 1.6 to 8.5 +/- 1.6 nmol per liter) (P = 0.01). The serum 17 alpha-hydroxyprogesterone values increased slightly in the placebo group. In the metformin group, the basal serum luteinizing hormone concentration decreased from 8.5 +/- 2.2 to 2.8 +/- 0.5 mlU per milliliter (P = 0.01), the serum free testosterone concentration decreased from 0.34 +/- 0.07 to 0.19 +/- 0.05 ng per deciliter (12 +/- 3 to 7 +/- 2 pmol per liter) (P = 0.009), and the serum sex hormone-binding globulin concentration increased from 0.8 +/- 0.2 to 2.3 +/- 0.6 microgram per deciliter (29 +/- 7 to 80 +/- 21 nmol per liter) (P < 0.001). None of these values changed significantly in the placebo group.. In obese women with the polycystic ovary syndrome, decreasing serum insulin concentrations with metformin reduces ovarian cytochrome P450c17 alpha activity and ameliorates hyperandrogenism.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adult; Blood Glucose; Female; Humans; Hydroxyprogesterones; Hyperandrogenism; Hypoglycemic Agents; Insulin; Leuprolide; Luteinizing Hormone; Metformin; Obesity; Polycystic Ovary Syndrome; Steroid 17-alpha-Hydroxylase; Testosterone

To study the beneficial effects of oral contraceptive (OC) therapy following gonadotropin-releasing hormone agonist (GnRH-a) administration in women with polycystic ovary disease (PCOD).. Twenty-three hyperandrogenic women (aged 15-39) were randomized into two groups; GnRH-a (depot every 28 days) for six months or combination therapy (GnRH-a plus OC "addback") for six months. Following six months of treatment with either therapy, all patients received OC therapy for at least six months. The hormonal state was evaluated at three-month intervals.. Hormone levels of luteinizing hormone (LH), testosterone (T) and free T remained suppressed within the normal range in 11 of 17 patients (65%) during the six months of OC only therapy, while the other six patients showed "escape" from suppression, with the LH, T and free T concentrations rising to pre-GnRH-a treatment levels. Use of OC addback therapy did not potentiate the long-acting therapeutic effect of GnRH-a pretreatment; three of six patients in the escape group were pretreated with combination therapy and three with GnRH-a only.. In the majority of women with PCOD, OC therapy following GnRH-a administration was effective in maintaining ovarian androgen suppression. Failure to maintain ovarian suppression in this patient population was associated with higher elevations of baseline free T concentrations.. Clinical investigators randomly allocated 24 hirsute women aged 15-39 years with polycystic ovary disease (PCOD) to either the treatment program offering an injection of leuprolide acetate (a highly potent gonadotropin-releasing hormone agonist [GnRH-a]) for depot suspension (3.75 mg) at 28-day intervals for six months or the treatment program offering both the same injection and a combined oral contraceptive (OC) as add-back for six months. At three months, one woman moved out of state and withdrew from the study. After six months of either GnRH-a treatment regimen, all remaining 23 women received only OCs for six more months. Six women did not successfully complete the OC therapy and were excluded from the statistical analyses. The investigators aimed to examine the benefits of OC use in the management of women with PCOD after six months of pretreatment with the GnRH-a. During the OC-only treatment period, 11 (65%) of 17 patients still had suppressed levels of luteinizing hormone (LH), testosterone (T), and free T within the normal range. These levels increased to pre-GnRH-a treatment levels in the remaining six women, indicating escape from ovarian suppression. Three of six women in the escape group received combination therapy for pretreatment, while the other three received only GnRH-a. The women in the escape group had a higher baseline free T concentration than the suppressed group (5.1 vs. 3.3 ng/dl; p = 0.02). The findings revealed that OC therapy following GnRH-a administration effectively maintained ovarian androgen suppression in most women with PCOD. They also indicated that failure to maintain this suppression had a significant association with higher baseline free T concentrations.

Topics: Adolescent; Adult; Contraceptives, Oral; Drug Therapy, Combination; Female; Humans; Hyperandrogenism; Leuprolide; Luteinizing Hormone; Polycystic Ovary Syndrome; Testosterone; Time Factors

To determine if combination GnRH agonist (GnRH-a) and oral contraceptive (OC) therapy was more effective than GnRH-a or OC alone in the treatment of hirsute women with ovarian hyperandrogenism.. Thirty-three hirsute women (ages 15 to 39 years) were randomized into three groups: 3.75 mg IM leuprolide acetate (LA) depot every 28 days for 6 months, combination monophasic oral contraceptive for 6 months (OC), or GnRH-a plus OC for 6 months (LA + OC).. Comparative studies of changes in hormonal and hair parameters were performed at baseline, 3, and 6 months after starting therapy.. After 6 months, serum T and LH levels were decreased significantly in all groups although reduction was greater in GnRH-a groups than OC alone. The reduction of free T was significantly greater with LA + OC compared with LA or OC alone. This could be a consequence of the significant rise in sex hormone-binding globulin (SHBG) in LA + OC and OC groups compared with LA in which there was no change in SHBG. Reduced facila hair density and decrease in hirsutism score was observed in both GnRH-a groups after 6 months.. "Add-back" OC therapy used in combination with a GnRH-a increases SHBG and more effectively lowers free T levels in women with ovarian hyperandrogenism. Enhanced suppression of "bioavailable" androgens with combined GnRH-a and OC therapy failed to improve significantly the therapeutic effect of GnRH-a treatment alone on hirsutism.

Topics: Adolescent; Adult; Contraceptives, Oral; Drug Therapy, Combination; Endometrium; Ethinyl Estradiol; Female; Hirsutism; Humans; Hyperandrogenism; Leuprolide; Luteinizing Hormone; Norethindrone; Ovarian Diseases; Testosterone

Hyperandrogenism is a relatively common clinical problem. However, severe hyperandrogenism causing virilisation is rare. A 27-year-old woman presented with generalised hirsutism, clitoromegaly, breast atrophy and secondary amenorrhoea. She had serum testosterone levels elevated to the adult male range. Administration of gonadotropin-releasing hormone (GnRH) analogue resulted in >50% suppression of serum testosterone which was suggestive of luteinising hormone-dependent ovarian hyperandrogenism. Imaging studies of abdomen and pelvis were normal, and ovarian venous sampling failed to show a gradient between the two sides. A presumptive diagnosis of ovarian hyperthecosis was, therefore, considered. Medical treatment with GnRH analogue and combined oral contraceptive pills was initiated to which an excellent clinical and biochemical response was noted. This case highlights a rare presentation of ovarian hyperthecosis in a young woman with severe hyperandrogenism mimicking a virilising neoplasm.

Topics: Adult; Amenorrhea; Contraceptives, Oral; Female; Humans; Hyperandrogenism; Hyperplasia; Leuprolide; Testosterone; Theca Cells; Treatment Outcome

Ovarian hyperandrogenism from polycystic ovary syndrome (PCOS) and hyperinsulinemia from insulin resistance are modulators of ovarian follicle development. We report on a woman with PCOS and hyperandrogenism and severe insulin resistance from metabolic syndrome who received long-term GnRH analogue therapy preceding bilateral salpingo-oophorectomy for massive ovarian enlargement. Ovarian histological examination showed proliferating granulosa cells within antral follicles coexistent with serous cystadenofibromas, demonstrating a unique link between hyperinsulinemia and granulosa cell mitogenesis.. A 30-year-old woman with PCOS with hyperandrogenism, severe insulin resistance from metabolic syndrome, and nonalcoholic steatohepatitis experienced abdominal pain from bilaterally enlarged ovaries. She had previously experienced a pulmonary embolism while taking oral contraceptives and hepatotoxicity from metformin and spironolactone therapies. Long-term GnRH analogue therapy to induce pituitary desensitization to GnRH successfully decreased gonadotropin-dependent steroidogenesis without improving insulin resistance. Despite GnRH analogue therapy, progressive ovarian enlargement in the presence of hyperinsulinemia from worsening metabolic function eventually required bilateral salpingo-oophorectomy for removal of massively enlarged ovaries. Histological examination showed both ovaries contained proliferating granulosa cells within antral follicles coexistent with serous cystadenofibromas.. In women with PCOS and hyperinsulinemia from severe insulin resistance due to metabolic syndrome, granulosa cell proliferation within antral follicles can occur despite long-term GnRH analogue therapy, implicating hyperinsulinemia as a granulosa cell mitogen in the absence of gonadotropin-dependent ovarian function.

Topics: Abdominal Pain; Adult; Cell Proliferation; Cystadenofibroma; Female; Fertility Agents, Female; Granulosa Cells; Humans; Hyperandrogenism; Hyperinsulinism; Insulin Resistance; Leuprolide; Organ Size; Ovarian Follicle; Ovarian Neoplasms; Polycystic Ovary Syndrome; Salpingo-oophorectomy; Severity of Illness Index; Tomography, X-Ray Computed; Ultrasonography

Polycystic ovary syndrome (PCOS), affecting more than 5-10% of woman at reproductive childbearing age, is characterized by anovulation and hyperandrogenism. Frozen-thawed embryo transfer (ET) has been widely used for PCOS women to minimize the risk of ovarian hyperstimulation syndrome. However, the hyperandrogenic status of PCOS women deteriorates endometrial function, which has subsequently increased miscarriage rates in PCOS women. Therefore, we conducted this retrospective study to compare the pregnancy outcomes of hyperandrogenic PCOS women with (n = 29) and without (n = 31, controls) pretreatment of gonadotropin-releasing hormone (GnRH) agonist before frozen-thawed ET. We found that pretreatment with GnRH agonist before frozen-thawed ETs could not significantly improve the clinical pregnancy rate in these hyperandrogenic PCOS women. However, the ongoing pregnancy rate was significantly increased in women with GnRH agonist pretreatment (odds ratio: 3.98, 95% confidence interval: 1.12-14.20, p = 0.033). We concluded that androgen deprivation status due to pretreatment with GnRH agonist might improve the ongoing pregnancy rate in hyperandrogenic PCOS women. Additional large, well-designed prospective studies are worthwhile and necessary.

Topics: Adult; Embryo Transfer; Female; Fertility Agents, Female; Humans; Hyperandrogenism; Infertility, Female; Leuprolide; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Rate; Retrospective Studies; Treatment Outcome

Hyperinsulinemia can lead to pathologic ovarian growth and androgen production.. A 29-year-old woman developed an autoantibody to the insulin receptor (type B insulin resistance), causing extreme insulin resistance and hyperinsulinemia. Testosterone levels were elevated to the adult male range. Treatment with gonadotropin-releasing hormone (GnRH) analog led to normalization of testosterone, despite persistent extreme insulin resistance.. This case demonstrates that gonadotropins are necessary for insulin to cause pathologic ovarian androgen production. Suppression of gonadotropins with GnRH analogs may be a useful therapeutic option in patients with severe hyperandrogenism or ovarian enlargement because of hyperinsulinemia.

Topics: Adult; Antineoplastic Agents, Hormonal; Autoantibodies; Cyclophosphamide; Dexamethasone; Diagnosis, Differential; Female; Gonadotropin-Releasing Hormone; Humans; Hyperandrogenism; Hyperinsulinism; Immunosuppressive Agents; Insulin Resistance; Leuprolide; Ovarian Diseases; Receptor, Insulin; Rituximab; Testosterone

To evaluate the ovarian function during early infancy in daughters of women with polycystic ovary syndrome (PCOS) treated with metformin throughout pregnancy (PCOSd+M), as a means to reduce androgen and insulin levels, compared with daughters of nontreated PCOS women (PCOSd-M) and daughters of women who belong to a healthy comparison group (HCd).. Descriptive and analytic study.. Unit of endocrinology and reproductive medicine.. Fifteen PCOSd+M, 23 PCOSd-M, and 35 HCd were studied at 2-3 months of age.. A GnRH analogue test was performed with determinations of gonadotropins, sex steroids, SHBG, and anti-Müllerian hormone (AMH).. Differences in AMH levels between PCOSd+M, PCOSd-M and HCd.. AMH and peak E(2) concentrations were significantly higher in PCOSd-M compared with HCd, whereas PCOSd+M exhibited AMH concentrations and peak E(2) levels similar to those observed in HCd.. The improvement of the altered endocrine-metabolic environment of PCOS mothers reduces AMH levels in their daughters, which might reflect a decrease in their follicular mass.

Topics: Adult; Anti-Mullerian Hormone; Birth Weight; Diabetes, Gestational; Female; Fertility Agents, Female; Humans; Hyperandrogenism; Hyperinsulinism; Hypoglycemic Agents; Infant, Low Birth Weight; Infant, Newborn; Insulin; Leuprolide; Metformin; Ovarian Follicle; Polycystic Ovary Syndrome; Pregnancy; Prenatal Exposure Delayed Effects; Testosterone; Young Adult

The most frequent cause of virilization in postmenopausal women is excessive androgen production of ovarian origin. Bilateral oophorectomy is usually performed, even in cases of benign tumors or hyperthecosis. This is the first report of a case series of long-term GnRH-agonist treatment of hyperandrogenism in postmenopausal women.. We present three women with postmenopausal hyperandrogenism of ovarian origin who were treated with GnRH agonists.. We describe three cases of postmenopausal women with virilization and hyperandrogenism of presumed ovarian origin, all with slight enlargement of the ovaries but without visualization of a tumor, who had long-term treatment with GnRH agonists. No histological diagnosis was available, and therefore all patients received careful follow-up, including periodic testing of androgen levels and ovarian imaging by computed tomography scans. The three patients responded in different ways to treatment with GnRH agonists.. Long-term GnRH agonist treatment is an acceptable choice for treatment of postmenopausal hyperandrogenism in patients where ovarian origin of androgen excess is ascertained, and especially in those patients who have an increased risk for surgery due to comorbidities or who are unwilling to undergo bilateral oophorectomy.

Topics: Aged; Alopecia; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Female; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Hirsutism; Humans; Hyperandrogenism; Hypertension; Leuprolide; Liver Cirrhosis, Alcoholic; Magnetic Resonance Imaging; Middle Aged; Obesity; Ovary; Postmenopause; Tomography, X-Ray Computed

To evaluate ovarian function, especially ovulation rate, in adolescents with McCune-Albright syndrome (MAS) and a history of peripheral precocious puberty.. Prospective cross-sectional study.. Academic center.. A total of eight adolescents with MAS were compared with 15 healthy adolescents matched by age, Tanner stage and body mass index.. We determined basal gonadotropins, sex steroids, sex hormone binding globulin, anti-Müllerian hormone, glucose and insulin. A leuprolide acetate test was performed to measure luteinizing hormone (LH) and follicle stimulating hormone (FSH) (at 0 and 3 h), and 17B-estradiol, testosterone and 17-OH-progesterone (at 0 and 24 h). Salivary progesterone levels were used to assess ovulation during the 13th, 18th, 23rd and 28th days of each menstrual cycle for three to five consecutive cycles, and one pelvic ultrasound was performed during the follicular phase.. Ovulation rate in adolescents with MAS.. The proportion of ovulatory cycles was 52.6% in controls compared with 35.7% in patients with MAS.. The adolescent girls with MAS appear to have a lower ovulatory rate compared with controls.

Topics: Adolescent; Adult; Cross-Sectional Studies; Female; Fibrous Dysplasia, Polyostotic; Follicle Stimulating Hormone, Human; Follicular Phase; Gonadotropin-Releasing Hormone; Humans; Hyperandrogenism; Leuprolide; Luteinizing Hormone; Ovary; Ovulation; Prospective Studies; Puberty, Precocious; Ultrasonography; Young Adult

Topics: 17-Hydroxysteroid Dehydrogenases; 3-Hydroxysteroid Dehydrogenases; Adenosine Triphosphate; Aldo-Keto Reductase Family 1 Member C3; Androstenedione; CCAAT-Enhancer-Binding Protein-beta; Diazoxide; Female; Gene Expression Regulation, Enzymologic; Humans; Hydroxyprostaglandin Dehydrogenases; Hyperandrogenism; Hyperinsulinism; Insulin; Leuprolide; Polycystic Ovary Syndrome; Testosterone; Thinness

Polycystic ovary syndrome (PCOS) is a reproductive disorder of ovarian hyperandrogenism and insulin resistance characterized by abnormal luteinization of small follicles. After exposure to GnRH analog/FSH stimulation for in vitro fertilization (IVF), however, it is unclear whether such PCOS follicles remain abnormally luteinized during the resumption of oocyte maturation in vivo.. The aim of this study was to determine whether PCOS follicles exposed to GnRH analog/FSH stimulation for IVF show abnormal luteinization.. This study was a prospective cohort.. The setting was an institutional practice.. Eleven PCOS and 30 normoandrogenic ovulatory women were included.. All subjects received GnRH analog/FSH therapy after basal serum hormone determinations.. Follicle fluid aspirated at oocyte retrieval from the first follicle of each ovary was assayed for gonadotropins, steroids, insulin, and glucose. LH receptor mRNA expression was determined in granulosa cells of the same follicle.. In PCOS patients with basal hyperandrogenemia and hyperinsulinemia, total oocyte number was increased and follicle diameter was decreased, despite normal maximal serum estradiol levels. Within PCOS follicles, progesterone levels were reduced (P < 0.01), despite comparable bioactive LH and insulin levels and granulosa cell LH receptor mRNA expression; estradiol levels were normal, despite diminished FSH availability (P < 0.004). Elevated androstenedione (P < 0.01), testosterone (P < 0.001), and glucose (P < 0.01) levels also occurred. In PCOS follicles containing mature oocytes, however, elevated androgen levels were accompanied by both normal progesterone concentrations and a normal inverse relationship between glucose depletion and lactate accumulation.. Hyperandrogenic follicles with mature oocytes from PCOS women receiving GnRH analog/recombinant human FSH therapy for IVF show sufficient glucose utilization for normal luteinization.

Topics: Adult; Body Mass Index; Female; Fertilization in Vitro; Humans; Hyperandrogenism; Leuprolide; Luteinization; Ovarian Follicle; Polycystic Ovary Syndrome; Prospective Studies; Receptors, LH; RNA, Messenger

We report a case of a virilized 59-yr-old woman with elevated serum testosterone levels and bilateral macronodular adrenal hyperplasia. The patient underwent laparoscopic right adrenalectomy, after which the elevated testosterone level transiently normalized. The immediate postoperative depression of the testosterone level suggested that the process was driven by gonadotropins that were suppressed by the stress of surgery. The excised right adrenal mass contained testosterone by immunohistochemistry and LH receptor mRNA by in situ hybridization. The recurrence of hyperandrogenemia suggested that the enlarged left adrenal was also secreting testosterone. The serum testosterone level increased in response to im injection of human chorionic gonadotropin, suggesting control by aberrant LH receptors. Injection of leuprolide acetate (7.5 mg im) to suppress LH levels resulted in normalization of the testosterone level 12 d later that persisted for several weeks. Ectopic receptors mediating Cushing's syndrome have been described in several cases of bilateral adrenal hyperplasia and adrenal adenoma. This is the first case to our knowledge in which pure androgen overproduction in adrenal hyperplasia has been shown to be controlled by LH receptors. In our patient, the control of androgen secretion by LH may explain the postmenopausal onset of virilization and the transient postoperative normalization of the serum testosterone level.

Topics: Adrenal Gland Diseases; Adrenal Glands; Adrenalectomy; Female; Humans; Hyperandrogenism; Injections, Intramuscular; Leuprolide; Luteinizing Hormone; Middle Aged; Receptors, LH; RNA, Messenger; Testosterone; Virilism

Hyperandrogenism of ovarian origin is rare in postmenopausal women. However, there is evidence that the ovaries of postmenopausal women are active endocrine glands, secreting mainly androgens.. A postmenopausal woman sought treatment for progressive hirsutism. Endocrine evaluation revealed androgen excess. Transvaginal ultrasound revealed enlarged ovaries. Hysterectomy and bilateral oophorectomy were recommended. However, surgery had to be withheld for 6 months while the patient recovered from an acute myocardial infarction. In the interim, the patient's hyperandrogenemia was successfully treated with monthly injections of the gonadotropin-releasing hormone agonist (GnRH), leuprolide acetate.. This report illustrates the potential for postmenopausal ovaries to become active androgen-secreting endocrine organs. It also demonstrates the efficacy of pharmacologic intervention for postmenopausal ovarian hyperthecosis when the patient is a poor surgical candidate.

Topics: Algorithms; Female; Humans; Hyperandrogenism; Leuprolide; Middle Aged; Ovary; Postmenopause

To evaluate the role of TNF-alpha in the pathogenesis of hyperandrogenism, we have evaluated the serum TNF-alpha levels, as well as several polymorphisms in the promoter region of the TNF-alpha gene, in a group of 60 hyperandrogenic patients and 27 healthy controls matched for body mass index. Hyperandrogenic patients presented with mildly increased serum TNF-alpha levels as compared with controls (mean[median] +/- SD: 7.2[7.0] +/- 3.3 pg/ml vs. 5.6[4.4] +/- 4.0 pg/ml, P < 0.02). Although no differences in body mass index and insulin resistance indexes were observed between patients and controls, when subjects were classified by body weight, serum TNF-alpha was increased only in lean patients as compared with lean controls, but this difference was not statistically significant when comparing obese patients with obese controls. The TNF-alpha gene polymorphisms studied here (-1196C/T, -1125G/C, -1031T/C, -863C/A, -857C/T, -316G/A, -308G/A, -238G/A, and -163G/A) were equally distributed in hyperandrogenic patients and controls. However, carriers of the -308A variant presented with increased basal and leuprolide-stimulated serum androgens and 17-hydroxyprogesterone levels when considering patients and controls as a group. No differences were observed in serum TNF-alpha levels, body mass index, and insulin resistance indexes, depending on the presence or absence of these variants. In conclusion, our present results suggest that the TNF-alpha system might contribute to the pathogenesis of hyperandrogenism, independent of obesity and insulin resistance. However, elucidation of the precise mechanisms underlying the relationship between the TNF-alpha system and androgen excess is needed before considering TNF-alpha as a significant contributing factor to the development of hyperandrogenism.

Topics: 17-alpha-Hydroxyprogesterone; Adrenocorticotropic Hormone; Adult; Androgens; Blood Glucose; Body Mass Index; DNA; Estradiol; Female; Follicle Stimulating Hormone; Genotype; Hirsutism; Humans; Hydrocortisone; Hyperandrogenism; Insulin; Leuprolide; Luteinizing Hormone; Menstrual Cycle; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Reference Values; Sex Hormone-Binding Globulin; Tumor Necrosis Factor-alpha

Hepatocellular dysfunction and perturbed portal hemodynamics alter steroid metabolism. Men with liver disease have gynecomastia, although women similarly affected rarely show virilization. We report a 10-yr-old girl with portal hypertension and shunting associated with precocious puberty and ovarian hyperandrogenism. This was one of premature twin girls; neither had clitoromegaly or genital ambiguity. In one child, neonatal respiratory problems led to umbilical vein catheterization with subsequent development of portal hypertension. Pubic hair was first noted at age 6 yr, breasts at 7 yr, and severe acne and clitoromegaly at 10 yr. Baseline sex hormones were elevated: androstenedione (A), 413 ng/dL; testosterone (T), 226 ng/dL; and estradiol (E2), 160 pg/mL. Liver transaminases were within the normal range, however, the coagulation profile was mildly abnormal. Cosyntropin adrenal stimulation revealed no steroidogenic defect. Dexamethasone suppression reduced A and T slightly. LH-releasing hormone stimulation produced a pubertal rise in LH and FSH. Pelvic sonography showed a large right ovary with numerous follicles. Surgical exploration revealed symmetrically enlarged ovaries with dense capsules. Histology of ovarian wedge resections showed hyperthecosis; immunohistochemistry showed stromal cells expressing steroidogenic enzymes and proteins. One month postoperatively, A and T were unchanged from baseline, whereas E2 decreased to 56 pg/mL. A single dose of depot leuprolide acetate significantly reduced T. Subsequent treatment with oral contraceptives reduced T to 50 ng/dL, and cyclical menses occurred. We conclude that precocious puberty and ovarian hyperthecosis were induced in this young girl by elevated circulating levels of sex hormones, a consequence of portasystemic shunting and impaired hepatic steroid metabolism.

Topics: Androstenedione; Child; Contraceptives, Oral; Diseases in Twins; Female; Gonadal Steroid Hormones; Humans; Hyperandrogenism; Hypertension, Portal; Immunohistochemistry; Leuprolide; Ovarian Diseases; Ovary; Puberty, Precocious; Testosterone; Theca Cells

To determine whether 3-month GnRH analogue (GnRH-a) administration to hyperandrogenic anovulatory patients and healthy women affects glucose utilization or endogenous glucose production (EGP) in the postabsorptive state and during variable hyperglycemic-hyperinsulinemic infusions.. Prospective, nonrandomized study.. Academic research environment.. Twelve hyperandrogenic anovulatory patients and 11 healthy women matched by body mass index and waist to hip circumference ratio.. Variable hyperglycemic-hyperinsulinemic infusions replicated physiological increases in circulating glucose and insulin levels before and after 3-month GnRH-a administration.. Glucose utilization and EGP.. In the postabsorptive state, plasma glucose and insulin levels, glucose utilization, and EGP were similar in hyperandrogenic patients and healthy women. During variable hyperglycemic-hyperinsulinemic infusions, glucose use increased and EGP decreased to similar degrees in both groups of women. Three-month GnRH-a administration to hyperandrogenic patients and healthy women did not affect plasma glucose and insulin levels, glucose utilization and EGP in the postabsorptive state, or glucose utilization and EGP during variable hyperglycemic-hyperinsulinemic infusions.. Glucose use and EGP in the postabsorptive state and during variable hyperglycemic-hyperinsulinemic infusions are similar in hyperandrogenic anovulatory patients and healthy women of similar body fat distribution and are unaffected by 3-month GnRH-a administration.

Topics: Adolescent; Adrenal Glands; Adult; Anovulation; Blood Glucose; Body Composition; C-Peptide; Female; Glucagon; Human Growth Hormone; Humans; Hyperandrogenism; Insulin; Insulin Resistance; Leuprolide; Middle Aged; Ovary; Prospective Studies; Steroids

Functional ovarian hyperandrogenism (FOH) is characterized by an abnormal ovarian response to challenge with the GnRH analogs nafarelin and leuprolide acetate, similar to that observed in women with well defined polycystic ovary syndrome, regardless of whether elevated LH levels or polycystic ovaries are present. We studied an unselected group of 42 hyperandrogenic adolescents (age range, 14-22 yr; mean, 18.1 +/- 2.5 yr) 1) to determine FOH incidence through the assessment of ovarian-steroidogenic response to a single dose of leuprolide acetate, 2) to assess the clinical characteristics of patients according to their responses to GnRH analog stimulation, and 3) to evaluate adrenal steroidogenic function and its relation to ovarian hyperandrogenism in patients with either normal or abnormal responses to leuprolide acetate challenge. All patients underwent leuprolide acetate and ACTH testing, dexamethasone and ovarian suppression tests, and pelvic ultrasonography. Twenty-four (58%) patients had supranormal plasma 17-hydroxyprogesterone (17-OHP) responses to leuprolide acetate characteristic of FOH, and in 18, the 17-OHP response was similar to that of controls (n = 24; age, 17.1 +/- 2.3 yr). Seven patients (5 with FOH and 2 with normal responses to leuprolide acetate) had an abnormal response to ACTH, but only 1 had conclusive evidence of 21-hydroxylase deficiency. In 16 patients, the response to both stimulation tests was normal. Only 13 (54%) of the 24 FOH patients had polycystic ovaries on ultrasonography, and in 11 (46%), basal plasma LH levels were elevated. In FOH patients, reduction in testosterone and androstenedione plasma levels was significantly greater after ovarian suppression than after dexamethasone challenge (P < 0.0005 and P < 0.02, respectively). Peak plasma 17-OHP levels postleoprolide acetate simulation correlated with dexamethasone-suppressed plasma testosterone concentrations, dexamethasone-suppressed plasma androstenedione levels, and the free androgen index postdexamethasone treatment (r = 0.4, P = 0.01; r+ 0.4, P < 0.05; and r = 0.41, P = 0.007, respectively), Plasma sex hormone-binding globulin levels after dexamethasone administration correlated negatively with the baseline free androgen index (r = -.0.67; P < 0.0001). Considering our diagnostic criteria, 26 (62%) of our collective of 42 patients had abnormal responses to one or both stimulation tests, whereas 16 (37%) had normal response. FOH is the most common cause in (58%) of

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adrenocorticotropic Hormone; Adult; Androstenedione; Dexamethasone; Female; Humans; Hydroxyprogesterones; Hyperandrogenism; Leuprolide; Luteinizing Hormone; Ovarian Diseases; Ovary; Polycystic Ovary Syndrome; Testosterone; Ultrasonography

The hyperandrogenic-insulin-resistant acanthosis nigricans syndrome affects between 2% and 5% of hirsute women and is characterized by INS resistance, elevated INS levels, acanthosis nigricans, and androgen excess. These patients' response to therapy is unclear, although long-acting GnRH-a suppression has been proposed. The objective of this study was to determine the success of OC in suppressing the hyperandrogenemia of five patients with the hyperandrogenic-insulin-resistant acanthosis nigricans syndrome and the subsequent response to GnRH-a suppression of those women failing initial therapy. After 6 months of OC and SPA therapy, four patients experienced adequate suppression of free T, an increase in SHBG levels, and a subjective improvement in hair growth rate. Two also reported an improvement in hair texture. The total and free T levels in the fifth patient did not suppress after 8 months of OC therapy. Nevertheless, in this patient the administration of a GnRH-a along with hormonal replacement and SPA adequately suppressed free and total T, increased SHBG, and dramatically decreased the shaving interval. In conclusion, although GnRH-a suppression and hormonal replacement can be helpful in patients not responding to standard therapy, the majority of patients with the hyperandrogenic-insulin-resistant acanthosis nigricans syndrome will respond favorably to OC treatment. It is also clear that although hyperinsulinemia augments LH-stimulated androgen biosynthesis in vivo, it does not appear to be able to initiate or maintain androgen production in the absence of adequate gonadotropin stimulation.

Topics: Acanthosis Nigricans; Adolescent; Contraceptives, Oral; Drug Therapy, Combination; Female; Humans; Hyperandrogenism; Insulin Resistance; Leuprolide; Medroxyprogesterone Acetate; Spironolactone

To examine if changes in insulin sensitivity and glucose effectiveness in women with polycystic ovarian disease (PCOD) occurred after ovarian androgen suppression with a GnRH agonist, leuprolide acetate (LA, Lupron; TAP Pharmaceuticals, Deerfield, IL) using the minimal model method.. Twelve patients with PCOD were tested in the untreated state (baseline) and after 6 weeks of LA treatment. Subjects were divided into two groups based on the degree of impairment of their baseline insulin sensitivity index (SI; (min-1) (microU/mL-1): mild insulin resistance (SI > 1) or severe insulin resistance (SI < 1).. In all patients, serum T was significantly decreased from elevated baseline levels to normal female concentrations after 6 weeks of LA therapy. Insulin sensitivity in PCOD patients with mild insulin resistance significantly improved from baseline after 6 weeks of LA therapy, whereas no change in SI on LA therapy was seen in PCOD women with severe insulin resistance. Glucose utilization independent of increased insulin secretion did not change as a function of LA treatment in either group.. These findings indicate a significant improvement in SI in mildly insulin-resistant women with PCOD after suppression of ovarian function with LA treatment.

Topics: Adult; Female; Glucose Tolerance Test; Humans; Hyperandrogenism; Injections, Intravenous; Insulin; Insulin Resistance; Leuprolide; Polycystic Ovary Syndrome; Testosterone