Randall B. Barnes

Detection of Functional Ovarian Hyperandrogenism in Women with Androgen Excess

BACKGROUND Distinguishing between ovarian and adrenal causes of androgen excess may be difficult. We have found that women with the polycystic ovary syndrome have supranormal plasma 17-hydroxyprogesterone responses to the gonadotropin-releasing hormone agonist nafarelin. We determined the usefulness of testing with nafarelin to distinguish ovarian causes of hyperandrogenism in women. METHODS We studied 40 consecutive women with hyperandrogenism who had oligomenorrhea, hirsutism, or acne. All 40 underwent testing with nafarelin, dexamethasone, and corticotropin with measurement of circulating concentrations of gonadotropins and steroid hormones, and 19 underwent ovarian ultrasonography. RESULTS The plasma 17-hydroxyprogesterone response to nafarelin was supranormal in 23 of the 40 women (58 percent), and the plasma androgen response to corticotropin was elevated in 23; 13 women had both abnormalities. Only one woman had conclusive evidence of a steroidogenic block; she had nonclassic adrenal 21-hydroxylase deficiency. Of the 23 women with abnormal responses to nafarelin, only 11 (48 percent) had elevated base-line serum luteinizing hormone concentrations. Of the 13 women with abnormal responses to nafarelin who underwent ultrasonography, 7 (54 percent) had polycystic ovaries. Peak plasma 17-hydroxyprogesterone concentrations after nafarelin administration correlated closely with plasma free testosterone concentrations after dexamethasone administration (r = 0.75, P less than 0.001). CONCLUSIONS Approximately half of women with oligomenorrhea, hirsutism, or acne have an abnormal response to the gonadotropin-releasing hormone agonist nafarelin, suggesting an ovarian cause of their androgen excess.

Pituitary-Ovarian Responses to Nafarelin Testing in the Polycystic Ovary Syndrome

To investigate the basis of polycystic ovary syndrome, we examined the responses of patients to nafarelin, a specific gonadotropin-releasing-hormone agonist, given to stimulate pituitary and gonadal secretion. We compared 16 normal women in the follicular phase, 5 normal men, 8 women with polycystic ovary syndrome, and 1 woman with polycystic ovary syndrome caused by a 3 beta-hydroxysteroid dehydrogenase deficiency. After 100 micrograms of nafarelin was given subcutaneously, serum follicle-stimulating hormone and luteinizing hormone increased rapidly to peak levels within four hours. The women with polycystic ovary syndrome had a pattern similar to that of the men, with greater early luteinizing-hormone responses (30 minutes to 1 hour) and lower peak follicle-stimulating-hormone responses than normal women (P less than 0.05). Patients with polycystic ovary syndrome responded to gonadotropin stimulation with normal to increased production of plasma estrogens and increased levels of androstenedione at 16 to 24 hours (P less than 0.05). Elevated production of 17 alpha-hydroxyprogesterone was found in all the women with polycystic ovary syndrome and in the men. These abnormal responses were unchanged by pretreatment with dexamethasone to suppress adrenal function. In the patient with the 3 beta-hydroxysteroid dehydrogenase deficiency, both basal and stimulated plasma levels of delta 5-3 beta-hydroxysteroids before the enzymatic block were elevated, whereas plasma levels of 17 alpha-hydroxyprogesterone and androstenedione--the steroids immediately beyond the block--were low. We conclude that women with polycystic ovary syndrome have masculinized pituitary and ovarian responses to stimulation by nafarelin. Our findings suggest that the regulation of the ovarian 17-hydroxylase and C-17,20-lyase activities is abnormal in such women.

Dysregulation of cytochrome P450c17α as the cause of polycystic ovarian syndrome

Polycystic ovarian syndrome (PCOS) appears to be due to a previously unrecognized type of steroidogenic abnormality, one in which hyperandrogenism arises from a regulatory abnormality (dysregulation) rather than from enzyme deficiency. It appears that PCOS typically arises from masculinized regulation of the androgen-forming enzyme (cytochrome P450c17 α ) within ovarian thecal cells. This may arise by either excessive stimulation by luteinizing hormone (LH) or by escape from desensitization to LH. We review evidence which is compatible with the concept that the latter situation may result from an intrinsic intraovarian flaw in the paracrine feedback mechanism by which thecal androgen biosynthesis is inhibited and that coexistent adrenal 17-ketosteroid hyper-responsiveness to corticotropin (ACTH) may be due to a similar type of dysregulation of adrenocortical P450c17 α .

The Polycystic Ovary Syndrome: Pathogenesis and Treatment

PURPOSE To propose a theory for the pathogenesis of the polycystic ovary syndrome that explains the endocrinologic abnormalities of the syndrome and provides a rational approach to therapy. DATA IDENTIFICATION An English-language literature search using MEDLINE (1975 to 1988) and extensive bibliographic reviews of identified articles. STUDY SELECTION We reviewed the literature and selected 169 articles considered most relevant for the definition of the endocrinologic abnormalities, elucidation of pathogenic mechanisms, or delineation of therapeutic interventions. DATA EXTRACTION The authors independently assessed study quality and data concerning endocrinologic abnormalities, pathogenic mechanisms, and therapy of the polycystic ovary syndrome. RESULTS OF DATA SYNTHESIS The polycystic ovary syndrome may be best defined as functional, gonadotropin-dependent ovarian hyperandrogenism. The polycystic ovary syndrome results when a primary defect increases one of three variables: the ratio of the serum concentrations of luteinizing hormone to follicle stimulating hormone, the ratio of the intraovarian concentrations of androgen to estrogen, or follicular atresia. An increase in one of these variables can then induce successive abnormalities in one or more of the remaining two variables in a to-and-fro manner. CONCLUSIONS Evidence suggests that several causes exist, each of which can produce the clinical syndrome by a to-and-fro interaction among pathogenic mechanisms. Treatment objectives for the syndrome include amelioration of hirsutism, induction of ovulation, and weight reduction.

Mononuclear-cell immunisation in prevention of recurrent miscarriages: a randomised trial.

BACKGROUND Couples with unexplained recurrent miscarriage may have an alloimmune abnormality that prevents the mother from developing immune responses essential for the survival of the genetically foreign conceptus. Immunisation with paternal mononuclear cells is used as a treatment for such alloimmune-mediated pregnancy losses. However, the published results on this treatment are conflicting. In this study (the Recurrent Miscarriage [REMIS] Study), we investigated whether paternal mononuclear cell immunisation improves the rate of successful pregnancies. METHODS Women who had had three or more spontaneous abortions of unknown cause were enrolled in a double-blind, multicentre, randomised clinical trial. 91 were assigned immunisation with paternal mononuclear cells (treatment) and 92 immunisation with sterile saline (control). The primary outcomes were the inability to achieve pregnancy within 12 months of randomisation, or a pregnancy which terminated before 28 weeks of gestation (failure); and pregnancy of 28 or more weeks of gestation (success). Two analyses were done: one included all women (intention to treat), and the other included only those who became pregnant. FINDINGS Two women in each group received no treatment, and eight (three treatment, five control) were censored after an interim analysis. In the analysis of all randomised women who completed the trial, the success rate was 31/86 (36%) in the treatment group and 41/85 (48%) in the control group (odds ratio 0.60 [95% CI 0.33-1.12], p=0.108). In the analysis of pregnant women only, the corresponding success rates were 31/68 (46%) and 41/63 (65%; odds ratio 0.45 [0.22-0.91], p=0.026). The results were unchanged after adjustment for maternal age, number of previous miscarriages, and whether or not the couple had had a previous viable pregnancy. Similar results were obtained in a subgroup analysis of 133 couples with no previous livebirth. INTERPRETATION Immunisation with paternal mononuclear cells does not improve pregnancy outcome in women with unexplained recurrent miscarriage. This therapy should not be offered as a treatment for pregnancy loss.

Anterior Abdominal Wall Adhesions after Laparotomy or Laparoscopy

STUDY OBJECTIVE To determine the frequency of postoperative adhesions to the anterior abdominal wall peritoneum that could affect safe placement of the initial laparoscopic umbilical cannula at subsequent procedures. DESIGN Prospective cohort study. SETTING Reproductive endocrinology and infertility service of a tertiary care referral hospital. PATIENTS Two hundred fifteen women, 124 with prior abdominal surgery and 91 with no prior surgery. INTERVENTIONS Surgical histories were reviewed, abdominal skin scars noted, and extent of anterior abdominal wall adhesions prospectively recorded. Statistical analysis was performed with the chi2 test. MEASUREMENTS AND MAIN RESULTS No anterior abdominal wall adhesions were present in 91 patients with no previous surgery or 45 patients with previous laparoscopy (12 had more than 1 laparoscopy; p <0.001 vs laparotomy). Seventeen (59%) of 29 patients with a midline vertical incision had anterior wall adhesions (p <0.05 vs suprapubic transverse incision). Eleven (28%) of 39 with a suprapubic transverse incision had anterior wall adhesions (p <0.001 vs no surgery or laparoscopy). Ninety-six percent of adhesions involved omentum and 29% included bowel. CONCLUSION Prior laparotomy, whether through a midline vertical or suprapubic transverse incision, significantly increased the frequency of anterior abdominal wall adhesions, and these adhesions may complicate the placement of the laparoscopic cannula through the umbilicus.

Response to challenge with gonadotropin-releasing hormone agonist in a mother and her two sons with a constitutively activating mutation of the luteinizing hormone receptor--a clinical research center study

The pituitary-gonadal axis was evaluated in a mother after two of her sons with familial male-limited pseudoprecocious puberty were found to have a constitutively activating mutation of the LH receptor (LHR). Genotyping demonstrated that all showed a mutation in one of the two alleles, a substitution of Gly for Asp578 in the sixth transmembrane segment of the LHR. Ovarian function was normal in the 36-yr-old mother as assessed by LH dynamics and FSH and androgen levels throughout the menstrual cycle. Hormonal responses to acute GnRH agonist (nafarelin) challenge, chronic GnRH agonist administration, and dexamethasone were also normal. Studies of the boys upon presentation at 2.4 and 3.5 yr of age revealed that acute LH responses to nafarelin were in the hypogonadotropic range, and the FSH responses were prepubertal despite the presence of late pubertal testosterone blood levels. Upon the inception of true puberty at 11 yr of age in the older brother, gonadotropin responses normalized for the state of development. The data show that this activating LHR mutation does not cause functional ovarian hyperandrogenism and causes only incomplete pubertal activation of Leydig cells. The results are compatible with relatively low constitutive activity associated with this structural abnormality of LHR.

Relationship between peak serum estradiol levels and treatment outcome in in vitro fertilization cycles after embryo transfer on day 3 or day 5

OBJECTIVE To examine the relationships between peak serum estradiol (E(2)) levels and treatment outcome in in vitro fertilization (IVF) cycles after embryo transfer (ET) on day 3 or day 5. DESIGN Retrospective analysis of 697 IVF-ET cycles between January 1999 and December 2001. SETTING A university-affiliated assisted reproduction program. PATIENT(S) Infertile patients undergoing IVF-ET cycles. INTERVENTION(S) Peak E(2) concentration in serum was determined on the day of human chorionic gonadotropin (hCG) administration. The IVF-generated embryos were cultured for 2 days until transfer on day 3. If more than four 8-cell embryos were present on day 3, embryo culture was continued until day 5 for blastocyst transfer. MAIN OUTCOME MEASURE(S) Clinical pregnancy rates. RESULT(S) High peak E(2) levels did not adversely affect treatment outcome. After the cycles were divided according to the day of ET, high peak E(2) levels were associated with improved pregnancy rates after ET on day 5 but not on day 3. CONCLUSION(S) Increasing peak E(2) levels in IVF cycles are associated with improved pregnancy rates after ET on day 5.

The pathogenesis of polycystic ovary syndrome: Lessons from ovarian stimulation studies

In polycystic ovary syndrome (PCOS) the ovary produces markedly increased amounts of both androgens and estrogens in response to gonadotropin stimulation. Distinctive responses of 17-hydroxyprogesterone and androstenedione to ovarian stimulation testing suggest that ovarian hyperandrogenism is a result of dysregulation of theca cell androgen production which is intrinsic to the ovary. The occurrence of hyperestrogenism together with hyperandrogenism in PCOS suggests that whatever the abnormality of local regulatory factors of steroidogenesis, it affects granulosa as well as theca cells. Dysregulation is often associated with an increase in the number of follicles which evade atresia and reach the 2–8 mm stage of development. Autocrine/paracrine factors, especially those which are FSH-dependent, likely play an important role in the pathogenesis of the ovarian abnormality. Both LH and insulin hypersecretion probably play a secondary role in PCOS by amplifying the preexisting ovarian dysregulation. Because FSH secretion is under tight long-loop negative-feedback control and LH is not, hyperandrogenism is the primary clinical manifestation of dysregulation of steroid production in PCOS. However, anovulation in PCOS is most likely a result of excessive estrogen and inhibin production by multiple, small follicles which inhibit FSH secretory dynamics sufficiently to prevent selection of a dominant follicle.

Diagnosis and therapy of hyperandrogenism

Diagnostic categories in hyperandrogenism include polycystic ovary syndrome (PCOS) and its variants, adrenal and ovarian steroidogenic enzyme deficiencies, adrenal and ovarian androgen secreting tumours and other endocrine disorders such as hyperprolactinaemia, Cushing syndrome and acromegaly. About 95% of hyperandrogenic women will have PCOS. Endometrial hyperplasia can be prevented in hyperandrogenic, anovulatory women by the oral contraceptive pill or progestins. Hirsutism is best treated by a combination of the oral contraceptive pill and an anti-androgen. The first line of therapy for ovulation induction is clomiphene citrate, with human menopausal gonadotrophins (hMG) or laparoscopic ovulation induction reserved for clomiphene failures. hMG together with gonadotrophin-releasing hormone agonist may decrease the risk of spontaneous abortion following ovulation induction in PCOS. Weight loss should be vigorously encouraged to ameliorate the metabolic consequences of PCOS.