Eric S. Knochenhauer

Screening for 21-hydroxylase–deficient nonclassic adrenal hyperplasia among hyperandrogenic women: a prospective study

OBJECTIVE To prospectively establish the specificity, sensitivity, and positive predictive value (PPV) of a basal 17-hydroxyprogesterone (17-HP) level for the screening of 21-hydroxylase-deficient nonclassic adrenal hyperplasia (NCAH) among hyperandrogenic women. DESIGN Prospective observational trial. SETTING Tertiary care academic medical centers. PATIENT(S) Eight healthy controls, 20 patients with NCAH, and 284 consecutively seen patients with hyperandrogenism. INTERVENTION(S) All controls and patients with NCAH, and select patients with hyperandrogenism, underwent acute ACTH (1-24) stimulation. MAIN OUTCOME MEASURE(S) Specificity was determined by measuring 17-HP every other day during one menstrual cycle in 8 healthy women with normal ovulation (107 samples). Sensitivity was determined by measuring 17-HP between 7 and 9 A.M. and 3 and 5 P.M. on the same day in 20 patients with genetically confirmed NCAH. The PPV was determined by prospectively measuring 17-HP in 284 consecutively seen hyperandrogenic women at their initial evaluation. The diagnosis of NCAH was established by a stimulated 17-HP level of >10 ng/mL. RESULT(S) Among controls, 17-HP levels of <2, <3, and <4 ng/mL all had a specificity of 100% when obtained in the follicular phase; when obtained in the luteal phase, they had specificities of 53%, 82%, and 82%, respectively. Among patients with NCAH, 17-HP levels of >2, >3, and >4 ng/mL had sensitivities of 100%, 90%, and 90%, respectively, for the detection of the disorder when obtained in the morning, and sensitivities of 95%, 90%, and 85%, respectively, when obtained in the afternoon. Among the 284 consecutively seen hyperandrogenic women, the PPVs of the first and second 17-HP levels were 7.3% and 19% for a cutoff level of >2 ng/mL, 13% and 43% for a cutoff level of >3 ng/mL, and 33% and 40% for a cutoff level of >4 ng/mL, respectively. CONCLUSION(S) A basal 17-HP level is a useful screening tool for NCAH. A cutoff level of 4 ng/mL has maximum specificity and PPV, with little loss in sensitivity if testing is performed in the morning and during the follicular phase. However, a lower cutoff level (e.g., 2 or 3 ng/mL) is preferable if testing is performed at odd hours of the day, as is common in many practices, and maximum sensitivity is desired.

Adrenal androgen excess in hyperandrogenism: relation to age and body mass

OBJECTIVE To determine whether DHEAS levels in hyperandrogenic (HA) women retain the normal age-related decrease. DESIGN Prospective study. SETTING Academic tertiary care medical center. PATIENT(S) One hundred forty-five HA patients with hirsutism and/or oligo-ovulation and 53 healthy women. INTERVENTION(S) Blood samples were obtained on days 3-8 of the menstrual cycle or after an IM progesterone-induced withdrawal bleed. MAIN OUTCOME MEASURE(S) Serum samples were assayed for progesterone, total testosterone, sex hormone-binding globulin, free testosterone, and DHEAS. RESULT(S) Controls and HA patients were similar in body mass index and age. A negative correlation between DHEAS levels and age, but not body mass index, was found among controls. In HA patients. DHEAS levels decreased with age. Dehydroepiandrosterone sulfate levels correlated with the hirsutism score in HA patients. When HA patients were subdivided into those with low, middle, and high DHEAS levels, those with low DHEAS levels were older and weighed more than those with high DHEAS levels. CONCLUSION(S) The negative association between DHEAS levels and age is preserved in HA women. Hyperandrogenic patients with high DHEAS levels are younger, thinner, and more hirsute than those with lower DHEAS levels. These findings suggest that the diagnosis of adrenal androgen excess in HA patients may require the use of age-adjusted normative values.

Advances in the diagnosis and treatment of the hirsute patient.

Most patients with hirsutism demonstrate hyperandrogenemia, which may be caused by polycystic ovary syndrome, nonclassic congenital adrenal hyperplasia, insulin resistance and, occasionally, neoplasms. In this review, current methods of diagnosis and recent advances in the medical treatment of hirsutism and hyperandrogenemia are discussed, including the use of gonadotropin-releasing hormone analogs, flutamide, spironolactone, finasteride, and ketoconazole.

Examination of the chin or lower abdomen only for the prediction of hirsutism.

OBJECTIVE To test the hypothesis that scoring terminal hair growth on only the chin or abdomen can serve as a reliable predictor for hirsutism. DESIGN A prospective observational study. PATIENT(S) Six hundred and ninety-five consecutive hyperandrogenic women seen between June 1987 and December 1997. MAIN OUTCOME MEASURE(S) All hirsutism exams were performed by one examiner. Hirsutism was scored using a modification of the Ferriman-Gallwey (F-G) method. An F-G score of > or = 8 defined hirsutism. RESULT(S) Of the 695 women examined 352 (50.1%) had hirsutism scores of 8. Thirty percent (79 of 344) of women who had an F-G score of <8 had previously underwent electrology. If either the chin or lower abdomen hair growth score was > or = 2, the sensitivity was 100% for the prediction of hirsutism, although the specificity was 27%. The positive predictive value (PPV) for hirsutism using a hair score of > or = 2 at either of these sites was 58%. CONCLUSION(S) A hair growth score of > or = 2 on the chin or lower abdomen only was found to be a highly sensitive predictor for hirsutism. However, because of its very low PPV, this screening method is virtually useless in populations where the hirsutism frequency is expected to be low, about 5%. However, this screening method for the detection of hirsutism would be useful for the study of high-risk populations with an expected hirsutism prevalence of >20% (e.g., family studies).

Adrenocortical hyperresponsivity to adrenocorticotropic hormone: a mechanism favoring the normal production of cortisol in 21-hydroxylase-deficient nonclassic adrenal hyperplasia

OBJECTIVE To test the hypothesis that patients with nonclassic adrenal hyperplasia (NCAH) exhibit a generalized exaggeration in their response to ACTH stimulation that favors the normal production of F. Patients with 21-hydroxylase (21-OH)-deficient NCAH do not demonstrate cortisol (F) deficiency. DESIGN Prospective controlled study. SETTING Tertiary university clinic. PATIENT(S) Twenty-four untreated patients with NCAH diagnosed by a 17 alpha-hydroxyprogesterone (17-HP) level of >30.3 nmol/L (>10 ng/mL), and 37 age- and body mass-matched healthy eumenorrheic nonhirsute controls. INTERVENTION(S) All study subjects underwent a 60 minute acute stimulation using 0.25 mg of ACTH-(1-24) i.v. MAIN OUTCOME MEASURE(S) Basal and stimulated serum levels of pregnenolone (PREG), 17-hydroxypregnenolone (17-HPREG), dehydroepiandrosterone (DHA), progesterone (P4), 17-HP, androstenedione (A4), 11-deoxycortisol (S), and cortisol (F). RESULT(S) The median basal (i.e., Steroid(0)) or ACTH-stimulated (i. e., Steroid(60)) serum levels of PREG, 17-HPREG, DHA, P4, 17-HP, A4 and, most importantly, S were higher in NCAH patients than in controls. In contrast, the levels of F at either 0 minute or 60 minutes of stimulation were similar between NCAH and control women. The proportion of NCAH patients with stimulated steroids levels of >the 95th percentile of controls were as follows: 84.21% for PREG(60), 87.5% for 17-HPREG(60), 95.8% for DHA(60), 89.5% for P4(60), 100% for 17-HP(60), 91.7% for A4(60), 29.2% for S(60), and 4. 1% for F(60). CONCLUSION(S) A generalized adrenocortical hyperresponsivity to ACTH stimulation seems to be present in patients with 21-OH-deficient NCAH, with an exaggerated production of S evident in approximately 30%. The excess production of S in these NCAH patients may, in part, account for their normal F production.

11β-hydroxyandrostenedione and δ5-androstenediol as markers of adrenal androgen production in patients with 21-hydroxylase–deficient nonclassic adrenal hyperplasia

OBJECTIVE To determine the sensitivity of 11beta-hydroxyandrostenedione (11-OHA4) and delta5-androstenediol (ADIOL) as markers of excessive adrenal androgen production. DESIGN Prospective study. SETTING Academic medical centers. PATIENT(S) Thirteen women with untreated 21-hydroxylase-deficient nonclassic adrenal hyperplasia (NCAH) and 18 healthy, eumenorrheic, nonhirsute controls matched for age and body mass index. INTERVENTION(S) All subjects were studied before and after acute adrenal stimulation with 0.25 mg of IV ACTH-(1-24). MAIN OUTCOME MEASURE(S) Basal levels of total testosterone, sex hormone-binding globulin, DHEAS, and free testosterone were measured. Levels of androstenedione (A4), DHEA, 11-OHA4, and ADIOL were determined before (Steroid0) and 60 minutes after (Steroid60) acute ACTH-(1-24) stimulation. RESULT(S) Patients with NCAH had higher median basal levels of DHEAS and total and free testosterone than controls. Patients with NCAH had higher median A4(0), A460, DHEA(0), DHEA60, 11-OHA4(0), ADIOL0, and ADIOL60 levels but similar 11-OHA4(60) levels compared with controls. Among patients with NCAH, 30%, 54%, 15%, and 85% had 11-OHA4(0), ADIOL0, 11-OHA4(60), and ADIOL(60) levels, respectively, above the 95th percentile of controls. CONCLUSION(S) Overall, serum levels of 11-OHA4 did not appear to be a very sensitive marker of excessive adrenal androgen production, at least in patients with NCAH. Although ACTH-stimulated ADIOL levels were elevated in 85% of the patients studied, they did not appear to have any advantage over the measurement of A4 or DHEA levels.

Early adrenarche in normal prepubertal girls: A prospective longitudinal study

OBJECTIVE To study basal and ACTH stimulated levels of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione (A4), and cortisol (F) in healthy girls during prepuberty. PATIENTS Six prepubertal girls, ages 3.7-10.9 years. STUDY DESIGN AND MEASUREMENTS The six girls underwent a physical examination and an acute ACTH stimulation test on a yearly basis. Serum DHEA, DHEAS, A4, and F at 0 min (Steroid0) and 60 min (Steroid60) after 0.25 mg ACTH1-24 i.v., and the net increment (delta Steroid60-0) were calculated. RESULTS DHEAS0, DHEAS60, DHEA0, DHEA60 and A40 were positively correlated to chronological age. DHEAS0 and DHEAS60 levels rose gradually beginning at 6.1-7.0 years of chronological age, and were found to be significantly different at 9.1-10.0 years and 10.1-11.0 years of age, compared to the median values obtained at < or =6.0 years of age. There was a tendency for DHEA0, DHEA60, and A40 to increase beginning at 9.1-10.0 years of age. Net increment values of all hormones did not change throughout the study. CONCLUSION An increase in the circulating level of DHEAS appears to be the first event observed during adrenarche, prior to clinical evidence of the process.

Subcutaneously administered repronex® in oligoovulatory female patients undergoing ovulation induction is as effective and well tolerated as intramuscular human menopausal gonadotropin treatment

OBJECTIVE To determine the efficacy and safety of Repronex SC as compared with Repronex IM and Pergonal IM in patients undergoing ovulation induction. DESIGN Randomized, open-label, multicenter, parallel group study. SETTING Ten academic and private fertility clinics with expertise in ovualtion induction. PATIENT(S) Premenopausal anovulatory and oligoovulatory females (n = 115) undergoing ovulation induction. INTERVENTION(S) Down-regulation with leuprolide acetate followed by up to 12 days of treatment with gonadotropins and hCG administration and luteal phase progesterone support. MAIN OUTCOME MEASURE(S) Percentage of patients ovulating; percentage of cycles with follicular development meeting criteria for hCG administration; number of follicles recruited per cycle meeting hCG criteria; peak serum E(2) levels; rates of chemical, clinical and ongoing pregnancies; adverse events; injection-site pain scores. RESULT(S) There was no statistically significant difference in the percentage of women who ovulated among the treatment groups. However, Repronex SC was significantly more effective than Pergonal IM in producing follicular development in patients who met hCG criteria. There were no significant differences in clinical, ongoing, or continuing pregnancy rates or in multiple pregnancies among the treatment groups. No differences were found in the safety assessments, proportions or seriousness of adverse events or treatment discontinuations. Also, there were no differences between the three treatment groups in patient-recorded scores of injection-site pain or injection-site reactions. CONCLUSION(S) Repronex SC is as efficacious and well tolerated as Repronex IM or Pergonal IM in ovulation induction. Self-administration of Repronex SC provides a convenient treatment alternative to daily IM injections.

The presence of multiple gestational sacs confers a higher live birth rate in women with infertility who achieve a positive pregnancy test after fresh and frozen embryo transfer: a retrospective local cohort

BackgroundAfter spontaneous conception, the rate of miscarriage is more common in multiple rather than singleton pregnancies. However, the incidence of miscarriage is lower in in-vitro fertilization twin versus singleton pregnancies. Most patients have little understanding of pregnancy outcomes once they achieve a positive pregnancy test. This study investigated the relationship between multiple pregnancy and miscarriage in women with infertility after fresh and frozen embryo transfer.MethodsRetrospective local cohort study of all consecutive patients undergoing in-vitro fertilization at our institution (n = 1130), fresh or frozen embryo transfer, between January 1, 2008 and December 31, 2012. Patient characteristics (age, body mass index, initial hCG, maximum follicle stimulating hormone levels) and in-vitro fertilization parameters (estradiol levels, eggs retrieved, and endometrial thickness) were collected and statistically analyzed using T-test and Chi-square test (Stata version 10). Linear and logistic regression were used when appropriate.ResultsOverall, live birth rate for all cycles was 30.44% and total pregnancy loss was 6.55% - similar for fresh and frozen cycles despite a higher rate of biochemical pregnancies for frozen cycles. Among all pregnant patients, 62.48% had a live birth. Although clinical pregnancy rate was higher for fresh cycles, live birth rates were similar. In pregnancies where multiple sacs were demonstrated on ultrasound, live birth rates were higher despite 31% of patients losing at least one sac. This finding was comparable between fresh and frozen cycles. However, in patients under age 35 and using donor egg, no live birth advantage was seen in patients with multiple sacs. In fact, transferring more than one embryo did not increase live birth rate either.ConclusionsDespite the many maternal and fetal risks of multiple pregnancies, patients who achieve a positive pregnancy test with fresh and frozen in-vitro fertilization and who have more than one pregnancy sac are more likely ultimately to deliver at least one baby. This finding is true of both fresh and frozen embryo transfer cycles. This pregnancy advantage is not seen in young patients and in patients using donor egg, and single embryo transfer maximizes birth outcomes.

Live birth of a normal mature healthy baby by in vitro fertilization-embryo transfer (IVF-ET) after an exploratory laparotomy and multiple myomectomy for leiomyomatosis peritonealis disseminata

OBJECTIVE To report a case of a live birth of a normal mature healthy baby by IVF-ET after an exploratory laparotomy and multiple myomectomy for leiomyomatosis peritonealis disseminata. DESIGN Case report. SETTING Academic university hospital. PATIENT(S) A 37-year-old female G2P0 with secondary infertility diagnosed with leiomyomatosis peritonealis disseminata who underwent surgical resection and IVF stimulation. INTERVENTION(S) One cycle of IVF-ET initiated with Gonal F and Menopur. MAIN OUTCOME MEASURE(S) Live birth of a normal mature healthy baby. CONCLUSION(S) IVF-ET can produce a normal healthy baby in a patient with leiomyomatosis peritonealis disseminata.