Clustering of PCOS-like traits in naturally hyperandrogenic female rhesus monkeys.

Study question: Do naturally occurring, hyperandrogenic (≥1 SD of population mean testosterone, T) female rhesus monkeys exhibit traits typical of women with polycystic ovary syndrome (PCOS)? Summary answer: Hyperandrogenic female monkeys exhibited significantly increased serum levels of androstenedione (A4), 17-hydroxyprogesterone (17-OHP), estradiol (E2), LH, antimullerian hormone (AMH), cortisol, 11-deoxycortisol and corticosterone, as well as increased uterine endometrial thickness and evidence of reduced fertility, all traits associated with PCOS. What is known already: Progress in treating women with PCOS is limited by incomplete knowledge of its pathogenesis and the absence of naturally occurring PCOS in animal models. A female macaque monkey, however, with naturally occurring hyperandrogenism, anovulation and polyfollicular ovaries, accompanied by insulin resistance, increased adiposity and endometrial hyperplasia, suggests naturally occurring origins for PCOS in nonhuman primates. Study design, size, duration: As part of a larger study, circulating serum concentrations of selected pituitary, ovarian and adrenal hormones, together with fasted insulin and glucose levels, were determined in a single, morning blood sample obtained from 120 apparently healthy, ovary-intact, adult female rhesus monkeys (Macaca mulatta) while not pregnant or nursing. The monkeys were then sedated for somatometric and ultrasonographic measurements. Participants/materials, setting, methods: Female monkeys were of prime reproductive age (7.2 ± 0.1 years, mean ± SEM) and represented a typical spectrum of adult body weight (7.4 ± 0.2 kg; maximum 12.5, minimum 4.6 kg). Females were defined as having normal (n = 99) or high T levels (n = 21; ≥1 SD above the overall mean, 0.31 ng/ml). Electronic health records provided menstrual and fecundity histories. Steroid hormones were determined by tandem LC-MS-MS; AMH was measured by enzymeimmunoassay; LH, FSH and insulin were determined by radioimmunoassay; and glucose was read by glucose meter. Most analyses were limited to 80 females (60 normal T, 20 high T) in the follicular phase of a menstrual cycle or anovulatory period (serum progesterone <1 ng/ml). Main results and the role of chance: Of 80 monkeys, 15% (n = 12) exhibited classifiable PCOS-like phenotypes. High T females demonstrated elevations in serum levels of LH (P < 0.036), AMH (P < 0.021), A4 (P < 0.0001), 17-OHP (P < 0.008), E2 (P < 0.023), glucocorticoids (P < 0.02-0.0001), the serum T/E2 ratio (P < 0.03) and uterine endometrial thickness (P < 0.014) compared to normal T females. Within the high T group alone, anogenital distance, a biomarker for fetal T exposure, positively correlated (P < 0.015) with serum A4 levels, while clitoral volume, a biomarker for prior T exposure, positively correlated (P < 0.002) with postnatal age. Only high T females demonstrated positive correlations between serum LH, and both T and A4. Five of six (83%) high T females with serum T ≥2 SD above T mean (0.41 ng/ml) did not produce live offspring. Large scale data: N/A. Limitations, reasons for caution: This is an initial study of a single laboratory population in a single nonhuman primate species. While two biomarkers suggest lifelong hyperandrogenism, phenotypic expression during gestation, prepuberty, adolescence, mid-to-late reproductive years and postmenopause has yet to be determined. Wider implications of the findings: Characterizing adult female monkeys with naturally occurring hyperandrogenism has identified individuals with high LH and AMH combined with infertility, suggesting developmental linkage among traits with endemic origins beyond humans. PCOS may thus be an ancient phenotype, as previously proposed, with a definable pathogenic mechanism(s). Study funding/competing interest(s): Funded by competitive supplement to P51 OD011106 (PI: Mallick), by P50 HD028934 (PI: Marshall) and by P50 HD044405 (PI: Dunaif). The authors have no potential conflicts of interest.

Relationship between 17-alpha hydroxyprogesterone caproate concentration and spontaneous preterm birth.

OBJECTIVE: 17-alpha hydroxyprogesterone caproate 250 mg weekly reduces recurrent spontaneous preterm birth in women with a prior spontaneous preterm birth by 33%. The dose is not based on pharmacologic considerations. A therapeutic concentration has not been determined hampering any attempt to optimize treatment. This study evaluated the relationship between 17-alpha hydroxyprogesterone caproate plasma concentrations and the rate of spontaneous preterm birth in women with singleton gestation. STUDY DESIGN: A single blood sample was obtained between 25 and 28 weeks' gestation from 315 women with a spontaneous preterm birth who participated in a placebo-controlled, prospective, randomized clinical trial evaluating the benefit of omega-3 supplementation in reducing preterm birth. All women in the parent study received 17-alpha hydroxyprogesterone caproate and 434 received omega-3 supplementation and 418 received a placebo. Plasma from 315 consenting women was analyzed for 17-alpha hydroxyprogesterone caproate concentration. RESULTS: There were no differences between placebo and omega-3 supplemented groups in demographic variables, outcomes or in mean 17-alpha hydroxyprogesterone caproate concentration. Plasma concentrations of 17-alpha hydroxyprogesterone caproate ranged from 3.7-56 ng/mL. Women with plasma concentrations of 17-alpha hydroxyprogesterone caproate in the lowest quartile had a significantly higher risk of spontaneous preterm birth (P = .03) and delivered at significantly earlier gestational ages (P = .002) than did women in the second to fourth quartiles. The lowest preterm birth rates were seen when median 17-alpha hydroxyprogesterone caproate concentrations exceeded 6.4 ng/mL. CONCLUSION: Low plasma 17-alpha hydroxyprogesterone caproate concentration is associated with an increased risk of spontaneous preterm birth. This finding validates efficacy of this treatment but suggests that additional studies are needed to determine the optimal dosage.

Adrenocortical adenoma associated with inadequately treated congenital adrenal hyperplasia.

We report a 6 year-old boy with the simple virilizing form of 21-hydroxylase deficiency in whom an adrenal adenoma developed following 5 years of steroid treatment. Extremely high levels of basal serum 17alpha-hydroxyprogesterone as well as an exaggerated response of 17alpha-hydroxyprogesterone to adrenocorticotropic hormone confirmed congenital adrenal hyperplasia at 7 years of age. Initially elevated serum steroid levels were restrained by high dose hydrocortisone therapy, but he chronically tended to take inadequate doses of glucocorticoid. At 12 years of age an adenoma was found in the cortex of the hyperplastic right adrenal gland. The importance of early diagnosis and compliance with medication in the simple virilizing form of 21-hydroxylase deficiency is stressed.

Reproductive efficiency and maternal-offspring transfer of gossypol in rainbow trout (Oncorhynchus mykiss) fed diets containing cottonseed meal.

In a preceding study, complete substitution of fish meal protein with cottonseed meal (CM) protein did not affect the survival or growth rate of adult rainbow trout over a 6-mo period. Gossypol, a naturally occurring compound in cottonseeds, has an antifertility effect in terrestrial animals, but information regarding salmonid fish is lacking. Female rainbow trout in this experiment were fed diets with either 0, 25, 50, 75, or 100% (diets 1 to 5) of the fish meal protein replaced with CM protein until first maturation and spawning to study long-term effects on growth and reproduction. Feeding diets containing CM over a total period of 10 mo did not result in differences in growth and mortality compared to the control group (P > 0.05). Increased CM incorporation levels resulted in decreased (P < 0.05) blood hemoglobin (10.6 +/- 1.3, 8.4 +/- 1.8, 7.3 +/- 1.1, 6.9 +/- 0.8, and 5.6 +/- 1.4 g/dL) and hematocrit (49.6 +/- 3.9, 38.5 +/- 9.3, 34.4 +/- 3.7, 34.8 +/- 4.9 and 28.0 +/- 6.8%) levels in diets 1 to 5, respectively. The CM incorporation level had no effect (P > 0.05) on the number of eggs produced per female but led to a reduction (P < 0.05) in egg weight. Eyed stage survival of embryos was low in all dietary groups and did not show differences (P > 0.05). However, an increasing CM incorporation level led to a linear increase (P < 0.05) in the number of females that produced no viable embryos (23.1, 37.5, 42.9, 60.0, and 71.4%). Gossypol in the diet was absorbed by the female trout and transferred to the eggs (0, 2.2 +/- 0.5, 6.7 +/- 1.6, 10.6 +/- 4.2, and 20.0 +/- 2.6 micrograms/g in diets 1 to 5, respectively). A high concentration of gossypol remained in the juveniles at the swim-up stage (endogenous yolk-absorbed) (0.6 +/- 0.3, 2.4 +/- 0.3, 3.4 +/- 0.0, and 4.7 +/- 1.0 micrograms/g, diets 2 to 5, respectively). The findings suggest that replacement of the dietary fish meal protein with CM protein has no effect on fish growth and mortality but may lead to a reduction in reproductive performance in female rainbow trout.

Changes in androgens during treatment with four low-dose contraceptives.

The aim of the present study was to compare changes in the endogenous androgen environment in healthy women while on low-dose oral contraceptives (OCs). One-hundred healthy women were randomized to receive one of four OCs during six months: 21 tablets of Cilest, Femodeen, Marvelon, or Mercilon. During the luteal phase of the pretreatment cycle, body weight and blood pressure were recorded and the following parameters were measured: sex hormone-binding globulin (SHBG), corticosteroid-binding globulin (CBG), testosterone (T), free testosterone (FT), 5 alpha-dihydrotestosterone (DHT), androstenedione (A), dehydroepiandrosterone-sulphate (DHEA-S) and 17 alpha-hydroxyprogesterone (170HP) while also the free androgen index (FAI) was calculated. Measurements were repeated during the 3rd week of pill intake in the 4th and the 6th pill month. There were no differences on body mass and blood pressure with the use of the four OCs. The mean serum DHEA-S decreased significantly in all groups though less in the Mercilon group when compared to Cilest and Marvelon (approximately 20% vs 45%). Mean serum SHBG and CBG increased significantly in all four groups approximately 250% and 100%, respectively. In each group CBG also increased significantly but less in women taking Mercilon (-75%) as compared to the others (-100%). Current low-dose OCs were found to have similar impact on the endogenous androgen metabolism with significant decreases of serum testosterone, DHT, A, and DHEA-S. They may be equally beneficial in women with androgen related syndromes such as acne and hirsutism.

PIP: Health researchers randomly assigned 100 healthy women aged 18-38 from the Netherlands and Saudi Arabia to one of four various oral contraceptive (OC) groups to undergo six cycles of OC therapy so they could evaluate changes in plasma concentrations of sex hormone binding globulin (SHBG), corticosteroid-binding globulin (CBG), albumin (Alb), testosterone (T), free testosterone (FT), dihydrotestosterone (DHT), androstenedione (A), dehydro-epiandrosterone-sulphate (DHEA-S), and 17 alpha-hydroxyprogesterone (17OHP). The four monophasic OCs were Cilest (35 mcg ethinyl estradiol [E2] and 250 mcg norgestimate), Femodeen (30 mcg E2 and 75 mcg gestodene), Marvelon (30 mcg E2 and 150 mcg desogestrel), and Mercilon (20 mcg E2 and 150 mcg desogestrel). There were 12 dropouts. Neither body weight nor blood pressure changed significantly during the study. All steroidal serum parameters (T, FT, DHT, A, DHEA-S, 17OHP, Alb) fell significantly during the six cycles of OC treatment (ratio of decrease, 1.3-3), regardless of OC type. These changes had appeared after cycle 4. The only significant difference between the OC groups was that the mean decrease of DHEA-S for Mercilon was lower than that for the other OC groups (21% vs. 43% for Cilest, 44% for Marvelon, and 34% for Femodeen; p 0.05). SHBG and CBG rose greatly during OC use in all four OC groups (mean increase = 263% and 94%, respectively; p 0.05). The increase in CBG was significantly less in the Mercilon group than in the other OC groups (74% vs. 96% for Cilest, 101% for Femodeen, and 102% for Marvelon; p 0.05). These findings show that OC use changed the endogenous androgen environment in the direction of hypoandrogenism. Thus, all four OCs can equally treat androgen-related syndromes (e.g., acne and hirsutism).

Hypothalamo-pituitary-adrenal function in human immunodeficiency virus-infected men.

We prospectively studied adrenal function in 51 human immunodeficiency virus-positive male patients, including heterosexuals, homosexuals, and iv drug users, classified according to 1987 CDC criteria as belonging to stages II/III or IVC. Basal serum concentrations of cortisol (F), progesterone (P4) and 17 alpha-hydroxyprogesterone (17 alpha-OHP4) were determined during the two stages. In stage IVC patients, the circadian rhythms of ACTH and F were assessed, and ovine CRH (oCRH) and immediate cosyntropin-stimulating tests were evaluated. Serum concentrations of hormones were analyzed in relationship to the absolute CD4 cell count in all subjects. The mean serum F concentration in stage IVC patients, the mean P4 concentration in stage II/III and IVC patients, and the mean 17 alpha-OHP4 level in stage II/III patients were significantly increased compared to control values (P < 0.0001, P < 0.0001, and P < 0.002, respectively). The mean serum F concentration in stage IVC patients was significantly increased compared to that in stage II/III patients (P < 0.004), and the mean serum 17 alpha-OHP4 concentration in stage II/III patients was significantly increased compared to that in stage IVC patients (P < 0.02). In the 22 stage IVC patients, the circadian rhythms of ACTH and F were normal in all but 7 for ACTH and 5 for F, whereas oCRH test results indicated that 14 of them had reduced or blunted responses. By contrast, cosyntropin stimulation results were normal. CD4 cell counts were significantly negatively correlated with the serum F concentration (P < 0.02). In conclusion, during human immunodeficiency virus infection, the serum F concentration was negatively correlated with CD4 cell counts. Cosyntropin test results were normal, but 63% of the stage IVC men had abnormal responses to oCRH.

Abnormalities of endocrine function in patients with clinically "silent" adrenal masses.

Because, in recent years, patients with incidentally discovered adrenal masses have been encountered increasingly, their endocrine function was investigated in basal conditions and after dynamic tests. Thirty-two patients (23 women and 9 men, aged 28-74 years) were studied. Lesion diameter, as documented by computed tomography and/or nuclear magnetic resonance imaging, ranged between 5 and 65 mm; the tumors were localized on the right in 22 patients, on the left in 5 and bilaterally in 5 cases. In basal conditions, urinary free cortisol (UFC) excretion, plasma adrenocorticotropin (ACTH) and cortisol levels were normal, except for 4 patients who showed high UFC and ACTH levels in the low-normal range. Ovine corticotropin-releasing hormone (CRH, 1 microgram/kg iv) was given to 18 patients, inducing normal ACTH and cortisol responses in 12, blunted responses in 4 and no response in 2 cases. No reduction in ACTH and cortisol levels after suppression tests was observed in 4 of 29 patients after dexamethasone (1 mg overnight) or in 6 of 29 after loperamide. The 4 patients who were unresponsive to both tests did not show any further inhibition after high-dose dexamethasone administration, had low plasma ACTH levels and showed impaired or absent responses to the CRH test: they were diagnosed as affected with preclinical Cushing's syndrome. An exogenous ACTH test performed in 30 patients caused a normal cortisol rise. Basal mean 17-hydroxy-progesterone (17-OHP) levels were not different from those in normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Specificity of low dose fadrozole hydrochloride (CGS 16949A) as an aromatase inhibitor.

CGS 16949A (fadrozole hydrochloride), a potent cytochrome P450-mediated steroidogenesis inhibitor, blocks aromatase at low doses, but other biosynthetic steps at higher concentrations. Recent studies demonstrated inhibition of C11-hydroxylase, corticosterone methyloxidase-II, and deoxycorticosterone to corticosterone conversion with this agent at some-what higher concentrations than those required for blockade of aromatase. Based upon phase I studies, we postulated that relatively selective inhibition of aromatase might be possible if sufficiently low doses of CGS 16949A were used. A phase II study in 54 postmenopausal women with metastatic breast cancer examined the effects of low dose CGS 16949A on estrogen, mineralocorticoid, and glucocorticoid secretion. Two dose schedules and two dose levels were chosen based upon our prior dose escalation protocol study. Plasma estrone, estradiol, and estrone sulfate as well as urinary estrone and estradiol fell equally with 1.8-4 mg CGS 16949A given either on a twice daily or three times daily dose schedule. Isotopic kinetic studies demonstrated an 84% decrease in the rate of conversion of androstenedione to estrone to 0.40 +/- 0.07% (patients receiving 1.8-4 mg CGS 16949A daily). With these three regimens, basal levels of aldosterone and cortisol did not change significantly over a 12-week period of observation. Clinical examination, plasma electrolytes, and urinary sodium/potassium ratios suggested no biological evidence of mineralo-corticoid deficiency. ACTH-stimulated cortisol concentrations, however, were blunted at each dose level compared to pretreatment values. Nonetheless, peak responses exceeded 550 nmol/L, or a basal to peak difference of 190 nmol/L or greater, in 97% of instances. This probably reflected inhibition of C11-hydroxylase, since basal and ACTH-stimulated levels of 11-deoxycortisol were increased in response to CGS 16949A. Androstenedione and 17 alpha-hydroxyprogesterone also exhibited an upward trend in response to drug treatment. ACTH-stimulated aldosterone levels were blunted to a greater extent than those of cortisol, probably as a reflection of corticosterone methyloxidase type II blockade. Overall, the results suggest that CGS 16949A, at doses of 1.8-2 mg daily, blocks aromatase effectively and does not produce clinically important inhibition of cortisol or aldosterone biosynthesis. Thus, this agent can probably be used safely without glucocorticoid or mineralocorticoid supplementation.

[A change in substitution therapy in patients with congenital adrenogenital syndrome within the scope of surgical interventions]. / Untersuchungen zur Anderung der Substitutionstherapie bei Patientinnen mit kongenitalem Adrenogenitalem Syndrom (AGS) im Rahmen operativer Eingriffe.

Stress response during genital surgery was investigated in 18 female patients with CAH. Changes were studied in blood pH and base excess, in serum concentrations of sodium- and potassium ions, in concentrations of 17 OHP in serum and saliva. The following conclusions may be drawn: On the day of operation patients should receive 100 mg Prednisolut per square metre of body surface area i.v., divided in three doses. On postoperative days 1 and 2 the 4 to 6 fold, on postoperative days 3 and 4 the 2 to 3 fold amounts of supplementary doses of hydrocortisone should be administered. Fludrocortisone is substituted with 3-5 mg DCA i.m. only on the day of operation. It is convenient to use a half-isotonic solution of electrolytes with 5% glucose for the infusion therapy. A dose of 25-50 mg Prednisolut i.v. can be added to the substitution therapy before short diagnostic and therapeutic procedures with or without anaesthesia such as endoscopy or change of bandage. Radenarcon (etomidate), used for induction of anesthesia, is contraindicated in patients with CAH.

[Changes in plasma levels of androgens and SHBG in patients with polycystic ovary syndrome (PCOs) treated with oral contraceptives containing desogestrel]. / Modificazione dei livelli plasmatici degli androgeni e della SHBG in pazienti con sindrome dell'ovaio policistico (PCOs) trattate con contraccettivi orali contenenti desogestrel.

PIP: 8 women, aged 17-25, with polycystic ovary syndrome (PCO) were treated with Practil 21 (Organon) containing 30 mcg of ethinyl estradiol and 150 mcg of desogestrel, or with Planum (Menarini). Checkups were conducted 3 and 6 months later to measure hormone levels. The average level of testosterone dropped significantly from 121.5 (+ or - 50.9) ng/dl to 23.1 (+ or - 10.6) ng/dl after 3 months. The level of androstenedione also decreased significantly from 265.2 (+ or - 101.4) ng.dl to 96.7 (+ or - 22.5) ng/dl. Similarly, the level of 17-hydroxyprogesterone declined from 120.5 (+ or - 69.8) ng/dl to 24.5 (+ or - 10.7) ng/dl . On the other hand, the level of sex hormone binding globulin rose from 1.3 (+ or - .6) mcg/100 ml to 3.9 (+ or - 1.8) mcg/100 ml. Cortisone level increased significantly from 15 (+ or - 3.2) mcg/100 ml to 30.6 (+ or - 10.4) mcg/100 ml after 3 months, but the normal range (5-20 mcg/100 ml) was attained at the end. Ecographic evaluation of the size of the ovaries indicated a 18.2-66.5% reduction after 3 months. In 3 cases, the number and dimension of follicles also diminished conspicuously. Acne, hirsutism, and other symptoms of hyperandrogenism also declined. Side effects were minor and included slight weight gain, spotting and headache; treatment was suspended in only 1 case because of a grand mal seizure. The administration of this new monophasic OC proved to be a valid alternative therapy for PCO.^ieng

High dose ketoconazole: endocrine and therapeutic effects in postmenopausal breast cancer.

Ketoconazole, an antifungal agent, inhibits in vitro C17-C20 lyase, an enzyme involved in androgen biosynthesis. Since adrenal and ovarian androgens are the main precursors of oestrogens in postmenopausal women, the endocrine and therapeutic effects of high dose ketoconazole (400 mg three times a day) were evaluated in 14 postmenopausal women with advanced breast cancer. Testosterone levels were suppressed significantly (37%, P less than 0.025), as was dehydroepiandrosterone sulphate, and androstenedione levels showed a similar but non-significant fall. Seventeen hydroxyprogesterone levels rose significantly, as would be expected if C17-C20 lyase was inhibited. There was no suppression of cortisol or oestrone levels. There was a small suppression of oestradiol concentrations, reflecting a decrease in its precursor, testosterone. Sex hormone binding globulin levels rose, which may be due to a decrease in testosterone. All the changes are compatible with C17-C20 lyase as a major site of action in vivo. No responses occurred in 12 patients treated with ketoconazole alone, but in 2 patients who were progressing on aminoglutethimide, testosterone levels were suppressed and in one patient a partial response occurred. Ketoconazole was poorly tolerated due to gastrointestinal toxicity. This study shows that C17-C20 lyase is a potential target for hormone therapy, and that sequential blockade of enzymes involved in oestrogen biosynthesis should be further evaluated.

Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

The need for a reliable screening test for classical congenital adrenal hyperplasia prompted development of newborn screening programs. Worldwide incidence of classical congenital adrenal hyperplasia in this report was taken from newborn screening programs in France, Italy, Japan, New Zealand, Scotland, and the United States. Two populations in which the occurrence of congenital adrenal hyperplasia among live births has been reported with greater than usual frequency are the Yupik Eskimos of southwestern Alaska (1:282) and the people of La Reunion, France (1:2,141). Aside from these populations, 1,093,310 newborns were screened between 1980 and 1988, of whom 77 had congenital adrenal hyperplasia. Thus, worldwide incidence of this disorder was estimated at 1:14,199 live births for homozygous patients, 1:60 for heterozygous subjects, with a gene frequency of 0.0083. Incidence of congenital adrenal hyperplasia among whites was estimated to be 1:11,909 (41:488,279) for homozygous patients, 1:55 for heterozygous subjects with a gene frequency of 0.0091. Incidence for the salt-wasting form of congenital adrenal hyperplasia was 1:18,850 (58:1,093,310) compared with 1:57,543 (19:1,093,310) for congenital adrenal hyperplasia in the simple virilizing form. Thus, salt-wasting congenital adrenal hyperplasia was three times more common than simple virilizing congenital adrenal hyperplasia. Estimated incidence of congenital adrenal hyperplasia in white populations in Italy and France (1:10,866) was higher than in Scotland (1:17,098), New Zealand (1:14,500). The incidence in an Asian population (Japan) (1:15,800) did not differ significantly from that of the white population. In four of five populations, overall incidence was higher than previously reported, as was the frequency of the salt-wasting form (75% v 50% to 66%), suggesting improved case detection by newborn screening.(ABSTRACT TRUNCATED AT 250 WORDS)

Pituitary-testicular reserve in men with low serum testosterone and normal serum luteinizing hormone.

Men with low serum testosterone levels who do not have elevated serum LH levels are generally thought to have hypothalamic-pituitary dysfunction. To evaluate this concept, seven men with a combination of low serum testosterone and normal serum LH underwent standard tests of hypothalamic-pituitary-testicular reserve. Pituitary reserve, tested with LHRH, showed exaggerated responses in two subjects, low-normal responses in one subject, and normal responses in the remaining four. Testing of hypothalamic-pituitary reserve with clomiphene showed normal gonadotropin responses in six subjects and blunted response in one (the same subject with the low LHRH response). Direct stimulation with hCG showed normal percentage increases in testosterone but low absolute levels, comparable to responses in patients with Klinefelter's syndrome. However, 17-OH-progresterone responses to hCG were lower in these subjects than in either controls or subjects with Klinefelter's syndrome. During follow-up, one subject developed frank primary testicular failure. It was concluded that men with low serum testosterone but normal serum LH are a heterogeneous group, and this pattern occasionally reflects early primary testicular failure rather than hypothalamic-pituitary dysfunction. Standard tests of pituitary-testicular reserve are generally not useful in defining abnormal hormonal output, although measurement of the 17-OH-progesterone response to hCG may improve their diagnostic utility.

Hormonal evaluation of boys born with undescended testes during their first year of life.

We studied pituitary-gonadal function during the first year of life in 48 boys born with 56 undescended testes in order to test the hypotheses that functional insufficiency of the hypothalamo-pituitary-gonadal axis and disorders of testosterone (T) biosynthesis occur in such boys. Cryptorchidism persisted for longer than 1 yr in 29 boys (30 testes; group I), whereas spontaneous descent occurred in 19 boys (20 testes; group II), in 6 after the sixth month. A control group (group III) included 160 boys. Basal and peak LHRH-stimulated serum LH and FSH and basal serum T values were determined at 3, 6, and 12 months. Serum T, dihydrotestosterone (DHT), progesterone (P), 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, and androstenedione before and after hCG administration were determined at age 1 yr. Comparing the 3 groups, cross-sectional evaluation revealed no significant differences in basal or peak LHRH-stimulated serum LH and FSH levels, except that basal serum LH levels were slightly higher in group II than in group III. Comparing groups I and II, longitudinal evaluation revealed similar basal and peak LHRH-stimulated serum LH and FSH values, with comparable changes with time. Basal serum T, DHT, and T precursor levels were similar in all three groups, with similar rises of T and DHT and variable minimal increases in androstenedione and dehydroepiandrosterone sulfate after hCG stimulation. We conclude that during the first year of life, boys with cryptorchidism have no functional insufficiency of the hypothalamo-pituitary-gonadal axis or disorders in T biosynthesis.

SHBG, testosterone, androstenedione, 17-OH-Progesterone plasma levels in PCO affected women treated with a triphasic oral contraceptive.

A triphasic oral contraceptive Trigynon (Schering) or Triphasil (Wyeth) was administered to 13 anovulatory women with hyperandrogenism, enlarged polycystic ovaries and reversal of LH/FSH ratio. After three months of treatment total Testosterone, Androstenedione and 17-OH-Progesterone levels significantly decreased while SHBG significantly increased. Reduction of hair growth and improvement of acne were noted. Side effects were minimal.

PIP: A trial of a triphasic oral contraceptive in 13 women with polycystic- ovary syndrome is presented, backed up with data on levels of sex hormone binding globulin (SHBG), testosterone, androstenedione, 17-OH-progesterone and other hormones. This illness is really a hyperandrogenic response of the ovary secondary to high gonadotropin levels and unopposed estrogens with low SHBG. Only mediocre results have been reported with low-dose oral contraceptive treatment, compared to earlier high-dose pills. The pills used here contained 50 mcg levonorgestrel (LNG) with 30 mcg ethinyl estradiol (EE) for 6 days, 75 mcg LNG and 40 mcg EE for 5 days, and 125 mcg LNG with 30 mcg EE for 10 days. After 3 months of treatment LH levels fell from 29.7 to 3.6 mIU/m1; FSH fell from 12.3 to 2.6 mIU/m1, and the LH/FSH ratio decreased from 2.34 to 1.38. All androgens declined significantly (p0.01), into the normal range. Serum cortisol rose significantly from 16.9-36.7 mcg/100 ml. SHBG rose from 1.67-3.0 mcg/100 ml, the high limit of normal. Hirsutism and acne improved in all but 1 patient. 1 woman dropped out because of weight gain, and another because of nausea and headache. These results suggest that triphasic oral contraceptives may be safe and effective for chronic anovulatory syndrome.

Effects of high dose ketoconazole therapy on the main plasma testicular and adrenal steroids in previously untreated prostatic cancer patients.

In vitro, ketoconazole has been shown to block testicular and adrenal 17,20-lyase, which converts progestins to androgens. At higher concentrations, it also inhibits 11 beta-hydroxylase, 20,22-desmolase and 17 alpha-hydroxylase. To determine the differential hormonal effects of a 2-week ketoconazole high-dose therapy, the plasma levels of 10 major androgens, gluco- and mineralocorticoids were measured in 14 previously untreated patients with metastatic prostate cancer. Within 24 h, plasma testosterone fell from 14.6 +/- 1.4 nmol/l (mean +/- SEM) to 3.7 +/- 0.7 nmol/l. Thereafter, it decreased to about 2.5 nmol/l and remained at that level. Plasma androstenedione and dehydroepiandrosterone decreased more gradually, respectively from 3.1 +/- 0.4 nmol/l to 0.64 +/- 0.17 nmol/l and from 6.6 +/- 1.0 nmol/l to 2.82 +/- 0.55 nmol/l (on day 14). In contrast, 17 alpha-hydroxyprogesterone and progesterone rose respectively 2- and 5-fold. Plasma cortisol and aldosterone levels remained unchanged whereas 11-deoxycorticosterone and 11-deoxycortisol rose by factors of 14 and 6.7 respectively. Plasma corticosterone also increased, but to a much lesser extent (3-fold). These results demonstrate that ketoconazole high dose therapy blocks mainly the 17,20-lyase of both adrenal and testis. In addition it inhibits mitochondrial 11 beta-hydroxylase to a lesser extent. The inhibition of 20,22-desmolase also seems to be of little clinical relevance. However, since clinical or laboratory symptoms suggestive of hypo-adrenalism have been reported in a small minority of patients, replacement therapy should be considered in such cases.

Intramuscular administration of hydroxyprogesterone caproate in patients with endometrial carcinoma. Pharmacokinetics and effects on adrenal function.

A radio-immunoassay for the determination of the serum concentration of hydroxyprogesterone caproate (HPC) was established. After a single intramuscular injection of 1000 mg, the mean serum level reached its maximum (44-81 nmol/l) after 2-7 days. Patients on long-term adjuvant HPC treatment (consisting of 1000 mg daily for 5 days followed by 1000 mg every 2 weeks) presented peak hormone levels 2 weeks after commencing treatment. After a drop at 5 weeks, the mean serum level slowly increased again to 130 nmol/l after 25 weeks of treatment. Patients being treated with weekly injections had significantly higher serum levels than those treated every 2 weeks. Considerable inter-individual differences were observed. The serum concentrations of HPC measured in this study compare favorably with those previously found in patients treated with medroxyprogesterone acetate. The patients on adjuvant HPC showed no significant change in the levels of cortisol, dehydroepiandrosterone sulphate, androstenedione, or estrone during the first 25 weeks of treatment.

Mechanism of adrenal suppression by high-dose medroxyprogesterone acetate in breast cancer patients.

To investigate the mechanism of adrenal suppression by high-dose MPA, we performed direct and indirect stimulation tests in postmenopausal women with disseminated breast cancer who were receiving MPA and in a postmenopausal breast cancer control group. A partial adrenal insufficiency was found during Synacthen stimulation, confirmed by a slight increase of 11-desoxycortisol after metyrapone, despite a sufficient rise in ACTH levels. Peak levels of androstenedione and 17-OH progesterone after Synacthen correlated with those after metyrapone. Peak cortisol levels after Synacthen also correlated with the sum of cortisol and 11-desoxycortisol values after metyrapone, indicating the presence of a maximum adrenal response and a sufficient rise of endogenous ACTH after metyrapone. As the peak levels of cortisol and androstenedione were highly correlated with baseline values, a short Synacthen stimulation test may give a good indication as to whether adrenal suppression by MPA is adequate. The adrenal androgen androstenedione is the precursor of the main postmenopausal oestrogen, oestrone. In this way, adrenal suppression may constitute an important therapeutic effect of high-dose MPA.

Interrelationships of circulating maternal steroid concentrations in third trimester pregnancies. III. Effect of intravenous cortisol infusion on maternal concentrations of estriol, 16 alpha-hydroxyprogesterone, 17 alpha-hydroxyprogesterone, progesterone, 20 alpha-dihydroprogesterone, delta 5-pregnenolone, delta5-pregnenolone sulfate, dehydroepiandrosterone sulfate, and cortisol.

The effect of a large dose (1000 mg) of iv cortisol-hemisuccinate on circulating steroid concentrations in five women, 28--34 weeks, gestational age, is reported. Maternal concentrations of estriol, 16 alpha-hydroxyprogesterone, 17 alpha-hydroxyprogesterone, progesterone, 20 alpha-dihydroprogesterone, delta 5-pregnenolone, delta 5-pregnenolone sulfate, dehydroepiandrosterone sulfate, and cortisol were measured by RIA before and at 8 and 12 h after iv cortisol infusions at 0 and 8 h. Data were evaluated by repeated measure analysis of variance. Estriol and 17 alpha-hydroxyprogesterone suppressed initially (P less than 0.05) and suppressed further with retreatment and increased treatment time (P less than 0.05). Dehydroepiandrosterone sulfate and progesterone suppressed initially (P less than 0.05) but did not suppress further with retreatment and increased treatment time (P greater than 0.05). delta 5-Pregnenolone and delta5-pregnenolone sulfate increased initially (P less than 0.05) but did not increase further (P greater than 0.05). Concentrations of 16 alpha-hydroxyprogesterone and 20 alpha-dihydroprogesterone were unchanged by cortisol infusion initially (P greater than 0.1) and with retreatment and increased treatment time (P greater than 0.1).