U. Schwartz

Ovarian and adrenal vein steroids in seven patients with androgen-secreting ovarian neoplasms: selective catheterization findings *

Standardized bilateral ovarian-adrenal vein catheterization was utilized to preoperatively assess glandular steroid release in seven consecutive cases of occult virilizing gonadal neoplasms. Peripheral testosterone (T) exceeded 1.5 ng/ml in all instances (range, 1.51 to 8.67 ng/ml). Endoscopy and radiography failed to locate the functional lesions. Catheterization showed a unilateral elevation of the ovarian-peripheral vein gradient for T greater than 2.7 ng/ml in six women. In the remaining patient, gradient analysis ruled out an adrenal tumor but did not facilitate lateralization of the gonadal lesion due to subselective ovarian effluent sampling. In addition to the consistent hypersecretion of T, variable excess gonadal output of dihydrotestosterone, androstenedione, dehydroepiandrosterone, and 17 alpha-hydroxyprogesterone was evident. Associated adrenal androgenic hyperfunction was documented in three subjects. Histologic evaluation of the implicated ovaries revealed three lipid cell, two Leydig cell, and two Sertoli-Leydig cell tumors, respectively, measuring between 0.6 and 2.2 cm in diameter. No correlation was found between any of the following parameters: peripheral or glandular vein steroid levels, androgen gradients, severity of symptoms, tumor morphology, and tumor size. In conclusion, appropriate application of selective catheterization may considerably reduce the frequency and extent of operative intervention.

Ovarian and adrenal vein steroids in patients with nonneoplastic hyperandrogenism: selective catheterization findings

Standardized bilateral ovarian-adrenal vein catheterization was utilized to assess directly glandular steroid release in 60 androgenized women without evidence of a functional neoplasm. Testosterone (T), dihydrotestosterone (DHT), androstenedione (delta 4 A), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), 17-hydroxyprogesterone (17-OHP), and cortisol (F) were measured by radioimmunoassay in samples obtained from a peripheral vein and the four glandular veins (all values are given as nanograms per milliliter, mean +/- standard deviation). Peripheral values were as follows: T, 0.68 +/- 0.43; DHT, 0.32 +/- 0.13; delta 4 A, 2.2 +/- 2.0; DHEA, 8.8 +/- 8.9; DHEA-S, 3137 +/- 1774; 17-OHP, 2.0 +/- 3.0; and F, 216 +/- 121. Peripheral elevations of at least one androgen were found in 80% of the 60 cases (T, 38%; DHT, 18%; delta 4 A, 50%; DHEA, 45%; and DHEA-S, 37%). Ovarian-peripheral vein gradients ( OPGs ) and adrenal-peripheral vein gradients ( APGs ) served as semiquantitative estimates of glandular secretion. OPGs were as follows: T, 0.4 +/- 1.1; DHT, 0.1 +/- 0.2; delta 4 A, 3.4 +/- 7.0; DHEA, 14.6 +/- 100; DHEA-S, -288 +/- 523; 17-OHP, 4.5 +/- 8.4; and F, -35 +/- 47. APGs were as follows: T, 0.88 +/- 1.3; DHT, 1.1 +/- 0.9; delta 4 A, 14.4 +/- 38.4; DHEA, 327 +/- 367; DHEA-S, 854 +/- 1223; 17-OHP, 20.8 +/- 41.3; and F, 1252 +/- 2023. Excess ovarian and/or adrenal androgen output was assumed in a given individual when one or more of the respective T, DHT, delta 4 A, DHEA, and DHEA-S gradients exceeded the upper 95% confidence limits of normal previously established in this laboratory.(ABSTRACT TRUNCATED AT 250 WORDS)

ANTIANDROGENS IN THE TREATMENT OF ACNE AND HIRSUTISM

The review discusses (1) the relationship between the endocrine actions of antiandrogens and their therapeutic efficacy and (2) recent chemical and pharmacokinetic data on cyproterone acetate (CPA). It also provides (3) a comparison of CPA and spironolactone regarding the tentative benefits and risks and offers (4) general rules for the drug treatment of androgenized women. Clinical results indicate that those agents are most effective which not only competitively inhibit androgen binding at the receptor level but also suppress androgen secretion and/or production. The combined mode of action is observed with CPA as well as spironolactone. Pharmacokinetic studies underline the necessity to restrict CPA administration in huge doses to the first half of a treatment cycle in order to avoid bleeding disturbances. Also it appears that individual differences in CPA bioavailability do not satisfactorily explain the lack of therapeutic response in about 30% of the cases. Data are presented hinting that the 15 beta-hydroxy-, metabolite of CPA may actually be the biologically active agent. In addition preliminary results are given indicating that intramuscular CPA is therapeutically more effective than oral CPA.

Medium dose cyproterone acetate (CPA): effects on hormone secretion and on spermatogenesis in men.

Medium dose cyproterone acetate (CPA; 10 mg daily p.o.) was administered to 10 fertile men for 12 weeks. Hormonal measurements and semen analyses were performed before, during (4th and 12th week) and after CPA treatment. At the hypothalamo-pituitary level CPA significantly reduced the hypophyseal storage and synthesis capacity for gonadotropins. Basal LH and FSH concentrations were suppressed by 30% and 40%, respectively; while basal prolactin was elevated by 75%. The episodic fluctuations of peripheral gonadotropins remained unaffected. At the testicular level CPA significantly decreased basal testosterone and dihydrotestosterone concentrations by 70% and 50%, respectively. The pulsatile pattern of androgen secretion was abolished. CPA also inhibited spermatogenesis and motility. No serious clinical side effects were observed. All changes appeared to be completely reversible. It is concluded that medium dose CPA induces progestational/anti-gonadotropic effects at the hypothalamo-pituitary level in addition to its antiandrogenic action at the testicular level.

Continuous oral low-dosage cyproterone acetate for fertility regulation in the male? — A trend analysis in 15 volunteers —☆

The effects of cyproterone acetate (CPA), administered orally in dos es of either 10 or 20 mg/day for 26 weeks, were studied in 15 healthy male volunteers. During treatment, there was a decrease in sperm density and in normal-shaped sperm and an increase in pathological and immature forms, an increase in dead spermatozoa, reduced motility of spermatozoa, an in vitro decrease in the speed of sperm transport, and decreased ability of spermatozoa to penetrate ovulatory cervical mucus. Blood plasma levels of testosterone declined to about 40% of basal values, though there were no effects on sex behavior. Plasma luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels were unaltered, while seminal plasma alkaline phosphatase values were considerably increased. Seminal plasma levels of fructose and sialic acid levels were unchanged, while the cortisol-binding capacity of transcortin was markedly increased. The results indicate that CPA has potential as a fertility control agent in males, though further study on a mass phase 3 scale is required before final conclusions can be made.

Technical difficulties of selective venous blood sampling in the differential diagnosis of female hyperandrogenism.

To determine glandular steroid release of adrenals and ovaries in female hyperandrogenism, a standardized method for percutaneous transfemoral venous blood sampling was developed. In eight volunteers and 67 patients, catheterization was performed during the early follicular phase (days 3–7; between 8 and 10 a.m.) to reduce interference from cyclic and circadian variations of secretion. Serial samplings reduced the episodic effluent changes. Anatomical variations and collateral flow as well as stress effects and the dosage of contrast media were studied. During catheterization, peripheral cortisol levels did not differ significantly from control groups. Collaterals had no effect on hormone levels. Contrast media increased cortisol effluent levels only when they were sampled following venography. Four-vessel venous sampling was found to be indicated if peripheral testosterone was more than 1.5 ng/ml and/or dehydroepiandrosterone sulfate more than 6.700 ng/ml. If an ovarian (adrenal)/peripheral gradient of testosterone exceeded 2.7 mg/ml, surgical intervention for tumor removal at the site of hormone excess was felt to be necessary.

Ovarian and adrenal vein steroids in healthy women with ovulatory cycles—selective catheterization findings

Bilateral ovarian-adrenal vein catheterization and androgen measurements in the efferent samples were utilized to directly assess glandular steroid release in 8 healthy volunteers with proven ovulatory cycles during the early follicular phase. Side effects did not occur in any of the women. Hormone levels were as follows (mean +/- SD; ng/ml) T: peripheral vein (PV) 0.36 +/- 0.16, ovarian veins (OV) 0.39 +/- 0.13, adrenal veins (AV) 0.85 +/- 0.63; dihydro-T (DHT): PV 0.25 +/- 0.09, OV 0.29 +/- 0.10, AV 0.93 +/- 0.65; delta 4-androstendione (A): PV 0.88 +/- 0.34, OV 1.82 +/- 1.04, AV 9.22 +/- 8.04; DHEA; PV 5.13 +/- 1.96, OV 6.73 +/- 2.69, AV 146.79 +/- 217.24; DS PV 1860 +/- 850, OV 1937 +/- 1039, AV 2567 +/- 1201; 17 alpha-hydroxyprogesterone (17P): PV 0.60 +/- 0.19, OV 1.46 +/- 1.64, AV 6.94 +/- 6.20; F: PV 170 +/- 50, OV 130 +/- 21, AV 788 +/- 1320; the bilateral differences of effluent levels were not significant. Glandular-peripheral vein steroid gradients served as semiquantitative estimates of momentary secretory activity; they were as follows (mean +/- SD; ng/ml) T: ovarian-peripheral vein gradient (OPG) 0.03 +/- 0.09, adrenal-peripheral vein gradient (APG) 0.48 +/- 0.57; DHT: OPG 0.05 +/- 0.05, APG 0.69 +/- 0.60; A: OPG 0.97 +/- 1.13, APG 8.33 +/- 7.86; DHEA: OPG 1.70 +/- 1.80, APG 141.80 +/- 216.60; DS: OPG 191 +/- 72, APG 706 +/- 824; 17P: OPG 0.87 +/- 1.67, APG 6.30 +/- 6.10; F: OPG 38 +/- 11, APG 610 +/- 1329. Gradient, analysis revealed that the ovaries produced significant quantities of A, DHEA and 17P, but no T, DHT or F between day 3-7 of the cycle; direct gonadal DS output was detected in 2 individuals. A significant OPG for DS was detected in two individuals possibly indicating its partially gonadal origin. The adrenals released larger amounts of A, DHEA and 17P than the ovaries at this stage (P less than 0.05); also, they consistently secreted T, DHT, DS and F.

Peripheral steroid-gonadotropin interactions and diagnostic significance of double-stimulation tests with luteinizing hormone-releasing hormone in polycystic ovarian disease

Abstract The endocrine characteristics of polycystic ovarian disease (PCO) remain ill defined as opposed to its histoiogic features. In this study the hypothalamic-pituitary-ovarian interactions were investigated in 26 patients with PCO and compared to those of nine hirsute, anovulatory and 13 healthy, ovulatory control subjects. The following hormones were determined during the early follicular phase: serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) before and after double stimulation with LH-releasing hormone (LHRH) (two doses of 25 μg intravenously at a 120 minute interval, maximal increments after the first injection, i.e., Δ 1 , and second injection, i.e., Δ 2 ), basal testosterone (T), dihydrotestosterone (DHT), astrone (E 1 ), and estradiol (E 2 ). LH Δ 2 was significantly increased in all PCO patients, while LH Δ 1 was elevated in 18 and basal LH in 12 cases. Basal FSH and FSH Δ 1 were normal in all subjects, whereas FSH Δ 2 was higher in two thirds of the women with PCO. A use of peripheral steroids was recorded in the majority Of PCO patients: T in 19, DHT in 16, E 1 in 19, and E 2 in 14 of 23 subjects. Patients with PCO were divided into three subgroups according to their basal LH levels and LH response to stimulation with LHRH. The extent of LH deviation from normal was correlated to the degree of steroidal elevation. The nine hirsute women showed normal gonadotropin patterns despite augmented peripheral androgens. It is concluded that an increase of LH Δ 2 (>12 ng/ml) after LHRH double stimulation combined with positive findings on laparoscopy may be characteristic of PCO in the differential diagnosis of hirsutism, anovulation, and oligomenorrhea.

ANTI-ESTROGENIC EFFECTS OF CONTRACEPTIVE PROGESTINS ON THE DYNAMICS OF GONADOTROPIN RELEASE

The hypophysiotropic effects of ethinylestradiol (EE) alone and in combination with three different progestins at various doses were assessed in 39 normal women. The compounds were given orally for 7 to 21 days. Serum LH and FSH were measured before and after GnRH double stimulation (2 x 25 micrograms i.v. at a two-hour interval); the ratio between second and first response served as an index of gonadotropin-synthesis capacity. Compared to pretreatment early follicular phase controls (LH and FSH ratios of 1.3 and 1.4), administration of 40 and 50 micrograms of EE daily elicited a significant amplification of LH and FSH synthesis (LH ratios of 2.2 and 3.3; FSH ratios of 2.8 and 3.3). By contrast, 80 micrograms of EE daily caused little change. The EE-induced rise of pituitary responsiveness to GnRH could be counteracted by the addition of progestins. The degree of inhibition as dependent on the type and dose of the progestational compound. It is concluded that the standardization GnRH double stimulation technique may serve as a pharmacodynamic model to quantitate the estrogenic and anti-estrogenic effects of contraceptive steroids at the pituitary level.

Oral contraceptives and pituitary response to GnRH: Comparative study of progestin-related effects

GnRH double stimulation (2 X 25 micrograms i.v. at a two-hour interval) was used to assess the dynamics of LH and FSH release in 25 healthy women on oral contraceptives, all containing 50 micrograms of ethinylestradiol (EE). The study included two sequential regimens (50 micrograms EE X 7 days, 50 micrograms EE + 0.125 mg desogestrel X 15 days; 50 micrograms EE X 7 days, 50 micrograms EE + 2.5 mg lynestrenol X 15 days) and three combined preparations (biphasic: 50 micrograms EE + 1 mg norethisterone acetate (NETA) X 11 days, 50 micrograms EE + 2 mg NETA X 10 days; monophasic: 50 micrograms EE + 2 mg cyproterone acetate X 21 days; 50 micrograms EE + 2.5 mg lynestrenol X 21 days). The tests were always performed on days 19 to 21 of the first treatment cycle and compared to results obtained in normally cycling controls and in women receiving 50 micrograms EE daily alone. It was found that the EE-induced augmentation of pituitary responsiveness to GnRH is diminished by the addition of progestins. LH and FSH reactions to stimulation were both affected. The degree of inhibition depended not only on the chemical structure and daily dose of the progestin component, but also on the duration of its administration per treatment cycle.