J. Hammerstein

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.

Effects of ethinyl estradiol on semen quality and various hormonal parameters in a eugonadal male

OBJECTIVE To determine the influence of estrogens on male fertility. DESIGN A 36-year-old eugonadal male was subjected to two different regimens of treatment with ethinyl estradiol (EE2). Sperm quality, immunoreactive luteinizing hormone (LH) and follicle-stimulating Hormone (FSH), testosterone (T), estrone (E1), estradiol (E2), dehydroepiandrosterone sulfate (DHEAS), prolactin (PRL) and sex hormone-binding globulin were determined at intervals of 2 weeks for 315 days. SETTING A gender dysphoria clinic. PATIENT A transsexual male nurse. MAIN OUTCOME MEASURES It was hypothesized (and confirmed) that by comparing the effects of increasing and constant dose of EE2 on fertility parameters, differences in estrogen-sensitivity would show more clearly. Furthermore, this procedure served to find the minimal dose of EE2 for complete testicular suppression. RESULTS Low doses of EE2 (20 micrograms/d) had no negative effect on sperm motility and density for a period of approximately 4 weeks, whereas high doses (60 micrograms/d) reduced motility already after a few days and led to a pronounced decrease in sperm density after 2 weeks. After discontinuation of therapy, motility normalized faster than sperm density. Under increasing doses of EE2 there was a constant decrease of FSH that occurred several weeks earlier than that of LH. Under constant dose of EE2 (60 micrograms/d) the decrease of LH was delayed (with respect to FSH) by only a few days. The decrease in T showed a stronger correlation with that of FSH than with that of LH. Volume and fructose content of the seminal fluid correlated with the decrease in T. Rebound effects were observed for FSH, LH, T, and fructose during the therapy-free interval. Ethinyl estradiol therapy had no influence on the serum concentrations of E1, E2, and PRL. Estrone was the dominant estrogen before and after therapy with EE2. Adrenal gland activity was markedly suppressed by EE2, as reflected by the decrease in DHEAS. CONCLUSION The suppressive effect of EE2 on FSH and sperm motility was more pronounced and consistent than on LH and sperm density. The T decrease appears to be mainly caused by a direct effect of EE2 on the testes.

Influence of gestodene and desogestrel as components of low-dose oral contraceptives on the pharmacokinetics of ethinyl estradiol (EE2), on serum CBG and on urinary cortisol and 6β-hydroxycortisol

A randomized controlled clinical trial was undertaken over a 6-month treatment period with two low-dose combined oral contraceptives (OC) to investigate whether the metabolism and elimination of ethinyl estradiol (EE2) is differently influenced by the two progestational components gestodene (G) and desogestrel (D), an issue which has been very controversial recently. The two formulations contained 30 micrograms EE2 each, together with either 75 micrograms G or 150 micrograms D. Of the 40 young women recruited for each formulation, 31 of each group were available for statistical evaluation. The pharmacokinetics of serum EE2 were studied on day 1, 10 and 21 of cycle 1, 3 and 6. There were no significant differences between the two groups in any cycle with respect to parameters measured. This was true for the distinct intracyclical rise in the mean EE2 serum levels from day 1 to day 10 and the smaller further increase between day 10 and day 21, with no change in this respect between the cycles studied. Respective changes were seen with regard to the area under the EE2 serum concentration curve up to 4 and 24 hours (AUC0-4 and AUC0-24), cmax and tmax of serum EE2. The estrogen-dependent corticoid-binding globulin (CBG) increased similarly in the two groups intracyclically and slightly also intercyclically at all times tested. Except for the first treatment cycle, urinary excretion of cortisol and 6 beta-hydroxycortisol displayed a tendency to lower values intracyclically as well as intercyclically, again with no differences between the two groups. Also, the 6 beta-hydroxycortisol-to-cortisol ratio was not different between the groups, showing a slight tendency to rise from about 4 at the beginning of the medication to around 5.5 at the end of the 6th treatment cycle in both groups. It is concluded that G and D as components of low-dose OCs exert comparable effects on the metabolism and elimination of EE2.

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.

Estradiol and progesterone receptor concentrations and 17β-hydroxysteroid-dehydrogenase activity in estrogenprogestin stimulated endometrium of women with gonadal dysgenesis☆

Four hypergonadotrophic women between 25 and 37 years of age with gonadal dysgenesis were treated sequentially with estrogens and a progestin. The hormonal environment induced by this therapy was similar to that of ovulating women, as demonstrated by serum levels of estradiol, endometrial histology and pituitary gonadotropin secretion before and after LH-RH double stimulation. The concentrations of estradiol and progesterone receptors (ER and PR) and the activity of the 17 beta-hydroxysteroid-dehydrogenase (17 beta-HSD) were determined in endometrial curettings obtained from the above patients at 5 different days of their 28-day artificial cycles. The results were correlated to the histology of the endometrium and the serum concentrations of estradiol at the corresponding days of the cycle. The cytoplasmic ER and PR concentrations in the endometrium were 3-6 times higher during the estrogen than progestin phase of the induced endometrial cycle. For the activity of the 17 beta-HSD, the contrary was the case, being 6-10 fold higher during the progestin phase. A 22-day administration of estrogens only did not lead to a rise in enzyme activity or decrease in receptor content as observed under progestin influence after day 14. Since ER and PR concentrations and 17 beta-HSD activities were similar to those in the endometrium of normally ovulating women, these results confirm experimentally the present concept concerning the dependence of the cytoplasmic ER and PR content and 17 beta-HSD activity on female sex hormone action.

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.