Reduced O6-methylguanine repair in fibroblast cultures from patients with lung cancer.

The activity of O6-methylguanine-DNA methyltransferase was determined in fibroblast cultures from 45 patients with lung cancer, 39 patients with cutaneous malignant melanoma, and 29 healthy controls. This enzyme is a critical parameter for the capacity to repair O6-methylguanine (O6-mGua) adducts in DNA, and a decreased activity might therefore be responsible for an enhanced susceptibility to cancer. The assay was performed with 8 x 10(6) fibroblasts which were homogenized and incubated with a known amount of O6-mGua containing DNA. The remaining substrate was determined fluorimetrically after high performance liquid chromatographic separation. O6-mGua repair was significantly reduced in lung cancer patients [6.64 +/- 4.32 (SD) pmol O6-methylguanine repaired/8 x 10(6) cells] as compared to healthy controls [10.35 +/- 5.42, P less than 0.0022] or patients with cutaneous malignant melanoma [10.83 +/- 6.66]. The lowest mean values were detected in a subgroup of 16 lung cancer patients with a tumor manifestation below 46 years of age (5.06 +/- 3.89). Fibroblasts from 4 patients with lung cancer had no detectable repair. We conclude that a reduced capacity to remove O6-mGua adducts may represent a further mechanism of individually enhanced lung cancer risk.

[Hyperthecosis ovarii--a tumor-like change in androgenized females]. / Hyperthecosis ovarii--eine tumorähnliche Veränderung bei androgenisierten Frauen.

Hyperthecosis has been repeatedly described as a disease entity separate from polycystic ovaries (PCO) as characterised by stromal luteinisation, obligatory virilism and purely ovarian androgen hypersecretion. This study compares the findings in patients with hyperthecosis (n = 10), PCO (n = 33) and androgen-secreting ovarian tumours (n = 7). It included selective ovarian-adrenal vein catheterisation with measurement of testosterone (T), dihydro-T, androstenedione, DHEA and its sulfate, 17 alpha-hydroxyprogesterone and cortisol before and after dexamethasone; determination of free T, oestrone, oestradiol and prolactin as well as LH and FSH before and after GnRH. In histologically proven hyperthecosis, signs of virilism were absent in 6 cases. A specific hormone profile could not be identified. Mixed ovarian-adrenal androgen hypersecretion was documented in 4 patients (purely ovarian: n = 6). Ovarian T output frequently fell within the tumour range (n = 4). It is concluded that the minor differences between hyperthecosis and PCO represent only variable manifestations of the same heterogeneous disturbance of androgen metabolism. However, it is of special clinical relevance to rule out a tumour in patients with hyperthecosis.

Gonadal and adrenal androgen secretion in hirsute females.

The pathophysiology of glandular androgen hypersecretion must be regarded as a continuous process without sharp borderlines from normal to non-tumorous conditions, such as polycystic ovaries and hyperthecosis, to neoplastic disease. Hirsutism and related symptoms are most often caused by excess androgens of ovarian and/or adrenal origin, i.e. testosterone, dihydrotestosterone, delta 4-androstenedione, dehydroepiandrosterone and its sulphate. As demonstrated by selective catheterization of glandular effluents, combined hypersecretion occurs more frequently then either purely gonadal or adrenal overproduction. No correlation can be found between the type, frequency and extent of hormonal changes and the clinical, laparoscopic, angiographic, or histological findings. Dynamic function tests do not reliably discriminate between the various aetiological subgroups due to extremely variable and even non-specific individual responsiveness. Selective catheterization is presently the most sensitive method for the preoperative identification and localization of androgen-secreting neoplasms.

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 ng/ml, surgical intervention for tumor removal at the site of hormone excess was felt to be necessary.

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.

[Polycystic ovaries: specific disease picture or nonspecific symptom?]. / Polyzystische Ovarien: eigenständiges Krankheitsbild oder unspezifisches Symptom?

This study compares the clinical, biochemical and laparoscopic findings in androgenized patients with (n = 33) and without (n = 17) polycystic ovaries (PCO). It included selective ovarian-adrenal vein catheterisation with measurement of testosterone, dihydrotestosterone, delta 4-androstendione, dehydroepiandrosterone and its sulfate, 17 alpha-hydroxyprogesterone and cortisol in peripheral and glandular venous samples; determination of free testosterone, oestradiol, oestron, LH, FSH and prolactin in peripheral blood; GnRH and TRH double stimulation, as well as dexamethasone suppression tests. There was no correlation between the morphological, clinical, and endocrine changes. A PCO-specific hormonal pattern was not identifiable. Based on catheterisation data, combined ovarian-adrenal androgen hypersecretion was found in 46% of PCO cases; purely ovarian (21%) or adrenal (12%) overproduction were not as frequent. The dynamic function tests proved to be non-specific; e.g., dexamethasone suppressed not only adrenal, but also ovarian androgen output. It is concluded from these data that PCO are not a nosologic entity, but rather a non-obligatory sign of hyperandrogenism. Laparoscopy is, therefore, without clinical relevance in these patients with non-neoplastic hyperandrogenaemia.

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.

[Differential use of sex hormones during the perimenopause]. / Differenzierte Anwendung von Sexualhormonen in der Perimenopause.

Various regimens are available for hormone replacement in perimenopausal patients. Their pharmacodynamic effects differ e.g. in respect to the relief of subjective climacteric symptoms, the risk of endometrial cancer, the prevention of osteoporosis and the alterations of lipid metabolism. In view of the conflicting epidemiologic data general long-term prophylaxis in all climacteric women cannot be recommended at present. The institution of therapy requires valid indications and careful assessment of relative risks. Today, the cyclic administration of oral estrogen-progestin combinations may be regarded as the method of choice. However, treatment can and should be individualized. The practical aspects of a differential management are discussed. With prudent use, the benefits of perimenopausal hormone replacement clearly outweigh their potential disadvantages.

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)

The diagnostic value of plasma free testosterone in non-tumorous and tumorous hyperandrogenism.

The clinical significance of total and free testosterone (T) estimates for the diagnostic approach to hirsute patients was assessed. Plasma T was measured by radioimmunoassay and its non-protein-bound fraction was determined by equilibrium dialysis, thus facilitating the calculation of apparent free T (AFT). The cases of 162 subjects were investigated; the subjects included 75 women in whom glandular androgen release had been defined by selective catheterization. A positive linear correlation was observed between both parameters over a wide range of concentrations (T, 153 to 10,700 pg/ml; AFT, 0.8 to 342 pg/ml; P less than 0.001). Significant differences of mean T and AFT levels were found between healthy control subjects (n = 8) and subjects with non-tumorous hyperandrogenism (n = 60; P less than 0.005). Individual values overlapped considerably; elevated T (greater than 640 pg/ml; 48%) or AFT (greater than 7.2 pg/ml; 52%) were present in only half the hirsute women. However, the upper 95% confidence limits of normal for both indices were exceeded in all patients with androgen-secreting ovarian tumors (n = 7). It is concluded that the indirect estimation of AFT in addition to T is time-consuming, costly, without practical value in selecting the proper treatment, and therefore not mandatory in the routine evaluation of androgenized women.

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.

[Treatment of virilized women with intramuscular administration of cyproterone acetate]. / Die Behandlung androgenisierter Frauen mit intramuskulär applizierbarem Cyproteronacetat.

Management of hirsutism with high-dose oral cyproterone acetate (CPA) is associated with a failure rate of about 30%. The present investigation analyses the efficacy of parenteral CPA administration in non-tumorous hyperandrogenism. Medium-dose CPA (300 mg) was injected intramuscularly once per month, followed by oral ethinylestradiol (40 micrograms daily) for 21 days in 42 patients (total of 293 treatment cycles). The onset of withdrawal bleeding was 3 to 8 days later. This regimen was used as primary therapy (group A; n = 18) as well as follow-up therapy in low-dose (group B; n = 10) and high-dose oral standard CPA failures (group C; n = 14). The following satisfactory or good response rates were observed in regard to hirsutism: group A 83,5%, group B 100%, group C 57%; seborrhea A and B 100%, C 89%; acne and androgenetic alopecia A and B and C 100%. Clinical side effects occurred in 20 patients; they corresponded in type and frequency to those elicited by the high-dose oral standard medication and resulted in termination of treatment in only 3 patients. Pilot studies regarding the pharmacokinetics of CPA as well as the effects on plasma total and free testosterone and prolactin failed to explain the therapeutic superiority of parenteral CPA (n = 7 women). Still, it may be concluded that intramuscular CPA administration represents a new and highly effective means of managing hirsute females.

A Sertoli-Leydig cell tumor and pregnancy. Clinical, endocrine, radiologic, and electron microscopic findings.

An extremely rare case of a conception occurring in a 26-year-old patient with a small virilizing Sertoli-Leydig cell tumor (diameter: 0.6 cm), bilateral polycystic ovaries and non-tumorous adrenal hyperandrogenism is presented. Prepregnancy findings included hirsutism, clitoromegaly, secondary amenorrhea, and elevated peripheral plasma testosterone (T; 5.7 ng/ml). Extensive basal steroid screening, dynamic function tests, conventional radiologic procedures, selective glandular vein catheterization, and laparoscopy failed to localize unequivocally the source of androgen excess, but suggested bilateral adrenal involvement. The patient conceived during the diagnostic work-up; peripheral T levels increased to 12.1 ng/ml within the first trimester. An exploratory laparotomy with left adrenalectomy, right adrenal biopsy and left ovarian wedge resection revealed an incompletely removed Sertoli-Leydig cell tumor, but normal adrenal histology. The pregnancy was terminated, a left oophorectomy and right ovarian wedge resection were performed at 14 weeks' gestation. Subsequently, peripheral androgens returned to normal, regular menses resumed, and hirsutism disappeared. Three years later the patient delivered a healthy female infant.

Effects of various replacement oestrogens on hepatic transcortin synthesis in climacteric women.

The influence of peri-menopausal oestrogen replacement therapy upon protein synthesis in the liver was investigated. Changes in the cortisol-binding capacity of transcortin (TC-BC) were utilized as an indicator of hepatic oestrogen sensitivity. Forty-two climacteric women were studied before and after treatment with various drugs at different doses (patients receiving identical compounds served as their own controls for the evaluation of dosage effects; duration of medication: 14 days at each dose). Oral administration of oestriol (1 and 2 mg daily; n = 6), oestriol (1 and 2 mg daily) + oestradiol-17 beta (2 and 4 mg daily; n = 8), oestradiol valerate (1, 2, 4 and 6 mg daily; n = 6), conjugated equine oestrogens (0.3 and 0.6 mg daily; n = 6), sodium oestrone sulphate (0.8 and 1.6 mg daily) + sodium equilin sulphate (0.2 and 0.4 mg daily; n = 6) and quinoestrol (25 micrograms daily; n = 6) failed to alter TC-BC. However, ingestion of higher doses of conjugated equine oestrogens (0.9 and 1.25 mg daily; n = 5) and quinoestrol (50 micrograms daily; n = 6) caused a significant rise (P less than 0.01). Ethinyloestradiol was given orally as a reference substance and elicited an elevation of expected magnitude. Vaginal administration of dienoestrol cream (1 mg daily; n = 4) did not change TC-BC. These data indicate that the hepatotrophic effects of replacement oestrogens vary depending on the preparation and dosage selected for treatment.

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.

[Operative complications of laparoscopic tubal sterilization with Bleier clips (author's transl)]. / Operative komplikationen der laparoskopischen Tubensterilisation mit dem Bleier-Clip (prospektive Studie).

The operative complications of 1613 laparoscopic tubal sterilization with Bleier clips were evaluated in a prospective study at the Stadtkrankenhaus Offenbach/M from March 1978 to July 1981 (1239 interval and 374 postabortal procedures; two-puncture technique under general endotracheal anaesthesia). No major complications requiring laparotomy occurred. Minor intraoperative complications were observed in 8.4% of cases. Clip-related problems were encountered in 1.9% (slight tubal or mesosalpingeal bleeding). Other complications included haemorrhage at the puncture site (2.4%), preperitoneal emphysema (1.8%) and uterine perforation during curettage (1,6%). Technical difficulties were recorded in 8,4% of sterilizations; in 6.6% more than one clip per tube was placed to effect complete tubal occlusion. Adnexal pathology prohibited bilateral clip application in 4 women (0.3%). Postoperative complications were negligible. No pregnancies have yet been reported during a mean follow-up period of 17 months. A successful refertilization procedure was performed on one patient. It is concluded that this technique represents a commendable alternative to convention methods of tubal sterilization due to its low operative morbidity, acceptable contraceptive safety and potential reversibility.

PIP: The operative complications of 1613 laparoscopic tubal sterilizations with Bleier clips were evaluated in a prospective study at the Stadtkrankenhaus Offenbach/M from March 1978-July 1981 (1239 interval and 374 postabortal procedures; 2-puncture technique under general endotracheal anesthesia). No major complications requiring laparotomy occurred. Minor intraoperative complications were observed in 8.4% of the cases. Clip-related problems were encountered in 1.9% (slight tubal or mesosalpingeal bleeding). Other complications included hemorrhage at the puncture site (2.4%), preperitoneal emphysema (1.8%), and uterine perforation during curettage (1.6%). Technical difficulties were recorded in 8.4% of sterilizations; in 6.6% more than 1 clip/tube was placed to effect complete tubal occlusion. Adnexal pathology prohibited bilateral clip application in 4 women (0.3%). Postoperative complications were negligible. No pregnancies have yet been reported during a mean follow-up period of 17 months. A successful refertilization procedure was performed on 1 patient. It is concluded that this technique represents a commendable alternative to the conventional methods of tubal sterilization due to its low operative morbidity, acceptable contraceptive safety, and potential reversibility. (author's)

Vaginal administration of ethinylestradiol: effects on ovulation and hepatic transcortin synthesis.

Ethinylestradiol (EE) was given vaginally to circumvent the intestinal metabolism and initial liver passage which follow oral intake. This route of administration was chosen in an effort to enhance the antiovulatory potency of EE, while decreasing adverse hepatic reactions. Vaginal tablets containing 20-30 micrograms of EE were taken daily by 7 ovulating volunteers from day 5 to day 25 of the menstrual cycle. The regimen resulted in serum EE levels of 62 +/- 27 pg/ml (mean +/- S.D.) 8-10 hours after insertion. Ovulation was inhibited in 5 women (monophasic basal body temperature curves, serum progesterone levels of 0.9 +/- 1.1 ng/ml during the second half of the treatment cycle). The cortisol-binding capacity of transcortin was significantly elevated in all subjects (52.3 +/- 6.4 micrograms/100 ml; controls 25.7 +/- 2.2 micrograms/100 ml). These findings indicate that intravaginal EE is twice as potent as oral EE in regard to inhibition of ovulation as well as stimulation of the hepatic transcortin synthesis. Vaginal administration apparently increases the bioavailability of EE; it does not facilitate a selective reduction of estrogenic effects upon the liver.

XY gonadal dysgenesis: aberrant testicular differentiation in the presence of H-Y antigen.

Six patients with pure nonmosaic 46,XY gonadal dysgenesis (XY GD) and histocompatibility H-Y antigen titers in the normal male range (H-Y+) are presented. Clinical characteristics included a female phenotype, masculine skeletal characteristics, signs of virilization, and primary amenorrhea. All individuals had unambiguous female external genitalia, a hypoplastic uterus, bilateral tubes, and streak gonads. Histomorphologic evaluation of the gonads revealed various abortive testicular and ovarian elements capable of steroid production. Gonadal tumors were found in 4 patients (gonadoblastoma, dysgerminoma, granulosa cell tumor, myxofibroma). Plasma and urinary androgens and basal and stimulated gonadotropin levels were elevated prior to gonadectomy. Data show that the presence of the H-Y antigen per se does not guarantee normal testicular organogenesis. It is hypothesized that defective H-Y antigen binding to its gonadal receptors triggers aberrant testicular differentiation in 46,XY H-Y+ GD.

[Clinical use of antiandrogens in the female]. / Die klinische Anwendung von Antiandrogenen bei der Frau.

PIP: The use of antiandrogens (principally cyproterone acetate CPA) to treat women with symptoms of hypersecretion of androgens is discussed. Several therapy schemata are presented. A high dosage "reverse sequential" therapy of 100 mg CPA on the 5th-14th days of the menstrual cycle and 40 mcg ethinyl estradiol (EE) on the 5th-25th days is used in severe cases. Low dosage (2mg CPA, 50 mcg EE) preparations are used for light cases of androgen hypersecretion. Parenteral application of 300 mg CPA per cycle with supplementary EE administration has also been tested. Hirsuitism is treated with good results in 65%-80% of those who use high dosage preparations and 50% of those who use the low dosage preparations. The effects of the therapy are apparent 9-12 months after it begins; the therapy is not as successful among patients whose problems are not related to their hormonal balance. Seborrhea and endogenous acne can be effectively treated with all types of antiandrogen preparations. Androgenetic alopecia can also be treated in a majority of cases with CPA preparations. CPA treatment should not last longer than 12 months. High dosage CPA use by ovulating women causes suppression of the preovulatory LH and FSH peaks but has little effect on basal levels; in postmenopausal women, the basal LH and FSH levels are significantly reduced. Use of CPA by itself causes a significant decrease in the levels of testosterone and delta-4-andostendion 3,17-dion. Use of CPA/EE combinations causes an increase in SHBG and the blood cortisol levels. Protein metabolism, hematopoesis, blood coagulation, and liver function are not affected by CPA use. Reduced glucose utilization and an increase in triglyceride levels are observed during CPA use. Pregnant women and women over 40 or with androgen-producing tumors should not use CPA.^ieng