Studies on the pattern of circulating steroids in the normal menstrual cycle. I. Simultaneous assays of progesterone, pregnenolone, dehydroepiandrosterone, testosterone, dihydrotestosterone, androstenedione, oestradiol and oestrone.

In an attempt to analyze the multiple changes and interactions in circulating steroid levels in the peri-ovulatory and peri-menstrual periods, the plasma levels of immunoreactive luteinizing hormone (LH), progesterone and unconjugated pregnenolone, dehydroepiandrosterone, testosterone, oestradiol and oestrone were assayed daily during a complete cycle in 17 normally menstruating women. In 14 of the 17 subjects studied androstenedione and unconjugated dihydrotestosterone were also estimated. The day of the LH-peak and the first day of menstruation, respectively, were used to synchronize the peri-ovulatory and peri-menstrual plasma levels of the various steroids. With the exception of dehydroepiandrosterone and dihydrotestosterone, the plasma levels of all steroids exhibited significant, but different changes during the cycle. Testosterone levels showed a slight but significant increase around the LH-peak, whereas the levels of pregnenolone and androstenedione were higher in the post-ovulatory than in the pre-ovulation periods. The levels of oestradiol and oestrone, as well as the ratios of oestradiol to oestrone gradually increased from the low values observed in the early proliferative phase to pre-ovulatory peak values. The relationship between peaks of oestradiol and oestrone and that of LH exhibited great individual variation. The same was true for the individual oestradiol to oestrone ratios. The combination of several steroidal signals did not improve the predictive value of the analyses. However, an increase of individual progesterone values by at least 0.35 ng/ml from the day preceding the LH-peak to the day of the LH-peak was observed in 13 of the 17 subjects. It is suggested that for the early detection of the LH surge and prediction of the subsequent ovulation daily assays of plasma progesterone are of more value than the assay of the other steroids investigated.     

ENDOCRINE EFFECTS OF VASECTOMY

In order to provide information on the endocrine effects of vasectomy, unconjugated pregnenolone, dehydroepiandrosterone, androstenedione, testosterone, dihydrotestosterone, oestrone and oestradiol were analysed in the blood plasma of twenty Mexican men on two occasions before and 1, 3, 6 and 12 months after vasectomy. Vasectomy appeared to be associated with a significant decrease in the plasma levels of pregnenolone, dehydroepiandrosterone and androstenedione and a significant increase in the levels of dihydrotestosterone and oestrone. A probably significant increase in oestradiol levels took place 12 months after vasectomy but not before. No consistent changes were found in testosterone (up to 12 months) or in FSH and LH levels (up to 6 months) after vasectomy. The unconjugated steroids indicated above, except oestrone, were also estimated, whenever possible, in seminal plasma specimens obtained from thirty-nine subjects (including the twenty indicated above) on the same occasions. Vasectomy was associated with a highly significant decrease of seminal plasma dihydrotestosterone levels on all occasions and a significant decrease in androstenedione levels after 6 and 12 months. After 12 months there was a decrease in dehydroepiandrosterone and an increase in oestradiol; these changes were both probably significant. In another preliminary study, the levels of pregnenolone sulphate, dehydroepiandrosterone sulphate, testosterone glucuronide, testosterone sulphate and dihydrotestosterone sulphate were estimated before and 1 month after vasectomy in the seminal plasma of fourteen to seventeen subjects. Testosterone glucuronide fell, probably significantly, but other conjugates were unchanged. The data indicate that vasectomy may be associated with significant changes in the circulating and in seminal plasma levels of several steroids. The gradual nature of some of the changes observed suggests the necessity of conducting in several centres large-scale, long-term studies on vasectomized subjects and on a carefully matched control group. During the last decade vasectomy has been widely practised in several parts of the world as a method of fertility control. However, information on the endocrine effects of this intervention appears to be scanty. In most of the human studies reported, a small number of individuals were investigated and the studies have been confined to the assessment of the short-term effects of the operation. Moreover, the hormonal indices assessed by the various investigators have been limited, in most cases, to gonadotrophins and testosterone in blood. The present study was designed to assess in the same subjects the levels of a number of unconjugated steroids, FSH and LH on two occasions before and 1, 3, 6 and 12 months after vasectomy. The studies were extended to include steroid analyses in seminal plasma in the hope that such assays might yield information as to the effects of vasectomy on the distribution of steroids in the fluids of the male reproductive tract.     

Effect of exposure to long days on the secretion of oestradiol, oestrone, progesterone, testosterone, androstenedione, cortisol and follicle-stimulating hormone in intact and spayed ferrets

The changes in concentration of plasma oestradiol, oestrone, progesterone, androstenedione, testosterone, cortisol and FSH were followed in intact female ferrets brought into oestrus by extension of the photoperiod from 8 to 16 h daily. An additional group of spayed females was similarly exposed to the extended photoperiod. There was no change in the blood oestrone, androstenedione and testosterone levels in the spayed females; the concentration of oestradiol, progesterone and FSH fell, while that of cortisol rose after 6 weeks. The intact females showed no change in plasma oestrone and cortisol concentrations, a rise in plasma oestradiol associated with the onset of oestrus, and falls in the blood levels of testosterone, androstenedione, progesterone and FSH. These results indicate that the changes in plasma gonadal steroid levels after extension of the photoperiod differ markedly from those in rodents or ruminants.     

Influence of nandrolondecanoate on the pituitary-gonadal axis in males

Different anabolic steroids can exercise different effects on the pituitary-gonadal axis in males. During a pilot study regarding the possible beneficial effect of the anabolic steroid nandrolondecanoate (ND) on bone metabolism in patients with rheumatoid arthritis additional endocrinological parameters were studies. A significant decrease was found in the serum levels of testosterone, androstenedione and FSH and the ratio of testosterone/oestradiol. There was a significant increase in the serum levels of oestrone. The levels of oestradiol, SHBG, LH and cortisol remained unchanged. An inhibitory effect of ND on testicular testosterone secretion is assumed. The decrease in androstenedione levels is explained by the diminished testosterone secretion. The rise in oestrone levels is explained by peripheral aromatizing of ND to oestrogens. The presented findings are in accordance with the hypothesis that sex steroids can act directly on the pituitary resulting in selective FSH and LH secretion. The possible role of the ratio testosterone/oestradiol in controlling gonadotrophin output is discussed.     

INDICES OF GONADAL FUNCTION IN THE HUMAN MALE

A radioimmunoassay technique for the simultaneous measurement of eight unconjugated steroids (progesterone, pregnenolone, dehydroepiandrosterone, androstenedione, testosterone, dihydrotestosterone, oestrone and oestradiol) in the peripheral plasma of human males is described. Determinations of these steroids and of immunoreactive FSH and LH were carried out on the plasma of twenty-one normal individuals and the levels were compared to those of eleven and ten males exhibiting oligospermia and azoospermia, respectively. Mean values and tolerance limits for each hormone, based on a lognormal distribution of individual values, are presented for all groups. Oligospermia was associated with a significant reduction in plasma dihydrotestosterone and testosterone levels. Azoospermic subjects also exhibited decreased dihydrotestosterone levels but a normal range of testosterone concentrations. Mean peripheral plasma levels of FSH were significantly elevated in both pathological groups and this was paralleled in the azoospermic men by increased concentrations of plasma LH.     

INDICES OF GONADAL FUNCTION IN THE HUMAN MALE

A radioimmunoassay method developed previously for the measurement of unconjugated pregnenolone, dehydroepiandrosterone, androstenedione, testosterone, dihydrotestosterone and oestradiol in peripheral plasma was applied to the assay of these steroids in seminal plasma of normal, oligospermic and azoospermic males. It was not possible to use the plasma assay method for the determination of progesterone and oestrone in seminal plasma, because some of the reliability criteria were not fulfilled. A detailed analysis of these steroids in the peripheral plasma of the same subjects has been described previously. The levels of all steroids in seminal plasma were significantly lower than the corresponding blood levels. The ratios of blood plasma/seminal plasma levels of the various steroids varied from 37 (testosterone) to 1.7 (dihydrotestosterone). There was a positive correlation between the testosterone and dihydrotestosterone levels of the seminal plasma of normal and azoospermic subjects. The concentrations of dihydrotestosterone, pregnenolone and oestradiol were significantly lower in azoospermic subjects than in normals. The only pathological finding in the seminal plasma of oligospermic subjects was a diminished level of dihydrotestosterone. Enzymic hydrolysis of a seminal plasma pool resulted in a 3- to 8-fold increase in the concentration of pregnenolone, dehydroepiandrosterone, testosterone, dihydrotestosterone and oestradiol, indicating that human seminal plasma contains large amounts of steroid conjugates. It is suggested that the analysis of steroids in the seminal plasma in combination with determinations in peripheral plasma may be a valuable aid to the assessment of testicular function.     

STEROIDS IN OVARIAN AND PERIPHERAL VENOUS BLOOD IN POLYCYSTIC OVARIAN DISEASE

Ovarian and peripheral venous blood samples were collected at operation in six patients with polycystic ovaries (PCO) and seven control subjects with normal ovarian function in the follicular phase of the cycle. Plasma concentrations of unconjugated testosterone, dihydrotestosterone (DHT), androsterone, androstenedione, dehydroepiandrosterone (DHEA), pregnenolone, progesterone, 17α-hydroxyprogesterone (17α-OH-P) and oestradiol were determined by specific radioimmunoassay techniques, and concentrations of DHEA, androsterone and pregnenolone sulphates by gas chromatography. In the control group, ovarian vein concentrations of all unconjugated steroids, except progesterone, were significantly higher than the corresponding peripheral vein concentrations, suggesting ovarian secretion. No significant differences were demonstrated between ovarian and peripheral plasma levels of steroid sulphates. Ovarian vein levels of androstenedione, testosterone and DHEA were markedly elevated in PCO patients compared with the control group, and the levels of DHT and androsterone to a lesser degree. Polycystic ovaries appear to secrete androsterone sulphate, but no significant secretion of DHEA sulphate could be demonstrated. Ovarian venous levels of oestradiol in the PCO group did not differ from those in the control group. Elevated ovarian venous androgen levels in the PCO group seemed to correlate with thecal cell hyperplasia as indicated by histological examination of ovarian biopsies. In one PCO patient, blood levels of different steroids were followed for a month after ovarian wedge resection. Testosterone fell to half the pre-operative value and a temporary fall was also noticed in other androgens. A marked rise in plasma progesterone concentration at the end of the follow-up period suggested that ovulation had occurred.     

Steroids in the amniotic fluid of the rhesus monkey (Macaca mulatta).

Representative C21, C19 and C18 steroids have been measured in the amniotic fluid and maternal femoral plasma of rhesus monkeys during the last 50 days of pregnancy. The concentrations of cortisol, progesterone, androstenedione, oestrone sulphate all increased in amniotic fluid before spontaneous parturition. In contrast, amniotic fluid oestradiol levels remained low and unchanged, and were always less than the concentrations in the maternal plasma. The changes in progesterone, cortisol and oestrone concentrations in amniotic fluid occurred independently of significant changes in the concentration of these steroids in the maternal plasma. Betamethasone administered to monkeys after day 150 of pregnancy suppressed amniotic fluid and maternal plasma cortisol. This treatment markedly suppressed the concentration of progesterone in amniotic fluid, but did not alter its concentration in maternal plasma. It is concluded that during late pregnancy in the rhesus monkey there is an increase in the concentration of some steroids in amniotic fluid independent of alterations in their concentrations in maternal plasma. These changes could reflect an increase in foetal adrenal steroid secretion.     

Hormonal changes during the menstrual cycle of the baboon (Papio hamadryas).

Eleven unconjugated steroids were measured daily during a complete cycle in the peripheral plasma of 6 normally menstruating baboons (Papio hamadryas) by means of a radioimmunoassay procedure and the levels were compared with those found previously in 17 normally menstruating women. The patterns of progesterone and 20alpha-dihydroprogesterone were very similar to those found in women throughout the entire menstrual cycle. However, the ratio of these steroids differed markedly from that found in women. A great similarity of the follicular phase and the peri-ovulatory period profiles was observed in both species for 17-hydroxy-progesterone, pregnenolone, androstenedione, oestradiol and oestrone. The pattern of oestradiol:oestrone ratios was similar in both species. However, an elevation of the above five steroids, typical for the human luteal phase, was not found in baboons. The increase of testosterone values, seen in women at mid-cycle, was not detected in baboons. The plasma concentrations were lower in baboons than in humans for all the above steroids.     

ABNORMAL ANDROGEN AND OESTROGEN METABOLISM IN MEN WITH STEROID SULPHATASE DEFICIENCY AND RECESSIVE X-LINKED ICHTHYOSIS

Serum levels of sex hormone binding globulin (SHBG), testosterone, free testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone sulphate, oestradiol, oestrone, oestrone sulphate, FSH, and LH were measured in 20 steroid sulphatase-deficient men with recessive X-linked ichthyosis and in normal men. The serum oestrone sulphate level was significantly higher than normal in the patients (P less than 0.0001). In affected men, there was a tendency towards higher dehydroepiandrosterone sulphate levels and no decline with age was seen in the patients as opposed to normal men (interaction: P less than 0.025). Serum androstenedione, and oestradiol levels were lower than normal in the patients (P less than 0.0005 and P = 0.055, respectively), while their LH level was higher than normal (P less than 0.0005). The serum levels of SHBG, total and free testosterone, dihydrotestosterone, oestrone, and FSH were not significantly different from normal in the icthyotic patients. We suggest that the observed abnormalities in these patients are a consequence of the enzyme deficiency which severely impairs the ability of tissues to hydrolyse steroid sulphates.     

SERUM STEROIDS AND PITUITARY HORMONES IN FEMALE PUBERTY: A PARTLY LONGITUDINAL STUDY

Pubertal development of 200 normal girls, 7--17 years of age, was investigated in a partly longitudinal manner with two examinations 1.5 years apart. Samples from postmenarchal girls were taken on days 6--9 and 20--23 of the menstrual cycle. Serum pregnenolone, progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, testosterone, 5 alpha-dihydrotestosterone, androsterone, oestradiol and cortisol as well as ACTH, FSH, LH and prolactin were measured radioimmunologically and were related to bone age, breast and pubic hair developmental stages, and gynaecological age. In the samples of premenarchal girls as well as the follicular phase of postmenarchal girls the concentration of all the steroids increased with age. Of all the steroids measured, serum dehydroepiandrosterone and pregnenolone displayed the earlier increase, from the youngest age group of 7.5 years onwards. Serum oestradiol testosterone and androstenedione in creased rapidly from the bone age group of 9.5 years (subjects 9.0--9.9 years of age) onwards, in close association with the appearance of the first physical signs of puberty. A marked increase in these three steroids continued until 13.5 years, the age at which menarche took place. Menarche was followed by a plateau of 1--2 years duration and then a second increase took place up to the two oldest age groups (17.5 and 18.5 years bone age), a trend seen in the follicular phase levels of all the steroids measured. The 5 alpha-dihydrotesterone/testosterone ratio decreased with increasing testosterone concentration. Serum oestradiol, testosterone, androstenedione, dehydroepiandrosterone and FSH showed no overlapping in the 2.5--97.5% range of concentrations and androsterone and LH in the 16--84% range between prepubertal and postmenarchal subjects. Pregnenolone, progesterone, 17-hydroxyprogesterone, 5 alpha-dihydrotesterone, cortisol, ACTH and prolactin overlapped even in the 16--84% range between these two groups of subjects. In postmenarchal girls, about 80% of the cycles were anovulatory in the first year after menarche, 50% in the third and 10% in the sixth year. The background of the majority of the anovulatory cycles seems to be a physiological variant of the pattern seen in the polycystic ovary syndrome: the levels of testosterone, and androstenedione and LH were increased in anovulatory cycles compared to ovulatory ones.     

Plasma levels of unconjugated steroids in male baboons (Papio hamadryas) and rhesus monkeys (Macaca mulatta).

In an attempt to find suitable animal models to aid in the study of the reproductive processes of the human male, plasma levels of unconjugated pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, 20alpha-dihydroprogesterone, 17-hydroxyprogesterone, androstenedione, testosterone, dihydrotestosterone, oestrone and oestradiol were measured in 18 male baboons and 10 male rhesus monkeys and the steroid levels were compared with those previously established in normospermic, middle-aged men. Significant species differences were found with regard to the three delta5-steroids studied; whereas the approximate relationship of pregnenolone to 17-hydroxypregnenolone and dehydroepiandrosterone was 1:2:4 in men, the corresponding relationship was 1:5:30 in rhesus monkeys and 1:10:10 in baboons. Similar levels of 20alpha-dihydroprogesterone were found in the three species. On the other hand, the 17-hydroxyprogesterone levels in baboons were much lower and the levels of androstenedione lower than those found in men and in rhesus monkeys. No species difference was found with regard to circulating testosterone levels. However, both rhesus monkeys and baboons exhibited much higher levels of dihydrostestosterone than did men. Oestrone levels were higher in baboons than in men and oestradiol levels were higher in rhesus monkeys than in men and in baboons. The significant differences in circulating steroid levels suggest that further studies (including i.a. steroid analyses in testicular tissue, seminal plasma and spermatic artery and vein following both stimulation and suppression of testicular endocrine function) are required before preference can be given to any of the two species studied as a suitable animal model for the study of new fertility regulating agents.     

Effects of o,p'-DDD on pituitary-gonadal function in patients with Cushing's disease

O,p'-DDD has a cytotoxic action and inhibits the cholesterol side chain cleavage enzyme, 11 beta-hydroxylase, 3 beta-hydroxysteroid dehydrogenase coupled with delta 5 to 4 isomerase and 21-hydroxylase of the adrenal cells. However, the effects of o,p'-DDD on gonadal steroidogenesis are still unknown. In the present study, the effects of o,p'-DDD on Plasma cortisol, pregnenolone, 17 alpha-hydroxypregnenolone (17-OH-pregnenolone), progesterone, 17 alpha-hydroxyprogesterone (17-OH-progesterone), 11-deoxycorticosterone (DOC), corticosterone, dehydroepiandrosterone (DHEA), delta 4-androstenedione (androstenedione), estradiol, and LH and FSH were investigated in 3 patients with Cushing's disease before and after the administration of o,p'-DDD. The results are presented here. In Case 1 (18 yr old female) who had had secondary amenorrhea for 2 years, the plasma levels of cortisol, pregnenolone, 17-OH-pregnenolone, DHEA, androstenedione, testosterone, estradiol and corticosterone were elevated. The basal levels of plasma LH and FSH and the responses of both gonadotropins were lower than those of women with eumenorrhea. The plasma levels of progesterone, DHEA and testosterone decreased to normal 2 months after the beginning of the administration of o,p'-DDD. She restored menstrual cycles ranging from 40 to 50 days 3 months after the administration of o,p'-DDD, but with anovulatory bleeding. She showed a biphasic body temperature pattern with plasma progesterone and estradiol levels indicating corpus luteum formation 11 months after the start of the treatment, when plasma cortisol as well as progesterone and androgen were reduced to normal. The basal levels of FSH and LH and responses of these gonadotropins were slightly improved at that time. The plasma levels of cortisol, DHEA and androstenedione were high in Case 2 (38 yr old male) and Case 3 (45 yr old male), whereas plasma testosterone level was normal in Case 2 and low in Case 3. The plasma levels of these 3 steroids were normalized 28 days after the beginning of the o,p'-DDD administration. These results suggest that o,p'-DDD does not interfere with gonadal steroidogenesis in Cushing's disease.     

HORMONAL CHANGES IN POSTMENOPAUSAL WOMEN WITH BREAST CANCER TREATED WITH TRILOSTANE AND DEXAMETHASONE

Postmenopausal women with metastatic breast cancer were treated with trilostane, initially 240 mg daily increasing after 3 days to 480 mg daily and after a further three days to 960 mg daily. After 3 days at this dose dexamethasone 1 mg daily was added and this combination was continued until disease progression occurred. Partial remission was seen in 26% and stabilization of previously progressive disease in a further 13% of the first twenty-three patients studied. During therapy with trilostane alone significant increases in DHEAS, androstenedione, 17-hydroxypregnenolone, progesterone, testosterone and oestradiol were seen. A significant fall in oestrone concentration occurred at the same time. After dexamethasone was added the elevated steroid concentrations fell back to the baseline while oestrone remained depressed below this and testosterone was also significantly lowered. No change was seen in cortisol or ACTH concentration while patients were on trilostane alone but cortisol levels were undetectable after dexamethasone was added though, in most patients, ACTH remained detectable. There was no change in the ratio of delta 5:delta 4 steroids at any stage of therapy but a highly significant increase in the androstenedione: oestrone ratio was seen. We conclude that in long-term use in vivo it is difficult to demonstrate that trilostane inhibits 3 beta-hydroxysteroid dehydrogenase but it may produce inhibition of aromatase.     

Steroidogenesis in cerebral metastatic chorionepithelioma tissue in vitro.

Homogenates of cerebral metastatic chorionepithelioma tissue were incubated with labelled dehydroepiandrosterone, pregnenolone or 20alpha-hydroxypregn-4-en-3-one. The metabolites of dehydroepiandrosterone which were isolated and identified were androstenedione, testosterone, oestrone, and oestradiol; no oestriol was detected. The only metabolite of pregnenolone and 20alpha-hydroxypregn-4-en-3-one isolated and identified was progesterone. No conversion of C-21 to C-19 steroids occurred in the metastatic chorionepithelioma tissue.     

ADRENAL AND GONADAL STEROIDS IN GIRLS DURING SEXUAL MATURATION

The peripheral venous plasma concentrations of gonadotrophins (LH and FSH), prolactin (Prl), cortisol, dehydroepiandrosterone (DHA), dehydroepiandrosterone-sulphate (DHA-S), pregnenolone (Δ₅P), progesterone (P), 17-hydroxyprogesterone (17P), androstenedione (A), testosterone (T), dihydrotestosterone (DHT) and oestradiol (E₂) were measured in girls at different stages of sexual development (from P1 to P4–5 according to Tanner, 1962). Both gonadotrophins increase progressively during sexual maturation, to reach the highest concentrations in P4–5. However, the FSH values were significantly lower in these P4–5 pre-menarchal girls than those found in adult women in the early follicular phase. No significant changes were found in plasma Prl, cortisol and 17P levels during pubertal development; in contrast, plasma concentrations of DHA tripled from P1 to P4–5, reaching adult levels. A progressive rise was also found in DHA-S plasma levels. A significant, but less evident increase was found in Δ₅P and P plasma concentrations, from group P1 to P4–5. A, T and DHT levels rose progressively and significantly from P1–2 to the end of sexual maturation. In the case of E₂, only a moderate increase was found during pubertal development. All these data indicate that during pubertal development, there is a progressive reduction in the sensitivity towards oestrogen of the hypothalamic centres controlling gonadotrophin secretion. Prl does not seem to be involved in human sexual maturation, while important changes have been found in adrenal androgens. The constant levels of 17P and cortisol, in comparison with the behaviour of DHA, DHA-S, T and A, seem to indicate that during this period of life, the adrenal gland is stimulated by unknown factors other than ACTH, acting on the adrenal androgen-producing cells and responsible for the reported rises in plasma adrenal androgens.     

Sex steroids and steroid binding proteins in female alcoholic liver disease

Blood levels of sex steroids and steroid binding proteins were measured in 21 females with alcoholic liver disease and in age matched healthy controls and correlated to type and severity of histological changes in concomitant liver biopsies. In patients with liver disease androstenedione levels were high in contrast to the low levels of dehydroepiandrosterone (DHA), dehydroepiandrosterone sulphate (DHAS) and albumin. Normal levels of testosterone and total oestrone were found in the patients. SHBG varied independently of albumin and decreased SHBG levels were found in patients with steatosis. DHA, DHAS and albumin levels were negatively correlated to the total biopsy score and a positive correlation was found between DHAS and albumin. The higher levels of androstenedione were found in patients with mild histological lesions. The findings are thought to reflect alcohol-induced changes in hepatic as well as in adrenocortical activity.     

Effect of short dexamethasone suppression on plasma steroids in prepubertal and pubertal girls

In 40 girls aged from 2 to 14 years, subdivided into groups according to age and pubertal development, and in 6 adult female volunteers, plasma cortisol (F), pregnenolone (delta 5), dehydroepiandrosterone (DHA) progesterone (P), 17-hydroxyprogesterone (17P), androstenedione (A), testosterone (T) and estradiol (E2) were measured before and after short dexamethasone (DXM) suppression. The results confirmed the capacity of DXM to inhibit plasma steroids in all age groups, except T in 2-9 year old and P1 Tanner's stage girls. The percentage suppression of each given steroid was constant over the age groups from 6-9 years to P4-5 Tanner's stage, while lower suppression was found in 17P, P and DHA in 2-5 year old girls and in 17P, DHA and E2 in adult women. These results emphasize the fundamental role of ACTH as the overall stimulating factor of adrenal steroidogenesis but do not negate the possibility of another factor responsible for the development of the adrenal androgen secreting cells throughout prepuberty and puberty.     

Differential effects of testosterone, 5 alpha-dihydrotestosterone and oestradiol-17 beta on plasma concentrations of LH in castrated ferrets

The biological activity of testosterone often depends on the conversion of testosterone within the target cell to an androgenic or oestrogenic metabolite. The purpose of this study was to compare the relative ability of testosterone and two of its metabolites, dihydrotestosterone (DHT) and oestradiol, to suppress LH secretion in castrated male ferrets. Castrated ferrets were treated with five different doses of steroid by implanting various numbers of s.c. silicone elastomer capsules packed with either testosterone, DHT or oestradiol. The lowest dose of oestradiol (0.1 mm capsule length/100 g body weight, mean estimated total release rate of 25 ng/day) significantly suppressed plasma concentrations of LH in castrated ferrets. Higher amounts of DHT (2.5 mm capsule length/100 g body weight, mean estimated total release rate of 88 ng/day) were required for a significant reduction in plasma concentrations of LH. Concentrations of LH were also significantly lowered by testosterone when administered at a 2.5 mm capsule length/100 g body weight; however, estimated total release rate was 312 ng/day from these capsules. The fact that oestradiol was more effective than DHT, and that DHT was more effective than testosterone in inhibiting LH secretion in castrated ferrets, suggests that in gonadally intact ferrets, testosterone may be converted to DHT or oestradiol within target cells that mediate steroid negative feedback on LH secretion.     

Elevated secretion of androstenedione in a patient with a Leydig cell tumour

In this study, we report the case of a 48-year old man with a well-encapsulated Leydig cell tumour, azoospermia, decreased libido and impotence. The basal peripheral blood levels of testosterone, dihydrotestosterone, 5 alpha-androstane-3 alpha,17 beta-diol and oestradiol were normal and oestrone was moderately increased. In contrast, androstenedione was extremely elevated at 521 ng/dl (normal: 88 +/- 60 ng/dl). Upon hCG stimulation, plasma testosterone increased 2.1-fold while androstenedione increased 1.4-fold. Plasma LH and FSH were also elevated and their response to LRH was exaggerated. At the time of surgery the levels of androstenedione in the spermatic vein plasma, as well as in the testicular tumour were elevated. In contrast, testosterone levels in the spermatic vein blood were decreased indicating a partial deficiency of 17 beta-hydroxysteroid dehydrogenase in the tumoural tissue. A follow-up study revealed that the contralateral testis did not respond to hCG although the sex steroid concentrations in the peripheral plasma were within normal limits. Plasma gonadotrophins remained elevated. These results demonstrate that this Leydig cell tumour secreted high amounts of androstenedione into the blood and that the contralateral testis exhibited an impaired androgenic function.